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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., (© Canadian Association for the Study of the Liver, 2023.)

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., (© Canadian Association for the Study of the Liver, 2023.)

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., (Copyright © 2022 Canadian Association for the Study of the Liver.)

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., (Copyright © 2022 Canadian Association for the Study of the Liver.)

Background: Hepatitis B virus (HBV) nucleos(t)ide analog (NA) therapy reduces liver disease but requires prolonged therapy to achieve hepatitis B surface antigen (HBsAg) loss. There is limited North American real-world data using non-invasive tools for fibrosis assessment and few have compared 1 st generation NA or lamivudine (LAM) to tenofovir disoproxil fumarate (TDF)., Aim: To assess impact of NA on virological response and fibrosis regression using liver stiffness measurement (LSM) ( i.e. , FibroScan ® )., Methods: Retrospective, observational cohort study from the Canadian HBV Network. Data collected included demographics, NA, HBV DNA, alanine aminotransferase (ALT), and LSM. Patients were HBV monoinfected patients, treatment naïve, and received 1 NA with minimum 1 year follow-up., Results: In 465 (median 49 years, 37% female, 35% hepatitis B e antigen + at baseline, 84% Asian, 6% White, and 9% Black). Percentage of 64 ( n = 299) received TDF and 166 were LAM-treated with similar median duration of 3.9 and 3.7 years, respectively. The mean baseline LSM was 11.2 kPa (TDF) vs 8.3 kPa (LAM) ( P = 0.003). At 5-year follow-up, the mean LSM was 7.0 kPa in TDF vs 6.7 kPa in LAM ( P = 0.83). There was a significant difference in fibrosis regression between groups ( i.e. , mean -4.2 kPa change in TDF and -1.6 kPa in LAM, P < 0.05). The last available data on treatment showed that all had normal ALT, but more TDF patients were virologically suppressed (< 10 IU/mL) ( n = 170/190, 89%) vs LAM-treated ( n = 35/58, 60%) ( P < 0.05). None cleared HBsAg., Conclusion: In this real-world North American study, approximately 5 years of NA achieves liver fibrosis regression rarely leads to HBsAg loss., Competing Interests: Conflict-of-interest statement: Dr. Alnoor Ramji and Dr. Carla S Coffin didn’t receive at any time payment from a third party for any aspect for the submitted work; there are no relevant conflict of interest; there are no patents related to this work; Dr. Alnoor Ramji and Dr. Carla S Coffin have nothing to disclosure., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Innate immune responses to gut-derived pathogen-associated molecular patterns (PAMPs) have been implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Whether NAFLD patients have increased sensitivity to PAMP exposure has yet to be reported., Methods: Peripheral blood mononuclear cell (PBMC)/monocytes were exposed to lipopolysaccharide (LPS), Pam3CSK4, or BSA conjugated palmitate in vitro . Changes in toll-like receptors (TLR), cytokines, and chemokine receptors (CR) expressions were documented by flow cytometry and/or enzyme-linked immunoabsorbent assays (ELISAs)., Results: TLR2 and TLR4 expression were similar at baseline and increased to a similar extent (TLR2) or remained unchanged (TLR4) following PAMP exposure in NAFLD and healthy control (HC) monocytes. Proinflammatory IL-1β and IL-6 levels were similar at baseline but increased in a concentration-dependent manner to a greater extent in NAFLD PBMCs. CCR1 and CCR2 expressions at baseline were similar and decreased to a similar extent in NAFLD and HC monocytes. The extent of PAMP-induced proinflammatory cytokine release correlated with evidence of hepatocyte injury (CK18M30 levels)., Discussion: NAFLD patients have increased proinflammatory cytokine responses following exposure to PAMPs relative to HC subjects. This response is concentration-dependent and correlates with the extent of hepatic injury., (© 2021 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Aim of the Study: Intra- and extrahepatic cholangiocarcinoma (I-CCA and E-CCA respectively) exhibit different growth features that contribute to different clinical outcomes. Cancer stem cells (CSCs) influence tumor growth and thereby may be responsible for these differences. The aim of this study was to document and compare the growth features of human I-CCA and E-CCA cell lines and determine whether any differences observed could be explained by differences in the prevalence and/or stem cell surface marker (SCSM) expression profiles of CSCs within the tumor cell lines., Material and Methods: Six CCA cells lines, three I-CCA and three E-CCA, were studied. Tumor cell growth features including cell proliferation, colony/spheroid formation, migration and invasion were documented. CSC prevalence and SCSM expression profiles were examined by flow cytometry., Results: I-CCA cells had significantly increased proliferative activity, shorter doubling times and were more invasive than E-CCA cells, while colony/spheroid formation and migration were similar in the two cell populations. There were no significant differences in CSC prevalence rates or SCSM expression profiles., Conclusions: These findings suggest that I-CCA cells proliferate at a more rapid rate and are more invasive than E-CCA cells but the differences cannot be explained by differences in the prevalence or SCSM expression profiles of CSCs within the tumor cell population., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Clinical and Experimental Hepatology.)

