|Year : 2015 | Volume
| Issue : 2 | Page : 80-84
Iron status and erythropoiesis in chronic hepatitis C patients on hemodialysis
Ashraf M El Hefni MD 1, Reda A Kamel Salem2, Huda Ebian3
1 Hematology & Oncology Unit, Faculty of Medicine, Zagazig University, Zagazig, Egypt
2 Nephrology Unit, Department of Internal Medicine, Faculty of Medicine, Zagazig University, Zagazig, Egypt
3 Department of Clinical Pathology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
|Date of Submission||06-Jul-2014|
|Date of Acceptance||21-Nov-2014|
|Date of Web Publication||22-Jul-2015|
Ashraf M El Hefni
Hematology & Oncology Unit, Faculty of Medicine, Zagazig University, Zagazig
Source of Support: None, Conflict of Interest: None
Introduction Anemia is an almost constant complication of advanced renal failure, which may worsen pre-existing heart disease and, as a consequence, accelerate the progression of renal dysfunction, and patients with hepatitis C virus (HCV) infection are associated with higher hemoglobin and hematocrit values compared with those without the infection.
Aim of the work The aim of this study was to evaluate iron status and erythropoiesis in patients with chronic hepatitis C infections who were on hemodialysis and to determine whether HCV infection would affect the iron status and erythropoiesis in such patients, through assessment of serum visfatin and prohepcidin.
Patients and methods All patients included in the study were subjected to the following: full medical history and clinical examination; routine laboratory investigations; serum ferritin and serum iron evaluation; total iron-binding capacity with transferrin saturation; evaluation of serum visfatin level using an enzyme immunoassay; and determination of serum prohepcidin concentration using available enzyme-linked immunosorbent assay kit.
Results A total of 107 chronic renal failure patients on hemodialysis (61 male and 46 female patients) were included in the study, and their ages ranged from 46 to 54 years, with a mean age of 50.5 ± 12.7. Of them, 61 were infected with HCV, and there was no significant relation with different causes of renal failure. Hemoglobin and hematocrit values were significantly higher in hemodialysis patients with HCV infection compared with those without HCV infection, with significant reduction of total iron supply and erythropoietin dosage/month. There were significant negative correlations between hemogloblin and hematocrit levels and iron supply and erythropoietin dosage/week, whereas significant positive correlation was observed between hemogloblin, hematocrit, serum iron, ferritin, transferrin saturation, as well as liver enzymes (aspartate transaminase, alanine transaminase) with serum visfatin and prohepcidin. Moreover, transferrin saturation, ferritin, and prohepcidin contributed independently to visfatin variance.
Conclusion Serum levels of visfatin and prohepcidin are higher in chronic renal failure patients on hemodialysis and correlates with chronic hepatitis C infection, which is associated with an increased erythropoiesis, leading to lowering of the necessary erythropoietin dose and iron therapy.
Keywords: chronic hepatitis C, erythropoiesis, prohepcidin, visfatin
|How to cite this article:|
El Hefni AM, Kamel Salem RA, Ebian H. Iron status and erythropoiesis in chronic hepatitis C patients on hemodialysis. Egypt J Haematol 2015;40:80-4
|How to cite this URL:|
El Hefni AM, Kamel Salem RA, Ebian H. Iron status and erythropoiesis in chronic hepatitis C patients on hemodialysis. Egypt J Haematol [serial online] 2015 [cited 2022 Jun 25];40:80-4. Available from: http://www.ehj.eg.net/text.asp?2015/40/2/80/161293
| Introduction|| |
Anemia is a universal complication of chronic renal failure and has multiple causes, the most important being decreased production of erythropoietin by the kidney  .
Hemodialysis per se, as well as disturbances in both innate and adaptive immunity, renders patients susceptible to infections, which is the major cause of morbidity and the second cause of death following cardiovascular events in patients on hemodialysis  .
Hepatitis C has infected nearly 200 million people worldwide, and 3-4 million people are infected every year, and it is a leading cause of cirrhosis and a common cause of hepatocellular carcinoma. As a result of these conditions, it is the leading reason for liver transplantation in the USA  .
Visfatin is a newly discovered adipocyte hormone with a direct relationship with type 2 diabetes mellitus. Visfatin is up regulated by hypoxia, inflammation, and hyperglycemia and down regulated by insulin, somatostatin, and statins  .
