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NAFLD vs NASH: Is your patient at risk?

Nonalcoholic fatty liver disease (NAFLD) vs Nonalcoholic steatohepatitis (NASH)

PART 2 of two CME articles that look at liver transaminase levels, signs, symptoms, causes, diagnosis, and management. (eligible for CME credit. Read both and follow the link for the online FibonacciCME test)

Part I. Transaminitis Part II. Nonalcoholic Fatty Liver Disease


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liver disease, NAFLD, NASH

by Madeleine Beckman and David Kauvar, MD

Nonalcoholic steatohepatitis (NASH), a form of liver disease, is associated with obesity, high blood pressure, type-2 diabetes, high cholesterol and triglyceride levels, use of certain medications, and genetics. In addition, it commonly is seen among patients with metabolic syndrome and insulin resistance. NASH is most prevalent during middle age, but it has been seen in pediatric populations. Primary complications of the disease include fibrosis, cirrhosis, and liver cancer.

Nonalcoholic fatty liver disease (NAFLD), a condition caused by fat accumulation in the liver, may progress to NASH, which includes further fat accumulation and progressive inflammation. Increased inflammation can lead to scarring of the liver and/or cirrhosis. Approximately 20% of people with NAFLD develop NASH, and some 12% of NASH patients develop cirrhosis.

Signs and symptoms associated with NAFLD include enlarged liver, obesity, elevated serum liver transaminase levels, and insulin resistance. Evidence of liver fibrosis can be identified by utilizing the NASH Fibrosure blood test, magnetic resonance elastography or vibration-controlled transient elastography. Consider one of these assessments if the patient is at higher risk for developing steatohepatitis (e.g., those with poorly controlled diabetes).

fatty liver biopsy
Fatty Liver Biopsy

Pathologic evaluation by biopsy is the most accurate way to truly distinguish NAFLD from NASH; however, the need for a biopsy should be decided by either a hepatologist or an experienced gastroenterologist. The primary physician should try to exclude other causes of elevated liver transaminases, such as alcohol consumption, viral hepatitis , autoimmune disease, or hemochromatosis.

Fatty Liver

The association between genetic variations and NAFLD and NASH is being widely studied. Results of one study by Speliotes et al. at the Massachusetts General Hospital showed that certain inherited variations in lipid metabolism precede and possibly lead to the development of liver disease. Variation of the PNPLA3 gene correlates with an increased risk of severe histologic features of NAFLD without having a strong effect on metabolic syndrome component traits. The PNPLA3 gene produces adiponutrin, a protein that seems to help regulate the production of adipocytes, lipogenesis, and lipolysis in hepatocytes and adipocytes. PNPLA3 appears to be part of a family of enzymes that affect lipid metabolism. Altered lipid metabolism, particularly within the liver, can affect fat accumulation, subsequent development of NAFLD, and possibly NASH. Genetic analyses may allow researchers to chart the causal pathways that lead to disease complications of NAFLD and other metabolic risk factors to potentially target them for therapeutic intervention.

Results from a recent Temple University study by Gerhard et al. showed that increased expression of the AEBP1 gene correlates with the severity of liver fibrosis in patients with NASH. Having the AEBP1 gene appears to correlate with the onset and severity of fibrosis in NASH patients, suggesting that AEBP1 may represent a specific therapeutic target to prevent development of NASH fibrosis.


NAFLD is usually asymptomatic. However, some patients report feeling tired or experience discomfort in the right upper quadrant of the abdomen if they have progressed to NASH or cirrhosis. NASH can be diagnosed using bloodwork (NASH Fibrosure) or imaging (Elastography) ; however, needle biopsy is considered to be the diagnostic “gold” standard.


A serious concern with respect to diagnosis and treatment of NASH is the growing obesity rate. In 10 years, there may be more than a 50% annual increase in NASH patients needing a liver transplant.

The basic and most effective strategy for treating NASH is for patients to improve their overall health by changing their lifestyles. Steps include:

  • Lowering high blood pressure

  • Eating a low-fat diet

  • Restricting alcohol

  • Lowering triglyceride and cholesterol levels

  • Losing weight

  • Getting more exercise

In patients with type II Diabetes Mellitus, pioglitazone (Actos), should be considered as it has been shown to reduce fibrosis, steatosis, and inflammation. Vitamin-E supplementation may also be useful in noncirrhotic patients with biopsy confirmed steatohepatitis.

Recently, use of obeticholic acid (Ocaliva), an agonist of the farnesoid X receptor that was approved by the US Food and Drug Administration to treat primary biliary cholangitis, was shown to significantly improve regression of fibrosis in NASH patients. The Randomized Global Phase 3 Study to Evaluate the Impact on NASH with Fibrosis of Obeticholic Acid Treatment (REGENERATE) was conducted by the National Institutes of Health and is now in phase-III testing with 931 patients. Results have shown a 28% rate of fibrosis regression, and a significant number of study patients showed normalization of liver enzyme levels.


NASH, whether driven by genetics, body composition, dietary indiscretion, use of toxic medications, or possible viral infections, still remains a mostly elusive condition in cause, prognosis, and management. More complete information on its etiology, diagnosis, and treatment ultimately will lead to a healthier population and a lesser demand for liver transplantation.


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This article is PART 2 of a CME topic on transaminitis and fatty liver disease.

Read PART 1: Transaminitis - What Does it Mean and What Should be Done When it Occurs? A Common Conundrum in Primary Care

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