|Year : 2022 | Volume
| Issue : 2 | Page : 103-110
The correlation between hepcidin levels and iron parameters in patients with end-stage renal disease on regular hemodialysis successfully treated from hepatitis C virus by directly acting antiretrovirals
Magdy M El Sharkawy, Heba W El Said, Maha A Behairy, Fatma A Ahmed, Mohamed A Sharaf, Lina E Khedr
Department of Internal Medicine, Ain Shams University, Cairo, Egypt
|Date of Submission||01-Nov-2021|
|Date of Acceptance||21-Dec-2021|
|Date of Web Publication||19-May-2022|
Dr. Lina E Khedr
Department of Internal Medicine, Ain Shams University, Cairo
Source of Support: None, Conflict of Interest: None
Background Hepcidin is a polypeptide secreted from the liver. It regulates iron metabolism by blocking further iron absorption when iron stores are high. Hepcidin levels are usually higher than the normal range in hemodialysis (HD) patients. Hepatitis C virus (HCV) infection leads to lowering of hepcidin levels, leading to more iron overload. The objectives were to determine whether there is a correlation between iron stores and hepcidin levels in HD patients after HCV treatment and to assess the level of hepcidin in those patients who were treated from HCV compared with those who have chronic HCV infection.
Patients and methods In total, 60 patients on regular HD were recruited and 30 healthy controls . Group I: 30 patients who have been successfully treated from HCV by directly acting antiretroviral drugs with a persistently negative PCR for at least 3 months, group II: 30 patients with chronic HCV infection, and 30 healthy controls form group III. Serum hepcidin levels, iron profile, and complete blood count were compared in all groups.
Results Hepcidin levels were significantly higher in the HCV-treated group versus the HCV-infected group (mean 226.77±144.13 and 87.77±40.77 ng/dl), respectively, significantly higher transferrin-binding capacity (TIBC), and mean levels 410.5±74.65 and 310.93±122.57 μg/dl . Ferritin levels were higher in the HCV-infected group (355.13±196, 899.5±1522 ng/dl) than in HCV-treated. There was a significant correlation between hepcidin and serum iron, TIBC, and transferrin saturation in the HCV-treated group. On regression analysis, only TIBC and transferrin saturation correlated significantly.
Conclusions Post HCV treatment with directly acting antiretroviral drugs, hepcidin levels are higher than during HCV-infection state and correlate significantly to higher TIBC . Further studies are needed to establish the effect of iron supplementation on hepcidin level in this subgroup of patients.
Keywords: anemia, hemodialysis, hepatitis-C virus, hepcidin
|How to cite this article:|
El Sharkawy MM, El Said HW, Behairy MA, Ahmed FA, Sharaf MA, Khedr LE. The correlation between hepcidin levels and iron parameters in patients with end-stage renal disease on regular hemodialysis successfully treated from hepatitis C virus by directly acting antiretrovirals. J Egypt Soc Nephrol Transplant 2022;22:103-10
|How to cite this URL:|
El Sharkawy MM, El Said HW, Behairy MA, Ahmed FA, Sharaf MA, Khedr LE. The correlation between hepcidin levels and iron parameters in patients with end-stage renal disease on regular hemodialysis successfully treated from hepatitis C virus by directly acting antiretrovirals. J Egypt Soc Nephrol Transplant [serial online] 2022 [cited 2022 Jul 5];22:103-10. Available from: http://www.jesnt.eg.net/text.asp?2022/22/2/103/345438
Authors’ contributions: Conceptualization, M.E.S.S., H.W.E.S., and L.E.K. Supervision, M.E.S.S., M.A.S., and H.W.E.S. Data collection and patient follow-up, M.A.S. and F.A.A. L.E.K. wrote the paper . All authors revised the paper.
| Introduction|| |
Hepcidin is a 25-amino-acid polypeptide protein synthesized in the liver, it is a key regulator of iron homeostasis and metabolism . In conditions where there is iron deficiency, hepcidin production is inhibited, whereas increased production is stimulated by increased plasma and stored iron . Elevated hepcidin inhibits intestinal iron absorption and leads to iron retention in hepatocytes and macrophages . Furthermore, hepcidin is an acute-phase reactant protein and its production is increased by inflammation .
The etiology of anemia in patients with end-stage renal disease on hemodialysis (HD) is multifactorial. Hepcidin levels in HD patients are elevated, which could be attributed to the proinflammatory state in those patients . The proinflammatory state is a result of circulating cytokines such as tumor-necrosis factor alpha, interleukin-1 (IL-1), IL-6, and interferon . These cytokines stimulate hepatocytes to release hepcidin . Hepcidin promotes iron sequestration in macrophages and monocytes and reduces duodenal absorption of iron by binding ferroportin, which is responsible for iron absorption . Additionally, they impair the biological activity of erythropoietin and subsequently, the process of erythropoiesis . All these factors contribute to the development of anemia of chronic illness .
