Ethnicity, disease severity, and survival in Canadian patients with primary biliary cholangitis.

BACKGROUND AND AIMS: We investigated associations between ethnicity, survival, and disease severity in a diverse Canadian cohort of patients with primary biliary cholangitis (PBC). APPROACH AND RESULTS: Patients with PBC were included from the Canadian Network for Autoimmune Liver Disease. Ethnicity was defined using a modified list adopted from Statistics Canada, and ethnicities with small samples were grouped. Clinical events were defined as liver decompensation, HCC, liver transplantation, or death. Clinical event-free and liver transplantation-free survival were analyzed using Cox regression. Trajectories of serum liver function tests were assessed over time using mixed-effects regression. Health-related quality of life was assessed using the Short Form 36, the PBC-40 questionnaire, and the 5-D Itch scale and analyzed using mixed-effects regression. The cohort included 1538 patients with PBC from six sites and was comprised of 82% White, 4.7% Indigenous, 5.5% East Asian, 2.6% South Asian, and 5.1% miscellaneous ethnicities. Indigenous patients were the only ethnic group with impaired liver transplant-free and event-free survival compared to White patients (HR, 3.66; 95% CI, 2.23-6.01; HR, 3.09; 95% CI, 1.94-4.92). Indigenous patients were more likely to have a clinical event before diagnosis (10%) than all other ethnic groups despite similar age at diagnosis. Indigenous patients presented with higher alkaline phosphatase, total bilirubin, and GLOBE scores than White patients; and these relative elevations persisted during follow-up. CONCLUSIONS: Indigenous Canadians with PBC present with advanced disease and have worse long-term outcomes compared to White patients.

Prospective Evaluation of Virtual MR Elastography With Diffusion-Weighted Imaging in Subjects With Nonalcoholic Fatty Liver Disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is increasingly common worldwide and can lead to the development of cirrhosis, liver failure and cancer. Virtual magnetic resonance elastography (VMRE), which is based on a shifted apparent diffusion coefficient (sADC), is a potential noninvasive method to assess liver fibrosis without the specialized hardware and expertise required to implement traditional MR elastography (MRE). Although hepatic steatosis is known to confound ADC measurements, previous studies using VMRE have not corrected for hepatic fat fraction. PURPOSE: To compare VMRE, corrected for the confounding effects of unsuppressed fat signal, to MRE and biopsy in subjects with suspected NAFLD. STUDY TYPE: Prospective, cross-sectional. POPULATION: A total of 49 adult subjects with suspected NAFLD (18 male; median age 55 years, range 33-74 years) who underwent liver biopsy. FIELD STRENGTH/SEQUENCE: 3T, diffusion-weighted spin echo planar, chemical-shift encoded (IDEAL IQ) and MRE sequences. ASSESSMENT: Two observers drew regions of interest on sADC, proton density fat fraction and MRE-derived stiffness maps. Fat-corrected sADC values were used to calculate the diffusion-based shear modulus according to the VMRE method. Predicted fibrosis stage for MRE and VMRE was determined using previously published cut-off values. STATISTICAL TESTS: The relationship between VMRE and MRE was assessed with least-squares linear regression (coefficient of determination, R2 ). Agreement between MRE and VMRE-predicted fibrosis stage was evaluated with a kappa coefficient and accuracy compared using McNemar's test. A one-way ANOVA determined if the fat-corrected sADC (VMRE) and MRE differed by fibrosis stage. A P value < 0.05 was considered statistically significant. RESULTS: Least squares regression of VMRE vs. MRE revealed R2  = 0.046 and a slope that was not significantly different from zero (P = 0.14). There was no agreement between MRE and VMRE-predicted fibrosis stage (kappa = -0.01). The proportion of correctly predicted fibrosis stage was significantly higher for MRE compared to VMRE. MRE was significantly associated with fibrosis stage, but fat-corrected sADC was not (P = 0.24). DATA CONCLUSION: Fat-corrected VMRE was not associated with fibrosis stage in NAFLD. Further investigation is required if VMRE is to be considered in subjects with NAFLD. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.

Rusfertide for the treatment of iron overload in HFE-related haemochromatosis: an open-label, multicentre, proof-of-concept phase 2 trial.