Background & Aims: HDV affects 4.5-13% of chronic hepatitis B (CHB) patients globally, yet the prevalence of HDV infection in Canada is unknown. To investigate the prevalence, genotype, demographics, and clinical characteristics of HDV in Canada, we conducted a retrospective analysis of (1) HDV antibody and RNA positivity among referred specimens, and (2) a cross-sectional subset study of 135 HDV seropositive +/-RNA (HDV+) patients compared with 5,132 HBV mono-infected patients in the Canadian HBV Network., Methods: Anti-HDV IgG-positive specimens collected between 2012 and 2019 were RNA tested and the genotype determined. Patients enrolled in the Canadian HBV Network were >18 years of age and HBsAg-positive. Clinical data collected included risk factors, demographics, comorbidities, treatment, fibrosis assessment, and hepatic complications., Results: Of the referred patients, 338/7,080 (4.8%, 95% CI 4.3-5.3) were HDV seropositive, with 219/338 RNA-positive (64.8%, 95% CI 59.6-69.7). The HDV+ cohort were more likely to be born in Canada, to be White or Black/African/Caribbean than Asian, and reporting high-risk behaviours, compared with HBV mono-infected patients. Cirrhosis, complications of end-stage liver disease, and liver transplantation were significantly more frequent in the HDV+ cohort. HDV viraemia was significantly associated with elevated liver transaminases and cirrhosis. Five HDV genotypes were observed among referred patients but no association between genotype and clinical outcome was detected within the HDV+ cohort., Conclusions: Nearly 5% of the Canadian HBV referral population is HDV seropositive. HDV infection is highly associated with risk behaviours and both domestic and foreign-born patients with CHB. HDV was significantly associated with progressive liver disease highlighting the need for increased screening and surveillance of HDV in Canada., Lay Summary: Evidence of HDV infection was observed in approximately 5% of Canadians who were infected with HBV referred to medical specialists. HDV-positive patients were more likely to be male, born in Canada, or White or Black/African/Caribbean compared to Asian, and to have reported high-risk activities such as injection or intranasal drug use or high-risk sexual contact compared with patients infected with only HBV. Patients infected with HDV were also more likely to suffer severe liver disease, including liver cancer, compared with HBV mono-infected patients., Competing Interests: CSC within past 36 months: Grant or contract from Gilead Sciences, Janssen Pharmaceuticals, GSK; Consulting fees from Janssen Pharmaceuticals; Payment or honoraria from Gilead Sciences (all made to the University of Calgary). The other authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Crown Copyright © 2022 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL).)

