Rhabdomyolysis associated with cranial diabetes insipidus.

Rhabdomyolysis has been reported to be associated with hyperosmolality in diabetic ketoacidosis and non-ketotic hyperosmolal state. Whether the rhabdomyolysis was due to hyperosmolality per se or whether hyperglycaemia also played a role is not clear. We hereby report a case of cranial diabetes insipidus with hypernatraemia and hyperosmolality complicated by rhabdomyolysis. None of the known risk factors, such as coma, hypokalaemia, hypophosphataemia, diabetic ketoacidosis or non-ketotic hyperosmolality, were present in this patient. We believe that severe hyperosmolality per se is an important predisposing factor for non-traumatic rhabdomyolysis, and serum muscle enzymes should be closely monitored in the management of patients with diabetes insipidus.

Effects of cranial irradiation on hypothalamic-pituitary function--a 5-year longitudinal study in patients with nasopharyngeal carcinoma.

The effects of cranial irradiation on hypothalamic-pituitary function were studied over a 5-year period in 31 adult patients with nasopharyngeal carcinoma. The estimated radiotherapy doses to the hypothalamus and pituitary were 3979 +/- 78 (+/- SD) and 6167 +/- 122 cGy, respectively. Within 2 years of radiotherapy, significant impairment in the secretion of growth hormone, gonadotrophins, corticotrophin and thyrotrophin were evident and 14 per cent of patients developed hyperprolactinaemia. Using life table analysis, the cumulative probability of endocrine dysfunction was estimated to be 62 per cent after 5 years with deficiencies in growth hormone, gonadotrophins, corticotrophin and thyrotrophin found in 63.5, 30.7, 26.7 and 14.9 per cent of patients, respectively. Growth hormone deficiency was the earliest endocrine dysfunction observed. Hyperprolactinaemia was uncommon in the male patients but occurred in five of eight women within 3 years of cranial irradiation. The alterations in gonadotrophin secretion suggest a defect in the pulsatile release of gonadotrophin releasing hormone. Twenty-eight patients developed a hypothalamic pattern of delayed thyrotrophin response to thyrotrophin releasing hormone one year after radiotherapy--four subsequently became hypothyroid. Patients who received radiotherapy for cervical lymph nodes were at greater risk of developing hypothyroidism. Thus, in these patients with no pre-existing disease in the hypothalamic-pituitary region, progressive impairment in hypothalamic pituitary function leading to endocrine dysfunction requiring treatment occurs in 50 per cent of patients 5 years after cranial irradiation. Regular endocrine assessment should be performed in all patients following cranial irradiation.

Propylthiouracil hypersensitivity with circumstantial evidence for drug-induced reversible sensorineural deafness: a case report.

Severe adverse reactions to propylthiouracil occur in 1-5% of patients. Three major side effects, namely agranulocytosis, hepatotoxicity and drug-induced hypersensitivity, have been described though these syndromes are not distinct entities and there can be overlaps in the clinical manifestations. The drug-induced hypersensitivity may be an immune-mediated reaction with multiorgan involvement in which a combination of polyarthritis, cutaneous vasculitis and fever is common. We report a patient with propylthiouracil-induced hypersensitivity with an unusual combination of high spiking fever, migratory polyarthritis, reversible sensorineural deafness, normochromic normocytic anaemia, leucocytosis and hepatotoxicity associated with polyclonal activation of multiple autoantibodies. This case illustrates the highly variable clinical manifestations of the syndrome. The prompt recovery upon withdrawal of the drug indicates the importance of early diagnosis.

Long-term results following 131I treatment for Graves' disease in Hong Kong Chinese--discriminant factors predicting hypothyroidism.

