Simple Fatty Liver and Non-Alcoholic Steatohepatitis (Part Three)

Prognosis in Untreated NASH

As mentioned above, NASH, if left untreated, will progress to fibrosis or often cirrhosis over 5-10 years in 10% of patients. Some studies place this figure at a higher level of over 40%. About 12% of patients, especially diabetics, may die within 10 years from complications of liver disease. However, in a large proportion of patients, NASH remains benign and does not progress to the final stages.

Keeping in mind that NASH may seem as common as chronic hepatitis C and possibly has a comparable risk of progression to cirrhosis, we should not overlook the fact that, unlike hepatitis C, there is no effective therapy for NASH. This puts the prognosis of NASH in an almost unfavorable light.

While patients with NASH have a higher 5 and 10-year survival rate compared to patients with ASH, they are reduced compared to the normal population. These data remain subject to confirmation.

Currently, only a few research groups are studying the various manifestations of fatty liver. Thus, the given statistics cannot be considered definitive. Despite disagreements in the prevalence of figures reported by different centers, it is clear that NASH is a common and often overlooked disease, the prognosis of which seems to be as uncertain as that of alcoholic steatohepatitis. Therefore, whenever patients present with high and prolonged transaminase levels, with the aforementioned risk factors and a reliable denial of significant alcohol consumption, the diagnosis of NASH should be considered.

Therapy

The prognosis of non-alcoholic steatohepatitis remains unclear. Thus, the ultimate goal of all therapeutic measures is to stop the progression of the disease and, if possible, prevent the development of cirrhosis. Since the pathogenesis of NASH is unknown, therapy remains empirical and is limited to treating conditions associated with NASH such as diabetes mellitus, obesity, and hyperlipidemia, as well as avoiding hepatotoxic pharmacological agents.

Weight Reduction

Rapid, but also slow weight loss of 10-30 kg can reduce or often normalize the fatty content of the liver in overweight patients. A reduction in body weight of about 10% of the initial weight of patients is extremely beneficial in improving laboratory parameters.

On the other hand, drastic weight loss can lead to portal fibrosis and inflammation. The most effective treatment is a low-calorie diet that should be maintained for a long period of time. Patients with diabetes mellitus, cardiovascular disease, or lipid metabolism disorders require special care.

The recommended daily diet in obese patients with NASH starts with 1200 kcal, and if it is ineffective, a reduction from 600-800 kcal/day is required. Protein: 45-100 gr. per day, carbohydrates less than 100 gr. per day, fats less than 10 gr. per day. The benefit of appetite suppressants is not confirmed. Such preparations may be associated with pulmonary side effects.

Diabetes Mellitus Therapy

Diabetics should start a dietary program and immediate administration of antidiabetic medication. These measures are important for diabetes but their effects on NASH are unconfirmed. In experiments on obese mice, antidiabetic agents (metformin) had a positive influence on NASH. Results in humans are not yet valid.

Pharmacological Therapy of NASH

Many studies are considered open, with a small number of patients, and this urgently necessitates further research. Pharmacological agents that have been used in the treatment of NASH are:

Clofibrate, which was found to reduce hepatic triglyceride content in rabbits, was ineffective in patients with NASH after 1 year of therapy with 2gr clofibrate per day.

Gemfibrozil not only lowers high serum VLDL triglycerides, but also reduces the mobilization of free fatty acids from peripheral adipose tissue and its use was associated with an improvement in serum transaminases with a dose of 600 mg per day for 4 weeks.

Ursodeoxycholic acid (UDCA) may be necessary in the treatment of NASH. Studies of patients with primary biliary liver disease have shown that UDCA displaces hydrophobic, hepatotoxic bile acids from the bile acid pool and in particular had immunomodulatory, cytoprotective, and antiapoptotic advantages.

Three studies with a total number of 78 patients have shown that UDCA with a dose of 10-15 mg/kg weight per day reduces or often normalizes AST in 40% of patients and γ-GT in 30%, especially when UDCA therapy is combined with a low-fat diet. In particular, UDCA reduces the fatty content in the liver. UDCA represents an improvement in bile acids and has the advantage of not causing side effects in patients with primary biliary liver disease who have been treated for more than 11 years.

Betaine glucuronate increases the concentration of S-adenosylmethionine (SAME) in the liver. SAME is a transmethylation component, which has been associated with improvement in fatty liver in animal experiments. In 8 patients with NASH, betaine with a daily dose of 20 gr showed improvement in transaminases, hepatic fatty content, inflammatory activity, and fibrosis in liver tissue.

Alfa – tocopherol (vit. E) and N-acetylcysteine (N-AC) are respectively direct and indirect antioxidants. Vitamin E captures free radicals and inhibits the appearance of TNF-α, IL-6, IL-8, and the appearance of the gene encoding for hepatic collagen. In 11 children with NASH, vitamin E led to an improvement in transaminase levels, and in 8 adults allowed a decrease in TGF-β1, a cytokine that plays a key role in fibrogenesis. Histological studies are not yet valid. N-AC is a glutathione that protects against oxidative stress. In a study of 11 patients with NASH, N-AC with a dose of 1 gr per day also led to a decrease in transaminase levels.

Metronidazole, an effective antibiotic agent against anaerobes, is effective in patients with NASH whose liver disease is dedicated to bacterial overgrowth, as can occur in the case of a large duodenal diverticulum or after intestinal bypass.

As the pathogenesis of non-alcoholic steatohepatitis remains unclear, medication schemes will also be based on the current, scarce, pathogenetic information. Thus, even in treating our patients, we first focused on reducing body weight, which led to the normalization of laboratory parameters. Only in two cases did we apply ursodeoxycholic acid for up to 6 months.

Summary

NASH is often an underestimated disease. The prevalence of NASH probably corresponds to that of hepatitis C, because a large proportion of patients with NASH are mistakenly labeled as alcoholics or the terminal stage of the disease is confused with cryptogenic cirrhosis. The diagnosis of NASH can be difficult and represents an exclusion diagnosis.

NASH is differentiated from alcoholic steatohepatitis only by the reliable absence of alcohol. Histology reveals fatty degeneration, inflammatory infiltrates, central and periportal fibrosis, and eventually cirrhosis. Risk factors for the development of NASH include obesity, type 2 diabetes mellitus, insulin resistance, medications, and various surgical procedures in the gastrointestinal tract.

A central role in the pathogenesis of the disease also plays the hepatic efflux and clearance of free fatty acids and oxidative stress. The prognosis of NASH is not different from that of alcoholic hepatitis and hepatitis C, which together are the subject of accurate therapeutic schemes. In NASH, the most important measure consists of reducing body weight.

Preliminary evidence of ursodeoxycholic acid, various antioxidants, and statins have shown promising results but no final conclusion on their respective merits is yet possible.

Literature

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3. Palmer M, Schaffner F. Effect of weight reduction on hepatic abnormalities in overweight patients. Gastroenterology 1990; 99: 1408-1413.

4. Raatziu V, Giral P, Charlotte F et al. Liver fibrosis in overweight patients. Gastroenterology 2000; 118: 1117-1123.

5. Wanless IR, Lentz JS. Fatty liver hepatitis and obesity: an autopsy study with analysis of risk factors. Hepatology 1990; 12: 1106-1110.