Accepted Article
Article type: Case Report
Severe hypomagnesemia and electrolyte disturbances induced by proton-pump inhibitors1 Matthew TURNOCK, Christian PAGNOUX, Kevin SHORE Department of Medicine, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada
Correspondence to: Christian PAGNOUX, Department of Medicine, Mount Sinai Hospital, University of Toronto, Room 2-220, 60 Murray Street, Toronto, ON, M5T 3L9,
Canada. Email: [email protected]
Conflicts of interest: none.
Running title: Hypomagnesemia caused by PPIs
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/1751-2980.12155 1 This article is protected by copyright. All rights reserved.
Accepted Article
INTRODUCTION The utility of proton-pump inhibitors (PPIs) to treat gastric acid-related disorders such as peptic ulcer, gastroesophageal reflux disease (GERD) and gastritis has increased drastically over the past decades.1–3 Unfortunately, PPIs are sometimes prescribed for
long-term use but in the absence of any reassessments, leading to an unnecessary overutilization of the drugs and a significant high medical cost burden to the healthcare system.4–6 Recent data has suggested that a long-term use of PPIs may be associated with an increased incidence of Clostridium difficile (C. difficile)-related diarrhea,7 increased
risk for osteoporosis-related fracture8 and gastric cancer through chronic gastric achlorhydria9. Hypomagnesemia, although less well-known, is another adverse event related to the chronic use of PPIs.10 PPIs-related hypomagnesemic hypoparathyroidism was first reported by Epstein et al. in 2006.11 Since then, several case reports have been published linking long-term PPI use with the episodes of symptomatic hypomagnesemia.1,3 A recent review of the United States Federal Drug Administration (U.S. FDA) Adverse Event Reporting System from 2004 to 2009 summerized 216 hypomagnesemic events related to omeprazole or esomeprazole use,5,10 which likely remains an underestimate of their true
incidence. As a result, the U.S. FDA issued a warning in 2011 announcing that long-term use of all PPIs could result in severe hypomagnesemia.12 Here we shared our experience
in a patient who was taking PPIs for several years and developed severe hypomagnesemia with associated hypocalcemia and hypokaliemia and discussed the
diagnostic challenges and differential diagnosis of this side effect and its management.
CASE REPORT An 84-year-old man was brought to the Department of Emergency of Mount Sinai Hospital, University of Toronto (Toronto, ON, Canada) due to progressive functional decline including worsening muscle cramps, fatigue, ankle pain, low mood during the preceding three months, and he developed watery diarrhea one week prior to his admission to the hospital. His past medical history was significant for hypertension, hyperlipidemia, gout, type 2 diabetes and GERD. His last gastroscopy was performed ten years ago, without showing 2 This article is protected by copyright. All rights reserved.
Accepted Article
any notable pathological findings. He was on a number of medications, including hydrochlorothiazide and pantoprazole (at a dose of 80 mg daily as, in the past, he had not tolerated dose reductions due to the worsening reflux symptoms), amlodipine, metoprolol, aspirin, metformin, atorvastatin, finasteride and tamsulosin, He was not taking any calcium supplementation, vitamin D or laxatives. There were no recent changes in any of his medications. On presentation, he was afebrile and hemodynamically stable, but appeared volume contraction and had a significant orthostatic drop in blood pressure (supine: 160/60 mmHg, standing: 120/50 mmHg). Cardiovascular, respiratory and abdominal physical examinations were normal. He was noted to have multifocal tremors in his arms and facial muscles and positive Trousseau and Chvostek signs. He also had tenderness along the inferior tip of the right lateral malleolus, but with no synovitis. Peripheral blood tests revealed hypomagnesemia (< 0.2 mmol/L; normal range 0.74–1.0 mmol/L), hypokalemia (3.0 mmol/L; normal range 3.5–5.0 mmol/L), hypocalcemia (1.58 mmol/L; normal range 2.2–2.6 mmol/L), with normal albumin (39 g/L; normal range 40–53 g/L), phosphate
(1.42 mmol/L; normal range 0.9–1.5 mmol/L) and creatinine levels (78 μmol/L; normal range 55–105 μmol/L). Complete blood count test including hemoglobin, white blood
cell and platelet counts, C-reactive protein (CRP) (4.7 mg/L [normal range: < 15 mg/L]) and thyroid stimulating hormone (TSH) (1.73 mIU/L [normal range 0.4–3.8 mIU/L]) were also within normal ranges. Chest X-ray examination was unremarkable and electrocardiography (ECG) showed sinus rhythm with a corrected QT interval at 439 ms.
