non-alcoholic steatohepatitis (NASH)

Last edited 11/2022 and last reviewed 07/2023

Non alcoholic fatty liver disease (NAFLD) is term which represents a spectrum of liver disease encompassing fatty liver to steatohepatitis and cirrhosis (1).

• non alcoholic fatty liver (NAFL)
• is the  first recognisable stage of NAFLD
• simple fatty infiltration of the liver or hepatic steatosis (fat content exceeds 5% of liver volume) without any evidence of hepatocellular injury in the form of ballooning of the hepatocytes or no evidence of fibrosis
• risk of developing cirrhosis and liver failure is minimal but due to its high prevalence it none the less represents an important cause of cirrhosis
  
  
• non-alcoholic steatohepatitis (NASH)
• is the next stage of NAFLD
• fat and inflammation with hepatocyte injury (ballooning) with or without fibrosis
• the risk of progressive liver fibrosis, cirrhosis, and hepatocellular carcinoma is much higher  (1)

Diagnosis of NAFLD requires evidence of fatty changes in the liver in the absence of excessive alcohol consumption.

• NAFLD should only be diagnosed in people who consume no or only modest amounts of alcohol (daily intake <20 g (2.5 units) in women and <30 g (3.75 units) in men) (2)

Due to the strong association with obesity, insulin resistance or type 2 diabetes mellitus, and dyslipidaemia, NAFLD has been described as the hepatic manifestation of the metabolic syndrome (3)

NAFLD is the most common cause of chronic liver disease in developed countries. It is now more common than alcoholic liver disease.

• around  one third of the population had evidence of steatosis on imaging,
• 70%–90% having simple steatosis
• 10%–30% of subjects with NAFLD have non-alcoholic steatohepatitis (NASH) (4)

The diagnosis may be suspected because of chronically elevated aminotransferase levels, typically with an AST:ALT ratio < 0.8 (see notes).

In the USA, non-acoholic fatty liver is the most common cause of abnormal liver function tests. Frequently there is an association between non-alcoholic fatty liver and diabetes - often these patients have a truncal obesity and a high BMI (5).

Most NASH patients will develop diabetes or impaired glucose tolerance in the long term (6)

Survival is lower in patients with NASH (6).

Management (7):

• treatment is generally limited to lifestyle intervention aimed at weight loss
• pioglitazone remains the drug of choice to reduce progression of fibrosis in people with diabetes, although it is often used off-label in the absence of diabetes
• vitamin E is mainly used in children and may be considered in adults without diabetes

NAFLD is associated with an increased long-term risk of fatal or non-fatal CVD events (10)

• review of 36 longitudinal studies with aggregate data on 5,802,226 middle-aged individuals (mean age 53 years) over a median follow-up of 6.5 years found a link between this condition and moderately increased risk of fatal or non-fatal CVD events (HR 1.45, 95% CI 1.31-1.61)
• CVD risk is further increased with more advanced liver disease, especially with higher fibrosis stage

Notes:

• typically patients with alcoholic fatty liver have an AST:ALT ratio >1.5 and a high red blood cell corpuscular volume (MCV) (2)
  
  
• in NASH, transaminases are usually, but not always elevated, with the AST:ALT ratio < 1 (8)
• if a patient with NASH has an AST:ALT > 1 then s/he is more likely to have more fibrosis and more progressive disease
• gamma glutamyl transferase is usually abnormal (> 35 U/L)
• alkaline phosphatase may be up to twice normal (ULN =125 U/L)
• serum ferritin may be raised as an acute phase response
• in about 1/3 of cases of NASH, non-organ specific autoantibodies are found
  • the presence of anti-nuclear antibodies is reported to be associated with more severe insulin resistance and more advanced liver disease
    
    
• NICE state that primary non-alcoholic fatty liver disease (NAFLD) is an excess of fat in the liver (steatosis) that is not a result of excessive alcohol consumption or other secondary causes (9)
  • these secondary causes include side effects of certain medications, hepatitis C virus infection and particular endocrine conditions
  • prevalence of NAFLD in the general population is estimated at 20-30%
    • around 2-3% of the population have NASH
    • NAFLD is more common in people who have type 2 diabetes or metabolic syndrome
    • prevalence of NAFLD is increasing
  • rate of progression of NAFLD is variable; being overweight and having diabetes are associated with an increased risk of progressive disease
  • average age of people with NASH is 40-50 years and for NASH-cirrhosis 50-60 years
  • do not use routine liver blood tests to rule out NAFLD
    
    
• being overweight or obese are among the main risk factors for developing non-alcoholic fatty liver disease (NAFLD), which is considered to be the most prevalent chronic liver disease worldwide (11)
  • global burden of non-alcoholic fatty liver disease (NAFLD) parallels increase in obesity rates across world. Analysis (151 studies; n=10028) found NAFLD prevalence in overweight population of 69.99%; NAFL 42.49%; non-alcoholic steatohepatitis 33.50%, similar to obese population
    

Reference:

• (1) Chalasani N et al. The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012;55(6):2005-23
• (2) Sattar N, Forrest E, Preiss D. Non-alcoholic fatty liver disease. BMJ. 2014;349:g4596
• (3) Anstee QM, McPherson S, Day CP. How big a problem is non-alcoholic fatty liver disease? BMJ. 2011;343:d3897
• (4) Dyson JK, Anstee QM, McPherson S. Republished: Non-alcoholic fatty liver disease: a practical approach to treatment. Postgrad Med J. 2015;91(1072):92-101.  
• (5) Pulse (2002), 62(27), 56.
• (6) Ekstedt M et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology. 2006 Oct;44(4):865-73.
• (7) Petroni ML et al. Management of non-alcoholic fatty liver disease. BMJ 2021;372:m4747http://dx.doi.org/10.1136/bmj.m4747
• (8) Br J Diabetes Vasc Dis 2006; 6: 251-60.
• (9) NICE (July 2016). Non-alcoholic fatty liver disease (NAFLD): assessment and management
• (10) Mantovani A et al. Non-alcoholic fatty liver disease and risk of fatal and non-fatal cardiovascular events: an updated systematic review and meta-analysis. The Lancet Gastroenterology and Hepatology September 20th 2021.
• (11) Quek J et al. Global prevalence of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in the overweight and obese population: a systematic review and meta-analysis. The Lancet Gastroenterology and Hepatology November 15th 2022.