|Year : 2015 | Volume
| Issue : 1 | Page : 127-132
A study on biochemical facet of anemia in cancers: A strong link between erythropoietin and tumor necrosis factor alpha in anemic cancer patients
P Kalyani, K Jamil
Department of Genetics, Bhagwan Mahavir Medical Research Centre, Hyderabad, Andhra Pradesh, India
|Date of Web Publication||3-Feb-2016|
Department of Genetics, Bhagwan Mahavir Medical Research Centre, Hyderabad, Andhra Pradesh
Source of Support: Department of Genetics, Bhagwan Mahavir
Medical Research Centre and Indo American Cancer Institute and
Research Centre (for resources like lab and equipments)., Conflict of Interest: None
Background: The three direct factors that could lead cancer patients to anemia, apart from therapy are iron deficiency, inflammatory cytokines surge and decreased erythropoietin (Epo). Our aim was to quantify biochemical and hematologic markers serum Epo, ferritin (Fe) and tumor necrosis factor-alpha (TNF-α) along with hemoglobin (Hb) to understand the associations between these factors, patient characteristics and anemia. Materials And Methods: The study group consisted of 100 anemic cancer patients and 80 controls. Biochemical marker levels were determined by the enzyme linked immunosorbent assay on an autoanalyser. Univarient analysis, t-test, ANOVA, Bonferroni test, linear regression was performed to find correlations and associations among various factors. Results: The baseline serum Epo (153.07 ± 173.88 vs. 23.607 ± 36.462) and Fe levels (233.53 ± 257.12 vs. 23.06 ± 20.04) were adequately high in cases compared with that controls (P ≤ 0.001). Considerable raise in TNF-α levels was also observed (16.26 ± 13.44 vs. 11.2375 ± 4.84) (P = 0.001). TNF-α correlated positively (P = 0.022) with Epo and Fe (P = 0.000), which was also evident from large effect size of Epo (r2 = 0.414), TNF-α (r2 = 0.369), Hb (r2 = 0.226). Epo and Hb were negatively correlated (β = −0.375, P = 0.001) and Epo production was found to be appropriate for the degree of anemia (O/P ratio of 3.51 ± 1.26 vs. 1.43 ± 0.47). A strong association was seen between Hb, Epo and TNF-α in hematological and gynecological malignancies for different grades of anemia. Men were more prone to life-threatening anemia (13%) than women (9%). Conclusion: Anemia in cancers was not because of inadequate Epo or Fe levels, but because of improper Epo response. Further studies on molecular analysis of Epo, biochemical and molecular interplay between Epo and TNF-α could explain a rationale for anemia in cancers.
Keywords: Anemia in cancers, erythropoietin, ferritin, hemoglobin, tumor necrosis factor alpha
|How to cite this article:|
Kalyani P, Jamil K. A study on biochemical facet of anemia in cancers: A strong link between erythropoietin and tumor necrosis factor alpha in anemic cancer patients. Indian J Cancer 2015;52:127-32
|How to cite this URL:|
Kalyani P, Jamil K. A study on biochemical facet of anemia in cancers: A strong link between erythropoietin and tumor necrosis factor alpha in anemic cancer patients. Indian J Cancer [serial online] 2015 [cited 2019 Aug 19];52:127-32. Available from: http://www.indianjcancer.com/text.asp?2015/52/1/127/175579
| » Introduction|| |
Over the recent years, our understanding of the effects of anemia in cancer patients and its consequences on treatment outcomes and quality-of-life (QoL) has dramatically increased., The clinical manifestation and severity of anemia vary considerably among individual patients. Moderate anemia can typically cause symptoms such as headache, palpitations, tachycardia and difficulty in breathing, whereas chronic anemia can result in severe organ damage. Studies also reveal that anemia may impair the efficacy of cancer therapies., Although many factors add to the fatigue experience, including the disease and its treatment, anemia perse, seems to play a major role in affecting daily living and QoL.
When some of the vital biochemical changes that occur are keenly observed, anemia can crop up for varied reasons in cancer patients. It could be simply because of improper nutrition and so inadequate iron levels, which leads to low hemoglobin, poor response of the cancer patients to hypoxia and so inadequate erythropoietin (Epo) production, which can lead to low red blood cell (RBC) count or could be because of the cytokine encounter.