The clinical outcome of 1028 Hong Kong Chinese patients with Graves' disease treated with radioiodine therapy and followed for a mean of 9.85 +/- 4.84 years (range 2-20) was analysed. Retreatment was required by 413 patients (40.2 per cent), with 134 patients (13.0 per cent) requiring more than two 131I doses. One hundred and eighty-nine patients received carbimazole after 131I until euthyroidism was achieved. The cumulative incidence of hypothyroidism at one, five, 10 and 15 years was 9.6 per cent, 31.4 per cent, 53.8 per cent and 65.8 per cent, respectively. The average incidence of hypothyroidism after the first two years was 3.3 per cent per annum. Stepwise logistic regression analysis of pretreatment variables suggested that a combination of adjunctive carbimazole therapy, absence of ophthalmopathy and longer effective half-lives of 131I were of value in predicting which patients were less likely to develop permanent hypothyroidism. However, the probability of accurately predicting permanent hypothyroidism based on the present model was only 60 per cent. We believe that no single pretreatment variable, or combination of variables, predicts long-term hypothyroidism with sufficient confidence to justify the use of a 'formula' approach for prescribing 131I therapy for Graves' disease.

Discriminant factors affecting early outcome of radioiodine treatment for Graves' disease.

Pretreatment clinical, biochemical, iodine-131 (131I) scan and tracer-kinetic parameters were studied in 827 Chinese patients with Graves' disease treated with radioactive iodine. One year after 131I therapy, 56.7% were euthyroid, 33.9% were still thyrotoxic and 9.4% were hypothyroid. Discriminant analysis of all pretreatment variables identified thyroid mass, presenting free thyroxine index and 4 h 131I uptake as the three variables most helpful in discriminating the early outcome group of 131I therapy. The findings suggest that patients with large goitres and severe disease may require higher doses of 131I for treatment of Graves' disease.

Circulating somatostatin after oral glucose in hypothyroidism.

The response of circulating somatostatin-like immunoactivity (SLI) to oral glucose and its relation to other pancreatic islet cell hormones were studied in 10 hypothyroid subjects before and after treatment. None of the patients suffered from diabetes mellitus or obesity. Compared with normal controls, the hypothyroid subjects had higher fasting and stimulated SLI levels but lower fasting pancreatic glucagon levels. Integrated glucose and insulin responses following glucose ingestion were normal, but the peak insulin response was delayed to 120 min suggesting impaired pancreatic beta-cell response to oral glucose. On the other hand, the peak response of plasma C-peptide was higher probably because of a reduction in metabolic clearance. In both hypothyroid subjects and controls, a significant correlation was found between the maximal increment of SLI and the maximal decrement of glucagon following oral glucose. In conclusion, plasma SLI is increased in hypothyroidism. The changes in SLI may be due to either an increased hormonal secretion or a reduced metabolic clearance in hypothyroidism. This elevated SLI might contribute to the slower gastrointestinal motility observed in hypothyroidism. Our data also suggest that the reduction in glucagon secretion may be secondary to the increase in circulating SLI.

Long-term effects of megavoltage radiotherapy in acromegaly.

The progress of 41 Chinese patients with acromegaly treated with megavoltage radiotherapy was reviewed after a mean follow-up of 4.5 (one-ten) years. Nine received prior surgery. Radiotherapy was delivered by a 3-field technique to a total of 4000-5000 cGy in 25 fractions. By life table analysis successful treatment of growth hormone (GH) hypersecretion, as defined by a mean GH concentration of less than or equal to 10 mu/L, could be expected in 6, 11, 26, 64 and 67% of the patients after one, two, five, eight and ten years respectively. Median intervals before achieving a mean GH level of less than or equal to 10 mu/L were 6.6 and 8.6 years following radiotherapy with the higher (4500-5000 cGy) and lower (4000 cGy) doses respectively, suggesting a tendency towards earlier response following radiotherapy with the higher dose. The prevalence of acquired hypopituitarism in patients followed up for over five years was 40% for gonadotrophins, 30% for TSH and 20% for ACTH deficiency respectively. In the majority of patients, acquired hypopituitarism was not apparent within five years after radiotherapy. No mortality or major side effects were noted following radiotherapy. In 34 patients on long-term bromocriptine treatment, mean GH concentrations were normalised in 26.5% of patients. We conclude that with judicious selection of patients and use of adjunctive medical therapy, megavoltage radiotherapy remains a safe and satisfactory form of treatment for acromegaly especially if expert transphenoidal surgery is not readily available.

Erythrocyte sodium-potassium pump in thyrotoxic periodic paralysis.

