Noninvasive scores are poorly predictive of histological fibrosis in paediatric fatty liver disease.

OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children. Roughly a quarter of paediatric patients with NAFLD develop nonalcoholic steatohepatitis and fibrosis. Here, we evaluated the diagnostic accuracy of previously published noninvasive fibrosis scores to predict liver fibrosis in a large European cohort of paediatric patients with NAFLD. METHODS: The 457 patients with biopsy-proven NAFLD from 10 specialized centers were included. We assessed diagnostic accuracy for the prediction of any (F ≥ 1), moderate (F ≥ 2) or advanced (F ≥ 3) fibrosis for the AST/platelet ratio (APRI), Fibrosis 4 score (FIB-4), paediatric NAFLD fibrosis score (PNFS) and paediatric NAFLD fibrosis index (PNFI). RESULTS: Patients covered the full spectrum of fibrosis (F0: n = 103; F1: n = 230; F2: n = 78; F3: n = 44; F4: n = 2). None of the scores were able to accurately distinguish the presence of any fibrosis from no fibrosis. For the detection of moderate fibrosis, area under the receiver operating characteristic curve (AUROC) were: APRI: 0.697, FIB-4: 0.663, PNFI: 0.515, PNFS: 0.665, while for detection of advanced fibrosis AUROCs were: APRI: 0.759, FIB-4: 0.611, PNFI: 0.521, PNFS: 0.712. Fibrosis scores showed no diagnostic benefit over using ALT ≤ 50/ > 50 IU/L as a cut-off. CONCLUSIONS: Established fibrosis scores lack diagnostic accuracy to replace liver biopsy for staging of fibrosis, giving similar results as compared to using ALT alone. New diagnostic tools are needed for Noninvasive risk-stratification in paediatric NAFLD.

Insights into genetic variants associated with NASH-fibrosis from metabolite profiling.

Several genetic discoveries robustly implicate five single-nucleotide variants in the progression of non-alcoholic fatty liver disease to non-alcoholic steatohepatitis and fibrosis (NASH-fibrosis), including a recently identified variant in MTARC1. To better understand these variants as potential therapeutic targets, we aimed to characterize their impact on metabolism using comprehensive metabolomics data from two population-based studies. A total of 9135 participants from the Fenland study and 9902 participants from the EPIC-Norfolk cohort were included in the study. We identified individuals with risk alleles associated with NASH-fibrosis: rs738409C>G in PNPLA3, rs58542926C>T in TM6SF2, rs641738C>T near MBOAT7, rs72613567TA>T in HSD17B13 and rs2642438A>G in MTARC1. Circulating levels of 1449 metabolites were measured using targeted and untargeted metabolomics. Associations between NASH-fibrosis variants and metabolites were assessed using linear regression. The specificity of variant-metabolite associations were compared to metabolite associations with ultrasound-defined steatosis, gene variants linked to liver fat (in GCKR, PPP1R3B and LYPLAL1) and gene variants linked to cirrhosis (in HFE and SERPINA1). Each NASH-fibrosis variant demonstrated a specific metabolite profile with little overlap (8/97 metabolites) comprising diverse aspects of lipid metabolism. Risk alleles in PNPLA3 and HSD17B13 were both associated with higher 3-methylglutarylcarnitine and three variants were associated with lower lysophosphatidylcholine C14:0. The risk allele in MTARC1 was associated with higher levels of sphingomyelins. There was no overlap with metabolites that associated with HFE or SERPINA1 variants. Our results suggest a link between the NASH-protective variant in MTARC1 to the metabolism of sphingomyelins and identify distinct molecular patterns associated with each of the NASH-fibrosis variants under investigation.

A Systematic Review of Animal Models of NAFLD Finds High-Fat, High-Fructose Diets Most Closely Resemble Human NAFLD.

