The pathologic effects of the thalassemias are primarily due to which pathophysiologic process

Genes that regulate both the synthesis and the structure of different globins are organized into 2 separate clusters. The alpha-globin genes are encoded on chromosome 16, and the gamma-, delta-, and beta-globin genes are encoded on chromosome 11. Healthy individuals have 4 alpha-globin genes, 2 on each chromosome 16 (αα/αα; see the image below). Alpha thalassemia syndromes are caused by deficient expression of 1 or more of the 4 alpha-globin genes on chromosome 16 and are characterized by absent or reduced synthesis of alpha-globin chains.

Abnormal production of alpha-globin chains results in a relative excess of gamma-globin chains in fetuses and newborns and of beta-globin chains in children and adults. Furthermore, the beta-globin chains are capable of forming soluble tetramers (β4, or hemoglobin H [HbH]); yet this form of hemoglobin is unstable and tends to precipitate within the cell, forming insoluble inclusions (Heinz bodies) that damage the red cell membrane.

In addition, diminished hemoglobinization of individual red blood cells results in damage to erythrocyte precursors and ineffective erythropoiesis in the bone marrow, as well as hypochromia and microcytosis of circulating red blood cells.

From a genetic standpoint, alpha thalassemia syndromes are extremely heterogeneous; however, their phenotypic expression may be described in simplified clinical terms related to the number of inherited alpha-globin genes. Alpha thalassemia may be broadly classified according to whether the loss of alpha-globin genes is complete or partial—that is, alpha(0) thalassemia or alpha(+) thalassemia. Some subclasses are present within the latter category, based on the number of genes affected. In all, there are four general forms of alpha thalassemia.

More than 20 different genetic mutations resulting in the functional deletion of both pairs of alpha-globin genes (--/--) have been identified. The resulting disorder is referred to as hydrops fetalis, alpha thalassemia major, or hemoglobin Bart’s. Individuals with this disorder cannot produce any functional alpha globin and thus are unable to make any functional hemoglobin A, F, or A2. Hydrops fetalis is incompatible with extrauterine life, and fetuses with this condition characteristically died either in utero or shortly after birth because of severe anemia. While the mortality rate for hydrops fetalis is still high, medical advances have permitted a portion of these infants to survive.

There are more than 15 different genetic mutations that result in decreased production of alpha globin, usually through functional deletion of 1 or more of the 4 alpha-globin genes. Alpha(+) thalassemia is subclassified into the following three general forms on the basis of the number of inherited alpha genes.

Silent carrier

Persons who inherit 3 normal alpha-globin genes (-α/αα) are referred to clinically as silent carriers. Other names for this condition are alpha thalassemia minima, alpha thalassemia-2 trait, and heterozygosity for alpha(+) thalassemia minor. The affected individuals exhibit no clinical abnormalities and may be hematologically normal or have slight reductions in RBC mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH).

Alpha thalassemia trait

Inheritance of 2 normal alpha-globin genes through either heterozygosity for alpha(0) thalassemia (αα/--) or homozygosity for alpha(+) thalassemia (-α/-α) results in the development of alpha thalassemia trait, also referred to as alpha thalassemia minor or alpha thalassemia-1 trait. If both alpha2- and alpha1-globin genes are deleted on the same chromosome (--/αα), the genotype is said to have the cis form; if the 2 alpha2 -globin genes of both alleles of chromosome 16 are deleted but the alpha1 -globin genes are intact (-α/-α), it is said to have the trans form.

The affected individuals are clinically normal but frequently have minimal anemia and reduced MCV and MCH. The RBC count is usually increased, typically exceeding 5.5 × 1012/L.

Hemoglobin H disease

Inheritance of only one out of the four normal alpha-globin genes (-α/--) leads to a condition known as HbH disease, or alpha thalassemia intermedia. The loss of 3 alpha-globin genes results in abundant formation of HbH, which is characterized by a high ratio of beta globin to alpha globin and a 2-fold to 5-fold excess in beta-globin production. The excess beta chains aggregate into tetramers, which account for 5-30% of the hemoglobin level in patients with HbH disease. [13]

HbH has a high affinity for oxygen and has no Bohr effect or heme-heme interaction; therefore, it is an ineffective supplier of oxygen to the tissues under physiologic conditions. Patients with significant amounts of HbH have a defect in oxygen-carrying capacity that is more severe than would be expected on the basis of the hemoglobin concentration alone. RBCs that contain HbH are sensitive to oxidative stress; thus, they may be more susceptible to hemolysis when oxidants such as sulfonamides are administered.

Aging erythrocytes contain more precipitated HbH than younger erythrocytes; consequently, they are removed from the circulation prematurely. Thus, HbH disease is primarily a hemolytic disorder. When bone marrow cells are examined, HbH inclusions are rare, and erythropoiesis is apparently effective. Erythroid hyperplasia can result in typical structural bone abnormalities with marrow hyperplasia, bone thinning, maxillary hyperplasia, and pathologic fractures.