BACKGROUND: Hereditary haemochromatosis protein (HFE)-related haemochromatosis, an inherited iron overload disorder caused by insufficient hepcidin production, results in excessive iron absorption and tissue and organ injury, and is treated with first-line therapeutic phlebotomy. We aimed to investigate the efficacy and safety of rusfertide, a peptidic mimetic of hepcidin, in patients with HFE-related haemochromatosis. METHODS: This open-label, multicentre, proof-of-concept phase 2 trial was done across nine academic and community centres in the USA and Canada. Adults (aged ≥18 years) with HFE-related haemochromatosis on a stable therapeutic phlebotomy regimen (maintenance phase) for at least 6 months before screening and who had a phlebotomy frequency of at least 0·25 per month (eg, at least three phlebotomies in 12 months or at least four phlebotomies in 15 months) and less than one phlebotomy per month, with serum ferritin of less than 300 ng/mL and haemoglobin of more than 11·5 g/dL, were eligible. Patients initiated 24 weeks of subcutaneous rusfertide treatment within 7 days of a scheduled phlebotomy at 10 mg once weekly. Rusfertide doses and dosing schedules could be adjusted to maintain serum transferrin iron saturation (TSAT) at less than 40%. During rusfertide treatment, investigators were to consider the need for phlebotomy when the serum ferritin and TSAT values exceeded the patient's individual pre-phlebotomy serum ferritin and TSAT values. No primary endpoint or testing hierarchy was prespecified. Prespecified efficacy endpoints included the change in the frequency of phlebotomies; the proportion of patients achieving phlebotomy independence; change in serum iron, TSAT, serum transferrin, serum ferritin, and liver iron concentration (LIC) as measured by MRI; and treatment-emergent adverse events (TEAEs). The key efficacy analyses for phlebotomy rate and LIC were conducted by use of paired t tests in the intention-to-treat population, defined as all patients who received any study drug and who had pretreatment and at least one post-dose measurement. We included all participants who received at least one dose of rusfertide in the safety analyses. This trial is closed and completed and is registered with ClinicalTrials.gov, NCT04202965. FINDINGS: Between March 11, 2020, and April 23, 2021, 28 patients were screened and 16 (ten [63%] men and six [38%] women) were enrolled. 16 were included in analyses of phlebotomy endpoints and 14 for the LIC endpoint. 12 (75%) patients completed 24 weeks of treatment. The mean number of phlebotomies was significantly reduced during the 24-week rusfertide treatment (0·06 phlebotomies [95% CI -0·07 to 0·20]) compared with 24 weeks pre-study (2·31 phlebotomies [95% CI 1·77 to 2·85]; p<0·0001). 15 (94%) of 16 patients were phlebotomy-free during the treatment period. Mean LIC in the 14 patients in the intention-to-treat population was 1·4 mg iron per g dry liver weight (95% CI 1·0 to 1·8) at screening and 1·1 mg iron per g dry liver weight (95% CI 0·9 to 1·3) at the end of treatment (p=0·068). Mean TSAT was 45·3% (95% CI 33·2 to 57·3) at screening, 36·7% (24·2 to 49·2) after the pretreatment phlebotomy, 21·8% (15·8 to 27·9) 24 h after the first dose of rusfertide, 40·4% (27·1 to 53·8) at the end of treatment, and 32·6% (25·0 to 40·1) over the treatment duration. Mean serum iron was 24·6 µmol/L (95% CI 18·6 to 30·6), 20·1 µmol/L (14·8 to 25·3), 11·9 µmol/L (9·2 to 14·7), 22·5 µmol/L (15·9 to 29·1), and 19·0 µmol/L (15·3 to 22·6) at these same timepoints, respectively. Mean serum ferritin was 83·3 µg/L (52·2 to 114.4), 65·5 µg/L (32·1 to 98·9), 62·8 µg/L (33·8 to 91·9), 150·0 µg/L (86·6 to 213.3), and 94·3 µg/L (54·9 to 133.6) at these same timepoints, respectively. There were only minor changes in serum transferrin concentration. 12 (75%) patients had at least one TEAE, the most common of which was injection site pain (five [31%] patients). All TEAEs were mild or moderate in severity, except for a serious adverse event of pancreatic adenocarcinoma, which was considered severe and unrelated to treatment and was pre-existing and diagnosed 21 days after starting rusfertide treatment. INTERPRETATION: Rusfertide prevents iron re-accumulation in the absence of phlebotomies and could be a viable therapeutic option for selected patients with haemochromatosis. FUNDING: Protagonist Therapeutics.

Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants.

BACKGROUND: Primary biliary cirrhosis is a chronic granulomatous cholangitis, characteristically associated with antimitochondrial antibodies. Twin and family aggregation data suggest that there is a significant genetic predisposition to primary biliary cirrhosis, but the susceptibility loci are unknown. METHODS: To identify genetic loci conferring a risk for primary biliary cirrhosis, we carried out a genomewide association analysis in which DNA samples from 2072 Canadian and U.S. subjects (536 patients with primary biliary cirrhosis and 1536 controls) were genotyped for more than 300,000 single-nucleotide polymorphisms (SNPs). Sixteen of the SNPs most strongly associated with primary biliary cirrhosis were genotyped in two independent replication sets. We carried out fine-mapping studies across three loci associated with primary biliary cirrhosis. RESULTS: We found significant associations between primary biliary cirrhosis and 13 loci across the HLA class II region; the HLA-DQB1 locus (encoding the major histocompatibility complex class II, DQ beta chain 1) had the strongest association (P=1.78x10(-19); odds ratio for patients vs. controls, 1.75). Primary biliary cirrhosis was also significantly and reproducibly associated with two SNPs at the IL12A locus (encoding interleukin-12alpha), rs6441286 (P=2.42x10(-14); odds ratio, 1.54) and rs574808 (P=1.88x10(-13); odds ratio, 1.54), and one SNP at the IL12RB2 locus (encoding interleukin-12 receptor beta2), rs3790567 (P=2.76x10(-11); odds ratio, 1.51). Fine-mapping analysis showed that a five-allele haplotype in the 3' flank of IL12A was significantly associated with primary biliary cirrhosis (P=1.15x10(-34)). We found a modest genomewide association (P<5.0x10(-5)) with the risk of disease for SNPs at the STAT4 locus (encoding signal transducer and activator of transcription 4) and the CTLA4 locus (encoding cytotoxic T-lymphocyte-associated protein 4) and 10 other loci. CONCLUSIONS: Our data show significant associations between primary biliary cirrhosis and common genetic variants at the HLA class II, IL12A, and IL12RB2 loci and suggest that the interleukin-12 immunoregulatory signaling axis is relevant to the pathophysiology of primary biliary cirrhosis. (ClinicalTrials.gov number, NCT00242125.)

Clinical characterization of patients with primary biliary cholangitis: A report from multiple Canadian centres.

Background: Primary biliary cholangitis (PBC) is a rare, chronic autoimmune, cholestatic liver disease affecting approximately 318 per million Canadians. There is limited information regarding the characterization of this patient population in Canada. Consequently, we aim to describe a cohort of PBC patients managed across liver centres serving this type of population. Methods: A cross-sectional examination of 1,125 PBC patient charts at 15 liver centres across Canada was conducted between January 2016 and September 2017. Results: Data from 1,125 eligible patients were collected from 7 Canadian provinces. The patient population was largely female (90.2%), had a median overall age of 61.3 years, and a median overall time since diagnosis of 6.4 years. Of the patients included in the study, 89% were on ursodeoxycholic acid (UDCA) therapy at a median dose of 14.0 mg/kg/day and 4.4% were previously treated with UDCA, whereas 6.6% were never treated with UDCA. Of the patients with available data (n = 1067), 289 (27.1%) presented with alkaline phosphatase (ALP) levels ≥200 IU/L and/or total bilirubin levels ≥21 µmol/L. Assessment of UDCA treatment response revealed that 26.6% and 38.3% of patients were inadequate responders according to the Toronto and Paris-II criteria, respectively. Mortality occurred in 1.2% (14) of patients, with liver-related adverse outcomes being more commonly observed in patients who discontinued UDCA compared to those who are currently on treatment (36.3% and 19.6%, respectively). Conclusion: This study showed that Canadian PBC patients present with demographics and features commonly reported in the literature for this disease. Over one third of PBC patients had inadequate response to UDCA treatment or were not currently being treated with UDCA. Consequently, there is a significant unmet therapeutic need in this Canadian PBC population.

Is pre-treatment liver biopsy necessary for all hepatitis C genotypes?

