The patient was admitted to the hospital and was given intravenous magnesium sulfate. His serum magnesium levels steadily increased to normal levels. Five days later, the patient was discharged on oral magnesium for one week and was completely pain free.
C. Discuss the main mechanisms leading to hypomagnesemia.
D. Explain the possibility of hypomagnesemia in patients with renal tubular disorders and/or patients receiving diuretics.
CTALH defect: loop diuretics, Bartter syndrome, familial hypomagnesemia with hypercalcuria and nephrocalcinosis, CNI
-loop diuretics: inhibit NKCC2 cotransporter hence paracellular transport -Bartter syndrome: Mutation in ROMK(mediating apical K recycling) or NKCC2 or CIC or CaSR could inhibit passive paracellular Ca& Mg transport. -familial hypomagnesemia with hypercalcuria and nephrocalcinosis: mutation in genes encoding tight junction proteins claudin 16 &19 results in decreased electric voltage driving force controlling paracellular transport.
Decreased Na reabsorption results in increased distal reabsorption in CD in exchange with K and H, which results in associated hypokalemia and metabolic alkalosis
C Hypomagnesemia can be due to decreased intake, decreased absorption or renal losses
Intake can be relatedot die/ alchoholism / refeeding syndrome
Decreased absorption – diarrhoea, PPI use , Drugs affect mg carriers
Renal losses involving mg carrier proteins structure or genes defect impairing function
D Giltelman affect NA/Cl co transporter mutation in solute carrier 12 in thiazide sensitive Na/Cl transporter. low mg and hypocalciuria . mimicks thiazide diuretic
Bartter affect na/k/cl transporter
mimicks loop diuretic hypokalaemia and hypocalcaemia and sometimes low mg
both GS/Bartter have metabolic alkalosis with low k and normal BP
1-gastrointestinal or renal losses. GIT loss occurs either from upper or lower gastrointestinal tract or drug induced like proton pump inhibitors.
Urinary magnesium losses can be inappropriately increased by inhibition of sodium reabsorption in those segments in which magnesium transport passively follows that of sodium or, by a primary defect in renal tubular magnesium
2-Either Bartter syndrome (genetic defect of Na-K-2Cl cotransporter) or Loop diuretics (act by competing for the chloride site on the Na-K-2Cl cotransporter). Inhibiting sodium chloride reabsorption also inhibits the back leak of potassium and the generation of the lumen-positive potential, thereby decreasing the electrical gradient for magnesium reabsorption and increasing urinary magnesium excretion. Chronic administration of thiazides or the genetic absence of the Na-Cl cotransporters (Gitelman syndrome) reduces renal expression levels of TRPM6. This mechanism explains the magnesium wasting seen in Gitelman syndrome, in which a mutation in the distal tubule Na-Cl cotransporter produces a situation equivalent to continuous thiazide diuretic administration. Chronic administration of thiazides is frequently associated with negative potassium balance and hypokalemia. Hypokalemia may in turn directly inhibit distal tubular cell magnesium uptake, thereby increasing magnesium excretion. Potassium – sparing diuretics: sodium reabsorption by collecting tubule cells is electrogenic because positively charged sodium is reabsorbed without an anion, making the lumen electronegative. This creates an unfavorable electrical gradient that inhibits magnesium reabsorption. Potassium-sparing diuretics (amiloride, triamterene, and spironolactone) decrease sodium entry mediated by epithelial sodium channels in the collecting tubule and cortical collecting tubule, an effect that enhances magnesium reabsorption. Thus, these agents decrease magnesium excretion and can be used in resistant cases of hypomagnesemia (3
Magnesium wasting can be from the intestines or kidneys. Diarrhea and malabsorption lead to hypomagnesemia.
Hypomagnesiemia can be seen in Bartters and gittelman. In Bartters s. there is a genetic defect in Na-K-2Cl cotransporter in TAL resembling furosemide). In Gittelman the defect is in the Na-CL cotrasnpoters.
Magnesium deficiency may be due to nutritional deficiency, intestinal malabsorption, redistribution into bone, or losses via cutaneous, lower gastrointestinal, or renal routes. Approximately 25% of alcoholics are chronically hypomagnesemic because of a combination of poor nutritional intake and increased renal loss. Magnesium deficiency can occur, rarely, in protein-calorie malnutrition and may be associated with acute hypomagnesemia during refeeding because of rapid cellular magnesium uptake. Fat malabsorption in conditions such as celiac disease, Crohn disease, and small intestinal resection causes magnesium deficiency because free fatty acids accumulate in the intestinal lumen, where they combine with magnesium to form insoluble soaps. Proton pump inhibitors also can cause hypomagnesemia, primarily in patients concurrently using diuretics.1 This is thought to be due to inhibition of intestinal absorption. Lower gastrointestinal tract secretions are rich in magnesium, so diarrhea of colonic origin is a common cause of hypomagnesemia. Sweat contains significant amounts of magnesium, and transient hypomagnesemia can occur after prolonged, intense exercise such as marathon runs. Magnesium is also lost from burned skin surfaces, and 40% of patients with severe burns are hypomagnesemic. In patients with severe hyperparathyroidism and high bone
turnover, continued sequestration of minerals within bone may continue for several days after parathyroidectomy and cause transient hypocalcemia, hypomagnesemia, and hypophosphatemia. Renal magnesium losses can occur in any polyuric state, including the recovery phase of acute tubular necrosis or
urinary tract obstruction. Hypomagnesemia is common in diabetes mellitus in which it is thought to be due to a combination of poor intestinal absorption owing to autonomic neuropathy, osmotic diuresis, and decreased renal tubule reabsorption. Failure of sodium reabsorption in the thick ascending limb of Henle as a result of the use of loop diuretics and in the distal convoluted tubule as a result of thiazide diuretics inhibits tubular magnesium reabsorption and leads to urinary magnesium wasting. Drugs that are tubular toxins are also common causes of renal magnesium wasting. Such drugs include cisplatin, carboplatin, amphotericin B, and aminoglycosides, which are commonly associated with hypokalemia and rarely with renal tubule acidosis, as well as calcineurin inhibitors such as cyclosporine and tacrolimus, which also cause hyperkalemia. Antibodies to the epidermal growth factor receptor, such as cetuximab and panitumumab, which are used to treat metastatic colorectal cancer, downregulate a distal tubule magnesium channel and are an increasingly common cause of isolated severe hypomagnesemia.Inherited hypomagnesemia is usually caused by renal magnesium loss and
can be subdivided into three main types, depending on the coexistence of other electrolyte disturbances: Bartter and Gitelman syndromes, which are associated with renal salt wasting and hypokalemic metabolic alkalosis; familial hypomagnesemia with hypercalciuria and nephrocalcinosis; and isolated hypomagnesemia, which is usually associated with hypocalcemia.