BACKGROUND AND AIMS: Animal models of human disease are a key component of translational hepatology research, yet there is no consensus on which model is optimal for NAFLD. APPROACH AND RESULTS: We generated a database of 3,920 rodent models of NAFLD. Study designs were highly heterogeneous, and therefore, few models had been cited more than once. Analysis of genetic models supported the current evidence for the role of adipose dysfunction and suggested a role for innate immunity in the progression of NAFLD. We identified that high-fat, high-fructose diets most closely recapitulate the human phenotype of NAFLD. There was substantial variability in the nomenclature of animal models: a consensus on terminology of specialist diets is needed. More broadly, this analysis demonstrates the variability in preclinical study design, which has wider implications for the reproducibility of in vivo experiments both in the field of hepatology and beyond. CONCLUSIONS: This systematic analysis provides a framework for phenotypic assessment of NAFLD models and highlights the need for increased standardization and replication.

A minority of somatically mutated genes in pre-existing fatty liver disease have prognostic importance in the development of NAFLD.

BACKGROUND: Understanding the genetics of liver disease has the potential to facilitate clinical risk stratification. We recently identified acquired somatic mutations in six genes and one lncRNA in pre-existing fatty liver disease. We hypothesised that germline variation in these genes might be associated with the risk of developing steatosis and contribute to the prediction of disease severity. METHODS: Genome-wide association study (GWAS) summary statistics were extracted from seven studies (>1.7 million participants) for variants near ACVR2A, ALB, CIDEB, FOXO1, GPAM, NEAT1 and TNRC6B for: aminotransferases, liver fat, HbA1c, diagnosis of NAFLD, ARLD and cirrhosis. Findings were replicated using GWAS data from multiple independent cohorts. A phenome-wide association study was performed to examine for related metabolic traits, using both common and rare variants, including gene-burden testing. RESULTS: There was no evidence of association between rare germline variants or SNPs near five genes (ACVR2A, ALB, CIDEB, FOXO1 and TNRC6B) and risk or severity of liver disease. Variants in GPAM (proxies for p.Ile43Val) were associated with liver fat (p = 3.6 × 10-13 ), ALT (p = 2.8 × 10-39 ) and serum lipid concentrations. Variants in NEAT1 demonstrated borderline significant associations with ALT (p = 1.9 × 10-11 ) and HbA1c, but not with liver fat, as well as influencing waist-to-hip ratio, adjusted for BMI. CONCLUSIONS: Despite the acquisition of somatic mutations at these loci during progressive fatty liver disease, we did not find associations between germline variation and markers of liver disease, except in GPAM. In the future, larger sample sizes may identify associations. Currently, germline polygenic risk scores will not capture data from genes affected by somatic mutations.

Comparison of the Lipidomic Signature of Fatty Liver in Children and Adults: A Cross-Sectional Study.

OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) is an increasingly common condition in children characterised by insulin resistance and altered lipid metabolism. Affected patients are at increased risk of cardiovascular disease (CVD) and children with NAFLD are likely to be at risk of premature cardiac events. Evaluation of the plasma lipid profile of children with NAFLD offers the opportunity to investigate these perturbations and understand how closely they mimic the changes seen in adults with cardiometabolic disease. METHODS: We performed untargeted liquid chromatography-mass spectrometry (LC-MS) plasma lipidomics on 287 children: 19 lean controls, 146 from an obese cohort, and 122 NAFLD cases who had undergone liver biopsy. Associations between lipid species and liver histology were assessed using regression adjusted for age and sex. Results were then replicated using data from 9500 adults with metabolic phenotyping. RESULTS: More severe paediatric NAFLD was associated with lower levels of long chain, polyunsaturated phosphatidylcholines (pC) and triglycerides (TG). Similar trends in pC and TG chain length and saturation were seen in adults with hepatic steatosis; however, many of the specific lipids associated with NAFLD differed between children and adults. Five lipids replicated in adults (including PC(36:4)) have been directly linked to death and cardiometabolic disease, as well as indirectly via genetic variants. CONCLUSION: These findings suggest that, whilst similar pathways of lipid metabolism are perturbed in paediatric NAFLD as in cardiometabolic disease in adults, the specific lipid signature in children is different.

Sclerosing Cholangitis in Pediatric Inflammatory Bowel Disease: Early Diagnosis and Management Affect Clinical Outcome.