Background and Aims: Fibroblast growth factor (FGF)19 has been implicated in the pathogenesis of murine hepatocellular carcinoma. Whether it plays a role in the development or course of human cholangiocarcinoma remains to be determined. The aim of this study was to determine whether prolonged exposure to FGF19 results in the transformation of non-malignant human cholangiocytes into cells with malignant features., Methods: Human SV-40 transfected non-malignant H69 cholangiocytes were cultured with FGF19 (0-50 ng/mL) for 6 weeks, followed by 6 weeks with medium alone. Cell proliferation, invasion, stem cell surface markers, oncofetoprotein expression, state of differentiation, epithelial-mesenchymal transition (EMT) and interleukin (IL)-6 expression were documented at various time intervals throughout the 12-week period., Results: FGF19 exposure was associated with significant increases in cell proliferation, de-differentiation, EMT and IL-6 expression. However, each of these effects returned to baseline or control values during the 6-week FGF19 free follow-up period. The remaining cell properties remained unaltered., Conclusions: Six weeks of FGF19 exposure did not result in the acquisition of permanent malignant features in non-malignant, human cholangiocytes., Competing Interests: The authors have no conflict of interests related to this publication., (© 2021 Authors.)

Patient ethnicity may influence the pharmacokinetics (PK) of tacrolimus. Because the Canadian First Nations (FN) constitute a large and increasing segment of the liver transplant population, we undertook to determine whether PK differences exist for a once-daily, extended release formulation of tacrolimus (Advagraf) in FN compared to Caucasian (CAUC) liver transplant recipients. Following achievement of a steady state with Advagraf, blood samples were drawn at 0, 1, 2, 4, 6, 8 and 24 hours for whole blood tacrolimus levels by commercial immunoassay and CYP3A4 and CYP3A5 allele analyses were performed by polymerase chain reactions. Nineteen subjects participated in the study (7 FN and 12 CAUC). The FN cohort had significantly higher AUC (214 ± 48 versus 168 ± 25, P < 0.05), Cmax (16.7 ± 4.4 ng/ml versus 11.3 ± 1.7 ng/ml, P < 0.05), Cmin (6.1 ± 1.0 ng/ml versus 4.7 ± 0.5 ng/ml, P < 0.05) and shorter Tmax (1.6 ± 0.2 hours versus 2.8 ± 0.3 hours, P < 0.05) values than CAUCs. CYP3A4 genotypes were C/C in both cohorts, while the CYP3A5 *1/*3 allele was present in 2/5 FN and 0/9 CAUC. The results of this study indicate that once-daily, extended release Advagraf results in higher blood tacrolimus levels and shorter times to Cmax in FN compared to CAUC liver transplant recipients., (© 2021 Steunstichting ESOT. Published by John Wiley & Sons Ltd.)

The impact of non-alcoholic fatty liver disease (NAFLD) on patients with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections has yet to be determined. In this retrospective, cross-sectional analysis, untreated chronic HBV, hepatitis B e-antigen (HBeAg)-positive patients with NAFLD had similar liver biochemistry and FIB-4 values as age-, gender-, and viral-load-matched HBeAg-positive patients without NAFLD. Among HBeAg-negative patients with NAFLD, although liver biochemistry findings were similar, mean FIB-4 values were significantly lower (0.98, SD 1.46, versus 1.51, SD 4.04, respectively; p < 0.05) and the percentage of patients with FIB-4 values in keeping with advanced fibrosis or cirrhosis was less (0.3% versus 3.9%, p < 0.015) than that of matched HBeAg-negative patients without NAFLD. Chronic HCV-infected patients with NAFLD had higher mean serum aminotransferase values than those without NAFLD (123 U/L, SD 247, versus 90 U/L, SD 128, respectively; p < 0.05). These results suggest that NAFLD adversely affects chronic HCV infections but not HBV infections., Competing Interests: The authors have nothing to disclose., (Copyright © 2021 Canadian Association for the Study of the Liver.)

Hepatic adenomatosis (HA) is a rare condition in which multiple adenomas exist in an otherwise healthy liver. The most common subtype (H-HA) is associated with bi-allelic, somatic hepatic nuclear factor 1-alpha (HNF1A) mutations. Maturity-onset diabetes of the young type 3 (MODY3) is most often seen in young individuals with heterozygous, germline mutations in HNF1A. In this report, we describe a 17-year-old woman with H-HA and non-familial MODY3., Competing Interests: The authors have nothing to disclose., (Copyright © 2021 Canadian Association for the Study of the Liver.)

