A 25-year-old woman is brought to the emergency department due to progressive lethargy. For the last 3 weeks, she has also had loss of appetite, constipation, muscle weakness, and increased thirst and urination. The patient's medical history is unremarkable. She takes no prescription medications but has been taking large doses of vitamin D supplements in the belief that they are beneficial for her health. The patient does not use tobacco, alcohol, or illicit drugs. On physical examination, she is stuporous and has dry mucous membranes. The metabolic abnormality most likely responsible for this patient's clinical findings can also occur in which of the following conditions?
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Moderate doses of vitamin D are often recommended for patients with inadequate dietary intake to improve bone mineralization. However, excessive vitamin D can cause symptomatic hypercalcemia, with impaired depolarization of neuromuscular membranes (eg, muscle weakness, constipation, confusion) and impaired concentration of urine in the distal tubule (polyuria/polydipsia). Chronic vitamin D intoxication can also lead to renal stone formation and bone demineralization with associated bone pain (although normal vitamin D levels facilitate bone mineralization, toxicity increases osteoclast activity and bone turnover).
Normally, 25-hydroxyvitamin D is converted to 1,25-dihydroxyvitamin D (the active form) by 1-α-hydroxylase in the kidneys, a process regulated by parathyroid hormone (PTH). However, patients with granulomatous diseases (eg, sarcoidosis, tuberculosis) can have PTH-independent conversion due to expression of 1-α-hydroxylase in activated macrophages. A similar process can occur in Hodgkin disease and some non-Hodgkin lymphomas.
(Choice A) Biliary obstruction is associated with altered lipid absorption and deficiencies of fat-soluble vitamins (eg, A, D, E, and K).
(Choice B) Carcinoid tumor cells synthesize excessive amounts of serotonin. When these cells metastasize to the liver, the release of serotonin into the systemic circulation results in carcinoid syndrome (eg, episodic cutaneous flushing, bronchospasm/wheezing, diarrhea).
(Choice C) Hemochromatosis is associated with excessive intestinal absorption of iron and accumulation in parenchymal organs. Patients classically develop liver cirrhosis, heart failure, skin hyperpigmentation, and diabetes mellitus ("bronze diabetes").
(Choice D) Pheochromocytoma is associated with elevated levels of metanephrines and catecholamines. Patients typically have paroxysmal headache, diaphoresis, tachycardia, and hypertension.
(Choice F) Wilson disease (hepatolenticular degeneration) is characterized by impaired incorporation of copper into ceruloplasmin and defective excretion of excess copper into bile. This leads to elevated blood free copper levels and deposition in the liver (cirrhosis) and brain (motor abnormalities, psychiatric symptoms).
Educational objective:
Excessive vitamin D intake can lead to hypercalcemia and cause mental status changes, muscle weakness, constipation, and polyuria/polydipsia. Activated macrophages in sarcoidosis and other granulomatous diseases express 1-α-hydroxylase, leading to excess production of 1,25-dihydroxyvitamin D and hypercalcemia.