1. Introduction

Sickle cell anemia (SCA) is an autosomal recessive genetic disorder caused by a defect in the HBB gene which codes for hemoglobin ß chain [1,2]. This leads to the production of abnormal hemoglobin chains within the red blood cell, which causes rigidity and sickling of the cell, leading to vascular occlusion and ischemia in multiple organs [3,4]. The normal human hemoglobin molecule is a heterotetramer composed of four hemoglobin chains (two α and two β) and the normal adult hemoglobin is Hemoglobin AA [3]. The abnormal genes occur as a result of glutamic acid-to-valine substitution at the sixth base position in the β hemoglobin gene on chromosome 11 [3]. Sickle cell anemia results from the inheritance of two sickle β hemoglobin genes as HbSS [4].

Sickle cell anemia is particularly common among people whose ancestors come from sub-Saharan Africa, India, Saudi Arabia, and Mediterranean countries. Each year about 300,000 infants are born with major hemoglobin disorders – including more than 200,000 cases of sickle-cell anemia in Africa [5,6]. In Nigeria, by far the most populous country in the sub-region, 24% of the population are the carriers of the mutant gene (HbAS) and the prevalence of sickle-cell anemia (HbSS) is about 2% [5, 7–9].

The resultant changes in the red blood cells causes chronic intermittent vaso-occlusive events resulting in tissue ischemia; chronic hemolytic anemia resulting in varying degrees of anemia; and multiple organ damage from microinfarcts that can affect any organ in the body, including the bones, lungs, liver, kidneys, brain, eyes, heart, skin, and joints [2]. Episodes of crisis also occur and these include hemolytic crisis, aplastic crisis, acute sequestration crisis, and vaso-occlusive crisis [4].

There are documented established markers (indices) of disease severity in patients with SCA in the literature (Item 1) and they determine the course of the disease. These markers include both clinical and laboratory parameters [10,11]. Identification of these markers of disease severity among adult SCA patients in steady state affords us the opportunity to know the course of the disease in these patients over the past years as well as to predict the likely course of the disease in the years to come. This would enable physicians to tailor management plans for the patients and also aid prompt intervention as the need arises, thereby preventing or reducing the complications that otherwise would have resulted. This would reduce the overall morbidity and mortality associated with SCA.

Presently, there is paucity of data in Nigeria on this topic. This study determined the pattern and the prevalence of the markers of disease severity in adult SCA patients in steady state in Ile-Ife, Nigeria, which now provides the much needed information for holistic management of these patients as well as scientific data for further research on this topic.

2. Materials and Methods

3. Results

The study group (HbSS patients) comprised of 21 (42%) males and 29 (58%) females. The ages ranged from 18 to 45 years with a mean( ±SD) of 27.6 ±7.607.

The BMI of the patients ranged from 15.10 to 26.50 kg/m² with a mean( ±SD) of 19.36 ±2.185. The mean BMI for the patients was within the normal range. Twenty-four (48%) of the patients were underweight, one (2 %) was overweight, and none was obese. Amongst the underweight patients, none fulfilled the criteria for failure to thrive (Table 1).

The mean( ±SD) age at first diagnosis of SCA in the patients was 6.46 ±4.827 with a range of 3 months – 19 years. All of them had had one form of sickle cell crisis or the other in the past as shown in Table 2. All the patients had had vaso-occlusive crisis (VOC) in the past. Nineteen (38%) patients experienced one episode of VOC per year while 15 (30%) and 13 (26%) experienced two and three episodes per year, respectively. Only 25 (50%) of the patients had had hemolytic crisis in the past. Out of these 25 patients, 20 (80%) and 3 (12%) had one and two episodes per year, respectively. Only one patient (2%) had hepatic sequestration crises in the past and only two (4%) had ever had a splenic sequestration crisis in the past. None had aplastic crisis. Forty (80 %) of the patients had had blood transfusion in the past. The units of blood received by the patients ranged from 1 to 30 units with a mean( ±SD) of 4.69 ±5.445. One patient had had exchange blood transfusions done four times on account of complications of SCA; mainly repeated episodes of priapism. Six (12%) patients had had ≥ 3 units of blood transfused per year to treat the complications of SCA.

Thirteen (26%) of the patients had dactylitis within the first year life. A 19-year old male patient (2%) had two past episodes of left ischemic stroke. Two (4%) patients had history of acute chest syndrome while four (8%) had had priapism in the past. Four (8%) patients had a past history of avascular necrosis of the femur, six (12%) had chronic leg ulcer, two (4%) had septic arthritis, and six (12 %) had a past history of chronic osteomyelitis (Table 2).

The full blood count and serum bilirubin results of the patients were as shown in Table 3. The range of the steady state hemoglobin concentration (g/dl) of the patients from their hospital records was 6.3–11.3g/dl with a mean( ±SD) of 8.52 ±1.114. The range of the newly analyzed hemoglobin concentration of the patients was 5–12g/dl with a mean( ±SD) of 8.52 ±1.329. Thirteen (26%) of the patients had a serum total bilirubin value greater than 51 µmol/L.