Discuss the main mechanisms leading to hypomagnesemia.
There are two major mechanisms by which hypomagnesemia can be induced: gastrointestinal or renal losses. GIT loss occurs either from upper or lower gastrointestinal tract or drug induced like proton pump inhibitors.
Urinary magnesium losses can be inappropriately increased by inhibition of sodium reabsorption in those segments in which magnesium transport passively follows that of sodium or, by a primary defect in renal tubular magnesium reabsorption
Explain the possibility of hypomagnesemia in patients with renal tubular disorders and/or patients receiving diuretics. Either Bartter syndrome (genetic defect of Na-K-2Cl cotransporter) or Loop diuretics (act by competing for the chloride site on the Na-K-2Cl cotransporter). Inhibiting sodium chloride reabsorption also inhibits the back leak of potassium and the generation of the lumen-positive potential, thereby decreasing the electrical gradient for magnesium reabsorption and increasing urinary magnesium excretion. Chronic administration of thiazides or the genetic absence of the Na-Cl cotransporters (Gitelman syndrome) reduces renal expression levels of TRPM6. This mechanism explains the magnesium wasting seen in Gitelman syndrome, in which a mutation in the distal tubule Na-Cl cotransporter produces a situation equivalent to continuous thiazide diuretic administration. Chronic administration of thiazides is frequently associated with negative potassium balance and hypokalemia. Hypokalemia may in turn directly inhibit distal tubular cell magnesium uptake, thereby increasing magnesium excretion. Potassium – sparing diuretics: sodium reabsorption by collecting tubule cells is electrogenic because positively charged sodium is reabsorbed without an anion, making the lumen electronegative. This creates an unfavorable electrical gradient that inhibits magnesium reabsorption. Potassium-sparing diuretics (amiloride, triamterene, and spironolactone) decrease sodium entry mediated by epithelial sodium channels in the collecting tubule and cortical collecting tubule, an effect that enhances magnesium reabsorption. Thus, these agents decrease magnesium excretion and can be used in resistant cases of hypomagnesemia (3). The patient admitted that he was not eating vegetables at all. Instead, his diet was based upon pizza, chips, and soft drinks.
C- Git loss or renal loss
d- loops diuretic and thiazides can increase excretion electrolytes
and RtA due defects excration acid lead acidosis and more loss Mg
C. Discuss the main mechanisms leading to hypomagnesemia.
I didn’t get the question well.
There are many causes of hypomagnesemia such as; GI loss, renal loss, genetic causes Gitelman’s disease, bartter syndrome, renal tubular acidosis, and meds like PPI, and diuretics. D. Explain the possibility of hypomagnesemia in patients with renal tubular disorders and/or patients receiving diuretics.
In RTA, the kidneys may not be able to properly excrete acid, leading to a build-up of acid in the body. This can cause the kidneys to excrete excess magnesium along with the acid, resulting in low magnesium levels.
Diuretics increased urine output can lead to increase excretion of electrolytes, including magnesium. Loop diuretics, type of diuretics, are associated with hypomagnesemia due to their ability to inhibit the reabsorption of magnesium in the kidneys.
GIT loss due
Diarrhea, Vomiting, Gut surgery, Alcoholism
Renal and genetic
Metabolic acidosis, Hypokalemia, Hypophosphatemia
diuretics, aminoglycosides, ampho B, CNIs, Cisplatin Recovery phase from obstruction or ATN
Both Bartter’s and loop diuretics interfere with NKCC transporter and thus reduce lumen positivity, consequently Mg reabsorption via paracellular pathway in TALH
Discuss the main mechanisms leading to hypomagnesemia. GIT
Diarrhea
Vomiting
Malabsorption
Gut surgery
Pancreatitis
Alcohol
PPi
Mutation in TRMP6
Renal and genetic
Metabolic acidosis
Hypokalemia
Hypophosphatemi
Drugs: diuretics, aminoglycosides, ampho B, CNIs, Cisplatin
Recovery phase from obstruction or ATN
EGF receptor antagonists FHHNC caused by mutations in claudin-16 and claudin-19
Bartter’s syndrome is caused by mutations in NKCC2 (type 1), ROMK (type II), ClC-Kb (type III), or CaSR (type V)
Dominant hypomagnesemia caused by mutations of the FXYD2 gene, HNF1B, or CNNM2
Isolated dominant hypomagnesemia caused by mutations of Kv1.1
Isolated recessive hypomagnesemia caused by mutations of pro-EGF
Gitelman’s syndrome is caused by mutations of NCC
EAST/SeSAME caused by mutations in Kir4.1
Explain the possibility of hypomagnesemia in patients with renal tubular disorders and/or patients receiving diuretics.
Hypokalemia, hypomagnesemia, and hypocalcemia are all symptoms that may be caused by Bartter’s syndrome or loop diuretics.
Hypokalemia and hypomagnesemia may be caused by Gitelman’s syndrome or by thiazides, however, hypercalcemia will result
hypomagnesemia is not present in all patients with Bartter’s syndrome
C. Discuss the main mechanisms leading to hypomagnesemia.
There are two major mechanisms by which hypomagnesemia can be induced: gastrointestinal or renal losses D. Explain the possibility of hypomagnesemia in patients with renal tubular disorders and/or patients receiving diuretics.
Loop diuretics and thiazides are involved in increased Mg excretion.
