Locoregional Therapy Protocols With and Without Radioembolization for Hepatocellular Carcinoma as Bridge to Liver Transplantation.

OBJECTIVE: The objective of this study was to compare posttransplant outcomes in patients undergoing bridging locoregional therapy (LRT) with Y-90 transarterial radioembolization (TARE) based protocol compared with transarterial chemoembolization based protocol for hepatocellular carcinoma (HCC) prior liver transplantation (LT). MATERIALS AND METHODS: Patients listed for LT with HCC within the Milan criteria at our center who had bridging LRT were treated according to transarterial chemoembolization (TACE) based protocol from May 2012 to April 2014 and a TARE based protocol from October 2014 to December 2017. Early posttransplant survival and tumor recurrence were compared between the groups. Tumor response to LRT, microvascular invasion (mVI), and the rate of delisting was also evaluated. RESULTS: One hundred three patients who were listed for LT with HCC within the Milan criteria received LRT. LT was performed in 65 patients, 28 treated with TARE protocol and 37 on TACE protocol. There were no statistical differences in baseline pretransplant characteristics and tumor recurrence. There was a trend toward improved 3-year survival in the TARE group (92.9% vs. 75.7%; P=0.052). The mVI was seen in 1/28 (3.6%) explants in the TARE group compared with 10/37 (27%) in the TACE group (P=0.013). The TARE group also required fewer LRT treatments (1.46 vs. 2.43; P=0.001) despite no difference in time on the transplant list. CONCLUSIONS: Despite requiring fewer LRT treatments, there was significantly less mVI in the explants of patients treated with TARE protocol LRT as a bridge to LT as well as a trend toward improved 3-year survival. Therefore, TARE may be associated with improved tumor control and reduced post-LT recurrence.

Role of Vitamin E for Nonalcoholic Steatohepatitis in Patients With Type 2 Diabetes: A Randomized Controlled Trial.

OBJECTIVE: While vitamin E has shown to improve nonalcoholic steatohepatitis (NASH) in patients without diabetes, information on patients with type 2 diabetes mellitus (T2DM) is lacking. The aim of this study was to determine whether vitamin E, alone or combined with pioglitazone, improves histology in patients with T2DM and NASH. RESEARCH DESIGN AND METHODS: This was a proof-of-concept, randomized, double-blind, placebo-controlled trial conducted from 2010 to 2016. Patients with T2DM and biopsy-proven NASH (n = 105) were randomized to vitamin E 400 IU b.i.d., vitamin E 400 IU b.i.d. plus pioglitazone 45 mg/day, or placebo. Eighty-six patients completed the 18-month study. The primary end point was a two-point reduction in the nonalcoholic fatty liver disease activity score from two different parameters, without worsening of fibrosis. Secondary outcomes were resolution of NASH without worsening of fibrosis, individual histological scores, and metabolic parameters. RESULTS: More patients on combination therapy achieved the primary outcome versus placebo (54% vs. 19%, P = 0.003) but not with vitamin E alone (31% vs. 19%, P = 0.26). Both groups showed improvements in resolution of NASH compared with placebo (combination group: 43% vs. 12%, P = 0.005; vitamin E alone: 33% vs. 12%, P = 0.04). While steatosis assessed by histology improved with combination therapy (P < 0.001) and vitamin E alone (P = 0.018), inflammation (P = 0.018) and ballooning (P = 0.022) only improved with combination therapy. No improvement in fibrosis was observed in any group. CONCLUSIONS: In this proof-of-concept study, combination therapy was better than placebo in improving liver histology in patients with NASH and T2DM. Vitamin E alone did not significantly change the primary histological outcome.

Hematochezia: An Uncommon Presentation of Colonic Tuberculosis.

