Clinical characteristics and treatment outcomes in acromegaly, a retrospective single-center case series from Thailand.

INTRODUCTION: acromegaly, an overproduction of growth hormone (GH), is associated with high rate of morbidity and mortality particularly in case of delayed in diagnosis and treatment. A wide variation of clinical presentations, treatment outcomes and morbidities have been reported. METHODS: a retrospective study was conducted to review clinical characteristics and treatment outcomes of patients with acromegaly treated in King Chulalongkorn Memorial Hospital, Bangkok, Thailand, between 2006 and 2018. RESULTS: eighty-four patients (31 males and 53 females) were reviewed, mean age at diagnosis was 45.7 ± 12.6 years (±SD), mean time of disease onset was 7.6 ± 6.4 years and mean follow-up period was 7.8 ± 5.3 years. The most common presenting symptoms were maxillofacial change (96.8%) and acral enlargement (94.7%). Hypertension (39.3%), diabetes mellitus (28.6%) and dyslipidemia (23.8%) were prevalent co-existing conditions. Four patients were identified having cancer at presentation; however, no additional malignancy was reported during the follow up. Most patients harbored macroadenomas, only 10 were found to have microadenomas. The outcomes of treatment were controlled disease in 70% of microadenoma and 64.9% of macroadenoma. Permanent loss of pituitary function was found in about 21.3% and there was one case reported of mortality. The logistic regression analysis for controlled disease outcome showed the IGF-I index after surgery was associated with controlled disease outcome with statistically significant result (P-value=0.006). CONCLUSION: our study offers descriptive clinical data of case series of acromegalic patients, which had favorable outcomes comparable with previous reports. In addition, IGF-I index after surgery is a predictive parameter for outcome of treatment.

Painful and non-painful diabetic polyneuropathy: Clinical characteristics and diagnostic issues.

Diabetic neuropathy (DN) is a common complication of diabetes and can be either painful or non-painful. It is challenging to diagnose this complication, as no biomarker or clear consensus on the clinical definition of either painful or non-painful DN exists. Hence, a hierarchical classification has been developed categorizing the probability of the diagnosis into: possible, probable or definite, based on the clinical presentation of symptoms and signs. Pain is a warning signal of tissue damage, and non-painful DN therefore represents a clinical and diagnostic challenge because it often goes unnoticed until irreversible nerve damage has occurred. Simple clinical tests seem to be the best for evaluation of DN in the general care for diabetes. Screening programs at regular intervals might be the most optimal strategy for early detection and interventions to possibly prevent further neuronal damage and to lower the economic burden of this complication.

DIFFERENCES IN MORTALITY BY EDUCATION LEVEL AMONG PATIENTS IN DIABETIC REGISTRY FOR THAILAND.

This study was conducted in order to determine the impact of education on mortality due cardiovascular, infectious and renal disease, and cancer among Thai diabetics using data from the Thailand diabetes registry cohort prospected and conducted between April 2003 and February 2006. The study population consisted of 9,370 registered diabetic patients attending ten diabetes clinics at tertiary medical centers in Bangkok and major provinces. The population was classified by education level: those who had not yet attained a bachelor's degree classified as having "lower education" (7,684: 82%) and those with a bachelor's degree or higher classified as having "higher education" (1,686:18%). The overall mortality rate among those in the higher education group was lower than those in the lower education group (8.9 vs 20.5 per 1,000 patient-years, respectively) with a hazard ratio (HR) of 0.43 (0.31-0.61). The higher education group also had lower mortality rates due to infectious disease [HR 0.10 (0.02-0.41)], renal disease [HR 0.24 (0.06-0.99)] and cardiovascular disease [HR 0.42 (0.22-0.80)]. There was no difference in cancer mortality between the two groups [HR 1.25 (0.74-2.11)].

Smoking and death in Thai diabetic patients: the Thailand Diabetic Registry cohort.

