Calcium-regulated parathyroid hormone release in primary hyperparathyroidism: studies in vitro with dispersed parathyroid cells.

Dispersed parathyroid cells were prepared from three normal human parathyroid glands as well as from pathologic parathyroid tissue of 30 patients with primary hyperparathyroidism (17 with adenoma, 12 with primary hyperplasia and one with carcinoma). Immunoreactive parathyroid hormone (PTH) release from cells of normal glands showed a “set-point” (the calcium concentration half-maximally inhibiting PTH release) of 1.0 mM, similar to that of normal bovine and canine parathyroid cells. Cells from parathyroid tissue of one patient each with multiple endocrine neoplasia type I (MEN I) and unclassified familial hyperparathyroidism, and from eight of 12 glands from patients with sporadic hyperplasia had “setpoints” of 1.0 to 1.1 mM. By contrast, only two of 17 cell preparations from adenomas had “set-points” of < 1.2 mM. Hormone secretion from cells of eight of 17 adenomas, four of 12 sporadic hyperplastic glands and a gland from a single patient with multiple endocrine neoplasia type II (MEN II) had “set-points” of 1.2 to 1.5 mM. PTH release from dispersed cells from the remaining seven adenomas, one sporadic hyperplastic gland and metastatic parathyroid carcinoma in a single patient showed relatively poor suppressibility (12 to 43 per cent) by 3.0 mM calcium.The present results and previous data from this laboratory in 20 additional patients with primary hyperparathyroidism suggest heterogeneous responsiveness to calcium in this disorder. In some cases (most primary hyperplasia and occasional adenomas), calcium-regulated PTH release is relatively normal. In others (most adenomas and some sporadic primary hyperplasia), maximal suppressibility of secretion is normal but with an elevated “set-point.” In the remaining adenomas, in rare primary hyperplasia and in the single carcinoma in this series, relative autonomy was observed. The relationship of these various secretory patterns to the pathophysiology of primary hyperparathyroidism is discussed.     

Hypercalcemia with suppressed parathyroid hormone in Burkitt's lymphoma.

Two patients with Burkitt's lymphoma presented with severe hypercalcemia, a previously unreported complication of this tumor. Roentgenograms and radionuclide scans showed multiple osteolytic lesions in both patients. Plasma parathyroid hormone (PTH) was undetectable during the hypercalcemia phase. Chemotherapy was followed by rapid tumor lysis, hyperphosphatemia, phosphaturia and hypocalcemia. The hypocalcemic phase persisted for two weeks despite rapid normalization of serum phosphorus and renal function. Measurement of urinary cyclic AMP, an index of PTH action, indicated that parathyroid function had been suppressed by the hypercalcemia and remained suppressed for almost one week despite marked hypocalcemia.     

Immune complex glomerulonephritis in sicca syndrome.

In three patients with the sicca syndrome (Sjögren's syndrome), who were followed for one to seven years, glomerulonephritis developed. None of these patients fulfilled the diagnostic criteria for systemic lupus erythematosus. All of these patients had circulating immune complexes as detected by the Clq binding assay.Glomerular histology by light and electron microscopy revealed changes compatible with membranoproliferative glomerulonephritis in two of the patients and membranous glomerulonephritis in the third.All patients showed rapid improvement in renal function following moderate doses of corticosteroids. In addition, the treatment decreased the level of circulating immune complexes in two patients who were followed for a sufficient period of time.     

Pseudomonas pneumonia. A retrospective study of 36 cases

The clinical course in 36 cases of Pseudomonas pneumonia collected over a 15 year period (1956 to 1970) at the Clinical Center of the National Institutes of Health were reviewed to identify factors which increased the risk of infection and affected prognosis. In all cases, the patients had a serious underlying disease which predisposed to infection, and the majority had neoplastic diseases, particularly acute leukemia; cardiac or pulmonary diseases were less frequent. Pseudomonas related mortality was 81 per cent and was not influenced by type of antibiotic therapy or by the year of occurrence. Many patients were neutropenic, usually subsequent to cytotoxic chemotherapy, and frequently had been treated with steroids or antibiotics just prior to the development of pneumonia. Adequate numbers of circulating granulocytes were essential to survival. No patient with a positive blood culture survived. Possibilities for new means of prevention and treatment of Pseudomonas pneumonia are discussed.     

