CHAPTER ONE
1.0 INTRODUCTION
Sickle cell anaemia is a severe haemolytic anaemia of genetic origin. The disease is thought to have developed as an evolutionary attempt to provide permanent protection against the scourge of plasmodial infection in the malarious areas of the world.
The resultant variant haemoglobin molecule, Haemoglobin S, appears to have achieved this purpose, at least to some extent, as it is protective against the severe effects of plasmodium falciparum in particular and malaria in general when present in the heterozygous form.
This heterozygous form, the sickle cell trait, is essentially a non- pathologic, clinically silent condition.
Problems however, arise when the variant haemoglobin gene is inherited in the homozygous form and practically all of the haemoglobin present in the individual is Haemoglobin S.
This situation results in a severe clinical condition in which the abnormal haemoglobin precipitates under hypoxic conditions in the microcirculation causing vascular obstruction and distal ischaemia and infarction in almost every organ in the body. 2, 3 The patients life is a precarious one, punctuated by unpredictable episodes of excruciatingly painful ‘vaso-occlusive crises’ and threatened by potentially lethal cerebral ischaemic attacks or sudden massive pooling of red blood cells in the splenic pulp - a ‘sequestration crisis’. 2, 3
In the ‘steady state’ the sickle cell anaemia patient is still plagued by the effects of a continuing disease in which constant haemolysis gives rise to a persistent jaundice, low haematocrit, permanent bony changes and a variety of chronic complications 2, 3 .
Popular cultural lore within the West African sub region has long held that the severity of sickle cell anaemia tends to decrease with age and a sickle cell child was generally felt to be more likely to survive if he or she lived past the first few years of life. Several researchers have found the very high infant mortality in sickle cell anaemia to be due to infections. 4, 5 . However one study has suggested that older sickle cell anaemia patients tend to have higher
Hb F levels
. Kotila et al (2000) found that patients with Hb F levels of greater than 7.4% were older compared with those with less than 7.4% and that the former group tended to have less bone pain crises per year, blood transfusion requirements and autosplenectomy
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. The incidence of mild to moderate increases in Hb F (usually less than 12%) with age, is distinct from those rare sickle cell disease patients who have, the hereditary persistence of haemoglobin F (HPHF) characterized by very high levels of Hb F (15-30%) due to major promoter mutations in the gamma globin genes and deletions of the beta globin gene cluster
. This small minority form an elite group consisting of less than 1% of sickle cell disease patients whose unusually high Hb F levels are as a result of specific genetic mutations peculiar to them
. Since the 1950’s researchers have realized that high levels of Hb F can ameliorate the clinical course of sickle cell anaemia and this has provided a promise of reasonably specific therapy directed at clear pathophysiologic mechanisms
. Thus it may be that the amelioration of the clinical severity of sickle cell anaemia with increasing age may be due to higher levels of Hb F, since Hb F does not participate in the polymerization process characteristic of the sickling phenomenon and its O2 content at a given Po2 is greater than that of Hb A because it binds to 2, 3-DPG less avidly
.
1.1 Epidemiology
The genes for sickle cell disease have a well defined geographical distribution. Sickle cell anaemia and the sickle cell trait are found principally in the ‘old world’ extending over areas of Africa, the Mediterranean, the Middle East and India. This distribution is coincident with other common haemoglobinopathies viz Hb C, D and E in so far as one considers that they all occur within the tropics and subtropics (latitudes 23
’ North and South of the equator) 9, 10 . However, Hb S is heavily concentrated in equatorial Africa (heterozygote frequency 20%)
which consists of the regions of West and Central Africa including Madagascar 9, 10. Concentrations also occur within the coastal areas of the Mediterranean countries forming a ring round the Mediterranean Sea that includes western Syria, southern Turkey, Greece and Italy, eastern Spain and the northern parts of Algeria, Libya and the Egypt. Small concentrations also occur around the southern end of the Suez gulf including the western tip of Yemen and the adjacent north – eastern area of Ethiopia and Eritrea. Areas of high prevalence are also found towards the southern end of the Persian Gulf around Abu Dhabi and Manama on the Arabian Peninsula and Shiraz in Iran. Within the Indian continent, high prevalence’s of Hb S occur in two major areas centering around the southern part of Pakistan including Karachi and the southern parts of India around the Mumbai and Bangalore Areas 9, 10 . Nigeria probably has the highest total number of people with the gene in tropical Africa on account of its relatively large total population (130 million -2003 estimate) and high prevalence of the sickle cell trait (25%)
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and sickle cell anaemia (1-3%)
The main focus for haemoglobin C is in West Africa with the highest frequency in Northern Ghana (20-21 %) and Burkina Faso
. Although Hb C has been described in
North Africa, Zaire and Cape Town it is very rare else where on the African continent
. In the USA where the Hb C trait is thought to have been transported through the slave trade the incidence is 2 – 3%
The incidence of Hb C disease is less common in Nigeria and the majority of patients with sickle cell disease in Nigeria tend to have the Hb SS Phenotype. Akinyanju
(1985) has reported that Hb C genotype is largely confined to the Yoruba people of southwestern Nigeria where he found an incidence of 6%.
In-breading i.e. consanguineous marriages and polygamy tend to be the operative predisposing epidemiological factors
. Socio-economic factors impact on the epidemiology of sickle cell disease mainly by a moderating influence on clinical severity and survival among patients with the disease due to differences in standards of living conditions and access to quality health care
.
1.2 Significance of the Study
The significance of this study arises out of its attempt to investigate the Hb F levels in relation to fundamental clinical and laboratory indices in various age groups so that the possibility of directing treatment, which raises Hb F levels in vulnerable age groups with low levels, may be evaluated. Future studies researching various problems in sickle cell anaemia patients will also take into cognizance differential Hb F levels, and interpret clinical observations in the light of this variable.
1.3 Rationale for the Study
The incidence of sickle cell anaemia in Nigeria is 1-3%
and that of the sickle cell trait is 20-25%
. The rationale for the study lies in the fact that relevant information can be exploited for therapeutic purposes. Such targeted treatment will reduce the number of
hospital admissions, blood transfusions and overall mortality in sickle cell anaemia. It will also reduce the economic burden of frequent admissions for ‘crises’, on the family, and lessen the strain on the meager public health facilities of the nation. This study will thus investigate a fundamental parameter which is an important determinant of the clinical course of sickle cell anaemia
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and which can be manipulated to lessen the severity of the disease and provide a variety of benefits to the individual, the family, the community and the nation as a whole.
1.4 Aims and Objectives
General Objective To determine the relationship between haemoglobin F levels, and clinical and laboratory indices of disease severity in patients with sickle cell anaemia. Specific Objectives 1. To determine the distribution of haemoglobin F levels with age in sickle cell anaemia patients. 2. To determine the distribution of the percentage of haemoglobin F and total haemoglobin levels in sickle cell anaemia patients. 3. To determine the relationship between haemoglobin F levels and the leukocyte count in sickle cell anaemia patients. 4. To determine the relationship between haemoglobin F levels and blood transfusion requirements in patients with sickle cell anaemia. 5. To determine the relationship between haemoglobin F levels and frequency of ‘crises’ in sickle cell anaemia patients. 6. To determine the relationship between haemoglobin F levels and physical skeletal complications in sickle cell anaemia patients.
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