34. Inherited Disorders of Hemoglobin

Introduction

If untreated, many of the inherited hemoglobin disorders result in death during the first few years of life. Their effect on the burden of disease has only recently been recognized, following an epidemiological transition caused by improvements in hygiene, nutrition, and control of infection that has reduced childhood mortality. Babies with severe hemoglobin disorders are now able to survive long enough to present for diagnosis and treatment. The impact of these diseases is being felt throughout the Indian subcontinent and much of Asia. Although the situation will worsen in Sub-Saharan Africa as it undergoes a similar transition, such diseases are already responsible for a major health burden. International health agencies and the governments of affected countries need to understand the future extent of the problem and to develop programs to control and manage these diseases.

Normal Hemoglobin

Hemoglobin (Hb), the pigment in the red blood cells that transfers oxygen to the tissues, changes structure during human development. In adults two components exist: a major hemoglobin, Hb A, and a minor hemoglobin, Hb A₂. The bulk of the hemoglobin during later fetal life is Hb F. These hemoglobins each consist of two pairs of unlike globin chains. The adult hemoglobins and fetal hemoglobin have Alpha chains combined with Beta (Hb A, Alpha₂Beta₂), Delta (Hb A₂, Alpha₂Delta₂), or Gamma chains (Hb F, Alpha ₂Gamma₂). Each of the different globin chains is controlled by distinct genes; two genes exist for the Alpha and Gamma chains and one for each of the other chains. Their structure and the regions of the genes that control the production of the different globin chains have been determined (Steinberg and others 2001; Weatherall and Clegg 2001b).

Spectrum of Inherited Hemoglobin Disorders

Inherited hemoglobin disorders fall into two main groups: the structural hemoglobin variants and the thalassemias, which are caused by defective globin production. They all follow a recessive form of inheritance. Those with a single defective globin gene—carriers or heterozygotes—are symptomless. If two carriers marry, a one in four chance exists that each child they produce will receive defective genes from each parent—that is, they are homozygous for the particular disorder.

The structural variants result mostly from single amino acid substitutions in the Alpha or Beta chains. Often these are innocuous, but in some cases they may alter the stability or functional properties of the hemoglobin and lead to a clinical disorder. They are designated by letters of the alphabet or by the place names where the condition was first discovered. Even though researchers have identified more than 700 structural hemoglobin variants, only three (Hb S, Hb C, and Hb E) are widespread. The homozygous state for the sickle cell gene results in sickle cell anemia, whereas the compound heterozygous state for the sickle cell and Hb C genes results in Hb SC disease. Hb SC disease, although milder, also has important public health implications. Hb E, the commonest variant globally, is innocuous in its heterozygous and homozygous states, but because it is synthesized less effectively than Hb A, it interacts with Beta thalassemia to produce an extremely common condition called Hb E Beta thalassemia, which is becoming an increasingly important health burden in many parts of Asia.

The thalassemias are classified according to the ineffectively synthesized globin chains. From a public health viewpoint, only the Alpha and Beta thalassemias are sufficiently common to be important.

Clinical Features

The inherited hemoglobin disorders are characterized by an extremely diverse series of clinical syndromes of varying severity.

Sickle Cell Anemia and Related Disorders

The clinical features of sickle cell disorders reflect the red blood cells' propensity to assume a sickle shape in deoxygenated blood, leading to shortened red cell survival and a tendency to block small blood vessels (Bunn 1997; Serjeant 1992). Even though patients may adapt to their anemia, their illness is interspersed with acute episodes, including: attacks of bone pain; sequestration of blood into the lungs, liver, or spleen; or thrombosis of cerebral vessels, which may cause a stroke. They are extremely prone to infection, particularly during early childhood, and to a wide range of chronic complications. For reasons not yet understood, the severity of the disease varies extensively. Even in populations in eastern Saudi Arabia and parts of India, which have a high frequency of Alpha thalassemia and an unusual ability to produce Hb F in adult life, both of which, when inherited with sickle cell disease, result in a milder form of the illness, morbidity is still high.

Although little is known about mortality from "sickling" disorders in developing countries, in Sub-Saharan Africa many children die early because of these conditions (Akinyanju 2001; Fleming and others 1979). Fleming and others, working in rural Nigeria, found that even though more than 2 percent of all newborns had sickle cell anemia, it was absent in the adolescent and adult populations. At the same time, they found that urban centers in Nigeria, where medical care was available, had an increasing number of affected adults, and by the late 1970s, a significant improvement in survival had clearly followed the introduction of antimalarial measures (Molineaux and others 1979). Both in Jamaica and in the United States, death appears to peak between one and three years of age, usually from infection. Recent U.S. data suggest that the median age of adult death is 42 for men and 48 for women (Dover and Platt 1998). Even though Hb SC disease is milder than sickle cell anemia, it is associated with many complications, including a higher frequency of proliferative retinopathy.

Thalassemias

The homozygous or compound heterozygous states for Beta thalassemia also run a variable course, although without transfusion, death usually occurs in the first few years (Weatherall and Clegg 2001b). With adequate transfusions and the administration of drugs to remove iron, children may develop well and survive to adulthood. However, these drugs are expensive, and even when they are available in poorer countries, many children receive inadequate dosages and die in childhood or adolescence from iron overload. The situation is further complicated because the common Beta thalassemias of intermediate severity—notably Hb E Beta thalassemia—exhibit a clinical spectrum ranging from transfusion-dependent disease to a condition compatible with normal survival and growth into adult life without treatment.

