PROGRESS
IN ENDOCRINOLOGY
AND METABOLISM
Pathogenesis and Management of Hypoparathyroidism and Other Hypocalcemic Disorders Arthur
B. Schneider
and Louis M. Sherwood
Hypocalcemia frequently presents as an acute medical emergency or a chronic disorder which is difficult to control. Occasionally, it is found in routine blood screening tests when it is not anticipated. Recent developments in basic endocrine science have contributed greatly to our understanding and treatment of hypocalcemic disorders. The maintenance of a normal serum calcium concentration depends on the balanced actions of parathyroid hormone (PTH), vitamin D, and, to a lesser extent, calcitonin. Recent work on PTH secretion has defTned the factors controlling its secretion in normal and abnormal states. In primary hypoparathyroidism, hormone secretion is decreased or absent, while in most other forms of hypocalcemia, secretion is stimulated recondarily by the hypocalcemia. However, acute or chronic disorders associated with hypomagneremia may also decrease effective PTH secretion. Patients with the rare disorder, pseudohypoparathyroidism, have defects of hormone action and usually have elevated levels of PTH prior to therapy. Several forms of pseudohypoparathyroidism have been recognized, each representing a defect at a different site of PTH action. Calcitonin excess, as noted in medullary carcinoma of the thyroid, could theoretically cause hypocalcemia, but rarely does so. Vitamin D undergoes a series of two carefully con-
trolled hydroxylation reactions leading to the final active metabolite, 1,25-dihyroxycholecalciferol. Chronic ingestion of certain drugs can lead to osteomalacia and hypocalcemia by potentiating the metabolism of vitamin D to inactive compounds. At least one form of rickets has been shown to result from a specific enzyme defect in the vitamin D pathway. Severe renal damage limits the conversion of vitamin D to its active form and contributes to vitamin D resistance. Current progress in the area depends on the development of procedures for the measurement of the metabolites in plasma and assessing the role of the vitamin (hormone) in normal and abnormal physiology. Although the therapy of acute hypocalcemia is usually readily accomplished, chronic hypocalcemia remains a very difficult therapeutic problem. Vitamin D, the hallmark of therapy, is a long-acting drug with a narrow therapeutic range. The complications of the disease and therapy are sometimes irreversible. The unraveling of vitamin D metabolism has led to the development of new therapeutic agents which might provide better relief of chronic hypocalcemic states. This review relates new information about calcium homeostasis to the clinical situation encountered in the patient with hypocalcemia.
From the Departments of Medicine, Michael Reese Medical Center and the Prirzker School of’ Medicine, University of Chicago, Chicago, Ill. Received for publicarion November 27. 1974. Supported in part by USPHS Grant HD 08225 and grants from the John A. Hartford Foundation and the Michael Reese Research Institute. Reprint requests should be addressed to Dr. Louis M. Sherwood, Department oJ‘ Medicine. Michael Reese Medical Center, 29th Street and Ellis Avenue. Chicago. III. 60616. G 1975 by Grune & Stratton, Inc.
Metabolism,
Vol.
24, No. 7
(July),
1975
871
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HE DRAMATIC CLINICAL picture of hypocalcemia reflects the critical role which calcium plays in maintaining normal physiologic processes. To prevent hypocalcemia, rapidly responsive, high-capacity, homeostatic mechanisms developed during vertebrate evolution. Much of this development occurred when animals left calcium-rich sea water and became terrestrial.’ In order to maintain constancy of the serum calcium concentration in the face of large variations in calcium intake, stable reserves of mineral were established. In addition, sensitive mechanisms for controlling ion flux at the sites of absorption, storage, and excretion appeared. In calcium-poor fresh water, fish developed calcium-storage organs similar to mammalian bone. In calcium-rich sea water, bone was either abandoned or became inactive. At this point, calcitonin-producing ultimobranchial glands appeared, presumably to prevent hypercalcemia. The evolutionary factors which brought about this development are not entirely clear, since a calcium-lowering effect of calcitonin in fish has not been consistently demonstrated.2 The pituitary gland and the Stannius corpuscles of fish appear to be more directly involved in teleost calcium metabolism. The former increases the serum calcium concentration, while the latter decreases it.3 A hypocalcemic factor has recently been identified in extracts of Killifish corpuscles.4 Neither of these mechanisms apparently has been preserved during subsequent evolution. In amphibia, both bone and paravertebral lime sacs serve as calcium reservoirs, and the parathyroid glands appear for the first time. Calcium-regulatory mechanisms are highly developed in birds to accommodate the large fluxes of calcium caused by eggshell formation. In mammals, the parathyroid glands and the skeleton itself are the princiwith calcitonin being relegated to a pal regulators of calcium homeostasis, minor role, if any at all, in this process5 The average daily intake of calcium in adult man is between 0.5 and 1.0 g. As the quantity of calcium in the diet decreases, adaptive mechanisms increase the fraction of intestinal calcium which is absorbed.6 This adaptation, the first defense against hypocalcemia, is now believed to be due to an increase in the efficiency of the conversion of vitamin D to its active metabolite.7 Net absorption of approximately 200 mg/day is needed to balance calcium losses in the urine and stool of normal man. When calcium absorption is inadequate and causes the serum calcium to fall, mobilization of mineral from the skeleton begins. Since there is normally a constant exchange of calcium between the surface of bone and extracellular fluid, mobilization of additional calcium represents an increase in the rate of bone resorption relative to the rate of bone formation. In normal adult subjects, rates of bone formation and resorption are equivalent; less than 1% of the total skeletal pool of calcium (1 kg) is readily available for exchange with extracellular fluid calcium. Additional calcium can be mobilized by the action of increased quantitites of parathyroid hormone (PTH) and/or vitamin D. The circulating level of PTH is responsive to the ionized calcium and magnesium concentration in the serum and related in first-order fashion to total divalent cation concentration.8 Recent studies in vivo suggest that PTH secretion is most carefully regulated near the physiologic concentrations of calcium and magnesium, so that the relation between PTH and divalent cation concentration re-