To search for a genetic marker in patients with thyrotoxic periodic paralysis (TPP), we studied the erythrocyte sodium-potassium pump activity in 13 patients with TPP; 30 thyrotoxic patients with no history of paralysis (T) and 69 euthyroid controls. In thyrotoxic patients (TPP and T), erythrocyte ouabain binding and ouabain sensitive sodium efflux rate constant were decreased while erythrocyte sodium content was increased. All these changes reverted to normal when the patients became euthyroid. Maximal ouabain binding capacity correlated positively with ouabain sensitive sodium efflux rate constant (r = 0.542; p less than 0.001; n = 155) and negatively with serum thyroxine concentration (r = -0.571; p less than 0.001; n = 60) and erythrocyte sodium content (r = -0.521; p less than 0.001; n = 155). In the thyrotoxic state, maximal ouabain binding capacity was just significantly higher in TPP when compared with T (0.268 +/- 0.014 and 0.234 +/- 0.009 pmol/10(9) cells respectively; p less than 0.05). This difference could not be demonstrated when the patients became euthyroid. Our findings suggest that patients with TPP respond to thyrotoxicosis with a smaller decrement in erythrocyte sodium-potassium ATPase activity than patients without a history of paralysis. However, the difference is too small to represent a useful genetic marker for this disease entity

Temporal lobe and hypothalamic-pituitary dysfunctions after radiotherapy for nasopharyngeal carcinoma: a distinct clinical syndrome.

Eleven patients with combined neurological and endocrine complications after external radiotherapy for nasopharyngeal carcinoma are described. Neurologically, memory disturbance, complex partial seizures and hypodense areas in one or both temporal lobes on CT were typical features. Endocrinologically, hypopituitarism was the prominent manifestation. This constellation of clinical features in a patient with previous radiotherapy to the nasopharynx characterises radiation injury to the inferomedial aspects of the temporal lobes and the hypothalamic-pituitary axis. While the parenchymal brain lesions may mimic metastases or glioma on CT, the associated endocrine disturbance would betray the correct diagnosis. The importance of recognising the hypopituitarism which may be clinically asymptomatic and which is amenable to therapy is emphasised, as is the need for a proper fractionation of the radiation dose to minimise the incidence of these disabling complications.

Primary hyperparathyroidism: its clinical pattern and results of surgical treatment in Hong Kong Chinese.

Primary hyperparathyroidism has been increasingly diagnosed among whites since the advent of the biochemical autoanalyzer. However, the condition remains uncommon among Orientals. Our experience with 31 patients at the Queen Mary Hospital, University of Hong Kong, in the periods before and after we began to use the biochemical autoanalyzer was reviewed. The prevalence of primary hyperparathyroidism rose slightly from 3.1 to 3.7 per 100,000 hospital population. In both periods skeletal manifestation was the major clinical presentation, followed by hypercalcemic symptoms and urologic disease. Asymptomatic hypercalcemia occurred in three of 31 patients despite the use of the biochemical autoanalyzer. Preoperative localization was carried out in 27 patients and was helpful in nine (33.3%) of them. The surgeon explored all four parathyroids, removed the diseased gland(s), and examined a biopsy specimen of one normal-appearing gland. There were 27 adenomas, two carcinomas, one four-gland hyperplasia, and one sarcoidosis. Twenty-eight patients had transient hypocalcemia after parathyroidectomy and required calcium supplements for variable periods. Before and after we began to use the biochemical autoanalyzer, there was minimal change in the prevalence and clinical pattern of primary hyperparathyroidism seen in our hospital. In our experience, successful parathyroidectomy depends more on the surgeon's operative technique than on preoperative localization.

C-peptide in non-alcoholic cirrhosis and hepatocellular carcinoma.