Objectives: A low serum alkaline phosphatase (ALP) level is an uncommon finding in patients with chronic liver disease (CLD). The prevalence of this finding and whether low ALP expression influences CLD remain to be determined. The objectives of this study were: (1) to document the prevalence of low serum ALP levels in adult CLD patients and (2) compare features of CLD in patients with low versus normal or elevated serum ALP levels., Methods: An adult, outpatient liver disease database was searched for patients with low serum ALP levels (<40 IU/L). Hepatic inflammation, function, fibrosis and disease severity were determined by serum aminotransferases, albumin, bilirubin and INR levels, Fib-4 calculations and MELD scores respectively., Results: Of 19,037 patients entered into the database, 47 (0.25%) had consistently low serum ALP levels, 51 (0.27%) low levels on the majority and 469 (2.44%) on the minority of determinations. Patients with consistently low levels were matched (1:2) by age, gender and nature of the underlying liver disease to patients with normal or elevated serum ALP levels. Matched patients with consistently low ALP levels had significantly lower serum aminotransferase and bilirubin levels at their initial visit and throughout the follow-up period (p < 0.05 respectively) while Fib-4 levels and MELD scores were similar at the initial and last follow-up visit., Conclusions: These results establish the prevalence of low serum ALP levels in adult CLD patients and describe a hitherto unreported association between low serum ALP levels and less biochemical evidence of active disease., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

The estimated global prevalence of alcohol abuse is 5%-15%, with 15%-20% of these individuals being considered binge drinkers. Despite the high prevalence, the effects of binge drinking on healthy and diseased livers remain unclear. This review focuses on the effects of binge drinking in adults with otherwise healthy livers and those with a variety of common underlying chronic liver diseases., Competing Interests: The authors have nothing to disclose., (Copyright © 2021 Canadian Association for the Study of the Liver.)

Background and Aim: Cholangiocarcinoma (CCA) is an often fatal primary cancer of the liver that tends to be resistant to chemotherapy. Multidrug resistance proteins (MRPs) contribute to the chemoresistance of these tumors. The objectives of the study were to document MRP expression profiles in two representative human intrahepatic and extrahepatic CCA cells lines (HuCCT1 and KMBC, respectively) and gemcitabine-induced cytotoxicity prior to and following MRP knockdown., Methods: Multidrug resistance protein mRNA and protein expression were documented by real-time reverse transcription-polymerase chain reaction and western blots, respectively. MRP knockdown was achieved with lentivirus small hairpin RNA constructs., Results: Prior to gemcitabine exposure, MRP1, MRP2, MRP4, MRP5, and MRP6 mRNA were expressed in HuCCT1 cells and MRP1, MRP3, MRP4, and MRP5 in KMBC cells. Following gemcitabine exposure, MRP5 and MRP6 expressions were significantly upregulated in HuCCT1 cells and MRP5 in KMBC cells. In HuCCT1 cells, although MRP5 knockdown had no effect, MRP6 knockdown significantly increased gemcitabine-induced cytotoxicity. In KMBC cells, MRP5 knockdown significantly increased gemcitabine cytotoxicity., Conclusions: Inhibition of MRP6 expression in intra-hepatic and MRP5 in extra-hepatic should be explored as potential treatments for CCA in humans., (© 2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: The impact of chronic cholestatic liver diseases such as primary biliary cholangitis (PBC) on non-alcoholic fatty liver disease (NAFLD) has yet to be described., Objectives: To document and compare the severity and course of liver disease in patients with NAFLD/PBC versus NAFLD alone., Methods: In this retrospective, case-control study 68 adult NAFLD/PBC patients were matched 1:2 for age and sex with 136 NAFLD alone patients. Disease activity and severity were documented by serum aminotransferases, albumin, bilirubin and international normalized ratio (INR) values and hepatic fibrosis by Fib-4 and aspartate aminotransferase/platelet ratio indices (APRI)., Results: On presentation (baseline), NAFLD/PBC patients had similar serum aminotransferase, albumin and bilirubin levels but lower INR values than NAFLD alone patients. Fib-4 and APRI levels were similar. Despite longer follow-up (favouring more advanced disease) in NAFLD/PBC patients, serum aminotransferases and bilirubin values were similar but albumin and INR levels significantly lower in NAFLD/PBC versus NAFLD alone patients at the end of follow-up. NAFLD/PBC patients also had significantly lower and less worsening of Fib-4 values at the end of follow-up. Transition from intermediate Fib-4 levels to those compatible with no or limited fibrosis was higher in NAFLD/PBC patients., Conclusion: These findings suggest PBC does not adversely affect the severity or course of NAFLD., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction and Objectives: Intrahepatic (I-CCA) and extrahepatic (E-CCA) cholangiocarcinoma (CCA) have different growth patterns and risks for tumor metastasis. Inhibition and/or activation of the chemokine receptor CCR subclasses have been reported to alter tumor cell biology in non-CCA cancers. In this study we documented CCR expression profiles in representative human I-CCA and E-CCA cell lines and the in vitro effects of CCR antagonists and agonists on tumor cell biology., Materials and Methods: CCR expression profiles were documented by real-time reverse transcription polymerase chain reaction; cell proliferation by WST-1; spheroid formation by sphere dimensions in anchorage-free medium; cell migration by wound healing and invasion by Transwell invasion chambers., Results: All 10 CCR motifs (CCR1-10) were expressed in the I-CCA, HuCCT1 cell line and six (CCR4, 5, 6, 8, 9 and 10) in the E-CCA, KMBC cell line. In HuCCT1 cells, CCR5 expression was most abundant whereas in KMBC cells, CCR6 followed by CCR5 were most abundant. The CCR5 antagonist Maraviroc significantly inhibited cell proliferation, migration and invasion in HuCCT1 cells, and spheroid formation and invasion in KMBC cells. The CCR5 agonist RANTES had no effect on HuCCT1 cells but increased cell proliferation, migration and invasion of KMBC cells., Conclusion: These results suggest that CCR expression profiles differ in I-CCA and E-CCA. They also indicate that CCR5 antagonists and agonists have cell-specific effects but in general, CCR5 inactivation inhibits CCA tumor cell aggressiveness. Additional research is required to determine whether CCR5 inactivation is of value in the treatment of CCA in humans., (Copyright © 2020 AEDV. Published by Elsevier España, S.L.U. All rights reserved.)

