Abstract
Prognostic factors for hepatocellular carcinoma (HCC) has been a dynamic study section. Different staging systems like TNM (tumor size, node status and metastasis) staging, Barcelona staging, Okuda staging, as well as albumin- bilirubin score, alfa fetoprotein (AFP) and many more are evaluated for prognostication of HCC patients. This is an invited commentary on our previously published paper, where we explored the role of the ratio of serum ferritin and transferrin level (FTR). We concluded that FTR >7.7 is associated with better overall survival and outperformed the Barcelona staging system.
Keywords
Ferritin, Ferritin Transferrin Ratio, Hepatocellular Carcinoma
Commentary
There is growing body of literature to identify novel prognostic markers in hepatocellular carcinoma (HCC), including serum ferritin (SF), transferrin levels, alfa fetoprotein (AFP), and neutrophil to lymphocyte ratio (NLR) [1-7]. Chronic inflammation and fibrogenesis are considered quite essential in the oncogenesis of HCC. The trigger for this inflammation could range from viral hepatitis, alcoholic cirrhosis, to non-alcoholic fatty liver disease [8-10]. Also, iron overload as in hereditary hemochromatosis is linked to one of the factors for HCC oncogenesis [11].
SF is a positive marker of inflammation and a marker of iron stores [12]. Prior studies using SF as a prognostic factor in HCC have been listed in Table 1 [1,2,13]. SF measured in 103 HCC patients treated with radiofrequency ablation (RFA) were found to predict overall survival and time to recurrence with a cut off value of 244 ng/ml [1]. Similar study done on 427 HCC patients undergoing curative hepatic resection showed SF to predict overall survival and recurrence free survival [2] with cut off being 267 ng/ml. A recent study done in 2018 contradicted the idea. This study evaluated 578 HCC patients undergoing RFA, with SF not able to significantly predict the survival [13]. Serum ferritin and iron stores vary according to race [14,15]. The mean ferritin among the patients in this study [13] was lower than other above-mentioned studies [1,2]. To note, the study was done in Japan where prevalence of hereditary hemochromatosis and SF and iron stores are very low. At the same time, most of the HCC patients studied were secondary to HCV [13]. So, this does not support SF as an inflammatory marker to predict the survival. SF has inflammatory and iron storage properties which can confound or exaggerate the predictive value of it as a survival parameter. In our study, the serum ferritin was significantly lower in survivors with mean SF of 193 ng/ml [16]. Further studies need to be done to build up the support for SF independently as a prognostic factor.
| Study | Number of Patients | Result of Study | P value | Patient Population | |
|---|---|---|---|---|---|
| 1. | Facciorusso et al., 2014 [1] | 103 | SF below 244ng/ml predicted significantly better overall survival | HCC patients treated with RFA | |
| 2. | Uchino et al., 2018 [13] | 578 | SF did not predict the OS (SF cut off 244ng/ml) | 0.45 | HCC patients treated with RFA |
| 3. | Wu et al., 2019 [2] | 427 | SF below 267ng/ml predicted significantly better overall survival | 0.001 | Patients received curative hepatic resection |
Abbreviations: HCC: Hepatocellular Carcinoma; SF: Serum Ferritin; RFA: Radiofrequency Ablation
Table 1: Summary of studies with use of ferritin as prognostic factor.
Another inflammatory marker and marker of iron stores is serum transferrin which is negative acute phase reactant [17]. Transferrin has also been studied to find its prognostic value in HCC survival. A retrospective study done in 44 HCC patients receiving hepatic arterial infusion therapy was found to correlate higher serum transferrin level to higher survival rates [3]. Another study supporting the idea found high ferritin along with low transferrin saturation independently predicted the mortality; it was done in 328 patients with end stage liver disease, out of which only 17% had HCC [4]. Not enough evidence is there to support serum transferrin alone to predict the survival rate. Prior studies evaluating the role of transferrin as a prognostic factor in HCC are shown in Table 2. SEPT6 mainly regulates actin dynamics, cell shape and microtubule dynamics, cytokinesis, cell proliferation, cell cycle progression, cell apoptosis and cell migration. But the role of SEPT6 and its mechanism in liver fibrosis has not been studied before. Therefore, in the manuscript entitled “Effect of SEPT6 on the biological behavior of hepatic stellate cells and liver fibrosis in rats and its mechanism”, we explored the role of SEPT6 in liver fibrosis and elucidated the underlying mechanism [22].
| Study | Number of HCC Patients | Result of study | P value | Patient population | |
|---|---|---|---|---|---|
| 1. | Zaitsu et al.,2014 | 44 | Transferrin level 190mg/dl or above with better overall survival rate | 0.001 [CI], 0.132-0.603; | Patient undergoing RFA |
| 2. | Weismüller et al., 2011 | 56 (out of 328 patients with chronic end stage liver disease) | Transferrin saturation (TS) less than 55% along with high SF >=365 mg/dl has lower survival rate than transferrin saturation more than 55% and high SF >=365 mg/dl. | 0.003 | SF higher than 365 independently predicted survival but TS did not independently show any survival benefit. |
Abbreviations: HCC: Hepatocellular carcinoma; CI: Confidence Interval; RFA: Radiofrequency ablation; SF: Serum Ferritin; TS: Transferrin Saturation
Table 2: Summary of studies using transferrin as prognostic factor.
We did not use SF and transferrin individually in the multivariate analysis due to the multicollinearity with ferritin transferrin ratio (FTR). An FTT cut off value of 7.7, yielded sensitivity and specificity of 87% and 88%, respectively, based on receiver operating curve analysis [16].
