Refer to: Jones KL, Murphy J, Nyhan WL: HypoparathyroidismUniversity of California, San Diego, Medical Center and U.S. Naval Regional Medical Center, San Diego (Specialty Conference). West J Med 131:298-304, Oct 1979
Specialty Conference Participants KENNETH LEE JONES, MD JAMES MURPHY, MD WILLAM L. NYHAN, MD, PhD
ypoparathyroid sm
From the Department of Pediatrics, University of California, San Diego, School of Medicine, the University of California Medical Center, San Diego, and the United States Naval Regional Medical Center, San Diego.
WILLIAM L. NYHAN, MD, PHD:* This conference has been designed to examine the variety of presentations of hypoparathyroidism. Dr. Jones will begin with a discussion of the physiology of parathyroid hormone (PTH) and the pathophysiology of hypoparathyroidism, as well as the clinical features, diagnosis and therapy. KENNETH LEE JONES, MD: t We shall discuss specific aspects of presentation, diagnosis and therapy, as well as reviewing three cases. A few comments on the physiology of parathyroid hormone (PTH) are necessary. Parathyroid hormone has a molecular weight of approximately 9,500. It is secreted following the cleavage of a larger prohormone whose molecular weight is 11,000 to 12,000. Upon release, PTH is rapidly cleaved into smaller fragments. Although biologically inactive, these fragments are immunologically active, thereby complicating the radioimmunoassy (RIA) of parathyroid hormone. Nevertheless, the ability of investigators to measure parathyroid hormone accurately by RIA has led to considerable advancement in our knowledge of the physiology of PTH. The actions of parathyroid hormone are given in Table 1. In the kidney, its primary actions are *Professor and Chairman, Department of Pediatrics. tAssociate Professor of Pediatrics; Chief, Division of Endocrinology and Metabolism. Reprint requests to: Kenneth Lee Jones, MD, Department of Pediatrics, Division of Endocrinology and Metabolism, University of California, San Diego, School of Medicine, La Jolla, CA 92093.
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to decrease the tubular reabsorption of phosphate, leading to phosphaturia and, concomitantly, to
increase the tubular reabsorption of calcium. In bone, PTH increases the release of calcium and promotes bone remodeling. In the intestine, PTH enhances the absorption of calcium, largely through its effect on the metabolism of vitamin D. Problems in distinguishing between primary and secondary actions of PTH complicate our understanding of this area of physiology. The absorption of calcium from the gut is an example. Results of recent investigations have shown that PTH increases l-a-hydroxylation of vitamin D in the kidney to form 1,25 dihydroxyvitamin D, the most active form of this vitamin. Therefore, it appears that enhancement of calcium absorption is not a primary effect of PTH but, rather, is secondary to promotion of increased production of 1,25 dihydroxyvitamin D. It is helpful, in view of the complicated interactions in calcium-phosphorus metabolism, to remember that the major function of PTH iS to maintain serum levels of calcium within the normal range. The pathophysiology of hypoparathyroidism follows logically from an understanding of the actions of PTH. If there is inadequate circulating parathyroid hormone, renal excretion of phosphorus and absorption of calcium from the kidney, bone and gut do not proceed efficiently. Therefore, the concentration of calcium in the serum falls and that of phosphorus rises. In pa-
HYPOPARATHYROIDISM ABBREVIATIONS USED IN TEXT DHT= dihydrotachysterol PTH=parathyroid hormone RIA = radioimmunoassay TABLE 1.-Actions of Parathyroid Hormone Kidney Increases tubular reabsorption of calcium Decreases tubular reabsorption of phosphorus Bone Increases release of calcium Promotes remodeling of bone Intestine Enhances absorption of calcium
tients with hypocalcemia and hyperphosphatemia there are a number of diagnostic possibilities. The availability of a radioimmunoassay for PTH facilitates diagnosis, permitting the classification of hypoparathyroidism into two major categories: one in which the levels of PTH are low and another in which they are elevated.' Low levels of PTH may result from an abnormality either in the reception of a feedback signal by the cells that secrete PTH or in the ability of these cells to respond. Failure to respond may be due to transient suppression of the cells or may result from more permanent problems including failure of the parathyroid glands to develop or their surgical removal or destruction due to disease. The three cases discussed later illustrate conditions in which circulating levels of PTH are low. In hypoparathyroid states associated with elevated levels of PTH that can be radioimmunoassayed, the pathophysiology is not completely clear; but, presumably, one or more of the following mechanisms is operative: (1) abnormal conversion of the hormone to an inactive form, (2) lack of a cofactor necessary for the functioning of the hormone, (3) presence of an inhibitor of hormone action, (4) defect in the receptor or second messenger system in one or more of the target cells, (5) defect in the cellular response to the second messenger system or (6) lack of substrate for the target cells. Specific examples of hypoparathyroidism in which PTH is deficient are listed in Table 2. One category of hypoparathyroidism results from absence of the parathyroid glands, or their damage or insufficiency. Surgical procedures on the thyroid or the parathyroid glands (case 2) may be
TABLE 2.-Hypoparathyroid States in Which Parathyroid Hormone is Deficient Hypoparathyroidism secondary to absence or damage of parathyroid glands Following surgical procedures Thyroid Parathyroid Radical neck Radioiodine Drug related I-Asparaginase Damage in hemochromatosis Damage by metastatic tumor Branchial dysembryogenesis DiGeorge syndrome Other branchial arch abnormalities Familial Sex linked Undetermined mode of transmission Idiopathic or sporadic (presumably autoimmune) Isolated deficiency of PTH Deficiency of PTH with other endocrine deficiencies Inadequate PTH synthesis in neonates Hypoparathyroidism secondary to suppression of parathyroid function Neonatal secondary to maternal hypercalcemia Secondary to hypercalcemia Post resection of parathyroid adenoma, hyperplasia Secondary to nonparathyroid hypercalcemia Deficiency of magnesium PTH = parathyroid hormone
