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Table of Contents
SHORT COMMUNICATION
Year : 2021  |  Volume : 64  |  Issue : 3  |  Page : 125-128

Effects of 100-km ultramarathon on erythropoietin variation in runners with hepatitis B virus carrier


1 Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital; PhD Program in Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
2 Department of Emergency Medicine, School of Medicine, College of Medicine, Taipei Medical University; Department of Emergency Medicine, Mackay Memorial Hospital, Taipei, Taiwan
3 Bavarian Center for Biomolecular Mass Spectrometry, Technische Universität München, Freising Deutschland, Germany
4 Department of Emergency Medicine, School of Medicine, College of Medicine, Taipei Medical University; Department of Emergency and Critical Care Medicine, Taipei Medical University Hospital, Taipei, Taiwan
5 Emergency Department, Taipei Veterans General Hospital; Department of Emergency Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan

Date of Submission19-Dec-2020
Date of Decision12-Mar-2021
Date of Acceptance07-Apr-2021
Date of Web Publication04-Jun-2021

Correspondence Address:
Dr. Chorng-Kuang How
No. 201, Sec. 2, Shih-Pai Rd., Taipei 112
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/cjp.cjp_106_20

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  Abstract 


Completing an ultramarathon leads to an immediate postrace surge of erythropoietin (EPO). Patients with chronic liver disease may have high plasma EPO concentrations. This study aims to explore whether plasma EPO concentrations vary between hepatitis B virus carrier (HBVc) and non-HBVc runners during long distance running. Blood samples were collected from 8 HBVc and 18 non-HBVc runners at 3 different time points: 1 week before, immediately following, and then 24 h after the 100-km ultramarathon race. Samples were analyzed for plasma EPO levels. EPO concentration had a statistically significant rise immediately after the race (8.7 [7.1–11.9] mU·mL−1 to 23.7 [14.8–37.2] mU·mL−1, P < 0.001) and maintained the high levels 24 h after the race finished (16.7 [11.5–21.0] mU·mL−1, P < 0.001) in all participants. The mean of EPO concentration was 8.9 (5.7–13.2) mU·mL−1 in HBVc runners and was 8.7 (7.7–11.2) mU·mL−1 in non-HBVc runners in the prerace. In HBVc runners, plasma EPO levels were no different at baseline (P = 0.657) and increased in the same fashion in response to ultramarathon compared with non-HBVc runners. Plasma EPO levels between the two groups were not statistically different at any time point. Prolonged endurance exercise led to a significant increase in EPO. A comparable increase in EPO levels was observed in HBVc and non-HBVc runners during and 24 h after 100-km ultramarathon. However, a small sample size might have affected the ability to detect a difference if it does exist.

Keywords: Endurance, erythropoiesis, exercise, inflammation, liver


How to cite this article:
Li LH, Chiu YH, Meng C, Kao WF, How CK. Effects of 100-km ultramarathon on erythropoietin variation in runners with hepatitis B virus carrier. Chin J Physiol 2021;64:125-8

How to cite this URL:
Li LH, Chiu YH, Meng C, Kao WF, How CK. Effects of 100-km ultramarathon on erythropoietin variation in runners with hepatitis B virus carrier. Chin J Physiol [serial online] 2021 [cited 2021 Jul 28];64:125-8. Available from: https://www.cjphysiology.org/text.asp?2021/64/3/125/317774




  Introduction Top


Completing an ultramarathon leads to an immediate postrace surge of erythropoietin (EPO), which may be due to hypoxia-inducible factors orchestrating this response.[1] EPO is a crucial glycoprotein hormone that regulates red blood cell (RBC) production, and the liver and kidney are the 2 major organs which produce EPO in response to hypoxia.[1] EPO concentrations were reported to be elevated or unchanged after different types of exercise.[2] A previous study indicates that healthy runners experience lasting high levels of EPO until day 5 after participating in an ultramarathon at moderate altitude, although the regulation of EPO synthesis in athletes is far from being fully understood.[2]

