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 Table of Contents  
Year : 2022  |  Volume : 19  |  Issue : 3  |  Page : 80-85

Elevated homocysteine and crises state in patients with sickle cell anemia: A comparative study

1 Department of Pathology, Haematology Unit, Alimosho General Hospital, Lagos, Nigeria
2 Department of Haematology and Blood Transfusion, College of Medicine, University of Lagos, Lagos, Nigeria

Date of Submission02-Apr-2022
Date of Acceptance20-Jun-2022
Date of Web Publication25-Aug-2022

Correspondence Address:
Dr. Adebukola K Orolu
Department of Pathology, Haematology Unit, Alimosho General Hospital, Igando, Lagos
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcls.jcls_33_22

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Background: High plasma concentration of homocysteine (Hcy) is a well-established risk factor for several disorders, including cardiovascular disease, stroke, venous thrombosis, and arteriosclerosis. Folic acid deficiency leads to an increase in homocysteine. This study aimed to test whether elevated serum homocysteine, diminished folate, and B12 levels correlate with the frequency of crisis in sickle cell disease (SCD). Methods: This was a comparative cross-sectional study conducted on 110 adults consisting of participants with SCD in vaso-occlusive crises (VOC), SCD in hyperhemolytic crises (HHC), SCD in steady-state (SS), and healthy controls. Serum homocysteine, folate, and B12 levels were determined using the Enzyme-linked immunosorbent assay method. The level of statistical significance was defined as P < 0.05, at a 95% confidence interval. Results: The mean age of all participants was 25.5 ± 5.8 years. There was a statistically significant difference in mean serum homocysteine levels with mean levels of (11.9 ± 4.5, 13.1 ± 5.4, 10.3 ± 2.3, 9.9 ± 2.5 μmol/L) in participants in VOC, HHC, SS, and controls, respectively (P = 0.016). With a cut-off of <15 μmol/L, hyperhomocysteinemia was seen in 31.% and 26.7% of participants in HHC and VOC, respectively. Conversely, no participant in the SS or the control group had hyperhomocysteinemia. Serum folate (nmol/L) level was lower, though not significantly, in the HHC group than in the other groups, with 9.9 ± 5.5 versus 12.7 ± 6.8, 11.8 ± 4.1 and 12.7 ± 2.2 nmol/L for the VOC, SS, and control group, respectively (P = 0.121). A significant inverse correlation was found between homocysteine and folate (correlation coefficient − 0.589 and P < 0.001) in all study participants. Conclusion: This study reveals significantly higher homocysteine levels in participants with sickle anemia in vaso-occlusive and hyperhemolytic crises (HHCs), highlighting homocysteine and folate role in the pathogenesis of these events.

Keywords: Homocysteine, sickle cell anemia, sickle cell crises

How to cite this article:
Orolu AK, Adeyemo TA, Akanmu AS. Elevated homocysteine and crises state in patients with sickle cell anemia: A comparative study. J Clin Sci 2022;19:80-5

How to cite this URL:
Orolu AK, Adeyemo TA, Akanmu AS. Elevated homocysteine and crises state in patients with sickle cell anemia: A comparative study. J Clin Sci [serial online] 2022 [cited 2023 Jun 2];19:80-5. Available from: https://www.jcsjournal.org/text.asp?2022/19/3/80/354673

  Introduction Top

Sickle cell anemia (SCA), an inherited hemoglobin (Hb) disease, remains a significant cause of morbidity and mortality in sub-Saharan Africa.[1] This mutation in Hb is thought to have originated in tropical regions due to its protective advantage against malaria.[2] As such, Nigeria, by virtue of its large population, represents the most considerable burden of sickle cell anemia in the world.[3] An estimated 2% of newborns in Nigeria have sickle cell anemia, representing 150,000 annual births with SCA.[4] However, due to the disease-related increased mortality, only about 1 million persons have sickle cell anemia in Nigeria.[5]

Common manifestations of SCA are often the consequence of the hypercoagulable state, vaso-occlusive crises (VOC), and chronic hemolysis that results from recurrent red blood cell sickling and loss of elasticity.[6] This chronic hemolysis, in turn, results in an accelerated drop in Hb concentration with rapid bone marrow turnover and increased demand for folate and predisposing them to a higher risk of folate deficiency.[7] Several studies have explored factors and determinants of the hypercoagulable state seen in patients with SCA.[8],[9] Some of these studies have signaled the possible role of hyperhomocysteinemia in its pathogenesis.[10],[11],[12] Hyperhomocysteinemia is especially problematic within the SCA population.[13],[14] Studies have shown a significant association between elevated homocysteine levels and increased risk for atherosclerosis and cardiovascular disease, resulting in increased morbidity and mortality in an already burdened population.[13],[14]

