Non alcoholic fatty liver disease (NAFLD): a waist problem
Whilst liver disease is normally associated with alcohol abuse there has been a significant increase in non-alcoholic fatty liver disease, a disease sharing features with alcoholic liver disease, but which is caused by obesity and diabetes rather than by alcohol abuse. Dr Norma McAvoy, Dr Khalida Lockman and Professor Peter Hayes review the evidence in relation to this increasing health problem.
- Non-alcoholic fatty liver disease (NAFLD) is a condition sharing features with alcoholic liver diseases, but associated with obesity, insulin resistance and diabetes mellitus.
- NAFLD is recognised increasingly as obesity becomes more common and liver function tests increasingly used.
- The early stages of NAFLD are usually asymptomatic and diagnosis follows investigation of abnormal liver function tests, but progression of disease leads to the features of cirrhosis and portal hypertension.
- NAFLD may explain many instances of cirrhosis considered previously as of unknown cause.
- Treatment involves mainly weight loss using diet and exercise, but also drugs such as metformin.
Declaration of interests: No conflict of interests declared
WHAT IS NAFLD
Non alcoholic fatty liver disease (NAFLD) is the term used for the liver disorder similar to alcoholic liver disease which is seen in patients with the metabolic syndrome (MS) (see previous article ED: WHICH ARTICLE, INSERT LINK).1 The term NALFD is used to encompass the various stages of the disorder from fatty liver through non alcoholic steatohepatitis (NASH) to cirrhosis. Compared with five years ago when the diagnosis was unusual, it now represents the commonest referral to liver clinics. There are a number of reasons for this. Firstly, the increasing prevalence of obesity and sedentary lifestyle in the population; secondly, the widespread use of statins in patients with the metabolic syndrome coupled with checking liver function tests after the commencement of statin therapy to look for hepatotoxicity; thirdly, increased recognition of a formerly under-diagnosed disorder.
Liver function tests in patients with NAFLD are seldom grossly abnormal and since the condition is generally asymptomatic, it is easily overlooked. For example, in diabetic clinics it has long been recognised that liver function tests are often abnormal; generally, this was thought to be of little or no consequence and patients with type 2 diabetes were seldom referred or investigated. However, the recent recognition of a high prevalence of cirrhosis in patients with type 2 diabetes (around 16% in autopsy studies) indicates that this disorder is not benign. Also with effective treatments of other components of the metabolic syndrome, reducing the life-threatening cardiovascular complications, more patients are likely to survive long enough to develop cirrhosis and its complications.
WHO GETS IT
Non alcoholic fatty liver disease and the metabolic syndrome are closely intertwined, with obesity and type 2 diabetes being the most frequent associations. Hepatic steatosis is almost invariable in morbid obesity and more severe steatosis and advanced liver disease is associated with increased number of components of the metabolic syndrome.2 Although the majority of NAFLD patients are obese, a minority are thin or have a normal BMI and, in these individuals, genetic rather environmental factors probably play a key role. Non alcoholic fatty liver disease is not just a disease of the middle-aged or elderly, but is increasingly recognised in teenagers and in this setting may progress to cirrhosis over a relatively short period.
HOW DO WE DIAGNOSE NAFLD
Non alcoholic fatty liver disease is usually recognised during investigation of abnormal liver function tests particularly elevated serum alanine transaminases (ALT) although, in a minority, NAFLD may be present with normal LFT’s (See Table 1). It has recently been recognised that the normal reference range for transaminases is too high and the serum ALT in healthy women should be less than 19 IU/l and less than 30 IU/l in men.3 Application of these new upper limits of normal would obviously result in many more patients being recognised with abnormal LFT’s. Application of these ALT limits to our type 2 diabetes mellitus population, resulted in 72% of patients having abnormal liver function tests compared with 46% using standard criteria.
