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    Nonalcoholic Steatohepatitis (NASH)

    Denis Marleau, MD
    Professor of Medicine
    Liver Unit
    Saint-Luc Campus
    Centre Hospitalier de l'Universite de Montreal (CHUM)
    University of Montreal

    Learning Objectives:
    To recognize NASH and its clinical and histological features
    To learn about the natural history and pathogenesis of NASH
    To review the management of NASH

    Abstract:
    In 1980, Ludwig and colleagues2 described the finding of an alcoholic hepatitis-like histological picture in nonalcoholic patients. This phenomenon has been designated by several terms, including pseudoalcoholic hepatitis, diabetic hepatitis, fatty-liver hepatitis, alcohol-like hepatitis, but currently nonalcoholic steatohepatitis (NASH) remains the most popular appellation.

    Analysis of liver biopsy specimens is the cornerstone of diagnosis. NASH is defined by the presence of macrovesicular fatty changes (steatosis) and lobular inflammation in the absence of alcoholism. NASH is most frequently associated with obesity, diabetes and hyperlipidemia and one could consider this combination as a primary entity (Primary NASH), while secondary disease is related to other metabolic factors, drug treatments, surgical procedures for treatment of obesity and miscellaneous factors (see Table 1).

    Table 1

    Nonalcoholic Steatohepatitis
    Primary Nash
    -Obesity
    -Diabetes
    -Hyperlipidemia

    Secondary Nash
    Drug Treatments
    -Amiodarone
    -Perhexilene Maleate
    - Glucocorticoids
    - Synthetic Estrogens
    - Tamoxifen

    Surgical Procedures
    - Jejunal bypass
    - Gastroplasty for Morbid Obesity
    - Biliopancreatic Diversion
    - Extensive Small-Bowel Resection

    Other Metabolic Factors
    - Total Parenteral Nutrition
    - Acute Starvation
    - Rapid Weight Loss

    - Miscellaneous
    - Bacterial overgrowth(jejunal diverticulosis)
    - Limb Lipodystrophy
    - Abetalipoproteinemia
    - Weber-Christian Disease

    The diagnosis of primary NASH depends on convincing evidence of negligible (? 20 g ethanol/day) alcohol consumption. In fact, it is difficult to differentiate patients with NASH from asymptomatic ambulatory patients with alcoholic hepatitis on the basis of clinical and biochemical evaluations.3 Among several markers used as indicators of excessive alcohol consumption, the ratio of desialyted transferrin to total transferrin is the best single marker and has been reported to be more sensitive and specific than such markers as mitochondrial isoenzyme of AST, g-glutamyltransferase (GGT), mean corpuscular volume (MCV) and AST-to-ALT ratio greater than 2.4

    The diagnosis of primary NASH must include a negative evaluation for chronic hepatitis C virus infection (antibody to hepatitis C virus) and hepatitis B virus infection (hepatitis B surface antigen). Ceruloplasmin levels, a-1- anti-trypsin levels are usually normal in patients with NASH. Idiopathic genetic hemochromatosis must be excluded even in the presence of elevated levels of serum ferritin and transferin saturation it was found in 58% of patients with NASH in one series.5 Autoimmune serology (antimitochondrial antibody, antinuclear antibody, antismooth muscle antibody, and anti-liver/kidney microsomal antibody) should remain negative in patients with NASH, except for some patients presenting with low titer antinuclear antibody positivity (ranging from 1:40 to 1:320).3,13

    Clinical Features:
    The majority of patients with primary NASH are women (65%-83%) and most are obese (69%-100%).2,7-10 Most patients are 10% to 40% heavier than ideal body weight and in one series, 49% of patients were more than 130% of ideal weight.9 Non-insulin-dependant diabetes mellitus is present in 25% to 75% of patients2,6-10 and it is a co-morbid factor with obesity. In one series, only 8% of the patients were neither obese nor diabetic.8

    The mean age at diagnosis is 50 years, but ages range from 16 to 80 years.2,6-10 A high proportion of patients (48% to 100%) have no symptoms of liver disease and a small percentage, especially children,11,12 have vague abdominal discomfort or pain in the right upper quadrant, and lethargy.9,10 Such patients present because of other conditions, (such as heart disease, hypertension, hypothyroidism, cholelithiasis, gynecologic or psychiatric conditions etc...) and are incidentally found to have abnormal liver function.8,9 Because of the associated conditions, these patients have frequently taken one or more medications.8,10 The diagnosis of primary NASH requires the exclusion of drugs which have been reported to produce secondary NASH, such as amiodarone, perhexilene maleate, synthetic estrogens, glucocorticoids and tamoxifen.

