Definition
Nonalcoholic fatty liver disease is a spectrum of liver diseases with histologic features of alcohol induced liver disease that occurs in individuals who do not consume significant quantities of alcohol. The spectrums of the liver diseases include hepatic steatosis (fatty liver); nonalcoholic steatohepatitis with histologic evidence of hepatitis, hepatocellular injury, necrosis and, fibrosis; and cirrhosis with eventual portal hypertension and other complications.
Nonalcoholic fatty liver disease is believed to be one of the most common causes of abnormal liver chemistry tests in American adults. It is thought to be the major cause of cryptogenic cirrhosis. Clinically, Nonalcoholic fatty liver disease should be a diagnosis of exclusion. It should be suspected as a cause of chronic liver disease in patients who deny alcohol consumption and have negative serologic tests for active viral, congenital, and acquired causes of liver disease.
Associated conditions
Obesity.
Obesity is the condition most often reported to be associated with Nonalcoholic fatty liver disease. Obesity is described in 40% to 100% of patients with nonalcoholic steatohepatitis. Nonalcoholic steatohepatitis has been documented in 9% to 36% of obese patients. The prevalence and severity of hepatic steatosis has been noted to be directly proportional to the grade of obesity and the severity of nonalcoholic steatohepatitis has been noted to be proportional to the degree of hepatic steatosis. The distribution of body fat seems to be important in the development of hepatic steatosis. In one study, a significant correlation was found between the degree of hepatic steatosis and waist-to-hip ratio suggesting a relationship between visceral and intraabdominal fat and accumulation of fat in the liver.
Hyperglycemia, insulin resistance, hyperinsulinemia, glucose intolerance, and type II diabetes mellitus have been described in 25% to 75% of adult patients with nonalcoholic steatohepatitis.
Hyperlipidemias including hypertriglyceridemia and hypercholesterolemia or both have been found to be present in 20% to 80% of patients with nonalcoholic steatohepatitis.
Most patients with nonalcoholic steatohepatitis seem to have multiple risk factors including obesity, type II diabetes mellitus, and hyperlipidemia.
Other risk factors include female gender, rapid weight loss, acute starvation, total parenteral nutrition, and small-bowel diverticulosis.
Genetic conditions associated with Nonalcoholic fatty liver disease include Wilson’s disease, homocystinuria, tyrosinemia, a-beta- and hypobetalipoproteinimia, and Weber-Christian disease.
Surgical procedures associated with Nonalcoholic fatty liver disease, particularly nonalcoholic steatohepatitis, include gastroplasty for morbid obesity, jejunoileal bypass, extensive small-bowel resection, and biliopancreatic diversion.
Drugs.
The use of a number of drugs has been implicated in the development of Nonalcoholic fatty liver disease. The list includes glucocorticoids, amiodorone, synthetic estrogens, tamoxifen citrate, 4,4’-diethylaminoethoxyhexesterol (DHEAH), isoniazid, methotrexate, perhexiline maleate, tetracycline, puromycin, bleomycin, dichloroethylene, ethionine, hydrazine, hypoglycin, L-asparaginase, azacytidine, azauridrine, and azaserine. Chronic industrial exposure to petrochemicals has also been reported as a risk factor for Nonalcoholic fatty liver disease.
Diagnosis
Clinical findings
Symptoms.
Most patients with Nonalcoholic fatty liver disease are asymptomatic; however, fatigue, malaise, or vague right upper quadrant pain or discomfort may cause patients to seek medical attention.
Signs.
Hepatomegaly may occur in up to 75% of patients. Splenomegaly may be present in 25% of patients. Stigmata of portal hypertension and cirrhosis occurs rarely. In a subset of patients with Nonalcoholic fatty liver disease, especially in association with certain drugs and toxins (i.e., certain nucleoside analogs, antimitotic agents or tetracycline) fulminant hepatic failure may develop rapidly. Cirrhosis may develop rapidly in patients with steatosis and inborn errors of metabolism (i.e., tyrosinemia).
Laboratory findings.
Laboratory features of Nonalcoholic fatty liver disease are nondiagnostic. Mild to moderate increases in serum aminotransferases (alanine [alanine aminotransferase] and aspartate [aspartate aminotransferase]) are the predominant laboratory abnormalities reported in patients with nonalcoholic steatohepatitis. Typically, these abnormalities are noted during routine testing or when patients seek medical attention for other complaints. There is no significant correlation between the degree of serum aminotransferase elevation and the histologic features or severity of the hepatic inflammation or fibrosis. Serum alanine aminotransferase levels are often higher then aspartate aminotransferase levels, in contrast to the pattern seen in alcoholic hepatitis in which the aspartate aminotransferase/alanine aminotransferase ratio is higher than 1.
