Case Study 1
A patient with recurrent diarrhea complains of severe muscle weakness. There is no history of carpopedal spasm, or physical findings of Trousseau or Chvostek sign, consistent with hypocalcemia. The electrocardiogram reveals ST-segment and T-wave changes with premature ventricular beats, which are felt to be compatible with hypokalemia. The following laboratory data are obtained: serum sodium 140 mmol/L, potassium 1.3 mmol/L, chloride 110 mmol/L, bicarbonate 10 mmol/L, albumin 4.1 g/dL, calcium 6.3 mg/dL, arterial pH 7.26, PCO 2 23 mmHg.
How would you correct this patient’s electrolyte disorders?
- A.
Treatment of hypokalemia should proceed the correction of hypocalcemia
- B.
Treatment of hypocalcemia should proceed the correction of hypokalemia
- C.
Treatment of acidosis should proceed before the correction of hypokalemia
- D.
Treatment of acidosis should proceed before the correction of hypocalcemia
The correct answer is A
Comment: Correction of the acidemia will drive potassium into the cells, further reducing the plasma potassium concentration. In this setting, in which the acidemia is not severe, alkali therapy should be withheld until potassium supplements have partially corrected the hypokalemia.
Hypocalcemia protects against the effects of hypokalemia via an uncertain mechanism. Thus, treatment of the hypokalemia should precede correction of the hypocalcemia. It should be noted that, for the same reasons, hypokalemia protects against the neuromuscular effects of hypocalcemia. Thus, increasing the plasma potassium concentration in this setting may precipitate hypocalcemic tetany. However, this risk is generally less serious.
Case Study 2
An 8-year-old girl presented with two episodes of generalized tonic-clonic seizures lasting less than 5 minutes, aborted with intravenous midazolam bolus. There was no history of fever, headache, vomiting, blurring of vision, deafness, or head trauma. There was no history of muscle cramps, abnormal sensations like tingling, burning or numbness of hands, or stridor. There was no history of polyuria. There was no family history of epilepsy or any neurological disorders in parents or siblings. Her development and scholastic performance were appropriate for age. There was no history of learning disabilities or behavioral problems. At presentation, the child was conscious, oriented, and afebrile. At admission, pulse rate was 94 beats/min, and blood pressure was 108/78 mmHg (50th to 90th percentile). The weight (26.5 kg), height (124 cm), and head circumference (51 cm) were appropriate for age. There were no neurocutaneous markers or dysmorphic facies. No cleft palate or dental anomalies were noted. Meningeal signs were absent. Neurological examination revealed positive Chvostek sign (twitching of facial muscles in response to tapping over the facial nerve) and positive Trousseau sign (carpopedal spasm induced by pressure applied to the arm by an inflated sphygmomanometer cuff). Examination of the other systems was unremarkable. Investigations showed capillary blood glucose of 124 mg/dL. Serum sodium (139 mmol/L) and potassium (4.4 mmol/L) were normal; however, serum calcium (6.1 mg/dL) and ionized calcium (0.54 mmol/L) were low, and serum phosphorus (10.5 mg/dL) was high. The blood urea (31 mg/dL), serum creatinine (0.3 mg/dL), magnesium (1.9 mg/dL), serum albumin (4.7 g/dL), and uric acid (2.8 mg/dL) were normal. Blood gas analysis (pH 7.39, bicarbonate 22 mEq/L) was normal. Serum 25 (OH) vitamin D level was 33 ng/mL, and iPTH level was 0.01 pg/mL (reference: 15 to 30 pg/mL). Spot urine calcium/creatinine ratio was 0.42, consistent with hypercalciuria. The 24-hour urine calcium levels were 90 mg/24 h (> 4 mg/kg/24 h). The skeletal survey was normal, with no evidence of osteosclerosis or cortical thickening. Kidney ultrasonogram (USG) revealed homogeneous diffusely hyperechoic medullary pyramids with acoustic shadowing in both kidneys suggestive of grade 3 nephrocalcinosis. Contrast-enhanced computed tomography (CECT) of brain revealed symmetrical, dense calcification in bilateral basal ganglia and bilateral frontal lobes. There was no evidence of cataract, microphthalmia, papilledema, or hyperopia. There were no corneal and retinal calcifications on ophthalmological evaluation. Echocardiogram was normal. Electrocardiogram showed prolonged QTc interval.