Ferritin (Fe) the most reliable indicator of total body iron status ,, and sufficient Epo levels are crucial for RBC production. Epo is the accelerator that drives erythropoiesis, whereas iron is the fuel for making of RBC's. When the two are in good concert, RBC production moves briskly and competently. Nearly 90% of Epo is produced in the peritubular cells of the adult kidney in response to hypoxia., In the presence of a normal stem cell reserve, erythropoiesis increases in proportion to the degree of anemia through an exponential increase of Epo. Tumor necrosis factor-alpha (TNF-α) was described to be involved in the pathogenesis of cancer related anemia. Not only through complex mechanisms of the purely inflammatory situation, but also through genetic regulatory pathways of erythropoiesis such as GATA-1, GATA-2 and other factors. Association studies proved the relation between the inflammatory cytokine interleukin 6 and Epo in anemic patients. Though contrasting results were observed with respect to Epo levels,,,, the scenario in Indian population is not known.
We assessed our study group of south Indian population to determine if the production of Epo acts in response to hemoglobin (Hb) levels appropriately, if so it's status in anemic cancer patients and the control group. This is to scrutinize if Epo imbalance is the basis of anemia of cancers and to assess Epo's potential as a diagnostic tool. We analyzed if there is any correlation between the hematological and biochemical factors such as Hb, Epo, Fe, TNF-α and if so, to understand the association between these biochemical parameters and patient characteristics such as type of cancer, age, gender, treatment status and severity of anemia.
| » Materials and Methods|| |
Study group and sample collection
The study group consisted of 100 anemic cancer patients diagnosed with neoplasia of various kinds by the Oncologists of the Hospital and 80 controls defined as healthy individuals without cancer or anemia. The enrollment of cancer patients with anemia was in accordance with the ethical standards of the hospital committee to participate in this investigation. Further, patients consent as voluntary participants in this investigation was obtained. The study group was of South Indian origin and of a particular region, i.e., Andhra Pradesh. At the time of enrollment, their medical history and the kind of neoplasm they were suffering from, was recorded. The characteristics recorded in the proforma were age, gender, dietary habits, occupation, history of previous malignancies, type of cancer they were suffering from, treatment modality, treatment status at the time of collection of data, QoL parameters etc., and all data was subjected to statistical analysis.
Inclusion and exclusion criteria
Blood samples were collected from cancer patients 10 days before or after the treatment, and from those cases whose treatment modalities were known. Serum creatinine reports were observed before collection of the sample to rule out cases with secondary anemia due to renal failure. Cases of primary erythrocytosis were excluded from the study, as they might result in abnormally low levels of serum Epo.
Estimation of serum Hb, Epo, TNF-α, and Fe levels
There are varying degrees of severity of anemia, generally based on Hb levels. The National Comprehensive Cancer Network anemia classifications were used to rate the severity of anemia. Standard Procedures were used for biochemical and hematological estimations. The blood Hb levels were analyzed both by drabkins method and by automated Beckman coulter. Whole blood was collected from patients and controls between 8 a.m. and 12 p.m. in serum vacutainers without anticoagulant to avoid diurnal variations of the Epo hormone., The whole blood was centrifuged for 10 min at 1500 rpm. The separated supernatant serum was stored at −80°C until the experiments were carried out. Grossly hemolyzed or lipemic samples were excluded from the study. Serum Epo, TNF-α and Fe levels were determined by the enzyme linked immunosorbent assay using the commercially available kits (DRG International Inc., USA; Diaclone; Aadaltis, Italy) on fully automated analyzer (Chemwell).
Univarient analysis was carried out for each of the parameters. Data was expressed as mean ± SD. Regression was carried out to observe the correlation between the quantified biochemical factors where P < 0.05 was considered to be significant in all the analysis executed. Independent sample t-test and linear regression were performed for finding the association between gender and various biochemical aspects, whereas for other categories such as age, type of cancer, severity of anemia and treatment status where more than two variables are involved, one-way analysis of variance (ANOVA) was performed. To overcome the fishing expedition problem, posthoc analysis was performed with bonferroni adjustments. This is also to identify the difference between subgroups. For these objectives the statistical analysis was carried out through IBM statistical package for social sciences (SPSS) software version 20 and other online software.
Serum Epo analysis
Log transformed values of serum Epo and Hb were taken to conduct exponential regression. Hb values in g/dL were converted to mM/L by multiplying with 0.6206, the standard conversion factor. Linear regression was carried out with log (observed Epo) versus Hb to obtain a regression equation (6.0+ (−0.54* Hb)) for cases and(8.18+ (−0.27* Hb)) for controls, which was in line with the standard equation y = α1+ β1 * x. i.e., Log (Epo) = intercept + slope * Hb. This equation was employed to predict the Epo value based on the Hb concentration and to derive observed/predicted (O/P) ratio by taking Log (Observed Epo)/Log (Predicted Epo) values. An O/P ratio less than 0.80 in an anemic patient was taken as an indicator of blunted Epo production., The mean O/P ratio of 1.01 ± 0.11 (95% CI; 0.80-1.22) in reference subjects was also considered as a standard.