Resistance to multiple hormones in patients with pseudohypoparathyroidism. Association with deficient activity of guanine nucleotide regulatory protein

Pseudohypoparathyroidism type I is characterized by resistance (defined as a deficient urinary cAMP response) to parathyroid hormone and, in most cases, hypocalcemia and hyperphosphatemia. Many patients with pseudohypoparathyroidism type I snow a peculiar somatic phenotype termed Albright's hereditary osteodystrophy, but patients without this feature who show identical parathyroid hormone resistance have been described. Parathyroid hormone resistance in pseudohypoparathyroidism type I has been attributed to a defective parathyroid hormone receptor-adenylate cyclase complex. Recent studies have demonstrated deficient activity of the guanine nucleotide regulatory protein (G unit) of adenylate cyclase in many patients with Pseudohypoparathyroidism. Since the G unit is common to all tissues, as opposed to hormone receptors, which are tissue specific, a defective G unit should lead to resistance to multiple hormones that act by stimulating adenylate cyclase. To test this hypothesis, we studied erythrocyte G unit activity and clinical endocrine function in 29 patients with pseudohypoparathyroidism type I. Thirteen patients had deficient erythrocyte G unit activity (43 ± 9 percent of control [mean ± 1 SD]); 16 patients had normal G unit activity (92 ± 8 percent of control) (p < 0.001). Patients with deficient erythrocyte G unit activity had significantly greater (p < 0.001) basal and thyrotropin-releasing hormonestimulated thyrotropin levels than patients with normal erythrocyte G unit activity or normal control subjects (15.0 ± 6.5 and 54.3 ±22.7; 4.5 ± 2.0 and 19.5 ± 6.6; 2.0 ± 1.1 and 16.5 ± 6.7 μU/ml, respectively). In the absence of goiter or antithyroid antibody, an elevated thyrotropin level in patients with deficient erythrocyte G unit activity is consistent with thyroid resistance to thyrotropin. Furthermore, patients with deficient erythrocyte G unit activity had significantly lower (p < 0.02) integrated plasma cAMP increases to glucagon stimulation than either patients with normal erythrocyte G unit activity or normal subjects (5.1 ± 2.2 versus 8.6 ± 3.9 versus 8.6 ± 3.6 μ M × minutes), consistent with impaired hepatic cyclase responsiveness to glucagon. Clinical evidence of gonadal dysfunction was common in patients with deficient erythrocyte G unit activity, but was not observed in patients with normal erythrocyte G unit activity. These observations suggest that patients with Pseudohypoparathyroidism and deficient erythrocyte G unit activity have a disorder that is generalized to cyclase-dependent tissues, and not limited to parathyroid hormone-sensitive tissues. Moreover, it appears that patients with pseudohypoparathyroidism and normal erythrocyte G unit activity may have a defect limited to parathyroid hormone-sensitive tissues. These data support the hypothesis that a deficiency of G units is the basis for multiple hormone resistance in pseudohypoparathyroidism.     

Cardiac sarcoma causing "ASH" and simulating coronary heart disease.

A patient is described in whom primary cardiac sarcoma preferentially infiltrated the ventricular septum while essentially sparing the left ventricular free wall, resulting in striking echocardiographic and morphologic asymmetry between septum and free wall (ASH). No reports have appeared previously of a patient with an intramural cardiac neoplasm demonstrated by echocardiogram. Additionally, the patient clinically had features typical of coronary heart disease, yet at necropsy the extramural coronary arteries showed insignificant (< 75 per cent) cross-sectional area luminal narrowing by atherosclerotic plaques.     

Alternate-day corticosteroid therapy

We treated five patients with persistent Staphylococcus aureus bacteremia and endocarditis. Surgical intervention or a “secondline” antistaphylococcal agent was required for bacteriologic cure in each. Special bacteriologic evaluation failed to demonstrate methicillin resistance or antibiotic “tolerance” among the strains of Staphylococcus tested. Cephalosporin agents were noted to be more susceptible to inoculum effect than either methicillin or nafcillin. All patients survived; the explanation for their atypical course is obscure. We present an approach to patients with persistent Staph. aureus bacteremia and endocarditis.     