Hypomagnesemia o Medications: Diuretics.Antibiotic; (aminoglycoside, amphotericin B, pentamidine, foscarnet).CyA and TAC.Platinum-based chemotherapy.EGFR receptor blocker (cetuximab, panitumumab, matuzumab).PPI. o Renal diseases: Chronic tubulointerstitial disease, Diuresis after ATN or obstruction.Osmotic diuresis.Renal tubular acidosis. o electrolyte abnormalities: Hypercalcemia.Hyperphosphatemia.Metabolic acidosis. o Gastrointestinal disease: Malabsorption. Diarrhea, vomiting, NG suction. Pancreatitis o Specific situation: Chronic alcoholism. DM, insulin, refeeding syndrome. Large volume transfusion. CRRT. Ethylene glycol intoxication. Sepsis Hypomagnesimia and renal tubular acidosis: RTA distal type whether complete or incomplete associated with hypomagnesemia. Hypomagnesemia and diuretics Loop diuretic: Reduce paracellular absorption of Mg in the thick ascending loop of Henle. Thiazide diuretic: Block the transcellular magnesium reabsorption of Mg. Combined use of loop and thiazide can aggravate more hypomagnesemi
D) Bartter syndrome
The electrical gradient in the thick ascending limb of the loop of Henle (TAL) generated by the active transport of sodium, potassium, and chloride by Na-K-Cl cotransporter (NKCC2) aids in the reabsorption of magnesium. Mutation in NKCC2 is seen in antenatal Bartter syndrome and leads to renal magnesium wasting and hypomagnesemia.
Loop diuretics : produce large increases in magnesium excretion through the inhibition of the electrical gradient necessary for magnesium reabsorption in the TAL. Long-term thiazide diuretic therapy also may cause magnesium deficiency, through enhanced magnesium excretion and, specifically, reduced renal expression levels of the epithelial magnesium channel TRPM6.
D: Renal Tubular Disorders causes mutations in the NKCC2 which leads to hypomagnesemia
Osmotic diuretics promote Mg excretion by predominantely inhibiting its reabsorption in Thich ascending limb of Henle(TALH) and also in the proximal tubule Loop diuretics inhibit Mg reabsorption in TALH and cause magnesuria Thiazide diuretics act in distal convulated tubules and increases Mg excretion
C .cause of hypomagnesemia are the loss of magnesium through the GIT due to chronic diarrhea, malnutrition, malabsorption syndrome, or the use of PPI.
Another cause is the loss of magnesium through the kidney due to tubular defects, such as those seen in Bartter’s syndrome or as a side effect of drugs like loop diuretics and thiazide .
D. Patients with renal tubular disorders or diuretic uses was
Mutation involves NKCC2 Chanel in thick ascending limb loop of henle lead to Mg wasting. Also occur in mutations involve ROMK, clc kb, and in Gitelman syndromes involve NCC channel in Distal convoluted tubule
*diuretic loop diuretic decrease the paracellular transport in thick limb loop of henle lead to Mg excretion
Thiazide diuretics blocks NCC channel in DCT lead to Mg wasting and hypomagnesemia.
C-mechanisms leading to hypomagnesemia
1-decreased intake
a-starvation
b-chronic alcoholism
C-protein caloric malnutrition
2-decreased intestinal absorption
Diarrhea
Prolonged nasogastric suction
Malabsorption
Excessive use of laxative
Intestinal and biliary fistula
Resection of small intestine
Familial hypomagnesemia with secondary hypocalcemia
3-increased urinary loss
A-inherited disorders of TALH
Familial hypomagnesemia with hypercalciuria and nephrocalcinosis
Familial hypomagnesemia with hypercalciuria and nephrocalcinosis and ocular manifestation
Bartter syndrome
B-inherited disorders of DCT
Familial hypomagnesemia with secondary hypocalcemia
Isolated recessive hypomagnesemia with normocalciuria
Isolated dominant hypomagnesemia with hpocalciuria
Loop diuretics inhibit chloride (Cl2) absorption by NKCC2 and also decrease basolateral Cl2 efflux. This re- sults in loss of lumen-positive potential, thereby decreasing the driving force for paracellular magnesium reabsorptionvia claudin-16 and claudin-19.
Thiazides diuretics enhance renal Na+ excretion through inhibition of the Na+-Cl– cotransporter (NCC) present in the apical membrane of distal convoluted tubule (DCT) cells.
C. HypoMg caused by the
*GIT loss like gastroenteritis, malabsorption, malnutrition, NG tube and others
*renal loss due to mutations defects involve protein or channel that are regulators of Mg like in familial hypoMg with hypercalciurea and NC, Bartter syndrome, Gitelman syndrome and others
Or use of diuretic like thiazide or loop diuretic
*drugs like aminoglycoside, amphotericin, immunosuppressive drugs
*hypokalemia
D. Mutation involves NKCC2 Chanel in thick ascending limb loop of henle lead to Mg wasting. Also occur in mutations involve ROMK, clc kb, and in Gitelman syndromes involve NCC channel in Distal convoluted tubule
*diuretic loop diuretic decrease the paracellular transport in thick limb loop of henle lead to Mg excretion
Thiazide diuretics blocks NCC channel in DCT lead to Mg wasting and hypomagnesemia
C. Discuss the main mechanisms leading to hypomagnesemia
GASTROINTESTINAL LOSSES:
More commonly due to diarrhoea than to vomiting (Mg content of lower tract secretions is significantly higher (up to 15 mEq/L versus approximately one mEq/L for upper tract).
Causes:
acute or chronic diarrhoea, malabsorption, and small bowel bypass surgery.
acute pancreatitis (saponification).
PPI (impaired Mg absorption by intestinal epithelial cells caused by PPI-induced inhibition of TRPM6 and TRPM7 channels).
RENAL LOSSES: Either acquired or intrinsic mechanisms
Causes:
medications
volume expansion
alcohol
uncontrolled DM
post-transplant
hyperCa (stimulation of CasR result in inhibition of ROMK and subsequent inhibition of NKCC2; resulting in reduced paracellular Ca and Mg reabsorption
tubular dysfunction.
D. Explain the possibility of hypomagnesemia in patients with renal tubular disorders and/or patients receiving diuretics.
LOOP DIURETICS:
Filtered NaCl enters the cells in the TAL via Na-K-2Cl cotransporters in the apical membrane.
Some of the reabsorbed potassium leaks back into the lumen to drive further NaCl transport.
This movement of cationic K+ makes the lumen relatively electropositive and creates an electrical gradient that promotes the passive paracellular reabsorption of Na and divalent cations (Mg and Ca).
Paracellular magnesium reabsorption appears to be facilitated by the tight junction proteins claudin-16 and -19.
Loop diuretics act by competing for the chloride site on the Na-K-2Cl cotransporter. Inhibiting NaCl reabsorption also inhibits the back leak of K and the generation of the lumen-positive associated with negative K+ balance and hypok.
