Case Study 1
You are asked to evaluate a family with a high incidence of hypercalciuria and nephrolithiasis, and you find that two children born to a sibling with hypercalciuria and nephrolithiasis died in early childhood of kidney failure and had nephrocalcinosis. An extensive work-up reveals that the family members affected with hypercalciuria also demonstrated hypermagnesuria.
Which one of the following is the most likely basis for this disorder?
- A.
Isolated recessive hypomagnesemia
- B.
Familial hypomagnesemia secondary to mutations in paracellin-1 gene
- C.
Familial defect in calcium-sensing receptor
- D.
Hypomagnesemia with secondary hypercalciuria associated with a defect in tubular transport of phosphate
- E.
Impaired proximal tubular oxalate transporter
The correct answer is B
Comment: Isolated recessive hypomagnesemia is not associated with hypercalciuria, and defects in the calcium-sensing receptor are not associated with nephrolithiasis or kidney failure in this fashion. Defects in the tubular reabsorption of phosphate are associated with hypocalcemia. An abnormality in oxalate transport would not produce hypercalciuria. The combination of hypomagnesemia, hypercalciuria, nephrocalcinosis, and kidney failure suggests the presence of familiar hypomagnesemia due to paracellin-1 gene mutation, a tight-junction protein-mediating paracellular transport.
Case Study 2
A 16-year-old girl complained of easy fatigability and generalized muscle weakness. She denied vomiting or the use of any medications. Physical examination revealed a thin anxious girl with a normal blood pressure. Her examination was otherwise unremarkable. Her serum sodium was 141 mmol/L; potassium, 2.1 mmol/L; chloride, 85 mmol/L; bicarbonate, 45 mmol/L; calcium, 9.5 mg/dL (reference: 8.5 to 10.3 mg/dL); phosphate, 3.2 mg/dL (reference: 2.8 to 4.5 mg/dL); magnesium, 1.2 mg/dL (reference: 1.8 to 2.3 mg/dL); and albumin, 4.6 g/dL (reference: 3.5 to 5.0 g/dL).
Which of the following statements is true? (Select all that may apply)
- A.
Hypokalemia can alter the renal handling of magnesium and cause hypomagnesemia
- B.
Hypomagnesemia can alter the renal handling of potassium and cause hypokalemia
- C.
Both statements are true
- D.
Neither statement is true
The correct answer is B
Comment: Magnesium is required for adequate renal health handling of potassium. Hypomagnesemia can cause hypokalemia because of the increased urinary loss of potassium, likely by opening potassium channels in the thick ascending loop of Henle. This may become apparent when hypokalemia persists despite potassium supplementation.
Case Study 3
Which of the following studies would be the best initial laboratory to determine the cause of the hypomagnesemia in this patient? (Select all that apply)
- A.
Urine diuretic screen
- B.
Plasma renin and aldosterone levels
- C.
Plasma cortisol level
- D.
Twenty-four-hour urine for potassium and aldosterone levels
- E.
Twenty-four-hour urine for magnesium, calcium, chloride, and creatinine levels
The correct answers are A and E
Comment: The findings of hypokalemia, metabolic alkalosis, and a normal blood pressure suggest the diagnosis of secondary hyperaldosteronism, vomiting, diuretic abuse, Bartter syndrome, or Gitelman syndrome. Measurement of urinary chloride, calcium, and magnesium is useful in the differentiation between these disorders. The urinary chloride concentration is typically less than 15 mmol/L in hypovolemia due to surreptitious vomiting. In contrast, a urinary chloride greater than 15 mmol/L suggests diuretic abuse, Bartter syndrome, or Gitelman syndrome. Measurement of the urine calcium will help to distinguish between Bartter syndrome and Gitelman syndrome. Screening urine for diuretics is indicated if surreptitious ingestion is suspected. Measurement of the urinary magnesium will help to distinguish between gastrointestinal (GI) and renal losses as the major contributor.
Case Study 4
The fractional excretion of magnesium was 6.5%, the urine chloride was 56 mEq/L, and the urine calcium-creatinine ratio was 3.2 (reference range: < 0.22).
What is the most likely diagnosis now? (Select all that apply)
- A.
Bartter syndrome
- B.
Primary hyperaldosteronism
- C.
Loop diuretic abuse
- D.
Apparent mineralocorticoid excess
- E.
Liddle syndrome
- F.
Gitelman syndrome
The correct answers are A and C
Comment: Bartter syndrome can cause hypokalemia, metabolic alkalosis, and renal magnesium wasting, and hypomagnesemia without hypertension in a manner similar to that of loop diuretics.
Bartter syndrome is caused by mutations in a furosemide-sensitive ion transport mechanism in the loop of Henle and is associated with hypercalciuria.
Case Study 5
Which study would you like now to differentiate between Bartter syndrome and diuretic abuse?
- A.
Plasma renin activity and plasma aldosterone level
- B.
Twenty-four-hour urine for calcium, magnesium, and creatinine
- C.
Twenty-four-hour urine for sodium, potassium, and creatinine
- D.
Urine diuretic screen
The correct answer is D
Comment: A diuretic screen is the only way to rule out diuretic abuse. The diuretic screen was negative.
Case Study 6
Suppose the laboratory staff call to tell you that the urinary calcium–creatinine ratio was misreported and the correct value is 0.20, not 3.2.
What is the most likely diagnosis now?
- A.
Gitelman syndrome
- B.
Bartter syndrome
- C.
Primary hyperparathyroidism
- D.
