Hyperparathyroidism for the ABIM

Hyperparathyroidism for the American Board of Internal Medicine Exam

Hyperparathyroidism is characterized by overproduction of parathyroid hormone (PTH), which regulates calcium and phosphate metabolism.
Parathyroid Hormone (PTH): Increases serum calcium by stimulating osteoclasts to resorb bone, enhancing renal calcium reabsorption, and increasing active vitamin D production to improve gastrointestinal calcium absorption. PTH also promotes renal phosphate excretion.
Primary Hyperparathyroidism: Results from autonomous overproduction of PTH by the parathyroid glands, leading to hypercalcemia. This is most often due to a single parathyroid adenoma (80-85%), but can also result from parathyroid hyperplasia (15%) or, rarely, parathyroid carcinoma (<1%).
Secondary Hyperparathyroidism: Occurs due to chronic hypocalcemia, which leads to compensatory overproduction of PTH. This is commonly seen in chronic kidney disease (CKD) due to impaired vitamin D synthesis and phosphate retention.
Tertiary Hyperparathyroidism: Develops when secondary hyperparathyroidism becomes autonomous and excessive, often seen in patients with long-standing CKD who have undergone renal transplantation.

Primary Hyperparathyroidism:
Parathyroid Adenoma: Most common cause, usually a benign tumor of a single parathyroid gland.
Parathyroid Hyperplasia: Involves diffuse enlargement of all parathyroid glands.
Parathyroid Carcinoma: Rare, accounting for less than 1% of cases, but usually presents with severe hypercalcemia.
Genetic Conditions: Multiple endocrine neoplasia type 1 (MEN1) and MEN2A are associated with parathyroid adenomas or hyperplasia.
Secondary Hyperparathyroidism:
Chronic Kidney Disease: The most common cause due to decreased 1,25-dihydroxyvitamin D production and phosphate retention, leading to hypocalcemia.
Vitamin D Deficiency: Can lead to compensatory parathyroid hormone release.
Malabsorption Syndromes: Such as celiac disease, can lead to secondary hyperparathyroidism due to decreased calcium and vitamin D absorption.

Primary Hyperparathyroidism:
Asymptomatic Hypercalcemia: Most patients are asymptomatic and diagnosed through routine lab work.
Symptomatic Hypercalcemia:
"Bones": Osteopenia, osteoporosis, and bone pain due to increased bone resorption.
"Stones": Nephrolithiasis (kidney stones) due to hypercalciuria.
"Abdominal Groans": Nausea, vomiting, constipation, and peptic ulcers.
"Psychic Moans": Depression, cognitive dysfunction, and fatigue.
Neuromuscular: Muscle weakness, myalgia, and decreased deep tendon reflexes.
Cardiovascular: Hypertension, shortened QT interval, and rarely, arrhythmias.
Secondary Hyperparathyroidism:
Symptoms are related to underlying chronic kidney disease or vitamin D deficiency, with hypocalcemia and elevated PTH.
Bone Pain and Muscle Weakness: Common due to high PTH and low calcium levels.
Tertiary Hyperparathyroidism:
Persistent hypercalcemia despite correction of the underlying cause, often after kidney transplantation.

Serum Calcium: Elevated in primary and tertiary hyperparathyroidism, while it is low or normal in secondary hyperparathyroidism.
Serum Phosphate: Typically low in primary hyperparathyroidism due to increased renal excretion. In secondary hyperparathyroidism (especially in CKD), phosphate levels may be elevated.
Parathyroid Hormone (PTH) Levels:
Primary Hyperparathyroidism: Elevated PTH despite high calcium levels.
Secondary Hyperparathyroidism: Elevated PTH with low or normal calcium.
Tertiary Hyperparathyroidism: Markedly elevated PTH with elevated calcium.
Vitamin D Levels: Assess for deficiency, particularly in secondary hyperparathyroidism.
24-hour Urine Calcium: High in primary hyperparathyroidism, distinguishing it from familial hypocalciuric hypercalcemia (FHH), which has low urinary calcium.
Bone Mineral Density (BMD): Osteopenia or osteoporosis is common, particularly at cortical bone sites (e.g., distal radius, femoral neck).
Imaging:
Sestamibi Scan: Localizes parathyroid adenomas in preparation for surgery.
Neck Ultrasound: May also help identify enlarged parathyroid glands.

Primary Hyperparathyroidism:
Parathyroidectomy: The definitive treatment for symptomatic hyperparathyroidism or in cases with complications (e.g., nephrolithiasis, osteoporosis). It is also recommended for asymptomatic patients with high calcium (>1 mg/dL above normal), reduced renal function, or young age (<50).
Medical Management:
Monitoring: For asymptomatic patients not undergoing surgery, regular monitoring of calcium, kidney function, and bone density is required.
Bisphosphonates: Used to treat osteoporosis by inhibiting bone resorption.
Cinacalcet: A calcimimetic that decreases PTH secretion, useful in patients with severe hypercalcemia who are not surgical candidates.
Hydration and Diuretics: Adequate hydration helps prevent kidney stones. Loop diuretics (e.g., furosemide) promote calcium excretion but should be used cautiously to avoid dehydration.
Secondary Hyperparathyroidism:
Treat the Underlying Cause: Address vitamin D deficiency or manage chronic kidney disease.
Phosphate Binders: Used in CKD to lower serum phosphate levels.
Vitamin D Supplementation: Calciferol (vitamin D2 or D3) or active forms (calcitriol) are used to suppress PTH in CKD.
Cinacalcet: Decreases PTH secretion and lowers serum calcium and phosphate levels.
Tertiary Hyperparathyroidism:
Parathyroidectomy: Often necessary in cases of persistent hypercalcemia post-transplantation or in patients with intractable symptoms.

Hypercalcemia Crisis: A severe, life-threatening condition characterized by extreme hypercalcemia (>14 mg/dL) that can cause dehydration, altered mental status, and cardiac arrhythmias. Treatment includes aggressive IV fluids, bisphosphonates, calcitonin, and dialysis in severe cases.
Osteoporosis and Fractures: Due to excessive bone resorption.
Nephrolithiasis: Kidney stones from hypercalciuria.
Renal Impairment: Chronic hypercalcemia can lead to nephrocalcinosis and renal insufficiency.
Cardiovascular Disease: Chronic hypercalcemia increases the risk of hypertension and arrhythmias.

Key Points

Primary Hyperparathyroidism is most commonly caused by a parathyroid adenoma and leads to hypercalcemia. Clinical features include "bones, stones, abdominal groans, and psychic moans." Diagnosis is confirmed by elevated calcium and PTH levels. Parathyroidectomy is the definitive treatment for symptomatic patients, while medical management may be used for asymptomatic cases.
Secondary Hyperparathyroidism occurs in response to chronic hypocalcemia, usually in chronic kidney disease. Treatment focuses on correcting the underlying cause, using phosphate binders, vitamin D supplementation, and calcimimetics like cinacalcet.
Tertiary Hyperparathyroidism occurs after long-standing secondary hyperparathyroidism becomes autonomous. Parathyroidectomy is often required for definitive management.
Complications of untreated hyperparathyroidism include osteoporosis, kidney stones, renal insufficiency, and cardiovascular disease.