Intractable hypoglycemia in a patient with renal failure.

A patient with chronic renal failure developed intractable hypoglycemia after 2 1/2 years of dialysis. Metabolic studies did not suggest that malnutrition, substrate limitation, hormone deficiency, or insulin excess were responsible for the low blood glucose level. Impaired gluconeogenesis may have been an important factor, but studies in this patient suggest that enhanced glucose utilization may also play a role in the pathogenesis of hypoglycemia in renal failure.

Pontine hemorrhage in a patient with pheochromocytoma.

A 24-year-old woman with a two-year history of hypertension was hospitalized for coma and quadriplegia secondary to pontine hemorrhage. A seven-year history of intermittent severe headaches, diaphoresis, and anxiety together with persistent severe hypertension led to the diagnosis of pheochromocytoma. This unusual but devastating manifestation of pheochromocytoma illustrates the importance of excluding remedial forms of hypertension in young patients before initiating antihypertensive therapy.

Fever in pheochromocytoma.

BACKGROUND: Fever is an infrequently reported finding in patients with pheochromocytoma. Fever in patients with pheochromocytoma may be caused by the tumor, an infection or other factors, each of which will dictate different treatment strategies. METHODS: To determine the incidence, cause, and significance of fever in patients with pheochromocytoma, we reviewed the medical records of 50 hospitalizations of 48 patients. Patients were categorized by the presence or absence of fever. Body temperature elevation, duration of hospitalization in the period prior to surgery or death, age, sex, race, other conditions that could have been responsible for the febrile episode (comorbid events), location, gross and microscopic features of the tumors, and plasma and urine hormone levels were tabulated. The results were compared between the two groups of patients. RESULTS: Fever was present in 14 (28%) of 50 hospitalizations, seven patients (50%) of whom had pheochromocytoma multisystem crisis. Patients with fever and pheochromocytoma were significantly more likely to have a comorbid event, larger tumor, necrosis within the tumor, higher urinary metanephrine levels, longer duration of hospitalization prior to surgery, and to be non-white. Comorbid events included both infectious and noninfectious potential causes of fever. CONCLUSIONS: Fever is common in patients with pheochromocytoma. The causes may be multifactorial and often include an associated illness. A thorough search for coexisting disease is indicated. While fever may prolong hospitalization, it does not portend a disastrous outcome.

Serum triiodothyronine concentration in thyroid storm.

Serum triiodothyronine levels were elevated in 6 patients with thyroid storm (769 plus or minus 181 ng/100 ml) but the values observed were not significantly different from those found in uncomplicated thyrotoxicosis (752 plus or minus 282 ng/100 ml). This observation suggests that the pathogenesis of thyroid storm resides in mechanisms other than a simple increase in serum triiodothyronine concentration.

Familial thyroid hormone resistance.

Eight patients with thyroid hormone resistance were found in four generations of a kindred containing 19 members. Results of studies in this family are consistent with an autosomal dominant mode of inheritance for this disorder. The affected family members were clinically euthyroid but all had goiters and markedly increased serum thyroid hormone levels: thyroxine (T4) = 21.1 +/- 2.1 microgram/dl; triiodothyronine (T3) = 323 +/- 60 ng/dl; free T4 = 5.4 +/- 0.9 ng/dl; and free T3 = 1,134 +/- 356 pg/dl (mean +/- SD). Serum thyrotropin (TSH) levels were normal or slightly elevated in six patients and responded normally to the administration of thyrotropin-releasing hormone (TRH) and L-triiodothyronine. Two patients who had previously undergone subtotal thyroidectomy had elevated baseline serum TSH levels and exaggerated TSH responses to the administration of TRH suggesting subclinical hypothyroidism despite elevated total and free thyroid hormone levels. The absence of thyrotoxicosis and normal serum TSH levels despite elevated serum free T3 and T4 levels in the untreated members of this family are consistent with resistance of pituitary and peripheral tissues to the actions of thyroid hormones. In addition, the absence of hypothyroidism and normal responsiveness of serum TSH to TRH and L-triiodothyronine administration in untreated family members suggest that the thyroid has compensated for the hormone resistance by increased secretory activity under the control of pituitary TSH secretion.

Thiophosphorylation and phosphorylation of saponin-permeabilized cultured chromaffin cells.

