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Nonalcoholic Fatty Liver Disease (NAFLD)


Danielle Tholey

, MD, Thomas Jefferson University Hospital

Last full review/revision Jan 2021| Content last modified Jan 2021
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Fatty liver is excessive accumulation of lipid in hepatocytes. Nonalcoholic fatty liver disease (NAFLD) includes simple fatty infiltration (a benign condition called fatty liver), whereas nonalcoholic steatohepatitis (NASH) is defined as the presence of fat leading to lipotoxicity and inflammatory damage to hepatocytes. Histologically, NASH is difficult to distinguish from alcoholic hepatitis. Thus to diagnosis NASH, underlying alcohol use must be ruled out. Differentiating simple steatosis from NASH can be difficult without a liver biopsy, and elevated liver enzymes are not a sensitive predictor for identifying NASH. The presence of metabolic syndrome (obesity, dyslipidemia, hypertension, and glucose intolerance) increases the likelihood that a patient has NASH rather than simple steatosis. Pathogenesis is poorly understood but seems to be linked to insulin resistance (eg, as in obesity or metabolic syndrome). Most patients are asymptomatic. Although noninvasive diagnostic tests are usually sufficient, liver biopsy remains the gold standard. Treatment includes elimination of causes and risk factors; new therapies are rapidly emerging but still in the clinical trial phase.

(See also the American Association for the Study of Liver Diseases [AASLD] 2018 practice guidance on the diagnosis and management of NAFLD.)

NAFLD includes simple fatty infiltration (a benign condition called fatty liver) and nonalcoholic steatohepatitis (NASH), a less common but more important variant. NASH (sometimes called steatonecrosis) is diagnosed most often in patients between 40 and 60 years but can occur in all age groups. Many affected patients have obesity, type 2 diabetes mellitus (or glucose intolerance), dyslipidemia, and/or metabolic syndrome.

Pathophysiology of NAFLD

Fatty liver develops for many reasons, involves many different biochemical mechanisms, and causes different types of liver damage. Pathophysiology involves fat accumulation (steatosis), inflammation, and, variably, fibrosis. Steatosis results from hepatic triglyceride accumulation. Possible mechanisms for steatosis include reduced synthesis of very low density lipoprotein (VLDL) and increased hepatic triglyceride synthesis (possibly due to decreased oxidation of fatty acids or increased free fatty acids being delivered to the liver). Inflammation may result from lipid peroxidative damage to cell membranes. These changes can stimulate hepatic stellate cells, resulting in fibrosis. If advanced, NASH can cause cirrhosis and portal hypertension.

Symptoms and Signs of NAFLD

Most patients are asymptomatic. However, some have fatigue, malaise, or right upper quadrant abdominal discomfort. Hepatomegaly develops in about 75% of patients. Splenomegaly may develop if advanced hepatic fibrosis is present and is usually the first indication that portal hypertension has developed. Patients with cirrhosis due to NASH can be asymptomatic and may lack the usual signs of chronic liver disease.

Diagnosis of NAFLD

  • History (presence of risk factors, absence of excessive alcohol intake)

  • Serologic tests that rule out hepatitis B and C

  • Ultrasound evidence of steatosis or MR elastography with fat fraction

The diagnosis of NASH should be suspected in patients with metabolic syndrome (obesity, type 2 diabetes mellitus, hypertension, or dyslipidemia) and in patients with unexplained laboratory abnormalities suggesting liver disease. Differentiating simple steatosis from NASH can be difficult and elevated liver enzymes are not a sensitive predictor for identifying NASH. The presence of metabolic syndrome as well as elevated ferritin increases the likelihood that a patient has NASH rather than simple steatosis. Further, clinical scoring systems such as the FIB4 score, NAFLD fibrosis score calculator or laboratory NASH FibroSure® can identify patients at risk for fibrosis and thus those more likely to have NASH and be at risk for progression to cirrhosis. When liver enzymes are elevated the most common laboratory abnormalities are elevations in aminotransferase levels. Unlike in alcohol-related liver disease, the ratio of aspartate aminotransferase (AST)/alanine aminotransferase (ALT) in NASH is usually < 1. Alkaline phosphatase and gamma–glutamyl transpeptidase (GGT) occasionally increase. Hyperbilirubinemia, prolongation of prothrombin time (PT), and hypoalbuminemia are uncommon.