The past medical history was notable. She was the first-born child of third-degree consanguineous parents. She had a smooth perinatal transition with normal birth weight (3 kg) and length (50 cm). There was normal postnatal growth period with age-appropriate developmental milestones. At 3 months of age, she presented with two episodes of multifocal clonic seizures to another hospital. There was no evidence of hypoglycemia. Meningitis was ruled out by cerebrospinal fluid analysis. However, her serum calcium (5.3 mg/dL) was low, and serum phosphorus (12.2 mg/dL) was high similar to the current episode. She had not been evaluated with urine calcium levels or kidney USG at that time. The blood urea (22 mg/dL), serum creatinine (0.12 mg/dL), magnesium (2.6 mg/dL), sodium (136 mmol/L), potassium (4.8 mmol/L), serum albumin (4.2 g/dL), uric acid (2.8 mg/dL), and alkaline phosphatase (276 U/L) were normal. Ultrasonogram of the cranium did not show any abnormality. Serum 25 (OH) vitamin D level was normal (reference: 24.3 ng/mL), and iPTH level was less than 2.5 pg/mL (reference: 15 to 30 pg/mL). She had been treated with intravenous calcium gluconate at that time for 2 days. There were no further episodes of seizures, and she was discharged from the hospital with oral calcium carbonate and calcitriol supplements. However, she was on irregular follow-up. On probing, it was revealed that she had recurrent episodes of tetany requiring intravenous calcium administration at another institution.
During the current admission at our hospital, the child was managed with intravenous calcium gluconate for 48 hours. Oral calcium carbonate and oral calcitriol doses were titrated to achieve near normal serum calcium levels. Therapy with oral hydrochlorothiazide and potassium citrate was initiated in view of hypercalciuria and nephrocalcinosis. Sevelamer was prescribed for hyperphosphatemia, which led to a decrease in serum phosphorus levels. A targeted genetic analysis by clinical exome sequencing was performed.
What is the MOST likely diagnosis and how would you treat it?
- A.
Pseudohypoparathyroidism
- B.
Familial isolated hypoparathyroidism (FIH)
- C.
DiGeorge syndrome
- D.
CHARGE syndrome
The correct answer is B
Comment: This child presented with recurrent episodes of tetany and seizures, in association with grade 3 nephrocalcinosis, who was confirmed to have hypoparathyroidism due to heterozygous missense variation in the GCM2 gene (autosomal dominant inheritance). Nephrocalcinosis can complicate hypoparathyroidism in a significant proportion of cases.
The differential diagnoses for hypocalcemia with nephrocalcinosis are familial isolated hypoparathyroidism (FIH), syndromic hypoparathyroidism, calcium-sensing receptor (CaSR)-activating mutations (sporadic and autosomal dominant), pseudohypoparathyroidism (insensitivity to PTH), and acquired causes of hypoparathyroidism (HPT). Familial hypoparathyroidism has autosomal recessive ( GCM2 , PTH gene mutations), autosomal dominant ( CaSR gene mutation and some cases of GCM2 mutations), or X-linked ( SOX3 gene mutation) inheritance. DiGeorge syndrome type 1 and type 2, CHARGE syndrome, autoimmune polyendocrine syndrome type 1, Kenny-Caffey syndrome type 1 and type 2, Sanjad-Sakati syndrome, Barakat syndrome, Kearns-Sayre syndrome, MELAS syndrome, mitochondrial trifunctional protein deficiency syndrome, Gracile bone dysplasia, and Pearson syndrome are the syndromic causes of hypoparathyroidism. Activating mutations of the CaSR gene cause autosomal dominant hypocalcemia type 1. Pseudohypoparathyroidism is caused by insensitivity to the PTH hormone due to mutations in genes PTHR1 , GNAS , PRKAR1A , and hypomagnesemia. The acquired causes of hypoparathyroidism include activating antibodies to the CasR , maternal hyperparathyroidism, post-surgical and radiation-induced damage to the parathyroid glands, deposition of iron or copper (thalassemia, hemochromatosis, Wilson disease), or infiltration (neoplastic invasion, sarcoidosis, amyloidosis).
