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Non-alcoholic steatohepatitis
Classification and external resources

Micrograph of non-alcoholic fatty liver disease, demonstrating marked macrovesicular steatosis. Trichrome stain.
ICD-10 K76.0
ICD-9 571.8
DiseasesDB 29786
eMedicine med/775

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 cirrhosis of the liver of unknown cause.[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. Some think that NASH is a diagnosis of exclusion, and that many cases may be in fact be due to other causes.[4]


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 25 ml/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).[1][2]

Secondary causes

NAFLD can also be caused by the following medications (termed secondary NAFLD):


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 that 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]

However, new non-invasives diagnosis are coming, with FibroTest (estimates liver fibrosis[5].) and its derivatives for estimating steatosis (SteatoTest [6]), and NASH inflammation (NashTest).

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. Hypothyroidism is more prevalent in NASH patients, which would be detected by determining the TSH.[7]

Some suggest that, in overweight patients whose blood tests do not improve on losing weight and exercising, a further search of underlying causes of fatty liver must be sought, as well as those with fatty liver that are very young or not overweight or insulin-resistant, those whose physical appearance indicates the possibility of a congenital syndrome, have a family history of liver disease, have abnormalities in other organs, and those that present with moderate to advanced fibrosis or cirrhosis.[4]


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]


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.[8]
    • 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[9] and thiazolidinediones[10]) have shown efficacy in some studies.
  • Antioxidants and ursodeoxycholic acid, as well as lipid-lowering drugs, have little benefit.

In a study using the NHANES III dataset, it has been shown that mild alcohol consumption (one glass of wine a day) reduces the risk of NAFLD by half.[11]

See also


  1. ^ a b c d e f g Adams LA, Angulo P (2006). "Treatment of non-alcoholic fatty liver disease". Postgrad Med J 82: 315–22. doi:10.1136/pgmj.2005.042200. PMID 16679470.  
  2. ^ a b Clark JM, Diehl AM (2003). "Nonalcoholic fatty liver disease: an underrecognized cause of cryptogenic cirrhosis". JAMA 289: 3000–4. doi:10.1001/jama.289.22.3000. PMID 12799409.  
  3. ^ Ludwig J, Viggiano TR, McGill DB, Oh BJ (1980). "Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease". Mayo Clin Proc 55. PMID 7382552.  
  4. ^ a b Cassiman D, Jaeken J (2008). "NASH may be trash". Gut 57 (2): 141–4. doi:10.1136/gut.2007.123240. PMID 18192446.  
  5. ^ Halfon P, Munteanu M, Poynard T (2008). "FibroTest-ActiTest as a non-invasive marker of liver fibrosis". Gastroenterol Clin Biol 32 (6): 22-39. PMID 18973844.  
  6. ^ Ratziu et al (2006). "Diagnostic value of biochemical markers (FibroTest-FibroSURE) for the prediction of liver fibrosis in patients with non-alcoholic fatty liver disease". BMC Gastroenterology 14 (6): 6. PMID 16503961.  
  7. ^ Liangpunsakul S, Chalasani N (2003). "Is hypothyroidism a risk factor for non-alcoholic steatohepatitis?". J Clin Gastroenterol 37: 340–3. doi:10.1097/00004836-200310000-00014. PMID 14506393.  
  8. ^ 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.  
  9. ^ 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.  
  10. ^ 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.  
  11. ^ Dunn W, Xu R, Schwimmer JB (February 2008). "Modest wine drinking and decreased prevalence of suspected nonalcoholic fatty liver disease". Hepatology 47 (6): 1947–1954. doi:10.1002/hep.22292. PMID 18454505.  

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