S.F. Stewart

Simple non-invasive fibrosis scoring systems can reliably exclude advanced fibrosis in patients with non-alcoholic fatty liver disease

Background Accurate evaluation of liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD) is important to identify patients who may develop complications. The aim of this study was to compare the diagnostic performance of simple non-invasive tests in identifying advanced fibrosis among patients with biopsy-proven NAFLD. Methods Consecutive patients with biopsy proven NAFLD were recruited from the Newcastle Hospitals Fatty Liver Clinic from 2003 to 2009. The AST/ALT ratio, AST to platelet ratio index, BARD (weighted sum of BMI>28=1 point, AST/ALT ratio>0.8=2 points, diabetes=1 point), FIB-4 (age×AST (IU/l)/platelet count (×109/litre)×√ALT (IU/l)) and NAFLD fibrosis scores were calculated from blood tests taken at time of biopsy. Results 145 patients (82 male (61%), mean age 51±12 years) were included. The mean body mass index was 35±5 kg/m2. 73 subjects (50%) had diabetes. 93 patients (64%) had non-alcoholic steatohepatitis. 27 (19%) had advanced fibrosis (Kleiner stage 3–4). The FIB-4 score had the best diagnostic accuracy for advanced fibrosis (area under receiver operator characteristic curve (AUROC) 0.86), followed by AST/ALT ratio (AUROC 0.83), NAFLD fibrosis score (AUROC 0.81), BARD (AUROC 0.77) and AST to platelet ratio index (AUROC 0.67). The AST/ALT ratio, BARD score, FIB-4 and NAFLD fibrosis scores had negative predictive values greater than 90% (93%, 95%, 95% and 92% respectively). Positive predictive values were modest. In order to exclude advanced fibrosis liver biopsy could potentially be avoided in 69% with AST/ALT ratio, 62% with FIB-4, 52% with NAFLD fibrosis score and 38% with BARD. Conclusions The ALT/AST ratio, FIB-4 and NAFLD fibrosis scores can reliably exclude advanced fibrosis in a high proportion of patients with NAFLD, allowing liver biopsy to be used in a more directed manner.

Analysis of factors predictive of mortality in alcoholic hepatitis and derivation and validation of the Glasgow alcoholic hepatitis score

Introduction: Alcoholic hepatitis is associated with a high short term mortality. We aimed to identify those factors associated with mortality and define a simple score which would predict outcome in our population. Methods: We identified 241 patients with alcoholic hepatitis. Clinical and laboratory data were recorded on the day of admission (day 1) and on days 6–9. Stepwise logistic regression was used to identify variables related to outcome at 28 days and 84 days after admission. These variables were included in the Glasgow alcoholic hepatitis score (GAHS) and its ability to predict outcome assessed. The GAHS was validated in a separate dataset of 195 patients. Results: The GAHS was derived from five variables independently associated with outcome: age (p = 0.001) and, from day 1 results, serum bilirubin (p<0.001), blood urea (p = 0.019) and, from day 6–9 results, serum bilirubin (p<0.001), prothrombin time (p = 0.002), and peripheral blood white blood cell count (p = 0.001). The GAHS on day 1 had an overall accuracy of 81% when predicting 28 day outcome. In contrast, the modified discriminant function had an overall accuracy of 49%. Similar results were found using information at 6–9 days and when predicting 84 day outcome. The accuracy of the GAHS was confirmed by the validation study of 195 patients The GAHS was equally accurate irrespective of the use of the international normalised ratio or prothrombin time ratio, or if the diagnosis of alcoholic hepatitis was biopsy proven or on the basis of clinical assessment. Conclusions: Using variables associated with mortality we have derived and validated an accurate scoring system to assess outcome in alcoholic hepatitis. This score was able to identify patients at greatest risk of death throughout their admission.

