Section 1: Epidemiology and aetiology
Non-alcoholic fatty liver disease (NAFLD) is now widely recognised as the leading cause of liver dysfunction in affluent societies and is the most common cause of chronic liver disease worldwide.
NAFLD is associated with obesity, metabolic syndrome, insulin resistance and type 2 diabetes. As such, it is better described as obesity-induced liver disease.
NAFLD is a spectrum of disease, ranging from hepatosteatosis and non-alcoholic steatohepatitis (NASH), to cirrhosis and hepatocellular carcinoma.
NASH is the more severe stage of NAFLD and progresses more rapidly to cirrhosis than hepatosteatosis.1 The prevalence ranges from 10-24% in the general population, to 60-95% in obese patients.2 This is not evenly distributed among ethnic groups and the prevalence of NAFLD is higher in Hispanic than in white populations. It is lowest overall in African-American populations.3
As can be deduced from its prevalence among the obese population, the predominant cause of NAFLD is obesity, with incidence reflecting the current obesity epidemic. It is projected that within a decade or so, a greater number of patients will receive a transplant for endstage NAFLD than for endstage liver disease secondary to chronic hepatitis C, currently the most common reason for liver transplantation.4
A commonly accepted pathogenesis model for NAFLD is the 'two hit' hypothesis,5 where the first hit is an accumulation of fat within hepatocytes, inducing vulnerability to the second hit, oxidative stress culminating in necro-inflammation and fibrosis.6
Section 2: Making the diagnosis
When NAFLD was first described in 1980, it was noted that most of the patients were moderately obese, with many presenting with obesity-related diseases.
Consequently, NAFLD is commonly associated with many components of metabolic syndrome - obesity, insulin resistance and hyperlipidaemia.
NAFLD is now regarded as the hepatic manifestation of metabolic syndrome. On examination, some patients with NAFLD may have hepatomegaly and mild abnormalities of liver function. Most patients are, however, asymptomatic, although some may report right upper quadrant discomfort or general fatigue.
Owing to the lack of definitive symptoms, a diagnosis of NAFLD is usually only suspected following findings of abnormal LFTs on routine testing, or incidental discovery of a fatty liver on ultrasound scanning. Therefore, ALT levels and ultrasound scanning are the initial diagnostic tests usually performed in detecting NAFLD.
Magnetic resonance spectroscopy (MRS) is, however, considered the most sensitive test in detecting a fatty liver, although it is not cost-effective.7,8
The Dionysos study reported that in its Italian cohort, 55% of patients with NAFLD had normal ALT levels.9 More recently, another study reported that more than two-thirds of patients with NAFLD could have normal LFTs at any given time.8 Therefore, it is crucial that LFTs are not used in isolation when investigating possible cases of NAFLD.
Although NAFLD can be diagnosed clinically, histopathology remains the standard.6
To stratify the disease and obtain prognostic information, a liver biopsy is usually considered essential. On biopsy, the disease can be staged using the NASH Clinical Research Network Scoring System.
In this commonly used system, a score of ≥5 suggests probable or definite NASH, while a score of less than 3 indicates that NASH is unlikely.
Fibrosis is scored separately, with a fibrosis score of zero indicating no fibrosis, 3, bridging fibrosis, and 4, cirrhosis.
Owing to the invasive nature of liver biopsy, however, it carries the risk of complications such as bleeding, so it is unsuitable for use as a screening tool.
Additionally, it is not possible to perform repeated liver biopsies to monitor disease progression and response to therapy.
Consequently, studies are currently in progress to detect markers that reflect oxidative stress, inflammation and fibrosis.
Identification of these markers should enable clinicians to monitor disease activity non-invasively, distinguish NASH from NAFLD6 and improve patient care.
Section 3: Managing the condition
Lifestyle modification, with controlled weight reduction, is the initial step in the management of NAFLD.
A loss of 5-10% of the initial body mass is recommended and has been shown to improve liver enzyme levels, reduce hepatic inflammation and fibrosis, improve liver histology and ameliorate metabolic syndrome and its associated risks.10,11
However, given that it is difficult to achieve and maintain weight loss in patients with NAFLD, it is crucial that other treatments are sought.
In patients failing to achieve weight loss through lifestyle modification, bariatric surgery, including intragastric balloon, can be considered. Bariatric intervention has been shown to reduce hepatic steatosis and fibrotic changes.12-14
CT scan of a 66-year-old patient with fatty liver: lifestyle modification is the first step in management (Photograph: SPL)
Emerging evidence suggests that statins and fibrates may act to reverse histological changes in NAFLD.15 With a postulated pathogenic role for insulin resistance,16 insulin-sensitising agents such as glitazones and metformin have been investigated in NAFLD with some success.2,17
Additionally, there is some evidence demonstrating a role for vitamin E,17 which is thought to improve biochemical and histological parameters.
Previous studies have suggested a role for the ARB olmesartan as a putative antifibrotic agent in an experimental model of NASH,18 and the recently commenced Fibrosis Effects of Losartan in NASH Evaluation (FELINE)19 trial seeks to confirm the efficacy of the ARB losartan in patients with biopsy-proven NASH.
