A METHOD FOR TREATMENT OF PATIENTS WITH CHRONIC LIVER DISEASE

Abstract: Patients with chronic liver disease and consequently very low concentrations of IGF-1 in the blood, in spite of increased GH concentrations, are treated with periodically injections of hGH for a period both parameters being individually adjusted for the patients.

Description: A METHOD FOR TREATMENT OF PATIENTS WITH CHRONIC LIVER DISEAS The present invention concerns a method for treatment o patients with chronic liver disease and an agent for use in th method. The frequency of patients with chronic liver diseases i unknown, but in Europe the number of patients with newl recognized liver diseases seems to be increasing concurrentl with the increasing consumption of alcohol. The chronic liver diseases includes the alcoholic live cirrhosis, which is dominating in number, liver cirrhosi caused by chronic infection after acute inflammation of th liver and last and more seldom occurring immunological live diseases characterized by chronic inflammation without know reason. Especially the alcoholic liver cirrhosis constitutes to day still increasing problem in national health care. The primar treatment available is of preventing character such a abstinence from alcohol in order to prevent aggravation of th disease. Once the alcoholic liver cirrhosis has taken place th present possibilities of therapeutic treatments are ver limited. Normally the alcoholic liver cirrhosis develops gradually an is often preceded by several years of alcoholic abuse. Th development of cirrhosis hepatis is preceded by a state o increasing accumulation of fat in the liver (steatosi hepatis) . This state is reversible and the liver can b normalised if consummation of alcohol is terminated. However, if the abuse goes on then the liver tissue will gradually b transformed to connective tissue which leads to badly workin liver tissue and consequently reduced function of the liver. Under normal conditions the liver plays an important role i metabolism including accumulation of nutrients, transformatio and excretion of waste products, production of proteins whic are important for the composition and coagulation of the blood. Furthermore, the liver functions as a gland by producing an secreting gall as well as various hormones comprising IGF-1. I case of reduced function of the liver all this above mentione functions are influenced in various degrees and the patient with chronic liver disease is especially characterized by having in the blood very low concentrations of the proteins and hormones which are produced in the liver. A reduced concentration of the protein albumin in the blood is of importance for the development of edema in the abdominal cavity such as ascites and in the legs, which problems are often connected with patients having a chronic liver disease. A reduced capability of production of coagulation factors, which are important for the normal coagulation of blood, leads to an increased tendency of bleeding in these patients and this tendency is used to express the degree of failure of the liver. Patients having a chronic liver disease are furthermore characterized by having a distorted regulation of a number of endocrine systems. As one result among others, is the ascertainment of greatly reduced concentrations of the growth factor IGF-1 (Insulin-like Growth Factor-1) in the blood. IGF-1 is a hormone which is mainly produced in the liver upon stimulation by GH (Growth Hormone) from the pituitary gland. IGF-1 plays an important role for the growth and development of children. Further IGF-1 is important for metabolism by stimulation of protein synthesis in the liver and other organs, besides it is important for regulation of the carbohydrate metabolism. IGF-1 is synthesized and released from the liver caused by GH stimulation, and children with GH-deficiency are characterized by having very low concentrations of IGF-1 in the blood. When a chronic liver disease has reached the state of incipien failure of the liver then the capability of the liver t produce IGF-1 is reduced and therefore very low concentration of IGF-1 is found in the blood. It appears that there is positive correlation between the reduction in IGF-1, the degre of the liver disease and the prognosis of the patients. As physiological reaction to the above mentioned condition increased basic GH concentrations are found in the blood o these patients. However, these concentrations are not capabl of normalizing the very low IGF-1 concentrations. Cirrhosis of the liver is associated with a very seriou prognosis. About one third of the patients will die within 2 years after a diagnosis has been made. Average expectation of life for these patients is under 4 years and adjusted for age the average death rate for this patients is 10 times higher than normal. The factors of particular importance for this prognosis seem to be reduced serum albumin, IGF-1 and prothrombin which last factor leads to reduced coagulation. To day the medical treatment of advanced cirrhosis of the liver is only symptomatic and directed against complications such as ascites, varices connected to the gullet and hepatic coma. Apart from total abstinence from alcohol all other attempts to stop or change the course of the cirrhotic process have only given poor results. Also numerous cures using particular dietetic treatments, multivitamin preparations, fructose etc. which cures were supposed to have an influence on the liver function, have shown to be without result. As mentioned above, in patients with liver cirrhosis the concentration of IGF-1 in the blood is very low, while GH, which stimulates the synthesis and release of IGF-1 from the liver, is present in a very high concentration. Therefore it seems that GH is present in relative excess, however an excess that cannot be used and which consequently is excreted in the urine. In the light of the poor possibilities given by the variou treatments known up till now, we have performed clinicall controlled trials on the subject. Surprisingly, during thi trials, we have found that in spite of the above mentione increased concentrations of GH in the blood of the patient leading to increased excretion of GH, then it is possible b admini-stration of GH to the already existing surplus t increase the also above mentioned very low IGF-1 concentration considerably. The invention is further explained but not limited by the following example. EXAMPLE 1 20 consecutive male patients with alcoholic cirrhosis were evenly randomized to either conventional medical treatment supplemented with injections of recombinant human growth hormone (rhGH) or conventional medical treatment alone. The treatment period lasted for 6 weeks in which measurements of the effect parameters were performed twice weekly. In order to achieve optimal compliance all patients, both the GH-group and the control group, were hospitalized during the trial. The injections of rhGH were administered by the nursing staff. The patients in the control group had a conventional medical treatment comprising vitamin B and thiamin in all 6 weeks. The patients in the GH-group had the same treatment but as a decisive factor supplemented with injections of rhGH (Norditropin ® ) , administered subcutaneously in a dose of 4 IU twice daily for all 6 weeks. After the end of the trial period the following results for the main parameter IGF-1 were found: TABLE 1 IGF-1 (nmol/1) Mean From the above results it can be seen that even if the patients had an increased concentration of GH in the blood it was possible to increase the IGF-1 concentration in the patients belonging to the GH-group compared to the patients belonging to the control group (Figure 1) . It is very likely that this increased IGF-1 concentration has a beneficial influence on the course of the liver disease and on the clinical state and prognosis of the patients. It is believed that the present invention creates an important contribution to the conventional treatment of patients with chronic liver disease, which treatment as it is known to day has very little possibilities and a very poor prognosis. When using this method it is to be understood that the parameters e.g. period of treatment and daily doses should be individually adjusted to the patients, based on a medical examination and judgement.

Claims: PATENT CLAIMS 1. A method for treating patients with chronic liver diseas and consequently low concentrations of IGF-1 in the blood, c h a r a c t e r i z e d by treating the patient wit injections of human growth hormone (hGH) . 2. A method according to claim 1, c h a r a c t e r i z e in that the period of treatment and the periodical doses ar individually adjusted to the patients. 3. Use of hGH for treatment of patients with chronic live disease. 4. Use of hGH for the production of a medicament for treatmen of patients with chronic liver disease. 5. An agent for use in treatment of patients with chroni liver disease, c h a ra c t e r i z e d in that it comprise hGH.

Inventors: MOELLER SOEREN, SKAKKEBAEK NIELS ERIK, MOELLER, SOEREN, SKAKKEBAEK, NIELS, ERIK
Applicants: NOVONORDISK AS, NOVO NORDISK A/S
Application year: 1992
Main classification: A61K37
IPC codes: A61K31, A61K38, A61P1, A61P3