2. An 18-year-old lady with CKD 5 due to an unknown cause underwent living-related donor kidney transplantation in 2013. She was given a short course of steroids (discontinued 1 week after transplantation), MMF, and tacrolimus. Pre-transplant serum EBV- and CMV-IgG were negative. The donor was seronegative for CMV but positive for EBV. Kidney transplantation was uncomplicated, with a stable kidney function (eGFR varied between 92 and 98 mL/min). Six months after transplantation, serum aminotransferase levels (ALT: 66 U/L; AST: 47 U/L) were found to be slightly elevated. CMV and EBV PCRs were negative. Four weeks later, liver enzymes decreased (ALT: 53 U/L; AST: 42 U/L) to near-normal levels. Six weeks thereafter, liver enzymes (ALT: 75 U/L; AST: 58 U/L) were again found to be elevated. HCV and HBV PCR were negative.
Viral hepatitis .HBV ,HCV ,CMV ,EBV ,WHICH ARE NEGATIVE HERE ,THE OTHER
MOST COMMON HEV RNA should be screened.
fatty liver disease,
autoimmune hepatitis,
pharmacological factors ,drug induced..
How would you manage this case?
Acute HEV hepatitis is treated by immunosuppression reduction and follow up of viral load.
The initial management of newly diagnosed or acute HEV infection in solid organ transplant recipients includes observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months. Dynamic viral monitoring and antibody profiling may help clinical decision-ma
the differential diagnosis in this post transplant patient are
Drug induced Hepatitis – most common after transplant due to CNI, NSAIDS, statins and antibiotics, antifungals like azoles, Cotrimoxazole etc
Infections – due to HAV, HBV, HCV, HDV, HEV, EBV, CMV
alcohol binge
NASH – due to over weight after renal transplant
autoimmune hepatitis – unlikely to flare up post transplant as post transplant itself is an immunosuppressed state…
PTLD presenting as isolated liver enzyme elevation is rare
We need more history of the induction agent used, tacrolimus trough levels, previous history of jaundice or hepatitis in the patient …..
HEV RNA levels need to be checked …if elevated it is known to cause chronic HEV infection unlike HAV..The variable percentage of chronic HEV in the general population ins 5-15%.. they have waxing an waning course of fluctuations in liver enzymes…. There are reports to show that this phenomenon can occur for more than 6 months..
It is known that MMF causes inhibition of proliferation of the virus….while HEV infection is promoted by tacrolimus..
the treatment is reduciton of CNI..And addition of ribavirn for 3 to 6 months ..Ribavirin usage should be monitored for drop in hemoglobin … .
Differential diagnosis is mainly for viral infections
Exclusion of HEV is a must by PCR for detection of viral replication as well as viral load.
Other viral infections can be EBV, CMV, HBV, and HCV.
Drug induced side effects.
Autoimmune hepatitis.
Management is dependent on reduction of immunosuppressive doses, withholding antimetabolites as MMF, minimizing CNI doses to maintain low levels or even switch to another mTORi would be better.
Using antiviral regimen as ribavirin is the best tolerated by most of patients. The patient has normal renal function profile, hence no need for renal adjustment with optimum dose for 4 weeks at least with regular monitoring of viral load, CBC, liver enzymes mainly.
Special attention to the common side effects as they could be non-specific in the form of fatigue, fever or headache. Moreover severe side effects as hemolytic anaemia or severe GIT manifestations could need dose modification.
The co-administration of statins aids to initiate early response as it minimizes viral load as well.
A. de Niet1 , H.L. Zaaijer2 , I. ten Berge3 , C.J. Weegink1 , H.W. Reesink1 , U. Beuers1 * Departments of 1 Gastroenterology & Hepatology, 2 Virology and 3 Nephrology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands, *corresponding author: tel. +31 (0)20-5662422, fax: +31 (0)20-5669582, e-mail: u.h.beuers@amc.uva.nl
** Viral infections ( EBV, CMV, HBV, HCV, HEV)
** Drug related
** Autoimmune hepatitis
● Management:
** PCR for HEV in blood and stool
** Abdominal US
The most possible it is a case of HEV infection so treatment will be :
☆ Reducing Immunosuppressive Therapy
** Immunosuppressive drugs (cyclosporine A, tacrolimus, sirolimus, and everolimus, increase HEV replication but only mycophenolic acid can decrease HEV replication in vitro .
** Two-thirds of patients remain those need an effective antiviral therapy :
☆ Pegylated Interferon
For three months and the sustained virological response (SVR) at six months was 100% but it increases the risk of acute rejection due to its immunostimulatory effect
☆ Ribavirin
** Ribavirin as a monotherapy has become the treatment of choice for chronic HEV infection.
** The recommended dose 600 to 800 mg/day
** In patients with impaired kidney function, ribavirin dose should be adapted to kidney function
** Three months after initiating ribavirin therapy, if HEV RNA is negative in both the sera and stools, ribavirin can be stopped.
** If HEV RNA remains positive in the stools after three months, even if it is negative in the sera, ribavirin therapy should be prolonged for an additional three months.
** If HEV viremia increases after ceasing ribavirin therapy, a longer course of ribavirin 6 months, can be proposed.
** In patients who present with a relapse under ribavirin or who are resistant to ribavirin, there is no alternative, except for liver-transplant patients for whom pegylated interferon can be proposed.
Nassim Kamar, Sébastien Lhomme, Florence Abravanel, Olivier Marion, Jean-Marie Peron, Laurent Alric, and Jacques Izopet . Treatment of HEV Infection in Patients with a Solid-Organ Transplant and Chronic Hepatitis . Viruses. 2016 Aug; 8(8): 222.
Q1: ΔΔ includes: · viral hepatitis A, B, C, D, E and CMV, EBV, adenovirus. · Drug-related due to tacrolimus, valganciclovir, acetaminophen or even herbal medicines · Autoimmune hepatitis · PTLD
Q2: lab test for diagnosis includes: CBC.diff, PLT, LFT, BUN, Cr, biochemistry, LDH, Tacrolimus level, albumin, PT, INR, ALK-p · Viral PCR for CMV, EBV, HBV, HCV, HEV stool HEV RNA · Ultrasonography of liver and biliary system.
The most probable diagnosis is HEV infection. Therefore, the treatment is: 1. Immunosuppression reduction according to tacrolimus level. 2. In case of no response for 3 months or severe disease: ribavirin 200 mg Q8h for at least or until stool HEV RNA became negative for two months in a row. During treatment monitoring for HEV RNA in stool and plasma is necessary. In addition, due to hemolytic anemia as a ribavirin side effect, CBC.diff at regular intervals is needed. During D reduction of immunosuppression, control for rejection, and after ribavirin treatment, control of relapses by HCV PCR are necessary.
Reference:
Einollahi, B., Ghadian, A., Ghamar-Chehreh, E., & Alavian, S. M. (2014). Non-viral related liver enzymes elevation after kidney transplantation. Hepatitis Monthly, 14(2). https://doi.org/10.5812/hepatmon.9036
Hansrivijit, P., Trongtorsak, A., Puthenpura, M. M., Boonpheng, B., Thongprayoon, C., Wijarnpreecha, K., Choudhury, A., Kaewput, W., Mao, S. A., Mao, M. A., Jadlowiec, C. C., & Cheungpasitporn, W. (2021). Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. In World Journal of Gastroenterology (Vol. 27, Issue 12). https://doi.org/10.3748/wjg.v27.i12.1240
What is your differential diagnosis? · Viral infections: She has negative HBV, HCV, CMV and EBV (high risk for EBV infection, but EBV PCR is negative, D+/R-). So we will ask about HEV RCR · Alcohol induced hepatitis · NASH · Autoimmune hepatitis ( young age) · Congestive hepatopathy · Drug induced (antibiotics including SMX-TMP, antifungal, Tacrolimus and MMF (need proper history, checking trough levels and improvement in liver enzymes after decreasing doses or discontinuation of the drug) · Metabolic causes as alpha 1 antitrypsin deficiency, Wilson and Hemochromatosis (ask for 24 h urine copper, serum ceruloplasmin and serum ferritin). How would you manage this case? Diagnosis: · MDT approach involving a hepatologist · Detailed history(including drug, travel history, alcohol consumption and eating uncooked meat) and physical examination · HEV RNA and/or antigen detection in blood and stool · Abdominal US to look at the liver. · Liver biopsy is the gold standard for diagnosis (if needed). · Treatment depends on the cause If confirmed to be chronic HEV:
Cautious reduction of Immunosuppression: keep MMF (may be associated with lower risk of HEV infection) but reduce Tacrolimus being associated with high risk of HEV infection (monitor trough level). This patient is on steroid free protocol.
Antiviral treatment: start ribavirin therapy for 3 months since the patient has chronic HEV infection. If relapse occur, the treatment should be restarted with a higher dose and for 6 months. Dose is 600-1000 mg/day, adjusted according to body weight and creatinine clearance
Blood HEV PCR should be done after 1 week of therapy to predict the duration of the therapy, the ribavirin is continued until 2 consecutive PCR results in the stool are negative one month apart
During therapy do monthly HEV RNA testing in plasma and stool and follow liver enzymes and hemoglobin level every 2 weeks as Ribavirin can cause hemolytic anemia.
After stopping Ribavirin treatment, ensure sustained viral response (SVR) by repeating the viral load every 3 months using blood or stool PCR for 6 months.
Treatment with PEG-interferon treatment in ribavirin-refractory persistent HEV (close monitoring for rejection is needed)
References: 1. Guidelines for Hepatitis B & Solid Organ Transplantation. British Transplantation Society Guidelines, 2018. 2. Einollahi B, Ghadian A, Ghamar-Chehreh E, Alavian SM. Non-viral related liver enzymes elevation after kidney transplantation. Hepat Mon. 2014 Feb 5; 14(2):e9036. 3. Dizdar OS, Ersoy A, Aksoy S, Ozel Coskun BD, Yildiz A. Analysis of liver function test abnormalities in kidney transplant recipients: 7 year experience. Pak J Med Sci. 2016 Nov-Dec; 32(6):1330-1335. doi: 10.12669/pjms.326.10725. PMID: 28083020; PMCID: PMC5216276.
Hepatitis E Virus infection the most probable diagnosis( fluctuation of liver enzymes) as Liver enzyme alteration without any preexisting liver disease is a frequent finding in renal transplant recipients Autoimmune hepatitis Certain medications, such as cholesterol-lowering drugs (statins) and acetaminophen. Fatty liver disease, including alcohol-related and non-alcohol-related conditions. Hemochromatosis. Hepatitis A, hepatitis B, hepatitis C, alcoholic hepatitis and autoimmune hepatitis. Herbal supplements and vitamin supplements, like chaparral, comfrey tea, iron and vitamin A. Management full history and examination do detect any other associated symptoms and signs with history of recent drug or alcohol consumption investigations: HEV RNA ANA Anti LKM1 Ab ALT , AST ,BILIRUBIN (total , direct), S alb. INR Hepatobiliary US Patient mostly has chronic HEV.
treatment Reduction of immunosuppression is considered the first-line approach, allowing HEV clearance in about one-third of patients. Ribavirin, an anti-viral agent, is considered in patients with severe acute or acute on chronic liver failure. acts by inhibiting HEV viral replication and increases the expression of interferon stimulating genes leading to immune modulation It can be given as for 3 months, 600 mg / day.
Common medication classes used in transplant that have been implicated in DILI include immunosuppressive medications,antibiotics, antihyperlipidemics,and drugs for hypertension and diabetes. In addition, numerous herbal and nonprescription agents have also been implicated in the development of DILI.
How would you manage this case?
This is probably a case of Hepatitis E infection.The initial management of newly diagnosed or acute HEV infection in solid organ transplant recipients includes observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months.Individuals with persistent HEV infection (documented or estimated duration of infection of more than three months) receive treatment with ribavirin with the aim of achieving sustained virological response HEV treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection.
1. Reduction of immunosuppression 2. Ribavirin, at least for 3-6 months, till reaching a sustained viral response (not detected virus in blood and stool twice one month apart and at 6 months after stopping the Ribavirin) 3. Adjust dose to GFR monitoring of CBC- hemolytic anemia is a common complication of Ribavirin, as well as liver function test and kidney function. 4. Failure of treatment: repeat the course with high dose Ribavern but observe for side effect as above 5. in cases of ribavirin-refractory persistent HEV infection ,PEG-interferon treatment may be considered. However, it carries a risk of rejection.
This is a case of post-transplantation raised transaminases, there are multiple causes until proven. Differentials are;
Could be drug induced,
Viral infection, like HEV, HAV, HBV, HCV etc.
There are case reports with CNIs, although according to current evidence this is a case of HEv. How you manage this case?
Needs further workup to confirm.
Baseline like Ultrasound abdomen, viral serology, further PCR test.
The main stay of treatment is medication (immunosuppression) reduction,
Anti-viral Ribavirin 600mg for six months,
Adjust dose according to eGFR,
Frequent LFTs,
With good monitoring of graft function to prevent rejection and dysfunction.
Continue treatment until negative serology or PCR for consecutive next two negative samples.
Chronic HEV, other forms of hepatitis like A,B,C
Drug induced hepatitis (Tacrolimus) , autoimmune hepatitis.
This case with chronic hepatitis and fluctuating liver enzyme is mostly goes with the diagnosis of chronic HEV.
How would you manage this case?
First we should confirm the diagnosis by full history, doing US , PT/INR, anti HEV Igm and IgG by ELIZA , PCR for HEV RNA in stool and plasma.
Treatment involves IS reduction and Ribavirin cap in a dose of 600 mg per day for 6 months adjusted according to body weight and GFR.
The treatment last until 2 consecutive sample are negative for virus with one month a part.
Reference:
BTS guidelines 2017.
What is your differential diagnosis? · This is a typical case of Chronic Hepatitis E infection – fluctuating liver enzymes. · D/D: other cause of hepatitis – drug induced (Tacrolimus) Hepatitis A viral infection (de novo), autoimmune hepatitis How would you manage this case? · First confirm the diagnosis – detail history (meet consumption), · PCR for HEV RNA in blood and stool should be done. · Ultrasound abdomen, PT/INR, RFT, Tac C0 level, CBC · IS reduction: prednisone and Tacrolimus to minimum level · close monitoring of graft function to look for rejection · Ribavirin (200 – 600 mg/ day) for 3- 6 months – for early viral clearance. · Frequent monitoring of LFT, monthly HEV RNA testing in plasma and stool. Therapy can be stopped if 2 consecutive stool samples for HEV-RNA at 1 month interval comes negative REFERENCES: 1-Guidelines for Hepatitis E & Solid Organ Transplantation. BTS, First edition 2017 April
2. Kamar N et al, Treatment of HEV Infection in Patients with a Solid-Organ Transplant and Chronic Hepatitis. Viruses 2016, 8, 222.
What is your differential diagnosis?
Six months post transplant derangement of liver function test can be due to multiple causes like viral infections (CMV,EBV,HEV) drugs like (CNIs ,NSAIDs,antibiotics,statins etc.)metabolic causes like NAFLD, inherited disorders like wilson disease etc.
The above scenario fits with the HEV infection case as all other viral causes have been ruled out ,and history mentioned above is not suggestive of other possibilities like inherited and metabolic causes.For HEV infection, Ultrasound abdomen,PT/INR followed by anti HEV IgM and IgG by ELISA, and PCR for HEV RNA in blood and stool should be done. Once confirmed, then modification of immunosuppression but with close monitoring of graft function ,and ribavirin (200 to 600 mg/ day) for 3- 6 months should be started for early virological clearance. Frequent monitoring of liver function tests and monthly HEV RNA testing in plasma and stool.
REFERENCES:
1-Guidelines for Hepatitis E & Solid Organ Transplantation, BTS, First edition.
2.Nassim Kamar et al, Treatment of HEV Infection in Patients with a Solid-Organ Transplant and Chronic Hepatitis. Viruses 2016, 8, 222.
This case of typical chronic hepatitis E , WITH FLUCTUATING liver enzymes .
This patient other c ause of hepatites could be due to drug induced specially Tacrolimus
other cause could be one of the hepatotropic virus like Hep A,B,C,D,OR E.
High LFT after kidney transplant could be related to autoimmune hepatites .
How would you manage this case?
We need first of all to confirm the diagnosis by full history taking and to do US to have a look to the liver echotexuer . will send HEV per and to follow the. case through LFT , need to check for serum and stool for HEVRNA.
Ribaverin is the treatment of choice with close monitoring for the Hb level .
treatment will take up to 3to 6 month .
references
uptodate
Deranged liver enzymes six months post transplant could be because of
HBV
HCV
HEV
CMV
EBV
DRUGS
ANY OTHER BIRAL OR BACTERIAL INFECTION
In this patient as all other tests are negative this is most likely HEV induced hepatitis.
MANAGEMENT
This patient needs
Reduction of immunosupression preferably CNI and steroids
Ribavirin 600 mg daily in divided doses for minimum three months, duration can be increased to six months
Montioring should be done closely specially looking for hemolytic anemia.
Two consecutive stool PCR should be negative one month apart to confirm clearance
The index patient is an 18 year old recipient who is EBV and CMV negative who received EBV positive donor tx. Who experienced elevation of liver enzymes with negative PCR to both HBV and HCV with stable graft functions.
Differential diagnosis is wide
On top of DD is HEV
Others include
A) Infections
Bacterial infections
Viral infections either Hepatotropic or non Hepatotropic viruses
Protozoa and fungi
B) Drug induced e.g CNI, Azathioprine, Statins, Antibiotics
E) Inherited causes as alpha one antitrypsin, Hemochromatosis, polycystic kidneys
How would you manage this case?
The management in this case
Full history and examination Detection of baseline stool and plasma HEV RNA test Reduction of immunosuppression is starred first especially MMF Ribavirin 600 mg daily for at least 3 months. Plasma and stool HEV are monitored every month. With initial 7 days monitor to check initial response. If persistent HEV test after 3 months continue treatment till 6 months or till 2 tests 1 month apart are negative If relapse post Ribavirin we shall repeat course of Ribavirin with higher dose and longer duration. Side effects of Ribavirin may include Hemolytic anemia so check of
What is your differential diagnosis? HEV/HDV MMF/CNI Cotrimoxazole + trimethoprim PTLD Management: Reduction of immunosuppression, particularly tacrolimus as it potentiates HEV replication. Monitor for rejection. Ribavirin with dose adjustment as per GFR Ribavirin is continued for at least 3 months until stool PCR is negative for HEV RNA on two occasions one month apart. Monitoring: Monthly HEV RNA testing in plasma and stool. Monitor Hb during ribavirin therapy (hemolytic anemia) Check for SVR by HEV RNA in plasma and stool at 3 and 6 months after stopping antiviral therapy
· In the case of elevated liver enzymes in the transplant recipient, drug-induced should be suspected, but in this case unlikely because mostly it will be progressive unless the offending drug was stopped.
· Non-infectious causes should be excluded such as NASH, or Autoimmune hepatitis also will be progressive if not treated.
· Mostly this patient has HEV, so serum HEV RNA should be requested, if detected she has mostly chronic hepatitis E, as she is asymptomatic and has a mild elevation in liver enzymes.
Management
1) Reduction of immunosuppression. Typically reduce tacrolimus first, if possible, since there is an association of chronic infection with tacrolimus.
-Reduction of immunosuppressive therapy resulted in viral clearance in about 30 % of patients
2) Antiviral therapy. If immunosuppressive therapy cannot be reduced, or if the patient has persistent HEV RNA despite a reduction in immunosuppressive therapy for 12 weeks
– a 12-week course of ribavirin monotherapy is suggested, with a dose of 600 to 1000 mg daily ( in two divided doses)
3) Monitoring for toxicity of ribavirin is recommended.
4) Ribavirin can be stopped if the HEV RNA is negative in the sera and stool at week 12.
This case of typical chronic hepatitis E , WITH FLUCTUATING liver enzymes .
This patient other c ause of hepatites could be due to drug induced specially Tacrolimus
other cause could be one of the hepatotropic virus like Hep A,B,C,D,OR E.
High LFT after kidney transplant could be related to autoimmune hepatites .
How would you manage this case?
We need first of all to confirm the diagnosis by full history taking and to do US to have a look to the liver echotexuer . will send HEV per and to follow the. case through LFT , need to check for serum and stool for HEVRNA.
Ribaverin is the treatment of choice with close monitoring for the Hb level .
treatment will take up to 3to 6 month .
DD:
-HEV.
-Drug induced hepatitis.
-Others: autoimmune hepatitis, CMV
Management:
-Testing for HEV RNA and HEV antigen.
.Baseline HEV RNA testing to help monitoring treatment.
.Frequent HEV RNA and liver enzymes monitoring hoping resolution spontaneously within three months.
.Immunosuppression reduction with monitoring of graft function.
.Start ribavirin if infection persists to achieve virologic response, ribavirin is to be maintained for 3-6 months targeting negative HEV RNA in at least 2 sequential tests one month apart.
.Ribavirin renal dosing according to eGFR; hemolytic anemia is a side effect,and drug dose reduced if hemoglobin falls below 100g/l.
.Pegylated INF is considered ribavirin-resistant cases..
References:
HEP E and SOT -BTS guidelines.
its case of hepatic dysfunction late post transplant for differential diagnosis
which maybe related to
infection:bacterial ,fungal, viral and protozoa.
infiltration:malignancy
autoimmune: as primary sclerosis cholangitis
drug induced: CNI toxicity and NSAID
metabolic: alcoholic and non alcoholic.
cholestatic: cased by bile stasis.
one of the common missed causes which present with this picture is HEV infection.
How would you manage this case?
complete history taking: including medical history,social history and travel history full clinical examination: search for hepatic dysfunction manifestations, lymph node involvement radiological assessment:ultrasound and doppler on liver followed by CT or MRCP if needed. histological assessment by liver biopsy sometimes needed. laboratory investigations: including HEV PCR
If positive just downgrade immunosuppresion is needed after proper counselling of patient about risk of rejection
if persistant positive after 3months trial of ribavirin should be tried for 3months with frequent monitoring of hemoglobin because of risk of hemolytic anemia cauased by ribavirn
ribavirin should be continued until 2 PCR negative 1-2w in between
HEV should be repeated after 6month of stopping treatment because of the risk of
relapse. References:
Gunderson A, Said A. Liver disease in kidney transplant recipients. Transplant Rev (Orlando). 2015 Jan;29(1):1-7. doi: 10.1016/j.trre.2014.08.002. Epub 2014 Aug 27. PMID: 25306468.
Ahsan N, Rao KV. Hepatobiliary diseases after kidney transplantation unrelated to classic hepatitis virus. Semin Dial. 2002 Sep-Oct;15(5):358-65. doi: 10.1046/j.1525-139x.2002.00087.x. PMID: 12358641.
Einollahi B, Ghadian A, Ghamar-Chehreh E, Alavian SM. Non-viral related liver enzymes elevation after kidney transplantation. Hepat Mon. 2014 Feb 5;14(2):e9036. doi: 10.5812/hepatmon.9036. PMID: 24693313; PMCID: PMC3950572.
Kamar N, Lhomme S, Abravanel F, Marion O, Peron JM, Alric L, Izopet J. Treatment of HEV Infection in Patients with a Solid-Organ Transplant and Chronic Hepatitis. Viruses. 2016 Aug 15;8(8):222. doi: 10.3390/v8080222. PMID: 27537905; PMCID: PMC4997584.
Hansrivijit P, Trongtorsak A, Puthenpura MM, Boonpheng B, Thongprayoon C, Wijarnpreecha K, Choudhury A, Kaewput W, Mao SA, Mao MA, Jadlowiec CC, Cheungpasitporn W. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021 Mar 28;27(12):1240-1254. doi: 10.3748/wjg.v27.i12.1240. PMID: 33828397; PMCID: PMC8006097.
We are dealing most probably with chronic hepatitis E virus
DDx
Including both viral and non viral hepatitis
The most common causes of nonviral liver disease that may present as a hepatitis include metabolic-associated fatty liver disease (MAFLD), alcohol-related liver disease (ALD) and drug-induced liver injury (DILI), Autoimmune hepatitis.
The most common causes of viral hepatitis are the five unrelated hepatotropic viruses hepatitis A,B,C,D and E .
Other viruses can also cause liver inflammation, including CMV ,EBV,and yellow fever .There also have been scores of recorded cases of viral hepatitis caused by HSV
How would you manage this case?
MDT should be involved in management of such case ( nephrology,hepatology and infectious )
medication history should be taken for patients with hepatitis, including prescription and over-the-counter medications as well as herbal and dietary supplements.
Targeted blood tests may reveal causes of nonviral hepatitis.
Patients with features of severe liver injury, liver failure or cirrhosis should be referred for urgent hepatology assessment and, in appropriate cases, hospitalisation.
serology of viruses
For chronic HEV
Chronic HEV infection is conservatively defined as the finding of detectable HEV RNA in the blood and/ or stool for greater than six months.
In order to help define the length of infection a review of the patient history, anti-HEV status and previous liver enzymes should be undertaken. If available, analysis of stored specimens from before the first finding of HEV RNA in the blood may also be helpful.
Detection of HEV RNA is important in the diagnosis, confirmation and monitoring of HEV infection.
Viral RNA can be detected a few weeks before the onset of clinical symptoms in both blood and stool samples.
Viral shedding in stool continues beyond plasma viral clearance in both acute and treated persistent infection.
Laboratory diagnosis of persistent HEV must be through detection of the virus itself, either through HEV RNA testing or HEV antigen testing, as antibody detection in the immunosuppressed population is not a reliable marker of infection.
It has now been demonstrated that spontaneous clearance of HEV rarely occurs between three and six months of infection.
Individuals with persistent HEV infection (documented or estimated duration of infection of greater that three months) should be treated with the aim of achieving a sustained virological response (HEV RNA non detected in plasma and stool six months after completing treatment).
Reduction of immunosuppression can lead to clearance of HEV infection in approximately 30% of individuals with persistent HEV.
It is important to recognise that changes in immunosuppression can precipitate rejection in more immunogenic individuals so the risk of rejection versus the potential benefits of modification of immunosuppression must be carefully balanced.
Using ribavirin with dose ranging from 200 mg to 1200 mg per day with a median dosage of 600 mg/day. The pharmacokinetics of ribavirin are variable in transplant recipients and clearance depends particularly on renal function .
In order to reduce the side effects of ribavirin and achieve a steady state of ribavirin in the therapeutic range, the starting dose can be adapted based on the creatinine clearance (the eGFR can be unreliable in transplant recipients so use creatinine clearance is preferred.
The most frequent side effect of ribavirin is a haemolytic anaemia, which required intervention in approximately 40% (dose reduction, epoetin or blood transfusion) of those subjects included in the previous systematic review .
Therefore, patients require regular monitoring of haemoglobin on treatment, initially every two weeks until the haemoglobin has reached nadir then monthly thereafter. Dose reduction of ribavirin is recommended when the haemoglobin falls below 100 g/L.
Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart, as continued shedding of HEV in stool is an important factor predicting relapse after ribavirin treatment.
PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection.
1- What is your differential diagnosis This patient has chronic active hepatitis for DD a- Viral hepatitis either hepatotropic viruses as HEV or non hepatotropic viruses as EBV , CMV b- Drug induced hepatitis . c- Metabolic disorders as Wilson disease. d- Autoimmune hepatitis either isolated or part of other autoimmune disorders as SLE.
How would you manage this case 1- History : to exclude congenital and heridetary hepatic diseases ,hepatotoxic drugs , symptoms of autoimmune diseases . 2- Examination :
– Signs of decompensated LCF.
– Extrahepatic manifestations or signs of autoimmune diseases as SLE such as malar flush , serositis.
– Manifestations of metabolic liver diseases as kayser fischer rings and neuropsychatric disturbance. 3- Investigations
– For HEV : plasma and stool quantitative RNA.
– For metabolic screen : serum ceruloplasmin .
– Autoimmune hepatitis and SLE: ANA , Anti DNA , anti smith Ab , C3, C4. 4- Treatment : according to specific pathology
– HEV :ribavirin
– Stop offending drug in caseof drug induced hepatitis
– Copper chelating with d pencillamine and treintene .
2. An 18-year-old lady with CKD 5 due to an unknown cause underwent living-related donor kidney transplantation in 2013. She was given a short course of steroids (discontinued 1 week after transplantation), MMF, and tacrolimus. Pre-transplant serum EBV- and CMV-IgG were negative. The donor was seronegative for CMV but positive for EBV. Kidney transplantation was uncomplicated, with a stable kidney function (eGFR varied between 92 and 98 mL/min). Six months after transplantation, serum aminotransferase levels (ALT: 66 U/L; AST: 47 U/L) were found to be slightly elevated. CMV and EBV PCRs were negative. Four weeks later, liver enzymes decreased (ALT: 53 U/L; AST: 42 U/L) to near-normal levels. Six weeks thereafter, liver enzymes (ALT: 75 U/L; AST: 58 U/L) were again found to be elevated. HCV and HBV PCR were negative.
Issues/ concerns
– 18yo lady, CKD5 ?cause, LRDKT in 2013
– Tacrolimus, MMF, short course steroids (discontinued 1-week post-transplant)
– pre-transplant serum EBV D+/R- and CMV D-/ R-
– uncomplicated kidney transplantation, stable kidney function (eGFR 92-98)
– 6months post-transplant – ALT (66) AST (47) were slightly elevated but CMV and EBV PCR were negative
– 4weeks later – ALT/ AST decreased to near normal levels ALT (53) AST (42)
– 6weeks later – ALT/ AST were found to be elevated again ALT (75) AST (58), HBV and HCV PCR were negative
– if HEV is confirmed, the 1st approach is to decrease total immunosuppression burden
– if reduction of immunosuppression is not sufficient, other additional management strategies which can be considered include pegylated interferon alpha-2b, ribavirin 12mg/kg daily for 12 weeks
– 1st pathway –
reduce immunosuppressive therapy (tacrolimus),
initiate ribavirin 12 weeks and recheck HEV RNA at the end of treatment,
if HEV RNA is absent, stop ribavirin and recheck the HEV RNA in 12 weeks, if still absent this is regarded as sustained virologic response and no further treatment or monitoring is required however if after the 12 weeks HEV RNA is still present reinitiate ribavirin for 24 weeks then recheck HEV RNA at the end of treatment; if HEV RNA is absent, stop ribavirin and recheck the HEV RNA in 12 weeks, if still absent this is regarded as sustained virologic response and no further treatment or monitoring is required however if after the 12 weeks HEV RNA is present consider this as treatment failure and follow up patient for signs of progressive liver disease
similarly, if HEV RNA is still present after 24 weeks of ribavirin, consider this as treatment failure and monitor the patient for signs of progressive liver disease
– 2nd pathway –
reduce immunosuppressive therapy (tacrolimus),
initiate ribavirin 12 weeks and recheck HEV RNA at the end of treatment,
if HEV RNA is still present continue with ribavirin for an additional 12 weeks and recheck HEV RNA at the end of treatment
if HEV RNA is present consider this as treatment failure and follow up patient for signs of progressive liver disease
if HEV RNA is absent, stop ribavirin and recheck the HEV RNA in 12 weeks, if still absent this is regarded as sustained virologic response and no further treatment or monitoring is required but if HEV RNA is present, consider this as treatment failure and follow up patient for signs of progressive liver disease
– preventive measures include thorough cooking of pork products and game meat
– currently there is no effective immunoprophylaxis against HEV that is available
– use of immunoglobulin from infected persons has not been found to be effective in preventing sporadic cases or outbreaks
– vaccination against HEV has been proposed but the efficacy is yet to be addressed
– long-term LFTs and HEV monitoring is recommended to ensure complete resolution of HEV infection
References
1. Dizdar OS, Ersoy A, Aksoy S, Ozel Coskun BD, Yildiz A. Analysis of liver function test abnormalities in kidney transplant recipients: 7 year experience. Pakistan journal of medical sciences. 2016 Nov-Dec;32(6):1330-5. PubMed PMID: 28083020. Pubmed Central PMCID: PMC5216276. Epub 2017/01/14. eng.
