Fatty Liver

Article Author:
Catiele Antunes
Article Editor:
Mohammadreza Azadfard
1/11/2019 12:50:06 PM
PubMed Link:
Fatty Liver


Non-alcoholic Fatty Liver Disease (NAFLD) or "Fatty Liver" corresponds to the presence of macrovesicular changes without inflammation (steatosis) and lobular inflammation in the absence of significant alcohol use. It can be divided into two subgroups: NAFL (Non-Alcoholic Fatty Liver) or simply Steatosis and NASH (Non-Alcoholic Steatohepatitis). NAFL is defined as the presence of hepatic steatosis with no evidence of hepatocellular injury in the form of ballooning of the hepatocytes. NASH is defined as the presence of hepatic steatosis and inflammation with hepatocyte injury (ballooning) with or without fibrosis. It is important to note that NAFL is a spectrum, with NAFL being the mildest form and NASH and cirrhosis being at the other end of the spectrum.

NAFLD is commonly associated with Metabolic Syndrome, obesity, diabetes, and hyperlipidemia. Nearly 80% of patients with Metabolic Syndrome have NAFLD.[1][2][3]


Fat accumulates in the liver for several reasons. Most commonly, it involves increased delivery of free fatty acids (FFAs) to the liver, increased synthesis of fatty acids in the liver, decreased oxidation of FFA, or decreased synthesis or secretion of very-low-density lipoprotein (VLDL).[4][5]

Oxidative stress in the hepatocytes can activate stellate cells and lead to the production of collagen and inflammation.

Other factors that may contribute to fatty liver include:

  • The use of medications (e.g., tamoxifen, amiodarone, methotrexate)
  • Metabolic abnormalities (e.g., glycogen storage disorders, homocystinuria)
  • Alcohol
  • Nutritional status (e.g., total parenteral nutrition, severe malnutrition, overnutrition, or a starvation diet)
  • Other health issues like Wilson disease and celiac sprue.


The prevalence of NAFLD varies dramatically depending on the population being studied. It is estimated that the prevalence of NAFLD is in the range of 20% in the United States population and between 11.5% and 46% in the general population. By contrast, the prevalence of NASH is in the range of 2% and 3%. The majority of cases are seen in women. Mean age at diagnosis is 50 years (range 16-80). It is more common in Hispanics when compared to Whites and more common in Whites than in Blacks.

Obesity is a well-known risk factor for NAFLD. In patients with severe obesity undergoing bariatric surgery, up to 90% are found to have NAFLD and some even have cirrhosis. The same study also concluded that insulin resistance was the main predictor for NASH.[6]


Current concepts point to insulin resistance as the primary metabolic defect leading to NAFLD. Insulin resistance leads to an increased influx of free fatty acids (FFA) into the liver. This happens due to the failure of insulin to suppress the hormone-sensitive lipase, causing more FFA to be released from the adipose tissue. Also, elevated insulin levels and insulin resistance promote continuous synthesis of triglycerides in the liver. These two sources of triglycerides result in accumulation of lipids in the hepatocytes causing macrovesicular hepatic steatosis.[4][7]

The current hypothesis is that NASH is an evolution from NAFLD caused by a second "hit." The evidence behind this second insult in not conclusive, but the most acceptable theories involve oxidative stress, specific cytokines, plus lipopolysaccharides. Free fatty acids and hyperinsulinemia potentiate lipid peroxidation and the release of hydroxy-free radicals, directly injuring the hepatocytes by recruiting neuroinflammatory mediators. Chronic liver injury over time will lead to activation of stellate cells, creating a potential for hepatic fibrosis.

The diagnosis of NASH can only be established with liver biopsy.

Biopsy findings can reveal the following.

  • Type 1: fatty liver alone; macrovesicular steatosis
  • Type 2: fatty accumulation and lobar inflammation
  • Type 3: fat accumulation and ballooning degeneration
  • Type 4: fat accumulation, ballooning degeneration and either Mallory hyaline of fibrosis.

Type 3 and Type 4 are NASH by definition.


Histologically, the fatty liver will reveal fat accumulation chiefly in the pericentral (centrilobular) zone. Universally one will note the presence of macrovesicular steatosis with the liver cells containing several large fat droplets which displace the nucleus. Sometimes the lipid deposits may be released due to rupture of the overtly distended liver cells and produce lipogranulomas, which are composed chiefly of macrophages and occasional lymphocytes.[8]

History and Physical

Patients are usually asymptomatic, and "fatty liver" is usually an incidental finding on imaging done for other purposes. When patients do have symptoms, they are usually nonspecific, constitutional or right upper quadrant discomfort. 

It is important to obtain detailed alcohol use, review past medical history, family history, current and past prescription medications, and use of over-the-counter drugs or supplements. Obesity, hyperlipidemia, and diabetes have a strong association with "fatty liver."


