INTRODUCTION

Fatty liver or steatosis refers to the accumulation of fat within the liver. The fatty liver disorders are the most common cause of disturbances of liver function tests in the Western world. While there are several causes of fatty liver, including that of excessive consumption of alcohol (see Chapter 40), the commonest cause is that of insulin resistance usually (but not always) associated with one or a combination of obesity, hyperlipidaemia and/or hyperglycaemia. Non-alcoholic fatty liver disease (NAFLD) is the term used to describe steatosis unrelated to excessive alcohol consumption. NAFLD is a form of metabolic liver disease nearly always associated with insulin resistance and very often with the metabolic, or insulin resistance (IR), syndrome.

NAFLD encompasses the entire pathological spectrum from bland steatosis to decompensated cirrhosis. It therefore includes:

The term non-alcoholic steatohepatitis (NASH) is defined by histological features resembling those of alcoholic hepatitis that are present in patients who have not consumed excessive quantities of alcohol. Most studies define the latter as alcohol consumption less than 20 g per day (i.e. less than 2 standard alcoholic drinks per day).

Natural history and prognosis

In the absence of steatohepatitis, NAFLD does not appear to cause fibrosis or progressive liver disease. In contrast, NASH may be associated with disease progression. The proportion of patients with NAFLD in the community who have cirrhosis is not known. Among those referred to liver clinics and selected for liver biopsy, the proportion with significant fibrosis is in the range of 20%–45%. NASH is a slowly progressing liver disorder. Factors associated with more severe disease include obesity, type 2 diabetes, age over 45 years and hypertriglyceridaemia. The role of gender is contentious. Some, studies have suggested that female gender is an independent risk factor for more severe liver disease.

Only those with advanced liver disease are likely to develop significant liver-related morbidity and mortality. Among those with cirrhosis, there is a risk of decompensation and liver failure.

Obesity and fatty liver disorders have been associated with the development of hepatocellular carcinoma, however the exact risk is not known. In a high proportion of patients with cryptogenic cirrhosis, the cirrhosis appears to be related to ‘burnt out’ NASH. That is, these patients fulfil the clinical profile of a patient with an underlying clinical profile of insulin resistance.

It is important to be aware that, as a consequence of insulin resistance, patients with NAFLD are at increased risk of type 2 diabetes mellitus and cardiovascular mortality.

CLINICAL PRESENTATION

The majority of patients are asymptomatic. They come to medical attention because of abnormal liver function tests or an incidental finding of diffusely increased echogenicity on hepatic ultrasound, which is suggestive of fatty liver. Patients may complain of fatigue and right upper quadrant discomfort. Some patients may have hepatomegaly. The consistency of the liver is usually firm, but not hard, and may be slightly tender. Peripheral stigmata associated with this form of liver disease are uncommon, and their presence may indicate the presence of cirrhosis.

A high proportion of patients have an elevated body mass index (BMI) and waist circumference. Patients of Asian background develop NAFLD at lower BMIs than their Caucasian counterparts.

PATHOGENESIS

Underlying insulin resistance favours lipolysis in adipose tissue with the release of free fatty acids. These are taken up by the liver and stored as lipid. In addition, there is increased lipid synthesis, reduced fat burning and reduced lipid export by the liver. The net effect is accumulation of fatty acids in hepatocytes. Fatty acids may directly injure liver cells or favour the development of oxidative stress and cytokine release. It is thought that genetic factors, at least in part, lead to individual susceptibility and disease severity.

DIAGNOSIS

NAFLD is a clinicopathological diagnosis that requires the exclusion of other liver disorders. In particular, significant alcohol consumption (>20 g ethanol per day) must be excluded. Other common conditions that need to be excluded are chronic viral hepatitis (B and C), drug-induced liver disease, haemochromatosis, Wilson’s disease and autoimmune liver disease. Certain drugs cause steatohepatitis (Table 39.3).

TABLE 39.3 Drugs that cause steatohepatitis

INVESTIGATIONS

MANAGEMENT

SUMMARY

NAFLD is already the most common cause of abnormal liver function tests in the Western world. This acronym includes bland steatosis, steatosis with inflammation and/or fibrosis. Obesity, hyperglycaemia and hyperlipidaemia are frequently associated with NAFLD. Therefore, it is not surprising that most patients with NAFLD have underlying insulin resistance. Furthermore, the prevalence of NAFLD is increasing, paralleling the rise in the obesity epidemic observed in the Western world. Patients usually come to medical attention because of the detection of elevated liver enzymes, particularly elevated transaminases with an ALT >AST (Figure 39.1). Liver ultrasound frequently reveals a pattern of increased echogenicity. It is important to be aware that patients with NAFLD have an increased prevalence of type 2 diabetes and cardiovascular disease. Investigations include the need to measure lipid and blood glucose levels. Liver biopsy is frequently performed to confirm the diagnosis of NAFLD, to differentiate steatosis from NASH and to stage the disease. A proportion of patients with NAFLD develop progressive liver disease, ultimately leading to the development of cirrhosis, hepatic decompensation and (less commonly) hepatocellular carcinoma. The basis of management is that of slow and steady weight loss with appropriate dietary measures and exercise. Hyperlipidaemia and hyperglycaemia may require pharmacotherapy including the use of HMG-CoA reductase inhibitors, fibrates, biguanides and thiazolidinediones.

FIGURE 39.1 Diagnosis of non-alcoholic fatty liver disease.

ALT = alanine aminotransferase; AST = aspartate aminotransferase; BMI = body mass index; HBV = hepatitis B virus; HCV = hepatitis C virus; NAFLD = non-alcoholic fatty liver disease; LFTs = liver function tests.