There is increasing evidence that phosphorylation of cellular proteins plays a role in the control of events surrounding secretion in neurons and chromaffin cells. In previous studies, we have used thiophosphorylation of cell proteins as a means of fixing cellular phosphorylation reactions in the phosphorylated state. Thiophosphorylation of permeabilized chromaffin cells with adenosine-5?-O-(3-thiotriphosphate) results in irreversible inhibition of secretion. Thiophosphate is incorporated primarily by two cellular proteins of 58 and 47 kDa. Calcium enhanced thiophosphorylation of the 47 kDa protein but not the 54 kDa protein. This pattern of thiophosphorylation differed markedly from that for phosphorylation under similar treatment conditions. The phosphoprotein composition of the cells depended upon the medium calcium and ATP concentration. In the absence of exogenous ATP, fewer phosphoproteins were seen in calcium stimulated cells than in unstimulated cells. Proteins labelled with (32)P or (35)S migrated to the same position on polyacrylamide gels containing sodium dodecyl sulfate. In the presence of exogenous ATP, (32)P incorporation was similar for both control and calcium-stimulated cells and was found primarily in a 64 kDa protein. Incorporation of [(32)P]phosphate by calcium-stimulated cells was reduced to the same extent by pretreatment of the cells with either adenosine-5?-O-(3-thiotriphosphate) or ATP. The different electrophoretic banding patterns for thiophosphorylation and phosphorylation are likely due to the irreversibility of the thiophosphorylation reaction and reversibility of the phosphorylation reaction. The inability to turn over thiophosphate groups, in association with changes in secretion, may permit identification of those phosphoproteins that are putatively involved in secretion.

Thiophosphorylated proteins in chromaffin cells are chromaffin vesicle matrix proteins.

Bovine adrenal chromaffin cells were incubated with inorganic thiophosphate, using a protocol similar to experiments with inorganic phosphate, in order to determine the source of previously observed thiophosphoproteins. Incubation of cultured cells with [35S]thiophosphate resulted in its incorporation into cell constituents within 2 min. SDS-PAGE of the treated cells showed incorporation of label into a broad 97-121 kDa band that was evident after 5 min of treatment and increased progressively to the 40 min exposure limit. Monolayers of chronically treated cells were fractionated into subcellular constituents. The only particulate fraction containing radiolabelled proteins was the chromaffin vesicle fraction. Two-dimensional electrophoresis of the treated cells and isolated chromaffin vesicles showed a majority of proteins in the acidic region of the first dimension gel. A fluorogram of the gel revealed two regions of radiolabelled proteins at acidic and neutral regions of the 2-D gel. These were within the boundaries of the 97-121 kDa band. The thiophosphorylated proteins were released as soluble proteins upon osmotic or freeze-thaw lysis of the vesicles. Chromaffin vesicles isolated from either cultured cells or adrenal medulla tissue were energized by 2 mM ATP but not by the analog adenosine 5'-O-(3-thiotriphosphate). The 97-121 kDa proteins in intact or lysed vesicles prepared from adrenal medulla tissue were not thiophosphorylated by either inorganic thiophosphate or adenosine 5'-O-(3-thiotriphosphate) in the presence or absence of energization by ATP. Nearly complete loss of radiolabel from matrix proteins treated with chondroitinase ABC suggests that it is a component of vesicle proteolgycans.(ABSTRACT TRUNCATED AT 250 WORDS)

Inorganic thiophosphate effects on chromaffin cell structure and function.

The effect was determined of replacing medium inorganic phosphate with thiophosphate on the structure and function of cultured bovine chromaffin cells. Cell cultures were incubated in normal medium containing fetal bovine serum, phosphate free medium or similar medium supplemented with inorganic phosphate or thiophosphate. In contrast to the other media, cells cultured with thiophosphate medium for 3-4 days showed seriously compromised structure and functions. The cells lost 75% of their catecholamine content and their ability to secrete remaining catecholamines in response to nicotine stimulation. Radiolabelled thiophosphate was rapidly taken up by the cells and, in long-term experiments, was incorporated largely into a 97-121 kDa protein band on SDS-PAGE. Additional minor bands were found to a lesser, variable extent. Transmission electron micrographs of cells treated with thiophosphate showed extensive depletion of chromaffin vesicles and disruption of mitochondria, suggesting that the functional damage noted with these cells could be associated with damage to mitochondria. Analysis of general cell metabolic activity by conversion of the dye (3-[3,4-dimethylthiazol-2-yl]-3,5-diphenyltetrazolium bromide) to its formazan derivative indicated increased metabolic activity at early stages of exposure to thiophosphate followed by a decline with continued exposure, supporting the argument for an overall depression of cell metabolism. Uptake of the dye neutral red, which is avidly accumulated by chromaffin cells, was also reduced for cells exposed to thiophosphate. The data suggest that thiophosphate enters chromaffin cells and disrupts energy dependent cell functions, including catecholamine storage and secretion.