Isolated recessive renal magnesium wasting
The correct answer is A
Comment: Gitelman syndrome is the only condition among the above, which is associated with hypocalciuria. Gitelman syndrome is a variant of Bartter syndrome, characterized by hypokalemia, metabolic alkalosis, hypomagnesemia, renal magnesium wasting, and normal blood pressure. Gitelman syndrome is caused by loss-of-function mutations in a thiazide-sensitive ion transport mechanism in the distal nephron and is associated with hypocalciuria. Bartter syndrome and primary hyperparathyroidism are associated with hypercalciuria. Isolated recessive magnesium wasting is characterized by renal magnesium wasting in the absence of hypocalcemia or hypercalciuria.
Case Study 7
Which of the following would be most beneficial therapeutic effects in a patient with Gitelman syndrome? (Select all that apply)
- A.
Thiazide diuretics
- B.
Potassium-sparing diuretics
- C.
Low-salt diet
- D.
Oral magnesium and potassium supplementation
- E.
Loop diuretic
The correct answers are B and D
Comment: Magnesium supplements are typically necessary to increase the serum magnesium and the serum potassium concentrations. Amiloride can be very useful in this condition, because it may help to enhance distal tubular reabsorption of magnesium, as well as inhibit potassium secretion. She was treated with magnesium and potassium supplementation and amiloride. Serum potassium level improved to 3.2 mEq/L and serum magnesium level rose to 2.2 mg/dL. Six months later, she was brought to the emergency department because of shock due to internal bleeding as a result of automobile accident. She received 7 units of blood transfusion and underwent repair of hepatic laceration. She was oliguric post operation for 4 days. The laboratory data revealed a hemoglobin of 12.6 g/dL; blood urea nitrogen (BUN), 55 mg/dL; serum creatinine, 3.9 mg/dL; serum sodium, 137 mmol/L; serum chloride, 95 mmol/L; serum potassium, 4.9 mmol/L; serum bicarbonate, 20 mmol/L; serum calcium, 5.5 mg/dL; serum phosphate, 5.5 mg/dL; and serum albumin, 3.9 g/dL. Urinalysis showed trace protein, negative for blood and glucose. The electrocardiography showed significant prolongation of the QT interval.
Case Study 8
What should be done next to define the likely cause of the hypocalcemia?
- A.
Draw blood for a parathyroid hormone (PTH) assay
- B.
Give intravenous magnesium
- C.
Draw blood for a plasma magnesium level
- D.
Draw blood for a calcidiol level
- E.
Draw blood for a calcitriol level
The correct answer is C
Comment: Hypermagnesemia can suppress parathyroid hormone level and can cause hypocalcemia. Checking the plasma magnesium level to look for hypermagnesemia as the cause of hypocalcemia is the best choice in this situation. The plasma magnesium level was 5.8 mg/dL. The physician in the emergency department rechecked her medications and realized that no one had discontinued the supplemental magnesium that she was receiving for Gitelman syndrome. Thus, hypermagnesemia and subsequent hypocalcemia may have ensued when she developed acute kidney failure. Hemodialysis was instituted and the magnesium supplements were discontinued. Hypermagnesemia resolved and hemodialysis was discontinued after two treatments. Serum creatinine level slowly returned to normal level over 7 days. She was subsequently returned on magnesium supplements.
Case Study 9
You are asked to see a 19-year-old woman complaining of cramps and tightening in her throat. Past medical history is significant for mild hypertension for which she is being treated with hydrochlorothiazide, 12.5 mg/day. She had a total thyroidectomy for a large toxic, multinodular goiter 6 months earlier and is maintained on 1-thyroxine, 100 μg/day. Bone densitometry was consistent with osteoporosis, and she was started on alendronate, 10 mg/day. Five days prior to admission, she began to note intermittent severe cramps in her hands and feet. On the day of admission, she noted some tightening in her throat and came to the emergency room. She denies the use of any other medications or over-the counter supplements. On examination, her blood pressure is 140/86 mmHg; pulse, 86 beats/min; respiration, 12 breaths/min; temperature, 37°C; weight, 52.5 kg; and height, 159 cm. The rest of the physical examination revealed no abnormal sign. Laboratory studies revealed a hemoglobin of 13.0 g/L; leukocyte count, 5.1 × 10 9 /L; sodium, 138 mmol/L; potassium, 4.1 mmol/L; chloride, 100 mmol/L; bicarbonate, 27 mmol/L; blood urea nitrogen, 6 mg/dL; creatinine, 0.7 mg/dL; calcium, 7.3 mg/dL (reference range: 8.5 to 10.3 mg/dL); phosphate, 6.3 mg/dL (reference range: 2.8 to 4.5 mg/dL); magnesium, 1.5 mg/dL (reference range: 1.8 to 2.3 mg/dL); and albumin, 4.2 g/dL (reference range: 3.5 to 5.0 g/dL). Urinalysis showed trace protein, and it was negative for glucose and blood. Her electrocardiography showed prolonged QT intervals.
What would you do at this point? (Select all that apply)
- A.
Draw parathyroid hormone level
- B.
Draw serum magnesium level
- C.
Draw calcitriol level
- D.
Draw calcidiol level
- E.
Give intravenous magnesium
The correct answers are A, B, and E
Comment: The combination of hypocalcemia and hypomagnesemia in the absence of kidney failure certainly suggests the presence of hypoparathyroidism. Hypomagnesemia can cause suppression of parathyroid hormone secretion and/or resistance to parathyroid hormone and produce acute hypocalcemia. It is appropriate to consider this and draw a serum magnesium level. In the absence of renal insufficiency, magnesium infusion is safe and reasonable while waiting for the results to come back from the laboratory. She remained symptomatic despite the intravenous magnesium administration. However, she responded to intravenous calcium and experienced relief of her acute symptoms. Her laboratory studies, which were obtained in the emergency department, returned as follows: PTH 15 ng/mL and serum magnesium 2.0 mg/dL.
