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Nonalcoholic Fatty Liver Disease (NAFLD)

By

Danielle Tholey

, MD, Sidney Kimmel Medical College at Thomas Jefferson University

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 Hepatic Fibrosis Hepatic fibrosis is overly exuberant wound healing in which excessive connective tissue builds up in the liver. The extracellular matrix is overproduced, degraded deficiently, or both. The trigger... read more . If advanced, NASH can cause cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic fibrosis that has resulted in widespread distortion of normal hepatic architecture. Cirrhosis is characterized by regenerative nodules surrounded by dense... read more and portal hypertension Portal Hypertension Portal hypertension is elevated pressure in the portal vein. It is caused most often by cirrhosis (in developed countries), schistosomiasis (in endemic areas), or hepatic vascular abnormalities... read more .

Symptoms and Signs of NAFLD

Diagnosis of NAFLD

The diagnosis of NASH should be suspected in patients with metabolic syndrome Metabolic Syndrome Metabolic syndrome is characterized by a large waist circumference (due to excess abdominal fat), hypertension, abnormal fasting plasma glucose or insulin resistance, and dyslipidemia. Causes... read more (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 Cirrhosis Cirrhosis is a late stage of hepatic fibrosis that has resulted in widespread distortion of normal hepatic architecture. Cirrhosis is characterized by regenerative nodules surrounded by dense... read more . When liver enzymes are elevated the most common laboratory abnormalities are elevations in aminotransferase levels. Unlike in alcohol-related liver disease Alcohol-Related Liver Disease Alcohol consumption is high in most Western countries. According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), 8.5% of US adults are estimated to have... read more 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 Serology Acute viral hepatitis is diffuse liver inflammation caused by specific hepatotropic viruses that have diverse modes of transmission and epidemiologies. A nonspecific viral prodrome is followed... read more 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 Portal Hypertension Portal hypertension is elevated pressure in the portal vein. It is caused most often by cirrhosis (in developed countries), schistosomiasis (in endemic areas), or hepatic vascular abnormalities... read more (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 Imaging Tests of the Liver and Gallbladder Imaging is essential for accurately diagnosing biliary tract disorders and is important for detecting focal liver lesions (eg, abscess, tumor). It is limited in detecting and diagnosing diffuse... read more Imaging Tests of the Liver and Gallbladder , 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 Imaging is essential for accurately diagnosing biliary tract disorders and is important for detecting focal liver lesions (eg, abscess, tumor). It is limited in detecting and diagnosing diffuse... read more , 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 Diagnosis references 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... read more ). 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 for NAFLD

Prognosis is driven by degree of fibrosis Hepatic Fibrosis Hepatic fibrosis is overly exuberant wound healing in which excessive connective tissue builds up in the liver. The extracellular matrix is overproduced, degraded deficiently, or both. The trigger... read more and is the only measure that correlates with liver-related mortality and need for liver transplantation (1 Prognosis references 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... read more ). Prognosis is hard to predict, although patients with NAFLD who have NASH on histology and evidence of fibrosis Hepatic Fibrosis Hepatic fibrosis is overly exuberant wound healing in which excessive connective tissue builds up in the liver. The extracellular matrix is overproduced, degraded deficiently, or both. The trigger... read more are more likely to develop cirrhosis (2 Prognosis references 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... read more ). It has been estimated that 10% of patients with NAFLD progress to cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic fibrosis that has resulted in widespread distortion of normal hepatic architecture. Cirrhosis is characterized by regenerative nodules surrounded by dense... read more over a 20-year period (3 Prognosis references 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... read more ). 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 Varices Varices are dilated veins in the distal esophagus or proximal stomach caused by elevated pressure in the portal venous system, typically from cirrhosis. They may bleed massively but cause no... read more Varices ) 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 Treatment Dyslipidemia is elevation of plasma cholesterol, triglycerides (TGs), or both, or a low high-density lipoprotein cholesterol level that contributes to the development of atherosclerosis. Causes... read more Treatment or treatment for hyperglycemia Treatment Diabetes mellitus is impaired insulin secretion and variable degrees of peripheral insulin resistance leading to hyperglycemia. Early symptoms are related to hyperglycemia and include polydipsia... read more . 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

  • 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.

Drugs Mentioned In This Article

Drug Name Select Trade
FLAGYL
GLUCOPHAGE
No US brand name
CYSTADANE
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