Abdominal tuberculosis (TB) is an uncommon entity in the United States. Colonic TB is reported in 2-3% of patients with abdominal TB. It is frequently misdiagnosed as Crohn's disease or carcinoma of the colon due to their shared clinical, radiographic, and endoscopic presentations. We present a case of a 72-year-old male with colonic tuberculosis presenting as hematochezia. Our patient presented with shortness of breath and weight loss. Chest X-ray demonstrated ill-defined bilateral parenchymal opacities in the perihilar, mid, and lower lung zones. The patient was diagnosed and treated for community acquired pneumonia, with no improvement. Hematochezia complicated by symptomatic hypotension developed later in the course of admission. Colonoscopy revealed multiple ulcers at the anus and transverse and ascending colon as well as the cecum with stigmata of bleeding. Biopsy of a sigmoid ulcer was consistent with colonic tuberculosis. Antitubercular therapy was initiated, but the patient passed away secondary to multiorgan failure 29 days into admission.

Metabolic and histological implications of intrahepatic triglyceride content in nonalcoholic fatty liver disease.

The cut-off point of intrahepatic triglyceride (IHTG) content to define nonalcoholic fatty liver disease (NAFLD) by proton magnetic resonance spectroscopy (1 H-MRS) was established based on the 95th percentile in a group of healthy individuals (i.e., ≥5.56%). Whether this threshold correlates with metabolic and histological changes and whether a further accumulation of IHTG is associated with worsening of these parameters has not been properly assessed in a large cohort of patients. In this cross-sectional study, 352 subjects were carefully characterized with the following studies: liver 1 H-MRS; euglycemic insulin clamp with measurement of glucose turnover; oral glucose tolerance test; and a liver biopsy. Hepatic insulin sensitivity (suppression of endogenous glucose production by insulin) was affected early on after IHTG content was ∼1.5% and remained uniformly impaired (∼40%-45%), regardless of further IHTG accumulation. Skeletal muscle insulin sensitivity showed a gradual impairment at low degrees of IHTG accumulation, but remained unchanged after IHTG content reached the ∼6 ± 2% threshold. A similar pattern was observed for metabolic changes typically associated with NAFLD, such as hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C). In contrast, adipose tissue insulin sensitivity (suppression of free fatty acids by insulin) showed a continuous worsening across the spectrum of IHTG accumulation in NAFLD (r = -0.38; P < 0.001). Histological severity of liver disease (inflammation, ballooning, and fibrosis) was not associated with the amount of IHTG content. CONCLUSION: IHTG accumulation is strongly associated with adipose tissue insulin resistance (IR), supporting the current theory of lipotoxicity as a driver of IHTG accumulation. Once IHTG accumulation reaches ∼6 ± 2%, skeletal muscle IR, hypertriglyceridemia, and low HDL-C become fully established. Histological activity appears to have an early threshold and is not significantly influenced by increasing amounts of IHTG accumulation. (Hepatology 2017;65:1132-1144).

Metabolic Impact of Nonalcoholic Steatohepatitis in Obese Patients With Type 2 Diabetes.

OBJECTIVE: Nonalcoholic steatohepatitis (NASH) is increasingly common in obese patients. However, its metabolic consequences in patients with type 2 diabetes mellitus (T2DM) are unknown. RESEARCH DESIGN AND METHODS: We studied 154 obese patients divided in four groups: 1) control (no T2DM or NAFLD), 2) T2DM without NAFLD, 3) T2DM with isolated steatosis, and 4) T2DM with NASH. We evaluated intrahepatic triglycerides by proton MRS ((1)H-MRS) and assessed insulin secretion/resistance during an oral glucose tolerance test and a euglycemic-hyperinsulinemic clamp with glucose turnover measurements. RESULTS: No significant differences among groups were observed in sex, BMI, or total body fat. Metabolic parameters worsened progressively with the presence of T2DM and the development of hepatic steatosis, with worse hyperinsulinemia, insulin resistance, and dyslipidemia (hypertriglyceridemia and low HDL cholesterol) in those with NASH (P < 0.001). Compared with isolated steatosis, NASH was associated with more dysfunctional and insulin-resistant adipose tissue (either as insulin suppression of plasma FFA [33 ± 3 vs. 48 ± 6%] or adipose tissue insulin resistance index [9.8 ± 1.0 vs. 5.9 ± 0.8 mmol/L ⋅ µIU/mL]; both P < 0.03). Furthermore, insulin suppression of plasma FFA correlated well with hepatic steatosis (r = -0.62; P < 0.001) and severity of steatohepatitis (rs = -0.52; P < 0.001). Hepatic insulin sensitivity was also more significantly impaired among patients with T2DM and NASH, both fasting and with increasing insulin levels within the physiological range (10 to 140 µIU/mL), compared with other groups. CONCLUSIONS: In obese patients with T2DM, the presence of NAFLD is associated with more severe hyperinsulinemia, dyslipidemia, and adipose tissue/hepatic insulin resistance compared with patients without NAFLD. The unfavorable metabolic profile linked to NAFLD should prompt strategies to identify and treat this population early on.