| » Results|| |
We have analyzed serum Hb, Fe, Epo and TNF-α levels in a total of 180 samples and the diagnosis included 100 anemic cancer cases and 80 healthy controls. Samples were gender matched with P = 0.510. Incidence of anemia was high in the age groups 30-60 years (68%). Grade II and Grade IV anemia was more prevalent in cases (42% and 22%) than Grade I and Grade III anemia (18%). The reference and mean values of the hematological and biochemical factors studied in cases and controls are shown in [Table 1]. The baseline serum Fe and Epo levels were significantly increased (P < 0.0001) in anemic cancer cases compared with that of controls. TNF-α levels also augmented considerably (P = 0.001) in patients against the control group [Table 1] [Figure 1].
|Figure 1: Variations in mean values of hemoglobin, erythropoietin, ferritin, tumor necrosis factor-alpha in cases and controls|
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Serum Hb ranged from 3.7 to 10.9 g/dl in cases and 12-14.1 g/dl in controls. Out of 66 women and 34 men, Grade IV anemia was prevalent in men (13%) than women (9%) whereas, Grade III anemia was observed in 4% men and 13% women. The average Fe level in Grade IV anemic cancer patients was found to be 240.46 ng/mL.
High Epo level was seen to be associated with Cases (χ 2 = 59.70; P < 0.001). Statistical difference in Epo levels between males and females was significant (P = 0.012). Men responded to anemia with better levels (212.41 ± 207.11) than women (121.51 ± 144.98). High circulating Epo levels were recorded in both patients with low and normal Hb levels. This huge deviation was evident from [Figure 1] and [Figure 2], especially in Head and Neck (H and N) cancers with levels ranging from 1 to 480 mU/ml.
In response to the highest number of life-threatening anemic cases recorded with hematological and gynecological malignancies [Table 2], significant increase in Epo levels was also seen [Table 3].
|Table 3: Relationship between the patient characteristics and biochemical parameters|
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Endogenous Epo production was apposite for the degree of anemia as seen from the mean O/P ratio (3.51 ± 1.26) in patients compared with that of controls (1.43 ± 0.47). 95% of the cases responded to anemia with an O/P ratio >1.4, whereas 3% of the cases were having O/P ratio between 1.0 and 1.39 and 2% with ratio <0.1. These 2% patients who did not respond to anemia were aged >60 years and were found to be suffering from cancer of the cervix and buccal mucosa and were not under chemo or radiotherapy.
No significant relation was present between age and biochemical parameters and so with the treatment status [Table 3] and [Table 4]. Hb, Epo and TNF-α were strongly associated in hematological and gynecological malignancies and all four grades of anemia. This was also evident from the significance observed between the three factors, a result of bonferroni test [Table 3]. TNF-α showed a relation (P = 0.022) with Fe and Epo (P = 0.000) in anemic cancer patients [Table 5]. When grouped by age, higher TNF-α level were evident with younger patients than the aged. Significantly high levels were observed in hematological malignancies and in Grade IV anemic patients [Table 3].
|Table 4: Incidence of hematological and biochemical status in relation to patient characteristics|
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|Table 5: Correlation between the hematological and biochemical parameters studied|
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A linear relationship among all four biochemical variables was observed as indicated by the significant ANOVA values [Table 5]. There was no considerable relation between Hb and TNF-α, serum Fe and Epo. A significant negative correlation was noticed between Hb and Epo (β = −0.375, P = 0.001) as expected. This inversely proportional relationship was also evident from the mean values observed in mild, moderate, severe and life-threatening anemic cases in response to Hb levels [Table 3].
A linear positive correlation was seen between rest of the biochemical factors i.e., Hb and Fe (β =0.209, P = 0.025); Fe and TNF-α (β =0.269, P = 0.026); Epo and TNF-α (β =0.506, P = 0.000). When the strength of relationship between the two variables was observed, significantly large effect size was evident with Hb (r2 = 0.226), Epo (r2 = 0.414) and TNF-α (r2 = 0.369), whereas medium effect size with Fe (r2 = 0.094).
Diagnostic role of Epo
High positive predictive value (PPV) 91.43 was observed [Table 6] which indicates that Epo has a good diagnostic role and is a reliable test in screening and determining the cause of anemia in cancers. This high PPV value is a critical measure of the performance of a diagnostic method, as it reflects the probability that a positive test reflects the underlying condition being tested for. The receiver operator characteristic curve indicating the higher overall accuracy of the test is shown in [Figure 3].
