The patient completed the investigations with the following:
|
Test |
value |
|
24-hour urinary calcium |
80 mg |
|
24-hour urinary creatinine |
|
C. What is the most possible diagnosis? and pathophysiology?
D. Why is it important to diagnose FHH?
E. How would you treat this case?
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in the setting of hypercalcemia and increased parathyroid hormone and low calcium excretion, diagnosis of familial hypercalciuric hypercalcemia is gained
– important to diagnose instead of incorrect diagnosis of primary hyperparathyroidism
– conservative management
C. What is the most possible diagnosis? and pathophysiology?
FHH
It is due to due to dysfunction of the calcium-sensing receptor. Reduced function of the calcium-sensing receptor causes the parathyroid glands to falsely “sense” hypocalcemia and inappropriately release slightly excessive amounts of PTH, The renal tubule calcium-sensing receptors are also affected, causing hypo calciuria. It is characterized by hypercalcemia, hypocalciuria (usually less than 50 mg/24 h), variable hypermagnesemia, and normal or minimally elevated serum levels of PTH. It can be diagnosed with family history and urinary calcium determination
D. Why is it important to diagnose FHH?
To differentiate from primary hyperparathyroidism and avoid surgery
E. How would you treat this case?
Benign condition need follow up and reassurance
C- FHH due CaSR mutation
B- it benign no need for any intervention
F- follow up
What is the most possible diagnosis? and pathophysiology?
UCCR 0.08 so its primary hyperpthyroid
UCCR is typically greater than 0.02 in PHPT patients and lower than 0.01 in FHH patients.
Primary hyperparathyroidism is due to the presence of an adenoma/single-gland disease in 80–85%. Multiple gland disease or hyperplasia accounts for 10–15% of cases of primary hyperparathyroidism. Atypical parathyroid adenoma and parathyroid carcinoma are both responsible for about 1.2–1.3% and 1% or less of primary hyperparathyroidism, respectively.hyperparathyroidism increase vit d increasing Ca absortion, phosphate excreation, bone
PTH secretion is, in turn, regulated by serum ionized calcium acting via an exquisitely sensitive calcium-sensing receptor (CaSR) on the surface of parathyroid cells.
Why is it important to diagnose FHH
to void missing parathyroid denoma UCCR is a limited test sometimes need genetic test
How would you treat this case?
assess full lab, isotop scan, remove the adenoma, or parathyredectomy
UCCR= 0.08 (>0.01),
suggesting primary hyper parathyroidism which increases vitamin D activation, increased calcium absorption and reabsorption, stimulate phosphorus excretion, indirectly stimulates osteoclasts inducing bone resorption and net hypercalcemia and hypo phosphatemia.
it is important to diagnose FHH as it does not require intervention
management of this case: isotope scanning for parathyroid gland, parathyroidectomy.
diagnosis FHH
it’s essential to differentiate from the primary hyperparathyroidism
and to avoid parathyroidectomy
this patient needs only follow-up and close monitoring of high calcium levels.
The most likely diagnosis is FHH
we must differentiate it from primary hyperparathyroidism in order to avoid unnecessary parathyroidectomy.
it is a bengin condition need only follow up.
FAMILIAL BENIGN HYPOCALCIURIC HYPERCALCEMIA
FHH is genetically heterogenous, with three reported variants—FHH1,
FHH2 and FHH3—whose loci are on chromosomes 3q21.1, 19p, and 19q13, respectively. FHH1 is due to heterozygous loss-offunction mutations of the CaSR, which is a GPCR that signals through Gαq and Gα11. The human CaSR, a 1078−amino acid cell surface GPCR encoded by the CaSR gene located on chromosome 3q21.1, is expressed in parathyroid cells, thyroid cells, and kidney . Approximately two thirds of FHH kindreds have unique heterozygous mutations of the CaSR, and expression studies of these mutations have demonstrated a loss of CaSR function whereby there is an increase in the calcium ion−dependent set point for PTH release from the parathyroid cell. FHH2 is due to loss-of-function mutations in the G-protein subunit α11 (Gα11) , which decrease the sensitivity of cells expressing the CaSR, probably by impairing the release of guanosine diphosphate. Such Gα11 loss-of-function mutations may occur in less than 5% of FHH patients. FHH3 is due to loss-of-function mutations of the adaptor protein 2 (AP2)
sigma subunit (AP2σ) . AP2 is a central component of clathrin-coated vesicles (CCVs) and is pivotal in clathrin-mediated endocytosis, which internalizes plasma membrane constituents such as GPCRs. AP2 is a heterotetramer of α, β, µ, and σ subunits and links clathrin to vesicle membranes and binds to tyrosine- and dileucine-based motifs of membraneassociated cargo proteins. The FHH3-associated AP2σ mutations, which all involve an Arg15 residue that forms key contacts with the dileucine-based motifs of CCV cargo proteins, result in a decreased sensitivity of CaSRexpressing cells to extracellular calcium and reduced CaSR endocytosis, probably through loss of interaction with a C-terminal CaSR dileucine-based motif, whose disruption also decreases intracellular signaling. Such AP2σ loss-of-function mutations occur in more than 5% of FHH patients. FHH1, FHH2, and FHH3 have similar clinical features, and thus genetic analysis is required to identify the relevant mutations.