IgA-containing circulating immune complexes in patients with IgA nephropathy

The role of circulating immune complexes in the pathogenesis of IgA nephropathy (Berger's disease) is controversial. Previous studies have shown that a minority of these patients have immune complexes, but the methods used have been able to detect only IgG- or IgM-containing circulating Immune complexes. Using a sensitive, specific Raji cell radioimmunoassay for IgA-containing circulating immune complexes, we have examined serum specimens from 12 patients with IgA nephropathy for the presence of IgA-containing circulating immune complexes. In addition, the Raji cell IgG assay and the ¹²⁵I-C1q binding assay were used for the detection of IgG-or IgM-containing circulating immune complexes. Purified monoclonal antibodies against human IgA₁ and IgA₂ were used to determine the subclass of IgA present in renal biopsy specimens from five of these patients. Six of 12 (50 percent) patients had IgA-containing circulating immune complexes, whereas only two of 12 (17 percent) had positive results in the Raji IgG assay and one of 12 (8 percent) in the ¹²⁵I-C1q binding assay. There was no correlation between serum IgA, C3, C4, or factor B levels and the presence or level of IgA-containing circulating immune complexes. None of the three patients with renal failure had circulating immune complexes of any type. Of the seven patients with disease duration of two years or less, five (71 percent) had IgA-containing circulating immune complexes, and three (43 percent) had IgG- or IgM-containing complexes. In all five renal biopsy specimens examined for IgA subclass, diffuse, heavy, mesangial deposits of IgA₁ were seen, whereas IgA₂ staining was absent or present in only trace amounts. These findings suggest that IgA₁ is the predominant antibody in renal biopsy specimens from patients with IgA nephropathy. The finding of IgA-containing circulating immune complexes in these patients—and their more frequent occurrence in patients with early stages of the disease—suggests that IgA-containing circulating immune complexes may play a role in the pathogenesis of IgA nephropathy.     

The extramural and intramural coronary arteries in juvenile diabetes mellitus: analysis of nine necropsy patients aged 19 to 38 years with onset of diabetes before age 15 years

This report describes the status of the coronary arteries in nine patients (average age, 29 years) with juvenile onset diabetes mellitus (average age at onset, nine years), and compares the clinical and morphologic observations in them to those in nine control subjects (average age, 29 years). The nine patients with juvenile diabetes had significantly more extramural coronary luminal narrowing by atherosclerotic plaques than did the control subjects. The lumens of one or more of the four major epicardial coronary arteries were narrowed more than 75 per cent in cross-sectioned area in six of the diabetic patients and in none of the control subjects. This difference in degree of narrowing of the epicardial coronary arteries was even more striking when the per cent of narrowing of the entire lengths of the four major coronary arteries was examined: of the 191 cm of major coronary artery examined in the nine diabetic patients, the lumen in 90.5 cm (47 per cent) was narrowed more than 50 per cent in cross-sectioned area, whereas of 155 cm of coronary artery examined in the nine control subjects, the lumen of only 2 cm (1 per cent) was narrowed to this degree.Minor degrees of intimal fibrous proliferation, considered of no functional consequence, were observed in the intramural coronary arteries in the ventricles (excluding papillary muscle) in six of the nine diabetic patients but in none of the nine control subjects. Periodic acid-Schiff-positive material was more frequent and of greater intensity in the diabetic patients (all nine) than in the control subjects (four of nine).     

