2.2. BASES TEÓRICAS
2.2.4. Reconocimiento de la Unión de hecho:
Diagnosis
Primary hyperparathyroidism is the most common cause of hypercalcemia in outpatients. Primary hyperparathyroidism com- monly presents as asymptomatic hypercalcemia. Less common presentations are kidney stones, osteoporosis, pancreatitis, and fractures (osteoporosis). Malignancy is the most common cause of hypercalcemia in hospitalized patients. Hypercalcemia may also occur with the use of lithium (PTH-mediated) or thiazide diuretics (non–PTH-mediated) and in the setting of excessive ingestion of vitamin D and calcium. Sarcoidosis may be associated with hypercalcemia (10% of patients) and hypercalciuria (50% of patients).
Measure the ionized calcium to exclude pseudohypercalcemia caused by an increase in plasma proteins capable of binding calcium; total calcium will be increased and ionized calcium will be normal.
If hypercalcemia is confirmed, check calcium, PTH, phosphate, creatinine, and 25-hydroxyvitamin D levels. If PTH is elevated or inappropriately “normal” in the setting of elevated serum calcium, the most likely cause is primary hyperparathyroidism.
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◆Don’t Be trickeD
• In patients with hypercalcemia and normal PTH levels, measure urinary calcium excretion to exclude familial hypocalciuric hypercalcemia.
If hyperparathyroidism is confirmed and surgery is indicated, do a sestamibi parathyroid scan to look for an adenoma.
StUDY tABLe: Causes of Hypercalcemia
Diagnosis Key features include hypercalcemia and …
Primary hyperparathyroidism PTH elevated (80%) or inappropriately normal (20%); phosphorus low
X-rays may show chondrocalcinosis or osteitis fibrosa cystica (rare) Humoral hypercalcemia of malignancy PTH suppressed; phosphorus normal or low
PTH-related protein may be elevated but is not needed for diagnosis
Local osteolytic lesions PTH suppressed; phosphorus normal or low
Lytic bone metastases result in increased mobilization of calcium from the bone
Multiple myeloma PTH suppressed; phosphorus elevated
Look for patients presenting with new kidney injury and anemia Diagnose with serum and urine protein immunoelectrophoresis Granulomatous disease (sarcoidosis and TB) and B-cell lymphoma PTH suppressed; phosphorus elevated; calcitriol elevated
(particularly in sarcoidosis)
Milk-alkali syndrome PTH suppressed; phosphorus, creatinine, carbon dioxide elevated Consider in healthy persons in whom primary hyperparathyroidism has been excluded
Excessive ingestion of calcium-containing antacids is a cause (rare)
Hyperthyroidism Hypercalcemia is a frequent incidental finding in hyperthyroidism due to direct stimulation of osteoclasts by thyroid hormone
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Endocrinology and Metabolism
Primary hyperparathyroidism is the most common manifestation of MEN1.
StUDY tABLe: Multiple Endocrine Neoplasia Types 1 and 2
MEN1 MEN2
Multigland hyperparathyroidism is the most common
manifestation Multigland hyperparathyroidism is the least common manifestation Pituitary neoplasms associated with prolactinoma (amenorrhea
and erectile dysfunction), acromegaly (enlargement of hands, feet, tongue, frontal bossing), Cushing disease (bruising, hypertension, central obesity, hirsutism)
Medullary thyroid cancer is the most common manifestation and may be associated with a palpable neck mass
Pancreatic NETs associated with gastrinoma (diarrhea, ulcers), insulinoma (fasting hypoglycemia), vasoactive intestinal polypeptide-secreting tumor (watery diarrhea, hypokalemia), carcinoid syndrome (diarrhea, flushing, right heart valvular lesion)
Pheochromocytoma (hypertension and palpitations)
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◆Don’t Be trickeD
• About 50% of patients with primary hyperparathyroidism have coexisting vitamin D deficiency, and serum and urine calcium levels may be decreased. Select measurement of serum vitamin D levels in all patients with hyperparathyroidism.
Therapy
Parathyroidectomy is indicated for patients with primary hyperparathyroidism and hypercalcemic complications, such as kid- ney stones, bone disease, or previous episodes of hypercalcemic crisis. Asymptomatic patients are surgical candidates if they have any of the following:
• serum calcium level >1 mg/dL above upper limit of normal
• estimated GFR <60 mL/min/1.73 m2
• reduction in bone mineral density (T-score <−2.5)
• age <50 years
Watch for a precipitous fall in the serum calcium level caused by relative hypoparathyroidism after parathyroidectomy (“hungry bone” syndrome). Monitor serum calcium after surgery, and give oral calcium if mild hypocalcemia develops.