followed by hypoparathyroidism. Postirradiation damage is a rare cause of hypoparathyroidism in children. There have been a few case reports in which patients had been treated with iodine 131 for hyperthyroidism and subsequently hypoparathyroidism has developed. Hemochromatosis and metastatic malignant replacement of the parathyroid glands occur rarely in children. Branchial dysembryogenesis is a more common cause of hypoparathyroidism in children. Perhaps the best known example is the DiGeorge syndrome in which the thymus as well as the parathyroids fail to develop. In this situation, hypoparathyroidism is associated with an immunodeficiency disease, and may be accompanied by facial abnormalities and congenital heart disease. The association of hypoparathyroidism with other abnormalities of branchial arch development has been recently reexamined. In approximately 150 patients with hypoparathyroidism,2 very few had the DiGeorge syndrome, but many had developmental abnormalities such as cleft palate. Familial hypoparathyroidism has been reported. In some, a sex-linked mode of inheritance has been estabTHE WESTERN JOURNAL OF MEDICINE
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HYPOPARATHYROIDISM lished. The form of hypoparathyroidism we most commonly see is also called sporadic, autoimmune or idiopathic hypoparathyroidism. The second major category of hypoparathyroidism (Table 2) includes conditions in which there is suppression of PTH secretion. We see this in newborn infants whose parathyroid glands have been suppressed by maternal hypercalcemia, or in those in whom there is a condition involving apparent immaturity of the neonatal parathyroid glands. The disease becomes symptomatic in the infants receiving large amounts of phosphorus contained in cow's milk formulas which depress the serum concentration of calcium and, in turn, prevent adequate secretion of PTH. PTH secretion may also be defective in those with magnesium deficiency. The primary clinical features of hypoparathyroidism are similar to those of hypocalcemia. They vary with the age of each patient gnd the severity of the depression of the serum concentration of calcium. Table 3 summarizes the signs and symptoms of hypoparathyroidism as they involve three systems-the neuromuscular, ectodermal and ocular. Neuromuscular irritability is the most common manifestation and may present as classic tetany. Muscle cramps and paresthesias are common, more often recognized in older persons who are able to describe thlir symptoms. Hoarseness may result from laryngospasm, as occurred in one of our patients. Carpopedal spasm may become evident or be accentuated by hyperventilation. The Chvostek and Trousseau signs, and the peroneal reflex are all signs which may be seen pn physical examination. Signs of increased intracranial pressures are often seen;
papilledema may be present although it is not always associated with increased intracranial pressure. Convulsions are frequently presenting signs and though usually generalized, they may be focal. Metastatic calcification may develop and frequently involves the basal ganglia. Cataracts also frequently occur. Ectodermal complaints include loss of hair, delayed eruption or premature loss of teeth, enamel hypoplasia and severe dental caries. Mucocutaneous monilial infections are common and persistent. The skin may be dry and scaly; rarely, an exfoliative dermatitis develops. Transverse ridging of the nails may occur. The primary laboratory findings for hypoparathyroidism are hypocalcemia and hyperphosphatemia. In the presence of these conditions, one can rule out only renal glomerular insufficiency, as there is little else in the differential diagnosis. The next task is to establish whether hypoparathyroidism is due to a deficiency of PTH. The major goal of therapy is to maintain the serum concentration of calcium in the normal range. Establishing normocalcemia will correct many of the symptoms and signs of hypoparathyroidism, especially the neuromuscular manifestations. Of course, hypoplasia of dental enamel, cataracts, and the chronic moniliasis seen in approximately 20 percent of patients will not resolve. The treatment of chronic hypoparathyroidism should be matched with the severity of the illness.4 In mild transient hypoparathyroidism which may follow surgical removal of parathyroid tissue5 or which occurs in newborn infants, calcium supplementation may be all that is required. In more severe and chronic hypoparathyroidism, seen in
TABLE 3.-Signs and Symptoms of Hypoparathyroidism
Signs
Symptoms Neuromuscular Tetany Convulsions
Carpopedal spasm-increased with hyperventilation
Muscle cramps Paresthesias Hoarseness secondary to
laryngospasm Ocular Cataracts
Papilledema
Ectodermal Hair loss Delayed dental eruption Premature loss of teeth Mucocutaneous candidiasis
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Chvostek sign Trousseau sign Peroneal sign Hyperreflexia Increased intracranial pressure
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Dry scaly skin Brittle, dull hair; alopecia Transverse ridging of nails Hypoplasia of dental enamel Severe dental caries
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patients following total removal of the parathyroid glands as well as in most patients with idiopathic hypoparathyroidism, therapy with vitamin D is required. It may be used either alone or with calcium supplementation. I prefer to use dihydrotachysterol (DHT) when vitamin D therapy is indicated. This drug has a more rapid onset and probably a better phosphaturic effect than other available preparations. In addition, DHT is inactivated more rapidly so that, if hypervitaminosis D and hypercalcemia develop, discontinuation of therapy results in a more rapid resolution. Furtherfmiore, DHT does not have the propensity to accumulate in fatty tissues that other vitamin D preparations have. The plan of vitamin D therapy should be dictated by the severity of symptoms. In a patient with prdhounced symptoms of hypocalcemia, it is useful to give a loading dose. In treating infants, We use 1 mg of DHT a day for four days and then decrease the dose (1 mg is approximately equivalent to 120,000 units of vitamin D). In severely ill older children we begin with 2.5 mg per day for four days before beginning to decrease the dose. In most patients symptoms are not severe and we can begin with much lower doses, starting with 0.125 to 0.2 mg of DHT, increasing the dose every week or two until serum calcium levels approach the normal range. DR. NYHAN: Dr. Murphy will present case 1.
JAMES MURPHY, MD: * A male infant weighing 2,693 grams was born to a 28-year-old mother after a 41-week gestation. The pregnancy was complicated by renal calculi, which required surgical removal at six ihonths, and by pyelonephritis, treated with sulfanilamide at 36 weeks of gestation. In retrospect, the mother also experienced polyuria, polydipsia, nervousness and constipation throughout the pregnancy. In addition, the mother had a history of asthma, for which she was receiving Marax (ephedrine sulfate, theophylline and hydroxyzine hydrochloride), hydroxyzine pamoate (Vistaril) and beclomethasone dipropionate. The delivery was uneventful. The infant was breast-fed for two days and then given a prepared formula after mastitis developed in the mother. Several formulas were tried because the child had symptoms of colic, but the symptoms did not resolve with the changes in formula. *Pediatric resident, US Naval Regional Medical Center, San Diego.