Case Study 10
What is the primary diagnosis?
- A.
Hypoparathyroidism
- B.
Alendronate toxicity
- C.
Vitamin D deficiency
- D.
Hypomagnesemia
- E.
Pseudohypoparathyroidism
The correct answer is A
Comment: She has hypocalcemia and a parathyroid hormone value that is inappropriately in the low-normal range, consistent with hyperparathyroidism. She likely had subclinical hypoparathyroidism that was undiagnosed and that now has been masked by alendronate therapy.
Case Study 11
A 16-year-old girl presented for evaluation of severe hypomagnesemia of more than 10 years’ duration (average serum magnesium concentration, 1.1; range, 0.5 to 2.8 mg/dL). She has a history of psychiatric disorders, including major depression, attention-deficit/hyperactivity disorder, anorexia nervosa, and past laxative abuse. Hypokalemia has rarely accompanied the hypomagnesemia (average serum potassium concentration, 4.0 (range, 3.4 to 4.8 mmol/L). There is no family history of renal or electrolyte disorders. She does not use tobacco, alcohol, or illicit substances. Based on psychiatric history, hypomagnesemia had previously been attributed to suspected surreptitious diuretic use. She denies vomiting, diuretic or laxative abuse, recent weight change, or diarrhea despite high-dose oral magnesium supplementation. Her concerns were diffuse myalgia and paresthesias of the upper extremities, upper back, neck, and thighs.
Relevant medications included intravenous magnesium sulfate infusions twice weekly and oral magnesium oxide, 4800 mg total daily dose. Examination revealed heart rate of 100 beats/min, blood pressure of 102/66 mmHg, body mass index of 23.4 kg/m 2 , and afebrile temperature. She had diffuse tenderness to neck and upper-back palpation. Chvostek sign was negative.
Serum chemistry revealed sodium 136 mmol/L, potassium 4.3 mmol/L, chloride 98 mmol/L, bicarbonate 31 mmol/L, BUN 31 mg/dL, creatinine 1.1 mg/dL, magnesium 1.0 mg/dL, calcium 9.1 mg/dL, phosphorous 3.5 mg/dL, albumin 4.1 g/dL, parathyroid hormone (PTH) 31 pg/dL, and 25-hydroxyvitamin D 30 ng/mL. A 24-hour urine collection showed hypermagnesuria (magnesium excretion, 50 mg) and likely hypocalciuria (calcium excretion, 59 mg). Fractional excretion of magnesium was 10.6%. Renal ultrasound revealed a 1.2-cm simple left upper pole cyst.
What is the most likely cause of hypomagnesemia in this patient?
- A.
Hypomagnesemia related to Bartter syndrome
- B.
Hypomagnesemia related to Gitelman syndrome
- C.
Isolated dominant hypomagnesemia
- D.
Autosomal dominant tubulointerstitial kidney disease (ADTKD)
The correct answers are A, B, C, and D
Comment: Hypomagnesemia is broadly classified by either excessive gastrointestinal or renal losses. Gastrointestinal causes include those caused by short bowel and gastric bypass surgeries, malabsorption syndromes, and medications such as laxatives and proton pump inhibitors. Renal causes consist of processes that increase filtration or interfere with the reabsorption of magnesium along the nephron. These include an array of medications, most notably thiazide and loop diuretics, as well as aminoglycosides, amphotericin, pentamidine, cisplatin, calcineurin inhibitors, and antibodies targeting epidermal growth factors. Genetic causes of renal magnesium losses include Bartter and Gitelman syndromes.
Case Study 12
What is the likely mechanism of hypomagnesemia in this patient?
- A.
Isolated dominant hypomagnesemia
- B.
Autosomal dominant tubulointerstitial kidney disease (ADTKD)
- C.
Gitelman syndrome
- D.
Bartter syndrome
The correct answers are A and B
Comment: The patient denied laxative abuse or diarrhea and was not taking medications that interfere with gastrointestinal magnesium absorption, such as a proton pump inhibitor. A renal magnesium wasting disorder was therefore considered and supported by elevated fractional excretion of magnesium (10.6%) despite a low serum magnesium concentration. The diuretic screen was negative. A genetic disorder was suspected. Classic Gitelman syndrome seemed less likely as the cause in the absence of hypokalemia, but a variant was considered.
Case Study 13
What diagnostic studies would you now order?
- A.
Genetic testing
- B.
Twenty-four-hour urine collection for potassium
- C.
Twenty-four-hour urine collection for magnesium
- D.
Malabsorption syndrome
The correct answer is A
Genetic testing revealed a heterozygous hepatocyte nuclear factor 1β(HNF1B) whole-gene deletion located on chromosome 17q12, which encodes a transcription factor involved in multisystem organogenesis. The variant is inherited in an autosomal dominant tubulointerstitial kidney disease (ADTKD) or de novo pattern. It manifests with a wide array of phenotypes, including hypomagnesemia, and is frequently associated with maturity-onset diabetes type 5. In one cohort, there was a 62% prevalence of hypomagnesemia associated with HNF1B mutations. Although not well understood, the encoded protein is thought to affect distal tubule magnesium handling. Although this patient’s presentation is atypical given the lack of notable organ system developmental abnormalities, it is intriguing to consider her psychiatric disease as a potential component of the phenotype, given reported associations. The finding did not alter treatment. However, confirming a diagnosis accorded the patient’s clinical and emotional validation, prevented further specialist referral and repetitive workup, and ultimately strengthened the patient-clinician relationship by promoting trust.