The Alpha thalassemias are equally heterogeneous. The extremely common milder forms (termed Alpha⁺ thalassemias because some Alpha chains are produced) produce only a mild hypochromic anemia in homozygotes. In contrast, the Alpha° thalassemias, so called because of the absence of Alpha chain synthesis, result in stillbirth in their homozygous states following pregnancies with toxemic and postpartum complications. The compound heterozygous states for Alpha⁺ and Alpha° thalassemias result in Hb H disease, which varies in severity and may be transfusion dependent.

The thalassemias are extremely heterogeneous at the molecular level: more than 200 different mutations of the Beta globin genes have been found, and the Alpha thalassemias are almost as varied. Every severely affected population in the world has a few common mutations unique to a particular region, together with varying numbers of rare ones.

Population Genetics and Dynamics

The high gene frequencies for the hemoglobin disorders are attributable to the effects of natural selection. Although severely affected homozygotes would, in the absence of medical interventions, have died early in life, asymptomatic heterozygotes for Hb S, Hb C, and probably Beta thalassemia and Hb E, as well as those with mild forms of Alpha thalassemia, are more resistant to severe malarial infection than normal persons. Hence, in environments in which malaria was common, carriers were protected and survived to have more children, and the gene frequencies rose until they were balanced by loss of severely affected homozygotes from the population. Although some decline in frequency among immigrant populations may occur because of lack of exposure to malaria and outbreeding, this decline will occur over many generations, and even if malaria were completely eradicated, an equally long time would pass before any significant fall occurred in the global frequency.

Changes resulting from variation in selection or in population dynamics will, however, be small compared with the effect of the demographic and epidemiological transitions that many countries have recently undergone. For example, thalassemia was not identified in Cyprus until 1944, when major improvements in public health revealed that the disease was common. By the early 1970s, estimates indicated that, in the absence of steps to control the disease, in about 40 years approximately 78,000 units of blood would be required each year to treat all the severely affected children, 40 percent of the population would be carriers, and the cost to the health system would equal or exceed the island's health budget (Weatherall and Clegg 2001b).

Global Distribution and Frequency of the Hemoglobinopathies

Figures 34.1a and 34.1b show the global distributions of the hemoglobinopathies. Table 34.1 shows approximate carrier frequencies by region.

The gene for Hb S is distributed throughout Sub-Saharan Africa, the Indian subcontinent, and the Middle East, where carrier frequencies range from 5 to 40 percent or more. Hb E is found in the eastern half of the Indian subcontinent and throughout Southeast Asia, where carrier rates may exceed 60 percent. Thalassemia is frequent in a broad band from the Mediterranean basin and parts of Africa, throughout the Middle East, the Indian subcontinent, Southeast Asia, and Melanesia and into the Pacific islands. The Alpha⁺ thalassemias occur right across the tropical zone, reaching extremely high frequencies in some populations, whereas the Alpha° thalassemias are restricted to parts of SoutheastAsia and the Mediterranean basin (table 34.1).

Several World Health Organization (WHO) workshops have attempted to estimate the global burden of the thalassemias and important structural hemoglobin variants (Angastiniotis and Modell 1998; Weatherall and Clegg 2001b, WHO 1989, 1994). There are perhaps 270 million carriers and 300,000 to 500,000 annual births of infants with sickle cell anemia or serious forms of thalassemia. Southeast Asia, where the thalassemias and Hb E predominate, is most severely affected. Sub-Saharan Africa has the second-highest burden, reflecting the high incidence of Hb S. Weatherall and Clegg (2001b) summarize information about the different thalassemia mutations in those regions.

These data only approximate the problems for health care services that the hemoglobin disorders will pose in the future. Unfortunately, few of the data are based on micromapping of incidence in different populations. Weatherall and Clegg's (2001b) review of studies in Indonesia, Sri Lanka, and Thailand reveals the extent of variability of incidence within relatively short geographic distances, suggesting that the number of annual births of babies with Beta thalassemia major or Hb E Beta thalassemia may be underestimated. Similarly, published data for the annual births of babies with sickle cell anemia in India and the Middle East are almost certainly too low, because estimates based on gene frequency suggest that the figure may be close to 100,000. The data in table 34.1 and figure 34.2, therefore, represent a minimal estimate of the future likely health burden resulting from inherited hemoglobin disorders. Furthermore, in many cases, the data are not based on projected increases in birth rates.
[Figure 34.2]

Because of these uncertainties, including how long countries will take to pass through the epidemiological transition, assessing the burden that the disorders will impose on health services is difficult. As more babies survive and present for treatment, the population on long-term therapy will steadily expand; the more effective the treatment, the greater the burden will be on health services. For example, from 2005 to 2025, an estimated 100,000 cases of Hb E Beta thalassemia will be added to the Thai population, and 20,000 Beta thalassemia homozygotes will be born each year in southern China (Weatherall and Clegg 2001b). If these children all survive to adulthood, they will account for a large proportion of health service expenditure.