Elsbeth Henderson

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.

Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: Implications for prognosis and clinical management

BACKGROUND AND AIMS There remains uncertainty about the natural history of non-alcoholic fatty liver disease (NAFLD). The spectrum of NAFLD includes non-alcoholic fatty liver (NAFL; steatosis without hepatocellular injury) and steatohepatitis (NASH; steatosis with hepatocyte ballooning degeneration±fibrosis). Our aim was to assess the histological severity of NAFLD in a cohort with serial biopsy data, and determine factors predicting progression. METHODS Patients with two liver biopsies more than a year apart were identified. Clinical and laboratory data were collected from the time of liver biopsy. RESULTS 108 patients had serial biopsies (median interval 6.6years, range 1.3-22.6). 81 (75%) patients had NASH and 27 had NAFL. Overall, 45 (42%) patients had fibrosis progression, 43 (40%) had no change in fibrosis, while 20 (18%) had fibrosis regression. Importantly, no significant difference in the proportion exhibiting fibrosis progression was found between those with NAFL or NASH at index biopsy (37% vs. 43%, p=0.65). Progression to NASH was seen in 44% of patients with baseline NAFL. Of 10 patients with NAFL who had fibrosis progression, 3 progressed by 1 stage, 5 by 2 stages and 2 by 3 stages; all had NASH on follow-up biopsy. Of concern, 6 of 27 (22%) patients with baseline NAFL, reached stage 3 fibrosis at follow-up biopsy. Among the patients with NAFL, 80% of those having fibrosis progression were diabetic at the follow-up liver biopsy compared with 25% of non-progressors (p=0.005). CONCLUSIONS Contrary to current dogma, this study suggests that steatosis can progress to NASH and clinically significant fibrosis.

Fatigue in Non-Alcoholic Fatty Liver Disease (NAFLD) is significant and associates with inactivity and excessive daytime sleepiness but not with liver disease severity or insulin resistance.

Objective: To quantify fatigue in non-alcoholic fatty liver disease (NAFLD), to determine whether perceived fatigue reflects impairment of physical function and to explore potential causes. Patients and methods: A cohort study was carried out on 156 consecutive patients with histologically proven NAFLD studied in two cohorts. Phase 1 determined the perceived fatigue experienced by NAFLD patients (assessed using the Fatigue Impact Scale (FIS)) in comparison with normal and liver disease controls, and the relationship to physical function (actigraphy). In phase 2, biological associations of fatigue in NAFLD were explored. Results: Fatigue was markedly higher in NAFLD patients than in controls (mean (SD) FIS 51 (38) vs 8 (12), p<0.001). NAFLD patients showed significantly lower physical activity over 6 days (7089 (2909) mean steps/day vs 8676 (2894), p = 0.02). A significant inverse correlation was seen between FIS and physical activity (r2 = 0.1, p = 0.02). Fatigue experienced by NAFLD patients was similar to that in primary biliary cirrhosis (n = 36) (FIS 64 (9) vs 61 (2), p = NS). No association was seen between FIS and biochemical and histological markers of liver disease severity or insulin resistance (homeostasis model assessment (HOMA)) (r2<0.005). Significant association was seen between fatigue severity and daytime somnolence (Epworth Sleepiness Scale) (r2 = 0.2, p<0.001). Conclusion: Fatigue is a significant problem in NAFLD, is similar in degree to that in primary biliary cirrhosis patients and is associated with impairment in physical function. Fatigue in NAFLD appears to be unrelated to either severity of underlying liver disease or insulin resistance, but is associated with significant daytime somnolence.

Non-Alcoholic Fatty Liver Disease in Older People

Background: Non-alcoholic fatty liver disease (NAFLD) is principally a disease of middle and old age. Previous studies reported it to be benign in old age, however more recent studies suggest an increased mortality in the >60-year-olds. Objectives: To define the prevalence of risk factors and the laboratory and histological differences between different age groups with NAFLD, in order to confirm/refute findings in previous smaller studies. Methods: Retrospective, cohort study set in a tertiary liver clinic in the UK. 351 consecutive patients with biopsy-proven NAFLD were divided into an older (≥60), a middle-aged (≥50 to <60) and a younger (<50) group. Blood pressure, body mass index, serum lipids, glucose, HbA1C, albumin, liver enzymes, bilirubin, mean cell volume (MCV), platelets, and insulin resistance were recorded. In addition, liver biopsy was analyzed for steatosis, inflammation and fibrosis. Results: Older patients had significantly more risk factors (hypertension, obesity, diabetes, hyperlipidaemia). Albumin, alanine aminotransferase (ALT), ALT/aspartate aminotransferase ratio and platelets significantly reduced with advancing age. MCV and alkaline phosphatase significantly increased with increasing age. Older patients had significantly greater fibrosis on biopsy with less percentage fat, with the cirrhotic patients being significantly older than non-cirrhotics. Insulin resistance was similar in younger and older groups. Conclusion: NAFLD affects mainly the middle-aged and the elderly. With advancing age come more risk factors for its development. Older patients show more severe biochemical, haematological and histological changes, with cirrhotics having a significantly greater age than those with milder disease.