Case Study 14
A 1-month-old male infant was admitted to the hospital with a history of recurrent convulsive seizures of 2 weeks duration. He was born at term (40-week gestation) at a normal birth weight of 2.76 kg following an uneventful pregnancy. He was the first child of healthy parents; there was no history of consanguinity. The infant was well until the 14th day of life when he developed convulsive seizures. On admission, the physicians observed tetanic manifestations, such as carpopedal spasms and convulsive seizures. The patient’s serum calcium level was 5.0 mg/dL (normal range 8.0 to 10.5 mg/dL), and the inorganic phosphate level was 6.2 mg/dL (normal range 2.5 to 4.5 mg/dL). Calcium gluconate and parathyroid hormone (PTH) were administered intramuscularly in high doses, but the tetanic convulsions did not resolve. At that time, the serum magnesium level was measured and found to be extremely low at 0.16 mmol/L (normal range 1.44 to 1.81 mmol/L). The urinary excretion of magnesium was also low at 0.13 mEq/day (normal 0.31 mEq/L).
Parenteral magnesium therapy (8 mmol/day) was started. After a few days, the serum concentrations of magnesium and calcium increased to nearly normal levels, and the tetanic manifestations disappeared completely. Oral magnesium therapy (magnesium chloride 1 mmol/kg/day) has been continued without any further tetanic manifestations. The magnesium supplement was discontinued on two occasions, and the tetanic convulsions reappeared promptly.
The fractional excretion of magnesium for this patient was 2.7% despite a very low level of serum magnesium (normal range 2.1% to 14.3% in normagnesemic individuals but is close to 0 if there is permanent depletion of magnesium), indicating the presence of a renal magnesium leak. The intestinal absorption of magnesium [(Mg in stool/Mg intake) × 100 (%)] was lower (19.6%) than the amount of absorption observed in people with normal levels of magnesium (50.2%). The serum calcium and magnesium levels of the parents were within normal limits.
What is the most likely cause of hypomagnesemia in this child?
- A.
Hypomagnesemia related to Bartter syndrome
- B.
Hypomagnesemia related to Gitelman syndrome
- C.
Hypomagnesemia related to tubulointerstitial disease
- D.
Hypomagnesemia with secondary hypocalcemia (HSH) due to TRPM6 mutation
The correct answer is D
Comment: HSH, also known as primary infantile hypomagnesemia or hypomagnesemic tetany, is a rare autosomal recessive disease characterized by profound hypomagnesemia associated with hypocalcemia. The basic abnormality in the condition is defective intestinal absorption of magnesium, usually associated with a tendency toward renal magnesium wasting. This condition usually presents during the newborn period. In affected individuals, hypocalcemia is caused by an impaired response to parathyroid hormone (PTH). Patients with HSH usually present during the first few months of life with symptoms of hypocalcemia including recurrent seizures and other symptoms of increased neuromuscular excitability (cramps, tetany) that fail to respond to Ca therapy. This condition usually requires life-long, high-dose Mg supplementation, which corrects both the hypocalcemia and the hypomagnesemia. The diagnosis of HSH can be challenging for pediatricians because the condition is rare, the symptoms are nonspecific, and it is associated with more common metabolic diseases, including hypocalcemia. As a result, late diagnoses or misdiagnoses have been reported in some patients. If an early diagnosis cannot be made or the treatment is not initiated immediately, any convulsions may be fatal or may result in chronic, irreversible neurological complications. Some patients develop moderate mental retardation and a failure to thrive, associated with pronounced diarrhea.
Hypomagnesemia in infancy can also be secondary to malabsorption, persistent diarrhea, or short-bowel syndrome. However, in these situations, the hereditary magnesium-losing disorders (Gitelman syndrome, isolated recessive hypomagnesemia, autosomal dominant hypocalcemia, autosomal dominant hypoparathyroidism, familial hypocalciuric hypercalcemia, and familial hypomagnesemia with hypercalciuria/nephrocalcinosis) should also be considered as potential diagnoses.
The treatment of HSH is administration of magnesium. At diagnosis, parenteral administration is preferred, whereas maintenance therapy consists of high doses orally. Some patients may need parenteral courses, particularly during hypomagnesemia outbreaks. Monthly IV infusions of magnesium may also be useful in some patients. In our patient, there were only occasional asymptomatic periods of mildly lowered magnesium levels during treatment with magnesium orally and occasional IV administration. Some patients present with significant diarrhea, which may be related to chronic magnesium supplementation orally and may be a major cause of the abandonment of therapy.
