The correct answer is D

Comment: In this patient, there are several life-threatening diagnoses that should be excluded, including a drug overdose, hypoglycemia, diabetic ketoacidosis, seizure, and head trauma. With a preliminary evaluation that is completely negative for these conditions, hyperkalemia is the likely cause.

Serum calcium level is regulated by parathyroid hormone (PTH), which senses serum calcium level through calcium-sensing receptors. PTH regulates serum calcium level through vitamin D-mediated calcium absorption by the gut, calcium resorption from bone, and calcium absorption by the kidney. The first diagnostic step therefore is to check serum PTH level. If PTH level is elevated, primary hyperparathyroidism (PHP) is likely. If PTH level is low/low normal, hypercalcemia could be due to PTH-related peptide (PTHrp) or vitamin D metabolites. Hypercalcemia due to PTHrp occurs in advanced malignancy, often with widespread metastasis. Therefore, measurement of PTHrp in the absence of clear malignancy should only be done when other causes of hypercalcemia have been ruled out. Granulomatous diseases will typically cause an elevation in 1,25-dihydroxyvitamin D level, whereas vitamin D intoxication presents with elevated 25-hydroxyvitamin D level. PTH-dependent hypercalcemia may be associated with mild hyperchloremic metabolic acidosis, while hypercalcemia due to vitamin D metabolites or excess calcium intake may be associated with mild metabolic alkalosis. If vitamin D metabolite and PTH levels are normal, hypercalcemia due to multiple myeloma should be ruled out. In patients with a personal and familial history of benign hypercalcemia, familial hypocalciuric hypercalcemia (FHH) should be considered. This patient had no family or personal history of hypercalcemia. Rarely, familial hypercalcemia may be caused by a defect in the conversion of 1,25-dihydroxyvitamin D to inactive forms. Finally, other causes such as milk-alkali syndrome should be considered.

The patient presented with hypercalcemia (calcium, 13.4 mg/dL), acute kidney injury (AKI; creatinine of 1.3 mg/dL), and metabolic alkalosis (total carbon dioxide of 34 mmol/L). Initial laboratory test results supported a diagnosis of milk-alkali syndrome. Further history revealed that he was ingesting at least one bottle of Tums (calcium carbonate) daily.

In the gut, both a transcellular and a paracellular pathway absorb calcium. Calcium will be poorly absorbed in the intestine if it forms insoluble salts or there is insufficient activated vitamin D, but very large calcium loads may be absorbed even in the absence of vitamin D through the paracellular pathway. Decades ago, the syndrome was seen in patients receiving high doses of sodium bicarbonate and calcinated-magnesia (Sippy Powder) for peptic ulcer disease, but now is often secondary to excessive self-administration of calcium and vitamin D. These supplements are widely used to treat osteoporosis. A more accurate term, as suggested, is calcium-alkali syndrome. Because calcium carbonate is often the trigger for calcium-alkali syndrome, serum phosphorus levels are usually normal, in contrast to classic milk-alkali syndrome, which is associated with hyperphosphatemia. Calcium-alkali syndrome is now the third most common cause of admission for hypercalcemia. The acuity of the patient’s presentation may be because hypercalcemia creates a vicious cycle resulting in renal retention of calcium. Calcium causes vasoconstriction in vascular beds, including the kidney, resulting in a decrease in the filtered load of calcium. In addition, hypercalcemia inhibits the sodium/potassium/chloride (Na ⁺ /K ⁺ /2Cl ^– ) cotransporter and aquaporin expression, leading to further volume depletion, AKI, and increased calcium absorption in the proximal and distal nephron. Last, ingestion of alkali leads to production of alkaline urine, which further promotes calcium reabsorption.

To summarize, excessive ingestion of calcium carbonate by the patient resulted in hypercalcemia, AKI, and metabolic alkalosis, a triad that is the hallmark of calcium-alkali syndrome.