2. Yiu V, Gao R, Mulroy S. Hepatitis in a renal transplant patient—beyond the usual. Clinical kidney journal. 2012;5(2):170-2.
3. Kamar N, Izopet J, Tripon S, Bismuth M, Hillaire S, Dumortier J, et al. Ribavirin for chronic hepatitis E virus infection in transplant recipients. The New England journal of medicine. 2014 Mar 20;370(12):1111-20. PubMed PMID: 24645943. Epub 2014/03/22. eng.
Viral Hepatitis – Highest possibility of HEV, lesser chance of HBV and HCV
Drug induced hepatitis
Occasionally CMV & autoimmune
Management of case
In post transplant patients, if transaminitis develops, then 2 most important things to be ruled out are hepatotoxicity due to drugs and viral infection.
So, first I will send PCR for Hep B,C,E.
If any thing comes out positive then I shall manage accordingly. If all negative, I will try to find out culprit drug responsible for the same.
If no such drug found responsible or drug dose reduction doesn’t make any improvement, I shall start thinking on lines of evaluating patient for chronic liver changes (coagulation profile, fibroscan, etc.). in such situations, expert opinion of hepatologist shall be sought.
REF:
Solà-Porta E, Redondo-Pachón D, Arias-Cabrales C, Navazo D, Buxeda A, Burballa C, Crespo M, García-Retortillo M, Pascual J, Pérez-Sáez MJ. Early Hypertransaminasemia after Kidney Transplantation: Significance and Evolution According to Donor Type. Journal of Clinical Medicine. 2021; 10(21):5168. https://doi.org/10.3390/jcm10215168
Alfandary Hadas, Davidovits Miriam, Dagan Amit. Transient abnormal liver enzyme level in the early stage after renal transplantation in children. Year : 2018 | Volume: 12 | Issue Number: 2 | Page: 90-94
The fluctuation of liver function tests and, as many colleagues proposed, can be as non-specific and related to drug toxicity, interaction etc., HEV, although not very common, as we learned from this module, should be kept in mind and sought for. The main management plan is reducing immunosuppression and use of 600 mg ribavirin (eGFR: normal)
Baseline HEV RNA established for monitoring treatment.
Frequent HEV RNA and liver enzymes monitored with possible resolution spontaneously in three months.
RIS with monitoring of graft function, decrease tac levels and maintain the MMF and monitor UECS and Urinalysis bearing in mind the pt is on dual immunosuppressive meds.
Start ribavirin if infection persists beyond three months aiming for virologic response, ribavirin is to be maintained for three to six months aiming for negative HEV RNA in at least 2 sequential tests done one month apart.
Ribavirin is to dosed according to eGFR and hemolytic anemia the expected side effect monitored and drug dose reduced once hemoglobin falls below 100g/l.
Pegylated interferon to be considered in cases of ribavirin treatment failure.
Detailed History- Travel history, Drug history, intake of alcohol, use of undercooked meat.
Thorough physical examination – Looking sign of CLD
Investigations
Blood CP. Renal functions, Liver functions, Clotting profile, Drug Levels, HEV IgG and IgM
Ultrasound of Billiary tract
Important to know HEV status pre transplant
Consultation with hepatology team
Treatment
In case of HEV infection, the first step will be to reduce immune Suppression. Tacrolimus should be reduced up to minimum possible levels. MMF can be maintained. It is important to monitor for drug levels and serial monitoring of liver enzymes. Most infections resolve spontaneously.
Antiviral agents like ribavarine can be used until 2 plasma and stool samples are negative. Serial monitoring of HEV RNA antigen should be done .It is sensisible to monitor for any side effects like hemolytic anemia.
Hansrivijit P, Trongtorsak A, Puthenpura MM, Boonpheng B, Thongprayoon C, Wijarnpreecha K, Choudhury A, Kaewput W, Mao SA, Mao MA, Jadlowiec CC, Cheungpasitporn W. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021 Mar 28;27(12):1240-1254.
2-others such as HAV, HDV, DRUD INDUCED, AND AUTOIMMUNE HEPATITIS
How would you manage this case?
confirm the diagnosis
KFT, CBC, CRP, detect HEV RNA in the serum
HAV,HDV, ASMA,LKM,ANA treatment
reduction of IS especially the TAC to the lower target level(4-6ng/ml)
ribavirin 600 1000mg/day in two divided doses for 12 weeks and the end of treatment recheck if the virus still so more 12 weeks of treatment should be offered if still the virus is detected that means treatment failure
if the virus after the treatment course is not detected further 12 weeks follow up if not detected no more treatment.
no dose adjustment needed as this patient’s eGFR is more than 98
follow up CBC if HB drops to less than 8.5 ribavirin should stop permanent
reference
update
Detailed history and examination for sign and sumptomes of liver disease (jaundiced ,hepatomegaly and lymph node enlargement )
Investigation :
HEV RNA levels, serology, and liver enzymes.
CBC,ESR,CRP .RFT.Urine analysis ,stool general
Treatment :
1-Modification of immune suppression:
Tacrolimus increased HEV replication in a cell culture model;
however, this effect was only seen at high dosages. mTOR inhibitors also appeared to potentiate HEV replication. Corticosteroids had no effect on HEV replication in these models Interestingly, mycophenolate was shown to inhibit HEV replication
2-Antiviral therapy
1-Ribavirin
two patients with persistent HEV were treated with ribavirin 12 mg/kg for
12 weeks, and both cleared HEV RNA from blood and stool by four weeks and remained HEV RNA negative during follow up.
2-PEG-interferon:In case of ribavirine failure
3-Sofosbuvir
Reference:
British Transplantation Society Guidelines: Guidelines for Hepatitis E & Solid Organ Transplantation.
1- DD
HEV (most common)
others: HDV, HAV, drug induced hepatitis II- Management:
proper history taking: alcohol intake, travelling abroad, contact with infected person, consuming inappropriate cooked meat (especially pork)
examination: for hepatomegally, spleenomegally
Lab: HEV RNA assay, re-examination of stored plasma samples for HEV RNA and HEV antibodies.
start treatment:
reduce IS: especially tacrolimus to the lowest target level (4-6 ng/ml)
start ribavirin : 200mg -1 gm per day in divided doses (2-5) for 3-6 months
monitor with HEV RNA after one month in plasma and stool
monitor hemoglobin fro associated hemolytic anemia
dose modified according to eGFR
maintain antiviral till two negative HEV RNA in stool assay 1 month apart
The recipient was pre-transplant (CMV IgG- EBV IgG) neg.
Donor was CMV IgG neg but EBV IgG pos.
This increases the risk of EBV primary and PTLD in recipient.
However, this patient had
CMV neg
EBV neg
HBV neg
HCV neg
The remaining differential diagnosis for this sitting
HEV infection
HDV infection
HAV infection but the LFT abnormalities that remained 6 months may exclude it.
Drug induced
Alchohol
Malignancy and PTLD
Autoimmune hepatitis
Strategy for management
Clinical evaluation for Hepatomegaly or lymphadenopathy
Lab tests
Complete liver function tests including (albumin- pt – glucose…)
PCR EBV RNA
Treatment
Best monitoring for liver enzymes
If EBV RNA is positive it is better to evaluate and compared with the samples stored before and after transplantation
If the positivity of HEV RNA is less than 3 months, the observation is enough
If it was a persistent HEV infection , reducing is and even ribavirin treatment should be considered
👉 ⭐ The differential diagnosis of elevated liver enzymes in transplant recipient:
_viral infections (the current case is high risk for EBV infection, but EBV PCR is negative). I will ask for HEV PCR.
_Autoimmune hepatitis in such young age (ask for ANA, anti LKMA and ASMA autoimmune markers).
_drug induced as SMX-TMP, antibiotics, antifungal, retinoic acid containing anti acne preparations, tacrolimus and MMF (diagnosed by history , trough level monitoring and therapeutic trial with improvement after decrease dose or discontinuation of the drug)
_Alcohol induced.
_NASH (none alcoholic steatohepatitis).
_other metabolic causes as Wilson and Hemochromatosis (so ask for 24 h urine cupper, serum ceruloplasmin and serum ferritin).
_alpha 1 antitrypsin deficiency.
_Liver biopsy is the golden standard for diagnosis.
👉 ⭐ Management:
_Through history taking and systematic examination.
_Order for HEV PCR as basal level, if postive repeated assessment is required.
_Abdominal ultrasonography to assess liver parenchyma and doppler study to screen for portal hypertension.
_Reduction of IS should be cautious (restart steroid again, keep CNI on lower window of therapeutic trough level, decrease dose of MMF).
_FU PCR and liver enzymes, if increasing after reduction of IS…start ribavirin 200-600 mg divided twice or thrice per day for 3-6 months until 2 negative stool PCR separated by 1 month.
_close follow up of CBC for fear of anemia.
_In case of Wilson, treatment with cupper chelation as penicillamine.
_in case of hemochromatosis ….need iron chelator.
_in case of autoimmune hepatitis…use of steroids and azathioprine (replace MMF with azathioprine) may be helpful.
_NASH treated by weight reduction, vitamin E , selenium.
A proper history and examination to assess for any extra hepatic symptoms and signs especially involvement of the CNS
Drug use history
Alcohol history
Laboratory investigations:
HEV RNA
ANA
AntiDS DNA
Anti smooth muscle antibodies
Anti LKM1 Ab
INR
Radiological Ix:
Hepatobiliary US
CT scan of the abdomen
If the transaminases are elevated for more than three months and the HEV RNA is positive, then the patient has chronic HEV. The patient should be started on Ribavarin
The differential diagnosis for mildly elevated liver enzymes in this case scenario who has negative PCR for HCV, HBV, CMV and EBV can be summarized in the attached table (1).
In agreement with my colleagues, I will start my management with proper history taking (including any recent drug use, e.g. recent antibiotics, or history of travelling abroad or any contact with sick patients).
The next step will be a detailed clinical examination with special concern for any skin rash or lymphadenopathy.
Then, I will proceed to an Abdominal ultrasound scan, Serology for autoimmune hepatitis (the patient is 18 years old female with an unknown cause of ESRD that may point to an underlying auto-immune disease). The attached table suggests a stepwise approach for cases with persistent, mild elevation of liver transaminases. In case all the performed investigations came negative or non-conclusive, then I will proceed to a liver biopsy (1).
In addition, would you consider Congestive hepatopathy, hemochromatosis, autoimmune hepatitis, Wilson disease and alpha-1 antitrypsin deficiency as well?
In addition, would you consider Congestive hepatopathy, hemochromatosis, autoimmune hepatitis, Wilson disease and alpha-1 antitrypsin deficiency as well?
Hepatitis infection A, B, C, and E
CMV infection
EBV infection
Autoimmune hepatitis
Drug induced hepatitis
How would you manage this case?
History and examination
CBC , Monitoring of renal function and liver enzymes, drug level and DSA level, HEV RNA igM, IgG, HEV RNA in plasma and stool
Ultrasound for liver to role out cirrhosis.
Start ribavirin with monitoring HEV RNA
Reducing Tacrolimus dose near to lower level and keep to steroid dose and MMF dose. with tight serial monitoring of drug level and DSA level to avoid kidney rejection and monthly monitoring of HEV RNA antigen in blood and stool.
Differential diagnosis
Viral hepatitis- HEV/HAV/HIV (this patient is already negative for CMV/HCV/EBV/HBV)
Drug induced hepatotoxicity -statins/antifungals/antibiotics
NAFLD/alcohol
Autoimmune hepatitis
Management
Detailed history- that should include history of any recent travel, recent drug use, alcohol use, illicit substance use, and consumption of raw/undercooked meat.
Thorough physical examination for stigmata of chronic liver disease
Workups- CBC, CRP, coagulation profile, tacrolimus trough levels, stool and plasma HEV RNA and ANA.
Imaging-abdominal U/S for liver.
If the patient has positive HEV RNA, then needs to be determined if this is an acute infection or persistent infection.
Retrospectively can be tested for HEV RNA when the liver enzymes were noted to be rising.
Also important to note the anti-HEV status prior to transplantation.
If acute infection, then monitoring for 3 months of the HEV RNA and liver enzymes can be done since 30% of infections spontaneously resolve.
If persistent infection, HEV RNA has been positive for more than 3 months, reduction of immunosuppression, this patient is already on 2 immunosuppressants thus should be monitored closely for rejection.
Antivirals- ribavirin can be used until 2 plasma and stool samples are negative, however CBC should be monitored due to the risk of haemolytic anaemia.
Ribavirin resistant cases there is a role of using pegylated interferon though comes with the risk of rejection other option sofosbuvir combined with ribavirin.
References
Guidelines for Hepatitis E & Solid Organ Transplantation First Edition Compiled by a Working Party of The British Transplantation Society Draft posted on http://www.bts.org.uk April 2017
Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: a case report Marcus Panning, Kristi Basho, Andreas Fahrner and Christoph Neumann-Haefelin
Hansrivijit P, Trongtorsak A, Puthenpura MM, Boonpheng B, Thongprayoon C, Wijarnpreecha K, Choudhury A, Kaewput W, Mao SA, Mao MA, Jadlowiec CC, Cheungpasitporn W. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021 Mar 28;27(12):1240-1254. doi: 10.3748/wjg.v27.i12.1240. PMID: 33828397; PMCID: PMC8006097.
Thank you prof.
Yes this patient is already on 2 IS so reduction would not be an option.
I would monitor if the LFT are worsening and increase of the HEV RNA then I would start ribavirin early instead of waiting for the 3 months.
1- infection viral :HAV,HEV,HBV,HCV,CMV,EBV-bacterial -parasitic
2-Medication related
3 part of cilliopathy as the cause of kidney disease unkown ?? Caroli??
4-autoimmune hepatitis
management
History
• Recent hospitalizations or illnesses
• Social/exposure history
• Comorbid conditions
• Exposure history indicative of possible pathogen
medication history -substance abuse labs and studies
virology screen /HEV RNA
panel for autoimmune disease
liver scan ?? we may consider liver biopsy if persistent transaminitis with no apparent cause
we should consider HEV infection ,HEV RNA should be done in current sample and in archived sample , if both positive this indicates chronic HEV
Treatment with antiviral ribavirin for at least 3 month
Monthly HEV RNA testing in plasma and stool the aim of treatment is achieving sustained virological response
Reduction of immunosuppression can lead to clearance of HEV infection
Dear Colleagues although this an 18 years old patient which is unlikely to be alcohol related please do not forget this as a cause of deranged liver enzymes in your differential.
Unlikely to add BK virus to the differential of deranged liver enzymes!
Whilst the case is high risk for de novo EBV infection, EBV PCR was negative and less likely to be CMV hepatitis with this protracted course without treatment and CMV PCR is negative.
Unclear about some unnecessary investigations such as CXR and missing very important one such as stool analysis for HEV PCR. This is very important test to ensure viral clearance
Drug regimen causes such as antiviral drugs, immunosuppressants like tacrolimus. Tacrolimus has been known to contribute to the development of infections of viral origin such as HEV infection.
Non alcoholic fatty liver disease
Polycystic disease of liver or kidneys or both
Autoimmune nature of disease
Management
Patient history regarding alcohol is to be obtained to rule out alcohol related causes, as well as previous history of liver disease.
Tac trough level checked and tac dosage reduced or altered
Antiviral therapy to resolve any HEV or HBV infection. Since the liver enzymes are elevated, even if anti HEV IgG is in high levels, patient can have active infection. Thus ribavirin can be given to resolve the infection, for 12 -24 weeks.
· What is your differential diagnosis?
There are many causes of raised liver enzymes in kidney transplant recipients, including sepsis, biliary tract dysfunc[1]tion, drugs and common hepatotropic virus-related infec[1]tious diseases such as hepatitis B and C plus HEV.
So our differential diagnoses include:
1-Drugs: Like cotrimoxazole, Valganciclovir, MMF, FK, statin, others. 2-Viral infection, HBV, HCV, HAV, HEV, CMV, EBV · How would you manage this case? Taking detailed history, specifically drug history, recent febrile illness, alcohol intake. Then routine investigation, plus coagulation profile, GGT, alkaline phosphatase , viral serology including HEV Abs, RNA if Abs positive, Ultrasound liver. Then specific treatment according to the cause. If HEV positive, then reduction of immunosuppression and if no response then to consider ribavirin. References: 1-Hepatitis in a renal transplant patient—beyond the usual, Clin Kidney J (2012) 5: 170–172 doi: 10.1093/ckj/sfs012
2-Guidelines for Hepatitis E & Solid Organ Transplantation British Transplantation Society Guidelines 2017.
Thanks Prof Dawlat.
management of HEV infection, as it is the most propable diagnoses is: Monitoring of liver enzymes and HEV RNA is important as up to 34% of cases may clear the infection without specific treatment. Another 21% may clear the virus with a reduction of immunosuppression. So, more than half of the patient cleared the infection without specific anti viral treatment. So initial management should be monitoring HEV RNA and liver enzymes with reduction of immunosuppression. If no improvement within 3months, then consideration for anti viral treatment is needed. Modifications of immunosuppression can cleat up to 30% of cases in some series. Steroid and CNI can increase virus replications and MMF, interestingly, was found to inhibit viral replications. So lowering level of CNI and steroid to the minimum possible 2.5mg to 5mg od could help in clearing the virus. Anti-virus therapy: Ribavirin: A sustained virological response (serum HEV RNA negative six months after treatment) was achieved in 78% of cases in one study. Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment will suffice
What is your differential diagnosis?
CMV/EBV/HCV/HBV were already excluded with PCR.
The differential diagnosis
HEV/HDV Drugs induce –
MMF/CNI
Cotrimoxazole + trimethoprim
Antimicrobial
Statins (less likely to be taking in 18 years age)
Steatohepatitis
PTLD
Autoimmune hepatitis How would you manage this case?
Reduction of drugs or Immunosuppression is the main stay of treatment in all cases.
serum and stool HEV RNA to diagnose HEV infection.
Reduce dose of tacrolimus, steroids and MMF
Close follow up of serum creatinine and liver enzyme.
Monitor the patient for 3 months.
See for Serum and stool HEV RNA clearance- if no clearance then start antiviral.
Antiviral Therapies
Ribavirin (600-800 mg/day), the dosage is adjusted according to creatinine clearance.
Liver enzymes (for response) and CBC (for side effects) should be closely monitored.
Duration of treatment of ribavirin should be 3 months
Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart.
If relapse occur after ceasing Ribavirin
Need to give it for 6 months
No response of ribavirin in 6 month or intolerance to ribavirin or relapse after 6 months ribavirin
Then need to give pegylated interferon alpha (no preferable as there is high chance of rejection)
Reference
1)Lecture : May A Hassaballa HEV in kidney transplant
2)Kamar N, Lhomme S, Abravanel F, Marion O, Peron J-M, Alric L, Izopet J. Treatment of HEV Infection in Patients with a Solid-Organ Transplant and Chronic Hepatitis. Viruses. 2016; 8(8):222. https://doi.org/10.3390/v8080222
3)Samala N, Wang RY, Auh S, Balla AK, Dakhoul L, Alter HJ, Farci P, Ghabril M, Lucey MR, Rangnekar AS, Reddy KR, Ghany MG. Hepatitis E prevalence and infection in solid-organ transplant recipients in the United States. J Viral Hepat. 2022 Dec;29(12):1134-1142. doi: 10.1111/jvh.13739. Epub 2022 Sep 21. PMID: 36036116.
4)Hansrivijit P, Trongtorsak A, Puthenpura MM, Boonpheng B, Thongprayoon C, Wijarnpreecha K, Choudhury A, Kaewput W, Mao SA, Mao MA, Jadlowiec CC, Cheungpasitporn W. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021 Mar 28;27(12):1240-1254. doi: 10.3748/wjg.v27.i12.1240. PMID: 33828397; PMCID: PMC8006097.
6 months Post Transplant patient with elevated and fluctuated liver enzymes suggestive for chronic nature of the process. Although HBV, HVC were negative therefore we should exclude other viruses. Chronic HEV infection is highly suspected in such cases, often asymptomatic, manifesting only with unexplained mild to moderate elevations in serum aminotransferase.
EBV mismatch D+/R- increase the risk of PTLD which needs to be considered during evaluation but both CMV and EBV were negative in this case.
Differential diagnosis
1. Infectious hepatitis.
viral Hepatitis A, B, C, E, D. CMV, EBV, HSV and adenovirus
2. Drugs induced hepatitis: CsA, Co-trimoxazole, Azathioprine, valganciclovir. 3. Toxic induced hepatitis. Acetaminophen, substance abuse 4.PTLD 5.Autoimmune hepatitis 6.NAFLD
management of this case?
Labs – CBC, LFT, RFT, LDH. – Tac level – Send PCRs of CMV, EBV, HBV, HCV, HEV. – serum and stool HEV, RNA. – Coagulation profile. – Serum albumin. –Abdominal and Liver US ; signs of chronicity, infiltrative disease. As the case is suspected HEV related complication of Post Tx treatment Treatment:
First line treatment would be Reduction of immunosuppression by reducing Tacrolimus as it potentiates HEV replication.
if no response to above measures for at least 3 months, or earlier in severe liver dysfunction or extrahepatic manifestations then
Second line treatment would be Ribavirin treatment dose adjusted according to GFR. Ribavirin is continued for at least 3 months until stool PCR are negative for HEV RNA on 2 occasions one month apart.
Relapse after a first course of ribavirin will need re-treatment for at least 6 months with ribavirin at dosages toward the higher side, if tolerated.
Monitoring: – Monthly HEV RNA testing in plasma and stool. – Monitor Hb% during ribavirin therapy as hemolytic anemia is major side effect – Check for SVR by HEV RNA in plasma and stool at 3rd & 6th months samples after stopping antiviral therapy – Monitor rejection during reduction in Tacrolimus and steroid dosages. References:
Einollahi B, Ghadian A, Ghamar-Chehreh E, Alavian SM. Non-viral related liver enzymes elevation after kidney transplantation. Hepat Mon. 2014;14(2):e9036. Published 2014 Feb 5.
Hansrivijit P, Trongtorsak A, Puthenpura MM, et al. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021;27(12):1240-1254.
Guidelines for Hepatitis E & Solid Organ Transplantation DRAFT Compiled by a Working Party of The British Transplantation Society Draft posted on April 2017 First Edition.
The index transplant patient is a living EBV seropositive donor renal recipient on Tacrolimus based steroid sparing immunosuppression with stable graft function and elevated liver enzymes 6 months post-transplant.
The differential diagnosis in a renal transplant recipient with hepatic dysfunction include (1-3):
a) Infections:
Hepatotrophic viral infections: Hepatitis B, Hepatitis C, Hepatitis E virus.
Detailed history and physical examination: Especially with respect to any illicit drug use, or medicine intake like NSAIDs, statins, Oral contraceptive pills (patient is a young female).
Investigations: Ultrasound abdomen for liver, Complete blood count, Liver function tests, autoimmune workup (ANA), and HBV, HCV, CMV, EBV, HEV RNA in plasma.
The index patient had negative CMV, EBV, HBV and HCV PCR. If autoimmune workup is negative, and HEV RNA comes as positive, then the patient is having acute HEV infection (analysis of pre-transplant historical serum samples, if available, should be done to assess presence of HEV RNA or Anti-HEV antibodies pre-transplant). Anti-HEV IgG and IgM should be tested.
If patient is diagnosed to have acute HEV infection:Observation, reduction in immunosuppression (lower tacrolimus trough levels – but patient should be counselled regarding risk of rejection), and serial monitoring of HEV RNA levels and liver enzymes for 3 months should be done (as >30% would spontaneously recover). Early treatment may be required in presence of jaundice, coagulopathy, or extrahepatic manifestations.
If there is persistence of HEV infection after 3 months, then a baseline plasma and stool HEV RNA test should be done and antiviral ribavirin should be started.
Antiviral: Ribavirin should be started with dosage of 600 mg/day(in 2 divided doses) for at least 3 months.
Plasma HEV RNA should be tested on day 7 (favorable response would require shorter duration of treatment).
Monthly testing of plasma and stool HEV should be done.
Ribavirin treatment should be stopped once 2 consecutive negative plasma and stool results (1 month apart) are obtained at 3 months.
If the plasma and stool HEV is still positive at 3 months, treatment should be continued till 2 consecutive negative plasma and stool results (1 month apart) are obtained or till 6 months.
Post-treatment completion, test for presence of HEV RNA in plasma and stool at 3 and 6 months to document sustained virological response.
Monitoring: Ribavirin is associated with hemolytic anemia; hence regular hemoglobin monitoring should be done. Dose should be adjusted as per creatinine clearance. Erythropoietin or blood transfusion might be required for managing anemia.
Ribavirin-refractory scenario: In case the patient does not respond to ribavirin, Pegylated interferon may be used, but would require close monitoring and counselling due to moderate risk of rejection.
Relapse post- ribavirin treatment: A course of Ribavirin can be repeated with higher dose and longer duration (6 months), as per creatinine clearance and the tolerability of the patient.
References:
Gunderson A, Said A. Liver disease in kidney transplant recipients. Transplant Rev (Orlando). 2015 Jan;29(1):1-7. doi: 10.1016/j.trre.2014.08.002. Epub 2014 Aug 27. PMID: 25306468.
Ahsan N, Rao KV. Hepatobiliary diseases after kidney transplantation unrelated to classic hepatitis virus. Semin Dial. 2002 Sep-Oct;15(5):358-65. doi: 10.1046/j.1525-139x.2002.00087.x. PMID: 12358641.
Einollahi B, Ghadian A, Ghamar-Chehreh E, Alavian SM. Non-viral related liver enzymes elevation after kidney transplantation. Hepat Mon. 2014 Feb 5;14(2):e9036. doi: 10.5812/hepatmon.9036. PMID: 24693313; PMCID: PMC3950572.
Kamar N, Lhomme S, Abravanel F, Marion O, Peron JM, Alric L, Izopet J. Treatment of HEV Infection in Patients with a Solid-Organ Transplant and Chronic Hepatitis. Viruses. 2016 Aug 15;8(8):222. doi: 10.3390/v8080222. PMID: 27537905; PMCID: PMC4997584.
Hansrivijit P, Trongtorsak A, Puthenpura MM, Boonpheng B, Thongprayoon C, Wijarnpreecha K, Choudhury A, Kaewput W, Mao SA, Mao MA, Jadlowiec CC, Cheungpasitporn W. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021 Mar 28;27(12):1240-1254. doi: 10.3748/wjg.v27.i12.1240. PMID: 33828397; PMCID: PMC8006097.
Young lady , LRD, pre transplant EBV , CMV were negative , donor was negative for CMV but positive for EBV, stable graft function, 6 months after Tx aminotransferase were slightly increased CMV and EBV were negative, PCR for HCV and HBV were negative. What is the differential diagnosis? · HEV infection · Other infectious hepatitis are excluded by PCR. · Alcoholic and non-alcoholic fatty liver · Drug induced like some antibiotics, NSAIDs, acetaminophen and statins. · Autoimmune hepatitis in a young lady. How to manage this case Diagnosis: This patient is most probably a case of HEV, it is recommended to investigate for HEV if other viral causes of raised liver enzymes are excluded · Involvement of hepatologist is important. · Do abdominal US to look at the liver.
· We check HEV RNA in blood using RT-PCR for diagnosis of HEV infection.
· Check serology for anti HEV IgM and IgG by ELISA.
· Analysis of stored plasma samples for HEV RNA to check for persistence of infection. If it is present for more than 3 months, this diagnose chronic HEV infection. Drug therapy
· If proved persistent HEV infection he should receive treatment with ribavirin at a dose of 200 to 600 mg/ day for 3- 6 months with the aim of achieving sustained virological response.
· Follow up with monthly HEV RNA testing in plasma is to be undertaken to make decision when to stop treatment.
· Check liver enzymes for the follow up and response.
· CBC for the development of anemia, if this developed we can use erythropoietin and we may we need to reduce the dose of ribavirin with monitoring of anemia as well as for viral response.
· After stopping ribavirin, test of sustained virological response is conducted by testing plasma for HEV RNA at three and six months.
· PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients as there is a moderate risk of precipitating organ rejection.
· Patients with persistent HEV who relapse after a first course of ribavirin are re-treated for at least six months with ribavirin at dosages toward the higher dose range.
· PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection.
References 1. Guidelines for Hepatitis E & Solid Organ Transplantation, BTS, First edition. 2. Nassim Kamar et al, Treatment of HEV Infection in Patients with a Solid-Organ Transplant and Chronic Hepatitis.Viruses 2016, 8, 222. 3. Panupong Hansrivijit, et al, Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis,March 28, 2021 Volume 27 Issue 12. 4. NassimK,et al Ribavirin for Chronic Hepatitis E Virus in Transplant Recipients. N Eng J Med 2014, 370:111-1120. 5. Stefan R, et al, Ribavirin – induced anemia: Mechanisms , risk factors and related targets for future research, Current medical chemistry volume 13, issue 27, 20063351-3357
Drug toxicity to liver antifungal , antibiotics and statin ,or toxicity related to CNI or MMF.
How would you manage this case?
First we need to take good history about any drug abuse ,recent use of any antibiotics or other drugs,any alchol use ,any contact with jaundiced patient.
Examine the patient of skin rash ,lymph nodes and jaundice area signs.
Investigate by abdominal US ,viral screening of HEV,serology of autoimmune hepatitis ,
Treatment if we establish HEV we reduce immune suppression ,if no improvement start RIBAVIRIN .
What is your differential diagnosis? Early post renal transplant hyper-transaminases causes: Drug induced: high dose methylprednisolone, azathioprine, CsA, MMF, … etc. Infectious causes: HCV, HBV, HEV, CMV, EBV,HIV, listeria…. etc Other causes: alcohol consumption, non-alcoholic fatty liver disease mushroom, male gender, anemia, dyslipidemia, hyperuricemia, and renal impairement..etc ALT was the liver enzyme with the highest prevalence of abnormalities among kidney transplant recipients (34.3%) How would you manage this case? Detailed history, travel, previous infections, exposure to animals, or any febrile ill person, and alcohol consumption. Laboratories: CBC. BUN, Creatinine, bilirubin, albumin, LDH, lipid profile, RBS, gamma GT, alkaline phosphatase, HCV+HBV+HEV+ HIV PCR(viral load), blood and urine cultures, and PT, PTT and INR. Radiological evaluation by ultrasound abdomen, CXR. Diagnosis: HEV It has been noted that tacrolimus and m-TOR inhibitors increase viral replication, but mycophenolate inhibits it, so in indexed case I would decrease the tac level up to the lower safe acceptable level (preventing rejection). The main stay treatment in his case is to start treatment with Ribavirin, at least for 3-6 months, till reaching a sustained viral response (not detected virus in blood and stool twice one month apart and at 3 and 6 months after stopping the Ribavirin) the HEV PCR (blood and stool) should be monitored monthly. During treatment close monitoring of CBC- hemolytic anemia is a common complication of Ribavirin, as well as liver function test and kidney function. PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection. ? HEV vaccine approved in china, for G1. Of note in indexed case, the donor seropositive EBV status, with negative recipient EBV serostatus, there were no significance of this mismatch, and doesnot predispose to PTLD. References: (1) Einollahi B, Ghadian A, Ghamar-Chehreh E, Alavian SM. Non-viral related liver enzymes elevation after kidney transplantation. Hepat Mon. 2014 Feb 5;14(2):e9036. doi: 10.5812/hepatmon.9036. PMID: 24693313; PMCID: PMC3950572. (2) Harwood JS, Gould FK, McMaster A, Hamilton JR, Corris PA, Hasan A, Gennery AR, Dark JH. Significance of Epstein-Barr virus status and post-transplant lymphoproliferative disease in pediatric thoracic transplantation. Pediatr Transplant. 1999 May;3(2):100-3. doi: 10.1034/j.1399-3046.1999.00019.x. PMID: 10389130.