Patients with abnormal liver function tests, even in the presence of the metabolic syndrome, should undergo a liver screen to exclude viral, autoimmune and other metabolic disorders of liver disease, including identification of alcohol abuse. Ultrasonography usually identifies a bright liver (increased echogenicity) reflecting increased fat content within the liver. Since all patients have insulin resistance a fasting glucose and insulin should be assayed and used to determine the Homeostatis Model Assessment of Insulin Resistance (HOMA-IR index). Formerly, liver biopsy was considered a prerequisite for the diagnosis but this has now been called into question. Firstly, the reliability of staging liver disease by liver biopsy in these patients has been shown to be variable when two biopsies have been taken4 and secondly, the use of fibrosis markers, such as hyaluronic acid, have been shown to be helpful in staging the severity of fibrosis. Liver biopsy is obviously still necessary where there is diagnostic doubt; for example, in approximately one third of patients autoantibodies are present in the blood and liver biopsy is generally required to exclude underlying autoimmune chronic hepatitis.
WHY IS RECOGNITION OF NAFLD IMPORTANT
The natural history of NAFLD remains somewhat unclear. Rather like alcoholic liver disease and hepatitis C, many patients who have steatosis do not go on to develop cirrhosis and identifying those patients who do progress is a clinical challenge. Once cirrhosis has developed, the natural history of NAFLD is regarded as similar to other causes of cirrhosis with complications arising secondary to portal hypertension, liver failure and hepatocellular carcinoma.
The pathogenesis of NAFLD remains to be fully understood, but it is clear that a number of factors including insulin resistance (both peripheral and hepatic) and dysregulation of fatty acid metabolism by hepatocytes and adipocytes are important. Fatty livers are more susceptible to injury and the involvement of a second hit, related to free radical production and the generation of reactive oxygen species has been emphasised. Mitochondrial dysfunction and the role of adipocytokines, particularly low levels of adiponectin and high levels of tumour necrosis factor alpha are thought to be important.
TREATMENT OF NAFLD
Unfortunately in this area there have been few randomised controlled trials. Treatment approaches that have been tried have been reported as being successful in improving liver function tests and liver histology. These include dietary manipulation and weight loss (see Table 2), increasing exercise and the use of insulin sensitising agents such as Metformin and piogliclazones (see Table 3). Metformin is the agent that has been most studied and its use is associated with improvement of liver function tests, weight loss, improvement in insulin resistance and improved histology. The use of drugs such as the angiotensin receptor blocker Losartan has been shown to improve transaminases and histology in patients with NAFLD. Further randomised trials are essential to allow evidence based treatment.
Non alcoholic fatty liver disease is the hepatic manifestation of the metabolic syndrome. It is common, under-diagnosed and increasing in prevalence, generally asymptomatic and may progress through steatosis to NASH to cirrhosis undiagnosed and present with such complications as variceal haemorrhage, liver failure or hepatocellular carcinoma. It is usually, although not invariably, associated with features of the metabolic syndrome, and more severe NAFLD is seen in patients as they show increasing components of the metabolic syndrome. The pathogenesis remains to be fully understood but insulin resistance appears to be the driving force. Reducing insulin resistance and treating the components of the metabolic syndrome appears to improve NAFLD but there is a clear need for prospective randomised controlled trials in this area. A multidisciplinary approach to treating NAFLD and its related co-morbidity is essential.
- Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults. 2001 Executive summary of the Third Report of the National Cholesterol Education program (VCEP). Expert panel on Detection, Evaluation and Treatment of High Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001; 285:2484-2497.
- Angelico F, Del Ben M, Conti R et al. Insulin resistance, the metabolic syndrome, and non alcoholic fatty liver disease. J Clin Endocrin Metab 2005; 90:1578-1582.
- Prati D, Taioli E, Zanella A et al. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med 2002; 137(1):1-10.
- Ratziu V, Charlotte F, Heurtier H et al. Sampling variability of liver biopsy in non alcoholic fatty liver disease. Gastroenterology 2005; 128(7):1898-906.