The correct answer is B

Comment: The initial treatment of symptomatic hypercalcemia should have three elements to provide some efficacy, both initially and several days later. Virtually all patients with significant hypercalcemia have some element of extracellular fluid volume contraction. For this reason, it is important to start therapy with intravenous saline. Calcitonin is effective in approximately 70% of patients. It is safe and relatively nontoxic, and it acts to lower serum calcium within several hours. For this reason, it should be the initial agent of choice to provide some benefit before the more potent bisphosphonates become maximally effective. It typically loses its effectiveness within 48 hours in most patients. For this reason, it is important to begin therapy with a bisphosphonate at this time, as well.

Bisphosphonates block the hypocalciuric effect of PTH. They act by interfering with metabolic activity of osteoclasts; they are cytotoxic to osteoclasts. Pamidronate, zoledronic acid, and etidronate are the currently available agents that are recommended for the treatment of malignancy-associated hypercalcemia. Zoledronate appears to be the most efficacious with a maximum effect occurring in 48 to 72 hours.

The correct answers are A, C, D, E, and G

Comment: Chronic hypercalcemia leads to a defect in concentrating ability that may induce polyuria and polydipsia in up to 20% of patients. This is due to down regulation of aquaporin-2 water channels and activation of the normal calcium-sensing receptor in the loop of Henle, which reduces sodium chloride reabsorption in this segment and thereby impairs the interstitial osmotic gradient.

Hypercalcemia directly shortens the myocardial action potential, which is reflected in a shortened QT interval. Band keratopathy, a reflection of subepithelial calcium phosphate deposits in the cornea, is a very rare finding in patients with hypercalcemia. It extends, as a horizontal band across the cornea in the area that is exposed between the eyelids. Calcium salts probably precipitate in that site because of the higher local pH induced by the evaporation of CO ₂ .

Constipation is the most common gastrointestinal complaint in patients with hypercalciuria. It is likely related to decreased smooth muscle tone. Personality changes and affective disorders have been described at a serum calcium level above 12 mg/dL. Confusion, organic psychosis, hallucinations, somnolence, and coma are seen until serum calcium concentration is above 16 mg/dL.

The correct answers are A, B, C, and D

Comment: Mild hypercalcemia is only rarely associated with renal insufficiency. Higher elevations in serum calcium concentration (12 to 15 mg/dL) can lead to a reversible fall in glomerular filtration rate that is mediated by direct renal vasoconstriction and natriuresis-induced volume contraction.

Long-standing hypercalcemia and hypercalciuria lead to the development of chronic hypercalcemic nephropathy, which may be irreversible and continue to progress despite cure of the underlying conditions such as hyperparathyroidism. Calcification, degeneration, and necrosis of the tubular cells lead to cell sloughing and eventual tubular atrophy as well as interstitial fibrosis and calcification. These changes are most prominent in the medulla but can also be seen in the cortex. Interstitial calcium deposition can be detected by radiographic imaging studies. Nephrocalcinosis that can be detected by plain radiography of the abdomen is advanced and reflects severe renal parenchymal involvement. Ultrasonography or CT can detect earlier stages of the disease. An interstitial nephritis with granuloma formations is common in sarcoidosis, but the development of clinical disease manifested by renal insufficiency is unusual.

The correct answers are A, B, and F

Comment: Diagnosis of PHP is always high on the list in an outpatient presenting with hypercalcemia. Granulomatous disease is certainly a possibility given the hilar adenopathy and hypercalcemia of several years duration. Measurement of calcitriol is therefore a good idea. An abdominal flat plate to look for nephrocalcinosis is reasonable in case of the history of kidney failure.