Fourteen normal controls, eleven patients with non-alcoholic cirrhosis, twenty-nine with hepatocellular carcinoma (HCC) and six with HCC and hypoglycemia were studied. The tests performed include iv glucose tolerance test (25 g) and glucagon challenge test (2 mg). In cirrhosis, glucose intolerance and insulin resistance were demonstrated. The fasting hyperinsulinemia in cirrhosis is the result of decreased degradation as shown by the normal fasting C-peptide. The increased insulin responses to glucose, despite a normal C-peptide response, further supports the importance of impaired degradation in the pathogenesis of hyperinsulinemia after challenge. Despite a strong etiological association between cirrhosis and HCC, patients with HCC do not have significant hyperinsulinemia or glucose intolerance. This provides metabolic evidence to support the clinico-pathological observation that HCC occurred when cirrhosis was not advanced or in a precirrhotic stage. In HCC patients with clinically overt hypoglycemia, the fasting glucose, insulin and C-peptide were very low. The C-peptide responses to glucose and glucagon challenges were suppressed despite pharmacologic stimulation. This can be explained by the suppression of insulin secretion by a circulating substance secreted by hepatoma. The results support the pathogenetic importance of insulin-like activities recently detected in HCC patients with hypoglycemia.

Strong association of HLA-DR3/DRw9 heterozygosity with early-onset insulin-dependent diabetes mellitus in Chinese.

Studies of Caucasian and Japanese patients with insulin-dependent diabetes mellitus (IDDM) have shown that heterozygosity for certain HLA-DR antigens confers a high risk of developing the disease. The HLA antigens of 75 Chinese patients and 100 Chinese controls in Hong Kong were studied to investigate the role of HLA-DR heterozygosity in Chinese individuals. Some of the patients and controls were also tested for allotypic variation in the complement components C2, C4, and BF. Three alleles, Aw33, B17, and DR3, had increased frequencies in patients compared with controls and frequently occurred together in the same phenotype, which suggested their existence as a haplotype. There were no statistically significant differences in complement allotype frequencies between patients and controls, although the C4B null allele seemed to be associated with Aw33, B17, and DR3. No other HLA-DR antigen appeared to be associated with IDDM. However, when the patients were separated on the basis of age at onset, the frequency of DR3/DRw9 heterozygosity was markedly increased in patients presenting in the first decade of life, but there was no increase in patients presenting at greater than 20 yr of age. DRw9 is strongly associated with autoimmune disease in Chinese, whereas DR3 is not. We suggest that the major IDDM susceptibility locus in Chinese is associated with HLA-DR3 and that patients with HLA-DR3 and HLA-DRw9 have an added predisposition to autoimmune disease and therefore develop IDDM earlier than patients without DRw9.

Prevention of hypoglycaemia in a patient with pancreatic microadenomatosis by a long-acting somatostatin analogue SMS 201-995.

Acute suppression of insulin secretion from pancreatic insulinomas by long-acting somatostatin analogue SMS 201-995 has been documented. We report the chronic use of the drug in a patient with persistent hypoglycaemia due to benign pancreatic microadenomatosis with satisfactory control of plasma glucose level and reduction of insulin production. There was no tachyphylaxis or untoward side-effect noted during the 6-month treatment period.

Symptomatic hypothalamic-pituitary dysfunction in nasopharyngeal carcinoma patients following radiation therapy: a retrospective study.

Endocrine assessment was performed in 32 relapse-free southern Chinese patients (21 males and 11 females, aged 27-50 years at the time of assessment) 5-17 years following radiation therapy (RT) alone for early nasopharyngeal carcinoma (NPC). Initial screening was done using questionnaires emphasizing on impaired sexual function and menstrual disturbance plus measurement of serum levels of thyroxine, free thyroxine index, thyrotropic hormone, prolactin, and additionally testosterone for males only. Those showing abnormalities were subjected to detailed pituitary function tests. Hypothalamic-pituitary dysfunction was found in 7 female patients and only 1 male patient. A delayed TSH response to thyrotropin releasing hormone suggesting a hypothalamic disorder was seen in 6 of the affected female patients, and hyperprolactinaemia in also 6. None of the patients had evidence of diabetes insipidus. Hypopituitarism became symptomatic 2-5 years after RT with a mean latent interval of 3.8 years. A practical protocol for regular endocrine assessment for NPC patients after RT has been proposed. Multiple linear regression analysis of the radiotherapeutic data from the 11 female patients indicates that the likelihood of late occurrence of symptomatic hypothalamic-pituitary dysfunction following RT is dependent on the TDF of the target dose to the nasopharyngeal region and the height of the upper margin of the opposed lateral facial fields above the diaphragma sellae (coefficient of multiple correlation = 0.9025). Except when the sphenoid sinus or the middle cranial fossa is involved, it is advisable to set the height of the upper margin of the lateral facial field at a level no higher than the diaphragma sellae. The hypothalamus and possibly the pituitary stalk as well may sustain permanent damage by doses of radiation within the conventional radiotherapeutic range for carcinomas.