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semblesa sigmoid dose-response curve.9 PTH maintains the serum calcium not only by mobilizing mineral from bone, but also by reducing renal excretion of calcium. The sensitivity of the latter mechanism is shown by the fact that 7- 10 g of calcium are filtered every 24 hr, but only 100-400 mg are excreted. At serum calcium concentrations below 7.5 mg/lOO ml, urine calcium falls to zero. Recent studies on the metabolism of vitamin D have shown that the actions of vitamin D are intimately related to those of PTH.” In the kidney, 25-hydroxycholecalciferol (25-OHD,) is transformed to 1,25-dihydroxycholecalciferol (1,25-diOHD,) which is the active metabolite of vitamin D.” This activation appears to be regulated either by the extra and/or intracellular calcium and phosphate concentrations, perhaps through a direct effect of PTH.“,‘-’ Whatever the details of this control mechanism, it is clear that vitamin D tends to maintain the calcium concentration by its actions on the intestine, bone, and possibly the kidney. Like steroid hormones, vitamin D carries out its metabolic effects by entering target cells, binding to cytoplasmic and then nuclear receptors, and initiating increases in protein synthesis. ‘4,‘5 In the intestine, vitamin D increases the active transport of calcium into the circulation, an effect which appears to be independent of PTH and which may be related to the stimulation by vitamin D of the synthesis of a calcium-binding protein.16 In bone. vitamin D increases the rate of entry of calcium into the circulation, but it also seems to play a permissive role for the action of PTH. The effect of vitamin D on the kidney is more complex and appears to be dose related. Renal calcium reabsorption may be increased so that calcium is retained in the body, and, m certain situations, phosphate is also retained. The role of vitamin D in bone formation has been discussed extensively.” The mechanism by which it causes the reversal of osteomalacia is not completely understood. Some investigators place the emphasis on its tendency to increase the calcium x phosphorus product which is favorable for the deposition of mineral in osteoid tissue.18 Others stress the ratio of bone-forming to resorbing cells whose formation is controlled by PTH and vitamin D.19 Calcitonin is an antagonist of the action of PTH, since it prevents mobilization of calcium and phosphorus from bone. ” In theory, excessive calcitonin activity could lead to hypocalcemia. However, it has been observed that the very large concentrations of calcitonin seen in medullary carcinoma of the thyroid gland do not usually lead to significant lowering of the serum calcium.5 In addition, the concentration of calcitonin in the human thyroid is considerably lower than that in other species. Calcitonin probably plays a small role, therefore, in calcium homeostasis. It has been suggested that calcitonin participates in the prevention of postprandial hypercalcemia, its secretion being stimulated by gastrin.21 A potential role of calcitonin in fetal development, where bone turnover is greater, needs to be evaluated more fully. The homeostatic mechanisms for calcium are sensitive to the concentration of the ionized fraction. This is normally about 45’!;, of the total serum calcium, the major fraction of the rest being bound to albumin, with smaller amounts being bound to other proteins or complexed with ions. It is now possible to determine accurately the concentration of ionized calcium in serum with an ionspecific electrode. This is not used in most clinical laboratories, however, and
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it is important to estimate potential alterations in the ionized fraction in disease states. The Hastings-McLean nomogram,22 available in most textbooks of physiology, accurately estimates the ionized calcium concentrations when serum protein concentrations are altered. A useful rule of thumb is that a decrease in the concentration of serum albumin of 1 g/100 ml will lower the total calcium by about 0.8 mg/lOO ml. In addition, the pH is critical in regulating the ionized fraction. In order to obtain a complete indication of the circulating calcium, therefore, it is necessary to know the total and ionized calcium, the serum protein concentration, and the serum pH. CLINICAL
MANIFESTATIONS
OF HYPOCALCEMIA
Maintaining a normal calcium concentration in the extracellular fluid is of such general importance that virtually every organ system can be affected by hypocalcemia. Calcium participates actively in a wide variety of cellular membrane and intravascular physiologic processes. Examples are ion transport at membrane surfaces and the maintenance of normal neuromuscular membrane potential. Calcium is a cofactor in many reactions, notably in the contraction of actomyosin and the activation of the coagulation cascade. More recently, it has become clear that calcium has important interactions with the adenyl cyclase system. Finally, it should not be forgotten that calcium is the principal mineral of hydroxyapatite of bone. Hypocalcemia most often presents clinically as one of several neuromuscular and neurologic syndromes, the most dramatic and common being tetany. Children may show jerking muscular contractions which represent rhythmic neural discharges, and these can culminate in generalized seizures. In adults, heightened muscle contractions can cause cramps and carpopedal spasm. Striking flexion occurs at the wrists and metacarpalphalangeal joints, with adduction of thumbs and extension of the interphalangeal joints. Similarly, spasm of muscles in the feet and eyes may present a characteristic picture, associated occasionally with urinary retention. In extreme cases, most frequently in children, spasm of the muscles of the glottis can cause inspiratory stridor. Chvostek’s sign and Trousseau’s sign reveal latent tetany, since hypocalcemia results in irritability of the peripheral nerves. In the latter test, local hypoxia at the blood pressure cuff site produces the contraction since replacement of a cuff on the same arm without allowing a return of circulation still relieves the spasm. Both signs, particularly Chvostek’s, can be found in some normal people, and neither are invariably present in hypocalcemia. Albright and Reifenstein state in their textbook that contraction of the eyelid muscles in response to striking the facial nerve only occurs in hypoparathyroidism.23 A sensory prodrome often occurs with tetany; characteristically it is a tingling sensation or parasthesias most evident in the extremities and around the mouth, as well as sensations of muscle tension or cramps. These sensory and motor changes are believed to be due to changes in resting membrane potential with increased nerve conduction rates. Hyperventilation can lead to a mild respiratory alkalosis, which in turn will exacerbate the symptoms of hypocalcemia. The diffuse effects of hypocalcemia on the central nervous system are manifested in changes which occur in the electroencephalogram (EEG).24 High-
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voltage slow waves occupy an increasing portion of the total record and appear to reflect the degree of hypocalcemia. In a recent case study reported by Swash and Rowan, sequential EEGs were recorded in a hypoparathyroid patient during periods of both hypo- and hypercalcemia. At both extremes there was an increase in the slow wave burst activity. These recordings could be distinguished, however, since sharp spike activity occurred only in hypocalcemia, while triphasic waves occurred only during hypercalcemia. In this particular patient, EEG changes were recorded when the serum calcium was below 7 mg/ 100 ml. Increased intracranial pressure with bilateral papilledema occasionally occurs in hypocalcemia, and this can be associated with seizures or other severe neurologic deficits. 26 With unilateral symptoms, a space-occupying lesion can represent a difficult differential diagnosis. Several conditions resulting from dysfunction of the extrapyramidal-motor system have been reported. These include Parkinsonism, chorea, and athetosis.27*28These conditions arise, in part, from calcification of the basal ganglia which may or may not be appreciated on x-ray. In addition, an effect of calcium on membrane stability must also be important, since restoration of serum calcium often leads to amelioration of the symptoms, even when basal ganglia calcification is present. Basal ganglia calcification occurs in hypoparathyroidism and pseudohypoparathyroidism and is not only a consequence of hypocalcemia and hyperphosphatemia, but also may be related to genetic factors (Fig. 1). One family has been described with congenital calcification of the
Fig. 1. Lateral skull x-ray (A) and frontal tomogmm (B) showing bilateml calcification of the basal ganglia in a patient with hypoparathyroidism.