OBJECTIVE: To describe the characteristics and clinical course of children and young persons with inflammatory bowel disease (IBD) and sclerosing cholangitis (SC). STUDY DESIGN: Retrospective analysis of clinical characteristics, management, and outcome of two separate cohorts of children and young persons with IBD-SC managed in a tertiary pediatric gastroenterology center and in a tertiary pediatric hepatology center in the UK. RESULTS: Eighty-two pediatric patients (31% female) with IBD-SC and a mean age at diagnosis of 11.9 ± 2.8 years were followed up for a mean of 6.8 ± 3.3 years. The most common type of IBD was ulcerative colitis (55%), followed by unclassified IBD (30%) and Crohn's disease (15%). Autoimmune SC (ASC) was diagnosed in 72%, and small duct SC was diagnosed in 28%. Complication-free and native liver survival were 96% and 100%, respectively, at 5 years after diagnosis and 75% and 88%, respectively, at 10 years after diagnosis. Patients in the gastroenterology center, who were diagnosed with liver disease sooner after diagnosis of IBD compared with the hepatology center cohort (mean, 2.7 ± 6.1 months vs 9.3 ± 19.4 months; P = .03), did not develop liver-related complications during follow-up. CONCLUSIONS: Our data suggest that children with IBD-SC have better clinical outcomes than have been reported previously, particularly if diagnosed early. We recommend prompt assessment for SC, including liver biopsy and biliary imaging, when liver function abnormalities are detected in a children diagnosed with IBD.

The global prevalence and genetic spectrum of lysosomal acid lipase deficiency: A rare condition that mimics NAFLD.

BACKGROUND & AIMS: Lysosomal acid lipase deficiency (LAL-D) is an autosomal recessive condition that may present in a mild form (cholesteryl ester storage disease [CESD]), which mimics non-alcoholic fatty liver disease (NAFLD). It has been suggested that CESD may affect 1 in 40,000 and is under-diagnosed in NAFLD clinics. Therefore, we aimed to estimate the prevalence of LAL-D using analysis of genetic variation in LIPA. METHODS: MEDLINE and EMBASE were systematically searched for previously reported disease variants and prevalence estimates. Previous prevalence estimates were meta-analysed. Disease variants in LIPA were annotated with allele frequencies from gnomAD and combined with unreported major functional variants found in humans. Pooled ethnicity-specific prevalences for LAL-D and CESD were calculated using the Hardy-Weinberg equation. RESULTS: Meta-analysis of existing genetic studies estimated the prevalence of LAL-D as 1 per 160,000 (95% CI 1 per 65,025-761,652) using the allele frequency of c.894G>A in LIPA. A total of 98 previously reported disease variants in LIPA were identified, of which 32/98 were present in gnomAD, giving a prevalence of 1 per 307,482 (95% CI 257,672-366,865). Wolman disease was associated with more loss-of-function variants than CESD. When this was combined with 22 previously unreported major functional variants in LIPA identified in humans, the pooled prevalence of LAL-D was 1 per 177,452 (95% CI 149,467-210,683) with a carrier frequency of 1 per 421. The prevalence is lowest in those of East Asian, South Asian, and Finnish ancestry. CONCLUSION: Using 120 disease variants in LIPA, these data can reassure clinicians that LAL-D is an ultra-rare disorder. Given the therapeutic capability of sebelipase alpha, investigation for LAL-D might be included in second-line metabolic screening in NAFLD. LAY SUMMARY: Lysosomal Acid Lipase Deficiency (LAL-D) is a rare genetic condition that can cause severe liver disease, but it is difficult to diagnose and sometimes can look like simple fatty liver. It was not clear how common LAL-D was and whether many cases were being missed. To study this, we searched for all genetic mutations that could cause LAL-D, calculated how common those mutations were, and added them up. This let us estimate that LAL-D affects roughly 1 in 175,000 people. We conclude that LAL-D is a very rare condition, but it is treatable so may be included in a 'second-line' of tests for causes of fatty liver.

