Non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is fatty inflammation of the liver when this is not due to excessive alcohol use. It is related to insulin resistance and the metabolic syndrome, and may respond to treatments originally developed for other insulin resistant states (e.g. diabetes mellitus type 2), such as weight loss, metformin and thiazolidinediones.^[1] Non-alcoholic steatohepatitis (NASH) is the most extreme form of NAFLD, which is regarded as a major cause of cryptogenic cirrhosis of the liver.^[2]

NASH was first described in 1980 in a series of patients of the Mayo Clinic.^[3] Its relevance and high prevalence were recognized mainly in the 1990s.

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Signs and symptoms

Symptoms and associations

Most patients with NAFLD have no or few symptoms. Infrequently, patients may complain of fatigue, malaise and dull right upper quadrant abdominal discomfort. Mild jaundice may, rarely, be noticed. More commonly NAFLD is diagnosed following abnormal liver function tests during routine blood tests. By definition, alcohol consumption of over 20 g/day (about 25ml/day) excludes the condition.^[1]

NAFLD is associated with insulin resistance and the metabolic syndrome (obesity, combined hyperlipidemia, diabetes mellitus (type II) and high blood pressure).^[2][1]

Secondary causes

NAFLD can also be caused by the following medications (termed secondary NAFLD):^{[citation needed]}

• Amiodarone
• Antiviral drugs (nucleoside analogues)
• Aspirin / NSAIDS
• Corticosteroids
• Methotrexate
• Nifedipine
• Perhexiline
• Tamoxifen
• Tetracycline
• Valproic acid

Diagnosis

Disturbed liver enzymes are common, and liver ultrasound may show steatosis; it may also be used to exclude gallstone problems (cholelithiasis). A biopsy (tissue examination) of the liver is the only test which is widely accepted as definitively distinguishing NASH from other forms of liver disease, and can be used to assess the severity of the inflammation and resultant fibrosis.^[1]

Other tests are often carried out. Relevant blood tests include erythrocyte sedimentation rate, glucose, albumin, and renal function etc. As the liver is important in coagulation, some coagulation studies are often carried out, especially the INR (international normalized ratio). Blood tests (serology) are usually carried out to rule out viral hepatitis (hepatitis A, B, C, EBV, CMV and herpes viruses), rubella, and autoimmune causes. TSH is warranted, as hypothyroidism is more prevalent in NASH patients.^[4]

Pathophysiology

NAFLD is considered to cover a spectrum of disease activity. This spectrum begins as fatty accumulation in the liver (hepatic steatosis). A liver can remain fatty without disturbing liver function, but by varying mechanisms and possible insults to the liver may also progress to outright inflammation of the liver. When inflammation occurs in this setting, the condition is then called NASH. Over time up to 20 percent of patients with NASH may develop cirrhosis. Cigarette smoking is not associated with an increased risk of developing NASH.

The exact cause of NAFLD is still unknown. However, both obesity and insulin resistance probably play a strong role in the disease process. The exact reasons and mechanisms by which the disease progresses from one stage to the next are the subject of much research and debate.

One debated mechanism proposes a "second hit", or further injury, enough to cause change that leads from hepatic steatosis to hepatic inflammation. Oxidative stress, hormonal imbalances and mitochondrial abnormalities are potential causes for this "second hit" phenomenon.^[1]

Treatment

Trials to optimise treatment of NASH are being conducted (2007), and no treatment has yet emerged as the "gold standard". General recommendations include improving metabolic risk factors and reducing alcohol intake.^[1]

A large number of treatments for NAFLD have been studied. While many appear to improve biochemical markers such as alanine transaminase levels, most have not been shown to reverse histological abnormalities or reduce clinical endpoints:^[1].

• Treatment of nutrition and excessive body weight:
  • Nutritional counseling: Diet changes have shown significant histological improvement.^[5]
  • Weight loss: gradual weight loss may improve the process in obese patients; rapid loss may worsen NAFLD. The bad effect of rapid weight loss is controversial: the results of a meta-analysis showed that the risk of progression is very low.[1]
  • A recent meta-analysis presented at the Annual Meeting of American Association for Study of Liver Diseases(AASLD) reported that weight-loss surgery leads to improvement and or resolution of NASH in around 80 % of patients.[2]
• Insulin sensitisers (metformin^[6] and thiazolidinediones^[7]) have shown efficacy in some studies.
• Antioxidants and ursodeoxycholic acid, as well as lipid-lowering drugs, have little benefit.

See also

• Fatty liver includes both non-alcoholic and alcoholic liver disease
• Alcoholic liver disease

References

1. ^ ^{a b c d e f g} Adams LA, Angulo P. Treatment of non-alcoholic fatty liver disease. Postgrad Med J 2006;82:315-22. PMID 16679470.
2. ^ ^{a b} Clark JM, Diehl AM. Nonalcoholic fatty liver disease: an underrecognized cause of cryptogenic cirrhosis. JAMA 2003;289:3000-4. PMID 12799409.
3. ^ Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc. 1980;55:434-438. PMID 7382552.
4. ^ Liangpunsakul S, Chalasani N. Is hypothyroidism a risk factor for non-alcoholic steatohepatitis? J Clin Gastroenterol 2003;37:340-3. PMID 14506393
5. ^ Huang MA, Greenson JK, Chao C, et al (2005). "One-year intense nutritional counseling results in histological improvement in patients with non-alcoholic steatohepatitis: a pilot study". Am. J. Gastroenterol. 100 (5): 1072–81. doi:10.1111/j.1572-0241.2005.41334.x. PMID 15842581.
6. ^ Bugianesi E, Gentilcore E, Manini R, et al (2005). "A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease". Am. J. Gastroenterol. 100 (5): 1082–90. doi:10.1111/j.1572-0241.2005.41583.x. PMID 15842582.
7. ^ Belfort R, Harrison SA, Brown K, et al (2006). "A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis". N. Engl. J. Med. 355 (22): 2297–307. doi:10.1056/NEJMoa060326. PMID 17135584.