Case Study 15
A 4-week-old female infant was admitted for evaluation of seizure disorder in the last 24 hours. The parents noted rhythmic limb movements associated with eyes deviated to the right, lasting for a few minutes without skin color change or fever. The infant appeared awake and alert among the episodes. She was born following an uneventful full-term pregnancy by spontaneous delivery. The birth weight was 3100 g. The infant presented a normal psychomotor development, was formula-fed, and did not receive any medication. There was no family history of febrile seizures, epilepsy, neurological disease, or early childhood death. On admission, axillary temperature was 36.5°C, heart rate 153 beats/min, oxygen saturation 99% while she was breathing ambient air, blood pressure 90/62 mmHg, body weight 4100 g. General conditions and results of neurologic examination were unremarkable. Twenty minutes after the admission, the baby experienced three new episodes of seizures characterized by mouth opening, staring with eyes deviated to the right and jerking of the right arm, followed by tonic extension of the left arm, jerking of the right leg, and vocalization. Each seizure lasted for approximately 2 minutes. Electroencephalography (EEG) showed a discharge of alpha rhythmic waves mixed with spikes starting from the left central region, then spreading to the left frontal, temporal, and right central regions. Routine blood tests revealed the following: sodium 134 mmol/L, potassium 5.5 mmol/L, chloride 97 mmol/L, calcium 6.8 mg/dL, phosphorus 9.4 mg/dL, magnesium 0.74 mg/dL, and glucose 86 mg/dL. Liver and kidney functions were normal. Intravenous phenobarbital (10 mg/kg) was administered, followed by 5 mg/kg for 5 days and no further seizure was observed. Oral magnesium sulfate (10% at 2 mL four times a day) was also provided. Five days after admission, blood exams revealed calcium level of 8.6 mg/dL, phosphorus of 6.5 mg/dL, and magnesium of 1.90 mg/dL. A second EEG showed normal cerebral activity. The patient was discharged in good condition without any evidence of neurological sequelae. Magnesium supplementation was prescribed for the following 2 months. In the subsequent 6 months, the patient was doing well and blood magnesium and calcium levels were within normal values.
What is the most likely cause of hypomagnesemia in this infant? (Select all that apply)
- A.
Prematurity
- B.
Immature renal tubular function
- C.
Maternal diabetes
- D.
Genetic disorders
The correct answer is B
Comment: The main causes for hypomagnesemia in newborns are maternal diabetes, prematurity, hypercalcemia, diuretics, rapid extracellular volume expansion, immature tubular function, and genetic disorders. In our patient, hypomagnesemia was likely due to a transient immature tubular function, considering that no risk factor for magnesium deficiency was present and that blood magnesium levels were normal during the following 6 months without any supplementation.
Case Study 16
A 17-year-old female complaining of cramps and tightening in her throat. Past medical history is significant for mild hypertension for which she is being treated with hydrochlorothiazide, 12.5 mg/day.
She had a total thyroidectomy for a large toxic, multinodular goiter 2 years ago and is maintained on 1-thyroxine 100 g/day. Bone densitometry was consistent with osteoporosis and she was started on alendronate 10 mg/day. Several days later, she began to note intermittent severe cramps in her hands and feet. Today, she noted some tightening in her throat and came to the emergency room. She denies the use of any other medications or over-the counter supplements. She avoids all dairy products.
Upon examination, her BP is 140/86 mmHg, pulse 86 beats/min, respirations 12 breaths/min, and temperature 37°C, weight 62.5 kg, and height 159 cm. The rest of the physical examination was normal. Laboratory studies revealed hemoglobin 13.0 g/L, white blood count 5100 cells/μL, sodium 138 mmol/L, potassium 4.1 mmol/L, chloride 100 mmol/L, bicarbonate 27 mmol/L, BUN 6 mg/dL, creatinine 0.7 mg/dL, calcium 7.7 mg/dL, phosphate 6.3 mg/dL, magnesium 1.9 mg/dL, and albumin 4.2 g/dL. Urinalysis showed trace protein, negative for glucose and blood. Her EKG showed prolonged QT intervals.
What would you do at this point? (Select all that apply)
- A.
Draw PTH level
- B.
Draw serum magnesium level
- C.
Draw calcitriol level
- D.
Draw calcidiol level
- E.
Give intravenous magnesium
The correct answers are A, B, and E
Comment: The combination of hypocalcemia and hypophosphatemia in the absence of renal failure certainly suggests the presence of hypoparathyroidism. Hypomagnesemia (usually due to diarrhea) can cause suppression of PTH secretion and/or resistance to PTH, and produce acute hypocalcemia.
It is appropriate to consider this and draw a serum magnesium level. In the absence of renal insufficiency, magnesium infusion is safe and reasonable while waiting for the results to come back from the laboratory.
Her symptoms did not abate and her serum calcium was unchanged following administration of magnesium. She was given intravenous calcium and experienced relief of her acute symptoms. She was maintained on intravenous calcium for several days until her laboratory studies, which were obtained in the ER, returned as follows: PTH 15 ng/mL, serum magnesium 2.0 mg/dL.
Case Study 17
What is the primary diagnosis?
- A.
Hypoparathyroidism
- B.
Alendronate toxicity
- C.
Vitamin D deficiency
- D.
Hypomagnesemia
- E.
Pseudohypoparathyroidism
The correct answer is A
Comment: She has hypocalcemia and a PTH value that is inappropriately in the low-normal range consistent with hypoparathyroidism. Permanent hypothyroidism occurs in 2% to 10% of cases after thyroid surgery. She likely had subclinical hypoparathyroidism that was undiagnosed and that now has been masked by alendronate therapy.
Case Study 18
A 12-year-old male presents to the ER with acute abdominal pain. He noted the onset of steady right upper quadrant pain yesterday. The pain radiates in a band-like fashion to the back and is relieved somewhat by bending forward. He has also experienced nausea and vomiting for the last 10 hours. He has had multiple hospitalizations in the past with similar presentation. Review of symptoms reveal that he has been having loose, greasy, foul-smelling stools that are difficult to flush for the last month. Current medications include Dilantin and phenobarbital for a history of generalized seizures over the last several years. Upon examination, he appears restless and is in significant pain. Vital signs reveal a temperature of 39°C, BP of 103/65 mmHg, a pulse of 110 beats/min, and a respiratory rate of 25 breaths/min with shallow respirations. The chest is clear. There is epigastric distention and tenderness with guarding. The liver and spleen are not palpable. There is no edema. The neurological examination is intact.