Gathering momentum for the way ahead: fifth report of the Lancet Standing Commission on Liver Disease in the UK.

This report presents further evidence on the escalating alcohol consumption in the UK and the burden of liver disease associated with this major risk factor, as well as the effects on hospital and primary care. We reiterate the need for fiscal regulation by the UK Government if overall alcohol consumption is to be reduced sufficiently to improve health outcomes. We also draw attention to the effects of drastic cuts in public services for alcohol treatment, the repeated failures of voluntary agreements with the drinks industry, and the influence of the industry through its lobbying activities. We continue to press for reintroduction of the alcohol duty escalator, which was highly effective during the 5 years it was in place, and the introduction of minimum unit pricing in England, targeted at the heaviest drinkers. Results from the introduction of minimum unit pricing in Scotland, with results from Wales to follow, are likely to seriously expose the weakness of England's position. The increasing prevalence of obesity-related liver disease, the rising number of people diagnosed with type 2 diabetes and its complications, and increasing number of cases of end-stage liver disease and primary liver cancers from non-alcoholic fatty liver disease make apparent the need for an obesity strategy for adults. We also discuss the important effects of obesity and alcohol on disease progression, and the increased risk of the ten most common cancers (including breast and colon cancers). A new in-depth analysis of the UK National Health Service (NHS) and total societal costs shows the extraordinarily large expenditures that could be saved or redeployed elsewhere in the NHS. Excellent results have been reported for new antiviral drugs for hepatitis C virus infection, making elimination of chronic infection a real possibility ahead of the WHO 2030 target. However, the extent of unidentified cases remains a problem, and will also apply when new curative drugs for hepatitis B virus become available. We also describe efforts to improve standards of hospital care for liver disease with better understanding of current service deficiencies and a new accreditation process for hospitals providing liver services. New commissioning arrangements for primary and community care represent progress, in terms of effective screening of high-risk subjects and the early detection of liver disease.

Evaluations of Lifestyle, Dietary, and Pharmacologic Treatments for Pediatric Nonalcoholic Fatty Liver Disease: A Systematic Review.

BACKGROUND & AIMS: There are no approved treatments for pediatric nonalcoholic fatty liver disease (NAFLD) and there is a lack of consensus on the best outcome measure for randomized controlled trials. We performed a systematic review of treatments tested for pediatric NAFLD, the degree of heterogeneity in trial design, and endpoints analyzed in these studies. METHODS: We searched publication databases and clinical trial registries through January 7, 2018 for randomized controlled trials (published and underway) of children (<18 years) with NAFLD. We assessed improvements in histologic features, radiologic and biochemical markers of reduced fibrosis, metabolic syndrome parameters, and adverse events. The quality of the trials was assessed using a modified version of the Cochrane risk of bias tool. RESULTS: Our final analysis included 21 randomized controlled trials, comprising 1307 participants (mean age, 12.6 years; 63% male; mean duration of intervention, 8 months). Most studies evaluated weight loss with lifestyle intervention (n=8), oral polyunsaturated fatty acid treatment (PUFAs, n=6), or oral antioxidant treatment (n=7). Biomarkers of NAFLD decreased with weight loss, but most studies did not include histologic data. Trials of antioxidants were heterogeneous; some reported reduced histologic features of steatohepatitis with no effect on triglycerides or insulin resistance. PUFAs and probiotics reduced radiologic markers of steatosis, insulin resistance, and levels of triglycerides. Only 38% of the trials had biopsy-proven NAFLD as an inclusion criterion. There was heterogeneity in trial primary endpoints; 10 studies (48%) used levels of aminotransferases or ultrasonography findings as a primary endpoint and only 3 trials (14%) used histologic features as the primary endpoint. We identified 13 randomized controlled trials that are underway in children with NAFLD. None of the protocols include collection of liver biopsies; 9 trials (69%) will use magnetic resonance imaging quantification of steatosis as a primary outcome. CONCLUSIONS: In a systematic review of published and active randomized controlled trials of children with NAFLD, we found a large amount of heterogeneity in study endpoints and inclusion criteria. Few trials included histologic analyses. Antioxidants appear to reduce some features of steatohepatitis. Effects of treatment with lifestyle modification, PUFAs, or probiotics have not been validated with histologic analysis. Trials that are underway quantify steatosis magnetic resonance imaging-outcomes are anticipated.