BACKGROUND: Current practice guidelines recommend liver biopsy prior to treatment of hepatitis C genotype-1 but not for genotype-2/3; this is based on expert opinion, not on published evidence. METHODS: In retrospective analysis of a large trial database prior to the publication of recent guidelines, we compared outcomes in 985 treatment-naïve patients with hepatitis C who did or did not undergo liver biopsy before starting peginterferon alfa-2a plus ribavirin. RESULTS: Physicians elected to treat 141/654 (21.6%) genotype-1 patients and 126/331 (38.1%) genotype-2/3 patients without liver biopsy. There were no differences in baseline characteristics among those with or without pre-treatment liver biopsy, except for female preponderance in genotype-1 patients with liver biopsy. The sustained viral response (SVR) rate was no different amongst genotype-2/3 patients who had a biopsy before treatment with 66.3% SVR vs. 69.8% of those treated without biopsy (p = 0.546), but significantly higher among genotype-1 patients with pre-treatment liver biopsy at 54.6 vs. 44.0% for those treated without a liver biopsy (p = 0.029). In genotype-1 patients with liver biopsy, more patients with cirrhosis had dose adjustments (p = 0.0057) rather than drug discontinuation. There was tendency for earlier discontinuation among patients without pre-treatment liver biopsy. CONCLUSIONS: Pre-treatment liver biopsy was associated with better SVR amongst genotype-1 patients. This improvement may reflect ongoing commitment to completing the treatment course by both patient and physician. In genotype-2/3 patients, pre-treatment liver biopsy may not be essential to maximize SVR rates. This study validates the recommendations of the most recent treatment guidelines for hepatitis C.

HBV coinfection and in-hospital outcomes for COVID-19: a systematic review and meta-analysis.

Background: Since December 2019, there are 30 million confirmed cases of a novel coronavirus disease (COVID-19) secondary to severe acute respiratory syndrome coronavirus 2. As of 2020, hepatitis B virus (HBV) affects more than 200 million people worldwide. Both are caused by viral agents. The short-term mortality rate from COVID-19 is much higher than that of HBV. Objective: We sought to understand the impact of HBV coinfection on hospitalized patients with COVID-19. Search Methods: Searches of the literature were conducted in the PubMed, Cochrane Library, and Embase electronic databases. Selection Criteria: We included cohort studies and randomized studies with information on rates of mortality and intensive care unit (ICU) admission from individuals coinfected by HBV and COVID-19. Data Collection and Analysis: Data from six cohort studies with 2,015 patients were collected between January and April 2020, and the results were analyzed by meta-analysis. Main Results: HBV coinfection did not lead to increased mortality or ICU admission rates among individuals hospitalized for COVID-19 (risk ratio 0.79, 95% CI 0.333-1.83, N = 2,015; adjusted OR = 0.79, 95% CI 0.31-1.98). During their hospital stay, coinfected patients did not appear to have an increased hospital length of stay or risk of hepatitis B reactivation. Conclusions: This systematic review and meta-analysis provides support that HBV is not a significant risk factor for serious adverse outcomes among patients hospitalized for COVID-19 infection.

Case Report: Combined Intra-Lesional IL-2 and Topical Imiquimod Safely and Effectively Clears Multi-Focal, High Grade Cutaneous Squamous Cell Cancer in a Combined Liver and Kidney Transplant Patient.

Cutaneous squamous cell carcinoma (cSCC) is the second most common non-melanoma skin cancer worldwide, with ever increasing incidence and mortality. While most patients can be treated successfully with surgical excision, cryotherapy, or radiation therapy, there exist a subset of patients with aggressive cSCC who lack adequate therapies. Among these patients are solid organ transplant recipients who due to their immunosuppression, develop cSCC at a dramatically increased rate compared to the normal population. The enhanced ability of the tumor to effectively undergo immune escape in these patients leads to more aggressive tumors with a propensity to recur and metastasize. Herein, we present a case of aggressive, multi-focal cSCC in a double organ transplant recipient to frame our discussion and current understanding of the immunobiology of cSCC. We consider factors that contribute to the significantly increased incidence of cSCC in the context of immunosuppression in this patient population. Finally, we briefly review current literature describing experience with localized therapies for cSCC and present a strong argument and rationale for consideration of an IL-2 based intra-lesional treatment strategy for cSCC, particularly in this immunosuppressed patient population.

Rescue therapy using a rifabutin-based regimen is effective for cure of Helicobacter pylori infection.

