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IT always seemed odd to make a diagnosis of both alcoholic liver disease and non-alcoholic fatty disease (NAFLD) in the same person. When cirrhosis is diagnosed in someone who drinks six schooners of beer a day, and has both type 2 diabetes and class 2 obesity, how should we describe the underlying cause?
“Metabolic (dysfunction)-associated fatty liver disease (MAFLD)” is the novel nomenclature proposed by an expert international consensus panel led by Australian researchers in 2020. Because the term NAFLD implies a diagnosis of exclusion, it is challenging to fully characterise liver disease in patients with metabolic risk factors who also happen to have another cause of liver injury such as harmful alcohol use, chronic viral hepatitis or autoimmune liver disease. Furthermore, the term NAFLD implies a less serious form of liver disease than that due to alcohol, and has been associated with stigmatisation of those with alcohol-related liver disease.
With increased knowledge of its pathogenesis, MAFLD is a term that recognises a distinct clinical entity that is diagnosed on its own merits, irrespective of other liver diseases. This represents a paradigm shift in the way clinicians now approach the disease.
MAFLD is the hepatic manifestation of excessive lipid accumulation due to underlying metabolic dysregulation and is often associated with obesity, hypertension, dyslipidaemia, type 2 diabetes mellitus, and insulin resistance. A positive diagnosis of MAFLD can now be easily made in individuals with evidence of hepatic steatosis in the setting of overweight/obesity or type 2 diabetes. It can also occur in lean or healthy weight individuals with at least two metabolic risk factors. Notably, MAFLD can be diagnosed irrespective of alcohol consumption or concomitant liver diseases.
MAFLD is the most common cause of chronic liver disease worldwide and is estimated to affect a quarter of the world’s population. The incidence of MAFLD has been increasing in Australia over the past three decades and is associated with increasing liver-related morbidity and mortality. There have been limited data regarding the prevalence of MAFLD in Australia, but two recent population-based studies reported a prevalence of 37–47% (here and here). The metabolic dysregulation leading to MAFLD is associated with multiple chronic diseases including cardiovascular disease (the commonest cause of death in people with MAFLD), chronic kidney disease, and extrahepatic cancers. The increasing prevalence is alarming, given that MAFLD now represents one of the most common indications for liver transplantation in many countries, including Australia and New Zealand. MAFLD-related liver cancer is also rising and is projected to increase by 75% by 2030.
In short, MAFLD is evolving into a major public health challenge, with its high prevalence, links with other chronic diseases, and its risk for progressive liver injury and liver cancer.
MAFLD encompasses a disease continuum from simple fatty liver (steatosis) to steatohepatitis, fibrosis and cirrhosis. As such, the clinical presentation can vary considerably from an abnormal ultrasound with fatty infiltration, mild asymptomatic elevations of liver enzymes, to diagnosis at the time of complications of cirrhosis or liver cancer. It is a tragedy to diagnose advanced liver cancer in someone who clearly had risk factors and evidence of liver disease for many years, but was never fully assessed or offered treatment, monitoring or surveillance.
It is therefore imperative that patients with MAFLD are identified early in multiple clinical settings including general practice and in diabetes and obesity services, so that significant fibrosis can be identified and strategies implemented to prevent fibrosis progression and to screen for complications.
A patient with severe obesity or type 2 diabetes has a 70% chance of having fatty liver (here, here and here). When both are present, over 90% of people will have MAFLD. Therefore, in the setting of significant metabolic dysfunction, MAFLD is likely to be present, and abnormal liver enzymes or liver ultrasound can be regarded as confirmatory. In all patients with abnormal liver enzymes, contributing causes to liver disease including chronic viral hepatitis and harmful alcohol consumption should be excluded.
The stage of hepatic fibrosis is the most important determinant of liver-related morbidity and mortality and, therefore, all patients with a diagnosis of MAFLD or with the key risk factors for MAFLD (obesity and type 2 diabetes) should be assessed for the severity of fibrosis.