An AGTR1 Variant Worsens Nonalcoholic Fatty Liver Disease and the Metabolic Syndrome.

Nonalcoholic fatty liver disease and hypertension are closely related but there has been little genetic evidence to link them. In this issue, Musso et al. provide evidence that a common variant in AGTR1 (A1166C) is associated with both incident hypertension and nonalcoholic fatty liver disease, as well as nonalcoholic steatohepatitis, fibrosis, dyslipidemia, and insulin resistance. AGTR1 is strongly expressed in adipose, liver, and arteries. The mechanism of this gain-of-function variant is unclear but may include adipose or endothelial dysfunction and immune activation. Despite previous unsuccessful clinical trials of angiotensin receptor blockers in nonalcoholic steatohepatitis, individuals with the rs5186A>C variant may have greater benefit from this therapy.

The global prevalence of Wilson disease from next-generation sequencing data.

PURPOSE: Wilson disease (WD) is an autosomal recessive disorder of copper metabolism, caused by pathogenic variants in ATP7B. We aimed to (1) perform a meta-analysis of previous WD prevalence estimates, (2) estimate the prevalence of WD from population sequencing data, and (3) generate an ATP7B gene variant database. METHODS: MEDLINE and EMBASE were systematically searched. Previous prevalence estimates were subjected to meta-analysis. All previously reported pathogenic ATP7B variants were compiled and annotated with gnomAD allele frequencies. Pooled global and ethnicity-specific genetic prevalences for WD were generated using the Hardy-Weinberg equation. RESULTS: Meta-analysis of genetic studies of WD prevalence gave an estimate 12.7 per 100,000 (95% confidence interval [CI]: 6.3-23.0). We developed a referenced, searchable ATP7B database comprising 11,520 variants including 782 previously reported disease variants, which can be found at http://www.wilsondisease.tk/ ; 216/782 of these were present in gnomAD, remained after filtering by allele frequency, and met American College of Medical Genetics and Genomics criteria. Based on these, the genetic prevalence of WD was 13.9 per 100,000 (95% CI: 12.9-14.9), or 1 per 7194. Combining this with 60 predicted pathogenic variants gave a birth prevalence of 15.4 per 100,000 (95% CI: 14.4-16.5). CONCLUSION: The genetic prevalence of Wilson disease may be greater than previous estimates.

Nonalcoholic Fatty Liver Disease in Children.

Nonalcoholic steatohepatitis, a progressive form of nonalcoholic fatty liver disease (NAFLD), is one of the most common hepatic diseases in children who present with particular risk factors including obesity, sedentary lifestyle, and/or a predisposing genetic background. The worldwide prevalence of NAFLD in children is a worrying phenomenon because this disease is closely associated with the development of both cirrhosis and cardiometabolic syndrome in adulthood. To date, the etiopathogenesis of primary NAFLD in children is unknown. Understanding the pathogenetic mechanisms provides the basis to characterize early predictors of the disease and noninvasive diagnostic tools and to design novel specific treatments and possible management strategies. Despite a few clinical trials on the use of antioxidants combined with lifestyle intervention for NAFLD, no treatment exists for children with NAFLD. In this review, the authors provide an overview of current concepts in epidemiology, histological features, etiopathogenesis, diagnosis, and treatment of NAFLD in pediatric population.

Fifteen-minute consultation: liver disease in children.

Liver disease in children can present in many ways from the frequently encountered prolonged neonatal jaundice to the comparatively rare acute liver failure. In this article, we will discuss 'red flags' of liver disease, the initial investigations required and when to refer to a specialist liver centre. Across all presentations, the degree of elevation of alanine aminotransferase or aspartate aminotransferase provides only little diagnostic information. Measurement of clotting is vital, and coagulopathy should be followed by a trial of intravenous vitamin K before being repeated.

