Health inequalities in the management of chronic hepatitis B virus infection in patients from sub-Saharan Africa in high-income countries.

Chronic hepatitis B virus disproportionately affects migrant communities in high-income countries, reflecting increased migration from sub-Saharan Africa. Chronic hepatitis B virus is endemic in sub-Saharan Africa, yet the natural history of chronic infection experienced by patients remains incompletely understood, with evidence of variability across genotypes and regions within sub-Saharan Africa. Clinical guidelines recommending treatment thresholds are not specific to sub-Saharan African patients and are based on natural history studies from Western Pacific Asian countries. Access to standard of care treatment is available for sub-Saharan African people with chronic hepatitis B virus infection in high-income countries; however, the evidence base for these treatments was not established in this cohort and areas of uncertainty remain, particularly regarding HCC surveillance and treatment discontinuation. Participation in phase III clinical trials for chronic hepatitis B therapies is almost non-existent amongst sub-Saharan African patients, even when residing in high-income countries that participate in multicentre trials. Engagement with sub-Saharan African patients with chronic hepatitis B in high-income countries is challenging because of the stigma associated with the diagnosis, absence of routine screening systems and the complexities involved in navigating the healthcare system. Nonetheless, improved engagement is critical if we are to achieve global hepatitis B virus elimination.

Hepatic Dry Copper Weight in Pediatric Autoimmune Liver Disease.

OBJECTIVES: Elevated hepatic dry copper weight is recognized in adults with autoimmune liver disease (AILD) and chronic cholestasis. We aim to review hepatic dry copper weight in pediatric AILD. METHODS: Retrospective review of pediatric AILD managed at our institution from 1999 to 2018, and 104 patients with hepatic dry copper weight assessment were included. RESULTS: Median age at presentation was 13.4 years (interquartile range, IQR, 11.7-14.9), 60% female, 54% autoimmune hepatitis, 42% autoimmune sclerosing cholangitis, and 4% primary sclerosing cholangitis. Histological features of advanced liver fibrosis in 68%. Median hepatic dry copper weight was 51.1 µg/g dry weight (IQR, 28.0-103.8). Elevated hepatic dry copper weight (>50 µg/g dry weight) was present in 51%, and was not associated with AILD subtype ( P = 0.83), age at presentation ( P = 0.68), or advanced fibrosis ( P = 0.53). Liver transplantation (LT) was performed in 10%, who had higher hepatic dry copper weight (148.5 µg/g dry weight [IQR, 39.5-257.3] vs 47.5 [IQR, 27.8-91.5], P = 0.04); however this was not associated with LT on multivariate analysis (hazard ratio 1.002, 95% CI 0.999-1.005, P = 0.23). In 8 (7.7%) patients ATP7B was sequenced and potentially disease causing variants were identified in 2 patients, both who required LT. CONCLUSIONS: Elevations in hepatic dry copper weight are common in pediatric AILD. Unlike in adults, it is not associated with AILD subtypes with cholestasis. Higher dry copper weight was detected in patients who required LT. While further work is needed to identify the significance of copper deposition in pediatric AILD, we recommend close monitoring of patients with elevated levels for progressive liver disease.

Clinical phenotype of adult-onset liver disease in patients with variants in ABCB4, ABCB11, and ATP8B1.

Variants in ATP8B1, ABCB11, and ABCB4 underlie the most prevalent forms of progressive familial intrahepatic cholestasis. We aim to describe variants in these genes in a cohort of patients with adult-onset liver disease, and explore a genotype-phenotype correlation. Patients with onset of liver disease aged above 18 who underwent sequencing of cholestasis genes for clinical purposes over a 5-year period were identified. Bioinformatic analysis of variants was performed. Liver histology was evaluated in patients with variants. Of the 356 patients tested, at least one variant was identified in 101 (28.4%): 46 ABCB4, 35 ABCB11, and 28 ATP8B1. Patients with ABCB4 variants had chronic liver disease (71.7%) and pregnancy-associated liver dysfunction (75%), with a younger age of onset in more severe genotypes (p = 0.046). ABCB11 variants presented with pregnancy-associated liver dysfunction (82.4%) and acute/episodic cholestasis (40%), with no association between age of onset and genotype severity. ATP8B1 variants were associated with chronic liver disease (75%); however, they were commonly seen in patients with an alternate etiology of liver disease and variants were of low predicted pathogenicity. In adults with suspected genetic cholestasis, variants in cholestasis genes were frequently identified and were likely to contribute to the development of liver disease, particularly ABCB4 and ABCB11. Variants were often in heterozygous state, and they should no longer be considered recessive Mendelian traits. Sequencing cholestasis genes in selected patients with adult-onset disease should be considered, with interpretation in close collaboration with histopathologists and geneticists.