Plasma DNA methylation: a potential biomarker for stratification of liver fibrosis in non-alcoholic fatty liver disease

Objective Liver biopsy is currently the most reliable way of evaluating liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). Its inherent risks limit its widespread use. Differential liver DNA methylation of peroxisome proliferator-activated receptor gamma (PPARγ) gene promoter has recently been shown to stratify patients in terms of fibrosis severity but requires access to liver tissue. The aim of this study was to assess whether DNA methylation of circulating DNA could be detected in human plasma and potentially used to stratify liver fibrosis severity in patients with NAFLD. Design Patients with biopsy-proven NAFLD and age-matched controls were recruited from the liver and gastroenterology clinics at the Newcastle upon Tyne Hospitals NHS Foundation Trust. Plasma cell-free circulating DNA methylation of PPARγ was quantitatively assessed by pyrosequencing. Liver DNA methylation was quantitatively assessed by pyrosequencing NAFLD explant tissue, subjected to laser capture microdissection (LCM). Patients with alcoholic liver disease (ALD) were also subjected to plasma DNA and LCM pyrosequencing. Results 26 patients with biopsy-proven NAFLD were included. Quantitative plasma DNA methylation of PPARγ stratified patients into mild (Kleiner 1–2) and severe (Kleiner 3–4) fibrosis (CpG1: 63% vs 86%, p<0.05; CpG2: 51% vs 65% p>0.05). Hypermethylation at the PPARγ promoter of plasma DNA correlated with changes in hepatocellular rather than myofibroblast DNA methylation. Similar results were demonstrated in patients with ALD cirrhosis. Conclusions Differential DNA methylation at the PPARγ promoter can be detected within the pool of cell-free DNA of human plasma. With further validation, plasma DNA methylation of PPARγ could potentially be used to non-invasively stratify liver fibrosis severity in patients with NAFLD. Plasma DNA methylation signatures reflect the molecular pathology associated with fibrotic liver disease.

Are simple noninvasive scoring systems for fibrosis reliable in patients with NAFLD and normal ALT levels

Background Nonalcoholic fatty liver disease (NAFLD) is common and many affected individuals have normal-range alanine aminotransferase (ALT) levels. There is a need for a robust screening tool to triage individuals with advanced fibrosis for specialist care. Aim The aim of this study was to assess the performance of noninvasive fibrosis tests in patients with biopsy-proven NAFLD and normal levels of ALT. Methods Patients presenting at a fatty liver clinic between 1999 and 2009 were included in the study. Liver biopsies were assessed using the Kleiner score. The aspartate aminotransferase (AST)/ALT ratio, BARD, FIB-4 and NAFLD fibrosis scores were calculated. Results A total of 305 patients were included [70 with normal ALT levels (women: ALT⩽30 IU/l, men: ALT⩽45 IU/l) and 235 with elevated levels]. In total, 24% of patients with normal ALT levels and 17% of those with elevated ALT levels had advanced fibrosis (Kleiner stage 3–4). The FIB-4 performed best in identifying advanced fibrosis in patients with normal ALT (area under receiver operating characteristic curve=0.86, 82% sensitivity, 77% specificity and 92% negative predictive value). The sensitivity of the AST/ALT ratio and BARD and NAFLD fibrosis scores for advanced fibrosis was good in patients with normal ALT levels (94, 94 and 82%, respectively), but the specificity was low (44, 26 and 51%, respectively). The FIB-4 yielded best results in patients with elevated ALT levels. Using the FIB-4, 61% of patients with normal ALT levels and 63% of those with elevated ALT levels could avoid liver biopsy to exclude advanced fibrosis. In contrast, AST/ALT ratio and BARD and NAFLD scores would have led to a high proportion of patients with mild disease having to undergo a biopsy. Conclusion The FIB-4 yielded good results in patients with normal or elevated ALT levels, reliably excluding advanced fibrosis and reducing the need for liver biopsy.