HypoK may directly inhibit distal tubular cell Mg uptake, thereby increasing Mg excretion potential, decreasing the electrical gradient for Mg reabsorption and increasing urinary Mg excretion.
THIAZIDE DIURETICS:
In DCT Mg reabsorption occurs via a transcellular mechanism.
Filtered Mg enters the cells in DCT via TRPM6, reabsorption enhanced by the favorable electrochemical gradient across the luminal membrane.
Mg exits the cell in the basolateral membrane through a sodium-magnesium exchange. The driving force for this exchange is the low sodium concentration inside the cell (10 to 15 mEq/L) compared with that in the extracellular fluid, thereby favoring sodium entry and subsequent magnesium exit.
Thiazide-type diuretics decrease NaCl reabsorption in the distal tubule by inhibiting electroneutral Na-Cl cotransporters in the apical membrane that are responsible for the entry of luminal Na and Cl into the cell.
Acute thiazide administration results in increased Mg uptake, while chronic administration leads to Mg renal wasting through:
reduces kidney expression levels of TRPM6.
through a negative potassium balance and hypokalemia. Hypokalemia directly inhibits distal tubular cell magnesium uptake, thereby increasing magnesium excretion.
C. The main mechanisms that can cause hypomagnesemia are the loss of magnesium through the GIT due to chronic diarrhea, malnutrition, malabsorption syndrome, or the use of PPI.
Another cause is the loss of magnesium through the kidney due to tubular defects, such as those seen in Bartter’s syndrome or as a side effect of loop diuretics.
D. Patients with renal tubular disorders or those receiving diuretics are at risk of developing hypomagnesemia. This is because conditions like Bartter’s syndrome or the use of loop diuretics can cause not only hypokalemia and hypocalcemia but also hypomagnesemia. Similarly, patients with Gitelman’s syndrome or those using thiazides may also develop hypomagnesemia, along with hypokalemia, but may experience hypercalcemia instead of hypocalcemia.
C- 1-extra renal loss (mainly GIT) as bowel resection or PPI or nasogastric aspiration
2- renal loss either by osmotic polyuria as DKA and HHS or by direct and indirect inhibition of mg transport as in CNI , cisplatin , acidosis , loop and thiazide diuretics
3- familial with hypercalciuria associated with nephrocalcinosis and renal stones
D- main site for renal action on mg is thick ascending limb of loop of henle which is impaired in case of loop diuretics and cause hypomagnesemia
C. Discuss the main mechanisms leading to hypomagnesemia.
GIT loss due to chronic diarrhea, malnutrition, malabsorption syndrome, or PPI use.
Renal loss due to tubular defects as in Bartter’s syndrome or use of loop diuretics.
D. Explain the possibility of hypomagnesemia in patients with renal tubular disorders and/or patients receiving diuretics.
Hypokalemia, hypomagnesemia, and hypocalcemia are all symptoms that may be caused by Bartter’s syndrome or loop diuretics. Hypokalemia and hypomagnesemia may be caused by Gitelman’s syndrome or by thiazides, however, hypercalcemia will result .
C. Discuss the main mechanisms leading to hypomagnesemia.
Metabolic acidosis, Hypercalcemia
Phosphate depletion, Potassium depletion, Diuretics (loop and thiazide)
Antibiotics (aminoglycosides) Antifungals (amphotericin B) Antivirals (foscarnet) Chemotherapy agents (cisplatin) Immunosuppressants (tacrolimus, cyclosporine,
rapamycin)
EGF receptor antagonists FHHNC caused by mutations in claudin-16 and claudin-19
HSH is caused by mutations in TRPM6
Bartter’s syndrome is caused by mutations in NKCC2 (type 1), ROMK (type II), ClC-Kb (type III), or CaSR (type V)
Dominant hypomagnesemia caused by mutations of the FXYD2 gene, HNF1B, or CNNM2
Isolated dominant hypomagnesemia caused by mutations of Kv1.1
Isolated recessive hypomagnesemia caused by mutations of pro-EGF
Gitelman’s syndrome is caused by mutations of NCC
EAST/SeSAME caused by mutations in Kir4.1
D. Explain the possibility of hypomagnesemia in patients with renal tubular disorders and/or patients receiving diuretics.
Hypokalemia, hypomagnesemia, and hypocalcemia are all symptoms that may be caused by Bartter’s syndrome or loop diuretics.
Hypokalemia and hypomagnesemia may be caused by Gitelman’s syndrome or by thiazides, however, hypercalcemia will result.
The incidence of hypomagnesemia is more common in Gitelman than in Bartter.
GIT losses e.g., diarrhea, prolonged NG suction, intestinal surgery or malabsorption.
Pancreatitis
Alcohol abuse
C.Genetics ( rare)
Autosomal recessive familial hypomagnesamia with hypercalcuria and nephrocalcinosis (claudins 16, 19)
Hypomagnesamia with secondary hypocalcemia (TRPM 6 mutation)
Bartter’s syndrome (mutations in NKCC2, ROMK, CIC-KB, CaSR)
Dominant hypomagnesaemia (mutations in FXYD2 gene, HNF1B or CNNM2)
Isolated dominant hypomagnesamia (mutations in KV1.1)
Isolated recessive hypomagnesamia (mutations in pro-EGF)
Gitelman’s syndrome (mutations in NCC)
D. Explain the possibility of hypomagnesemia in patients with renal tubular disorders and/or patients receiving diuretics.
Loop diuretics’: inhibit NKCC2 & also decrease basolateral Cl- efflux. This results in loss of lumen-positive potential and thereby decreasing the driving force for paracellular Mg reabsorption via claudin 16 and claudin 19.
Barter’s syndrome = loop diuretics
Thiazide diuretics: this cause Hypo Mg by blocking the NCC. This transporter facilitate Mg reabsorption by generating Na gradients. The Na is transported from apical lumen into the cytosol and the absorbed Mg is then extruded via Mg/Na exchanger SLC4A1 family.
IF IT IS CORRECTED WITH REPLACEMENT AND NO DIARRHEA OR RENAL LOSSES OR MEDICATION THAT CAN CAUSED HYPOMAGNESEMIA THEN DETAILED HISTORY FOR HIS DIET AND FLUIED INTAKE , ? ALCOHOL ,
LOOP DIURETICS CAN CAUSED HYPOMAGNESEMIA , RTA CAN ALSO AFFECT THE MAGNESIUM BALANCE
C. Discuss the main mechanisms leading to hypomagnesemia.
volume expansion decrease PCT reabsorption of Mg .
acidosis increase Mg excretion by suppressing TRPM6 expression and activity
in DCT .