Portal inflammation is independently associated with fibrosis and metabolic syndrome in pediatric nonalcoholic fatty liver disease.

UNLABELLED: Pediatric nonalcoholic fatty liver disease (NAFLD) histology demonstrates variable amounts of portal inflammation, which may be associated with more severe liver disease and fibrosis. We assessed the relationship between portal inflammation, hepatic fibrosis, and the metabolic syndrome in pediatric NAFLD. Children with biopsy-proven NAFLD were eligible for inclusion. Histology was assessed using Kleiner fibrosis stage and the Nonalcoholic Steatohepatitis Clinical Research Network system for portal inflammation. Patients were divided by histology into type 1, type 2, and overlap NAFLD. Multivariable ordinal logistic regression was used to determine factors associated with fibrosis and portal inflammation. The 430 Caucasian children were divided into 52 with type 1, 95 with type 2, and 283 with overlap NAFLD. Those with type 2 had a more severe metabolic phenotype, with higher body mass index z score (2.0 versus 1.6, P < 0.0001), waist circumference centile (96th versus 90th, P < 0.0001), and triglycerides (84 versus 77 mg/dL, P = 0.01) and lower high-density lipoprotein (46 versus 60 mg/dL, P = 0.004) than those with type 1. Similarly, those with overlap NAFLD had a more severe phenotype. Stage 2-3 fibrosis was present in 69/283 (24%) with overlap NAFLD. Portal inflammation was associated with stage 2-3 fibrosis on multivariable analysis (95% confidence interval 1.4-5.2, odds ratio = 3.7). Waist circumference centile was associated with portal inflammation (95% confidence interval 1.2-3.4, odds ratio = 2.0). CONCLUSION: Portal inflammation is associated with more advanced pediatric NAFLD and features of the metabolic syndrome.

Update on lipid species and paediatric nonalcoholic fatty liver disease.

PURPOSE OF REVIEW: To describe the recent advances in our understanding of fatty acids and lipids in paediatric nonalcoholic fatty liver disease (NAFLD) and their future implications. RECENT FINDINGS: Data have been accumulated to suggest that ceramides are the main drivers of hepatic insulin resistance in NAFLD, and inhibition of ceramide synthesis improves histology in mice.Saturated fatty acids formed by de novo lipogenesis generate increased lipotoxicity compared with dietary-derived saturated fatty acids.Hepatic lipogenesis and associated insulin resistance have been found to be influenced by several novel proteins, including E2F1, cyclic AMP response element binding protein transcriptional coactivator 2, Raptor, and eukaryotic initiation factor 6. There are encouraging data from animal models that modulation of these could be therapeutic targets.Human and animal metabolomics and lipidomics data have been used to generate a lipid signature for NAFLD and nonalcoholic steatohepatitis. Serum lipidomics appears to correlate with hepatic lipidomics.Therapeutic trials of polyunsaturated fatty acids in children have had mixed results, with some reductions in noninvasive biomarkers. SUMMARY: Multiple new pathways for drug targets have been identified, and use of lipidomics is likely to become a noninvasive method for assessing disease. However, much of the data for paediatric NAFLD are extrapolated from adult or animal studies.

Management and outcomes of neonates with down syndrome admitted to neonatal units.

BACKGROUND: Neonates with Down syndrome have an increased risk of being admitted to a neonatal unit compared with unaffected neonates. We aimed to estimate the proportion of neonates with Down syndrome admitted to a neonatal unit and compare their management and outcomes with other neonatal admissions. METHODS: Case-control study of neonates born from 2009 to 2011 admitted to 122 NHS Neonatal Units in England using data from the National Down Syndrome Cytogenetic Register and the National Neonatal Research Database. For each neonate with Down syndrome, three neonates admitted to the same unit in the same month and born at the same gestation were identified. RESULTS: Forty-six percent of neonates with Down syndrome were admitted to a neonatal unit. Boys were more likely to be admitted than girls (odds ratio = 1.7; 95% confidence interval, 1.4-2.0). Neonates with Down syndrome required more intensive or high dependency care compared with unaffected neonates (37% vs. 27%. p < 0.01) and stayed in neonatal units for longer (11 days vs. 5 days, p < 0.01). A total of 31% of neonates with Down syndrome required respiratory support compared with 22% (p < 0.001) of unaffected neonates, and 11% were discharged requiring oxygen supplementation compared with 3% (p < 0.001) of unaffected neonates. A total of 3% of neonates with Down syndrome died in a neonatal unit compared with 1% (p = 0.01) of unaffected neonates. CONCLUSION: Neonates with Down syndrome are more likely than unaffected neonates to be admitted to a neonatal unit, have a prolonged stay, and be discharged home on supplemental oxygen. Birth Defects Research (Part A) 106:468-474, 2016. © 2016 Wiley Periodicals, Inc.