The ultrasonographic liver span measurement of the patients ranged from 12.30 to 25.57 cm with a mean( ±SD) of 16.56 ±2.357. The patients had a significantly long liver span (see Figure 1). Thirty-two (64%) of the patients had a liver span longer than 15.5 cm.

Figure 1: Sonogram showing massive hepatomegaly in a patient with sickle cell anemia (SCA). The lower lobe of the liver extends well below the lower pole of right kidney and the liver measures 22.3 cm in span exceeding the normal limit of 15.5 cm.

Table 4 shows the markers of disease severity identified in the patients with SCA. Hepatomegaly (64%), frequent episodes of vaso-occlusive crisis, that is, ≥ 3 episodes per year (30%), and dactylitis in infanthood (26%) were the most common clinical parameters identified in these patients in that order, while a high serum total bilirubin of > 51µmol/L (26%) was the most common laboratory parameter seen in these patients.

Table 5 shows the total number of markers of SCA disease severity identified in the patients. Four (8%) of the patients had no identified marker of disease severity while 43 (86%) patients had between 1 and 4 identified markers of disease severity. Two (4%) patients had five identified markers of disease severity and only one patient (2%) had up to seven identified markers of disease severity. As shown in Table 6, more patients had clinical parameters than laboratory parameters; 43 (86%) patients versus 23 (46%) patients.

4. Discussion

Xandra et al. [13] defined the concept of severity as “the rate and extent of reversible and irreversible damage to organs brought on by the sickle cell disease process, resulting in impairment requiring medical intervention.” Several attempts have been made till date by researchers to develop a universally accepted system for assessing disease severity in SCA patients and these include the Cooperative Study of Sickle Cell Disease (CSSCD) and the Bayesian Network Modeling (developed by Boston Medical Centre) [10].

Presently, there is no consensus scoring system for assessing the severity of disease in patients with SCA but a large number of indices have been used by researchers as markers of disease severity in SCA, and these markers include clinical and laboratory parameters (Table 1) [10,11]. The presence of any of these markers in a patient with SCA connotes severe disease, and the severity of the disease increases with an increasing number of these markers present in an individual patient.

A high serum total bilirubin ( >51µmol/L) was the most common laboratory parameter observed in this study with a prevalence of 26%. Elevated serum bilirubin levels, predominantly the unconjugated fraction, are universal in sickle cell patients even in steady state due to chronic hemolysis but a persistently high total bilirubin suggests chronic significant hemolysis in these patients signifying a severe disease course and there is a need to follow them up very closely.

Hepatomegaly (64%) was the most common clinical parameter identified in this study. Frequent episodes of vaso-occlusive crisis ( ≥3 episodes per year) and Dactylitis (occurring before the age of one year) were the other common clinical parameters identified in this study. Hepatomegaly is a common finding in SCA, and it is largely due to the extramedullary hematopoiesis in response to the chronic anemia in this condition [3,4]. Hepatomegaly can also be due to transfusional hemosiderosis and chronic viral hepatitis [14,15]. However, in Nigeria, which is a malaria endemic area, frequent episodes of malaria is also a major cause of the hepatomegaly seen in these patients [15]. In this study, the most common indication for hospital admission in the SCA patients apart from a sickle cell crisis was malaria; this could have contributed to the development of the hepatomegaly seen in these patients.

Olaniyi et al. found a prevalence of hepatomegaly of 62.2% among SCA patients in Ibadan, Nigeria [15]. Balci et al. found a prevalence of 72.6% among SCA patients in Turkey [16], and Papadaki et al. found a prevalence of 70.5% among sickle cell disease patients in Greece [17]. In this study, hepatic ultrasonographic evaluation of the patients revealed hepatomegaly with a prevalence of 64% (32 patients).

Persistent hepatomegaly is one of the established markers of disease severity in SCA patients [10,11]. Olatunji et al. in Ilorin, Nigeria, also established that persistent hepatomegaly is an index of disease severity in patients with SCA [18]. Persistent hepatomegaly in patients with SCA implies that such patients have the tendency to run a more severe clinical course than those without and there is a need to pay more attention to them [18].

5. Conclusion

Hepatomegaly, frequent episodes of vaso-occlusive crisis, dactylitis in infanthood, and a high total bilirubin were the most common markers of disease severity identified in this study. A significantly larger number of patients had the clinical parameters compared to the laboratory parameters. Previous research had shown that the presence of any of these markers in an SCA patient connotes severe disease and the severity of the disease increases with increasing number of these markers present in an individual patient. Patients with more markers of disease severity have the tendency to run a more severe clinical course than those without or less markers and there is a need to pay more attention to these patients by following them up more closely.

Therefore, efforts should be stepped-up to maintain SCA patients in steady state as much as possible as this would prevent or limit complications or additional severity markers from arising, which could occur as a result of frequent crisis. Such efforts would reduce the overall morbidity and mortality associated with SCA.

Acknowledgement

The authors would like to thank the members of the staff of Hematology and Radiology departments of Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Nigeria, for their support towards making this research a success.

Funding

The authors bore the entire cost of the research and did not receive any financial support from any organization.

Conflict of Interest

The authors declared no conflicts of interest.