Influence of immunoheterogeneity of circulating parathyroid hormone on results of radioimmunoassays of serum in man

We describe the practical consequences of the immunoheterogeneity of circulating parathyroid hormone (PTH) in the routine evaluation of patients by radioimmunoassay of serum PTH, based on our experience with two radioimmunoassays of PTH using antiserums of widely different specificities. One antiserum is directed against the COOH-terminal region of the human PTH molecule, and it recognizes a major portion of the immunoreactive PTH in hyperparathyroid serum. The other antiserum is directed against the NH₂-terminal region of human PTH, and it recognizes only “native” molecules (molecular weight 9,500 daltons) and a low molecular weight form of the hormone; these comprise a relatively small proportion of the total immunoreactive species of PTH in hyperparathyroid serum. Assays of “total serum PTH” using the COOH-terminal antiserum correlated much better with the presence of suspected or proved hyperparathyroidism as well as with osteoclast counts in bone biopsy specimens from patients with primary hyperparathyroidism. On the other hand, results of assays using the NH₂-terminal antiserum better reflected acute changes in glandular secretion of PTH.     

The clinical course, early prognosis and coronary anatomy of subendocardial infarction.

The following prospective study was undertaken to observe the clinical course, early prognosis and coronary anatomy of patients with subendocardial infarction. Subendocardial infarction was defined as typical chest apin (greater than 15 minutes), serum enzyme elevation and persistent (greater than 48 hours) new T wave inversion and/or S-T segment depression in the absence of new pathologic Q waves. Fifty consecutive patients were defined, followed in a prospective manner and subjected to early coronary arteriography. A prior history of unstable angina was found in 33 patients (66 per cent); 22 patients (44 per cent) had significant dysrhythmias during the acute hospital phase, and seven patients (14 per cent) had evidence of mild left ventricular failure. Coronary arteriography demonstrated significant lesions (greater than 75 per cent narrowing in at least one vessel) in all 50 patients, with 30 patients (60 per cent) having either double- or triple-vessel disease. Follow-up (mean 10.6 months) revealed that 15 patients (30 per cent) had stable angina, 23 patients (46 per cent) unstable angina and only 12 patients (24 per cent) remained free of angina. Of 28 patients in a medically treated group, acute transmural infarctions developed in six (21 per cent) and one died (3 per cent). We conclude that subendocardial infarction is symptomatically an unstable entity, is associated with severe coronary artery disease and, in a medically treated group, is followed by a significant incidence of early transmural myocardial infarction (21 per cent). Therefore, these patients require in-hospital monitoring, careful follow-up and consideration for early coronary arteriography.     

Neurocrest and colonic tumors: new clinical syndrome. Report of three cases

This report describes three patients with both multiple intestinal polyps and tumors of neural crest origin. This combination of findings may represent a new clinical syndrome. The embryologic relationships between tumors derived from endoderm and tumors derived from neurocrest are described. An inherent defect in tissue proliferation or repair is postulated to explain the abnormal growth in these two different cell lines.     

Monoclonal gammopathy of undetermined significance. Natural history in 241 cases

Two hundred forty-one patients with a monoclonal protein in the serum but initially no evidence of multiple myeloma, macroglobulinemia, amyloidosis or lymphoma were followed up for more than five years. At the conclusion of the studies the patients were classified as follows: Group 1, patients without significant increase in monoclonal protein, 57 per cent; group 2, patients with more than 50 per cent increase in monoclonal serum protein or development of monoclonal urine protein, 9 per cent; group 3, patients who died without five-year serum studies, 23 per cent; and group 4, patients in whom myeloma, macroglobulinemia or amyloidosis developed, 11 per cent. Initially, the hemoglobin level, size of serum monoclonal protein peak, number of plasma cells in the bone marrow and levels of normal immunoglobulins were not significantly different among the four groups. The median interval from recognition of the monoclonal protein to diagnosis of multiple myeloma was 64 months, of macroglobulinemia 103 months and of amyloidosis 92 months. A significant increase of the monoclonal protein or development of myeloma, macroglobulinemia or amyloidosis occurred in 18 per cent of the patients with monoclonal immunoglobulin G(IgG), in 28 per cent with immunoglobulin A (IgA) and in 25 per cent with immunoglobulin M (IgM). Retrospective analysis of age, sex, presence of organomegaly, hemoglobin level, size and type of serum monoclonal protein peak, presence of small amounts monoclonal light chain in the urine, serum albumin level, levels of uninvolved immunoglobulins, IgG subclass and level of plasma cells in the bone marrow did not show how to distinguish initially between stable benign disease and progressive disease. Therefore, periodic reexamination of patients with monoclonal gammopathy is essential.     

