liver dr clipboardNonalcoholic Fatty Liver Disease (NAFLD), is a spectrum of disorders characterized by hepatic steatosis in the absence of significant alcohol consumption. The spectrum of fatty liver diseases ranges from 70 percent of patients with simple steatosis, a benign condition with low risk of progression to 30 percent with nonalcoholic steatohepatitis (NASH), a more serious and progressive condition. While there are many possible causes of nonalcoholic fatty liver, the most common cause is the metabolic syndrome. Metabolic syndrome is defined as having any three of the following: central obesity, high triglycerides, low high-density lipoprotein (HDL) cholesterol, hypertension or insulin resistance.

Due to the obesity epidemic, NAFLD is now the most common chronic liver disease in adults in the United States, Australia, Asia and Europe. Twenty to 30 percent of adults and 2.6 percent of children in the United States have NAFLD. It is also gaining prominence as a cause of liver disease in children as well. Other causes of NAFLD include protein-calorie malnutrition, starvation or rapid weight loss, total parenteral nutrition, jejuno-ileal bypass, medications, and metabolic disorders.


The pathogenesis of NAFLD in humans is not fully understood but is thought to reflect the hepatic manifestation of insulin resistance and metabolic syndrome as well as a complex interplay between multiple genetic and environmental factors. The current theory of pathogenesis suggests a 2-hit hypothesis. The first hit appears to be insulin resistance, which is almost uniformly present, even in lean patients with NAFLD. Insulin resistance leads to abnormal adipogenesis and deposition of triglycerides in the hepatocyte. It is believed that obesity and excessive macronutrient intake such as glucose and lipid leads to hypertrophic adipocytes in the viscera. These adipocytes produce cytokines and chemokines that activate the inflammatory signaling pathways in various cells (not yet clearly elucidated), leading to increases in oxidative stress and additional release of inflammatory mediators, which, in turn, lead to increased insulin resistance. The exact mechanism for how the deposition of triglycerides in hepatocytes leads to inflammation and fibrosis is unclear and multiple theories for this second hit have been proposed. Potential second hits include oxidative stress secondary to mitochondrial dysfunction and excess iron deposition or lipid peroxidation. Several effectors of liver injury including elevated levels of TNF-alpha, TGF-beta, adiponectin and leptin have all been proposed as mediators of inflammation and injury.

Risk Factors

The most well-recognized clinical risk factors for NAFLD are obesity (especially truncal obesity), type 2 diabetes mellitus and metabolic syndrome. The prevalence of NAFLD in obese persons is estimated to be 57.5 percent to 74 percent, and is perhaps 50 percent in persons with hyperlipidemia. In addition to increasing the risk of having NAFLD, metabolic syndrome and type 2 diabetes mellitus both increase the severity of the disease. Although the majority of NAFLD patients are obese, a minority are thin or have a normal BMI and, in these individuals, genetic rather environmental factors probably play a key role.


Nonalcoholic fatty liver disease is usually recognized during investigation of abnormal liver function tests (LFT), particularly elevated serum alanine transaminases (ALT). However, a minority of people with NAFLD may present with normal LFT. Patients with abnormal LFT, even in the presence of the metabolic syndrome, should undergo a work-up to exclude viral, autoimmune and other metabolic disorders of liver disease, including identification of alcohol abuse. Ultrasonography usually identifies a bright liver (increased echogenicity) reflecting increased fat content within the liver. Currently, liver biopsy is the only reliable way of distinguishing NASH from simple steatosis. However, the evolving field of diagnostic imaging for NAFLD holds promise. A combination of clinical predictors, serum biomarkers and radiologic modalities may one day provide the best diagnostic approach for patients with NAFLD, and potentially replace the necessity for liver biopsy in most patients. At our NAFLD Center, we are currently investigating noninvasive evaluation of NAFLD.

Treatment of NAFLD and NASH

There is currently no standard medical treatment for NAFLD and NASH. The main principles of management include improving lifestyle measures and increasing physical activity aiming for a gradual loss of 10 percent body weight. Surgical weight loss procedures can be considered where appropriate. It is also important to optimize the treatment of insulin resistance, diabetes and hyperlipidemia when present.

Many medications are presently being evaluated for people with NAFLD. These include insulin sensitizers, lipid lowering agents, antifibrotics, ursodeoxycholic acid, antihypertensives and antioxidants. At the 2009 Annual meeting of the American Association for the Study of Liver Diseases, Arun Sanyal presented the results of a prospective randomized double-blind placebo-controlled trial comparing vitamin E, pioglitazone, and placebo in patients with NASH. Forty-three percent of the group of patients on vitamin E (alpha-tocopherol) 800IU daily had significant histologic improvement in the area of inflammation, steatosis, hepatocyte ballooning (compared to 34 percent in the pioglitazone group and 19 percent in the placebo group). However, there were no significant improvement in the fibrosis score for any of the groups. While patients in the pioglitazone had improvement in insulin resistance, they also had more weight gain.

There are ongoing clinical trials at our NAFLD Center.

Evaluation for NAFLD

Step 1

History and physical examination to screen for risk factors for NAFLD and other liver diseases (including alcohol) including assessment for:

  • Metabolic syndrome and cardiovascular risk factors
  • Signs, symptoms, or physical findings of chronic liver disease (e.g. spider angiomata, palmar erythema, ascites, edema, encephalopathy, etc.)
  • Anthropometry (BMI, waist circumference, etc.)
Step 2

Counsel patient on risk reduction strategies and check liver function tests and ultrasound in the following patients:

  • BMI >25 or central obesity and one of the following:
    • Type II diabetes mellitus
    • Hypertension
    • Hyperlipidemia
  • Any signs, symptoms, or physical findings of chronic liver disease
  • Discuss with patient risk reduction strategies:
    • Lifestyle measures (such as gradual weight loss, regular exercise, dietary measures, and alcohol cessation)
    • Drug treatments for hyperglycemia, hypertension, and lowering cholesterol
Step 3

If there are abnormal LFTs and/or increased liver echogenicity on ultrasound, then refer to hepatologist or proceed to further work-up.

  • Further work-up: serologic tests to rule out other liver diseases, liver biopsy.
  • To refer patients to our NAFLD program for further evaluation, management and close follow-up.
Contact Us

For more information or questions, please call Angelica Francescucci (Clinical Research Assistant ) at 617-632-1068 or email Michelle Lai, MD, MPH.