Chronic Liver Disease and Metabolic Comorbidities in Healthy Young Males Followed for 65 Years: The Manitoba Follow-up Study.

BACKGROUND & AIMS: The prevalence of chronic liver disease (CLD) is largely derived from cross-sectional epidemiologic surveys. The goal of this long-term, prospective study was to document the lifetime risk of developing chronic liver disease and determine the impact of common metabolic conditions associated with metabolic syndrome (MetS) on the development and outcomes of CLD. METHODS: 3,983 air force men were enrolled in the Manitoba Follow-up Study in 1948. The comprehensive database on results of routine physicals and health encounters was examined for evidence of CLD and MetS. The joint relationship between CLD and components of MetS on mortality was examined using Cox proportional hazard model. RESULTS: In 65 follow-up years, 5.2% of men developed CLD and 6.4% MetS. Hypertension was the strongest predictor of CLD (HR 2.958, 95% CI - 2.065 to 4.236, p < .0001), followed by insulin resistance /diabetes mellitus (IR/DM) (2.008, 95% CI - 1.332 to 3.027, p = .0009) and obesity (1.958, 95% CI - 1.419 to 2.703, p < .0001). Relative to men without MetS comorbidities, an increasing gradient of risk for CLD was apparent with increasing numbers of MetS components; the HR of 3.67, 5.97 and 14.3 for IR/DM, IR/DM + one component, and IR/DM + two or more components respectively. The relative risk of mortality in men with vs. without CLD was 3.33 (95% CI - 2.83 to 3.91, p < .0001) and 1.505 (95% CI - 1.31 to 1.73, p < .0001) in men with vs. without MetS. CONCLUSIONS: CLD and MetS independently increase the relative risk of mortality; the magnitude of the effect is greater in CLD.

Spontaneous Flares of Chronic Hepatitis B Virus in Hepatitis Be Antigen Negative Carriers Who Subsequently Clear Hepatitis B Surface Antigen.

BACKGROUND: Acute exacerbations of chronic hepatitis B virus (HBV) infections can occur in HBV-infected, hepatitis e antigen (HBeAg)-negative patients in the absence of recent withdrawal of antiviral or immunosuppressive therapies. Whether these spontaneous "flares" predict subsequent loss of hepatitis B surface antigen (HBsAg) has yet to be determined. OBJECTIVES: To document the percent of patients who experience spontaneous HBV flares and severity of the flares in chronic HBeAg-negative carriers. METHODS: A retrospective review of an HBV database identified and followed HBeAg-negative patients for biochemical evidence of flares (ALT > 5× normal) and subsequent HBsAg status. Patients that subsequently cleared HBsAg were matched 1:1 with those who remained HBsAg positive. RESULTS: Of 1299 HBeAg-negative patients followed for 10.2 ± 6.1 years, 88 (6.8%) developed spontaneous HBV flares. Flares occurred in 14/115 (12.2%) patients who subsequently cleared HBsAg and 4/111 (3.6%) matched patients who remained HBsAg positive (p = 0.025). The severity of flares was similar in the two study cohorts. Following multivariate analyses, only low HBV-DNA levels at baseline identified patients likely to subsequently clear HBsAg. CONCLUSIONS: Although more common in patients who subsequently clear HBsAg, spontaneous HBV flares do not predict subsequent HBsAg clearance.

Social determinants and spatio-temporal variation of Ischemic Heart Disease in Manitoba.