Serum immunoglobulin levels predict fibrosis in patients with non-alcoholic fatty liver disease

BACKGROUND & AIMS A third of the population are estimated to have NAFLD of varying severity. Serum immunoglobulins are frequently elevated in patients with chronic liver disease, but little is known about serum immunoglobulin levels in patients with NAFLD. Aim of this study was to evaluate serum immunoglobulin levels (IgA, IgG, and IgM) in a large cohort of patients with biopsy-proven NAFLD and determine if immunoglobulin levels are associated with clinical or histological features. METHODS Patients seen in a tertiary fatty liver clinic between 1999 and 2009 were included. Liver biopsies were assessed using the Kleiner score. Immunoglobulin levels and other blood tests were taken at time of biopsy. RESULTS 285 patients (110 simple steatosis and 175 NASH) had serum immunoglobulins measured within 6months of liver biopsy. 130 (46%) patients had elevated (>1× upper limit of normal) serum IgA levels, 28 (10%) patients had elevated IgG and 22 (8%) raised IgM. Serum IgA levels were elevated more frequently in patients with NASH compared with subjects with simple steatosis (55% vs. 31%, p<0.001). Overall, 55 (19%) patients had advanced liver fibrosis (Kleiner stage 3-4). There was a significant positive association between serum IgA levels and the stage of fibrosis (p<0.001). Serum IgA, age, platelets, AST/ALT ratio and BMI were all independently with advanced fibrosis following multivariate analysis. A model constructed from these independent predictors accurately predicted advanced fibrosis (AUROC 0.87). CONCLUSIONS The serum IgA level was frequently elevated in patients with NAFLD and was an independent predictor of advanced fibrosis.

Theophylline improves steroid sensitivity in acute alcoholic hepatitis.

Corticosteroid therapy has shown some benefit in severe acute alcoholic hepatitis (AAH); however, this is limited by uncertainty in patient selection and variable clinical response. Theophylline has been shown to ameliorate impaired steroid sensitivity in chronic obstructive pulmonary disease by facilitating corticosteroid‐induced silencing of proinflammatory genes. We aimed to explore the mechanistic basis of the variable response to corticosteroid therapy seen in patients with AAH and to address the extent to which theophylline can improve this response. The ability of dexamethasone to inhibit phytohemagglutinin‐induced lymphocyte proliferation was assessed by 3H‐thymidine incorporation in 12 severe AAH patients and age‐matched and sex‐matched controls. Steroid sensitivity was measured in terms of Imax, the maximum inhibition of proliferation. The effect of 10−5 M theophylline and, in survivors, change in Imax during recovery were observed. Lymphocyte steroid sensitivity was found to be significantly reduced in AAH compared with controls (Imax 67[±4.5]% versus 95[±2.3]%, P = 0.0002) and correlated with clinical markers of steroid responsiveness. In survivors, Imax increased in recovery. Theophylline 10−5 M significantly increased lymphocyte steroid sensitivity (Imax 86[±6.6]% versus 67[±5.0]%, P = 0.027). Conclusion: Acute alcoholic hepatitis is associated with significant lymphocyte steroid insensitivity, which improves in recovery and can be ameliorated ex vivo by theophylline. This offers potential to rationalize corticosteroid prescribing in AAH and, furthermore, justifies investigation of this novel role for an existing pharmacological agent in this common and frequently fatal condition. (HEPATOLOGY 2010;)

Clinical but not histological factors predict long-term prognosis in patients with histologically advanced non-decompensated alcoholic liver disease.

Alcoholic liver disease (ALD) is a significant threat to public health and a leading cause of death. Despite this, the long‐term clinical course and predictive factors of survival in histologically advanced ALD are not well described.

Cognitive impairment in non-cirrhotic chronic liver disease is unrelated to liver disease severity but associated with ineffective baroreflex function

We read with interest the commentary by Bercik1 emphasising the influence that gut intestinal microflora may have on cognitive function—a model with clear therapeutic implications. We would like to propose, however, that a third party—the presence of autonomic nervous system dysfunction—complicates the relationship between cognitive impairment and gut microflora. In a number of diseases, autonomic dysfunction has been associated with cognitive impairment,2 3 and its presence is associated with impaired gastrointestinal motility, a risk factor for changes in bacterial colonisation. Autonomic dysfunction is a common problem in patients with chronic liver disease (CLD)4—the group of patients highlighted in the commentary as having obvious cognitive problems, as benefiting from treatment aimed at modifying the …