Serum alkaline phosphatase levels may be mildly elevated; serum bilirubin and albumin levels are usually normal. Prolongation of prothrombin time (Prothrombin time) is suggestive of hepatic decompensation. A small percentage of patients with nonalcoholic steatohepatitis may have positive low-titer antinuclear antibody levels. However antimitochondrial antibody, antibody to hepatitis C virus, and hepatitis B surface antigen are negative and serum ceruloplasmin and antitrypsin levels are normal. Elevated serum ferritin and transferrin saturation seem to occur commonly in patients with nonalcoholic steatohepatitis. Men with nonalcoholic steatohepatitis may have higher iron stores then women. One third of patients with nonalcoholic steatohepatitis may have one or two copies of the Cys282Tyr mutation in the HFE gene (genetic marker for hemochromatosis). Trends toward more severe hepatic fibrosis in patients with nonalcoholic steatohepatitis with this gene mutation have been reported.
Imaging modalities.
Several noninvasive imaging techniques including abdominal ultrasound (Ultrasound), computerized tomography (computed tomography) and magnetic resonance imaging (Magnetic resonance imaging) can reveal hepatic steatosis. None of the tests are significantly sensitive for the detection of hepatic inflammation or fibrosis. Computed tomography and Magnetic resonance imaging may be helpful only when extrahepatic manifestations of cirrhosis and portal hypertension (i.e., ascites, splenomegaly, varices) are present. Thus, none of these imaging modalities is sensitive or specific enough to definitively establish the diagnosis of nonalcoholic steatohepatitis or reliably grade its severity. Liver biopsy is the only diagnostic test for confirming the clinical suspicion of Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, staging the severity of the liver disease, and determining the extent of fibrosis. It is still uncertain as to whether liver biopsy is essential in the average patient, because biopsy results may not change clinical management.
Histology.
Nonalcoholic fatty liver disease is histologically indistinguishable from alcoholic liver disease. Histologic stages of Nonalcoholic fatty liver disease include steatosis, steatohepatitis and cirrhosis. Steatosis involves macrovesicular fat accumulation in the hepatocytes. Nonalcoholic steatohepatitis histology includes macrovesicular steatosis, lobular inflammation, hepatocyte degeneration, hepatocyte ballooning, and hepatic fibrosis. Steatosis may be diffuse or located primarily in the central zones of hepatic lobules. Parenchymal inflammation of varying degrees is present in all cases and the cellular infiltrate may consist of neutrophils, mononuclear cells, and lymphocytes. Hepatocyte necrosis with ballooning and cellular dropout, Mallory’s hyaline and Councilman’s bodies may be present.
Stainable iron may be present in 15% to 65% of patients. Pericellular, perisinusoidal, and periportal fibrosis have been described in 35% to 85% of patients with nonalcoholic steatohepatitis. The extent of fibrosis may vary considerably from patient to patient, ranging from mild fibrosis around small veins or groups of cells (chicken-wire fibrosis) to extensive, severe fibrosis with bridging of portal tracts and central veins and distortion of the hepatic architecture. Cirrhosis is found at initial liver biopsy in 7% to 16% of patients with nonalcoholic steatohepatitis and is indistinguishable from Laennec’s cirrhosis.
The pathogenesis of Nonalcoholic fatty liver disease is not known. However, because the histology of Nonalcoholic fatty liver disease resembles the histology of alcoholic liver disease closely, it is thought that alcohol may contribute to the pathogenesis of the liver disease in some obese patients with Nonalcoholic fatty liver disease. These patients may be unusually sensitive to alcohol-mediated hepatotoxicity even though they report to ingest less then the threshold doses of alcohol (i.e., 80 g ethanol per day for men and 20 g ethanol per day for women).
There is also some evidence from recent studies in animal models of Nonalcoholic fatty liver disease that endogenously produced ethanol may play a role in Nonalcoholic fatty liver disease pathogenesis. In these animals, increased production of ethanol by the gastrointestinal flora was demonstrated. Elevated blood ethanol levels have been noted in some morbidly obese patients who have undergone jejunoileal bypass surgery. It has been shown that breath ethanol content increases progressively with body mass index, suggesting that endogenous ethanol might promote steatosis and possibly the other stages of Nonalcoholic fatty liver disease.
Hepatis C virus or hepatitis G virus infections are not implicated as causes of Nonalcoholic fatty liver disease; however, Nonalcoholic fatty liver disease may increase the severity of Hepatitis C virus-related liver disease. Obesity-related steatosis seems to have deleterious effects similar to those of alcohol-induced steatosis on Hepatitis C virus-infected patients, exacerbating the liver damage.