Long-term treatment of hyperprolactinaemia with bromocriptine: effect of drug withdrawal.

Fifty-one patients with hyperprolactinaemia (23 with macroadenoma, 23 with microadenoma, and five with idiopathic hyperprolactinaemia) were treated with bromocriptine for 2-12 years (4.9 +/- 2.9 years, mean +/- SD). During therapy, the serum PRL levels were suppressed into the normal range in all but five patients. In these five patients, despite the high circulating PRL, gonadal function returned to normal in three, while in the other two gonadotrophin reserve was impaired even before therapy. Gel chromatography showed that one of these patients had a high proportion of a large molecular weight form of PRL. Twenty-four patients received bromocriptine as the sole method of treatment for over 2 years (3.4 +/- 2.3 years). In five out of the 24 subjects (21%), serum PRL remained normal with no clinical symptoms after prolonged drug withdrawal (1-4 years). Twenty-one patients received radiotherapy in conjunction with bromocriptine therapy. Of these 11 had prior surgery. After a follow-up of 6.0 +/- 3.0 years after radiotherapy, serum PRL remained within the normal range in 6 out of 21 subjects (29%), 1-4 years after bromocriptine withdrawal. One of the patients had impaired GH response to insulin hypoglycaemia developing after radiotherapy. We conclude that prolonged bromocriptine treatment is an effective treatment for prolactinomas.

Myopathy in acute hypothyroidism.

Hypothyroid myopathy has so far been reported in long standing cases of hypothyroidism. We describe two adult patients with myopathy associated with acute transient hypothyroidism. Both presented with severe muscle aches and cramps, stiffness and spasms. Muscle enzymes were markedly elevated and electromyography in one patient showed myopathic features. Histological changes were absent in muscle biopsy, probably because of the short duration of metabolic disturbance. The myopathy subsided promptly when the hypothyroid state was reversed.

Strong association between HLA DRw9 and Hashimoto's thyroiditis in southern Chinese.

The distribution of HLA-A, -B, and -DR antigens in 53 Southern Chinese patients with Hashimoto's thyroiditis including 33 with goitre and 20 without goitre was compared with the distribution in 100 Southern Chinese controls. There was a significantly increased prevalence of HLA Bw46 in the nongoiterous patients and of HLA DRw9 in both groups of patients, but only for HLA DRw9 in the goiterous group was the increase significant after adjustment for the number of antigens studied. Based on these findings and those in other autoimmune diseases it is considered that the haplotype Bw46, DRw9 in Chinese takes the place of B8, DR3 in Caucasians in carrying genes which predispose to the development of auto-immune disease.

Early effects of cranial irradiation on hypothalamic-pituitary function.

Hypothalamic-pituitary function was studied in 31 patients before and after cranial irradiation for nasopharyngeal carcinoma. The estimated radiotherapy (RT) doses to the hypothalamus and pituitary were 3979 +/- 78 (+/- SD) and 6167 +/- 122 centiGrays, respectively. All patients had normal pituitary function before RT. One year after RT, there was a significant decrease in the integrated serum GH response to insulin-induced hypoglycemia. In the male patients, basal serum FSH significantly increased, while basal serum LH and testosterone did not change. Moreover, in response to LHRH, the integrated FSH response was increased while that of LH was decreased. Such discordant changes in FSH and LH may be explained by a defect in LHRH pulsatile release involving predominantly a decrease in pulse frequency. The peak serum TSH response to TRH became delayed in 28 patients, suggesting a defect in TRH release. Twenty-one patients were reassessed 2 yr after RT. Their mean basal serum T4 and plasma cortisol levels had significantly decreased. Hyperprolactinemia associated with oligomenorrhoea was found in 3 women. Further impairment in the secretion of GH, FSH, LH, TSH, and ACTH had occurred, and 4 patients had hypopituitarism. Thus, progressive impairment in hypothalamic-pituitary function occurs after cranial irradiation and can be demonstrated as early as 1 yr after RT.