Syndrome of anosmia with hypogonadotropic hypogonadism (kallmann syndrome): Clinical and laboratory studies in 23 cases

We have studied 23 patients (14 men, nine women) in 18 kindreds with anosmia and hypogonadotropic hypogonadism. Seven kindreds had more than one affected member, and included five eugonadal persons with anosmia and two eusomic women with hypogonadotropic hypogonadism. Other clinical abnormalities observed included: obesity (in nine), cryptorchidism (six), osteopenia (six), mild neurosensory hearing loss (five), gynecomastia (five), diabetes mellitus (four), cleft lip or palate or both (three), high-arched palate (two), short fourth metacarpal (two), and clinodactyly, camptodactyly, shortened frenulum of the tongue, multiple facial anomalies, right-sided aortic arch, malrotation of the gut, renal diverticulum, and mild red-green color blindness (one each).Normal secondary sex characteristics developed in all 20 patients treated on a long-term basis with chorionic gonadotropin or gonadal steroids. Responses to a single injection of gonadotropin-releasing hormone were heterogeneous. Five men had no luteinizing hormone response, five had a depressed response, and one an exaggerated response; two had no follicle-stimulating hormone response, five responses were depressed, three were normal, and one was ex-aggerated. None of seven women achieved a normal luteinizing hormone response to gonadotropin-releasing hormone; two had depressed follicle-stimulating hormone response, four responses were normal, and one was exaggerated. None of 11 patients tested responded to clomiphene. Two men fathered children. Each of two other men who underwent biopsy of the testes before and after long-term chorionic gonadotropin therapy showed mildly increased spermatogenesis. Little or no maturation beyond primordial follicles was observed in two ovarian biopsy specimens. Fifteen of 17 patients had normal basal prolactin levels and 14 of 16 had normal thyrotropin-releasing hormone-induced prolactin increase, but nine of 15 tested had a decreased or absent response of prolactin to chlorpromazine. Circulating concentrations of thyroid hormones were normal, but four of 17 patients tested had depressed TSH (thyroid-stimulating hormone) responses to thyrotropin-releasing hormone, and one man had an exaggerated response. Three of 12 patients had a depressed cortisol response to insulin-induced hypoglycemia, and two of seven patients had slightly depressed deoxycortisol responses to metyrapone. Growth hormone and vasopressin release in all 14 and all 12 patients, respectively, studied were essentially normal.Patients with anosmia and hypogonadotropic hypogonadism may have hypothalamic defect(s) responsible for the hypogonadotropism and perhaps for certain additional deficiencies of anterior pituitary function found in some. The cause of less frequent phenotypic abnormalities has not been established. In certain pedigrees, the evidence suggests that the major manifestations of the syndrome are inherited as an autosomal recessive trait.     

Vascular complications of thorium dioxide.

Vascular complications occurring late after exposure to thorium dioxide (thorotrast) are described in two patients. One patient had both cerebral andmyocardial infarcts and died at age 25 years. Necropsy disclosed both adventitial and intimal fibrosis of the left carotid artery and greater than 75 per cent cross-sectional area luminal narrowing of both the left main and left anterior descending coronary arteries. The other patient, a 33 year old man, had no cerebral symptoms in life but total obstruction of the right carotid artery secondary to a thorotrastoma was found at necropsy. Vascular complications due to thorotrast appear to represent consequences of chronic alpha irradiation.     

Divalent cation metabolism: Familial hypocalciuric hypercalcemia versus typical primary hyperparathyroidism

Twenty-three members of three families with a syndrome of hypercalcemia without hypercalciuria (familial hypocalciuric hypercalcemia) were compared to a group of 64 subjects with hypercalcemia due to typical primary hyperparathyroidism. Patients with familial hypocalciuric hypercalcemia had higher creatinine clearance values than those with primary hyperparathyrodism (115 ± 27 versus 87 ± 27 ml/min/1.73 m² (mean ± 1 standard deviation [SD] p < 0.0001). Although renal function was well preserved, the group with familial hypocalciuric hypercalcemia showed a mean serum magnesium concentration of 2.05 ± 0.17 meq/liter, significantly higher than that in normal subjects (1.74 ± 0.12 meq/liter, p < 0.0001) or than in the group with primary hyperparathyroidism (1.71 ± 0.21 meq/liter, p < 0.0001). In familial hypocalciuric hypercalcemia the degree of hypermagnesemia was directly proportional to the degree of hypercalcemia (R = +0.54, p < 0.01), contrasting with an inverse relation of serum calcium and magnesium concentrations in primary hyperparathyroidism (R = ?0.32, p < 0.02). Urinary excretion of both calcium (calcium:creatinine clearance ratio 0.006 ± 0.004 versus 0.024 ± 0.01, p < 0.0001) and magnesium (magnesium:creatinine clearance ratio 0.031 ± 0.0008 versus 0.047 ± 0.03, p < 0.003) was significantly lower in familial hypocalciuric hypercalcemia than in primary hyperparathyroidism. There was no evidence that abnormal protein binding of cations in serum from those with familial hypocalciuric hypercalcemia accounted for the hypercalcemia and hypermagnesemia or for the disproportionately low urinary excretion of divalent cations by rendering them resistant to glomerular filtration. After fractionation by electrophoresis on cellulose acetate, the major plasma protein components were quantitatively similar in both groups. Furthermore, ionized and ultrafiltrable calcium and ultrafiltrable magnesium showed consistent relations to total calcium and total magnesium concentrations in plasma from both groups. Therefore, in familial hypocalciuric hypercalcemia there are increased serum concentrations of the physiologically active forms of both calcium and magnesium, and the renal handling of the filtered load of these divalent cations differs in familial hypocalciuric hypercalcemia and primary hyperparathyroidism.     