The man was admitted to hospital and his electrolyte levels were gradually replaced intravenously with magnesium sulfate (initiated with a rapid 2 g infusion), calcium gluconate and normal saline with potassium chloride supplements. Hydrochlorothiazide and pantoprazole were discontinued. The following day, his urine specimen was collected, showing urine magnesium of 0.21 mmol/L and urine creatinine of 4.6 μmol/L. At the time these samples were collected, his plasma magnesium level was elevated to 0.27 mmol/L and plasma creatinine reduced to 69 μmol/L. Fractional excretion of magnesium
was calculated at 1.67%. On day 3, parathyroid hormone (PTH) was measured to be 7.8 pmol/L (normal range 1.6–6.9 pmol/L). Stool culture and C. difficile polymerase chain reaction (PCR) were both negative. 3 This article is protected by copyright. All rights reserved.
Accepted Article
With the therapy, his symptoms and signs were improved and he returned to his baseline cognitive and functional state by the third day in hospital. After discontinuing the intravenous electrolyte replacement, he was given oral magnesium gluconate 500 mg twice daily and calcium carbonate 1250 mg thrice daily. He was started on ranitidine instead of pantoprazole with good control of his gastroesophageal reflux symptoms and was discharged one week after admission with normal calcemia and kalemia and plasma magnesium of 0.7 mmol/L. One month later, after tapering his oral magnesium gluconate to 500 mg daily and calcium carbonate to 1250 mg daily, his plasma magnesium level was 0.80 mmol/L and remained stable thereafter.
DISCUSSION Our patient’s symptoms and signs, including muscle cramps, fatigue, low mood and positive Trousseau and Chvostek signs, were suggestive of hypocalcemia or hypomagnesemia, or both, as these disorders can present with similar cognitive, neuromuscular and electrophysiologic changes (Table 1). Our patient had right ankle arthralgia without effusion, which was not specific and was rapidly resolved with electrolyte replacement, suggesting that this symptom was possibly related to hypomagnesium-induced chondrocalcinosis.1,3,13 However, no joint aspiration was performed to confirm this diagnosis in the absence of overt or persistent joint effusion.
Hypomagnesemia of our patient was severe compared with mild to moderately reduced serum calcium (1.58 mmol/L) and potassium (3.0 mmol/L). Notably, hypomagnesemia can secondarily induce hypocalcemia via the suppression of PTH release10,14 and induction of PTH resistance15. In our case, PTH level was only slightly above the upper
limit of normal, which was considered an inappropriately near-normal value based on his
low calcium level. Potassium regulation is also affected by hypomagnesemia through uninhibited potassium secretion in the renal tubule.11,16 His recent diarrheal disease, likely coincidental and/or the result of viral gastroenteritis, may have contributed to the development of his electrolyte disorders and dehydration, but the degree of total body depletion, the initiation of other symptoms prior to the onset of diarrhea, its brief 24-h duration and a low fractional excretion of magnesium suggested a more chronic cause of magnesium malabsorption. Thiazide diuretic may also have played 4 This article is protected by copyright. All rights reserved.
Accepted Article
an aggravating role. However, thiazides typically do not induce hypocalcemia, but rather hypercalcemia. Hypomagnesemia is predominantly an acquired condition, the causes of which can be divided into impaired absorption or increased loss in either the gastrointestinal tract or renal systems. Our patient had a low fractional excretion of magnesium (1.67%), as observed at day 3 post-admission, suggesting malabsorption issues.4,17 In the absence of renal diseases or other overt causes of malabsorption, we therefore made a presumptive diagnosis of pantoprazole-induced hypomagnesemia. The sustained improvement of our patient’s electrolyte disorders following the discontinuation of pantoprazole and its substitution for ranitidine could also be considered indirect evidence for this infrequent but not widely known side effect of PPIs.
PPIs interfere with the intestinal absorption of magnesium.15,18 The precise mechanism is unknown but is believed to be due to the inhibition of transient receptor potential melastatin 6 (TRPM6), the transmembrane receptor protein channel that is responsible for active magnesium transport at low luminal concentrations.19 The isolated impact of PPIs on the TRPM6 transporters explains the observation of magnesium wasting in the absence of a general malabsorption syndrome. TRPM6 gene mutations may place certain individuals at a higher risk of this adverse medication effect.19 Polypharmacy, recent changes in longstanding medications and/or any other additional causes for magnesium loss might be the triggers, as likely in our patient. There is also evidence, but more conflicting, that PPI use impairs calcium absorption and decreases serum calcium levels.20 One recent review of published case reports from 2006 to 2011, in which the age of patients at diagnosis ranged from 30 to 83 years (mean 67.4 years), suggested that the incidence of hypomagnesemia was greater in women than men by a ratio of 2:1.3,6,21
In contrast, another review reported that gender, age and diuretic use did not determine the severity of magnesium depletion, which is often profound (magnesium level is commonly
Article type: Case Report
Severe hypomagnesemia and electrolyte disturbances induced by proton-pump inhibitors1 Matthew TURNOCK, Christian PAGNOUX, Kevin SHORE Department of Medicine, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada
Correspondence to: Christian PAGNOUX, Department of Medicine, Mount Sinai Hospital, University of Toronto, Room 2-220, 60 Murray Street, Toronto, ON, M5T 3L9,
Canada. Email: [email protected]
Conflicts of interest: none.
