Nonalcoholic Fatty Liver Disease

 

Essentials

Nonalcoholic fatty liver disease (NAFLD) - also known as nonalcoholic steatohepatitis - is the commonest liver disorder in the developed world, affecting 20 to 30% of Western adults. It comprises a spectrum of disease ranging from simple steatosis through nonalcoholic steatohepatitis (NASH) to fatty fibrosis and ultimately cirrhosis. It is a manifestation of the metabolic syndrome, strongly associated with obesity, insulin resistance, and dyslipidaemia, with dietary and genetic factors determining susceptibility to the disease and its progression.

Most patients present with incidentally found abnormal liver blood tests. Diagnosis is usually one of exclusion: liver biopsy is not required for diagnosis in a typical patient, but is required for disease staging. Treatment is directed at components of the metabolic syndrome: diet and exercise have been shown to reduce steatosis; metformin and pioglitazone can have beneficial effects on steatosis, inflammation and fibrosis in patients with type 2 diabetes; pharmacological antiobesity agents and other treatments are under evaluation.

 

Nonalcoholic fatty liver disease (NAFLD) in detail - technical article

Introduction

Nonalcoholic fatty liver disease (NAFLD) is considered to be the commonest liver disorder in Western countries. It comprises a disease spectrum ranging from simple steatosis through nonalcoholic steatohepatitis (NASH) to fatty fibrosis and ultimately cirrhosis. It is strongly associated with obesity, insulin resistance, and dyslipidaemia and is now regarded as the liver manifestation of the metabolic syndrome.

Epidemiology

The prevalence of NAFLD appears to be around 20 to 30% in Western adults, with around 1 in 10 of NAFLD patients having NASH. The prevalence of NAFLD is much higher in obesity and type 2 diabetes, with recently reported prevalences of 90% and 70% respectively. There are no accurate data regarding temporal changes in the prevalence of NAFLD; however, the rising prevalence of obesity, diabetes, and the metabolic syndrome seems likely to be reflected in an increasing prevalence of NAFLD. This trend is of particular concern in the paediatric population where the prevalence of NAFLD has been reported to be as high as 50% in obese children, and primary school children with NAFLD-related cirrhosis have already been reported.

Natural history of NAFLD

The long-term hepatic prognosis of patients with NAFLD depends on the histological stage of disease at presentation. Among patients with simple steatosis 12–40% will develop NASH with early fibrosis after 8–13 years follow-up. Of patients presenting with NASH and early fibrosis, around 15% will develop cirrhosis and/or evidence of hepatic decompensation over the same time period. About 7% of subjects with compensated cirrhosis associated with NAFLD will develop a hepatocellular carcinoma (HCC) within 10 years, while 50% will require a transplant or die from a liver-related cause. NAFLD is becoming one of the most common indications for liver transplantation in the United Kingdom and the United States of America. The overall survival of patients with NAFLD is less than that of an age- and sex-matched population with liver disease the third leading cause of death in NAFLD patients compared to the thirteenth leading cause in a general population.

Clinical presentation

NAFLD is a largely asymptomatic condition. Right upper quadrant discomfort, fatigue, and lethargy have been reported in up to 50% of patients but are uncommon modes of presentation. Most patients with NAFLD are diagnosed after they are found to have hepatomegaly, or more commonly, unexplained abnormalities of liver blood tests performed as part of routine health checks or during drug monitoring (e.g. statin therapy). NAFLD is the commonest cause of incidental abnormal liver blood tests, accounting for between 60 and 90% of such cases. Importantly, the vast majority (c.80%) of patients with NAFLD have normal liver blood tests. NAFLD should therefore be suspected and sought in all patients with established risk factors, regardless of liver blood tests. These risk factors include the presence of polycystic ovary syndrome and obstructive sleep apnoea, both of which have been associated with NAFLD. History is based on determining the presence/absence of conditions associated with NAFLD and excluding alternative causes of steatosis including excess alcohol intake, previous abdominal surgery, and drugs such as amiodarone and tamoxifen.

Investigation

Blood tests are aimed at detecting associated conditions and excluding alternative causes of abnormal liver blood tests. Serum ferritin is often raised in NAFLD patients and has been associated with advanced fibrosis. HFE genotyping should be carried out when hyperferritemia is associated with raised transferrin saturation. Currently available imaging modalities, including ultrasound, CT, and MRI, are all excellent at detecting steatosis but none can reliably detect NASH or fibrosis. Newer imaging techniques, including proton magnetic resonance spectroscopy and transient elastography, show promise but require further study prior to routine use for disease staging. Liver biopsy is not required for diagnosis in a typical patient with classical risk factors and compatible imaging although may be required when other blood tests suggest an alternative or coexistent diagnosis. The main indication to perform a biopsy is accurate disease staging since (1) different stages have different prognoses and therefore require different management strategies, and (2) no currently available imaging techniques can perform this role. Clinical or laboratory features associated with advanced disease include advanced age (>45 years), body mass index more than 30 kg/m2, type 2 diabetes, serum aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio greater than 1, hyperferritinaemia, and positive autoantibodies At present, it would therefore seem reasonable to restrict liver biopsy to patients with at least some, if not all, of these risk factors. Some of these factors have recently been combined together with platelet count and serum albumin into a NAFLD fibrosis ‘score’ which accurately predicts the presence or absence of advanced disease in the majority of patients, and a recent serum test capable of accurately identifying the presence of NASH has also been described.

Management strategy for NAFLD

Almost no large randomized controlled trials (RCTs) have been published on which to establish evidence-based treatment recommendations for NAFLD. Accordingly, current management strategies are directed at treating, where present, the individual components of the metabolic syndrome since this will reduce risk of cardiovascular disease and may also be beneficial for the liver. This is particularly important in light of recent evidence that NAFLD may be an independent risk factor for cardiovascular disease in patients with obesity and type 2 diabetes. Alcohol intake should not exceed ‘sensible’ limits. In view of their largely benign prognosis, these strategies are all that is required for patients with simple steatosis who can be managed by general or primary care physicians. In contrast, patients with more advanced NAFLD require long-term follow-up by gastroenterologists/hepatologists in light of their increased propensity for disease progression. These patients will also be candidates for emerging second-line therapies currently being evaluated in large RCTs. The rationale for NAFLD therapies is based on a growing understanding of disease pathogenesis with a particular focus on reducing insulin resistance, hepatic free fatty acid levels, and oxidative, endoplasmic reticulum and cytokine-mediated stress; and also influencing the balance and effects of profibrotic, proinflammatory and antifibrotic, anti-inflammatory adipokines released from adipose tissue.

Treatment of obesity with diet and exercise is the first-line therapy and has been shown to reduce steatosis with less effect on inflammation and fibrosis. Encouraging results have been reported for gastric bypass and banding surgery with studies with longer follow-up reporting improvements in necroinflammation and fibrosis as well as steatosis. Pharmacological antiobesity agents are currently under evaluation. For patients with associated type 2 diabetes, insulin-sensitizing agents including metformin and glitazones would be the rational choice given their mode of action. Small RCTs of metformin and pioglitazone have recently reported beneficial effects on steatosis, inflammation, and fibrosis. There is, as yet, no evidence that any particular lipid-lowering agents are beneficial for NAFLD although there is considerable evidence that statin therapy is safe.

With respect to treatments directed primarily at the liver rather than the associated metabolic syndrome, there have been encouraging pilot studies with antioxidants and anticytokine agents, including pentoxifylline, though as yet no RCT-based evidence. Liver transplantation is successful for patients with NAFLD but the high risk of disease recurrence makes management of the metabolic syndrome a priority both prior to and following transplantation.