Ectopic secretion of a growth hormone-releasing factor. Report of a case of acromegaly with bronchial carcinoid tumor

Rarely, acromegaly is produced by neuroendocrine neoplasms elaborating a substance similar to or identical with growth hormone-releasing factor. This report reviews the cases described to date and presents the clinicopathologic features of a patient with acromegaly, mild sellar enlargement, and elevated growth hormone levels associated with a large bronchial carcinoid tumor. Normalization of serum growth hormone levels and regression of acromegaly followed resection of the bronchial tumor, which was shown, by bioassay and immunocytochemistry, to contain a growth hormone-releasing factor.     

Familial pheochromocytoma and islet cell tumor of the pancreas

The occurrence of pheochromocytoma(s) or pancreatic islet cell tumor(s), or both, in two or more members of three unrelated families in a manner consistent with autosomal dominant inheritance suggests that this tumor association is a genetically determined syndrome. Among 11 affected patients (aged five to 53 years), 10 had pheochromocytoma (bilateral in six), four had islet cell tumor (multicentric in one), and three had both tumors. Clinical presentation was due to pheochromocytoma in 10 cases (symptoms or signs commencing before age 10 years in three patients) and islet cell carcinoma in one case. Four patients are dead as a result of the tumors--two from pheochromocytoma and two from islet cell carcinoma.     

Erythroderma with atypical lymphocytes. (Sézary syndrome)

A clinical, histopathologic and cytologic study of erythroderma with atypical lymphocytes (Sézary syndrome) was carried out in 19 patients observed at the Mayo Clinic. Cutaneous lesions may begin as dermatitis or infiltration. Erythroderma, pruritis and edema, alopecia, keratoderma and onychodystrophy were cutaneous features of the syndrome. Benign lymphadenopathy and hepatomegaly were observed; spleen and bone marrow findings were normal. The atypical lymphocyte is present in the skin and in the blood. Four patients died of aggressive chemotherapy. Lymphoma developed in three patients. In five recent patients remission has been achieved with the use of cortico-steroids and chlorambucil.     

Treatment of primary hyperparathyroidism

We present four treatment categories for patients with primary hyperparathyroidism and describe the results of studies of patients in each category. These categories are primary surgical, secondary surgical, “biochemical” hyperparathyroidism and medical management with oral administration of neutral phosphate. The importance of the parathyroid surgeon as a diagnostician during parathyroid exploration is stressed from the point of view of the detection and aggressive surgical treatment of parathyroid chief cell hyperplasia. Short-term (1 to 2 weeks) and long-term (5 to 29 months) studies of the state of parathyroid function in relation to calcium homeostasis after successful resection of hyperfunctioning parathyroid tissue are described.Although incomplete, our 5 year prospective study of “biochemical” hyperparathyroidism shows that in approximately 20 per cent of these patients the disease progresses to where our criteria for surgical intervention are met and that no one criterion or combination of criteria has been identified as being of predictive value in determining which patients will ultimately require surgical intervention. In patients with persistent or recurrent hyperparathyroidism, chronic oral treatment with neutral phosphate was successful in decreasing serum calcium from more than 12.0 mg/dl to less than 11.0 mg/dl in four of seven patients, but significant increases in serum creatinine occurred in three of these seven patients. Significant decreases in serum calcium did not occur in patients with serum calcium values less than 11.0 mg/dl, and there were no changes in serum creatinine in this group. Nephrolithiasis was controlled in seven of eight patients, but the specific effectiveness of neutral phosphate treatment in all these patients could not be assessed because only two had metabolically active disease at the start of treatment.     

Radioimmunoassay of parathyroid hormone in hypercalcemic patients with malignant disease

Serum immunoreactive parathyroid hormone (iPTH) concentration was determined in 108 unselected hypercalcemic patients with malignant disease utilizing a sensitive radioimmunoassay system that is specific for the COOH-terminal region of the parathyroid hormone (PTH) molecule. In 103 (95.3 per cent) of these patients, serum iPTH concentration was abnormal for the concomitant serum calcium level. In the 48 patients in this series with clinically evident skeletal metastasis or bone marrow involvement, serum iPTH values were similar to those in the other patients. These results do not support a recent suggestion that ectopic production, by malignant tissue, of a non-PTH osteolytic substance is at least as common as ectopic production of PTH in hypercalcemic patients with cancer. Rather, ectopic hyperparathyroidism seems to be present in the overwhelming majority of hypercalcemic patients with cancer even when clinically evident bone metastasis is present. Also, the radioimmunoassay system used in this study was of practical help in differentiating ectopic from primary hyperparathyroidism. On the basis of a lower serum iPTH value for a given serum calcium increase, ectopic hyperparathyroidism could be separated from primary hyperparathyroidism with an overlap of the two groups of 7.7 per cent.     