In 1978, the hepatitis B virus (HBV) had infected 10%–17% of the population of Taiwan and was responsible for approximately 80% of chronic liver diseases.[3] After the success of universal infant immunization drive initiated in Taiwan in 1984, seropositivity rates for hepatitis B surface antigen decreased to 0.5%–1.7% in children younger than 15 years in 2004.[4] However, many young and middle-aged endurance athletes are HBV carriers (HBVc) and may conceivably trigger an HBV flare-up because of fatigue, malnutrition, or alteration in immune function.[5] Dialysis patients with HBV infection have higher plasma EPO concentrations than those without.[6] In dialysis patients with hepatitis virus infection, the stimulation of hepatic EPO production is considered an explanation for lessened anemia.[6]

EPO production is primarily stimulated by hypoxia. Endurance exercise is associated with the large-scale stimulation of cytokines storm and oxidative stress.[5] EPO synthesis can be decreased by inflammatory cytokines, such as tumor necrosis factor alpha and interleukin-1.[7] The primary functions of EPO are to maintain RBC mass and act as a cytoprotective agent for several nonhematopoietic tissues.[1] Locally produced EPO has protective effects following tissue injury and inflammation.[8] A delicate balance exists between EPO and proinflammatory cytokines.[8] EPO is produced in the liver during fetal life, but after birth, the production shifts to the kidneys. The liver maintains a production capacity of 10% of the total EPO production but can be up-regulated to 90%–100%.[9] Patients with chronic liver disease may have high plasma EPO concentrations. An ultramarathon is an exhausting exercise that can lead to an inflammatory-like reaction of immune system.[5] To examine the hypothesis whether plasma EPO concentrations vary between HBVc and non-HBVc runners during long distance running, EPO levels were measured between HBVc and non-HBVc runners in response to this level of exercise intensity.


  Materials and Methods Top


The research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. Before conducting the study, ethical approval was obtained from the Taipei Veterans General Hospital Institutional Review Board (VGHIRB No: 2011-01-060IC). All subjects had given their written informed consent before participation. Blood samples were collected from 8 HBVc (with age 48.3 ± 6.6 years) and 18 non-HBVc runners (with age 46.3 ± 10.0 years) at 3 different time points: 1 week before, immediately following, and 24 h after the 100-km ultramarathon race. All 8 HBVc runners were ensured in the nonreplicative phase with positive hepatitis B surface antigen and antibodies against hepatitis B e antigen, and negative for hepatitis B e antigen assessed 1 week before the race. Plasma EPO and HBV-DNA levels were taken at all time points. Plasma EPO was determined by an Architect I-2000 analyzer (Siemens Healthcare Diagnostics Inc., Los Angeles, CA, USA), which used a chemiluminescent microparticle immunoassay. The precision of EPO assay was acceptable with within-run coefficients of variation (CVs) of 2.3%–5.0% and between-run CVs of 4.1%–9.5%. Linearity extended beyond the manufacturer's stated claims, and recovery ranged from 96.8% to 100.9% across the concentrations tested.[10] HBV-DNA levels were tested by quantitative real-time polymerase chain reaction for virus reactivity. Shapiro–Wilk test was used to test the normality of our data. Descriptive data were expressed as median (interquartile range). The plasma EPO values obtained immediately and 24 h postrace were compared to the prerace values using Wilcoxon Signed-Rank test. Mann–Whitney U-test was applied to evaluate the difference between HBVc and non-HBVc runners. All statistical analyses were completed with R (3.1.2) statistical environment, and P < 0.05 was considered statistically significant.


