Pathology of Nonalcoholic Fatty Liver Disease (NAFLD)

Home , Ballooning degeneration, Megamitochondria, Steatosis

Clinical hepatology update

Pathology of nonalcoholic fatty liver disease (NAFLD)

Eun Sun Jung

The Catholic University of Korea, College of Medicine, Seoul St. Mary’s Hospital, Department of Pathology, Korea

Keywords: Nonalcoholic Fatty Liver Disease, Histopathologic Features, Nonalcoholic Hepatitis, Histological Criteria, Histological Scoring

Nonalcoholic fatty liver disease (NAFLD) is a clinicopathological spectrum characterized by hepatic steatosis without a history of significant alcohol use or other known liver disease. The commonly associated factors include obesity, insulin resistance syndrome, hyperlipidemia. Other associations include jejuno-ileal bypass/gastroplasty sur- gery for morbid obesity, parenteral nutrition, forms of malnutrition, bacterial contamination of the small bowel, certain inherited metabolic disorders and a wide range of drugs and environmental toxin.1 The natural history and histological spectrum of NAFLD range from stable simple steatosis to progressive to advanced disease, such as steatohepatitis and cirrhosis (even hepatocellular carcinoma).2-5

1. Histopathologic features of NAFLD

The representative pathologic features of NAFLD are Steatosis, Lobular inflammation, Ballooning degeneration, Fibrosis. In addition to these, portal inflammation, Lipogranuloma, Acidophilic bodies, Mallory hyaline bodies, Glycogenated nuclei, Megamitochondria and Vascular alteration can be observed in the liver of NAFLD. The defi- nition of abnormal lipid accumulation had been different from 5% to 33% depending on researchers.6 Recently “more than 5%” has been used as a standard value for defining pathologic hepatic lipid accumulation.7-8 Fibrosis of NAFLD characteristically starts around zone 3 with pericellular pattern and can progress to bridging fibrosis and even cirrhosis. Ballooning degeneration of hepatocytes, which is known as an important histologic features of progressive form of NAFLD, is defined as enlarged round cell with loss of polygonal features and heterogenous granular cytoplasm.9

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2. Histological Criteria of Nonalcoholic Hepatitis (NASH)

Unlike simple steatosis, NASH is considered to be an aggressive form of NAFLD. The well-recognized histological features of NASH include steatosis, ballooning degeneration, mixed acute and chronic lobular inflammation and zone 3 perisinusoidal fibrosis. However, the histological criteria of NASH have been still debatable among researchers. There are two streams for histological criteria of NASH. One is loose criteria, which were applied in many clinical studies published in around 2000’s, is only steastosis and inflammatory cell infiltration into lobular areas regardless of ballooning degeneration and fibrosis.10-13 The other is strict criteria, recently developed after 2000’s, in which ballooning denegeration is required for the diagnosis of NASH.14-16 However, the difficulty in cor- rectly identifying ballooning degeneration subsequently became a critical issue.17 Despite many proposals and re- visions, the histological criteria for NASH have not been perfected yet and still remain to be improved.

3. Histological scoring system of NAFLD

Since the first description of NASH by Ludwig et al at 1980,18 several NAFLD semiquantitative scoring schemes have been proposed by Brunt et al19, Matteoni et al20, and Promrat et al21 and Kleiner et al.22 For the first time Brunt et al.(1999)19 proposed to classify steosis, inflammation, ballooning degeneration into three grades, re- spectively, and fibrosis to four stages. Since then, Kleiner et al. (2005) of NASH Clinical Research Network(CRN) proposed a more relevant and popular classification (NAFLD activity score; NAS) than Brunt’s classification.22 The NAS is defined as the unweighted sum of the score for steatosis (0-3), lobular inflammation (0-3), and ballooning (0-2); thus the NAS ranging from 0 to 8. Fibrosis was not included as a NAS component. Also they scored each finding and suggested that at a score more than 5 points indicate NASH. However, in original proposal, the pur- pose of NAS was for comparisons of liver biopsies in longitudinal studies and NAS score itself does not mean the histological diagnosis of NASH. As yet, NAFLD scoring system for histological diagnosis has not been stand- ardized, which still has caused confusion for clinicians and pathologists. Hence, more reliable scoring system should be studied.

References

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Hepatology 1995, 22:1714-1719. 5. Ong JP, Younossi ZM: Epidemiology and natural history of NAFLD and NASH. Clinics in liver disease 2007, 11:1-16, vii. 6. Ikura Y. Transitions of histopathologic criteria for diagnosis of nonalcoholic fatty liver disease during the last three decades. World J Hepatol 2014; 6: 894-900. 7. Wanless IR, Lentz JS. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology 1990; 12: 1106-1110. 8. Kwiterovich PO, Sloan HR, Fredrickson DS. Glycolipids and other lipid constituents of normal human liver. J Lipid Res 1970; 11: 322-330. 9. Jung ES, Lee K, Yu E, Kang YK, Cho MY, Kim JM, et al. Interobserver Agreement on Pathologic Features of Liver Biopsy Tissue in Patients with Nonalcoholic Fatty Liver Disease. J Pathol Transl Med 2016;50:190-196. 10. Powell EE, Cooksley WG, Hanson R, Searle J, Halliday JW, Powell LW. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology 1990; 11: 74-80. 11. Bacon BR, Farahvash MJ, Janney CG, Neuschwander-Tetri BA. Nonalcoholic steatohepatitis: an expanded clinical entity. Gastroenterology 1994; 107: 1103-1109 12. Laurin J, Lindor KD, Crippin JS, Gossard A, Gores GJ, Ludwig J, et al. Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatology 1996; 23: 1464-1467. 13. George DK, Goldwurm S, MacDonald GA, Cowley LL, Walker NI, Ward PJ, et al. Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis. Gastroenterology 1998; 114: 311-318. 14. Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 1999; 116: 1413-1419. 15. Dixon JB, Bhathal PS, O’Brien PE. Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology 2001; 121: 91-100. 16. Bedossa P, Poitou C, Veyrie N, Bouillot JL, Basdevant A, Paradis V, et al. Histopathological algorithm and scoring system for evaluation of liver lesions in morbidly obese patients. Hepatology 2012; 56: 1751-1759. 17. Lackner C. Hepatocellular ballooning in nonalcoholic steatohepatitis: the pathologist’s perspective. Expert Rev Gastroenterol Hepatol 2011; 5: 223-231. 18. Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 1980; 55: 434-438 19. Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR: Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. The American journal of gastroenterology 1999, 94:2467-2474. 20. Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ: Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 1999, 116:1413-1419. 21. Promrat K, Lutchman G, Uwaifo GI, Freedman RJ, Soza A, Heller T, et al. A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology 2004, 39:188-196. 22. Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Nonalcoholic Steatohepatitis Clinical Research N: Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005, 41:1313-1321.