Serum visfatin concentration increases significantly in hepatitis C patients, and these findings suggest that visfatin is important in the pathogenesis of the inflammatory process in chronic hepatitis C. Moreover, hepatitis C virus (HCV)-infected patients are associated with higher serum iron, ferritin, transferrin saturation, and increased red blood cell (RBC) count , .
| Aim of the work|| |
The aim of our study was to evaluate iron status and erythropoiesis in patients with chronic hepatitis C infections on hemodialysis and to determine whether HCV infection would affect iron status and erythropoiesis in chronic hepatitis C hemodialysis patients, through assessment of serum visfatin and prohepcidin.
| Patients and methods|| |
This study was designed to assess the influence of chronic hepatitis C infections on iron status and erythropoiesis in chronic hepatitis C hemodialysis patients and was carried out in the Hematology/Oncology Unit, the Nephrology Unit, and the Internal Medicine Department, and it included 107 hemodialysis patients. Of them, 61 were male and 46 were female, and their ages ranged from 46 to 54 years, with a mean ± SD of 50.5 ± 12.7 years. All of them had been on regular hemodialysis for at least 6 months, 4 h/day, three times a week.
Patients were labeled as HCV-positive if they had positive anti-HCV antibodies on two separate occasions or on one occasion, along with a confirmatory HCV polymerase chain reaction testing. Forty-six hemodialysis patients were negative for HCV antibody; their ages ranged from 45 to 55 years, with a mean age of 52.5 ± 14.7, and were used as controls; in contrast, 61 hemodialysis patients were positive for HCV antibody, which was confirmed by PCR, and their ages ranged from 45 to 56 years, with a mean of 54 ± 12.8. All patients with a history of blood transfusion, massive blood loss in the last 6 months, polycystic kidney, cryoglobinemia, active malignancy, hemopiotic disorder, gastrointestinal bleeding, and those undergoing active treatment with interferon or ribavirin and borderline positive tests or with a history of HCV with negative serologic tests were excluded from the study. Informed consent was obtained with the approval of local ethical committee.
All patients included in the study were subjected to full medical history and clinical examination, including routine laboratory investigations: ABO blood grouping and Rh, parathyroid hormone evaluation, complete blood count, and erythrocyte sedimentation rate determination. Serum ferritin, serum iron, total iron-binding capacity (TIBC) with transferrin saturation (serum iron × 100/TIBC), lipid profile (LDL, cholesterol, and triglycerides), fasting blood sugar, liver profile, creatinine, urea, uric acid, sodium, potassium, chloride, prothrombin time/international normalized ratio, and activated partial thromboplastin time were evaluated. Viral markers were analyzed and a pelvic abdominal ultrasound was performed. Serum visfatin concentrations were measured using an enzyme immunoassay (Phoenix Peptides, Karlsruhe, Germany), with a sensitivity of 0.1 ng/ml. The intra-assay and interassay CV was 6%. Serum prohepcidin concentrations were also measured using a commercially available enzyme-linked immunosorbent assay with antibodies specific for peptides 28-47 of the proregion of the molecule (DRG, Heidelberg, Germany). The detection limit was 4 ng/ml. The intra-assay and interassay CV was 7%.
Data were analyzed using IBM SPSS advanced statistics, version 20 (SPSS Inc., Chicago, Illinois, USA). Numerical data of scores were expressed as mean and SD or median and range, as appropriate. Qualitative data were expressed as frequency and percentage. The χ2 -test (Fisher's exact test) was used to examine the relation between qualitative variables. For not normally distributed quantitative data, comparison between the two groups was made using the Mann-Whitney test (nonparametric t-test). The Spearman-ρ method was used to test correlation between numerical variables. The receiver operating characteristic curve was used for the prediction of cutoff values, and P-value less than 0.05 was considered significant.
| Results|| |
A total of 107 hemodialysis patients (61 male and 46 female patients) were included in the study and their ages ranged from 46 to 54 years, with a mean age of 50.5 ± 12.7. All of them had been on regular hemodialysis for at least 6 months, 4 h/day, three times a week, with a mean of 57.3 ± 37.4 in the control group and 51.8 ± 35.9 in the HCV-infected patient group. No significant relation was detected with different causes of renal failure ([Table 1] and [Table 2]).
