Clinical utility of late-night and post-overnight dexamethasone suppression salivary cortisone for the investigation of Cushing's syndrome.

INTRODUCTION: There is a pressing need to identify diagnostic testing for Cushing's syndrome that can be achieved with ease and at low cost. This study aimed to explore the usefulness of late-night and post-overnight 1-mg dexamethasone suppression salivary cortisone, as measured by liquid chromatography-tandem mass spectrometry, for investigation of hypercortisolism. METHODS: Salivary cortisone data of subjects were investigated according to a pre-specified protocol. Subjects were classified as having 'hypercortisolism' or 'eucortisolism' on the basis of histological or biochemical criteria. Receiver operating characteristic curves were drawn to identify the cut-off values and study their performance characteristics. We measured 24-hour urinary free cortisol; late-night salivary cortisol and cortisone; and post-overnight 1-mg dexamethasone suppression serum cortisol, and salivary cortisol and cortisone. Saliva and urine samples were assayed by liquid chromatography-tandem mass spectrometry. RESULTS: In this study, 21 subjects were classified as having hypercortisolism and 78 as having eucortisolism. A late-night salivary cortisone cut-off of 13.50 nmol/L had a sensitivity of 94.7% and a specificity of 87.2%. After taking 1-mg dexamethasone the night before, a salivary cortisol cut-off of 0.85 nmol/L had a sensitivity of 76.2% and a specificity of 96.2%; a salivary cortisone cut-off of 7.45 nmol/L had a sensitivity of 85.7% and a specificity of 94.9%, while a salivary cortisone cut-off of 3.25 nmol/L had a sensitivity of 95.2% and a specificity of 79.5%. Many salivary cortisol samples were below the detection limit of liquid chromatography-tandem mass spectrometry. In comparison with salivary cortisol, salivary cortisone had a better correlation with total serum cortisol and better diagnostic performance following dexamethasone suppression. CONCLUSIONS: Both late-night and post-overnight dexamethasone suppression salivary cortisone levels are of diagnostic value in the investigation of hypercortisolism.

Hypertriglyceridaemia-induced pancreatitis: a contributory role of capecitabine?

Capecitabine is an orally administered pro-drug of 5-fluorouracil that confers superior disease-free survival and presumably has a more favourable side-effect profile. Here we report on a patient who developed acute necrotising pancreatitis and very high triglyceride levels as well as hand-foot syndrome after receiving capecitabine for colonic cancer. Increased awareness of this potential side-effect and close monitoring of lipid levels may be warranted, especially in patients who have other conditions predisposing them to severe secondary hyperlipidaemia when using this drug.

Hyperammonaemic encephalopathy in an adult patient with citrin deficiency associated with a novel mutation.

We report on an adult patient with citrin deficiency in Hong Kong, in whom a novel mutation was identified. The patient presented with recurrent hyperammonaemic encephalopathy due to impairment of the liver urea cycle enzyme argininosuccinate synthetase. This autosomal recessive condition is also characterised by interesting food preferences, notably aversion to carbohydrates and craving for protein-rich and/or lipid-rich foods, as well as neuropsychiatric symptoms. Plasma amino acid analysis is very useful in revealing urea cycle disorders, and mutational analysis of the SLC25A13 gene can confirm the diagnosis.

Molecular analysis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency in Hong Kong Chinese patients.

BACKGROUND: Congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency (21OHD) is an autosomal recessive disorder due to mutation in the CYP21A2 gene. OBJECTIVE: To elucidate the genetic basis of 21-hydroxylase-deficient CAH in Hong Kong Chinese patients. PATIENTS AND METHODS: Mutational analysis of the CYP21A2 gene was performed on 35 Hong Kong Chinese patients with 21OHD using direct DNA sequencing and multiplex ligation-dependent probe amplification (MLPA). RESULTS: The genetic findings of 21 male and 14 female patients are the following: c.293-13A/C>G (intron 2 splice site; 20 alleles), p.I172N (13), p.R356W (7), p.Q318X (4). A total of 20 mutant alleles contained gross deletion/conversion of all or part of the CYP21A2 gene. A novel mutation, c.1367delA (p.D456fs), was detected in one patient. One patient had only a heterozygous mutation detected. Out of 35 patients, 16 would have been incorrectly genotyped if either DNA sequencing or MLPA alone was used for molecular analysis. CONCLUSIONS: The frequency of various mutations in the studied patients differs from those reported in other Asian populations. Gross deletion/conversion accounts for nearly one-third of the genetic defects. Therefore, laboratories must include methods for detecting point mutations as well as gross deletions/conversions to avoid misinterpretation of genotype. Genotyping has increasingly been proven to be a useful tool for supplementing, if not replacing, hormonal profiling for the diagnosis of 21OHD.