Metabolic alkalosis increase Mg reabsorption .
Cyclic AMP -mediated hormone as PTH increase Mg reabsorption .
mutation in claudin16 protein.
Explain the possibility of hypomagnesemia in patients with renal tubular disorders and/or patients receiving diuretics.
loop diuretic and Barter syndrome defect in NaK2CL PUMP in TALH cause hypokalemia, hypomagnesemia and hypocalcemia and hypercalciuria with hearing impairment.( SNHL).
defect in NaCL CO TRANSPORTER and TRPM6 CHANNELS .
thiazide and Gitelman S
hypokalemia, hypomagnesemia and hypocalciuria
Mutation of Nacl channels in collecting duct ( amiloride )
Hypomagnesemia occurs due to
-loop diuretics: inhibit NKCC2 cotransporter hence paracellular transport
-Bartter syndrome: Mutation in ROMK(mediating apical K recycling) or NKCC2 or CIC or CaSR could inhibit passive paracellular Ca& Mg transport.
-familial hypomagnesemia with hypercalcuria and nephrocalcinosis: mutation in
genes encoding tight junction proteins claudin 16 &19 results in decreased electric voltage driving force controlling paracellular transport.
Decreased Na reabsorption results in increased distal reabsorption in CD in exchange with K and H, which results in associated hypokalemia and metabolic alkalosis
C Hypomagnesemia can be due to decreased intake, decreased absorption or renal losses
Intake can be relatedot die/ alchoholism / refeeding syndrome
Decreased absorption – diarrhoea, PPI use , Drugs affect mg carriers
Renal losses involving mg carrier proteins structure or genes defect impairing function
D Giltelman affect NA/Cl co transporter mutation in solute carrier 12 in thiazide sensitive Na/Cl transporter. low mg and hypocalciuria . mimicks thiazide diuretic
Bartter affect na/k/cl transporter
mimicks loop diuretic hypokalaemia and hypocalcaemia and sometimes low mg
both GS/Bartter have metabolic alkalosis with low k and normal BP
1-gastrointestinal or renal losses. GIT loss occurs either from upper or lower gastrointestinal tract or drug induced like proton pump inhibitors.
Urinary magnesium losses can be inappropriately increased by inhibition of sodium reabsorption in those segments in which magnesium transport passively follows that of sodium or, by a primary defect in renal tubular magnesium
2-Either Bartter syndrome (genetic defect of Na-K-2Cl cotransporter) or Loop diuretics (act by competing for the chloride site on the Na-K-2Cl cotransporter). Inhibiting sodium chloride reabsorption also inhibits the back leak of potassium and the generation of the lumen-positive potential, thereby decreasing the electrical gradient for magnesium reabsorption and increasing urinary magnesium excretion.
Chronic administration of thiazides or the genetic absence of the Na-Cl cotransporters (Gitelman syndrome) reduces renal expression levels of TRPM6. This mechanism explains the magnesium wasting seen in Gitelman syndrome, in which a mutation in the distal tubule Na-Cl cotransporter produces a situation equivalent to continuous thiazide diuretic administration.
Chronic administration of thiazides is frequently associated with negative potassium balance and hypokalemia. Hypokalemia may in turn directly inhibit distal tubular cell magnesium uptake, thereby increasing magnesium excretion.
Potassium – sparing diuretics: sodium reabsorption by collecting tubule cells is electrogenic because positively charged sodium is reabsorbed without an anion, making the lumen electronegative. This creates an unfavorable electrical gradient that inhibits magnesium reabsorption. Potassium-sparing diuretics (amiloride, triamterene, and spironolactone) decrease sodium entry mediated by epithelial sodium channels in the collecting tubule and cortical collecting tubule, an effect that enhances magnesium reabsorption. Thus, these agents decrease magnesium excretion and can be used in resistant cases of hypomagnesemia (3
Magnesium wasting can be from the intestines or kidneys. Diarrhea and malabsorption lead to hypomagnesemia.
Hypomagnesiemia can be seen in Bartters and gittelman. In Bartters s. there is a genetic defect in Na-K-2Cl cotransporter in TAL resembling furosemide). In Gittelman the defect is in the Na-CL cotrasnpoters.
Discuss the main mechanisms leading to hypomagnesemia.
hypomagnesemia can be either due to GI loss or renal loss
or can be induced by PPI
Magnesium deficiency may be due to nutritional deficiency, intestinal malabsorption, redistribution into bone, or losses via cutaneous, lower gastrointestinal, or renal routes. Approximately 25% of alcoholics are chronically hypomagnesemic because of a combination of poor nutritional intake and increased renal loss. Magnesium deficiency can occur, rarely, in protein-calorie malnutrition and may be associated with acute hypomagnesemia during refeeding because of rapid cellular magnesium uptake. Fat malabsorption in conditions such as celiac disease, Crohn disease, and small intestinal resection causes magnesium deficiency because free fatty acids accumulate in the intestinal lumen, where they combine with magnesium to form insoluble soaps. Proton pump inhibitors also can cause hypomagnesemia, primarily in patients concurrently using diuretics.1 This is thought to be due to inhibition of intestinal absorption. Lower gastrointestinal tract secretions are rich in magnesium, so diarrhea of colonic origin is a common cause of hypomagnesemia. Sweat contains significant amounts of magnesium, and transient hypomagnesemia can occur after prolonged, intense exercise such as marathon runs. Magnesium is also lost from burned skin surfaces, and 40% of patients with severe burns are hypomagnesemic. In patients with severe hyperparathyroidism and high bone
turnover, continued sequestration of minerals within bone may continue for several days after parathyroidectomy and cause transient hypocalcemia, hypomagnesemia, and hypophosphatemia. Renal magnesium losses can occur in any polyuric state, including the recovery phase of acute tubular necrosis or
urinary tract obstruction. Hypomagnesemia is common in diabetes mellitus in which it is thought to be due to a combination of poor intestinal absorption owing to autonomic neuropathy, osmotic diuresis, and decreased renal tubule reabsorption. Failure of sodium reabsorption in the thick ascending limb of Henle as a result of the use of loop diuretics and in the distal convoluted tubule as a result of thiazide diuretics inhibits tubular magnesium reabsorption and leads to urinary magnesium wasting. Drugs that are tubular toxins are also common causes of renal magnesium wasting. Such drugs include cisplatin, carboplatin, amphotericin B, and aminoglycosides, which are commonly associated with hypokalemia and rarely with renal tubule acidosis, as well as calcineurin inhibitors such as cyclosporine and tacrolimus, which also cause hyperkalemia. Antibodies to the epidermal growth factor receptor, such as cetuximab and panitumumab, which are used to treat metastatic colorectal cancer, downregulate a distal tubule magnesium channel and are an increasingly common cause of isolated severe hypomagnesemia.Inherited hypomagnesemia is usually caused by renal magnesium loss and
can be subdivided into three main types, depending on the coexistence of other electrolyte disturbances: Bartter and Gitelman syndromes, which are associated with renal salt wasting and hypokalemic metabolic alkalosis; familial hypomagnesemia with hypercalciuria and nephrocalcinosis; and isolated hypomagnesemia, which is usually associated with hypocalcemia.