Typically, hyperhomocysteinemia results from genetic defects in the enzymes needed for its metabolism or nutritional deficiencies of specific vitamins (folate, Vitamin B12, Vitamin B6) that serve as coenzymes for the enzymes involved in homocysteine metabolism.[15] It has been postulated that deficiency of one or more of these vitamins may be responsible for approximately two-thirds of all cases of hyperhomocysteinemia.[16] Within the sickle cell disease (SCD) population, although previous studies have reported hyperhomocysteinemia, there is still much unknown.[17],[18] There is a paucity of evidence regarding its relationship to folate and Vitamin B12 levels in patients with SCA, as varying studies have reported inconsistent findings of low, normal, and elevated levels of these vitamins reported in the presence of hyperhomocysteinemia.[17],[18],[19] Finally, although Ventura et al.[20] demonstrated that homocysteine accumulation due to Vitamin B12 and folate deficiency increased hemolysis in vitro, it is unclear if the same holds accurate as a possible cause of hemolysis in the clinical setting.

Therefore, this study aimed to determine serum homocysteine, folate, and Vitamin B12 levels in adult patients with SCA in steady-state (SS), HHCs, VOC, and healthy controls.

  Methods Top

Using a comparative cross-sectional design, this study was conducted at Lagos University Teaching Hospital (LUTH), Idi-Araba, Lagos. This facility is one of southwest Nigeria's largest tertiary care centers within the Lagos Metropolitan area.[21] The center is a 761-bedded government-funded facility that receives patients for tertiary from all over the country and from neighboring states.[21]

Participants were recruited into one of four arms of the study. The first and the second arms consisted of patients with SCA admitted to the emergency room because of a vaso-occlusive crisis (Group A) or in HHC (Group B). The third arm consisted of patients with SCA recruited from the follow-up clinics in SS (Group C). Finally, the fourth arm consisted of apparently healthy controls with Hb AA and served as controls. Participants were recruited from follow-up clinics and emergency rooms between December 2014 and April 2015. Apparently, healthy controls with no known medical conditions were recruited from among members of staff of the hospital and volunteer blood donors.

All participants were at least 18 years with a confirmed diagnosis of SCA (in Groups A-C) and Hb AA genotype (in Group D) by cellulose acetate electrophoresis at pH 8.4. Potential participants were excluded if there was evidence of kidney disease or a history of thyroid dysfunction. Participants with a history of using medications known to influence plasma homocysteine levels, such as phenytoin and methotrexate, were excluded. Sample size determination was done using the Cochran formula for sample size and mean homocysteine levels from a previous study.[22],[23]

Ethical clearance was obtained from the Health Research Ethics Committee of the Lagos University Teaching Hospital. All participants signed a written informed consent form before recruitment into the study. Before obtaining consent, information was provided to each participant (verbally and written) about the nature of the study, its objectives, potential benefits, and risks. All potential participants were also informed about their rights, including confidentiality, privacy, and the ability to withdraw from the study when they chose.

A predesigned study pro forma collected information about study participants' sociodemographic, medical history, and laboratory values: ten milliliters of venous blood were obtained from each study participant. For patients in crises state, samples were collected within 24 h of presentation for laboratory investigations, including packed cell volume and white blood cell count. The white blood cell count was corrected for nucleated red blood cell count since their values could falsely increase white blood cell count, particularly in HHCs. In addition, serum homocysteine, folate, and Vitamin B12 were determined by the enzyme-linked immunosorbent assay method. Reference range of total homocysteine is 5–<15 μmol/L.[24] Hyperhomocysteinemia occurs with levels above 15 μmol/L, and it has been classified as mild - 15–30 μmol/L, moderate - >30–100 μmol/L, and severe >100 μmol/L.[24]

Data obtained were analyzed using the IBM SPSS Statistics for Windows, Version 25.0 (Armonk, NY, USA: IBM Corp) and presented using tables and figures. Continuous variables are presented as means and standard deviation (SD), while categorical variables are presented as percentages. Comparison of means was carried out using the Student's t-test and analysis of variance where appropriate, while the Chi-square test was used to compare data from categories-discontinuous variables. Correlation analysis was used to determine the relationship between variables. The level of statistical significance was defined as P < 0.05, at a 95% confidence interval.