Our patient had tetany, convulsions with hypocalcemia, hyperphosphatemia, low serum PTH, nephrocalcinosis, and calcifications in basal ganglia and frontal lobes. Hence, a provisional diagnosis of hypoparathyroidism was considered. Syndromic and acquired causes of hypoparathyroidism were considered unlikely, as there were no features or history suggestive of the same. Pseudohypoparathyroidism was ruled out, as serum PTH was low. A targeted genetic analysis by clinical exome sequencing was performed in our case which revealed a heterozygous missense variation c.1151C > T in exon 5 of the GCM2 gene (Chr 6: 10874598G > A) , confirming the diagnosis of familial isolated hypoparathyroidism-type 2 (autosomal dominant inheritance).
Management of such cases includes evaluation, treatment of acute hypocalcemia, and long-term follow-up. The index case presented with seizures to our pediatric emergency unit. At admission, there were no features suggestive of meningitis, and the blood glucose was normal. The index case had hypocalcemia, hyperphosphatemia with low PTH levels, and normal serum creatinine, confirming hypoparathyroidism. Another condition with similar clinical manifestations (tetany, seizures), hypocalcemia, hyperphosphatemia, and ectopic calcifications in brain and kidneys is pseudohypoparathyroidism. However, specific clinical features (short stature, obesity, rounded face, and brachydactyly mostly affecting the 4th and 5th metacarpals and metatarsals in Albright hereditary osteodystrophy) and high serum PTH levels in pseudohypoparathyroidism differentiate it from hypoparathyroidism.
Hypoparathyroidism is associated with ectopic calcifications. Hence, screening for calcifications in the kidney and brain is recommended. This includes urinary calcium/creatinine ratio and renal ultrasonogram to look for nephrocalcinosis and computed tomography (CT) of cranium for basal ganglia and intracerebral calcifications. Ophthalmological evaluation for posterior subcapsular cataract should be done which can occur due to elevated calcium-phosphorus products accumulating in the lens of the eyes. Our index case had elevated urinary calcium/creatinine ratio (0.42) and grade 3 nephrocalcinosis with bilateral symmetrical calcification in basal ganglia and frontal lobes.
Treatment of acute hypocalcemia aims at control of seizures and correction of hypocalcemia to prevent further seizures. Intravenous calcium gluconate (elemental calcium 9.3 mg/mL) 1 to 2 mL/kg (total dose should not exceed 10 mL) diluted with an equal amount of dextrose should be given slowly at the rate of 0.5 to 1 mL/min under strict cardiac monitoring, followed by infusion of the same solution every 4 to 6 hours until calcium is normalized. Long-term goals in the management of hypoparathyroidism are to achieve a near normal range of serum calcium (8 to 9 mg/dL) to prevent seizures and tetany and decrease calcium–phosphate products to prevent ectopic calcifications. Targeting higher serum calcium levels and overzealous treatment with oral calcium and calcitriol should be avoided which can result in hypercalciuria and nephrocalcinosis leading to renal impairment or chronic kidney disease in some cases. To achieve this, oral calcium (calcium carbonate or calcium citrate) and active form of vitamin D3 (calcitriol) or vitamin D2 should be supplemented. Severe hyperphosphatemia needs to be treated with phosphate binders such as sevelamer. Thiazide diuretics (hydrochlorothiazide) effectively reduce urinary calcium excretion and are often used in cases where normocalcemia (lower normal) is not achieved with adequate calcium and calcitriol doses; they are also used in cases with nephrocalcinosis. On follow-up, serum calcium and phosphate levels, 6-monthly urinary calcium/creatinine ratio, and renal ultrasonogram (for nephrocalcinosis) should be done to titrate the doses of oral calcium and calcitriol supplementations. The newer treatment regimens for hypoparathyroidism are teriparatide and recombinant human PTH. Recent trials with teriparatide (recombinant human PTH1-34 [rhPTH1-34]) in children with hypoparathyroidism showed promising results with a decrease in the requirement of oral calcium and calcitriol supplementation, steady serum calcium concentration, and decrease in urinary calcium excretion. Our patient responded well to calcitriol and calcium supplements, along with hydrochlorothiazide and sevelamer, resulting in an increase in serum calcium levels and decrease in serum phosphorus levels on follow-up. Therefore, teriparatide was not prescribed.
