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Hereditary disorders of erythrocytes are common in many areas of the world, including the Middle East. In some regions of the Middle East more than 10% of the population are carriers of a gene for one of these conditions. When patients from the Middle East seek medical care in the West, an unrecognized but clinically important erythrocyte disorder can result in serious complications during routine medical care, such as a drug-induced hemolytic crisis. This article reviews the most important and most common inherited red blood cell disorders in Middle Eastern patients, including glucose-6-phosphate dehydrogenase deficiency, the thalassemias, and sickle cell disorders. We discuss when to suspect such conditions, how to determine their presence, and how to avoid potential complications related to them. Although a detailed discussion of treatment of erythrocyte disorders is beyond the scope of this article, some general management principles are described.
A 68-year-old man from Saudi Arabia traveled to a large American medical center for a total knee arthroplasty. Preoperative evaluation revealed mild microcytosis. Extensive evaluation for an occult bleeding source (including several endoscopic procedures) was unrevealing. Eventually, hemoglobin electrophoresis was performed, and the patient was found to have ×-thalassemia trait.
The orthopedic procedure was uncomplicated, but during convalescence the patient developed a urinary tract infection related to bladder catheterization. Trimethoprim-sulfamethoxazole and phenazopyridine were administered. This was followed by hemoglobinuria and mild icterus. He recalled a similar episode when he was treated for malaria during military service 40 years earlier. Hemolysis due to glucose-6-phosphate dehydrogenase (G6PD) deficiency was suspected, and further exposure to oxidative drugs was avoided. A subsequent assay confirmed G6PD deficiency. He was advised to avoid taking oxidative drugs such as sulfonamides and to avoid ingestion of fava beans. The patient returned home.
Red blood cell (RBC) abnormalities are extremely common in human populations. More than 700 abnormal hemoglobins have been described,
Human erythrocyte abnormalities have a broad spectrum of importance, from mutations that are lethal in utero or in childhood to incidental, inconsequential mutations detected either serendipitously or as part of large screening programs. Approximately 4.5% of all humans have a hemoglobin abnormality or thalassemia mutation. These genetic lesions are a major cause of morbidity and mortality around the world.
In this article, we review some of the most common RBC disorders seen in persons from the Middle East. This review does not include an exhaustive list of hemoglobin variants in Middle Eastern populations, since many of these variants have been found in only a single family or individual or have no clinical consequence. Instead, we focus on the most common and most important conditions, those most likely to be seen by Western clinicians. Much of the discussion also applies to patients living in the West who are of Middle Eastern descent.
WHEN TO SUSPECT AN RBC ABNORMALITY
The illustrative example at the beginning of this article points to the potential hazard of failing to recognize an RBC disorder in patients from regions of the world with a high prevalence of these mutations, such as the Middle East. Some hemoglobin and enzyme abnormalities are much more common in particular ethnic groups. Preventive health organizations recognize these epidemiological patterns and have adopted recommendations about which groups of adults should be screened for hemoglobinopathies and thalassemias.
The systematic screening of young adults before they attempt conception and the availability of genetic counseling have markedly reduced the incidence of homozygous thalassemia in some areas of the world such as Cyprus, Turkey, Greece, and Italy.
Patients from the Middle East frequently seek medical care in North America and Western Europe. Some medical centers in the West care for thousands of patients from this region each year (unpublished data, 1993–1998 Mayo Clinic, obtained January 2000). Occasionally, during the evaluation of a Middle Eastern patient for another medical condition, microcytosis, anemia, or another anomaly is discovered that raises the possibility of an RBC disorder (Table 1). Unexplained anemia or polycythemia, microcytosis or macrocytosis (especially macrocytosis due to reticulocytosis), or biochemical evidence of hemolysis (elevated levels of indirect bilirubin, lactate dehydrogenase, aspartate aminotransferase, etc) can all be clues to the presence of abnormal erythrocytes. Unexplained growth retardation, splenomegaly or hyposplenism, paradoxical results on assays for glycosylated hemoglobin,
hematuria, isosthenuria, and evidence of recurrent vaso-occlusive episodes (bone or abdominal pain, priapism, digital infarction, etc) are all nonspecific signs and symptoms that may suggest a hemoglobinopathy in the appropriate clinical setting. A hemolytic episode after starting a drug known to precipitate hemolysis in G6PD-deficient patients should raise strong suspicion of this enzyme deficiency.
