MAFLD – who and how should we screen?

13th February 2023, Dr Chee L Khoo

Steatosis

Now that I know how common metabolic-dysfunction associated fatty liver disease (MAFLD) is especially amongst those patients with elements of metabolic syndrome, it’s hard not to assume that every second patient have MAFLD. We also know that not all MAFLD has abnormal liver function tests (LFTs). So, if you only suspect or screen only those with abnormal LFts, then you are going to miss many MAFLD. We saw in the last issue that there are significant morbidity and mortality implications with the diagnosis and we don’t want to miss a MAFLD. So, who should we screen and how should we screen both for MAFLD and MAFLD with fibrosis or cirrhosis?

Universal screening for MAFLD has not reached a consensus, while the European guidelines have supported screening for MAFLD in high-risk patients with obesity (BMI > 30 kg/m2) or metabolic syndrome, the American Association for the Study of Liver Disease (AASLD) still argues the utility of routine screening for MAFLD in these high-risk subjects, due to the lack of cost-effective tests and an established effective pharmacologic treatment for the disease. However, new guidelines from the Asian-Pacific Association for the study of the Liver (APASL) developed new guidelines for the diagnosis and management for MAFLD, considering the new definition and criteria.

In the interim, who should we consider may have MAFLD? Because the core component in MAFLD is pretty much metabolic dysfunction, we should look at what that is. So, what is metabolic dysfunction? We could define metabolic health based on lipid profile, which measures four specific variables (including total cholesterol, triglycerides, high density lipoprotein (HDL)- and low density lipoprotein (LDL)-cholesterol levels) and the presence of insulin resistance. Patients with dyslipidaemia (especially hypertriglyceridaemia and low HDL) and diabetes or prediabetes nicely fit the bill.

The concept of metabolic healthy but obese has long been disbanded as the healthy obese isn’t healthy and harmless after all. Nonetheless, obesity without metabolic dysfunction may not quite suggest that MAFLD should be looked for. However, we must not forget our lean MAFLD. In a 2020 meta-analysis, the overall prevalence of non-obese MAFLD was calculated to be 40.8% among the MAFLD population and 12.1% in the general population (1). Interestingly, the same study showed that the overall liver- and cardiovascular-specific mortality rates were 12.1, 4.1 and 4 per 1000 person-years, respectively, in patients with lean MAFLD. By contrast, the rates were 7.5, 2.4 and 2.4 per 1000 person-years, respectively, among patients with obesity and MAFLD. In other words, lean MAFLD carries higher cardiovascular-specific mortality rates.

We could also consider MAFLD in patients with risk factors for metabolic syndrome. Patients with a family history of obesity, type 2 diabetes, dyslipidaemia (especially extreme dyslipidaemia), metabolic syndrome, cardiovascular diseases and gout have a higher risk of developing MAFLD whether obese or not. Women with or has a history of PCOS are essentially candidates with insulin resistance and hence, also have a higher likelihood of MAFLD. Oestrogen’s role in fatty liver development has been deeply studied, with interesting results suggesting a protective effect of oestrogens on women, as suggested by a study carried out in premenopausal, postmenopausal and women with polycystic ovarian syndrome (PCOS) (2). Men and women in lower oestrogen states would have increased risk and therefore more reason for MAFLD screening, when evaluated with other risk factors.

Ethnicity plays an important role in the stratification of patients at risk of developing MAFLD. This occurs as a result of genetic variations as well as the diversity of gut microbiome among different populations. As a broad example, the I148M (rs738409 C/G) mutation on the patatin-like phospholipase domain-containing 3 gene (PNPLA3) determines hepatic fat accumulation and progression of simple steatosis into steatohepatitis and fibrosis (3,4). Consequently, populations with increased expression of this variant have higher susceptibility to the development of MAFLD, such as the Hispanic population, while African-Americans constitute the group with least susceptibility and lowest PNPLA3 variant expression (5,6). Asians (especially south Asians) and Pacific Islanders are also in the high risk category.

How should we screen for MAFLD?

We may stumble across steatosis in our investigations for abnormal LFTs or when we were scanning something else. “By the way, there is mild steatosis” is not an infrequent side comment. Otherwise, abdominal ultrasound is generally the first-line screening tool for defining steatosis since it offers 67–94% sensitivity (depending of the degree of damage) and up to 97% specificity for hepatic steatosis, especially through bright liver echo pattern (7,8). However, ultrasound may not fare as well in assessing the degree of fibrosis.

