December 19, 2019
4 min read

What is the best way to screen very high-risk patients for fatty liver or fibrosis?

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Click here to read the Cover Story, "Early action required for prevention, management of fatty liver in type 2 diabetes"


Safe, accurate and easier-to-perform blood tests are needed to make diagnosis in the clinic easier.

Christos S. Mantzoros

Screening patients for NAFLD or NASH is an area largely underestimated in primary care and clinical endocrinology, mainly due to a lack of appropriate diagnostic and therapeutic tools.

Most clinicians who screen high-risk patients would recommend a step-by-step approach. First, when NAFLD is suspected, confirm that there is ectopic fat deposition in the liver — more than 5% by ultrasound and more than 5.8% by MRI elastography — usually accompanied by elevated alanine aminotransferase.

For people with obesity aged at least 40 years who have multiple components of metabolic syndrome, also measure the liver indexes Fibrosis-4, aspartate transaminase-platelet ratio index and/or NAFLD fibrosis score. Use of FibroScan (Echosens) in many of these individuals would reveal low levels of involvement, and thus this is a useful tool in the hands of experienced people to screen out individuals not at very high risk. Higher FibroScan readings would necessitate a referral to a liver center and/or a biopsy. The above tests are far from optimal, as they misclassify a relatively high percentage — 20% to 30% — of patients. Liver biopsy has an approximately 0.5% incidence of morbidity and mortality at 1 in 10,000. Even if we could biopsy each of the 80 million Americans who have fat in their liver, tens of thousands would experience complications and about 8,000 would die. This is unacceptable.

Thus, the lack of diagnostic tests with a high enough specificity and sensitivity is stifling progress for clinical trials and accurate diagnosis of the disease. The field is still evolving rapidly, and the hope is that there will soon be a noninvasive test available immediately to those who have obesity and a high index of suspicion to classify them along the NAFLD spectrum.

A major step in this direction is a forthcoming noninvasive diagnostic test we have developed using machine learning and artificial intelligence that has a sensitivity and specificity higher than 95% compared with liver biopsy in differentiating healthy individuals vs. those with NAFLD vs. NASH.

If validated, this noninvasive test has the potential to revolutionize care. It will make screening people for inclusion in clinical trials and/or more aggressive care much easier and much less risky.

In any case, development of safer and easier-to-perform blood tests is the direction the field needs to take in the foreseeable future for us to make diagnosis in the clinic easier. This will also facilitate the performance of clinical trials and, hopefully, the delivery of better and safer drugs for our therapeutic armamentarium, which in turn, would bring tangible benefits to our fellow human beings living with NASH.

Christos S. Mantzoros, MD, DSc, PhD, is professor of medicine at Harvard Medical School and chief of endocrinology, diabetes and metabolism at the Boston VA Healthcare System. Disclosure: Mantzoros reports he serves as a consultant for Ansh Labs, Coherus, Intarcia and Novo Nordisk.



We need to focus on the 10% of people who are going to develop advanced fibrosis or cirrhosis.

Rohit Loomba

The key question to ask is, screening for what? If the question is framed as screening for NAFLD, what do we do with these people once we know? There are recommendations for diabetic nephropathy; there are recommendations for diabetic retinopathy; yet, there are no recommendations for liver disease.

We recently looked at a cohort of about 100 patients with type 2 diabetes derived from primary care in the San Diego area in 2016. We found that 65% had fatty liver disease and 7% had fibrosis or cirrhosis. We need a guideline not for screening for NAFLD, but for advanced fibrosis and cirrhosis.

The best approach is still being sorted out. The most important thing is accepting and acknowledging that education is needed for diabetologists. Do your patients have liver disease? If you think the answer is no, we have to change that to yes. That is where the conversation should be right now. Once diabetologists start accepting it, then they can do something about it. You can have the very best test in the world, but if clinicians are not ready to do anything about the condition, they are not going to perform them.

We need to focus on developing evidence systematically in the U.S. that we can apply to our patients. I don’t want people to start randomly using FibroScan on patients without understanding the criteria related to it. There are a lot of caveats associated with how to use these noninvasive tests. Making people familiar with those would be important. We are currently conducting studies to develop exact cutoff points for whom to biopsy and whom to monitor. This is going to take a few years.

In the meantime, things should be made simple for diabetologists. A person with a FIB-4 score above 2.67, for example, should be referred to a hepatologist, because 40% to 50% of those people may have advanced fibrosis.

Rohit Loomba, MD, is professor of medicine in the division of gastroenterology and adjunct professor in the division of epidemiology at the University of California, San Diego, and is a founding director of the UCSD NAFLD Translational Research Unit. Disclosure: Loomba reports receiving grant or research support from Adheron, Allergan, Arisph, Bristol-Myers Squibb, Eli Lilly, Galectin, Galmed, GE, Genfit, Gilead, Immuron, Intercept, Kinemed, Merck, NGM, NuSirt, Octeta, Promedior, Shire and Siemens; participating in advisory committees or review panels for Arrowhead Research, Conatus, Gilead, Galmed, Gemphire, Intercept, Median Technologies, Octeta and Second Genome; holding patents for LipoNexus; consulting for Allergan, Arrowhead Research, BirdRock Bio, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Cirius, CohBar, Conatus, Cymabay, Eli Lilly, Gemphire, Gilead, Glympse Bio, GNI, GRI, Intercept, Ionis, Janssen, Metacrine, NGM, Novo Nordisk, Pfizer and Second Genome Technologies; and holding stock in Viking Therapeutics.