MASLD: Another Disease Label for a Risk Factor that Leads to Overtesting

We pay close attention to issues of overdiagnosis and overtreatment at Sensible Medicine. This article considers what happens when we conflate risk factors and diseases, and how this affects overdiagnosis and overtreatment.

Adam Cifu

In the past decade, hepatitis C cirrhosis has slowly been declining as the major cause of chronic liver disease in North America, being overshadowed by a newly emergent entity: MASLD/MASH cirrhosis. MASLD/MASH is the new term for Metabolic-Associated Steatotic Liver Disease or Steatohepatits, formerly encompassed by the term NAFLD/NASH (Non-Alcoholic Fatty Liver Disease/ Non-Alcoholic Steatohepatitis). The newer term aims to link the disease to its cause: metabolic syndrome.

24 to 48% of North Americans are thought to be affected by this disease, leading many experts to sound the alarm on the “MASLD epidemic”. We have been told that other epidemics are also raging in the US: prediabetes/diabetes, dyslipidemia, hypertension, and obesity. Are people really sicker than ever?

Yes and No.

We are facing an epidemic of labeling risk factors for future clinical morbidity as diseases. MASLD is no exception. Like many other asymptomatic ‘diseases’, MASLD is a direct consequence of a sedentary lifestyle and unhealthy eating. People are not actually sick—yet.

When we label a healthy person (or a risk-naive person) with medical terms like prediabetes, dyslipidemia, or MASLD, we should carefully consider the potential consequences. Giving patients a diagnosis can help them understand their condition and act. However, studies demonstrating this effect are lacking. It can also harm patients’ perception of their health. Patients are not sick yet, but we can make them feel as though they are. Sick labels can be anxiogenic, especially if no simple medical solution exists.

We all want the same thing: to decrease the mortality and morbidity of an identified condition. For liver health, the focus of recent guidelines (AASLD, EASL, ADA) is reducing progression to major liver outcomes (MALO), like decompensated cirrhosis, esophageal bleeding, and hepatic cancer. Like any risk factor, knowing your baseline risk matters, as people at the highest risk will have the most absolute risk benefit. We do not have tools or data to predict one’s personal 10-year risk of MALO. At best, an observational study in the UK found that 3.2% of patients with diabetes followed for 12.5 years developed MALO.

Screening

The prevalence of MASLD in the US ranges from a third to half the population. Imagine the number needed to screen, let alone treat, in order to prevent one MALO. Guidelines suggest screening at-risk populations for advanced fibrosis: prediabetic/diabetic, obesity, and at least 2 CV risk factors, hepatic steatosis on imaging, or AST or ALT above 30. Using diabetes alone, 38% of Americans are eligible for screening.

Looking at recommended screening strategies, guidelines suggest using the FIB-4 test, followed by ELF or elastography to identify high-risk patients. Patients identified at high risk should then be referred to a hepatologist. Using the FIB-4 test alone, true positives would represent only 6.8% of positive tests in a guideline-targeted population. Adding elastography to positive FIB-4 tests makes sensitivity and specificity better, above 90% . This seems great, but when we apply these numbers to low-prevalence populations, about half of the patients referred to hepatologists would be false positives. Although this might seem fair, current approaches are drifting away from biopsies towards these non-invasive strategies to label patients as having advanced fibrosis. Meaning half of the patients would be mislabeled using these tests alone.

Furthermore, screening for advanced fibrosis requires a CBC, ALT, and AST at regular intervals. These tests can lead to low-yield investigation cascades. Patients with diabetes often have increased ALTs, with a prevalence as high as 57%. In the general population, elevated liver enzymes are as common as 10%. The same is true for CBCs. The AASLD guidelines encourage providers to rule out other causes of abnormal tests. The panel of tests to assess a chronically elevated ALT includes an ANA (to rule out autoimmune hepatitis). Of course, up to 15% of patients have positive ANAs in the absence of disease. Tests beget more tests, further exacerbating low-value resource utilization and increasing patient anxiety.

Treatment

Looking at RCT data on treatment, the only markers of efficacy reported are reductions in fibrosis stage or inflammation on biopsy. This is a surrogate marker and does not guarantee a reduction of MALO.

What we know works to reduce mortality and morbidity in this population are targeted approaches aimed at reducing CV risk in primary prevention. Keeping in mind, people with MASLD and metabolic syndrome are at increased risk of CVD. There is good data supporting interventions targeting known modifiable risk factors like diabetes, hypertension, and dyslipidemia to reduce CVD burden in primary prevention. Furthermore, in the UK prospective study cited earlier, the risk of MASLD and MALO in patients with type 2 diabetes was greatly decreased for each controlled traditional CV risk factor. Targeting these risk factors in patients with MASLD can improve patient-important outcomes. Some medications show promise, like GLP-1 and GIP agonists, which are indicated for co-occurring patient risk factors (other than MASLD specifically). The same thing goes for bariatric surgery, which can be targeted to prevent MALO, among other outcomes. Resmetirom, a thyroid hormone receptor-beta agonist, has only been shown to reduce surrogate outcomes, and solid data are lacking for its rollout in primary care.

Conclusion

In summary, although MASLD is prevalent and efforts should be made to decrease the overall burden of disease, there are no simple medical solutions. Healthy eating, staying active, and maintaining a healthy weight are recommendations that apply to all patients and don’t require a MASLD diagnosis. Addressing risk factors with proven benefits on outcomes is the best we can offer in primary care. There are just too many uncertainties in relying on imperfect tests and surrogate markers to address this risk.

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Julie Laurence is a registered adult care nurse practitioner specializing in internal medicine at a community hospital outpatient clinic.

Emma Glaser is a family physician practicing in a family medicine clinic.

Both are based in Montreal, Quebec, Canada, and are affiliated with the Choosing Wisely campaign. Dr. Glaser teaches future family physicians at the Université de Montréal, while Julie is involved in training future nurse practitioners at both the Université de Montréal and McGill University.

They have no conflicts of interest to declare.