Large Karolinska study: Successive blood tests to predict liver cirrhosis risk

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Repeated measurements of the biomarker FIB-4 in the blood every few years can predict the risk of developing severe liver disease, according to a study from Karolinska Institutet. The risk of liver cirrhosis increases if the levels of this biomarker rise between two testing occasions.

Fat accumulation in the liver is common and is often seen in people with obesity or diabetes. In the worst case, fatty liver can lead to cirrhosis or liver cancer. It is unusual for this to occur but in those affected, symptoms often only occur at a late stage when there is no available treatment.

“It is difficult to predict the risk of cirrhosis, although you can get some guidance in using regular blood tests that measure liver damage,” says lead author Dr Hannes Hagström, hepatologist at the Karolinska University Hospital and docent at Karolinska Institutet. “Therefore, we wanted to investigate whether what is known as the FIB-4 score can increase the accuracy of the identification of people at high risk, in particular with information from repeated measurements.”

The new study shows that repeated sampling and measurements of the FIB-4 score, rather than measuring FIB-4 on one sole occasion, can increase the prediction of future liver cirrhosis. The researchers used the AMORIS cohort that contains laboratory test data in a very large population, surveyed between 1985 and 1996. More than 40,000 people had blood test data for FIB-4 from several sampling occasions. They were followed in national registers to identify those who developed cirrhosis after up to 27 years. The main finding was that the risk increases in people where the FIB-4 score rises between two testing occasions and decreases when it falls. In this way, almost half of those who were later affected by cirrhosis could be identified. One problem, however, was that the accuracy was relatively low, with a risk of false positive tests.

The study also established that it took a long time to develop cirrhosis, and that it may be enough to recalculate the FIB-4 score at intervals of several years. “We show that this biomarker is useful for identifying people in primary care with an increased risk of cirrhosis who may need to be more carefully investigated and to exclude people who do not need this,” says Hagström. “But the method needs to be further developed to reduce the risk of false positive findings, which can lead to unnecessary examinations in healthy people.”
The study was funded with grants from pharmaceutical company AstraZeneca, region Stockholm and the Gunnar & Ingmar Jungner Foundation for Laboratory Medicine. Hagström has received consulting fees from Novo Nordisk, Gilead Sciences Inc, IQVIA and Intercept Pharmaceuticals, and has been advisory board member of Bristol Myers-Squibb and Gilead Sciences (all unconnected to the present study). Hagström’s departments have received research grants from Gilead Sciences Inc department of medicine, Huddinge) and Intercept Pharmaceuticals (Karolinska University Hospital).

Background & Aims: It is unclear as to whether the identification of individuals at risk of cirrhosis using non-invasive tests can be improved by repeated measurements.
Methods: Data were derived from the population-based Swedish AMORIS cohort with baseline examinations from 1985-1996. The Fibrosis-4 index (FIB-4) was calculated at two time points within 5 years. Thereafter, we associated changes in FIB-4 with outcomes. Incident severe liver disease was ascertained through linkage with Swedish national registers until 2011. Hazard ratios (HRs) and confidence intervals (CIs) for outcomes were calculated using Cox regression.
Results: Of 126,942 persons with available FIB-4 data, 40,729 (32.1%) underwent a second test within 5 years (mean interval 2.4 years). During 613,376 person-years of follow-up, 581 events of severe liver disease were documented (0.95/1,000 person-years). An increase of one unit in FIB-4 was associated with an elevated risk of severe liver disease (aHR=1.81, 95%CI=1.67-1.96). Transitioning from a low- or intermediate- to a high-risk group was associated with an increased risk of severe liver disease compared with those consistently in the low-risk group (aHR=7.99 and 8.64, respectively). A particularly increased risk of severe liver disease was found in persons defined as high-risk at both tests (aHR=17.04, 95%CI=11.67-24.88). However, almost half of all events occurred in those consistently in the low-risk group.
Conclusions: Repeated testing of FIB-4 within 5 years improves the identification of individuals in the general population at an increased risk of severe liver disease. However, the sensitivity is comparatively low and improved tests are needed for screening in a general population or primary care setting.

Hannes Hagström, Mats Talbäck, Anna Andreasson, Göran Walldius, Niklas Hammar


Karolinska Institutet material


Journal of Hepatology abstract

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