Thank you Prof. dawlat
difference in host gene expression, G3 usually lower viral load than G1
G1 infects humans while G3 all mammals
G1 in Asia and Africa, G3 worldwide.
Reference: Sayed IM, Verhoye L, Cocquerel L, Abravanel F, Foquet L, Montpellier C, Debing Y, Farhoudi A, Wychowski C, Dubuisson J, Leroux-Roels G, Neyts J, Izopet J, Michiels T, Meuleman P. Study of hepatitis E virus infection of genotype 1 and 3 in mice with humanised liver. Gut. 2017 May;66(5):920-929. doi: 10.1136/gutjnl-2015-311109. Epub 2016 Mar 22. PMID: 27006186.
What is your differential diagnosis?
o In kidney transplant (KT) recipients, hypertransaminasemia is a freque finding, affecting 7 to 24% of patients
Hypertransaminasemia after Kidney Transplantation:
o This patient is low risk of CMV, and both HCV and HBV PCR were negative
o This patient is high risk of EBV (R-/D+). Although last EBV PCRs 6 weeks ago was negative, still EBV is a possible cause of hypertransaminasemia, and needs also monitoring for possible PTLD
o Another differential diagnosis for this fluctuating liver enzyme is HEV. Liver transaminases are usually only very modestly raised and few patients present with any symptoms. It can be transmitted at the time of SOT, either with the transplanted organ or through blood components from an HEV-infected donor. A plasma sample for transplant recipients taken at the time of transplantation and stored for a minimum of one and tested retrospectively for HEV or other infections is important
o Lorber et al. in 1987, mentioned that 49% of their renal allograft patients had post-transplant hepatotoxicity with CsA, including hyperbilirubinemia (48% of patients), elevated AST (47%), ALT (73%), LDH (84%), and ALP (59%)
o High dose calcineurin inhibitors frequently cause mild elevation of liver tests. Although rare, severe hepatotoxicity may occur
o Hepatotoxicity sometimes makes it necessary to switch between these two drugs
o Tacrolimus hepatotoxicity is characterized by elevated levels of hepatocellular enzymes, either alone or with minimal cholestasis and hyperbilirubinemia. hepatotoxicity did not decrease after dose reduction. Normalization of liver enzymes occurred after discontinuing tacrolimus
o Cyclosporine hepatotoxicity may also cause cause cholestasis, but reduction of the cyclosporine dosage alone is sufficient to resolve the hepatotoxicity
o Elevated aminotransferase is more commonly associated with SRL rather than CyA treatments or SRL + CyA treatments
How would you manage this case?
o Detailed history and comprehensive examination (eating raw or undercooked meat, alcohol, drugs, and neurological symptoms)
o CBC, LFT and ALP, clooting factors, immunosuppressive levels, RFT and electrolytes, ERS, and CRP
o HEV RNA and/or antigen detection in blood and stool (antibody detection is unreliable)
o U/S for liver or extra-hepatic obstruction
o Liver biopsy may be indicated if unexplained high liver enzymes
o Treat the underlying cause
If confirmed to be chronic HEV:
o Modification of immunosuppression (Lead to clearance of HEV infection in 30%)
o Start treatment with ribavirin with the aim of achieving sustained virological response (HEV RNA not detected in plasma and stool six months after completion of treatment)
o Do baseline quantitative HEV RNA on both plasma and stool at the start of treatment
o Treatment with ribavirin for at least three months (3-6 months for most patients)
o Do monthly HEV RNA testing in plasma and stool during treatment
o Continue ribavirin until stool tests are negative for HEV RNA on two occasions one month apart
o Do plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy (a test of sustained virological response)
o Regular haemoglobin monitoring during ribavirin therapy
o In relapse after a first course of ribavirin, re-treat for at least six months (higher dose)
o Treatmt with PEG-interferon treatment in ribavirin-refractory persistent HEV (close monitoring for rejection)
References
1. Solà-Porta, E.; Redondo-Pachón, D.; Arias-Cabrales, C.; Navazo, D.; Buxeda, A.; Burballa, C.; Crespo, M.; García-Retortillo, M.; Pascual, J.; Pérez-Sáez, M.J. Early Hypertransaminasemia after Kidney Transplantation: Significance and Evolution According to Donor Type. J. Clin. Med. 2021, 10, 5168.
2. Einollahi B, Ghadian A, Ghamar-Chehreh E, Alavian SM. Non-viral related liver enzymes elevation after kidney transplantation. Hepat Mon. 2014 Feb 5;14(2):e9036. doi: 10.5812/hepatmon.9036. PMID: 24693313; PMCID: PMC3950572.
3. Dizdar OS, Ersoy A, Aksoy S, Ozel Coskun BD, Yildiz A. Analysis of liver function test abnormalities in kidney transplant recipients: 7 year experience. Pak J Med Sci. 2016 Nov-Dec;32(6):1330-1335. doi: 10.12669/pjms.326.10725. PMID: 28083020; PMCID: PMC5216276.
4. Vivian Yiu, Rui Gao, Sharon Mulroy, Hepatitis in a renal transplant patient—beyond the usual, Clinical Kidney Journal, Volume 5, Issue 2, April 2012, Pages 170–172.
5. Guidelines for Hepatitis E & Solid Organ Transplantation. British Transplantation Society Guidelines, 2017.
6. Guidelines for Hepatitis B & Solid Organ Transplantation. British Transplantation Society Guidelines, 2018.
· High aminotransferase 6 months post-transplant, followed with reduced level, near to normal, 4 weeks later. After 6 weeks, liver enzymes were found to be elevated.
· No evidence of infection or reactivation of CMV and EBV as PCRs were negative for CMV and EBV. No evidence of infection by HBV nor HCV as PCRs were negative for both. Increased susceptibility for CsA-induced hepatotoxicity was noticed in cases of chronic HCV infection.It is likely that hepatitis C virus infection interferes with CsA metabolism and/or biliary CsA-excretion and thus is responsible for CsA and/or metabolite-induced hepatotoxicity despite very low doses of CsA(1). The index case was not on a regimen containing CsA.
· Needs to rule out viral hepatitis after HAV, HDV and HEV.
The likely differential diagnosis for this case scenario:
· Hepatitis A, D or E . HDV is very unlikely provided that HBV is negative. Hepatitis D infection cannot occur in the absence of hepatitis B virus.
· Adverse effects of statins and other medications.
· The liver enzyme elevation (LEE) is a common finding among kidney transplant recipients. Serial monitoring of aminotransferases, particularly ALT, should be performed in all patients after kidney transplantation(2).
· Very unlikely to think of autoimmune hepatitis(AIH) as a differential in this case as he was on TAC and MMF which were both considered as the second line of treatment for AIH. TAC/Prednisolone were the best combination for the second line treatment of AIH(3,4).
How would you manage this case?
1. Full supportive measures; hydration and avoidance of hepatotoxic drugs.
2. To keep immunosuppressants at the lower level of target, ensuring no adverse effects and be aware of possibility of rejection.
3. To screen for HAV, and HEV:
· HDV is very unlikely provided that HBV is negative.
· HAV-IgM and HAV RNA(using RT-PCR) may be needed.
· HEV IgG &IgM and HEV RNA level.
4. Viral hepatitis due to HAV is self-limiting disease and needs only supportive therapy and monitoring. Few cases may progress to fulminant hepatitis.
5. HEV infection, initially needs supportive measures as more than 30% may resolve spontaneously. Dynamic viral monitoring and antibody profiling may help clinical decision-making(5).
6. Early treatment with ribavirin may be considered in specific cases of acute hepatitis E, such as patients who develop severe liver dysfunction (jaundice and coagulopathy) or extra-hepatic manifestations, although evidence for this recommendation is currently limited(5).
7. A test of sustained virological response is conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy.
1. PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection.
References
1. Horina JH, Wirnsberger GH, Kenner L, Holzer H, Krejs GJ. Increased susceptibility for CsA-induced hepatotoxicity in kidney graft recipients with chronic viral hepatitis C. Transplantation. 1993 Nov;56(5):1091-4. doi: 10.1097/00007890-199311000-00008. PMID: 8249106.
2. Einollahi B, Ghadian A, Ghamar-Chehreh E, Alavian SM. Non-viral related liver enzymes elevation after kidney transplantation. Hepat Mon. 2014 Feb 5;14(2):e9036. doi: 10.5812/hepatmon.9036. PMID: 24693313; PMCID: PMC3950572.
3. Ferre-Aracil C, Riveiro-Barciela M, Trapero-Marugán M, Rodríguez-Perálvarez M, Llovet LP, Téllez L, Sánchez-Torrijos Y, Díaz-Fontenla F, Salcedo-Plaza M, Álvarez-López P, de la Mata M, Londoño MC, Bañares-Cañizares R, Calleja JL. Tacrolimus as an Effective and Durable Second-Line Treatment for Chronic Autoimmune Hepatitis: A Multicentric Study. Dig Dis Sci. 2021 Aug;66(8):2826-2832. doi: 10.1007/s10620-020-06569-9. Epub 2020 Aug 29. PMID: 32860579.
4. De Lemos-Bonotto M, Valle-Tovo C, Costabeber AM, Mattos AA, Azeredo-da-Silva ALF. A systematic review and meta-analysis of second-line immunosuppressants for autoimmune hepatitis treatment. Eur J Gastroenterol Hepatol. 2018 Feb;30(2):212-216. doi: 10.1097/MEG.0000000000001019. PMID: 29227329.
5. Guidelines for Hepatitis E & Solid Organ Transplantation; first edition (BTS guidelines)
What is your differential diagnosis? -Viral hepatitis HEV.HAV, HBV,HCV,HDV,CMV -Drugs like statins ,high dose CNI level -Autoimmune hepatitis -Alcoholic hepatitis -Wilson disease or hemochromatosis.
How would you manage this case?
Proper history ( any history of blood transfusion,eating undercooked meats,alcohol consumption or family history of hereditary hepatitis )and full clinical examination, then serology of HEV.HAV, HBV,HCV,HDV , CMV and viral load for each as recommended .
Graft function test. and liver function test .
Full blood count.
Serum and stool HEV RNA level .
Tacrolimus level
Hepatobiliary US ,and liver fibroscan .
. Hence HBV,HCV,CMV AND EBV all negative this is most likely HEV .
*If diagnosis of HEV is confirmed, reduction of immunosuppression is considered the first-line approach; it allows HEV clearance in about one-third of patients.
*Ribavirin is considered in patients with severe acute or acute chronic liver failure or if there is no response to reduction of immunosuppressants.
*Monitor the viral load and the response to ribavirin ,the duration is 3-6 months depending on presence of 2 consecutive negative HEV RNA in plasma and stool in one month apart .
DDx Viral infection Hepatitis ABCDE CMV, or EBV Druge induced : immunosuppressive, cotrimoxasol statins Other cause of elevated liver enzymes as associated condition with K. transplant : nonalcoholic fatty liver disease How to manage Good history taking focusedon history of exposure ( travel ) occupational history drug history and system related symptoms Clinical examination for signs of CLD or local abdominal tenderness or organomegally Lab : Serology for Hepatitis ABCDE CMV virology EBV PCR CBC KFT S.Albumin and Coagulation profile Abdominal US / CT According to the results treatment will be
-Differential diagnosis
· According to case scenario mostly a case of HEV hepatitis in renal transplant recipient
· HCV ,HBV ,HDV ,HAV ,HIV,EBV ,CMV ,BK viral infections
· Drug induced liver injury
· Alcoholic hepatitis
· Autoimmune hepatitis
· Inherited causes as Wilson disease ,Hemochromatosis
– Management
· Likely a case of HEV hepatitis since HBV,HCV ,EBV(after repetition) ,CMV PCR were negative along with mild elevation of liver enzymes that decreased then increased again.
· Detailed history need to be retaken from the recipient as well as the donor as living donor regarding previous blood transfusion ,operations or consumption of under cooked meat or alcohol intake
· Clinical exam for signs of liver affection and lymph node exam
· Investigations
-HEV RNA ,HEV Ig M and Ig G have to be done on serum and stool samples at the time being and retrospectively on preserved samples at transplantation time for the recipient and the donor as well
-GGT , liver function tests ,serum albumin ,INR , total bilirubin ,direct bilirubin ,following liver enzymes,
-labs to assess graft function
-routine labs as CBC and inflammatory markers .
-US to evaluate liver status and renal graft status
· Treatment
-Reduction of immunosuppression as graft function is well maintained along with monitoring of Tac and MMF trough levels and graft function
-Ribavirin corrected to creatinine clearance can be started with CBC monitoring along with liver enzymes and duration of therapy ranges from 3-6 months
-HEV RNA testing in stool 2 time on 1 month apart if both negative then ribavirin can be stopped
-Sustained viral response need to be assessed by monitoring HEV RNA in stool every 3 months for 6 months
Reference
– Guidelines forHepatitis E & Solid OrganTransplantation.BTS April,2017.
– Lim, Mary A. MD1; Kamili, Saleem PhD2; Cohen, Jordana B. MD, MSCE1,3; Green-Montfort, Tracy BS2; Tejada-Strop, Alexandra MS2; Kohli, Jatinder MD1; Drobeniuc, Jan MD, PhD2; Patel, Priyanka MS1; Vanderveen, Mary BS1; Bloom, Roy D. MD1. Hepatitis E Virus Infection in Kidney Transplant Patients: A Single-Center Study. Transplantation 102(4):p e126-e127, April 2018.
-Remy P .Hepatitis E Differential Diagnoses.Medscape 2019
An 18-year-old lady with CKD 5 due to an unknown cause underwent living-related donor kidney transplantation in 2013. She was given a short course of steroids (discontinued 1 week after transplantation), MMF, and tacrolimus. Pre-transplant serum EBV- and CMV-IgG were negative. The donor was seronegative for CMV but positive for EBV. Kidney transplantation was uncomplicated, with a stable kidney function (eGFR varied between 92 and 98 mL/min). Six months after transplantation, serum aminotransferase levels (ALT: 66 U/L; AST: 47 U/L) were found to be slightly elevated. CMV and EBV PCRs were negative. Four weeks later, liver enzymes decreased (ALT: 53 U/L; AST: 42 U/L) to near-normal levels. Six weeks thereafter, liver enzymes (ALT: 75 U/L; AST: 58 U/L) were again found to be elevated. HCV and HBV PCR were negative.
What is your differential diagnosis?
How would you manage this case?
What is your differential diagnosis? 1st DD is Details History for any new drugs intake, Alcohol intake, fever, weight loss, don’t forget MMF is the most common cause of Elevated LFTs immediately post-Transplant, others Like Statin, antibiotics from my clinical practices.
2nd DD is Viral infection in including HAV, HBV, HEV, HCV, CMV, EBV, BKV all excluded except HEV so I will order HEV PCR 3rdis NAFLD. 4this Autoimmune hepatitis. 5this Hereditary conditions such as Wilson’s disease, Hemochromatosis. Other Actions:
LFTs, TSH, HEV PCR and U/S Hepatobiliary.
Hepatology Consult. (Expert opinion).
How would you manage this case?
Reduce immunosuppression and monitor viral load monthly for 3 months.
Monitor kidney function, and TAC trough level.
HEV DNA level, anti-HEV IgG titer, HEV RNA level, HEV IgM, IgG.
Ribavirin for 3 months started immediately by monitoring liver function, and HEV RNA.
Monitor ribavirin side effects and adjust the dose accordingly.
I will monitor PCR in blood after 1 week of therapy to predict the duration of therapy,
then I will perform PCR in blood and stool monthly.
Continue ribavirin until HEV RNA level be -ve. for 2 consecutive tests 1 month apart, (3-6 months).
After stopping ribavirin, I will monitor viral load every 3 months using blood or stool PCR for 6 months if negative this means SVR.
I will monitor CBC every 2 weeks and adjust the dose of ribavirin according to Hb level. I will monitor liver enzymes every 2 weeks initially then monthly.
I will inform the patient to avoid consuming processed undercooked meat especially pork.
PEG-interferon in persistent infection despite ribavirin treatment with cautiously monitoring graft function. References:
*UpToDate
*Guidelines for Hepatitis E & Solid Organ Transplantation *European Association for the Study of the Liver. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on hepatitis E virus infection. J Hepatol. 2018 Jun;68(6):1256-1271. doi: 10.1016/j.jhep.2018.03.005. Epub 2018 Mar 31. PMID: 29609832
HEV DNA level, anti-HEV IgG titer, HEV RNA levl, HEV IgM, IgG.
Reduce tacrolimus level cautiously and monitor drug level and graft function.
Ribavirin started immediately by monitoring liver function, and HEV RNA.
Monitor ribavirin side effects and adjust the dose accordingly.
Continue ribavirin until HEV RNA level be -ve for 2 consecutive tests 1 month apart, (3-6 months).
PEG-interferon in persistent infection despite ribavirin treatment with cautiously monitoring graft function.
References
Patra S, Kumar A, Trivedi SS, Puri M, Sarin SK. Maternal and fetal outcomes in pregnant women with acute hepatitis E virus infection. Ann Intern Med. 2007;147:28–33. – PubMed
Aggarwal A, Perumpail RB, Tummala S, Ahmed A. Hepatitis E virus infection in the liver transplant recipients: Clinical presentation and management. World J Hepatol. 2016;8:117–122. – PMC – PubMed
Koning L, Pas SD, de Man RA, Balk AH, de Knegt RJ, ten Kate FJ, Osterhaus AD, van der Eijk AA. Clinical implications of chronic hepatitis E virus infection in heart transplant recipients. J Heart Lung Transplant. 2013;32:78–85. – PubMed
In addition, would you consider Congestive hepatopathy, hemochromatosis, autoimmune hepatitis, Wilson disease and alpha-1 antitrypsin deficiency as well?
Differential diagnosis
-Infectious hepatitis; viral Hepatitis A, B, C, E – CMV, EBV, HSV and adenovirus
-Drugs induced hepatitis: CsA, Co-trimoxazole, Azathioprine, valganciclovir.
-Toxic induced hepatitis; Acetaminophen, substance abuse
-PTLD
-Autoimmune hepatitis
-NAFLD ————————–
-KTR with elevated and fluctuated liver enzymes noticed 6 months post-Tx.
-This suggestive for chronic nature of the process as HBV, HVC were negative other viruses need to be ruled out.
-EBV mismatch D+/R- increase the risk of PTLD which needs to be considered during evaluation.
-Chronic HEV infection is highly suspected, often asymptomatic, manifesting only with unexplained mild to moderate elevations in serum aminotransferase. ————————— Elevated liver enzymes in KTRs: – It is a frequent finding, affecting 7 to 24% of patients depending on the series. – In immediate post-KT period, 36.6 and 43.4% of KT recipients who receive ATG induction – It is more frequent in deceased donor KTRs than in living donor ones. – The main causes during the first months; viral infections (HCV,HBV,CMV,EBV), previous liver disease (hepatorenal polycystic disease), and pharmacological hepatotoxicity (immunosuppressants, antibiotics, antifungals and antiviral agents).
——————————- How would you manage this case? * work up;.
– CBC, LFT, RFT, CrCL
– Tac level
– Repeat CMV, EBV, HBV, HCV, HEV.
– serum and stool HEV, RNA.
– Test any previous collected sample for HEV RVA.
– Liver US ;signs of chronicity, infiltrative disease.
– Coagulation profile.
– Serum albumin.
**Treatment will be guided by result of work up, If confirmed as HEV infection; *Treatment: – First line: Reduction of immunosuppression RIS to facilitate viral, by reducing Tacrolimus as it potentiate virus replication. – Ribavirin RBV started if no response to RIS for at least 3 months, or earlier in severe liver dysfunction (jaundice and coagulopathy) or extrahepatic manifestations. – RBV dose adjusted to CrCL – RBV is continued for at least 3 months until stool tests are negative for HEV RNA on 2 occasions one month apart. – Relapse after a first course of ribavirin are re-treated for at least 6 months with ribavirin at dosages toward the higher dose range, where tolerated. – PEG-IFN may be considered in ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection *Monitoring: – HEV RNA at day 7 of Ribavirin therapy to predict SVR at 3 months.help determine the likely length of treatment required – Monthly HEV RNA testing in plasma and stool. – Monitor Hg during ribavirin therapy as hemolytic anemia is side effect – Check for SVR by HEV RNA in plasma and stool at 3 & 6 months samples after stopping antiviral therapy – Monitor rejection during RIS. References:
Ahsan, N. and Rao, K.V. (2002), Renal Transplantation Update Series Editors: V. Ram Peddi and M. Roy First: Hepatobiliary Diseases After Kidney Transplantation Unrelated to Classic Hepatitis Virus. Seminars in Dialysis, 15: 358-365.https://doi.org/10.1046/j.1525-139X.2002.00087.x
Einollahi B, Ghadian A, Ghamar-Chehreh E, Alavian SM. Non-viral related liver enzymes elevation after kidney transplantation. Hepat Mon. 2014;14(2):e9036. Published 2014 Feb 5. doi:10.5812/hepatmon.9036
Te H, Doucette K. Viral hepatitis: Guidelines by the American Society of Transplantation Infectious Disease Community of Practice. Clin Transplant. 2019 Sep;33(9):e13514. doi: 10.1111/ctr.13514. Epub 2019 Apr 14. PMID: 30817047.
Hansrivijit P, Trongtorsak A, Puthenpura MM, et al. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021;27(12):1240-1254. doi:10.3748/wjg.v27.i12.1240
Guidelines for Hepatitis E & Solid Organ Transplantation DRAFT Compiled by a Working Party of The British Transplantation Society Draft posted on April 2017 First Edition.
Differential diagnosis of hepatic dysfunction after renal transplantation includes
Drug induced, so all drugs such as NSAIDS, antibiotics should be reviewed, and if suspected the drug should be withdrawn
Consumption of alcohol can lead to alcoholic hepatitis, this can be obtained from history
Viral infection in including HBV, HEV, HCV, CMV, EBV, all excluded except HEV so I will order HEV PCR
Fatty liver can lead to steatohepatitis (NASH)
Hepatic infiltration is an important cause of liver dysfunction after transplantation including PTLD, malignancies, so I will order us abdomen and pelvis and if suspicious I will order CT chest, abdomen and pelvis with contrast
Calcular gall bladder disease
Congestive hepatopathy due to heart failure, IVC will be dilated, other manifestation of heart failure will be present
Endocrinal causes including hyperthyroidism and addision
Other rare disease like hemochromatosis, autoimmune hepatitis, wilson disease and alpha-1 antitrypsin deficiency
So
I will take through history (drug history, fever, weight loss)
Perform full liver function tests, TSH, HEV PCR and Us abdomen initially
If normal I will refer to hepatology consultant for further evaluation
If diagnosis of HEV is settled
I will reduce immunosuppression and monitor viral load monthly for 3 months
If no response I will start ribavirin for 3 months
I will monitor PCR in blood after 1 week of therapy to predict the duration of therapy, then I will perform PCR in blood and stool monthly
I will continue ribavirin till 2 consecutive PCR in stool are negative 1 month apart
After stopping ribavirin I will monitor viral load every 3 months using blood or stool PCR for 6 months, if negative this means SVR
I will monitor CBC every 2 weeks and adjust the dose of ribavirin according to Hb level
I will monitor liver enzymes every 2 weeks initially then monthly
I will inform the patient to avoid consuming processed undercooked meat especially pork
References
Up-to-date
Guidelines for Hepatitis E & Solid Organ Transplantation
Medications (steroids , MMF, and tacrolimus) Corticosteroids also have major effects on the liver, particularly when given long term and in higher than physiologic doses. Glucocorticoid use can result in hepatic enlargement and steatosis or glycogenosis. Corticosteroids can trigger or worsen nonalcoholic steatohepatitis. Long term use can also exacerbate chronic viral hepatitis. Importantly, treatment with corticosteroids followed by withdrawal or pulse therapy can cause reactivation of hepatitis B and worsening or de novo induction of autoimmune hepatitis, both of which can be fatal. Finally, high doses of intravenous corticosteroids, largely methylprednisolone, have been associated with acute liver injury which can result in acute liver failure and death. Thus, the hepatic complications of corticosteroids are mostly associated with high intravenous dosing usually represent the worsening or triggering of an underlying liver disease and rarely are the result of drug hepatotoxicity.
Tacrolimus therapy is associated with mild to moderate elevations in serum aminotransferase levels in 5% to 10% of patients. These elevations are usually mild, asymptomatic and self-limited, but are occasionally persistent and may require dose modification.
Tacrolimus has also been implicated in instances of cholestatic hepatitis, but clinically apparent liver injury is rare. Because tacrolimus is used in the context of organ transplantation and often in liver transplantation, the causes of liver test abnormalities arising during therapy are many, and drug induced liver injury due to tacrolimus is sufficiently rare that its clinical features and typical course have not been defined. Likelihood score: C (probable rare cause of clinically apparent liver injury).
Mechanism of Injury Tacrolimus undergoes extensive hepatic metabolism largely via the cytochrome P450 system (CYP 3A4) and is susceptible to many drug-drug interactions. Liver test abnormalities during therapy may be due to direct hepatotoxicity, its effects on levels of other medications, or its effects on the immune system.
Serum enzyme elevations occur in a small proportion of patients on mycophenolatemofetil, but the abnormalities are usually mild, asymptomatic and resolve spontaneously or with dose reduction. A small number of cases of clinically apparent liver injury have been reported in patients on mycophenolate. The onset of injury is usually during the first month of therapy and the pattern of serum enzyme elevations is hepatocellular or mixed. The liver injury is usually mild and self-limiting. Autoimmune and immunoallergic features are uncommon. Likelihood score: D (possible rare cause of clinically apparent liver injury).
Mechanism of Injury Mycophenolatemofetil is a prodrug and undergoes extensive metabolism to mycophenolicacid which is pharmacologically active and undergoes enterohepatic recirculation. Mycophenolicacid is converted to a glucuronide by glucuronyl transferase and excreted largely in the urine. Idiosyncratic liver injury is likely due to a toxic or immunogenic metabolite. Mycophenolate does not seem to affect cytochrome P450 enzymes.
MILD-MODERATE ELEVATION DD *Chronic viral hepatitis (hepatitis B, C, D) ●Alcoholic liver disease ●Hemochromatosis ●Nonalcoholic fatty liver disease ●Autoimmune hepatitis ●Wilson disease ●Alpha-1 antitrypsin deficiency ●Congestive hepatopathy ●Adult bile ductopenia ●Malignant infiltration (most often breast cancer, small cell lung cancer, lymphoma, melanoma, or myeloma) ●Muscle disorders (eg, subclinical inborn errors of muscle metabolism) ●Thyroid disorders ●Celiac disease ●Adrenal insufficiency ●Anorexia nervosa ●Macro-AST (moderate elevations in plasma AST levels due to the presence AST-immunoglobulin complexes, usually IgG)
How would you manage this case?
HISTORY TAKEN SYSTEMIC EXAMINATION -ABDOMIAL EXAMINATION -EXLUDE LL EDEMA -ASCITES -SIGNS OF LIVER FAILURE
LAB TROUGH LEVEL OF TACROLIMUS
US ABDOMEN
EXCLUDE SEPSIS -CBC -URINE BLOOD -STOOL CULTURES
SERUM BILIRUBIN -LDH
HEV RNA
-The liver injury due to tacrolimus is usually mild and self-limiting and responses rapidly to dose adjustment or drug discontinuation
-The liver injury due to mycophenolate is usually mild and self-limited, resolving by itself or responding rapidly to dose modification or discontinuation. Mycophenolate has not been linked to instances of acute liver failure or vanishing bile duct syndrome.
I appreciate your step-wise clinical approach in managing this patient that is well supported by evidence.I appreciate your differential diagnosis.Please use headings and sub-headings to make easier to read your write-up. Please use bold or underline to highlight headings and sub-headings.
Viral infections – BK virus, CMV, EBV, Hepatitis A, B, C, E
Drugs such as statins
Toxic hepatitis from illicit substance use
NAFLD
Autoimmune hepatitis
Hereditary conditions such as Wilson’s disease, Hemochromatosis
Management
Management of HEV depends upon the immune status of the patient and the stage of disease (eg, acute versus chronic). A subset of patients who undergo solid organ transplantation (eg, kidney, liver, and kidney-pancreas) appear to develop chronic HEV infection The natural history of chronic HEV infection in transplant recipients is incompletely understood, but rapid progression of liver disease to cirrhosis has been reported.
We suggest a 12-week course of ribavirin monotherapy with chronic HEV infection.
In solid organ transplant recipients, we administer ribavirin in conjunction with reducing immunosuppressive therapy.
For others, we administer antiviral therapy if immunosuppressive therapy cannot be reduced, or if the patient has persistent HEV RNA despite a reduction in immunosuppressive therapy for 12 weeks
History of undercooked meat ingestion, alcohol consumption, history of travel & drug history.
Measurement of drug level (CNI).
CBC, LFT, serum feritine.
Plasma HEV RNA if positive the diagnosis will be HEV infection
After confirming diagnosis of HEV infection:
baseline stool & plasma HEV RNA needed.
Start rivavirin for 3-6 months with monthly HEV RNA
Duration of treatment depend on achievement of 2 negative stool sample for HEV RNA 1 month apart with sustained virological response( negative HEV RNA test in stool & plasma sample at 3-6 months after treatment discontinuation).
Close monitoring of Hb level(ribavirin frequent adverse event is anemia).
References:
Einollahi B., Ghadian A., Ghamar-Chehreh E. and Alavian S. Non-Viral Related Liver Enzymes Elevation after Kidney Transplantation. Hepatitis Mon,2014;14(2).
Vieira G., Amaral A., Filho R., Souza A., Medina-Pestana J., et al. Hepatic alteration in kidney transplant recipients from the largest kidney transplant center in Brazil. Are Gastroentrol,2022.
Guidelines for Hepatitis E & Sold Organ Transplantation, BTS,2017.
Viral infections – BK virus, CMV, EBV, Hepatitis A, B, C, E
Drugs such as statins
Toxic hepatitis from illicit substance use
NAFLD
Autoimmune hepatitis
Hereditary conditions such as Wilson’s disease, Hemochromatosis
Management
A. Thorough history and examination
History of induction therapy with ATG, acute rejection episodes, preoperative viral serologies. History of statin use, illicit substance use. On examination- peripheral stigmata of chronic liver disease, injection marks etc.
Investigation – Hepatitis A, B, C, E RNA, BK; toxicologic screen, autoimmune antibody panel, liver scan.
B. If found to be hepatitis E positive, then it’s likely chronic. Management is as follows.
Get a baseline HEV RNA in serum and stool.
Reduce immunosuppression if possible – tacrolimus trough target of 4ng/ml.