On the tenth day after delivery when diarrhea developed, the infant had several episodes of vomiting and a left-sided major motor seizure involving the face, arm and leg. lie was admitted to a local hospital. On admission, the baby was lethargic. Serum levels of calcium and magnesium were 6.1 and 1.0 mg per dl, respectively. Values for blood urea nitrogen (BUN), electrolytes, glucose and creatinine were within normal limits. The leukocyte count was 27,400 per cu mm with a normal differential and the hematocrit was 56 percent. Cerebrospinal fluid concentrations of glucose and protein were normal. All cultures were negative and x-ray films of the long bones and skull showed no abnormalities. The infant was given calcium intravenously and supplemental calcium was given orally. In addition, he was fed a formula in which the ratio of calcium to phosphorus was 2:1. On the day following admission his serum concentrations of calcium and phosphorus were each 7.9 mg per dl. A repeat measurement of the magnesium level was 1.5 mg per dl and the total serum protein was 4 mg per dl. On day six, administration of vitamin D was begun. The infant's PTH was 50 pg per ml (normal 275 to 675 pg per ml), exceptionally low in view of the patient's low serum concentration of calcium. The infant's mother was found to have a serum concentration of calcium of 11.4 mg per dl and a phosphorus level of 3.6 mg per dl. We made a diagnosis of neonatal hypoparathyroidism secondary to maternal hyper-
parathyroidism. DR. JONES: This infant presented with classic neonatal tetany. In patients with this disorder, symptoms develop in the first two weeks of life. Symptoms followed a feeding change from breast milk, which has a calcium/phosphorus ratio of 2:1, to a formula which has a calcium/phosphorus ratio of about 1:1. Furthermore, the concentration of phosphorus in the formula is three times greater than that in breast milk. Symptoms of hypocalcemia with jitteriness, colic and seizure developed in the infant. The laboratory confirmed the presence of hypocalcemia and hyperphosphatemia. There are several differential diagnostic considerations. The most common condition seen at this age is that of transient hypoparathyroidism of the newborn. With current feeding regimens, this syndrome is seen less frequently, although it THE WESTERN JOURNAL OF MEDICINE
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still occurs in premature infant-s following obstetrical complications, and in infants of diabetic mothers. In the past it was also seen in term infants who were given whole milk or evaporated milk formulas, both having phosphate contents about 61/2 times greater than that of breast milk. Another diagnostic possibility was the DiGeorge syndrome. The absence of facial abnormalities, cardiovascular abnormalities and immunodeficiency, and the presence of the thymus ruled out this diagnosis. This infant may also have had congenital absence or hypoplasia of the parathyroid glands, or one of the varieties of familial hypoparathyroidism. The diagnosis in this patient was dependent on the diagnosis of hyperparathyroidism in his mother.6 The mother had emotional difficulties, renal stones, polyuria, recurrent urinary tract infections and constipation. The serum concentrations of calcium and PTH were elevated. To distinguish permanent forms of hypoparathyroidism from transient forms7 such as that associated with maternal hyperparathyroidism,8 one must decrease the therapy and follow the patient closely for recurrence of hypocalcemia. This task is easier if it has not been necessary to use vitamin D. While waiting for an infant's suppressed parathyroid glands to begin functioning appropriately we increase the dietary calcium supplement to achieve a calcium/phosphorus ratio of 4:1. In this infant an intake of 720 ml of formula per day in combination with the calcium supplement produced a calcium/phosphorus ratio of 3:1. He was also treated with vitamin D and aluminum hydroxide and his serum concentrations of calcium and phosphorus were corrected. When therapy was withdrawn, it was discontinued in reverse order: the phosphate complexing agents first, vitamin D second and calcium supplementation last. DR. NYHAN: Dr. Murphy will present case 2 which illustrates a different problem. DR. MURPHY: A 15-year-old boy was healthy until the age of 8 years, when he noted the onset of abdominal pain, vomiting and dysuria. Analysis of the urine showed pyuria. He was treated with antibiotics, but urine cultures were negative. The symptoms recurred four months later and findings of a urine analysis at that time showed hematuria and pyuria, and the boy was treated with a sulfonamide. Cultures of the urine were again negative. An intravenous pyelogram and voiding cystourethrogram were normal. Serum levels 'of 302
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calcium and phosphorus were also normal. Three months later, after recurrent urinary tract symptoms, a urine culture yielded greater than 100,000 Escherichia coli, but multiple repeat cultures in the absence of therapy showed no bacterial growth. Findings of a roentgenogram of the abdomen showed a density in the left kidney. A 24-hour urine specimen showed normal calcium but low phosphate excretion. Hematuria and pyuria were documented intermittently. Nine serial measurements of the serum concentrations of calcium and phosphorus were obtained. Five determinations of calcium were in the range of 12 to 13 mg per dl and the phosphorus values were in the range of 2.5 to 3.0 mg per dl. Polyuria, polydipsia and worsening of abdominal pain developed. X-ray films showed a urethral stone which was subsequently surgically removed. A diagnosis of hyperparathyroidism was made. When the surgical procedure was done, no adenoma was clearly identified'but 21/2 parathyroid glands were removed. Pathologic evaluation showed an adenoma in the parathyroid gland from the left upper pole of the thyroid. The remainder of the glandular tissue was normal. Hypocalcemia developed in the patient postoperatively, and treatment was begun with calcium and vitamin D. Four years following surgical operation, the patient appeared to require gradually increasing amounts of vitamin D and, eventually, a dosage in excess of 300,000 units per day was prescribed. Noncompliance was suspected. Subsequentlyr the patient became intoxicated with vitamin D, presumably as a result of beginning to take all of the medications' which were being prescribed. His medications were discontinued and his serum level of calcium returned to normal and then became slightly low. On reinstitution of calcium supplementation and DHT normal serum concentrations of calcium and phosphorus were maintained. DR. JONES: Two interesting points are illustrated by this boy's course. The first is relevant to hyperparathyroidism and its surgical treatment, and the second to the development of hypercalcemia secondary to excessive vitamin D therapy. Hyperparathyroidism is an unusual condition in children. Only 36 cases had been reported up to 1970.9 Manifestations include urinary tract infections, polyuria, polydipsia, hematuria and other symptoms associated with calculi. The ther-
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apy of hyperparathyroidism is surgical. In the literature the incidence of permanent hypoparathyroidism secondary to parathyroid excision for the removal of adenomata or hyperplastic glands should be 1 percent to 2 percent, or less. When adenomas are present, either singly or multiply, they should be removed. When parathyroid hyperplasia is found, the approach is to reduce the number of glands to 11/2 or 2, leaving approximately 150 mg of tissue. In this patient there was difficulty identifying the adenomatous gland. I think that if the surgeon had been able to identify the adenoma, he would have removed it without doing a more extensive surgical procedure. The surgeon apparently removed too much tissue (particularly in view of the fact that the other three glands were suppressed) which resulted in permanent hypoparathyroidism. Therapy was a problem, probably because of noncompliance. One of the factors that may have led to this boy's poor compliance was the large number of medications he was required to take. When he came to San Diego he was receiving 1.75 mg of DHT, which amounted to 15 tablets (0.125 mg per tablet) and provided the equivalent of 210,000 units of vitamin D. In most patients satisfactory control can be achieved with between 80,000 and 120,000 units per day. The patient was also receiving calcium supplementation in the form of a combination medication which contained calcium and 2,500 units of vitamin D per tablet and, in addition, 150,000 units of vitamin D2. The total exceeded 360,000 units of vitamin D per day. It is not surprising that, with improved