Treat patients who are not candidates for parathyroidectomy with cinacalcet or bisphosphonates. Hypercalcemia requiring acute intervention is most common in the setting of malignancy. Select:
• volume resuscitation with normal saline
• furosemide if the calcium level has not normalized following volume repletion • IV bisphosphonates
• oral glucocorticoid therapy if hypercalcemia is due to multiple myeloma or sarcoidosis
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❖test Yourself
A 44-year-old man has a 1-year history of fatigue and poor concentration. His serum calcium level is 10.9 mg/dL, serum phosphorus level is 2.8 mg/dL, and PTH level is 75 pg/mL.
ANSWER: Diagnose primary hyperparathyroidism, measure serum vitamin D levels, and select parathyroidectomy.
Endocrinology and Metabolism
Hypocalcemia
Diagnosis
Most cases of hypocalcemia are due to low serum albumin levels; the ionized calcium concentration is normal. Total calcium declines by 0.8 mg/dL for each 1 g/dL decrement in serum albumin concentration.
The most common cause of acquired hypocalcemia is surgical excision of or vascular injury to the parathyroid glands. Other causes include:
• neck irradiation
• congenital hypoparathyroidism (DiGeorge syndrome) • autoimmune destruction
• infiltrative diseases
• complication of plasmapheresis
Autoimmune hypoparathyroidism occurs as an isolated defect or as part of polyglandular autoimmune syndrome type 1 in association with mucocutaneous candidiasis, adrenal insufficiency, hypogonadism, and malabsorption.
In addition to hypoparathyroidism, hypocalcemia may result from pseudohypoparathyroidism, vitamin D deficiency, hypomagnesemia, or pancreatitis, or may occur in the setting of rhabdomyolysis, kidney failure, and tumor lysis syndrome. Look for:
• circumoral and acral paresthesias • carpal-pedal spasm
• positive Trousseau sign • positive Chvostek sign
Order calcium, phosphate, magnesium, creatinine, PTH, 25-hydroxyvitamin D, albumin, and/or ionized calcium tests. Order an ECG to evaluate for QTc interval prolongation.
StUDY tABLe: Differential Diagnosis of Hypocalcemia
Diagnosis Key features include hypocalcemia and…
Hypoparathyroidism Hyperphosphatemia; low PTH and variable vitamin D levels Pseudohypoparathyroidism (resistance to PTH) Hyperphosphatemia; elevated PTH and normal vitamin D levels
CKD Hyperphosphatemia; elevated PTH and low 1,25-dihydroxyvitamin D levels
Vitamin D deficiency Hypophosphatemia; bone tenderness or fibromyalgia-like syndrome, weakness, gait difficulty, osteomalacia
Impaired PTH secretion and PTH resistance Magnesium deficiency (small bowel bypass, diarrhea, alcoholism, diuretic therapy) “Hungry bone” syndrome Recent parathyroidectomy
Therapy
Treat acute symptomatic hypocalcemia with IV calcium gluconate and vitamin D. Chronic hypocalcemia is treated with oral calcium supplements and vitamin D. Choose the type of vitamin D based on the presence of underlying disease:
• kidney disease: calcitriol (1,25-dihydroxyvitamin D) • liver disease: 25-hydroxycholecalciferol
• any other cause of hypocalcemia: cholecalciferol (D3) or ergocalciferol (D2)
The main side effect of therapy is hypercalciuria and nephrolithiasis. Remember to correct hypomagnesemia with magnesium supplements.
Endocrinology and Metabolism
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❖test Yourself
A 46-year-old woman has cramps in her hands and feet. She has pernicious anemia and Hashimoto thyroiditis. Her serum calcium level is 7.9 mg/dL and her serum phosphorus level is 4.1 mg/dL.
ANSWER: Diagnose autoimmune hypoparathyroidism and select a serum PTH level.
Osteoporosis
Screening
DEXA is indicated for all women >65 years of age and in women <65 years with risk factors for osteoporosis:
• glucocorticoid therapy • low body weight
• current cigarette smoking • alcohol use
• family history of hip fracture
Screen men and women with risk factors for secondary osteoporosis (glucocorticoid use, hyperparathyroidism, ADT [men], malabsorption).
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• Do not repeat annual DEXA in women with normal DEXA results without risk factors. Although the optimal screening interval is unknown, most experts recommend 10 to 15 years for women with normal or slightly low bone mineral density and no risk factors.
Diagnosis
Osteoporosis is a silent skeletal disorder characterized by compromised bone strength and an increased predisposition to fractures.
• DEXA T-score of −1.0 to −2.4 defines osteopenia • DEXA T-score of ≤−2.5 defines osteoporosis
• Osteoporosis is also diagnosed by a history of fragility fracture (fracture from a fall at standing height or lower).