The correct answers are A, D, and F

Comment: The elevated calcitriol and low PTH levels are consistent with granulomatous disease. There is hilar adenopathy on the radiography image, which makes the diagnosis of sarcoidosis very likely. It is very unlikely that exposure to a tanning salon alone would lead to elevated calcitriol level as calcitriol production is normally feedback regulated. However, in a patient with a granulomatous disease where calcitriol production is not feedback regulated, increased production of calcidiol, 25-hydroxyvitamin D, would aggravate hypercalcemia.

The correct answers are A, B, D, and E

Comment: Treatment of hypercalcemia or hypercalciuria is aimed at reducing intestinal calcium absorption and calcitriol synthesis. This can be achieved by reducing the calcium intake (no more than 400 mg/dL), reducing oxalate intake, elimination of dietary vitamin D supplements, avoidance of sun exposure, and low-dose glucocorticoid therapy (prednisone, 10 to 30 mg/dL). Serum calcium concentration typically begins to fall in 2 days, but the full hypocalcemic response may take 7 to 10 days depending upon the prednisone dose. Inhibition of calcitriol synthesis by the activated mononuclear cells is thought to play a major role in this response, although inhibition of intestinal calcium absorption and of osteoclast may also actively contribute.

Concurrent restriction of dietary oxalate is required to prevent a marked increase in oxalate absorption and hyperoxaluria. The latter may increase the risk of kidney calculus formation, even though urinary calcium excretion is reduced.

Oxalate absorption is normally limited by the formation of insoluble calcium oxalate salts in the intestinal lumen. Dietary calcium restriction leads to more free oxalate than can then be absorbed if oxalate intake is unchanged.

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 PHP. This occurs in 5% to 20% of patients with this condition.

The correct answer is B

Comment: This patient has PHP and fulfills the criteria for surgical removal of parathyroid glands, because her 24-hour urinary calcium excretion is greater than 250 mg and her serum calcium is greater than 1 mg/dL above the normal level. The indications for surgery in patients with hyperparathyroidism include (1) a serum calcium concentration of 1.0 mg/dL or more above the upper limit of normal, (2) hypercalciuria (urinary calcium excretion > 400 mg/day) while having a usual diet, (3) a creatinine clearance 30% or more below the age-matched normal level, (4) 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), (5) age less than 50 years old, and (6) problem with periodic follow-up.

The correct answers are B, E, and F

Comment: Foscarnet (trisodium phosphonoformate) has been shown to chelate calcium. The plasma-ionized calcium typically falls by 0.4 mg/dL with a 120 mg/kg dose. These changes are clinically significant and can be associated with paresthesia and seizures. Acute respiratory alkalosis associated with hyperventilation due to pain or anxiety can also reduce the ionized calcium concentration. This is because the binding of calcium to protein is pH-dependent.

The correct answer is C

Comment: The pathophysiology underlying hypercalcemia of malignancy can be compared with its counterpart-primary hyperparathyroidism. Both syndromes are humoral in nature, with one being caused by PTH and the other by PTHrp. Both are associated with hypercalcemia, accelerated osteoclastic bone resorption, and reductions in renal phosphate reabsorption; both display increases in nephrogenous cyclic adenosine monophosphate excretion as a result of the interaction of PTH or PTHrp with the proximal tubular PTH/PTHrp receptor/adenyl cyclase complex.

The correct answer is B

Comment: Many clinical disorders are associated with hypercalcemia including hyperparathyroidism, malignancies, granulomatous disease, tubulointerstitial nephritis with uveitis (TINU), vitamin A and vitamin D intoxications, thiazide diuretic use, excessive calcium supplementation leading to milk-alkali syndrome, prolonged immobilization, and calcium-sensing receptor mutation.

In our patient, diagnosis of hyperparathyroidism was excluded as the blood PTH level was suppressed. Although our patient had normocytic anemia and leukopenia, normal bone marrow aspirate and chest imaging made a diagnosis of malignancy unlikely. In our case, there was no history of excessive vitamin D supplementation and levels of 25(OH)-vitamin D and 1,25(OH) ₂ -vitamin D were normal, so excluding this as a cause. Likewise, there was no history of retinoic acid use in our patient, so this was excluded. There was no history of diuretic use. Our patient was quite active at presentation, with no reported debilitating injury, so immobilization cause was also excluded. Calcium-sensing receptor was excluded, as this mutation is associated with familial hypercalcemia and our patient-appropriate hypercalciuria.

