Acute Liver Cell Damage in Patients With Anorexia Nervosa: A Possible Role of Starvation-Induced Hepatocyte Autophagy

Pôle des Maladies de l'Appareil Digestif, Service d'Hépatologie, Hôpital Beaujon, AP-HP, Clichy, France.
Gastroenterology (Impact Factor: 16.72). 09/2008; 135(3):840-8, 848.e1-3. DOI: 10.1053/j.gastro.2008.05.055
Source: PubMed


Acute liver insufficiency is a rare complication of anorexia nervosa. The mechanisms for this complication are unclear. The aim of this study was to describe patient characteristics and clarify the mechanisms involved.
Liver specimens from 12 patients (median age, 24 years; median body mass index, 11.3 kg/m(2)), with a prothrombin index <50% and/or an International Normalized Ratio >1.7 and anorexia nervosa as the only cause for acute liver injury were analyzed. A detailed pathologic examination was performed, including under electron microscopy.
Liver cell glycogen depletion was a constant finding. There was a contrast between the increase in serum alanine aminotransferase (56 times normal on average; 1,904 IU/L) and the absence of significant hepatocyte necrosis on histology. Centrilobular changes (trabecular atrophy and/or sinusoidal fibrosis) were observed in 6 patients. There were rare or no (<5%) terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive hepatocytes, suggesting that apoptosis was not the primary mechanism. Hepatocytes from 4 patients showed numerous autophagosomes, a morphologic hallmark of autophagy, on electron microscopy. In contrast, the mitochondria, endoplasmic reticulum, and nuclei were normal in most cells. These features were absent in 11 control patients. The outcome was favorable in all patients, with a rapid return to normal liver function.
Anorexia nervosa with extremely poor nutritional status should be added to the list of conditions causing acute liver insufficiency. Our findings show that starvation-induced autophagy in the human liver may be involved in liver cell death during anorexia nervosa, even though other mechanisms of liver cell damage could also play a role.

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    • "For decades, dietary deficiencies were considered the major factor responsible for the development of liver disease in alcoholics (Korourian et al. 1999), because ethanol displaces normal nutrients, causing malnutrition (Liber 2004; Comporti et al. 2010). Moreover, it has been experimentally proved that nutritional deficiencies cause liver damage (Di Pascoli et al. 2004; Rautou et al. 2008; Caballero et al. 2011). Therefore, it was postulated that the combination of these factors cause ALD (Comporti et al. 2010). "
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    • "This seeming discrepancy may be explained by the re-elevation in serum HMGB1 and the reduction in intracellular HMGB1 aggregates after 2-d-relative to 1-d-fasting (considering that protection is lost upon concomitant HMGB1 injection into 1-d-fasted mice). Furthermore, human liver displays an accumulation of autophagosomes along with signs of increased cell permeability and elevations in liver enzymes following prolonged starvation [42]. Analogously, we observed an increase in AST, ALT, and the cell death marker LDH in mouse liver fasted for two/three days compared to 1-d-fasted or unfasted mice (Supplementary Fig. 5). "
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    • "Usually, autophagy is considered as a protective mechanism , but hyperactive autophagy has also been reported in pathological conditions such as liver inflammation in a rat model of diabetes mellitus (Hagiwara et al. 2010) and as a possible cause of hepatocyte death in anorexia nervosa patients (Rautou et al. 2008) suggesting that both diminished or excessive autophagy could be deleterious. It has also been reported that leptin treatment might have unfavorable consequences via an overactivated leptin system and an SOCS3 inhibitory effect might lead to insulin resistance, hepatic steatosis and liver fibrosis (Polyzos et al. 2011). "
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