Use of urinary steroid profiling for diagnosing and monitoring adrenocortical tumours.

It has been suggested that urinary steroid profiling may be used to provide information aiding the diagnosis and monitoring of adrenocortical carcinoma. Nonetheless, the abnormal patterns suggestive of adrenal malignancy are not well defined. We retrospectively studied the urinary steroid profiles of five patients with adrenocortical carcinoma at presentation and at follow-up, and compared these results with those from 76 patients with benign adrenocortical adenoma and 172 healthy controls. Three abnormal patterns of urinary steroid excretion were identified in patients with adrenocortical carcinoma at presentation and/or follow-up of residual disease: (1) hypersecretion in multiple steroid axes; (2) excretion of unusual metabolites, notably 5-pregnene-3alpha,16alpha,20alpha-triol, 5-pregnene-3beta,16alpha,20alpha-triol, and neonatal steroid metabolites in the post-neonatal period; (3) increase of tetrahydro-11-deoxycortisol relative to total cortisol metabolites. These preliminary findings offer ways in which urinary steroid profiling performed using gas chromatography-mass spectrometry can be helpful in the diagnosis and monitoring of adrenocortical carcinoma.

Prevalence and significance of white-coat hypertension and masked hypertension in type 2 diabetics.

OBJECTIVES: To explore the prevalence of various categories of hypertension in diabetic patients, and assess any corresponding associations with end-organ complications. DESIGN: Cross-sectional study. SETTING: Tertiary centre of a regional hospital in Hong Kong. PATIENTS: All ambulatory type 2 diabetic patients attending our clinics from January 2002 to November 2004 were invited to participate in the protocol. RESULTS: A total of 133 diabetic patients were included; 82 had normal clinic blood pressures, 15 (18%) of whom had masked hypertension, the remaining 67 (82%) had 'normotension'. The remaining 51 patients had high clinic blood pressures, of whom 28 (55%) had white-coat hypertension and 23 (45%) had sustained hypertension. Urinary albumin excretion rate was higher in patients with masked hypertension (10 mg/day; range, 7-580 mg/day) and sustained hypertension (7 mg/day; 7-3360 mg/day) in comparison to those with white-coat hypertension (7 mg/day; 7-109 mg/day) or 'normotension' (7 mg/day; 7-181 mg/day) [P<0.01]. Likewise, the prevalence of albuminuria was significantly higher in patients with masked hypertension (40%) and sustained hypertension (26%) than in those with 'normotension' (6%) and white-coat hypertension (11%) [P<0.01]. The prevalence of left ventricular hypertrophy was significantly higher in subjects with masked hypertension (38%) and sustained hypertension (26%) compared to patients with 'normotension' (8%) or white-coat hypertension (11%) [P<0.01]. Left ventricular diastolic dysfunction was more prevalent in patients with masked hypertension (46%), sustained hypertension (48%), and white-coat hypertension (43%) in comparison to subjects with 'normotension' (18%) [P=0.01]. CONCLUSION: Masked hypertension is associated with a higher prevalence of albuminuria, left ventricular diastolic dysfunction, and hypertrophy. White-coat hypertension carries a more benign prognosis than sustained hypertension and masked hypertension. Our cross-sectional study supports the recommendation to performing ambulatory blood pressure measurements in type 2 diabetic patients.

Reference intervals of urinary steroid metabolites using gas chromatography-mass spectrometry in Chinese adults.