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basal ganglia in the absence of abnormalities of serum calcium and phosphorus.29 One report describes an exaggerated tendency to extrapyramidal side effects of chlorpromazine and related compounds in patients who are hypocalcemic.30 Cataracts are a serious complication of hypoparathyroidism and are not reversible with correction of the metabolic disturbance. The prevalence of this complication of hypocalcemia is illustrated by the study of Ireland et a1.3’ In patients with surgically-produced hypoparathyroidism, nine had macroscopic cataracts, and an additional seven had undergone lens extraction. Of 18 patients who had neck surgery more than 5 yr previously, seven had macroscopic cataracts, and five had undergone iridectomy. The typical cataract in these patients had one or more layers of cortical opacity separated from the capsule and each other by clear cortex. Hypocalcemia appears to interfere with the normal hydration of the lens by disturbing the active cation-transport processes. In no instance did restoration of a normal serum calcium with vitamin D result in regression of the cataracts. Moniliasis involving the skin and mucous membranes, and even the bowel, occurs in association with idiopathic hypoparathyroidism, but only rarely with 32The data indicate that hypocalcemia per se does other forms of hypocalcemia. not predispose to monilial infection (vide infra). Hypocalcemia causes a characteristic change in the electrocardiogram.33 The Q-T interval, when corrected for the rate, i.e., Q-Tc, is abnormally prolonged. This is due to prolongation of the S-T segment without change in the QRS configuration, the T wave, or the voltage of the S-T segment. An improved correlation with serum calcium is obtained with the Q-OTC interval.” This is obtained from Q - OTC = Q - oT/m where oT is the onset of the T wave. It is reported that this interval is particularly useful in the evaluation of newborn infants. A value above 0.19 set in a full term and above 0.20 in a premature infant is abnormal. Severe hypocalcemia can result in congestive heart failure, presumably due to decrease in inotropic activity of the heart.35 The relationship of hypocalcemia to the skeletal system depends on the cause. In those situations where there is inadequate PTH, hypocalcemia is at least partly due to decreased mobilization of mineral from bone. On the other hand, where secondary hyperparathyroidism occurs as a response to hypocalcemia, extensive bone changes varying from osteomalacia to osteitis fibrosa cystica may be observed. An intermediate state exists in some patients with pseudohypoparathyroidism where there may be resistance to the effects of PTH, principally at the kidney, increased secretion of PTH secondary to the hypocalcemia, and bony changes due to parathyroid hormone excess. This will be described in more detail in the discussion of individual disorders below. The role of calcium ion in the secretion of hormones and their actions on target tissues is presently under active investigation. Physiologic effects of a hypocalcemic state on these phenomena are theoretically possible and merit further investigation. Release of the peptide hormones, insulin,36 thyrotropin, hormone,3* and ACTH, prolactin, luteinizing hormone, 37 follicle-stimulating presumably from storage granules into the extracellular growth hormone,39
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space, can be inhibited by a reduction in extracellular calcium concentration. The parathyroid glands and the pancreatic glucagon-secreting cellsN appear to be unusual in this regard, since decreasing calcium concentrations results in increased, rather than decreased, hormone release. Rasmussen and his colleagues have studied the role of calcium in the actions of hormones which activate the adenyl cyclase system. 4’ It is apparent from their work that complex interactions may occur, but the exact mechanisms and clinical consequences are not yet completely clear. ETIOLOGY
OF HYPOCALCEMIA
Although a number of disorders may be associated with hypocalcemia, it is a relatively uncommon condition. The factors or disorders responsible for the reduced calcium concentration are usually relatively easy to determine. Because of the rapid progress which has occurred in understanding calcium homeostasis, new diagnostic and therapeutic modalities are becoming available. In order to understand their applicability and rationale, the following description of the causes of hypocalcemia stresses the pathophysiology of each condition. Hypoparathyroidism Hypoparathyroidism is most often an iatrogenic disease occurring after thyroid or parathyroid surgery. The population at risk is therefore clearly defined. However, the onset of biochemical or clinical signs suggestive of the disease can begin anywhere from a few days to many years following surgery. In 23 postoperative hypoparathyroid patients followed from 1954 to 1964 by Dimich et al.,42 14 developed symptoms within 2 wk, and five developed symptoms between 6 and 12 mo after surgery (symptoms in the other four patients were of uncertain duration). In five patients there was a delay in the diagnosis of l-19 yr. Spontaneous (idiopathic) hypoparathyroidism is a rare condition. Since the onset of symptoms can be insidious, a long delay in establishing the diagnosis is not uncommon. In the series reported by Dimich et a1.,42 6 mo27 yr (mean, 10.6 yr) elapsed from the onset of symptoms to a definite diagnosis. Bronsky et al.32 reviewed 50 reported cases in the literature in 1958 and noted that over half of the patients manifested symptoms before 10 yr of age, while the average age of onset was 17. One of Dimich’s patients was 68 yr old. Kunstadter et a1.43 reported the occurrence of idiopathic hypoparathyroidism in two newborns. This extremely unusual occurrence is very difficult to distinguish, at the present time, from idiopathic neonatal hypocalcemia. Measurements of circulating PTH may be useful in this regard. Three forms of idiopathic hypoparathyroidism can be delineated, although they may in fact be closely related. In the DiGeorge syndrome, absence of the parathyroid glands is associated with thymic aplasia.44 This disorder presumably results from maldevelopment of the third pharyngeal pouch during embryogenesis. A second form of idiopathic hypoparathyroidism is associated variously with hypofunction of the adrenal cortical glands, ovarian failure, pernicious anemia, Hashimoto’s thyroiditis, hypothyroidism, diabetes, moniliasis, and occasionally malabsorption. This is a familial disorder with those who manifest disease before 6 mo of age conforming to an X-linked recessive in-
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heritance pattern while the remainder probably represent autosomal recessive inheritance.45*46 Blizzard, Chee, and Davis4’ demonstrated that humoral antibodies against a variety of endocrine tissues could be found in these patients. Specifically, they showed that 28 of 74 sera (38%) from patients with idiopathic hypoparathyroidism contained anti-parathyroid gland antibodies. Of the 74 patients, 18 had Addison’s disease, seven had pernicious anemia, 21 had moniliasis, two had cirrhosis, four had alopecia totalis, two had premature menopause, four had nontoxic goiter, one had Hashimoto’s thyroiditis, and one had myxedema. In addition to those with clinically apparent disease, six patients showed antiadrenal antibodies, nine showed antithyroid antibodies, and ten showed parietal cell antibodies in their sera. In 93 patients with idiopathic Addison’s disease, anti-parathyroid gland antibodies were present in 26%. Blizzard et a1.47 stress that there is no evidence that the circulating antibodies play any role in the pathogenesis of the disease, but they do indicate the likelihood that a common underlying genetic or pathophysiologic mechanism exists. In addition to susceptibility to candidiasis, these patients are more susceptible to infection. This abnormality reflects a defect in cellular immunity which is often abnormal to a variable degree.48-50 The third form of idiopathic hypoparathyroidism is not associated with other disorders. Clinical diagnosis is based on the criteria first delineated by Drake, Albright, Bauer, and Castleman. 5’ The concentration of serum calcium is low and that of serum phosphorus high. Renal failure, malabsorption, and alkalosis must be ruled out. Rickets must be absent and a history suggestive of chronic tetany or other compatible symptoms is usually present. The symptom complex found in hypoparathyroidism results from the lack of adequate parathyroid hormone, with at least three factors contributing to the development of hypocalcemia: (1) Breakdown of hydroxyapatite and release of bone mineral is reduced by the lack of the hormone, (2) the conversion of vitamin D to its active metabolite is reduced, accounting for a decrease in calcium absorption by the gut and decreased bone resorption, and (3) renal conservation of calcium is impaired. Urinary calcium in patients with hypoparathyroidism is low, but such patients also have a decreased ability to retain a calcium load. Therefore, renal wasting of calcium contributes to hypocalcemia. Hyperphosphatemia results from the reduced phosphate clearance secondary to PTH deficiency. When hypocalcemia is present during the period of tooth formation, severe dental abnormalities may occur. 52The earliest changes are in the dentin which remains uncalcified and shows transverse ridging. Hypoplasia of the enamel, severe caries, delayed eruption, and premature loss of teeth also occur. On x-ray, shortening of the roots and absence of the lamina dura are seen. Occasionally a physiologic form of hypoparathyroidism is seen in the newborn of hypercalcemic mothers. 53 Ionized calcium crosses the placental membrane readily and, if elevated in maternal serum, can cause an increase in the serum calcium in the fetus. Persistent hypercalcemia in the fetus causes trasient suppression of its parathyroid glands, leading to hypocalcemia after birth. In any child who manifests neonatal hypocalcemia, the diagnosis of maternal hyperparathyroidism should be suspected. The hypocalcemic condition can per-
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Fig. 2. The original patient described by Albright et al.“’ with pseudohypoparathyroidism shown at age 28 in 1948 on the left and 21 yr later on the right. Although seizures and symptoms of hypocalcemia wwe prominent early in life, when the potient was seen by the authors in 1969, they were not. The major clinical manifestations were mental retardation and abnormal movements suggestive of extrapymmidal dysfunction.