Which of the following may be contributing to the hypocalcemia? (Select all that apply)
- A.
Hypophosphatemia
- B.
Hyperphosphatemia
- C.
Hypomagnesemia
- D.
Hypermagnesemia
- E.
Low calcidol
- F.
Extravascular deposition of calcium
The correct answers are C, E, and F
Comment: Vitamin D deficiency, hypomagnesemia, and precipitation of calcium soaps in the abdominal cavity all may play a role in patients with chronic pancreatitis.
Case Study 19
Which of the following may be contributing to the low levels of calcidiol in this patient? (Select all that apply)
- A.
Renal failure
- B.
Malabsorption
- C.
Dietary deficiency of vitamin D
- D.
Dilantin
- E.
Liver disease
The correct answers are B, C, D, and E
Comment: Liver disease (loss of 80% to 90% of functioning tissue) can be associated with reduced hydroxylation of vitamin D to calcidiol. Penobarbital and Dilantin increase the activity of the p450 mitochondrial system, which can metabolize calcidiol into inactive metabolites. Dilantin may also interfere with the absorption of vitamin D. Dietary vitamin D deficiency and/or malabsorption associated with chronic pancreatitis is typically a feature in alcoholic patients.
Case Study 20
A 19-year-old, HIV-positive male noted the onset of blurring vision several weeks ago. Indirect ophthalmoscopy revealed white, fluffy retinal lesions, located close to retinal vessels and associated with hemorrhage. Cytomegalovirus (CMV) retinitis was diagnosed and he was begun on intravenous therapy with foscarnet, 120 mg/kg IV, twice daily. This was to be continued for 2 weeks to be followed by maintenance therapy with intravenous 90 mg/kg, once daily. He complained of several episodes of numbness and tingling, particularly around his mouth, with the first several treatments. This morning he experienced a generalized seizure immediately following completion of his treatment.
Laboratory studies included a hemoglobin 10.0 g/dL, white blood count 4600 cells/μL, BUN 8 mg/dL, creatinine 1.0 mg/dL, sodium 140 mmol/L, potassium 4.0 mmol/L, chloride 108 mmol/L, bicarbonate, 25 mmol/L, calcium 9.9 mg/dL, phosphate 3.5 mg/dL, magnesium 1.9 mg/dL, and albumin 3.7 g/dL.
His clinicians are concerned and confused. His symptoms sound like hypocalcemia but his serum calcium concentration and serum albumin concentration are normal.
What would you recommend be done next? (Select all that apply)
- A.
Measure a PTH level
- B.
Reduce the foscarnet dose and measure the serum-ionized calcium at the end of the net infusion
- C.
Measure a calcidol level
- D.
Measure serum ionized magnesium level
- E.
Order a head CT scan
- F.
Check a blood gas during the infusion
The correct answers are B, E, and F
Comment: Foscarnet (trisodium phosphonoformate) has been shown to chelate serum calcium. The plasma-ionized calcium (but not total) typically falls by a mean value of 0.17 mmol/L with a 90 mg/kg dose, and by 0.29 mmol/L with a 120 mg/kg dose. These changes are clinically significant and can be associated with paresthesias and seizures. Acute respiratory alkalosis associated with hyperventilation due to pain or anxiety can also reduce the ionized calcium concentration.
Case Study 21
The patient is a 14-year-old female who presents with a 7-month history of aching in her bones affecting her arms and legs. More recently, she has noted the onset of muscle weakness such that her gait has become cautious and she uses her arms to rise from a sitting position. She has no significant past medical history and she does not smoke or drink alcohol. She denies the use of any medications. Her most recent office visit was 6 months ago, at which time there were no abnormal physical or laboratory findings. Upon examination, she appears as a thin female in no acute distress. BP is 126/78 mmHg, pulse 76 beats/min, respirations 12 breaths/min, and temperature 37°C, weight 55.0 kg, and height 160 cm. The rest of the physical exam is normal.
Laboratory studies showed normal hemoglobin, white cell count, and urinalysis. Serum sodium is 140 mmol/L, potassium 3.9 mmol/L, chloride 101 mmol/L, bicarbonate, 28 mmol/L, BUN 8 mg/dL, creatinine 1.0 mg/dL, calcium 9.8 mg/dL, phosphate 1.9 mg/dL, magnesium 1.7 mg/dL, and albumin 4.2 g/dL.
Which of the following symptoms can be associated with her electrolyte abnormalities?
- A.
Muscle weakness
- B.
Osteoporosis
- C.
Osteopenia
- D.
Osteomalacia
- E.
Hypertension
- F.
Hyperparathyroidism
The correct answer is A
Comment: Muscle weakness and osteomalacia (often presenting as bone pain) are classic signs of marked hypophosphatemia. Hypophosphatemia-induced manifestations of muscle dysfunction include a proximal myopathy, affecting skeletal muscle, and dysphasia and ileus, affecting smooth muscle. Metabolic bone disease refers to conditions that produce a diffuse decrease in bone density (osteopenia) and/or strength because of an increase in bone resorption and/or a decrease in bone formation. These conditions include osteoporosis, osteomalacia, and hyperparathyroidism.
Case Study 22
Which diagnostic tests should be done first in attempting to distinguish the diagnosis? (Select all that apply)
- A.
