Hemoglobinopathies (Part One)

Hemoglobinopathies are inherited diseases, caused by the defective production of hemoglobin's protein chains. This includes a large group of diseases, but the most primary and common in our country are Sickle Cell Disease and Thalassemias. They are more widespread in the Mediterranean, South America, India, Africa, Caribbean.

Every year in the world, 300,000 patients with homozygous forms (30% Thalassemia Major and 60% Sickle Cell Anemia) are born, and 7% of the population (420 million) are carriers (heterozygous forms). Albania is a country with a high endemicity of beta-Thalassemia.

In Albania, there are about 300,000 carriers of Hemoglobinopathies or 8% of the population (there should be more, due to the fact that new cases are constantly discovered and by examining other family members who have no complaints, many others are discovered). The distribution of carriers is heterogeneous, and the highest frequency is found in the areas of the Western Lowland; Fier, Lushnja, Vlora, Saranda, Berat, Kavaja, Shijak, but also in Korça, Tirana, Dibra.

The fact that they are more widespread in former malarial areas (near swamps) prompted the hypothesis that Malaria influences the high prevalence of hemoglobinopathies (1948 by Haldane). Erythrocytes with small dimensions in Thalassemias carriers are more resistant to the malaria parasite. Similarly, the higher prevalence of Sickle Cell Disease carriers in hyperendemic areas for Malaria suggests the protective role of pathological hemoglobin HbS against lethal forms of Malaria.

Hemoglobinopathies are hemolytic (from the destruction of erythrocytes), non-immune, inherited anemias, based on the damage in the synthesis of hemoglobin's protein chains. In Thalassemia, there is quantitative damage = reduced production of polypeptide chains, in Sickle Cell Disease there is qualitative damage = production of abnormal protein chains, but in normal quantity.

The basic function of the erythrocyte (red blood cell) is the transportation of hemoglobin. Hemoglobin is a metallo-protein that occupies most of the cytoplasm of erythrocytes and is the main transporter of oxygen in the body. It consists of four protein chains, each of which has its corresponding Heme group in the center of which is the iron atom.

It should be noted that it is the iron pigment (Fe) that provides the red color of hemoglobin, thus to the erythrocytes and consequently to the blood itself (the remaining part of the blood without erythrocytes does not have red color).

In the blood of a normal adult person, we distinguish these types of Hemoglobin (Hb);

HbA  (two α chains and two β chains)    ≥ 96.5 %.
HbA2 {two α chains and two δ (delta) chains} < 3.5 %.

Sickle Cell Disease is a qualitative defect of beta chains, resulting in the formation of pathological HbA consisting of two α chains and two pathological beta chains, called HbS. Thus, in the Hemoglobin Electrophoresis (phenotypic analysis, which is the basis in Albania for the detection and diagnosis of Hemoglobinopathies) there will be reduced HbA, HbS, and HbA2.

Thalassemia is a quantitative defect (reduction) of alpha (alpha-Thalassemia), beta (beta-Thalassemia), or both together (a rarer combination). In the case of alpha-Thalassemias, there will be a reduction of both types of hemoglobin HbA and HbA2 (alpha chains occur in both types), but the ratio between them does not change (HbA2 will not have compensatory increase as with beta forms). In the case of beta-Thalassemias, there will be a reduction of HbA (which has beta chains), with compensatory increase of HbA2 and HbF (the surplus α chains that should have bound with beta chains will bind with δ chains for HbA2 and γ chains for HbF, resulting in their increase).

The homozygous forms (pathological genes responsible for the production of hemoglobin's protein chains, inherited from both parents) of the diseases, which are compatible with life (Sickle Cell Anemia and beta -Thalassemia Major/Intermedia), have pronounced clinic, significant complications, high expenses, and are cases followed in Specialized Medical Centers (Tirana, Fier, Lushnja).

The discussion is valid for the heterozygous forms of the disease (only half of the genes responsible for the production of hemoglobin's protein chains are pathological and inherited from one parent) that are more diseases with laboratory changes than clinical, therefore called "healthy carriers". These individuals by marrying each other, have the risk of giving birth to patients with severe forms of the diseases. Ideally for medicine would be the complete elimination of hemoglobinopathies, but it is impossible. The goal is to reduce as much as possible, ideally no case of severe forms of the disease and that is possible by doing a simple, cheap, non-traumatic, legally mandatory analysis like Hemoglobin Electrophoresis.