Wait for about 3 months for response to reduction in immunosuppressive medications.
Monitor serum and stool HEV RNA monthly.
Commence a 3 – month course of ribavirin after 3 months in absence of HEV clearance from stool.
Monitor FBC for anemia and dose ribavirin based on GFR using the serum creatinine levels.
Continue treatment until stool is negative for HEV RNA on 2 occasions one month apart.
In cases of relapse after ceasing ribavirin, restart treatment for a 6-month course.
No other options of treatment in this patient if viremia persists despite ribavirin. However, adherence and proper dosing of medications should be ensured.
Reference
European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu; European Association for the Study of the Liver. EASL Clinical Practice Guidelines on hepatitis E virus infection. J Hepatol. 2018 Jun;68(6):1256-1271. doi: 10.1016/j.jhep.2018.03.005. Epub 2018 Mar 31. PMID: 29609832
Hansrivijit P, Trongtorsak A, Puthenpura MM, Boonpheng B, Thongprayoon C, Wijarnpreecha K, Choudhury A, Kaewput W, Mao SA, Mao MA, Jadlowiec CC, Cheungpasitporn W. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021 Mar 28;27(12):1240-1254. doi: 10.3748/wjg.v27.i12.1240. PMID: 33828397; PMCID: PMC8006097.
What is your differential diagnosis? Given that the PCR results for CMV, EBV, HCV, and HBV were negative, the case of increased liver enzymes likely attributed to other causes. Infectious and non-infectious conditions can also result in high liver enzyme levels following kidney donation. Hepatitis E virus is at the top of the list of infectious causes, along with Hepatitis A and D viruses. Non-infectious causes include alcohol, malignancy, immunosuppressive medications adverse effects, autoimmune disease, and metabolic disorders. How would you manage this case?
The complete history of past blood transfusions, history of liver illness, trough level of CNI, and PCR HEV are the first steps in managing this patient.
Management of infectious causes should focus on detection of viral illnesses, with an emphasis on HEV infection. Prior to starting treatment, we should measure the baseline quantitative HEV RNA in both plasma and feces.
Initial step includes decreasing immunosuppression while closely observing for laboratory signs of acute rejection.
Ribavirin should be started for 3- 6 months, along with monthly HEV RNA testing in plasma and stool, until stool tests for HEV RNA are negative on two occasions, one month apart.
Renal function tests should be measured frequently to adjust ribavirin does according to eGFR.
PEG-interferon can be used instead with careful monitoring for rejection if the infection is resistant to therapy with ribavirin.
2. Infectious etiology like bacterial fungal, Viral hepatitis (CMV, EBV, and acute viral hepatitis including HEV less likely as the screen negative and being fluctuation of liver enzymes level for more than 3 months so we should think about the possibility of chronic Hepatitis E viral infection.
3. Malignancy like PTLD and early post-PTLD are still possible as she is EBV seronegative young candidate from donor positive (high risk), however, her repeated EBV was negative.
How would you manage this case?
Further history including drug history and tacrolimus trough level, previous infection including HEV RNA positive in the previously stored blood samples, presence of anti-HEV IgG antibodies do not confer universal protection and need to send for quantitive HEV PCR level, history of previous HEV infection, blood transfusion, food ingestion
in immunosuppressed patients, the acute HEV can progress to a chronic course (HEV RNA detectable > 6 months) with high morbidity and mortality rates. Usually need to be confirmed by viral PCR level and depends on viral load will decide the treatment duration which mainly depends on the reduction of IS, in particular, MMF and ribavirin for 3-6 months duration and FU with viral load and monitor for ribavirin side effects like hemolytic anemia.
Immunosuppressive therapies might also interfere with the HEV replication cycle as recently demonstrated by Wang and colleagues (2). They showed that tacrolimus promoted the infection of liver cells with HEV, whereas mycophenolate mofetil inhibited HEV replication and steroids showed no effect at all. up to 30% of HEV‐infected patients show a spontaneous clearance of HEV after reduction of immunosuppression at a follow-up of 6 months as per one report (3).
Serial measurements of HEV‐RNA are helpful to determine the optimal duration of ribavirin treatment (4).
Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression (1).
immunosuppressed patients including SOT at risk of chronic HEV infection, reactivation is worth counseling patients to avoid the consumption of raw/ undercooked pig products. References
1. Panning M, Basho K, Fahrner A, Neumann-Haefelin C. Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: a case report. BMC Infect Dis. 2019 Jul 30;19(1):675. doi: 10.1186/s12879-019-4307-6.
2. Wang Y, Zhou X, Debing Y, Chen K, Van Der Laan LJ, Neyts J, et al.Calcineurin inhibitors stimulate and mycophenolic acid inhibits the replication of the hepatitis E virus. Gastroenterology. 2014;146(7):1775–83.
3. Kamar N, Abravanel F, Selves J, et al. Influence of immunosuppressive therapy on the natural history of genotype 3 hepatitis‐E virus infection after organ transplantation. Transplantation. 2010;89(3):353‐360. 10.1097/TP.0b013e3181c4096c [PubMed] [CrossRef] [Google Scholar]
4. Affeldt P, Di Cristanziano V, Grundmann F, Wirtz M, Kaiser R, Benzing T, Stippel D, Kann M, Kurschat C. Monitoring of hepatitis E virus RNA during treatment for chronic hepatitis E virus infection after renal transplantation. Immun Inflamm Dis. 2021 Jun;9(2):513-520.
Differential diagnosis of elevated liver enzymes ELE:
1] Chronic liver disease.
2] Drug induced hepatitis.
3] HEV infection associated hepatitis.
4] other viruses might be implicated such as Herpez virus
5]Non alcoholic and alcoholic fatty liver disease NAFLD Management:
Exclusion of chronic liver disease by performing Fibroscan and MRI .
If its abnormal then referral to hepatologist and liver biopsy might be indicated in addition to full list of investigations to find out about chronic liver disease.
For HEV infection will request for plasma and stool PCR and Anti HEV antibodies, IgM and IgG, if its positive , then reduction of immune suppression and Ribavirin therapy are indicated. Drug induced hepatitis:
The most common cause of drug induced hepatitis is CNI Tacrolimus and Cyclosporin, particularly when its plasma level is elevated.
Therefore, checking the trough level of Tacrolimus is indicated in this context, if its elevated , then will reduce Tac dose accordingly.
Consequently, if No improvement is reported then switching to Cyclosporin is the next step forward.
When no improvement in liver enzymes is reported , then changing to Sirolimus is the best option.
lastly, if ELE is still lingering, then MMF might be the culprit, therefore reducing the dose of MMF of switching to AZA might be sought after. References: 1] Gustavo de Almeida VIEIRA et al. Hepatic alterations in kidney transplant recipients from the largest kidney transplant center in Brazil. Arq Gastroenterol • 2022. v. 59 nº 1 jan/mar • 65
Patients who come with an increase in aminotransferases, whether or not they also have hepatitis symptoms, have a wide range of infectious and noninfectious factors to consider in their differential diagnosis. Liver disease caused by infectious
Hepatitis A
Hepatitis E
Acute/chronic HBV
Chronic HCV
HDV superimposed on HBV
Other viruses like herpes simplex, EBV, CMV Liver disease caused by toxins:
ALCHOL AND DRUGS
Liver disease by metabolic disorders:
NASH, autoimmune hepatitis and Wilson disease Laboratory
CBC, CRP, HEV-IgM,igG. HEV RNA in stool
Rest of al viruses serology including A,B, C.
TREATMENT
Reduction in immunosupression
Ribavirine for 3 to 6 month until two stool HEV RNA tests, one month apart, are negative, along with monthly HEV RNA testing in plasma and stool.
1- Pawlotsky JM. Hepatitis E screening for blood donations: an urgent need? Lancet 2014; 384:1729.
2- Anwar N, Sherman KE. Viral hepatitis other than A, B, or C. In: Scientific American Gastroenterology, Hepatology, and Endoscopy, Burakoff R. (Ed), Decker Intellectual Properties, Toronto 2016.
3- British Transplantation Society Guidelines
Guidelines for Hepatitis E & Solid Organ Transplantatio
What is your differential diagnosis?
A case of PKX with elevated transaminases with CMV, EBV, HCV and HBV PCR negative.
Hepatitis E virus – on top of the list.
Hepatitis A virus.
Hepatitis D virus.
Other infectious causes (bacterial, fungal or parasitic source).
Non-infectious cause such as (alcohol, drugs such as (steroid or MMF), autoimmune diseases, and metabolic diseases). How would you manage this case?
Treatment of the cause such as stop drugs or alcohol consumption.
Treatment of other source of infection and here will stress on HEV infection .
1-We should collect a baseline quantitative HEV RNA on both plasma and stool at the start of treatment.
2-Ribavirin should be started for 3- 6 months and until stool tests are negative for HEV RNA on two occasions one month apart with monthly HEV RNA testing in plasma and stool.
3-Ribavirin dose should be adjusted according to renal function tests.
4-F/U Hemoglobin during Ribavirin course.
5-If infection resistant to Ribavirin, we can use PEG-interferon with close monitoring for rejection.
6-Reduction of immunosuppression with close monitoring of RFT. References:
1- British Transplantation Society Guidelines: Guidelines for Hepatitis E & Solid Organ Transplantation 2017.
2- Hansrivijit P, Trongtorsak A, Puthenpura MM, et al. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021;27(12):1240-1254. doi:10.3748/wjg.v27.i12.1240.
3-Dizdar OS, Ersoy A, Aksoy S, Ozel Coskun BD, Yildiz A. Analysis of liver function test abnormalities in kidney transplant recipients: 7 year experience. Pak J Med Sci. 2016;32(6):1330-1335. doi:10.12669/pjms.326.10725
What is your differential diagnosis?
Renal transplant patient with high liver enzymes post transplant with fluctuating course.
Virology screen for CMV,EBV,HCV and HBV came negative.
Generally speaking ,Elevation of liver aminotransferases, ALT and AST, is suggestive of hepatocellular injury. It is important to consider also the transient elevation of serum aminotransferases within the first 3 months after transplantation was commonly seen in 22% of all transplant recipients. Persistent elevation of liver enzymes Six months after transplantation is considered chronic hepatitis.
It is can be viral related and non viral related causes: -Non viral causes like alcohol, fatty liver, autoimmune hepatitis and pharmacological causes as immunosuppressants including CNIs ,antibiotics, antifungals ,acetaminophine toxicity ,herbal supplements and illicit drugs and antiviral agents. -Viral causes: Hepatotropic viruses HBV, HCV, CMV, Hepatitis A virus infection, EBV, HSV and hepatitis E viral infection.
How would you manage this case?
-Proper history including alcohol intake, medications, symptoms and signs. -Physical examination of GI system: Any hepatomegaly, accompanied splenomegaly, ascites if there.
-Investigations:
Blood tests including CBC,liver enzymes,Bilirubin and serum albumin
Antibody screening for HEV IgG and IgM, HEV PCR
Imaging including abdominal US
-If confirmed chronic HEV infection ,the aim for viral clearance with reduction of immunosuppression and 12-weeks course of ribavirin monotherapy. The dose of ribavirin is 600 to 1000 mg daily with close monitoring for toxicity.
The main causes during the first months after transplant are attributed to viral infections (hepatitis C virus, hepatitis B virus, cytomegalovirus, HEV, and Epstein Barr virus), previous liver disease (hepatorenal polycystic disease), and pharmacological hepatotoxicity (immunosuppressants, antibiotics, antifungals, and antiviral agents), and PTLD(as the donor is positive for EBV and recipient is negative)
How would you manage this case?
Confirm the result of viral serology
repeat LVT, Coagulation profile, CBC, CRP, and renal function
Request U/S abdomen.
If confirmed HBE:
More than 30% of solid organ transplant patients with acute HEV infection will spontaneously eliminate the illness within three months, thus HEV RNA levels and liver enzymes are monitored. Real-time viral surveillance and antibody profiling may aid clinical decision-making.
In individuals with acute or chronic HEV, reducing immunosuppression may help viral clearance, although the risk of rejection must be addressed.
Acute hepatitis E patients with severe liver dysfunction (jaundice and coagulopathy) or extrahepatic symptoms may benefit from early ribavirin therapy
Upon treatment onset, plasma and stool HEV RNA are quantified.
HEV-infected solid organ transplant patients should take ribavirin for three months. Ribavirin therapy usually lasts 3-6 months.
Once the medication is stopped, plasma and stool HEV RNA are tested monthly.
Ribavirin is maintained until stool tests are negative for HEV RNA on two occasions one month apart since HEV shedding in stool predicts recurrence following therapy.
Regular haemoglobin monitoring is conducted during ribavirin therapy as haemolytic anaemia is a common treatment-related side effect.
Reference: British Transplantation Society Guidelines: Guidelines for Hepatitis E & Solid Organ Transplantation.
2. An 18-year-old lady with CKD 5 due to an unknown cause underwent living-related donor kidney transplantation in 2013. She was given a short course of steroids (discontinued 1 week after transplantation), MMF, and tacrolimus. Pre-transplant serum EBV- and CMV-IgG were negative. The donor was seronegative for CMV but positive for EBV. Kidney transplantation was uncomplicated, with a stable kidney function (eGFR varied between 92 and 98 mL/min). Six months after transplantation, serum aminotransferase levels (ALT: 66 U/L; AST: 47 U/L) were found to be slightly elevated. CMV and EBV PCRs were negative. Four weeks later, liver enzymes decreased (ALT: 53 U/L; AST: 42 U/L) to near-normal levels. Six weeks thereafter, liver enzymes (ALT: 75 U/L; AST: 58 U/L) were again found to be elevated. HCV and HBV PCR were negative.
Acute hepatitis E virus (HEV) infection is diagnosed in immunocompetent individuals based on the detection of anti-HEV immunoglobulin M (IgM).
HEV RNA can be detected just before the onset of clinical symptoms and is undetectable for 3 weeks after the onset of symptoms.
However, immunocompromised individuals should be tested for HEV RNA if there is suspicion of infection.
Detection of elevated reactivity in an IgG assay indicates the presence of acute hepatitis E, but the determination of immunity or previous exposure to HEV by detection of IgG antibodies is problematic.
Abdominal ultrasonography is recommended to rule out extra hepatic causes of biliary obstruction, HEV infection, and advanced liver disease.
Management should focus on clean drinking water, good sanitation, and proper personal hygiene to prevent HEV infection.
Ribavirin therapy can improve liver enzymes and functions in severe acute hepatitis E, but is contraindicated in pregnancy due to teratogenicity.
1- Reduce immunosuppressive therapy to reduce HEV replication in transplant recipients.
2-Ribavirin (600–1000 mg/day) for at least 3 months monotherapy is the first treatment option for patients with chronic hepatitis E who are not able to clear HEV after immunosuppression is reduced, but G1634 mutation in RdRp domain of HEV ORF1 protein is associated with failure.
Treatment with ribavirin achieved sustained virological response, HEV RNA not detected 6 months after treatment.
Monitoring HEV RNA levels and liver enzymes to improve clinical decision-making.
HEV RNA assessment, monthly testing, and haemoglobin monitoring.
In patients in whom HEV RNA is still detectable in the serum and/or in the stool after 12 weeks, ribavirin monotherapy may be continued for an additional 3 months (6 months therapy overall).
3-Pegylated interferon alfa may be an alternative treatment optionif there is no contraindication.
Immunization
Recombinant vaccines from genotype 1 HEV have shown efficacy in China, but their efficacy for other HEV genotypes has not been established.
Kidney Tx in patients with HBV May A. Hassaballa Prof Internal Medicine & Nephrology, Cairo University
Hansrivijit P, Trongtorsak A, Puthenpura MM, et al. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021;27(12):1240-1254. doi:10.3748/wjg.v27.i12.1240
Guidelines for Hepatitis E & Solid Organ Transplantation DRAFT Compiled by a Working Party of The British Transplantation Society Draft posted on http://www.bts.org.uk April 2017 First Edition.
EASL clinical practice guidelines on hepatitis E virus infection. European Association for the Study of the Liver. J Hepatol. 2018 Jun;68(6):1256-71.
Secondary spread of hepatitis E virus (HEV) infection occurs often in endemic settings in developing countries.
The host immune signatures contributing to protection against subsequent HEV reinfection are unknown.
Preexisting antibody and high IgG avidity index are important factors for protection against HEV reinfection, as HEV-specific T-cell responses were elevated in reinfected animals after subsequent exposure.
Choi Y, Zhang X, Skinner B. Analysis of IgG Anti-HEV Antibody Protective Levels During Hepatitis E Virus Reinfection in Experimentally Infected Rhesus Macaques. J Infect Dis. 2019;219(6):916-924. doi:10.1093/infdis/jiy603
Apart from routine lab tests, repeat EBV and CMV PCR
Plasma and stool HEV PCR
look for HEV RNA and HEV antibody during the last archive blood sample
history of eating undercooked or raw meat esp pork.
Ultrasound of liver
Management of HEV
The initial management of newly diagnosed or acute HEV infection would be observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months.
strategic reduction in immunosuppression is possible
Persistent HEV infection should be diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test.
If so, then he shouldreceive treatment with ribavirin with the aim of achieving sustained virological response (HEV RNA not detected in plasma and stool six months after completion of treatment).
A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment.
Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection.
Monthly HEV RNA testing in plasma and stool should be undertaken until a decision is made to stop treatment.
Ribavirin should be continued until stool tests are negative for HEV RNA on two occasions one month apart
A test of sustained virological response should be conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy.
Regular haemoglobin monitoring should be conducted during ribavirin therapy as haemolytic anaemia is a common treatment-related side effect.
Ribavirin dose reduction may be required during treatment to maintain an adequate haemoglobin concentration.
McPherson S, Elsharkawy AM, Ankcorn M, Ijaz S, Powell J, Rowe I, Tedder R, Andrews PA. Summary of the British Transplantation Society UK guidelines for hepatitis E and solid organ transplantation. Transplantation. 2018 Jan
–It is quiet clear that this young lady had a successful kidney transplantation with excellent allograft function
-She is on steroid free regimen
-She might be at risk of PLTD given the fact that she EBV negative & her donor is EBV positive
-She had liver abnormal liver function test 6 months after transplantation with fluctuating ALTs & ASTs
-Because HBV and HCV PCR were negative, one may consider other hepatitis infections e.g., HEV infection. Given the time lines for fluctuations of LFTs this patient may be persistent HEV infection.
-We need to check now for plasma and stool HEV RVA
-We need to look back at any history or stored samples at time of transplantation for any evidence of HEV infection
-HEV infection can be transmitted through HEV contaminate meat, blood transfusion or organ transplantation
-The differential diagnosis to keep in mind are:
Other hepatotrophic viruses e.g., HEV, HAV infection or CMV
Drug induced hepatitis : e.g., co-trimoxazole commonly used as prophylaxis for PCP
Toxins e.g., Alcoholic hepatitis
Auto immune hepatitis
PTLD
How would you manage this case?
-If HEV infection is confirmed, it is likely to be persistent infection
-Liver ultrasoungraphy is important
-The rest of the management is as follows:
Baseline plasma & stool HEV RNA
Ribavirin for 3 to 6 months until two negative consecutive stool samples one month apart
Plasma HEV RNA after 7 days to predict the duration of treatment
Aim for sustained virologic response (Negative plasma or stool HEV RNA 6 months after treatment)
Monthly HEV RNA
Regular hemoglobin monitoring as ribavirin may induced hemolytic anemia
In an event of relapse, he can be retreated with higher doses of ribavirin for at least 6 months
He must be advised in a written to avoid consumption of under cooked meat (processed pork) due to high risk of HEV contamination
1-What is your differential diagnosis? Liver disease 2ry to infectious causes includes: -Hepatitis E virus infection (most likely) -Hepatitis due to Epstein-Barr virus infection -Hepatitis A virus infection -Acute or chronic hepatitis D infection -Hepatitis due to herpes simplex virus infection -Hepatitis due to cytomegalovirus infection Liver disease 2ry to toxins: -Alcoholic hepatitis -Acetaminophen toxicity -Toxin-induced hepatitis (eg, mushroom poisoning, carbon tetrachloride) -Prophylactic medications; (INH, Valganciclovir) Liver disease by metabolic disorders: -Nonalcoholic steatohepatitis -Autoimmune hepatitis Liver disease by other causes: -Ischemic hepatitis -Elevated aminotransferases may also be seen in patients with systemic disease, such as: (Muscle diseases – Thyroid disease – Celiac disease – Adrenal insufficiency – Anorexia nervosa). 2-How would you manage this case? Further investigations; IgM anti-HEV – The IgG response – HEV RNA assay EBV serology – Virology – LFTs – Renal Profile – CBC U/S on Liver According British Transplantation Society Guidelines;
-Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals. (1B) -Solid organ transplant recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay. (1C)
-Transplant recipients have a plasma sample taken at the time of transplantation and stored for a minimum of one year that could be tested retrospectively for HEV or other infections. (2D)
-Individuals with unexplained acute on chronic or acute liver failure should be tested for HEV. (2C) Management of newly diagnosed or acute HEV infection; According British Transplantation Society Guidelines;
-The initial management includes observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months. Dynamic viral monitoring and antibody profiling may help clinical decision-making. (2C)
-A reduction in immunosuppression is considered in patients with acute or persistent HEV as this may facilitate viral clearance, but the risk of rejection should be carefully assessed. (2C)
-Early treatment with ribavirin may be considered in specific cases of acute hepatitis E, such as patients who develop severe liver dysfunction (jaundice and coagulopathy) or extrahepatic manifestations, although evidence for this recommendation is currently limited. (2D) Management of Perisistent HEV infection; According British Transplantation Society Guidelines;
-Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C)
-Individuals with persistent HEV infection (documented or estimated duration of infection of more than three months) receive treatment with ribavirin with the aim of achieving sustained virological response (HEV RNA not detected in plasma and stool six months after completion of treatment). (1C)
-A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment. (1C)
-Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment will suffice. (1C)
-Monthly HEV RNA testing in plasma and stool is undertaken until a decision is made to stop treatment. (1C)
-Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart, as continued shedding of HEV in stool is an important factor predicting relapse after ribavirin treatment. (1C)
-A test of sustained virological response is conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy. (1C) Monitoring for drug toxicity; According British Transplantation Society Guidelines;
-Regular haemoglobin monitoring is conducted during ribavirin therapy as haemolytic anaemia is a common treatment-related side effect. Ribavirin dose reduction may be required during treatment to maintain an adequate haemoglobin concentration. Epoetin therapy and/or blood transfusion may be indicated to allow continued antiviral therapy without avoidable drug reduction. (1A)
-PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients as there is a moderate risk of precipitating organ rejection. (1D)
Thanks so much our, Prof. Ribavirin in treatment of Hepatitis E infection: Oral: -Optimal dosing has not been established: -typically 600 to 800 mg/day (range: 400 mg to 1 g/day) in 1 to 2 divided doses. (De Winter 2018; Kamar 2020; Protin 2019; Rivero-Juárez 2020; Tavitian 2015). -Optimal duration is unknown, but is typically ≥3 months based on virologic response. (AST-IDCOP [Te 2019]; EASL 2018; Kamar 2020; Rivero-Juárez 2020; Tavitian 2015). Hepatitis D virus (HDV): -HDV is a virus that requires hepatitis B virus (HBV) for its replication. -Hepatitis D virus (HDV) affects globally nearly 5% of people who have a chronic infection with hepatitis B virus (HBV). -HDV infection occurs when people become infected with both hepatitis B and D simultaneously (co-infection) or get hepatitis D after first being infected with hepatitis B (super-infection). -Populations that are more likely to have HBV and HDV co-infection include indigenous populations, recipients of haemodialysis and people who inject drugs. -Worldwide, the number of HDV infections has decreased since the 1980s, due mainly to a successful global HBV vaccination programme. -The combination of HDV and HBV infection is considered the most severe form of chronic viral hepatitis due to more rapid progression towards liver-related death and hepatocellular carcinoma. -Hepatitis D infection can be prevented by hepatitis B immunization, but treatment success rates are low.
Management would be according to etiology in case of HEV which is most likely diagnosis than
Reduction in immunosuppressants particularly CNI with close observation for graft rejection. Repeat HEV PCR at 12 weeks if no reduction which would be most cases than
Ribavirin 600 to 1000mg in two divided doses for 12 weeks if still no response than for another 12 weeks with observation for ribavirin toxicity and renal function.
Pegylated interferon but not a good choice in this case.
Reference
Goyal R, Kumar A, Panda SK, Paul SB, Acharya SK. Ribavirin therapy for hepatitis E virus-induced acute on chronic liver failure: a preliminary report. Antivir Ther. 2012;17(6):1091-6. doi: 10.3851/IMP2317. Epub 2012 Aug 16. PMID: 22910532.
Goyal R, Kumar A, Panda SK, Paul SB, Acharya SK. Ribavirin therapy for hepatitis E virus-induced acute on chronic liver failure: a preliminary report. Antivir Ther. 2012;17(6):1091-6. doi: 10.3851/IMP2317. Epub 2012 Aug 16. PMID: 22910532.
elevated liver enzymes in renal allograft recipient:
1- drug induced
2-infection either bacterial or viral like CMV, EBV, HCV, HBV, HEV
3-malignancy
management:
1- PCR for HEV should be done
2-CBC, CRP, procalcitonin
3-liver function test
this is a case of HEV infection
4-Ribavirin should be started in the case of HEV PCR positive for 3 months 2-Pegylated interferon-alfa has antiviral activity against HEV, however, cannot be used in patients with stem cell or organ transplants due to a high risk of rejection. 3-reduction of MPA daily dose RIS may be not enough alone to clear HEV, and should be accompanied by antiviral therapy which is Ribavirin 4-monitoring by CBC, liver function test, graft function, regular monitoring by HEV PCR
Viral infections – BK virus, CMV, EBV, Hepatitis A, B, C, E
Drugs such as statins
Toxic hepatitis from illicit substance use
NAFLD
Autoimmune hepatitis
Hereditary conditions such as Wilson’s disease, Hemochromatosis
Management
A. Thorough history and examination
History of induction therapy with ATG, acute rejection episodes, preoperative viral serologies. History of statin use, illicit substance use. On examination- peripheral stigmata of chronic liver disease, injection marks etc.
Investigation – Hepatitis A, B, C, E RNA, BK; toxicologic screen, autoimmune antibody panel, liver scan.
B. If found to be hepatitis E positive, then it’s likely chronic. Management is as follows.
Get a baseline HEV RNA in serum and stool.
Reduce immunosuppression if possible – tacrolimus trough target of 4ng/ml.
Wait for about 3 months for response to reduction in immunosuppressive medications.
Monitor serum and stool HEV RNA monthly.
Commence a 3 – month course of ribavirin after 3 months in absence of HEV clearance from stool.
Monitor FBC for anemia and dose ribavirin based on GFR using the serum creatinine levels.
Continue treatment until stool is negative for HEV RNA on 2 occasions one month apart.
In cases of relapse after ceasing ribavirin, restart treatment for a 6-month course.
No other options of treatment in this patient if viremia persists despite ribavirin. However, adherence and proper dosing of medications should be ensured.
Reference
European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu; European Association for the Study of the Liver. EASL Clinical Practice Guidelines on hepatitis E virus infection. J Hepatol. 2018 Jun;68(6):1256-1271. doi: 10.1016/j.jhep.2018.03.005. Epub 2018 Mar 31. PMID: 29609832
Hansrivijit P, Trongtorsak A, Puthenpura MM, Boonpheng B, Thongprayoon C, Wijarnpreecha K, Choudhury A, Kaewput W, Mao SA, Mao MA, Jadlowiec CC, Cheungpasitporn W. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021 Mar 28;27(12):1240-1254. doi: 10.3748/wjg.v27.i12.1240. PMID: 33828397; PMCID: PMC8006097.
What is your differential diagnosis? 1st DD is Details History for any new drugs intake, Alcohol intake, fever, weight loss, don’t forget MMF is the most common cause of Elevated LFTs immediately post-Transplant, others Like Statin, antibiotics from my clinical practices.
2nd DD is Viral infection in including HAV, HBV, HEV, HCV, CMV, EBV, BKV all excluded except HEV so I will order HEV PCR
3rd is NAFLD.
4th is Autoimmune hepatitis.
5th is Hereditary conditions such as Wilson’s disease, Hemochromatosis.
Other Actions:
LFTs, TSH, HEV PCR and U/S Hepatobiliary.
Hepatology Consult. (Expert opinion).
How would you manage this case?
Reduce immunosuppression and monitor viral load monthly for 3 months.
Monitor kidney function, and TAC trough level.
HEV DNA level, anti-HEV IgG titer, HEV RNA level, HEV IgM, IgG.
Ribavirin for 3 months started immediately by monitoring liver function, and HEV RNA.
Monitor ribavirin side effects and adjust the dose accordingly.
I will monitor PCR in blood after 1 week of therapy to predict the duration of therapy,
then I will perform PCR in blood and stool monthly.
Continue ribavirin until HEV RNA level be -ve. for 2 consecutive tests 1 month apart, (3-6 months).
After stopping ribavirin, I will monitor viral load every 3 months using blood or stool PCR for 6 months if negative this means SVR.
I will monitor CBC every 2 weeks and adjust the dose of ribavirin according to Hb level.
I will monitor liver enzymes every 2 weeks initially then monthly.
I will inform the patient to avoid consuming processed undercooked meat especially pork.
PEG-interferon in persistent infection despite ribavirin treatment with cautiously monitoring graft function.
References:
*UpToDate
*Guidelines for Hepatitis E & Solid Organ Transplantation
*European Association for the Study of the Liver. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on hepatitis E virus infection. J Hepatol. 2018 Jun;68(6):1256-1271. doi: 10.1016/j.jhep.2018.03.005. Epub 2018 Mar 31. PMID: 29609832
The differential diagnosis for mildly elevated liver enzymes in this case scenario which has negative PCR for HCV, HBV, CMV and EBV can be summarized in the attached table (1).
In agreement with my colleagues, I will start my management with proper history taking (including any recent drug use, e.g. recent antibiotics, or history of travelling abroad or any contact with sick patients).
The next step will be a detailed clinical examination with special concern for any skin rash or lymphadenopathy.
Then, I will proceed to an Abdominal ultrasound scan, Serology for autoimmune hepatitis (the patient is 18 years old female with an unknown case of ESRD that may point to underlying auto-immune disease). The attached table suggests a stepwise approach for cases with persistent, mild elevation of liver transaminases. In case all the performed investigations came negative or non-conclusive, then I will proceed to a liver biopsy (1).
What is your differential diagnosis?