is important to distinguish FHH patients from those with primary hyperparathyroidism because the hypercalcemia in FHH is generally benign and does not result in sequelae. Moreover, parathyroidectomy does not correct the hypercalcemia in FHH
Just follow up
C-FHH mutation in Ca SR
D)avid unnecessary parathyroidectomy
E)follow up as it is a benign condition
C: The Calcium-Creatinine ratio is 0.08.
The following article:
Urine Calcium: Laboratory Measurement and Clinical Utility
Kevin F. Foley, Lorenzo Boccuzzi Author Notes
Laboratory Medicine, Volume 41, Issue 11, November 2010, Pages 683 Published: 01 November 2010
It states the following:
Guidelines have been suggested stating that a CCCR of <0.010 implicates FHH, whereas a CCCR of >0.020 is highly suspicious of PH
Based on this I would go for a diagnosis of PHPT
D: FHH is a benign disease, and does not require a parathyroidectomy
E: I would do a parathyroid scintigram, and evaluate the 25(OH) levels – as work-up
for PHPT
C
Familial Hypocalciuric Hypercalcemia
in this condition there is mutation in the CaSR leading ultimately to decreased Ca secretion and hypercalcemia in addition to higher PTH
D
to avoid unnecessary Parathyroidectomy
E
Needs follow up, usually benign course
C. What is the most possible diagnosis? and pathophysiology?
the diagnosis is familial hypocalciuric hypercalcemia.
D. Why is it important to diagnose FHH?
to avoid parathyroidectomy that is needed only if it is primary hyperparathyroidism.
E. How would you treat this case?
benign condition need follow up and reassurance.
C. Familial hypocalciuric hypercalcimia :autosomal dominant mutation causes decrease Calcium sensing Receptor mediated calcium sensing, decrease excretion of Ca and Mg lead to hypercalcimia with increase PTH secretion.
D. To differentiate it from primary hyperparathyroidism.
E. Is a benign condition need follow up and reassurance
What is the most possible diagnosis? and pathophysiology?
Familial Hypocalciuric HypercalcemiaFamilial hypocalciuric hypercalcemia (FHH) is a rare autosomal dominant condition.
FHH is usually a benign condition in patients who have the heterozygous mutation. In most of the cases, familial hypocalciuric hypercalcemia (FHH1) results from loss-of-function mutations in the calcium-sensing receptor (CaSR) gene on the long arm of chromosome 3 (over 85%).
The patients with a homozygous mutation can have severe hypercalcemia with marked hyperparathyroidism, fractures, and failure to thrive.
Other rare cases of familial hypocalciuric hypercalcemia, FHH2 and FHH3 are linked to a mutation on chromosome 19. FHH linked to chromosome 19q13 is called the Oklahoma variant.
FHH can rarely be caused by autoantibodies directed against the calcium-sensing receptor leading to decreased calcium-sensing receptor (CaSR) activity.This type of FHH should be considered in case of a strong family history of autoimmune disorders.
The loss of function mutations in the (CaSR) gene in the parathyroid gland increases the set point for calcium sensing. It makes the parathyroid glands less sensitive to calcium, and a higher than normal serum calcium level is required to reduce PTH release. In the kidney, this defect leads to an increase in tubular calcium and magnesium reabsorption resulting in hypercalcemia, hypocalciuria, and frequently high normal levels of serum magnesium.
Why is it important to diagnose FHH?
To avoid unnecessary and expensive monitoring and unnecessary parathyroid exploration in the patient and relatives.
How would you treat this case?
Educating and reassuring the patient and affected family members about the benign nature of this condition.
Rarely, in a patient with atypical features, such as pancreatitis, total parathyroidectomy may be indicated to reduce the risk of further attacks of pancreatitis.
