Non-alcoholic fatty liver disease overview

# Overview
A non-alcoholic fatty liver disease is a form of chronic hepatitis that shares the histologic features of alcohol-induced hepatitis but is found in patients without prior history of alcohol abuse. Based on the severity of the disease non-alcoholic fatty liver disease encompasses a range of disorders including mild steatosis, steatohepatitis, advanced fibrosis, cirrhosis, and less commonly fulminant hepatic failure. Risk factors for non alcoholic liver disease include obesity, diabetes mellitus type 2, hyperlipidemia, and sudden dramatic weight loss. The diagnosis of NAFLD should be considered in any patient presenting with elevated transaminases without any underlying condition or pathological process. NAFLD must be distinguished from steatosis and steatohepatitis due to secondary causes. These include various forms of malnutrition, drugs (eg, warfarin, methotrexate, amiodarone, glucocorticoids, synthetic estrogens, tamoxifen, and various antibiotic and antiviral agents), metabolic and genetic disorders (eg lipodystrophy, dysbetalipoproteinemia, and acute fatty liver of pregnancy), use of total parenteral nutrition, and gastric bypass and other weight loss surgeries. NAFLD is mostly seen in obese individuals but may be encountered in thin or normal weight patients. Insulin resistance is a core feature of NAFLD, diabetes, obesity, and dyslipidemia. NAFLD can therefore be considered part of the insulin resistance (or metabolic) syndrome. Insulin resistance leads to accumulation of fat within hepatocytesvialipogenesis (and inhibition of lipolysis) and hyperinsulinemia. The pathogenesis of NAFLD and its progression to NASH appears to result from a two-step process, whereby an initial insult in the form of insulin resistance due to genetic and acquired factors leads to hyperinsulinemia and accumulation of fat within hepatocytes (steatosis). The steatotic liver is then vulnerable to further insult; hepatocellular injury and fibrosis may develop in the presence of oxidative stress and the proinflammatory activity of cytokines and similar agents. This leads to exacerbation of insulin resistance; further oxidative stress; and acceleration of inflammatory, degenerative, and fibrotic processes. The natural history of NAFLD is dependent on the stage of the disease. The prognosis of simple steatosis seems to be relatively benign, with a 1% to 2% risk of developing cirrhosis over 15 to 20 years. Patients with NASH and fibrosis can progress to cirrhosis, which can lead to end-stage liver disease; hepatic decompensation; or hepatocellular carcinoma, a rare, end-stage outcome. Imaging techniques can be helpful by showing steatosis, but liver biopsy is the only way to assess the severity of inflammation and fibrosis. The mainstay of treatment for NAFLD is lifestyle modifications and treatment of underlying risk factors such as obesity, diabetes mellitus type 2, and hyperlipidemia.

# Historical Perspective
Ludwig was the first physician to describe the non-alcoholic fatty liver disease as a separate medical entity from other fatty liver diseases.

# Classification
Non-alcoholic fatty liver (NAFLD) disease may be classified into:
- Non-alcoholic fatty liver or hepatic steatosis
- Non-alcoholic steatohepatitis

# Pathophysiology
The exact pathogenesis of NAFLD is not fully understood, but is believed due to interaction of multiple factors such as obesity, Insulin resistance, and metabolic syndrome. Pathogenesis of non-alcoholic liver disease can be best explained by 2 hit hypothesis. The first hit is steatosis. The second hit is controversial and is likely cause changes that leads from hepatic steatosis to hepatic inflammation and fibrosis by way of lipid peroxidation.

# Causes
Common causes in the development of nonalcoholic fatty liver disease is related to obesity which will result in insulin resistance and metabolic syndrome. Less commonly patients with hypertension and dyslipidemia are also associated with developing nonalcoholic fatty liver disease

# Differentiating Non-alcoholic fatty liver disease from Other Diseas
Usually, NAFLD presents with no or few symptoms but if symptomatic NAFLD must be differentiated from other diseases that cause jaundice and abdominal pain which include Wilson's disease, hemochromatosis, alcoholic hepatitis and cholestatic jaundice.

