Efficacy of Serum Ferritin-Zinc Ratio for Predicting Advanced Liver Fibrosis in Patients with Autoimmune Hepatitis

Abstract

Background/Aims: The search for noninvasive biomarkers that can efficiently estimate the extent of liver fibrosis progression is ongoing. Although Fibrosis-4 (FIB-4), the aspartate transaminase-to-platelet ratio index (APRI), and the Forns index have been reported as useful biomarkers, their investigation in autoimmune hepatitis (AIH) is limited. This study aimed to examine the usefulness of these serological indices and a newly developed index in predicting liver fibrosis progression in AIH. Methods: The study analyzed data from 190 patients diagnosed with AIH at our institution between 1990 and 2015. Their histological liver fibrosis progression and clinical long-term prognosis were evaluated retrospectively (cohort 1). In 90 patients, receiver operating characteristic (ROC) curves were compared to choose severe fibrosis cases with respect to existing indices (FIB-4, APRI, and Forns index) and the ferritin-zinc ratio (cohort 2). Results: In cohort 1, liver-related death and hepatocellular carcinoma rates were significantly higher in the severe (n = 27) than in the mild (n = 63) fibrosis group (p = 0.0001 and 0.0191, respectively). In cohort 2, liver-related death in the severe fibrosis group was significantly frequent (p = 0.0071), and their ferritin-zinc ratio was higher (median 2.41 vs. 0.62, p = 0.0011). ROC analyses were performed to compare the ability of the ferritin-zinc ratio, FIB-4, APRI, and the Forns index to predict severe and mild fibrosis. Accordingly, areas under the ROC were 0.732, 0.740, 0.721, and 0.729, respectively. Conclusions: The serum ferritin-zinc ratio can noninvasively predict liver fibrosis progression in AIH and be applied to predict long-term prognosis.

Keywords: autoimmune hepatitis; biomarker; ferritin; liver fibrosis; zinc.

Figure 1

Flow chart of patients in this study. In cohort 1, liver-related death-free survival and HCC-free survival were evaluated in patients with AIH. In cohort 2, the efficacy of serum biomarkers for predicting long-term prognosis was evaluated in patients with AIH. AIH, autoimmune hepatitis; HCC, hepatocellular carcinoma.

Figure 2

Relations between the degree of liver fibrosis progression and major clinical outcomes. (a) Liver-related death-free survival in the mild and severe liver fibrosis groups in cohort 1 (n = 198). (b) HCC-free survival in the mild and severe liver fibrosis groups in cohort 1 (n = 198). (c) Liver-related death-free survival in the mild and severe liver fibrosis groups in cohort 2 (n = 90). (d) HCC-free survival in the mild and severe liver fibrosis groups in cohort 2 (n = 90). HCC, hepatocellular carcinoma.

Figure 3

Relationship between blood inorganic salt balance and liver fibrosis progression in patients with AIH. (a) Relations between serum zinc and ferritin concentration in patients with autoimmune hepatitis. (b) Serum ferritin–zinc ratio classified by liver fibrosis progression. AIH, autoimmune hepatitis.

Figure 4

Efficacy of various serum biomarkers in predicting severe hepatic fibrosis of patients with AIH. ROC curve analysis. (a) ROC curve for ferritin–zinc ratio (AUC = 0.732, sensitivity = 62%, specificity = 80%). (b) ROC curves for FIB-4 (AUC = 0.740, sensitivity = 71%, specificity = 74%). (c) ROC curves for APRI (AUC = 0.721, sensitivity = 64%, specificity = 80%). (d) ROC curves for Forns index (AUC = 0.729, sensitivity = 54%, specificity = 89%). AIH, autoimmune hepatitis; APRI, aspartate transferase to platelet ratio index; AUC, area under the curve; ROC, receiver operating characteristic.

Figure 5

Relations between the level of ferritin–zinc ratio and major clinical outcomes. (a) Liver-related death-free survival in cohort 2 (n = 90). (b) HCC-free survival in cohort 2 (n = 90). FZR, ferritin–zinc ratio; HCC, hepatocellular carcinoma.