sist in the neonate for as long as several months. Neonatal hypocalcemia is not usually associated with maternal hyperparathyroidism, however, and is usually a transient disorder of unknown etiology which is more common in premature newborns. Reports of neonatal hypocalcemia in association with the use of high phosphate formulas have appeared.s4 Pseudo- and Pseudopseudohypoparathyroidism In 1942, Albright and his associates” recognized a syndrome with hypocalcemia and hyperphosphatemia in which (in contrast to simple hypoparathyroidism) there was a markedly diminished response to administered parathyroid extract. They suggested that this was a syndrome of organ unresponsiveness to PTH (a human counterpart of the Seabright-Bantam syndrome in fowl). To this disorder and its associated skeletal adnormalities, i.e., short stature, round face, shortened metacarpals (Fig. 2). they gave the appelation pseudohypoparathyroidism. Recent laboratory efforts, particularly those by Chase and Aurbach and their colleagues,56 have confirmed the inability of PTH to evoke its usual metabolic responses in patients with this syndrome. Sufficient evidence has now accumulated to establish the fact that PTH normally acts at its target tissues, bone and kidney, in a manner analogous to other peptide hormones. Specific membrane-bound receptors are present in the target tissue cells which transform the recognition and binding of the hormone into a stimulation of the adenyl cyclase system. It has been possible to prepare adenyl cyclase-containing cell-free extracts from kidney which remain sensitive to PTH.57 The stimulation of cyclic AMP formation has been shown to evoke hypercalcemia and increased phosphate clearance. The exact pathway from cyclic AMP formation to the metabolic responses of the hormone has not yet been established. In other systems, hormonally induced cyclic AMP interacts with a protein kinase system to enhance the phosphorylation of key enzymes needed for the hormone response. Recent work by Winikoff and Aurbach’* suggests a similar mechanism in the target tissues of PTH. Chase et al.59 showed that the increase in urinary cyclic AMP caused by
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140
6
PSEUDOHYPOPARATHYROIDISM
I20 ; a . I00 _: P 5 0
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0
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IDIOPATHIC HYPOPARATHYROIOISM
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PSEUDOPSEUOOHYPOPARATHYROlDlSh
40
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-
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Fig. 3. Urinary cyclic 3’,5’-AMP response to parathyroid hormone infused in patients with a variety of parathyroid disorders. Note absence of increase in patients with pseudohypoporothyroidism (by permission5’).
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PTH provided the most sensitive test for the detection of hormonal response (Fig. 3). In normal individuals and those with hypocalcemic disorders due to PTH deficiency, the increase in urinary cyclic AMP was greater than tenfold. In pseudohypoparathyroidism there was usually no response and rarely more than a twofold increase. The test is performed with 300 U of PTH, with urine collections being obtained for a control period, two 30-min periods and then two 60min periods. The locus of the defect in pseudohypoparathyroidism is still under active studied a patient with the syninvestigation. Marcus, Wilbur, and Aurbacha drome who had classic inability to increase phosphate excretion following PTH administration. When the patient died suddenly of pulmonary embolization, renal tissue was obtained at autopsy and studied in vitro. The adenyl cyclase system was isolated, and it was not only active but also responsive to added PTH. Bell and his colleagues6’ studied the response of normal and pseudohypoparathyroid patients to dibutyryl cyclic AMP. Dibutyryl cyclic AMP mimicked the action of PTH, not only in the normal subjects, but also in those with the syndrome. If the former study reflected the in vivo situation (i.e., receptor sites are not uncovered by the isolation procedures), then the receptor and adenyl cyclase response appear to be intact, at least in the patient studied. The latter study indicated that the ability to respond to cyclic AMP, or at least its analogue, was intact. This rather complex situation needs to be clarified by further studies. As might be anticipated, the levels of PTH in patients with pseudohypoparathyroidism are elevated.59p62 This elevation is the appropriate physiologic response to a hypocalcemic stimulus. If the serum calcium is transiently brought to normal by an infusion of calcium, the concentration of circulating PTH falls into the normal range. Therefore, the hallmark for the diagnosis of end-organ unresponsiveness is (1) inability of PTH to increase cyclic AMP excretion and (2) elevated circulating PTH. The hormone secreted by the patients with pseudohypoparathyroidism is presumably normal in structure and may be relatively effective in bone or kidney in some patients; detailed chemical or immunologic comparisons of this hormone with the molecule normally secreted are not yet available however (vide infra). Pseudohypoparathyroidism is an inherited disorder.63 The exact mode of inheritance is not known with certainty, but the occurrence of a 2: 1 ratio of females to males and the absence of male-to-male transmission suggest a sexlinked dominant mode. Several characteristic physical findings are associated with the syndrome. These are not related to the PTH unresponsiveness, since the same alterations can often be observed in the same family with no abnormalities of mineral metabolism. The latter situation is known as pseudopseudohypoparathyroidism. The somatotype of these patients includes short stature, round face, and brachydactyly (Fig. 4). Shortened metacarpals are made clinically evident by dimpling over the knuckles when a fist is made. Mental retardation and subcutaneous calcification are more common in pseudohypoparathyroidism than in idiopathic hypoparathyroidism, while monilial infections are characteristic of idiopathic hypoparathyroidism. The diagnosis of pseudohypoparathyroidism depends on the demonstration
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Fig. 4. Photograph and x-ray of hands of patient shown in Fig. 2. illustrating shortening of the metacarpal and absence of “knuckles” on fourth and fifth tingers.
of end-organ refractoriness to injected PTH. The protocol for urinary cyclic AMP measurements after PTH injection is given above. The classic EllsworthHoward test is performed by studying hourly phosphate excertion before and after PTH.& The results must be interpreted carefully since there is usually a small rise in pseudohypoparathyroid subjects which is not greater than 100%. In hypoparathyroid patients, there is a response which is even greater than normal, and a four- to sixfold increase should be observed. It has been sug-
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OF HYPOPARATHYROIDISM
gested by Bijvoet et al. 65 that the tubular corrected for glomerular filtration rate, sponse.
maximum is the most
of phosphate sensitive
reabsorption, indicator
of re-
Other Rare Forms of Hypoparathyroidism Three recent reports have described variants of hypoparathyroidism which deserve attention (despite their rarity) because of their physiologic significance. Frame et a1.66 described two girls of normal phenotype who combined the findings of renal resistance to PTH with osteitis fibrosa cystica. In both, no phosphaturic response to PTH was noted, and, in the one in whom it was tested, no increase in urinary cyclic AMP occurred after injecting PTH. The concentrations of circulating PTH were elevated, but the distinctive feature was that the bone seemed to be responsive to increased PTH secretion. Both radiographic and histologic evidence of osteitis fibrosa cystica were obtained. Nevertheless, hypocalcemia occurred in both patients. These patients appeared to represent the occurrence of renal resistance to PTH with normal skeletal responsiveness. If this is correct, renal resistance would result in the following sequence of events: (1) hyperphosphatemia, (2) hypocalcemia, (3) secondary hyperparathyroidism, and, finally, (4) bone resorption. It was suggested by Frame et a1.66 that the action of PTH on bone does not restore the serum calcium to normal because of persistent hyperphosphatemia. Several other cases in the literature, in both phenotypically normal and pseudohypoparathyroid patients, appear to fit this syndrome. The authors proposed the descriptive names “renal resistance to parathyroid hormone with osteitis fibrosa” or “pseudohypohyperparathyroidism with osteitis fibrosa” for this syndrome. N usynowitz and Klein6’ studied a hypocalcemic 20-yr-old college student with a normal phenotype, the characteristic chemical findings of hypoparathyroidism, and normal responsiveness to PTH. Injected PTH produced a prompt rise in urinary cyclic AMP and urinary phosphate. Nevertheless, when the patient’s serum was submitted to PTH radioimmunoassay in four separate laboratories, elevated values were found. It was suggested, but not proven, that the circulating immunoreactive substance was pro-PTH which had not undergone proper conversion to the active form. In view of the current body of information pertaining to the metabolism of PTH, this case was particularly interesting. 