|Table 2 Biochemical characteristics and significant difference of the studied patients |
Click here to view
RBC count and hemoglobin and hematocrit values were significantly higher in hemodialysis patients with HCV infection compared with noninfected patients. Serum iron, TIBC, and transferrin saturation were also significantly higher in patients with HCV infection compared with noninfected patients, with significant reduction of total iron supply and erythropoietin dosage/month, and a significant reduction of platelet number in HCV-infected patients was seen ([Table 3]).
|Table 3 Correlation coefficient between HB and HCT with other variable in HCV group |
Click here to view
There were significant negative correlations between hemogloblin and hematocrit levels and iron supply and erythropoietin dosage/week, whereas significant positive correlation was seen between hemogloblin, hematocrit and serum iron, ferritin and transferrin saturation, as well as liver enzymes [aspartate transaminases (AST), alanine transaminases (ALT)]. Moreover, serum visfatin was significantly correlated with serum ferritin as well as hemoglobin and hematocrit. A significant positive correlation was detected between prohepcidin, visfatin, and transferrin receptor saturation ([Table 4]).
|Table 4 Multiple regression analysis with serum visfatin as the dependent variable |
Click here to view
When regression analysis was applied, transferrin saturation, ferritin, and prohepcidin contributed independently to visfatin variance (P = 0.04, 0.006, and 0.02, respectively).
| Discussion|| |
Chronic kidney disease is a public health problem. It is one of the most important causes of death worldwide and also a major cause of anemia in developing countries. The long-term survival and good quality of life of patients with chronic renal failure depend, among other factors, on hemoglobin, iron status, and bone marrow response to erythropoiesis stimulating agents  . In general, anemia is normocytic, normochromic, and usually well tolerated until the advanced stages of kidney disease, whereas other factors may contribute to its establishment, maintenance, or aggravation ,, . Anemia is an almost constant complication of advanced renal failure, which might worsen pre-existing heart disease and, as a consequence, accelerate the progression of renal dysfunction  . The specific treatment of choice for anemia due to chronic renal failure is recombinant human erythropoietin (rHuEPO), a drug considered a historic milestone since the time of its clinical use  and a major therapeutic advancement in the treatment of anemia due to chronic renal failure. Erythropoietin remains a cornerstone in the treatment of anemia of renal failure  .
Patients with HCV infection were associated with higher hemoglobin and hematocrit compared with noninfected patients. Chan and colleagues found that chronic hepatitis C infection has an effect on RBC status and that the hemoglobin level of patients with HCV infection was higher than that of noninfected patients. A highly significant association of hemoglobin and hematocrit with HCV infection and the relation between HCV infection and erythropoiesis has been proposed to be either due to the secretion of erythropoietin from regenerating liver cells  or due to alternations in iron metabolism  . The similar findings in our study were found along with an increment in visfatin level, which correlated with serum ferritin, hemoglobin, and hematocrit level, and transferrin saturation reflecting erythropoiesis, which occurred in HCV-infected patients on hemodialysis. Our findings were in agreement with those of Sahin et al.  , who concluded that 49 patients had higher hemogloblin and hematocrit levels in HCV-infected patients compared with HCV noninfected patients, and this attributed to increased production of erythropoietin from HCV-infected patient's hepatocyte.
Sabry et al.  concluded that HCV-infected patients and HCV noninfected chronic hemodialysis patients in Egypt had comparable hemoglobin as well as hematocrit levels. This was in contrast to our findings, which showed that HCV-infected hemodialysis patients had higher hemoglobin and hematocrit levels. The difference may be attributed to the variation in the selection criteria of patients. It was also found that higher levels of AST, ALT in HCV-infected patients reflecting a higher inflammatory state significantly correlated with hemoglobin and hematocrit.
Also, HCV-infected patients needed lower erythropoietin and iron doses than HCV noinfected patients. This data supported by Kranthi et al.  , who reported that lesser erythropoietin and iron requirements in HCV-infected patients compared with HCV noninfected patients, as a result of higher endogenous serum erythropoietin concentrations and changes in iron. metabolism in liver diseases. However, Sabry et al.  concluded that the erythropoietin dose was not influential, as its lower value in HCV-infected patients did not reach a statistically significant level. This may be attributed to resistance to erythropoietin action secondary to chronic infection, with impaired iron availability, or perhaps suppressed erythropoiesis by humoral factors, other cytokines, or growth factors; however, our data showed that serum visfatin, which is an inflammatory marker, increased during chronic hepatitis C infection, and prohepcidin was correlated significantly with serum iron ferritin and transferrin saturation, which are the endogenous indices of erythropoiesis, which might be another explanation  . These findings are also supported by Chan et al.  , who concluded that HCV infection is associated with high ALT levels, which is independently associated with higher hemoglobin and hematocrit levels.
