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Non-alcoholic fatty liver disease

Synonym(s) NAFLD
Prevalence >1 / 1000
Inheritance Not applicable
Age of onset Adult
  • K75.8
  • K76.0
  • C0400966
  • C541083
  • 10053219


Nonalcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of conditions associated with over-accumulation of fat in the liver, in the absence of significant alcohol consumption (less than 2 drinks/day), ranging from nonalcoholic fatty liver or simple steatosis to nonalcoholic steatohepatitis (NASH) which may progress to cirrhosis, liver failure, and hepatocellular carcinoma.

NAFLD is not a rare disease, with an estimated prevalence of 20%-50% in the general population and is tightly associated with metabolic syndrome (central obesity, high glucose and triglycerides levels, low HDL cholesterol and hypertension). The estimated prevalence of NASH is 2%-9%. A higher prevalence is observed among diabetics and obese individuals. The severity of liver disease is also greater in Hispanic subjects and milder in African Americans.

NAFLD can occur at any age, but most often patients are middle-aged and overweight or obese. Most patients suffering from NAFLD are asymptomatic. Vague right upper quadrant abdominal pain, fatigue, and occasionally hepatomegaly are present. Most subjects with NASH have features of metabolic syndrome.

NAFLD may be caused by an increased delivery of free fatty acids (FFA) to the liver from the adipose tissue, thereby constituting the main source of liver fat. The key factor for progression to NASH is lipotoxicity (due to excessive oxidation of FFA), leading to oxidative stress, apoptosis and liver damage. Single nucleotide polymorphisms in the genes apolipoprotein C3 APOC3 and Patatin-like phospholipase domain containing 3 (PNPLA3 or adiponutrin) have been associated with NAFLD.

Diagnosis of NAFLD is based on personal and familial history. NAFLD is suspected with increased liver enzymes and/or bright liver at ultrasonography. Imaging techniques cannot distinguish between simple fatty liver and NASH. Liver biopsy thus remains the gold standard to confirm NASH. Histological findings typically include ballooning degeneration of hepatocytes, Mallory bodies and fibrosis in the late stages. In children, the fibrosis and inflammation are often portal-based in contrast to patterns seen in adults. A NAFLD activity score (NAS) has been developed and is defined as the unweighted sum of steatosis, lobular inflammation, and ballooning scores. A NAS of >5 correlates with NASH and a NAS <3 correlates with ''not NASH.'' Non-invasive biochemical markers of liver injury and fibrosis have been developed to identify NASH, they include cytokeratin-18, adipocytokines and Fibrotest. However, their accuracy is still questionable. Transient elastography (Fibroscan) is the most used imaging technique for non-invasive diagnosis of NASH, although it has several limitations.

Differential diagnosis includes alpha 1-antitrypsin deficiency, autoimmune hepatitis, celiac disease, hereditary hemochromatosis, Wilson disease (see these terms), alcoholic liver disease, drug-induced hepatotoxicity, and viral hepatitis.

There is currently no approved therapy for NASH. Lifestyle modification represents the first-line of therapy. It consists of weight loss, dietary changes, reduction of sedentariness and physical exercise. Liver transplantation is the only treatment for advanced cirrhosis with liver failure and for NASH. Experimental approaches under evaluation in patients with NASH include insulin sensitizers, lipid lowering-drugs, anti-hypertensive drugs, antioxidants, anti-TNF-alpha, probiotics and prebiotics.

NAFLD often follows a benign course but the evolution to NASH has been found in 25%-33% of cases. Progression is favored by the metabolic syndrome.

Expert reviewer(s)

  • Dr Elisabetta BUGIANESI

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