Ferritin and transferrin saturation are both currently used as biomarkers for iron stores. However, they are influenced by inflammation and are often unreliable as biomarkers for iron stores in HD patients . Current data suggest that hepcidin is a more accurate reflection of iron stores and iron bioavailability in HD patients than ferritin .
Elevated iron stores and ferritin have been found in about 30–40% of patients chronically infected with hepatitis C virus (HCV) . Increased cellular and systemic iron levels are associated with a poor prognosis in HCV-infected patients . The connection between iron overload and HCV infection has been explored in different studies, and in several of those studies, iron has been found to promote HCV replication ,.
It has been established that serum hepcidin levels are significantly lower in HD patients with chronic HCV compared with HCV-negative HD patients . HCV can induce free reactive oxygen radicals, leading to inhibition of hepcidin transcription in hepatocytes . Additionally, a higher level of IL-6 in HCV-infected patients can impair induction of hepcidin synthesis in such patients .
Since 2014, interferon-free treatment of HCV by directly acting antiretroviral drugs has revolutionized HCV treatment. Several regimens such as ombitasvir/paritaprevir/ritonavir combination and elbasvir/grazoprevir dual regimen have been approved for treatment of dialysis patients chronically infected with HCV .
It is not clear if treatment of hepatitis C in dialysis patients abolishes the effect chronic HCV infection has on hepatocytes and restores higher hepcidin levels in this population. Our study aims at determining whether patients post HCV treatment have restored hepcidin levels as opposed to those with chronic HCV infection.
| Patients and methods|| |
In total, 90 patients were recruited in this study. In total, 30 healthy recruits and 60 patients were on regular HD treatment 3 times per week for at least 6 months in Nasser Institute Hospital. None of the patients received iron therapy in the last 3 months.
Group I included 30 patients treated with directly acting antiretrovirals in the past year and currently have persistently negative HCV PCR. Group II included 30 patients with positive HCVAb and no treatment to HCV given. Group III consisted of 30 healthy controls.
Modality of dialysis was with a standard bicarbonate-containing dialysate, using biocompatible HD membrane (Polysulphone, F6 series, Fresenius, Germany). Blood-flow rates ranged from 250 to 300 ml/min, while dialysate flow rate at 500 ml/min.
The following patients were excluded from the study: (a) patients with nonrenal causes of anemia, (b) hepatitis B virus Ab-positive patients, (c) patients who received blood transfusion or iron therapy in the last 4 months preceding the study, (d) patients with evidence of active or occult bleeding, (e) patients with a history of malignancy or chronic hypoxia, and (f) patients with evidence of decompensated liver disease.
Written and informed consent was taken from all study participants.
All blood samples were collected before the mid-week HD session.
Fasting serum samples were obtained in the early morning. All blood samples were collected predialysis. Laboratory values, including complete blood-cell counts, kidney functions, and iron parameters, were measured by standard enzymatic procedures. Transferrin saturation (Tsat) was calculated as serum iron/total iron-binding capacity. High-sensitivity C-reactive protein (hsCRP) was assessed by nephelometry. Kt/V was calculated using Daugirdas method. Hepcidin blood withdrawn was left to clot for 20 min, then centrifuged at 1400 r.p.m., serum was separated and kept frozen at −20 degrees, and then analysis by enzyme-linked immunosorbent assay was done. The HCV antibody status was examined using the third generation of HCV-enzyme immunoassay. HCV PCR by quantitative reverse transcription PCR. HCV mRNA was quantified in the serum by the Cobas Ampli Prep/Cobas TaqMan HCV-RNA assay v 2.0 (Roche Molecular Diagnostics, California, USA) with a lower detection limit at 15 IU/ml for those who received HCV treatment.
Data analysis was performed using the software SPSS (Statistical Package for the Social Sciences) version 20. Quantitative variables were described using their means and standard deviations. Categorical variables were described using their absolute frequencies and were compared using χ2 and Fisher exact test/Monte Carlo test when appropriate. Kolmogorov–Smirnov (distribution-type) and Levene (homogeneity of variances) tests were used to verify assumptions for use in parametric tests. To compare quantitative data between two groups, Mann–Whitney test (for not normally distributed data) and independent-sample t-test (for normally distributed data) were used. To compare quantitative data between more than two groups, one-way analysis of variance test (for normally distributed data) and Kruskal–Wallis test (for not normally distributed data) were used. When P-value is significant, Tukey honestly significant difference post hoc test (for one-way analysis of variance) and pairwise comparison (for Kruskal–Wallis test) were used to uncover specific differences between each of the two groups. Spearman rank-correlation coefficient was used to determine direction and strength of correlation between two quantitative variables (where one of them or both are not normally distributed). Linear stepwise regression analysis was used to predict the value of a variable based on the value of another variable The level of statistical significance was set at P less than 0.05. A highly significant difference was present if P was greater than or equal to 0.001.
