European Journal of Cardiovascular Medicine

The condition known as sickle-cell anaemia is a hereditary disorder characterised by the presence of sickle-cell haemoglobin genes in both parents. The erythrocytes undergo a transformation into a crescent-shaped, slender, and elongated structure, resembling the blade of a sickle. The deoxygenation process of sickle cell haemoglobin, also known as haemoglobin S, results in its insolubility and the formation of polymers that collect into tubular fibres. In contrast,

normal haemoglobin, sometimes referred to as haemoglobin A, retains its solubility. (1) 

The alteration of haemoglobin S results in modifications to the membrane's permeability, hence influencing the equilibrium of electrolytes. The spleen experiences an increase in sodium and potassium fluxes when there is a gain of Na+ ions and a loss of K+ ions, resulting in an imbalance in the ionic strength of the cell membrane. Sickle cell patients exhibit heightened and persistent obligatory excretion of bodily fluids and electrolytes, resulting in dehydration and various metabolic disruptions (2–4).

Sodium (Na+), potassium (K+), and chloride (Cl-) are indispensable electrolytes that play a crucial role in facilitating the proper functioning of cells and organs. Any disparity between them results in significant issues. The occurrence of dehydration in individuals with sickle cell anaemia results in an alteration of electrolyte levels, hence inducing sickling, sequestration, and hemolysis.

Numerous investigations have been undertaken in several geographical areas, revealing disparate estimations of the mean sodium, potassium, and chloride levels, along with their corresponding standard deviations, among both case and control patients. These findings are presented in tables 1 to 3 of the present study. The clinician's decision regarding the appropriate 

measurement of the respective parameters is influenced by these data, as there is a dearth of systematic research on this significant health concern. Therefore, the current investigation was conducted to assess and establish the correlation between electrolyte levels in individuals diagnosed with Sickle cell anaemia. This study focuses on the serum electrolytes sodium, potassium, and chloride.

Meta-analysis was conducted using papers pertaining to Case-control, Cross-Sectional, and case series that were published or unpublished before to August 31, 2020. The inclusion criteria for comparison between case and control groups were the measurement of serum levels of sodium, potassium, and chloride.

Categories of participants

Individuals of all age groups diagnosed with Sickle-cell anaemia. The studies were evaluated using the IOM, PRISMA, and MOOSE criteria for study selection. Figure 1 provides a concise summary of the research selection processes. The publications were searched using the PubMed and Google Scholar databases, employing the keywords "Sickle-Cell" and "Serum electrolyte". This study included studies that were authored in the English language and published in their entirety.

Their list of references was also consulted for supplementary assistance.

Categories of outcome measures

1. Serum sodium concentration 2. Serum potassium concentration 3. Serum chloride concentration

Extraction of data

The meta-analysis of observational studies adhered to the prescribed guidelines, and the subsequent data was retrieved from each study:

The final name of the primary author, the year of publication of the study, and the population of patients. In this study, we examine the mean and standard deviation of sodium, potassium, and chloride individually.

Statistical analysis

Sodium, potassium, and chloride were assigned distinct contingency tables. The STATA-16 statistical programme was utilised to do statistical analysis. Meta-analytical analysis of Sodium, potassium, and chloride levels was conducted using forest plots. These plots provide summary statistical estimates, 95% confidence intervals, and relative weights, which are represented by the central point of the square, the horizontal line, and the relative size of the square, respectively. The estimation of heterogeneity across trials was conducted using the I2 statistic, where values exceeding 50% were deemed to indicate significant heterogeneity. The study employed a random-effects model to ensure that the data utilised in the study was selected randomly among all possible studies. The study's bias was assessed by employing a funnel graph, as depicted in Figures 2B, 3B, and 4B.

The study comprised ten publications that met the qualifying criteria and focused on the correlation between Sickle cell anaemia and serum electrolytes. Out of the total, 9 were linked to serum sodium levels (3-11), ten were linked to serum potassium levels (2-11), and 5 were linked to serum chloride levels (4-6, 10, 11). Table 1 presents a concise overview of the combined average, minimum, and maximum values of sodium. Table 2 provides a summary of potassium levels,

whereas Table 3 presents the chloride levels.

Sodium
All nine studies examining the association between Sickle cell anaemia and control groups reported serum sodium levels. The average value of sickle cell anaemia was calculated to be 130.50 mEq/L (95% CI: 126.62 – 134.38), with an interquartile range (I2) of 53.40%. On the other hand, the control group exhibited a pooled mean of 137.49 mEq/L (95% CI: 134.61 – 140.37) with an I2 value of 60.40%. The results demonstrated a notable decrease in sodium levels among sickle cell patients in comparison to the control group, as depicted in figure 1A.  The presence of research publication bias was found to be minimal, as the majority of studies were concentrated towards the upper and inner regions of the funnel figure, as depicted in Figure 1B.

Potassium

There were ten investigations conducted on serum potassium levels in individuals with Sickle cell anaemia and a standard control group. In the sickle cell group, the overall mean of all studies was found to be 4.60 mEq/L (95% CI: 4.25 – 4.95) with an I2 value of 16.60%. This value was significantly higher compared to the control group, which had a mean of 3.87 mEq/L (95% CI: 3.47 – 4.28) and an I2 value of 75.54%, as depicted in Figure 2A. The presence of minor research publication bias can be attributed to the concentration of studies within the inner region of the funnel figure, as depicted in

Figure 2B.