An initial assessment can be easily performed using readily available blood tests to rule out significant fibrosis. Using the patient’s age, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and platelet count, a Fibrosis-4 (FIB-4) Index can be determined using an online calculator or a smart phone application. An FIB-4 score of ≤ 1.3 rules out advanced fibrosis. Such patients are at risk of non-hepatic complications of metabolic dysfunction, which should be the focus of management, and do not require specialist liver assessment. An FIB-4 score of ≥ 2.67 suggests advanced fibrosis, and these patients should be referred to a liver clinic or specialist. Patients with an indeterminate score require further assessment with transient elastography (FibroScan [Echosens]). Although it is the best validated test in this setting, transient elastography is not widely available outside of liver clinics. If it is unavailable, shear wave elastography available on many ultrasound machines may be helpful in second line assessment.
Where imaging-based assessment is not available, patented serum panels of fibrosis markers such as the enhanced liver fibrosis (ELF) test or hepascore can effectively exclude advanced fibrosis (here and here). Unfortunately, these blood panels are not currently funded on the Medical Benefits Schedule. Commonwealth funding of these investigations would enable accurate risk stratification in a much larger number of people at risk for advanced fibrosis and cirrhosis in regional and remote Australia. Referral to specialist liver services is recommended for patients with indeterminate or advanced fibrosis or cirrhosis, or when concurrent liver disorders or liver cancer are suspected.
Hepatocellular carcinoma (HCC) is the most rapidly rising cause of cancer death in Australia. It also has one of the lowest survival rates, with only 22% of patients surviving 5 years. Early diagnosis through surveillance using 6-monthly ultrasound and serum α-fetoprotein (AFP) levels has a dramatic impact on the chance of accessing curative therapies and improving survival. Previously over 80% of HCC occurred in patients with chronic viral hepatitis; however, with widespread availability of effective treatments for hepatitis C and hepatitis B, the proportion of MAFLD-associated HCC is rising. Patients with cirrhosis are at highest risk of developing HCC and surveillance is strongly recommended.
However, 37% of MAFLD-associated HCC occurs in the absence of cirrhosis, posing a significant public health challenge considering the large number of patients living with MAFLD in Australia. There are currently no guidelines recommending HCC surveillance in patients with MAFLD who do not have cirrhosis. Sadly, when patients without cirrhosis develop HCC, it is too commonly a late presentation without curative treatment options.
With the growing burden of MAFLD, GPs have a crucial role in long term management to prevent complications. As there are no approved pharmacotherapies specifically for MAFLD, the cornerstone of therapy remains lifestyle intervention including dietary modification. Weight loss can result in reduction of liver fat content, resolution of steatohepatitis and regression of fibrosis. These benefits are typically seen with weight loss of at least 7–10%. A low fat, low carbohydrate or Mediterranean style diet is recommended, along with regular moderate or vigorous physical exercise, smoking cessation, and reduction or avoidance of alcohol consumption. There should be consideration to adjunctive weight loss pharmacotherapy.
As in other metabolic disorders, dietary interventions are particularly challenging with the ease of access and affordability of energy-dense and ultraprocessed foods and beverages, and rising prices for fresh foods. Along with dietary intervention, aggressive management of cardiometabolic risk factors such as diabetes, hyperlipidaemia and hypertension are essential.
Currently, there is a lack of consensus on the optimal strategy for long term monitoring of MAFLD patients. Given fibrosis progression in MAFLD alone is slow, it has been suggested that MAFLD patients without fibrosis can be monitored with non-invasive scores such as FIB-4 at intervals of 2–3 years in the absence of worsening metabolic risk factors. Patients with advanced fibrosis or dual liver diseases should be monitored annually and be referred for hepatology opinion. Those with cirrhosis should have 6-monthly liver cancer surveillance and should be assessed for other complications including oesophageal varices and hepatic decompensation.
The prevalence of MAFLD is rising, bringing with it immense health and economic consequences. Prevention policy, community engagement and health care delivery focusing on the underlying risk factors and the increasing burden of MAFLD and its complications will be paramount in managing the MAFLD epidemic.
Dr Rachael Jacob is a hepatology Fellow at the AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital.
Associate Professor Simone Strasser is Senior Staff Specialist at the AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, and Director of the Liver Foundation.
The statements or opinions expressed in this article reflect the views of the authors and do not necessarily represent the official policy of the AMA, the MJA or InSight+ unless so stated.
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