INTRODUCTION: The aim was to study any spatial and/or temporal patterns of ischemic heart disease (IHD) prevalence and measure the effects of selected social determinants on these spatial and space-time patterns. METHODS: Data were obtained from the Population Research Data Repository housed at the Manitoba Centre for Health Policy to identify persons who were diagnosed with IHD between 1995 and 2018. These persons were geocoded to 96 geographic regions of Manitoba. An area-level socioeconomic factor index (SEFI-2) and the proportion of the population who was Indigenous were calculated for each geographic region using the 2016 Canadian Census data. Associations between these factors and IHD prevalence were measured using Bayesian spatial Poisson regression models. Temporal trends and spatio-temporal trends were measured using Bayesian spatio-temporal Poisson regression models. RESULTS: Univariable models showed a significant association with increased regional Indigenous population proportion associated with a higher prevalence of IHD (RR: 0.07, 95% CredInt: (0.05, 0.10)) and for SEFI-2 (RR: 0.17, 95% CredInt: (0.11, 0.23)). Using a multivariable model, after accounting for the proportion of the population that was Indigenous, there was no evidence of an association between IHD prevalence and area-level socioeconomic factor. Spatio-temporal models showed no significant overall temporal trend in IHD prevalence, but there were significant spatially varying temporal trends within the 96 regions. CONCLUSIONS: Association between Indigenous population proportion and IHD is consistent with previous research. No significant overall temporal trend was measured. However, regions with significantly increasing trends and significantly decreasing trends in IHD prevalence were identified.

The relative expression of hepatocellular and cholestatic liver enzymes in adult patients with liver disease.

INTRODUCTION AND OBJECTIVES: Hepatocellular liver injury is characterized by elevations in serum alanine (ALT) and aspartate (AST) aminotransferases while cholestasis is associated with elevated serum alkaline phosphatase (ALP) levels. When both sets of enzymes are elevated, distinguishing between the two patterns of liver disease can be difficult. The aim of this study was to document the predicted ranges of serum ALP values in patients with hepatocellular liver injury and ALT or AST values in patients with cholestasis. MATERIALS AND METHODS: Liver enzyme levels were documented in adult patients with various types and degrees of hepatocellular (non-alcoholic fatty liver disease, hepatitis B and C, alcohol and autoimmune hepatitis) and cholestatic (primary biliary cholangitis and primary sclerosing cholangitis) disease. RESULTS: In 5167 hepatocellular disease patients with ALT (or AST) values that were normal, 1-5×, 5-10× or >10× elevated, median (95% CI) serum ALP levels were 0.64 (0.62-0.66), 0.72 (0.71-0.73), 0.80 (0.77-0.82) and 1.15 (1.0-1.22) fold elevated respectively. In 252 cholestatic patients with ALP values that were normal, 1-5× or >5× elevated, serum ALT (or AST) values were 1.13 (0.93-1.63), 2.47 (2.13-2.70) and 4.57 (3.27-5.63) fold elevated respectively. In 56 patients with concurrent diseases, ALP levels were beyond predicted values for their hepatitis in 38 (68%) and ALT (or AST) values beyond predicted values for their cholestatic disorder in 24 (43%). CONCLUSIONS: These data provide health care providers with predicted ranges of liver enzymes in patients with hepatocellular or cholestatic liver disease and may thereby help to identify patients with concurrent forms of liver disease.

The effects of hyperthermia on human hepatocellular carcinoma stem and mature cancer cells.

INTRODUCTION AND OBJECTIVES: Hepatocellular carcinoma (HCC) can recur following radiofrequency ablation and other hyperthermic treatment modalities. Cancer stem cells (CSCs) are a subpopulation of HCC cells that are difficult to eradicate and largely responsible for tumor recurrences. Thus, the principal objective of this study was to determine whether human HCC CSCs are relatively thermal-resistant compared to non-stem or mature cancer cells (MCCs). MATERIALS AND METHODS: Epithelial cell adhesion molecule (EpCAM) positive enriched CSCs and EpCAM- MCCs were derived from a human HCC cell line using fluorescence activated cell sorting. Each cell population was exposed to 65°C heat for 0-16min and survival documented at various time points. RESULTS: Cell survival curves were similar in CSC and MCCs throughout the 16min heat exposure period. Maximum killing was obtained after 12-14min of heat exposure. Cytoprotective, heat shock proteins-70 (HSP70) and -90 (HSP90) mRNA expression were not disproportionately increased in CSCs. CONCLUSIONS: These results suggest that human HCC CSCs are not more thermal resistant than MCCs and therefore, do not support the hypothesis that HCC recurrences following hyperthermic treatment reflect CSC thermal-resistance.

