Not the Usual Suspects: Don't Overlook NAFLD in Lean Patients

Nancy S. Reau, MD


August 30, 2022

The prevalence of nonalcoholic fatty liver disease (NAFLD) is experiencing an alarming rise worldwide. This trend is often viewed through the lens of the parallel increase in obesity and type 2 diabetes. Less discussed is the presence of NAFLD in lean patients, which was the focus of a recent review article published in Gastroenterology.

Medscape contributor Nancy S. Reau, MD, chief of the hepatology section at Rush University Medical Center in Chicago, spoke with the review's co-author, Michelle T. Long, MD, associate professor of preventive medicine and epidemiology at Boston University School of Medicine. They discussed why it's important for clinicians not to overlook NAFLD in their lean patients, how to identify them, and what interventions might prove most useful in treating them.

Highlighting an Overlooked Population

Given the strong association with body mass index (BMI), why is lean NAFLD an important condition to highlight?

Awareness regarding NAFLD at all levels needs to be improved. NAFLD is one of the most common chronic liver diseases, yet many patients and providers are unaware of the potential seriousness of this condition. In the past several years, we have started to see an improvement in the general knowledge around NAFLD; however, we are still far behind what is needed. In particular, although a significant minority of those with NAFLD are lean (approximately 10%), such patients are often diagnosed late or told they have a benign disease.

Recently, several longitudinal studies have observed that lean individuals with NAFLD have a lower risk for fibrosis at baseline. However, if followed over time, the risk for disease progression is higher compared with non-lean persons with NAFLD.

We wrote this review to highlight this important patient population with NAFLD, as well as some of the recent developments and special considerations for the diagnosis and management.

How do you propose finding patients with lean NAFLD? Screening is only recommended in patients with type 2 diabetes and who are older than 40 years. Is this the only at-risk population?

Making the diagnosis of NAFLD in lean individuals can be challenging. We hope to highlight that NAFLD should be considered as a possibility in lean persons with increased liver fat on imaging or elevated liver biochemical tests.

There are several conditions that may cause increased liver fat in the absence of obesity. Within the review, we provide a practical management and treatment algorithm for clinicians in how to approach ruling out alternative causes of increased liver fat in lean persons with suspected NAFLD.

Specifically, more common conditions, such as covert alcohol use, hepatitis C, celiac disease, hypothyroidism, and drug-induced liver injury, should be considered in most patients.

Other conditions, such as familial lipodystrophy syndromes or growth hormone deficiency, may be considered depending on the clinical presentation.

We also reviewed the current evidence on genetic testing; however, we found that it is still lacking. We do not recommend routine genetic testing at this time.

In terms of screening, the prevalence of NAFLD among lean individuals is relatively low, so we do not advise screening for NAFLD among the general lean population. However, emerging data suggest that screening and risk-stratification pathways are cost-effective when applied to patients with type 2 diabetes, regardless of BMI.

Until additional data on cost effectiveness are available, we do not advise screening for NAFLD among other groups. That said, we do expect individuals with two or more metabolic conditions, such as high blood pressure or high triglycerides, are also at high risk for NAFLD, regardless of BMI.

Do you have recommendations on identifying which individuals with lean NAFLD actually have alcohol-associated steatosis?

Assessing alcohol use is challenging for multiple reasons. I think it must start in the context of a trusting patient-clinician relationship. Most patients report that they have not discussed alcohol use with their healthcare providers, so it's important to remember to discuss it with your patients.

Detailed information about alcohol use, including quantity, frequency, type, and binge drinking behavior, should be assessed on all patients with suspected liver disease.

If there is a strong suspicion for covert alcohol use, biomarkers such as PEth (phosphatidylethanol) may be helpful.

Once Identified, How Do You Treat Lean NAFLD?

You recommend lifestyle modifications for patients with lean NAFLD, but what objective measurement do you give them? Is waist circumference vs weight more impactful, for example?

This question brings up a great point. Evidence suggests that lifestyle modifications can have multiple benefits beyond weight loss.

In our review, we emphasize that a modest weight reduction of 3%-5% of body weight may be associated with improved NAFLD in lean persons.

And, although lifestyle interventions may improve NAFLD, the improvements may not always be reflected by weight loss or changes in waist circumference.

In my clinic, I often use vibration-controlled transient elastography to show my patients how physical activity or other lifestyle changes may be having a positive benefit on the liver by demonstrating reductions in measures of liver fat (ie, the controlled attenuation parameter).

Patients also can feel themselves getting stronger or having more energy, which are signs that lifestyle interventions are having a positive impact.

You recommend interval assessments of 6 months to 2 years. Please help a clinician understand whether their patient should have intensive vs less intensive monitoring and how this affects management.

The interval for monitoring really depends on the current disease state and the treatment plan. In general, patients at low risk for advanced fibrosis should be monitored for disease progression and focus on lifestyle interventions, which will help their overall cardiometabolic health.

Liver disease progression is slow though, so it can be difficult to remember if the interval is not regular. There is also uncertainty inherent to noninvasive testing.

So, for those at low risk for advanced fibrosis, we recommend that clinicians assess liver health as a part of the annual physical examination.

For patients who are at high risk for advanced fibrosis, the risk for liver-related events or progression to cirrhosis is higher; therefore, more regular follow-up, on a 6-month to 1-year basis, may be appropriate. If a patient is offered a clinical trial, it may be even more frequent.

What are the key takeaway messages for clinicians?

First, up to one fifth of individuals with NAFLD have a lean body habitus or a BMI < 25 (non-Asian persons) or < 23 (Asian persons).

Second, lean NAFLD is associated with increased cardiovascular, liver, and all-cause mortality.

Third, lifestyle intervention with diet and exercise to target a modest weight loss of 3%-5% is recommended for patients with lean NAFLD.

Finally, staging (or evaluation for hepatic fibrosis) should be done in lean individuals with NAFLD to identify those with advanced fibrosis or cirrhosis.

Nancy S. Reau, MD, is chief of the hepatology section at Rush University Medical Center in Chicago and a regular contributor to Medscape. She serves as editor of Clinical Liver Disease, a multimedia review journal, and recently as a member of, a web-based resource from the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America, as well as educational chair of the AASLD hepatitis C special interest group. She continues to have an active role in the hepatology interest group of the World Gastroenterology Organisation and the American Liver Foundation at the regional and national levels.

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