Clinical course of inflammatory bowel disease and impact on liver disease outcomes in patients with autoimmune sclerosing cholangitis.

BACKGROUND & AIMS: Autoimmune sclerosing cholangitis (ASC) is a childhood sclerosing cholangitis frequently associated with inflammatory bowel disease (IBD). We describe the IBD phenotype in ASC patients and associated liver disease outcomes. METHODS: Single center retrospective observational review of ASC patients, with a control population of pediatric IBD. Demographic and clinical parameters were obtained. Clinical endpoints were escalation of IBD therapy (biologic or colectomy) and transplant-free survival. RESULTS: In 93 ASC patients (53.8% female) and median follow up of 172 months: 70% had IBD, 25.8% underwent liver transplant. Median age at liver transplant was 21.7 years, at 131 months from ASC diagnosis. There was no association between presence of IBD and transplant-free survival, whilst those requiring second-line immunomodulators for ASC had poorer long-term liver prognosis. During follow-up 22 (33.8%) ASC-IBD required biologic or colectomy. On multivariate analysis ASC was associated with a lower risk of escalation of IBD therapy (HR 0.14, 95% CI 0.05-0.42; P=.001), including biologic therapy (HR 0.21, 95% CI 0.08-0.55, P=.002), but not colectomy on univariate analysis (HR 1.54, 95% CI 0.43-5.44, P=.51). CONCLUSIONS: IBD is common in ASC and during longterm follow up a third of ASC-IBD required escalation of IBD therapy; however ASC-IBD was lower risk compared to IBD alone. IBD does not appear to impact on transplant-free survival in patients with ASC, however second-line immunomodulators for ASC are associated with poorer IBD and liver outcomes.

Epstein-Barr virus status and immunosuppression use in paediatric autoimmune liver disease.

BACKGROUND: Since azathioprine is associated with lymphoproliferative disorders in Epstein-Barr virus (EBV)-naïve patients with inflammatory bowel disease, guidelines advise avoidance. No recommendations exist for autoimmune liver disease (AILD). AIMS: To evaluate EBV status and EBV-related complications in paediatric AILD. METHODS: Single-centre, retrospective, observational study of paediatric AILD. RESULTS: In 245 paediatric patients with AILD, azathioprine was used in 168 (68.6%) and mycophenolate mofetil in 69 (28.2%). EBV status was assessed in 18 (10.7%) prior to azathioprine and 6 (8.7%) MMF. Acute EBV infection was diagnosed in five patients while on immunosuppression, resulting in one transient hepatitis and one persistent hepatitis. There were no cases of lymphoproliferative disorder in native livers. Liver transplantation (LT) was performed in 39 (15.9%) patients, with 8 EBV IgG-negative at LT. Post-LT EBV viraemia developed in 29 (74.4%), first detected at median 26 days (IQR, 13-86). EBV IgG-negative recipients had higher peak viraemia (266 984 IU/mL [IQR, 41108-2429050] v 5333 [IQR, 2036-38770], P = .004) and longer time to peak viraemia (375 days [IQR, 251-884] v 70 [IQR, 21-604], P = .04). Early EBV-associated post-transplant lymphoproliferative disorder (PTLD) was diagnosed in two patients, both EBV-IgG negative with prior azathioprine. CONCLUSIONS: Real-world data demonstrate that EBV serostatus is not routinely checked before immunosuppression for paediatric AILD. Lymphoproliferative disorder was not diagnosed in those with native livers; however, EBV IgG-negative LT recipients receiving EBV IgG-positive donor organs are at risk of early PTLD. Large multicentre studies with longer follow-up are required to further evaluate the risk.

