Published in UAB Insight, Winter 2006

ABSTRACT: Fatty liver disease is a growing problem among increasingly obese Americans. Weight loss slows or reverses the disease.

CME OBJECTIVE: The reader will appreciate the different etiologies for nonalcoholic fatty liver disease and appropriate evaluations and interventions.
Gary A. Abrams, MD, no conflicts of interest

Nonalcoholic fatty liver disease (NAFLD) describes a spectrum of chronic conditions characterized by a pattern of liver injury that includes macrovesicular steatosis, hepatocellular ballooning degeneration, hepatocyte necrosis, and fibrosis. The liver lesions of NAFLD are similar to those of alcoholic liver disease, but occur in individuals who consume little or no alcohol. NAFLD’s histologic continuum includes fatty liver disease alone and nonalcoholic steatohepatitis (NASH), a more aggressive form of disease that in some individuals can progress to cirrhosis and hepatocellular carcinoma.

NAFLD is now recognized as the most common form of liver injury, UAB hepatologist Gary A. Abrams, MD, says. “In the last decade, prevalence of nonalcoholic fatty liver disease has significantly increased along with rising numbers of Americans affected by obesity and diabetes — both strong independent risk factors for NAFLD. Most patients are asymptomatic, but estimates indicate about 20% of the US population have fatty liver disease and 2.5% to 5% have NASH.”

An important study reports within 10 years of diagnosis, 3% of patients with fatty liver disease progress to cirrhosis. In comparison, progression is more common in individuals with NASH; during a 5- to 10-year period, between 30% and 40% of patients with NASH develop cirrhosis (Gastroenterology. 1999;116:1413-1419).

Histologic Features and Diagnosis

Ballooning hepatocytes in zone 3 of the liver or pericellular or perivenular fibrosis distinguish NASH from fatty liver disease alone, Abrams says. Some patients have atypical features, primarily portal fibrosis and fatty liver without liver cell injury. A recent publication attempts to standardize histologic diagnostic criteria for NASH that include grades of steatosis, lobular inflammation, ballooning, and stages of fibrosis (Hepatology. 2005;41:1313-1321).

FATTY DISORDERS
OF THE LIVER

Histologic Nomenclature 1. Fatty liver (grade) 2. Steatohepatitis a. Grade: degree of necro-inflammatory activity b. Stage: degree of fibrosis Clinical Association 1. Alcohol 2. Insulin resistance 3. Drugs 4. Lipid disorders 5. Toxic 6. Obesity 7. Idiopathic Source: American Gastroenterological Association (Gastroenterology. 2002; 123:1705-1725)

“NAFLD is the primary cause of elevated liver function tests found during routine laboratory analysis,” Abrams says. “Once other common causes of liver enzyme elevation — hepatitis A, B, and C, alpha-1 antitrypsin deficiency, autoimmune processes, and iron overload — are excluded, clinicians should order an ultrasound to check for hepatic fat infiltration. CT scans and MRI also detect fat, but ultrasound is more sensitive and less expensive.”

Ultrasound is the most sensitive imaging test for fatty liver, but 30% fatty infiltration must occur for detection. “Normal hepatic fat levels range up to 5%,” he says. “Therefore, some patients with fat levels between 5% and 30% will have normal ultrasounds, yet have fatty liver disease.”

To diagnose NAFLD, clinicians must also rule out excessive alcohol consumption. Cutoffs for damaging levels of alcohol consumption vary, but the American Gastroenterological Association (AGA) reports a fatty liver rarely develops when consumption is <20 g/day.

These criteria allow clinicians to diagnose NAFLD, but fatty liver disease alone cannot be distinguished from NASH without a liver biopsy, Abrams says. “There are no noninvasive tests that accurately diagnose NASH, and experts disagree about the value of liver biopsies. Some argue for always performing a biopsy in order to adequately counsel patients on prognosis and consideration for clinical trials. Others counter that therapy for fatty liver disease and NASH are identical and liver biopsies have risks and exhibit sampling variability that limit utility.”

In a recent study, investigators collected paired liver biopsy specimens from 51 patients with NAFLD. The authors report steatosis grade was the only feature showing substantial agreement among specimens, whereas ballooning degeneration, a key diagnostic criteria for NASH, would have been missed in 25% of patients if only one biopsy had been performed (Gastroenterology. 2005;128[7]:1898-1906).

“I do not use liver biopsies to prognosticate,” Abrams says. “I tell patients they have fatty liver disease, they may have NASH, they could progress to end-stage liver disease, and explain weight loss is the only currently successful therapy for both fatty liver disease and NASH.”

Damaging Triad

Fatty liver disease and NASH can occur in individuals of all ages, including children. AGA’s review notes that studies published before 1999 suggested NAFLD was more common among women, but later investigations support equal frequency in men (Gastroenterology. 2002;123:1705-1725). “Obesity is the most common risk factor for NAFLD,” Abrams says. “In a UAB study of 195 bariatric surgery patients, liver biopsies taken at the time of surgery found 90% of patients had fatty liver disease and 36% had NASH,” he says. “In a recent study conducted exclusively in type 2 diabetics, ultrasound revealed 50% had fat in their liver. Diabetics also are more likely to progress to NASH,” he says. “An autopsy study found individuals with diabetes had a 7% higher incidence of NASH than nondiabetics.” The metabolic syndrome — the clustering of central adiposity, dyslipidemia, hypertension, and glucose intolerance as manifested by insulin resistance — is also commonly associated with NAFLD.

AGA reports other factors that increase risk for fatty liver disease and NASH include several rare disorders of lipid metabolism (abetalipoproteinemia); rare syndromes characterized by severe insulin resistance (lipoatrophic diabetes and Mauriac syndrome); Weber-Christian syndrome; certain medications (diltiazem, amiodarone, tamoxifen); and treatment with highly active antiretroviral therapy.

Halting Progression, Healing Injury

Progression from fatty liver disease to NASH is not well understood. Abrams is principal investigator for a study that seeks to define the mechanisms through which individuals develop NASH. “Hepatocellular injury caused by oxidative stress may involve post-translational modification of proteins, particularly those in mitochondria,” he says. “Using a clinical repository of liver tissue from patients with both fatty liver disease alone and NASH, our research team is isolating hepatic mitochondria and performing proteomic analysis to tease out factors that promote disease progression.”

Abrams emphasizes primary care physicians should have a high suspicion of NAFLD in patients who are obese, diabetic, or dyslipidemic and perform an ultrasound to check for hepatic fat. Routine liver blood tests are not useful in identifying patients with NAFLD, he says.

“Although we do not know why some patients progress to NASH, cirrhosis, and hepatocellular carcinoma, we do know weight loss and resultant glucose normalization slow disease progression and heal liver injury. Even patients who have already advanced to cirrhosis may experience some resolution of fibrosis,” Abrams says. “If patients understand they have a chronic condition that could progress to end-stage liver disease, they may have additional motivation to normalize their weight.”

For more information
Dr. Gary Abrams
1.800.UAB.MIST
mist@uabmc.edu