Case Study 3
The patient was a 12-year-old girl, who had been born after 36 weeks of gestation by cesarean section after an uneventful pregnancy with birth weight of 2450 g, height of 47 cm, and head circumference of 37 cm. She was the first-born infant of healthy parents (24-year-old mother and 28-year-old father); however, the patient was consanguineous as the parents were second-degree cousins.
The patient was first brought to another center with afebrile seizures at the age of 5 months. During investigation of the cause of the seizures, her serum calcium level was found to be 6.8 mg/dL. Two doses of oral vitamin D injection and oral calcium lactate were given to treat the hypocalcemia. However, oral calcium lactate treatment was ineffective, and she had two more afebrile seizures by the age of 8 months. In addition to hypocalcemic seizures, there was a history of recurrent febrile urinary tract infections up to the age of 1 year.
The patient was admitted to the hospital with a diagnosis of acute pyelonephritis at the age of 14 months. The patient’s height was 66 cm (< 3rd percentile), weight was 6700 g (3rd to 10th percentile), and head circumference was 42.5 cm (< 3rd percentile) at admission. The patient was first able to hold her head up at 6 months and was able to sit without support at the age of 1 year. The patient could not walk at admission. She had a syndromic facial appearance characterized by trigonocephaly with square head, hypertrophy of the right cheek, broad forehead, hypertelorism, low nasal bridge, micrognathia, and underdeveloped and low-set ears.
The patient had hypernatremic dehydration. Laboratory investigations revealed a hemoglobin level of 8.6 g/dL, mean erythrocyte corpuscular volume of 84 fL, total leukocyte count of 12 × 10 9 /L, platelet count of 299 × 10 9 /L, urine density of 1025, pH 6, and abundant leukocytes in urine sediment examination. The results of serum analysis were as follows: blood urea nitrogen (BUN), 85 mg/dL; creatinine, 1.3 mg/dL; sodium, 153 mmol/L; potassium, 4.6 mmol/L; albumin, 4.8 g/dL; alkaline phosphatase, 206 U/L; calcium, 8.3 mg/dL; phosphorus, 7.2 mg/dL; magnesium, 2 mg/dL; 25-hydroxy vitamin D, 36 ng/mL; C-reactive protein, 46 mg/L; parathyroid hormone (PTH), 10.5 pg/mL (reference: 15 to 65 pg/mL); and spot urine calcium/creatinine ratio, 0.33. On blood gas analysis, pH was 7.30 and bicarbonate level was 13.5 mEq/L. The patient was treated with appropriate antibiotic therapy and intravenous hydration. Ultrasonography revealed dilation in the left proximal ureter, hydronephrosis in the left kidney, and right renal hypoplasia. Voiding cystourethrography (VCUG) showed left-grade IV vesicoureteral reflux (VUR). Dimercaptosuccinic acid scan showed absence of right kidney activity and multiple scars in the left kidney.
In post-discharge follow-up, serum analysis showed an average urea level of 62 mg/dL, creatinine level of 1.2 mg/dL, metabolic acidosis, anemia (mean 8.5 g/dL), hypocalcemia (mean 8.5 mg/dL), and hyperphosphatemia (mean 6.9 mg/dL). Therefore, calcium acetate, Shohl solution, calcitriol, and erythropoietin treatments were started with the diagnosis of chronic kidney disease. Despite the presence of hypocalcemia and hyperphosphatemia, the mean serum PTH level was 11.7 pg/mL (range: 5.7 to 13 pg/mL).