Model answer approved by the board:
Discuss the main mechanisms leading to hypomagnesemia.
There are two major mechanisms by which hypomagnesemia can be induced: gastrointestinal or renal losses. GIT loss occurs either from upper or lower gastrointestinal tract or drug induced like proton pump inhibitors.
Urinary magnesium losses can be inappropriately increased by inhibition of sodium reabsorption in those segments in which magnesium transport passively follows that of sodium or, by a primary defect in renal tubular magnesium reabsorption
Explain the possibility of hypomagnesemia in patients with renal tubular disorders and/or patients receiving diuretics.
Either Bartter syndrome (genetic defect of Na-K-2Cl cotransporter) or Loop diuretics (act by competing for the chloride site on the Na-K-2Cl cotransporter). Inhibiting sodium chloride reabsorption also inhibits the back leak of potassium and the generation of the lumen-positive potential, thereby decreasing the electrical gradient for magnesium reabsorption and increasing urinary magnesium excretion.
Chronic administration of thiazides or the genetic absence of the Na-Cl cotransporters (Gitelman syndrome) reduces renal expression levels of TRPM6. This mechanism explains the magnesium wasting seen in Gitelman syndrome, in which a mutation in the distal tubule Na-Cl cotransporter produces a situation equivalent to continuous thiazide diuretic administration.
Chronic administration of thiazides is frequently associated with negative potassium balance and hypokalemia. Hypokalemia may in turn directly inhibit distal tubular cell magnesium uptake, thereby increasing magnesium excretion.
Potassium – sparing diuretics: sodium reabsorption by collecting tubule cells is electrogenic because positively charged sodium is reabsorbed without an anion, making the lumen electronegative. This creates an unfavorable electrical gradient that inhibits magnesium reabsorption. Potassium-sparing diuretics (amiloride, triamterene, and spironolactone) decrease sodium entry mediated by epithelial sodium channels in the collecting tubule and cortical collecting tubule, an effect that enhances magnesium reabsorption. Thus, these agents decrease magnesium excretion and can be used in resistant cases of hypomagnesemia (3).
The patient admitted that he was not eating vegetables at all. Instead, his diet was based upon pizza, chips, and soft drinks.
C- Git loss or renal loss
d- loops diuretic and thiazides can increase excretion electrolytes
and RtA due defects excration acid lead acidosis and more loss Mg
C. Discuss the main mechanisms leading to hypomagnesemia.
I didn’t get the question well.
There are many causes of hypomagnesemia such as; GI loss, renal loss, genetic causes Gitelman’s disease, bartter syndrome, renal tubular acidosis, and meds like PPI, and diuretics.
D. Explain the possibility of hypomagnesemia in patients with renal tubular disorders and/or patients receiving diuretics.
In RTA, the kidneys may not be able to properly excrete acid, leading to a build-up of acid in the body. This can cause the kidneys to excrete excess magnesium along with the acid, resulting in low magnesium levels.
Diuretics increased urine output can lead to increase excretion of electrolytes, including magnesium. Loop diuretics, type of diuretics, are associated with hypomagnesemia due to their ability to inhibit the reabsorption of magnesium in the kidneys.
GIT loss due
Diarrhea, Vomiting, Gut surgery, Alcoholism
Renal and genetic
Metabolic acidosis, Hypokalemia, Hypophosphatemia
diuretics, aminoglycosides, ampho B, CNIs, Cisplatin Recovery phase from obstruction or ATN
Both Bartter’s and loop diuretics interfere with NKCC transporter and thus reduce lumen positivity, consequently Mg reabsorption via paracellular pathway in TALH
Discuss the main mechanisms leading to hypomagnesemia.
GIT
Diarrhea
Vomiting
Malabsorption
Gut surgery
Pancreatitis
Alcohol
PPi
Mutation in TRMP6
Renal and genetic
Metabolic acidosis
Hypokalemia
Hypophosphatemi
Drugs: diuretics, aminoglycosides, ampho B, CNIs, Cisplatin
Recovery phase from obstruction or ATN
EGF receptor antagonists FHHNC caused by mutations in claudin-16 and claudin-19
Bartter’s syndrome is caused by mutations in NKCC2 (type 1), ROMK (type II), ClC-Kb (type III), or CaSR (type V)
Dominant hypomagnesemia caused by mutations of the FXYD2 gene, HNF1B, or CNNM2
Isolated dominant hypomagnesemia caused by mutations of Kv1.1
Isolated recessive hypomagnesemia caused by mutations of pro-EGF
Gitelman’s syndrome is caused by mutations of NCC
EAST/SeSAME caused by mutations in Kir4.1
Explain the possibility of hypomagnesemia in patients with renal tubular disorders and/or patients receiving diuretics.
Hypokalemia, hypomagnesemia, and hypocalcemia are all symptoms that may be caused by Bartter’s syndrome or loop diuretics.
Hypokalemia and hypomagnesemia may be caused by Gitelman’s syndrome or by thiazides, however, hypercalcemia will result
hypomagnesemia is not present in all patients with Bartter’s syndrome
C. Discuss the main mechanisms leading to hypomagnesemia.
There are two major mechanisms by which hypomagnesemia can be induced: gastrointestinal or renal losses
D. Explain the possibility of hypomagnesemia in patients with renal tubular disorders and/or patients receiving diuretics.