An Iranian study, by Farashi et al, of 66 patients with HbH disease found that point mutations produced a more severe form of the condition than did deletional mutations. [14]  The clinical severity of HbH disease may depend on which alpha-globin gene is deleted, since one of the alpha genes may produce only 25% of the alpha-globin chains, while the other provides 75% of them.

A study by Xu et al found that in individuals with HbH disease, HbA1c values are significantly below those found in controls or in patients with two or three functional alpha-globin genes. This finding is significant because alpha thalassemia frequently occurs in patients with diabetes mellitus. Nondiabetic patients were used in the study. [15]

The prevalence of anemia in population studies of healthy, nonpregnant people depends on the Hb concentration chosen for the lower limit of normal values. The World Health Organization (WHO) chose 12.5 g/dL for both adult males and females. In the United States, limits of 13.5 g/dL for men and 12.5 g/dL for women are probably more realistic. Using these values, approximately 4% of men and 8% of women have values lower than those cited. A significantly greater prevalence is observed in patient populations. Less information is available regarding studies using RBC or Hct.

The prevalence of anemia in Canada and northern Europe is believed to be similar to that in the United States.

A retrospective cohort study of tertiary hospital admissions in Western Australia found that 45,675 of 80,765 inpatients (56.55%) had anemia during their hospital stay. More than one third of patients who were not anemic on admission developed anemia during their stay. Even mild anemia was independently associated with increased mortality and length of stay. [6]

In underprivileged countries, limited studies of purportedly healthy subjects show the prevalence of anemia to be 2-5 times greater than that in the United States. Although geographic diseases, such as sickle cell anemia, thalassemia, malaria, hookworm, and chronic infections, are responsible for a portion of the increase, nutritional factors with iron deficiency and, to a lesser extent, folic acid deficiency play major roles in the increased prevalence of anemia. Populations with little meat in the diet have a high incidence of iron deficiency anemia, because heme iron is better absorbed from food than inorganic iron.

Sickle cell disease is common in regions of Africa, India, Saudi Arabia, and the Mediterranean basin. The thalassemias are the most common genetic blood diseases and are found in Southeast Asia and in areas where sickle cell disease is common.

Certain races and ethnic groups have an increased prevalence of genetic factors associated with certain anemias. Diseases such as the hemoglobinopathies, thalassemia, and G-6-PD deficiency have different morbidity and mortality in different populations due to differences in the genetic abnormality producing the disorder. For example, G-6-PD deficiency and thalassemia have less morbidity in African Americans than in Sicilians because of differences in the genetic fault. Conversely, sickle cell anemia has greater morbidity and mortality in African Americans than in Saudi Arabians.

Race is a factor in nutritional anemias and anemia associated with untreated chronic illnesses to the extent that socioeconomic advantages are distributed along racial lines in a given area; [7] socioeconomic advantages that positively affect diet and the availability of health care lead to a decreased prevalence of these types of anemia. [8, 9, 10] For instance, iron deficiency anemia is much more prevalent in the populations of developing nations, who tend to have little meat in their diets, than it is in populations of the United States and northern Europe.

Similarly, anemia of chronic disorders is commonplace in populations with a high incidence of chronic infectious disease (eg, malaria, tuberculosis, acquired immunodeficiency syndrome [AIDS]), and this is at least in part worsened by the socioeconomic status of these populations and their limited access to adequate health care.

Overall, anemia is twice as prevalent in females as in males. This difference is significantly greater during the childbearing years due to pregnancies and menses.

Approximately 65% of body iron is incorporated into circulating Hb. One gram of Hb contains 3.46 mg of iron (1 mL of blood with an Hb concentration of 15 g/dL = 0.5 mg of iron). Each healthy pregnancy depletes the mother of approximately 500 mg of iron. While a man must absorb about 1 mg of iron to maintain equilibrium, a premenopausal woman must absorb an average of 2 mg daily. Further, because women eat less food than men, they must be more than twice as efficient as men in the absorption of iron to avoid iron deficiency.

Women have a markedly lower incidence of X-linked anemias, such as G-6-PD deficiency and sex-linked sideroblastic anemias, than men do. In addition, in the younger age groups, males have a higher incidence of acute anemia from traumatic causes.

Previously, severe, genetically acquired anemias (eg, sickle cell disease, thalassemia, Fanconi syndrome) were more commonly found in children because they did not survive to adulthood. However, with improvement in medical care and breakthroughs in transfusion and iron chelation therapy, in addition to fetal hemoglobin modifiers, the life expectancy of persons with these diseases has been significantly prolonged. [11]

Acute anemia has a bimodal frequency distribution, affecting mostly young adults and persons in their late fifties. Causes among young adults include trauma, menstrual and ectopic bleeding, and problems of acute hemolysis. During their childbearing years, women are more likely to become iron deficient.

In people aged 50-65 years, acute anemia is usually the result of acute blood loss in addition to a chronic anemic state. This is the case in uterine and GI bleeding.

Neoplasia increases in prevalence with each decade of life and can produce anemia from bleeding, from the invasion of bone marrow with tumor, or from the development of anemia associated with chronic disorders. The use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), and warfarin also increases with age and can produce GI bleeding.