Non‐alcoholic fatty liver disease (NAFLD) covers a spectrum of lesions ranging from steatosis (Non‐alcoholic Fatty Liver or NAFL) to a complex pattern with hepatocellular injury and inflammation ...(non‐alcoholic steatohepatitis; NASH) in the absence of alcohol intake. However, it is increasingly clear that intermediate patterns may exist. The histopathological evaluation of liver biopsy samples is central in the diagnosis of NAFLD and NASH in the absence of sufficiently accurate non‐invasive tests because a precise definition of each group is a key issue. When at least 5% of hepatocytes display steatosis, patients can be defined as having NAFLD in an appropriate clinical context. When, in addition, lobular inflammation and liver cell clarification/ballooning are present, then the lesion is usually defined as NASH. Evaluation of the stage of fibrosis is even more fundamental than necroinflammation since it is the main prognostic factor of this disease. Semi‐quantitative histological scoring systems have been proposed for NAFLD, but they are not useful in clinical practice and each has certain limitations. For comprehensive purposes, we suggest describing histopathological lesions in NAFLD using the SAF (Steatosis, Activity, Fibrosis) score which assesses separately the grade of steatosis (S, from S0 to S3), the grade of activity (A from A0 to A4 by adding grades of ballooning and lobular inflammation, both from 0 to 2) and the stage of fibrosis (F from F0 to F4).
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
The pattern of non‐alcoholic fatty liver disease is complex with an association of several lesions, each of them related to different pathophysiological mechanisms. Despite the progress in ...non‐invasive tools, liver biopsy remains the only diagnostic procedure that can reliably assess these various patterns, their related severity and associations. The most important difficulties of liver biopsy can be avoided if this procedure is performed by an experienced hepatologist and read by a liver pathologist. However, for obvious reasons, biopsy should be restricted to selected patients, especially in the context of clinical trials. Indeed, liver biopsy is considered mandatory by regulatory authorities as a surrogate to assess drug efficacy in Phase 3 clinical trials. In addition to the clinical diagnosis, liver biopsy can be used to score the various histological patterns of disease (NASH‐CRN, SAF scores) and accurately assess the extent of fibrosis, both of which are useful when follow‐up biopsies are performed. When treatment becomes available in the near future, liver biopsy could remain useful for choosing the most suitable therapeutic option based on the main predominant histological features (activity, steatosis, fibrosis).
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
The end point of liver fibrosis in almost all chronic liver diseases including HBV chronic hepatitis is cirrhosis. Progression to cirrhosis is associated with annular deposition of fibrous tissue and ...vascular remodeling with a shift from a lobular to nodular organization. Although advanced liver fibrosis was previously thought to be irreversible, today there is compelling evidence that cirrhosis can be reversed if the underlying cause of liver injury is eliminated. Indeed, most clinical trials with antiviral therapy and histological follow‐up have shown that fibrosis can regress and that in some cases even cirrhosis can reverse following long‐term HBV‐DNA suppression, although the return to a fully normal liver is rarely observed and difficult to prove. Nevertheless, a marked percentage of cirrhosis will not reverse even after effective antiviral therapy. Generally cirrhosis is more likely to regress if it is recent, there is effective and long‐lasting viral suppression, an internal capacity to regenerate and no vascular thrombosis. HBV treatment in patients with cirrhosis is associated with an improved clinical outcome although there may still be a risk of hepatocellular carcinoma. Nevertheless it has not yet been determined if a favorable outcome depends on histological regression or whether the reversal of cirrhosis is merely a surrogate marker of viral suppression. The significance of the reversal of cirrhosis is still a subject of debate because neither the histological scoring systems nor non‐invasive markers to evaluate the reversal of cirrhosis have been validated.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Nonalcoholic fatty liver disease (NAFLD) comprises a spectrum of histopathologic features, ranging from isolated hepatic steatosis, to steatohepatitis with evidence of hepatocellular injury and ...fibrosis, to cirrhosis. The diagnosis and determination of NAFLD prognosis requires clinical and histopathologic assessments. Liver biopsy still is regarded as the reference for differentiating steatosis (NAFL) from nonalcoholic steatohepatitis, for staging hepatic fibrosis, and for identifying NAFLD in patients with other chronic liver disease. Standardized grading and staging histologic scoring systems, such as the NAFLD activity score and the steatosis, activity, and fibrosis score, can help guide clinical decisions and assess outcomes of clinical trials. Improved understanding of the pathophysiology of NAFLD and technologic advances have led to algorithms that can be used to assess serum biomarkers and imaging methods that are noninvasive alternatives to biopsy collection and analysis. We review the advantages and limitations of biopsy analysis and noninvasive tests as diagnostic and prognostic tools for patients with NAFLD. We also discuss techniques to improve dynamic histopathology assessment, and emerging blood and imaging biomarkers of fibrogenesis.
