Pathophysiology^[4]

Fatty liver (steatosis) involves the accumulation of triglycerides and other lipids in hepatocytes. When there is inflammation and cell death associated with this fatty change it is called steatohepatitis. Suggested mechanisms for such change include:

• Reduced mitochondrial oxidation of fatty acids.
• Increased synthesis or delivery of fatty acids to hepatocytes.
• Reduced removal of triglycerides from hepatocytes.
• Vulnerability then to secondary insults (oxidative stress, adipocytokines, gut derived bacterial endotoxins) leading to hepatocellular inflammation and fibrosis.

Aetiology

Causes of fatty liver:

• Metabolic syndrome (the most common association): comprising type 2 DM, obesity with or without raised triglycerides
• Alcohol Excess
• Obesity
• Protein-calorie malnutrition
• Starvation or rapid weight loss
• Total parenteral nutrition
• Medication:
  • Amiodarone
  • Tamoxifen
  • Glucocorticoids
  • Tetracycline
  • Oestrogens
  • Methotrexate
  • Thallium
• Metabolic disorders
  • Wilson's disease
  • Glycogen storage disorders
  • Abetalipoproteinaemia and Hypobetalipoproteinemia
  • Galactosaemia
  • Hereditary fructose intolerance
  • Homocystinuria
  • Refsum's disease
  • Systemic carnitine deficiency
  • Tyrosinaemia
  • Weber-Christian disease
• Jejuno-ileal bypass

Epidemiology^[5]

There is a rising incidence and prevalence of NASH.^[5][6] NAFLD is the most common liver disease in Western countries.^[7] More research is called for to identify patients at risk of progression of NAFLD.^[5]

• Simple steatosis occurs in about a third of the general population and 80% of obese patients in the United States of America.
• NASH has been reported in between 2% and 9% of patients undergoing routine liver biopsy.
• Steatohepatitis is most commonly caused by alcohol, particularly in association with obesity. Other causes include nutritional disorders and obesity.
• NASH is the most common liver disease in adolescents in the United States of America. Incidence is rising in children.^[8]

Presentation

• History:
  • The majority of patients with steatosis have no symptoms, although on direct questioning half of patients with steatohepatitis report persistent fatigue, malaise or right upper quadrant pain.
  • Cirrhosis may present with symptoms from ascites, oedema and even jaundice.
  • Routine medicals and blood tests may reveal abnormal liver function tests (for example, raised alanine transaminase).
• Examination:
  • Hepatomegaly is very common.
  • Splenomegaly with or without portal hypertension may occur with cirrhosis.
  • Stigmata of chronic liver disease may be seen in patients with cirrhosis.
  • Fulminant liver failure may follow drug-induced steatohepatitis.
  • Stigmata of alcohol abuse may be apparent ( for example, muscle wasting, pancreatitis, alcoholic cardiomyopathy).

Differential diagnosis

• Alcoholic hepatitis
• Alpha 1-antitrypsin deficiency
• Autoimmune hepatitis
• Coeliac sprue
• Cirrhosis
• Drug-induced hepatotoxicity
• Haemochromatosis
• Viral hepatitis in all forms
• Thyroid disease
• Primary biliary cirrhosis
• Primary sclerosing cholangitis
• Vitamin A toxicity
• Wilson's disease
• Pregnancy-related liver disease

Investigations

A definitive diagnosis can only be achieved by liver biopsy and histopathological analysis.^[9] Efforts are being made to find non-invasive markers of disease which can distinguish the stages of fibrosis, fibrosis from NASH and NASH from simple steatosis.^[6][9] However, the following investigations, including liver biopsy, may be performed in pursuit of the diagnosis and work-up of patients:

• Blood tests:
  • Full blood count.
  • Liver function tests:
    • Raised AST or ALT may be the only abnormality (up to 10 times increase).
    • AST and ALT may be normal in steatosis and steatohepatitis.
    • The AST:ALT ratio tends to be <1 in NASH and >1 in alcohol-related steatohepatitis(in the absence of cirrhosis).
    • Alkaline phosphatase may be raised in NASH (but not usually more than three times normal).
  • Fasting lipid profile:
    • Hyperlipidaemia is usually present.
    • Triglycerides may be raised.
  • Iron studies:
    • Ferritin may be raised in NASH.
    • Iron overload is more harmful when associated with NASH and screening for haemochromatosis is recommended if the ferritin is significantly elevated.
  • Serum caeruloplasmin.
  • Autoimmune studies:
    • Antinuclear antibodies (ANAs) and anti-smooth muscle antibody (ASMA) may be raised in NASH.
    • Cirrhosis may give positive results.
    • Autoimmune liver disease may be suggested by serum protein electrophoresis if appropriate.
  • Viral studies are done to exclude viral hepatitis.
  • Blood sugar: fasting levels may demonstrate impaired fasting glycaemia or diabetes characteristic of the metabolic syndrome.
• Diagnostic imaging. These techniques may be used to define extent and course of disease. Steatohepatitis is usually diffuse, whereas steatosis may be focal or diffuse.
  • Ultrasound:
    • Shows a hyperechogenic, bright image.
    • Ultrasound has some diagnostic accuracy in detecting steatosis.^[6]
    • Ultrasound is not good at distinguishing NASH and fibrosis within NAFLD (non-alcoholic fatty liver disease).^[6]
  • CT scanning may be helpful to monitor the course of the disease.
  • MRI scan can be used to exclude fatty infiltration and the course and extent of this and other liver disease (used with phase contrast imaging)
• Combinations of tests:
  • A combination of non-invasive biomarkers has been tested to diagnose steatosis accurately and reduce the need for liver biopsy.^[9]
  • SteatoTest® combines six components (FibroTest-ActiTest®, body mass index, serum cholesterol, triglycerides, serum glucose, age and sex). A study revealed it may reduce the need for liver biopsy.^[9]
• Liver biopsy:
  • The only definitive test.
  • An NAFLD (non-alcoholic fatty liver disease) score can be performed. This scores for steatosis, inflammation, ballooning and fibrosis.^[6][10]
• Possible future tests:
  • Elastography. A novel technique involving a vibrating probe to measure 'liver stiffness'.^[6]
  • Genomics analysis may reveal new markers.^[11]
  • Proteomics analysis may reveal new markers.^[11]
  • It is most likely that new combinations, involving simple blood tests, novel biomarkers, and imaging (possibly functional) will improve diagnostic accuracy.^[6] This will allow better differentiation of the stages of fibrosis, and better diagnosis. Fibrosis is important in prognosis and better accuracy in measuring it will be important.

