Association between CTLA-4 polymorphisms and the susceptibility to systemic lupus erythematosus and Graves’disease in Thai population.

Background: Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a cell surface molecule involved in the regulation of T cells. Single nucleotide polymorphisms (SNPs) of CTLA-4 gene are known to be associated with susceptibility to several autoimmune diseases, including systemic lupus erythematosus (SLE) and Graves’ disease (GD). Objective: The aim of this study was to determine whether the common SNPs +49A/G on exon1 and CT60A/G in 3’UTR of the CTLA-4 gene are associated with susceptibility to SLE and GD in Thai population. Methods: Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to analyze these two SNPs in 151 patients with SLE, 132 patients with GD and 153 healthy controls. Results: Our study showed that there were no statistically significant differences in the allele and genotype frequencies of +49A/G and CT60A/G SNPs between patients with SLE and healthy controls as well as patients with GD vs. healthy controls (P >0.05). However, the GG genotypes of +49A/G and CT60A/G were likely to be risk factors (OR >1) for GD but not in SLE. The effect of the +49G allele was similar to that of an autosomal recessive gene in the presence of the GG genotype, when compared to AA and AG, with an OR of 1.58 (95% CI =0.95-2.61, p =0.061) in GD. We also observed a dose response effect of the CT60G allele on GD susceptibility with an OR of 1.43 for GG homozygous and 1.17 for AG heterozygous subjects, when compared to the AA genotype, although these were not statistically significant (P >0.05). Conclusion: We found no association between two functional polymorphisms (+49A/G and CT60A/G) of the CTLA-4 gene and susceptibility to SLE and GD. However, the association study utilizing a larger sample size should be performed to confirm this.

Normal reference range of serum insulin-like growth factor (IGF)-I in healthy Thai adults.

BACKGROUND: Serum insulin-like growth factor (IGF)-I level is growth hormone (GH) dependent and reflects GH secretion. Analysis of IGF-I is a component in the diagnosis of GH-related disorders and is going to be of interest in determining the risk of many disorders such as cancer or atherosclerosis. The diagnosis value of IGF-I is dependent on the establishment of an accurate reference ranges, which can be affected by parameters such as age, gender, ethnicity, medications, chronic illness, or assay methodologies. OBJECTIVE: To determine reference ranges of IGF-I for healthy Thai adults. MATERIAL AND METHOD: Eight hundred sixteen healthy Thai adults aged between 21-70 years were recruited in the present study. Serum IGF-I was measured by using immunochemiluminescent (ICMA; Roche, USA). Subjects were recorded by their age and gender groups. Data were presented in mean and +/- 2 standard deviation (SD). Correlation analysis between serum IGF-I and physical parameters including sex, age, weight, height, and body mass index (BMI) was also made. RESULTS: The present study demonstrated normal reference range of serum IGF-I by using mean +/- 2 SD value. The well-known age dependency of serum IGF-I levels was also revealed. Levels decreased with increasing age in both genders. The mean value of serum IGF-I was slightly higher in women at the age of 30-40 years compared with men in the same age group, but not statistically insignificant. In addition, serum IGF-I was found to correlate directly with the height and negatively with BMI. However, age-adjusted IGF-I level did not show correlation with these physical parameters. CONCLUSION: This reference range will be beneficial for using IGF-I assay as a tool in the diagnosis of GH function abnormalities in Thai subjects.

Association of TNF-alpha, TNF-beta, IFN-gamma and IL-1Ra gene polymorphisms with Graves' disease in the Thai population.

Cytokines play a key role in the regulation of immune and inflammatory responses. Therefore, cytokine genes are potentially related to susceptibility to Graves' disease (GD). The aim of this study was to investigate the putative functional polymorphisms within tumor necrosis factor-alpha (TNF-alpha), tumor necrosis factor-beta (TNF-beta), interferon-gamma (IFN-gamma), and interleukin-1 receptor antagonist (IL-1Ra) genes, in patients with GD (n = 137) compared to a healthy Thai control group (n = 137). The results showed no statistically significant difference between the study groups for TNF-beta (Ncol site in intron 1), IFN-gamma (+874 in intron 1), and IL-1Ra (variable numbers of tandem repeats in intron 2) gene polymorphisms. Only the -863A allele within the promoter region of the TNF-alpha gene, which may affect the affinity of the promoter nuclear factor (NF)-kappab interaction, was found to be increased in GD patients compared to the controls (p = 0.009, OR = 1.8, 95% CI = 1.15 to 2.84). The effect of the -863A allele of the TNF-alpha gene was similar to the autosomal dominance mode of inheritance (p = 0.01, OR = 2, 95% CI = 1.16 to 3.44). This polymorphism may be involved in the susceptibility to GD in part through its higher promoter activity of TNF-alpha production.

Functioning adrenocortical carcinoma with superior vena cava and upper airway obstructions.

BACKGROUND: Adrenocortical carcinoma (ACC) is one of the most aggressive endocrine malignancies with a dismal prognosis. Typically, the tumor is large and has regional invasion or distant metastasis at initial presentation. OBJECTIVE: To describe an unusual case of functioning ACC presenting with superior vena cava (SVC) and upper airway obstruction. MATERIAL AND METHOD: A 23-year-old man with cushingoid appearance was evaluated for a neck mass and SVC syndrome. Hormonal assessment and neck mass biopsy including immunohistochemistry study were performed RESULTS: Cushing's syndrome was confirmed by elevated 24-hr urinary free cortisol and no suppressible cortisol level after standard low dose (2 mg/day) of dexamethasone suppression test. Computerized tomography (CT) study revealed a huge left suprarenal mass and multiple mediastinal lymph nodes compressing SVC and trachea. Histopathological findings of the neck mass were compatible with metastatic ACC. CONCLUSION: The present report describes a functioning ACC patient with an unusual metastatic site causing SVC and upper airway obstruction. His hospital course was progressively worsened due to peptic perforation and decompensated respiratory failure, which led him to expire.

