Growing Burden of Metabolism-Associated Fatty Liver Disease

It always seemed odd to be diagnosed with both alcoholic liver disease and non-alcoholic fatty liver disease (NAFLD) in the same person. When cirrhosis is diagnosed in a person 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 new nomenclature proposed by an international consensus expert group led by Australian researchers in 2020. Because the term NAFLD implies a diagnosis of exclusion, it is difficult to fully characterize liver disease in patients with metabolic risk factors who also have another cause of liver injury, such as harmful consumption of alcohol, chronic viral hepatitis or autoimmune liver disease. Additionally, the term NAFLD implies a milder form of liver disease than that caused by alcohol and has been associated with the stigma of people with alcohol-related liver disease.

With increased knowledge of its pathogenesis, MAFLD is a term that recognizes a distinct clinical entity that is diagnosed on its own merits, independent of other liver diseases. This represents a paradigm shift in how clinicians now approach disease.

MAFLD is the hepatic manifestation of excessive lipid accumulation due to underlying metabolic dysregulation and is often associated with obesity, hypertension, dyslipidemia, type 2 diabetes mellitus and insulin resistance . A positive diagnosis of MAFLD can now be easily made in people with signs of fatty liver disease in the setting of overweight/obesity or type 2 diabetes. It can also occur in lean or healthy weight people with at least two metabolic risk factors. Notably, MAFLD can be diagnosed independently of alcohol consumption or concurrent liver disease.

MAFLD is the most common cause of chronic liver disease worldwide and is estimated to affect a quarter of the world’s population. The the incidence of MAFLD has increased in Australia over the past three decades and is associated with increased liver-related morbidity and mortality. There are few data regarding the prevalence of MAFLD in Australia, but two recent population-based studies reported a prevalence of 37–47% (here and here). Metabolic dysregulation leading to MAFLD is associated with multiple chronic diseases, including cardiovascular disease (the most common cause of death in people with MAFLD), chronic kidney disease and extrahepatic cancers. The increase in 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 on the rise and is expected to increase by 75% by 2030.

In short, MAFLD is evolving into a major public health challenge, with its high prevalence, its links to other chronic diseases, and its risk of progressive liver injury and liver cancer.

MAFLD encompasses a continuum of disease from simple fatty liver disease (steatosis) to steatohepatitis, fibrosis, and cirrhosis. Thus, the clinical presentation can vary widely from abnormal ultrasound with fatty infiltration, mild asymptomatic elevations of liver enzymes, to diagnosis at the time of complications from cirrhosis or liver cancer. It is a tragedy to be diagnosed with advanced liver cancer in a person who had had clear risk factors and signs of liver disease for many years, but was never fully evaluated or offered treatment, follow-up or monitoring.

It is therefore imperative that patients with MAFLD are identified early in multiple clinical settings, including general practice and in diabetes and obesity wards, so that significant fibrosis can be identified and strategies implemented to prevent the progression of fibrosis and screen for complications.

A patient with severe obesity or type 2 diabetes has a 70% chance of having fatty liver disease (here, here and here). When both are present, more than 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 taken as confirmation. In all patients with abnormal liver enzymes, contributory causes of liver disease, including chronic viral hepatitis and harmful alcohol use, 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 main risk factors for MAFLD (obesity and type 2 diabetes) should be evaluated for the severity of fibrosis.

An initial evaluation 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 index-4 (FIB-4) can be determined using a online calculator or smartphone app. A FIB-4 score ≤ 1.3 excludes advanced fibrosis. These patients are at risk for non-hepatic complications of metabolic dysfunction, which should be the focus of management, and do not require specialized liver assessment. A FIB-4 score ≥ 2.67 suggests advanced fibrosis, and these patients should be referred to a liver clinic or specialist. Patients with an indeterminate score require further evaluation 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 not available, shear wave elastography available on many ultrasound devices can be helpful in second line assessment.

When imaging-based assessment is not available, proprietary serum panels of fibrosis markers such as the enhanced liver fibrosis (ELF) test or hepascore can effectively rule out advanced fibrosis (here and here). Unfortunately, these blood panels are currently not funded under the Medical Benefits Schedule. Commonwealth funding of these surveys would allow for accurate risk stratification in a much larger number of people at risk of advanced fibrosis and cirrhosis in remote areas and areas of Australia. Referral to specialized liver services is advised for patients with indeterminate or advanced fibrosis or cirrhosis, or when concurrent liver disorders or liver cancer are suspected.

Hepatocellular carcinoma (HCC) is the fastest growing 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 monitoring using biannual ultrasound and serum α-fetoprotein (AFP) levels has a significant impact on the chances of accessing curative therapies and improving survival. Previously, more than 80% of HCCs occurred in patients with chronic viral hepatitis; however, with the widespread availability of effective treatments for hepatitis C and hepatitis B, the proportion of HCC associated with MAFLD is increasing. Patients with cirrhosis are most at risk of developing HCC and monitoring is strongly recommended.

However, 37% of HCCs associated with MAFLD occur in the absence of cirrhosis, posing a significant public health challenge given the large number of patients living with MAFLD in Australia. There are currently no guidelines recommending monitoring for HCC in patients with MAFLD who do not have cirrhosis. Unfortunately, when patients without cirrhosis develop HCC, it is too often a late presentation with no 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 drug therapies specifically for MAFLD, the cornerstone of therapy remains lifestyle intervention, including diet modification. Weight loss can lead to a reduction in liver fat content, resolution of steatohepatitis, and regression of fibrosis. These benefits are typically seen with at least 7-10% weight loss. A low-fat, low-carbohydrate, or Mediterranean-style diet is recommended, along with regular moderate to vigorous exercise, smoking cessation, and the reduction or avoidance of alcohol consumption. Adjunctive pharmacotherapy for weight loss should be considered.

As in other metabolic disorders, dietary interventions are particularly challenging due to the ease of access and affordability of energy-dense and ultra-processed foods and beverages, and the rising prices of fresh foods. . Along with dietary intervention, aggressive management of cardiometabolic risk factors such as diabetes, hyperlipidemia, and hypertension is essential.

Currently, there is no consensus on the optimal strategy for the long-term follow-up of MAFLD patients. Since the progression of fibrosis in MAFLD alone is slow, it was suggested that MAFLD patients without fibrosis can be followed with noninvasive scores such as FIB-4 at 2-3 year intervals in the absence of worsening metabolic risk factors. Patients with advanced fibrosis or double liver disease should be monitored annually and referred for hepatology advice. People with cirrhosis should be monitored biannually for liver cancer and should be evaluated for other complications, including esophageal varices and hepatic decompensation.

The prevalence of MAFLD is increasing, leading to immense health and economic consequences. Prevention policy, community engagement and health care delivery focused on the underlying risk factors and growing burden of MAFLD and its complications will be paramount in managing the MAFLD epidemic.

Dr Rachael Jacob is a Fellow in Hepatology at the AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital.

Associate Professor Simone Strasser is Senior Personnel Specialist at the AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital and Director of the Liver Foundation.

Statements or opinions expressed in this article reflect the views of the authors and do not necessarily represent the official policy of WADA, the MJA Where Preview+ unless otherwise stated.

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