The CaSR represents a potentially important therapeutic target for FHH. Calcimimetics and calcilytics (CaSR antagonists) can play a pharmacological role in improving defective calcium sensing of the CaSR.
What is the most possible diagnosis? and pathophysiology?
This is a case of Familial Hypocalciuric Hypercalcemia
Familial Hypocalciuric Hypercalcemia(FHH) is due to due to dysfunction of the calcium-sensing receptor. Reduced function of the calcium-sensing receptor causes the parathyroid glands to falsely “sense” hypocalcemia and inappropriately release slightly excessive amounts of PTH, The renal tubule calcium-sensing receptors are also affected, causing hypo calciuria. it is characterized by hypercalcemia, hypocalciuria (usually less than 50 mg/24 h), variable hypermagnesemia, and normal or minimally elevated serum levels of PTH. It can be diagnosed with family history and urinary calcium determination.
Why is it important to diagnose FHH?
is to differentiate from primary hyperparathyroidism and avoid surgery
How would you treat this case?
FHH is usually benign and no need for any treatment observation is advised, calcimimetics are advised for severe cases.
C. What is the most possible diagnosis? and pathophysiology?
CCCR is 0.01, but I need to mention here that I am not sure when was the plasma Ca and creatinine were collected. I did my calculation based on available data.
Having 24 urine Ca, within normal, and CCCR 0.01, it is less likely FHH but still not conclusive for PHPT. I might repeat the test again. If my pretest probability for PHPT, will proceed with localization study, or If my pretest probability for FHH, will do nothing.
D. Why is it important to diagnose FHH?
FHH is a benign condition resulted from inactivation of CasR, causing less sensing to Calcium level leading to increase PTH secretion. PTH would not have a negative impact on bone, renal or CV system. Hence, no need to treat FHH either medically with cinacalcet or surgically with PTx.
E. How would you treat this case?
If proves to have PHPT, would recommend surgery as the patient is young.
If proves to have FHH, reassurance and no need for Rx.
What is the most possible diagnosis? and pathophysiology?
familial benign hypercalcemia.
D. Why is it important to diagnose FHH?
avoid parathyroidectomy.
E. How would you treat this case?
reassurance and follow up .
The possible diagnosis is FHH overlapped with PHPT
Pathophysiology
FHH caused by inactivation mutation in the calcium sensing receptor (CaSR) gene, which lead to general calcium-hyposensitivity, so compensatory hypercalcemia and hypocalciuria.
Autosomal dominant inheritance, similar to PHPT.
Treatment;
The condition usually does not require treatment as all cases are asymptomatic or have mild disease
exclude PHPT and assess level of 25(HO)vitD
C- the most possible diagnosis familial hypocalciuric hypercalcimia.dueto low level of 24 hr urinary ca.
The Pathophysiology of this condition
It is autosomal dominant a genetic disorder with mutation of the gens of CaSR, which sense as Serum Ca is always low and leads to increased kidney reabsorption of Ca, leading to hyperparathyroidism .
D- Important to diagnosis this condition to be differentisted from hyperparathyroidism and avoid surgery
C- treatment of these case follow up and reassurance
C. What is the most possible diagnosis? and pathophysiology?
This is a case of FHH Vs PHPT
Ca/creatinine ratio is 0.08. This is > 0,02. which supports the diagnosis of PHPH
The creatinine excretion of 1 gram needs to be repeated for confirmation. because 24-hour calcium is low, while ca /creatinine is > 0,02
FHH is an autosomal dominant genetic disorder due to a defect of extracellular calcium-sensing in the parathyroid glands as well as in the kidneys.
the set point at which extracellular calcium concentration is sensed and stimulates/inhibits PTH secretion is shifted to a higher level
UCCR is typically greater than 0.02 in PHPT patients and lower than 0.01 in FHH patients. Unfortunately, UCCR values can also overlap in FHH and PHPT patients and genetic testing may be required to distinguish these conditions.
D. Why is it important to diagnose FHH?
Differentiation between PHPT and FHH could prevent unnecessary surgery in FHH patients.
This patient is less than 40 years. Despite that, it is difficult to differentiate primary hyperparathyroidism from FHH. the key is, in this case, 24 hr ca excretion of less than 100 mg. the ratio of ca/creatinine help in differentiating (low as 0.1). Early detection. concomitant vitamin d deficiency may mask this (here, vitamin D is normal). calcium excretion may be low in the presence of primary hyperparathyroidism (when minimal).
What is the possible diagnosis? And pathophysiology?