Parathyroid carcinoma in familial hyperparathyroidism

We present the first reported occurrence of parathyroid carcinoma in familial parathyroid hyperplasia or multiple endocrine adenomatosis, type I. The patient's hypercalcemia persisted through 8 years even though abnormal parathyroid tissue was removed from three separate sites in the neck. The original clinical presentation and review of tissue removed initially from the left thyroid lobe suggested the possibility of parathyroid carcinoma; tissue from the second and third operations (on the right) was histologically benign, showing chief cell hyperplasia. A fourth operation then revealed implants of parathyroid carcinoma unilaterally in the left side of the neck. The patient's brother and sister also had parathyroid hyperplasia, and his mother died of a pancreatic tumor of undocumented cell type. The patient himself had no evidence of pancreatic or pituitary tumor.     

Differences in the clinical manifestations of sicca syndrome in the presence and absence of rheumatoid arthritis.

In this restrospective study we review the clinical features of patients with the sicca syndrome in the presence and absence of rheumatoid arthritis. All patients were followed at the National Institutes of Health for at least five years after the diagnosis of sicca syndrome was established. Twenty-two patients had sicca syndrome alone, and 21 patients had definite rheumatoid arthritis and the sicca syndrome. Rheumatoid arthritis tended to precede the developement of sicca syndrome. The mean age at diagnosis of sicca syndrome is the same in both groups. No significant differences in serum innumoglobulins, the third component of complement (C3), rheumatoid factor titer and salivary histopathology were found. However, the clinical features were quite distinct. Patients with sicca syndrome alone had a significantly greater frequency of recurrent parotitis, Raynaud's phenomenon, purpura, lymphadenopathy, myositis and renal involvement. The clinical characteristics of these two groups coupled with the known serologic and genetic differences suggest that sicca syndrome alone is a distinct pathologic entity.     

Cystic fibrosis in adults. 75 cases and a review of 232 cases in the literature.

Cystic fibrosis is now the most common cause of chronic obstructive pulmonary disease (COPD) and of pancreatic insufficiency in the first three decades of life in the United States. In this report we describe 75 patients with cystic fibrosis aged 18 to 47 years and review another 232 cases reported in the literature. All of these 307 patients had elevated sweat chloride and sodium levels, which proved excellent discriminants for cystic fibrosis even in patients in the older age group. COPD, present in 97 per cent, was the major cause of morbidity and mortality, and differed from COPD of other etiologies. The progressive downhill course in these patients was punctuated by recurrent symptomatic exacerbations of chronic bacterial bronchitis caused by Pseudomonas aeruginosa and Staphyloccocus aureus, and terminated in pulmonary insufficiency, cor pulmonale and death. COPD was complicated by minor hemoptysis in 60 per cent, massive hemoptysis in 7 per cent and pneumothorax in 16 per cent, problems rare in children. Sinusitis was present in all those examined roentgenographically, and 48 per cent had nasal polyposis. Pancreatic insufficiency was present in 95 per cent of the patients, but in contrast to younger patients it was seldom symptomatic although steatorrhea and azotorrhea were still massive. Intussusception and meconium ileus equivalent (fecal accumulation) are frequent in adults (21 per cent) but rare in children, and they require immediate diagnostic and therapeutic intervention with enemas of diatrizoate sodium. Glycosuria, biliary cirrhosis, cholelithiasis and aspermia were among other complications. Height and weight were usually within the lower limits of normal, but 17 per cent of the men were above 180 cm in height and 7 per cent were overweight. Therefore, a high index of suspicion is needed to make the diagnosis, because older patients with cystic fibrosis may look quite well.     

