Non-alcoholic fatty liver disease (NAFLD) is the term for a range of conditions caused by a build-up of fat in the liver. It’s usually seen in people who are overweight or obese.
The principal causes of NAFLD are obesity (present in 40% or more of affected patients), diabetes mellitus (in 20% or more), and hypertriglyceridemia (in 20% or more) in association with insulin resistance as part of the metabolic syndrome. The risk of NAFLD in persons with metabolic syndrome is 4 to 11 times higher than that of persons without insulin resistance. Nonobese persons (more frequently Asians) account for 3–30% of persons with NAFLD and have metabolic profiles characteristic of insulin resistance.
Other causes of fatty liver include corticosteroids, amiodarone, diltiazem, tamoxifen, irinotecan, oxaliplatin, antiretroviral therapy, toxins (vinyl chloride, carbon tetrachloride, yellow phosphorus), endocrinopathies such as Cushing syndrome and hypopituitarism, polycystic ovary syndrome, hypothyroidism, hypobetalipoproteinemia and other metabolic disorders, obstructive sleep apnea (with chronic intermittent hypoxia), excessive dietary fructose consumption, starvation and refeeding syndrome, and total parenteral nutrition.
Gut dysbiosis and genetic factors play a role, and may account in part for an increased risk in Hispanics.
The risk of NAFLD is increased in persons with psoriasis and appears to correlate with the activity of psoriasis.
Soft drink consumption and cholecystectomy have been reported to be associated with NAFLD.
Physical activity protects against the development of NAFLD.
Signs and symptoms
Most patients with NAFLD are asymptomatic or have mild right upper quadrant discomfort. Hepatomegaly is present in up to 75% of patients, but stigmata of chronic liver disease are uncommon. Rare instances of subacute liver failure caused by previously unrecognized NASH have been described. Signs of portal hypertension generally signify advanced liver fibrosis or cirrhosis, but occasionally occur in patients with mild or no fibrosis and severe steatosis.
Treatment consists of lifestyle changes to remove or modify the offending factors. Weight loss, dietary fat restriction, and even moderate exercise (through reduction of abdominal obesity) often lead to improvement in liver biochemical tests and steatosis in obese patients with NAFLD.
A Mediterranean diet can reduce liver fat without weight loss and is often recommended. Loss of 3–5% of body weight appears necessary to improve steatosis, but loss of at least 10% may be needed to improve necroinflammation and fibrosis.
Exercise may reduce liver fat with minimal or no weight loss and no reduction in ALT levels. Resistance training and aerobic exercise are equally effective in reducing hepatic fat content in patients with NAFLD and type 2 diabetes mellitus.
Various drugs are under study. Vitamin E 800 international units/day (to reduce oxidative stress) appears to be of benefit in patients with NASH who do not have diabetes mellitus; there is concern that vitamin E may increase the risk of prostate cancer in men.
Thiazolidinediones reverse insulin resistance and, in most relevant studies, have improved both serum aminotransferase levels and histologic features of steatohepatitis but lead to weight gain.
Metformin, which reduces insulin resistance, improves abnormal liver chemistries but may not reliably improve liver histology.
Pentoxifylline improves liver biochemical test levels but is associated with a high rate of side effects, particularly nausea.
Ursodeoxycholic acid, 12–15 mg/kg/day, has not consistently resulted in biochemical and histologic improvement in patients with NASH but may be effective when given in combination with vitamin E.
Hepatic steatosis due to total parenteral nutrition may be ameliorated—and perhaps prevented— with supplemental choline.
Other approaches under study include obeticholic acid, a semisynthetic bile acid analog that has been approved for the treatment of primary biliary cholangitis as well as orlistat, an inhibitor of gastrointestinal lipases; recombinant human leptin; liraglutide, a glucagon-like protein-1-analog that promotes insulin secretion; L-carnitine, which regulates the turnover of fatty acids in phospholipid membranes; omega-3 fatty acids, which alter hepatic gene expression to favor fatty acid oxidation over lipogenesis; probucol, a lipid-lowering agent; elafibranor, an agonist of the peroxisome proliferator-activated receptor-alpha and -delta; losartan, an angiotensin antagonist; selective caspase inhibitors; and iron depletion therapy.
Statins are not contraindicated in persons with NAFLD and may protect against histologic progression in some patients.
Bariatric surgery may be considered in patients with a body mass index greater than 35 and leads to histologic regression of NASH in most patients.
Liver transplantation is indicated in appropriate candidates with advanced cirrhosis caused by NASH, now the third most common (and most rapidly increasing) indication for liver transplantation in the United States.
Liver transplantation for NASH with advanced cirrhosis may be associated with increased mortality from cardiovascular disease and sepsis compared with liver transplantation for other indications.