Non-alcoholic fatty liver disease

Contributed by Dr Emma Paulon, specialist registrar, and Dr Jude Oben, senior lecturer, consultant hepatologist and gastroenterologist, University College London Hospitals and Guys' and Thomas' Hospital, London.

Section 1: Epidemiology and aetiology
Obesity-induced liver disease, or non-alcoholic fatty liver disease (NAFLD), is now the most common cause of chronic liver disease in affluent countries.

NAFLD describes a spectrum from steatosis (fat in the liver) to steatohepatitis (fat with inflammation - non-alcoholic steatohepatitis, NASH) through to inflammation with fibrosis, to cirrhosis and primary liver cancer.


NAFLD is the most common cause of chronic liver disease

The population prevalence of NAFLD has been estimated at 35 per cent, with the more severe stage of NASH at 3.5 per cent. Given that the primary driver for NAFLD is obesity, the prevalence of NAFLD is predicted to rise.1,2

Besides obesity, type-2 diabetes is also associated with NAFLD, and rates are higher with more severe stages of the disease. Other metabolic disorders such as hyperlipidaemia and hypertension are also well-described risk factors.

Type-1 diabetes is not associated with NAFLD.2 The presence of deranged LFTs and an appearance of fatty infiltration on ultrasound in the context of type-1 diabetes is usually secondary to increased glycogen storage driven by poor glycaemic control and referred to as Mauriac's syndrome or glycogenic hepatopathy.

NAFLD is believed to be the liver's manifestation of the metabolic syndrome. Insulin resistance, in association with obesity, is the key mechanism leading to hepatic steatosis. Resistance to insulin enhances peripheral lipolysis and delivery of free fatty acids to the liver.

Insulin resistance has been referred to as the first hit in the pathogenesis of NAFLD. Insulin resistance then leads to defective fatty acid oxidation in the hepatic mitochondria, reduced export of triglycerides and increased de novo synthesis of triglycerides within the liver.

The second hit is the increased oxidant stress secondary to increased lipid peroxidation and the increase in pro-fibrogenic and pro-inflammatory cytokines. Consequent hepatocyte death and an unchecked repair-regenerative response including fibrosis can then progress to architectural distortion (cirrhosis) and carcinogenesis.3,4

Recreational drugs such as cannabis may enhance the progression of NAFLD.

Section 2: Diagnosis
NAFLD is largely asymptomatic until the disease is fairly advanced. Symptoms, when they occur, include right upper quadrant pain and fatigue. On examination there may be hepatomegaly and right upper quadrant tenderness.

Palmar erythema, jaundice, spider naevae, gynaecomastia, ascites or splenomegaly may be present if cirrhosis develops.

Besides a biochemical profile indicative of NAFLD, a history excluding excessive alcohol, currently defined as <18 units per week for men and <9 units per week for women,5 plus serological exclusion of other liver diseases is mandatory.

The diagnosis of NAFLD is therefore to be suspected in patients with recognised risk factors, elevated liver enzymes or evidence of fatty liver on ultrasound or CT and negative serology.

Blood tests
NAFLD is usually detected by laboratory tests, which often show a raised alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT) and alkaline phosphatase (ALP).

ALT and AST levels are not usually above three to five times the upper limit of normal and are usually correlated with the degree of liver inflammation and the presence of NASH.

There is increasing evidence that NASH can be seen in patients with normal transaminases. In this regard the upper limits of normal from many laboratories are deemed too high and the American Association for the Study of the Liver Diseases recommends an upper limit of 19 - women and 30 - men: the so-called '1930 rule'.6

Several imaging techniques can detect the presence of steatosis. The preferred method for screening is ultrasonography. It is the most cost-effective modality and detects steatosis with a sensitivity of 66-100 per cent.

Ultrasound sensitivity decreases significantly if the degree of fat infiltration is less then 30 per cent. NAFLD is defined by fat accumulation in the liver exceeding 5-10 per cent. Therefore, the absence of hyper-echogenicity, reflective of fat, on ultrasound does not always exclude the presence of NAFLD.

CT has about the same sensitivity and specificity as ultrasonography but is more expensive.

Magnetic resonance spectroscopy (MRS) has a lower limit of detection for steatosis, of about 5 per cent. However, MRS remains largely a research tool because of the expense and its restricted availability.

Fibroscan, an ultrasound-based imaging modality that assesses the degree of fibrosis presently offers limited utility in NAFLD because of its inaccuracy in obese patients.

The introduction of a new probe, that has recently become available might overcome this problem in the future, and make this non-invasive test a very appropriate tool in NAFLD diagnosis and management.6

A liver biopsy is considered mandatory both to confirm diagnosis and stage the disease.

Liver biopsy is an invasive test with potential complications; as it represents only 1/50,000 of the total mass of the liver it is therefore subject to sampling error.

Histological features of NAFLD include macrovesicular steatosis, an acute or chronic inflammatory cell infiltrate, ballooning degeneration of hepatocytes, Mallory's hyaline and on connective staining, peri-cellular fibrosis.

These features are also found in alcohol-induced liver disease and reinforce the importance of a non-excessive alcohol history.

Section 3: Management
There is at present no proven therapy for NAFLD. As a significant proportion of patients with NAFLD are obese, have type-2 diabetes or are dyslipidaemic, initial therapy is aimed at reducing obesity and insulin resistance.

