Overview of nonalcoholic fatty liver disease (NAFLD)

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world. Severity ranges from mild disease with steatosis (buildup of fat in the liver) to more severe disease with inflammation and hepatocyte (liver cell) injury known as nonalcoholic steatohepatitis (NASH). NASH is projected to be the leading liver transplant indication by the year 2020. The most common cause of death in patients with NAFLD is a cardiovascular cause.

Assessment

Causes

The exact cause of NAFLD is not known. However, NAFLD is often associated with metabolic conditions such as high cholesterol, hyperglycemia (including prediabetes and type 2 diabetes), insulin resistance, and obesity. These conditions are believed to increase the risk of developing NAFLD. These conditions increase fat deposits within the liver (fatty liver). Patients with NASH may develop fibrosis or cirrhosis. Concomitant NAFLD and type 2 diabetes may be associated with an increased rate of progression to more severe disease, including NASH, cirrhosis, and hepatocellular carcinoma.

Signs and symptoms

Patients with NAFLD are often asymptomatic. It is not routinely screened for, but can be identified after a negative workup for abnormal LFTs or detection of steatosis during an abdominal scan. If signs and symptoms are present, they may include elevated liver enzymes (up to five times the upper limit of normal), an enlarged liver, fatigue, or abdominal pain. For patients with more severe disease (e.g., NASH, cirrhosis), signs and symptoms may include ascites (abdominal swelling), esophageal varices (dilated veins in the esophagus), lower extremity edema, enlarged breasts (men), enlarged spleen, spider-like blood vessels visible through the skin, jaundice (yellowing of the eyes and skin), itching, and confusion.

Diagnosis

The following criteria must be met for a diagnosis of NAFLD...

1. Hepatic steatosis (>5% by histology or >5.6% by nuclear techniques)
2. Limited alcohol consumption, defined as <21 drinks/week (men) or <14 drinks/week (women).
3. Excluding other causes of steatosis (e.g., hepatitis C, medications [e.g., amiodarone, methotrexate], parenteral nutrition).

Management

Lifestyle changes

Lifestyle modifications including weight loss, diet, and exercise (with weight loss being the most impactful) are recommended in patients with NAFLD. There is NO specific diet can be recommended. In addition, the goal intensity and duration of exercise are not well established. However, combining some type of calorie-restriction diet (reducing caloric intake by about 500 to 1,000 calories per day) and exercise appears to be the most effective way to achieve sustained weight loss. Weight loss of 3% to 5% has been associated with improved steatosis, while weight loss of about 7% to 10% has been associated with improved fibrosis.

Recommend that patients with NAFLD avoid heavy alcohol consumption, defined as more than 14 drinks/week for men and more than 7 drinks/week for women. Some clinicians go beyond this and recommend limiting consumption to no more than one drink per day. In addition to lifestyle modifications, metabolic conditions and cardiovascular risk factors should be managed.

Pharmacotherapy

ANTIHYPERTENSIVE MEDICATIONS ― Blood pressure control is important to minimize cardiovascular risk in patients with NAFLD. Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are commonly used in patients with concomitant type 2 diabetes, for renoprotection. A small, uncontrolled studies suggest that ACEIs and ARBs may prevent liver fibrosis. However to date, data do not clearly support one particular medication or class of medications over another when controlling blood pressure in patients with NAFLD.

DIABETES MEDICATIONS ― Type 2 diabetes is a known risk factor for cardiovascular disease. Metformin is considered first-line in the management of diabetes for most patients, including those with mild NAFLD and NASH. In fact, several studies have shown liver enzyme reductions and improved insulin resistance with metformin use. However, metformin does not appear to improve liver histology (e.g., steatosis, fibrosis).

          Thiazolidinediones have also been evaluated in patients with NAFLD, in patients with and without diabetes. To date, rosiglitazone has not shown positive outcomes. Pioglitazone at doses up to 45 mg/day has been shown to improve liver injury (e.g., lower liver enzymes) and reduce fibrosis is patients with prediabetes or type 2 diabetes and biopsy-proven NASH. Pioglitazone is associated with adverse effects, including edema, heart failure, possible bladder cancer, and weight gain. Adverse effects and potential benefits should be considered together prior to starting pioglitazone therapy.

HYPERLIPIDEMIA MEDICATIONS ― Lipid profiles in patients with NAFLD are typically characterized by elevated triglyceride levels, small dense low density lipoprotein (LDL), and low levels of high density lipoprotein (HDL). Statins are the lipid-lowering agents of choice because of their robust evidence for reducing cardiovascular events, including death. Though liver injury was a concern with statin therapy in the past, several studies have demonstrated their safety in patients with liver disease, even with elevated baseline liver enzyme levels. However, statins should be avoided in patients with decompensated cirrhosis. In addition to or instead of statins, fibrates are sometimes used for significantly elevated triglycerides ≥ 500 mg/dL (~5 mmol/L). However, there’s no good evidence that lowering triglycerides reduces cardiovascular events or prevents pancreatitis. For further information, see topic on Prescribing medications in patients with liver cirrhosis "section, Lipid lowering agent".

OTHER THERAPIES ― Oxidative stress may play a role in liver injury in patients with NASH. Vitamin E has been proposed as a possible therapy for NASH due to its antioxidant properties. In patients with NASH, without diabetes, doses of 800 IU/day may improve liver inflammation and/or steatosis.

Vitamin E has not consistently been shown to improve fibrosis. However, vitamin E is not without risk. It has been linked to hemorrhagic stroke (400 IU every other day), prostate cancer, all-cause mortality, and heart failure (400 IU/day). Potential adverse effects and benefits should be considered together prior to starting therapy. More data are needed before vitamin E should be considered for patients with mild NAFLD or coexisting type 2 diabetes.

Milk thistle, also known as Silybum marianum or silymarin, has also been evaluated for its antioxidant properties as a treatment option for NASH. Small preliminary studies indicate milk thistle might improve liver enzymes and steatosis, especially when combined with vitamin E and phospholipids.

Summary

For all patients with NAFLD, encourage lifestyle modifications including diet and exercise to achieve a minimum weight loss of 3% to 5% with a goal of at least 7% to 10%. In addition, recommend avoiding heavy alcohol consumption. Comorbid conditions should also be addressed. Continue to use metformin first-line to control blood sugar in patients with type 2 diabetes. Rely on statins first-line to manage high cholesterol. Control blood pressure with evidence-based therapies, taking comorbid conditions into account. For patients with NASH, weigh the risks and benefits of using pioglitazone in patients requiring additional glucose control or even in those without diabetes. Encourage vitamin E 800 IU daily in NASH patients without diabetes.

References

• Musso G, Cassader M, Paschetta E, Gambino R. Thiazolidinediones and advanced liver fibrosis in nonalcoholic steatohepatitis: a meta-analysis. JAMA Intern Med 2017;177:633-40

  Rinella ME. Nonalcoholic fatty liver disease: a systematic review. JAMA 2015;313:2263-73

  Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidelines from the American Association for the Study of Liver Diseases. Hepatology 2017 Jul 17. doi: 10.1002/hep.29367

  Spengler EK, Loomba R. Recommendations for diagnosis, referral for liver biopsy, and treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Mayo Clin Proc 2015;90:1233-46

  Bril F, Cusi K. Management of nonalcoholic fatty liver disease in patients with type 2 diabetes: a call to action. Diabetes Care 2017;40:419-30