Normal serum thyroxine values in patients with acute psychiatric illness

The medical records of 278 consecutive patients with acute psychiatric illness admitted to a closed psychiatric unit after admission from the emergency room were reviewed. Serum thyroxine levels had been determined within 72 hours of admission in 106 patients (38 percent); in 74 of these patients (70 percent), the determination had been made within 24 hours. Ten patients (9 percent) were hypothyroxinemic, but further thyroid testing revealed that they were functionally euthyroid. Only one patient had hyperthyroxinemia, which was considered secondary to her postpartum state. The prevalence of hypothyroxinemia in the population studied is consistent with that in previous reports. However, the striking absence of hyperthyroxinemia in these patients is contrary to findings in several recent reports. Further prospective studies should clarify this issue.     

Hypocomplementemia in rheumatoid arthritis

Over a two and a half year period, we saw 16 patients with classic rheumatoid arthritis and serum complement values below normal. In addition to severe joint involvement, high rheumatoid factor titers and increased immunoglobulin M (IgM) values, extra-articular manifestations were particularly prominent. There was an unusually high incidence of recurrent serious bacterial infections during the period of observation. Complement values were lowest during subacute exacerbations of the joint disease or development of extra-articular complications. Studies of individual components of complement revealed low values for C4 (all of 14 tested) and C2 (six of 12 tested). Other components were mostly normal. Anticomplementary activity could be demonstrated in several hypocomplementemic serums. Rheumatoid factor and IgM (both 19S and 7S) levels were highest when whole complement was lowest. Fourteen serums produced precipitin bands against heat-aggregated immunoglobulin G (IgG).The low levels of whole hemolytic complement (CH₅₀) and the presence of complement-fixing material in these serums suggest utilization of complement by immune complexes. The pattern of decreased C4 and C2 with more normal amounts of other components implies complement activation via C1. The concurrence of hypocomplementemia with exacerbations and complications of rheumatoid arthritis suggests that complement-fixing immune complexes may contribute to these events. In addition, the frequent infections may mean that these immunologic abnormalities lead to impaired host resistance to infection.     

Acquired aortocaval fistulas

Collective experience at the Mayo Clinic with nine cases of acquired aortocaval fistula revealed a difference between the presenting features of patients with traumatic fistula and those of patients with spontaneous fistula. In addition, patients with spontaneous aortocaval fistula, rather than presenting with a single distinct clinical syndrome, present with at least three different clinical pictures: (1) the classic syndrome of high-output heart failure of recent onset with palpable aneurysm and continuous bruit, (2) hypotension and oliguria or anuria in the presence of an abdominal aortic aneurysm, which may not be tender and in which a characteristic bruit may be absent and (3) back pain or abdominal pain associated with a tender pulsatile mass, shock and retroperitoneal hemorrhage. (The fistula may not be suspected prior to surgery.)     

Idiopathic bence jones proteinuria—A distinct entity?

Bence Jones proteinuria has been a recognized part of multiple myeloma, macroglobulinemia of Waldenstrom, primary amyloidosis and occasionally Iymphoma. Two patients who have excreted more than 1 g of Bence Jones protein daily for more than 7 years without evidence of the development of myeloma or other malignant disease have been studied. These patients also had a monoclonal protein in the serum which remained unchanged for the same period. Although the possibility that myeloma may develop in the future cannot be excluded, the disease is not yet manifest. Thus, in view of these observations, we have concluded that appreciable Bence Jones proteinuria may not always be an ominous finding.     

The bimodal mortality pattern of systemic lupus erythematosus.

The changing pattern of mortality in systemic lupus erythematosus (SLE) led to an examination of the deaths in a long-term systematic analysis of 81 patients followed for five years at the University of Toronto Rheumatic Disease Unit. During the follow-up 11 patients died; six patients died within the first year after diagnosis (group I) and five patients died an average of 8.6 years (from 2.5 to 19.5 years) after diagnosis (group II). In those who died early, the SLE was active clinically and serologically, and nephritis was present in four. Their mean prednisone dose was 53.3 mg/day. In four patients a major septic episode contributed to their death. In those who died late in the course of the disease, only one patient had active lupus and none had active lupus nephritis. Their mean prednisone dose was 10.1 mg/day taken for a mean of 7.2 years. In none was sepsis a contributing factor to their death. All five of these patients had had a recent myocardial infarction at the time of death; in four, ti was the primary cause of death. Mortality in SLE follows a bimodal pattern. Patients who die early in the course of their disease, die with active lupus, receive large doses of steroids and have a remarkable incidence of infection. In those who die late in the course of the disease, death is associated with inactive lupus, long duration of steroid therapy and a striking incidence of myocardial infarction due to atherosclerotic heart disease.     