Two STING (subureteral transurethral injection) procedures for VUR were performed at the age of 2 years, and ureteroneocystostomy was performed at the age of 4 years, and VUR was not detected in repeated VCUG.
Bilateral sensorineural hearing loss requiring cochlear implantation was diagnosed at 3 years. Auditory brainstem response testing revealed that the patient had moderate sensorineural deafness, with hearing loss of 70 dB at mid and higher frequencies in both ears.
Hypomagnesemia (1.4 mg/dL) began to develop at 5 years. The patient showed increased fractional excretion of magnesium (11%; N : < 2%), and, therefore, oral magnesium supplementation was started.
The father, mother, and brother were healthy and had no kidney or auditory problems; their serum magnesium, calcium, and phosphorus levels were normal.
What is the MOST likely diagnosis?
- A.
Barakat syndrome
- B.
Hypoparathyroidism
- C.
Pseudohypoparathyroidism
- D.
Renal osteodystrophy
The correct answer is A
Comment: The patient was diagnosed with Barakat syndrome due to the triad of the presence of hypoparathyroidism, deafness, and renal anomalies (HDR). Barakat syndrome is characterized by mutations or deletions in the GATA3 gene. The serum PTH levels did not increase despite chronic kidney disease due to hypoparathyroidism. As in this case, hypomagnesemia along with hypermagnesuria have been reported in patients with HDR syndrome, but no relationship has been demonstrated between the GATA3 gene and hypomagnesemia.
In a chromosomal karyotype study (GTG-banding analysis) performed because of the syndromic facial appearance, de novo 46 XX, deletion (p13–14) was detected. The GATA binding protein 3 ( GATA3 ) gene is located at 10p14, and our patient had a deletion in this region. Treatment of HDR syndrome is symptomatic. The condition that most requires treatment is hypocalcemia. Depending on the severity of hypocalcemia, oral calcium or calcitriol is given, with severe cases receiving intravenous calcium gluconate. Deafness can be detected at an early stage in routine newborn screening programs, which is important for language and educational development.
The prognosis of the disease is generally related to the severity of the kidney disease. When chronic kidney disease develops, it should be detected in the early stages and should be prevented from progressing to stage 5, kidney failure, although successful kidney transplantation has been reported in this syndrome.
Case Study 4
You are asked to see a 7-year-old boy because of hypokalemia during a hospitalization for the evaluation of a recent seizure disorder, which occurred 3 days ago. Phenytoin has been given for his seizure. Past medical history is significant for chronic kidney disease of unknown etiology. He has been taking sevelamer hydrochloride for the control of mild hyperphosphatemia, and he has received no vitamin D products. Shortly after admission, he undergoes a magnetic resonance imaging scan of the brain with gadolinium contrast that shows signs of a small, healed, left-sided cerebral infarct. The patient feels well. His vital signs are BP 110/70 mmHg, pulse 80 beats/min, respirations 15 breaths/min, temperature 37°C. The remainder of physical examination is unremarkable and includes the absence of Chvostek and Trousseau signs. His laboratory data include the following: calcium 5.8 mg/dL, phosphate 4.1 mg/dL, albumin 3.8 g/dL, sodium 139 mmol/L, potassium 4.2 mmol/L, chloride 105 mmol/L, bicarbonate 22 mmol/L, BUN 33 mg/dL, and creatinine 1.3 mg/dL.
Which ONE of the following is the MOST likely cause of hypocalcemia in this patient?
- A.
Hypoparathyroidism
- B.
Gadolinium-induced pseudohypocalcemia
- C.
Hypomagnesemia
- D.
Vitamin D deficiency
- E.
Sevelamer administration
The correct answer is B
Comment: Macrocyclic gadolinium complexes used in MR scanning are known to interfere with the colorimetric determination of calcium by binding with the test reagents. Patients with renal insufficiency can have spuriously low serum calcium.