compliance, hypercalcemia developed. Following admittance to hospital for hypervitaminosis D, the patient was given 0.4 mg of DHT. The dose has been increased gradually to 0.8 mg of DHT (about 100,000 units of vitamin D) and he is doing well. The most recent test showed a serum calcium level of 10.1 mg per dl, which is much higher than we seek in the management of hypoparathyroidism. In the presence of PTH deficiency there is decreased reabsorption of calcium in the kidney and increased urinary excretion of calcium.4 Therefore, we aim to keep serum values lower to prevent nephrocalcinosis. DR. NYHAN: Dr. Murphy will now present case 3. DR. MURPHY: A 13-year-old boy was noted to have a decrease in the rate of linear growth, although he continued to gain weight. He was found to have dry, scaly skin and to be lethargic. The
thyroxine (T4) level was 2.3 jug per dl and the serum concentration of calcium was 8.1 mg per dl. Treatment was begun with administration of 0.2 mg of L-thyroxine per day and there was improvement in the boy's lethargy and dry skin. He also began to lose weight. The patient's condition was evaluated at Camp Pendleton Naval Hospital after discontinuing thyroid replacement for three weeks. T4 was 2.6 Mug per dl and the triiodothyronine (T3) resin uptake was 32 percent. There were positive antithyroid antibodies. A diagnosis of Hashimoto thyroiditis was made. The boy's bone development was normal for his age. He had mild papilledema, but no other evidence of increased intracranial pressure. Visual fields were normal, and there was no enlargement of his blind spot. Computerized axial tomography (CAT) of the skull and brain scan showed no abnormalities. He was discharged from hospital on a regimen of 0.15 mg of L-thyroxine per day. He did well for a year but then had a generalized seizure without fever which lasted four to five minutes. Administration of phenobarbital was begun. The boy had had a history of several febrile seizures as a child and had received phenobarbital between the ages of 5 and 7. He said he had not had headaches, nausea, vomiting, muscle twitches, cramps, blurred vision or diarrhea. There was a history of recurrent pneumonia between the ages of 1 and 5, requiring 40 admissions to hospital. There was no family history of endocrine disease. Findings of a physical examination on admission to the Naval Regional Medical Center showed that the boy's height was at the 3rd percentile and his weight at the 84th percentile. Other results of the physical exahinination were normal, except for dry, scaly skin and slightly blurred optic disks. There was no palpable thyroid and reflexes were hypoactive. Laboratory findings showed serum levels of calcium and phosphorus of 7.4 and 7.5 mg per dl, respectively. The level of PTH was 156 pg per ml. An electroencephalographic study displayed epileptiform discharges in the frontal regions. A diagnosis of hypothyroidism and hypoparathyroidism was made. DR. JONES: Another chapter has been added to this patient's story. His physician recently informed me that polyuria and polydipsia had developed. The blood glucose level was 625 mg per THE WESTERN JOURNAL OF MEDICINE
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dl. Therefore, diabetes mellitus has been added to his spectrum of endocrine hypofunction.10 There are several interesting points about this case: one is that there are three disorders of endocrine function. The treatment of the hypothyroidism may be relevant to the development of symptomatic hypocalcemia. Thyroid hormone decreases the absorption of calcium from the gut, and we often find mild hypocalcemia in patients who have hyperthyroidism and normal parathyroid function. The thyroxine therapy may have precipitated the symptoms and worsened the laboratory manifestations of his hypoparathyroidism. States of endocrine hypofunction which are associated with hypoparathyroidism include Hashimoto thyroiditis and diabetes mellitus, which are the two conditions seen most commonly in the pediatric age range. In adults, pernicious anemia and ovarian failure are being reported with increasing frequency. Addison disease is a particular problem because, in initiating therapy with cortisol, we add another antagonist to the action of PTH, decrease calcium absorption and often alter the effective dose of vitamin D." QUESTION FROM THE AUDIENCE: What is the polyuria due to? DR. JONES: In hyperparathyroidism, it is due to hypercalciuria. The urinary Sulkowitch reaction, which measures calcium excretion in the urine, may be a helpful procedure in the follow-up of patients receiving treatment with vitamin D, although the serum level of calcium remains the best measure and must be followed as well. PTH increases renal calcium reabsorption, while vitamin D increases the absorption of calcium from the gut and also the mobilization of calcium from bone. In a patient who has no parathyroid hormone and who is treated with administration of vitamin D, normocalcemia is often achieved at the expense of calciuria developing. It is most advisable to keep such a patient's calcium level in
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the low normal (8.5 to 9 mg per dl) or even slightly low (8 to 8.5 mg per dl) range. When there are higher serum levels of calcium in such patients, excretion of calcium in the urine increases and nephrolithiasis or nephrocalcinosis (or both) may occur. QUESTION FROM THE AUDIENCE: Does neonatal hypoparathyroidism associated with maternal hyperparathyroidism appear to result from suppression of parathyroid hormone or calcium in the mother?
DR. JONES: Most polypeptide hormones cross the placenta very poorly. The severity of depression of the neonatal parathyroid glands seems to correlate with maternal hypercalcemia. In summary, we have reviewed-the physiology of parathyroid hormone and the pathophysiology of hypoparathyroidism including clinical signs and symptoms as well as possible causes. Case reports for three patients have been presented to illustrate the problems that may occur in such clinical situations. REFERENCES 1. Nusynowitz ML, Frame B, Kolb FO: The spectrum of the hypoparathyroid states: A classification based on physiologic principles. Medicine 55:105-119, Mar 1976 2. Miller MJ, Frame B, Poznanski AK: Branchial anomalies in idiopathic, hypoparathyroidism: Branchial dysembryogenesis. Henry Ford Hospital Med J 20:3-14, 1972 3. Peden VH: True idiopathic hypoparathyroidism as a sexlinked recessive trait. Am J Hum Genet 12:323-337, Sep 1960 4. Avioli LV: The therapeutic approach to hypoparathyroidism. Am J Med 57:34-42, Jul 1974 5. Wade JSH, Goodall P, Deane L, et al: The course of partial parathyroid insufficiency after thyroidectomy. Br J Surg 52:497503, Jul 1965 6. Hartenstein H, Gardner LI: Tetany of the newborn associated with maternal parathyroid adenoma. N Engl J Med 274:266268, Feb 1966 7. Rosenbloom AL: Transient congenital idiopathic hypoparathyroidism. South Med J 66:667-670, Jun 1973 8. Wagner G, Transbol I, Melchior JC: Hyperparathyroidism and pregnancy. Acta Endocr 47:549-564, Dec 1964 9. Biernulf A, Hall K, Sjogren L, et al: Primary hyperparathyroidism in children: Brief review of the literature and a case report. Acta Paediatr Scand 59:249-258, May 1970 10. Blizzard RM, Chee D, Davis W, et al: The incidence of parathyroid and other antibodies in the sera of patients with idiopathic hypoparathyroidism. Clin Exp Immunol 1:119-128, Apr 1966 11. Lukert BP, Adams JS: Vitamin D metabolism in man: Effect of corticosteroids. Arch Intern Med 136:1241-1248, Nov 1976
Specialty Conference Participants KENNETH LEE JONES, MD JAMES MURPHY, MD WILLAM L. NYHAN, MD, PhD
ypoparathyroid sm
From the Department of Pediatrics, University of California, San Diego, School of Medicine, the University of California Medical Center, San Diego, and the United States Naval Regional Medical Center, San Diego.