The most common cause of osteoporosis in women is estrogen deficiency and in men, testosterone deficiency. Secondary causes include:
• hyperthyroidism, hyperparathyroidism, Cushing syndrome • malabsorption (Crohn disease, intestinal resection, celiac disease) • rheumatoid arthritis
• medications (excessive thyroid hormone, glucocorticoids, phenobarbital, phenytoin, thiazolidinediones) • multiple myeloma
• CKD, chronic liver disease • vitamin D deficiency
Reasonable tests include: CBC; TSH; calcium, phosphorus, and creatinine levels; liver chemistry tests; ESR; serum 25-hydroxy- vitamin D level (if vitamin D deficiency is suspected); and tTG antibodies (if celiac disease is suspected). In the absence of fractures, primary osteoporosis is associated with no abnormalities on laboratory testing.
Endocrinology and Metabolism
Therapy
Encourage all patients to stop smoking, reduce alcohol intake, and begin resistance exercises. Exposure to sunlight is especially important for home-bound persons or nursing-home residents. Supplement calcium and vitamin D intake.
Indications for antiresorptive therapy:
• osteoporosis
• osteopenia (if additional high-risk factors are present) • previous fragility fracture
• vertebral or hip fracture
The Fracture Risk Assessment Tool (FRAX) estimates the 10-year probability of hip fracture and major osteoporotic fracture. Antiresorptive treatment is cost effective when the risk of major osteoporotic fracture is ≥20% or the risk of hip fracture is ≥3%. Treatment options:
• alendronate, ibandronate, or risedronate as first-line therapy • raloxifene for patients who cannot tolerate bisphosphonates
• teriparatide (synthetic recombinant human PTH 1-34) for severe osteoporosis with fractures • calcitonin for pain from osteoporotic fractures
Oral bisphosphonates are taken on an empty stomach, and patients must remain upright for at least 30 minutes. These agents are contraindicated in patients with CKD or esophageal disease. IV zoledronate (once yearly) or IV ibandronate (once every 3 months) are alternative therapeutic options.
No recommended duration of therapy is available. Stopping therapy after 5 years is reasonable in women who have a stable BMI, no history of fracture, and are at low risk for fracture. The duration of the drug holiday is unknown but may be determined by changes in DEXA measurements.
Drugs for osteoporosis have various adverse effects:
• oral bisphosphonate therapy may lead to erosive esophagitis and atypical hip fracture • IV bisphosphonate therapy can lead to osteonecrosis of the jaw
• raloxifene is associated with thromboembolic disease • teriparatide is associated with osteosarcoma
Treatment with teriparatide should be limited to 2 years.
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◆Don’t Be trickeD
• Do not use estrogen replacement therapy for osteoporosis in postmenopausal women.
• Do not combine teriparatide with a bisphosphonate.
• IV bisphosphonates are contraindicated in patients with severe hypocalcemia and CKD.
• Raloxifene has not been shown to reduce hip fracture risk.
Follow-up
Although no consensus exists, DEXA 24 months after beginning therapy for osteoporosis is reasonable.
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❖test Yourself
An 82-year-old woman has been taking thyroid hormone since age 31 years. She has lost about 7.6 cm (3.0 in) in height. Serum TSH level is <0.01 μU/mL (normal 0.5 to 5.0 μU/mL).
ANSWER: The diagnosis is thyroid hormone–induced osteoporosis. Reduce the thyroid hormone dose and schedule DEXA.
Endocrinology and Metabolism
Osteomalacia
Diagnosis
Osteomalacia is a metabolic bone disease resulting from failure of the organic matrix of bone to mineralize because of lack of available calcium or phosphorus. Many cases of osteomalacia are related to abnormalities in vitamin D but may also result from deficiencies of calcium or phosphate.
Look for:
• fatigability, malaise, and bone pain • generalized bone tenderness • proximal muscle weakness
• Looser zones (bands perpendicular to the bone surface visible on x-rays) • hypocalcemia and hypophosphatemia
• elevated serum alkaline phosphatase level
Evaluate for underlying conditions that may lead to intestinal malabsorption of vitamin D, such as celiac disease, or abnormali- ties in vitamin D metabolism, such as liver and kidney disease. Diagnosis is confirmed with bone biopsy when necessary.
Therapy
If osteomalacia is secondary to vitamin D deficiency, treat with oral ergocalciferol 1000 to 2000 U/d and elemental calcium 1 g/d.
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◆Don’t Be trickeD
• Not all fractures in older adult patients are due to osteoporosis. Look for osteomalacia, particularly in nursing-home residents.