    The most common finding at initial presentation is hepatomegaly,7-9 but splenomegaly, ascites and spider nevi are rare.

    Laboratory Features:
    The most frequently noted abnormality is a two-to threefold elevation of serum levels of ALT and AST.3,7-10 In the individual patient, the AST/ALT ratio will not discriminate alcoholic from non-alcoholic disease. Even if an AST/ALT ratio of greater than three is found significantly more often (p>0.001) in patients with alcoholic liver disease (82%), the ratio also exceeds three in 32% of nonalcoholics in one study.8 In another study,7 ratios of more than one are seen in 40% of nonalcoholics. Bilirubin levels are usually normal,3,6,8,9 and hyperbilirubinemia that barely exceeds 25 to 35 mmol/L is found in 12% to 17% of patients.8,9 Alkaline phosphatase levels are modestly elevated in 39% to 59% of the patients.6,9 Hypoalbuminemia and hypoprothrombinemia are unusual.3,8,9

    Immunoserologic findings compatible with autoimmune hepatitis are commonly present with primary NASH. Hypergammaglobulinemia is present in 13% to 30% of patients with primary NASH.6,13 Smooth muscle antibodies are absent but antinuclear antibodies, ranging in titer from 1:40 to 1:320, are reported in 40% of patients.13

    Hyperlipemia (hypertriglyceridemia and hypercholesterolemia) is found in about 20% of the patients overall.2,8 In a group of overweight patients (150 to 300% of ideal weight for height), lipoprotein abnormalities, particularly type IV hyperlipidemia are common (54%) and are mostly found in the those with less fibrotic lesions.

    Histologic Features:
    The strict definition for the histologic diagnosis of NASH includes in addition to steatosis and inflammation, either hepatocyte ballooning or degeneration or hepatic fibrosis.

    The fatty liver is mainly macrovesicular and primarily in zone 3 (centrilobular), but it may be microvesicular or mixed, accompanied by fat cysts and distributed also in zone 2 and 3.2

    Focal necrosis are usually centrilobular9 and the cellular response involves lymphocytes, mononuclear cells and neutrophils. Hepatocyte ballooning is present and Mallory hyaline bodies are described in 0% to 91% of cases.2,6-10 These hyaline bodies are usually sparse, small and centrilobular. The ultrastructure of Mallory bodies in patients with NASH are similar to those seen in patients with alcoholic hepatitis.14

    Fibrosis associated with NASH is characterized by early zone 3 pericellular or perivenular involvement. The prevalence of mild to moderate fibrosis is recorded in 76% to 100% of cases,2,7-9 while severe fibrosis varies from 15% to 50%.2,7-10 Cirrhosis is described less frequently in adults, 7% to 16%2,9,10 and is absent in children.

    Natural History:
    Longitudinal studies with serial biopsies and comparable follow-up are limited. In the results of three series combined for which the follow-up histopathology of 28 patients is available, only one improved (3%), 15 of 28 (54%) were unchanged, and 12 of 28 (43%) developed progression of fibrosis during one- to seven-year periods.5,9,10 During a similar follow-up period, the progression to cirrhosis occurs in approximately 8% to 17% of patients with NASH,9,10 compared with 38% to 50% of patients with alcoholic hepatitis.15,16

    The survival rates of 65 patients with alcoholic hepatitis were compared with those of 30 patients with NASH using a Kaplan-Meir curve. Five-year and ten-year survival probabilities of patients with alcoholic hepatitis were 38% and 15%; by comparison survival rates with NASH were 67% and 59%, respectively.17