# Epidemiology and Demographics
The estimated annual incidence of non alcoholic liver disease with steatosis in the United States is approximately 9,255 per 100,000 individuals. The prevalence of non-alcoholic liver disease in the United States is estimated to be 10,000 to 24,000 cases per 100,000 individuals annually. Non-alcoholic fatty liver disease may occur at any age, but is diagnosed most commonly in patients aged 50 to 60 years. Hepatic steatosis is more prevalent in the hispanics.

# Risk Factors
The most potent risk factor in the development of NAFLD is obesity. Other risk factors include insulin resistance and metabolic syndrome.

# Screening
There is insufficient evidence to recommend routine screening for NAFLD in general population. However, screening is recommended in high-risk population groups(obesity, insulin resistance and patients with metabolic syndrome) as more than 50 million Americans have been estimated to have metabolic syndrome and about 80% of them have NAFD.

# Natural History, Complications and Prognosis
If left untreated non alcoholic fatty liver disease may progress to fibrosis and, later cirrhosis. Studies of serial liver biopsies estimate a 26-37% rate of hepatic fibrosis and 2-15% rate of cirrhosis in less than 6 years. Common complications of NAFLD include fibrosis, cirrhosis, internal bleeding, encephalopathy. The presence of fibrosis and cirrhosisassociated with a particularly poor prognosis among patients with NAFLD.

# Diagnosis

## History and Symptoms
The majority of patients with non-alcoholic fatty liver disease are asymptomatic. However, very rarely patients may complain of fatigue, malaise and dull right upper quadrant abdominal discomfort. Mild jaundice can also be noticed. Often following an asymptomatic course, the disease may present first with cirrhosis and/or the complication of portal hypertension.

## Physical Examination
Patients with non-alcoholic fatty liver disease usually appear normal. Physical examination of patients with non-alcoholic fatty liver disease is usually unremarkable.

## Laboratory Findings
There are no specific diagnostic laboratory findings associated with non alcoholic fatty liver disease. Laboratory findings include abnormal liver function tests but are unspecific. Other laboratory tests are generally performed to rule out other diagnosis.

## Electrocardiogram
There are no ECG findings associated with NAFLD.

## X-ray
There are no x-ray findings associated with NAFLD.

## Ultrasound
Ultrasound may be helpful in the diagnosis of non-alcoholic fatty liver disease. Increased echogenicity and coarsened echotexture of the liver is the most prominent and diagnostic finding on an ultrasound in patients diagnosed non-alcoholic fatty liver disease.

## CT scan
CT scan may be helpful in the diagnosis of non-alcoholic fatty liver disease. Findings on a CT scan diagnostic for non-alcoholic liver disease include a diffuse, low-density hepatic parenchyma without mass effect.

## MRI
An MRI is one of the best tools in imaging modalities available to diagnose NAFLD. An MRI is simple to test which allows quantification of the hepatic steatosis. MRI has a sensitivity of 96% and specificity of 93% in diagnosing NAFLD. However, it uses is limited because of the cost.

## Other Imaging Findings
There are no other imaging findings associated with non-alcoholic fatty liver disease.

## Other Diagnostic Studies
Liver biopsy may be helpful in the diagnosis of non-alcoholic fatty liver disease. Findings on biopsy include macrovesicular steatosis, inflammation, ballooning degeneration, zone 3 perivenular/periportal/perisinusoidal fibrosis and, finally, mallory bodies.

# Treatment

## Medical Therapy
Weight loss, withdrawal of hepatotoxic agents, and management of underlying insulin resistance/metabolic syndrome is the mainstay of treatment in non-alcoholic fatty liver disease (NAFLD).

## Surgery
Surgery is not the first-line treatment option for patients with non- Alcoholic fatty liver disease (NAFLD). However, gastric bypass surgery is recommended in patients with non-alcoholic fatty liver disease whose BMI is greater than 40 who psychologically stable and failed medical therapy.

## Primary Prevention
Effective measures for the primary prevention of non-alcoholic fatty liver disease include eating a healthy diet and regular exercise.

## Secondary Prevention
There are no established measures for the secondary prevention of non-alcoholic fatty liver disease.