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High, but not low, dietary retinoids aggravate manifestation of rat liver fibrosis


Dr Brigitte Vollmar, Institute for Clinical and Experimental Surgery, University of Saarland, 66421 Homburg/Saar, Germany. Email:


AbstractBackground : Although there is strong implication that retinoids regulate Ito cell proliferation and collagen synthesis, results from in vivo studies on the relationship between vitamin A and liver fibrosis are conflicting. The present study focuses on the role of vitamin A in carbon tetrachloride (CCl4)-induced fibrosis by chronic feeding of rats with either a vitamin A-supplemented or -depleted diet.

Methods and results : In animals with high dietary hepatic retinoid levels, liver fibrosis was more pronounced and was associated with an increased CCl4-toxicity resulting in high mortality (73%). Enhanced liver fibrosis was confirmed by in vivo fluorescence microscopic determination of both collagen deposits (7.4 ± 1.1 vs 3.9 ± 0.3% in high vitamin A diet-fed and standard diet-fed fibrotic animals, respectively; P < 0.05) and rarefication of sinusoids (1.5 ± 0.2 vs 2.4 ± 0.2 sinusoids/200 µm in high vitamin A diet-fed and standard diet-fed fibrotic animals, respectively; P < 0.05). It was further associated with decreased bile flow and increased parenchymal cell damage. CCl4 reduced hepatic retinoid levels in high vitamin A diet-fed animals, but restored hepatic retinoid levels in animals fed with a vitamin A-deficient diet, implying major interference of vitamin A metabolism with hepatotoxic agents such as CCl4. Low vitamin A feeding did not modulate liver fibrogenesis and caused no mortality.

Conclusions : These results show that the vitamin A status of the liver plays an important role in liver fibrogenesis. While dietary vitamin A shortage does not promote liver fibrogenesis, high levels of vitamin A have the potential to increase systemic and hepatic toxicity of CCl4. Thus, the narrow therapeutic window for nutritional vitamin A substitution must take into account that liver fibrotic patients may display enhanced susceptibility to the adverse effects of vitamin A.

© 2002 Blackwell Publishing Asia Pty Ltd