  Results Top

A total of 110 participants were recruited for this study, with 84 patients with SCA and 26 controls. There were 30, 29, and 25 patients with sickle cell anemia in Groups A (VOC), B (HHCs), and C (SS), respectively.

Sociodemographic and clinical characteristics of study participants

The mean age of all participants was 25.5 ± 5.8 years, ranging from 18 to 41 years. Participants in all four groups did not significantly differ in mean age (P = 0.250). Across all groups, there was a slight male preponderance (51.8% vs. 48.2%) [Table 1].
Table 1: Sociodemographic characteristics of study participants (n=110)

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The mean Hb (g/L) in participants with sickle cell anemia in vaso-occlusive crises, HHCs, and SS were 8.1 ± 1.2, 6.4 ± 0.9, 8.3 ± 2.1, respectively; there was a significant difference between groups (P ≤ 0.001). On post hoc analysis, the mean Hb significantly differed in those in VOC compared to those in HHCs (P < 0.001) and in those in HHCs compared to SS (P < 0.001). However, the Hb level did not significantly differ in VOC participants compared to SS participants (P = 0.760). The white blood cell count (×109/L) followed a similar pattern (12.6 ± 6.1, 15.0 ± 5.0, 8.7 ± 3.4, P < 0.001). On post hoc analysis, white blood cell count was significantly higher in participants in participants in VOC compared to those in SS (P = 0.011) and in those in HHCs compared to SS (P < 0.001). This pattern was not seen in VOC compared to those in HHCs (P = 0.194). The mean age (±SD) of diagnosis of study participants with sickle cell anemia was 3.4 (±3.3) years.

Serum homocysteine, folate, and Vitamin B12 levels in study participants

The mean serum homocysteine level was highest in participants with SCA in hyperhemolytic state (13.1 ± 5.4 μmol/L) and lowest in controls (9.9 ± 2.5 μmol/L) [Figure 1]. The mean serum homocysteine level was significantly different across the groups (P = 0.016). And although the mean serum homocysteine level in each SCA group was higher than in the control group, only the mean serum homocysteine levels in participants in HHCs significantly differed from SS participants (P = 0.041). The mean serum homocysteine level in patients with SCA who were in VOC (P = 0.194) or in SS (P = 0.676) did not significantly differ from those seen in controls. The prevalence of hyperhomocysteinemia in participants with SCA in HHCs and vaso-occlusive crises were 31.0% and 26.7%, respectively. None of the participants in SS or controls had hyperhomocysteinemia (P < 0.001).
Figure 1: Comparison of serum homocysteine levels in study participants. VOC = Vaso-occlusive crises, HHC = Hyperhemolytic crises, SS = Steady state

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In all study participants, the mean folate and Vitamin B12 levels were 11.7 ± 5.1 nmol/L and 98.3 ± 5.1 pmol/L, respectively. The mean serum folate level in each SCA group was lowest in study participants with SCA in HHCs. However, no significant difference was observed in the mean serum folate level between groups; P > 0.05. Similarly, the mean serum Vitamin B12 levels were lowest in SCA participants in HHCs (91.2 ± 38.5 pmol/L). However, there was no significant difference in the mean serum Vitamin B12 level between the Hb SS study groups and controls [Table 2].
Table 2: Comparison of serum homocysteine, folate, and Vitamin B12 levels in study participants

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Relationship between serum homocysteine, folate, and Vitamin B12 in study participants

In all study participants, serum folate levels were significantly negatively correlated with serum homocysteine levels (r = −0.589, P < 0.001). The same was not seen when serum Vitamin B12 and homocysteine levels were correlated (r = −0.162, P = 0.091) [Figure 2].
Figure 2: Correlation between serum folate and homocysteine levels in study participants

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When this relationship between serum homocysteine levels and folate levels were assessed in specific groups, participants in HHCs had the best inverse correlation (r = −0.747, P < 0.001), followed by those in VOC (r = −0.705, P < 0.001) and those in the control group (r = −0.408, P = 0.039). The correlation pattern seen in participants in SS was nonsignificant (r = 0.266, P = 0.198).

Within groups (i.e., participants in VOC, hemolytic state, SS, controls), there was no significant correlation between serum Vitamin B12 levels and homocysteine levels in patients with SCA in vaso-occlusive crises (r = −0.214, P = 0.255). A similar pattern was seen in participants with SCA in HHCs (r = −0.081, P = 0.678), in participants with SCA in SS (r = −0.346, P = 0.091) and in controls (r = −0.058, P = 0.777).