Twenty-four-hour urine phosphate collection
- B.
Twenty-four-hour urine creatinine collection
- C.
Twenty-four-hour urine calcium collection
- D.
Serum calcidiol level
- E.
Serum calcitriol level
The correct answers are A and B
Comment: The first step in the diagnostic approach to hypophosphatemia is to establish whether or not there is GI loss or urinary loss as the causative factor. This is done by evaluating the appropriateness of urinary phosphate excretion. Thus the 24-hour urinary collection for phosphorus and creatinine is necessary to ensure the adequacy of the collection and to allow estimation of the fractional excretion of phosphate. The 24-hour urine phosphate and creatinine excretion were 800 and 1250 mg, respectively. The fractional phosphate excretion was 43%.
Case Study 23
What medical conditions should now be considered in the differential diagnosis? (Select all that apply)
- A.
Primary hyperparathyroidism
- B.
Poor phosphate intake and diarrhea
- C.
Excess ingestion of phosphate-binding antacids
- D.
Vitamin D deficiency
- E.
Fanconi syndrome
- F.
X-linked hypophosphatemic rickets
- G.
Oncogenic osteomalacia
The correct answers are E, F, and G
Comment: The fractional phosphate excretion indicated reduced phosphate transport. The causes include hyperparathyroidism and vitamin D deficiency (with secondary hypoparathyroidism).
The normal calcium concentration is not consistent with primary or secondary hyperparathyroidism. The causes of primary renal phosphate wasting include a generalized defect in proximal tubule transport (Fanconi syndrome), hereditary hypophosphatemic rickets, and oncogenic osteomalacia.
Case Study 24
Further evaluation revealed the following: normal blood levels of 25 (OH) Vitamin-D, PTH (3 pg/mL), uric acid (5 mg/dL), and 1,25 (OH) 2 vitamin D level (10 pg/mL). Urine contained no glucose or amino acids with normal uric acid excretion.
What is the most likely diagnosis now?
- A.
Fanconi syndrome
- B.
Hereditary hypophosphatemic rickets
- C.
Oncogenic osteomalacia
- D.
Vitamin D deficiency
The correct answer is C
The condition appears to be acquired and the calcitriol level is very low, consistent with this diagnosis.
Case Study 25
What is the presumed pathogenesis of this disorder?
- A.
Tumor secretion of cyclic adenosine monophosphate (AMP)
- B.
Tumor production of the phosphatonin FG23
- C.
Tumor production of PTH
- D.
Tumor production of calcitonin
- E.
None of the above
The correct answer is B
Comment: There are several phosphatonins that have been identified. Overproduction of FG23 appears to be the most common in patients with these tumors. These substances lead to under expression of the cotransporter that is responsible for phosphate reabsorption in the proximal tubule.
Case Study 26
What should be done next? (Select all that apply)
- A.
Treat with oral phosphate
- B.
Treat with 1,25 (OH) 2 vitamin D
- C.
Total body magnetic resonance imaging (MRI)
- D.
Scintigraphy using octreotide labeled with indium-111
- E.
Treat with 25 (OH) vitamin D
The correct answers are A, B, C, and D
Comment: Patients with this syndrome require a combination of oral phosphate and calcitriol. This is because the use of phosphate alone may lower ionized calcium and lead to secondary hyperparathyroidism. Therapy should continue until the tumor can be identified and removed. Removal of the tumor leads to prompt reversal of the biochemical abnormalities and healing of the bone disease.
Identification of the tumor can involve total body magnetic resonance imaging or scintigraphy using octreotide labeled with indium-111 (since the tumors typically express somastatin receptors).
The patient underwent scanning with indium-11 labeled octreotide. Intense nasopharyngeal uptake was demonstrated indicating an occult octreotide avid hemangiopericytoma. Surgery was recommended.
The patient asks what the likely prognosis is with successful removal of the tumor.
Case Study 27
What do you tell her?
- A.
The tumors are typically benign and do not recur; in all likelihood she will be cured.
- B.
Tumors often recur.
The correct answer is A
Comment: The tumors are typically benign and do not recur; in all likelihood she will be cured. The patient underwent surgery. Her weakness subsequently improved and her serum phosphate returned to normal. She has been well for 5 years.
Case Study 28
A 15-year-old female returns for her annual check-up. When seen last year, physical examination and laboratory studies were within normal limits. Routine bone densitometry revealed low bone density (more than 2.5 standard deviations below normal) and she was placed on alendronate. She now returns for her annual check-up with no complaints. Laboratory studies show hematocrit 46%, BUN 14 mg/dL, serum creatinine 1.1 mg/dL, sodium 140 mmol/L, potassium 3.9 mmol/L, chloride 105 mmol/L, bicarbonate 26 mmol/L, calcium 11.3 mg/dL, phosphate 3.4 mg/dL, magnesium 1.9 mg/dL, and albumin 4.2 g/dL. Urinalysis shows trace protein, glucose negative, no blood, and no casts, RBC, or WBC. The PTH level was 57 pg/mL (normal range 10 to 65 pg/mL).
What is the most likely diagnosis based upon the laboratory studies?
- A.
Familial hypocalciuric hypercalcemia
- B.
Primary hyperparathyroidism
- C.
Malignancy
- D.
Granulomatous disease
- E.
I am not sure, I would like to order a sestamibi scan for verification
The correct answer is B
Comment: A PTH level in the high normal range is inappropriate in a patient with hypercalcemia, and indicates the presence of primary hyperparathyroidism. This occurs in 15% to 20% of patients with this condition.
Case Study 29
What would you like to do now?