BACKGROUND: Urinary steroid profiling by GC or GC-MS are established clinical tools to complement other biochemical tests in the diagnosis and investigation of a wide range of adrenocortical disorders, but normative data on adults using the more specific GC-MS are lacking. Our objective was to set up the reference intervals of commonly detected urinary steroid metabolites as well as marker metabolites seen in disease states. METHOD: Apparently healthy adult Chinese males and females were recruited by completing health questionnaires. A 24-h urine specimen was collected from all the participants for urinary steroid profiling by GC-MS in cyclic scan mode. The analyzer was calibrated by using authentic steroid standards. Statistical methods recommended by the National Committee for Clinical Laboratory Standards were followed for setting up the reference intervals of various steroid metabolites. After outliers were excluded, the data were tested for the necessity to partition into sex-, menopausal status- and age-specific reference intervals. RESULTS: 83 males and 89 females were recruited for the study. Necessity to partition into sex-specific reference intervals was demonstrated for almost all steroid metabolites. Menopausal status and age also had a significant impact on steroid metabolite excretion, making separate reference intervals necessary. CONCLUSIONS: We have set up the normative data on the levels of urinary steroid metabolite excretion in Chinese adults for future reference in patient management and research in steroid metabolism.

Spinal subdural haematoma: a rare complication of low-molecular-weight heparin therapy.

A 52-year-old man presented with chest pain, diarrhoea, rash, and arthritis. The use of low-molecular-weight heparin for suspected pulmonary embolism or angina led to a spinal subdural haematoma 3 days later. He was retrospectively confirmed to have Salmonella paratyphi infection. The clinical presentation and management of spinal subdural haematomas, and the incidence and manifestations of reactive arthritis related to Salmonella infections are briefly discussed.

Use of lithium in the treatment of thyrotoxicosis.

OBJECTIVES: To evaluate the efficacy and safety of lithium in the treatment of thyrotoxicosis, and to study the dose and serum levels at which therapeutic response occurs. DESIGN: Retrospective study. SETTING: Thyroid clinic of a regional hospital in Hong Kong. PATIENTS: Thirteen patients with thyrotoxicosis pending therapy with radioiodine or surgery, in whom thionamides were contra-indicated due to adverse reactions or failure of treatment. MAIN OUTCOME MEASURES: Free thyroxine levels, time to euthyroidism, and side-effects of lithium. RESULTS: A satisfactory response, defined as a fall by 40% or more in free thyroxine levels and clinical improvement, was achieved in eight patients within 1 to 2 weeks of lithium therapy. In four others, response occurred in 3 to 5 weeks. Response was slow and inadequate in one patient due to 'escape'. The median dosage of lithium was 750 mg daily, with a range of 500 to 1500 mg daily. The median serum lithium level was 0.63 mmol/L. Lithium toxicity was observed in one patient. CONCLUSIONS: A relatively low dose of lithium offers a safe and effective alternative means of controlling thyrotoxicosis in patients who cannot tolerate or do not respond to thionamides.

Combined orbital irradiation and systemic steroids compared with systemic steroids alone in the management of moderate-to-severe Graves' ophthalmopathy: a preliminary study.

OBJECTIVE: To assess the efficacy and safety of combined orbital irradiation and systemic steroids in the management of moderate-to-severe Graves' ophthalmopathy. DESIGN: Single-blind randomised prospective study. SETTING: Regional hospital, Hong Kong. PATIENTS: Sixteen patients with active moderate-to-severe Graves' ophthalmopathy who were randomly assigned to steroid therapy (ST group) or combination therapy of orbital irradiation and systemic steroids (SRT group) between June 2000 and June 2003. MAIN OUTCOME MEASURES: NOSPECS scoring system, total eye score, subjective eye score, and extra-ocular muscle thickness as determined by either computed tomographic or magnetic resonance imaging scans. RESULTS: The study was completed by 15 of 16 patients. Both groups experienced improvement in total eye score, soft tissue swelling, ocular motility, visual acuity, and subjective eye score at 52-week follow-up. Total eye score improved earlier in the SRT group, achieving statistical significance (P<0.05) at as early as 4 weeks of follow-up. Improvement in ocular parameters was greater and led to a significantly greater reduction in total eye score than in the ST group at weeks 16, 24, and 52. Maximum extra-ocular muscle thickness was significantly reduced in the SRT group only. No change was observed in proptosis in either group. No serious adverse effect was observed with the addition of orbital irradiation to steroid therapy. CONCLUSION: A combination of orbital irradiation and systemic steroids is well tolerated and more effective than steroids alone in the treatment of active moderate-to-severe Graves' ophthalmopathy. It achieves greater and more rapid improvement in soft tissue swelling, ocular motility, and visual acuity.

