Fatty liver

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  • 1.THE EPIDEMIOLOGY, PATHOGENESIS AND HISTOPATHOLOGY OF FATTY LIVER DISEASEAdam P Levene and Robert D Goldin Department of Histopathology,Imperial College Faculty of Medicine at St Marys Hospital,London.UK (Histopathology 2012, 61, 141-152)

2. INTRODUCTION Fatty liver disease consists of alcoholic liverdisease (ALD) and non-alcoholic fatty liverdisease (NAFLD), with a subset of these groupsdeveloping alcoholic steatohepatitis (ASH) andnon-alcoholicsteatohepatits(NASH),respectively. The increasing prevalence of obesity anddiabetes, and the associated metabolic syndromeis leading to an increased incidence of NAFLD. 3. The increasing prevalence of NAFLD isparticular worrying because patientsappear to have a higher mortality fromnon-liver related and recent data havealso highlighted an increased risk forcardiovascular disease. 4. Underlying pathogenesis of NAFLD is still incompletelyunderstood. Majority of patients with NAFLD have a stable disease, withisolated steatosis and an indolent course with no progressionto advanced liver disease or clinical sequelae. However, a subset develop NASH and are at risk progressivefibrosis, cirrhosis and liver failure, or hepatocellularcarcinoma (HCC). The distinction between isolated steatosis and NASH isimportant, as their prognoses and management are different 5. The gold standard for identification ofpatients with NASH is liver biopsy. 6. EPIDEMIOLOGY AND DISEASENATURAL HISTORYNAFLD: Estimates of NAFLD prevalence based oncryptogenic abnormal liver function test results,autopsy samples, ultrasound and magneticresonance spectroscopy range between 3% and37%, with the usual figure quoted being around30%. 7. Studies suggest that ethnic background plays arole in the incidence of NAFLD were provided bya study that revealed a significantly higherprevalence of NAFLD in Hispanics than in non-Hispanic whites, even after controlling forobesity and body fat distribution. 8. Studies show that NAFLD is not always associatedwith raised alanine transaminase (ALT) or gamma-glutamyl transpeptide positivity. NAFLD was more likely in the presence of obesity,hyperglycemia,hyperinsulinaemia,hypertriglyceridaemia, and systolic hypertension, allfeatures of the metabolic syndrome. Although total fat consumption is not significantlyassociated with the risk of cirrhosis or liver cancer,cholesterol consumption is. 9. Recent clinical and experimental studieshave shown that coffee protects the liveragainst the development of fat-inducedliver damage. 10. The prevalence of NASH is difficult todetermine, as large population-basedstudies are not possible, because a liverbiopsy is still, currently, required fordiagnosis. An autopsy study found NASH in 18.5% ofmarkedly obese patients and 2.7% of leanpatients. This highlights the possible effect thatweight has on the incidence of NASH. 11. Normal liver 30% Fatty liver Stabledisease 30%NASH20%Progressive fibrosis cirrhosis 30-40%0-10%Liver failureLiver cell cancer 12. A well recognized complication of cirrhosisresulting from NAFLD is HCC. HCC has also been noted as a rare complication ofNAFLD prior to cirrhosis. This may be explained by the association ofdiabetes and obesity with the development ofHCC, as well as the carcinogenic factorsassociated with cirrhosis in general. 13. ALD: Studies in unselected heavy drinkers ofalcohol suggest that 80% developsteatosis, which is the earliest and mostcommon histopathological manifestation ofALD. Steatosis occurs in most people consumingalcohol in excess of 80 g/day, and canresolve within 2-4 weeks of abstinence. 14. Normal liver Alcohol intake80%Alcohol abstinenceFatty liver?Abstinence effect20-40% ASH fibrosis40%cirrhosis 15. Severe ASH has a very poor prognosis,whereas patients with mild and moderateASH can improve with abstinence. 16. It is extremely difficult to predict histologicalstage clinically in ALD patients before thedevelopment of decompensated cirrhosis. A small subset of ALD patients presenting withdecompensated chronic liver disease has severeASH without cirrhosis on biopsy. Conversely, some ALD patients who are clinicallywell but have abnormal liver function test resultsand undergo liver biopsy are found to haveadvanced ALD with severe ASH. 17. Staging Of ALD is most accuratelyperformed histologically by performingliver biopsy, which may need to be via thetransjugular route in patients withimpaired clotting. 18. PATHOGENESISNAFLD: NAFLD is closely linked to obesity, insulinresistance, and the metabolic syndrome. The initial theory for the pathogenesis ofNAFLD was the two-hit hypothesis. The first hit, steatosis, sensitives the liver tothe induction of inflammation by a secondinsult that promotes oxidative stress andsteatohepatitis. 19. This model has subsequently been revised,in recognition that a combination ofsecond hits (both environmental andgenetic) may lead to the development ofsteatohepatitis. 