Initial diagnosis of lipoprotein lipase deficiency in a 75-year-old man

Lipoprotein lipase deficiency, characterized by recurrent pancreatitis, profound hypertriglyceridemia, and delayed clearance of chylomicrons, is generally first diagnosed in childhood. Although patients with this condition have died during episodes of acute pancreatitis in the fourth and fifth decades, no patient older than 50 years has been previously reported. The de novo diagnosis of lipoprotein lipase deficiency in a 75-year-old man illustrates important points about this disease. This inborn error in metabolism may have a relatively benign clinical course resulting in normal life span, particularly if there is strict adherence to a low-fat diet and abstinence from alcohol. Moreover, measurement of lipoprotein lipase activity in persons with severe hypertriglyceridemia and recurrent abdominal pain, even in elderly patients, should lead to the correct diagnosis and treatment of this condition.     

Diffuse histiocytic lymphoma in a patient treated with cyclophosphamide for Wegener's granulomatosis

Diffuse histiocytic lymphoma developed in a 48-year-old man with Wegener's granulomatosis after nine years of therapy with cyclophosphamide. He died despite aggressive surgical and medical therapy for the lymphoma. This may be the first report of diffuse histiocytic lymphoma following treatment of Wegener's granulomatosis with cyclophosphamide. Recommendations for the approach towards extended therapy of smoldering Wegener's granulomatosis are discussed.     

Preoperative localization of abnormal parathyroid tissue: Cumulative experience with venous sampling and arteriography

Selective venous catheterization has been utilized with radioimmunoassay for parathyroid hormone as a preoperative localization technic in 94 patients with primary hyperparathyroidism. Sampling from thyroid veins provided localizing data in 82 per cent of patients with adenoma and 74 per cent of patients with hyperplasia. Failures were due to inability to catheterize important draining thyroid veins. Large vein sampling was much less helpful, localizing disease in only 29 per cent of patients with adenoma and 13 per cent of patients with hyperplasia. Thyroid venous sampling was also successful in patients who had had previous neck surgery (72 per cent). In addition, this technic differentiated between adenoma and hyperplasia; 98 per cent of patients with unilateral gradients had adenoma; 85 per cent of patients with bilateral elevations had hyperplasia. Selective thyroid venous sampling was more reliable (78 per cent) than arteriography (39 per cent). Venous sampling alone would not be useful for diagnostic purposes because high concentrations of parathyroid hormone were also detected in the inferior thyroid veins of control populations.The results indicate that selective venous sampling and radioimmunoassay of parathyroid hormone are useful preoperative adjuncts to surgical exploration especially in patients who have had previous neck surgery.     

Mucocutaneous candidiasis and thymoma.

The clinical, pathologic and immunologic features of 27 patients with chronic mucocutaneous candidiasis and thymic tumors are reviewed. This form of chronic candidiasis is unique in that the infections do not occur until after the third decade and, in contrast to patients in whom candidiasis develops during infancy or childhood, it is not accompanied by failure of endocrine organs. Instead, the patients have the disorders that often accompany thymoma, such as myasthenia gravis, hypogammaglobulinemia, and abnormalities of the bone marrow and circulating blood elements. Evidence of impaired cell-mediated immunity was found in 16 of the 21 patients in whom studies were made. The pathogenesis of the immunodeficiency in these patients is unknown. Immunosuppressive activities in the plasma of four patients were found, but none of the five patients in whom the appropriate studies were made was found to have suppressor cells. The features of this disorder are unique enough that it should be considered a syndrome, and patients in whom candidiasis develops during their adult years should be studied for the presence of thymoma.