NAFLD/NASH progresses through stages from fatty liver to steatohepatitis to fibrosis and can eventually lead to cirrhosis. Studies have shown that around 10% of patients with NASH progress to fibrosis within 5 years, while 15% may develop cirrhosis. Long-term follow up studies of NAFLD patients found that around 50% had no change in their condition, while 27% developed fibrosis, 19% developed cirrhosis, and only 4% improved over periods of 1-9 years. Patients with more severe NASH had worse outcomes, with 26% developing cirrhosis and 44% dying in one study that followed patients for up to 18 years.

1. NAFLD/NASH: Natural History

2. Stages in the Progression of NAFLD Fatty Liver (Hepatosteatosis) Steatohepatitis Steatohepatitis with Fibrosis Cirrhosis (Decrease in Fat) Bacon BR et al. Gastroenterology. 1994;107:1103-1109. Powell EE et al. Hepatology. 1990;11:74-80. Adapted from Sanyal A. Gastroenterology. 2002;123:1705-1725.

3. Progression of NAFLD NASH NAFLD (steatosis) 10% * 5-year risk for patient with NASH Reviewed in Neuschwander-Tetri BA, Caldwell SH. Hepatology . 2003;37(5):1202-1219. Increased Fibrosis (35% * )  Cirrhosis (15% * )  Terminal Liver Failure  Hepatocellular Carcinoma

4. NASH: Natural History Progressive fibrosis in 15-40% Possibly responsible for most cryptogenic cirrhosis 14% of transplants due to cryptogenic cirrhosis 2% of transplants are for NASH NASH can recur post-transplant Matteoni CA et al. Gastroenterology. 1999;116:1413-1419. Caldwell SH et al. Hepatology. 1999;29:664-669. Ong J et al. Liver Transpl. 2001 Sep;7(9):797-801. Adapted from material provided to CLDF Slide Collection courtesy of BR Bacon.

5. Histologic Changes in 26 NAFLD Patients Followed up to Nine Years Falck-Ytter Y et al. Semin Liver Dis 2001;21:17-26, STUDY FOLLOW-UP (years) N SUBSEQUENT HISTOLOGY Improved No Change Progressed to Fibrosis Cirrhosis Lee (1989) 1.2 – 6.9 12 0/12 7/12 3/12 2/12 Powell (1990) 1 – 9 12 1/12 5/12 4/12 2/12 Bacon (1994) 4 - 7 2 0/2 1/2 0/2 1/2 Combined (%) 26 1/26 (4) 13/26 (50) 7/26 (27) 5/26 (19)

6. Histologic Changes in 26 NAFLD Patients Followed up to Nine Years NAFLD Improved 4% Fibrosis 27% No Change 50% Cirrhosis 19% Lee RG. Hum Pathol. 1989;20:594-598. Powell EE et al. Hepatology. 1990;11:74-80. Bacon BR et al. Gastroenterology. 1994;107:1103-1109. Reviewed in Falck-Ytter Y et al. Semin Liver Dis 2001;21:17-26,

7. Comparison of Outcomes* of NAFLD by Histologic Pattern * Retrospective analysis of 132 patients followed up to 18 years. † Fat alone; ‡ Fat + lobular inflammation; § Fat + ballooning; ¶ Fat + ballooning + Mallory bodies or perisinusoidal fibrosis Matteoni CA et al. Gastroenterology 1999;116:1413-1419. OUTCOME TYPE 1 † (n=49) TYPE 2 ‡ (n=10) NASH TYPE 3 § (n=19) TYPE 4 ¶ (n=54) Cirrhosis 2 (4%) 0 (0%) 4 (21%) 14 (26%) Death 16 (33%) 3 (30%) 5 (26%) 24 (44%) Liver-related Death 1 (2%) 0 (0%) 1 (5%) 7 (13%)