OBJECTIVE: To evaluate the efficacy of rescue therapy using rifabutin, amoxicillin and a proton pump inhibitor (PPI) in the eradication of Helicobacter pylori in patients who have failed at least one course of PPI-based triple therapy. METHODS: The present study was a single-centre case series of 16 consecutive patients who had received at least one course of standard eradication therapy. Pretreatment evaluation included endoscopy with biopsies for histology and culture for H pylori infection. Treatment consisted of a one-week regimen containing a PPI twice daily, amoxicillin (A) 1 g twice daily and rifabutin (R) 300 mg once daily (PPI-AR). Post-treatment evaluation consisted of a repeat endoscopy with biopsy for histology and culture, or a validated urea breath test at least four weeks after treatment was completed. Pretreatment antibiotic susceptibility to metronidazole, clarithromycin and A was evaluated using a validated epsilometer test. RESULTS: Of the 16 patients, four had previously received one course of triple therapy, 10 had received two courses and two had received more than two courses. The overall success rate of PPI-AR was 63% (10 of 16). Resistance to A was 0% (0 of 13), metronidazole 77% (10 of 13), clarithromycin 70% (seven of 10), and both metronidazole and clarithromycin 60% (six of 10). There was no correlation between resistance patterns and cure rate. CONCLUSIONS: An R-containing regimen such as PPI-AR is a viable option as rescue therapy for H pylori infection.

The 1F7 idiotype is selectively expressed on CD5+ B cells and elevated in chronic hepatitis C virus infection.

Antibodies against different chronic viruses, including hepatitis C virus (HCV), express a public cross-reactive idiotype (Id) designated as 1F7. The prominence of this Id may reflect selective engagement of B1 B cells by chronic pathogens. We investigated this by comparing 1F7 Id expression on CD5(+) and CD5(-) B cells, total IgG, total IgM and anti-HCV core antibodies in different HCV exposure settings. By flow cytometry, we observed a selective increase in 1F7 Id(+)CD5(+) B cells in chronic HCV infection. 1F7 Id levels in different immunoglobulin compartments were measured by enzyme-linked immunosorbent assay. 1F7 Id expression was prominent in anti-HCV core antibodies of approximately 90% of 141 HCV-exposed individuals tested. In the Canadian and Armenian study groups, participants who spontaneously cleared HCV infection had lower median 1F7 Id levels on total plasma IgG and anti-HCV core antibodies. Armenian spontaneous clearers, who were younger and more recently infected than their Canadian counterparts, also had had lower median 1F7 Id levels on total plasma IgM. Engagement by HCV of B-cell receptors within, or overlapping with the CD5(+) B1 B-cell repertoire is reflected in the production of 1F7 Id(+) anti-HCV antibodies and expansion of 1F7 Id(+)CD5(+) B cells. Higher 1F7 Id expression levels are associated with chronic infection.

Safety and effectiveness of ezetimibe in liver transplant recipients with hypercholesterolemia.

Hypercholesterolemia is a common problem among transplant recipients. Despite package-insert warnings about the potential side effects of the use of statins in patients with chronic liver disease, they are often prescribed for liver transplant recipients. Unlike statins, ezetimibe acts through inhibition of enterohepatic recirculation of lipids. We report the effectiveness and safety of ezetimibe among liver transplant recipients because this has been evaluated previously only in kidney and heart transplant patients. A consecutive cohort of 25 liver graft recipients with serum low-density lipoprotein (LDL) levels > 100 mg/dL (2.5 mmol/L) after a mean (+/-standard deviation) of 55 +/- 21 months following liver transplantation received ezetimibe (10 mg orally every day) for at least 6 months. Serum lipid profiles, liver and renal function tests, and dosages and blood levels of the immunosuppression drugs at baseline, 3 months, and 6 months were prospectively collected. The overall mean age was 58 +/- 12 years, and 56% were males. Statin therapy and fibrates were already being used in 32% and 20% of recipients for elevated LDL and/or triglycerides, respectively. The immunosuppression regimen included cyclosporine in 48% of subjects, tacrolimus in 32%, sirolimus in 48%, and mycophenolate mofetil in 44%; only 12% were on oral prednisone with a maximum daily dose of 5 mg. After ezetimibe was started, an 18% reduction in LDL values was observed [at baseline, 147 +/- 35 mg/dL (3.8 +/- 0.9 mmol/L), and at 6 months, 120 +/- 31 mg/dL (3.1 +/- 0.8 mmol/L); P = 0.010]. After 6 months, an additional 32% achieved the target LDL level of <100 mg/dL. None of the remaining variables, including immunosuppression drug levels, varied significantly during ezetimibe therapy. None of the subjects required adjustments in their pharmacological dosages. One discontinued ezetimibe 3 months later because of cost, 2 subjects had minimal nausea, 1 subject had myalgias without a rise in creatine phosphokinase, and 1 subject had a transient elevation (3-5 times) in liver enzymes from baseline with increases in the total and indirect bilirubin levels. In conclusion, among liver transplant recipients, hypercholesterolemia can be effectively treated with ezetimibe with few side effects and no interaction with immunosuppressive regimens.

