Nonalcoholic steatohepatitis

doi:10.1053/gast.2001.27126

Gastroenterology

Volume 121, Issue 3, September 2001, Pages 710-723

https://doi.org/10.1053/gast.2001.27126 Get rights and content

Abstract

Nonalcoholic steatohepatitis (NASH) is a condition characterized by hepatomegaly, elevated serum aminotransferase levels, and a histologic picture similar to alcoholic hepatitis in the absence of alcohol abuse. Most patients with NASH are obese women, and many have diabetes mellitus, hypercholesterolemia, or hypertriglyceridemia. NASH has also been associated with a number of metabolic conditions, surgical procedures, and drug treatments. Most patients are asymptomatic. The most common sign of NASH is hepatomegaly. Stigmata of chronic liver disease are rare. Laboratory abnormalities include a 2–4-fold elevation of serum aminotransferase levels; other liver function test results are usually normal. Histologically, there is moderate to severe macrovesicular steatosis and lobular hepatitis with necrosis or ballooning degeneration and/or fibrosis. The pathogenesis of NASH is poorly understood, but lipid peroxidation and oxidative stress are the leading culprits. The natural history of NASH is unknown, but NASH seems to be a stable disease in most patients. Treatment of NASH is unproven, but weight reduction is recommended in obese patients. Small pilot studies of several drugs have shown promise, but large randomized clinical trials are awaited. Orthotopic liver transplantation is the treatment of choice for end-stage liver disease secondary to NASH.

GASTROENTEROLOGY 2001;121:710-723

Section snippets

Epidemiology of NASH

NASH has been reported worldwide, although geographic variations in prevalence are evident. NASH is the histologic diagnosis in 7%–11% of patients undergoing liver biopsy in the United States and Canada1, 2 but is found in only 1.2% of patients undergoing liver biopsy in Japan.³ In a recent histologic study, NASH was documented in 26% of 81 nonalcoholic patients with marker-negative abnormal liver function test results.⁴ NASH may be even more prevalent among asymptomatic patients with elevated

Clinical and laboratory features

The clinical and laboratory features of NASH are summarized in Table 3.NASH is asymptomatic in a large proportion (48%–100%) of patients.8, 12, 47, 48, 49, 50 Symptoms that have been described include vague right upper quadrant pain, fatigue, and malaise. These symptoms may be more prominent in adolescents with NASH.6, 7 NASH is often discovered incidentally during evaluation for an unrelated medical condition.1, 12 Most patients with NASH have elevated liver function test results and/or

Histology

NASH is indistinguishable histologically from alcoholic hepatitis. The major histologic features of NASH are summarized in Table 4.

. Histologic features of NASH

Features present in all or most cases

Macrovesicular steatosis

Parenchymal inflammation

Hepatocyte necrosis

Ballooning hepatocyte degeneration

Features observed with variable frequency

Perivenular, perisinusoidal, or periportal fibrosis

Mallory bodies

Glycogenated nuclei

Councilman bodies

Lipogranulomas

Stainable hepatic iron

Unfortunately, minimal

Pathogenesis

The pathogenesis of NASH is poorly understood. Hepatic steatosis, one of the hallmark histologic features of NASH, develops in the setting of multiple clinical conditions including obesity, diabetes mellitus, alcohol abuse, protein malnutrition, total parenteral nutrition, acute starvation, corticosteroid therapy, and carbohydrate overload. To understand how steatosis develops, one has to first understand how the liver metabolizes lipids under normal conditions. In the fed state, dietary

Natural history of NASH

The natural history of NASH is unknown, largely because there have been few long-term, prospective, longitudinal studies with histologic follow-up in patients with NASH. The available data suggest that NASH is a benign disease in most patients. However, in some patients, NASH can lead to cirrhosis, liver failure, or hepatocellular carcinoma. In 2 clinical series, the incidence of hepatic decompensation caused by progression of NASH was 2%–3%.10, 12 Only 3 studies have included histopathologic

Diagnostic strategies

The keys to establishing a diagnosis of NASH are presented in Table 5.

. Keys to the diagnosis of NASH

Clinical

History of chronic mild elevation of serum aminotransferases

No history of significant alcohol use or abuse, confirmed by discussions with family members and primary care physician

Asymptomatic or nonspecific constitutional symptoms

No stigmata of chronic liver disease (except in patients with NASH-associated cirrhosis)

Laboratory

Serum aminotransferase levels 2–4 times the upper limits of

Treatment of NASH

The optimal therapy for NASH has not been established in adults (Table 6).

. Possible treatment for NASH

Moderate, sustained weight loss

Control of diabetes mellitus and hyperlipidemia

Ursodeoxycholic acid

Gemfibrizol

Metformin

Betaine

Vitamin E, other antioxidants

Thiazolidinediones

None of these treatments have been evaluated in large clinical trials of adult patients with NASH.

Weight loss has resulted in normalization of biochemical and ultrasonographic abnormalities in children with NASH,¹⁰³ but this

Summary

NASH is a chronic disorder that is recognized increasingly in patients with abnormal liver function test results. Most patients are female and obese with evidence of type 2 diabetes mellitus and/or hyperlipidemia. However, NASH can also occur in lean male and female patients without these associated conditions. NASH is indistinguishable histologically from alcoholic hepatitis and is usually characterized by macrovesicular steatosis, necroinflammation, ballooning hepatocyte degeneration, and

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