Medullary thyroid carcinoma in Hong Kong Chinese patients.

OBJECTIVE: To study the clinical parameters and treatment outcome of medullary thyroid carcinoma in Hong Kong Chinese patients. DESIGN: Retrospective study. SETTING: Regional oncology unit, Hong Kong. PATIENTS: Patients with medullary thyroid carcinoma who were identified among 1656 patients with thyroid malignancies seen in a single institute in Hong Kong from January 1960 to June 2003. MAIN OUTCOME MEASURES: Ten-year cause-specific survival, locoregional failure-free survival, and distant metastasis failure-free survival. RESULTS: Twenty-two (1.3%) patients with medullary thyroid carcinoma were identified. The mean age at diagnosis was 43.7 (standard deviation, 16.5) years. The sex ratio was 1:1. The 10-year cause-specific survival, locoregional failure-free survival, and distant metastasis failure-free survival were 75.4%, 82.0%, and 62.4%, respectively. Lymph node metastasis was present in seven (31.8%) patients at diagnosis. Distant metastasis developed in nine (40.9%) patients: lung, 3 (13.6%); bone, 5 (22.7%); liver, 2 (9.1%); mediastinum, 4 (18.2%). Seven (31.8%) patients died of distant metastasis. Mediastinal (n=3) and bone metastases (n=3) were important causes of death. Genetic study confirmed multiple endocrine neoplasia type 2A in 3 (25.0%) of 12 patients who all had bilateral and multifocal diseases. Younger age (<45 years) was associated with better survival, better locoregional control, and less distant metastasis. Patients with pT1N0 disease (n=3) had an excellent prognosis: all were disease-free following total thyroidectomy. Among eight patients who received external radiation therapy, seven achieved good locoregional control. In seven patients with lymph node metastasis, external radiation therapy gave 100% (4/4) locoregional control compared with 33.3% (1/3) in those without external radiation therapy. Chemotherapy using dacarbazine and 5-fluorouracil was tried in three patients with poor response. CONCLUSIONS: Early stage (T1N0) medullary thyroid carcinoma is associated with a very good prognosis. Postoperative external radiation therapy can achieve good locoregional control in patients with lymph node metastasis or locally advanced disease.

N-methyl-D-aspartate receptor and apoptosis in Alzheimer's disease and multiinfarct dementia.

This study investigates the role of excitotoxicity in Alzheimer's disease and in multiinfarct dementia by examining, via immunohistochemical methods, the number of cells that are positive for N-methyl-D-aspartate (NMDA) receptor and the degree of colocalization between NMDA receptor and apoptosis markers such as TUNEL or activated caspase-3 in the frontal cortex of individuals with these two conditions, comparing the results with those from subjects who died of normal aging. We showed an increased number of NMDA receptor-positive cells and an increased number of TUNEL-labeled cells in the frontal cortex of subjects with Alzheimer's disease, especially in the deeper layers of the cortex. However, only about 10% of cells showed colocalization of NMDA receptor with the apoptosis markers studied, suggesting that NMDA-mediated excitotoxicity does not play a major role in neuronal apoptosis in Alzheimer's disease or in multiinfarct dementia.

Resistance to thyroid hormone in a Chinese family with R429Q mutation in the thyroid hormone receptor beta gene.