At this point, TINU and sarcoidosis remained on our differentials.

To differentiate TINU and various granulomatous diseases such as tuberculosis, cat-scratch disease, and berylliosis, the following investigations were undertaken: angiotensin-converting enzyme (ACE) test, conjunctival biopsy, renal biopsy, Mantoux tuberculosis testing, and Bartonella henselae serologies. Results led to a final diagnosis of sarcoidosis.

Sarcoidosis is a multisystem granulomatous disease of unknown etiology that rarely presents in childhood. Classically, clinical features of sarcoidosis in older children include pulmonary infiltration and lymphadenopathy. As outlined above, however, our patient presented with renal manifestations including elevated creatinine, hypertension, and associated hypercalcemia, hypercalciuria, and nephrocalcinosis. Renal involvement occurs in approximately 10% to 20% of adult patients with sarcoidosis, and impairment is most commonly a result of disorders of calcium homeostasis, leading to nephrocalcinosis and nephrolithiasis. In children, sarcoidosis-related renal disease occurs with comparable frequency (11%) and can manifest in a variety of similar ways. Like in adults, nephrocalcinosis and nephrolithiasis leading to obstructive uropathy are the most common causes of renal injury in childhood disease.

Sarcoidosis can also affect the kidney directly through inflammatory processes targeting the tubular interstitium and glomerulus, leading to granulomatous interstitial nephritis (GIN), the most common renal lesion on biopsy, and a spectrum of glomerular diseases, respectively. Membranous glomerulonephritis (GN) is the most frequent glomerular disease reported in the setting of sarcoidosis and has curiously been linked to antiphospholipase A2 receptor antibodies (anti-PLA2R), suggesting that perhaps primary and secondary membranous GN share this specific pathophysiologic process. Other reported renal complications of sarcoidosis include proliferative or crescentic GN, focal segmental glomerulosclerosis, and immunoglobulin A (IgA) nephropathy.

Treatment is required when renal manifestations of sarcoidosis are present due to the significant risk of progression to renal failure. To target the disease process, the mainstay of treatment is corticosteroids. Not only do steroids decrease inflammation, they decrease calcium absorption from the intestine and block activity of 1-alpha hydroxylase in macrophages, thereby inhibiting production of 1,25-vitamin D and depressing 24-vitamin D hydroxylase. There is no standard protocol for dose and duration of corticosteroid therapy; however, most studies recommend a starting dose of 0.5 to 1.0 mg/kg, which should be maintained for at least 4 weeks. Both hyperhydration and treatment with steroids were used as initial therapies in our patient and were effective in improving both hypercalcemia and renal function.

Mycophenolate mofetil (MMF) can be used as a steroid-sparing therapy. Although evidence for use of MMF is limited, several case reports and case series demonstrate benefit. Usually MMF is started after approximately 4 weeks of steroid therapy.

Methotrexate has been used for treating some extrarenal manifestations of sarcoidosis; however, importantly, it is not recommended for treatment of renal sarcoidosis due to its exclusive excretion via the kidneys.

Tumor necrosis factor α (TNF-α) is thought to play a significant role in granuloma formation and maintenance in sarcoidosis; therefore, anti-TNF therapy has long been a proposed target for treatment. Efficacy of treatment with infliximab (an anti-TNF-α monoclonal antibody) has been demonstrated (though the evidence is supported by case reports only) and has been shown to improve renal function in the setting of steroid-resistant disease. Conversely, etanercept (a soluble TNF-α receptor blocker) induces sarcoidosis. Although the pathogenesis of sarcoidosis induced by etanercept remains unclear, multiple mechanisms may contribute to granuloma formation, including inability to induce complement-mediated cell lysis, as is accomplished with anti-TNF-α antibodies (infliximab) that inhibit both soluble and membrane forms of TNF-α.

