Approach to the Pathogenesis and Treatment of Nonalcoholic Steatohepatitis

  1. Jesús Medina, PHD1,
  2. Luis I. Fernández-Salazar, MD2,
  3. Luisa García-Buey, MD1 and
  4. Ricardo Moreno-Otero, MD1
  1. 1Liver Unit, University Hospital La Princesa, Autonomous University, Madrid, Spain
  2. 2Digestive Diseases Service, University Hospital, Valladolid, Spain
  1. Address correspondence and reprint requests to Ricardo Moreno-Otero, Unidad de Hepatología (planta 3), Hospital Universitario de la Princesa, Diego de León 62, E-28006 Madrid, Spain. E-mail: rmoreno.hlpr{at}


Nonalcoholic steatohepatitis (NASH) represents an advanced stage of fatty liver disease developed in the absence of alcohol abuse. Its increasing prevalence in western countries, the diagnostic difficulties by noninvasive tests, and the possibility of progression to advanced fibrosis and even cirrhosis make NASH a challenge for hepatologists. NASH is frequently associated with type 2 diabetes and the metabolic syndrome, and several genetic and acquired factors are involved in its pathogenesis. Insulin resistance plays a central role in the development of a steatotic liver, which becomes vulnerable to additional injuries. Several cyclic mechanisms leading to self-enhancement of insulin resistance and hepatic accumulation of fat have been recently identified. Excess intracellular fatty acids, oxidant stress, tumor necrosis factor-α, and mitochondrial dysfunction are causes of hepatocellular injury, thereby leading to disease progression and to the establishment of NASH. Intestinal bacterial overgrowth also plays a role, by increasing production of endogenous ethanol and proinflammatory cytokines. Therapeutic strategies aimed at modulating insulin resistance, normalizing lipoprotein metabolism, and downregulating inflammatory mediators with probiotics have promising potential.


  • J.M. and L.I.F.-S. contributed equally to this work.

    A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

    • Accepted April 29, 2004.
    • Received October 24, 2003.
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