Modern Pathology (2007) 20, S40–S48 & 2007 USCAP, Inc All rights reserved 0893-3952/07 $30.00 www.modernpathology.org Pathology of fatty liver disease Elizabeth M Brunt Department of Pathology, Saint Louis University School of Medicine, St Louis, MO, USA Fatty liver disease is currently recognized as a common cause of liver test elevation, paralleling the worldwide ‘epidemic’ of obesity in adults and children. In many clinical practices, there is recognition that liver biopsy evaluation is the only means of diagnosis (or exclusion) of fatty liver disease, as neither laboratory tests nor imaging studies to date can provide complete data related to amount of steatosis, inflammation, liver cell injury, fibrosis, and architectural remodeling. Liver biopsy evaluation also provides a means of ‘grading and staging’ the lesions of fatty liver disease and of detecting clinically unsuspected processes. Liver biopsy evaluation is often the primary end point in clinical trials of treatment, thus, standardization of diagnosis and methods of grading and staging have become important. In this review, these concepts as well as the pathophysiologic bases for them are discussed. Modern Pathology (2007) 20, S40–S48. doi:10.1038/modpathol.3800680 Keywords: fatty liver disease; insulin resistance; grading; staging The normal adult human liver may have up to 5% of Nonalcoholic fatty liver disease (NAFLD) its mass as lipid. The size of triglyceride droplets (macrovesicular or microvesicular) may be a clue to Background the underlying cause of the accumulation. When The significance of excess fat accumulation in the discussing ‘fatty liver disease’, most often we are liver was recognized by pathologists in the 19th referring to diseases that are characterized by century. Associations of hepatic steatosis and cirro- predominantly large droplet steatosis (macrovesi- hosis with obesity, diabetes and alcohol have been cular steatosis), or mixed large and small droplet documented in numerous large studies of American steatosis. Small droplets that do not fill the entire and European pathologists in the 20th century. hepatocyte are usually included in the macrovesi- Although not the first to use the term, credit is due cular category. Several primary liver diseases, such to the study from the Mayo Clinic published in 1980 as hepatitis C and Wilson disease, hepatocellular for establishing the moniker ‘NASH’ in the nomen- adenoma and carcinoma, and certain drugs and clature of fatty liver disease.1 In this study, Ludwig toxins, such as steroids and alcohol, commonly et al1 carefully established the nonalcoholic nature show these forms of steatosis (Figure 1a). In contrast, of the 20 subjects with liver biopsies; 90% were ‘true’ microvesicular steatosis consists of much obese, 65% were women, 25% were diabetic and/or smaller, uniform fat droplets dispersed throughout hyperlipidemic, and 15% had hypertension. The the hepatocyte, and often requires special stains subjects had been accrued based on a liver biopsy such as oil red O to detect (Figure 1b). This latter with features that had been characterized as ‘alco- form is a manifestation of severe, recent liver injury, hol-like’. Over the course of the next decade, the such as in Reye’s syndrome and acute fatty liver of concept of NAFLD became accepted, in no small pregnancy and other processes of deranged mito- part due to pathologists’ contributions in clinico- chondrial b oxidation. pathologic studies. Today, we recognize that hepatic steatosis cannot be ignored as a mere histologic oddity, but rather is a significant finding or marker for potentially progressive liver disease. Most often, we see steatosis in the setting of alcohol-related liver disease, and hepatitis C (especially genotype 3), and in NAFLD and nonalcoholic steatohepatitis (NASH). Correspondence: Dr EM Brunt, MD, Department of Pathology, In addition, in the setting of liver transplantation, Saint Louis University School of Medicine, 4th Floor, FDT 3635 large amounts of large droplet fat have been Vista Avenue, St Louis, MO 63110, USA. E-mail: [email protected] associated with initial poor function of the liver Received 14 July 2006; accepted 26 July 2006 graft. Pathology of fatty liver disease EM Brunt S41 Figure 1 (a) Steatosis can be seen in varying amounts in a variety of liver diseases. The etiology of the steatosis may be due to a toxin, hepatitis C viral infection or host factors, but often cannot be determined by histologic evaluation. This is an example of steatosis, large and small droplet type, in hepatitis C in an overweight, diabetic individual. (b) Microvesicular steatosis is often initially considered as swollen, ‘ballooned’ hepatocytes. As shown in this example of acute fatty liver of pregnancy, the hepatocytes