A SPINK1 gene mutation in a Thai patient with fibrocalculous pancreatic diabetes.

Fibrocalculous pancreatitis diabetes (FCPD), a late stage of tropical chronic pancreatitis (TCP), is classified as a secondary cause of diabetes mellitus resulting from pancreatic exocrine dysfunction. The distinctive features of FCPD and TCP are young age at onset, presence of large intraductal pancreatic calculi, and reported mainly in tropical developing countries. Their etiology is still obscure, but the autodigestion due to aberrant intraductal activation of zymogens by trypsin is thought to be a primary common event. Recently, mutations in SPINKI gene encoding a pancreatic secretory trypsin inhibitor have been reported in association with an increased risk of pancreatitis. We describe a heterozygous mutation, IVS3+2 T>C, of SPINK1 gene in a young Thai female patient with typical presentation of FCPD. To our knowledge, this is the first report of the SPINK1 gene mutation in a FCPD patient in Southeast Asia.

Adrenal crisis due to bilateral adrenal hemorrhage in primary antiphospholipid syndrome.

The authors report a case of a 56-year-old Thai woman with a history of recurrent venous thrombosis, spontaneous abortion and Graves' disease who presented with bilateral flank pain, nausea, vomiting and low-grade fever followed by hypotension. Adrenal crisis from bilateral adrenal hemorrhage was diagnosed by a low serum cortisol level during hypotension and bilateral hyperdense oval masses in each of the adrenal glands in a computerized tomographic study. Her hemostatic and serologic profile was compatible with primary antiphospholipid syndrome. Rapid improvement was observed after the administration of intravenous hydrocortisone. She was discharged on long-term glucocorticoid replacement for her primary adrenal insufficiency as well as an anticoagulant for prevention of thrombosis. The antiphospholipid syndrome should be suspected in a patient presenting with adrenal crisis without a distinct etiology.

A germline mutation in a Thai family with familial multiple endocrine neoplasia type 1.

Multiple endocrine neoplasia type 1, caused by the mutation in the MEN1 gene, is an autosomal dominant disorder with over 95% penetrance characterized by hyperparathyroidism, pancreatic endocrine tumor and pituitary tumor. The authors performed a molecular analysis to identify a mutation in a Thai man with MEN1. He was found to be heterozygous for IVS6 + 1G to A. Two of his three children were also found to carry this mutation. The newly available genetic test for patients with MEN1 in Thailand makes it possible to accurately DNA-based diagnose clinically suspected individuals and their presymptomatic members, which has important therapeutic impacts on them.

A more appropriate algorithm of thyroid function test in diagnosis of hyperthyroidism for Thai patients.

BACKGROUND: Thyroid function test is an essential tool in the diagnosis of thyroid dysfunction. To date, it is still controversial which diagnostic algorithm is best applicable to clinically hyperthyroidism patients. OBJECTIVE: To compare various algorithms of thyroid function tests in the diagnosis of hyperthyroidism. METHOD: Patients from the endocrine clinic, King Chulalongkorn Memorial Hospital were investigated for thyroid function tests (T3, T4, FT3, FT4 and TSH). Hyperthyroidism was defined as an elevated either FT3 or FT4 with suppressed TSH. The authors compared the effectiveness in hyperthyroidism diagnosis among algorithms by using sensitivity, specificity, positive predictive value and negative predictive value. RESULTS: Of all 452 patients in the present study, 94.24 percent were women. There were 206 hyperthyroidism, 30 subclinical hyperthyroidism, 1 subclinical hypothyroidism, 8 primary hypothyroidism and 207 normal subjects. The incidence of T3 toxicosis was 16.02% while that of T4 toxicosis was 2.16%. After the effectiveness analysis of these algorithms, FT3 and TSH is the most optimal test with 97.57% sensitivity and 100% specificity. Compared to FT4 and TSH, it gave 83.98% sensitivity and 100% specificity. CONCLUSION: According to the high incidence of T3 toxicosis in the present study, FT3 and TSH should be the initial test for diagnosis of hyperthyroid patients in an outpatient setting and FT4 should be measured subsequently in case of suspected T4 toxicosis.

No association between an interleukin 4 gene promoter (-589) polymorphism and Graves' disease in Thai patients.

Cytokines play a key role in the regulation of immune and inflammatory responses and therefore are potential candidate genes for autoimmune thyroid disease. Polymorphisms in cytokine genes may effect gene transcription, causing individual variations in cytokine production. Several investigators have linked the interleukin-4 (IL-4) gene and autoimmune disease. The present population-based study was to investigate the polymorphisms of IL-4 gene promoter (-589C/T) in GD patients compared with a control group and determine the association with GD in a Thai population. The subjects included 137 GD patients and 137 healthy control subjects with similar ethnic and geographic backgrounds. The IL-4 gene polymorphism at position -589 in the promoter was analyzed using the PCR-RFLP. The protective effect of the -589T allele as suggested by Hunt et al in a Caucasian population was not observed in the present study. The -589T allele frequencies were similar between patients and control subjects (69% vs 69.3%) suggesting that this polymorphism can not be used as a genetic marker for GD susceptibility in Thais.