1. Viral infections: HEV, EBV, and less likely HBV, and EBV
2. Drug induced: hepatotoxic drugs (immunosuppressants, antibiotics, antifungals, antiviral agents, statins, and allopurinol)
3. previous liver disease (hepatorenal polycystic disease)
4. Alcohol (NAFLD)
5. Sepsis
6. Autoimmune diseases
o Lorber et al. in 1987, mentioned that 49% of their renal allograft patients had post-transplant hepatotoxicity with CsA, including hyperbilirubinemia (48% of patients), elevated AST (47%), ALT (73%), LDH (84%), and ALP (59%)
o High dose calcineurin inhibitors frequently cause mild elevation of liver tests. Although rare, severe hepatotoxicity may occur
o Hepatotoxicity sometimes makes it necessary to switch between these two drugs
o Tacrolimus hepatotoxicity is characterized by elevated levels of hepatocellular enzymes, either alone or with minimal cholestasis and hyperbilirubinemia. hepatotoxicity did not decrease after dose reduction. Normalization of liver enzymes occurred after discontinuing tacrolimus
o Cyclosporine hepatotoxicity may also cause cause cholestasis, but reduction of the cyclosporine dosage alone is sufficient to resolve the hepatotoxicity
o Elevated aminotransferase is more commonly associated with SRL rather than CyA treatments or SRL + CyA treatments
How would you manage this case?
o Detailed history and comprehensive examination (eating raw or undercooked meat, alcohol, drugs, and neurological symptoms)
o CBC, LFT and ALP, clooting factors, immunosuppressive levels, RFT and electrolytes, ERS, and CRP
o HEV RNA and/or antigen detection in blood and stool (antibody detection is unreliable)
o U/S for liver or extra-hepatic obstruction
o Liver biopsy may be indicated if unexplained high liver enzymes
o Treat the underlying cause
References
1. Solà-Porta, E.; Redondo-Pachón, D.; Arias-Cabrales, C.; Navazo, D.; Buxeda, A.; Burballa, C.; Crespo, M.; García-Retortillo, M.; Pascual, J.; Pérez-Sáez, M.J. Early Hypertransaminasemia after Kidney Transplantation: Significance and Evolution According to Donor Type. J. Clin. Med.2021, 10, 5168.
2. Einollahi B, Ghadian A, Ghamar-Chehreh E, Alavian SM. Non-viral related liver enzymes elevation after kidney transplantation. Hepat Mon. 2014 Feb 5;14(2):e9036. doi: 10.5812/hepatmon.9036. PMID: 24693313; PMCID: PMC3950572.
3. Dizdar OS, Ersoy A, Aksoy S, Ozel Coskun BD, Yildiz A. Analysis of liver function test abnormalities in kidney transplant recipients: 7 year experience. Pak J Med Sci. 2016 Nov-Dec;32(6):1330-1335. doi: 10.12669/pjms.326.10725. PMID: 28083020; PMCID: PMC5216276.
4. Vivian Yiu, Rui Gao, Sharon Mulroy, Hepatitis in a renal transplant patient—beyond the usual, Clinical Kidney Journal, Volume 5, Issue 2, April 2012, Pages 170–172.
5. Guidelines for Hepatitis E & Solid Organ Transplantation. British Transplantation Society Guidelines, 2017.
– if HEV infection is the culprit, I would start with reduction in immunosuppression
– if HEV is confirmed, the 1st approach is to decrease total immunosuppression burden
– if reduction of immunosuppression is not sufficient, other additional management strategies which can be considered include pegylated interferon alpha-2b, ribavirin 12mg/kg daily for 12 weeks
– recheck HEV RNA at the end of treatment
– if HEV RNA is absent, stop ribavirin and recheck the HEV RNA in 12 weeks, if still absent this is regarded as sustained virological response (SVR) and no further treatment or monitoring is required
– but if the HEV RNA is still present after the first 12 weeks of treatment with ribavirin, reinitiate the ribavirin for another 24 weeks and recheck the HEV RNA at the end of treatment, if absent, stop ribavirin and recheck HEV RNA in 12 weeks, if still absent then this is regarded as SVR, if present this is regarded as treatment failure and the patient needs to be monitored for signs of progressive liver disease
– similarly, if HEV RNA is still positive after the 24weeks of ribavirin, consider this as treatment failure and monitor patient for signs of progressive liver disease
– on the other hand, if HEV RNA is still present after the first 12-week course of ribavirin, the patient should get an additional 12 weeks of ribavirin, then recheck HEV RNA levels
– if HEV RNA is still present, consider this as treatment failure and follow up patient for signs of progressive liver disease
– however, if HEV RNA is absent, stop ribavirin and recheck the HEV RNA in 12 weeks, if still absent this is regarded as SVR and no further treatment or monitoring is required but if HEV RNA is present, consider this as treatment failure and follow up patient for signs of progressive liver disease
– preventive measures include thorough cooking of pork products and game meat
– currently there is no effective immunoprophylaxis against HEV that is available
– use of immunoglobulin from infected persons has not been found to be effective in preventing sporadic cases or outbreaks
– vaccination against HEV has been proposed but the efficacy is yet to be addressed
References
1. Dizdar OS, Ersoy A, Aksoy S, Ozel Coskun BD, Yildiz A. Analysis of liver function test abnormalities in kidney transplant recipients: 7 year experience. Pakistan journal of medical sciences. 2016 Nov-Dec;32(6):1330-5. PubMed PMID: 28083020. Pubmed Central PMCID: PMC5216276. Epub 2017/01/14. eng.
2. Yiu V, Gao R, Mulroy S. Hepatitis in a renal transplant patient—beyond the usual. Clinical kidney journal. 2012;5(2):170-2.
3. Kamar N, Izopet J, Tripon S, Bismuth M, Hillaire S, Dumortier J, et al. Ribavirin for chronic hepatitis E virus infection in transplant recipients. The New England journal of medicine. 2014 Mar 20;370(12):1111-20. PubMed PMID: 24645943. Epub 2014/03/22. eng.
What is your differential diagnosis?
Tacrolimus induced
MMF induced
Any other medication like statin
HEV infection , Hep B,C,D
Transient elevation of liver enzymes
Only positive CMV IgM testing
immunosuppressants used for induction treatment, specifically thymoglobulin(36.6 and 43.4% of KT recipients who receive thymoglobulin induction suffer AST and ALT elevation, respectively)
EBV induced
liver-kidney crosstalk.
KT recipients from uDCD are 5 to 13 times more inclined to elevate transaminases than cDCD or DBD ones. more frequent in deceased donor KT recipients than in living donor ones.
Analysis of liver function test abnormalities in kidney transplant recipients: 7 year experience
Oguzhan Sitki Dizdar et al
Early Hypertransaminasemia after Kidney Transplantation: Significance and Evolution According to Donor Type
by Eulàlia Solà-Porta 1
How would you manage this case?
Drug history to see for use of statins, alcohol abuse, recreational drug abuse.
Investigate with-
Tacrolimus level
CBC
RFT
SE
Usg abdomen and pelvis
HEV igA , HEV RNA
HBV DNA
HCV RNA
Referral to hepatology unit
Stop any hepatotoxic drug like statins,anti fungals,antivirals
If tacrolimus level is high ,decrease dose
Treat viral infection if found
alcohol intake.
Viral hepatitis .HBV ,HCV ,CMV ,EBV ,WHICH ARE NEGATIVE HERE ,THE OTHER
MOST COMMON HEV RNA should be screened.
fatty liver disease,
autoimmune hepatitis,
pharmacological factors ,drug induced..
Acute HEV hepatitis is treated by immunosuppression reduction and follow up of viral load.
The initial management of newly diagnosed or acute HEV infection in solid organ transplant recipients includes observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months. Dynamic viral monitoring and antibody profiling may help clinical decision-ma
the differential diagnosis in this post transplant patient are
We need more history of the induction agent used, tacrolimus trough levels, previous history of jaundice or hepatitis in the patient …..
HEV RNA levels need to be checked …if elevated it is known to cause chronic HEV infection unlike HAV..The variable percentage of chronic HEV in the general population ins 5-15%.. they have waxing an waning course of fluctuations in liver enzymes…. There are reports to show that this phenomenon can occur for more than 6 months..
It is known that MMF causes inhibition of proliferation of the virus….while HEV infection is promoted by tacrolimus..
the treatment is reduciton of CNI..And addition of ribavirn for 3 to 6 months ..Ribavirin usage should be monitored for drop in hemoglobin …
.
Differential diagnosis is mainly for viral infections
Exclusion of HEV is a must by PCR for detection of viral replication as well as viral load.
Other viral infections can be EBV, CMV, HBV, and HCV.
Drug induced side effects.
Autoimmune hepatitis.
Management is dependent on reduction of immunosuppressive doses, withholding antimetabolites as MMF, minimizing CNI doses to maintain low levels or even switch to another mTORi would be better.
Using antiviral regimen as ribavirin is the best tolerated by most of patients. The patient has normal renal function profile, hence no need for renal adjustment with optimum dose for 4 weeks at least with regular monitoring of viral load, CBC, liver enzymes mainly.
Special attention to the common side effects as they could be non-specific in the form of fatigue, fever or headache. Moreover severe side effects as hemolytic anaemia or severe GIT manifestations could need dose modification.
The co-administration of statins aids to initiate early response as it minimizes viral load as well.
A. de Niet1 , H.L. Zaaijer2 , I. ten Berge3 , C.J. Weegink1 , H.W. Reesink1 , U. Beuers1 * Departments of 1 Gastroenterology & Hepatology, 2 Virology and 3 Nephrology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands, *corresponding author: tel. +31 (0)20-5662422, fax: +31 (0)20-5669582, e-mail: u.h.beuers@amc.uva.nl
● Differential diagnosis:
** Viral infections ( EBV, CMV, HBV, HCV, HEV)
** Drug related
** Autoimmune hepatitis
● Management:
** PCR for HEV in blood and stool
** Abdominal US
The most possible it is a case of HEV infection so treatment will be :
☆ Reducing Immunosuppressive Therapy
** Immunosuppressive drugs (cyclosporine A, tacrolimus, sirolimus, and everolimus, increase HEV replication but only mycophenolic acid can decrease HEV replication in vitro .
** Two-thirds of patients remain those need an effective antiviral therapy :
☆ Pegylated Interferon
For three months and the sustained virological response (SVR) at six months was 100% but it increases the risk of acute rejection due to its immunostimulatory effect
☆ Ribavirin
** Ribavirin as a monotherapy has become the treatment of choice for chronic HEV infection.
** The recommended dose 600 to 800 mg/day
** In patients with impaired kidney function, ribavirin dose should be adapted to kidney function
** Three months after initiating ribavirin therapy, if HEV RNA is negative in both the sera and stools, ribavirin can be stopped.
** If HEV RNA remains positive in the stools after three months, even if it is negative in the sera, ribavirin therapy should be prolonged for an additional three months.
** If HEV viremia increases after ceasing ribavirin therapy, a longer course of ribavirin 6 months, can be proposed.
** In patients who present with a relapse under ribavirin or who are resistant to ribavirin, there is no alternative, except for liver-transplant patients for whom pegylated interferon can be proposed.
Nassim Kamar, Sébastien Lhomme, Florence Abravanel, Olivier Marion, Jean-Marie Peron, Laurent Alric, and Jacques Izopet . Treatment of HEV Infection in Patients with a Solid-Organ Transplant and Chronic Hepatitis . Viruses. 2016 Aug; 8(8): 222.
Viral infections, Hepatitis E virus,B, C,CMV, EBV
Drug related
Autoimmune hepatitis
Metabolic causes
Q1: ΔΔ includes:
· viral hepatitis A, B, C, D, E and CMV, EBV, adenovirus.
· Drug-related due to tacrolimus, valganciclovir, acetaminophen or even herbal medicines
· Autoimmune hepatitis
· PTLD
Q2: lab test for diagnosis includes: CBC.diff, PLT, LFT, BUN, Cr, biochemistry, LDH, Tacrolimus level, albumin, PT, INR, ALK-p
· Viral PCR for CMV, EBV, HBV, HCV, HEV stool HEV RNA
· Ultrasonography of liver and biliary system.
The most probable diagnosis is HEV infection.
Therefore, the treatment is:
1. Immunosuppression reduction according to tacrolimus level.
2. In case of no response for 3 months or severe disease: ribavirin 200 mg Q8h for at least or until stool HEV RNA became negative for two months in a row.
During treatment monitoring for HEV RNA in stool and plasma is necessary. In addition, due to hemolytic anemia as a ribavirin side effect, CBC.diff at regular intervals is needed. During D reduction of immunosuppression, control for rejection, and after ribavirin treatment, control of relapses by HCV PCR are necessary.
Reference:
Einollahi, B., Ghadian, A., Ghamar-Chehreh, E., & Alavian, S. M. (2014). Non-viral related liver enzymes elevation after kidney transplantation. Hepatitis Monthly, 14(2). https://doi.org/10.5812/hepatmon.9036
Hansrivijit, P., Trongtorsak, A., Puthenpura, M. M., Boonpheng, B., Thongprayoon, C., Wijarnpreecha, K., Choudhury, A., Kaewput, W., Mao, S. A., Mao, M. A., Jadlowiec, C. C., & Cheungpasitporn, W. (2021). Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. In World Journal of Gastroenterology (Vol. 27, Issue 12). https://doi.org/10.3748/wjg.v27.i12.1240
What is your differential diagnosis?
· Viral infections:
She has negative HBV, HCV, CMV and EBV (high risk for EBV infection, but EBV PCR is negative, D+/R-). So we will ask about HEV RCR
· Alcohol induced hepatitis
· NASH
· Autoimmune hepatitis ( young age)
· Congestive hepatopathy
· Drug induced (antibiotics including SMX-TMP, antifungal, Tacrolimus and MMF (need proper history, checking trough levels and improvement in liver enzymes after decreasing doses or discontinuation of the drug)
· Metabolic causes as alpha 1 antitrypsin deficiency, Wilson and Hemochromatosis (ask for 24 h urine copper, serum ceruloplasmin and serum ferritin).
How would you manage this case?
Diagnosis:
· MDT approach involving a hepatologist
· Detailed history(including drug, travel history, alcohol consumption and eating uncooked meat) and physical examination
· HEV RNA and/or antigen detection in blood and stool
· Abdominal US to look at the liver.
· Liver biopsy is the gold standard for diagnosis (if needed).
· Treatment depends on the cause
If confirmed to be chronic HEV:
References:
1. Guidelines for Hepatitis B & Solid Organ Transplantation. British Transplantation Society Guidelines, 2018.
2. Einollahi B, Ghadian A, Ghamar-Chehreh E, Alavian SM. Non-viral related liver enzymes elevation after kidney transplantation. Hepat Mon. 2014 Feb 5; 14(2):e9036.
3. Dizdar OS, Ersoy A, Aksoy S, Ozel Coskun BD, Yildiz A. Analysis of liver function test abnormalities in kidney transplant recipients: 7 year experience. Pak J Med Sci. 2016 Nov-Dec; 32(6):1330-1335. doi: 10.12669/pjms.326.10725. PMID: 28083020; PMCID: PMC5216276.
The differential diagnosis includes:
Hepatitis E Virus infection the most probable diagnosis( fluctuation of liver enzymes) as Liver enzyme alteration without any preexisting liver disease is a frequent finding in renal transplant recipients
Autoimmune hepatitis
Certain medications, such as cholesterol-lowering drugs (statins) and acetaminophen.
Fatty liver disease, including alcohol-related and non-alcohol-related conditions.
Hemochromatosis.
Hepatitis A, hepatitis B, hepatitis C, alcoholic hepatitis and autoimmune hepatitis.
Herbal supplements and vitamin supplements, like chaparral, comfrey tea, iron and vitamin A.
Management
full history and examination do detect any other associated symptoms and signs with history of recent drug or alcohol consumption
investigations:
HEV RNA
ANA
Anti LKM1 Ab
ALT , AST ,BILIRUBIN (total , direct), S alb.
INR
Hepatobiliary US
Patient mostly has chronic HEV.
treatment
Reduction of immunosuppression is considered the first-line approach, allowing HEV clearance in about one-third of patients.
Ribavirin, an anti-viral agent, is considered in patients with severe acute or acute on chronic liver failure.
acts by inhibiting HEV viral replication and increases the expression of interferon stimulating genes leading to immune modulation
It can be given as for 3 months, 600 mg / day.
What is your differential diagnosis?
Viral infections–
HEV Hepatitis
EBV infection
Herpes Simplex Virus
DRUG-INDUCED HEPATOTOXICITY(DILI)
Common medication classes used in transplant that have been implicated in DILI include immunosuppressive medications,antibiotics, antihyperlipidemics,and drugs for hypertension and diabetes. In addition, numerous herbal and nonprescription agents have also been implicated in the development of DILI.
How would you manage this case?
This is probably a case of Hepatitis E infection.The initial management of newly diagnosed or acute HEV infection in solid organ transplant recipients includes observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months.Individuals with persistent HEV infection (documented or estimated duration of infection of more than three months) receive treatment with ribavirin with the aim of achieving sustained virological response HEV treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection.
HCV, HBV, HEV, CMV, EBV, BK Viral nephropathy
1. Reduction of immunosuppression
2. Ribavirin, at least for 3-6 months, till reaching a sustained viral response (not detected virus in blood and stool twice one month apart and at 6 months after stopping the Ribavirin)
3. Adjust dose to GFR monitoring of CBC- hemolytic anemia is a common complication of Ribavirin, as well as liver function test and kidney function.
4. Failure of treatment: repeat the course with high dose Ribavern but observe for side effect as above
5. in cases of ribavirin-refractory persistent HEV infection ,PEG-interferon treatment may be considered. However, it carries a risk of rejection.
– Fluctuation of transaminases is common in HEV infection;
– Food and alcohol consumption issues also deserve to be investigated
– the use of medications should also be observed – including Tacrolimus.
Would assess the patient’s dietary and medication issues
– Would perform HEV dosage. And if so, the first strategy would be a decrease in immunosuppression and if necessary, evaluate the use of Ribavirin
– If HEV is negative, I would consider changing Tacrolimus
This is a case of post-transplantation raised transaminases, there are multiple causes until proven.
Differentials are;
Could be drug induced,
Viral infection, like HEV, HAV, HBV, HCV etc.
There are case reports with CNIs, although according to current evidence this is a case of HEv.
How you manage this case?
Needs further workup to confirm.
Baseline like Ultrasound abdomen, viral serology, further PCR test.
The main stay of treatment is medication (immunosuppression) reduction,
Anti-viral Ribavirin 600mg for six months,
Adjust dose according to eGFR,
Frequent LFTs,
With good monitoring of graft function to prevent rejection and dysfunction.
Continue treatment until negative serology or PCR for consecutive next two negative samples.
Chronic HEV, other forms of hepatitis like A,B,C
Drug induced hepatitis (Tacrolimus) , autoimmune hepatitis.
This case with chronic hepatitis and fluctuating liver enzyme is mostly goes with the diagnosis of chronic HEV.
First we should confirm the diagnosis by full history, doing US , PT/INR, anti HEV Igm and IgG by ELIZA , PCR for HEV RNA in stool and plasma.
Treatment involves IS reduction and Ribavirin cap in a dose of 600 mg per day for 6 months adjusted according to body weight and GFR.
The treatment last until 2 consecutive sample are negative for virus with one month a part.
Reference:
BTS guidelines 2017.
What is your differential diagnosis?
· This is a typical case of Chronic Hepatitis E infection – fluctuating liver enzymes.
· D/D: other cause of hepatitis – drug induced (Tacrolimus)
Hepatitis A viral infection (de novo), autoimmune hepatitis
How would you manage this case?
· First confirm the diagnosis – detail history (meet consumption),
· PCR for HEV RNA in blood and stool should be done.
· Ultrasound abdomen, PT/INR, RFT, Tac C0 level, CBC
· IS reduction: prednisone and Tacrolimus to minimum level
· close monitoring of graft function to look for rejection
· Ribavirin (200 – 600 mg/ day) for 3- 6 months – for early viral clearance.
· Frequent monitoring of LFT, monthly HEV RNA testing in plasma and stool.
Therapy can be stopped if 2 consecutive stool samples for HEV-RNA at 1 month interval comes negative
REFERENCES:
1-Guidelines for Hepatitis E & Solid Organ Transplantation. BTS, First edition 2017 April
2. Kamar N et al, Treatment of HEV Infection in Patients with a Solid-Organ Transplant and Chronic Hepatitis. Viruses 2016, 8, 222.
What is your differential diagnosis?
Six months post transplant derangement of liver function test can be due to multiple causes like viral infections (CMV,EBV,HEV) drugs like (CNIs ,NSAIDs,antibiotics,statins etc.)metabolic causes like NAFLD, inherited disorders like wilson disease etc.
The above scenario fits with the HEV infection case as all other viral causes have been ruled out ,and history mentioned above is not suggestive of other possibilities like inherited and metabolic causes.For HEV infection, Ultrasound abdomen,PT/INR followed by anti HEV IgM and IgG by ELISA, and PCR for HEV RNA in blood and stool should be done. Once confirmed, then modification of immunosuppression but with close monitoring of graft function ,and ribavirin (200 to 600 mg/ day) for 3- 6 months should be started for early virological clearance. Frequent monitoring of liver function tests and monthly HEV RNA testing in plasma and stool.
REFERENCES:
1-Guidelines for Hepatitis E & Solid Organ Transplantation, BTS, First edition.
2.Nassim Kamar et al, Treatment of HEV Infection in Patients with a Solid-Organ Transplant and Chronic Hepatitis. Viruses 2016, 8, 222.
This case of typical chronic hepatitis E , WITH FLUCTUATING liver enzymes .
This patient other c ause of hepatites could be due to drug induced specially Tacrolimus
other cause could be one of the hepatotropic virus like Hep A,B,C,D,OR E.
High LFT after kidney transplant could be related to autoimmune hepatites .
We need first of all to confirm the diagnosis by full history taking and to do US to have a look to the liver echotexuer . will send HEV per and to follow the. case through LFT , need to check for serum and stool for HEVRNA.
Ribaverin is the treatment of choice with close monitoring for the Hb level .
treatment will take up to 3to 6 month .
references
uptodate
Deranged liver enzymes six months post transplant could be because of
HBV
HCV
HEV
CMV
EBV
DRUGS
ANY OTHER BIRAL OR BACTERIAL INFECTION
In this patient as all other tests are negative this is most likely HEV induced hepatitis.
MANAGEMENT
This patient needs
Reduction of immunosupression preferably CNI and steroids
Ribavirin 600 mg daily in divided doses for minimum three months, duration can be increased to six months
Montioring should be done closely specially looking for hemolytic anemia.
Two consecutive stool PCR should be negative one month apart to confirm clearance
The index patient is an 18 year old recipient who is EBV and CMV negative who received EBV positive donor tx. Who experienced elevation of liver enzymes with negative PCR to both HBV and HCV with stable graft functions.
Differential diagnosis is wide
On top of DD is HEV
Others include
A) Infections
Bacterial infections
Viral infections either Hepatotropic or non Hepatotropic viruses
Protozoa and fungi
B) Drug induced e.g CNI, Azathioprine, Statins, Antibiotics
C) Autoimmune hepatitis
D) Metabolic causes : Wilson, NASH, Alcoholic cirrhosis
E) Inherited causes as alpha one antitrypsin, Hemochromatosis, polycystic kidneys
How would you manage this case?
The management in this case
Full history and examination
Detection of baseline stool and plasma HEV RNA test
Reduction of immunosuppression is starred first especially MMF
Ribavirin 600 mg daily for at least 3 months.
Plasma and stool HEV are monitored every month. With initial 7 days monitor to check initial response.
If persistent HEV test after 3 months continue treatment till 6 months or till 2 tests 1 month apart are negative
If relapse post Ribavirin we shall repeat course of Ribavirin with higher dose and longer duration.
Side effects of Ribavirin may include Hemolytic anemia so check of
What is your differential diagnosis?
HEV/HDV
MMF/CNI
Cotrimoxazole + trimethoprim
PTLD
Management:
Reduction of immunosuppression, particularly tacrolimus as it potentiates HEV replication.
Monitor for rejection.
Ribavirin with dose adjustment as per GFR
Ribavirin is continued for at least 3 months until stool PCR is negative for HEV RNA on two occasions one month apart.
Monitoring:
Monthly HEV RNA testing in plasma and stool.
Monitor Hb during ribavirin therapy (hemolytic anemia)
Check for SVR by HEV RNA in plasma and stool at 3 and 6 months after stopping antiviral therapy
· In the case of elevated liver enzymes in the transplant recipient, drug-induced should be suspected, but in this case unlikely because mostly it will be progressive unless the offending drug was stopped.
· Non-infectious causes should be excluded such as NASH, or Autoimmune hepatitis also will be progressive if not treated.
· Mostly this patient has HEV, so serum HEV RNA should be requested, if detected she has mostly chronic hepatitis E, as she is asymptomatic and has a mild elevation in liver enzymes.
Management
1) Reduction of immunosuppression. Typically reduce tacrolimus first, if possible, since there is an association of chronic infection with tacrolimus.
-Reduction of immunosuppressive therapy resulted in viral clearance in about 30 % of patients
2) Antiviral therapy. If immunosuppressive therapy cannot be reduced, or if the patient has persistent HEV RNA despite a reduction in immunosuppressive therapy for 12 weeks
– a 12-week course of ribavirin monotherapy is suggested, with a dose of 600 to 1000 mg daily ( in two divided doses)
3) Monitoring for toxicity of ribavirin is recommended.
4) Ribavirin can be stopped if the HEV RNA is negative in the sera and stool at week 12.
1.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7022260/#:~:text=Ribavirin%20as%20a%20First%20Treatment%20Approach%20for%20Hepatitis%20E%20Virus%20Infection%20in%20Transplant%20Recipient%20Patients
2.https://www.uptodate.com/contents/hepatitis-e-virus-infection?search=HEV&source=search_result&selectedTitle=1~18&usage_type=default&display_rank=1#:~:text=Back-,Hepatitis%20E%20virus%20infection,-Topic
3.https://pubmed.ncbi.nlm.nih.gov/21192851/#:~:text=Hepatitis%20E%20virus%20infection%20without%20reactivation%20in%20solid%2Dorgan%20transplant%20recipients%2C%20France
All possible causes of hepatotoxicity should be considered
drugs induced
autoimmune
viral hepatitis including HEV
alcohol induced
Cholestatic
if HEV serology is positive , antiviral ribavarin can be started
FOR ME IT IS A GOOD LEARNING TO SUSPECT HEV IN SUCH SCENARIO WHICH I DID NOT ON THE OUTSET
This case of typical chronic hepatitis E , WITH FLUCTUATING liver enzymes .
This patient other c ause of hepatites could be due to drug induced specially Tacrolimus
other cause could be one of the hepatotropic virus like Hep A,B,C,D,OR E.
High LFT after kidney transplant could be related to autoimmune hepatites .
We need first of all to confirm the diagnosis by full history taking and to do US to have a look to the liver echotexuer . will send HEV per and to follow the. case through LFT , need to check for serum and stool for HEVRNA.
Ribaverin is the treatment of choice with close monitoring for the Hb level .
treatment will take up to 3to 6 month .
references
uptodate
DD:
-HEV.
-Drug induced hepatitis.
-Others: autoimmune hepatitis, CMV
Management:
-Testing for HEV RNA and HEV antigen.
.Baseline HEV RNA testing to help monitoring treatment.
.Frequent HEV RNA and liver enzymes monitoring hoping resolution spontaneously within three months.
.Immunosuppression reduction with monitoring of graft function.
.Start ribavirin if infection persists to achieve virologic response, ribavirin is to be maintained for 3-6 months targeting negative HEV RNA in at least 2 sequential tests one month apart.
.Ribavirin renal dosing according to eGFR; hemolytic anemia is a side effect,and drug dose reduced if hemoglobin falls below 100g/l.
.Pegylated INF is considered ribavirin-resistant cases..
References:
HEP E and SOT -BTS guidelines.
We need to include hepatitis E in the classic investigation established in local protocols.
In addition to the classics
– Drug-induced (mainly tacrolimus)
– Graft rejection
– Infectious diseases
– Scheduled biopsies
In the case in question, USG with elastase, viral load count for HEV, and liver function are necessary to understand the extent of the disease.
Ribavirin is the drug of choice but it has dose interference due to weight, Creatinine Clearance, and side effects such as hemolytic anemia.
its case of hepatic dysfunction late post transplant for differential diagnosis
which maybe related to
one of the common missed causes which present with this picture is HEV infection.
complete history taking: including medical history,social history and travel history
full clinical examination: search for hepatic dysfunction manifestations, lymph node involvement
radiological assessment:ultrasound and doppler on liver followed by CT or MRCP if needed.
histological assessment by liver biopsy sometimes needed.
laboratory investigations: including HEV PCR
If positive just downgrade immunosuppresion is needed after proper counselling of patient about risk of rejection
if persistant positive after 3months trial of ribavirin should be tried for 3months with frequent monitoring of hemoglobin because of risk of hemolytic anemia cauased by ribavirn
ribavirin should be continued until 2 PCR negative 1-2w in between
HEV should be repeated after 6month of stopping treatment because of the risk of
relapse.
References:
We are dealing most probably with chronic hepatitis E virus
DDx
Including both viral and non viral hepatitis
Other viruses can also cause liver inflammation, including CMV ,EBV,and yellow fever .There also have been scores of recorded cases of viral hepatitis caused by HSV
MDT should be involved in management of such case ( nephrology,hepatology and infectious )
For chronic HEV
Chronic HEV infection is conservatively defined as the finding of detectable HEV RNA in the blood and/ or stool for greater than six months.
In order to help define the length of infection a review of the patient history, anti-HEV status and previous liver enzymes should be undertaken. If available, analysis of stored specimens from before the first finding of HEV RNA in the blood may also be helpful.
Detection of HEV RNA is important in the diagnosis, confirmation and monitoring of HEV infection.
Viral RNA can be detected a few weeks before the onset of clinical symptoms in both blood and stool samples.
Viral shedding in stool continues beyond plasma viral clearance in both acute and treated persistent infection.
Laboratory diagnosis of persistent HEV must be through detection of the virus itself, either through HEV RNA testing or HEV antigen testing, as antibody detection in the immunosuppressed population is not a reliable marker of infection.
It has now been demonstrated that spontaneous clearance of HEV rarely occurs between three and six months of infection.
Individuals with persistent HEV infection (documented or estimated duration of infection of greater that three months) should be treated with the aim of achieving a sustained virological response (HEV RNA non detected in plasma and stool six months after completing treatment).
Reduction of immunosuppression can lead to clearance of HEV infection in approximately 30% of individuals with persistent HEV.
It is important to recognise that changes in immunosuppression can precipitate rejection in more immunogenic individuals so the risk of rejection versus the potential benefits of modification of immunosuppression must be carefully balanced.
Using ribavirin with dose ranging from 200 mg to 1200 mg per day with a median dosage of 600 mg/day. The pharmacokinetics of ribavirin are variable in transplant recipients and clearance depends particularly on renal function .
In order to reduce the side effects of ribavirin and achieve a steady state of ribavirin in the therapeutic range, the starting dose can be adapted based on the creatinine clearance (the eGFR can be unreliable in transplant recipients so use creatinine clearance is preferred.
The most frequent side effect of ribavirin is a haemolytic anaemia, which required intervention in approximately 40% (dose reduction, epoetin or blood transfusion) of those subjects included in the previous systematic review .
Therefore, patients require regular monitoring of haemoglobin on treatment, initially every two weeks until the haemoglobin has reached nadir then monthly thereafter. Dose reduction of ribavirin is recommended when the haemoglobin falls below 100 g/L.
Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart, as continued shedding of HEV in stool is an important factor predicting relapse after ribavirin treatment.
PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection.
1- What is your differential diagnosis
This patient has chronic active hepatitis for DD
a- Viral hepatitis either hepatotropic viruses as HEV or non hepatotropic viruses as EBV , CMV
b- Drug induced hepatitis .
c- Metabolic disorders as Wilson disease.
d- Autoimmune hepatitis either isolated or part of other autoimmune disorders as SLE.
How would you manage this case
1- History : to exclude congenital and heridetary hepatic diseases ,hepatotoxic drugs , symptoms of autoimmune diseases .
2- Examination :
– Signs of decompensated LCF.
– Extrahepatic manifestations or signs of autoimmune diseases as SLE such as malar flush , serositis.