The correct answer is C

Comment: This infant presented with failure to thrive, excessive irritability, polyuria, polydipsia, and severe hypercalcemia. PHP was ruled out as the child had undetectable PTH and normal serum phosphorus levels. Malignancy as a cause of hypercalcemia was less likely as serum alkaline phosphatase levels were at the upper limit of normal and there was no organomegaly or abdominal mass detected on physical examination or by ultrasonography of the abdomen. There was no contact history of tuberculosis, and a chest x-ray did not reveal any evidence of sarcoidosis or tuberculosis. CASR mutation was ruled out, as this condition is associated with low urinary calcium excretion and normal to high serum PTH level.

Finally, the elevated serum 25(OH) vitamin D (> 450 ng/mL) established the diagnosis of vitamin D intoxication as a cause for hypercalcemia. Hypercalciuria in this patient is the cause of diabetes insipidus (polyuria). Hypercalciuria can cause polyuria by impairing calcium-sensor receptors on the apical membrane of the collecting duct cells leading to inhibition of aquaporin-2 expression in the collecting duct.

Vitamin D is a fat-soluble vitamin, which can be acquired exogenously from fish, oysters, and fortified dairy products or can be synthesized in the skin from 7-dehydrocholesterol after exposure to ultraviolet radiation. According to the American Academy of Pediatrics, 200 IU/day of vitamin D supplementation is recommended in all breastfed infants or non-breastfed infants on fortified milk of < 500 mL/day. There are limited data on safe upper tolerable limits of vitamin D in children. The stated safe upper limit vitamin D tolerability is 4000 IU/day in adults but varies from 2500 to 4000 IU/day in young children.

Vitamin D intoxication has been reported in infants/children consuming fortified milk products and even in children receiving pharmacological doses of vitamin D for treatment of documented or suspected vitamin D-deficient rickets. Vitamin D interplays with PTH to maintain normal serum levels of calcium. Both PTH and calcitriol increase serum calcium levels by activating osteoclastic bone resorption and increasing renal absorption of filtered calcium. Calcitriol also causes increased absorption of calcium from the intestine. Normal serum levels of calcium are 8.8 to 10.3 mg/dL during childhood. An overdose of vitamin D leads to hypercalcemia, hyperphosphatemia, and high calcium/phosphorus product-associated complications. Following the administration of an excess of vitamin D, the vitamin can be found in the circulation for several months, as it is stored in fatty tissues.

Treatment of vitamin D intoxication includes removal of the exogenous source, forced diuresis by adequate hydration and loop diuretics as well as the use of glucocorticoids, which decrease production of 1,25 (OH) ₂ -vitamin D3 and thereby decrease intestinal reabsorption of calcium. In patients with alarmingly high levels or hypercalcemia refractory to conventional therapy, intravenous pamidronate in doses of 0.5 to 1 mg/kg or even lower doses of 0.35 mg/kg are used.

The correct answer is D

Comment: Hypercalcemia results when the entry of calcium into the circulation exceeds its excretion into the urine or deposition into bone. This can occur when there is accelerated bone resorption, excessive gastrointestinal absorption, decreased renal excretion of calcium, or in some disorders, a combination. It is often a clue to an underlying disease process. The differential diagnoses for hypercalcemia in children are wide, which include PHP, FHH, hypercalcemia of malignancy, vitamin D intoxication, chronic granulomatous disorders such as tuberculosis and sarcoidosis, drug-induced hyperkalemia (thiazide diuretics, lithium, theophylline), prolong immobilization, milk-alkali syndrome, and other conditions such as hyperthyroidism, adrenal insufficiency pheochromocytoma.