Plasma thyroid hormone concentration is associated with hepatic triglyceride content in patients with type 2 diabetes.

The underlying mechanisms responsible for the development and progression of non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM) are unclear. Since the thyroid hormone regulates mitochondrial function in the liver, we designed this study in order to establish the association between plasma free T4 levels and hepatic triglyceride accumulation and histological severity of liver disease in patients with T2DM and NAFLD. This is a cross-sectional study including a total of 232 patients with T2DM. All patients underwent a liver MR spectroscopy ((1)H-MRS) to quantify hepatic triglyceride content, and an oral glucose tolerance test to estimate insulin resistance. A liver biopsy was performed in patients with a diagnosis of NAFLD. Patients were divided into 5 groups according to plasma free T4 quintiles. We observed that decreasing free T4 levels were associated with an increasing prevalence of NAFLD (from 55% if free T4≥1.18 ng/dL to 80% if free T4<0.80 ng/dL, p=0.016), and higher hepatic triglyceride accumulation by (1)H-MRS (p<0.001). However, lower plasma free T4 levels were not significantly associated with more insulin resistance or more severe liver histology (ie, inflammation, ballooning, or fibrosis). Decreasing levels of plasma free T4 are associated with a higher prevalence of NAFLD and increasing levels of hepatic triglyceride content in patients with T2DM. These results suggest that thyroid hormone may play a role in the regulation of hepatic steatosis and support the notion that hypothyroidism may be associated with NAFLD. No NCT number required.

Hepatic Steatosis and Insulin Resistance, But Not Steatohepatitis, Promote Atherogenic Dyslipidemia in NAFLD.

CONTEXT: Patients with nonalcoholic fatty liver disease (NAFLD) are at increased risk of cardiovascular disease, and atherogenic lipoproteins may play an important role. OBJECTIVE: The objective of the study was to determine the contribution of the severity of steatohepatitis to atherogenic dyslipidemia in patients with NAFLD. DESIGN: This was a cross-sectional study. SETTING: The study was conducted at a university hospital. PATIENTS: Patients were recruited from outpatient clinics or from the general population (n = 188). INTERVENTIONS: Measurement of hepatic triglyceride content by magnetic resonance spectroscopy, histology (liver biopsy), metabolic profile by means of an oral glucose tolerance test, and lipoprotein analyses were performed. OUTCOMES: Outcomes measured included standard lipids, lipoprotein subfraction analysis (apolipoprotein B/A1 levels, low-density lipoprotein (LDL) particle size/phenotype, and LDL/high-density lipoprotein subfractions), and insulin resistance. RESULTS: Patients with NAFLD had severe insulin resistance, especially at the level of the adipose tissue, when compared with patients without NAFLD. Despite small differences in triglycerides and high-density lipoprotein-cholesterol, patients with NAFLD had a significantly higher plasma apolipoprotein B to apolipoprotein A1 ratio (0.66 ± 0.02 vs 0.58 ± 0.02, P = .01) and smaller LDL particle size (216.2 ± 0.7 vs 219.4 ± 1.1 Å, P = .01). Of note, these differences between patients with/without NAFLD were independent of the presence of obesity. Severity of steatohepatitis did not significantly influence the lipoprotein profile. Worse atherogenic dyslipidemia was best predicted by the degree of liver fat accumulation and adipose tissue and systemic insulin resistance. CONCLUSIONS: NAFLD was associated with a worse atherogenic lipoprotein profile, regardless of similar body mass index and other clinical parameters. We speculate that this lipoprotein profile is driven mostly by liver fat content and insulin resistance and appears not to be worsened by obesity or the severity of liver disease (nonalcoholic steatohepatitis).