By order No.439, dated 25/1/2011 "For the prevention of new births with hemoglobinopathy" it has been made mandatory to control pregnant women for carriers of hemoglobinopathies in the first trimester of pregnancy and in case of finding the disease carriage, the control of the spouse.

Heterozygous Sickle Cell Disease

Heterozygous Sickle Cell Disease (carrier of Sickle Cell Disease, Sickle Cell Trait, Sickle Cell Anemia Stigma) has no clinical complaints, nor specific signs. A major problem for detection is the fact that there are no changes in the routine peripheral blood analysis and is not detected even by a specialist doctor. Only taking medical history, the origin of both parents, and often it is discovered accidentally as a result of people's awareness, medical personnel, and law compliance.

The lifespan and mortality are the same as in the normal population. Hematuria (loss of erythrocytes in urine) is their main sign (as a result of infarcts in renal papillae) and splenic infarcts. Splenic infarcts are described only in conditions of environments with low oxygen pressure. The concentrating ability for urine is affected. However, many carriers of Sickle Cell Disease tolerate high altitudes well (reduction of oxygen).

Crises only erupt in extreme cases e.g. from hypoxia (reduction of oxygen), acidosis, frequent infections, dehydration, and thrombotic phenomena. In these cases, a higher frequency of complications and deaths is expected compared to the normal population. For carriers of Sickle Cell Disease, the structure of the kidneys, their function, and complete urine for proteinuria (Sickle Cell Nephropathy) should be checked. Retinal damage (Sickle Cell Retinopathy) should be checked.

Contain both HbA and HbS, HbS varies from 25-45% and HbA is always higher than HbS.

Care should be taken during pregnancy, high altitude travels, and anesthesia (adequate oxygenation should be done and postoperative dehydration avoided). In many cases of sudden deaths in soldiers and athletes doing heavy physical exercises, the presence of relative amounts of HbS and HbA has been discovered. The sickle cell test is positive.

The goal of the doctor is to prevent the homozygous forms of the disease (which are anyway compatible with life), which happens when both parents are sick with Sickle Cell Anemia (homozygous form) which is generally known, when one of the parents is with Sickle Cell Anemia and the other is a carrier of Sickle Cell Disease, but the biggest problem in practice is when both future parents are carriers (without clinic, without changes in the routine peripheral blood analysis) and without family history for Sickle Cell Anemia. This last case is what the implementation of the above law aims to prevent (pregnant woman mandatorily doing Hemoglobin Electrophoresis).

Attention Hemoglobin Electrophoresis is a phenotypic analysis, it does not have the accuracy of genetic analysis. Its interpretation should be done by a specialist doctor.

Thalassemias

The term Thalassemia comes from the Greek (thalassa ("sea") and -emia ("blood") and indicates that it is a disease characteristic of coastal areas, typical for the Mediterranean basin.

They are a large group of inherited diseases, which are characterized by the reduction of various degrees of synthesis of hemoglobin chains (quantitative deficit of α or β hemoglobin chains). For α-Thalassemia viable forms are heterozygous (homozygous forms die during pregnancy) and when we talk about Thalassemia in general, we refer to α forms of Thalassemias (where even the Major form despite its many problems is compatible with life).

Clinical classification of thalassemic syndromes

1. Fetal Hydrops (lack of 4 alpha genes) with death during pregnancy (in utero) of the fetus.
2. beta-Thalassemia Major – homozygous, dependent on regular blood transfusion and its respective consequences.
3. Thalassemia Intermedia – very heterogeneous, does not need regular blood transfusion.
4. alpha, beta - Thalassemia Minor – Thalassemia carriers, do not need blood transfusion.

Depending on the protein chain deficit, there is alpha-Thalassemia (which has a deficit of α chains, or their dysfunction) and beta-Thalassemia (which has a deficit of β chains or their dysfunction). For α chains, four alleles (genes) code and for β chains only two. α chains are essential for Hb synthesis both in intrauterine life and after birth. Whereas β chains are necessary only for HbA, which appears after the 6th month of life when it replaces HbF, therefore the deficit of α chains is clinically manifested from intrauterine life, while that of β chains only after the 6th month, when HbA will be the main hemoglobin. Thus, the clinic and laboratory of beta-Thalassemias and Sickle Cell Disease will only be evident after the 6th month.