In our 12-year-old patient with lymphadenopathy and hepatosplenomegaly, the hypercalcemia is likely secondary to malignancy or chronic granulomatous disease. The diagnosis of sarcoidosis was confirmed with the finding of a normal bone marrow biopsy, coupled with a raised serum ACE level and lymph node biopsy showing multiple noncaseating epithelioid cell granulomata. Supporting this is the fact that hypercalcemia in our patient was associated with a suppressed serum PTH and PTHrp, increased fractional excretion of calcium, and a high 1,25-dihydroxycholecalciferol level. His presentation with polyuria is attributable to a concentrating defect secondary to hypercalcemia, which in turn led to the increased sensation of thirst.

Symptomatic sarcoidosis is rare in children. In infants and children below the age of 4 years, the most common presentation is with the triad of skin, joint, and eye involvement without the typical pulmonary disease, whereas in older children, involvement of the lungs, lymph nodes, and eyes predominates. In a series of Danish children with sarcoidosis, the most common presenting features were erythema nodosum and iridocyclitis. Other features of sarcoidosis include fatigue, malaise, fever, and weight loss. African American children tend to have a higher incidence of lymph node involvement, hyperglobulinemia, and hypercalcemia. Although the lungs are the most frequently affected organs, the disease can affect any organ system in the body. Up to 30% of patients present with extrapulmonary disease; the most prominent sites involve the skin, eyes, reticuloendothelial system, musculoskeletal system, exocrine glands, heart, kidney, and central nervous system.

The correct diagnosis is B

Comment: This patient was given 400,000 IU/week of vitamin D for 3 months, giving a total dose of 4,800,000 IU. The elevated serum calcium and vitamin D levels along with hypercalciuria and low PTH level, after excluding other causes of hypercalciuria, supported the diagnosis of vitamin D intoxication.

Hydration with saline, use of loop diuretics and corticosteroids followed by pamidronate (1 mg/kg) are the main stay of treatment. Although bisphosphonate is frequently used to treat childhood hypercalcemia due to malignancies, osteogenesis imperfect, and osteoporosis, its use in vitamin D intoxication is very limited. The nitrogen-containing bisphosphonates, including alendronate, ibandronate, pamidronate disodium, risedronate, and zoledronic acid, induce osteoclast apoptosis and are powerful inhibitors of bone resorption. Calcitonin (2 to 4 U/kg bid) given by subcutaneous injection is effective when given early during the course of disease. However, as resistance to the hormone occurs quite rapidly, it is rarely used. Both pamidronate disodium and zoledronic acid can rapidly lower serum and urinary calcium levels in patients with hypercalcemia due to a variety of causes, and the effects can last for weeks.

The correct answer is B

Comment: The patient was a 10-month-old girl who presented with irritability, macrocephaly, loss in milestones, hepatomegaly, anemia, thrombocytopenia, coagulopathy, and severe hypercalcemia of uncertain etiology causing hypertension and renal insufficiency. She underwent an extensive workup to define the etiology of hypercalcemia. She had appropriately low PTH for the degree of hypercalcemia and normal serum phosphorus, which ruled out PHP. Her 25-hydroxyvitamin D levels were normal, ruling out hypervitaminosis D. Her 1,25-dihydroxyvitamin D level was also normal, which was inconsistent with transient hypercalcemia. Transient hypercalcemia is a rare autosomal recessive trait with mutation in the CYP24A1 gene, the product of which is involved in breakdown of 1,25-dihydroxyvitamin D. Chest x-ray showed no evidence of granulomatous disease (sarcoidosis or tuberculosis). Based on other laboratory and x-ray findings, malignancy-related paraneoplastic syndrome was also a less likely cause of hypercalcemia. FHH was also considered. This condition is inherited as an autosomal dominant trait and results from heterozygous mutations in the CASR causing hypocalciuria and hypercalcemia with inappropriately normal PTH levels. The patient had low urine calcium to creatinine ratio for age, but with no family history of hypercalcemia and low PTH, FHH was a less likely diagnosis. Another rare bone disease is hypophosphatasia, which can result in hypercalcemia with metaphyseal dysplasia and severe rachitic changes similar to the findings in our patient. Hypophosphatasia is inherited either in an autosomal dominant or recessive fashion. The latter condition is due to a mutation in the alkaline phosphatase, liver/bone/kidney ( ALPL ) gene, which results in decrease in tissue-nonspecific alkaline phosphatase (TNSALP) in osteocytes and chondrocytes, which impairs bone mineralization leading to rickets. Hypercalcemia is hypothesized to be related to bone resorption in conjunction with impaired bone mineralization. Plasma pyridoxal 5′-phosphate and urinary phosphoethanolamine are elevated in such cases. Our patient had very low serum alkaline phosphatase levels, which ruled out hypophosphatasia.