– Manifestations of metabolic liver diseases as kayser fischer rings and neuropsychatric disturbance.
3- Investigations
– For HEV : plasma and stool quantitative RNA.
– For metabolic screen : serum ceruloplasmin .
– Autoimmune hepatitis and SLE: ANA , Anti DNA , anti smith Ab , C3, C4.
4- Treatment : according to specific pathology
– HEV :ribavirin
– Stop offending drug in caseof drug induced hepatitis
– Copper chelating with d pencillamine and treintene .
2. An 18-year-old lady with CKD 5 due to an unknown cause underwent living-related donor kidney transplantation in 2013. She was given a short course of steroids (discontinued 1 week after transplantation), MMF, and tacrolimus. Pre-transplant serum EBV- and CMV-IgG were negative. The donor was seronegative for CMV but positive for EBV. Kidney transplantation was uncomplicated, with a stable kidney function (eGFR varied between 92 and 98 mL/min). Six months after transplantation, serum aminotransferase levels (ALT: 66 U/L; AST: 47 U/L) were found to be slightly elevated. CMV and EBV PCRs were negative. Four weeks later, liver enzymes decreased (ALT: 53 U/L; AST: 42 U/L) to near-normal levels. Six weeks thereafter, liver enzymes (ALT: 75 U/L; AST: 58 U/L) were again found to be elevated. HCV and HBV PCR were negative.
Issues/ concerns
– 18yo lady, CKD5 ?cause, LRDKT in 2013
– Tacrolimus, MMF, short course steroids (discontinued 1-week post-transplant)
– pre-transplant serum EBV D+/R- and CMV D-/ R-
– uncomplicated kidney transplantation, stable kidney function (eGFR 92-98)
– 6months post-transplant – ALT (66) AST (47) were slightly elevated but CMV and EBV PCR were negative
– 4weeks later – ALT/ AST decreased to near normal levels ALT (53) AST (42)
– 6weeks later – ALT/ AST were found to be elevated again ALT (75) AST (58), HBV and HCV PCR were negative
What is your differential diagnosis? (1, 2)
– Hepatotropic virus-related infectious diseases – CMV, HEV, EBV
– Drug-induced hepatitis – immunosuppressants (MMF, Azathioprine, high-dose CNIs), antibiotics (TMP-SMX), antiviral agents, antifungal agents
– Autoimmune hepatitis
– Sepsis
– Alcohol resulting in hepatitis
– Biliary tract dysfunction
How would you manage this case? (2, 3)
– Autoimmune screen, EBV PCR, CMV PCR, HEV RNA PCR, anti-HEV IgM and IgG
– HEV RNA screen (plasma and stool)
– liver ultrasound for features duct dilatation, doppler flows
– liver biopsy – inflammation, steatosis, fibrosis
– if HEV is confirmed, the 1st approach is to decrease total immunosuppression burden
– if reduction of immunosuppression is not sufficient, other additional management strategies which can be considered include pegylated interferon alpha-2b, ribavirin 12mg/kg daily for 12 weeks
– 1st pathway –
– 2nd pathway –
– preventive measures include thorough cooking of pork products and game meat
– currently there is no effective immunoprophylaxis against HEV that is available
– use of immunoglobulin from infected persons has not been found to be effective in preventing sporadic cases or outbreaks
– vaccination against HEV has been proposed but the efficacy is yet to be addressed
– long-term LFTs and HEV monitoring is recommended to ensure complete resolution of HEV infection
References
1. Dizdar OS, Ersoy A, Aksoy S, Ozel Coskun BD, Yildiz A. Analysis of liver function test abnormalities in kidney transplant recipients: 7 year experience. Pakistan journal of medical sciences. 2016 Nov-Dec;32(6):1330-5. PubMed PMID: 28083020. Pubmed Central PMCID: PMC5216276. Epub 2017/01/14. eng.
2. Yiu V, Gao R, Mulroy S. Hepatitis in a renal transplant patient—beyond the usual. Clinical kidney journal. 2012;5(2):170-2.
3. Kamar N, Izopet J, Tripon S, Bismuth M, Hillaire S, Dumortier J, et al. Ribavirin for chronic hepatitis E virus infection in transplant recipients. The New England journal of medicine. 2014 Mar 20;370(12):1111-20. PubMed PMID: 24645943. Epub 2014/03/22. eng.
Differential diagnosis
Management of case
In post transplant patients, if transaminitis develops, then 2 most important things to be ruled out are hepatotoxicity due to drugs and viral infection.
So, first I will send PCR for Hep B,C,E.
If any thing comes out positive then I shall manage accordingly. If all negative, I will try to find out culprit drug responsible for the same.
If no such drug found responsible or drug dose reduction doesn’t make any improvement, I shall start thinking on lines of evaluating patient for chronic liver changes (coagulation profile, fibroscan, etc.). in such situations, expert opinion of hepatologist shall be sought.
REF:
The fluctuation of liver function tests and, as many colleagues proposed, can be as non-specific and related to drug toxicity, interaction etc., HEV, although not very common, as we learned from this module, should be kept in mind and sought for. The main management plan is reducing immunosuppression and use of 600 mg ribavirin (eGFR: normal)
DDX
MGT
REF;
What is your differential diagnosis?
This would include-
· Drug induced hepatitis
· Autoimmune hepatitis
· Hepatitis A,B,C, HEV
· CMV
· Wilson disease
· Hemochromatosis
How would you manage this case?
Detailed History- Travel history, Drug history, intake of alcohol, use of undercooked meat.
Thorough physical examination – Looking sign of CLD
Investigations
Blood CP. Renal functions, Liver functions, Clotting profile, Drug Levels, HEV IgG and IgM
Ultrasound of Billiary tract
Important to know HEV status pre transplant
Consultation with hepatology team
Treatment
In case of HEV infection, the first step will be to reduce immune Suppression. Tacrolimus should be reduced up to minimum possible levels. MMF can be maintained. It is important to monitor for drug levels and serial monitoring of liver enzymes. Most infections resolve spontaneously.
Antiviral agents like ribavarine can be used until 2 plasma and stool samples are negative. Serial monitoring of HEV RNA antigen should be done .It is sensisible to monitor for any side effects like hemolytic anemia.
Hansrivijit P, Trongtorsak A, Puthenpura MM, Boonpheng B, Thongprayoon C, Wijarnpreecha K, Choudhury A, Kaewput W, Mao SA, Mao MA, Jadlowiec CC, Cheungpasitporn W. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021 Mar 28;27(12):1240-1254.
confirm the diagnosis
KFT, CBC, CRP,
detect HEV RNA in the serum
HAV,HDV, ASMA,LKM,ANA
treatment
reduction of IS especially the TAC to the lower target level(4-6ng/ml)
ribavirin 600 1000mg/day in two divided doses for 12 weeks and the end of treatment recheck if the virus still so more 12 weeks of treatment should be offered if still the virus is detected that means treatment failure
if the virus after the treatment course is not detected further 12 weeks follow up if not detected no more treatment.
no dose adjustment needed as this patient’s eGFR is more than 98
follow up CBC if HB drops to less than 8.5 ribavirin should stop permanent
reference
update
Differential diagnosis:
1-HEV
2-Drug induced hepatitis
Management :
Detailed history and examination for sign and sumptomes of liver disease (jaundiced ,hepatomegaly and lymph node enlargement )
Investigation :
HEV RNA levels, serology, and liver enzymes.
CBC,ESR,CRP .RFT.Urine analysis ,stool general
Treatment :
1-Modification of immune suppression:
Tacrolimus increased HEV replication in a cell culture model;
however, this effect was only seen at high dosages. mTOR inhibitors also appeared to potentiate HEV replication. Corticosteroids had no effect on HEV replication in these models Interestingly, mycophenolate was shown to inhibit HEV replication
2-Antiviral therapy
1-Ribavirin
two patients with persistent HEV were treated with ribavirin 12 mg/kg for
12 weeks, and both cleared HEV RNA from blood and stool by four weeks and remained HEV RNA negative during follow up.
2-PEG-interferon:In case of ribavirine failure
3-Sofosbuvir
Reference:
British Transplantation Society Guidelines: Guidelines for Hepatitis E & Solid Organ Transplantation.
1- DD
HEV (most common)
others: HDV, HAV, drug induced hepatitis
II- Management:
monitor with HEV RNA after one month in plasma and stool
monitor hemoglobin fro associated hemolytic anemia
dose modified according to eGFR
maintain antiviral till two negative HEV RNA in stool assay 1 month apart
The recipient was pre-transplant (CMV IgG- EBV IgG) neg.
Donor was CMV IgG neg but EBV IgG pos.
This increases the risk of EBV primary and PTLD in recipient.
However, this patient had
CMV neg
EBV neg
HBV neg
HCV neg
The remaining differential diagnosis for this sitting
HEV infection
HDV infection
HAV infection but the LFT abnormalities that remained 6 months may exclude it.
Drug induced
Alchohol
Malignancy and PTLD
Autoimmune hepatitis
Strategy for management
Clinical evaluation for Hepatomegaly or lymphadenopathy
Lab tests
Complete liver function tests including (albumin- pt – glucose…)
PCR EBV RNA
Treatment
Best monitoring for liver enzymes
If EBV RNA is positive it is better to evaluate and compared with the samples stored before and after transplantation
If the positivity of HEV RNA is less than 3 months, the observation is enough
If it was a persistent HEV infection , reducing is and even ribavirin treatment should be considered
Thanks, All
This is a classic case of HEV infection that you will miss unless you look for it
DDx.:
this case scenario require comprehensive history and work up
most of virals were checked …..negative but not focusing on HEV which make a high suspicious
removing or decreasing dose of hepatotoxic medications
close monitoring
Thanks, Delshad
This is a classic case of HEV infection that you will miss unless you look for it
👉 ⭐ The differential diagnosis of elevated liver enzymes in transplant recipient:
_viral infections (the current case is high risk for EBV infection, but EBV PCR is negative). I will ask for HEV PCR.
_Autoimmune hepatitis in such young age (ask for ANA, anti LKMA and ASMA autoimmune markers).
_drug induced as SMX-TMP, antibiotics, antifungal, retinoic acid containing anti acne preparations, tacrolimus and MMF (diagnosed by history , trough level monitoring and therapeutic trial with improvement after decrease dose or discontinuation of the drug)
_Alcohol induced.
_NASH (none alcoholic steatohepatitis).
_other metabolic causes as Wilson and Hemochromatosis (so ask for 24 h urine cupper, serum ceruloplasmin and serum ferritin).
_alpha 1 antitrypsin deficiency.
_Liver biopsy is the golden standard for diagnosis.
👉 ⭐ Management:
_Through history taking and systematic examination.
_Order for HEV PCR as basal level, if postive repeated assessment is required.
_Abdominal ultrasonography to assess liver parenchyma and doppler study to screen for portal hypertension.
_Reduction of IS should be cautious (restart steroid again, keep CNI on lower window of therapeutic trough level, decrease dose of MMF).
_FU PCR and liver enzymes, if increasing after reduction of IS…start ribavirin 200-600 mg divided twice or thrice per day for 3-6 months until 2 negative stool PCR separated by 1 month.
_close follow up of CBC for fear of anemia.
_In case of Wilson, treatment with cupper chelation as penicillamine.
_in case of hemochromatosis ….need iron chelator.
_in case of autoimmune hepatitis…use of steroids and azathioprine (replace MMF with azathioprine) may be helpful.
_NASH treated by weight reduction, vitamin E , selenium.
Thanks, Mai
This is a classic case of HEV infection that you will miss unless you look for it
Thanks dear professor, this is in concordance with the notion that any elevation of liver enzymes in transplant recipient , we should ask for HEV RNA.
The differential diagnosis includes:
Management:
If the transaminases are elevated for more than three months and the HEV RNA is positive, then the patient has chronic HEV. The patient should be started on Ribavarin
In addition, would you consider congestive hepatopathy, hemochromatosis, Wilson disease and alpha-1 antitrypsin deficiency as well?
Thanks
What is your differential diagnosis?
The differential diagnosis for mildly elevated liver enzymes in this case scenario who has negative PCR for HCV, HBV, CMV and EBV can be summarized in the attached table (1).
References:
1) Lawrence S Friedman. Approach to the patient with abnormal liver biochemical and function tests. © 2023 UpToDate (accessed on 7 March 2023).
How would you manage this case?
In agreement with my colleagues, I will start my management with proper history taking (including any recent drug use, e.g. recent antibiotics, or history of travelling abroad or any contact with sick patients).
The next step will be a detailed clinical examination with special concern for any skin rash or lymphadenopathy.
Then, I will proceed to an Abdominal ultrasound scan, Serology for autoimmune hepatitis (the patient is 18 years old female with an unknown cause of ESRD that may point to an underlying auto-immune disease). The attached table suggests a stepwise approach for cases with persistent, mild elevation of liver transaminases. In case all the performed investigations came negative or non-conclusive, then I will proceed to a liver biopsy (1).
References:
1) Lawrence S Friedman. Approach to the patient with abnormal liver biochemical and function tests. © 2023 UpToDate (accessed on 7 March 2023).
In addition, would you consider Congestive hepatopathy, hemochromatosis, autoimmune hepatitis, Wilson disease and alpha-1 antitrypsin deficiency as well?
In addition, would you consider Congestive hepatopathy, hemochromatosis, autoimmune hepatitis, Wilson disease and alpha-1 antitrypsin deficiency as well?
Thanks, Ahmed
This is a classic case of HEV infection that you will miss unless you look for it
Hepatitis infection A, B, C, and E
CMV infection
EBV infection
Autoimmune hepatitis
Drug induced hepatitis
History and examination
CBC , Monitoring of renal function and liver enzymes, drug level and DSA level, HEV RNA igM, IgG, HEV RNA in plasma and stool
Ultrasound for liver to role out cirrhosis.
Start ribavirin with monitoring HEV RNA
Reducing Tacrolimus dose near to lower level and keep to steroid dose and MMF dose. with tight serial monitoring of drug level and DSA level to avoid kidney rejection and monthly monitoring of HEV RNA antigen in blood and stool.
Thankyou this patient was on a steroid free regimen.
how does this affect your plan?
Differential diagnosis
Viral hepatitis- HEV/HAV/HIV (this patient is already negative for CMV/HCV/EBV/HBV)
Drug induced hepatotoxicity -statins/antifungals/antibiotics
NAFLD/alcohol
Autoimmune hepatitis
Management
Detailed history- that should include history of any recent travel, recent drug use, alcohol use, illicit substance use, and consumption of raw/undercooked meat.
Thorough physical examination for stigmata of chronic liver disease
Workups- CBC, CRP, coagulation profile, tacrolimus trough levels, stool and plasma HEV RNA and ANA.
Imaging-abdominal U/S for liver.
If the patient has positive HEV RNA, then needs to be determined if this is an acute infection or persistent infection.
Retrospectively can be tested for HEV RNA when the liver enzymes were noted to be rising.
Also important to note the anti-HEV status prior to transplantation.
If acute infection, then monitoring for 3 months of the HEV RNA and liver enzymes can be done since 30% of infections spontaneously resolve.
If persistent infection, HEV RNA has been positive for more than 3 months, reduction of immunosuppression, this patient is already on 2 immunosuppressants thus should be monitored closely for rejection.
Antivirals- ribavirin can be used until 2 plasma and stool samples are negative, however CBC should be monitored due to the risk of haemolytic anaemia.
Ribavirin resistant cases there is a role of using pegylated interferon though comes with the risk of rejection other option sofosbuvir combined with ribavirin.
References
Guidelines for Hepatitis E & Solid Organ Transplantation First Edition Compiled by a Working Party of The British Transplantation Society Draft posted on http://www.bts.org.uk April 2017
Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: a case report Marcus Panning, Kristi Basho, Andreas Fahrner and Christoph Neumann-Haefelin
Hansrivijit P, Trongtorsak A, Puthenpura MM, Boonpheng B, Thongprayoon C, Wijarnpreecha K, Choudhury A, Kaewput W, Mao SA, Mao MA, Jadlowiec CC, Cheungpasitporn W. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021 Mar 28;27(12):1240-1254. doi: 10.3748/wjg.v27.i12.1240. PMID: 33828397; PMCID: PMC8006097.
A more structured plan is needed ie.
what if there is worsening of LFTs after 10 days ?
Remember she is on 2 IS drugs only!
Thank you prof.
Yes this patient is already on 2 IS so reduction would not be an option.
I would monitor if the LFT are worsening and increase of the HEV RNA then I would start ribavirin early instead of waiting for the 3 months.
1- infection viral :HAV,HEV,HBV,HCV,CMV,EBV-bacterial -parasitic
2-Medication related
3 part of cilliopathy as the cause of kidney disease unkown ?? Caroli??
4-autoimmune hepatitis
management
History
• Recent hospitalizations or illnesses
• Social/exposure history
• Comorbid conditions
• Exposure history indicative of possible pathogen
medication history -substance abuse
labs and studies
virology screen /HEV RNA
panel for autoimmune disease
liver scan ?? we may consider liver biopsy if persistent transaminitis with no apparent cause
we should consider HEV infection ,HEV RNA should be done in current sample and in archived sample , if both positive this indicates chronic HEV
Treatment with antiviral ribavirin for at least 3 month
Monthly HEV RNA testing in plasma and stool
the aim of treatment is achieving sustained virological response
Reduction of immunosuppression can lead to clearance of HEV infection
Dear Colleagues although this an 18 years old patient which is unlikely to be alcohol related please do not forget this as a cause of deranged liver enzymes in your differential.
Unlikely to add BK virus to the differential of deranged liver enzymes!
Whilst the case is high risk for de novo EBV infection, EBV PCR was negative and less likely to be CMV hepatitis with this protracted course without treatment and CMV PCR is negative.
Unclear about some unnecessary investigations such as CXR and missing very important one such as stool analysis for HEV PCR. This is very important test to ensure viral clearance
Differential diagnosis
Management
More details for management plan.
· What is your differential diagnosis?
There are many causes of raised liver enzymes in kidney transplant recipients, including sepsis, biliary tract dysfunc[1]tion, drugs and common hepatotropic virus-related infec[1]tious diseases such as hepatitis B and C plus HEV.
So our differential diagnoses include:
1-Drugs: Like cotrimoxazole, Valganciclovir, MMF, FK, statin, others.
2-Viral infection, HBV, HCV, HAV, HEV, CMV, EBV
· How would you manage this case?
Taking detailed history, specifically drug history, recent febrile illness, alcohol intake.
Then routine investigation, plus coagulation profile, GGT, alkaline phosphatase , viral serology including HEV Abs, RNA if Abs positive, Ultrasound liver.
Then specific treatment according to the cause.
If HEV positive, then reduction of immunosuppression and if no response then to consider ribavirin.
References:
1-Hepatitis in a renal transplant patient—beyond the usual, Clin Kidney J (2012) 5: 170–172 doi: 10.1093/ckj/sfs012
2-Guidelines for Hepatitis E & Solid Organ Transplantation British Transplantation Society Guidelines 2017.
Can you elaborate more on the management in the index case.
Thanks Prof Dawlat.
management of HEV infection, as it is the most propable diagnoses is:
Monitoring of liver enzymes and HEV RNA is important as up to 34% of cases may clear the infection without specific treatment. Another 21% may clear the virus with a reduction of immunosuppression.
So, more than half of the patient cleared the infection without specific anti viral treatment. So initial management should be monitoring HEV RNA and liver enzymes with reduction of immunosuppression. If no improvement within 3months, then consideration for anti viral treatment is needed.
Modifications of immunosuppression can cleat up to 30% of cases in some series.
Steroid and CNI can increase virus replications and MMF, interestingly, was found to inhibit viral replications. So lowering level of CNI and steroid to the minimum possible 2.5mg to 5mg od could help in clearing the virus.
Anti-virus therapy:
Ribavirin: A sustained virological response (serum HEV RNA negative six months after treatment) was achieved in 78% of cases in one study. Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment will suffice
What is your differential diagnosis?
The differential diagnoses include:
Viral infections:
Previous liver disease:
Pharmacological hepatotoxicity:
==============================
How would you manage this case?
References
Eulàlia Solà-Porta, Dolores Redondo-Pachón, Carlos Arias-Cabrales, Diego Navazo,Anna Buxeda, and et al., Early Hypertransaminasemia after Kidney Transplantation: Significance and Evolution According to Donor Type, J. Clin. Med. 2021, 10(21),5168; https://doi.org/10.3390/ jcm 10215168
WAXES and WANES in transaminases would direct your suspicion to which virus in the index case panel mentioned.
Infections :
o Hepatotrophic viral
Hepatitis B.
Hepatitis C .
Hepatitis E.
Non-hepatotrophic viral:
Cytomegalovirus .
Epstein–Barr virus .
Herpes simplex virus .
Varicella–Zoster virus .
o Bacterial :
Hepatic abscess (polymicrobial) .
Mycobacteria.
Inherited
o ADPKD .
o ARPKD .
o Alpha-1 antitrypsin deficiency.
o Hemochromatosis o Wilson disease.
• Drug-induced liver injury :
o Hepatocellular pattern:
Acetaminophen .
Allopurinol .
Amiodarone .
Fluoxetine .
INH .
NSAIDs .
Rifampin .
HMG-CoA reductase inhibitors .
Tetracycline.
o Mixed pattern:
Amitriptyline .
Azathioprine .
Clindamycin .
Nitrofurantoin .
Phenytoin .
TMP/SMX .
Verapamil
o Cholestatic pattern :
Amox/Clav .
Anabolic steroids .
OCPs .
Erythromycins.
Terbinafine .
Tricyclic antidepressant.
Metabolic
o NAFLD
o Alcoholic liver disease
• Autoimmune :
o Autoimmune hepatitis .
o Primary biliary cirrhosis.
Management:
CBC.
LFT.
RBG,HA1C.
Lipid profile.
Echo.
Viral screening ,HCV ,HBV,HEV,HIV.
USS.
Drugs level.
Treatment according to etiology .
Antiviral treatment: for HCV ,HBV and HEV.
IS reduction or stop.
References:
2014Transplantation reviews.
where is your management plan!!
What is your differential diagnosis?
CMV/EBV/HCV/HBV were already excluded with PCR.
The differential diagnosis
HEV/HDV
Drugs induce –
MMF/CNI
Cotrimoxazole + trimethoprim
Antimicrobial
Statins (less likely to be taking in 18 years age)
Steatohepatitis
PTLD
Autoimmune hepatitis
How would you manage this case?
Reduction of drugs or Immunosuppression is the main stay of treatment in all cases.
serum and stool HEV RNA to diagnose HEV infection.
Reduce dose of tacrolimus, steroids and MMF
Close follow up of serum creatinine and liver enzyme.
Monitor the patient for 3 months.
See for Serum and stool HEV RNA clearance- if no clearance then start antiviral.
Antiviral Therapies
Ribavirin (600-800 mg/day), the dosage is adjusted according to creatinine clearance.
Liver enzymes (for response) and CBC (for side effects) should be closely monitored.
Duration of treatment of ribavirin should be 3 months
Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart.
If relapse occur after ceasing Ribavirin
Need to give it for 6 months
No response of ribavirin in 6 month or intolerance to ribavirin or relapse after 6 months ribavirin
Then need to give pegylated interferon alpha (no preferable as there is high chance of rejection)
Reference
1)Lecture : May A Hassaballa HEV in kidney transplant
2)Kamar N, Lhomme S, Abravanel F, Marion O, Peron J-M, Alric L, Izopet J. Treatment of HEV Infection in Patients with a Solid-Organ Transplant and Chronic Hepatitis. Viruses. 2016; 8(8):222. https://doi.org/10.3390/v8080222
3)Samala N, Wang RY, Auh S, Balla AK, Dakhoul L, Alter HJ, Farci P, Ghabril M, Lucey MR, Rangnekar AS, Reddy KR, Ghany MG. Hepatitis E prevalence and infection in solid-organ transplant recipients in the United States. J Viral Hepat. 2022 Dec;29(12):1134-1142. doi: 10.1111/jvh.13739. Epub 2022 Sep 21. PMID: 36036116.
4)Hansrivijit P, Trongtorsak A, Puthenpura MM, Boonpheng B, Thongprayoon C, Wijarnpreecha K, Choudhury A, Kaewput W, Mao SA, Mao MA, Jadlowiec CC, Cheungpasitporn W. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021 Mar 28;27(12):1240-1254. doi: 10.3748/wjg.v27.i12.1240. PMID: 33828397; PMCID: PMC8006097.
What would be you management if 2 weeks after reduction of IS Bilirubin doubled as well as transaminases.
Thank you for the question, Prof.
Will start the antiviral early.
Needs to monitor his lab- coagulation profile, renal function
6 months Post Transplant patient with elevated and fluctuated liver enzymes suggestive for chronic nature of the process. Although HBV, HVC were negative therefore we should exclude other viruses. Chronic HEV infection is highly suspected in such cases, often asymptomatic, manifesting only with unexplained mild to moderate elevations in serum aminotransferase.
EBV mismatch D+/R- increase the risk of PTLD which needs to be considered during evaluation but both CMV and EBV were negative in this case.
Differential diagnosis
1. Infectious hepatitis.
viral Hepatitis A, B, C, E, D.
CMV, EBV, HSV and adenovirus
2. Drugs induced hepatitis:
CsA, Co-trimoxazole, Azathioprine, valganciclovir.
3. Toxic induced hepatitis.
Acetaminophen, substance abuse
4. PTLD
5. Autoimmune hepatitis
6. NAFLD
management of this case?
Labs
– CBC, LFT, RFT, LDH.
– Tac level
– Send PCRs of CMV, EBV, HBV, HCV, HEV.
– serum and stool HEV, RNA.
– Coagulation profile.
– Serum albumin.
–Abdominal and Liver US ; signs of chronicity, infiltrative disease.
As the case is suspected HEV related complication of Post Tx treatment
Treatment:
Monitoring:
– Monthly HEV RNA testing in plasma and stool.
– Monitor Hb% during ribavirin therapy as hemolytic anemia is major side effect
– Check for SVR by HEV RNA in plasma and stool at 3rd & 6th months samples after stopping antiviral therapy
– Monitor rejection during reduction in Tacrolimus and steroid dosages.
References:
Thankyou.
The index transplant patient is a living EBV seropositive donor renal recipient on Tacrolimus based steroid sparing immunosuppression with stable graft function and elevated liver enzymes 6 months post-transplant.
The differential diagnosis in a renal transplant recipient with hepatic dysfunction include (1-3):
a) Infections:
b) Drug induced: Calcineurin inhibitors, azathioprine, sirolimus, steroids, statins, Acetaminophen, NSAIDs, antibiotics (Cotrimoxazole, Amox/clav, nitrofurantoin, tetracyclins), Oral contraceptive pills.
c) Autoimmune cause: Autoimmune hepatitis, Primary biliary cirhhosis
d) Metabolic causes: Non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease.
e) Inherited causes: Hemochromatosis, Wilson disease, Alpha-1 antitrypsin deficiency, polycystic kidney disease (ADPKD, ARPKD).
The management in this scenario includes (4-6):
References:
Thankyou Amit but the index case had no HEV PCR was done !
your assumptions are accepted to differentiate between acute and chronic HEV.
Thank you Professor.
My assumptions are on the basis that other workup is negative, and the patient’s HEV PCR comes out to be positive.
Young lady , LRD, pre transplant EBV , CMV were negative , donor was negative for CMV but positive for EBV, stable graft function, 6 months after Tx aminotransferase were slightly increased CMV and EBV were negative, PCR for HCV and HBV were negative.
What is the differential diagnosis?
· HEV infection
· Other infectious hepatitis are excluded by PCR.
· Alcoholic and non-alcoholic fatty liver
· Drug induced like some antibiotics, NSAIDs, acetaminophen and statins.
· Autoimmune hepatitis in a young lady.
How to manage this case
Diagnosis:
This patient is most probably a case of HEV, it is recommended to investigate for HEV if other viral causes of raised liver enzymes are excluded
· Involvement of hepatologist is important.
· Do abdominal US to look at the liver.
· We check HEV RNA in blood using RT-PCR for diagnosis of HEV infection.
· Check serology for anti HEV IgM and IgG by ELISA.
· Analysis of stored plasma samples for HEV RNA to check for persistence of infection. If it is present for more than 3 months, this diagnose chronic HEV infection.
Drug therapy
· If proved persistent HEV infection he should receive treatment with ribavirin at a dose of 200 to 600 mg/ day for 3- 6 months with the aim of achieving sustained virological response.
· Follow up with monthly HEV RNA testing in plasma is to be undertaken to make decision when to stop treatment.
· Check liver enzymes for the follow up and response.
· CBC for the development of anemia, if this developed we can use erythropoietin and we may we need to reduce the dose of ribavirin with monitoring of anemia as well as for viral response.
· After stopping ribavirin, test of sustained virological response is conducted by testing plasma for HEV RNA at three and six months.
· PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients as there is a moderate risk of precipitating organ rejection.
· Patients with persistent HEV who relapse after a first course of ribavirin are re-treated for at least six months with ribavirin at dosages toward the higher dose range.
· PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection.
References
1. Guidelines for Hepatitis E & Solid Organ Transplantation, BTS, First edition.
2. Nassim Kamar et al, Treatment of HEV Infection in Patients with a Solid-Organ Transplant and Chronic Hepatitis. Viruses 2016, 8, 222.
3. Panupong Hansrivijit, et al, Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis, March 28, 2021 Volume 27 Issue 12.
4. NassimK,et al Ribavirin for Chronic Hepatitis E Virus in Transplant Recipients. N Eng J Med 2014, 370:111-1120.
5. Stefan R, et al, Ribavirin – induced anemia: Mechanisms , risk factors and related targets for future research, Current medical chemistry volume 13, issue 27, 20063351-3357
Well done.
What is your differential diagnosis?
Early post renal transplant hyper-transaminases causes:
Drug induced: high dose methylprednisolone, azathioprine, CsA, MMF, … etc.
Infectious causes: HCV, HBV, HEV, CMV, EBV,HIV, listeria…. etc
Other causes: alcohol consumption, non-alcoholic fatty liver disease mushroom, male gender, anemia, dyslipidemia, hyperuricemia, and renal impairement..etc
ALT was the liver enzyme with the highest prevalence of abnormalities among kidney transplant recipients (34.3%)
How would you manage this case?
Detailed history, travel, previous infections, exposure to animals, or any febrile ill person, and alcohol consumption.
Laboratories: CBC. BUN, Creatinine, bilirubin, albumin, LDH, lipid profile, RBS, gamma GT, alkaline phosphatase, HCV+HBV+HEV+ HIV PCR(viral load), blood and urine cultures, and PT, PTT and INR.
Radiological evaluation by ultrasound abdomen, CXR.
Diagnosis: HEV
It has been noted that tacrolimus and m-TOR inhibitors increase viral replication, but mycophenolate inhibits it, so in indexed case I would decrease the tac level up to the lower safe acceptable level (preventing rejection).
The main stay treatment in his case is to start treatment with Ribavirin, at least for 3-6 months, till reaching a sustained viral response (not detected virus in blood and stool twice one month apart and at 3 and 6 months after stopping the Ribavirin) the HEV PCR (blood and stool) should be monitored monthly.
During treatment close monitoring of CBC- hemolytic anemia is a common complication of Ribavirin, as well as liver function test and kidney function.
PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection.
? HEV vaccine approved in china, for G1.
Of note in indexed case, the donor seropositive EBV status, with negative recipient EBV serostatus, there were no significance of this mismatch, and doesnot predispose to PTLD.