Laboratory studies lack specificity and cannot distinguish NASH from NAFLD; however, initial evaluation should include an assessment of a complete hepatic panel, lipid panel, and iron. 

Transaminitis of 2 to 3 times the upper limit of normal and AST/ALT < 1 are highly suggestive of alcoholic-liver disease.

Imaging studies play a key role in the diagnosis of NAFLD. The mainstay is ultrasonography; it is least invasive, and relatively inexpensive. The sensitivity for an ultrasound to detect NAFLD is in the range of 60% to 90% with a specificity around 90%. Abdominal computed tomography and magnetic resonance are alternatives but are more costly and are not significantly superior to ultrasonography.[9][1][10]

Diagnosis of NASH requires a liver biopsy; however, not all patients with NAFLD require a liver biopsy. The decision to proceed with histological examination depends on risk factors, laboratory workup, and disease severity. According to the 2012 guidelines from American Association for the Study of Liver Disease (AASLD), liver biopsy should be reserved for subjects who will 'benefit,' for subjects with potentially competing diagnosis, and for children with either an unclear diagnosis or in whom consideration is being given for medication.

Treatment / Management

Lifestyle modifications and weight loss are the mainstays of the treatment. Treatment also involves glycemic and lipid control. For patients with significant obesity, gastric bypass or other weight loss surgical modalities should be considered. Weight loss is proven to reduce hepatic steatosis. Evidence available suggests that loss of 3% to 5% of body weight is necessary to notice an improvement in steatosis, but a greater loss (up to 10%) is necessary to improve necroinflammation. [11][12][13]

Patients should abstain from alcohol or hepatotoxic drugs.

Pharmacological options include Metformin, Vitamin E, fish oil, Orlistat (an inhibitor of gastric and pancreatic lipase), and Sibutramine. It is important to notice that the evidence behind these pharmacological modalities is weak. Studies have shown that metformin has no significant effect on liver histology; therefore, its use is only recommended if there is another indication for it. Vitamin E is currently only recommended for non-diabetic patients with biopsy-proven NASH. Pioglitazone can be used to treat patients with biopsy-proven steatohepatitis, but its long-term effects are not known.

For patients with advanced disease and cirrhosis, liver transplantation might have to be considered.

Differential Diagnosis

  • Viral Hepatitis
  • Alcoholic hepatitis
  • Alpha1 Antitrypsin Deficiency
  • Primary sclerosing cholangitis
  • Wilson disease
  • Primary biliary cholangitis
  • Cirrhosis


  • Cirrhosis
  • Ascites
  • Esophageal varices
  • Liver failure
  • Liver cancer
  • Type 2 diabetes

Postoperative and Rehabilitation Care

  • Patients should be tested for other causes of liver injury like hepatitis B and offer vaccination
  • All drugs that affect the liver must be discontinued
  • The disease progression should be monitored for signs of liver dysfunction like ascites, palmar erythema, decreasing levels of albumin and elevated levels of INR.
  • Levels of blood alcohol should be checked regularly to check for abstinence from alcohol.
  • Patients with end-stage liver disease should be screened for liver cancer and gastroesophageal varices.


  • General and bariatric surgeon
  • Radiologist for TIPS
  • Gastroenterologist

Deterrence and Patient Education

  • The patient should refrain from alcohol
  • Malnutrition is common in these patients and a dietary consult should be obtained. A low-fat diet and weight loss is recommended. 
  • Participating in a regular exercise program is highly recommended.

Pearls and Other Issues

Although the overall risk of cirrhosis due to NAFLD is modest, certain groups are at particular risk. Important risk factors for NASH are obesity, diabetes, and advanced age. 

Enhancing Healthcare Team Outcomes

Fatty liver is on the rise in the US primarily because of an increase in obesity, type 2 diabetes, and consumption of alcohol. The condition can be reversed if detected early but it requires an interprofessional approach.

Education of the patient is vital to ensure that there is complete abstinence from alcohol. For those who do not remain compliant, end-stage liver disease can develop which carries a high morbidity and mortality.

The nurse should also emphasize the importance of lifestyle changes and a healthy diet. Exercise and a healthy weight can help reverse the disorder and markedly improve the quality of life.

The pharmacist must be closely involved in the management of these patients because several studies show that the use of oral hypoglycemics and lipid-lowering agents may be helpful by lowering the risk of heart disease.

For patients who are not able to lose weight with conservative measures, a bariatric surgery consult may be helpful. There is evidence showing that appropriate weight loss surgery can significantly lower the risk of diabetes and heart disease.[11][14] (Level II)


Several studies show that if there is early intervention before the onset of fibrosis, the prognosis is excellent. However, if the treatment is delayed, and end-stage liver disease develops, the prognosis is poor. In order to reduce the morbidity of fatty liver, evidence suggests that one should adopt an aggressive multidisciplinary strategy for managing obesity, diabetes, and the metabolic syndrome.[15][8][16] (Level V)