The role of liver fat and insulin resistance as determinants of plasma aminotransferase elevation in nonalcoholic fatty liver disease.

UNLABELLED: Plasma aminotransferases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) are usually increased in patients with nonalcoholic fatty liver disease (NAFLD). However, the factors behind their elevation remain unclear. The aim of this study was to assess the role of insulin resistance (IR) and liver triglyceride content in relation to histology in patients with NAFLD/nonalcoholic steatohepatitis (NASH) with normal or elevated ALT levels. To this end, we enrolled 440 patients, divided into three groups: no NAFLD (n = 60); NAFLD with normal ALT (n = 165); and NAFLD with elevated ALT (n = 215). We measured: (1) liver fat by proton magnetic resonance spectroscopy ((1)H-MRS); (2) severity of liver disease by biopsy (n = 293); and (3) insulin sensitivity in liver, muscle, and adipose tissue by a euglycemic hyperinsulinemic clamp with 3-(3)H-glucose. Patients with NAFLD and elevated ALT, even when well matched for body mass index to those with normal ALT, had worse adipose tissue insulin resistance (ATIR; P < 0.0001), higher liver triglyceride content (P < 0.0001), and lower plasma adiponectin (P < 0.05), but no differences in hepatic insulin resistance. Similar results were found when only patients with NASH were compared: both ATIR (P < 0.0001) and liver triglyceride content by (1)H-MRS (P < 0.0001) were worse in NASH with elevated ALT. Consistent with the (1)H-MRS data, steatosis on liver biopsy was also significantly increased in patients with NASH and elevated ALT levels (P < 0.0001). However, and most important, there were no differences in inflammation (P = 0.62), ballooning (P = 0.13), or fibrosis (P = 0.12). CONCLUSION: In patients with NAFLD or NASH, ATIR (but not HIR) and liver triglyceride content are major factors in the elevation of plasma aminotransferase levels. Patients with normal versus elevated ALT had similar severity of NASH, suggesting that plasma aminotransferase levels are misleading parameters for guiding clinical management.

Relationship of vitamin D with insulin resistance and disease severity in non-alcoholic steatohepatitis.

BACKGROUND & AIMS: The role of plasma vitamin D deficiency in the development of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) remains poorly understood. Previous studies have suggested a role for vitamin D deficiency in the pathogenesis of NAFLD/NASH, but they have been rather small, and/or NAFLD was diagnosed using only aminotransferases or liver ultrasound. This study aimed to assess the role of vitamin D deficiency in relationship to liver fat accumulation and severity of NASH. METHODS: A total of 239 patients were recruited and state-of-the-art techniques were used to measure insulin resistance (euglycemic insulin clamp with 3-(3)H-glucose), liver fat accumulation (magnetic resonance spectroscopy or (1)H-MRS), total body fat (dual energy X-ray absorptiometry), and severity of liver disease (liver biopsy). RESULTS: Patients were divided into 3 groups according to plasma 25-hydroxyvitamin D levels (normal: >30 ng/ml; insufficiency: 20-30 ng/ml; deficiency: <20 ng/ml). When well-matched for clinical parameters (BMI, total adiposity, or prevalence of prediabetes/type 2 diabetes), no significant differences were observed among groups in terms of skeletal muscle, hepatic, or adipose tissue insulin sensitivity, the amount of liver fat by (1)H-MRS, or the severity of histological inflammation, ballooning, or fibrosis. Patients were then divided according to liver histology into those with definite NASH and those without NASH. Although patients with NASH had higher insulin resistance, plasma vitamin D concentrations were similar between both groups. CONCLUSIONS: Our results suggest that plasma vitamin D levels are not associated with insulin resistance, the amount of liver fat accumulation, or the severity of NASH.

