The liver is the target of attack for a wide range of diseases. These diseases include infectious, autoimmune, as well as non-infectious processes such as chemicals. Examples of infectious diseases include: (i) viral hepatitis, e.g., hepatitis A, B, C, D, E, and G and (ii) parasitic hepatitis, e.g., Schistosoma mansoni, Schistosoma hematobium, and Schistosoma japonicum. (Harrison's Principles of Internal Medicine, Fauci et al. eds., 1998, pgs 1660-1725). Examples of noninfectious diseases affecting the liver, include autoimmune diseases, such as, (i) autoimmune hepatitis and (ii) primary biliary cirrhosis. (Harrison's Principles of Internal Medicine, Fauci et al. eds., 1998, pgs 1701-1709). Regardless of whether the attack on the liver is infectious, autoimmune or noninfectious, the liver responds to injury by pouring inflammatory cells into the site of attack. The types of inflammatory cells entering the site of attack consist primarily of macrophages and neutrophils. After entry into the site of injury, the cells release various inflammatory cytokines, such as tumor necrosis factor (TNF). These cytokines mediate the local inflammatory response by inducing local changes, for example, proliferation of fibroblasts or vasodilation.
If left untreated, repeated, chronic damage to the liver from infection, autoimmune disease or any other noninfectious processes causes scarring or fibrosis. This is a direct consequence of local proliferation of fibroblasts. (Kaplowitz, Biliary Diseases, pg. 139, Williams & Wilkins, 1992). In the case of the liver, the end-stage of fibrosis is cirrhosis. Pathologically, cirrhosis is defined as extensive fibrosis in the liver in association with the formation of regenerative nodules. Cirrhosis is the final common pathway for many, if not all, types of chronic liver damage and is typically progressive. (Kaplowitz, Biliary Diseases, pg. 140, Williams & Wilkins, (1992).
Because of the morbidity and mortality of untreated liver disease, either of an infectious or autoimmune nature, there is a need for developing effective treatments for preventing or reducing liver fibrosis and cirrhosis. Anti-thyroid hormone therapy offers a new way to treat the damaging effects of these diseases on the liver. Orrego et al. (New Eng. J. Med. 317(3)1427 (1987)) described long-term treatment of alcoholic liver disease with propylthiouracil (PTU), an antithyroid drug that blocks formation of thyroid hormones. (Goodman & Gilman, The Pharmacological Basic of Therapeutics, McGraw-Hill, pgs. 1398-1399 (1996)). The authors report a significant reduction in the mortality of patients with alcoholic liver disease. Other studies found that PTU protects the liver from damage resulting from chemical injury. For example, Yamada et al. (J. Clin. Invest. 67688 (1981)) and Raheja et al. (J. Pharm. Exper. Therapeutics 220:427 (1982)) found that PTU protected rats from acetaminophen-induced hepatocytotoxicity.
However, before the present invention, there had been no attempt to associate a hypothyroid condition with treating liver damage caused by infection. More particularly, there had been no attempt to treat humans afflicted with infectious diseases such as hepatitis. This was due, in part, to the fact that PTU is a hepatotoxic material that can cause severe liver damage, including death, and the damage to the liver in alcoholic or chemically-induced liver disease is completely different from that of either virally-induced or autoimmune mediated liver disease.
First, using PTU to induce a hypothyroid-state is fraught with danger. Williams et al. showed that PTU-associated heptotoxicity is a well-recognized life-threatening complication of antithyroid drug treatment. (J. Clin. Endocrin. & Metabol. 82:1727 (1997)). Although the incidence of PTU-associated heptotoxicity was less than 0.5%, PTU-hepatoxicity can occur in all age groups and is often fatal. Consequently, the effects on the liver of treating patients with PTU are unpredictable.
Second, the pathophysiology of chemically-induced, i.e., alcohol, liver disease is completely different from damage caused by viral or autoimmune liver disease. Specifically, damage to the liver caused by alcohol comprises hypoxic damage to the central vein area which is accompanied by fatty changes to the liver. In contrast, damage to the liver caused by infectious or autoimmune disease comprises infiltration of inflammatory cells near the portal zone. (Kaplowitz, Biliary Diseases, pg. 140, Williams & Wilkins, 1992). Because the pathology of viral or autoimmune liver disease is completely different from either alcoholic or acetoaminophen-induced liver disease and in view of the hepatotoxicity of using PTU, prior to the present invention there was no reason to believe that inducing hypothyroidism could be used to treat damage to the liver caused by infection or autoimmune disease.
Because of the large number of affected individuals, there exists an overwhelming need to effectively treat damage to the liver resulting from infectious or autoimmune diseases. To date, there is no satisfactory treatment for preventing or reversing the fibrotic process that results from this type of injury to the liver. (Kaplowitz, Biliary Diseases, pg. 330, Williams & Wilkins, 1992). This need is clearly shown by the magnitude of the clinical problem worldwide. For example, there are more than 300 million carriers of hepatitis B. (Kaplowitz, Biliary Diseases, pg. 330, Williams & Wilkins, 1992). Every cancer patient being treated for leukemia or Hodgkin's lymphoma is particularly susceptible to infection with hepatitis B. (Kaplowitz, Biliary Diseases, pg. 330, Williams & Wilkins, 1992). In some tropical countries, the prevalence of hepatitis B is as high as 30% of the adult population. Moreover, infection with hepatitis B places the patient at risk for developing heptocellular carcinoma. (Kaplowitz, Biliary Diseases, pg. 399, Williams & Wilkins, 1992). Hepatitis C is the major form of transfusion-hepatitis and the number of reported cases worldwide is growing rapidly. (Kaplowitz, Biliary Diseases, pg. 333, Williams & Wilkins, 1992). In the general population, hepatitis C is responsible for over half the cases of acute viral hepatitis. (Kaplowitz, Biliary Diseases, pg. 297, Williams & Wilkins, 1992). The number of people infected with the parasitic form of hepatitis caused by Schistosoma is staggering. Worldwide over 200 million people are infected with this parasite. (Harrison's Principles of Internal Medicine, Fauci et al. eds., 1998, pgs 1217-1224). Schistosoma causes significant fibrotic damage to the liver. (Harrison's Principles of Internal Medicine, Fauci et al. eds., 1998, pgs 1217-1224).
Therefore, there is a long-standing need in the art for effective treatments for preventing or arresting liver damage resulting from infection or autoimmunity.
The present invention relates to methods for treating liver damage by making patients biochemically hypothyroid. The patients can be made biochemically hypothyroid using drugs such as PTU, partial thyroidectomy or by radiation with radioactive iodine.