Within 4 days of admission, vitamin A and E levels became available: vitamin A levels were retinol 1.48 mg/L (0.2 to 0.5 mg/L), retinyl palmitate 2.71 mg/L (0 to 0.1 mg/L); vitamin E level was alpha tocopherol 12 mg/L (3.5 to 8 mg/L). Based on history, clinical, biochemical, and radiological evidence, the child was diagnosed with hypervitaminosis secondary to chronic ingestion of excessive amounts of vitamin A. The mother was supplementing about 10 drops of vitamin A with each bottle of goat milk. The infant received 40 to 50 oz of goat milk daily. This resulted in the ingestion of 20,100 IU/day of vitamin A from a medicinal supplement; the Recommended Daily Allowance for 1 to 3 years is 1000 IU/day. This was in addition to an estimated ingestion of 1936 IU from goat milk per day, which makes the total ingestion 22,000 U daily.

The treatment for vitamin A toxicity is mainly supportive. All sources of vitamin A ingestion must be eliminated from the diet. Intralipids have been used for cardiotoxic lipid-soluble drug intoxications but are of no proven benefit in hypervitaminosis A.

The correct answer is B

Comment: This patient has PHP and fulfills the criteria for surgical removal of hyperparathyroidism because his 24-hour urinary calcium excretion is greater than 250 mg, and his serum calcium is greater than 1 mg/dL above normal.

The correct answer is A

Comment: In the study cited, low dietary protein was associated with secondary hyperparathyroidism because it led to reduce dietary calcium absorption. Recent data also suggest that high dietary protein intake is not associated with a reduction in bone mineral content—in fact, the opposite was found.

The correct answer is E

Comment: Bisphosphonates do not produce hypercalciuria. Zoledronic acid (bisphosphonate) is 100 times more potent that pamidronate. Bisphosphonates are most effective as an initial treatment for hypercalcemia. PTHrp-induced hypercalciuria is not influenced by bisphosphonates.

The correct answers are A, C, and E

Comment: The most likely cause of the hypocalcemia is deposition of calcium in osteoblastic metastasis from acute leukemia. Elevated levels of PTH, alkaline phosphatase, and calcitriol characterize this condition.

The correct answers are A, C, D, E, and G

Comment: Chronic hypercalcemia leads to a defect in concentrating ability that may induce polyuria and polydipsia in up to 20% of patients. This is due to down regulation of aquaporin-2 water channels and activation of the normal calcium-sensing receptor in the loop of Henle, which reduces sodium chloride reabsorption in this segment and thereby impairment of the interstitial osmotic gradient.