This patient has low Ca in 24 hr urine Ca which is supposed to be between 100 to 300mg/24 hr , so in our patient, he has high serum Ca and low urine Ca which is in favor of FHH.
The Pathophysiology of this condition:
It is a genetic disorder with mutation of the gens of CaSR, which sense as Serum Ca is always low and leads to increased kidney reabsorption of Ca, leading to hyperparathyroidism .
Why is it important to diagnose FHH?
For misdiagnosis of primary hyperparathyroidism and avoid parathyroidectomy
How would you treat this case?
just follow up and conservative managment
I think if only for high serum calcium will lead to decrease PTh secretion no increase.
I think in this scenario the high PTH is due to downregulation of sensitivity of Calcium sensor receptor of parathyroid gland which lead to high PTH secretion in response to false sense of hypocalcemia
24-hour urinary calcium concentration hypocalciuria
Familial hypocalciuric hypercalcemia (FHH)
Abenign condition there is adefect in the caSR in the kidney and parathyroid glands
present with high plasma ca but low urinary ca with high or normal PTH
Observation and fu referre to endocrinology
C.Familial Hypocalciuric Hypercalcemia.excessive renal absorption of calcium. Excessive PTH Production.
Because CaSR are mutated . They sense calcium level always as ‘low’ and this will cause more renal reabsorption of calcium, +excessive secretion of PTH.
The patient has a low calcium in urine, what is not typical for hypercalcemia due to ingestion of calcium or vitamin d and not typical for primary hyperparathyroidism where
(I think we should also exclude if the patient on high sodium diet what cause also hypercalcemia due to paracellular renal calcium transition).
. The reference range is 100-300mg/24hours. It is higher than upper limit in primary hyperparathyroidism and lower than lower limit in FHH.
D. The therapy of pHPT is surgery and we don’t want this in the case of FHH
Case of primary hyperparathyroidism 1/1000.
Case of FHH 1/10.000(so ten times less frequent than pHPT)
E.Observation, may consider cinacalcet
C. What is the most possible diagnosis? and pathophysiology?
with low calcium urine ( less than 100pg/ml ) diagnosis : familial benign hypercalcemia.
D. Why is it important to diagnose FHH?
for misdiagnosis of primary hyperparathyroidism and avoid parathyroidectomy.
E. How would you treat this case?
benign disease no treatment
reassurance and follow up .
WITH HIGH S.CALCIUM EXPECTED HIGH CALCIUM EXCRETION WITH THIS FINDING MOSTLIKLY FAMILIAL HYPOCALCIURIC HYPERCALCEMIA WHICH IS AN INHERITED DISORDERS USUALY THOSE PEOPLE DO NOT HAVE ANY SYMPTOMS AND DIAGNOSED ONLY DURING INVESTIGATION FOR ANY OTHER REASON LIKE OUR PATIENT , IT IS IMPORTANT TO KONW IT AND TO REASSURE THE PATIENT THAT NO NEED FOR TREATMENT THIS IS IMPORTANT TO AVOID UNNECESSARY INVESTIGATION OR INTERVENTIONFOR PRIMARY HYPERPARA
fracrtional excretion of calcium 0.01 suggesting familial hypocalciuric hypercalcemia
this disorder is begnin and does nor require ttt
it is important to diagnose it to avoid misdiagnosis of 1ry hyperparathyroidism and unnecessary parathyroidectom
FHH
Genetic mutation in Casr leading to higher calcium required to suppress PTH
D- avoid parathyroidectomy
E reassurance consider cinecalcet if ca very high and genetic testing and counselling
C. What is the most possible diagnosis? and pathophysiology?
*This patient had low 24h urine calcium, and the ratio of 24h urinary calcium clearance to 24h urinary creatinine clearance = 80 mg/1000 mg = 0.08 which is < 0.01 and suggestive for FHH. Keep in mind ~20% of patients with FHH have ratio > 0.01 and the definitive diagnosis is by genetic testing.
D. Why is it important to diagnose FHH?
E. How would you treat this case?
C:
Familial hypocalciuric hypercalcemia
AD disease
Caused by inactivation mutation of CaSR
D:
important to diagnose FHH because it is a benign inherited disorder and not require parathyroidectomy
Family screening and education are mandatory to avoid unnecessary surgery in the hypercalcemic family members.
E:
Benign condition ,no treatment is necessary
Possible parathyroidectomy is considered in adult patient with relapsing pancreatitis and serum calcium level>14 mg/dl
C. What is the most possible diagnosis? and pathophysiology?
D. Why is it important to diagnose FHH?
E. How would you treat this case?