Table 1Clinical and Laboratory Findings That May Raise Concern About the Presence of a Red Blood Cell Disorder
Anemia of any degree
Microcytosis (with or without anemia), especially with normal iron studies and red blood cell distribution width
Macrocytosis (especially due to reticulocytosis)
Target cells or basophilic stippling
Evidence of hemolysis, especially during an infection or after administration of an oxidative drug
Elevated lactate dehydrogenase
Elevated indirect (unconjugated) bilirubin
Elevated aspartate aminotransferase
Hemoglobinuria or hemosiderinuria
Hematuria or isosthenuria
Splenomegaly and/or hyposplenism (including indirect evidence such as Howell-Jolly inclusions on a peripheral blood smear)
Paradoxical or implausible glycosylated hemoglobin measurements
Unexplained vaso-occlusive episodes
Bone pain or avascular necrosis of bone
Colicky abdominal pain
Retinal infarction and vitreous hemorrhage
Digital ischemia and dactylitis (sometimes mistaken for arthritis)
Although the more severe RBC disorders are often diagnosed in the patients’ native countries, patients with milder RBC variants may arrive in the West without foreknowledge of the diagnosis. Medical care in many areas of the Middle East is excellent, but mild anemia is extremely common as a result of the high prevalence of iron deficiency. Therefore, mild anemia or microcytosis may not engender a high level of concern.
SPECIAL CONCERNS WITH RESPECT TO MIDDLE EASTERN POPULATIONS
In common parlance, the term Middle East is sometimes used nonspecifically. The Encyclopaedia Britannica states, “The term Middle East has come to be applied to the lands around the southern and eastern shores of the Mediterranean Sea, extending from Morocco to the Arabian Peninsula and Iran and sometimes beyond.” The Britannica definition is similar to that of the US State Department designation, “Middle East and North African Region,” which includes Algeria, Bahrain, Egypt, Iran, Iraq, Israel, Jordan, Kuwait, Lebanon, Libya, Morocco, Oman, Qatar, Saudi Arabia, Syria, Tunisia, United Arab Emirates, and Yemen. With the addition of Cyprus, Turkey, and Sudan, the State Department definition is the one used in this article (Figure 1).
The region has traditionally been divided into a western zone (the Maghrib, which encompasses North Africa west of Egypt) and an eastern zone (the Mashriq, extending from Egypt to Iran). The World Health Organization's Eastern Mediterannean Region includes most of the states in the Mashriq and some in the Maghrib. Table 2 shows some data on the prevalence of hemoglobinopathies in the Eastern Mediterannean Region. The World Health Organization estimates that approximately 5% of the population in the Eastern Mediterannean Region have a hemoglobin disorder.
These figures include thalassemias and hemoglobinopathies but not enzymopathies (such as G6PD deficiency, which affects tens of millions of people) or membrane disorders. Numbers rounded to the nearest whole percent. Data derived from Angastiniotis and Modell.16
Proportion of population
Cyprus (17%), Bahrain (13%)
Saudi Arabia, Morocco, Sudan, Iraq, Oman, Qatar, Syria, Yemen
Tunisia, United Arab Emirates, Pakistan, Libya, Iran, Kuwait, Lebanon
Jordan, Afghanistan, Egypt, Ethiopia
* These figures include thalassemias and hemoglobinopathies but not enzymopathies (such as G6PD deficiency, which affects tens of millions of people) or membrane disorders. Numbers rounded to the nearest whole percent. Data derived from Angastiniotis and Modell.
The practice is ancient and serves to keep property within families. In addition, populations around oases are often small and isolated, and this may favor consanguinity. First-cousin marriages are traditional.
The climate in the Middle East can be extreme. The daily high temperature in certain areas of the Arabian Peninsula can reach 54×C (130×F) for extended periods. In some areas, no rain at all may fall between April and October. The mean daily high temperature in Kuwait can reach 47.8×C during the summer months.
Such conditions favor dehydration, which increases the likelihood of sickling crises in patients with sickle cell anemia. There is a relationship between the frequency of sickle cell crises in Kuwait and meteorological conditions.
Infections that are rare in the West are common in certain areas of the Middle East. Malaria, schistosomiasis, and Old World hookworm parasites contribute to anemia and may obscure the presence of hemoglobin disorders. Thalassemias, sickle hemoglobin, and G6PD deficiency are protective against falciparum malaria, and the geographic distribution of these conditions parallels the distribution of Plasmodium falciparum.
The population of some of the oil-producing Gulf states now comprises more immigrant workers than native Arabs. In the United Arab Emirates, for example, only 20% of the 1.8 million residents are citizens of the Emirates; the rest of the population consists of Arabs from other countries, Filipinos, Pakistanis, and Indians.
Although this might lead to a more diverse set of erythrocyte genes locally, the more wealthy native populations of such nations are most likely to seek medical care in the West.
G6PD AND RBC ENZYMOPATHIES
The story of RBC enzyme abnormalities worldwide is overwhelmingly the story of G6PD deficiency. This is especially true in the Middle East. Pyruvate kinase deficiency, the most common enzyme-related cause of hereditary nonspherocytic anemia, appears to be quite rare in the Middle East.
An important “housekeeping” enzyme, G6PD helps protect RBCs from oxidative stress. It performs this function by catalyzing the initial step in a series of critical oxidation-reduction reactions: the conversion of oxidized nicotinamide adenine dinucleotide phosphate (NADP+) to its reduced form, NADPH. NADPH maintains glutathione in a reduced state, which in turn keeps sulfhydryl groups on hemoglobin and other proteins in a reduced state by preventing the formation of disulfide bonds. This housekeeping function is critically important to prevent hemoglobin precipitation and hemolysis. Hemoglobin precipitated in this way may form a Heinz body, an erythrocyte inclusion that is detected by staining with crystal violet.