  Results Top


The physiological characteristics and hematological parameters of the study subjects are summarized in [Table 1]. As shown in [Table 2], EPO concentration had a statistically significant rise immediately after the race (8.7 [7.1–11.9] mU·mL−1 to 23.7 [14.8–37.2] mU·mL−1, P < 0.001) and maintained the high levels 24 h after the race finished (16.7 [11.5–21.0] mU·mL−1, P < 0.001) in all participants. HBVc runners completed the ultramarathon in 654 (629–753) min and non-HBVc subjects finished the race in 687 (594–733) min. Our data indicated that EPO concentration in HBVc runners had a statistically significant rise immediately after the race (8.9 [5.7–13.2] mU·mL−1 to 26.3 [21.9–38.3] mU·mL−1, P = 0.012) and maintained that significant increase compared to prerace levels up to 24 h after the race (17.7 [15.4–21.0] mU·mL−1, P = 0.012). For non-HBVc runners, EPO levels increased considerably immediately after the race (8.7 [7.7–11.2] mU·mL−1 to 23.7 [12.8–36.2] mU·mL−1, P < 0.001) and elevated until 24 h after the race finished (16.0 [10.0–20.9] mU·mL−1, P = 0.002) compared to prerace. Ultramarathon increased EPO production in HBVc and non-HBVc runners. Plasma EPO levels between the two groups were not statistically different at any time point. In HBVc runners, plasma EPO levels were no different at baseline (P = 0.657) and increased in the same fashion in response to ultramarathon compared with non-HBVc runners [Figure 1]. Our findings demonstrated an increase of EPO levels by 3.2-fold in HBVc and 2.4-fold in non-HBVc runners immediately after the run. However, there was not a significantly greater increase in EPO levels immediately after the race (P = 0.345) and 24 h after the race (P = 0.222) in the HBVc group. None of the HBVc runners had HBV reactivation with a tenfold increase of the HBV-DNA levels immediately and 24 h after the race.
Table 1: Demographic characteristics and hematological parameters of the study subjects

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Table 2: Erythropoietin concentration throughout the 100 km ultramarathon race between 18 non-hepatitis B virus carrier and 8 hepatitis B virus carrier runners

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Figure 1: Changes of plasma erythropoietin levels after the 100-km ultramarathon in 18 non-hepatitis B virus carrier and 8 hepatitis B virus carrier runners at 3 time points: prerace, postrace, and 24 h postrace. The time profiles in the figures are presented by boxplots (minimum, 25th percentile, median, 75th percentile, and maximum). Each dot represents the erythropoietin level of a subject, and the erythropoietin level of the same subject at different time points are linked by dotted lines. *P < 0.05 versus prerace.

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  Discussion Top


EPO is essential for erythropoiesis. Exercise-induced hypoxia caused by the reduction of blood flow stimulates the synthesis of EPO in the kidney and liver.[2] The lasting high levels of EPO may increase RBC mass to maintain tissue oxygen levels after long distance running.[2] In our study, the 100-km ultramarathon resulted in apparent rise in EPO concentrations in both HBVc and normal human controls groups during and 24 h after the run. This finding is consistent with the results of previous research indicating an increase in EPO levels after an ultramarathon run at moderate altitude.[2] Furthermore, our results revealed that plasma EPO levels between the 2 groups are not statistically different at any time point.

The main function of EPO is to maintain RBC mass. However, the EPO elevation for several hours does not translate in effective erythropoiesis. In a narrative review, although a significant increase in EPO levels during altitude training is observed, hematological variables may not improve.[11] Recent evidence suggests that EPO has nonhematopoietic functions, including angiogenesis and tissue protection through cell growth stimulation, differentiation, and antiapoptosis.[8] The clinical relevance of the presented findings needs further research for clarifications.

EPO response against long-distance exercise was reported to be either increased or unchanged after the run. Increased EPO concentrations immediately after the marathon were observed in athletes with low baseline blood iron levels.[12] The modulation of blood iron and oxidative stress may affect exercise-induced changes in EPO levels.[12] Moreover, in some cases, elevated EPO levels were noted in the recovery period (3–8 days after a marathon run). The late lasting raise in EPO concentrations might be indicative of erythropoietic stimulation in response to sports anemia in long-distance runners.[13]

Plasma volume is influenced by posture, heat stress, hydration, and/or exercise. Given the plasma can change markedly during and over the days following prolonged endurance exercise, plasma EPO values were corrected for plasma volume changes, using the equations of Dill and Costill.[14] Even after plasma EPO levels had been adjusted for correction, statistical results did not change as shown in [Table 2].

Taken together, our study demonstrates prolonged endurance exercise leads elevations of plasma EPO, not presenting effective erythropoiesis. Postrace elevations of EPO levels are physiological adaptation to exercise. Plasma EPO levels showed consistent changes in both HBVc and non-HBVc runners during and 24 h after 100-km ultramarathon. This information may assist sports physicians in making decisions about clinical management.