Lipid peroxidation contributes to immune reactions associated with alcoholic liver disease

Increasing evidence indicates the involvement of immune reactions in the pathogenesis of alcoholic liver disease. We have investigated whether ethanol-induced oxidative stress might contribute to immune response in alcoholics. Antibodies against human serum albumin modified by reaction with malondialdehyde (MDA), 4-hydroxynonenal (HNE), 2-hexenal, acrolein, methylglyoxal, and oxidized arachidonic and linoleic acids were measured by ELISA in 78 patients with alcoholic cirrhosis and/or hepatitis, 50 patients with nonalcoholic cirrhosis, 23 heavy drinkers with fatty liver, and 80 controls. Titers of IgG-recognizing epitopes derived from MDA, HNE, and oxidized fatty acids were significantly higher in alcoholic as compared to nonalcoholic cirrhotics or healthy controls. No differences were instead observed in the titers of IgG-recognizing acrolein-, 2-hexenal-, and methylglyoxal-modified albumin. Alcoholics showing high IgG titers to one adduct tended to have high titers to all the others. However, competition experiments showed that the antigens recognized were structurally unrelated. Anti-MDA and anti-HNE antibodies were significantly higher in cirrhotics with more severe disease as well as in heavy drinkers with cirrhosis or extensive fibrosis than in those with fatty liver only. We conclude that antigens derived from lipid peroxidation contribute to the development of immune responses associated with alcoholic liver disease.

Mycophenolate mofetil monotherapy in liver transplantation

Chronic renal failure is a major cause of morbidity and mortality after orthotopic liver transplantation. We did a randomised controlled trial of mycophenolate mofetil monotherapy in liver transplant patients who developed renal failure associated with calcineurin-inhibitor (ciclosporin or tacrolimus) immunosuppressive therapy. Although renal failure improved when the calcineurin-inhibitor dose was reduced and ultimately stopped, the trial was stopped when three of five patients on monotherapy developed organ rejection requiring a second transplantation.

AFP, PIVKAII, GP3, SCCA-1 and follisatin as surveillance biomarkers for hepatocellular cancer in non-alcoholic and alcoholic fatty liver disease

BackgroundThe incidence and mortality of hepatocellular cancer (HCC) complicating alcoholic and non-alcoholic fatty liver diseases (ALD and NAFLD) is rising in western societies. Despite knowing the at risk populations for HCC development, the lack of sensitive and specific means of surveillance hampers disease detection at curable stages. The most widely used serum HCC marker is alpha-fetoprotein (AFP), while PIVKA-II, glypican-3 (GP3) and Squamous Cell Carcinoma Antigen -1 (SCCA-1) have been proposed as new biomarkers. Assessment of these HCC biomarkers has largely been performed in patients with viral hepatitis. We conducted a cross sectional study assessing the value of these serum proteins, as well a novel candidate biomarker -follistatin – in patients with HCC arising on a background of ALD or NAFLD.MethodsPre-treatment serum samples from 50 patients with HCC arising on a background of ALD (n = 31) or NAFLD (n = 19) were assessed by specific ELISA assay for PIVKAII, Glypican-3, SCCA-1 and Follistatin. Results were compared and contrasted with a control patient group with biopsy proven steatohepatitis-related cirrhosis (n = 41). The diagnostic accuracy of each of the candidate biomarkers was evaluated using receiver operating characteristic (ROC) curve analysis, reporting the area under the curve (AUC) and its 95% confidence interval (CI). Performance was compared to that of the established biomarker, AFP.ResultsSerum levels of all proteins were assessed by specific ELISA assays. GP3, SCCA-1 and follistatin had no HCC surveillance benefit in these patients. AFP and PIVKAII were superior to the other markers, particularly in combination.ConclusionWe conclude that while novel means of surveillance are urgently required, the combination of AFP and PIVKAII for HCC is an improvement on AFP alone in ALD/NAFLD patients. Furthermore, our data in this homogenous subset of patients- particularly that confirming no role for SCCA-1 – suggests that the choice of optimal biomarkers for HCC surveillance may be determined by the aetiology of underlying chronic liver disease.