OBJECTIVE: To determine the impact of smoking and quit smoking on mortality rate. MATERIAL AND METHOD: This prospective cohort was a three-year follow-up of Thai Diabetes Registry project that registered 9,370 diabetic patients from 10 diabetic clinics in tertiary medical centers in Bangkok and major provinces between April 2003 and February 2006. RESULTS: The groups of 7,487 (80%), 1,315 (14%), and 568 (6%) patients were classified as non-smokers, ex-smokers, and current smokers. The crude death rate of ex-smokers (Hazard Ratio (HR) 1.52 (95% CI 1.19-1.95)) and current smokers (HR 1.55 (1.10-2.19)) were higher than death rate of non-smokers. After control for covariates, the HR comparing ex-smokers with non-smokers was not different (1.10 (0.81-1.50)), while the HR comparing current smokers with non-smokers remained statistical significant (1.74 (1.17-2.61)). CONCLUSION: Smoking increases mortality rate in diabetic patients by about 74%. Quitting smoking decreased mortality rate to the same rate as of diabetic non-smokers.

NAFLD fibrosis score: a prognostic predictor for mortality and liver complications among NAFLD patients.

AIM: To study whether the severity of liver fibrosis estimated by the nonalcoholic fatty liver disease (NAFLD) fibrosis score can predict all-cause mortality, cardiac complications, and/or liver complications of patients with NAFLD over long-term follow-up. METHODS: A cohort of well-characterized patients with NAFLD diagnosed during the period of 1980-2000 was identified through the Rochester Epidemiology Project. The NAFLD fibrosis score (NFS) was used to separate NAFLD patients with and without advanced liver fibrosis. We used the NFS score to classify the probability of fibrosis as < -1.5 for low probability, > -1.5 to < 0.67 for intermediate probability, and > 0.67 for high probability. Primary endpoints included all-cause death and cardiovascular- and/or liver-related mortality. From the 479 patients with NAFLD assessed, 302 patients (63%) greater than 18 years old were included. All patients were followed, and medical charts were reviewed until August 31, 2009 or the date when the first primary endpoint occurred. By using a standardized case record form, we recorded a detailed history and physical examination and the use of statins and metformin during the follow-up period. RESULTS: A total of 302/479 (63%) NAFLD patients (mean age: 47 ± 13 year) were included with a follow-up period of 12.0 ± 3.9 year. A low probability of advanced fibrosis (NFS < -1.5 at baseline) was found in 181 patients (60%), while an intermediate or high probability of advanced fibrosis (NSF > -1.5) was found in 121 patients (40%). At the end of the follow-up period, 55 patients (18%) developed primary endpoints. A total of 39 patients (13%) died during the follow-up. The leading causes of death were non-hepatic malignancy (n = 13/39; 33.3%), coronary heart disease (CHD) (n = 8/39; 20.5%), and liver-related mortality (n = 5/39; 12.8%). Thirty patients had new-onset CHD, whereas 8 of 30 patients (27%) died from CHD-related causes during the follow-up. In a multivariate analysis, a higher NFS at baseline and the presence of new-onset CHD were significantly predictive of death (OR = 2.6 and 9.2, respectively; P < 0.0001). Our study showed a significant, graded relationship between the NFS, as classified into 3 subgroups (low, intermediate and high probability of liver fibrosis), and the occurrence of primary endpoints. The use of metformin or simvastatin for at least 3 mo during the follow-up was associated with fewer deaths in patients with NAFLD (OR = 0.2 and 0.03, respectively; P < 0.05). Additionally, the rate of annual NFS change in patients with an intermediate or high probability of advanced liver fibrosis was significantly lower than those patients with a low probability of advanced liver fibrosis (0.06 vs 0.09, P = 0.004). The annual NFS change in patients who died was significantly higher than those in patients who survived (0.14 vs 0.07, P = 0.03). At the end of the follow-up, we classified the patients into 3 subgroups according to the progression pattern of liver fibrosis by comparing the NFS at baseline to the NFS at the end of the follow-up period. Most patients were in the stable-fibrosis (60%) and progressive-fibrosis (37%) groups, whereas only 3% were in the regressive fibrosis. CONCLUSION: A higher NAFLD fibrosis score at baseline and a new onset of CHD were significantly predictive of death in patients with NAFLD.

Thailand Diabetic Registry cohort: predicting death in Thai diabetic patients and causes of death.