68 The authors suggested the trivial name “pseudoidiopathic hypoparathyroidism.” Drezner et a1.69 observed a 22-mo-old boy with an 18-mo history of seizures who had clinical hypoparathyroidism with an elevated serum PTH. Intravenous infusion of PTH produced neither a phosphaturic response nor a rise in the serum calcium. The distinctive finding was that infused PTH caused marked increase in the concentration of urinary cyclic AMP. The authors suggested the name “pseudohypoparathyroidism Type II” and raised the possibility of the absence of a cyclic AMP receptor protein. Figure 5 summarizes the gamut of possible deficiencies in PTH secretion or effectiveness. Hypomagnesemia Magnesium normal adults
deficiency by itself leads to hypocalcemia. Shils’O placed seven on a magnesium-free diet for l-3 mo. In six of these subjects, the
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Absent gland IX deficient hormone
A
B
Q-X
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IN ENDOCRINOLOGY
AND METABOLISM
Pathogenesis and Management of Hypoparathyroidism and Other Hypocalcemic Disorders Arthur
B. Schneider
and Louis M. Sherwood
Hypocalcemia frequently presents as an acute medical emergency or a chronic disorder which is difficult to control. Occasionally, it is found in routine blood screening tests when it is not anticipated. Recent developments in basic endocrine science have contributed greatly to our understanding and treatment of hypocalcemic disorders. The maintenance of a normal serum calcium concentration depends on the balanced actions of parathyroid hormone (PTH), vitamin D, and, to a lesser extent, calcitonin. Recent work on PTH secretion has defTned the factors controlling its secretion in normal and abnormal states. In primary hypoparathyroidism, hormone secretion is decreased or absent, while in most other forms of hypocalcemia, secretion is stimulated recondarily by the hypocalcemia. However, acute or chronic disorders associated with hypomagneremia may also decrease effective PTH secretion. Patients with the rare disorder, pseudohypoparathyroidism, have defects of hormone action and usually have elevated levels of PTH prior to therapy. Several forms of pseudohypoparathyroidism have been recognized, each representing a defect at a different site of PTH action. Calcitonin excess, as noted in medullary carcinoma of the thyroid, could theoretically cause hypocalcemia, but rarely does so. Vitamin D undergoes a series of two carefully con-
trolled hydroxylation reactions leading to the final active metabolite, 1,25-dihyroxycholecalciferol. Chronic ingestion of certain drugs can lead to osteomalacia and hypocalcemia by potentiating the metabolism of vitamin D to inactive compounds. At least one form of rickets has been shown to result from a specific enzyme defect in the vitamin D pathway. Severe renal damage limits the conversion of vitamin D to its active form and contributes to vitamin D resistance. Current progress in the area depends on the development of procedures for the measurement of the metabolites in plasma and assessing the role of the vitamin (hormone) in normal and abnormal physiology. Although the therapy of acute hypocalcemia is usually readily accomplished, chronic hypocalcemia remains a very difficult therapeutic problem. Vitamin D, the hallmark of therapy, is a long-acting drug with a narrow therapeutic range. The complications of the disease and therapy are sometimes irreversible. The unraveling of vitamin D metabolism has led to the development of new therapeutic agents which might provide better relief of chronic hypocalcemic states. This review relates new information about calcium homeostasis to the clinical situation encountered in the patient with hypocalcemia.
From the Departments of Medicine, Michael Reese Medical Center and the Prirzker School of’ Medicine, University of Chicago, Chicago, Ill. Received for publicarion November 27. 1974. Supported in part by USPHS Grant HD 08225 and grants from the John A. Hartford Foundation and the Michael Reese Research Institute. Reprint requests should be addressed to Dr. Louis M. Sherwood, Department oJ‘ Medicine. Michael Reese Medical Center, 29th Street and Ellis Avenue. Chicago. III. 60616. G 1975 by Grune & Stratton, Inc.
Metabolism,
Vol.
24, No. 7
(July),
1975
871
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HE DRAMATIC CLINICAL picture of hypocalcemia reflects the critical role which calcium plays in maintaining normal physiologic processes. To prevent hypocalcemia, rapidly responsive, high-capacity, homeostatic mechanisms developed during vertebrate evolution. Much of this development occurred when animals left calcium-rich sea water and became terrestrial.’ In order to maintain constancy of the serum calcium concentration in the face of large variations in calcium intake, stable reserves of mineral were established. In addition, sensitive mechanisms for controlling ion flux at the sites of absorption, storage, and excretion appeared. In calcium-poor fresh water, fish developed calcium-storage organs similar to mammalian bone. In calcium-rich sea water, bone was either abandoned or became inactive. At this point, calcitonin-producing ultimobranchial glands appeared, presumably to prevent hypercalcemia. The evolutionary factors which brought about this development are not entirely clear, since a calcium-lowering effect of calcitonin in fish has not been consistently demonstrated.2 The pituitary gland and the Stannius corpuscles of fish appear to be more directly involved in teleost calcium metabolism. The former increases the serum calcium concentration, while the latter decreases it.3 A hypocalcemic factor has recently been identified in extracts of Killifish corpuscles.4 Neither of these mechanisms apparently has been preserved during subsequent evolution. In amphibia, both bone and paravertebral lime sacs serve as calcium reservoirs, and the parathyroid glands appear for the first time. Calcium-regulatory mechanisms are highly developed in birds to accommodate the large fluxes of calcium caused by eggshell formation. In mammals, the parathyroid glands and the skeleton itself are the princiwith calcitonin being relegated to a pal regulators of calcium homeostasis, minor role, if any at all, in this process5 The average daily intake of calcium in adult man is between 0.5 and 1.0 g. As the quantity of calcium in the diet decreases, adaptive mechanisms increase the fraction of intestinal calcium which is absorbed.6 This adaptation, the first defense against hypocalcemia, is now believed to be due to an increase in the efficiency of the conversion of vitamin D to its active metabolite.7 Net absorption of approximately 200 mg/day is needed to balance calcium losses in the urine and stool of normal man. When calcium absorption is inadequate and causes the serum calcium to fall, mobilization of mineral from the skeleton begins. Since there is normally a constant exchange of calcium between the surface of bone and extracellular fluid, mobilization of additional calcium represents an increase in the rate of bone resorption relative to the rate of bone formation. In normal adult subjects, rates of bone formation and resorption are equivalent; less than 1% of the total skeletal pool of calcium (1 kg) is readily available for exchange with extracellular fluid calcium. Additional calcium can be mobilized by the action of increased quantitites of parathyroid hormone (PTH) and/or vitamin D. The circulating level of PTH is responsive to the ionized calcium and magnesium concentration in the serum and related in first-order fashion to total divalent cation concentration.8 Recent studies in vivo suggest that PTH secretion is most carefully regulated near the physiologic concentrations of calcium and magnesium, so that the relation between PTH and divalent cation concentration re-