Neutrophil-lymphocyte ratio predicts overall and recurrence-free survival after liver transplantation for hepatocellular carcinoma.

AIM: The goal of this study is to evaluate whether an elevated neutrophil-lymphocyte ratio (NLR) at the time of diagnosis predicts survival of patients with hepatocellular carcinoma (HCC) after liver transplantation (LT). We hypothesize that the NLR is predictive of overall survival (OS) and recurrence-free survival (RFS) in patients with HCC who undergo LT. METHODS: This is a retrospective analysis of adult patients undergoing LT for HCC between 2000 and 2008 at our institution. We define an elevated NLR as a ratio of 5 or greater. RESULTS: We included 160 patients who underwent LT for HCC in the time period, of whom 28 had an elevated NLR. Seventeen subjects experienced recurrent HCC during the study period. The cumulative survival among subjects with an elevated NLR was significantly lower than among subjects with a normal NLR. On univariate analysis, several factors (including an elevated NLR) predicted decreased OS and RFS. However, after multivariate analysis, only three factors (including elevated NLR) remained significant as predictors of OS. Additionally, multivariate analysis revealed that an elevated NLR was the only significant independent predictor of RFS. CONCLUSION: Preoperative NLR is a powerful independent predictor of OS and RFS in patients undergoing LT for HCC. Measurement of NLR could serve as a useful and easily obtained adjunct to the Model for End-Stage Liver Disease score and Milan criteria when evaluating this patient population and determining which patients will gain the most survival benefit from transplantation.

Safety of cardiac surgery for patients with cirrhosis and Child-Pugh scores less than 8.

BACKGROUND & AIMS: Advanced liver disease is a significant risk factor for perioperative complications after cardiac surgery. However, no published studies have adjusted the observed outcomes for other well-known, non-liver-related factors that affect mortality. We evaluated the effects of cirrhosis on operative mortality and morbidity after cardiac surgery, after adjusting for nonrelated risk factors associated with liver disease. METHODS: We analyzed data from patients with cirrhosis who underwent cardiac surgery with cardiopulmonary bypass from 1992 to 2009 (n = 54). Patients who underwent cardiac surgery at the same institution were identified during the same time period and matched 1:4 by using propensity score matching (controls, n = 216). Child-Pugh (CP) class and score were calculated for the patients with cirrhosis. Mortality and morbidity were determined after 30 and 90 days. RESULTS: Within 90 days, 4.6% of patients with CP score <8 and 70% of patients with CP score ≥ 8 died (P < .017). Mortality of patients with CP score <8 was comparable to that of matched controls. Patients with CP scores <8 had significantly shorter average length of hospital stay (15.6 vs 26 days; P < .017) and were less likely to develop renal failure (P < .017) and require dialysis (P < .017) than patients with CP scores ≥ 8; these values were similar between patients with CP scores <8 and their matched controls. CONCLUSIONS: After adjusting for non-liver-related risk factors, patients with compensated cirrhosis (defined by CP score <8) can undergo cardiac surgery with cardiopulmonary bypass with no significant increases in postoperative mortality and morbidity. For this group of patients, comorbidities, rather than liver failure, appear to account for the occasional death.

Randomized, controlled trial of standard, large-capacity versus jumbo biopsy forceps for polypectomy of small, sessile, colorectal polyps.

