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Etiopathogenesis of Hepatic Osteodystrophy in Wistar Rats with Cholestatic Liver Disease

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Abstract

The pathophysiology of hepatic osteodystrophy (HO) remains poorly understood. Our aim was to evaluate bone histomorphometry, biomechanical properties, and the role of the growth hormone (GH)/insulin-like growth factor-I (IGF-I) system in the onset of this disorder. Forty-six male Wistar rats were divided into two groups: sham-operated (SO, n = 23) and bile duct–ligated (BDL, n = 23). Rats were killed on day 30 postoperatively. Immunohistochemical expression of IGF-I and GH receptor was determined in liver tissue and in the proximal growth plate cartilage of the left tibia. Histomorphometric analysis was performed in the right tibia, and the right femur was used for biomechanical analysis. The maximal force at fracture and the stiffness of the mid-shaft femur were, respectively, 53% and 24% lower in BDL compared to SO. Histomorphometric measurements showed low cancellous bone volume and decreased cancellous bone connectivity in BDL, compatible with osteoporosis. This group also showed increased mineralization lag time, indicating disturbance in bone mineralization. Serum levels of IGF-I were lower in BDL (basal 1,816 ± 336 vs. 30 days 1,062 ± 191 ng/ml, P < 0.0001). BDL also showed higher IGF-I expression in the liver tissue but lower IGF-I and GH receptor expression in growth plate cartilage than SO. Osteoporosis is the most important feature of HO; BDL rats show striking signs of reduced bone volume and decreased bone strength, as early as after 1 month of cholestasis. The endocrine and autocrine–paracrine IGF-I systems are deeply affected by cholestasis. Further studies will be necessary to establish their role in the pathogenesis of HO.

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Acknowledgments

We thank Sebastião L. Brandão Filho, Sebastião Assis, Carlos Alberto Moro, Auristela de Melo Martins, Adalberto Vallada Verceze, Mauricio Rodrigues de Arantes, and Roni Charles Fabbris for technical help and laboratory assistance and Elettra Greene for revising the English text. This work was supported by grants from FAPESP (06/56890-0) and FAEPA.

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Authors and Affiliations

  1. Department of Internal Medicine, School of Medicine of Ribeirão Preto, University of São Paulo, Av. Bandeirantes 3900, Ribeirão Preto, SP, Brazil

    F. A. Pereira & Francisco J. A. de Paula

  2. Department of Pediatrics, School of Medicine of Ribeirão Preto, University of São Paulo, Av. Bandeirantes 3900, Ribeirão Preto, SP, Brazil

    Inalda Facincani

  3. Department of Nephrology, School of Medicine, University of São Paulo, Av. Dr. Arnaldo 455, São Paulo, SP, Brazil

    Vanda Jorgetti & Luciene M. dos Reis

  4. Department of Pathology, School of Medicine of Ribeirão Preto, University of São Paulo, Av. Bandeirantes 3900, Ribeirão Preto, SP, Brazil

    Leandra N. Z. Ramalho

  5. Department of Biomechanical and Rehabilitation of the Locomotor System, School of Medicine of Ribeirão Preto, University of São Paulo, Av. Bandeirantes 3900, Ribeirão Preto, SP, Brazil

    José B. Volpon

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  1. F. A. Pereira
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Correspondence to Francisco J. A. de Paula.

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Pereira, F.A., Facincani, I., Jorgetti, V. et al. Etiopathogenesis of Hepatic Osteodystrophy in Wistar Rats with Cholestatic Liver Disease. Calcif Tissue Int 85, 75–83 (2009). https://doi.org/10.1007/s00223-009-9249-3

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