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semblesa sigmoid dose-response curve.9 PTH maintains the serum calcium not only by mobilizing mineral from bone, but also by reducing renal excretion of calcium. The sensitivity of the latter mechanism is shown by the fact that 7- 10 g of calcium are filtered every 24 hr, but only 100-400 mg are excreted. At serum calcium concentrations below 7.5 mg/lOO ml, urine calcium falls to zero. Recent studies on the metabolism of vitamin D have shown that the actions of vitamin D are intimately related to those of PTH.” In the kidney, 25-hydroxycholecalciferol (25-OHD,) is transformed to 1,25-dihydroxycholecalciferol (1,25-diOHD,) which is the active metabolite of vitamin D.” This activation appears to be regulated either by the extra and/or intracellular calcium and phosphate concentrations, perhaps through a direct effect of PTH.“,‘-’ Whatever the details of this control mechanism, it is clear that vitamin D tends to maintain the calcium concentration by its actions on the intestine, bone, and possibly the kidney. Like steroid hormones, vitamin D carries out its metabolic effects by entering target cells, binding to cytoplasmic and then nuclear receptors, and initiating increases in protein synthesis. ‘4,‘5 In the intestine, vitamin D increases the active transport of calcium into the circulation, an effect which appears to be independent of PTH and which may be related to the stimulation by vitamin D of the synthesis of a calcium-binding protein.16 In bone. vitamin D increases the rate of entry of calcium into the circulation, but it also seems to play a permissive role for the action of PTH. The effect of vitamin D on the kidney is more complex and appears to be dose related. Renal calcium reabsorption may be increased so that calcium is retained in the body, and, m certain situations, phosphate is also retained. The role of vitamin D in bone formation has been discussed extensively.” The mechanism by which it causes the reversal of osteomalacia is not completely understood. Some investigators place the emphasis on its tendency to increase the calcium x phosphorus product which is favorable for the deposition of mineral in osteoid tissue.18 Others stress the ratio of bone-forming to resorbing cells whose formation is controlled by PTH and vitamin D.19 Calcitonin is an antagonist of the action of PTH, since it prevents mobilization of calcium and phosphorus from bone. ” In theory, excessive calcitonin activity could lead to hypocalcemia. However, it has been observed that the very large concentrations of calcitonin seen in medullary carcinoma of the thyroid gland do not usually lead to significant lowering of the serum calcium.5 In addition, the concentration of calcitonin in the human thyroid is considerably lower than that in other species. Calcitonin probably plays a small role, therefore, in calcium homeostasis. It has been suggested that calcitonin participates in the prevention of postprandial hypercalcemia, its secretion being stimulated by gastrin.21 A potential role of calcitonin in fetal development, where bone turnover is greater, needs to be evaluated more fully. The homeostatic mechanisms for calcium are sensitive to the concentration of the ionized fraction. This is normally about 45’!;, of the total serum calcium, the major fraction of the rest being bound to albumin, with smaller amounts being bound to other proteins or complexed with ions. It is now possible to determine accurately the concentration of ionized calcium in serum with an ionspecific electrode. This is not used in most clinical laboratories, however, and
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it is important to estimate potential alterations in the ionized fraction in disease states. The Hastings-McLean nomogram,22 available in most textbooks of physiology, accurately estimates the ionized calcium concentrations when serum protein concentrations are altered. A useful rule of thumb is that a decrease in the concentration of serum albumin of 1 g/100 ml will lower the total calcium by about 0.8 mg/lOO ml. In addition, the pH is critical in regulating the ionized fraction. In order to obtain a complete indication of the circulating calcium, therefore, it is necessary to know the total and ionized calcium, the serum protein concentration, and the serum pH. CLINICAL
MANIFESTATIONS
OF HYPOCALCEMIA
Maintaining a normal calcium concentration in the extracellular fluid is of such general importance that virtually every organ system can be affected by hypocalcemia. Calcium participates actively in a wide variety of cellular membrane and intravascular physiologic processes. Examples are ion transport at membrane surfaces and the maintenance of normal neuromuscular membrane potential. Calcium is a cofactor in many reactions, notably in the contraction of actomyosin and the activation of the coagulation cascade. More recently, it has become clear that calcium has important interactions with the adenyl cyclase system. Finally, it should not be forgotten that calcium is the principal mineral of hydroxyapatite of bone. Hypocalcemia most often presents clinically as one of several neuromuscular and neurologic syndromes, the most dramatic and common being tetany. Children may show jerking muscular contractions which represent rhythmic neural discharges, and these can culminate in generalized seizures. In adults, heightened muscle contractions can cause cramps and carpopedal spasm. Striking flexion occurs at the wrists and metacarpalphalangeal joints, with adduction of thumbs and extension of the interphalangeal joints. Similarly, spasm of muscles in the feet and eyes may present a characteristic picture, associated occasionally with urinary retention. In extreme cases, most frequently in children, spasm of the muscles of the glottis can cause inspiratory stridor. Chvostek’s sign and Trousseau’s sign reveal latent tetany, since hypocalcemia results in irritability of the peripheral nerves. In the latter test, local hypoxia at the blood pressure cuff site produces the contraction since replacement of a cuff on the same arm without allowing a return of circulation still relieves the spasm. Both signs, particularly Chvostek’s, can be found in some normal people, and neither are invariably present in hypocalcemia. Albright and Reifenstein state in their textbook that contraction of the eyelid muscles in response to striking the facial nerve only occurs in hypoparathyroidism.23 A sensory prodrome often occurs with tetany; characteristically it is a tingling sensation or parasthesias most evident in the extremities and around the mouth, as well as sensations of muscle tension or cramps. These sensory and motor changes are believed to be due to changes in resting membrane potential with increased nerve conduction rates. Hyperventilation can lead to a mild respiratory alkalosis, which in turn will exacerbate the symptoms of hypocalcemia. The diffuse effects of hypocalcemia on the central nervous system are manifested in changes which occur in the electroencephalogram (EEG).24 High-
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voltage slow waves occupy an increasing portion of the total record and appear to reflect the degree of hypocalcemia. In a recent case study reported by Swash and Rowan, sequential EEGs were recorded in a hypoparathyroid patient during periods of both hypo- and hypercalcemia. At both extremes there was an increase in the slow wave burst activity. These recordings could be distinguished, however, since sharp spike activity occurred only in hypocalcemia, while triphasic waves occurred only during hypercalcemia. In this particular patient, EEG changes were recorded when the serum calcium was below 7 mg/ 100 ml. Increased intracranial pressure with bilateral papilledema occasionally occurs in hypocalcemia, and this can be associated with seizures or other severe neurologic deficits. 26 With unilateral symptoms, a space-occupying lesion can represent a difficult differential diagnosis. Several conditions resulting from dysfunction of the extrapyramidal-motor system have been reported. These include Parkinsonism, chorea, and athetosis.27*28These conditions arise, in part, from calcification of the basal ganglia which may or may not be appreciated on x-ray. In addition, an effect of calcium on membrane stability must also be important, since restoration of serum calcium often leads to amelioration of the symptoms, even when basal ganglia calcification is present. Basal ganglia calcification occurs in hypoparathyroidism and pseudohypoparathyroidism and is not only a consequence of hypocalcemia and hyperphosphatemia, but also may be related to genetic factors (Fig. 1). One family has been described with congenital calcification of the
Fig. 1. Lateral skull x-ray (A) and frontal tomogmm (B) showing bilateml calcification of the basal ganglia in a patient with hypoparathyroidism.