BACKGROUND: Polypectomy with cold biopsy forceps is a frequently used technique for removal of small, sessile, colorectal polyps. Jumbo forceps may lead to more effective polypectomy because of the larger size of the forceps cup. OBJECTIVE: To evaluate the efficiency of cold jumbo biopsy forceps compared with standard forceps for polypectomy of small, sessile, colorectal polyps. DESIGN: Randomized, controlled trial. SETTING: Outpatient endoscopy center. PATIENTS: This study involved 140 patients found to have at least one eligible polyp defined as a sessile polyp measuring ≤6 mm. INTERVENTION: Polypectomy with cold biopsy forceps. MAIN OUTCOME MEASUREMENTS: Complete visual polyp eradication with one forceps bite. RESULTS: In 140 patients, a total of 305 eligible polyps were detected (151 removed with jumbo forceps and 154 with standard forceps). Complete visual eradication of the polyp with one forceps bite was achieved in 78.8% of the jumbo forceps group and 50.7% of the standard forceps group (P < .0001). Biopsies from the polypectomy sites of adenomatous polyps thought to be visually completely eradicated with one bite showed a trend toward a higher complete histologic eradication rate with the jumbo forceps (82.4%) compared with the standard forceps (77.4%), but the difference did not reach statistical significance (P = .62). The withdrawal time for visual inspection of the colon and time to perform polypectomies were significantly shorter in the jumbo forceps group (mean 21.43 vs 18.23 minutes; P = .02). LIMITATIONS: Lack of blinding to the type of forceps used. CONCLUSION: The jumbo biopsy forceps is superior to the standard forceps in removing small, sessile polyps. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT00855790.).

The use of cyclosporine for recurrent hepatitis C after liver transplant: a randomized pilot study.

BACKGROUND: Cyclosporine has antiviral activity in vitro against hepatitis C (HCV). We performed a pilot study to prospectively determine the antiviral effect of cyclosporine during therapy with PEGalfa-2a and ribavirin in liver transplant recipients with recurrent HCV infection. METHODS: Patients with HCV recurrence (Ishak Fibrosis Stage > or = 2) were enrolled for 2 years at the University of Florida. Thirty-eight patients were randomized to continued tacrolimus or switched to cyclosporine. Both groups received PEGalfa-2a and ribavirin. RESULTS: Twenty patients received tacrolimus and 18 cyclosporine, with a mean age of 53. Eighty-two percent were men, 84% Caucasian, and 90% genotype 1. In patients switched from tacrolimus to cyclosporine, HCVRNA levels decreased by a mean of 0.39 million IU/ml during the 1 month prior to initiating PEG/RBV. Sustained viral response for cyclosporine was higher than in patients on tacrolimus receiving PEG/RBV therapy. CONCLUSIONS: This randomized controlled pilot study is the first in vivo study evaluating cyclosporine versus tacrolimus in liver transplant recipients undergoing antiviral therapy. Change from tacrolimus to cyclosporine led to a modest HCV RNA drop and appeared to enhance the antiviral response of PEG/RBV. A larger randomized study is necessary to see if cyclosporine offers any advantage over tacrolimus.

Bouveret's syndrome: case report and review of the literature.

Bouveret's syndrome is defined as gastric outlet obstruction caused by duodenal impaction of a large gallstone which passes into the duodenal bulb through a cholecystogastric or cholecystoduodenal fistula. Initial attempts at endoscopic retrieval with or without mechanical or extracorporeal lithotripsy should be performed as first-line treatment, though success rates with endoscopic treatment are variable. We describe a case of Bouveret's Syndrome in an elderly patient that was successfully treated with endoscopic extraction combined with mechanical lithotripsy, and review the literature on this uncommon condition.

Assessing the risk of surgery in patients with liver disease.

Recent studies have defined objective criteria for determining whether surgery is safe for patients with liver disease. Using these criteria, we may extend the benefit of surgery to more patients with liver disease without increasing the risk.

