Fatty Liver Disease "The Real Deal"

From Medscape Gastroenterology

The Emerging Epidemic of Nonalcoholic Fatty Liver Disease

Rowen K. Zetterman, MD
Authors and Disclosures
Posted: 01/21/2011


The Spectrum of Nonalcoholic Fatty Liver
Nonalcoholic fatty liver disease (NAFLD) includes the clinical-pathologic entities of steatosis (nonalcoholic fatty liver, or NAFL) and nonalcoholic steatohepatitis (NASH) with or without fibrosis and cirrhosis.[1] Ludwig and colleagues[2] first described NASH in 1980 when they recognized a histologic pattern of fatty liver associated with lobular hepatitis, similar to alcoholic hepatitis but developing in the absence of alcoholism. Most of their patients were modestly obese and some had diabetes mellitus. NAFLD is the most frequent cause of abnormal liver tests in both adults and children.[3]

NAFLD is common.
The National Health and Nutrition Examination Survey (NHANES) III of American adults indicates that up to 23% may be affected.[5,6] Hepatic steatosis is more common in white men than in white women.[7,8] Hispanic whites have greater steatosis and risk for progressive liver disease than do blacks,[5] and blacks have a reduced risk for hepatic fibrosis compared with whites.[8] NAFLD also affects all ages: An autopsy study found fatty liver in nearly 10% of adolescents,[9] with boys having a greater prevalence of NAFLD than girls.[10]

Associated Diseases
Components of metabolic syndrome, including obesity, hyperlipidemia, and type 2 diabetes mellitus, are frequently present in NAFLD.[11] Metabolic syndrome is defined by the presence of truncal obesity, increased waist circumference, hyperlipidemia with elevated triglyceride and low HDL-cholesterol levels, insulin resistance with hyperglycemia, and systemic hypertension.[12] Affected patients are typically middle-aged (in their fifth decade), obese, and often more than 20% above their ideal body weight.[13] NAFLD also develops in patients of normal body weight.[14] Early cases of NASH were described following jejunoileal or jejunocolic bypass and were associated with hepatic failure and death.[15] Non-insulin-dependent diabetes mellitus (NIDDM) is present in up to 75% of cases, although diabetes mellitus is less likely in children with NASH. Morbidly obese patients presenting for gastric bypass surgery often have NAFLD and metabolic syndrome.[8]

Hyperlipidemia, rapid weight loss following gastric bypass for obesity, short bowel syndrome, prolonged use of total parenteral nutrition, small bowel bacterial overgrowth from jejunal diverticulosis, abetalipoproteinemia, hypobetalipoproteinemia, and Weber-Christian disease are associated with NAFLD[7,16] (Table 1). Lipodystrophy with fat mobilization from peripheral fat stores can result in fat accumulation and inflammation of the liver.

Table 1. Medical Conditions Associated With NAFLD

Obesity
Hyperlipidemia
Type 2 diabetes mellitus
Metabolic syndrome
Jejunoileal bypass for obesity
Jejunocolic bypass for obesity
Gastric bypass for obesity
Adult polycystic ovary syndrome
Partial limb lipodystrophy
Rapid weight loss
Short bowel syndrome
Abeta- or hypobetalipoproteinemia
Weber-Christian disease
Jejunal diverticulosis


The use of some pharmaceutical agents is also associated with NAFLD
[7, 17] (Table 2).

Table 2.

Medications and Therapies Associated With NAFLD

Coralgil
Perhexilene maleate
Amiodarone
Thiazolidinediones (glitazones)
Total parenteral nutrition
Chloroquine
Tamoxifen
Glucocorticoids
Calcium channel blockers
Estrogens
Diethystilbestrol
Methotrexate
Thioridazine
Lamivudine
Valproic acid
Tetracyclines

Clinical Features

History
Patients with NAFLD may lack symptoms of liver disease, or such symptoms can be found during evaluation of other medical conditions or symptoms. A common presentation is finding abnormal liver tests on routine blood testing. Some patients present with continuous, burning right upper quadrant pain or hepatomegaly. NAFLD might be discovered during an evaluation of fatigue, malaise, or weakness, following the identification of a fatty liver on ultrasound, or when testing a patient for suspected hemochromatosis. A careful history for ethanol ingestion should also be obtained; a diagnosis of NAFLD should be applied only to patients who consume <> 1 in patients with NASH may be associated with cirrhosis.[22] Alkaline phosphatase and gamma glutamyltranspeptidase levels are normal or slightly elevated. Circulating cytokeratin 18 fragment levels, a marker of apoptosis, are elevated in patients with NASH.[23,24]

Both serum ferritin levels and transferrin saturation may be high, although levels consistent with hemochromatosis are not observed.[25] The ratio of desialylated transferrin to total transferrin is said to separate patients with NASH from alcoholic fatty liver because the ratio is elevated in alcoholic fatty liver and not in NASH.[26] Its clinical utility remains to be defined. Glucose intolerance and hyperlipidemia are frequent, and low-titer antinuclear antibody levels occur.[27]

Pathologic Features
Liver biopsy remains the gold standard for the diagnosis of NAFLD and NASH.[28] NAFL includes simple fatty change of > 5% of hepatocytes and is typically macrovesicular and perivenular (centrilobular).[29] Nuclear vacuolation of hepatocytes is frequent, and megamitochondria and siderosis are observed.

