Algorithm SAFE to Detect Liver Disease in General Population

Becky McCall

June 26, 2023

VIENNA — An algorithm, the Steatosis-Associated Fibrosis Estimator (SAFE), was developed to detect clinically significant fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). It is effective at detecting chronic liver disease from all causes with or without NAFLD in the general population, according the results of a US population-based study. The algorithm was designed for use in primary care to help slow the steep rise in liver disease burden.

On the basis of the SAFE score, 61.3% of participants were at low risk for clinically significant fibrosis; 11.2% were at high risk; and 27.5% were at intermediate risk. Upon validation, very few of the low-risk participants had liver fibrosis, while nearly a third of those with a high-risk score had clinically significant fibrosis. In addition, a high percentage of the patients with high-risk SAFE scores had viral hepatitis and elevations in ferritin level.

"This is the first time that there has been a test that provides a score to detect low-risk liver disease in primary care," said Ray Kim, MD, senior investigator, from Stanford University School Medicine, Stanford, California, who was speaking to Medscape Medical News at the International Liver Congress (ILC) 2023.

"Primary care doctors currently detect liver disease through a serendipitous abnormal finding on ultrasound or blood tests that detect elevated transaminases, and then the patient is referred to a hepatologist, who figures out what is really going on," said Kim.

"This approach is limited, so we need to get SAFE into primary care so these doctors can automatically calculate their scores, and if the patient is over 100 [high risk of chronic liver disease], then they need help [referral to a hepatologist]."

Liver Deaths Sharply Rising

Public health data show that more people are dying of liver disease today than previously. Deaths in the US have doubled over the past 20 years, said Kim. "If our mission is to help these patients and prevent death, [things are] moving in the wrong direction."

He stressed that in order to change the direction, "primary care doctors need to engage with the issue and have appropriate tools to identify people with liver disease."

Most often, the reason for this rise in deaths is that cases are being diagnosed at advanced stages of disease in which reversibility is limited, he added. "We want to move upstream where people might have early-stage disease and where we can intervene and make a difference."

In an effort to help earlier detection of liver disease, the SAFE score was developed and validated by Kim and his colleagues to detect clinically significant (greater than stage 2) fibrosis in patients with NAFLD in primary care. The score is based upon age, body mass index, diabetes, platelet level, aspartate and alanine aminotransferase levels, and globulin level. A score of less than zero signifies that a patient is at low risk for liver fibrosis, while a score greater than 100 signifies a high risk of fibrosis. A score between 0 and 99 denotes intermediate risk of fibrosis.

"Unlike other noninvasive tests that detect advanced fibrosis, this one detects early-stage fibrosis. We've shown that the SAFE estimator is better than all other blood-based markers," explained Kim.

Applying SAFE to the General Population

In the study presented here at EASL, Kim aimed to expand the horizon for SAFE testing to the US general population and to assess whether SAFE was effective in screening for chronic liver disease regardless of steatosis of the liver.

Together with first author Nakia Chung, MD, also from Stanford University, Kim applied the SAFE score to data from 7156 participants of the National Health and Nutrition Examination Survey (NHANES) for 2017–2020. NHANES is representative of the noninstitutionalized, civilian population of the US. It includes broad demographic, clinical, and laboratory data, including transient elastography data. FibroScans were first used in 2017, so the investigators had 3 years of FibroScan data with which to validate the score.

The researchers extrapolated the NHANES sample data to the US population. They found that the proportion of adults with steatosis (CAP score >274 dB/m) and significant fibrosis (LSM >8.0 kPa) were 42.7% (95% CI: 41.0% to 44.3%) and 8.9% (7.6% to 10.2%), respectively. In addition, 11.3% (10.2% to 12.5%) of the adult US population demonstrated a significant amount of alcohol use, 2.3% (1.4% to 3.3%) showed evidence of hepatitis B or C, and 5.4% (4.6% - 6.2%) had elevated serum ferritin levels.

The researchers then stratified the patients according to previously defined SAFE tiers of low, intermediate, and high risk and projected findings to the US general population.

"When we applied our score to the general population, we found multiple abnormalities in the high-risk groups [SAFE >100] having Fibroscan data that are consistent with stage 2 or higher fibrosis regardless of etiology, " Kim pointed out.

Results also showed that very few patients with SAFE <0 had liver fibrosis (4% among those with liver stiffness measure [LSM] >8kPa, and 0.8% with LSM >12kPa). Among those with SAFE >100, nearly a third (31.5%) had LSM of >8kPa, and 16.5% had LSM >12kPa.

In addition to fibrosis, liver abnormalities were common among patients with SAFE >100, including steatosis (68.0%), viral hepatitis (7.0%), and abnormal ferritin levels (12.9%); 10.8% of these patients used alcohol.

"Right now, some patients are referred, but on examination and FibroScan, they might actually be okay, so it it's a waste of time and money for everyone. We can preempt all of this by doing a blood test and focusing on those people who really need a scan," said Kim.

The researcher is now working with primary care colleagues to help further develop and integrate SAFE into the primary care setting.

Fibrosis Score in Patients With Metabolic Dysfunction

Also presenting at the same session on population health was Willem Pieter Brouwer, MD, PhD, from Erasmus University Medical Center, Rotterdam, the Netherlands. He reported results of a validation study of a new risk score ― the Metabolic Dysfunction-Associated Fibrosis–5 (MAF-5) score ― for use for people with metabolic dysfunction who are recommended for screening for liver fibrosis.

"We believe the MAF-5 score may be a good alternative to the FIB-4 [a liver fibrosis biomarker] for use in the referral pathway for liver health evaluation," remarked Brouwer. "The clinical practice guidelines recommend using FIB-4 scores, but these have a poor-moderate performance in the population setting.

"We developed and validated our score in a population of 5500 from the NHANES 2017–2020 cycle and validated the score in populations from Rotterdam, which is a cohort of elderly participants, and in fibrosis among patients with biopsy-proven NAFLD from Colombia and Belgium," he explained.

He also validated the score against different existing scoring systems and different methods of measuring liver stiffness and validated it for prognostic use to predict all-cause mortality in the NHANES III cohort.

Brouwer removed age as a factor of his new MAF-5 score; the score is thus stable for patients of all ages and is suitable for detecting liver disease in younger patients. "This is very important because these patients are currently underserved and have most years of life to win."

Referring to the SAFE score discussed by Kim, as well as other scores, he said, "The FIB-4, SAFE, and NFS [NAFLD fibrosis score] all include age in the scores, which causes problems and limitations in aging populations, as more and more patients will be referred due to an increasing score. Hence, the elderly are mostly all referred for liver checkups."

Kim and Brouwer have disclosed no relevant financial relationships.

International Liver Congress (ILC) 2023: Abstract OS-115-YI. Presented on June 24, 2023.

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