Total thyroidectomy and parathyroid autotransplantation for radiation-associated thyroid cancer.

In seventy patients with nodular thyroids and a history of radiation exposure, total thyroidectomy disclosed a 54% incidence of carcinoma; more than half of them had cervial node metastases; four had distant metastases. Fourteen patients required radical neck dissection. The carcinoma was multicentric (both lobes) in 45%. In four patients the carcinoma was found in the lobe contralateral to the one containing the palpable nodule. These findings support the advocates of total thyroidectomy for patients with a nodular thyroid and a history of radiation exposure, provided this operation can be performed with a low incidence of recurrent nerve palsy and hypoparathyroidism.

Successful adrenal autotransplantation in Cushing's disease.

Since Cushing's disease was delineated as a distinct entity, a wide array of therapeutic modalities has been employed to treat its symptoms, which are primarily the result of hypercortisolism. With the advent of pituitary polytomography and the concept of microadenomas, a wave of enthusiasm has developed in recent years in favor of transsphenoidal microdissection. In a recent national survey, however, one third of 30 endocrinologists reported cure rates below 60% and, according to several respondents, recurrence was a serious problem at 50% or greater incidence. We report on four patients treated by bilateral adrenalectomy and autotransplantation. They were weaned off all corticosteroid medication for up to 6 years. Two of the four patients have demonstrable iodocholesterol uptake at the site of autotransplantation. We also report on three additional patients who are taking reduced doses of cortisone. All seven patients have no demonstrable iodocholesterol uptake in the adrenal fossae or other possible ectopic sites. We believe that bilateral adrenalectomy with autotransplantation is a worthy alternative in the long-term treatment of Cushing's disease.

Long-term results of adrenal autotransplantation in Cushing's disease.

Many advances have been made in the diagnosis and treatment of patients with Cushing's disease. Currently, partial or total transsphenoidal resection of the pituitary gland is the surgical approach favored by many authorities, with cure rates of 80% to 90% reported for selected patients. However, long-term follow-up is still needed for this treatment modality, and recurrence rates of up to 50% have been reported. In addition, less favorable results are seen with this approach when there is recurrence after initial transsphenoidal surgery or when there is not a single microadenoma responsible for the disease of the pituitary gland. We report a series of 14 patients who were treated with bilateral adrenalectomy and autotransplantation. Follow-up is 4 to 14 years. Four patients show iodocholesterol uptake at the site of autotransplantation. Of these, three patients have been weaned from cortisone for 12, 10, and 2 years. The fourth patient, after being weaned from all medications, underwent partial resection of a hyperfunctioning autotransplant and currently, 7 years after the original operation, is being weaned from cortisone. A fifth patient was weaned to a reduced dose of cortisone for 8.5 years, but the dose was recently increased. There is no evidence of Nelson's syndrome in any of these patients with clinical evidence of functioning autotransplants. We believe that bilateral adrenalectomy with autotransplantation still plays an important role in the long-term management of selected cases of Cushing's disease and that autotransplantation, when successful, results in few complications and allows long-term freedom from exogenous steroid medication.

Plasma catecholamine changes during excision of pheochromocytoma.

Sequential changes in plasma norepinephrine (NE) and epinephrine (EPI) concentration were correlated with changes in blood pressure and cardiac rate in 14 patients undergoing surgery because of pheochromocytoma. All patients had elevated preoperative plasma catecholamine levels that increased during induction of anesthesia, intubation, and skin incision, but mean values did not become significantly higher than preoperative values until tumor manipulation. Episodes of hypertension were associated with increased plasma catecholamine levels, and plasma catecholamine levels and blood pressure decreased dramatically after tumor resection. NE and EPI were usually secreted simultaneously, but release of either NE or EPI alone occurred on some occasions. There were marked variations in the concentration ratio of NE to EPI in plasma at different periods of observation, which suggests that pheochromocytomas release varying amounts of catecholamines in a random fashion. Studies of the effect of the duration of preoperative preparation on intraoperative blood pressure, pulse rate, and cardiac arrhythmias failed to demonstrate that treatment for 14 days or longer was more effective than treatment for 4 to 7 days. Neither the brief nor the prolonged period of therapy prevented development of severe hypertension during tumor manipulation.