Abdalla et al.  reported a higher erythropoietin requirement in HCV-infected versus HCV noninfected patients, which was a result of altered iron metabolism induced by chronic infection; however, the mechanism by which infection and inflammatory disease impaired erythropoiesis was still poorly understood.
Lemos et al.  found that HCV-infected patients had significantly higher ALT levels compared with the noninfected patients; they also suggested that the serum ALT level in predialysis patients may be a good marker of HCV infection. A study by Fabrizi et al.  showed that patients on dialysis in general tend to have lower ALT levels. Cotler et al.  also found that the serum ALT levels were significantly lower in patients with chronic renal failure and this might be attributed to liver cell protection by hepatocyte growth factor, which showed higher concentration in patients with chronic renal failure on hemodialysis. The lower ALT activity in hemodialysis patients might also be a consequence of a smaller serum HCV viral load either due to the adsorption of the virus genome in the dialyzer membrane or due to the induction of endogenous interferon caused by hemodialysis  . Hepatitis C had a greater tendency toward intermittent exacerbations and remissions, with a very variable and fluctuating ALT profile. Thus, patients with HCV, on dialysis may have normal ALT levels despite significant histological liver damage  .
Our study has shown HCV-infected patients to be associated with higher serum iron, ferritin, and transferrin saturation, and this supported the findings of Kalantar-Zadeh et al.  . Moreover, there was increased RBC count, and this was in consistence with a study by Simon et al.  , who found that there was increased endogenous erythropoietin secretion in HCV-infected patient. The major requirement for erythropoiesis was adequate iron stores, which was assessed mainly by calculating serum TSAT (serum iron/serum TIBC ×100) and measuring circulating ferritin levels. After dialysis, almost all patients require periodic intravenous-iron supplementation to keep iron saturation in the range of 20-50% and ferritin levels between 100 and 800 ng/ml based on guidelines.
Patients with chronic hepatitis C infection tended to have a higher ferritin level when compared with non-HCV-infected patients. This can be explained by romfferritin is an acute phase reactant that is released the liver with hepatic cell and inflammation. Also, I was significantly correlated with prohepcidin and aslvisfatin reflecting its link with increased iron leve fowell as hepatic inflammation  . Increased levels visfatin which correlated with severity of HCV inflammation  and high level of prohepcidin might provide further explanation as both of them were correlated with increased ferritin level subsequently increment of iron level and erythropoiesis without increment of iron supply  .
| Conclusion|| |
Serum levels of visfatin and prohepcidin correlate with chronic hepatitis C infection, which was associated with an increased number of RBCs and higher values of hemoglobin and hematocrit, which led to lowering of the necessary erythropoietin dose and iron therapy.
| Acknowledgements|| |
Conflicts of interest
There are no conflicts of interest.
| References|| |
Berentsen S, Beiske K, Tjønnfjord GE. Primary chronic cold agglutinin disease: an update on pathogenesis, clinical features and therapy. Hematology
Eleftheriadis T, Kartsios C, Yiannaki E, Kazila P, Antoniadi G, Liakopoulos V, Markala D Chronic inflammation and CD16+ natural killer cell zeta-chain downregulation in hemodialysis patients. Blood Purif
Alter MJ. Epidemiology and prevention of hepatitis B. Semin Liver Dis
Adeghate E. Visfatin: structure, function and relation to diabetes mellitus and other dysfunctions. Curr Med Chem
Kukla M, Zwirska-Korczala K, Gabriel A, Waluga M, Warakomska I, Berdowska A, et al.
Visfatin serum levels in chronic hepatitis C patients. J Viral Hepat
Huang JF, Huang CF, Yu ML, Dai CY, Huang CI, Yeh ML, et al.