Biopsy is still the gold standard for the diagnosis of nonalcoholic steatohepatitis but the definition may vary among pathologists, a drawback especially in evaluation of biopsies for clinical ...trials. We previously developed a scoring system (steatosis, activity, fibrosis SAF) allowing the use of an algorithm (fatty liver inhibition of progression FLIP) for the classification of liver injury in morbid obesity. The aim of this study was to determine whether the use of the SAF score and FLIP algorithm can decrease interobserver variations among pathologists. In a first session, pathologists categorized 40 liver biopsies of patients with nonalcoholic fatty liver disease (NAFLD) according to their own experience. In a second reading session, each pathologist reclassified the same slides by using the FLIP algorithm and SAF score, blinded to their first evaluation. The experiment was repeated with two different groups of pathologists at varying levels of training in liver pathology. The percentage of biopsy interpretation concordant with reference evaluation increased from 77% to 97% in Group 1 and from 42% to 75% in Group 2 after the use of the SAF score and FLIP algorithm. The strength of concordance in classification increased in Group 1 from moderate (κ = 0.54) to substantial (κ = 0.66) and from fair (κ = 0.35) to substantial (κ = 0.61) in Group 2 with application of the algorithm. With regard to the SAF score, concordance was substantial in Group 1 for steatosis (κ = 0.61), activity (κ = 0.75), and almost perfect for fibrosis (κ = 0.83 after pooling 1a, 1b, and 1c together into a single score F1). Similar trends were observed in Group 2 (κ = 0.54 for S, κ = 0.68 for A, and κ = 0.72 for F). Conclusion: The FLIP algorithm based on the SAF score should decrease interobserver variations among pathologists and are likely to be implemented in pathology practice. (Hepatology 2014;60:565–575)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The exclusion of other chronic liver diseases including “excess” alcohol intake has until now been necessary to establish a diagnosis of metabolic dysfunction-associated fatty liver disease (MAFLD). ...However, given our current understanding of the pathogenesis of MAFLD and its rising prevalence, “positive criteria” to diagnose the disease are required. In this work, a panel of international experts from 22 countries propose a new definition for the diagnosis of MAFLD that is both comprehensive and simple, and is independent of other liver diseases. The criteria are based on evidence of hepatic steatosis, in addition to one of the following three criteria, namely overweight/obesity, presence of type 2 diabetes mellitus, or evidence of metabolic dysregulation. We propose that disease assessment and stratification of severity should extend beyond a simple dichotomous classification to steatohepatitis vs. non-steatohepatitis. The group also suggests a set of criteria to define MAFLD-associated cirrhosis and proposes a conceptual framework to consider other causes of fatty liver disease. Finally, we bring clarity to the distinction between diagnostic criteria and inclusion criteria for research studies and clinical trials. Reaching consensus on the criteria for MAFLD will help unify the terminology (e.g. for ICD-coding), enhance the legitimacy of clinical practice and clinical trials, improve clinical care and move the clinical and scientific field of liver research forward.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Nonalcoholic fatty liver disease (NAFLD) is highly prevalent and being overweight is a significant risk factor. The aim was to build an algorithm along with a scoring system for histopathologic ...classification of liver lesions that covers the entire spectrum of lesions in morbidly obese patients. A cohort of 679 obese patients undergoing liver biopsy at the time of bariatric surgery was studied. An algorithm for segregating lesions into normal liver, NAFLD, or nonalcoholic steatohepatitis (NASH) was built based on semiquantitative evaluation of steatosis, hepatocellular ballooning, and lobular inflammation. For each case, the SAF score was created including the semiquantitative scoring of steatosis (S), activity (A), and fibrosis (F). Based on the algorithm, 230 obese patients (34%) were categorized as NASH, 291 (43%) as NAFLD without NASH, and 158 (23%) as not NAFLD. The activity score (ballooning + lobular inflammation) enabled discriminating NASH because all patients with NASH had A ≥ 2, whereas no patients with A < 2 had NASH. This score was closely correlated with both alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (P < 0.0001, analysis of variance ANOVA). Comparison of transaminase levels between patients with normal liver and pure steatosis did not reveal significant differences, thus lending support to the proposal not to include steatosis in the activity score but to report it separately in the SAF score. In the validation series, the interobserver agreement for the diagnosis of NASH was excellent (κ = 0.80) between liver pathologists. There was no discrepancy between the initial diagnosis and the diagnosis proposed using the algorithm. Conclusion: We propose a simple but robust algorithm for categorizing liver lesions in NAFLD patients. Because liver lesions in obese patients may display a continuous spectrum of histologic lesions, we suggest describing liver lesions using the SAF score. (HEPATOLOGY 2012;56:1751–1759)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Insulin resistance and hepatic lipid accumulation constitute the metabolic underpinning of nonalcoholic steatohepatitis (NASH). We tested the hypothesis that saroglitazar, a PPAR α/γ agonist would ...improve NASH in the diet-induced animal model of NAFLD. Mice received chow diet and normal water (CDNW) or high fat western diet and ad lib sugar water (WDSW). After 12 weeks, WDSW fed mice were randomized to receive (1) WDSW alone, (2) WDSW + vehicle, (3) WDSW + pioglitazone or (4) WDSW + saroglitazar for an additional 12 weeks. Compared to mice on WDSW and vehicle controls, mice receiving WDSW + saroglitazar had lower weight, lower HOMA-IR, triglycerides, total cholesterol, and ALT. Saroglitazar improved steatosis, lobular inflammation, hepatocellular ballooning and fibrosis stage. NASH resolved in all mice receiving saroglitazar. These effects were at par with or superior to pioglitazone. Molecular analyses confirmed target engagement and reduced oxidative stress, unfolded protein response and fibrogenic signaling. Transcriptomic analysis further confirmed increased PPAR-target expression and an anti-inflammatory effect with saroglitazar. Lipidomic analyses demonstrated that saroglitazar also reduced triglycerides, diglycerides, sphingomyelins and ceramides. These preclinical data provide a strong rationale for developing saroglitazar for the treatment of NASH in humans.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Lanifibranor is a pan–peroxisome proliferator–activated receptor agonist that modulates metabolic and inflammatory pathways. In this 24-week, phase 2b, placebo-controlled trial involving patients ...with NASH, 1200 mg of lanifibranor, but not 800 mg, significantly improved histologic features of NASH. Weight gain, anemia, peripheral edema, diarrhea, and nausea occurred more frequently with lanifibranor than with placebo.
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