Multivariate analysis of elevated serum homocysteine levels

[Figure 3] displays multivariate analysis results of factors associated with serum homocysteine levels in all study participants. With every 1 nmol/L decrease in serum folate for study participants, the odds of elevated serum homocysteine levels were increased by 2.995 times. Only serum folate levels of study participants remained significantly associated with elevated serum homocysteine in study participants.
Figure 3: Multivariable analysis of factors associated with serum homocysteine levels in study participants

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  Discussion Top

Similar to the findings of the current study, several previous studies conducted globally have reported abnormal homocysteine, Vitamin B12, and folate levels among the SCD population.[18],[19],[25] Especially within this population, these studies have reported a potential role of homocysteine, Vitamin B12, and folate levels in patients with SCD.[25],[26] The current study corroborated this pattern with higher mean serum homocysteine levels in participants with sickle cell anemia compared to healthy controls. This was similar to the finding by Sati'Abbas et al.[26] in India, who also demonstrated higher mean homocysteine levels in patients with sickle cell thalassemia when compared with Hb AA controls, although in that study, this difference was not statistically significant (P > 0.05). This difference may be the consequence of the comparatively smaller sample size compared to the current study. However, the current study contrasts the findings of a similar study also conducted in southwest Nigeria, Olaniyi et al.,[27] who reported significantly lower mean plasma homocysteine levels in 60 patients with SCD compared with the Hb AA controls. Consequently, it was posited that these reduced levels, despite the SCD state, could be a reflection of regular folic acid supplementation in SCA subjects.[27]

Oral folate supplementation has been reported to lower serum homocysteine levels, with meta-analysis revealing that an estimated dosage of 1 mg/dl produces maximum homocysteine reduction of about 25% (or 3 μmol/L from an average of 12 μmol/L).[28] Consequently, it was not surprising to note a significant association between serum folate levels and serum homocysteine levels in participants in the current study. Although it is still unclear the exact pathological process by which serum homocysteine, serum folate, and sickle cell crises are lined, given the increased hemolysis in patients with SCD, an increased folate demand may result, requiring folate supplementation to improve the clinical course of the disease and perhaps reduce the incidence of crises.[26],[29] This is further supported by the finding of significantly lower mean serum folate in HHC subjects compared with controls and other SCA groups. This is not surprising given that hyperhemolysis is a state of more folate demand compared to the SS or VOC state.[30] Similar to the finding of previous studies on the subject, the current study found that the mean serum Vitamin B12 levels of study participants regardless of SCA state did not significantly differ.[19],[26]

It has been shown that folate and Vitamin B12 are essential for erythropoiesis; they also serve as co-enzymes involved in homocysteine metabolism.[31] It was in keeping with the finding of this study which showed significantly lower mean serum folate level in participants with elevated serum homocysteine levels (homocysteine >15 μmol/L) when compared with subjects with normal serum homocysteine levels (homocysteine 5–15 μmol/L). Other studies have also reported a significant negative correlation.[10],[32] Although it can be posited that folate deficiency may lead to elevated serum homocysteine levels, the cross-sectional nature of this study makes it difficult to establish a temporal association.

Previous studies have posited that hyperhomocysteinemia contributes to the initiation of vaso-occlusive crisis through the occlusion of small blood vessels.[26],[33] This was corroborated in the current study by the prevalence of hyperhomocysteinemia in 31%, and 26.7% of participants in HHCs and VOC and none in participants in SS and controls. However, more studies will be needed to establish a temporal association and definitively clarify the role of elevated serum homocysteine levels in patients with SCD, especially within the Nigerian population.

  Conclusion Top

This study found significantly higher serum homocysteine levels in participants with sickle cell anemia compared to controls. This study also highlights a significant association between serum homocysteine, serum folate, and crisis state in SCD. Since sickle cell anemia remains a considerable burden, especially with sub-Saharan as such, there is a need for continuous review of practices such as folate supplementation, which may improve the clinical outcome of these patients.

Authors' contributions

Adebukola Khairat Orolu: Conception and design, Acquisition of data, analysis and interpretation of data, drafting of the manuscript, revising the manuscript, Final approval of Manuscript, Accountability for all aspects of work.

Titilope Adenike Adeyemo: Conception and design, data analysis and interpretation Revising manuscript, Final approval of Manuscript.

Alani Sulaiman Akanmu: Data analysis and interpretation, Revising manuscript, Final approval of Manuscript.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

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  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2]


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