Predicting outcome after cardiac surgery in patients with cirrhosis: a comparison of Child-Pugh and MELD scores.

BACKGROUND & AIMS: This study aims to quantify the risk of cardiac surgery in patients with cirrhosis. METHODS: Records of all adult patients with cirrhosis undergoing cardiac surgery using cardiopulmonary bypass at the Cleveland Clinic (Cleveland, OH) from January 1992 to June 2002 were analyzed for any relationship of Child-Pugh class and/or score and Model for End-Stage Liver Disease (MELD) score with outcome measures of hepatic decompensation and death during the first 3 months after surgery. RESULTS: Forty-four patients underwent coronary artery bypass grafting (16 patients), valve surgery (16 patients), a combination of the 2 procedures (10 patients), or pericardiectomy (2 patients). Twelve patients (27%) developed hepatic decompensation, and 7 patients (16%) died. Proportions of hepatic decompensation were 3 of 31, 8 of 12, and 1 of 1 patients, and death, 1 of 31, 5 of 12, and 1 of 1 patients in Child-Pugh classes A, B, and C, respectively. The association of hepatic decompensation and mortality with Child-Pugh class, Child-Pugh score, and MELD score was significant (P < 0.005). Areas under the receiver operating characteristic curves for mortality were similar for Child-Pugh (0.84 +/- 0.09) and MELD scores (0.87 +/- 0.09). A cutoff Child-Pugh score >7 was found to have a sensitivity and specificity of 86% and 92% for mortality, with a negative predictive value of 97% (95% confidence interval [CI], 83-99) and positive predictive value of 67% (95% CI, 31-91), respectively. However, a similar cutoff value for MELD score could not be established. CONCLUSIONS: Child-Pugh score and/or class and MELD score are significantly associated with hepatic decompensation and mortality after cardiac surgery using cardiopulmonary bypass in patients with cirrhosis. Such surgery can be conducted safely in patients with a Child-Pugh score /=8 have a significant risk for mortality.

SPINK1/PSTI mutations are associated with tropical pancreatitis and type II diabetes mellitus in Bangladesh.

BACKGROUND & AIMS: Tropical pancreatitis, including tropical calcific pancreatitis and fibrocalculous pancreatic diabetes, is endemic in parts of Asia and Africa. In a preliminary study, we found serine protease inhibitor, Kazal type 1 (SPINK1) mutations in 6 of 8 patients with fibrocalculous pancreatic diabetes in Bangladesh. A more extensive investigation of patients with pancreatic diseases in Bangladesh, including non-insulin-dependent diabetes mellitus, was undertaken. METHODS: Patients with fibrocalculous pancreatic diabetes (n = 22), tropical calcific pancreatitis (n = 15), and non-insulin-dependent diabetes mellitus (n = 43) and controls (n = 76) from Bangladesh were studied. DNA was extracted, and the SPINK1 gene was sequenced in all patients and 50 controls. Exon 3 was sequenced in an additional 26 controls. RESULTS: SPINK1 N34S mutations appeared in 1 of 76 controls (1.3%), 12 of 22 patients with fibrocalculous pancreatic diabetes (55%; odds ratio, 83; P < 0.00001), 3 of 15 with tropical calcific pancreatitis (20%; odds ratio, 11.2; P = 0.04), and 6 of 43 with non-insulin-dependent diabetes mellitus (14%; odds ratio, 11.9; P = 0.009). P55S was present in 2 of 76 controls (3%) and in 1 of 22 patients with fibrocalculous pancreatic diabetes (5%; P = not significant). A novel Y54H (160T>C) mutation was identified in 1 of 15 tropical calcific pancreatitis patients. CONCLUSIONS: In Bangladesh, the SPINK1 N34S mutation increases the risk of several forms of pancreatic disease, including fibrocalculous pancreatic diabetes, tropical calcific pancreatitis, and non-insulin-dependent diabetes mellitus.