Weight control
Lifestyle modification is the first and most sensible approach. Even a modest degree of weight loss is associated with enhanced insulin sensitivity and improvement of transaminases, hepatic steatosis, inflammation and fibrosis.

Too rapid or extreme weight loss has been associated with accelerated progression of NAFLD in some patients.

Ideally, controlled weight loss should be the result of a planned, structured approach by a dedicated bariatric service including dieticians and psychologists/psychiatrists or, as necessary, endoscopic or surgical approaches.7

There is some evidence that orlistat and sibutramine are of benefit in NAFLD.8

Bariatric surgery is being increasingly performed as the prevalence of obesity continues to rise. Several studies have demonstrated its efficacy in improving steatosis, inflammation and fibrosis in patients with NAFLD. This option should be considered in patients with NAFLD and a BMI>35 kg/m2.

Other pharmacotherapies
Another therapeutic approach to NAFLD is aimed at reducing insulin resistance. Drugs commonly used to treat type-2 diabetes have been used in numerous trials to assess their efficacy in NAFLD.7

Metformin has been used in several trials with mixed results.

Thiazolidinediones (TZDs) such as pioglitazone and rosiglitazone also offer promise as treatments for NAFLD, although the use of these drugs might be limited by their side-effects.

Statins appear safe in NAFLD and have shown therapeutic benefit in small groups of patients.7

Finally, there is emerging evidence from in vivo laboratory studies that angiotensin- receptor blockers (ARBs) and alpha-1 receptor antagonists (ARAs) may slow the course to fibrosis in patients with NAFLD.9-11

Section: 4 Prognosis
NAFLD is no longer considered a benign condition. Studies have clearly shown that patients with steatosis can progress to a more advanced stage of the disease (steatohepatitis and cirrhosis).

The natural history of NAFLD is imprecisely known but probably the best longitudinal study is from two Scandinavian hospitals, with a mean follow-up of 14 years.12

This study showed that steatosis progresses but with a low risk of cirrhosis and that NASH progresses more aggressively: about 20 per cent of the patients with NASH at inception of the study progressed to cirrhosis over the follow-up period.

Conversely, although none of the hepatosteatosis group progressed to cirrhosis, there was some progression to a more severe stage of fibrosis in about half of these patients. This finding implies that a still unknown proportion of patients with hepatosteatosis will probably progress to cirrhosis.

CVD risk
Several studies have also shown that the survival of patients with NASH is lower than that of the general population.13 The risk of cardiovascular disease is increased in NAFLD and is the leading cause of death in these patients.

This is not to denigrate the importance of liver-related mortality because in one of these studies liver disease was the third leading cause of death in patients with NAFLD compared with 13th in the general population.12

The risk of hepatocellular carcinoma has also been shown to be increased in patients with NAFLD.14 Although certain risk factors, such as diabetes or morbid obesity, appear to be associated with more advanced liver disease, what determines clinical outcome is not yet entirely clear, although hypertension and increased circulating cathecholamines may be an important contender.

In conclusion, NAFLD as a cause of chronic liver disease is increasing in prevalence in tandem with rising rates of obesity. Its trajectory is not benign and it may lead to endstage liver disease with cirrhosis and hepatocellular cancer.

Staging the disease with a liver biopsy offers the best chance of directed robust intervention, especially as there are emerging safe therapies including metformin, TZDs, ARBs and ARAs.


1. Zaninotto P, Head J, Stamatakis E et al. Trends in obesity among adults in England from 1993 to 2004 by age and social class and projections of prevalence to 2012. J Epidemiol Community Health 2008; Dec 11 (Epub ahead of print).

2. Lazo M, Clark J M. The epidemiology of nonalcoholic fatty liver disease: a global perspective. Semin Liver Dis 2008; 28(4): 339-50.

3. Day C P, James S. Steatohepatitis: a tale of two "hits"? Gastroenterology 1998; 114: 842-5.

4. Jou J, Choi S S, Diehl A M. Mechanisms of disease progression in nonalcoholic fatty liver disease. Semin Liver Dis 2008; 28(4): 370-9.

5. National Institutes of Health USA, NASH Clinical Research Network.

6. Wieckowska A, Feldstein A. Diagnosis of nonalcoholic fatty liver disease: invasive versus noninvasive. Semin Liver Dis 2008; 28(4): 386-95.

7. Kashi M R, Torres D M, Harrison SA. Current and emerging therapies in nonalcoholic fatty liver disease. Semin Liver Dis 2008; 28(4): 396-406.

8. Clark J M. Weight loss as a treatment for nonalcoholic fatty liver disease. J Clin Gastroenterol 2006; 40: S39-43.

9. Hirose A, Ono M, Saibara T et al. Angiotensin II type 1 receptor blocker inhibits fibrosis in rat nonalcoholic steatohepatitis. Hepatology 2007; 45: 1,375-81.

10. Oben J A, Diehl A M. Sympathetic nervous system regulation of liver repair. Anatomical Record 2004; 280A: 874-83.

11. Oben J A, Roskams T, Li Z et al. Hepatic fibrogenesis requires sympathetic neurotransmitters. Gut 2004; 53(3): 438-45.

12. Adams L A, Lymp J F, St Sauver J et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 2005; 129: 113-21.

13. Ekstedt M, Franzen L E, Mathiesen UL et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2006; 44: 865-73.

14. El-Serag H B, Tran T, Everhart J E et al. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 2004; 126: 460-8.

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