Running title: Hypomagnesemia caused by PPIs
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/1751-2980.12155 1 This article is protected by copyright. All rights reserved.
Accepted Article
INTRODUCTION The utility of proton-pump inhibitors (PPIs) to treat gastric acid-related disorders such as peptic ulcer, gastroesophageal reflux disease (GERD) and gastritis has increased drastically over the past decades.1–3 Unfortunately, PPIs are sometimes prescribed for
long-term use but in the absence of any reassessments, leading to an unnecessary overutilization of the drugs and a significant high medical cost burden to the healthcare system.4–6 Recent data has suggested that a long-term use of PPIs may be associated with an increased incidence of Clostridium difficile (C. difficile)-related diarrhea,7 increased
risk for osteoporosis-related fracture8 and gastric cancer through chronic gastric achlorhydria9. Hypomagnesemia, although less well-known, is another adverse event related to the chronic use of PPIs.10 PPIs-related hypomagnesemic hypoparathyroidism was first reported by Epstein et al. in 2006.11 Since then, several case reports have been published linking long-term PPI use with the episodes of symptomatic hypomagnesemia.1,3 A recent review of the United States Federal Drug Administration (U.S. FDA) Adverse Event Reporting System from 2004 to 2009 summerized 216 hypomagnesemic events related to omeprazole or esomeprazole use,5,10 which likely remains an underestimate of their true
incidence. As a result, the U.S. FDA issued a warning in 2011 announcing that long-term use of all PPIs could result in severe hypomagnesemia.12 Here we shared our experience
in a patient who was taking PPIs for several years and developed severe hypomagnesemia with associated hypocalcemia and hypokaliemia and discussed the
diagnostic challenges and differential diagnosis of this side effect and its management.
CASE REPORT An 84-year-old man was brought to the Department of Emergency of Mount Sinai Hospital, University of Toronto (Toronto, ON, Canada) due to progressive functional decline including worsening muscle cramps, fatigue, ankle pain, low mood during the preceding three months, and he developed watery diarrhea one week prior to his admission to the hospital. His past medical history was significant for hypertension, hyperlipidemia, gout, type 2 diabetes and GERD. His last gastroscopy was performed ten years ago, without showing 2 This article is protected by copyright. All rights reserved.
Accepted Article
any notable pathological findings. He was on a number of medications, including hydrochlorothiazide and pantoprazole (at a dose of 80 mg daily as, in the past, he had not tolerated dose reductions due to the worsening reflux symptoms), amlodipine, metoprolol, aspirin, metformin, atorvastatin, finasteride and tamsulosin, He was not taking any calcium supplementation, vitamin D or laxatives. There were no recent changes in any of his medications. On presentation, he was afebrile and hemodynamically stable, but appeared volume contraction and had a significant orthostatic drop in blood pressure (supine: 160/60 mmHg, standing: 120/50 mmHg). Cardiovascular, respiratory and abdominal physical examinations were normal. He was noted to have multifocal tremors in his arms and facial muscles and positive Trousseau and Chvostek signs. He also had tenderness along the inferior tip of the right lateral malleolus, but with no synovitis. Peripheral blood tests revealed hypomagnesemia (< 0.2 mmol/L; normal range 0.74–1.0 mmol/L), hypokalemia (3.0 mmol/L; normal range 3.5–5.0 mmol/L), hypocalcemia (1.58 mmol/L; normal range 2.2–2.6 mmol/L), with normal albumin (39 g/L; normal range 40–53 g/L), phosphate
(1.42 mmol/L; normal range 0.9–1.5 mmol/L) and creatinine levels (78 μmol/L; normal range 55–105 μmol/L). Complete blood count test including hemoglobin, white blood
cell and platelet counts, C-reactive protein (CRP) (4.7 mg/L [normal range: < 15 mg/L]) and thyroid stimulating hormone (TSH) (1.73 mIU/L [normal range 0.4–3.8 mIU/L]) were also within normal ranges. Chest X-ray examination was unremarkable and electrocardiography (ECG) showed sinus rhythm with a corrected QT interval at 439 ms.