WILLIAM L. NYHAN, MD, PHD:* This conference has been designed to examine the variety of presentations of hypoparathyroidism. Dr. Jones will begin with a discussion of the physiology of parathyroid hormone (PTH) and the pathophysiology of hypoparathyroidism, as well as the clinical features, diagnosis and therapy. KENNETH LEE JONES, MD: t We shall discuss specific aspects of presentation, diagnosis and therapy, as well as reviewing three cases. A few comments on the physiology of parathyroid hormone (PTH) are necessary. Parathyroid hormone has a molecular weight of approximately 9,500. It is secreted following the cleavage of a larger prohormone whose molecular weight is 11,000 to 12,000. Upon release, PTH is rapidly cleaved into smaller fragments. Although biologically inactive, these fragments are immunologically active, thereby complicating the radioimmunoassy (RIA) of parathyroid hormone. Nevertheless, the ability of investigators to measure parathyroid hormone accurately by RIA has led to considerable advancement in our knowledge of the physiology of PTH. The actions of parathyroid hormone are given in Table 1. In the kidney, its primary actions are *Professor and Chairman, Department of Pediatrics. tAssociate Professor of Pediatrics; Chief, Division of Endocrinology and Metabolism. Reprint requests to: Kenneth Lee Jones, MD, Department of Pediatrics, Division of Endocrinology and Metabolism, University of California, San Diego, School of Medicine, La Jolla, CA 92093.
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to decrease the tubular reabsorption of phosphate, leading to phosphaturia and, concomitantly, to
increase the tubular reabsorption of calcium. In bone, PTH increases the release of calcium and promotes bone remodeling. In the intestine, PTH enhances the absorption of calcium, largely through its effect on the metabolism of vitamin D. Problems in distinguishing between primary and secondary actions of PTH complicate our understanding of this area of physiology. The absorption of calcium from the gut is an example. Results of recent investigations have shown that PTH increases l-a-hydroxylation of vitamin D in the kidney to form 1,25 dihydroxyvitamin D, the most active form of this vitamin. Therefore, it appears that enhancement of calcium absorption is not a primary effect of PTH but, rather, is secondary to promotion of increased production of 1,25 dihydroxyvitamin D. It is helpful, in view of the complicated interactions in calcium-phosphorus metabolism, to remember that the major function of PTH iS to maintain serum levels of calcium within the normal range. The pathophysiology of hypoparathyroidism follows logically from an understanding of the actions of PTH. If there is inadequate circulating parathyroid hormone, renal excretion of phosphorus and absorption of calcium from the kidney, bone and gut do not proceed efficiently. Therefore, the concentration of calcium in the serum falls and that of phosphorus rises. In pa-
HYPOPARATHYROIDISM ABBREVIATIONS USED IN TEXT DHT= dihydrotachysterol PTH=parathyroid hormone RIA = radioimmunoassay TABLE 1.-Actions of Parathyroid Hormone Kidney Increases tubular reabsorption of calcium Decreases tubular reabsorption of phosphorus Bone Increases release of calcium Promotes remodeling of bone Intestine Enhances absorption of calcium
tients with hypocalcemia and hyperphosphatemia there are a number of diagnostic possibilities. The availability of a radioimmunoassay for PTH facilitates diagnosis, permitting the classification of hypoparathyroidism into two major categories: one in which the levels of PTH are low and another in which they are elevated.' Low levels of PTH may result from an abnormality either in the reception of a feedback signal by the cells that secrete PTH or in the ability of these cells to respond. Failure to respond may be due to transient suppression of the cells or may result from more permanent problems including failure of the parathyroid glands to develop or their surgical removal or destruction due to disease. The three cases discussed later illustrate conditions in which circulating levels of PTH are low. In hypoparathyroid states associated with elevated levels of PTH that can be radioimmunoassayed, the pathophysiology is not completely clear; but, presumably, one or more of the following mechanisms is operative: (1) abnormal conversion of the hormone to an inactive form, (2) lack of a cofactor necessary for the functioning of the hormone, (3) presence of an inhibitor of hormone action, (4) defect in the receptor or second messenger system in one or more of the target cells, (5) defect in the cellular response to the second messenger system or (6) lack of substrate for the target cells. Specific examples of hypoparathyroidism in which PTH is deficient are listed in Table 2. One category of hypoparathyroidism results from absence of the parathyroid glands, or their damage or insufficiency. Surgical procedures on the thyroid or the parathyroid glands (case 2) may be
TABLE 2.-Hypoparathyroid States in Which Parathyroid Hormone is Deficient Hypoparathyroidism secondary to absence or damage of parathyroid glands Following surgical procedures Thyroid Parathyroid Radical neck Radioiodine Drug related I-Asparaginase Damage in hemochromatosis Damage by metastatic tumor Branchial dysembryogenesis DiGeorge syndrome Other branchial arch abnormalities Familial Sex linked Undetermined mode of transmission Idiopathic or sporadic (presumably autoimmune) Isolated deficiency of PTH Deficiency of PTH with other endocrine deficiencies Inadequate PTH synthesis in neonates Hypoparathyroidism secondary to suppression of parathyroid function Neonatal secondary to maternal hypercalcemia Secondary to hypercalcemia Post resection of parathyroid adenoma, hyperplasia Secondary to nonparathyroid hypercalcemia Deficiency of magnesium PTH = parathyroid hormone
followed by hypoparathyroidism. Postirradiation damage is a rare cause of hypoparathyroidism in children. There have been a few case reports in which patients had been treated with iodine 131 for hyperthyroidism and subsequently hypoparathyroidism has developed. Hemochromatosis and metastatic malignant replacement of the parathyroid glands occur rarely in children. Branchial dysembryogenesis is a more common cause of hypoparathyroidism in children. Perhaps the best known example is the DiGeorge syndrome in which the thymus as well as the parathyroids fail to develop. In this situation, hypoparathyroidism is associated with an immunodeficiency disease, and may be accompanied by facial abnormalities and congenital heart disease. The association of hypoparathyroidism with other abnormalities of branchial arch development has been recently reexamined. In approximately 150 patients with hypoparathyroidism,2 very few had the DiGeorge syndrome, but many had developmental abnormalities such as cleft palate. Familial hypoparathyroidism has been reported. In some, a sex-linked mode of inheritance has been estabTHE WESTERN JOURNAL OF MEDICINE
