Nonalcoholic Steatohepatitis: Risk Factors and Diagnosis

Leon A Adams; Ariel E Feldstein

Disclosures

Expert Rev Gastroenterol Hepatol. 2010;4(5):623-635. 

In This Article

Clinical Significance of NASH

Subjects with NAFLD are at an increased risk of death compared with the general population, with death related to liver disease being the third most common cause of death.[21,22] However, the prognosis of subjects with NAFLD reflects the histological subtype of disease. Subjects with fatty liver have a relatively benign course and are at low risk of developing liver-related morbidity or mortality.[23,24] For example, Dam-Larsen and colleagues followed 109 patients with biopsy-proven hepatic steatosis without inflammation or fibrosis, for a median of 16.7 years; only one patient developed cirrhosis and subsequently died from their liver disease.[24] By contrast, NASH is more frequently progressive and may lead to cirrhosis with complications of hepatocellular carcinoma (HCC), liver failure and liver-related death or the requirement for liver transplantation. Subfulminant liver failure is a rare presentation of NASH, but has been reported in patients with presumed unrecognized cirrhosis who decompensate owing to an unknown insult.[25,26] In addition to liver-related morbidity and mortality, subjects with NASH are at an increased risk of cardiac morbidity and mortality.[27,28]

Cirrhosis & Liver-related Death

Natural history studies of NASH have small numbers of subjects (<80) and generally originate from referral centers with subjects having undergone liver biopsy.[21,27,29,30] Thus, all studies that suffer a degree of bias and generalization of results to the wider community need to be evaluated with some caution. The prevalence of cirrhosis in these studies ranges from 4 to 14% over follow-up periods of 8–21 years. A cohort of 71 NASH subjects from Sweden found that 10% developed end-stage liver disease over a mean of 13.7 years.[27] These subjects were more likely to die from liver-related causes compared with age- and gender-matched controls from the general population (2.8 vs 0.2%; p = 0.04). Similarly, 6% of subjects from a cohort of 51 NASH subjects, also from Sweden, died from complications of liver disease over a median of 24 years.[21] The highest liver-related death rate of 17.5% has been reported in a cohort of 57 NASH subjects from the Cleveland Clinic (OH,USA) followed over a median of 18.5 years.[29] It is unclear what proportion of subjects had cirrhosis at baseline, which would lead to a higher liver-related mortality over time.

Once subjects with NASH develop cirrhosis, they are at risk of decompensation and death. In a cohort of 152 NASH subjects with cirrhosis followed over 10 years, 45% had developed an episode of decompensation, whereas 14% died from liver-related causes.[31] The liver-related death rate was significantly lower than a matched group of subjects with cirrhosis due to chronic hepatitis C (29%). An Australian cohort of 23 NASH cirrhotic patients found similar overall survival of 84% at 10 years.[32] However, survival was not different when compared with patients with cirrhosis due to chronic hepatitis C, although this may have been related to a relatively small sample size.[32] In summary, the liver-related death rate for subjects with NASH is higher than the general population and is probably in the order of 2–5% every 10 years, although it is higher in the presence of cirrhosis.

Hepatocellular Carcinoma

Although case reports have demonstrated that HCC may occur in NASH in the absence of cirrhosis, this is distinctly unusual.[33] The cumulative annual incidence of HCC in subjects with NASH -related cirrhosis is approximately 2.6%, although this is two- to three fold lower than with chronic hepatitis C cirrhosis.[31,34] Risk factors for HCC development are older age and previous alcohol consumption.

Liver Transplantation

Once subjects with NASH-related cirrhosis develop an episode of decompensation or HCC, they may be suitable for liver transplantation. Rates of transplantation performed for NASH have increased in the USA over the past 10 years, rising from 0.1% in 1996 to 4.7% in 2007.[35] Liver transplantation may be indicated in a greater number of subjects with NASH cirrhosis, however, old age, vascular disease and diabetic complications may be barriers to activation. Outcomes for liver transplantation for NASH are equivalent to transplantation for other etiologies, with 5-year survival rates in the order of 71–75%.[35–37] Recurrent NASH in the donor liver is relatively common, occurring in 20–33% of cases. While fibrosis development with moderate peri-portal fibrosis can be observed in close to 20% of patients by 18 months post-transplant'.[36–38] Cumulative steroid dose may be a risk factor for the development of recurrent NASH, however, it has not been associated with increased graft loss.[39] One study found subjects transplanted for NASH had a higher risk of acute rejection, however, this needs to be confirmed in larger studies from other centers.[36]

Cardiovascular Disease

Nonalcoholic fatty liver disease is closely associated with e metabolic syndrome, which is a risk factor for cardiovascular disease.[40] Therefore, it is not surprising that cardiovascular disease is a leading cause of death in subjects with NAFLD.[22] Subjects with NASH-related cirrhosis are more likely to have metabolic risk factors and cardiovascular disease compared with subjects with cirrhosis related to other etiologies.[41,42] Patients with NAFLD have an adverse proatherogenic lipid profile with small dense low-density lipoprotein levels and reduced large high-density lipoprotein levels, increased systemic levels of proatherogenic cytokines and altered cardiac metabolism compared with matched controls.[43,44] Furthermore, subjects with NAFLD have a higher incidence of cardiovascular disease compared with matched controls independent of other cardiovascular risk factors.[28,45] Similarly, a meta-analysis of large cohort studies have demonstrated that γ-glutamyltransferase levels are predictive of incidence of vascular events, with each unit increase in γ-glutamyltransferase increasing the risk by 34%.[46] Individuals with NASH appear likely to have a higher risk of vascular disease compared with those with simple steatosis, with a greater carotid intima media thickness and a higher risk of and an elevated risk of cardiovascular-related death in individuals with NASH.[27,47]

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