Case Study 5
You are called for a curbside consult about a 3-year-old child who has developed growth failure, muscle weakness, and bone pain. Radiographic studies indicate the presence of rickets, including bowed legs, thick fuzzy growth plates, and widened knee joints. Laboratory data reveal serum sodium 140 mmol/L, potassium 3.9 mmol/L, chloride 104 mmol/L, bicarbonate 29 mmol/L, BUN 12 mg/dL, creatinine 0.4 mg/dL, calcium 8.1 mg/dL, phosphate 2.5 mg/dL, magnesium 1.9 mg/dL, albumin 3.9 g/dL, PTH 87 pg/mL, calcidiol 45 ng/mL, calcitriol 98 pg/mL, hemoglobin 14.0 g/dL, and white blood count 5600 cell/μL. Urinalysis was normal.
What is the correct diagnosis?
- A.
Pseudo-vitamin D-deficient rickets (1-alpha hydroxylase deficiency, vitamin D-dependent rickets type 1)
- B.
Vitamin D deficiency
- C.
Hypoparathyroidism
- D.
Pseudohypoparathyroidism
- E.
Hereditary vitamin D-resistant rickets (HVDRR)
The correct answer is E
Comment: Hereditary resistance to vitamin D is an autosomal recessive disorder. It is associated with end-organ resistance to calcitriol usually caused by mutations in the gene encoding the vitamin D receptor; the defect in the receptor interferes with binding of the hormone-receptor complex to DNA, thereby preventing calcitriol action and leading to hypocalcemia and secondary hyperparathyroidism.
Case Study 6
A 2-year-old North African boy was brought to our hospital because of absent teeth development and failure to walk. The patient appeared to be well nourished and content. His body mass index was 19.1 kg/m (90th percentile), he was 86 cm long (25th percentile), and he weighed 13.6 kg (75th percentile). Palpation of the patient’s extremities revealed prominent, flared distal radii, humeral and femurs. The result of a total serum calcium test was 1.4 mmol/L (normal 2.1 to 2.6).
What is the MOST likely diagnosis?
- A.
Hyperparathyroidism
- B.
Hypoparathyroidism
- C.
Vitamin D-deficiency rickets
- D.
X-linked hypophosphatemia rickets
The correct answer is C
Comment: This patient was found to have low serum calcium, phosphate, and 25-hydroxyvitamin D, as well as high levels of parathyroid hormone.
A combination of factors, including the patient’s low milk intake and the results of his physical examination, raised the likelihood of vitamin D-deficiency rickets. The results of laboratory tests confirmed this diagnosis.
Case Study 7
A 6-year-old boy presented with hard, nodular skin lesions on his torso. The patient was short (< 3rd percentile), and he had mild developmental delays and obesity. Because a skin biopsy demonstrated subcutaneous calcification, his total serum calcium level was measured and found to be 7.6 mg/dL.
What is the MOST likely diagnosis? (Select all that apply)
- A.
Pseudohypothyroidism
- B.
Hypoparathyroidism
- C.
Vitamin D efficiency rickets
- D.
Albright hereditary osteodystrophy
The correct answers are B and D
Comment: This patient had high levels of phosphate and very high levels of parathyroid hormone. Test results also revealed normal 25-hydroxyvitamin D levels and a high ratio of calcium to creatinine in his urine.
A laboratory profile that is consistent with hypoparathyroidism except for a high level of parathyroid hormone supports a diagnosis of pseudohypoparathyroidism. This patient also had a short stature, obesity, a round face and brachydactyly of his fourth and fifth fingers. These are all features of Albright hereditary osteodystrophy, a disorder in which a maternally inherited mutated copy of the GNAS1 gene leads to parathyroid-hormone resistance.
Case Study 8
A 12-year-old boy presented with concerns about intermittent numbness of his extremities. He reported having had one episode where he “lost control” of his right leg and fell. A computed tomography (CT) scan showed calcification of the basal ganglia. His total serum calcium level was 7.1 mg/dL.
What is the MOST likely diagnosis?
- A.
Vitamin D deficiency rickets
- B.
Hypoparathyroidism
- C.