INTRODUCTION: The prevalence of type 2 diabetes in Thailand is 9.8 percent which is double the number forecast by World Health Organization. There is inadequate information to statistically represent all Thai diabetic patients for their causes of death. OBJECTIVE: To determine the clinical characteristics that predicted death and causes of death in Thai diabetic patients. MATERIAL AND METHOD: This prospective cohort was a 3-year follow-up study of the Thai Diabetes Registry project done between April, 2003, and February, 2006, which registered 9,419 diabetic patients attending 11 diabetic clinics in tertiary medical centers in Bangkok and major provinces of Thailand. The dead or alive status (99.5%) was determined. The causes of death were defined by reviewing the medical records. RESULTS: Of the 9,370 diabetic patients registered, 425 patients died, 1.84 percent per year. There was an increased risk of death associated with age, type of healthcare plan, lower education, insulin use, smoking, history of coronary artery disease and cerebrovascular disease, serum creatinine and high HbA1c. Lipid-lowering medication and metformin decreased the risk of death. Cardiovascular disease, infection and cancer were the prevalent causes of death. CONCLUSION: The present study showed risk factors that influenced death and causes of death in Thai diabetics.

A novel germline mutation, IVS4+1G>A, of the POU1F1 gene underlying combined pituitary hormone deficiency.

BACKGROUND: POU1F1 is a pituitary transcription factor that plays a pivotal role in pituitary development and expression of the GH, PRL and TSH beta genes. Therefore, abnormalities of the POU1F1 gene are known to be responsible for a phenotype causing combined pituitary hormone deficiency (CPHD) involving growth hormone, prolactin and thyrotropin. METHODS: We described an 18-year-old Thai man, from a consanguineous family, who presented with short stature and cognitive deficit. He underwent endocrinological and molecular investigations. RESULTS: Hormonal studies showed that the patient had GH deficiency and secondary hypothyroidism, consistent with CPHD. Direct DNA sequencing revealed a novel homozygous mutation at the splice site of exon 4, IVS4+1G>A. It is the first splice site mutation in the POU1F1 gene described to date. Of the 7 other family members studied for this mutation by restriction enzyme digestions, 5 were heterozygous. They were all unaffected, suggesting a recessive pattern of inheritance. CONCLUSIONS: We described a novel POU1F1 splice site mutation, IVS4+1G>A, the first of its kind, in a Thai patient with CPHD. Recessive inheritance is suggested. We also noted preventable morbidities which resulted from delay in diagnosis of concomitant pituitary hormone defects in newborns suspected of CPHD.

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.

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.

Early detection of endothelial injury and dysfunction in conjunction with correction of hemodynamic maladjustment can effectively restore renal function in type 2 diabetic nephropathy.

This paper was aimed to investigate (1) the early marker of endothelial injury in type 2 diabetes, (2) the intrarenal hemodynamics and renal function, and (3) the therapeutic strategy aiming to restore renal function. Fifty patients (35 normoalbuminuric and 15 albuminuric type 2 diabetes) were examined. Blood was collected for determination of circulating vascular endothelial cells (CEC) and the serum was prepared for determination of transforming growth factor beta (TGFbeta), ratio of CEC/TGFbeta, and soluble vascular cell adhesion molecule. Intrarenal hemodynamics and renal function were also assessed. The results showed that increased number of circulating EC, elevated TGFbeta and depleted ratio of CEC/TGFbeta were significantly observed. Intrarenal hemodynamic study revealed a hemodynamic maladjustment characterized by preferential constriction of the efferent arteriole, intraglomerular hypertension and reduction in peritubular capillary flow. It was concluded that early marker of endothelial injury is reflected by increasing number of CEC. Such markers correlate with the glomerular endothelial dysfunction associated with hemodynamic maladjustment. Early detection of endothelial injury and appropriate correction of hemodynamic maladjustment by multidrug vasodilators can effectively restore renal function in type 2 diabetic nephropathy.

Thailand diabetes registry project: prevalence of diabetic retinopathy and associated factors in type 1 diabetes mellitus.