Concomitant nonalcoholic fatty liver disease does not alter the activity, severity or course of primary biliary cholangitis.

BACKGROUND & AIMS: The impact of nonalcoholic fatty liver disease (NAFLD) on the natural history of primary biliary cholangitis (PBC) has yet to be described. The aim of this study was to document the activity, severity and progression of PBC in patients with concomitant NAFLD and compare the findings to those with PBC alone. METHODS: Disease activity was assessed by serum liver enzyme levels; severity, by Fib-4 scores and percent of patients with APRI >1.5; and progression, by changes in Fib-4 and prevalence of APRI >1.5 during follow-up. RESULTS: The study populations consisted of 168 PBC alone and 68 PBC/NAFLD patients. The mean ages and gender distributions of the two cohorts were similar. At presentation, PBC alone patients had greater disease activity (higher serum ALP and GGT values, P = .003 and 0.01, respectively) and advanced disease (higher Fib-4 (P = .04) scores) than PBC/NAFLD patients. Although the prevalence of APRI >1.5 was also higher in PBC alone (11.1%) vs PBC/NAFLD (4.7%) patients, the difference was not significant (P = .16). During mean follow-up of 6.7 ± 5.5 (PBC alone) and 6.4 ± 4.4 (PBC/NAFLD) years (ranges: 0.5-21 years) annual increases in Fib-4 and prevalence of ≥ APRI 1.5 were greater in PBC alone patients but the differences did not reach statistical significance. CONCLUSIONS: The results of this retrospective, single centre study suggest that the activity, severity and progression of PBC are not adversely affected by concomitant NAFLD.

Predicting Pre-transplant Abstinence in Patients with Alcohol-Induced Liver Disease.

BACKGROUND: Some patients with alcohol-induced liver failure will succumb to their disease prior to demonstrating compliance with the six months abstinence rule for liver transplantation. PURPOSE: The purpose of this study was to determine whether a patient's self-reported, longest period of abstinence predicts subsequent abstinence. METHODS: Adult patients (n=63) with alcohol-induced liver disease were asked to recall their longest period of abstinence prior to their initial hepatology visit. Compliance with instructions to remain abstinent was then documented. RESULTS: Nineteen patients (30%) achieved abstinence and 44 (70%) relapsed within six months of seeing their hepatologist. Relapses were more common in patients who self-reported previous periods of abstinence exceeding six months (19/44, 43%) compared with 2/19 (11%) in those with periods of less than six months (p=0.01). Serum albumin levels were lower in relapsers but other tests of liver function (bilirubin level and international ratio of prothrombin time) and predictors of post-transplant recidivism did not associate with relapses. On multivariate analysis, self-reported abstinence (OR: 0.11, 95% CI: 0.02-0.57, p=0.008) and serum albumin levels (regression coefficient 0.113, p=0.02) predicted relapses. CONCLUSIONS: A self-reported period of abstinence in excess of six months was associated with an increased risk of subsequent relapse following a hepatologist's instructions to remain abstinent. These counter-intuitive findings should be confirmed by larger, prospective studies.

Establishing diagnostic criteria for occult hepatitis B virus infections in community based populations.