The pathophysiologic mechanisms involved in the progression from steatosis to steatohepatitis in Nonalcoholic fatty liver disease may be similar to those in alcoholic liver disease. Chronic oxidative stress has been implicated with formation of lipid hydroperoxides, induction of certain microsomal enzymes such as cytochrome P4502EI, mitochondrial damage with inhibition of mitochondrial electron transport chain activity, increased release of mitochondrial-derived reactive oxygen species (free radicals), and depletion of mitochondrial glutathione pools. Free-oxygen radicals induce lipid peroxidation of hepatocyte membranes, initiate an inflammatory response, and stimulate fibrosis. Hepatic steatosis is also thought to promote Kupffer’s cell dysfunction, impaired phagocytosis, and chronic low-grade endotoxemia.
Endotoxin and endotoxin-induceable cytokines such as tumor necrosis factor-О± (tumor necrosis factor-О±), interleukin (IL)-6, and IL-8 are also implicated in pathogenesis of nonalcoholic steatohepatitis as in alcoholic hepatitis. Endotoxemia has been shown to stimulate hepatic production of tumor necrosis factor-О±, which induces the synthesis of other cytokines (e.g., IL-6 and IL-8), which promote neutrophil chemotaxis and an inflammatory response. In addition, leukocytes and Kupffer’s cells may stimulate the lipocytes to proliferate and activate and release fibrogenic cytokines that stimulate and sustain fibrosis. Hepatic iron may also contribute to the pathogenesis of nonalcoholic steatohepatitis by induction of lipid peroxidation of organelle membranes resulting in membrane disruption, impaired mitochondrial oxidative metabolism, and hepatocyte injury and death. Iron also activates lipocytes and stimulates collagen type I gene activation and fibrosis.
In summary, although the specific mechanisms involved in the pathogenesis of nonalcoholic steatohepatitis are unknown, it is thought that nonalcoholic steatohepatitis develops as a consequence of a two-hit process. The first hit is steatosis and the second hit involves oxidative stress, lipid peroxidation, inflammation, and fibrosis. These may be mediated by several factors including P4502EI induction, bacterial endotoxin, cytokines (i.e., tumor necrosis factor-О±), Kupffer’s cell dysfunction, and altered adenosine diphosphate [ATP] homoeostasis).
Natural history and prognosis.
The prognosis for hepatic steatosis is favorable. Although nonalcoholic steatohepatitis is generally thought to be a clinically stable disease in most patients, it can progress to significant liver disease in a subgroup of patients. The risk factors for developing fibrosis and cirrhosis with nonalcoholic steatohepatitis include older age, obesity, diabetes mellitus, and aspartate aminotransferase/alanine aminotransferase higher than 1. Liver related mortality has been found in 11% of patients with Nonalcoholic fatty liver disease with hepatic fibrosis who were followed up for 10 years. Nonalcoholic fatty liver disease may be as important as alcohol or Hepatitis C virus infection in causing cirrhosis in the United States. In fact, orthotopic liver transplantation is currently being performed for decompensated liver disease caused by Nonalcoholic fatty liver disease. Better understanding of the mechanisms involved in the pathogenesis of Nonalcoholic fatty liver disease is expected to help identify patients with hepatic steatosis who are at high risk of developing progressive liver disease, portal hypertension, and other complications of cirrhosis.
Treatment.
There is no effective therapy for Nonalcoholic fatty liver disease. Current treatment modalities attempt to eliminate the factors that are commonly associated with Nonalcoholic fatty liver disease. Weight loss, treatment of hyperglycemia, hyperlipidemia, and discontinuation of alcohol and potentially toxic drugs are recommended. In small, short-term studies, the use of ursodeoxycholic acid, gemfibrizol, betaine (a metabolite of choline), metronidazole and vitamin E resulted in improvement in liver chemistry tests and hepatic steatosis but no significant change in histological grade of inflammation or fibrosis has been observed. Newer treatment modalities using anticytokines (e.g., TNFО± antibodies, antioxidants, glutathione prodrugs, and insulin sensitizers) are being evaluated. Patients with Nonalcoholic fatty liver disease who develop hepatic decompensation should be evaluated for liver transplantation. In a number of patients nonalcoholic steatohepatitis has been observed to recur after successful liver transplantation.
Jennifer is a clinical pharmacologist. She helps doctors of all medical specialties choose medications. Jennifer consults about drug dosage, interactions, and side effects.