Of course, if cost is not an issue, vibration-controlled transient elastography (VCTE also known as Fibroscan) or MRI will be more accurate in diagnosis and in quantifying fibrosis. Some of our local radiology providers also offer shear elastography at no extra cost to a normal abdominal ultrasound. We will explore the role of shear elastography in the assessment of liver fibrosis next month.

Serum biochemical markers is increasingly used to quantify liver tissue damage. They can come directly either from the turnover of the extracellular matrix (ECM) and fibrogenic cell changes or from an altered function of the liver. Traditional markers such as total cholesterol, triglycerides, measure of insulin resistance through HOMA and C-peptide have been used in the past but novel serum biochemical markers such as apolipoprotein A1, apolipoprotein B, leptin, adiponectin, ghrelin and tumour necrosis factor-alpha (TNF-α), have been proposed as valuable complementary tools alongside the traditional markers.

A marker of type III collagen formation, PRO-C3 is been evaluated as a marker of advanced fibrosis in MAFLD. PRO-C3 is used in the ADAPT algorithm to evaluate the disease progression (see below).

Fatty liver scores

There are a number of specific scores that combine different variables and biochemical markers for the evaluation of MAFLD. These scores range from the diagnosis of fatty liver to quantification of fibrosis:

  • Fatty liver index (FLI) – incorporates BMI, waist, GGT and triglycerides
  • APRI – AST:Platelet ratio index
  • NAFLD Fibrosis Score – incorporates fasting BSL, albumin, AST:platelet ratio index (APRI)
  • FIB-4 –
  • BARD – BMI, AST:ALT ratio and presence of Diabetes
  • ADAPT

Both the APRI and BARD may not perform well in lean MAFLD.

In summary, MAFLD is prevalent. Naturally, patients who have or at high risk of metabolic syndrome is very likely to have steatosis and if they do, they have MAFLD. Many but not all patients with obesity also have MAFLD. However, there are significant proportion MAFLD who are lean who probably carry a higher cardiorenal morbidity and mortality. Not all patients with MAFLD have abnormal LFTs. MAFLD is not just the flavour of the month for names but it makes steatosis a serious condition and it is worth making the diagnosis and raise the seriousness of the condition with your patient. It’s not “just a little fatty liver”.

Thus, a high index of suspicion is important to not miss a MAFLD. After diagnosis, one should consider assessing the degree of fibrosis. This can be done using one of those fibrosis score. Access to Fibroscan is limited but shear elastography might be a good compromise. MAFLD is associated with heightened cardiovascular mortality and diagnosis should lead to reappraisal of his/her cardiovascular risk. Treatment is not just targeting and managing the metabolic syndrome elements but also assessing and treating the CV risks. Next month, we will look at shear elastography.

References:

  1. Ye Q, Zou B, Yeo YH, et al. Global prevalence, incidence, and outcomes of non-obese or lean non-alcoholic fatty liver disease: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol 2020; 5: 739–752.
  2. Gutierrez-Grobe Y, Ponciano-Rodríguez G, Ramos MH, et al. Prevalence of non alcoholic fatty liver disease in premenopausal, posmenopausal and polycystic ovary syndrome women. The role of estrogens. Ann Hepatol 2010; 9: 402–409.
  3. Sookoian S, Pirola CJ. Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease. Hepatology 2011; 53: 1883–1894
  4. Li JZ, Huang Y, Karaman R, et al. Chronic overexpression of PNPLA3 I148M in mouse liver causes hepatic steatosis. J Clin Invest 2012; 122: 4130–4144.
  5. Romeo S, Kozlitina J, Xing C, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008; 40: 1461–1465.
  6. Chinchilla- López P, Ramírez -Pérez O, Cruz-Ramón V, et al. More evidence for the genetic susceptibility of Mexican population to nonalcoholic fatty liver disease through PNPLA3. Ann Hepatol 2018; 17: 250–255.
  7. Saverymuttu SH, Joseph AEA, Maxwell JD. Ultrasound scanning in the detection of hepatic fibrosis and steatosis. Br Med J 1986; 292: 13–15.
  8. Palmentieri B, de Sio I, La Mura V, et al. The role of bright liver echo pattern on ultrasound B-mode examination in the diagnosis of liver steatosis. Dig Liver Dis 2006; 38: 485–489