| Results|| |
Overall, the study population was 90. In total, 69 males and 21 females were included in the study, the mean age was 51.2±3.4 years. In total, 60 patients had end-stage renal disease on HD, their original kidney disease included; 4 patients with adult polycystic kidney disease, 17 patients with diabetic kidney disease, chronic interstitial nephritis in 5 patients, glomerulonephritis in 3 patients, 2 patients with obstructive uropathy, and 1 patient with chronic pyelonephritis. In total, 12 patients listed other causes for their original kidney disease, including reflux nephropathy and unknown cause, among others. Comorbid conditions included hypertension, diabetes mellitus, and ischemic heart disease ([Table 1]).
|Table 1 Comparison between the studied groups regarding demographic and clinical data|
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There was no significant difference between group I and group II as regards dialysis adequacy and dry weight, however, HCV-positive patients had a longer duration on dialysis treatment ([Table 2]). No patients in group I were using temporary dialysis catheter. In total, 24 patients in group I and 25 in group II were using erythropoietin, the median dose per week was 8000 units per week for both groups.
|Table 2 Comparison between the two HD groups as regards dialysis parameters and epoeitin dose|
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[Table 3] compares laboratory parameters. There is a statistically nonsignificant difference between the studied groups regarding hemoglobin, serum ferritin, or transferrin saturation. There is a statistically significant difference between the studied groups regarding serum iron. On pairwise comparison, the difference is significant between the control group and each of the other groups (significantly higher in the control group), while the level did not significantly differ between the treated hepatitis-C group and hepatitis-C-positive group.
Hemoglobin levels were higher in the control group, there was no difference between group I and group II regarding hemoglobin levels. Ferritin levels were the highest in the HCV-positive group, although that was not found statistically significant.
Serum hepcidin was significantly higher in group I who have completed their HCV treatment, mean levels were 226.77±144 ng/dl. It was the lowest in the control group with mean levels 24.75±7.07 ng/dl ([Figure 1]). This was found statistically significant with a P-value less than 0.001.
|Figure 1 Simple bar chart showing comparison between the studied groups regarding serum hepcidin.|
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hsCRP was the highest in the HCV-positive group, which was found to be statistically significant.
[Table 4] shows that in the treated HCV group, there is a significant negative correlation between serum hepcidin and serum iron. Tsat, ferritin, and transferrin-binding capacity (TIBC) correlated with hepcidin levels in group I, while only TIBC correlated with hepcidin levels in the control group. .
|Table 4 Correlation between serum hepcidin and the studied parameters among the studied groups|
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There is a nonsignificant correlation between it and age, hsCRP, dry weight, K/tv, disease duration, epoetin dose, or hemoglobin level. In the HCV-positive group, there is a nonsignificant negative correlation between serum hepcidin and any of the studied parameters. In the control group, there is a significant negative correlation between serum hepcidin and TIBC.
In [Table 5], regression analysis for factors influencing hepcidin level in group I, only TIBC (unstandardized β=0.814, P=0.013) and transferrin saturation (unstandardized β=6.838, P=0.028) were significantly independently associated with it.
|Table 5 Linear stepwise regression analysis of factors significantly associated with serum hepcidin in the treated HCV group|
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| Discussion|| |
We have demonstrated in the current study that serum hepcidin levels in patients on HD treated from HCV with directly acting antiretroviral drugs are higher than those on HD with chronic HCV infection. Hepcidin levels in treated HCV patients correlated significantly with Tsat and TIBC.
Almost 20 years ago, chronic inflammation was recognized as a major complication of HD . In addition, it is a major cause for significant morbidity and mortality in those patients . Although the pathophysiology of this condition is still not completely understood, several factors, including oxidative stress, dialysis membrane, tissue hypoxia, volume overload, and sodium overload, in addition to retention of uremic toxins such as indoxyl sulfate, are contributing factors . This has been implicated as a contributing factor for high hepcidin levels in dialysis patients compared with the normal population among other causes. In the current study, hepcidin levels were higher in the dialysis population than the control group (mean 226.77±144.13, 87.77±40.77 vs. 24.75±7.07 ng/dl). Furthermore, hsCRP levels in HD patients (groups I and II) were higher than the control group (4.95±2.13, 5.75±2.41 vs. 3.57±2.1 mg/dl).