Present diagnostic criteria for occult hepatitis B virus (HBV) infection requires blood or liver samples to test positive for at least two HBV DNA targets in hepatitis B surface antigen (HBsAg) negative individuals. These criteria were derived from studies involving referred or selected patient populations. The objective of the present study was to determine whether the present definition of occult HBV infection also applies within a nonselected community based population. HBV DNA testing was performed in 1,007 HBsAg negative sera by real time PCR with primer sets targeting the Enhancer I (ENHI), precore/core and surface/polymerase (S) genomic regions. Real time PCR positive cases were analyzed further by nested PCR. The results were then correlated with serologic findings among HBV DNA negative and occult positive individuals. Fifty-five sera (5.5%) were positive for at least one of the three genomic regions. Positive results with at least two primer/probe sets (thereby satisfying present diagnostic criteria for occult HBV infection) were identified in 8 (0.8%) samples (3 ENHI plus S, 2 ENHI plus precore/core and 3 having positive results with all three primer/probe sets). The prevalence of HBV serologic markers in samples that tested positive for only one primer set were similar to those of HBV DNA negative matched controls, thereby arguing against their representing occult infection. The results of this study suggest that the present diagnostic criteria for occult HBV infection are also appropriate for population based studies. However, further studies are required to confirm that impression.

Predicting Hepatocellular Carcinoma Recurrence and Survival.

BACKGROUND/AIMS: Beta blockers can inhibit tumor growth and metastases, while necroinflammation can enhance these tumor properties. The aim of this study was to determine whether beta blockers and necroinflammatory disease predict tumor recurrence and/or overall survival following potentially curative therapeutic interventions for patients with hepatocellular carcinoma (HCC). METHODOLOGY: The medical records of 36 adults with non-metastatic HCC who had undergone surgical resections and/or radiofrequency ablation (RFA) were retrospectively reviewed. In addition to post-intervention beta blocker usage and serum alanine aminotransferase levels greater than 2xULN, other variables commonly associated with recurrences such as number and size of tumors, state of differentiation and vascular invasion were included in univariate and multivariate analyses for recurrence and survival. RESULTS: Vascular invasion (OR 29.3, 95% CI 2.6-33.6) and surgical resection (OR 0.19, 95% CI 0.04-0.90) emerged from univariate (p = 0.003 and 0.03 respectively) and multivariate (p = 0.005 and 0.048 respectively) regression as predictors of tumor recurrence whereas beta blocker usage (OR 0.03, 95% CL 0.04-0.9, p = 0.03) and tumor recurrence (OR 6.7, 95% CI 1.6-28.1, p = 0.026) correlated with overall mortality. CONCLUSIONS: Neither beta blocker usage nor serum ALT levels predict HCC recurrences, but beta blocker usage is associated with improved overall survival following potentially curative therapeutic interventions for HCC in adults.

Recipient ineligibility after liver transplantation assessment: a single centre experience.

BACKGROUND: Candidacy for liver transplantation is determined through standardized evaluation. There are limited data on the frequency and reasons for denial of transplantation after assessment; analysis may shed light on the short-term utility of the assessment. We sought to describe the frequency and reasons for ineligibility for liver transplantation among referred adults. METHODS: We studied all prospectively followed recipient candidates at a single centre who were deemed unsuitable for liver transplantation after assessment. Inclusion criteria were age 18 years and older and completion of a standard liver transplantation evaluation over a 3-year period. Patients were excluded if they had a history of prior assessment or liver transplantation within the study period. Demographic and baseline clinical data and reasons for recipient ineligibility were recorded. RESULTS: In all, 337 patients underwent their first liver transplantation evaluation during the study period; 166 (49.3%) fulfilled inclusion criteria. The mean age was 55.4 years, and 106 (63.9%) were men. The 3 most common reasons for denial of listing were patient too well (n = 82, 49.4%), medical comorbidities and/or need for medical optimization (n = 43, 25.9%) and need for addiction rehabilitation (n = 28, 16.9%). CONCLUSION: Ineligibility for transplantation after assessment was common, occurring in nearly half of the cohort. Most denied candidates could be identified with more discriminate screening before the resource-intensive assessment; however, the assessment likely provides unforeseen positive impacts on patient care.