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.

Background: Activation of innate immunity by gut-derived immunogens such as lipopolysaccharides (LPS) may play an important role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Whether NAFLD-associated lipid disturbances and polyunsaturated fatty acid (PUFA) metabolism in particular contribute to heightened innate immunity, remains to be determined., Objective: To determine if oxylipins, metabolic products of PUFA metabolism, enhance innate immune reactivity alone and/or following exposure to LPS., Methods: Plasma and peripheral blood mononuclear cells (PBMC) were collected from 35 NAFLD patients and 8 healthy controls. Oxylipin levels were documented by HPLC-MS/MS, cytokines (IL-1, IL-6, IL-10, and TNF-α) by ELISA, and chemokine receptors (CCR1 and CCR2) by flow cytometry., Results: Mean plasma levels of four pro-inflammatory oxylipins (Tetranor 12-HETE, 20-HETE, 8-HETrE, and 7-HDoHE) were significantly elevated in NAFLD patients compared to healthy controls. However, the levels did not correlate with the severity of liver injury as reflected by serum aminotransferases, ck18M30, and Fib-4 determinations. In vitro, 20-HETE (0.01-100 nM), the plasma oxylipin with the most significantly elevated plasma levels, did not alter NAFLD or control PBMC cytokine release or enhance the increases in cytokine release following 24 h of LPS exposure. Similarly, 20-HETE alone did not alter PBMC CCR1 or CCR2 expression or LPS-induced downregulation of these receptors., Conclusions: Pro-inflammatory oxylipin levels are increased in NAFLD, but these metabolites do not appear to drive short-term direct or LPS-induced increases in PBMC cytokine release or chemotaxis.

