Prof Dato’ Dr K.L Goh, University Malaya Medical Centre, Kuala Lumpur

The diagnosis of "fatty liver" is commonly encountered in clinical practice. With the popularity of routine blood screening as part of health "check-ups" and "executive screening programs" in Malaysia, many otherwise completely healthy patients are now detected to have raised alanine aminotransferase and aspartate aminotransferase levels. These patients are referred to physicians with the diagnosis of fatty liver, following an ultrasound examination of the liver showing increased echogenicity with no other abnormalities. The rise in liver enzymes is usually mild and not exceeding 4x the upper limit of normal. It is imperative in every case before such a "diagnosis" is accepted that we go through a checklist excluding diagnoses such as chronic hepatitis B and C infection, surreptitious alcohol intake and "drug induced" hepatitis associated with commonly used drugs such as the "statins" for hypercholesterolaemia, ticlodipine and non-steroidal anti-inflammatory drugs. Many patients in the local context also take traditional and herbal remedies, which may cause a rise in liver enzymes. In young adults, Wilson's disease must be considered as a differential diagnosis. Autoimmune hepatitis may also present with raised liver enzymes with few symptoms.

Fatty liver is a generic term that refers to all types of fatty deposition in the liver. In a western population, where alcohol intake is generally higher, fatty liver is often associated with alcoholic hepatitis. In 1980, Ludwig and colleagues [1] from the Mayo clinic in 1980 coined the term nonalcoholic hepatitis (NASH) to describe the morphologic pattern of liver injury in 20 patients seen over a 10 year period of time. These patients had evidence of alcoholic hepatitis and steatosis on liver biopsy, but no history of alcohol abuse. No cause of liver disease could be identified. Sixty percent of the patients were women with a mean age of 54 years and ninety percent were obese (> 110% of ideal body weight) and 25% had a history of hyperlipoproteineamia and adult-onset diabetes mellitus or both. Most patients were evaluated for abnormal liver function test and were otherwise well. Hepatomegaly was found in 75% of patients. Hyperglycemia was noted in 50%, hypertriglyceridaemia in 75% and hypercholesterolaemia in 50%. The hallmark features on liver biopsy were moderate to severe macrovesicular steatosis with lobular inflammation.

NASH however represents only a stage in the spectrum of non-alcoholic fatty liver disease. The spectrum of NAFLD is wide and ranges from simple accumulation in hepatocytes (steatosis) without biochemical or histological evidence of fibrosis, to fat accumulation and necroinflammatory activity with or without fibrosis (steatohepatitis), to the development of advanced liver fibrosis or cirrhosis. NASH should be differentiated from benign steatosis, which runs a relatively uncomplicated course.
 

The pathogenesis of fatty liver is unknown. The frequent association of steatosis and NASH with obesity, type II diabetes mellitus and dyslipidemia suggests a potential role of tissue resistance to insulin as the cause of liver disease. Additionally, obesity and type II diabetes have been shown to be risk factors for the development of severe disease in NASH patients. Insulin and hyperinsulinemia may lead to steatosis, because high levels of insulin block mitochondrial fatty acid oxidation leading to accumulation of triglycerides and fatty acid in the liver [2]. Increased concentrations of intracellular fatty acids may be directly toxic to hepatocytes or lead to oxidative stress leading to inflammation and fibrogenesis. Sanyal and colleagues [3] have shown that peripheral insulin resistance, increased fatty beta oxidation and hepatic oxidative stress are present in both benign steatosis and NASH but mitochondrial structural defects are found only in NASH.
 

Patients with benign steatosis should be firmly reassured that they have a completely benign disease. The natural history of NASH however, is not entirely established. In the majority of patients it is still largely a benign disease. In studies where histological diagnosis is available, histological stability was seen in 54% of patients, improvement in 4% and progression to fibrosis and cirrhosis in 43% [4,5.6]. Histological deterioration however was not accompanied by clinical deterioration in most cases and based on limited data; NASH appears to be an indolent disease.
 

Treatment options are indeed limited for patients with NASH. Weight loss has been shown to result in normalization of liver enzymes in some studies [7,8,9] and remains the most viable option for our patients with NASH who is obese. Medical treatment is largely unestablished. Several drugs including the lipid lowering agents, gemfibrozil and clofibrate have been used without much success. Ursodeoxycholic acid has resulted in liver enzyme improvement but no change in the grade of inflammation nor fibrosis [10]. The association of hyperinsulinemic insulin resistance has provided a target for treatment. Metformin, a biguanide that reduces hyperinsulinemia and improves hepatic insulin resistance has been shown to greatly reduce hepatomegaly and steatosis in mice and may potentially be useful in the treatment of NASH in humans [11]. The new PPAR-gamma receptor agonist that improves insulin resistance is another potential useful treatment agent. In fact, a trial utilizing troglitazone has shown encouraging results [12]. Unfortunately, because of reports of rare but serious hepatotoxicity, the drug has now been withdrawn from the market. Rosglitazone has not been used in NASH patients so far.

References:
1.      Ludwig J, ViggianoT, McGill D, Ott B. Nonalcoholic steatohepatitis. Mayo clinic experiences with a hitherto unnamed disease Mayo Clin Proc 1980;55:434-8.

2.      Reid AE. Nonalcoholic steatohepatitis. Gastroenterology 2001;121:710-23.

3.      Sanyal AJ, Campbell-Sargent C, Mirshahi F, et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 2001; 120:1183-92.

4.      Bacon B, Faravash M, Janney C, Neuschwander-Tetri B. Non-alcoholic steatohepatitis. Hepatology 1999; 30:1103-9.

5.      Lee R. Nonalcoholic steatohepatitis: a study of 49 patients. Hum Pathol 1989;20:594-8.

6.      Powell E, Cooksley W, Hanson R, Searle J, Halliday J, Powell L. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology 1990; 11:74-80.

7.      Knobler H, Schattner A, Zhirnicki T, et al. Fatty liver-an additional and treatable feature of the insulin resistance syndrome. Q J Med 1999; 92: 87-96.

8.      Vajro P, Fonatanella A, Perna C, Orso G, Tedesco M, DeVincenzo A. Persistent hyperaminotransferasmeia resolving after weight reduction in obese children. J Pediatr 1994; 125:239-41

9.      Erikkson S, Eriksson K, Bondesson L. Nonalcoholic steatohepatitis in obesity: a reversible condition. Acta Med Scand 1986; 220: 83-8.

10.  Laurin J, Lindor K, Crippin J, et al. Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatology 1996; 23:1464-7.

11.  Lin H, Yang S, Chuckaree C, Kuhadja F, Ronnet G, Deihl A.  Metformin reverses fatty liver disease in obese leptin-deficient mice. Nat Med 2000; 6: 998-1003

12.  Battle E, Hespenheide E, Caldwell S. Pilot study of trosglitazone (Rezulin) for nonalcoholic steatohepatitis (abstr) hepatology 1998; 28:304A.

13.  Angulo P, Lindor KD. Insulin resistance and mitochondrial abnormalities in NASH: a cool look into a burning issue (editorial). Gastroenterology2001; 120:1281-5.

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