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basal ganglia in the absence of abnormalities of serum calcium and phosphorus.29 One report describes an exaggerated tendency to extrapyramidal side effects of chlorpromazine and related compounds in patients who are hypocalcemic.30 Cataracts are a serious complication of hypoparathyroidism and are not reversible with correction of the metabolic disturbance. The prevalence of this complication of hypocalcemia is illustrated by the study of Ireland et a1.3’ In patients with surgically-produced hypoparathyroidism, nine had macroscopic cataracts, and an additional seven had undergone lens extraction. Of 18 patients who had neck surgery more than 5 yr previously, seven had macroscopic cataracts, and five had undergone iridectomy. The typical cataract in these patients had one or more layers of cortical opacity separated from the capsule and each other by clear cortex. Hypocalcemia appears to interfere with the normal hydration of the lens by disturbing the active cation-transport processes. In no instance did restoration of a normal serum calcium with vitamin D result in regression of the cataracts. Moniliasis involving the skin and mucous membranes, and even the bowel, occurs in association with idiopathic hypoparathyroidism, but only rarely with 32The data indicate that hypocalcemia per se does other forms of hypocalcemia. not predispose to monilial infection (vide infra). Hypocalcemia causes a characteristic change in the electrocardiogram.33 The Q-T interval, when corrected for the rate, i.e., Q-Tc, is abnormally prolonged. This is due to prolongation of the S-T segment without change in the QRS configuration, the T wave, or the voltage of the S-T segment. An improved correlation with serum calcium is obtained with the Q-OTC interval.” This is obtained from Q - OTC = Q - oT/m where oT is the onset of the T wave. It is reported that this interval is particularly useful in the evaluation of newborn infants. A value above 0.19 set in a full term and above 0.20 in a premature infant is abnormal. Severe hypocalcemia can result in congestive heart failure, presumably due to decrease in inotropic activity of the heart.35 The relationship of hypocalcemia to the skeletal system depends on the cause. In those situations where there is inadequate PTH, hypocalcemia is at least partly due to decreased mobilization of mineral from bone. On the other hand, where secondary hyperparathyroidism occurs as a response to hypocalcemia, extensive bone changes varying from osteomalacia to osteitis fibrosa cystica may be observed. An intermediate state exists in some patients with pseudohypoparathyroidism where there may be resistance to the effects of PTH, principally at the kidney, increased secretion of PTH secondary to the hypocalcemia, and bony changes due to parathyroid hormone excess. This will be described in more detail in the discussion of individual disorders below. The role of calcium ion in the secretion of hormones and their actions on target tissues is presently under active investigation. Physiologic effects of a hypocalcemic state on these phenomena are theoretically possible and merit further investigation. Release of the peptide hormones, insulin,36 thyrotropin, hormone,3* and ACTH, prolactin, luteinizing hormone, 37 follicle-stimulating presumably from storage granules into the extracellular growth hormone,39
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space, can be inhibited by a reduction in extracellular calcium concentration. The parathyroid glands and the pancreatic glucagon-secreting cellsN appear to be unusual in this regard, since decreasing calcium concentrations results in increased, rather than decreased, hormone release. Rasmussen and his colleagues have studied the role of calcium in the actions of hormones which activate the adenyl cyclase system. 4’ It is apparent from their work that complex interactions may occur, but the exact mechanisms and clinical consequences are not yet completely clear. ETIOLOGY
OF HYPOCALCEMIA
Although a number of disorders may be associated with hypocalcemia, it is a relatively uncommon condition. The factors or disorders responsible for the reduced calcium concentration are usually relatively easy to determine. Because of the rapid progress which has occurred in understanding calcium homeostasis, new diagnostic and therapeutic modalities are becoming available. In order to understand their applicability and rationale, the following description of the causes of hypocalcemia stresses the pathophysiology of each condition. Hypoparathyroidism Hypoparathyroidism is most often an iatrogenic disease occurring after thyroid or parathyroid surgery. The population at risk is therefore clearly defined. However, the onset of biochemical or clinical signs suggestive of the disease can begin anywhere from a few days to many years following surgery. In 23 postoperative hypoparathyroid patients followed from 1954 to 1964 by Dimich et al.,42 14 developed symptoms within 2 wk, and five developed symptoms between 6 and 12 mo after surgery (symptoms in the other four patients were of uncertain duration). In five patients there was a delay in the diagnosis of l-19 yr. Spontaneous (idiopathic) hypoparathyroidism is a rare condition. Since the onset of symptoms can be insidious, a long delay in establishing the diagnosis is not uncommon. In the series reported by Dimich et a1.,42 6 mo27 yr (mean, 10.6 yr) elapsed from the onset of symptoms to a definite diagnosis. Bronsky et al.32 reviewed 50 reported cases in the literature in 1958 and noted that over half of the patients manifested symptoms before 10 yr of age, while the average age of onset was 17. One of Dimich’s patients was 68 yr old. Kunstadter et a1.43 reported the occurrence of idiopathic hypoparathyroidism in two newborns. This extremely unusual occurrence is very difficult to distinguish, at the present time, from idiopathic neonatal hypocalcemia. Measurements of circulating PTH may be useful in this regard. Three forms of idiopathic hypoparathyroidism can be delineated, although they may in fact be closely related. In the DiGeorge syndrome, absence of the parathyroid glands is associated with thymic aplasia.44 This disorder presumably results from maldevelopment of the third pharyngeal pouch during embryogenesis. A second form of idiopathic hypoparathyroidism is associated variously with hypofunction of the adrenal cortical glands, ovarian failure, pernicious anemia, Hashimoto’s thyroiditis, hypothyroidism, diabetes, moniliasis, and occasionally malabsorption. This is a familial disorder with those who manifest disease before 6 mo of age conforming to an X-linked recessive in-
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heritance pattern while the remainder probably represent autosomal recessive inheritance.45*46 Blizzard, Chee, and Davis4’ demonstrated that humoral antibodies against a variety of endocrine tissues could be found in these patients. Specifically, they showed that 28 of 74 sera (38%) from patients with idiopathic hypoparathyroidism contained anti-parathyroid gland antibodies. Of the 74 patients, 18 had Addison’s disease, seven had pernicious anemia, 21 had moniliasis, two had cirrhosis, four had alopecia totalis, two had premature menopause, four had nontoxic goiter, one had Hashimoto’s thyroiditis, and one had myxedema. In addition to those with clinically apparent disease, six patients showed antiadrenal antibodies, nine showed antithyroid antibodies, and ten showed parietal cell antibodies in their sera. In 93 patients with idiopathic Addison’s disease, anti-parathyroid gland antibodies were present in 26%. Blizzard et a1.47 stress that there is no evidence that the circulating antibodies play any role in the pathogenesis of the disease, but they do indicate the likelihood that a common underlying genetic or pathophysiologic mechanism exists. In addition to susceptibility to candidiasis, these patients are more susceptible to infection. This abnormality reflects a defect in cellular immunity which is often abnormal to a variable degree.48-50 The third form of idiopathic hypoparathyroidism is not associated with other disorders. Clinical diagnosis is based on the criteria first delineated by Drake, Albright, Bauer, and Castleman. 5’ The concentration of serum calcium is low and that of serum phosphorus high. Renal failure, malabsorption, and alkalosis must be ruled out. Rickets must be absent and a history suggestive of chronic tetany or other compatible symptoms is usually present. The symptom complex found in hypoparathyroidism results from the lack of adequate parathyroid hormone, with at least three factors contributing to the development of hypocalcemia: (1) Breakdown of hydroxyapatite and release of bone mineral is reduced by the lack of the hormone, (2) the conversion of vitamin D to its active metabolite is reduced, accounting for a decrease in calcium absorption by the gut and decreased bone resorption, and (3) renal conservation of calcium is impaired. Urinary calcium in patients with hypoparathyroidism is low, but such patients also have a decreased ability to retain a calcium load. Therefore, renal wasting of calcium contributes to hypocalcemia. Hyperphosphatemia results from the reduced phosphate clearance secondary to PTH deficiency. When hypocalcemia is present during the period of tooth formation, severe dental abnormalities may occur. 52The earliest changes are in the dentin which remains uncalcified and shows transverse ridging. Hypoplasia of the enamel, severe caries, delayed eruption, and premature loss of teeth also occur. On x-ray, shortening of the roots and absence of the lamina dura are seen. Occasionally a physiologic form of hypoparathyroidism is seen in the newborn of hypercalcemic mothers. 53 Ionized calcium crosses the placental membrane readily and, if elevated in maternal serum, can cause an increase in the serum calcium in the fetus. Persistent hypercalcemia in the fetus causes trasient suppression of its parathyroid glands, leading to hypocalcemia after birth. In any child who manifests neonatal hypocalcemia, the diagnosis of maternal hyperparathyroidism should be suspected. The hypocalcemic condition can per-
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Fig. 2. The original patient described by Albright et al.“’ with pseudohypoparathyroidism shown at age 28 in 1948 on the left and 21 yr later on the right. Although seizures and symptoms of hypocalcemia wwe prominent early in life, when the potient was seen by the authors in 1969, they were not. The major clinical manifestations were mental retardation and abnormal movements suggestive of extrapymmidal dysfunction.
