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NAFLD/NASH at Penn Medicine

NAFLD Image depicts the liver with fat deposits
Hepatic steatosis with ballooning hepatocytes and lobular inflammation; pericellular fibrosis may be present.

At Penn GI & Hepatology, the diagnosis and treatment of nonalcoholic fatty liver disease (NAFLD) occurs within the Liver Metabolism and Fatty Liver Program. Led by Rotonya Carr, MD, the program is the first of its kind in the Philadelphia region to offer a comprehensive approach to the diagnosis and management of metabolic and fatty liver disorders.

In addition to NAFLD, program specialists treat metabolic liver disorders and alcoholic fatty liver disease.

What Causes Fatty Liver Disease?

A chronic and often debilitating condition, fatty liver disease (defined as >5% fat in the liver) has two forms distinguished by the presence or absence of alcohol as a precipitating factor: alcoholic fatty liver disease and non-alcoholic fatty liver disease (NAFLD).

We have long recognized from practical and clinical experience the signs of alcohol abuse and its effects on the liver. NAFLD, on the other hand, is ill-defined, caused not by alcohol consumption, but by a combination of factors, including insulin resistance, the metabolic syndrome, nutritional dysbiosis and heredity. Because the etiology of NAFLD is diverse and multifactorial, it now exceeds hepatitis as the leading cause of chronic liver disease in the world.

For an excellent primer on the epidemiology and pathogenesis of NAFLD, including the roles of insulin resistance, hormones, genetics, inflammation, nutrition and intestinal dysbiosis, see Carr, Oranu, et al.1

Fatty invasion of the liver is measured in stages of severity. In the absence of inflammation or fibrosis, the presence of hepatic fat is termed simple hepatic steatosis; add either or both of these complications to hepatic fat and the result is termed nonalcoholic steatohepatitis, or NASH. A leading cause of idiopathic cirrhosis, NASH can progress to hepatocellular carcinoma (HCC), particularly in patients with visceral adiposity and insulin resistance.

How is Nonalcoholic Fatty Liver Disease/NASH Diagnosed?

NAFLD and NASH can be confounding conditions, and their identification is no simple task. For example, despite their utility elsewhere as markers for liver damage, liver enzymes, including alanine aminotransferase (ALT), are not a part of the NAFLD diagnostic criteria. As many as 60% of persons with NAFLD and normal ALT have NASH or advanced fibrosis; however, these disorders are absent in more than half of persons with both NAFLD and elevated ALT.2 One in five persons with NAFLD, moreover, will have abnormal antibody titers, suggesting the need for differential diagnosis.

NAFLD/NASH: Early Diagnosis and Intervention

Early diagnosis and intervention in NAFLD is critical for individuals at high risk for NASH, cirrhosis and HCC, and according to Dr. Carr, persons considered susceptible to these conditions are closely monitored and evaluated at the Liver Metabolism and Fatty Liver Program.

“When we see fatty liver disease, we’re concerned about the individual,” she says. “We’re asking who this person is. We want to know whether he or she has a family history of liver disease, diabetes, or cancer and heart disease. We want to know about personal risk factors for viral and hepatic disease, alcohol intake, medications, weight loss and gain and other potentially contributing factors. And we want to know about lifestyle factors.”

If NAFLD is suspected on the basis of any of the above, patients at Penn are assessed for fibrosis risk to determine prognosis, staging and the appropriate course of treatment.  Staging was once achieved through liver biopsy, but is now accomplished at Penn GI for most patients via transient ultrasound elastography (UE), a noninvasive mobile procedure that can be performed as an in-office procedure.

“Ultrasound elastography provides an accurate measure of fibrosis in the liver,” says Dr. Carr. "The amount of stiffness in the liver can then be used to establish disease stage.”

An alternative way to assess fibrosis is with a fibrosis risk score based on an algorithm that calculates the probability of advanced fibrosis from serum markers (aspartate transaminase, ALT, fasting glucose, platelets, albumin), the presence of impaired fasting glucose or diabetes and physical factors (e.g., age, BMI). A high score can suggest severe fibrosis or cirrhosis. Some patients may still require liver biopsy, however, including those with indeterminate scores on UE evaluation, and persons considered likely to have significant fibrosis (and more specifically) NASH, a condition with prognostic significance.

Treatment of NAFLD/NASH

The objective of fatty liver disease management at Penn GI is to prevent, slow or reverse fibrosis and cirrhosis, thereby reducing the risk of cardiovascular comorbidities and liver-related mortality.

“Fatty liver disease can be reversed if caught early,” says Dr. Carr. “Which is possible here because our program encompasses primary care, cardiology, endocrinology and nutrition.”

Thus, initial therapy at Penn GI & H consists of dietary, lifestyle and behavioral modification. Patients who do not sufficiently respond to these measures are candidates for medical intervention. Medications (i.e., insulin sensitizers and vitamin E) may be administered to target the insulin resistance and oxidative stress that contribute to NASH. 

Patients with NAFLD, especially those whose disease is complicated by advanced fibrosis or cirrhosis, are referred to Penn GI & Hepatology for consultation. “It’s important that patients with suspected advanced fibrosis avoid alcohol completely in addition to standard dietary modification,” says Dr. Carr.

In addition, all patients with advanced fibrosis and cirrhosis require endoscopic variceal screening and q-6 monthly radiologic surveillance for HCC, she adds. Finally, bariatric surgery has been shown to improve hepatic steatosis and steatohepatitis in persons unable to pursue weight loss through dietary modification.

NASH/NAFLD Clinical Research at Penn Medicine

Penn has several ongoing research trials investigating medications that may improve NASH, including a small molecule irreversible caspase inhibitor, a modified bile acid and FXR agonist and a pegylated fibroblast growth factor.

Dr. Carr recently received a Penn Center for Precision Medicine Award for "Advanced Imaging Genome-Wide Association Studies of Non-Alcoholic Fatty Liver Disease," an investigation that applied radiogenomics to NAFLD diagnosis.

Contacting the Liver Metabolism and Fatty Liver Program at Penn GI & H

Information for individuals wishing to contact Dr. Carr is available on the Penn Medicine website. Physicians may refer patients here or by calling 877-937-7366.


1. Carr RM, Oranu A, et al. Nonalcoholic Fatty Liver Disease: Pathophysiology and Management. Gastroenterol Clin North Am 2016;45:639-652. doi:10.1016/j.gtc.2016.07.003.

2. Verma S, Jensen D, Hart J, et al. Liver Int 2013;33:1398–405.

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The Penn Physician Blog is a resource for health care professionals featuring Penn Medicine physicians and their research, innovations, programs and events. 

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