Long-term follow-up of patients with difficult to treat type 1 autoimmune hepatitis on Tacrolimus therapy.

INTRODUCTION: Autoimmune hepatitis (AIH) is an immune-mediated liver disease, which requires long-term immunosuppression. Ten to fifteen percent of patients experience insufficient/intolerance response to standard therapy. Although alternate immunosuppression has been applied, there is little long-term data reported on safety, efficacy, steroid-dose reduction and disease evolution in patients with difficult AIH who were on Tacrolimus therapy. MATERIALS AND METHODS: Clinical, biochemical, immunological profiles, treatment response and side effects of 17 AIH patients treated with Tacrolimus between 2003 and 2014 were analyzed from two tertiary referral liver centers. RESULTS: Tacrolimus was started on 16/17 (94%) patients due to insufficient response to standard therapy. The median duration of treatment was 24 months and patients were followed up for median of 60 months. Tacrolimus dosage was 2 mg/day (median). During first year of therapy, there was a significant improvement in immunoglobulin G and Aspartate transaminase level. 9/17 (52%) compliant and definite AIH patients remained on Tacrolimus at end of follow-up and prednisolone dose reduction was achieved from 10 to 5 mg. All patients are alive and one patient underwent liver transplantation. 4/17 (24%) patients developed overlap with primary sclerosing cholangitis over follow-up period. No significant side effects were observed with Tacrolimus therapy. CONCLUSION: Tacrolimus could be used in compliant patients with difficult to treat AIH in experienced centers. Its use is safe and can improve liver biochemistry, IgG and reduce steroid requirement. However, due to the lack of immunomodulatory effect, unmet need for effective immune-regulatory therapies still remain for AIH patients.

Co-morbidities and mortality associated with intracranial bleeds and ischaemic stroke.

Stroke is a leading cause of mortality and acquired disability; however, there has been no comprehensive comparison of co-morbid risk factors between different stroke subtypes. The aim of this study was to compare risk factors and mortality for subdural haematoma (SDH), subarachnoid haemorrhage (SAH) and ischaemic and haemorrhagic stroke. We compiled a database of all patients admitted with these conditions to a large teaching hospital in Birmingham, United Kingdom during the period 2000-2007 using the International Classification of Disease (ICD) 10th revision codes. Generalised linear models were constructed to calculate relative risks (RRs) associated with co-morbidities. In total, 4804 patients were admitted with diagnoses of SDH (1004), SAH (807), ischaemic stroke (2579) and haemorrhagic stroke (414). Patients with SDH were less likely to have pneumonia (0.492, 95% CI, 0.330-0.734; p < 0.001), whereas alcohol abuse (4.21, 95% CI, 2.82-6.28; p < 0.001) was more common. In SAH, ischaemic heart disease (0.56, 95% CI, 0.40-0.79; p < 0.001) was less common. As expected, a range of cardiovascular risk factors were associated with ischaemic stroke. Epilepsy was positively associated with ischaemic stroke (1.94, 95% CI, 1.36-2.76; p < 0.001), indicating a role for targeted primary prevention in patients with epilepsy. Five-year survival was lower in ischaemic and haemorrhagic strokes (41% and 40% respectively, vs. 73% in SDH and 64% in SAH; p < 0.001). These findings may guide clinical risk stratification, and improve the prognostic information given to patients.