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HYPOPARATHYROIDISM lished. The form of hypoparathyroidism we most commonly see is also called sporadic, autoimmune or idiopathic hypoparathyroidism. The second major category of hypoparathyroidism (Table 2) includes conditions in which there is suppression of PTH secretion. We see this in newborn infants whose parathyroid glands have been suppressed by maternal hypercalcemia, or in those in whom there is a condition involving apparent immaturity of the neonatal parathyroid glands. The disease becomes symptomatic in the infants receiving large amounts of phosphorus contained in cow's milk formulas which depress the serum concentration of calcium and, in turn, prevent adequate secretion of PTH. PTH secretion may also be defective in those with magnesium deficiency. The primary clinical features of hypoparathyroidism are similar to those of hypocalcemia. They vary with the age of each patient gnd the severity of the depression of the serum concentration of calcium. Table 3 summarizes the signs and symptoms of hypoparathyroidism as they involve three systems-the neuromuscular, ectodermal and ocular. Neuromuscular irritability is the most common manifestation and may present as classic tetany. Muscle cramps and paresthesias are common, more often recognized in older persons who are able to describe thlir symptoms. Hoarseness may result from laryngospasm, as occurred in one of our patients. Carpopedal spasm may become evident or be accentuated by hyperventilation. The Chvostek and Trousseau signs, and the peroneal reflex are all signs which may be seen pn physical examination. Signs of increased intracranial pressures are often seen;
papilledema may be present although it is not always associated with increased intracranial pressure. Convulsions are frequently presenting signs and though usually generalized, they may be focal. Metastatic calcification may develop and frequently involves the basal ganglia. Cataracts also frequently occur. Ectodermal complaints include loss of hair, delayed eruption or premature loss of teeth, enamel hypoplasia and severe dental caries. Mucocutaneous monilial infections are common and persistent. The skin may be dry and scaly; rarely, an exfoliative dermatitis develops. Transverse ridging of the nails may occur. The primary laboratory findings for hypoparathyroidism are hypocalcemia and hyperphosphatemia. In the presence of these conditions, one can rule out only renal glomerular insufficiency, as there is little else in the differential diagnosis. The next task is to establish whether hypoparathyroidism is due to a deficiency of PTH. The major goal of therapy is to maintain the serum concentration of calcium in the normal range. Establishing normocalcemia will correct many of the symptoms and signs of hypoparathyroidism, especially the neuromuscular manifestations. Of course, hypoplasia of dental enamel, cataracts, and the chronic moniliasis seen in approximately 20 percent of patients will not resolve. The treatment of chronic hypoparathyroidism should be matched with the severity of the illness.4 In mild transient hypoparathyroidism which may follow surgical removal of parathyroid tissue5 or which occurs in newborn infants, calcium supplementation may be all that is required. In more severe and chronic hypoparathyroidism, seen in
TABLE 3.-Signs and Symptoms of Hypoparathyroidism
Signs
Symptoms Neuromuscular Tetany Convulsions
Carpopedal spasm-increased with hyperventilation
Muscle cramps Paresthesias Hoarseness secondary to
laryngospasm Ocular Cataracts
Papilledema
Ectodermal Hair loss Delayed dental eruption Premature loss of teeth Mucocutaneous candidiasis
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Chvostek sign Trousseau sign Peroneal sign Hyperreflexia Increased intracranial pressure
* 4
Dry scaly skin Brittle, dull hair; alopecia Transverse ridging of nails Hypoplasia of dental enamel Severe dental caries
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patients following total removal of the parathyroid glands as well as in most patients with idiopathic hypoparathyroidism, therapy with vitamin D is required. It may be used either alone or with calcium supplementation. I prefer to use dihydrotachysterol (DHT) when vitamin D therapy is indicated. This drug has a more rapid onset and probably a better phosphaturic effect than other available preparations. In addition, DHT is inactivated more rapidly so that, if hypervitaminosis D and hypercalcemia develop, discontinuation of therapy results in a more rapid resolution. Furtherfmiore, DHT does not have the propensity to accumulate in fatty tissues that other vitamin D preparations have. The plan of vitamin D therapy should be dictated by the severity of symptoms. In a patient with prdhounced symptoms of hypocalcemia, it is useful to give a loading dose. In treating infants, We use 1 mg of DHT a day for four days and then decrease the dose (1 mg is approximately equivalent to 120,000 units of vitamin D). In severely ill older children we begin with 2.5 mg per day for four days before beginning to decrease the dose. In most patients symptoms are not severe and we can begin with much lower doses, starting with 0.125 to 0.2 mg of DHT, increasing the dose every week or two until serum calcium levels approach the normal range. DR. NYHAN: Dr. Murphy will present case 1.
JAMES MURPHY, MD: * A male infant weighing 2,693 grams was born to a 28-year-old mother after a 41-week gestation. The pregnancy was complicated by renal calculi, which required surgical removal at six ihonths, and by pyelonephritis, treated with sulfanilamide at 36 weeks of gestation. In retrospect, the mother also experienced polyuria, polydipsia, nervousness and constipation throughout the pregnancy. In addition, the mother had a history of asthma, for which she was receiving Marax (ephedrine sulfate, theophylline and hydroxyzine hydrochloride), hydroxyzine pamoate (Vistaril) and beclomethasone dipropionate. The delivery was uneventful. The infant was breast-fed for two days and then given a prepared formula after mastitis developed in the mother. Several formulas were tried because the child had symptoms of colic, but the symptoms did not resolve with the changes in formula. *Pediatric resident, US Naval Regional Medical Center, San Diego.