The combination of elevated serum levels of free thyroid hormones with non-suppressed thyroid-stimulating hormone suggests the differential diagnoses of resistance to thyroid hormone or thyroid-stimulating hormone-secreting pituitary tumour. Clinical differentiation of these two conditions can be difficult, because patients with thyroid hormone resistance may exhibit various combinations of hypermetabolic and hypometabolic features, and laboratory results have limited sensitivity and specificity. We report a case of resistance to thyroid hormone in a Chinese family that illustrates this difficulty. The diagnosis could only be confirmed by the identification of a known disease-causing mutation in the thyroid hormone receptor beta gene in peripheral leukocytes. Availability of genetic tests will identify more cases in the future and improve our understanding of this condition.

Consensus statement on iodine deficiency disorders in Hong Kong.

This article reviews the available data on the study of iodine deficiency disorders in Hong Kong and to discuss the approach towards preventing such disorders in Hong Kong. The importance of iodine and iodine deficiency disorders is described, and the available data on the dietary iodine intake and urinary iodine concentration in different populations of Hong Kong are summarised and discussed. Dietary iodine insufficiency among pregnant women in Hong Kong is associated with maternal goitrogenesis and hypothyroxinaemia as well as neonatal hypothyroidism. Borderline iodine deficiency exists in the expectant mothers in Hong Kong. Women of reproductive age, and pregnant and lactating women should be made aware and educated to have an adequate iodine intake, such as iodised salt, as an interim measure. A steering group involving all stakeholders should be formed to advise on the strategy of ensuring adequate iodine intake, including universal iodisation of salt in Hong Kong. Continuous surveillance of iodine status in the Hong Kong population is necessary.

A Chinese family with familial dysalbuminaemic hyperthyroxinaemia.

We report the results of biochemical and genetic studies in a Chinese family with familial dysalbuminaemic hyperthyroxinaemia. Total thyroxine levels were 1.2 to 1.7 times the upper limit of the reference range and free thyroxine levels were 1.2 to 1.6 times the upper reference limit. Concentrations of thyroid-stimulating hormone (thyrotropin) and free tri-iodothyronine were normal in all family members tested. Overall, thyroid function tests showed high total thyroxine levels in five males and two females over two generations in the family. The diagnosis of familial dysalbuminaemic hyperthyroxinaemia was confirmed by the detection of a guanine to adenine missense mutation in the second nucleotide of codon 218 of the gene encoding human serum albumin, showing that the mutation in this family is the same as that previously found in Caucasian populations.

Effects of treatment with Sandostatin LAR on small dense LDL and remnant-like lipoproteins in patients with acromegaly.

OBJECTIVE: Acromegalic patients have been shown to have an increase in the concentrations of small dense low-density lipoprotein (LDL) and remnant-like lipoprotein particles (RLP). These lipoproteins are atherogenic and may contribute to the cardiovascular risk of these patients. The aim of this study was to determine whether treatment of acromegaly using Sandostatin LAR could lower these atherogenic lipoproteins. METHODS: Fourteen patients with active acromegaly were recruited and Sandostatin LAR, a long-acting somatostatin analogue, was given every 4 weeks by intramuscular injection for 6 months. Fasting lipids, lipoproteins, lipolytic enzymes were determined at baseline, 12 and 24 weeks after treatment. Small dense LDL was measured using density gradient ultracentrifugation and RLP-cholesterol (RLP-C) by an immunoseparation assay. RESULTS: There was already a marked reduction in GH and IGF-1 by week 8 and, in all subjects, IGF-1 levels within their respective age-specific normal range were achieved. At week 12, plasma triglyceride significantly decreased (P < 0.01) and both HDL2 (P < 0.01) and HDL3 (P < 0.01) subfractions increased. A reduction was seen in small dense LDL concentration (P < 0.05) and RLP-C (P < 0.05). Lipoprotein lipase (LPL) activity increased (P < 0.01) and the magnitude of the increase in LPL activity correlated with the increase in HDL at 3 months (r = 0.55, P < 0.05) but not with the changes in plasma triglyceride, small dense LDL or RLP-C. The improvement in plasma lipids and lipoproteins persisted until the end of the study. CONCLUSION: Sandostatin LAR is effective in the treatment of acromegaly and is associated with favourable changes in plasma lipids and a reduction in small dense LDL and RLP-C.