X-linked hypophosphatemia rickets
- D.
Pseudohypoparathyroidism
The correct answer is B
Comment: This patient had high levels of phosphate but normal levels of magnesium and parathyroid hormone. The results of laboratory investigations supported a diagnosis of hypoparathyroidism. A subsequent genetic workup identified a rare activating mutation of the calcium receptor. This mutation causes the receptor to inappropriately sense low calcium levels as being normal.
Hypocalcemia in children may be asymptomatic or there may be a wide range of signs and symptoms such as laryngospasm, tetany, muscle cramps, seizures, paresthesia, numbness, Chvostek sign, Trousseau sign, and prolonged QTc intervals (> 450 ms). Because very young patients cannot accurately verbalize symptoms, they are more likely to present with signs such as weakness, feeding problems, facial spasms, jitteriness, or seizures. In addition, features of conditions known to be associated with hypocalcemia may be identified, including growth failure, developmental delay, lymphadenopathy, hepatosplenomegaly, bone abnormality, and facial deformity.
There are multiple causes of hypocalcemia in children; thus, diagnosis must follow a systematic approach.
Since pediatric hypocalcemia can represent the first manifestation of a genetic disorder, a definitive diagnosis may eventually require further testing at a specialized center.
Under normal circumstances, calcium homeostasis maintains total calcium levels within the narrow range of 2.1 to 2.6 mmol/L (ionized calcium 1.0 to 1.3 mmol/L). The first step in maintaining a healthy calcium balance is adequate dietary intake of calcium. Normal intake of breast milk or infant formula supplies age-appropriate amounts of calcium. Older children require a balanced diet that provides 500 mg (children aged 1 to 3 years), 800 mg (4 to 8 years), or 1300 mg (> 8 years) of calcium daily. One cup of milk contains about 300 mg of calcium.
Calcium homeostasis depends on multiple interacting organ systems. The parathyroid glands sense hypocalcemia via membrane-bound receptors and rapidly generate parathyroid hormone. (Release of parathyroid hormone requires adequate magnesium levels.) Once released, the hormone promotes a shift from net bone formation to calcium-liberating bone resorption. In the kidneys, parathyroid hormone up regulates retention of urinary calcium and enhances renal activation of potent 1,25-dihydroxy vitamin D, whose major role is to increase intestinal calcium absorption. Formation of 1,25-dihydroxy vitamin D requires adequate amounts of precursor vitamin D from diet or exposure to UV light. Finally, normalization of calcium feeds back to inhibit parathyroid hormone secretion.
Case Study 9
A 15-year-old man that showed symptoms and signs of severe and prolonged hypocalcemia due to unrecognized vitamin D deficiency. He presented at the emergency room reporting abdominal pain and vomiting since the evening before. Blood tests showed increased levels of rhabdomyolysis markers, severe hypocalcemia, hypophosphatemia, hypomagnesemia, normal renal function, elevated levels of alkaline phosphatase, extremely high levels of parathyroid hormone, and hypovitaminosis D. Radiological skeletal features of bone demineralization and bone abnormalities suggestive of osteomalacia were additionally detected. Other secondary causes of hypocalcemia were excluded. Clinical and biochemical resolution were progressively obtained only after an intramuscular loading dose of cholecalciferol was added to the standard calcium intravenous replacement therapy.
How would you treat this patient’s severe hypocalcemia?
- A.
Intramuscular loading dose of cholecalciferol
- B.
Intravenous calcium replacement therapy
- C.
Combination of vitamin D and calcium administration
- D.
None of the above
The correct answer is C
Comment: This case report shows that osteomalacia consequent to a severe vitamin D deficiency can present with acute symptoms and signs of severe hypocalcemia requiring hospital admission. In such cases, vitamin D administration, and not intensive calcium supplementation alone, is essential to achieve clinical resolution of symptoms and normalization of mineral metabolism parameters.