- A.
Order a sestamibi scan
- B.
Call the surgeon
- C.
Follow the patient and schedule follow-up in 6 months
- D.
Follow-up in 6 months
The correct answer is B
Comment: Surgery is indicated in the following patients:
Patients with a serum calcium level of 1.0 mg/dL or above the upper limit of normal.
- 1.
Patients with hypercalciuria (> 400 mg/day) while eating their usual diet
- 2.
Patients with a creatinine clearance that is 30% or lower than that of age matched normal subjects
- 3.
Patients with bone density at the hip, lumbar spine, or distal radius that is more than 2.5 standard deviations below peak bone mass (T score <−2.5)
- 4.
Patients who are less than 50 years old
- 5.
Patients in whom periodic follow-up will be difficult
The patient has a serum calcium level, which is more than 1 mg/dL above normal and has a significant decrease in bone density. She is in good health otherwise and should be offered surgery as the first option.
Case Study 30
A 14-year-old male presents with nausea, dizziness, weakness, and muscle cramps. His past medical history is significant for hypertension (HTN) and gastroesophageal reflux disease (GERD). His medication regimen includes amlodipine 5 mg daily and hydrochlorothiazide 12.5 mg daily for HTN and pantoprazole 40 mg daily for GERD. He has been taking both medications for 2 years. A chemistry panel was obtained and was significant for potassium 3.3 mEq/L, magnesium 1 mg/dL, Ca 7.7 mg/dL, and albumin 4.1 g/dL.
What is the most likely etiology of his symptoms?
- A.
Amlodipine
- B.
Pantoprazole
- C.
Hydrochlorothiazide
- D.
None of the above
The correct answer is B
Comment: He has hypomagnesemia due to chronic use of pantoprazole. Pantoprazole leads to GI Mg loss due to decreased absorption via down regulation of TRPM6 channels. Hypomagnesemia leads to hypokalemia and hypocalcemia.
Case Study 31
A 19-year-old man with congestive heart failure (ejection fraction is 20%) presents with serum magnesium of 1.4 mg/dL. He is on lisinopril 40 mg daily, furosemide 40 mg twice daily, and carvedilol 25 mg twice daily. His blood pressure control is optimal, serum creatinine is stable at 0.8 mg/dL, and serum potassium is 3.4 mmol/L.
What is the best approach to his hypokalemia and hypomagnesemia? (Select all that apply)
- A.
Discontinue furosemide
- B.
Discontinue potassium supplement
- C.
Start spironolactone
- D.
All of the above
The correct answer is C
Comment: Discontinuation or dose reduction of furosemide may lead to fluid overload. Supplementation with oral potassium and magnesium salts would significantly increase the number and frequency of his medications. Given his diagnosis of congestive heart failure with low ejection fraction, spironolactone 25 mg daily was started to mitigate both hypokalemia and hypomagnesemia resulting from his loop diuretic. Spironolactone decreases morbidity and mortality in patients with severe heart failure.
Case Study 32
A 17-year-old woman with a known history of stage 4 chronic kidney disease (CKD) secondary to diabetic nephropathy presents with nausea, dizziness, muscle cramps, and fasciculations. Her medications include glimepiride 4 mg daily, atorvastatin 40 mg daily, lisinopril 40 mg daily, furosemide 40 mg daily, and patiromer 8.4 daily. Patiromer (a potassium binder) was started due to hyperkalemia resulting from the increase in lisinopril dose. A chemistry panel was ordered, creatinine 3.1 mg/dL, potassium 4.9 mmol/L, magnesium 1 mg/dL.
What should be done next? (Select all that apply)
- A.
Discontinue furosemide
- B.
Discontinue patiromer
- C.
Start magnesium oxide supplement
- D.
Start calcium gluconate salt
The correct answers are A and C
Comment: Her symptoms are due to hypomagnesemia. Patiromer binds both potassium and magnesium. In this patient with stage 4 CKD, the use of patiromer allowed her to continue the use of lisinopril at an optimal dose. Furosemide aggravated her hypomagnesemia. In this case patiromer was continued and the patient was supplemented with magnesium oxide 400 mg PO twice daily.
Case Study 33
A 7-year-old girl presents for evaluation of chronic kidney disease (CKD). She is complaining of muscle cramps and fasciculations, polyuria, and polydipsia. Her past medical history is significant for recurrent urinary tract infections and severe myopia. Physical exam revealed that her growth is in the 40th percentile. She is noted to have corneal calcifications. Laboratory evaluation was remarkable for microhematuria, serum creatinine 1 mg/dL, serum magnesium 1.2 mg/dL, serum calcium 9 mg/dL, fractional excretion of magnesium was elevated at 15%, urine calcium was elevated at 12 mg/kg/24 h (normal < 4 mg/kg/24 h). Intact parathyroid hormone level was elevated at 131 pg/mL (normal range 10 to 65 pg/mL). Renal ultrasound revealed nephrocalcinosis.
What is the most likely diagnosis? (Select all that apply)
- A.
Familial hypomagnesemia type 2
- B.
Chronic kidney disease
- C.
Chronic urinary tract infection
- D.
Diabetes insipidus
The correct answer is A
Comment: This presentation is consistent with familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) type 2. Ocular abnormalities are seen only in type 2 FHHNC. This rare genetic disorder is due to a mutation in the tight junction protein claudin 19. A detailed family history is paramount, including inquiring about consanguineous parents. This patient exhibited many of the characteristic features of FHHNC type 2. Genetic testing is required to ascertain the diagnosis.
References
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