On the tenth day after delivery when diarrhea developed, the infant had several episodes of vomiting and a left-sided major motor seizure involving the face, arm and leg. lie was admitted to a local hospital. On admission, the baby was lethargic. Serum levels of calcium and magnesium were 6.1 and 1.0 mg per dl, respectively. Values for blood urea nitrogen (BUN), electrolytes, glucose and creatinine were within normal limits. The leukocyte count was 27,400 per cu mm with a normal differential and the hematocrit was 56 percent. Cerebrospinal fluid concentrations of glucose and protein were normal. All cultures were negative and x-ray films of the long bones and skull showed no abnormalities. The infant was given calcium intravenously and supplemental calcium was given orally. In addition, he was fed a formula in which the ratio of calcium to phosphorus was 2:1. On the day following admission his serum concentrations of calcium and phosphorus were each 7.9 mg per dl. A repeat measurement of the magnesium level was 1.5 mg per dl and the total serum protein was 4 mg per dl. On day six, administration of vitamin D was begun. The infant's PTH was 50 pg per ml (normal 275 to 675 pg per ml), exceptionally low in view of the patient's low serum concentration of calcium. The infant's mother was found to have a serum concentration of calcium of 11.4 mg per dl and a phosphorus level of 3.6 mg per dl. We made a diagnosis of neonatal hypoparathyroidism secondary to maternal hyper-
parathyroidism. DR. JONES: This infant presented with classic neonatal tetany. In patients with this disorder, symptoms develop in the first two weeks of life. Symptoms followed a feeding change from breast milk, which has a calcium/phosphorus ratio of 2:1, to a formula which has a calcium/phosphorus ratio of about 1:1. Furthermore, the concentration of phosphorus in the formula is three times greater than that in breast milk. Symptoms of hypocalcemia with jitteriness, colic and seizure developed in the infant. The laboratory confirmed the presence of hypocalcemia and hyperphosphatemia. There are several differential diagnostic considerations. The most common condition seen at this age is that of transient hypoparathyroidism of the newborn. With current feeding regimens, this syndrome is seen less frequently, although it THE WESTERN JOURNAL OF MEDICINE
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still occurs in premature infant-s following obstetrical complications, and in infants of diabetic mothers. In the past it was also seen in term infants who were given whole milk or evaporated milk formulas, both having phosphate contents about 61/2 times greater than that of breast milk. Another diagnostic possibility was the DiGeorge syndrome. The absence of facial abnormalities, cardiovascular abnormalities and immunodeficiency, and the presence of the thymus ruled out this diagnosis. This infant may also have had congenital absence or hypoplasia of the parathyroid glands, or one of the varieties of familial hypoparathyroidism. The diagnosis in this patient was dependent on the diagnosis of hyperparathyroidism in his mother.6 The mother had emotional difficulties, renal stones, polyuria, recurrent urinary tract infections and constipation. The serum concentrations of calcium and PTH were elevated. To distinguish permanent forms of hypoparathyroidism from transient forms7 such as that associated with maternal hyperparathyroidism,8 one must decrease the therapy and follow the patient closely for recurrence of hypocalcemia. This task is easier if it has not been necessary to use vitamin D. While waiting for an infant's suppressed parathyroid glands to begin functioning appropriately we increase the dietary calcium supplement to achieve a calcium/phosphorus ratio of 4:1. In this infant an intake of 720 ml of formula per day in combination with the calcium supplement produced a calcium/phosphorus ratio of 3:1. He was also treated with vitamin D and aluminum hydroxide and his serum concentrations of calcium and phosphorus were corrected. When therapy was withdrawn, it was discontinued in reverse order: the phosphate complexing agents first, vitamin D second and calcium supplementation last. DR. NYHAN: Dr. Murphy will present case 2 which illustrates a different problem. DR. MURPHY: A 15-year-old boy was healthy until the age of 8 years, when he noted the onset of abdominal pain, vomiting and dysuria. Analysis of the urine showed pyuria. He was treated with antibiotics, but urine cultures were negative. The symptoms recurred four months later and findings of a urine analysis at that time showed hematuria and pyuria, and the boy was treated with a sulfonamide. Cultures of the urine were again negative. An intravenous pyelogram and voiding cystourethrogram were normal. Serum levels 'of 302
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* 4
calcium and phosphorus were also normal. Three months later, after recurrent urinary tract symptoms, a urine culture yielded greater than 100,000 Escherichia coli, but multiple repeat cultures in the absence of therapy showed no bacterial growth. Findings of a roentgenogram of the abdomen showed a density in the left kidney. A 24-hour urine specimen showed normal calcium but low phosphate excretion. Hematuria and pyuria were documented intermittently. Nine serial measurements of the serum concentrations of calcium and phosphorus were obtained. Five determinations of calcium were in the range of 12 to 13 mg per dl and the phosphorus values were in the range of 2.5 to 3.0 mg per dl. Polyuria, polydipsia and worsening of abdominal pain developed. X-ray films showed a urethral stone which was subsequently surgically removed. A diagnosis of hyperparathyroidism was made. When the surgical procedure was done, no adenoma was clearly identified'but 21/2 parathyroid glands were removed. Pathologic evaluation showed an adenoma in the parathyroid gland from the left upper pole of the thyroid. The remainder of the glandular tissue was normal. Hypocalcemia developed in the patient postoperatively, and treatment was begun with calcium and vitamin D. Four years following surgical operation, the patient appeared to require gradually increasing amounts of vitamin D and, eventually, a dosage in excess of 300,000 units per day was prescribed. Noncompliance was suspected. Subsequentlyr the patient became intoxicated with vitamin D, presumably as a result of beginning to take all of the medications' which were being prescribed. His medications were discontinued and his serum level of calcium returned to normal and then became slightly low. On reinstitution of calcium supplementation and DHT normal serum concentrations of calcium and phosphorus were maintained. DR. JONES: Two interesting points are illustrated by this boy's course. The first is relevant to hyperparathyroidism and its surgical treatment, and the second to the development of hypercalcemia secondary to excessive vitamin D therapy. Hyperparathyroidism is an unusual condition in children. Only 36 cases had been reported up to 1970.9 Manifestations include urinary tract infections, polyuria, polydipsia, hematuria and other symptoms associated with calculi. The ther-
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apy of hyperparathyroidism is surgical. In the literature the incidence of permanent hypoparathyroidism secondary to parathyroid excision for the removal of adenomata or hyperplastic glands should be 1 percent to 2 percent, or less. When adenomas are present, either singly or multiply, they should be removed. When parathyroid hyperplasia is found, the approach is to reduce the number of glands to 11/2 or 2, leaving approximately 150 mg of tissue. In this patient there was difficulty identifying the adenomatous gland. I think that if the surgeon had been able to identify the adenoma, he would have removed it without doing a more extensive surgical procedure. The surgeon apparently removed too much tissue (particularly in view of the fact that the other three glands were suppressed) which resulted in permanent hypoparathyroidism. Therapy was a problem, probably because of noncompliance. One of the factors that may have led to this boy's poor compliance was the large number of medications he was required to take. When he came to San Diego he was receiving 1.75 mg of DHT, which amounted to 15 tablets (0.125 mg per tablet) and provided the equivalent of 210,000 units of vitamin D. In most patients satisfactory control can be achieved with between 80,000 and 120,000 units per day. The patient was also receiving calcium supplementation in the form of a combination medication which contained calcium and 2,500 units of vitamin D per tablet and, in addition, 150,000 units of vitamin D2. The total exceeded 360,000 units of vitamin D per day. It is not surprising that, with improved