Simultaneous primary hyperparathyroidism and nodular thyroid disease.

Of 351 patients treated for primary hyperparathyroidism from 1966 to 1981, 70 (20%) had grossly evident nodular thyroid disease at the time of subtotal parathyroidectomy. These patients have been reviewed to determine if prior radiation exposure may play a role in their coexistence and if combined subtotal parathyroidectomy and thyroidectomy are safe and efficacious. Thirty-three of the 70 patients (47%) had received prior radiation therapy for benign conditions of the head and neck. Nine of 15 patients with nonmedullary thyroid carcinoma had received previous irradiation. In addition to subtotal parathyroidectomy, 28 patients underwent total thyroidectomy, 14 underwent bilateral subtotal thyroidectomy, and 28 underwent unilateral lobectomy. There were no deaths and no permanent recurrent laryngeal nerve injury from combined subtotal parathyroidectomy and thyroidectomy. Two patients in whom parathyroid tissue was not autotransplanted required calcium and vitamin D supplementation. This study shows that (1) primary hyperparathyroidism and nodular thyroid disease occur simultaneously with sufficient frequency to warrant careful preoperative and intraoperative evaluation of both glands, (2) radiation probably does play a role in the pathogenesis of coexistent primary hyperparathyroidism and nodular thyroid disease, and (3) in experienced hands combined subtotal parathyroidectomy and thyroidectomy can be safely performed.

Follicular cell predominance in the cytologic examination of dominant thyroid nodules indicates a sixty percent incidence of neoplasia.

The interpretation of aspiration cytologic smears that contain a predominance of follicular components often presents a dilemma to the clinician who is treating a patient who has a dominant thyroid nodule, especially when thyroid-stimulating hormone suppression does not produce any significant involution of the dominant nodule. We reviewed a consecutive series of 555 fine-needle aspiration cytologic examinations of dominant thyroid nodules. All specimens that contained colloid or follicular cells mixed with lymphocytes or Hürthle cells were excluded from this review. Additionally, nine aspirates contained degenerated follicular cells with insufficient material for cytologic diagnosis. The remaining 76 specimens contained a predominance of follicular cells: 27 specimens were interpreted as containing "normal" follicular cells, and the remaining 49 specimens were read as "atypical" follicular cells. Histopathologic examination of the resected specimens indicated a 60% incidence of neoplasia (30% carcinoma, 30% adenoma) in which the aspiration cytologic study was interpreted as "normal" follicular cells. On the other hand, a 63% incidence of neoplasia (27% carcinoma, 36% adenoma) occurred in which the cytologic study was read as "atypical." In conclusion, aspirates showing a predominance of follicular cells, whether "normal" or "atypical" indicate a 60% incidence of neoplasia in dominant thyroid nodules that do not decrease significantly in size with thyroid-stimulating hormone suppression.

The continued importance of adrenalectomy in the treatment of Cushing's disease.

Eighteen patients with pituitary-dependent Cushing's disease have been treated during a ten-year period. Eleven of these received a total of 14 alternative forms of therapy in an attempt to control the clinical manifestations of Cushing's disease prior to adrenalectomy. However, no substantial improvement was noted in these patients, who included four receiving conventional pituitary irradiation, five receiving cyproheptadine, two receiving mitotane, and one each receiving metyrapone and phenytoin. One patient had an attempted transsphenoidal hypophysectomy that could not be accomplished because of hemorrhage. A complete remission of the signs, symptoms, and laboratory abnormalities of Cushing's disease occurred in all 18 patients following bilateral adrenalectomy. There was no operative mortality and morbidity was minimal. This experience confirms that bilateral adrenalectomy is a rapid, safe, and permanent means of reversing hypercortisolism and that it should remain an integral part of the treatment of Cushing's disease.

Unexpected parathyroid disease discovered at thyroidectomy in irradiated patients.