Interplay between oxidative stress and immunity in the progression of alcohol-mediated liver injury

Inflammation is recognized increasingly as having an important role in the pathogenesis of alcoholic liver disease (ALD). Nonetheless, the mechanisms by which alcohol maintains hepatic inflammation are still characterized incompletely. Several studies have demonstrated that ethanol-induced oxidative stress promotes immune responses in ALD by stimulating both humoral and cellular reactions against liver proteins adducted to hydroxyethyl free radicals and several lipid peroxidation products. Moreover, ALD patients have autoantibodies targeting cytochrome P4502E1 and oxidized phospholipids. In both chronic alcohol-fed rats and heavy drinkers, the elevation of IgG against lipid peroxidation-derived antigens is associated with tumor necrosis factor-alpha production and the severity of liver inflammation. On this basis, we propose that allo- and autoimmune reactions associated with oxidative stress might contribute to fueling hepatic inflammation in ALD.

The Glasgow Alcoholic Hepatitis Score Identifies Patients Who May Benefit From Corticosteroids.

Introduction: There is no consensus on the pharmacological treatment of alcoholic hepatitis. The Glasgow alcoholic hepatitis score (GAHS) has been shown to be more accurate than the modified Maddrey’s discriminant function (mDF) in the prediction of outcome from alcoholic hepatitis. This study aimed to determine whether the GAHS was able to identify those patients who would benefit from corticosteroids. Methods: 225 patients with an mDF greater than or equal to 32 from five hospital centres in the United Kingdom were reviewed. Patient survival relative to the GAHS and the use of corticosteroids was recorded. Results: 144 patients with an mDF greater than or equal to 32 (64%) also had a GAHS greater than or equal to 9. There was no difference in survival between untreated or corticosteroid-treated patients for those with a GAHS less than 9. For patients with a GAHS greater than or equal to 9 the 28-day survival for untreated and corticosteroid-treated patients was 52% and 78% (p = 0.002), and 84-day survival was 38% and 59% (p = 0.02), respectively. Conclusions: Among patients with an mDF greater than or equal to 32, there was no appreciable benefit from treatment with corticosteroids in patients with a GAHS less than 9. Patients with a GAHS greater than or equal to 9 have an extremely poor prognosis if they are not treated with corticosteroids, or if such treatment is contraindicated.

White cell count and platelet count associate with histological alcoholic hepatitis in jaundiced harmful drinkers

BackgroundPatients with suspected alcoholic hepatitis and a Discriminant Function ≥32 underwent liver biopsy to confirm the diagnosis. Of these (n = 58), 43 had histological features of alcoholic hepatitis and 15 (25%) did not.We aimed to determine the laboratory features that differentiated those patients with a histological diagnosis of alcoholic hepatitis from those without, and assess potential clinical utility.MethodsLaboratory investigations at presentation for each of the histologically confirmed cases of alcoholic hepatitis (n = 43) were compared to those without (n = 15) to determine whether there were differences between the two groups. Univariate analysis was by Mann Whitney U Test and Multivariate analysis was by a stepwise approach.ResultsWhite cell count (16.2 ± 10.5 v 6.9 ± 3.5 (× 109/L); p = 0.0001) and platelet count (178 ± 81 v 98.4 ± 43 (× 109/L); p = 0.0005) were higher in the patients with histological features of alcoholic hepatitis than in those without. The area under the ROC curve for AH diagnosis was estimated to be 0.83 (0.73, 0.94) and 0.81 (0.69, 0.93) for white cell count and platelet count respectively.ConclusionsClinicians cannot accurately differentiate patients with or without alcoholic hepatitis without liver biopsy. This is critically important when deciding on specific therapies such as corticosteroids or when interpreting data from future trials in which biopsy is not mandated. In situations where liver biopsy is unsuitable or unavailable the white cell and platelet counts can be used to determine the likelihood of histological alcoholic hepatitis and guide treatment.