This study has several limitations. First, the sample size is small, which can produce an underpowered state. It is possible that this could lead to a Type II error. Second, due to the lack of a long follow-up period beyond 1 d, the integral variation of EPO in response to ultramarathon cannot be confirmed.


  Conclusion Top


Prolonged endurance exercise led to a significant increase in EPO. A comparable increase in EPO levels was observed in HBVc and non-HBVc runners during and 24 h after the 100-km ultramarathon. However, the small sample size might affect the validity of these conclusions.

Acknowledgments

We would like to thank all the ultramarathon runners who participated in this study, and all the doctors, nurses, and emergency medical technicians who provided professional care at this ultramarathon race. We also thank our colleagues at Soochow University, Taipei, Taiwan and the Chinese Taipei Association of Ultra Runners, Taipei, Taiwan, who assisted during the ultramarathon event.

Financial support and sponsorship

This study was supported by grants from Taipei Veterans General Hospital, Taipei, Taiwan (V100C-202 and V106C-130).

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Jelkmann W. Regulation of erythropoietin production. J Physiol 2011;589:1251-8.  Back to cited text no. 1
    
2.
Schobersberger W, Hobisch-Hagen P, Fries D, Wiedermann F, Rieder-Scharinger J, Villiger B, et al. Increase in immune activation, vascular endothelial growth factor and erythropoietin after an ultramarathon run at moderate altitude. Immunobiology 2000;201:611-20.  Back to cited text no. 2
    
3.
Chen DS, Sung JL. Hepatitis B virus infection and chronic liver disease in Taiwan. Acta Hepatogastroenterol (Stuttg) 1978;25:423-30.  Back to cited text no. 3
    
4.
Chang MH. Breakthrough HBV infection in vaccinated children in Taiwan: Surveillance for HBV mutants. Antivir Ther 2010;15:463-9.  Back to cited text no. 4
    
5.
Chiu YH, Hou SK, How CK, Li LH, Kao WF, Yang CC, et al. Influence of a 100-km ultra-marathon on hepatitis B carrier runners. Int J Sports Med 2013;34:841-5.  Back to cited text no. 5
    
6.
Ifudu O, Fowler A. Hepatitis B virus infection and the response to erythropoietin in end-stage renal disease. ASAIO J 2001;47:569-72.  Back to cited text no. 6
    
7.
La Ferla K, Reimann C, Jelkmann W, Hellwig-Bürgel T. Inhibition of erythropoietin gene expression signaling involves the transcription factors GATA-2 and NF-kappaB. FASEB J 2002;16:1811-3.  Back to cited text no. 7
    
8.
French C. Erythropoietin in critical illness and trauma. Crit Care Clin 2019;35:277-87.  Back to cited text no. 8
    
9.
Risør LM, Fenger M, Olsen NV, Møller S. Hepatic erythropoietin response in cirrhosis. A contemporary review. Scand J Clin Lab Invest 2016;76:183-9.  Back to cited text no. 9
    
10.
Benson EW, Hardy R, Chaffin C, Robinson CA, Konrad RJ. New automated chemiluminescent assay for erythropoietin. J Clin Lab Anal 2000;14:271-3.  Back to cited text no. 10
    
11.
Płoszczyca K, Langfort J, Czuba M. The effects of altitude training on erythropoietic response and hematological variables in adult athletes: A narrative review. Front Physiol 2018;9:375.  Back to cited text no. 11
    
12.
Tomczyk M, Kortas J, Flis D, Kaczorowska-Hac B, Grzybkowska A, Borkowska A, et al. Marathon run-induced changes in the erythropoietin-erythroferrone-hepcidin axis are iron dependent. Int J Environ Res Public Health 2020;17:2781.  Back to cited text no. 12
    
13.
Roecker L, Kowoll R, Fraszl W, Battal K, Brechtel L, Brachmann S, et al. Observation of serum erythropoietin concentrations in female athletes for up to eight days after a marathon run. Clin Lab 2006;52:511-3.  Back to cited text no. 13
    
14.
Dill DB, Costill DL. Calculation of percentage changes in volumes of blood, plasma, and red cells in dehydration. J Appl Physiol 1974;37:247-8.  Back to cited text no. 14
    


    Figures

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    Tables

  [Table 1], [Table 2]



 

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