The importance of matrix metalloproteinases and their inhibitors in predicting F4 fibrosis (cirrhosis) in case of chronic hepatic disorders


DOI: https://dx.doi.org/10.18565/therapy.2025.1.108-115

Koroy P.V., Yagoda A.V., Dudov T.R.

Stavropol State Medical University of the Ministry of Healthcare of Russia
Abstract. Data on the predictive value of matrix metalloproteinases (MMP) and their tissue inhibitors (TIMP) in relation to cirrhosis in case of chronic hepatic disorders diseases (CHD) are limited. It is advisable to search for non-invasive biomarkers of liver cirrhosis (LC) with an emphasis on the components of the MMP system.
The aim: to evaluate the prognostic significance of MMP and TIMP in combination with clinical and laboratory markers for F4 fibrosis (LC) diadnostics in case of CHD.
Material and methods. The study included 76 patients with histologically confirmed CHD of viral or alcoholic etiology. Patients underwent standard clinical, laboratory and morphological examination. Fibrosis F0–F3 was found in 77.6% of patients, F4 – in 22.4%. The enzyme immunoassay method was used to determine the content of MMP-1, MMP-9, TIMP-1 in the blood, TIMP-1/MMP-1 and TIMP- 1/ MMP-9 ratios were calculated.
Results. An increased risk of LC developing (F4 fibrosis) was associated with the following values: TIMP-1 ≥ 624 ng/ml, gamma-glutamyl transpeptidase (GGT) ≥ 67.8 U/l, liver stiffness ≥ 11.1 kPa, albumin ≤ 39.3 g/l, platelets ≤ 173 × 109/l, age ≥ 45 years, TIMP-1/MMP-1 ≥ 37.1 RU, aspartate aminotransferase ≥ 49.3 U/l, TIMP-1/MMP-9 ≥ 7.33 RU, erythrocyte sedimentation rate ≥ 9 mm/h, MMP-1 ≤ 15.3 ng/ml, total bilirubin ≥ 16 μmol/l, direct bilirubin ≥ 8.4 μmol/l, alanine aminotransferase ≥ 65 U/l, as well as the presence of cholestatic, mesenchymal-inflammatory syndromes, moderate/high biochemical activity. According to multivariate regression analysis, F4 fibrosis was associated with TIMP-1/MMP-1 ratio, GGT activity, and age. Model which included these indexes had a sensitivity of 82.4% and a specificity of 94.9% in diagnosing F4 fibrosis (LC) among patients having CHD.
Conclusion. An increased TIMP-1/MMP-1 ratio, increased GGT activity and elderly age are independent risk factors for LC (F4 fibrosis) in case of CHD, due to their influence at fibrogenesis processes. The developed model, designed for non-invasive diagnostics of cirrhosis, can contribute to the timely detection and correction of the disease at early stages.
Keywords: gamma-glutamyl transpeptidase, non-invasive diagnostics, chronic hepatic diseases, age, liver cirrhosis, tissue inhibitors of matrix metalloproteinases, matrix metalloproteinases
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About the Autors

Pavel V. Koroy, MD, Dr. Sci. (Medicine), professor, professor of the Department of hospital therapy, Stavropol State Medical University of the Ministry of Healthcare of Russia. Address: 355017, Stavropol, 310 Mira St.
E-mail: paule75@yandex.ru
ORCID: https://orcid.org/0000-0001-6392-8461
Alexander V. Yagoda, MD, Dr. Sci. (Medicine), professor, Honored Scientist of the Russian Federation, head of the Department of hospital therapy, Stavropol State Medical University of the Ministry of Healthcare of Russia. Address: 355017, Stavropol, 310 Mira St.
E-mail: alexander.yagoda@gmail.com
ORCID: https://orcid.org/0000-0002-5727-1640
Temirlan R. Dudov, MD, assistant at the Department of hospital therapy, Stavropol State Medical University of the Ministry of Healthcare of Russia. Address: 355017, Stavropol, 310 Mira St.
E-mail: timur222123@mail.ru
ORCID: https://orcid.org/0009-0006-7244-3507


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