References:
(1) Einollahi B, Ghadian A, Ghamar-Chehreh E, Alavian SM. Non-viral related liver enzymes elevation after kidney transplantation. Hepat Mon. 2014 Feb 5;14(2):e9036. doi: 10.5812/hepatmon.9036. PMID: 24693313; PMCID: PMC3950572.
(2) Harwood JS, Gould FK, McMaster A, Hamilton JR, Corris PA, Hasan A, Gennery AR, Dark JH. Significance of Epstein-Barr virus status and post-transplant lymphoproliferative disease in pediatric thoracic transplantation. Pediatr Transplant. 1999 May;3(2):100-3. doi: 10.1034/j.1399-3046.1999.00019.x. PMID: 10389130.
Thank you.
Is there a difference beween G1,G3
Thank you Prof. dawlat
difference in host gene expression, G3 usually lower viral load than G1
G1 infects humans while G3 all mammals
G1 in Asia and Africa, G3 worldwide.
Reference:
Sayed IM, Verhoye L, Cocquerel L, Abravanel F, Foquet L, Montpellier C, Debing Y, Farhoudi A, Wychowski C, Dubuisson J, Leroux-Roels G, Neyts J, Izopet J, Michiels T, Meuleman P. Study of hepatitis E virus infection of genotype 1 and 3 in mice with humanised liver. Gut. 2017 May;66(5):920-929. doi: 10.1136/gutjnl-2015-311109. Epub 2016 Mar 22. PMID: 27006186.
What is your differential diagnosis?
o In kidney transplant (KT) recipients, hypertransaminasemia is a freque finding, affecting 7 to 24% of patients
Hypertransaminasemia after Kidney Transplantation:
o This patient is low risk of CMV, and both HCV and HBV PCR were negative
o This patient is high risk of EBV (R-/D+). Although last EBV PCRs 6 weeks ago was negative, still EBV is a possible cause of hypertransaminasemia, and needs also monitoring for possible PTLD
o Another differential diagnosis for this fluctuating liver enzyme is HEV. Liver transaminases are usually only very modestly raised and few patients present with any symptoms. It can be transmitted at the time of SOT, either with the transplanted organ or through blood components from an HEV-infected donor. A plasma sample for transplant recipients taken at the time of transplantation and stored for a minimum of one and tested retrospectively for HEV or other infections is important
Other differential diagnoses are:
1. Drug induced: hepatotoxic drugs (immunosuppressants, antibiotics, antifungals, antiviral agents, statins, and allopurinol)
2. previous liver disease (hepatorenal polycystic disease)
3. Alcohol (NAFLD)
4. Sepsis
5. Autoimmune diseases
o Lorber et al. in 1987, mentioned that 49% of their renal allograft patients had post-transplant hepatotoxicity with CsA, including hyperbilirubinemia (48% of patients), elevated AST (47%), ALT (73%), LDH (84%), and ALP (59%)
o High dose calcineurin inhibitors frequently cause mild elevation of liver tests. Although rare, severe hepatotoxicity may occur
o Hepatotoxicity sometimes makes it necessary to switch between these two drugs
o Tacrolimus hepatotoxicity is characterized by elevated levels of hepatocellular enzymes, either alone or with minimal cholestasis and hyperbilirubinemia. hepatotoxicity did not decrease after dose reduction. Normalization of liver enzymes occurred after discontinuing tacrolimus
o Cyclosporine hepatotoxicity may also cause cause cholestasis, but reduction of the cyclosporine dosage alone is sufficient to resolve the hepatotoxicity
o Elevated aminotransferase is more commonly associated with SRL rather than CyA treatments or SRL + CyA treatments
How would you manage this case?
o Detailed history and comprehensive examination (eating raw or undercooked meat, alcohol, drugs, and neurological symptoms)
o CBC, LFT and ALP, clooting factors, immunosuppressive levels, RFT and electrolytes, ERS, and CRP
o HEV RNA and/or antigen detection in blood and stool (antibody detection is unreliable)
o U/S for liver or extra-hepatic obstruction
o Liver biopsy may be indicated if unexplained high liver enzymes
o Treat the underlying cause
If confirmed to be chronic HEV:
o Modification of immunosuppression (Lead to clearance of HEV infection in 30%)
o Start treatment with ribavirin with the aim of achieving sustained virological response (HEV RNA not detected in plasma and stool six months after completion of treatment)
o Do baseline quantitative HEV RNA on both plasma and stool at the start of treatment
o Treatment with ribavirin for at least three months (3-6 months for most patients)
o Do monthly HEV RNA testing in plasma and stool during treatment
o Continue ribavirin until stool tests are negative for HEV RNA on two occasions one month apart
o Do plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy (a test of sustained virological response)
o Regular haemoglobin monitoring during ribavirin therapy
o In relapse after a first course of ribavirin, re-treat for at least six months (higher dose)
o Treatmt with PEG-interferon treatment in ribavirin-refractory persistent HEV (close monitoring for rejection)
References
1. Solà-Porta, E.; Redondo-Pachón, D.; Arias-Cabrales, C.; Navazo, D.; Buxeda, A.; Burballa, C.; Crespo, M.; García-Retortillo, M.; Pascual, J.; Pérez-Sáez, M.J. Early Hypertransaminasemia after Kidney Transplantation: Significance and Evolution According to Donor Type. J. Clin. Med. 2021, 10, 5168.
2. Einollahi B, Ghadian A, Ghamar-Chehreh E, Alavian SM. Non-viral related liver enzymes elevation after kidney transplantation. Hepat Mon. 2014 Feb 5;14(2):e9036. doi: 10.5812/hepatmon.9036. PMID: 24693313; PMCID: PMC3950572.
3. Dizdar OS, Ersoy A, Aksoy S, Ozel Coskun BD, Yildiz A. Analysis of liver function test abnormalities in kidney transplant recipients: 7 year experience. Pak J Med Sci. 2016 Nov-Dec;32(6):1330-1335. doi: 10.12669/pjms.326.10725. PMID: 28083020; PMCID: PMC5216276.
4. Vivian Yiu, Rui Gao, Sharon Mulroy, Hepatitis in a renal transplant patient—beyond the usual, Clinical Kidney Journal, Volume 5, Issue 2, April 2012, Pages 170–172.
5. Guidelines for Hepatitis E & Solid Organ Transplantation. British Transplantation Society Guidelines, 2017.
6. Guidelines for Hepatitis B & Solid Organ Transplantation. British Transplantation Society Guidelines, 2018.
Well done but keep in mind during IS reduction that she is on duel IS .
What is your differential diagnosis?
The index case in summary:
· Uncomplicated KT after living related donation, followed with stable KFT.
· Pre-transplant serostatus; CMV D-/R-, EBV D+/R-.
· High aminotransferase 6 months post-transplant, followed with reduced level, near to normal, 4 weeks later. After 6 weeks, liver enzymes were found to be elevated.
· No evidence of infection or reactivation of CMV and EBV as PCRs were negative for CMV and EBV. No evidence of infection by HBV nor HCV as PCRs were negative for both. Increased susceptibility for CsA-induced hepatotoxicity was noticed in cases of chronic HCV infection. It is likely that hepatitis C virus infection interferes with CsA metabolism and/or biliary CsA-excretion and thus is responsible for CsA and/or metabolite-induced hepatotoxicity despite very low doses of CsA(1). The index case was not on a regimen containing CsA.
· Needs to rule out viral hepatitis after HAV, HDV and HEV.
The likely differential diagnosis for this case scenario:
· Hepatitis A, D or E . HDV is very unlikely provided that HBV is negative. Hepatitis D infection cannot occur in the absence of hepatitis B virus.
· Adverse effects of statins and other medications.
· The liver enzyme elevation (LEE) is a common finding among kidney transplant recipients. Serial monitoring of aminotransferases, particularly ALT, should be performed in all patients after kidney transplantation(2).
· Very unlikely to think of autoimmune hepatitis(AIH) as a differential in this case as he was on TAC and MMF which were both considered as the second line of treatment for AIH. TAC/Prednisolone were the best combination for the second line treatment of AIH(3,4).
How would you manage this case?
1. Full supportive measures; hydration and avoidance of hepatotoxic drugs.
2. To keep immunosuppressants at the lower level of target, ensuring no adverse effects and be aware of possibility of rejection.
3. To screen for HAV, and HEV:
· HDV is very unlikely provided that HBV is negative.
· HAV-IgM and HAV RNA(using RT-PCR) may be needed.
· HEV IgG &IgM and HEV RNA level.
4. Viral hepatitis due to HAV is self-limiting disease and needs only supportive therapy and monitoring. Few cases may progress to fulminant hepatitis.
5. HEV infection, initially needs supportive measures as more than 30% may resolve spontaneously. Dynamic viral monitoring and antibody profiling may help clinical decision-making(5).
6. Early treatment with ribavirin may be considered in specific cases of acute hepatitis E, such as patients who develop severe liver dysfunction (jaundice and coagulopathy) or extra-hepatic manifestations, although evidence for this recommendation is currently limited(5).
7. A test of sustained virological response is conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy.
1. PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection.
References
1. Horina JH, Wirnsberger GH, Kenner L, Holzer H, Krejs GJ. Increased susceptibility for CsA-induced hepatotoxicity in kidney graft recipients with chronic viral hepatitis C. Transplantation. 1993 Nov;56(5):1091-4. doi: 10.1097/00007890-199311000-00008. PMID: 8249106.
2. Einollahi B, Ghadian A, Ghamar-Chehreh E, Alavian SM. Non-viral related liver enzymes elevation after kidney transplantation. Hepat Mon. 2014 Feb 5;14(2):e9036. doi: 10.5812/hepatmon.9036. PMID: 24693313; PMCID: PMC3950572.
3. Ferre-Aracil C, Riveiro-Barciela M, Trapero-Marugán M, Rodríguez-Perálvarez M, Llovet LP, Téllez L, Sánchez-Torrijos Y, Díaz-Fontenla F, Salcedo-Plaza M, Álvarez-López P, de la Mata M, Londoño MC, Bañares-Cañizares R, Calleja JL. Tacrolimus as an Effective and Durable Second-Line Treatment for Chronic Autoimmune Hepatitis: A Multicentric Study. Dig Dis Sci. 2021 Aug;66(8):2826-2832. doi: 10.1007/s10620-020-06569-9. Epub 2020 Aug 29. PMID: 32860579.
4. De Lemos-Bonotto M, Valle-Tovo C, Costabeber AM, Mattos AA, Azeredo-da-Silva ALF. A systematic review and meta-analysis of second-line immunosuppressants for autoimmune hepatitis treatment. Eur J Gastroenterol Hepatol. 2018 Feb;30(2):212-216. doi: 10.1097/MEG.0000000000001019. PMID: 29227329.
5. Guidelines for Hepatitis E & Solid Organ Transplantation; first edition (BTS guidelines)
Well done Assafi but please note that the 30% spontaneous cure is in an immuncompetant patient. but here you will need to manage her IS.
What is your differential diagnosis?
-Viral hepatitis HEV.HAV, HBV,HCV,HDV,CMV
-Drugs like statins ,high dose CNI level
-Autoimmune hepatitis
-Alcoholic hepatitis
-Wilson disease or hemochromatosis.
How would you manage this case?
Proper history ( any history of blood transfusion,eating undercooked meats,alcohol consumption or family history of hereditary hepatitis )and full clinical examination, then serology of HEV.HAV, HBV,HCV,HDV , CMV and viral load for each as recommended .
.
Hence HBV,HCV,CMV AND EBV all negative this is most likely HEV .
*If diagnosis of HEV is confirmed, reduction of immunosuppression is considered the first-line approach; it allows HEV clearance in about one-third of patients.
*Ribavirin is considered in patients with severe acute or acute chronic liver failure or if there is no response to reduction of immunosuppressants.
*Monitor the viral load and the response to ribavirin ,the duration is 3-6 months depending on presence of 2 consecutive negative HEV RNA in plasma and stool in one month apart .
Reference :
1.World J Hepatol. 2022 Mar 27; 14(3): 516–524. Published online 2022 Mar 27. doi: 10.4254/wjh.v14.i3.516
2.Treatment of HEV Infection in Patients with a Solid-Organ Transplant and Chronic Hepatitis .Viruses 2016, 8(8), 222; https://doi.org/10.3390/v8080222
Thankyou.
DDx
Viral infection Hepatitis ABCDE CMV, or EBV
Druge induced : immunosuppressive, cotrimoxasol statins
Other cause of elevated liver enzymes as associated condition with K. transplant : nonalcoholic fatty liver disease
How to manage
Good history taking focusedon history of exposure ( travel ) occupational history drug history and system related symptoms
Clinical examination for signs of CLD or local abdominal tenderness or organomegally
Lab :
Serology for Hepatitis ABCDE CMV virology EBV PCR CBC KFT S.Albumin and Coagulation profile
Abdominal US / CT
According to the results treatment will be
-Differential diagnosis
· According to case scenario mostly a case of HEV hepatitis in renal transplant recipient
· HCV ,HBV ,HDV ,HAV ,HIV,EBV ,CMV ,BK viral infections
· Drug induced liver injury
· Alcoholic hepatitis
· Autoimmune hepatitis
· Inherited causes as Wilson disease ,Hemochromatosis
– Management
· Likely a case of HEV hepatitis since HBV,HCV ,EBV(after repetition) ,CMV PCR were negative along with mild elevation of liver enzymes that decreased then increased again.
· Detailed history need to be retaken from the recipient as well as the donor as living donor regarding previous blood transfusion ,operations or consumption of under cooked meat or alcohol intake
· Clinical exam for signs of liver affection and lymph node exam
· Investigations
-HEV RNA ,HEV Ig M and Ig G have to be done on serum and stool samples at the time being and retrospectively on preserved samples at transplantation time for the recipient and the donor as well
-GGT , liver function tests ,serum albumin ,INR , total bilirubin ,direct bilirubin ,following liver enzymes,
-labs to assess graft function
-routine labs as CBC and inflammatory markers .
-US to evaluate liver status and renal graft status
· Treatment
-Reduction of immunosuppression as graft function is well maintained along with monitoring of Tac and MMF trough levels and graft function
-Ribavirin corrected to creatinine clearance can be started with CBC monitoring along with liver enzymes and duration of therapy ranges from 3-6 months
-HEV RNA testing in stool 2 time on 1 month apart if both negative then ribavirin can be stopped
-Sustained viral response need to be assessed by monitoring HEV RNA in stool every 3 months for 6 months
Reference
– Guidelines forHepatitis E & Solid OrganTransplantation.BTS April,2017.
– Lim, Mary A. MD1; Kamili, Saleem PhD2; Cohen, Jordana B. MD, MSCE1,3; Green-Montfort, Tracy BS2; Tejada-Strop, Alexandra MS2; Kohli, Jatinder MD1; Drobeniuc, Jan MD, PhD2; Patel, Priyanka MS1; Vanderveen, Mary BS1; Bloom, Roy D. MD1. Hepatitis E Virus Infection in Kidney Transplant Patients: A Single-Center Study. Transplantation 102(4):p e126-e127, April 2018.
-Remy P .Hepatitis E Differential Diagnoses.Medscape 2019
I like your DD.
I like your well structured detailed summary. I appreciate your strategy in relation to Hep E infection and transplant.
An 18-year-old lady with CKD 5 due to an unknown cause underwent living-related donor kidney transplantation in 2013. She was given a short course of steroids (discontinued 1 week after transplantation), MMF, and tacrolimus. Pre-transplant serum EBV- and CMV-IgG were negative. The donor was seronegative for CMV but positive for EBV. Kidney transplantation was uncomplicated, with a stable kidney function (eGFR varied between 92 and 98 mL/min). Six months after transplantation, serum aminotransferase levels (ALT: 66 U/L; AST: 47 U/L) were found to be slightly elevated. CMV and EBV PCRs were negative. Four weeks later, liver enzymes decreased (ALT: 53 U/L; AST: 42 U/L) to near-normal levels. Six weeks thereafter, liver enzymes (ALT: 75 U/L; AST: 58 U/L) were again found to be elevated. HCV and HBV PCR were negative.
What is your differential diagnosis?
1st DD is Details History for any new drugs intake, Alcohol intake, fever, weight loss, don’t forget MMF is the most common cause of Elevated LFTs immediately post-Transplant, others Like Statin, antibiotics from my clinical practices.
2nd DD is Viral infection in including HAV, HBV, HEV, HCV, CMV, EBV, BKV all excluded except HEV so I will order HEV PCR
3rd is NAFLD.
4th is Autoimmune hepatitis.
5th is Hereditary conditions such as Wilson’s disease, Hemochromatosis.
Other Actions:
How would you manage this case?
Reduce immunosuppression and monitor viral load monthly for 3 months.
Monitor kidney function, and TAC trough level.
HEV DNA level, anti-HEV IgG titer, HEV RNA level, HEV IgM, IgG.
Ribavirin for 3 months started immediately by monitoring liver function, and HEV RNA.
Monitor ribavirin side effects and adjust the dose accordingly.
I will monitor PCR in blood after 1 week of therapy to predict the duration of therapy,
then I will perform PCR in blood and stool monthly.
Continue ribavirin until HEV RNA level be -ve. for 2 consecutive tests 1 month apart, (3-6 months).
After stopping ribavirin, I will monitor viral load every 3 months using blood or stool PCR for 6 months if negative this means SVR.
I will monitor CBC every 2 weeks and adjust the dose of ribavirin according to Hb level.
I will monitor liver enzymes every 2 weeks initially then monthly.
I will inform the patient to avoid consuming processed undercooked meat especially pork.
PEG-interferon in persistent infection despite ribavirin treatment with cautiously monitoring graft function.
References:
*UpToDate
*Guidelines for Hepatitis E & Solid Organ Transplantation
*European Association for the Study of the Liver. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on hepatitis E virus infection. J Hepatol. 2018 Jun;68(6):1256-1271. doi: 10.1016/j.jhep.2018.03.005. Epub 2018 Mar 31. PMID: 29609832
I like your well structured detailed summary. I appreciate your strategy in relation to Hep E infection and transplant.
Typing whole sentence in bold amounts to shouting.
Differential diagnosis
Management of the case;
References
In addition, would you consider Congestive hepatopathy, hemochromatosis, autoimmune hepatitis, Wilson disease and alpha-1 antitrypsin deficiency as well?
Differential diagnosis
-Infectious hepatitis; viral Hepatitis A, B, C, E – CMV, EBV, HSV and adenovirus
-Drugs induced hepatitis: CsA, Co-trimoxazole, Azathioprine, valganciclovir.
-Toxic induced hepatitis; Acetaminophen, substance abuse
-PTLD
-Autoimmune hepatitis
-NAFLD
————————–
-KTR with elevated and fluctuated liver enzymes noticed 6 months post-Tx.
-This suggestive for chronic nature of the process as HBV, HVC were negative other viruses need to be ruled out.
-EBV mismatch D+/R- increase the risk of PTLD which needs to be considered during evaluation.
-Chronic HEV infection is highly suspected, often asymptomatic, manifesting only with unexplained mild to moderate elevations in serum aminotransferase.
—————————
Elevated liver enzymes in KTRs:
– It is a frequent finding, affecting 7 to 24% of patients depending on the series.
– In immediate post-KT period, 36.6 and 43.4% of KT recipients who receive ATG induction
– It is more frequent in deceased donor KTRs than in living donor ones.
– The main causes during the first months; viral infections (HCV,HBV,CMV,EBV), previous liver disease (hepatorenal polycystic disease), and pharmacological hepatotoxicity (immunosuppressants, antibiotics, antifungals and antiviral agents).
——————————-
How would you manage this case?
* work up;.
– CBC, LFT, RFT, CrCL
– Tac level
– Repeat CMV, EBV, HBV, HCV, HEV.
– serum and stool HEV, RNA.
– Test any previous collected sample for HEV RVA.
– Liver US ;signs of chronicity, infiltrative disease.
– Coagulation profile.
– Serum albumin.
**Treatment will be guided by result of work up, If confirmed as HEV infection;
*Treatment:
– First line: Reduction of immunosuppression RIS to facilitate viral, by reducing Tacrolimus as it potentiate virus replication.
– Ribavirin RBV started if no response to RIS for at least 3 months, or earlier in severe liver dysfunction (jaundice and coagulopathy) or extrahepatic manifestations.
– RBV dose adjusted to CrCL
– RBV is continued for at least 3 months until stool tests are negative for HEV RNA on 2 occasions one month apart.
– Relapse after a first course of ribavirin are re-treated for at least 6 months with ribavirin at dosages toward the higher dose range, where tolerated.
– PEG-IFN may be considered in ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection
*Monitoring:
– HEV RNA at day 7 of Ribavirin therapy to predict SVR at 3 months.help determine the likely length of treatment required
– Monthly HEV RNA testing in plasma and stool.
– Monitor Hg during ribavirin therapy as hemolytic anemia is side effect
– Check for SVR by HEV RNA in plasma and stool at 3 & 6 months samples after stopping antiviral therapy
– Monitor rejection during RIS.
References:
Ahsan, N. and Rao, K.V. (2002), Renal Transplantation Update Series Editors: V. Ram Peddi and M. Roy First: Hepatobiliary Diseases After Kidney Transplantation Unrelated to Classic Hepatitis Virus. Seminars in Dialysis, 15: 358-365. https://doi.org/10.1046/j.1525-139X.2002.00087.x
Einollahi B, Ghadian A, Ghamar-Chehreh E, Alavian SM. Non-viral related liver enzymes elevation after kidney transplantation. Hepat Mon. 2014;14(2):e9036. Published 2014 Feb 5. doi:10.5812/hepatmon.9036
Te H, Doucette K. Viral hepatitis: Guidelines by the American Society of Transplantation Infectious Disease Community of Practice. Clin Transplant. 2019 Sep;33(9):e13514. doi: 10.1111/ctr.13514. Epub 2019 Apr 14. PMID: 30817047.
Hansrivijit P, Trongtorsak A, Puthenpura MM, et al. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021;27(12):1240-1254. doi:10.3748/wjg.v27.i12.1240
Guidelines for Hepatitis E & Solid Organ Transplantation DRAFT Compiled by a Working Party of The British Transplantation Society Draft posted on April 2017 First Edition.
I appreciate your clinical approach to patient who might have altered LFT due to a range of viruses, bacterial infection or non-infective causes.
Your list of differential diagnosis is good. .
Differential diagnosis of hepatic dysfunction after renal transplantation includes
So
If diagnosis of HEV is settled
References
I appreciate your step-wise clinical approach in managing this patient that is well supported by evidence. I appreciate your differential diagnosis.
What is your differential diagnosis?
Medications (steroids , MMF, and tacrolimus)
Corticosteroids also have major effects on the liver, particularly when given long term and in higher than physiologic doses. Glucocorticoid use can result in hepatic enlargement and steatosis or glycogenosis. Corticosteroids can trigger or worsen nonalcoholic steatohepatitis. Long term use can also exacerbate chronic viral hepatitis. Importantly, treatment with corticosteroids followed by withdrawal or pulse therapy can cause reactivation of hepatitis B and worsening or de novo induction of autoimmune hepatitis, both of which can be fatal. Finally, high doses of intravenous corticosteroids, largely methylprednisolone, have been associated with acute liver injury which can result in acute liver failure and death. Thus, the hepatic complications of corticosteroids are mostly associated with high intravenous dosing usually represent the worsening or triggering of an underlying liver disease and rarely are the result of drug hepatotoxicity.
Tacrolimus therapy is associated with mild to moderate elevations in serum aminotransferase levels in 5% to 10% of patients. These elevations are usually mild, asymptomatic and self-limited, but are occasionally persistent and may require dose modification.
Tacrolimus has also been implicated in instances of cholestatic hepatitis, but clinically apparent liver injury is rare. Because tacrolimus is used in the context of organ transplantation and often in liver transplantation, the causes of liver test abnormalities arising during therapy are many, and drug induced liver injury due to tacrolimus is sufficiently rare that its clinical features and typical course have not been defined.
Likelihood score: C (probable rare cause of clinically apparent liver injury).
Mechanism of Injury
Tacrolimus undergoes extensive hepatic metabolism largely via the cytochrome P450 system (CYP 3A4) and is susceptible to many drug-drug interactions. Liver test abnormalities during therapy may be due to direct hepatotoxicity, its effects on levels of other medications, or its effects on the immune system.
Serum enzyme elevations occur in a small proportion of patients on mycophenolate mofetil, but the abnormalities are usually mild, asymptomatic and resolve spontaneously or with dose reduction. A small number of cases of clinically apparent liver injury have been reported in patients on mycophenolate. The onset of injury is usually during the first month of therapy and the pattern of serum enzyme elevations is hepatocellular or mixed. The liver injury is usually mild and self-limiting. Autoimmune and immunoallergic features are uncommon.
Likelihood score: D (possible rare cause of clinically apparent liver injury).
Mechanism of Injury
Mycophenolate mofetil is a prodrug and undergoes extensive metabolism to mycophenolic acid which is pharmacologically active and undergoes enterohepatic recirculation. Mycophenolic acid is converted to a glucuronide by glucuronyl transferase and excreted largely in the urine. Idiosyncratic liver injury is likely due to a toxic or immunogenic metabolite. Mycophenolate does not seem to affect cytochrome P450 enzymes.
MILD-MODERATE ELEVATION DD
*Chronic viral hepatitis (hepatitis B, C, D)
●Alcoholic liver disease
●Hemochromatosis
●Nonalcoholic fatty liver disease
●Autoimmune hepatitis
●Wilson disease
●Alpha-1 antitrypsin deficiency
●Congestive hepatopathy
●Adult bile ductopenia
●Malignant infiltration (most often breast cancer, small cell lung cancer, lymphoma, melanoma, or myeloma)
●Muscle disorders (eg, subclinical inborn errors of muscle metabolism)
●Thyroid disorders
●Celiac disease
●Adrenal insufficiency
●Anorexia nervosa
●Macro-AST (moderate elevations in plasma AST levels due to the presence AST-immunoglobulin complexes, usually IgG)
How would you manage this case?
HISTORY TAKEN
SYSTEMIC EXAMINATION -ABDOMIAL EXAMINATION -EXLUDE LL EDEMA -ASCITES -SIGNS OF LIVER FAILURE
LAB
TROUGH LEVEL OF TACROLIMUS
US ABDOMEN
EXCLUDE SEPSIS -CBC -URINE BLOOD -STOOL CULTURES
SERUM BILIRUBIN -LDH
HEV RNA
-The liver injury due to tacrolimus is usually mild and self-limiting and responses rapidly to dose adjustment or drug discontinuation
-The liver injury due to mycophenolate is usually mild and self-limited, resolving by itself or responding rapidly to dose modification or discontinuation. Mycophenolate has not been linked to instances of acute liver failure or vanishing bile duct syndrome.
I appreciate your step-wise clinical approach in managing this patient that is well supported by evidence. I appreciate your differential diagnosis.Please use headings and sub-headings to make easier to read your write-up. Please use bold or underline to highlight headings and sub-headings.
THANKS .Prof. Ajay Sharma
Noted
Differential diagnosis
Management
Management of HEV depends upon the immune status of the patient and the stage of disease (eg, acute versus chronic).
A subset of patients who undergo solid organ transplantation (eg, kidney, liver, and kidney-pancreas) appear to develop chronic HEV infection
The natural history of chronic HEV infection in transplant recipients is incompletely understood, but rapid progression of liver disease to cirrhosis has been reported.
We suggest a 12-week course of ribavirin monotherapy with chronic HEV infection.
In solid organ transplant recipients, we administer ribavirin in conjunction with reducing immunosuppressive therapy.
For others, we administer antiviral therapy if immunosuppressive therapy cannot be reduced, or if the patient has persistent HEV RNA despite a reduction in immunosuppressive therapy for 12 weeks
I appreciate your clinical approach to patient who might have altered LFT due to a range of viruses, bacterial infection or non-infective causes.
Management plan:
References:
I appreciate your clinical approach to patient who might have altered LFT due to a range of viruses, bacterial infection or non-infective causes.
Differential diagnosis
Management
A. Thorough history and examination
B. If found to be hepatitis E positive, then it’s likely chronic. Management is as follows.
Reference
I appreciate your step-wise clinical approach in managing this patient that is well supported by evidence. I appreciate your differential diagnosis.
What is your differential diagnosis?
Given that the PCR results for CMV, EBV, HCV, and HBV were negative, the case of increased liver enzymes likely attributed to other causes.
Infectious and non-infectious conditions can also result in high liver enzyme levels following kidney donation.
Hepatitis E virus is at the top of the list of infectious causes, along with Hepatitis A and D viruses.
Non-infectious causes include alcohol, malignancy, immunosuppressive medications adverse effects, autoimmune disease, and metabolic disorders.
How would you manage this case?
The complete history of past blood transfusions, history of liver illness, trough level of CNI, and PCR HEV are the first steps in managing this patient.
Management of infectious causes should focus on detection of viral illnesses, with an emphasis on HEV infection. Prior to starting treatment, we should measure the baseline quantitative HEV RNA in both plasma and feces.
Initial step includes decreasing immunosuppression while closely observing for laboratory signs of acute rejection.
Ribavirin should be started for 3- 6 months, along with monthly HEV RNA testing in plasma and stool, until stool tests for HEV RNA are negative on two occasions, one month apart.
Renal function tests should be measured frequently to adjust ribavirin does according to eGFR.
PEG-interferon can be used instead with careful monitoring for rejection if the infection is resistant to therapy with ribavirin.
I appreciate your clinical approach in managing this patient
What is your differential diagnosis?
1. Drug-induced hepatitis (CNI, statin, cotrimoxazole).
2. Infectious etiology like bacterial fungal, Viral hepatitis (CMV, EBV, and acute viral hepatitis including HEV less likely as the screen negative and being fluctuation of liver enzymes level for more than 3 months so we should think about the possibility of chronic Hepatitis E viral infection.
3. Malignancy like PTLD and early post-PTLD are still possible as she is EBV seronegative young candidate from donor positive (high risk), however, her repeated EBV was negative.
How would you manage this case?
Further history including drug history and tacrolimus trough level, previous infection including HEV RNA positive in the previously stored blood samples, presence of anti-HEV IgG antibodies do not confer universal protection and need to send for quantitive HEV PCR level, history of previous HEV infection, blood transfusion, food ingestion
in immunosuppressed patients, the acute HEV can progress to a chronic course (HEV RNA detectable > 6 months) with high morbidity and mortality rates. Usually need to be confirmed by viral PCR level and depends on viral load will decide the treatment duration which mainly depends on the reduction of IS, in particular, MMF and ribavirin for 3-6 months duration and FU with viral load and monitor for ribavirin side effects like hemolytic anemia.
Immunosuppressive therapies might also interfere with the HEV replication cycle as recently demonstrated by Wang and colleagues (2). They showed that tacrolimus promoted the infection of liver cells with HEV, whereas mycophenolate mofetil inhibited HEV replication and steroids showed no effect at all. up to 30% of HEV‐infected patients show a spontaneous clearance of HEV after reduction of immunosuppression at a follow-up of 6 months as per one report (3).
Serial measurements of HEV‐RNA are helpful to determine the optimal duration of ribavirin treatment (4).
Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression (1).
immunosuppressed patients including SOT at risk of chronic HEV infection, reactivation is worth counseling patients to avoid the consumption of raw/ undercooked pig products.
References
1. Panning M, Basho K, Fahrner A, Neumann-Haefelin C. Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: a case report. BMC Infect Dis. 2019 Jul 30;19(1):675. doi: 10.1186/s12879-019-4307-6.