CONTEXTE: Les candidats à une greffe du foie sont sélectionnés au moyen d'une évaluation standardisée. On dispose de peu de données au sujet de la fréquence et des motifs des refus de transplantation consécutifs à cette évaluation. Une analyse pourrait faire la lumière sur l'utilité de l'évaluation à court terme. Nous avons voulu décrire la fréquence de ces refus et les raisons pour lesquelles des adultes adressés pour consultation se voient refuser la greffe. MÉTHODES: Nous avons étudié tous les candidats à la greffe suivis prospectivement dans 1 seul centre et à qui, après évaluation, la greffe du foie a été refusée. Les critères d'inclusion étaient l'âge de 18 ans et plus et les résultats de l'évaluation standard en vue de la greffe du foie sur une période de 3 ans. Les patients étaient exclus s'ils avaient déjà subi une évaluation ou une greffe du foie au cours de la période de l'étude. Les données démographiques et cliniques de départ, de même que les raisons de l'exclusion des candidats ont été consignées. RÉSULTANTS: En tout, 337 patients ont subi leur première évaluation en vue d'une greffe du foie au cours de la période de l'étude; 166 (49,3 %) répondaient aux critères d'inclusion. L'âge moyen était de 55,4 ans et 106 (63,9 %) étaient des hommes. Les 3 raisons les plus souvent invoquées pour refuser l'accès à la greffe chez ces candidats étaient qu'ils étaient suffisamment bien (n = 82, 49,4 %), qu'ils présentaient des comorbidités et(ou) qu'ils devaient améliorer leur état de santé (n = 43, 25,9 %) ou qu'il leur fallait une cure de désintoxication (n = 28, 16,9 %). CONCLUSIONS: De nombreux patients, soit près de la moitié de la cohorte, ont été jugés mauvais candidats à la greffe après l'évaluation. Il serait possible de reconnaître les patients qui sont mauvais candidats à la greffe en faisant un dépistage plus précis avant même d'aller de l'avant avec l'évaluation standard, qui draine d'importantes ressources. Toutefois, l'évaluation a probablement des répercussions positives imprévues sur le soin des patients.

Binge drinking does not appear to have an adverse effect on non-alcoholic fatty liver disease: Findings from a study of four First Nations communities.

BACKGROUND: Binge drinking and non-alcoholic fatty liver disease (NAFLD) are common health problems throughout the world. However, the impact of binge drinking on NAFLD has yet to be described. The objective of this study was to document the extent of liver disease in community-based NAFLD patients who self-reported monthly binge drinking and compare the findings to NAFLD patients from the same communities who denied binge drinking (controls). METHODS: The study was undertaken in four Manitoba First Nations communities where the sale and consumption of alcoholic beverages are prohibited but visits to urban centres are common. Binge drinkers were retrospectively matched 1:2 by age, sex, and body mass index (BMI) with controls. NAFLD was diagnosed by ultrasonographic features of excess fat in the liver in individuals with no alternative, non-metabolic explanation for fatty infiltration of the liver. Hepatic inflammation and function were determined by standard liver biochemistry testing and fibrosis by FIB-4 levels and hepatic elastography. RESULTS: Of 546 NAFLD patients, 88 (16%) attested to binge drinking. The mean age of binge drinkers was 40 (SD 13) years; 51% were male; and the mean BMI was 34 (SD 7). Compared with controls, binge drinkers had similar liver biochemistry results (alanine and aspartate aminotransferases: 41 [SD 39] and 36 [SD 30] versus 36 [SD 36] and 31 [SD 27] U/L, p = 0.35 and p = 0.37, respectively), FIB-4 values (0.75 [SD 0.55] versus 0.72 [SD 0.44], p = 0.41, respectively), and hepatic elastrography (6.6 [SD 3.9] versus 6.2 [SD 2.9] kPa, p = 0.37, respectively) findings. CONCLUSIONS: In this study population, monthly binge drinking did not appear to impact the severity of NAFLD.

Insulin secretion in liver transplant recipients following conversion to a prolonged release tacrolimus formulation.