Cannabis and the liver: Things you wanted to know but were afraid to ask.

Many Canadians use cannabis for medicinal and recreational purposes. We describe the current understandings of how cannabis is metabolized in the liver and its potential interactions with other common drugs. We also summarize how cannabis may exert various effects in chronic liver diseases (CLDs), especially in chronic hepatitis C virus (HCV) and fatty liver disease.

Enhanced IL-10 production in response to hepatitis C virus proteins by peripheral blood mononuclear cells from human immunodeficiency virus-monoinfected individuals.

BACKGROUND: Multiple immune evasion strategies by which HCV establishes chronic infection have been proposed, including manipulation of cytokine responses. Prior infection with HIV increases the likelihood of chronic HCV infection and accelerates development of HCV-related morbidity. Therefore, we investigated in vitro cytokine responses to HCV structural and non-structural proteins in peripheral blood mononuclear cells (PBMC) from uninfected, HIV-infected, HCV-infected and HIV/HCV-coinfected individuals. RESULTS: Intracellular flow cytometry was used to assess IL-2, IL-10, IL-12, and IFN-gamma production by freshly isolated PBMC incubated for 16 hours with recombinant HCV core, non-structural protein 3 (NS3), and NS4 proteins. Anti-HCV cellular responses were assessed in HIV/HCV-coinfected individuals by 3H-thymidine proliferation assay. Exposure to HCV antigens increased IL-10 production by PBMC, especially in uninfected and HIV-monoinfected individuals. This IL-10 response was attenuated in chronic HCV infection even with HCV/HIV-coinfection. The cells producing IL-10 in response to HCV proteins in vitro matched a PBMC subset recently shown to constitutively produce IL-10 in vivo. This subset was found at similar frequencies in uninfected, HIV-infected, HCV-infected and HIV/HCV-coinfected individuals before exposure to HCV proteins. HCV-specific T cell proliferation was detectable in only one HIV/HCV-coinfected individual who demonstrated no HCV-induced IL-10 response. CONCLUSION: This pattern suggests that selective induction of IL-10 in uninfected individuals and especially in HIV-monoinfected individuals plays a role in establishing chronic HCV infection and conversely, that attenuation of this response, once chronic infection is established, favours development of hepatic immunopathology.

Epidemiology and liver transplantation burden of primary biliary cholangitis: a retrospective cohort study.

BACKGROUND: There is a wealth of data documenting the epidemiology of primary biliary cholangitis (PBC) globally; however, the epidemiology of PBC has not been as well studied in Canada. Our study characterized the Canadian prevalence of PBC and the number of liver transplantations because of PBC. METHODS: For this retrospective cohort study we used national hospital administrative records from the Canadian Institute for Health Information, with the exception of Quebec for the prevalence estimate and Quebec and British Columbia for the transplant analysis. Prevalent patients were identified through a diagnostic code for PBC of the Canadian version of the 10th revision of the International Classification of Diseases. PBC transplant patients were identified from their transplant record. Descriptive statistics were used to summarize the characteristics of the study cohorts. RESULTS: In 2015, 8680 patients with PBC were identified in Canada, translating to a prevalence of 318 cases per million. Annual prevalence by province varied, ranging from 283 (95% confidence interval [CI] 269-297) cases per million to 465 (95% CI 426-504) cases per million, and the 6-year PBC liver transplantation rate ranged from 3.17 (95% CI 1.27-6.54) to 5.92 (95% CI 3.71-9.08) per million. The Atlantic provinces exhibited the highest PBC prevalence and close to the highest 6-year liver transplantation rate (465 [95% CI 426-504] cases per million and 5.70 [95% CI 426-504, 3.19-9.56] cases per million, respectively). We observed the lowest PBC prevalence (283 [95% CI 269-297] cases per million) and the second lowest 6-year liver transplantation rate in Ontario (3.37 [95% CI 2.47-4.50] cases per million). INTERPRETATION: The prevalence of PBC that we found in Canada is similar to the prevalence reported in other studies, but our work also indicates geographic variation within this country. Given our finding of geographic clustering of PBC across Canada, we hypothesize that environmental and genetic factors contribute to the pathogenesis of this condition.