2. Wang Y, Zhou X, Debing Y, Chen K, Van Der Laan LJ, Neyts J, et al.Calcineurin inhibitors stimulate and mycophenolic acid inhibits the replication of the hepatitis E virus. Gastroenterology. 2014;146(7):1775–83.
3. Kamar N, Abravanel F, Selves J, et al. Influence of immunosuppressive therapy on the natural history of genotype 3 hepatitis‐E virus infection after organ transplantation. Transplantation. 2010;89(3):353‐360. 10.1097/TP.0b013e3181c4096c [PubMed] [CrossRef] [Google Scholar]
4. Affeldt P, Di Cristanziano V, Grundmann F, Wirtz M, Kaiser R, Benzing T, Stippel D, Kann M, Kurschat C. Monitoring of hepatitis E virus RNA during treatment for chronic hepatitis E virus infection after renal transplantation. Immun Inflamm Dis. 2021 Jun;9(2):513-520.
I appreciate your clinical approach in managing this patient
Differential diagnosis of elevated liver enzymes ELE:
1] Chronic liver disease.
2] Drug induced hepatitis.
3] HEV infection associated hepatitis.
4] other viruses might be implicated such as Herpez virus
5]Non alcoholic and alcoholic fatty liver disease NAFLD
Management:
Exclusion of chronic liver disease by performing Fibroscan and MRI .
If its abnormal then referral to hepatologist and liver biopsy might be indicated in addition to full list of investigations to find out about chronic liver disease.
For HEV infection will request for plasma and stool PCR and Anti HEV antibodies, IgM and IgG, if its positive , then reduction of immune suppression and Ribavirin therapy are indicated.
Drug induced hepatitis:
The most common cause of drug induced hepatitis is CNI Tacrolimus and Cyclosporin, particularly when its plasma level is elevated.
Therefore, checking the trough level of Tacrolimus is indicated in this context, if its elevated , then will reduce Tac dose accordingly.
Consequently, if No improvement is reported then switching to Cyclosporin is the next step forward.
When no improvement in liver enzymes is reported , then changing to Sirolimus is the best option.
lastly, if ELE is still lingering, then MMF might be the culprit, therefore reducing the dose of MMF of switching to AZA might be sought after.
References:
1] Gustavo de Almeida VIEIRA et al. Hepatic alterations in kidney transplant recipients from the largest kidney transplant center in Brazil. Arq Gastroenterol • 2022. v. 59 nº 1 jan/mar • 65
I appreciate your clinical approach to patient who might have altered LFT due to a range of viruses, bacterial infection or non-infective causes.
Patients who come with an increase in aminotransferases, whether or not they also have hepatitis symptoms, have a wide range of infectious and noninfectious factors to consider in their differential diagnosis.
Liver disease caused by infectious
Hepatitis A
Hepatitis E
Acute/chronic HBV
Chronic HCV
HDV superimposed on HBV
Other viruses like herpes simplex, EBV, CMV
Liver disease caused by toxins:
ALCHOL AND DRUGS
Liver disease by metabolic disorders:
NASH, autoimmune hepatitis and Wilson disease
Laboratory
CBC, CRP, HEV-IgM,igG. HEV RNA in stool
Rest of al viruses serology including A,B, C.
TREATMENT
Reduction in immunosupression
Ribavirine for 3 to 6 month until two stool HEV RNA tests, one month apart, are negative, along with monthly HEV RNA testing in plasma and stool.
1- Pawlotsky JM. Hepatitis E screening for blood donations: an urgent need? Lancet 2014; 384:1729.
2- Anwar N, Sherman KE. Viral hepatitis other than A, B, or C. In: Scientific American Gastroenterology, Hepatology, and Endoscopy, Burakoff R. (Ed), Decker Intellectual Properties, Toronto 2016.
3- British Transplantation Society Guidelines
Guidelines for Hepatitis E & Solid Organ Transplantatio
I appreciate your clinical approach to patient who might have altered LFT due to a range of viruses, bacterial infection or non-infective causes.
What is your differential diagnosis?
A case of PKX with elevated transaminases with CMV, EBV, HCV and HBV PCR negative.
Hepatitis E virus – on top of the list.
Hepatitis A virus.
Hepatitis D virus.
Other infectious causes (bacterial, fungal or parasitic source).
Non-infectious cause such as (alcohol, drugs such as (steroid or MMF), autoimmune diseases, and metabolic diseases).
How would you manage this case?
Treatment of the cause such as stop drugs or alcohol consumption.
Treatment of other source of infection and here will stress on HEV infection .
1-We should collect a baseline quantitative HEV RNA on both plasma and stool at the start of treatment.
2-Ribavirin should be started for 3- 6 months and until stool tests are negative for HEV RNA on two occasions one month apart with monthly HEV RNA testing in plasma and stool.
3-Ribavirin dose should be adjusted according to renal function tests.
4-F/U Hemoglobin during Ribavirin course.
5-If infection resistant to Ribavirin, we can use PEG-interferon with close monitoring for rejection.
6-Reduction of immunosuppression with close monitoring of RFT.
References:
1- British Transplantation Society Guidelines: Guidelines for Hepatitis E & Solid Organ Transplantation 2017.
2- Hansrivijit P, Trongtorsak A, Puthenpura MM, et al. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021;27(12):1240-1254. doi:10.3748/wjg.v27.i12.1240.
3-Dizdar OS, Ersoy A, Aksoy S, Ozel Coskun BD, Yildiz A. Analysis of liver function test abnormalities in kidney transplant recipients: 7 year experience. Pak J Med Sci. 2016;32(6):1330-1335. doi:10.12669/pjms.326.10725
I appreciate your clinical approach to patient who might have altered LFT due to a range of viruses, bacterial infection or non-infective causes.
What is your differential diagnosis?
This is a case of post-KTP with good allograft function but persistently elevated liver enzymes.
The following are possible differential diagnoses ruled out by the investigation done:
Other differential diagnoses not ruled out from the clinical history are:
How will you manage this case?
Investigations
The treatment will depend on the final diagnosis for the investigation.
The following will be done if the final diagnosis is HEV
Thankyou
Is there any suspected finding in the generous panel of investigations?
How can HSV cause this transaminases abnormality.!
What is your differential diagnosis?
Renal transplant patient with high liver enzymes post transplant with fluctuating course.
Virology screen for CMV,EBV,HCV and HBV came negative.
Generally speaking ,Elevation of liver aminotransferases, ALT and AST, is suggestive of hepatocellular injury. It is important to consider also the transient elevation of serum aminotransferases within the first 3 months after transplantation was commonly seen in 22% of all transplant recipients. Persistent elevation of liver enzymes Six months after transplantation is considered chronic hepatitis.
It is can be viral related and non viral related causes:
-Non viral causes like alcohol, fatty liver, autoimmune hepatitis and pharmacological causes as immunosuppressants including CNIs ,antibiotics, antifungals ,acetaminophine toxicity ,herbal supplements and illicit drugs and antiviral agents.
-Viral causes: Hepatotropic viruses HBV, HCV, CMV, Hepatitis A virus infection, EBV, HSV and hepatitis E viral infection.
How would you manage this case?
-Proper history including alcohol intake, medications, symptoms and signs.
-Physical examination of GI system: Any hepatomegaly, accompanied splenomegaly, ascites if there.
-Investigations:
Blood tests including CBC,liver enzymes,Bilirubin and serum albumin
Antibody screening for HEV IgG and IgM, HEV PCR
Imaging including abdominal US
-If confirmed chronic HEV infection ,the aim for viral clearance with reduction of immunosuppression and 12-weeks course of ribavirin monotherapy. The dose of ribavirin is 600 to 1000 mg daily with close monitoring for toxicity.
Very good answer but you need to monitor Ribaverin side effects as well.
Confirm the result of viral serology
repeat LVT, Coagulation profile, CBC, CRP, and renal function
Request U/S abdomen.
If confirmed HBE:
More than 30% of solid organ transplant patients with acute HEV infection will spontaneously eliminate the illness within three months, thus HEV RNA levels and liver enzymes are monitored. Real-time viral surveillance and antibody profiling may aid clinical decision-making.
In individuals with acute or chronic HEV, reducing immunosuppression may help viral clearance, although the risk of rejection must be addressed.
Acute hepatitis E patients with severe liver dysfunction (jaundice and coagulopathy) or extrahepatic symptoms may benefit from early ribavirin therapy
Reference:
British Transplantation Society Guidelines: Guidelines for Hepatitis E & Solid Organ Transplantation.
Thankyou
Is the 30% spontaneous cure with out reduction of IS , would it depend on PCR log,degree of Transaminase elevation!
just without a reduction of immunosuppressive medication.
2. An 18-year-old lady with CKD 5 due to an unknown cause underwent living-related donor kidney transplantation in 2013. She was given a short course of steroids (discontinued 1 week after transplantation), MMF, and tacrolimus. Pre-transplant serum EBV- and CMV-IgG were negative. The donor was seronegative for CMV but positive for EBV. Kidney transplantation was uncomplicated, with a stable kidney function (eGFR varied between 92 and 98 mL/min). Six months after transplantation, serum aminotransferase levels (ALT: 66 U/L; AST: 47 U/L) were found to be slightly elevated. CMV and EBV PCRs were negative. Four weeks later, liver enzymes decreased (ALT: 53 U/L; AST: 42 U/L) to near-normal levels. Six weeks thereafter, liver enzymes (ALT: 75 U/L; AST: 58 U/L) were again found to be elevated. HCV and HBV PCR were negative.
====================================================================
What is your differential diagnosis?
Hepatitis can be caused by both infectious and noninfectious causes:-
Infrequent causes of viral hepatitis include:-
====================================================================
How would you manage this case?
1- History
========================
2- Lab.
============================================
Serology
====================================================================
Medical Manegement
Immunization
====================================================================
Reference
Thankyou but do you HEV IgG can be protective? against a new infection.!?
Many thanks for you Prof.Dalwat
====================================================
Reference
Differential diagnosis:
How to manage this case:
McPherson S, Elsharkawy AM, Ankcorn M, Ijaz S, Powell J, Rowe I, Tedder R, Andrews PA. Summary of the British Transplantation Society UK guidelines for hepatitis E and solid organ transplantation. Transplantation. 2018 Jan
Thankyou for the well structured answer but this virus can not clear spontaneously in this patient with IS as you managed in the following sentence.
1.What is your differential diagnosis?
–It is quiet clear that this young lady had a successful kidney transplantation with excellent allograft function
-She is on steroid free regimen
-She might be at risk of PLTD given the fact that she EBV negative & her donor is EBV positive
-She had liver abnormal liver function test 6 months after transplantation with fluctuating ALTs & ASTs
-Because HBV and HCV PCR were negative, one may consider other hepatitis infections e.g., HEV infection. Given the time lines for fluctuations of LFTs this patient may be persistent HEV infection.
-We need to check now for plasma and stool HEV RVA
-We need to look back at any history or stored samples at time of transplantation for any evidence of HEV infection
-HEV infection can be transmitted through HEV contaminate meat, blood transfusion or organ transplantation
-The differential diagnosis to keep in mind are:
How would you manage this case?
-If HEV infection is confirmed, it is likely to be persistent infection
-Liver ultrasoungraphy is important
-The rest of the management is as follows:
Reference: BTS guidelines 2017
This is an exellent well planed answer,concise and comprehensive.
Thnxs, prof
1-What is your differential diagnosis?
Liver disease 2ry to infectious causes includes:
-Hepatitis E virus infection (most likely)
-Hepatitis due to Epstein-Barr virus infection
-Hepatitis A virus infection
-Acute or chronic hepatitis D infection
-Hepatitis due to herpes simplex virus infection
-Hepatitis due to cytomegalovirus infection
Liver disease 2ry to toxins:
-Alcoholic hepatitis
-Acetaminophen toxicity
-Toxin-induced hepatitis (eg, mushroom poisoning, carbon tetrachloride)
-Prophylactic medications; (INH, Valganciclovir)
Liver disease by metabolic disorders:
-Nonalcoholic steatohepatitis
-Autoimmune hepatitis
Liver disease by other causes:
-Ischemic hepatitis
-Elevated aminotransferases may also be seen in patients with systemic disease, such as: (Muscle diseases – Thyroid disease – Celiac disease – Adrenal insufficiency – Anorexia nervosa).
2-How would you manage this case?
Further investigations;
IgM anti-HEV – The IgG response – HEV RNA assay
EBV serology – Virology – LFTs – Renal Profile – CBC
U/S on Liver
According British Transplantation Society Guidelines;
-Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals. (1B)
-Solid organ transplant recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay. (1C)
-Transplant recipients have a plasma sample taken at the time of transplantation and stored for a minimum of one year that could be tested retrospectively for HEV or other infections. (2D)
-Individuals with unexplained acute on chronic or acute liver failure should be tested for HEV. (2C)
Management of newly diagnosed or acute HEV infection;
According British Transplantation Society Guidelines;
-The initial management includes observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months. Dynamic viral monitoring and antibody profiling may help clinical decision-making. (2C)
-A reduction in immunosuppression is considered in patients with acute or persistent HEV as this may facilitate viral clearance, but the risk of rejection should be carefully assessed. (2C)
-Early treatment with ribavirin may be considered in specific cases of acute hepatitis E, such as patients who develop severe liver dysfunction (jaundice and coagulopathy) or extrahepatic manifestations, although evidence for this recommendation is currently limited. (2D)
Management of Perisistent HEV infection;
According British Transplantation Society Guidelines;
-Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C)
-Individuals with persistent HEV infection (documented or estimated duration of infection of more than three months) receive treatment with ribavirin with the aim of achieving sustained virological response (HEV RNA not detected in plasma and stool six months after completion of treatment). (1C)
-A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment. (1C)
-Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment will suffice. (1C)
-Monthly HEV RNA testing in plasma and stool is undertaken until a decision is made to stop treatment. (1C)
-Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart, as continued shedding of HEV in stool is an important factor predicting relapse after ribavirin treatment. (1C)
-A test of sustained virological response is conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy. (1C)
Monitoring for drug toxicity;
According British Transplantation Society Guidelines;
-Regular haemoglobin monitoring is conducted during ribavirin therapy as haemolytic anaemia is a common treatment-related side effect. Ribavirin dose reduction may be required during treatment to maintain an adequate haemoglobin concentration. Epoetin therapy and/or blood transfusion may be indicated to allow continued antiviral therapy without avoidable drug reduction. (1A)
-PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients as there is a moderate risk of precipitating organ rejection. (1D)
References;
–British Transplantation Society Guidelines: Guidelines for Hepatitis E & Solid Organ Transplantation.
– Litin SC, O’Brien JF, Pruett S, et al. Macroenzyme as a cause of unexplained elevation of aspartate aminotransferase. Mayo Clin Proc 1987; 62:681.
–Daniel S, Ben-Menachem T, Vasudevan G, et al. Prospective evaluation of unexplained chronic liver transaminase abnormalities in asymptomatic and symptomatic patients. Am J Gastroenterol 1999; 94:3010.
–Skelly MM, James PD, Ryder SD. Findings on liver biopsy to investigate abnormal liver function tests in the absence of diagnostic serology. J Hepatol 2001; 35:195.
Thankyou
Can HDV occur on its own?
Can HEV cause acute liver failure!
Well done.
What is the Ribaverin dose in this exellent GFR 98ml/min!!!! be?
Thanks so much our, Prof.
Ribavirin in treatment of Hepatitis E infection:
Oral:
-Optimal dosing has not been established:
-typically 600 to 800 mg/day (range: 400 mg to 1 g/day) in 1 to 2 divided doses.
(De Winter 2018; Kamar 2020; Protin 2019; Rivero-Juárez 2020; Tavitian 2015).
-Optimal duration is unknown, but is typically ≥3 months based on virologic response.
(AST-IDCOP [Te 2019]; EASL 2018; Kamar 2020; Rivero-Juárez 2020; Tavitian 2015).
Hepatitis D virus (HDV):
-HDV is a virus that requires hepatitis B virus (HBV) for its replication.
-Hepatitis D virus (HDV) affects globally nearly 5% of people who have a chronic infection with hepatitis B virus (HBV).
-HDV infection occurs when people become infected with both hepatitis B and D simultaneously (co-infection) or get hepatitis D after first being infected with hepatitis B (super-infection).
-Populations that are more likely to have HBV and HDV co-infection include indigenous populations, recipients of haemodialysis and people who inject drugs.
-Worldwide, the number of HDV infections has decreased since the 1980s, due mainly to a successful global HBV vaccination programme.
-The combination of HDV and HBV infection is considered the most severe form of chronic viral hepatitis due to more rapid progression towards liver-related death and hepatocellular carcinoma.
-Hepatitis D infection can be prevented by hepatitis B immunization, but treatment success rates are low.
Differential Diagnosis
Management
investigation;
Management would be according to etiology in case of HEV which is most likely diagnosis than
Reference
Thankyou.
elevated liver enzymes in renal allograft recipient:
1- drug induced
2-infection either bacterial or viral like CMV, EBV, HCV, HBV, HEV
3-malignancy
management:
1- PCR for HEV should be done
2-CBC, CRP, procalcitonin
3-liver function test
this is a case of HEV infection
4-Ribavirin should be started in the case of HEV PCR positive for 3 months
2-Pegylated interferon-alfa has antiviral activity against HEV, however, cannot be used in patients with stem cell or organ transplants due to a high risk of rejection.
3-reduction of MPA daily dose
RIS may be not enough alone to clear HEV, and should be accompanied by antiviral therapy which is Ribavirin
4-monitoring by CBC, liver function test, graft function, regular monitoring by HEV PCR
Marcus Panning, Kristi Basho, Andreas Fahrner, Christoph Neumann-Haefelin. Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: a case report. BMC Infectious Diseases volume 19, Article number: 675 (2019).
Rivero-Juarez, A.; Vallejo, N.; Lopez-Lopez, P.; Díaz-Mareque, A.I.; Frias, M.; Vallejo, A.; Caballero-Gómez, J.; Rodríguez-Velasco, M.; Molina, E.; Aguilera, A. Ribavirin as a First Treatment Approach for Hepatitis E Virus Infection in Transplant Recipient Patients. Microorganisms 2020, 8, 51.
Patrick Affeldt , Veronica Di Cristanziano , Franziska Grundmann , Maike Wirtz , Rolf Kaiser , Thomas Benzing , Dirk Stippel , Martin Kann , Christine Kurschat. Monitoring of hepatitis E virus RNA during treatment for chronic hepatitis E virus infection after renal transplantation. Immun Inflamm Dis. 2021 Jun;9(2):513-520.
Kanter Berga, J, Rodriguez Mendez, G., Crespo Albiach, J., Sancho Calabuig, A., Gavela Martinez, E., Anton Conejero, M. D., Pallardo Mateu, L. Hepatitis E Virus Infection in Renal Transplantation: Report of Four Cases. Transplantation 94(10S):p 886, November 27, 2012.
Diana Vassallo, Mir Mubariz Husain, Shaun Greer, Stephen McGrath, Samreen Ijaz, Durga Kanigicherla. Hepatitis E Infection in a Renal Transplant Recipient.Case Rep Nephrol. 2014; 2014: 865471.
Thankyou for always remembering drugs as a cause of disturbed liver enzymes.!
What is your differential diagnosis?
How would you manage this case?
Differential diagnosis
Management
A. Thorough history and examination
B. If found to be hepatitis E positive, then it’s likely chronic. Management is as follows.
Reference
I appreciate your step-wise clinical approach in managing this patient that is well supported by evidence.
viral versus non viral causes
First viral cause :
1-HCV -HBV -HEV HDV
2-CMV infection .
3-Pyloma virus.
4-EBV VIRUS.
NON-VIRAL :
1-hepatorenal polycystic kidney disease .
2- Drug hepatotoxicity (antibiotics -antifungal )
3-Immunosuppressants(CNI-MMF).
First to roll out and discontinue any hepatotoxic drug then I will order HBE virus antibodies and PCR .
Immunsuppresion drug levels .
IF HEV virus come positive I will reduce immunosuppression drug .
If not respond I will add ribavirin .
I appreciate your clinical approach to patient who might have altered LFT due to a range of viruses, bacterial infection or non-infective causes.
Your list of differential diagnosis is good. .
What is your differential diagnosis?
1st DD is Details History for any new drugs intake, Alcohol intake, fever, weight loss, don’t forget MMF is the most common cause of Elevated LFTs immediately post-Transplant, others Like Statin, antibiotics from my clinical practices.
2nd DD is Viral infection in including HAV, HBV, HEV, HCV, CMV, EBV, BKV all excluded except HEV so I will order HEV PCR
3rd is NAFLD.
4th is Autoimmune hepatitis.
5th is Hereditary conditions such as Wilson’s disease, Hemochromatosis.
Other Actions:
How would you manage this case?
Reduce immunosuppression and monitor viral load monthly for 3 months.
Monitor kidney function, and TAC trough level.
HEV DNA level, anti-HEV IgG titer, HEV RNA level, HEV IgM, IgG.
Ribavirin for 3 months started immediately by monitoring liver function, and HEV RNA.
Monitor ribavirin side effects and adjust the dose accordingly.
I will monitor PCR in blood after 1 week of therapy to predict the duration of therapy,
then I will perform PCR in blood and stool monthly.
Continue ribavirin until HEV RNA level be -ve. for 2 consecutive tests 1 month apart, (3-6 months).
After stopping ribavirin, I will monitor viral load every 3 months using blood or stool PCR for 6 months if negative this means SVR.
I will monitor CBC every 2 weeks and adjust the dose of ribavirin according to Hb level.
I will monitor liver enzymes every 2 weeks initially then monthly.
I will inform the patient to avoid consuming processed undercooked meat especially pork.
PEG-interferon in persistent infection despite ribavirin treatment with cautiously monitoring graft function.
References:
*UpToDate
*Guidelines for Hepatitis E & Solid Organ Transplantation
*European Association for the Study of the Liver. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on hepatitis E virus infection. J Hepatol. 2018 Jun;68(6):1256-1271. doi: 10.1016/j.jhep.2018.03.005. Epub 2018 Mar 31. PMID: 29609832
Thankyou ,remember this patient is on dual IS so close follow up of graft function is a must.
What is your differential diagnosis?
The differential diagnosis for mildly elevated liver enzymes in this case scenario which has negative PCR for HCV, HBV, CMV and EBV can be summarized in the attached table (1).
References:
1) Lawrence S Friedman. Approach to the patient with abnormal liver biochemical and function tests. © 2023 UpToDate (accessed on 7 March 2023).
How would you manage this case?
In agreement with my colleagues, I will start my management with proper history taking (including any recent drug use, e.g. recent antibiotics, or history of travelling abroad or any contact with sick patients).
The next step will be a detailed clinical examination with special concern for any skin rash or lymphadenopathy.
Then, I will proceed to an Abdominal ultrasound scan, Serology for autoimmune hepatitis (the patient is 18 years old female with an unknown case of ESRD that may point to underlying auto-immune disease). The attached table suggests a stepwise approach for cases with persistent, mild elevation of liver transaminases. In case all the performed investigations came negative or non-conclusive, then I will proceed to a liver biopsy (1).
References:
1) Lawrence S Friedman. Approach to the patient with abnormal liver biochemical and function tests. © 2023 UpToDate (accessed on 7 March 2023).
What is your differential diagnosis?
1. Viral infections: HEV, EBV, and less likely HBV, and EBV
2. Drug induced: hepatotoxic drugs (immunosuppressants, antibiotics, antifungals, antiviral agents, statins, and allopurinol)
3. previous liver disease (hepatorenal polycystic disease)
4. Alcohol (NAFLD)
5. Sepsis
6. Autoimmune diseases
o Lorber et al. in 1987, mentioned that 49% of their renal allograft patients had post-transplant hepatotoxicity with CsA, including hyperbilirubinemia (48% of patients), elevated AST (47%), ALT (73%), LDH (84%), and ALP (59%)
o High dose calcineurin inhibitors frequently cause mild elevation of liver tests. Although rare, severe hepatotoxicity may occur
o Hepatotoxicity sometimes makes it necessary to switch between these two drugs
o Tacrolimus hepatotoxicity is characterized by elevated levels of hepatocellular enzymes, either alone or with minimal cholestasis and hyperbilirubinemia. hepatotoxicity did not decrease after dose reduction. Normalization of liver enzymes occurred after discontinuing tacrolimus
o Cyclosporine hepatotoxicity may also cause cause cholestasis, but reduction of the cyclosporine dosage alone is sufficient to resolve the hepatotoxicity
o Elevated aminotransferase is more commonly associated with SRL rather than CyA treatments or SRL + CyA treatments
How would you manage this case?
o Detailed history and comprehensive examination (eating raw or undercooked meat, alcohol, drugs, and neurological symptoms)
o CBC, LFT and ALP, clooting factors, immunosuppressive levels, RFT and electrolytes, ERS, and CRP
o HEV RNA and/or antigen detection in blood and stool (antibody detection is unreliable)
o U/S for liver or extra-hepatic obstruction
o Liver biopsy may be indicated if unexplained high liver enzymes
o Treat the underlying cause
References
1. Solà-Porta, E.; Redondo-Pachón, D.; Arias-Cabrales, C.; Navazo, D.; Buxeda, A.; Burballa, C.; Crespo, M.; García-Retortillo, M.; Pascual, J.; Pérez-Sáez, M.J. Early Hypertransaminasemia after Kidney Transplantation: Significance and Evolution According to Donor Type. J. Clin. Med. 2021, 10, 5168.
2. Einollahi B, Ghadian A, Ghamar-Chehreh E, Alavian SM. Non-viral related liver enzymes elevation after kidney transplantation. Hepat Mon. 2014 Feb 5;14(2):e9036. doi: 10.5812/hepatmon.9036. PMID: 24693313; PMCID: PMC3950572.
3. Dizdar OS, Ersoy A, Aksoy S, Ozel Coskun BD, Yildiz A. Analysis of liver function test abnormalities in kidney transplant recipients: 7 year experience. Pak J Med Sci. 2016 Nov-Dec;32(6):1330-1335. doi: 10.12669/pjms.326.10725. PMID: 28083020; PMCID: PMC5216276.
4. Vivian Yiu, Rui Gao, Sharon Mulroy, Hepatitis in a renal transplant patient—beyond the usual, Clinical Kidney Journal, Volume 5, Issue 2, April 2012, Pages 170–172.
5. Guidelines for Hepatitis E & Solid Organ Transplantation. British Transplantation Society Guidelines, 2017.
What is your differential diagnosis? (9, 10)
– Hepatotropic virus-related infectious diseases – CMV, HEV, EBV, HAV, HBV, HCV
– Drug-induced hepatitis – immunosuppressants (MMF, Azathioprine, high-dose CNIs), antibiotics (TMP-SMX), antiviral agents, antifungal agents, statins
– Autoimmune hepatitis
– Sepsis
– Alcohol resulting in hepatitis
– NAFLD (non-alcoholic fatty disease)
– Biliary tract dysfunction
How would you manage this case? (4, 10)
– detailed history: trying to rule out/ rule in the possible etiological factors
– thorough physical exam
– baseline investigations: CBC, UECs, LFTs, tacrolimus trough level, autoimmune screen, HEV RNA PCR, anti-HEV IgM and IgG, HEV RNA screen (plasma and stool), HIV Ab, EBV PCR, CMV PCR
– liver ultrasound for features duct dilatation, doppler flows
– liver biopsy – inflammation, steatosis, fibrosis
– multidisciplinary approach: hepatologist
– management depends on the underlying cause
– if HEV infection is the culprit, I would start with reduction in immunosuppression
– if HEV is confirmed, the 1st approach is to decrease total immunosuppression burden
– if reduction of immunosuppression is not sufficient, other additional management strategies which can be considered include pegylated interferon alpha-2b, ribavirin 12mg/kg daily for 12 weeks
– recheck HEV RNA at the end of treatment
– if HEV RNA is absent, stop ribavirin and recheck the HEV RNA in 12 weeks, if still absent this is regarded as sustained virological response (SVR) and no further treatment or monitoring is required
– but if the HEV RNA is still present after the first 12 weeks of treatment with ribavirin, reinitiate the ribavirin for another 24 weeks and recheck the HEV RNA at the end of treatment, if absent, stop ribavirin and recheck HEV RNA in 12 weeks, if still absent then this is regarded as SVR, if present this is regarded as treatment failure and the patient needs to be monitored for signs of progressive liver disease
– similarly, if HEV RNA is still positive after the 24weeks of ribavirin, consider this as treatment failure and monitor patient for signs of progressive liver disease
– on the other hand, if HEV RNA is still present after the first 12-week course of ribavirin, the patient should get an additional 12 weeks of ribavirin, then recheck HEV RNA levels
– if HEV RNA is still present, consider this as treatment failure and follow up patient for signs of progressive liver disease
– however, if HEV RNA is absent, stop ribavirin and recheck the HEV RNA in 12 weeks, if still absent this is regarded as SVR and no further treatment or monitoring is required but if HEV RNA is present, consider this as treatment failure and follow up patient for signs of progressive liver disease
– preventive measures include thorough cooking of pork products and game meat
– currently there is no effective immunoprophylaxis against HEV that is available
– use of immunoglobulin from infected persons has not been found to be effective in preventing sporadic cases or outbreaks
– vaccination against HEV has been proposed but the efficacy is yet to be addressed
References
1. Dizdar OS, Ersoy A, Aksoy S, Ozel Coskun BD, Yildiz A. Analysis of liver function test abnormalities in kidney transplant recipients: 7 year experience. Pakistan journal of medical sciences. 2016 Nov-Dec;32(6):1330-5. PubMed PMID: 28083020. Pubmed Central PMCID: PMC5216276. Epub 2017/01/14. eng.
2. Yiu V, Gao R, Mulroy S. Hepatitis in a renal transplant patient—beyond the usual. Clinical kidney journal. 2012;5(2):170-2.
3. Kamar N, Izopet J, Tripon S, Bismuth M, Hillaire S, Dumortier J, et al. Ribavirin for chronic hepatitis E virus infection in transplant recipients. The New England journal of medicine. 2014 Mar 20;370(12):1111-20. PubMed PMID: 24645943. Epub 2014/03/22. eng.
please, sirs, there is no question to answer
What is your differential diagnosis?
Tacrolimus induced
MMF induced
Any other medication like statin
HEV infection , Hep B,C,D
Transient elevation of liver enzymes
Only positive CMV IgM testing
immunosuppressants used for induction treatment, specifically thymoglobulin(36.6 and 43.4% of KT recipients who receive thymoglobulin induction suffer AST and ALT elevation, respectively)
EBV induced
liver-kidney crosstalk.
KT recipients from uDCD are 5 to 13 times more inclined to elevate transaminases than cDCD or DBD ones.
more frequent in deceased donor KT recipients than in living donor ones.
Analysis of liver function test abnormalities in kidney transplant recipients: 7 year experience
Oguzhan Sitki Dizdar et al
Early Hypertransaminasemia after Kidney Transplantation: Significance and Evolution According to Donor Type
by Eulàlia Solà-Porta 1
How would you manage this case?
Drug history to see for use of statins, alcohol abuse, recreational drug abuse.
Investigate with-
Tacrolimus level
CBC
RFT
SE
Usg abdomen and pelvis
HEV igA , HEV RNA
HBV DNA
HCV RNA
Referral to hepatology unit
Stop any hepatotoxic drug like statins,anti fungals,antivirals
If tacrolimus level is high ,decrease dose
Treat viral infection if found