Background: Post liver transplant diabetes mellitus (PLTDM) occurs in 10-40% of liver transplant recipients and is associated with increased morbidity and mortality. An important cause of PLTDM is tacrolimus induced, concentration-dependent, inhibition of insulin secretion. Objective: To determine if a newly licenced formulation of tacrolimus (Envarsus-PA), which achieves peak tacrolimus concentrations 20-30% lower than other tacrolimus formulations has less of an inhibitory effect on insulin secretion. Methods: Homeostatic model assessment (HOMA) for insulin secretion (HOMA-S) values and c-peptide levels were determined in 19 adult liver transplant recipients while being maintained on immediate- or slow-release tacrolimus formulations and repeated a minimum of 30 days following conversion to Envarsus-PA. Results: Insulin secretion was unchanged following conversion to Envarsus-PA (HOMA-S pre-conversion: 154 ± 133 vs. 129 ± 75, post-conversion [p = 0.32], and c-peptide levels; 1059 ± 602 and 934 ± 463 respectively, p = 0.42). Fasting blood glucose (FBG) and hemoglobin A1c (HbA1c) levels were also unchanged (FBG 5.7 ± 0.8 pre-conversion vs. 5.6 ± 0.7 post-conversion; p = 0.36 and HbA1c 4.9±1.2 pre-conversion versus 5.5±0.2 post-conversion, p = 0.34). Conclusions: Envarsus-PA had no significant effect on insulin secretion or glucose homeostasis beyond that associated with other tacrolimus formulations in adult liver transplant recipients.

Comparison of different definitions of metabolic syndrome and their associations with non-alcoholic fatty liver disease: a retrospective study.

Background: Metabolic syndrome (MetS) is considered an important risk factor for non-alcoholic fatty liver disease (NAFLD). The aim of this study was to measure the prevalence of MetS based on six different MetS definitions and compare the performance of various definitions for identifying diabetes, hypertension, and dyslipidemia among NAFLD patients. Methods: The definitions compared were those developed by the World Health Organization (WHO), National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III), International Diabetes Federation (IDF), American Association of Clinical Endocrinologists (AACE), American Heart Association/National Heart, Lung and Blood Institute (AHA/NHLBI), and Interim Joint Statement "harmonized" criteria. Receiver operator characteristic (ROC) curves were plotted for the six MetS definitions with NAFLD diagnosis. The diagnosis for NAFLD was established based on liver imaging or biopsy compatible with fatty liver disease. Results: A total of 500 NAFLD patients were analyzed. The mean age was 61.2 (SD 13.2) years, and BMI was 32.7 (SD 8.0) kg/m2. The most prevalent MetS component was dyslipidemia (83%), followed by hypertension (60%), obesity (61%), and diabetes (57%). The prevalence of MetS according to the WHO, NCEP/ATP-III, IDF, AACE, AHA/NHLBI, and harmonized criteria was 69%, 59%, 54%, 64%, 78%, and 79%, respectively. The highest area under the ROC curve for diabetes and hypertension was with the WHO definition (0.7405) and (0.8120), respectively. Conclusions: The prevalence of MetS in NAFLD patients varies according to the definitions of MetS employed. The modified WHO definition appeared to be most useful for the screening of MetS in NAFLD patients.

A population-based study of the epidemiology of hepatitis C in a North American population.