Staging

The gold standard for precise diagnosis and staging remains liver biopsy, but this is invasive and reserved for patients in whom diagnosis is uncertain, and to rule out cirrhosis.
Classifications have been used for:

• Stages of fibrosis:
  • Recently, a scoring system specifically for NASH has been developed using several components (steatosis, fibrosis, lobular inflammation, ballooning).^[10]
  • If this scoring system is widely used and accepted it could facilitate better comparative trials in treatment and diagnosis of NAFLD.^[6]
• Differentiating fibrosis from NASH.
• Differentiating NASH from simple steatosis.

Management^[12][13][14]

This will depend on the specific diagnosis. The following key points should be kept in mind:

• Where possible, treatment should be aimed at the cause of the steatosis and steatohepatitis.
• There is no specific established treatment for NASH.
• Abstinence from alcohol may reverse steatosis in alcohol-related steatosis.
• Management is concentrated on treatment of comorbid conditions, weight loss and abstinence from alcohol (as for all types of liver disease).^[13]

As steatosis is so common it will not be unusual for GPs to be faced with presenting features suggestive of this diagnosis and hence the need for succinct assessment and management.^[15]

Further detail

• Diet:
  • Gradual weight loss is important (approximately 1-2 pounds per week).
  • Diets should have a high protein to calorie ratio.
  • A typical low fat diabetic-type diet is recommended.
  • Abstinence from alcohol is recommended for all types of steatosis and steatohepatitis.
• Exercise:
  • Exercise with diet increases muscle mass and increases insulin sensitivity.
  • Improving cardiovascular fitness and weight training should improve NASH but, as yet, there are no randomised trials to confirm that this works in practice (the logic being that this helps reverse the underlying derangements).
• Drugs:
  • Trials are underway to evaluate lipid-lowering agents and drugs which are insulin sensitisers.
  • Improvements histologically and biochemically have been shown with thiazolidinediones, metformin (radiological and biochemical improvement), gemfibrizol (no histological data) and atorvastatin.
  • Orlistat improves histological and biochemical improvements but studies are only short-term so far.
• Surgery:
  • Bariatric surgery can bring about histological and biochemical improvements in NASH.
  • Recent studies have not shown worsening hepatic function seen in earlier studies of bypass surgery (for example, gastric bypass with Roux-en-Y) in NASH.
• Referral:
  • To a hepatologist is recommended for staging and prognosis (liver biopsy still usually required).
  • May be necessary to exclude alcohol-related liver disease, haemochromatosis, autoimmune hepatitis or where there is doubt over the diagnosis.
  • To a gastroenterologist or hepatologist when there are complications, such as cirrhosis or liver failure, is mandatory.
• Follow-up:
  • All patients with chronic liver disease or at risk of disease progression should be followed up. Follow-up with the GP is appropriate. Follow-up should aim to detect any progression of disease (signs of liver disease, abnormal blood results, development of symptoms).
  • Education of patients should be an ongoing process. Avoidance of alcohol and hepatotoxic drugs should be part of this.
  • Promotion of gradual weight loss and an increase in exercise should continue.

Complications

• Steatohepatitis can progress to cirrhosis and liver failure just like any chronic liver disease.
• Progression to cirrhosis is more rapid when there is alcoholic liver disease or, indeed, any form of concomitant liver disease (for example, chronic viral hepatitis). Poor control of hyperlipidaemia or diabetes will also accelerate progression of fibrosis.
• Hepatocellular carcinoma can occur at the same rate as with other forms of liver disease.

Prognosis^[12]

The prognosis depends on disease stage:

• Steatosis:
  • Has a good prognosis with abstinence and gradual weight loss.
  • Cirrhosis develops in 1% to 2% over 20 years.^[15]
  • Central obesity and insulin resistance are risk factors for DM, cardiovascular and renal disease.
• Steatohepatitis:
  • 10% to 12% of patients will progress to cirrhosis within 8 years.^[15] This is similar to the rate of progress towards cirrhosis in alcohol-related liver disease.

Prevention

It may be possible to prevent steatohepatitis by actively screening for patients at risk of steatosis and educating them about diet, exercise and alcohol.^[16] There are no trials to support this hypothesis but there is an opportunity to test the hypothesis in primary healthcare.

Practice tips

• Fatty liver is not an entirely benign condition.
• At-risk patients should be identified and screened for liver disease (particularly steatosis and steatohepatitis). This will involve history, examination and blood tests but may involve further investigation if results are abnormal or the risk of liver disease is high.
• All patients at risk of steatosis or steatohepatitis should be educated about the condition (causes, management, prevention and follow-up).
• Patients with steatosis or steatohepatitis should be appropriately managed, educated and, in a few cases, referred.
• Beware of even minor abnormalities of liver function in at-risk groups.