32. Nonalcoholic Fatty Liver Disease

  1. Eugene R. Schiff MD, MACP, FRCP2,
  2. Willis C. Maddrey MD, MACP, FRCP3 and
  3. Michael F. Sorrell MD, FACP4
  1. Stephen H. Caldwell MD,
  2. Curtis K. Argo MD, MS and
  3. Abdullah M. S. Al-Osaimi MBBS, FACP, FACG

Published Online: 31 OCT 2011

DOI: 10.1002/9781119950509.ch32

Schiff's Diseases of the Liver, Eleventh Edition

Schiff's Diseases of the Liver, Eleventh Edition

How to Cite

Caldwell, S. H., Argo, C. K. and Al-Osaimi, A. M. S. (2011) Nonalcoholic Fatty Liver Disease, in Schiff's Diseases of the Liver, Eleventh Edition (eds E. R. Schiff, W. C. Maddrey and M. F. Sorrell), Wiley-Blackwell, Oxford, UK. doi: 10.1002/9781119950509.ch32

Editor Information

  1. 2

    Center for Liver Diseases and Schiff Liver Institute, University of Miami Miller School of Medicine, Miami, FL, USA

  2. 3

    Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA

  3. 4

    University of Nebraska College of Medicine, Omaha, NE, USA

Author Information

  1. Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Virginia Health System, Charlottesville, VA, USA

Publication History

  1. Published Online: 31 OCT 2011
  2. Published Print: 9 DEC 2011

ISBN Information

Print ISBN: 9780470654682

Online ISBN: 9781119950509



  • Steatosis;
  • steatohepatitis;
  • obesity;
  • diabetes;
  • hyperlipidemia;
  • metabolic syndrome;
  • PNPLA3 (patatin-like phospholipase 3) gene;
  • lipogenesis;
  • apolipoprotein;
  • lipid peroxidation;
  • lipotoxicity;
  • cellular ballooning;
  • keratin;
  • keratin fragments;
  • small fat droplets;
  • endoplasmic reticulum (ER) stress;
  • liver biopsy;
  • liver fibrosis;
  • cirrhosis;
  • cryptogenic cirrhosis;
  • exercise;
  • thiazolidinediones;
  • vitamin E


Nonalcoholic fatty liver disease is one of the most common liver disorders. It is defined as liver fat exceeding 5–10% by weight and exists as a spectrum. Nonalcoholic steatohepatitis (NASH), with cellular ballooning, necroapoptosis, inflammation, and fibrosis, progresses to cirrhosis in 15–20% over 5–10 years. Obesity and insulin resistance (metabolic syndrome) are the most common risks. Ethnic variation (and probably familial associations) is explained to a large extent by the genetics of a lipase called PNPLA3. Lipid accumulation results from de novo synthesis, uptake of free fatty acids, uptake of low-density liposome/chylomicron remnants and inadequate very low-density lipoprotein (apoB) secretion. Cell injury results from a cascade of events initiated by lipid peroxidation, which triggers lipid droplet dysfunction, endoplasmic reticulum (ER) “stress,” autophagosome formation, and mitochondrial dysfunction. Fatty acids cause activation of apoptosis through changes in lysosome and mitochondrial permeability. Cytoskeletal injury, fat droplet accumulation, and ER dilatation contribute to ballooning, and necroapoptotic cell death stimulates fibrotic pathways amplified by systemic factors such as cytokines. Mortality in NASH is increased and results from cardiovascular death, non-liver cancer, and cirrhosis. Predicting which will dominate is difficult and many patients will suffer from both coronary disease and cirrhosis. Therapy hinges on diet and exercise. Bariatric surgery is an option in selected patients but carries some risk. High-dose vitamin E possibly combined with cytoprotective agents is promising but not yet established. Thiazolidinediones (i.e., pioglitazone) also appear effective but side effects have diminished interest in these agents. Antihyperlipidemic agents remain to be fully evaluated but appear ineffective in early studies.