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Chapter 567 Hyperparathyroidism
Daniel A. Doyle
Excessive production of parathyroid hormone (PTH) can result from a primary defect of the parathyroid glands such as an adenoma or hyperplasia (primary hyperparathyroidism).
More often, the increased production of PTH is compensatory, usually aimed at correcting hypocalcemic states of diverse origins (secondary hyperparathyroidism). In vitamin D–deficient rickets and the malabsorption syndromes, intestinal absorption of calcium is deficient but hypocalcemia and tetany may be averted by increased activity of the parathyroid glands. In pseudohypoparathyroidism, PTH levels are elevated because a mutation in the Gsα protein interferes with response to PTH. Early in chronic renal disease, hyperphosphatemia results in a reciprocal fall in the calcium concentration with a consequent increase in PTH, but in advanced stages of renal failure, production of 1,25(OH)2D3 is also decreased, leading to worsening hypocalcemia and further stimulation of PTH. In some instances, if stimulation of the parathyroid glands has been sufficiently intense and protracted, the glands continue to secrete increased levels of PTH for months or years after kidney transplantation, with resulting hypercalcemia.
Childhood hyperparathyroidism is rare. Onset during childhood is usually the result of a single benign adenoma. It usually becomes manifested after 10 yr of age. There have been a number of kindreds in which multiple members have hyperparathyroidism transmitted in an autosomal dominant fashion. Most of the affected family members are adults, but children have been involved in about 30% of the pedigrees. Some affected patients in these families are asymptomatic, and disease is detected only by careful study. In other kindreds, hyperparathyroidism occurs as part of the constellation known as the multiple endocrine neoplasia (MEN) syndromes or of the hyperparathyroidism–jaw tumor syndrome.
Neonatal severe hyperparathyroidism is a rare disorder. Symptoms develop shortly after birth and consist of anorexia, irritability, lethargy, constipation, and failure to thrive. Radiographs reveal subperiosteal bone resorption, osteoporosis, and pathologic fractures. Symptoms may be mild, resolving without treatment, or can have a rapidly fatal course if diagnosis and treatment are delayed. Histologically, the parathyroid glands show diffuse hyperplasia. Affected siblings have been observed in some kindreds, and parental consanguinity has been reported in several kindreds. Most cases have occurred in kindreds with the clinical and biochemical features of familial hypocalciuric hypercalcemia. Infants with neonatal severe hyperparathyroidism may be homozygous or heterozygous for the mutation in the Ca2+-sensing receptor gene, whereas most persons with 1 copy of this mutation exhibit autosomal dominant familial hypocalciuric hypercalcemia.
MEN type I is an autosomal dominant disorder characterized by hyperplasia or neoplasia of the endocrine pancreas (which secretes gastrin, insulin, pancreatic polypeptide, and occasionally glucagon), the anterior pituitary (which usually secretes prolactin), and the parathyroid glands. In most kindreds, hyperparathyroidism is usually the presenting manifestation, with a prevalence approaching 100% by 50 yr of age and occurring only rarely in children <18 yr of age. With appropriate DNA probes, it is possible to detect carriers of the gene with 99% accuracy at birth, avoiding unnecessary biochemical screening programs.
The gene for MEN type I is on chromosome 11q13; it appears to function as a tumor suppressor gene and follows the two-hit hypothesis of tumor development. The first mutation (germinal) is inherited and is recessive to the dominant allele; this does not result in tumor formation. A second mutation (somatic) is required to eliminate the normal allele, which then leads to tumor formation.
Hyperparathyroidism–jaw tumor syndrome is an autosomal dominant disorder characterized by parathyroid adenomas and fibro-osseous jaw tumors. Affected patients can also have polycystic kidney disease, renal hamartomas, and Wilms tumor. Although the condition affects adults primarily, it has been diagnosed as early as age 10 yr.
MEN type II may also be associated with hyperparathyroidism (Chapter 563.2).
Transient neonatal hyperparathyroidism has occurred in a few infants born to mothers with hypoparathyroidism (idiopathic or surgical) or with pseudohypoparathyroidism. In each case, the maternal disorder had been undiagnosed or inadequately treated during pregnancy. The cause of the condition is chronic intrauterine exposure to hypocalcemia with resultant hyperplasia of the fetal parathyroid glands. In the newborn, manifestations involve the bones primarily, and healing occurs between 4 and 7 mo of age.
At all ages, the clinical manifestations of hypercalcemia of any cause include muscle weakness, fatigue, headache, anorexia, abdominal pain, nausea, vomiting, constipation, polydipsia, polyuria, weight loss, and fever. When hypercalcemia is of long duration, calcium may be deposited in the renal parenchyma (nephrocalcinosis), with progressively diminished renal function. Renal calculi can develop and can cause renal colic and hematuria. Osseous changes can produce pain in the back or extremities, disturbances of gait, genu valgum, fractures, and tumors. Height can decrease from compression of vertebrae; the patient can become bedridden. Detection of completely asymptomatic patients is increasing with the advent of automated panel assays that include serum calcium determinations.
Abdominal pain is occasionally prominent and may be associated with acute pancreatitis. Parathyroid crisis can occur, manifested by serum calcium levels >15 mg/dL and progressive oliguria, azotemia, stupor, and coma. In infants, failure to thrive, poor feeding, and hypotonia are common.
Mental retardation, convulsions, and blindness can occur as sequelae of long-standing hypercalcemia. Psychiatric manifestations include depression, confusion, dementia, stupor, and psychosis.
The serum calcium level is elevated; 39 of 45 children with adenomas had levels >12 mg/dL. The hypercalcemia is more severe in infants with parathyroid hyperplasia; concentrations ranging from 15 to 20 mg/dL are common, and values as high as 30 mg/dL have been reported. Even when the total serum calcium level is borderline or only slightly elevated, ionized calcium levels are often increased. The serum phosphorus level is reduced to about 3 mg/dL or less, and the level of serum magnesium is low. The urine can have a low and fixed specific gravity, and serum levels of nonprotein nitrogen and uric acid may be elevated. In patients with adenomas who have skeletal involvement, serum phosphatase levels are elevated, but in infants with hyperplasia the levels of alkaline phosphatase may be normal even when there is extensive involvement of bone.
Serum levels of intact PTH are elevated, especially in relation to the level of calcium. Calcitonin levels are normal. Acute hypercalcemia can stimulate calcitonin release, but with prolonged hypercalcemia, hypercalcitoninemia does not occur.
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