BACKGROUND & AIMS: Chronic hepatitis C virus (HCV) infection is a major public health problem with approximately 3% of the world's population thought to be chronically infected. However, population-based data regarding HCV incidence rates, prevalence, residence, age, and gender distributions within North America are limited. We aimed at providing a detailed descriptive epidemiology of HCV infection in a North American population with a focus on time trends in incidence rates and prevalence of newly diagnosed HCV infection since 1991, the time when laboratory testing for HCV infections became first available. METHODS: A Research Database was developed linking records from multiple administrative sources. HCV positive residents of the Canadian province of Manitoba were identified during a twelve-year period (1991-2002). The cumulative and annual incidence rates and the prevalence of newly diagnosed HCV infection in Manitoba were examined and compared between different demographic groups and urban vs. rural residents. RESULTS: A total of 5018 HCV positive cases were identified over a 12-year period. The annual number of newly diagnosed HCV infections peaked in 1998 (59.2/100,000). On the other hand, the known prevalence of HCV continued to increase (4.6-fold during the 12-year study period) among both men and women reflecting the chronic nature of the disease. Males were 1.7 times more often infected than females. HCV infections were more common in urban centers. CONCLUSIONS: Between 1995 and 2002, there was a fairly constant trend for newly diagnosed HCV infection, ranging from approximately 500 to 600 new cases annually. Hence, with a stable population size, and a low case fatality rate, the prevalence of HCV infected persons in our population has been steadily rising. There is no evidence to suggest that the incidence of HCV infection will raise, however, the burden of chronic HCV infection will continue to increase, particularly amongst older males and those residing in urban centers.

Unconjugated hyperbilirubinemia may exacerbate certain underlying chronic liver diseases.

BACKGROUND: Negative correlations have been described between elevated serum unconjugated bilirubin levels and the prevalence/severity of various chronic inflammatory conditions. Whether a similar association exists for patients with unconjugated hyperbilirubinemia (UCB) and underlying chronic liver diseases (CLD) has yet to be reported. The aim of this study was to document hepatic necro-inflammatory disease activity and fibrosis in CLD patients with and without UCB and otherwise normal liver function tests (albumin and INR). METHODS: Necro-inflammatory disease activity was assessed by serum aminotransferase levels and fibrosis by APRI and FIB-4 calculations. UCB patients were matched 1:2 by age, gender, and underlying CLD to patients with normal bilirubin levels. RESULTS: From a database of 9,745 CLD patients, 208 (2.1%) had UCB and 399 served as matched controls. Overall, UCB patients had significantly higher serum aminotransferase levels, APRI, and FIB-4 scores. The differences were driven by patients with underlying chronic viral or immune mediated liver disorders rather than non-alcoholic fatty liver disease, alcohol-related liver disease, or 'other' CLDs. CONCLUSIONS: These results suggest UCB is associated with increased rather than decreased hepatic necro-inflammatory disease activity and fibrosis in patients with certain CLDs.

Post-transplant diabetes mellitus in Canadian liver and renal transplant recipients.

BACKGROUND: Post-transplant diabetes mellitus (PTDM) occurs in 10%-40% of liver and renal transplant recipients. Whether the risk factors for PTDM in liver and renal transplant recipients are similar and whether Indigenous Canadians, who have a high underlying prevalence of diabetes mellitus (DM), are at increased risk of developing PTDM have yet to be determined. OBJECTIVE: To describe and compare those variables associated with PTDM in adult Canadian liver and renal transplant recipients. METHODS: A retrospective chart review of adult liver and renal transplant recipients attending four transplant follow-up clinics in three Canadian provinces was undertaken. RESULTS: De novo PTDM was diagnosed in 184/905 (20.3%) liver and 179/390 (45.9%) renal transplant recipients. Older age, higher pre-transplant BMI, underlying immune-mediated liver disease, lower trough tacrolimus levels and longer duration of follow-up were independently associated with PTDM in liver transplant recipients and non-Caucasian race, higher pre-transplant BMI, and incidence of organ rejection in renal transplant recipients. Compared with Caucasians, Indigenous Canadians who had undergone renal transplantation had a significantly increased prevalence of PTDM (56.5% versus 40.0%, p = 0.035). The prevalence of PTDM in liver transplant recipients was similar in Indigenous Canadians and Caucasians (27.9% versus 20.1%, p = 0.215). CONCLUSIONS: The variables associated with PTDM differ in liver and renal transplant recipients. Compared with Caucasians, Indigenous Canadians undergoing renal transplantation are at increased risk of developing PTDM.

Clinical Outcomes and Quantitative HBV Surface Antigen Levels in Diverse Chronic Hepatitis B Patients in Canada: A Retrospective Real-World Study of CHB in Canada (REVEAL-CANADA).