20. Currently, it is not fully understood why somepatients develop isolated steatosis and othersdevelop steatohepatitis. However, it appears that insulin resistance andincreased levels of free fatty acids in the liverare strongly associated with NASH. When insulin resistance develops, free fattyacids are inappropriately moved to non-adiposetissues such as the liver by decreased inhibitionof lipolysis and increased de novo lipogenesis. 21. There is currently increasing work on theinteraction between cytokines andadipokines (cytokines secreted by adiposetissue) in an attempt to understand themechanismsinvolvedin NAFLDdevelopment. 22. Insulin resistance is thought to beregulated by proinflammatory cytokines,such as tumour necrosis factor-a (TNF-a),and adipokines such as adiponectin andleptin. Oxidative stress and apoptosis also appearto contribute to the development andprogression of NASH. 23. ALD: Pathogenesis is still incompletely understood. Recent discoveries - Many pathways leading tooxidative stress, and the new mechanism ofendoplasmic reticulum stress. There are many similarities with NAFLD, such asthe proinflammatory cytokine TNF-a and theadipokines adiponectin and leptin. Obesity being implicated as a risk factor for thedevelopment of ASH and cirrhosis in people withheavy alcohol consumption. 24. HISTOPATHOLOGYNAFLD Histological analysis of a liver biopsy remains thegold standard for and only accurate way ofassessing thedegree ofsteatosis,necroinflammatory changes and fibrosis ofNASH, and therefore distinguishing NASH fromisolated steatosis. 25. The pathology committee of the NASH CRNgroup developed and histological scoring systemfor use in NAFLD. For each case, an NAFLD activity score (NAS)and a separate fibrosis stage was given. The NAS comprised 14 histological features, nineof which were recorded as present or absent(such as Mallory-Denk bodies), and three ofwhich were semiquantitatively [steatosis (0-3),lobular inflammation (0-3), and hepatocellularballooning (0-2)], to give a score of between 0and 8. 26. Steatosis grade (0-3) Lobular inflammation (0-3) Hepatocyte ballooning (0-2)0: 4 foci/*20 fieldNAFLD activity score (NAS): 0-8 0-2 not NASH3-4 uncertain for NASH5-8 NASHNon-alcoholic steatohepatitis (NASH) Clinical Research Network Fibrosis Staging System 27. Fibrosis: based on the use of Massons trichrome stain0: None1a: Mild zone 3 perisinusoidal fibrosisRequires trichrome stain to identify1b: Moderate zone 3 perisinusoidal fibrosis May be appreciated on haemotoxylin and eosin1c: Portal fibrosis only2: Zone 3 perisinusoidal fibrosis andd periportal fibrosis3: Bridging fibrosis4: CirrhosisNon-alcoholic steatohepatitis (NASH) Clinical Research Network Fibrosis Staging System 28. The lobular inflammatory infiltrate is usuallycomposed predominantly of neutrophils, butlymphocytes and macrophages are commonly seen.In practice, the presence of balloonedhepatocytes is a sine qua non for the diagnosis ofNASH rather than steatosis. In a meticuluos histological study, serial stainingconsistently demonstrated that hepatocellularballooning was associated with fat droplets, asshown by oil red O positivity and CK-18-positiveMallory-Denk bodies. 29. Histological features recorded but not scored inNASinclude Mallory-Denkbodies,megamitochondria, and nuclear vacuolation. In NAFLD, Mallory-Denk bodies are often smalland poorly formed, and may be difficult to detectin routinely stained sections. Immunohistochemistry for ubiquitin, p62, CK-8and CK-18 can be used to demonstrate antigensassociated with Mallory-Denk bodies andballooned hepatocytes. 30. Summary, Histological spectrum of NAFLD ischaracterized by steatosis, lobular inflammation,ballooning of hepatocytes, fibrosis, and otherfeatures that may or may not be present, such asMallory-Denk bodies and portal inflammation. The NASH CRN grading and staging system ofNASH is based on the use of haematoxylin andeosin and Massons trichrome stain, so it can beused routinely by histopathologies. 31. Nonspecific steatosis, predominantly macrovesicular, withoccasional foci of inflammatory cells in the hepatic lobules andmany hepatocytes with glycogenated nuclei (H&E, 200). 32. Steatohepatitis with several hepatocytes showing ballooning degenerationintermixed with steatosis and foci of inflammatory cells in the hepaticlobules (H&E, 200). 33. Mallory hyaline showing eosinophilic and ropy inclusions in thecytoplasm (H&E, 400). 34. Perivenular/pericellular fibrosis in zone 3 (Masson trichrome,200). 35. ALD: The diagnosis of ALD is usually easy to make witha clear history of excessive alcohol consumptionand negative markers for other chronic liverdiseases. However, one needs to remember that the liverdisease seen in patients who drink excessively isnot always caused by alcohol 36. The role of Liver biopsy in ALD is controversialbut it is still the gold standard investigation andused to clarify cases with an unusual clinical course, to better define the contribution of alcohol in patients with possible non-alcohol-related co