Loop diuretics and thiazides are involved in increased Mg excretion.
Hypomagnesemia
o Medications: Diuretics. Antibiotic; (aminoglycoside, amphotericin B, pentamidine, foscarnet). CyA and TAC. Platinum-based chemotherapy. EGFR receptor blocker (cetuximab, panitumumab, matuzumab). PPI.
o Renal diseases: Chronic tubulointerstitial disease, Diuresis after ATN or obstruction. Osmotic diuresis. Renal tubular acidosis.
o electrolyte abnormalities: Hypercalcemia. Hyperphosphatemia. Metabolic acidosis.
o Gastrointestinal disease: Malabsorption. Diarrhea, vomiting, NG suction. Pancreatitis
o Specific situation: Chronic alcoholism. DM, insulin, refeeding syndrome. Large volume transfusion. CRRT. Ethylene glycol intoxication. Sepsis
Hypomagnesimia and renal tubular acidosis: RTA distal type whether complete or incomplete associated with hypomagnesemia.
Hypomagnesemia and diuretics
Loop diuretic: Reduce paracellular absorption of Mg in the thick ascending loop of Henle.
Thiazide diuretic: Block the transcellular magnesium reabsorption of Mg.
Combined use of loop and thiazide can aggravate more hypomagnesemi
C)Causes of hypomagnesemia related to decreased magnesium intake include the following
Causes related to the redistribution of magnesium from the extracellular to the intracellular space include the following:
Causes related to gastrointestinal magnesium loss include the following:
Hypomagnesemia due to renal magnesium loss can result from inherited renal tubular defects or medications, including the following:
D) Bartter syndrome
The electrical gradient in the thick ascending limb of the loop of Henle (TAL) generated by the active transport of sodium, potassium, and chloride by Na-K-Cl cotransporter (NKCC2) aids in the reabsorption of magnesium. Mutation in NKCC2 is seen in antenatal Bartter syndrome and leads to renal magnesium wasting and hypomagnesemia.
Loop diuretics : produce large increases in magnesium excretion through the inhibition of the electrical gradient necessary for magnesium reabsorption in the TAL.
Long-term thiazide diuretic therapy also may cause magnesium deficiency, through enhanced magnesium excretion and, specifically, reduced renal expression levels of the epithelial magnesium channel TRPM6.
C: Mechanisms underlying the development of Hypomagnesemia, includes:
D: Renal Tubular Disorders causes mutations in the NKCC2 which leads to hypomagnesemia
Osmotic diuretics promote Mg excretion by predominantely inhibiting its reabsorption in Thich ascending limb of Henle(TALH) and also in the proximal tubule
Loop diuretics inhibit Mg reabsorption in TALH and cause magnesuria
Thiazide diuretics act in distal convulated tubules and increases Mg excretion
C .cause of hypomagnesemia are the loss of magnesium through the GIT due to chronic diarrhea, malnutrition, malabsorption syndrome, or the use of PPI.
Another cause is the loss of magnesium through the kidney due to tubular defects, such as those seen in Bartter’s syndrome or as a side effect of drugs like loop diuretics and thiazide .
D. Patients with renal tubular disorders or diuretic uses was
Mutation involves NKCC2 Chanel in thick ascending limb loop of henle lead to Mg wasting. Also occur in mutations involve ROMK, clc kb, and in Gitelman syndromes involve NCC channel in Distal convoluted tubule
*diuretic loop diuretic decrease the paracellular transport in thick limb loop of henle lead to Mg excretion
Thiazide diuretics blocks NCC channel in DCT lead to Mg wasting and hypomagnesemia.
C-mechanisms leading to hypomagnesemia
1-decreased intake
a-starvation
b-chronic alcoholism
C-protein caloric malnutrition
2-decreased intestinal absorption
Diarrhea
Prolonged nasogastric suction
Malabsorption
Excessive use of laxative
Intestinal and biliary fistula
Resection of small intestine
Familial hypomagnesemia with secondary hypocalcemia
3-increased urinary loss
A-inherited disorders of TALH
Familial hypomagnesemia with hypercalciuria and nephrocalcinosis
Familial hypomagnesemia with hypercalciuria and nephrocalcinosis and ocular manifestation
Bartter syndrome
B-inherited disorders of DCT
Familial hypomagnesemia with secondary hypocalcemia
Isolated recessive hypomagnesemia with normocalciuria
Isolated dominant hypomagnesemia with hpocalciuria
4-acquired causes
Drugs
Loop diuretics disrupt tha NaK2cl channel
Thiazide prevent distal absorption of magnesium
Causes of hypomagnesemia related to decreased magnesium intake include the following :
Causes related to the redistribution of magnesium from the extracellular to the intracellular space include the following:
Causes related to gastrointestinal magnesium loss include the following:
Hypomagnesemia due to renal magnesium loss can result from inherited renal tubular defects or medications, [78] including the following:
Loop diuretics inhibit chloride (Cl2) absorption by NKCC2 and also decrease basolateral Cl2 efflux. This re- sults in loss of lumen-positive potential, thereby decreasing the driving force for paracellular magnesium reabsorptionvia claudin-16 and claudin-19.
Thiazides diuretics enhance renal Na+ excretion through inhibition of the Na+-Cl– cotransporter (NCC) present in the apical membrane of distal convoluted tubule (DCT) cells.
C. HypoMg caused by the
*GIT loss like gastroenteritis, malabsorption, malnutrition, NG tube and others
*renal loss due to mutations defects involve protein or channel that are regulators of Mg like in familial hypoMg with hypercalciurea and NC, Bartter syndrome, Gitelman syndrome and others
Or use of diuretic like thiazide or loop diuretic
*drugs like aminoglycoside, amphotericin, immunosuppressive drugs
*hypokalemia
D. Mutation involves NKCC2 Chanel in thick ascending limb loop of henle lead to Mg wasting. Also occur in mutations involve ROMK, clc kb, and in Gitelman syndromes involve NCC channel in Distal convoluted tubule
*diuretic loop diuretic decrease the paracellular transport in thick limb loop of henle lead to Mg excretion
Thiazide diuretics blocks NCC channel in DCT lead to Mg wasting and hypomagnesemia
C. Discuss the main mechanisms leading to hypomagnesemia
GASTROINTESTINAL LOSSES:
Causes:
RENAL LOSSES:
Either acquired or intrinsic mechanisms
Causes:
D. Explain the possibility of hypomagnesemia in patients with renal tubular disorders and/or patients receiving diuretics.