Serum visfatin is correlated with disease severity and metabolic syndrome in chronic hepatitis C infection. J Gastroenterol Hepatol
Maz HB, Abderrahim E, Zouaghi K. Anemia and end-stage renal disease in the developing world. Artif Organs
Belonje AM, de Boer RA,Voors AA. Recombinant human EPO treatment: beneficial in chronic kidney disease, chronic heart failure, or both? editorial to: ′correction of anemia with erythropoietin in chronic kidney disease (stage 3 or 4): effects on cardiac performance by pappas et al.
′. Cardiovasc Drugs Ther
Tsubakihara Y, Nishi S, Akiba T, Hirakata H, Iseki K, Kubota M, et al.
2008 Japanese Society for Dialysis Therapy: guidelines for renal anemia in chronic kidney disease. Ther Apher Dial
Chamney M, Pugh-Clarke K, Kafkia T, Wittwer I. CE: Continuing Education Article: management of anaemia in chronic kidney disease. J Ren Care
Silverberg DS The role of erythropoiesis stimulating agents and intravenous (IV) iron in the cardio renal anemia syndrome. Heart Fail Rev
Winearls CG, Oliver DO, Pippard MJ, Reid C, Downing MR, Cotes PM. Effect of human erythropoietin derived from recombinant DNA on the anaemia of patients maintained by chronic haemodialysis. Lancet
Schmid H, Schiffl H. Erythropoiesis stimulating agents and anaemia of end-stage renal disease. Cardiovasc Hematol Agents Med Chem
Ando M, Iwamoto Y, Suda A, Tsuchiya K, Nihei H. New insights into the thrombopoietic status of patients on dialysis through the evaluation of megakaryocytopoiesis in bone marrow and of endogenous thrombopoietin levels. Blood
Sahin I, Arabaci F, Sahin HA, Ilhan M, Ustun Y, Mercan R, Eminov L Does hepatitis C virus infection increase hematocrit and hemoglobin levels in hemodialyzed patients? Clin Nephrol
Sabry AA, K.El-Dahshan, K Mahmoud, A El-Husseini, et al.
Effect of hepatitis C virus on hemoglobin and hematocrit levels in Saudi hemodialysis patients. Ren Fail
Kranthi K, SS Faujdar, A Singh, R Prabhu. Hepatitis viruses in heamodialysis patients: an added insult to injury?. Hepat Res Treat
Skikne BS, Flowers CH, Cook JD. Serum transferrin receptor: a quantitative measure of tissue iron deficiency. Blood 1990; 75
Chan HL, Tsand SW, Leung NW, et al.
Occult HBV infection in cryptogenic liver cirrhosis in area with high prevalence of HBV infection. Am J Gastroenterol
Abdalla A, Owda A, Fedail H et al.
Influence of hepatitis C virus infection upon parenteral iron and erythropoietin responsiveness in regular hemodialysis patients. Ren Fail
Lemos LB, Perez RM, Lemos MM, et al.
Hepatitis C among predialysis patients: prevalence and characteristics in a large cohort of patients. Nephron Clin Pract
Fabrizi F, Lunghi G, Finazzi S, et al.
Decreased serum aminotransferase activity in patients with chronic renal failure: Impact on the detection of viral hepatitis. Am J Kidney Dis
Cotler SJ, Diaz G, Gundlapalli S, et al.
Characteristics of hepatitis C in renal transplant candidates. J Clin Gastroenterol
Rampino T, Arbustini E, Gregorini M, et al.
Hemodialysis prevents liver disease caused by hepatitis C virus: role of hepatocyte growth factor. Kidney Int
Contreras AM, Ruiz I, Polanco-Cruz G, et al.
End-stage renal disease and hepatitis C infection, comparison of alanine aminotransferase levels and liver histology in patients with and without renal damage. Ann Hepatol
Kalantar-Zadeh K, McAllister CJ, Miller LG. Clinical characteristics and mortality in hepatitis C-positive haemodialysis patients: a population based study. Nephrol Dial Transplant
Simon P, Meyrier A, Tanquerel T, Ang KS. Improvement of anaemia in haemodialysed patients after viral or toxic hepatic cytolysis. Br Med J
Shan Y, Lambrecht RW, Bonkovsky HL. Association of hepatitis C virus infection with serum iron status: analysis of data from the third national health and nutrition examination survey. Clin Infect Dis
[Table 1], [Table 2], [Table 3], [Table 4]