For diagnosis, strong evidence (such as a history corroborated by friends and relatives) that alcohol intake is not excessive (eg, is < 20 g/day) is needed, and serologic tests should show absence of hepatitis B and C (ie, hepatitis B surface antigen and hepatitis C virus antibody should be negative). Liver biopsy reveals damage similar to that seen in alcoholic hepatitis, usually including large fat droplets (macrovesicular fatty infiltration) as well as pericellular or "chicken wire" fibrosis. Indications for biopsy include unexplained signs of portal hypertension (eg, splenomegaly, cytopenia) and unexplained elevations in aminotransferase levels that persist for > 6 months in a patient with diabetes, obesity, or dyslipidemia.

Liver imaging tests, including ultrasonography, CT, and particularly MRI, may identify hepatic steatosis. Noninvasive measures of fibrosis such as transient elastography (a test that uses both ultrasound and low-frequency elastic waves), ultrasound elastography, or MR elastography can assess severity of steatosis as well as estimate fibrosis, thereby obviating the need for liver biopsy in many cases (1, 2). Transient elastography and ultrasound elastography can be limited by body habitus (too big/fat for ultrasound waves to penetrate adequately), whereas MR elastography is not. However, these tests cannot identify the inflammation typical of NASH and cannot differentiate NASH from other causes of hepatic steatosis.

Diagnosis references

  • 1. Cassinotto C, Boursier J, de Ledinghen V, et al: Liver stiffness in nonalcoholic fatty liver disease: A comparison of supersonic shear imaging, FibroScan, and ARFI with liver biopsy. Hepatology 63(6):1817-1827, 2016. doi: 10.1002/hep.28394. 

  • 2. Lee MS, Bae JM, Joo SK, et al: Prospective comparison among transient elastography, supersonic shear imaging and ARFI for predicting fibrosis in nonalcoholic fatty liver disease. PLoS One 12(11)e:0188321, 2017. doi: 10.1371/journal.pone.0188321. eCollection 2017. Erratum in: PLoS One 3(6):e0200055, 2018. doi: 10.1371/journal.pone.0200055. eCollection 2018.

Prognosis of NAFLD

Prognosis is driven by degree of fibrosis and is the only measure that correlates with liver-related mortality and need for liver transplantation (1). Prognosis is hard to predict, although patients with NAFLD who have NASH on histology and evidence of fibrosis are more likely to develop cirrhosis (2). It has been estimated that 10% of patients with NAFLD progress to cirrhosis over a 20-year period (3). Alcohol as well as some drugs (eg, cytotoxic drugs) and metabolic disorders are associated with acceleration of nonalcoholic steatohepatitis (NASH). As a result, even modest alcohol use should be avoided given the risk of accelerated progression to fibrosis. Prognosis is often good unless complications (eg, variceal hemorrhage) develop.

Prognosis references

Treatment of NAFLD

  • Elimination of causes and control of risk factors

The only widely accepted treatment goal is to eliminate potential causes and risk factors. Such a goal may include discontinuation of drugs or toxins, weight loss, and treatment for dyslipidemia or treatment for hyperglycemia. Preliminary evidence suggests that thiazolidinediones and vitamin E can help correct biochemical and histologic abnormalities in NASH but does not improve fibrosis. Further, vitamin E is contraindicated in patients with diabetes, which limits its usefulness. Many other treatments (eg, ursodeoxycholic acid, metronidazole, metformin, betaine, glucagon, glutamine infusion) have not been proved definitively effective.

There are currently many emerging therapies for NASH targeting several different molecular pathways including peroxisome proliferator-activated receptor-alpha (PPAR-alpha), glucagon-like peptide-1 (GLP-1) modulators, and farnesoid X receptor (FXR) ligands. These new therapies show promise with respect to both resolution of NASH as well as reversal of preexisting fibrosis. Further study with several phase 3 clinical trials is ongoing.

Key Points about NAFLD

  • NAFLD includes a benign condition called fatty liver as well as nonalcoholic steatohepatitis (NASH).

  • NASH causes histologic liver damage similar to that in alcoholic hepatitis but occurs in patients who are not alcoholics and who often are obese or have type 2 diabetes mellitus or dyslipidemia.

  • Symptoms are usually absent, but some patients have right upper quadrant discomfort, fatigue, and/or malaise.

  • Signs of portal hypertension and cirrhosis can eventually occur and may be the first manifestations.

  • Rule out alcoholism (based on corroborated history) and hepatitis B and C (with serologic tests) and do a liver biopsy.

  • Eliminate causes and control risk factors when possible.

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