LOOP DIURETICS:
Loop diuretics act by competing for the chloride site on the Na-K-2Cl cotransporter. Inhibiting NaCl reabsorption also inhibits the back leak of K and the generation of the lumen-positive associated with negative K+ balance and hypok.
HypoK may directly inhibit distal tubular cell Mg uptake, thereby increasing Mg excretion potential, decreasing the electrical gradient for Mg reabsorption and increasing urinary Mg excretion.
THIAZIDE DIURETICS:
Thiazide-type diuretics decrease NaCl reabsorption in the distal tubule by inhibiting electroneutral Na-Cl cotransporters in the apical membrane that are responsible for the entry of luminal Na and Cl into the cell.
Acute thiazide administration results in increased Mg uptake, while chronic administration leads to Mg renal wasting through:
Hypomagnesemia; mechanism
2. Renal diseases
3. Other electrolyte abnormalities
4. Gastrointestinal disease
5. Specific situation
Hypomagnesimia and renal tubular acidosis
RTA distal type whether complete or incomplete associated with hypomagnesemia.
Hypomagnesemia and diuretics
Reduce paracellular absorption of Mg in the thick ascending loop of Henle.
Block the transcellular magnesium reabsorption of Mg.
C. The main mechanisms that can cause hypomagnesemia are the loss of magnesium through the GIT due to chronic diarrhea, malnutrition, malabsorption syndrome, or the use of PPI.
Another cause is the loss of magnesium through the kidney due to tubular defects, such as those seen in Bartter’s syndrome or as a side effect of loop diuretics.
D. Patients with renal tubular disorders or those receiving diuretics are at risk of developing hypomagnesemia. This is because conditions like Bartter’s syndrome or the use of loop diuretics can cause not only hypokalemia and hypocalcemia but also hypomagnesemia. Similarly, patients with Gitelman’s syndrome or those using thiazides may also develop hypomagnesemia, along with hypokalemia, but may experience hypercalcemia instead of hypocalcemia.
C- 1-extra renal loss (mainly GIT) as bowel resection or PPI or nasogastric aspiration
2- renal loss either by osmotic polyuria as DKA and HHS or by direct and indirect inhibition of mg transport as in CNI , cisplatin , acidosis , loop and thiazide diuretics
3- familial with hypercalciuria associated with nephrocalcinosis and renal stones
D- main site for renal action on mg is thick ascending limb of loop of henle which is impaired in case of loop diuretics and cause hypomagnesemia
C. Discuss the main mechanisms leading to hypomagnesemia.
D. Explain the possibility of hypomagnesemia in patients with renal tubular disorders and/or patients receiving diuretics.
Hypokalemia, hypomagnesemia, and hypocalcemia are all symptoms that may be caused by Bartter’s syndrome or loop diuretics.
Hypokalemia and hypomagnesemia may be caused by Gitelman’s syndrome or by thiazides, however, hypercalcemia will result .
C. Discuss the main mechanisms leading to hypomagnesemia.
Metabolic acidosis, Hypercalcemia
Phosphate depletion, Potassium depletion, Diuretics (loop and thiazide)
Antibiotics (aminoglycosides) Antifungals (amphotericin B) Antivirals (foscarnet) Chemotherapy agents (cisplatin) Immunosuppressants (tacrolimus, cyclosporine,
rapamycin)
EGF receptor antagonists FHHNC caused by mutations in claudin-16 and claudin-19
HSH is caused by mutations in TRPM6
Bartter’s syndrome is caused by mutations in NKCC2 (type 1), ROMK (type II), ClC-Kb (type III), or CaSR (type V)
Dominant hypomagnesemia caused by mutations of the FXYD2 gene, HNF1B, or CNNM2
Isolated dominant hypomagnesemia caused by mutations of Kv1.1
Isolated recessive hypomagnesemia caused by mutations of pro-EGF
Gitelman’s syndrome is caused by mutations of NCC
EAST/SeSAME caused by mutations in Kir4.1
D. Explain the possibility of hypomagnesemia in patients with renal tubular disorders and/or patients receiving diuretics.
Hypokalemia, hypomagnesemia, and hypocalcemia are all symptoms that may be caused by Bartter’s syndrome or loop diuretics.
Hypokalemia and hypomagnesemia may be caused by Gitelman’s syndrome or by thiazides, however, hypercalcemia will result.
The incidence of hypomagnesemia is more common in Gitelman than in Bartter.
Main mechanism is magnesium loos due to inhibition of Mg reabsorption in TAL
C. Discuss the main mechanisms leading to hypomagnesemia.
A. Renal
B.GUT
C.Genetics ( rare)
D. Explain the possibility of hypomagnesemia in patients with renal tubular disorders and/or patients receiving diuretics.
IF IT IS CORRECTED WITH REPLACEMENT AND NO DIARRHEA OR RENAL LOSSES OR MEDICATION THAT CAN CAUSED HYPOMAGNESEMIA THEN DETAILED HISTORY FOR HIS DIET AND FLUIED INTAKE , ? ALCOHOL ,
LOOP DIURETICS CAN CAUSED HYPOMAGNESEMIA , RTA CAN ALSO AFFECT THE MAGNESIUM BALANCE
C. Discuss the main mechanisms leading to hypomagnesemia.
Explain the possibility of hypomagnesemia in patients with renal tubular disorders and/or patients receiving diuretics.
loop diuretic and Barter syndrome
defect in NaK2CL PUMP in TALH cause hypokalemia, hypomagnesemia and hypocalcemia and hypercalciuria with hearing impairment.( SNHL).
defect in NaCL CO TRANSPORTER and TRPM6 CHANNELS .
thiazide and Gitelman S
hypokalemia, hypomagnesemia and hypocalciuria
Mutation of Nacl channels in collecting duct ( amiloride )
C. Discuss the main mechanisms leading to hypomagnesemia.
D. Explain the possibility of hypomagnesemia in patients with renal tubular disorders and/or patients receiving diuretics.
Great answers Dr. Ibrahim. Just note that maGnesium disorders are more with Gitelman than barter.