sist in the neonate for as long as several months. Neonatal hypocalcemia is not usually associated with maternal hyperparathyroidism, however, and is usually a transient disorder of unknown etiology which is more common in premature newborns. Reports of neonatal hypocalcemia in association with the use of high phosphate formulas have appeared.s4 Pseudo- and Pseudopseudohypoparathyroidism In 1942, Albright and his associates” recognized a syndrome with hypocalcemia and hyperphosphatemia in which (in contrast to simple hypoparathyroidism) there was a markedly diminished response to administered parathyroid extract. They suggested that this was a syndrome of organ unresponsiveness to PTH (a human counterpart of the Seabright-Bantam syndrome in fowl). To this disorder and its associated skeletal adnormalities, i.e., short stature, round face, shortened metacarpals (Fig. 2). they gave the appelation pseudohypoparathyroidism. Recent laboratory efforts, particularly those by Chase and Aurbach and their colleagues,56 have confirmed the inability of PTH to evoke its usual metabolic responses in patients with this syndrome. Sufficient evidence has now accumulated to establish the fact that PTH normally acts at its target tissues, bone and kidney, in a manner analogous to other peptide hormones. Specific membrane-bound receptors are present in the target tissue cells which transform the recognition and binding of the hormone into a stimulation of the adenyl cyclase system. It has been possible to prepare adenyl cyclase-containing cell-free extracts from kidney which remain sensitive to PTH.57 The stimulation of cyclic AMP formation has been shown to evoke hypercalcemia and increased phosphate clearance. The exact pathway from cyclic AMP formation to the metabolic responses of the hormone has not yet been established. In other systems, hormonally induced cyclic AMP interacts with a protein kinase system to enhance the phosphorylation of key enzymes needed for the hormone response. Recent work by Winikoff and Aurbach’* suggests a similar mechanism in the target tissues of PTH. Chase et al.59 showed that the increase in urinary cyclic AMP caused by
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140
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PSEUDOHYPOPARATHYROIDISM
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Fig. 3. Urinary cyclic 3’,5’-AMP response to parathyroid hormone infused in patients with a variety of parathyroid disorders. Note absence of increase in patients with pseudohypoporothyroidism (by permission5’).
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PTH provided the most sensitive test for the detection of hormonal response (Fig. 3). In normal individuals and those with hypocalcemic disorders due to PTH deficiency, the increase in urinary cyclic AMP was greater than tenfold. In pseudohypoparathyroidism there was usually no response and rarely more than a twofold increase. The test is performed with 300 U of PTH, with urine collections being obtained for a control period, two 30-min periods and then two 60min periods. The locus of the defect in pseudohypoparathyroidism is still under active studied a patient with the syninvestigation. Marcus, Wilbur, and Aurbacha drome who had classic inability to increase phosphate excretion following PTH administration. When the patient died suddenly of pulmonary embolization, renal tissue was obtained at autopsy and studied in vitro. The adenyl cyclase system was isolated, and it was not only active but also responsive to added PTH. Bell and his colleagues6’ studied the response of normal and pseudohypoparathyroid patients to dibutyryl cyclic AMP. Dibutyryl cyclic AMP mimicked the action of PTH, not only in the normal subjects, but also in those with the syndrome. If the former study reflected the in vivo situation (i.e., receptor sites are not uncovered by the isolation procedures), then the receptor and adenyl cyclase response appear to be intact, at least in the patient studied. The latter study indicated that the ability to respond to cyclic AMP, or at least its analogue, was intact. This rather complex situation needs to be clarified by further studies. As might be anticipated, the levels of PTH in patients with pseudohypoparathyroidism are elevated.59p62 This elevation is the appropriate physiologic response to a hypocalcemic stimulus. If the serum calcium is transiently brought to normal by an infusion of calcium, the concentration of circulating PTH falls into the normal range. Therefore, the hallmark for the diagnosis of end-organ unresponsiveness is (1) inability of PTH to increase cyclic AMP excretion and (2) elevated circulating PTH. The hormone secreted by the patients with pseudohypoparathyroidism is presumably normal in structure and may be relatively effective in bone or kidney in some patients; detailed chemical or immunologic comparisons of this hormone with the molecule normally secreted are not yet available however (vide infra). Pseudohypoparathyroidism is an inherited disorder.63 The exact mode of inheritance is not known with certainty, but the occurrence of a 2: 1 ratio of females to males and the absence of male-to-male transmission suggest a sexlinked dominant mode. Several characteristic physical findings are associated with the syndrome. These are not related to the PTH unresponsiveness, since the same alterations can often be observed in the same family with no abnormalities of mineral metabolism. The latter situation is known as pseudopseudohypoparathyroidism. The somatotype of these patients includes short stature, round face, and brachydactyly (Fig. 4). Shortened metacarpals are made clinically evident by dimpling over the knuckles when a fist is made. Mental retardation and subcutaneous calcification are more common in pseudohypoparathyroidism than in idiopathic hypoparathyroidism, while monilial infections are characteristic of idiopathic hypoparathyroidism. The diagnosis of pseudohypoparathyroidism depends on the demonstration
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Fig. 4. Photograph and x-ray of hands of patient shown in Fig. 2. illustrating shortening of the metacarpal and absence of “knuckles” on fourth and fifth tingers.
of end-organ refractoriness to injected PTH. The protocol for urinary cyclic AMP measurements after PTH injection is given above. The classic EllsworthHoward test is performed by studying hourly phosphate excertion before and after PTH.& The results must be interpreted carefully since there is usually a small rise in pseudohypoparathyroid subjects which is not greater than 100%. In hypoparathyroid patients, there is a response which is even greater than normal, and a four- to sixfold increase should be observed. It has been sug-
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gested by Bijvoet et al. 65 that the tubular corrected for glomerular filtration rate, sponse.
maximum is the most
of phosphate sensitive
reabsorption, indicator
of re-
Other Rare Forms of Hypoparathyroidism Three recent reports have described variants of hypoparathyroidism which deserve attention (despite their rarity) because of their physiologic significance. Frame et a1.66 described two girls of normal phenotype who combined the findings of renal resistance to PTH with osteitis fibrosa cystica. In both, no phosphaturic response to PTH was noted, and, in the one in whom it was tested, no increase in urinary cyclic AMP occurred after injecting PTH. The concentrations of circulating PTH were elevated, but the distinctive feature was that the bone seemed to be responsive to increased PTH secretion. Both radiographic and histologic evidence of osteitis fibrosa cystica were obtained. Nevertheless, hypocalcemia occurred in both patients. These patients appeared to represent the occurrence of renal resistance to PTH with normal skeletal responsiveness. If this is correct, renal resistance would result in the following sequence of events: (1) hyperphosphatemia, (2) hypocalcemia, (3) secondary hyperparathyroidism, and, finally, (4) bone resorption. It was suggested by Frame et a1.66 that the action of PTH on bone does not restore the serum calcium to normal because of persistent hyperphosphatemia. Several other cases in the literature, in both phenotypically normal and pseudohypoparathyroid patients, appear to fit this syndrome. The authors proposed the descriptive names “renal resistance to parathyroid hormone with osteitis fibrosa” or “pseudohypohyperparathyroidism with osteitis fibrosa” for this syndrome. N usynowitz and Klein6’ studied a hypocalcemic 20-yr-old college student with a normal phenotype, the characteristic chemical findings of hypoparathyroidism, and normal responsiveness to PTH. Injected PTH produced a prompt rise in urinary cyclic AMP and urinary phosphate. Nevertheless, when the patient’s serum was submitted to PTH radioimmunoassay in four separate laboratories, elevated values were found. It was suggested, but not proven, that the circulating immunoreactive substance was pro-PTH which had not undergone proper conversion to the active form. In view of the current body of information pertaining to the metabolism of PTH, this case was particularly interesting. 68 The authors suggested the trivial name “pseudoidiopathic hypoparathyroidism.” Drezner et a1.69 observed a 22-mo-old boy with an 18-mo history of seizures who had clinical hypoparathyroidism with an elevated serum PTH. Intravenous infusion of PTH produced neither a phosphaturic response nor a rise in the serum calcium. The distinctive finding was that infused PTH caused marked increase in the concentration of urinary cyclic AMP. The authors suggested the name “pseudohypoparathyroidism Type II” and raised the possibility of the absence of a cyclic AMP receptor protein. Figure 5 summarizes the gamut of possible deficiencies in PTH secretion or effectiveness. Hypomagnesemia Magnesium normal adults
deficiency by itself leads to hypocalcemia. Shils’O placed seven on a magnesium-free diet for l-3 mo. In six of these subjects, the
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Absent gland IX deficient hormone
A
B
Q-X
c
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