In literature, studies have shown AFP to independently predict the risk of pathological grade of HCC, its progression and survival. Halazun et al., addressed AFP cut off of 200 ng/ml while Bai et al., used AFP positive or negative without using a discrete value to show relation of AFP to lower survival [5,6]. A metanalysis of 4,726 HCC patients showed that post treatment AFP response was significantly associated with overall survival, progression free survival and recurrence free survival [7]. In our study, AFP >350 ng/mL was associated with lower overall survival with hazard ratio (HR) of 2.58, P=0.018 (CI 1.68-2.95) on multivariate analysis [16].
Cox regression analysis showed that FTR, advanced liver disease with Barcelona liver staging D and AFP had significant impact on mortality. Area under curve (AUC) for FTR is greater than that of Barcelona staging for HCC [16]. This further emphasizes the prognostic importance of FTR, making it better than Barcelona staging for HCC. FTR is an easily available tool that can be used to predict survival in HCC.
Contributions
I) Conception and design: Ishaan Vohra; (II) Administrative support: Bashar Attar; (III) Provision of study materials, collection and assembly of data: Vatsala Katiyar; (IV) Manuscript writing: All authors.
References
2. Wu SJ, Zhang ZZ, Cheng NS, Xiong XZ, Yang L. Preoperative serum ferritin is an independent prognostic factor for liver cancer after hepatectomy. Surgical Oncology. 2019 Jun 1;29:159-67.
3. Zaitsu J, Yamasaki T, Saeki I, Harima Y, Iwamoto T, Harima Y, Matsumoto T, Urata Y, Hidaka I, Marumoto Y, Ishikawa T. Serum transferrin as a predictor of prognosis for hepatic arterial infusion chemotherapy in advanced hepatocellular carcinoma. Hepatology Research. 2014 May;44(5):481-90.
4. Weismüller TJ, Kirchner GI, Scherer MN, Negm AA, Schnitzbauer AA, Lehner F, et al. Serum ferritin concentration and transferrin saturation before liver transplantation predict decreased long-term recipient survival. Hepatology. 2011 Dec;54(6):2114-24.
5. Bai DS, Zhang C, Chen P, Jin SJ, Jiang GQ. The prognostic correlation of AFP level at diagnosis with pathological grade, progression, and survival of patients with hepatocellular carcinoma. Scientific Reports. 2017 Oct 9;7(1):1-9.
6. Halazun KJ, Najjar M, Abdelmessih RM, Samstein B, Griesemer AD, Guarrera JV, et al. Recurrence after liver transplantation for hepatocellular carcinoma. Annals of Surgery. 2017 Mar 1;265(3):557-64.
7. He C, Peng W, Liu X, Li C, Li X, Wen TF. Post-treatment alpha-fetoprotein response predicts prognosis of patients with hepatocellular carcinoma: A meta-analysis. Medicine. 2019 Aug;98(31): e16557.
8. Block TM, Mehta AS, Fimmel CJ, Jordan R. Molecular viral oncology of hepatocellular carcinoma. Oncogene. 2003 Aug;22(33):5093-107.
9. Sanyal AJ, Yoon SK, Lencioni R. The etiology of hepatocellular carcinoma and consequences for treatment. Oncologist. 2010 Nov 2; 15 Suppl 4:14-22.
10. Waller LP, Deshpande V, Pyrsopoulos N. Hepatocellular carcinoma: A comprehensive review. World journal of hepatology. 2015 Nov 18;7(26): 2648- 2663.
11. Kew MC. Hepatic iron overload and hepatocellular carcinoma. Liver Cancer. 2014;3(1):31-40.
12. Kell DB, Pretorius E. Serum ferritin is an important inflammatory disease marker, as it is mainly a leakage product from damaged cells. Metallomics. 2014;6(4):748- 73.
13. Uchino K, Tateishi R, Nakagomi R, Fujiwara N, Minami T, Sato M, Enooku K, Nakagawa H, Asaoka Y, Kondo Y, Shibahara J. Serum levels of ferritin do not affect the prognosis of patients with hepatocellular carcinoma undergoing radiofrequency ablation. PloS one. 2018;13(7): e0200943.
14. Zacharski LR, Ornstein DL, Woloshin S, Schwartz LM. Association of age, sex, and race with body iron stores in adults: analysis of NHANES III data. American Heart Journal. 2000 Jul 1;140(1):98-104.
15. Adams PC, Reboussin DM, Barton JC, McLaren CE, Eckfeldt JH, McLaren GD, Dawkins FW, Acton RT, Harris EL, Gordeuk VR, Leiendecker-Foster C. Hemochromatosis and iron-overload screening in a racially diverse population. New England Journal of Medicine. 2005 Apr 28;352(17):1769-78.
16. Vohra I, Attar B, Katiyar V, Palacios P, Randhawa T, Baig MA, et al. Evaluation of Ferritin and Transferrin Ratio as a Prognostic Marker for Hepatocellular Carcinoma. Journal of Gastrointestinal Cancer. 2020 Mar 4:1-6.
17. Ritchie RF, Palomaki GE, Neveux LM, Navolotskaia O, Ledue TB, Craig WY. Reference distributions for the negative acute-phase serum proteins, albumin, transferrin and transthyretin: a practical, simple and clinically relevant approach in a large cohort. Journal of Clinical Laboratory Analysis. 1999;13(6):273-9.