Arteriosclerosis obliterans in young women

Thirty-one nondiabetic women with the onset of symptomatic peripheral vascular disease before the age of 46 years were studied to determine the risk factors important in the development of the disease and the natural history of the disease in a young population. Patients with vasculitis or embolic occlusion were excluded from analysis. All 31 women were smokers at the time of onset of symptoms, and cigarette use in general was heavy. Of the 31 patients, 20 (65 per cent) had hyperlipidemia and 14 (45 per cent) had hypertension; 16 (52 per cent) had positive family histories of atherosclerosis. Menstrual status did not appear significant as 27 (90 per cent) patients were premenopausal at the time of onset of the disease; of these, 11 (41 per cent) had used birth control pills. As is seen in older populations, the atherosclerosis involved more than one vascular bed, and 14 patients (45 per cent) had clinical evidence of cerebrovascular involvement. Five patients (16 per cent) had coronary artery disease.Angiographically, two groups were discernible: 21 patients (68 per cent) with localized disease of the aortoiliac system and normal distal vessels, and 10 patients (32 per cent) with diffuse atherosclerosis. There was no evidence that the aortoiliac tree was intrinsically smaller than normal.Twenty-five patients underwent surgery, and 22 had improved pulses during the immediate postoperative period. The mean follow-up for these 22 patients was 48 months. Surgical results depended on the location and severity of the disease. Thirteen of the 15 patients with proximal disease and normal distal vessels were markedly improved, whereas only one of seven patients with diffuse disease was similarly improved.     

Renal stones in Wilson's disease.

Fifty-four patients with Wilson's disease were studied with regard to renal stones. Seven of the 45 patients (16 per cent) who underwent roentgenographic procedures of the urinary tract had unequivocal evidence of renal stones. In four of the seven patients with Wilson's disease who had renal stones, the stones were discovered at the time or before the diagnosis of Wilson's disease was made. Of the several possible factors that may predispose patients with Wilson's disease to renal stone formation, the renal tubular acidosis pattern of abnormality in acid-base excretion is probably the most significant. In general, patients with renal stones and unexplained neurologic, bony or hepatic abnormalities should be screened for Wilson's disease by slit-lamp examination, determination of serum copper and ceruloplasmin concentrations, and urinary excretion of copper, particularly if they have relatively alkaline urine.     

Triiodothyronine thyrotoxicosis complicating primary hypothyroidism in a patient with autoimmune thyroiditis

It is increasingly recognized that autoimmune thyroiditis can have a multifaceted presentation. Documented triiodothyronine thyrotoxicosis developed in a patient with a six-year history of primary hypothyroidism that was left untreated. Serologic and cytologic evidence confirmed the thyroid dysfunction as being on an autoimmune basis. Chronic lymphocytic thyroiditis may be seen with hyperthyroidism, hypothyroidism, or euthyroidism, and in an individual patient, spontaneous progression from one metabolic state to another may occur.     

Somatostatin and diabetes

Somatostatin, a tetradecapeptide originally isolated from the hypothalamus on the basis of its ability to inhibit the secretion of growth hormone, is now known to be widely distributed in various endocrine and gastrointestinal tissues and to have diverse actions, including inhibition of insulin and glucagon secretion. The location of somatostatin in pancreatic islet D cells suggests that it may act as a local regulator of insulin and glucagon secretion. Changes in islet D-cell function in experimentally-induced and spontaneous diabetes in animals suggest that the peptide may be involved in the pathogenesis of diabetes. Clinical studies with the peptide have provided insight into the physiologic roles of glucagon and growth hormone, and have indicated a potential therapeutic use for somatostatin in diabetes in man.     

Combined deficiency of glucose-6-phosphatase and fructose-1, 6-diphosphatase. Studies of glucagon secretion and fuel utilization.

An adult woman with hypoglycemia, hyperlactatemia, hyperuricemia, hypertriglyceridemia, hyperketonemia and inability to make new glucose from galactose, fructose, glycerol and alanine was found to have no hepatic glucose-6-phosphatase and deficient fructose-1,6-diphosphatase. Nonautonomous hyperglucagonemia was demonstrated and shown to contribute to the hyperlactatemia and hyperketonemia. A paradoxic hyperlactatemic response to glucose and galactose was observed. Studies of substrate utilization showed prompt adaptation to changes in dietary supply of energy which probably accounted for her never having experienced symptoms of hypoglycemia.