By Douglas Miller, MD
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder worldwide. NAFLD is essentially fat deposition in the liver in the absence of significant alcohol consumption and is increasing in incidence in developing countries and non-developing countries in parallel to the increasing prevalence of obesity. It is felt that nonalcoholic fatty liver disease is the liver correlate to the metabolic syndrome. Metabolic syndrome is characterized by hyperinsulinemia, insulin resistance, diabetes, obesity, hypertension and hyperlipidemia. Nonalcoholic fatty liver disease is felt to be a clinical spectrum of diseases ranging from the more common situation of a benign fatty liver which does not progress to chronic liver disease or NASH (non-alcoholic steatohepatitis) which is found in about 4% of patients with NAFLD and will progress to fibrosis/cirrhosis in about 20% of these patients. Many patients who had previously been diagnosed with cryptogenic cirrhosis (cirrhosis of unclear origin) may have had NASH. Most patients are asymptomatic and many are diagnosed based upon the finding of an elevated liver function test or an abdominal ultrasound that suggests a fatty liver. Approximately 75% of patients with an elevated ALT without obvious cause have NAFLD. Liver enzymes may be persistently normal even in the presence of NASH and cirrhosis. The majority of patients with NAFLD have the metabolic syndrome (more than 80% of patients), but NAFLD may occur in the absence of this syndrome. The presence of NAFLD is directly proportional to the degree of obesity, with an 80% risk for patients with a body mass index greater than 35.
Insulin resistance is thought to play a critical role in the development and severity of NAFLD. Fatty tissue (adipose cells) is a metabolically active tissue producing various substances that are locally and systemically active. Adiponectin is an insulin sensitizing hormone whose release decreases as adipose tissue increases. In fact, it is thought that decreased levels of adiponectin in the appropriate clinical setting may be the hallmark of the metabolic syndrome. Adipokines are released in increasing amounts by fatty tissue and cause macrophages to infiltrate adipose tissue. Macrophages release cytokines which are chemicals that mediate inflammation and promote insulin resistance. They also promote lipolysis which is the breakdown of triglycerides into free fatty acids which muscle cells will then use preferentially for energy metabolism. This shift to free fatty acid metabolism leads to elevated glucose levels which causes increased insulin secretion by the pancreas. In the liver insulin will cause fat accumulation in the liver cells. It is not known why some patients will accumulate fat in the liver without ever developing disease of the liver, while others will develop NASH and cirrhosis.
NAFLD should be suspected in any patient with abnormal liver enzymes without other obvious cause. Imaging with ultrasound may be helpful with diagnosis. CT scanning and MRI may be more sensitive and specific. Liver biopsy is the only test that can reliably distinguish between NAFLD and NASH but is not always required. NASH is more likely with increasing age and degree of obesity. Other signs that may suggest NASH are low platelet count, presence of diabetes/hypertension, more severe insulin resistance , greater degree of ALT elevation and an AST to ALT ratio greater than one. Studies suggest that elevated levels of cytokeratin 18, which is released by dying hepatocytes, may distinguish between NAFLD and NASH. Transient hepatic elastography (Fibroscan) which is a noninvasive method to detect liver fibrosis may be a helpful tool in estimating the severity of fibrosis and thereby avoiding the need for liver biopsy.
Treatment for NAFLD is primarily directed at those individuals who are at risk to develop NASH or who already have NASH and are at risk to develop cirrhosis. Approaches to increase insulin sensitivity are a reasonable first step and include diet and exercise. Pharmacologic weight loss treatments may be recommended for moderately obese patients and gastric bypass for those with more significant obesity and greater degree of insulin resistance. Avoidance of alcohol is of prime importance, alcohol is a known cause of fatty liver disease. Recent studies suggested that treatment with an insulin sensitizing drug (pioglitazone) may be helpful particularly in diabetics and antioxidants, such as vitamin E, may be helpful in nondiabetics.
It needs to be remembered that in general NAFLD has an excellent prognosis. NASH, on the other hand, progresses to cirrhosis in more than 20% of patients. Some of these patients may go on to develop liver failure and is associated with an increased risk of hepatocellular carcinoma. At the current time, about one in seven liver transplantations is related to NASH. There is a high rate of recurrent fat deposition in patients who have undergone transplant and some of these patients will develop recurrent steatohepatitis.. It is anticipated that over time, and with eradication of hepatitis C related liver disease, NASH may become one of the leading indications for liver transplantation. This raises significant public health implications related to the poor diet and inadequate exercise habits of the general population.