A more recent study confirmed that losartan in conjunction with the iron chelator deferasirox suppressed fibrogenesis and hepatocarcinogenesis in a NASH model.20
The prevalence of NAFLD continues to rise in tandem with increasing rates of obesity. NAFLD may lead to cirrhosis and a requirement for liver transplantation.
The implications for screening are worrying, given the prevalence of obesity and NAFLD. Besides targeting obesity and reducing metabolic syndrome in patients with NAFLD, emerging treatments targeting fibrosis include ARBs.
Section 4: Prognosis
Generally, patients who have unstratified NAFLD have a higher mortality compared with the general population and are at higher risk of developing obesity-related diseases, such as cardiovascular disease and diabetes.10
Studies in the US and Sweden have identified the predominant causes of death in patients with NAFLD to be cardiovascular, followed by malignancy and liver-related pathology.3,10,11,21
Patients with NASH have been documented as having increased mortality compared not only to the general population, but also to patients with hepatosteatosis.21
Progression to cirrhosis or severe fibrosis and risk of decompensation with loss of liver function is dependent on the stage of the disease at inception; that is, whether hepatosteatosis or NASH is present.1
Results from a study cohort in 2006 revealed that 10% of patients with NASH at baseline developed endstage liver disease during follow-up, whereas none of the patients with steatosis, with or without non-specific inflammation, developed complications related to chronic liver disease during follow-up.
Furthermore, there is an accepted risk of hepatocellular carcinoma (HCC) with cirrhosis, and evidence is emerging that NAFLD may progress to HCC independent of cirrhosis,22-24 with implications for screening. The documented increase in the rates of HCC in type 2 diabetes suggests the mediator may be NAFLD.25-27
There is also evidence that NAFLD acts synergistically with other risk factors for HCC, such as hepatitis C and alcoholic liver disease, further increasing rates of HCC in parallel with obesity.22
Section 5: Case study
A 42-year-old woman was seen in the liver clinic with a referral for deranged LFTs.
She had recently been diagnosed with type 2 diabetes after presenting to her GP with polydypsia, polyuria and recurrent thrush. A fasting glucose test confirmed diabetes and dietary control was started, with good resolution of symptoms.
The LFTs obtained by her GP as part of the initial routine blood tests showed bilirubin 23, ALP 130, ALT 57 and GGT 120.
ExaminationThe patient was asymptomatic and had no specific risk factors for liver disease. She took no medications or supplements. She smoked 25 cigarettes a day. She was a light social drinker (less than 10 units per week and denied illicit drug use there was no family history of liver disease.
On clinical examination, she was obese (BMI 39kg/m2), with a waist circumference of 97cm.
She was normotensive, with no stigmata of chronic liver disease and no evidence of an enlarged liver. Cardiovascular and respiratory examinations were unremarkable.
Subsequent further investigations included a full liver disease aetiology screen and abdominal ultrasound. The comprehensive liver disease aetiology screen (liver disease autoantibodies, hepatitis A, B and C, alpha-1- antitrypsin, iron and copper studies and alpha-fetoprotein) was normal.
Her abdominal ultrasound revealed a normal liver size, with a bright echotexture consistent with steatosis. No focal liver lesions were seen. Her spleen, kidneys and bladder were normal. Repeat LFTs revealed persistent abnormalities (bilirubin 22, ALP 126, ALT 86, GGT 134).
Based on the history and results of investigations, a diagnosis of NAFLD was made. To stratify her risk of progression, a liver biopsy was performed. This confirmed the diagnosis of NAFLD at NASH stage, with evidence of moderate fibrosis.
She was referred to a dietitian for weight loss advice. Not wishing to participate in a clinical trial, she was commenced off-label on losartan as a putative antifibrotic agent.
Section 6: Evidence base
- Kaji K, Yoshiji H, Kitade M et al. Combination treatment of angiotensin II type I receptor blocker and new oral iron chelator attenuates progression of nonalcoholic steatohepatitis in rats. Am J Physiol Gastrointest Liver Physiol 2011; 300(6): G1094-104.
The role of ARBs in conjunction with iron chelators is an emerging potential therapy in NASH.
- FELINE study: Fibrosis effects of losartan in NASH evaluation. More information available from: www.britishlivertrust.org.uk/home/research/get-involved-in-research/feline-trial.aspx
The role of ARBs is being investigated in theFELINE trial.
- Ratziu V, Bellentani S, Cortez-Pinto H et al. A position statement on NAFLD/NASH based on the EASL 2009 special conference. J Hepatol 2010; 53(2): 372-84.
- Matthew M, Yeh MD. Practical Hepatic Pathology: A Diagnostic Approach. Chapter 31. London, Elsevier, 2011.
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- Contributed by Rebeca Carter, Angelina Mouralidarane, Dr Junpei Soeda and Dr Jude Oben, University College London, Royal Free Hospital, London, and Dr Shuvra Ray, Guy's and St Thomas' Hospital, London.
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