The man was admitted to hospital and his electrolyte levels were gradually replaced intravenously with magnesium sulfate (initiated with a rapid 2 g infusion), calcium gluconate and normal saline with potassium chloride supplements. Hydrochlorothiazide and pantoprazole were discontinued. The following day, his urine specimen was collected, showing urine magnesium of 0.21 mmol/L and urine creatinine of 4.6 μmol/L. At the time these samples were collected, his plasma magnesium level was elevated to 0.27 mmol/L and plasma creatinine reduced to 69 μmol/L. Fractional excretion of magnesium
was calculated at 1.67%. On day 3, parathyroid hormone (PTH) was measured to be 7.8 pmol/L (normal range 1.6–6.9 pmol/L). Stool culture and C. difficile polymerase chain reaction (PCR) were both negative. 3 This article is protected by copyright. All rights reserved.
Accepted Article
With the therapy, his symptoms and signs were improved and he returned to his baseline cognitive and functional state by the third day in hospital. After discontinuing the intravenous electrolyte replacement, he was given oral magnesium gluconate 500 mg twice daily and calcium carbonate 1250 mg thrice daily. He was started on ranitidine instead of pantoprazole with good control of his gastroesophageal reflux symptoms and was discharged one week after admission with normal calcemia and kalemia and plasma magnesium of 0.7 mmol/L. One month later, after tapering his oral magnesium gluconate to 500 mg daily and calcium carbonate to 1250 mg daily, his plasma magnesium level was 0.80 mmol/L and remained stable thereafter.
DISCUSSION Our patient’s symptoms and signs, including muscle cramps, fatigue, low mood and positive Trousseau and Chvostek signs, were suggestive of hypocalcemia or hypomagnesemia, or both, as these disorders can present with similar cognitive, neuromuscular and electrophysiologic changes (Table 1). Our patient had right ankle arthralgia without effusion, which was not specific and was rapidly resolved with electrolyte replacement, suggesting that this symptom was possibly related to hypomagnesium-induced chondrocalcinosis.1,3,13 However, no joint aspiration was performed to confirm this diagnosis in the absence of overt or persistent joint effusion.
Hypomagnesemia of our patient was severe compared with mild to moderately reduced serum calcium (1.58 mmol/L) and potassium (3.0 mmol/L). Notably, hypomagnesemia can secondarily induce hypocalcemia via the suppression of PTH release10,14 and induction of PTH resistance15. In our case, PTH level was only slightly above the upper
limit of normal, which was considered an inappropriately near-normal value based on his
low calcium level. Potassium regulation is also affected by hypomagnesemia through uninhibited potassium secretion in the renal tubule.11,16 His recent diarrheal disease, likely coincidental and/or the result of viral gastroenteritis, may have contributed to the development of his electrolyte disorders and dehydration, but the degree of total body depletion, the initiation of other symptoms prior to the onset of diarrhea, its brief 24-h duration and a low fractional excretion of magnesium suggested a more chronic cause of magnesium malabsorption. Thiazide diuretic may also have played 4 This article is protected by copyright. All rights reserved.
Accepted Article
an aggravating role. However, thiazides typically do not induce hypocalcemia, but rather hypercalcemia. Hypomagnesemia is predominantly an acquired condition, the causes of which can be divided into impaired absorption or increased loss in either the gastrointestinal tract or renal systems. Our patient had a low fractional excretion of magnesium (1.67%), as observed at day 3 post-admission, suggesting malabsorption issues.4,17 In the absence of renal diseases or other overt causes of malabsorption, we therefore made a presumptive diagnosis of pantoprazole-induced hypomagnesemia. The sustained improvement of our patient’s electrolyte disorders following the discontinuation of pantoprazole and its substitution for ranitidine could also be considered indirect evidence for this infrequent but not widely known side effect of PPIs.
PPIs interfere with the intestinal absorption of magnesium.15,18 The precise mechanism is unknown but is believed to be due to the inhibition of transient receptor potential melastatin 6 (TRPM6), the transmembrane receptor protein channel that is responsible for active magnesium transport at low luminal concentrations.19 The isolated impact of PPIs on the TRPM6 transporters explains the observation of magnesium wasting in the absence of a general malabsorption syndrome. TRPM6 gene mutations may place certain individuals at a higher risk of this adverse medication effect.19 Polypharmacy, recent changes in longstanding medications and/or any other additional causes for magnesium loss might be the triggers, as likely in our patient. There is also evidence, but more conflicting, that PPI use impairs calcium absorption and decreases serum calcium levels.20 One recent review of published case reports from 2006 to 2011, in which the age of patients at diagnosis ranged from 30 to 83 years (mean 67.4 years), suggested that the incidence of hypomagnesemia was greater in women than men by a ratio of 2:1.3,6,21
In contrast, another review reported that gender, age and diuretic use did not determine the severity of magnesium depletion, which is often profound (magnesium level is commonly