Clinical but not histological factors predict long-term prognosis in patients with biopsy proven advanced alcoholic liver disease

Introduction Alcoholic liver disease (ALD) is a significant and increasing threat to the health of the British population. It remains one of the commonest indications for liver transplantation and a leading cause of death. Despite this, the long term clinical course and predictive factors of survival in advanced ALD have not been well described. We aimed to identify factors that predict 15-year survival in out-patients with biopsy-proven advanced ALD. Methods Patients attending clinic in our institution during early 1996 (n=134) with biopsy proven advanced (stage III or IV) ALD were followed-up for 15 years or until death or transplantation. At baseline, clinical data including alcohol and smoking history, BMI and features of portal hypertension were recorded. Laboratory data (bilirubin, creatinine, sodium, PT, INR and platelet count) were collected. On biopsy, the presence of cirrhosis and histological features (fat severity, lymphocyte and neutrophil infiltration) were scored semi-quantitatively. Results Median age was 51 (29–67) and the majority (72%) were male. All patients had a history of alcohol excess (>80 g/day for men, 50 g/d for women). Patients were followed until death (n=97; median 62 m), OLT (n=5; median 96 m) or are still alive (n=32; median 187 m). Overall, the 5, 10 and 15-year survival was 64, 40 and 26%, respectively. Patient baseline characteristics are shown according to outcome (Abstract PWE-285 table 1). In multivariate analysis age (p=0.01), smoking (p=0.01), persistent drinking (p<0.01) and serum albumin at baseline (p=0.02) were associated with significantly increased risk of death. No histological features correlated with prognosis.Abstract PWE-285 Table 1 Characteristics of cohort according to 15-year survival Characteristic Alive n=32 Dead n=102 OR (95% CI) p Value Age* 48 (44–54) 53 (47–58) 1.08 (1.02 to 1.13) 0.01 Male gender 18 (56.3) 78 (76.5) 2.53 (1.10 to 5.83) 0.03 Smoker 12 (50.0) 72 (72.7) 2.67 (1.07 to 6.65) 0.04 Subsequent abstinence 13 (41.9) 17 (16.8) 0.28 (0.12 to 0.687) 0.01 Ascites 2 (7.1) 20 (20.8) 3.42 (0.75 to 15.64) 0.11 HE 1 (3.6) 4 (4.3) 1.20 (0.13 to 11.20) 0.87 Prev features PHT 8 (26.7) 44 (44.0) 2.16 (0.88 to 5.32) 0.09 Albumin* 44 (42–47) 39 (32–44) 0.83 (0.75 to 0.92) 0.01 Childs Pugh 9 (9–10) 10 (9–12) 1.26 (1.19 to 2.59) 0.01 Conclusion In out-patients with biopsy-proven advanced ALD, clinical but not histological factors determine prognosis. Age, persistent alcohol intake, smoking habit and serum albumin are independent poor prognostic factors. Abstinence from alcohol and smoking cessation should be the priorities in the long-term management of ALD. Competing interests None declared.

Dataset Supplementing The Article A Randomised Controlled Trial Of Losartan As An Anti-Fibrotic Agent In Non-Alcoholic Steatohepatitis

These data supplement the article A randomised controlled trial of Losartan as an antifibrotic agent in non-alcoholic steatohepatitis. Stuart McPherson, Nina Wilkinson, Dina Tiniakos, Jennifer Wilkinson, Alastair Burt, Elaine McColl, Deborah D. Stocken, Nick Steen, Jane Barnes, Nicola Goudie, Stephen Stewart, Yvonne Bury5, Derek Mann, Quentin M. Anstee, Christopher P. Day. Use is free for academic purposes, provided the aforementioned article is appropriately cited. The data consists of anonymised csv data files, described in DataDictionaryFELINE.csv, the final protocol and a blank copy of the case report forms used (both pdf).