are enlarged and the cytoplasm is reticulated by the small aggregates of steatosis. Because of the significance of the clinical situations in which microvesicular steatosis is the dominant finding, stains on frozen sections are highly recommended for confirmation (photograph courtesy of Dr Linda Ferrell). The epidemic of obesity throughout the world has study, 21% of 742 such patients were found to have brought awareness of NAFLD to the forefront of NAFLD. Each of these types of studies have hepatology and medicine in the past quarter cen- recognized drawbacks and liver tissue evaluation tury. Currently, NAFLD is ‘billed’ as the most remains the ‘gold standard’ in the clinico-pathologic common form of chronic liver disease for adults in diagnosis of NAFLD for confirmation (or exclusion) the United States and is growing to be such in Asia. of the diagnosis, for distinguishing NAFLD and The problem is now recognized in both adults and NASH, and to establish severity of inflammation children. In all populations, obese and diabetic and fibrosis.8 subjects are at higher risk than lean, nondiabetic Studies have confirmed that routine clinical tests individuals. It is unethical and impractical to per- alone may misdiagnose (overdiagnose) NASH in a form population screening with liver biopsies, so significant proportion of cases,9 and that not all several methods have been used to determine ‘unexplained’ liver test abnormalities are the result prevalence of NAFLD. Three cited studies are based of fatty liver disease.10 In Skelly et al’s10 study, liver on the data collected from the third National Health biopsy made a clinically significant and previously and Nutrition Evaluation Survey;2–4 all three studied unsuspected diagnosis in 13% of cases, confirmed ALT values in nonalcoholic subjects without ser- cryptogenic liver disease in 9% and documented ologic markers of liver disease; some additionally normal liver in 6%. Recent reports of liver disease in included values for AST2 and GGT,3 and only one diabetics also confirm the value of tissue evaluation specifically excluded diabetics.4 These studies to identify entities other than fat, such as glycogenic found ‘unexplained’ elevated liver tests in US adults hepatopathy, characterized by diffuse glycogeno- in 5.45, 23 and 2.8%, respectively. The latter study sis,11 and diabetic hepatosclerosis, which consists of showed that 68% of those could be accounted for by dense perisinusoidal fibrosis and basement mem- increased body mass index (BMI).4 An Italian brane deposition12 (Figure 2a and b). Neither of population survey based on ultrasound evaluation these entities is characterized by significant steato- of a cohort of 257 nondiabetic adults with no sis. These studies also emphasize the value of serologic evidence of liver disease showed evidence adequate clinical information, as both of these of steatosis (‘bright liver’) in 58%.5 This study also entities occur in the setting of insulin-dependent showed that the risk of steatosis was related to diabetes rather than obesity. obesity and alcohol use. Another imaging study6 that measured hepatic triglyceride content in a multiethnic cohort of 2287 subjects in the US Role of Liver Biopsy documented steatosis in 30% of subjects; interest- ingly, 79% of these subjects had normal ALT values. Histologic evaluation has also played an important The ethnic distribution of steatosis reflected the role in broadening the concept of NAFLD from a well-documented ethnic distribution of NAFLD- liver disease of only obese individuals with elevated related cirrhosis: Hispanic4Caucasian4African ALT, to an entity that can involve lean indivi- American. A novel approach to detect prevalence duals,13,14 or subjects with normal ALT values as has come from evaluation of newly diagnosed liver well.15 Most studies of NAFLD focus on subjects in disease patients in a large clinic setting;7 in this whom other forms of liver disease have been Modern Pathology (2007) 20, S40–S48 Pathology of fatty liver disease EM Brunt S42 Figure 2 (a) Glycogenic hepatopathy. The hepatocyte cytoplasm is markedly expanded by excess glycogen, imparting a ‘glassy’ appearance. The parenchyma is diffusely involved. Small amounts of steatosis may also be present. (b) Diabetic hepatosclerosis, with patches of dense perisinusoidal fibrosis (trichrome stain). excluded, but some have documented NAFLD/ and thus in ‘grade’ and ‘stage’ have been shown in NASH in subjects with concurrent chronic liver recent studies.28,29 As in all liver diseases, the type disease.16–18 A feature that often leads to diagnostic of liver biopsy (for instance, wedge biopsy, intra- difficulties for clinicians is the presence of abnormal operative biopsy, etc) available for evaluation and ANA, ASMA and