Patients between 30 and 60 years were more prone to anemia in cancers. The highest number of cases recorded were of gynecological malignancies (43%), followed by gastro intestinal cancers (18%), hematological malignancies (13%), H and N cancers (12%), lung cancers (11%) and others (3%). Though, females were more prone to anemia (66%), during, before and after cancer treatment, men are not to be neglected for their blood Hb levels and QoL. Unlike the iron deficiency anemia, men were 7.6% more prone to Grade IV anemia in cancers.
Very few studies have been conducted in cancer patients to see the association between various biochemical factors through which basic cause of anemia could be traced. It was evident from our observation and previous studies that Hb and Epo are correlated and inversely proportional to each other. Contrasting results have also been observed in the literature where the expected inverse relation between serum levels of immunoreactive Epo and of Hb was absent and Epo inadequacy was observed in cancer patients with anemia., The reason for these variations in Epo levels of cancer patients is not completely understood. Divergent from a study where no gender difference was found, men responded to anemia with better Epo levels than women.
Extreme Epo hormone fluctuations observed in H and N cancers was in line with our previous studies where vast Hb fluctuations were evident with H and N cancers  indicating that Epo levels correlate with Hb levels. This can also be justified by the O/P Epo ratios observed.
Evidence of the interplay between iron and Epo is in existence from a long time. Drawing together the entire observations, though Epo levels have significantly increased in cases compared with controls and high Fe levels recorded, anemic conditions were still prevalent. This was also evident from lack of significance between Fe and circulating serum Epo levels. Hence, association between Hb, Epo and TNF-α noticed especially in hematological and gynecological malignancies at all stages of anemia indicates that anemia in cancer is an outcome of inflammation, not decreased Epo response to anemia or iron deficiency anemia. Chronic inflammatory cytokines might have reduced the effects of Epo and iron utilization within the erythroid bone marrow. Though there are studies which stated no correlation between serum Epo, TNF-α and showed the inhibitory effect of TNF-α on Epo production, by activation of the TNF/TNF-R system ,, this is not yet proved in anemic cancer patients. Studies showing an association between these two factors and the path that leads to the same in anemic cancer patients is barely studied so far. This is the primary study to confirm a significant positive linear correlation between serum Epo and circulating TNF-α levels in anemic cancer patients, though negative correlation between these two factors was reported in a small group of patients. Furthermore, taken collectively, observations suggests that particularly in hematological and gynecological malignancies, this is the foremost study to report the association between of these three biochemical factors Hb, Epo and TNF–α, which could have exerted a negative effect on erythropoiesis in anemic cancer patients.
Unlike the condition seen in anemia of chronic disease, in this study group Epo and TNF-α are strongly linked. Though TNF-α significantly suppresses late-stage erythropoiesis, leading to anemia in chronically treated mice  and addition of TNF-α resulted in a dose-dependent inhibition of hypoxia-induced Epo production by as much as 89%, the molecular link between these two factors is yet to be established. These erythropoietic effects could affect the clinical role of TNF-α as a biomarker.
Although immunomodulatory drugs are being tried in combination with erythropoietic agents  and drugs that target inflammation are available and corrects anemia, they do not improve cancer control or survival. Hence, it is not about tracing out anemia in patients with cancer, but figuring out the cause and treating the patients appropriately is vital. This is the first report from south Indian population indicating the importance of biochemical factors in association with anemia in cancers, which was not because of inadequate Epo or Fe, but could be because of inflammatory cytokines.
Anemia should be considered as an indicator of ill-health, as it was recorded in the maximum number of cases at the time of admission, even before the diagnosis of cancer and is the major factor contributing to poor QoL in cancer patients. Our data reveal that a standardized, easy to perform serum Epo, Fe and TNF-α determination provides a reliable and precise biological norm and serves as a diagnostic adjunct to find the basic cause of anemia in cancer patients and treat them appropriately. Further studies are necessary to understand molecular link between TNF-α and Epo and pathway it takes up, which leads to anemia. A better understanding of the molecular mechanisms involved in the repression of the erythropoiesis might lead to potential conclusions and meet the need for better therapies.
| » Acknowledgment|| |
We would like to sincerely thank all the patients who volunteered to form our study group. We are thankful to the Oncologists and Pathologists who took part in discussions and guided us to select the patients for enrolment. We like to thank the management of Bhagwan Mahavir Medical Research Center and Indo American Cancer Institute and Research Center, Hyderabad, who encouraged us to take up this study and supported with the resources. We would like to extend our warm gratitude to Mr. Venkata Rao, statistician who helped us analyze data.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]