Chloride
In the sickle cell group, the pooled mean of studies was 101.53 mEq/L (95%CI: 95.81 – 107.25) with an I2 value of 32.31%. In the control group, the pooled mean was 100.93 mEq/L (95% CI: 97.33 – 104.53) with an I2 value of 0.01%. There is evidence from five research that suggests a correlation between serum chloride levels in individuals with Sickle cell anaemia and a control group. No significant statistical difference was seen between these groups, as depicted in figure 3A. The presence of minor publication bias in the research can be attributed to the concentration of studies inside the inner region of the funnel figure, as depicted in Figure 3B.

The present meta-analysis aims to assess the predictive significance of electrolyte levels in individuals diagnosed with sickle cell anaemia. This analysis included a total of 10 investigations on sickle cell anaemia. Among these studies, 9 demonstrated a correlation with sodium, 10 demonstrated a correlation with potassium, and five focused on chloride. The research employed a random effect model, operating under the assumption that a random sample was picked for analysis in each study. The found high variability in the research pertaining to each variable category can be attributed to the varying time periods during which the investigations were conducted, as well as the diverse range of places, cultures, and economic statuses under investigation.

Advantages and constraints: In blood testing, electrolytes such as sodium (Na+), potassium (K+), and chloride (Cl-) are commonly tested. Sodium was the predominant cation found in the extracellular fluid, where it coexists with the anion

chloride in the form of NaCl.(12,13)

Sodium plays a crucial role in maintaining the overall water balance inside the human body, while also facilitating electrical communication across various physiological systems such as the neurological, muscular, and brain systems. The typical range for sodium levels in the serum is between 135 and 145 milliequivalents per litre (meq/L).(12,14).
Intracellular cationic potassium plays a crucial role in maintaining the proper functioning of cells. The primary role is the modulation of cardiac rhythm and muscular activity. The standard blood level ranges from 3.5 to 5.0 milliequivalents per litre (meq/L).(12,15) Sickle cell anaemia resulting from deoxygenation is characterised by a reduced permeability of sodium and potassium cations. Dehydration in individuals with sickle cell disease leads to an elevated excretion of electrolytes through urine (12-15).

Comparative analysis with prior research: This study demonstrates that the average sodium levels in individuals with sickle cell anaemia were lower than those in control patients. This decrease can be attributed to dehydration caused by the migration of sodium into the sickle cell. The aforementioned findings were consistent with the research conducted by Hagag AA et al. (7), Meshram AW (3), Nnodim JK et al. (8), Gupta V et al. (9), Madan KA et al. (5), and Madhuri M et al. (10). Nevertheless, the findings of Antwi-Boasiako et al. (6), Rath et al. (4), and Hassan RYA et al. (11) have shown

conflicting outcomes in comparison to our investigation.

According to this study, it was shown that the pooled mean level of potassium was greater in sickle cell patients compared to the control group. However, both groups were within the normal range of 3.5-5.0 mEq/l. One potential explanation is that individuals with sickle cell disease commonly experience cellular dehydration and hypoxia, resulting in the extracellular release of potassium from the cell into the surrounding fluid (6, 16, 17,18,19,20). The studies conducted by Hagag AA et al. (7), Antwi-Boasiako C et al. (6), Meshram AW (3), Nnodim JK et al. (8), Rath D et al. (4), Madan KA et al. (5), Bernard KFC et al. (2), Madhuri M et al. (10), and Hassan RYA et al. (11) yielded comparable findings to our own study. However, the study conducted by Gupta V et al. (9) presented conflicting results. According to this study, no significant disparity in chloride levels was seen between the sickle cell group and the control group.

This review summarizes research that has looked at the link between sickle cell disease (SCD), anemia, and serum electrolyte levels. Electrolyte levels varied in sickle cell patients; those with the disease had lower blood pressure and body mass indexes, higher potassium and chloride levels, and no discernible rise in sodium levels. When compared to non-anemic individuals, those with anemia had higher levels of potassium and chloride and lower levels of sodium. Sodium, chloride, calcium, magnesium, osmolality, and albumin levels were all shown to be lowered in SCD patients, especially during crisis stages. Sodium-albumin ratios were also elevated, and serum albumin, calcium, and sodium levels were low. In order to properly manage sickle cell disease (SCD) and anemia, and to avoid problems, it is crucial to monitor serum electrolyte levels.(18,19,20)

A study has documented the pooled mean values for serum sodium, potassium, and chloride levels in individuals with sickle cell anaemia, as these electrolytes are frequently assessed in standard clinical practice. The serum sodium levels in individuals with sickle cell anaemia exhibited a reduction, while the potassium levels demonstrated an increase. Moreover, the findings of this study indicate that the regular quantification of sodium and potassium levels can be beneficial in the treatment of sickle cell anaemia

1. Nelson DL, Cox MM. Lehninger Principles of Biochemistry: David L. Nelson, Michael M. Cox: 9780716771081: Amazon.com: Books [Internet]. 5th Edition. 2012 [cited 2020 Sep 13]. 202–213 p. Available from: https://books.google.co.in/books/about/Lehninger_Principles_of_Biochemistry.html?id=7chAN0UY0LYC