OBJECTIVE: To determine the prevalence and factors associated with Diabetic Retinopathy (DR) of type 1 diabetes mellitus in Thailand. MATERIAL AND METHOD: A cross-sectional, multicenter hospital-based study was carried out from April to December 2003. Diabetic patients in diabetic clinics of 11 tertiary centers were registered. Retinopathy was evaluated by the ophthalmologists. RESULTS: Seven thousand one hundred and ni neteen diabetic patients received retinal examination. The number of patients with type 1 diabetes was 347. The prevalence of DR in type 1 diabetes was 21.6% (75). This consisted of Non-Proliferative DR (NPDR) 10.9% (38) and Proliferative DR (PDR) 10.7%. Patients with DR were significantly older, predominantly female, longer duration ofdiabetes, had higher BMI, systolic Blood Pressure (BP), diastolic BP serum creatinine, and TriGlycerides (TG) levels than those without DR. Both groups ofpatients were not different in term ofplasma glucose and glycosylated hemoglobin levels. Although the patients with DR had a higher percentage of overt proteinuria than those without DR, there was no difference in percentage of patients with positive microalbuminuria in both groups. This may be explained by limitation of data (only 16% had results of microalbuminuria and 19% had results of proteinuria). After adjusted for duration of diabetes, serum creatinine and smoking status, factors (adjusted odds ratio [95% confidence interval]) associated with DR were duration of diabetes 5-9.9 years (4.0 [1.49-10.91]), 10-14.9 years (6.86 [2.45-19.20]), 15-19.9 years (21.13 [7.22-61.78]), > or =20 years (22.15 [7.32-66.99]) when compared with duration of diabetes less than 5 years, serum creatinine >2 mg/dl (6.0 [2.09-17.22]) when compared with creatinine less than 2 mg/dl. From the presented model, age, gender, systolic BP >140 mmHg, diastolic BP >90 mmHg, serum TG and smoking status were not factors associated with DR. CONCLUSION: Diabetic retinopathy affects about one fifth of type 1 diabetic patients in our study. The authors found the factors associated with DR in type 1 DM were duration of diabetes and serum creatinine. Regular screening for DR and more aggressive management of metabolic factors should be done to reduce the prevalence ofDR.

Thailand diabetes registry project: prevalence, characteristics and treatment of patients with diabetic nephropathy.

OBJECTIVES: To identify the prevalence and characteristics of patients with Diabetic Nephropathy (DN) and to evaluate adequacy of glycemic and blood pressure control of these patients in the authors' registry. MATERIAL AND METHOD: A cross-sectional, multicenter, hospital-based diabetic registry was carried out in diabetes clinics of 11 tertiary centers in Thailand. DN was defined as the presence of at least two out of three of these symptoms; positive microalbuminuria, positive dipstick proteinuria or creatinine levels equal to or greater than 2 mg/dl. One center that did not perform urine microalbumin measurement was excludedfrom the analysis. Overt nephropathy was defined as the presence of gross proteinuria or renal insufficiency. RESULTS: The study included 4875 patients (females 63.8%) with a mean (SD) duration ofdiabetes of 12.8 (8.2) years. The prevalence of DN was 42.9% (microalbuminuria 19.7% and overt nephropathy 23.2%). There were 373 (7.7%) patients with renal insufficiency and 24 (0.47%) with end-stage renal disease. By multivariate analysis, factors associated with DN were age, duration of diabetes, male sex, smoking, blood pressure, HbA1c, dyslipidemia and presence of diabetic retinopathy. Prevalence of ischemic heart disease and cerebrovascular disease in patients with DN was 11.5% and 6.6% respectively. Mean (SD) HbA1c in patients with nephropathy was 8.2 (2.6)%. Only 25% of subject had HbA1c of less than 7%, 46% had blood pressure ofmore than 140/90 mmHg and 84% received at least one antihypertensive drug. However, the target blood pressure of less than 130/80 mmHg could be achieved in only 18% of these patients. The mean (SD) number of antihypertensive drugs was 1.7 (1.1). Nearly 60% of patients received either ACE inhibitors or ARBs. CONCLUSION: DN was very common. The overall picture of DN in the present survey suggests the seriousness of the problem and prompts more aggressive intervention.

Thailand diabetes registry project: prevalence and risk factors of stroke in thai diabetic patients.

