Non-alcoholic fatty liver diseaseBMJ 2009; 339 doi: http://dx.doi.org/10.1136/bmj.b2474 (Published 16 July 2009) Cite this as: BMJ 2009;339:b2474
- Neeraj Bhala, research fellow1,
- Tim Usherwood, professor of general practice2,
- Jacob George, professor of gastroenterology and hepatic medicine1
- 1Storr Liver Unit, Westmead Millennium Institute, University of Sydney and Westmead Hospital, Sydney, NSW 2145, Australia
- 2University of Sydney and Westmead Hospital
- Correspondence to: N Bhala
- Accepted 19 May 2008
A 45 year old man with known hypertension, type 2 diabetes mellitus, and central obesity presents with fatigue and mild discomfort in the abdominal right upper quadrant. Repeated blood tests show a persistent alanine aminotransferase concentration of 100 IU/l (reference range 10-50) and a γ glutamyl transferase concentration of 80 IU/l (range 10-50) with serum bilirubin and other liver test results in the normal range. He drinks two glasses of wine a month and denies any history of excessive alcohol consumption. Tests (including negative serology for hepatitis B and C viruses) exclude other causes of liver dysfunction. You explain that he is likely to have non-alcoholic fatty liver disease.
What issues you should cover
Non-alcoholic fatty liver disease, the hepatic manifestation of the metabolic syndrome, occurs predominantly in patients with central obesity, hypertension, abnormal glucose tolerance, and dyslipidaemia. It is now the most common cause of abnormal liver function test results, with a prevalence approaching 30% in unselected patients throughout the world.
Fatigue and abdominal pain are sometimes reported but are uncommon. Most patients are asymptomatic and come to attention only because of incidental findings on liver tests or hepatic ultrasound (which you should ask for if you suspect non-alcoholic fatty liver disease). As well as the metabolic syndrome, other disorders can predispose patients to the disease, such as rapid weight loss, starvation, and some drugs (such as tamoxifen and corticosteroids).
No biochemical threshold has been specified for diagnosis of non-alcoholic fatty liver disease, and reference ranges for liver function tests vary between laboratories and the sexes. Patients with advanced liver disease can have normal liver function blood tests so this cannot exclude the diagnosis. Therefore, always consider blood test findings on a case by case basis and remember that persistent elevation of alanine aminotransferase or γ glutamyl transferase, for example, warrant further assessment.
Non-alcoholic fatty liver disease covers a range of conditions from simple “fatty liver” (steatosis) to non-alcoholic steatohepatitis, which can lead to cirrhosis, liver decompensation, and hepatocellular cancer. Non-alcoholic fatty liver disease is thought to be driven by insulin resistance, predisposing to steatosis and inflammation, and subsequently to scarring (fibrosis).
It occurs in patients who have not consumed excessive quantities of alcohol, but it may coexist with and worsen liver damage from any other cause. Conservative levels of alcohol consumption are used as cut offs for diagnosis: no more than 70 g ethanol per week for women (about one standard drink daily) and 140 g for men (two standard drinks daily).
The prognosis depends on disease stage. Patients with simple steatosis have a relatively benign course, with cirrhosis developing in 1-2% over 15-20 years. However, their central obesity and insulin resistance put them at risk of diabetes mellitus and of cardiovascular and renal disease. Approximately 12% of patients with non-alcoholic steatohepatitis and fibrosis progress to cirrhosis within eight years. Currently no specific tests can distinguish non-alcoholic steatohepatitis from simple steatosis. However, increasing age, hyperglycaemia, a high body mass index, low platelet count, and low serum albumin are all independent risk factors for advanced liver fibrosis. The gold standard for diagnosis remains liver biopsy, but this investigation is reserved for patients in whom diagnosis is uncertain and to rule out cirrhosis.
Although some evidence suggests that gastric banding surgery, metformin, and most recently glitazones improve liver histology, interpretation is limited by deficiencies in trial design and small cohort sizes. No treatment to date has been shown to alter clinical outcomes, but non-pharmacological measures, such as gradual weight loss and regular exercise, and treatments of the components of the underlying metabolic syndrome remain important. A possible algorithm for the management of non-alcoholic fatty liver disease is shown in the figure ⇓.
What you should do
Diagnose non-alcoholic fatty liver disease with relative confidence if the patient has classical risk factors for the metabolic syndrome, such as a persistent elevated alanine aminotransferase or γ glutamyl transferase, an ultrasound consistent with hepatic steatosis, and if other common or treatable causes of abnormal liver tests have been excluded (such as viral hepatitis, haemochromatosis, Wilson’s disease, and alcohol and drug misuse).
Explain that abnormal liver findings are caused by inflammation that is probably due to excess fat, and that it is most important to treat the metabolic syndrome and its components using non-pharmacological lifestyle measures (such as gradual weight loss, regular exercise, dietary measures, and alcohol cessation) and drug treatments, including hypoglycaemic, antihypertensive, and lipid lowering drugs.
Assess cardiovascular risk, hepatic complications, and anthropometry (including waist circumference). Ideally any abnormal blood tests should be repeated—ask for a full blood count, liver function tests, serology for hepatitis B and C viruses, autoantibodies (including antinuclear antibodies, antismooth muscle antibodies, and antimitochondrial antibody), iron studies, serum caeruloplasmin, fasting lipids and glucose, and a liver ultrasound.
Consider specialist referral if you are uncertain about the diagnosis, if the GP or patient are concerned, or if you need advice about pharmacological therapies.
Box 1 Useful blood tests for the assessment of non-alcoholic fatty liver disease and its complications
Alanine aminotransferase and γ glutamyl transferase usually raised above reference range
Alanine aminotransferase usually greater than serum aspartate aminotransferase
Increased bilirubin and decreased albumin in cirrhosis
Low platelet count in cirrhosis
Elevated mean cell volume raises possibility of excessive alcohol intake
Increased prothrombin time in cirrhosis
Decreased high density lipoprotein cholesterol
Impaired fasting blood glucose (consider an oral glucose tolerance test)
Elevated serum uric acid
Angulo P, Hui JM, Marchesini G, Bugianesi E, George J, Farrell GC, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology 2007;45(4):846-54
Chitturi S, Farrell GC, Hashimoto E, Saibara T, Lau GK, Sollano JD: Asia-Pacific Working Party on NAFLD. Non-alcoholic fatty liver disease in the Asia-Pacific region: definitions and overview of proposed guidelines. J Gastroenterol Hepatol 2007;22(6):778-87
Harrison SA, Day CP. Benefits of lifestyle modification in NAFLD. Gut 2007;56(12):1760-9
British Liver Trust: non-profit medical research charity in the UK offering patient information and support (www.britishlivertrust.org.uk/home/the-liver/liver-diseases/fatty-liver-and-non-alcoholic-steatohepatitis-nash.aspx)
Cite this as: BMJ 2009;339:b2474
This is part of a series of occasional articles on common problems in primary care. The BMJ welcomes contributions from GPs
Funding: NB was funded by the Dame Sheila Sherlock (Royal College of Physicians of London) and Berkeley (Gonville and Caius College, Cambridge, and Royal Free and University College Medical School, UCL) Travelling Fellowships for his study in Sydney.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally reviewed.