compliance, hypercalcemia developed. Following admittance to hospital for hypervitaminosis D, the patient was given 0.4 mg of DHT. The dose has been increased gradually to 0.8 mg of DHT (about 100,000 units of vitamin D) and he is doing well. The most recent test showed a serum calcium level of 10.1 mg per dl, which is much higher than we seek in the management of hypoparathyroidism. In the presence of PTH deficiency there is decreased reabsorption of calcium in the kidney and increased urinary excretion of calcium.4 Therefore, we aim to keep serum values lower to prevent nephrocalcinosis. DR. NYHAN: Dr. Murphy will now present case 3. DR. MURPHY: A 13-year-old boy was noted to have a decrease in the rate of linear growth, although he continued to gain weight. He was found to have dry, scaly skin and to be lethargic. The
thyroxine (T4) level was 2.3 jug per dl and the serum concentration of calcium was 8.1 mg per dl. Treatment was begun with administration of 0.2 mg of L-thyroxine per day and there was improvement in the boy's lethargy and dry skin. He also began to lose weight. The patient's condition was evaluated at Camp Pendleton Naval Hospital after discontinuing thyroid replacement for three weeks. T4 was 2.6 Mug per dl and the triiodothyronine (T3) resin uptake was 32 percent. There were positive antithyroid antibodies. A diagnosis of Hashimoto thyroiditis was made. The boy's bone development was normal for his age. He had mild papilledema, but no other evidence of increased intracranial pressure. Visual fields were normal, and there was no enlargement of his blind spot. Computerized axial tomography (CAT) of the skull and brain scan showed no abnormalities. He was discharged from hospital on a regimen of 0.15 mg of L-thyroxine per day. He did well for a year but then had a generalized seizure without fever which lasted four to five minutes. Administration of phenobarbital was begun. The boy had had a history of several febrile seizures as a child and had received phenobarbital between the ages of 5 and 7. He said he had not had headaches, nausea, vomiting, muscle twitches, cramps, blurred vision or diarrhea. There was a history of recurrent pneumonia between the ages of 1 and 5, requiring 40 admissions to hospital. There was no family history of endocrine disease. Findings of a physical examination on admission to the Naval Regional Medical Center showed that the boy's height was at the 3rd percentile and his weight at the 84th percentile. Other results of the physical exahinination were normal, except for dry, scaly skin and slightly blurred optic disks. There was no palpable thyroid and reflexes were hypoactive. Laboratory findings showed serum levels of calcium and phosphorus of 7.4 and 7.5 mg per dl, respectively. The level of PTH was 156 pg per ml. An electroencephalographic study displayed epileptiform discharges in the frontal regions. A diagnosis of hypothyroidism and hypoparathyroidism was made. DR. JONES: Another chapter has been added to this patient's story. His physician recently informed me that polyuria and polydipsia had developed. The blood glucose level was 625 mg per THE WESTERN JOURNAL OF MEDICINE
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dl. Therefore, diabetes mellitus has been added to his spectrum of endocrine hypofunction.10 There are several interesting points about this case: one is that there are three disorders of endocrine function. The treatment of the hypothyroidism may be relevant to the development of symptomatic hypocalcemia. Thyroid hormone decreases the absorption of calcium from the gut, and we often find mild hypocalcemia in patients who have hyperthyroidism and normal parathyroid function. The thyroxine therapy may have precipitated the symptoms and worsened the laboratory manifestations of his hypoparathyroidism. States of endocrine hypofunction which are associated with hypoparathyroidism include Hashimoto thyroiditis and diabetes mellitus, which are the two conditions seen most commonly in the pediatric age range. In adults, pernicious anemia and ovarian failure are being reported with increasing frequency. Addison disease is a particular problem because, in initiating therapy with cortisol, we add another antagonist to the action of PTH, decrease calcium absorption and often alter the effective dose of vitamin D." QUESTION FROM THE AUDIENCE: What is the polyuria due to? DR. JONES: In hyperparathyroidism, it is due to hypercalciuria. The urinary Sulkowitch reaction, which measures calcium excretion in the urine, may be a helpful procedure in the follow-up of patients receiving treatment with vitamin D, although the serum level of calcium remains the best measure and must be followed as well. PTH increases renal calcium reabsorption, while vitamin D increases the absorption of calcium from the gut and also the mobilization of calcium from bone. In a patient who has no parathyroid hormone and who is treated with administration of vitamin D, normocalcemia is often achieved at the expense of calciuria developing. It is most advisable to keep such a patient's calcium level in
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the low normal (8.5 to 9 mg per dl) or even slightly low (8 to 8.5 mg per dl) range. When there are higher serum levels of calcium in such patients, excretion of calcium in the urine increases and nephrolithiasis or nephrocalcinosis (or both) may occur. QUESTION FROM THE AUDIENCE: Does neonatal hypoparathyroidism associated with maternal hyperparathyroidism appear to result from suppression of parathyroid hormone or calcium in the mother?
DR. JONES: Most polypeptide hormones cross the placenta very poorly. The severity of depression of the neonatal parathyroid glands seems to correlate with maternal hypercalcemia. In summary, we have reviewed-the physiology of parathyroid hormone and the pathophysiology of hypoparathyroidism including clinical signs and symptoms as well as possible causes. Case reports for three patients have been presented to illustrate the problems that may occur in such clinical situations. REFERENCES 1. Nusynowitz ML, Frame B, Kolb FO: The spectrum of the hypoparathyroid states: A classification based on physiologic principles. Medicine 55:105-119, Mar 1976 2. Miller MJ, Frame B, Poznanski AK: Branchial anomalies in idiopathic, hypoparathyroidism: Branchial dysembryogenesis. Henry Ford Hospital Med J 20:3-14, 1972 3. Peden VH: True idiopathic hypoparathyroidism as a sexlinked recessive trait. Am J Hum Genet 12:323-337, Sep 1960 4. Avioli LV: The therapeutic approach to hypoparathyroidism. Am J Med 57:34-42, Jul 1974 5. Wade JSH, Goodall P, Deane L, et al: The course of partial parathyroid insufficiency after thyroidectomy. Br J Surg 52:497503, Jul 1965 6. Hartenstein H, Gardner LI: Tetany of the newborn associated with maternal parathyroid adenoma. N Engl J Med 274:266268, Feb 1966 7. Rosenbloom AL: Transient congenital idiopathic hypoparathyroidism. South Med J 66:667-670, Jun 1973 8. Wagner G, Transbol I, Melchior JC: Hyperparathyroidism and pregnancy. Acta Endocr 47:549-564, Dec 1964 9. Biernulf A, Hall K, Sjogren L, et al: Primary hyperparathyroidism in children: Brief review of the literature and a case report. Acta Paediatr Scand 59:249-258, May 1970 10. Blizzard RM, Chee D, Davis W, et al: The incidence of parathyroid and other antibodies in the sera of patients with idiopathic hypoparathyroidism. Clin Exp Immunol 1:119-128, Apr 1966 11. Lukert BP, Adams JS: Vitamin D metabolism in man: Effect of corticosteroids. Arch Intern Med 136:1241-1248, Nov 1976