Hypercalcemia directly shortens the myocardial action potential, which is reflected in a shortened QT interval. Band keratopathy, a reflection of subepithelial calcium phosphate deposits in the cornea, is a very rare finding in patients with hypercalcemia. It extends, as a horizontal band across the cornea in the area that is exposed between the eyelids. Calcium salts probably precipitate in that site because of the higher local pH induced by the evaporation of CO ₂ . Constipation is the most common gastrointestinal complaint in patients with hypercalcemia. It is likely related to decreased smooth muscle tone. Personality changes and affective disorders have been described at serum calcium concentrations above 12 mg/dL-confusion, organic psychosis, hallucinations, somnolence, and coma is rare until the serum calcium concentration is above 16 mg/dL.

The correct answers are A, B, C, and D

Comment: Mild hypercalcemia is only rarely associated with renal insufficiency. Higher elevations in the serum calcium concentration (serum calcium 12 to 15 mg/dL) can lead to a reversible fall in glomerular filtration rate that is mediated by direct renal vasoconstriction and natriuresis-induced volume contraction. Long-standing hypercalcemia and hypercalciuria lead to the development of chronic hypercalcemic nephropathy, which may be irreversible and continue to progress despite cure of the underlying condition, such as hyperparathyroidism. Calcification, degeneration, and necrosis of the tubular cells lead to cell sloughing and eventual tubular atrophy as well as interstitial fibrosis and calcification (nephrocalcinosis).

These changes are most prominent in the medulla but can also be seen in the cortex. Interstitial calcium deposition can be detected radiographically. Nephrocalcinosis that can be detected by a plain film of the abdomen is advanced and reflects severe renal parenchymal involvement. Ultrasonography or CT can detect earlier stages of the disease. An interstitial nephritis with granuloma formation is common in sarcoidosis, but the development of clinical disease manifested by renal insufficiency is unusual.

While the patient is receiving therapy, and you are monitoring the serum calcium, it is time to begin ordering diagnostic studies.

The correct answers are A, B, and F

Comment: The diagnosis of PHP is always high on the first list in a patient presenting with hypercalcemia.

Granulomatous disease is certainly a possibility given the hilar adenopathy and hypercalcemia of several years duration. Measurement of calcitriol is therefore a good idea. An abdominal flat plate to look for nephrocalcinosis is reasonable given the history of renal failure.

The PTH level was 2 pg/mL (normal is 10 to 65 pg/mL) and the 1,25(OH) ₂ D (calcitriol) was 72 ng/mL (normal range is 9 to 47 ng/mL). The abdominal flat plate shows bilateral nephrocalcinosis.

The correct answers are C, D, and F

Comment: The elevated calcitriol and low PTH are consistent with granulomatous disease. There is hilar adenopathy on the chest x-ray, which makes the diagnosis of sarcoidosis very likely. It is very unlikely that exposure to a tanning salon alone would lead to elevated calcitriol production that is normally feedback-regulated. However, in a patient with a granulomatous disease where calcitriol production is not feedback-regulated, increased production of 25 (OH) D would aggravate the hypercalcemia.

The correct answers are A, B, D, and E

Comment: Treatment of the hypercalcemia and hypercalciuria is aimed at reducing intestinal calcium absorption and calcitriol synthesis.

This can be achieved by reducing calcium intake (no more than 400 mg/day), reducing oxalate intake, eliminating dietary vitamin D supplements, avoidance of sun exposure, and low-dose glucocorticoid therapy (10 to 30 mg/day of prednisone). The serum calcium concentration typically begins to fall in 2 days, but the full hypocalcemic response may take 7 to 10 days, depending upon the prednisone dose. Inhibition of calcitriol synthesis by the activated mononuclear cells is thought to play a major role in this response, although inhibition of intestinal absorption and of osteoclast activity also may contribute.

Concurrent restriction of dietary oxalate is required to prevent a marked increase in oxalate absorption and hyperoxaluria. The latter may increase the risk of kidney stone formation, even though urinary calcium excretion is reduced. Oxalate absorption is normally limited by the formation of insoluble calcium oxalate salts in the intestinal lumen. Dietary calcium restriction leads to more free oxalate than can then be absorbed if oxalate intake is unchanged.