Review article: liver disease in adults with variants in the cholestasis-related genes ABCB11, ABCB4 and ATP8B1.

BACKGROUND: Children with intrahepatic cholestasis and genetic variants which result in the disruption of the formation and maintenance of bile (ABCB11, ABCB4 and ATP8B1) generally have a rapidly progressive clinical course. Adults with different phenotypes of cholestasis are increasingly being evaluated for variants in these genes associated with childhood diseases. AIMS: To review the literature with respect to the presence of variants in cholestasis-related genes in adults with various liver phenotypes, and provide clinical implications of the findings. METHODS: A search of the literature on variants in specific cholestasis-related genes in adults was conducted. RESULTS: The common variant p.Val444Ala in ABCB11 confers increased risk of drug-induced liver injury and intrahepatic cholestasis of pregnancy (ICP). Individuals with variants in ABCB4 are at risk of ICP and low phospholipid-associated cholelithiasis. Variants in ABCB4, and possibly ABCB11 and ATP8B1, can be identified in up to a third of patients with cryptogenic chronic cholestasis. CONCLUSIONS: Individuals with variants in ABCB11 rarely develop cholestasis until BSEP function dips below a threshold, which is also affected by other factors (e.g., drugs, hormones). However, variants in ABCB4 and consequent reduction in MDR3 protein, have a more linear dose-response curve. In individuals with an ABCB11 variant, medications known to reduce BSEP activity should be used cautiously; they should be monitored during pregnancy for ICP; and first-degree relatives should be counselled and screened. No proven management strategy exists, although ursodeoxycholic acid may be beneficial. Further work is needed to define the genotype-phenotype correlation and natural history, and to evaluate the penetrance.

Abdominal tuberculosis: Diagnosis and demographics, a 10-year retrospective review from a single centre.

AIM: To review all cases of abdominal tuberculosis (ATB) for demographic details, diagnostic work up and evidence of vitamin D deficiency. METHODS: This was a retrospective analysis of all patients diagnosed with ATB from June 2003 to August 2013 at St George's Hospital, London. Demographic data was available from the local tuberculosis database. Further clinical information was collected from electronic patient records, including radiology, endoscopy, microbiology, histology, biochemistry and serology. Patients were classified as either confirmed ATB [if mycobacteria tuberculosis (MTB) was cultured from abdominal site] or presumed ATB (if suggestive findings or high clinical suspicion). Subtypes of ATB were classified as tuberculosis (TB) peritonitis, luminal TB, solid organ TB or from a combination of sites. RESULTS: There were a total of 65 cases identified in this time period, with a mean of 6.5 cases per year (range 4-9). Mean age 42 years, 49.2% females. Fifty-two point three percent were South Asian, 38.5% African. Forty-nine point two percent had gastrointestinal endoscopy, 30.8% paracentesis and 24.6% surgery in order to obtain samples. Forty-seven point seven percent were defined as confirmed ATB with positive culture of MTB from abdominal sites, the rest were treated as presumed ATB. Twenty-four point six percent had co-existing sputum culture positive for MTB, and 30.8% had an abnormal chest X-ray. Subtypes of ATB: 35.4% had TB peritonitis; 27.7% luminal TB; 3.1% solid organ TB; and 33.8% TB at a combination of abdominal sites. Thirteen point nine percent were human immunodeficiency virus positive, all with CD4 count less than 300 cells/µL. Seventy point five percent had severe vitamin D deficiency, and 25% were vitamin D deficient. CONCLUSION: ATB mainly affects young South Asian and African patients, with difficulties in confirming diagnosis despite a range of non-invasive and invasive diagnostic tests.

Controversies in the management of primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) remains a rare but significant disease, which affects mainly young males in association with inflammatory bowel disease. There have been few advances in the understanding of the pathogenesis of the condition and no therapeutics with proven mortality benefit aside from liver transplantation. There remain areas of controversy in the management of PSC which include the differentiation from other cholangiopathies, in particular immunoglobulin G4 related sclerosing cholangitis, the management of dominant biliary strictures, and the role of ursodeoxycholic acid. In addition, the timing of liver transplantation in PSC remains difficult to predict with standard liver severity scores. In this review, we address these controversies and highlight the latest evidence base in the management of PSC.