Case Study 10
A 19-year-old female was hospitalized to the intensive care unit for the management of severe preeclampsia during her 17th week of gestation. Her past medical history was unremarkable. She presented with symptoms of headache, palpitations, abdominal pain, nausea, and vomiting of 1 week duration. Upon initial evaluation, she was noted to have severe hypertension, BP 173/114 mmHg. The rest of the vital signs were pulse 98 beats/min, temperature 36.5°C, and oxygen saturation of 99% in room air. Physical examination revealed mild, diffuse abdominal tenderness to palpation and mild, symmetric peripheral edema. The remainder of the systemic examination was normal. Laboratory investigations were significant for marked proteinuria, bland urine sediment examination, and mild elevation of hepatic enzymes, elevated serum uric acid, and a normal renal function. Her admission blood gas showed a nonanion gap metabolic acidosis with mild respiratory alkalosis (pH: 7.37, bicarbonate: 15 mmol/L, PCO 2 : 27 mmHg and PO 2 : 106 mmHg, anion gap: 8 mmol/L).
An obstetric ultrasound was done revealing holoprosencephaly, enlarged anterior placenta with extremely elevated βHCG levels (2,285,500 mIU/mL), suggesting partial molar pregnancy.
A diagnosis of early severe preeclampsia was made and the patient was managed with antihypertensive therapy; she was given three doses of intravenous (IV) hydralazine (total 25 mg), one dose of IV Labetalol 20 mg, and then was started on nicardipine infusion with a mean arterial pressure goal of 120 mmHg. She was also given multiple doses of furosemide to manage her volume status. One dose of sodium polystyrene sulfonate (Kayexalate) suspension (15 g) was given to manage her mild hyperkalemia. Infusion of magnesium sulfate in Lactate Ringer (40 g/500 mL) was started at a rate of 25 mL/h for seizure prophylaxis; the infusion was continued for the first 3 days of hospitalization with close neurologic and electrolytes monitoring. An urgent delivery of the fetus was indicated due to severe preeclampsia and fetal ultrasound findings incompatible with life, so a cesarean section was performed as per patient’s preference. Chromosomal examination of the fetal tissue led to a diagnosis of fetal triploid.
After delivery, the patient’s blood pressure started to improve gradually over the following few days. However, she was noted to have significant changes in serum calcium (6.5 mg/dL) and potassium (5.7 mEq/L) levels during that period, corresponding to high serum magnesium levels.
Work up for etiology of hyperkalemia included plasma aldosterone concentration (PAC) (19.2 ng/dL), plasma renin activity (PRA) (9.6 ng/mL/h), and a trans-tubular potassium gradient (TTKG) of 4.6. There was no evidence of hemolysis, acute decline in renal function, or administration of medications known to affect serum potassium levels such as NSAIDs, beta blockers, heparin, etc. Additionally, the patient was tested negative for HIV, hepatitis serology, and serum antinuclear antibodies (ANA). Also, her serum thyroid stimulating hormone (TSH) level was normal.
What is the etiology of hypocalcemia and hyperkalemia in this patient?
- A.
Hypermagnesemia-induced hyperkalemia
- B.
Pseudohypocalcemia
- C.
Hypoparathyroidism
- D.
Vitamin D deficiency
The correct answer is A
Comment: Iatrogenic hypermagnesemia should be considered in the differential diagnoses of hypocalcemia and hyperkalemia whenever magnesium infusions are used, especially for obstetric indications. Stopping the magnesium infusion will likely reverse the electrolyte changes, if the renal function is intact, but sometimes temporary stabilizing measures for management of hypocalcemia and hyperkalemia may be required.
After excluding other causes of hyperkalemia, a diagnosis of hypermagnesemia-induced hyperkalemia was made. The serum potassium level started to decline after the discontinuation of magnesium infusion on day 3 of hospitalization. Patient was noted to have slight hypokalemia after normalization of serum magnesium levels, which was attributed to administration of IV furosemide (utilized for management of volume overload and hypertension). The calcium level started to decline, corresponding to increasing magnesium levels. Serum parathyroid hormone (PTH) was obtained and was 86 pg/mL (normal). Serum calcium normalized after normalization of serum magnesium levels.
References
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