Complementary and alternative medicine use by patients chronically infected with hepatitis C virus.

Complementary and alternative medicine (CAM) is becoming increasingly popular in North America. The use of CAM is also popular in patients with chronic liver disease but is not well documented. The extent of use of CAM in chronic hepatitis C virus (HCV) infected patients was determined, and the demographic and clinical data between users and nonusers of CAM was compared. Seventy-six patients (30% female) with chronic HCV were interviewed. The mean age was 43+/-8 years. Current use of CAM for HCV was reported by 35 of 76 patients (46%). Eighteen of 76 patients within this group used herbal supplements (24%). The most commonly used herb was Silybum marianum (milk thistle), reported by 10 of 76 patients (13.2%). Commonly reported benefits of CAM use included reduction in fatigue, boost in the immune system and improved gastrointestinal function. No adverse effects of CAM use were reported. In the present study, four of 18 patients (22%) with chronic liver disease taking herbal therapies were on herbs that increased bleeding time. The use of CAM in chronic HCV patients is significant. Patients should be asked specifically about their use of CAM. CAM use may have implications affecting conventional treatment and management of HCV.

Tacrolimus as intervention in the treatment of hyperlipidemia after liver transplant.

BACKGROUND: To measure the effect on serum lipids and other risk factors for cardiovascular disease, we converted the primary immunosuppression of dyslipidemic stable liver transplant recipients from cyclosporine A to tacrolimus. METHODS: Patients underwent a four-month dietary stabilization period (American Heart Association Step II diet) and serum lipid samples were collected for analysis at a central laboratory. After conversion, dietary counseling and lipid analyses were performed over a six-month postconversion observation period. RESULTS: Enrollment was terminated prematurely due to low patient recruitment rates. Thirteen patients were enrolled and provided postconversion data showing surprisingly strong results. At six months postconversion, total cholesterol (C) was reduced by a mean of 0.61 mmol/L (P=0.017), high density lipoprotein cholesterol (HDL-C) remained unchanged; the mean total C:HDL-C ratio was reduced by 0.87 (P=0.001). Low density lipoprotein cholesterol (LDL-C) reductions were not statistically significant, but we observed a significant and persistent decrease in apolipoprotein B (-0.15 g/L six months postconversion, P=0.031). No changes in homocysteine or in vitamins B6 and B12 were discerned, but although red cell folate remained stable, serum folate increased after conversion. We observed no rejection episodes or any other clinically notable events following conversion. CONCLUSIONS: In this study, conversion from cyclosporine to tacrolimus provided a safe and well-tolerated alternative that reduced hyperlipidemia and other recognized cardiovascular risk factors.

Poor prediction of the glomerular filtration rate using current formulas in de novo liver transplant patients.

The utility of formulas estimating glomerular filtration rate (GFR) in liver transplant patients has not been well described. The purpose is to determine the correlation between the radionuclide GFR (rGFR) with formulas commonly used to estimate GFR. This study represented a secondary outcome measure of a multicenter randomized trial comparing the effectiveness of two immunosuppressive regimens in adult liver transplant patients (n=148). A total of 68 rGFR were measured, 33 at baseline and at 35 at three months after transplantation. GFR was estimated using 1/Scr and Cockcroft-Gault, MDRD, and Nankivell equations. At both time points assessed, all correlations with rGFR were poor: 1/Scr (r: 0.17 and 0.25), Cockcroft-Gault (r: 0.31 and 0.35), MDRD (r: 0.27 and 0.35), and Nankivell (r: 0.11 and 0.20). Accepted formulas to estimate GFR correlate poorly with rGFR during the first three months after liver transplantation. Recalibration of these formulas is required to improve the estimation of GFR in liver transplant patients.