Cyanobacteria or blue-green algae are becoming increasingly abundant in North American fresh water lakes. Toxins produced by cyanobacteria have been associated with gastrointestinal injury, liver failure, and nephrotoxicity. They have also been implicated in the pathogenesis of gastrointestinal and liver cancers. The purpose of the present study was to determine whether the incidence rates of gastrointestinal, liver, and urologic cancers are increasing in the province of Manitoba and, if so, whether these increases spatially and/or temporally correlate with areas where cyanobacterial contamination of fresh water lakes have been identified. Cancer incidence data were obtained from the Manitoba Cancer Registry. Cyanobacterial contamination data, as reflected by microcystin toxin concentrations, were available from the Manitoba Water Stewardship. ArcGIS mapping was employed to document spatial and temporal relationships between cancer incidence and cyanobacterial data. The results revealed that although the incidence rates for all three cancers have increased over the past 20-25 years, these increases were not disproportionally higher in zones with high microcystin toxin determinations. The results of this study argue against increased exposure to cyanotoxins as an explanation for the increase in gastrointestinal, liver and urologic cancers in Manitoba.

Introduction and Aim: Low serum ceruloplasmin levels can occur in patients without Wilson's disease (WD) liver disorders. When present, extensive, costly, and potentially harmful additional investigations for WD may be undertaken. The purpose of this study was to document the prevalence of low serum ceruloplasmin levels in adult patients without WD and describe the features commonly associated with this finding., Materials and Methods: Serum ceruloplasmin levels were measured by an enzymatic assay in 3040 adult patients attending an urban, liver diseases outpatient clinic., Results: A total of 122 (4.0%) patients without WD had serum ceruloplasmin levels less than the lower limit of normal documented at their initial visit. Their mean age was 44 ± 14 years, and 80 (66%) were men. The Model for End-stage Liver Disease (MELD) score was 9.0 ± 4.0. Approximately, one half (65/122, 53%) had underlying viral hepatitis (52% hepatitis B and 48% hepatitis C). When compared with 64 MELD-matched control patients with normal or elevated serum ceruloplasmin levels, there were no significant differences in liver enzyme/function tests, ferritin, creatinine values, or survival. However, the low serum ceruloplasmin cohort patients were younger (43 ± 14 versus 52 ± 13 years, p = 0.0002), less often men (66% vs. 88%, p = 0.001), and viral hepatitis was significantly more common (53% versus 27%, p = 0.0005)., Conclusion: Low serum ceruloplasmin levels were documented in 4.0% of adult patients without WD attending this urban liver diseases outpatient clinic. These patients tend to be younger, less often men, and more often have viral hepatitis as the underlying cause of their liver disease., (© 2019 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Recent data suggest intestinal immunity including immunoglobulin A (IgA) may contribute to the pathogenesis of alcohol-induced liver disease (ALD)., Methods: We documented serum IgA levels in ALD patients and determined whether those with elevated levels of IgA (E-IgA) had similar, more, or less advanced disease and different rates of progression than those with normal levels of IgA (N-IgA). Standard liver function tests (bilirubin, international normalized ratio [INR], and albumin), model for end-stage liver disease (MELD), and Fibrosis-4 (FIB-4) scores were used as indicators of disease severity., Results: From the study centre's clinical database, we identified 175 adult patients with ALD, 107 (61%) with E-IgA and 68 (39%) with N-IgA. Gender distribution and mean age of the two cohorts were similar. E-IgA patients had biochemical evidence of more advanced liver disease (higher serum bilirubin and INR and lower albumin levels) than N-IgA patients ( p s < .05). E-IgA patients also had significantly higher median MELD and FIB-4 scores ( p s < .01). A higher percentage of E-IgA patients had FIB-4 values in keeping with advanced fibrosis or cirrhosis (55% versus 28%, p = .02). After mean follow-up periods of approximately 4 years, liver biochemistry and MELD and FIB-4 scores changed to similar extents in the two cohorts., Conclusions: Serum IgA levels were increased in approximately 70% of ALD patients. Although these patients had biochemical and non-invasive indicators of more advanced disease, elevations in serum IgA levels do not predict disease progression; therefore, IgA is unlikely to be of importance in the pathogenesis of ALD., Competing Interests: None to declare., (Copyright © 2020 Canadian Association for the Study of the Liver.)