With NASH, focal hepatocellular necrosis, steatosis, ballooning degeneration of hepatocytes, and lobular inflammation may extend throughout the lobule.[30] Mononuclear and polymorphonuclear leukocyte parenchymal inflammation is usually mild. Bile duct injury may develop but not result in duct loss. Perivenular alcoholic hyalin (Mallory bodies) may be present. Cholestasis is infrequent. Fibrosis may be minimal or severe and initially is pericellular or perisinusoidal. Bridging fibrosis is uncommon. Cirrhosis is initially micronodular, with transition to macronodular cirrhosis over time. Hepatocellular carcinoma can develop in 5%-7% of patients.[31]

A histologic NAFLD activity score can be determined by estimating the sum of the degree of steatosis (score 0-3), lobular inflammation (0-2), and hepatocellular ballooning (0-2).[32] A score of 5 or more indicates NASH.

Radiologic Features
Hepatic ultrasound is the best screening test for fatty liver, but it fails to identify fatty change in one third of affected patients.[33] The ultrasound image appears hyperechoic or bright from the associated fat. Liver fat distribution may be diffuse or focal. Ultrasound transient elastography can estimate the presence of hepatic fibrosis,[34] although its effectiveness is limited if marked fatty change of the liver is present.[35] CT may also be used to screen for fatty liver with hepatic density less than that of the spleen (liver/spleen ratio < 0.9). With MRI, the T1-weighted image will also identify fatty change. None of these modalities can separate patients with simple fatty liver from those with NASH.[33]

Clinical Course
NAFLD is underrecognized clinically. It is often identified only in patients with abnormal liver tests or enlarged livers. Whereas the diagnosis of NAFLD can be suspected by the presence of associated disorders or by ultrasound screening, the proven diagnosis rests on liver histology and exclusion of significant ethanol intake. The evaluation of patients suspected of having NAFLD should include confirmation of diagnosis, evaluation of their prognosis, and assessment of coexisting disorders.

In patients with pure fatty liver who lack necroinflammatory changes or NASH, progressive liver disease may not occur. In those with NASH, at least one third will have progressive disease.[36] In a recent trial, 22% of patients had progression of fibrosis, whereas fibrosis remained stable in 46% and regressed in 18% over 2 years.[37] Factors associated with development of advanced fibrosis in NASH include increased age, low initial fibrosis stage, and lobular inflammation at initial liver biopsy.[38] Hepatocellular carcinoma develops in 5%-7% of patients with cirrhosis or advanced fibrosis from NASH.[39,40]

Who Should Be Screened for NAFLD?

Practitioners should screen the following patients:

Those who manifest components of metabolic syndrome, including truncal obesity, increased waist circumference, hyperlipidemia, and type 2 diabetes mellitus, and those with systemic hypertension and other features of metabolic syndrome;
Those with morbid obesity;
Those with fatty liver at radiologic testing;
Those with elevation of serum aminotransferases;
Those with elevated aminotransferases and suspect medications;
Those with rapid weight loss and elevated aminotransferases; and
Those being considered for surgical therapy of obesity.
How Should You Screen for NAFLD?
Although liver histology is the gold standard for diagnosis of NAFLD, patients can be screened by a careful history and physical examination that includes looking for associated conditions or hepatomegaly, assessment of serum aminotransferases and laboratory studies suggestive of metabolic syndrome, and ruling out other causes of liver disease, such as alcoholism, hemochromatosis, and hepatitis B or C. Radiographic imaging with liver ultrasound ("bright liver") or abdominal CT or MRI suggesting fatty liver, hepatomegaly, or complications of advanced liver disease can be used. Ultrasound of the liver is considered first-line screening for most patients.[4] Patients should also be monitored for the increased cardiovascular risk associated with NAFLD.[41]

Therapy for NAFLD
The initial therapy for NAFLD should be directed at changes in lifestyle and the associated underlying conditions.[42-44] Weight reduction and exercise should be as starting points for those who are obese.[45] Clinical information suggests that a loss of 10% of body weight may have a significant effect on improvement of liver tests and of symptoms, such as right upper quadrant pain. For patients with glucose intolerance, blood sugar control is crucial. Hyperlipidemia can be treated with medications when needed. Currently, no specific dietary program can be recommended, although diets low in fat and carbohydrates and supplemented by probiotics may be appropriate.[46]

Current medications should be evaluated; if known to be associated with NAFLD, they should discontinued when possible. With suspected bacterial overgrowth of the small bowel, periodic administration of broad-spectrum antibiotics may be considered.

Pharmacologic therapy of NASH is limited and no specific therapy is currently approved for treatment. Although it seems intuitive that insulin-sensitizing agents should be effective, thiazolidinediones (glitazones) may only be partially effective[47,48] and metformin not at all.[49] Vitamin E seems to improve liver histology in patients who have NASH but not diabetes mellitus[50]; additional studies are needed. A preliminary trial of pentoxifylline improved aminotransferases and liver histology.[51]

For patients with morbid obesity, gastric bypass surgery can improve hepatic inflammation, steatosis, and fibrosis.[52] Orthotopic liver transplantation is used for those with end-stage disease, although recurrence of NASH posttransplantation is frequent.[53] Patients who undergo liver transplantation must closely control weight gain and hyperlipidemia.

Summary of Key Points
NAFLD can develop in association with truncal obesity, type 2 diabetes mellitus, hyperlipidemia, and selected medications. Many patients are asymptomatic, although right upper quadrant pain may be present. End-stage liver disease can develop, and NASH is now recognized as a cause of cryptogenic cirrhosis. Therapy of NAFLD should be directed at associated conditions. Gastric bypass for obesity can improve hepatic changes in those with morbid obesity.

The Spectrum of Nonalcoholic Fatty Liver
Clinical Features
Clinical Course
Who Should Be Screened for NAFLD?
Therapy for NAFLD
Summary of Key Points
References