OBJECTIVE: To determine the prevalence of stroke and its risk factors in Thai diabetic patients who attended the diabetes clinics of university and tertiary-care hospitals. MATERIAL AND METHOD: A cross-sectional, multi-center hospital-based diabetes registry was carried out at diabetes clinics of 11 university and tertiary-care hospitals. Demographic data, clinical characteristics, common drugs used and laboratory parameters were analyzed for prevalence and risk factors associated with stroke. RESULTS: The prevalence of stroke in the patients studied was 3.5%. Most of the patients were type 2 diabetes and had ischemic stroke. One of the risk factors associated with stroke was age greater than 60 years, and the risk appeared to be highest if the patients' age was greater than 70 years (adjust OR = 3.29, p = 0.012). Other risk factors included male sex, systolic blood pressure of > or =140 mmHg, use of oral hypoglycemic agents, lipid lowering agents and aspirin. There was no association between stroke and duration of diabetes, occupation, educational level, BMI, smoking, alcohol drinking, diastolic blood pressure, use of antihypertensive drugs or insulin, glycemic control, lipid profiles and kidney function. CONCLUSION: Ischemic stroke was common among Thai patients with diabetes especially in the elderly. The present result emphasizes the relationship between level of systolic blood pressure and the occurrence of stroke. Optimal blood pressure control should be underscored in caring for diabetic patients.

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 novel germline mutation, 1793delG, of the MEN1 gene underlying multiple endocrine neoplasia type 1.

Pulmonary carcinoids are rare neuroendocrine tumors which comprise 1-2% of all lung tumors. They usually occur sporadically; however, their association with multiple endocrine neoplasia type 1 (MEN1) syndrome has been documented. We report a case of a Thai woman with a pulmonary carcinoid tumor and a null cell pituitary tumor. Her family history was unremarkable for any MEN-related lesions. Genetic testing revealed a novel deletion mutation at exon 10 (1793delG) of the MEN1 gene, resulting in a stop codon 26 amino acids downstream. This mutation is predicted to cause a loss of the second nuclear localization signal of the menin protein.

Comparing the effect of short term post meals and bedtime calcium supplementation on the C-terminal telopeptide crosslinks and PTH levels in postmenopausal osteopenic women.

BACKGROUND: Calcium supplement for postmenopausal osteopenic women can significantly reduce bone loss and the risk of fractures. However, the optimal time for calcium supplementation remains controversial. OBJECTIVE: The aim of the present study was to compare the effect of twice daily post meals and bedtime calcium supplementation for a two week periods, on C-terminal telopeptide crosslinks and PTH levels in postmenopausal osteopenic women. DESIGN: A randomized double blind placebo-control, crossover design, was carried out on 3 consecutive periods 3 of a 2-week treatment regimen. In the first period, all the subjects randomly received either two calcium carbonate tablets (Chalk Cap all subjects randomly received either two calcium 334 mg per tab) or placebo at bedtime with one tablet of calcium tablet or placebo after breakfast and dinner for two weeks. In the second period, subjects received only placebo tablets after the meals and at bedtime for 2 weeks. In the third period subjects received either calcium carbonate or placebo for another two weeks. The C-terminal telopeptide crosslinks were measured at 8.00 am and serum PTH were sampled at 8 time points (12.00 am, 2.00 am, 4.00 am, 6.00 am, 8.00 am, 9.00 am, 5.00 pm, and 7.00 pm respectively by the end of each study at the first and third period. RESULTS: The present study showed thirty-six postmenopausal subjects (mean age 63.9 + 3.66 years) participated in the present study. The mean T-score BMD of the spine and hip were -2.96 + 0.87 and -2.96 + 0.77 gm/cm2. C-terminal telopeptide crosslinks levels of the bedtime supplementation were significantly lower than the post meal supplementation (0.228 + 0.002 ng/ml vs 0.313 + 0.003 ng/ml, p < 0.001). The mean night time serum PTH level during the bedtime was significantly lower than the post meal period. (25.17 + 2.31 pg/ml vs 31.930 + 2.677 pg/ml, p < 0.001). No differences in the post meal PTH level between two periods were observed CONCLUSION: The bedtime calcium supplementation appeared to reduce the bone resorption marker and night time serum PTH levels greater than the post meal calcium supplementation in this short term period study. However, long term comparison may be needed.