Transforming growth factors beta-1 and alpha in chronic liver disease: effects of interferon alfa therapy

Article Abstract:

Advanced chronic inflammatory disease of the liver is characterized by several structural changes in the organ, including the proliferation of fibrous tissue (fibrosis). This is a complex process during which liver cells and the surrounding material become transformed, losing the ability to function normally. Transforming growth factors (TGFs) beta-1 and alpha are two substances associated with hepatic fibrosis; for example, TGF beta-1 induces the synthesis of collagen, one of the main components of fibrous tissue, in some types of liver cells, and, in animal studies, appears to increase in liver infections. To learn more about the role of these proteins in human liver disease, several experiments were carried out on tissue specimens from 46 patients with chronic liver disease or histories of such disease, and from eight controls (people with no liver disease who underwent gall bladder surgery). Results showed that the extent of TGF beta-1 mRNA expression (a measure of the amount of TGF beta-1 synthesized) correlated well with levels of certain proteins essential for collagen synthesis. Higher TGF beta-1 levels were also associated with greater degrees of tissue inflammation, determined by analyzing the specimens microscopically. In contrast, TGF alpha mRNA (mRNA for a different TGF) was present in patients whose livers contained regenerative nodules, indicative of partial liver recovery. The livers of these patients also contained mRNA for another protein (H3 histone) associated with cell division (proliferation), another sign of recovery. Eight patients with hepatitis C (a chronic liver infection caused by a virus) were treated with interferon alfa, an antiviral agent that slows cell proliferation; after one year, six improved clinically and had normal levels of TGF beta-1 after treatment. The results indicate that TGF beta-1 may play an important role in the generation of fibrous tissue characteristic of chronic hepatitis and cirrhosis (another serious liver condition). TGF alpha, on the other hand, may be involved in cell proliferation in these disorders. (Consumer Summary produced by Reliance Medical Information, Inc.)

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Hepatic fibrosis - new therapeutic approaches

Article Abstract:

In treating chronic liver diseases, emphasis is often placed on the complications resulting from portal hypertension (increased pressure in the portal vein, which carries blood from the digestive organs to the liver). Less is known about treating the progressive fibrosis (growth of tough, fibrous tissue) characteristic of cirrhosis and other liver disorders. A review is presented of drugs that have been developed for this purpose. They include colchicine, ursodiol (ursodeoxycholic acid), cyclosporine, and methotrexate. The development of better drugs against hepatic fibrosis relies upon improved understanding of the pathological processes that give rise to the condition. Inflammation of the liver and tissue degeneration stimulate certain lipocytes (fat cells) to synthesize collagen, the main component of fibrous tissue. Factors released in the course of inflammation (cytokines) may cause the lipocytes to manufacture fibrous tissue. Thus, the production of fibrous tissue could be inhibited by drugs that act at any of several points in the synthetic pathway. For example, colchicine inhibits the production of collagen, while cyclosporine and methotrexate reduce inflammation. Another factor that may be significant is the cytokine called transforming growth factor (TGF) beta-1, which stimulates the production of proteins that form the extracellular material that holds tissue together. In an article in the April 4, 1991 issue of The New England Journal of Medicine, the levels of TGF beta-1 mRNA (instrumental in synthesizing the factor) were higher in patients with chronic hepatitis. It is suggested that measurement of this factor could become a way of monitoring the development of fibrosis. Interferon alfa, which inhibits cell proliferation, appeared to reduce the synthesis of fibrous tissue. This drug is now licensed for treating chronic viral hepatitis C, which infects 170,000 new patients each year, half of whom will develop chronic disease. Long-term trials of the effectiveness of this drug against hepatic fibrosis are needed. (Consumer Summary produced by Reliance Medical Information, Inc.)

Liver cirrhosis

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Long-term response of recurrent respiratory papillomatosis to treatment with lymphoblastoid interferon alfa-n1

Article Abstract:

Recurrent respiratory papillomatosis is a rare infection caused by the human papillomavirus types 6 and 11, the same subtypes associated with genital condylomata (venereal warts). The disease is characterized by benign growths in the respiratory tract, especially on the larynx, but also in the airway and lungs. The growths are usually removed with a carbon dioxide laser passed through the mouth. Although the growths are removed, the virus remains in other tissue. Beginning in 1976, natural leukocyte interferon (a natural cell protein) was used to treat recurrent respiratory papillomatosis, and in 1988, lymphoblastoid interferon alfa-n1 was tried in a group of 57 patients. The lesions were reduced in the treated group, and remission was obtained in eight of the patients in the latter study. A similar study of leukocyte interferon also found a strong effect during the first six months of therapy, but it diminished during the second six months. In this study, 60 patients receiving lymphoblastoid interferon alfa-n1 were followed for over 500 days. Thirteen patients did not respond to treatment; however, 22 achieved complete remission, and 25 achieved partial remission. Complete response required six months, but half of the patients continued therapy for one year. Treatment with lymphoblastoid interferon alfa-n1 was superior to surgery in achieving remission of the disease. Treatment should end when complete remission is obtained; there is no indication that maintenance therapy is necessary. (Consumer Summary produced by Reliance Medical Information, Inc.)

Papillomavirus infections, Airway obstruction (Medicine), Airway obstruction

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