Nonalcoholic fatty liver steatosis (NAFL) is defined by the accumulation of lipids in the hepatocyte greater than 5% in subjects in whom chronic alcohol abuse or other conditions that may generate hepatic steatosis are excluded (Table1).

Table1. Main causes of steatosis

Steatosis, with or without inflammation, is often associated with fibrosis and may progress to cirrhosis. Generally, benign NAFL can be distinguished from Nonalcoholic Steatohepatits (NASH) with or without fibrosis, which may progress to cirrhosis, liver failure, and hepatocarcinoma. There is no significant evidence of inflammation in hepatic steatosis, whereas, in steatohepatitis, steatosis is associated with hepatic inflammation, which may be indistinguishable from alcoholic steatohepatitis on histological examination.

Nonalcoholic Fatty Liver Disease (NAFLD), which includes the entire spectrum of nonalcoholic liver diseases ranging from steatosis to steatohepatitis and cirrhosis, is the most frequent chronic liver disease in Western countries, where its main risk factors – central obesity, type 2 diabetes mellitus, dyslipidemia, and metabolic syndrome – show an increasing prevalence. In Europe, the incidence of NAFLD in the adult population is 20–30% but reaches up to 70% when considering diabetic subjects.

NAFLD is most frequently diagnosed during the fifth or sixth decade of life, while the association with sex has not yet been clarified since some studies report it to be more frequent in men and others in women. Patients with NAFLD, especially the subgroup with NASH, frequently present one or more components of the metabolic syndrome, particularly central obesity, arterial hypertension, dyslipidemia, and insulin resistance. However, the association between NAFLD and cardiovascular disease appears independent of the metabolic syndrome. Other conditions associated with NAFLD are cystic ovary syndrome, hypothyroidism, obstructive sleep apnea, hypopituitarism, and hypogonadism.

The pathogenesis of NAFLD has not yet been elucidated in many aspects, but insulin resistance would seem to play an important role. It has also been proposed that a second insult, such as oxidative damage, is required for the inflammatory necrosis typical of steatohepatitis. Intrahepatic iron accumulation, leptin, deficiency of antioxidant agents, and an imbalance in the intestinal microbiota have been proposed as potential pro-oxidant elements against the hepatocyte.

Most patients with NAFLD are asymptomatic. Fatigue, generalized malaise, and diffuse right upper abdominal pain may occasionally be observed in patients with NASH. Patients often come to the physician’s attention for the occasional finding of increased serum transaminase values or steatohepatitis on abdominal imaging. On physical examination, patients with NAFLD may present with hepatomegaly caused by fatty liver infiltration, which is sometimes the first sign. However, the presence of hepatomegaly is highly variable in these patients.

From a biochemical-clinical point of view, patients with NAFLD have a slight-to-moderate increase in ALT. However, normal transaminases should not exclude NAFLD. When elevated, transaminases are two to five times the upper reference limit, with an AST/ALT ratio of less than 1. The increase in transaminases does not predict the severity of inflammation or fibrosis, just as transaminase values in the normal range do not rule out clinically relevant diseases. Alkaline phosphatase may exceed two to three times the upper reference limit. Albuminemia and bilirubinemia are typically in the normal range but may show variation in patients in whom the disease has progressed to cirrhosis. Similarly, prolonged prothrombin time, thrombocytopenia, and neutropenia are observed in patients with cirrhosis.

Patients with NAFLD may present with increased serum ferritin or transferrin saturation. Ferritin values greater than 1.5 times the upper reference limit have been shown to be associated with greater disease severity and more advanced liver fibrosis. Patients with NAFLD may also have positivity for antinuclear autoantibodies (ANA) and antismooth muscle autoantibodies (ASMA); however, the nature of this association remains controversial.

A diagnosis of NAFLD is made when all the following conditions are met:

• Evidence of steatosis on liver biopsy or imaging

• Exclusion of chronic alcohol abuse

 • Exclusion of other causes of steatosis

 • Absence of concomitant chronic liver disease.

 Most often, imaging, along with a detailed history, is sufficient to diagnose NAFLD. Although not recommended for most patients, biopsy examination is indicated in doubtful cases or to determine the degree of hepatocellular injury. In addition, liver biopsy is currently the only diagnostic tool to differentiate NAFLD from NASH. Although often altered in patients with NAFLD, laboratory tests are not useful for diagnostic purposes but are essential to evaluate other conditions in the differential diagnosis. To this end, serologic tests for HCV, HAV, and HBV infection should be performed, and other chronic liver diseases, such as autoimmune hepatitis and hemochromatosis, should be excluded (Table 2).

Table2. Main laboratory tests for the differential diagnosis of NAFLD

Based on the patient’s symptomatology and personal and family history, Wilson’s disease, hypo- or hyperthyroidism, celiac disease, α1-antitrypsin deficiency, HELLP syndrome during pregnancy, and Budd–Chiari syndrome should be ruled out.

Radiological diagnosis usually requires an abdominal ultrasound. Although steatosis can also be detected by computed tomography or magnetic resonance imaging, none of these investigations allows differentiation of NAFL from NASH. The radiographic diagnosis should include radio graphic findings of fatty liver infiltration, exclusion of other causes of steatosis, absence of signs or symptoms of cirrhosis, and low risk of advanced fibrosis. If these criteria are not met, a liver biopsy should be performed for diagnostic confirmation and to ascertain the degree of severity of the disease.

Regarding the opportunity to screen individuals at risk of NAFLD, such as obese or diabetic individuals, several scientific societies, such as the American Association for the Study of Liver Diseases, have expressed some skepticism toward this approach, given the uncertainty regarding which diagnostic tests to use and how to treat affected individuals.