    The effect of weight loss is variable; improvement occurs after gradual weight reduction,18 although rapid weight loss may aggravate the histologic lesions of steatohepatitis.19

    Pathogenesis:
    The pathogenesis of Nash is unknown. Accumulation of fat in the liver can occur because of:

    1. increased delivery of free fatty acids (FFA) to the liver;
    2. increased synthesis of fatty acids in the liver;
    3. decreased b-oxidation of FFA; and
    4. decreased synthesis or secretion of very-low-density lipoprotein.20

    Fatty liver without inflammation is a common histological finding encountered in protein-energy malnutrition, obesity, acute starvation, carbohydrate overload, and corticosteroid therapy. Obese patients have greater stores of FFA in adipose tissue, are resistant to insulin, have normal or elevated levels of insulin and have higher plasma levels of (FFA). Insulin increases the synthesis of FFA and triglyceride and inhibits the oxidation of FFA in the liver, thereby increasing levels of FFA in the liver.21-22 Accumulation of FFA may be responsible for liver dysfunction because fatty acids are highly reactive and can impair membrane integrity, cause mitochondrial swelling, increase lysosomal fragility, thereby initiating and perpetuating a necro-inflammatory reaction.23

    Fatty liver alone without hepatitis occurs more frequently than does NASH, and the relationships between steatosis, steatohepatitis, and fibrogenesis have not been established. It is not clear whether the accumulation of fat in the liver is responsible for the subsequent inflammation or whether inflammation induced by some stimulus causes hepatocyte dysfunction to result in steatosis. Steatosis is not always associated with inflammation and fibrosis, and fatty liver may be a secondary phenomenon in the pathogenesis of NASH rather than a primary initiating factor;24 however, some studies tend to demonstrate a correlation between the degree of steatosis and the degree of fibrosis.25

    Treatment Strategies:
    There is no established therapy for NASH, however empiric treatment strategies have been proposed (see Table 2).

    Table 2
    Treatment Strategies

    Dieting
    Weight Reduction -Gradual
    -Moderate
    -Not Complete
    Antibiotics
    Metronidazole (for jejunoileal bypass)

    Surgery
    -Gastroplasty
    -Gastric Bypass
    Drug with Lipid-altering Properties and Direct Cytoprotective Effects:
    -Ursodeoxycholic Acid Trial

    Dieting
    Weight reduction can improve laboratory abnormalities, histologic changes and liver size,26 however, improvements can be achieved even if the patient remains obese. On the other hand, striking weight losses have also been associated with progression of the disease.19 Supplemented fasting with weight loss that is moderate and gradual can safely improve biochemical liver tests, decrease liver size and resolve fatty change in the chronic liver dicrease associated with obesity and diabetes.18 The long-term benefit of weight loss is difficult to evaluate however, because patients with NASH would have to maintain sustained reductions in weight.

    Surgical Procedures (Gastroplasty or Gastric Bypass)
    Gastric bypass or gastroplasty performed in obese patients (75% overweight) have significantly reduced steatosis from 73% to 40% one year after surgery. Discrete inflammatory changes also largely disappeared and serum alkaline phosphatase was significantly reduced. Reduction in weight during this period ranged from 12% to 42%.27 In contrast, the weight loss induced by jejunoileal (J-I) bypass operations, in most cases, seems to be accompanied by a further increase in liver steatosis and fibrosis.28

    Antibiotics
    After jejunoileal bypass, steatohepatitis has resolved with metronidazole therapy,29 but this treatment has not been evaluated in primary NASH.

    Ursodeoxycholic Acid (UDCA)
    UDCA may have a membrane - stabilizing and cytoprotective effect. Treatment of NASH with UDCA for 12 months in a pilot study resulted in significant improvements in alkaline phosphatase, alanine transaminase (ALT), g-glutamyl transpeptidase (GGT) and hepatic steatosis, although there was no significant change in mean weight.30 Clofibrate therapy for one year in patients with NASH and hypertriglyceridemia was not found to be beneficial, in the same pilot study,30 despite its lipid lowering properties. The possible benefit of UDCA therapy should be further investigated in the context of a randomized, controlled trial.

     






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