BACKGROUND: Hepatitis B surface antigen (HBsAg) loss is associated with improved clinical outcomes for individuals with chronic hepatitis B (CHB); however, the effects of varying HBsAg levels on clinical outcomes in diverse cohorts are understudied. METHODS: In this cross-sectional, multicentre, retrospective study, the data on adult subjects enrolled in the Canadian HBV Network with CHB seen from 1 January 2012 to 30 January 2021 with the treatment and virologic data within 1 year of HBsAg testing were analyzed. Patients were tested for HBsAg using qualitative (for HBsAg-negative samples) and/or commercial quantitative assays. Fibrosis or hepatic necroinflammation was determined by the liver stiffness measurement (LSM). The baseline data were summarized using descriptive statistics and compared by using univariable/multivariable analyses. RESULTS: This study included 844 CHB patients, with a median age of 49.6 years (IQR 40.1-60.5), and 37% were female. In total, 751 patients (78.6%) had known ethnicity data, and 76.7% self-reported as Asian, 11.4% as Black, 6.8% as White, and 4.8% as other. Among the 844 patients, 237 (28.0%) were HBsAg (-) (1000 IU/mL. Overall, 80% (682) had known HBeAg status at the last follow-up, and the majority (87.0%) were HBeAg-negative. In addition, 54% (461/844) had prior antiviral therapy, 19.7% of which (16.3, 23.7, n = 91) were HBsAg (-). The treated patients had a lower risk of cirrhosis (16.46, 95% CI 1.89-143.39, p = 0.01) or HCC (8.23, 95% CI 1.01-67.39, p = 0.05) than the untreated patients. A lower proportion of the HBsAg-loss group had cirrhosis (5.7% vs. 10.9%, p = 0.021) and HCC (0.9% vs. 6.2%, p = 0.001). CONCLUSION: In this retrospective, ethnically diverse cohort study, CHB patients who received antiviral therapy and/or had HBsAg loss were less likely to develop cirrhosis and HCC, confirming the results of the studies in less diverse cohorts. No association was found between the qHBsAg level and fibrosis determined with LSM. Individuals who achieved HBsAg loss had low-level qHBsAg within 1 year of seroclearance.

GABA-B receptor activation inhibits the in vitro migration of malignant hepatocytes.

There are conflicting data regarding whether activation of γ-aminobutyric acid-B (GABA-B) receptors results in inhibition of tumor growth and invasion. The objectives of this study were to document the effects of the GABA-B receptor agonist baclofen on malignant hepatocyte proliferation and migration. We also sought to determine whether any effects on cell migration were mediated by changes in cyclic adenosine monophosphate (cAMP) signaling or matrix metalloproteinase (MMP) expression. Finally, GABA-B(1) and -B(2) receptor expression was documented in 2 malignant hepatocyte cell lines (PLC/PRF/5 and Huh-7) and 12 sets of human hepatocellular carcinoma and adjacent nontumor tissues. Cell proliferative activity was documented by WST-1 absorbance, migration by wound healing assays, cAMP levels by enzyme-linked immunoassay (ELISA), MMP by immunohistochemistry and ELISA, and GABA-B receptor expression by flow cytometry and reverse transcriptase - polymerase chain reaction. Although baclofen had no effect on cell proliferation, wound healing was delayed, an effect that was reversed by the GABA-B receptor antagonist CGP. cAMP levels were decreased in Huh-7 but not PLC cells exposed to baclofen. MMP expression remained unaltered in both cell lines. Finally, GABA-B(1) receptor expression was present and consistently expressed, but GABA-B(2) expression was limited and varied with the number of cell passages and (or) duration of culture. In conclusion, activation of GABA-B receptors has no effect on malignant hepatocyte proliferation but does decrease cell migration. This inhibitory effect may involve cAMP signaling but not MMP expression. GABA-B(2) receptor expression is limited and variable, which may help to explain discrepancies with previously published results.