Eight of 23 patients undergoing total thyroidectomy for radiation-associated nodular thyroid disease were found to have unsuspected parathyroid hyperplasia or adenoma at operation. The total serum calcium level was normal preoperatively in each patient. Serum ionized calcium and parathyroid hormone levels were measured in five patients preoperatively and were normal in each case. These pathologic findings in normocalcemic patients may represent a preclinical form of hyperparathyroidism, which would be further evidence linking radiation to the pathogenesis of hyperparathyroidism. The parathyroid glands should be evaluated both pre-operatively and at operation in all patients who have a history of radiation and require thyroidectomy.

Pregnancy in Sheehan's syndrome. Report of a case and review.

Detailed endocrinological studies were performed during and after the eighth pregnancy of a 38-year-old woman who had eight spontaneous pregnancies after the onset of hypopituitarism secondary to massive postpartum hemorrhage. Hormonal replacement therapy was not provided during seven pregnancies and all terminated in spontaneous abortions. Studies of pituitary function during and after the eighth pregnancy demonstrated that the patient had measurable amounts of growth hormone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyrotropin (TSH), adrenocorticotropin (ACTH), and prolactin in her plasma under basal conditions but that these hormones did not increase approximately in response to pregnancy, stress, and specific stimuli. Evaluation of placental function at 26 weeks gestation by measurement of estradiol, progesterone, human placental lactogen, and chorionic gonadotropin revealed no abnormality. Hormone replacement therapy during the eighth pregnancy was associated with the delivery of normal premature infant at 32 weeks gestation. In addition to these studies, a critical review of the literature was undertaken to more clearly define the clinical and laboratory features of pregnancy in Sheehan's syndrome.

A spurious markedly increased serum estradiol level due to an IgA lambda.

OBJECTIVE: To alert physicians about the potential for erroneous laboratory determinations of hormone levels and emphasize the need to assess the overall clinical situation as well. METHODS: We present a case report of a woman with a dramatically increased serum estradiol (E(2)) level on radioimmunoassay and review the studies that led to the conclusion that this laboratory finding did not reflect her true estrogen status. RESULTS: In a 41-year-old woman, an unnecessary surgical procedure was performed because of a falsely increased serum E(2) level and a unilateral ovarian mass. The markedly increased serum E(2) measured by radioimmunoassay was found to be attributable to an IgA lambda that bound to the 125 I-labeled tracer of the assay. CONCLUSION: When repeatedly abnormal hormone levels and the clinical picture seem discrepant, use of a different assay method should be considered.

Effect of fine needle aspiration biopsy on the histology of thyroid neoplasms.

We evaluated the effect of fine needle aspiration biopsy (FNAB) upon the histology of thyroid adenoma and differentiated thyroid carcinoma. When surgery was performed within three months of FNAB, infarction was found histologically in 8/82 (9.8%) of the tumors. It was extensive in four patients, with one patient having no residual neoplastic cells identifiable within the nodule. No infarction was seen in the histologic specimens from patients with similar pathology whose surgery was performed without prior FNAB. These findings confirm previous reports that infarction may be caused by FNAB and can be so extensive as to interfere with the histologic diagnosis.

The effect of fine-needle aspiration biopsy on the thyroid scan.

Fine-needle aspiration biopsy (FNAB) is the most sensitive and specific procedure in diagnosing benign from malignant thyroid nodular disease. The effects of a FNAB on the thyroid scan, however, have never been studied. This assumes importance because a hot nodule on scan has been advocated as useful to differentiate certain benign from malignant follicular neoplasms. Thyroid scans were performed before and after FNAB on 11 patients with nodular thyroid disease and an area of normal or increased uptake either in the nodule or in a contralateral enlarged lobe to determine if the biopsy changed the pattern of isotope uptake. For this study, biopsies were done in the area of normal or increased uptake. In two patients, there was a reduction in isotope concentration in three nodules after FNAB, whereas no change was demonstrable in nine other patients. Review of the literature revealed a number of prior reports of hemorrhage, necrosis, or infarction of thyroid nodules after FNAB. Based on these data and the demonstration of a change in scan pattern in a patient following FNAB, it is concluded that FNAB may decrease the isotope uptake in thyroid nodules; therefore, the concept of clinical judgments being based on the scan pattern after FNAB should be reevaluated.