Inflammation is not the only factor affecting hepcidin metabolism and production. In addition to impaired excretion in dialysis patients, hepcidin levels in blood are regulated by iron status and erythropoiesis . In the current study, we found that hepcidin correlated negatively with serum iron in group I, while Tsat, ferritin, and TIBC correlated positively with hepcidin levels. In the control group, only TIBC correlated with hepcidin levels . A study by Kamal et al. documented a positive correlation between serum hepcidin and serum ferritin level and found no correlation between serum hepcidin and serum iron in HD patients independent of HCV status . A study by Rhubab et al. in 2015 found no significant correlation between iron parameters and hepcidin in dialysis patients . This variability in the results among studies could be due to the fact that iron status in HD patients is influenced by other factors such as iron dosing, degree of inflammation, and dialysis adequacy among others.
Several in vitro studies have demonstrated that HCV has an inhibitory effect on serum hepcidin levels ,,,,,,,,,. However, those studies did not take into consideration the effect of inflammation on hepcidin. Girelli et al.  compared HCV-infected patients with healthy controls and determined that hepcidin levels were lower in HCV-infected patients. Tsochatzis et al.  confirmed the same findings in Greek population.
When studying the relation between hepcidin and HCV in dialysis patients, the situation is even more complex. Hepcidin was significantly higher in the HCV-treated group (group I) than the HCV-infected group (group II) (mean levels 226.77±144.13 vs. 87.77±40.77 ng/dl, P-value >0.001).
It is likely that HCV infection directly modulates hepcidin expression by inducing reactive oxygen species and raising iron levels, thus reducing hepcidin transcription . A study by El Said et al.  in 2018 found significantly lower hepcidin levels in dialysis patients infected with HCV than those who were HCV negative. This agrees with the findings in our study of significantly lower hepcidin in chronic HCV-infected dialysis patients than the treated group who were restored to a status possibly similar to HCV-negative dialysis patients as regards elevated hepcidin levels.
The suppression of hepcidin by chronic HCV infection can contribute to lower erythropoietin and iron demands in these patients . Follow-up of these patients is required for the differences in erythropoietin and iron requirements. However, it was notable that hemoglobin levels were comparable in both groups (mean 10.3±1.53 vs. 10.54±1.6 g/dl) on the same mean erythropoietin weekly dose in treated HCV and HCV-positive patients.
In our study, there was a statistically significant difference between HCV-infected and HCV-treated groups as regards iron levels and Tsat. Tsat was lower in the HCV-treated than in the HCV-infected group (23.5±7.75% vs. 25.57±13.58%), respectively. Furthermore, ferritin levels were more elevated in the HCV-infected group than those treated from HCV (899.5±1522 vs. 355.13±196 ng/dl, respectively). The liver is the main organ that stores iron, it synthesizes both transferrin and ferritin . Several studies , have shown that HCV-infected HD patients may have higher hemoglobin, transferrin saturation, and ferritin levels, and lower iron and erythropoiesis-stimulating agent requirements than dialysis patients without HCV infection.
Studies that report elevated iron biomarkers in chronic HCV-infected patients explain these elevations by the release of iron from damaged hepatocytes ,. The differences between the two groups in the current study might not have reached the level of iron overload expected from chronically HCV-infected patients and might not be the single contributing factor to lower hepcidin level in those patients compared with HCV-treated patients.
It is of note that the pathogenesis of anemia and iron homeostasis in HD patients is multifactorial and that the level of liver affection by HCV infection was not taken into consideration in this study. Several studies have found contradictory data regarding iron effects on HCV replication ,. It is not clear whether iron facilitates disease progression post HCV infection through increased oxidative stress and inflammation or by direct effect on HCV replication .
In the current study, hepcidin levels correlated with TIBC, Tsat, and ferritin in the hepatitis-C-treated group. On regression analysis, only Tsat and TIBC correlated significantly (unstandardized β=0.814, P=0.013 and unstandardized β=6.838, P=0.028).
Studies are contradictory about the relation between hepcidin and ferritin since ferritin is an acute-phase reactant. Damien et al.  found no correlation between hepcidin and ferritin, while a study by Takahiro found no correlation between them .
| Conclusion|| |
It is clear that treatment of HCV in dialysis patients abolishes the inhibitory effect that HCV has on hepcidin and brings back these patients to the state of high hepcidin and iron deficiency induced by dialysis, however, its beneficial effect in decreasing iron overload in the liver and other organs is expected and yet to be determined in further studies. Careful consideration should be taken when using hepcidin as a marker for anemia in dialysis patients as levels can be affected by several other factors.
Financial support and sponsorship
Nil.Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]