Worldwide, G6PD deficiency affects hundreds of millions of people.
Commonly, however, intermittent episodes of hemolytic anemia with or without chronic hemolysis may be associated with G6PD deficiency. Hemolytic crises may be precipitated by oxidative drugs or by infections such as hepatitis and pneumonitis.
Although the list of drugs and chemicals alleged to precipitate hemolysis in G6PD-deficient patients is long, relatively few of these agents are both still marketed and definitely associated with hemolytic crises (Table 3). Other drugs are clearly safe to give to G6PD-deficient patients, such as aspirin and acetaminophen in standard doses. Some drugs that cause hemolysis in experimental assays are probably safe in the clinical setting, such as trimethoprim-sulfamethoxazole.
The small subset of drugs linked to clinically important hemolysis in G6PD-deficient patients should be used with caution in patients who come from ethnic groups with a high prevalence of this condition, unless the enzyme disorder has been ruled out.
Table 3A Select List of Currently Available Drugs and Chemicals to Avoid in Patients Who May Have G6PD Deficiency
The half-life of the Mediterranean variant enzyme in RBCs is very short (several hours) in comparison with several other common G6PD variants (eg, the A–type that is associated with hemolysis in sub-Saharan Africa has a half-life of 13 days) and normal G6PD (a half-life of 60 days).
Since enucleated RBCs cannot synthesize new G6PD, all except the very youngest RBCs of affected Middle Eastern patients are severely deficient in G6PD and therefore vulnerable to oxidative destruction.
The diagnosis is easily made by assay of conversion of NADP+ to NADPH, but false negatives may be seen in some groups (eg, African Americans, who commonly have the A– enzyme) during the weeks following an acute hemolytic episode. This phenomenon occurs because the senescent RBCs most deficient in G6PD are also those most likely to be destroyed by an oxidative stress, leaving a select population of younger RBCs with anomalously high G6PD levels. If hemolysis due to G6PD deficiency is suspected in an African American, it is best to wait several weeks before pursuing laboratory testing. However, this does not normally apply to Middle Eastern patients, who have the much more severe Mediterranean variant of G6PD deficiency. Supportive care during hemolytic crises (including the transfusion of healthy G6PD-containing erythrocytes if necessary) and avoidance of fava beans and other oxidative stresses are appropriate management strategies for G6PD-deficient patients.
The thalassemias are a diverse group of disorders that result from any of the numerous genetic mutations associated with decreased synthesis of 1 or more globin chains. The name thalassemia reflects a former belief that the disorder affected only the people of the Mediterranean Sea region: the term is derived from the Greek words ?α?αssα (“thalassa”: sea, referring to the Mediterranean) and α?µα (“[h]aima”: blood). However, thalassemia has a worldwide equatorial distribution. The first description of severe thalassemia as a unique disorder discernible from the other anemias of childhood was by Thomas Cooley, a pediatrician in Detroit, Mich and a colleague, Pearl Lee.
The term Cooley anemia is still commonly used to describe homozygous ×-thalassemia.
Humans have 4 α globin genes on chromosome 16 and 2 × globin genes on chromosome 11, so symptomatic α-thalassemia is rarer than ×-thalassemia. This is particularly true in the Middle East, where symptomatic α-thalassemia is encountered only sporadically, but ×-thalassemia is widespread. Homozygous ×-thalassemia and the severe forms of α-thalassemia are usually diagnosed at birth or in early childhood. However, the milder forms of α-thalassemia and some heterozygous ×-thalassemia mutations may escape detection until adulthood. The clinical and laboratory findings classically associated with the various thalassemias are detailed in Table 4, Table 5.
Table 4Typical Clinical and Laboratory Manifestations of α-Thalassemia
The α symbol represents the presence of a functional globin gene, while the minus sign (−) symbolizes a dysfunctional gene. The absence of a functional globin gene may be due to simple deletion or to the Saudi polyadenylation mutation described in the text.
Hemoglobin A2 molecule contains 2 α globin chains and 2 δ chains and normally represents 2.0% to 3.3% of the total hemoglobin. Hemoglobin H consists of 4 β globin chains and is unstable and inefficient at carrying oxygen to tissues. Hemoglobin Bart's represents 4 γ chains and is almost completely ineffective at delivering oxygen.
α-Thalassemia-2 trait (silent carrier state) (1)
None; detectable only by genetic analysis
None or mild microcytosis
Usually normal; hemoglobin A2 may be low
α-Thalassemia-1 trait (2)
α–/α– or αα/−−
Mild microcytosis, with or without mild anemia
May be normal or hemoglobin A2 may be low
Hemoglobin H disease (3)
Moderate hemolytic anemia
Markedly microcytic anemia with many target cells
Hemoglobin Bart's and hydrops fetalis (4)
– –/– –
Catastrophic; death in utero or early infancy
Severe anemia, abundant nucleated red cells
* The α symbol represents the presence of a functional globin gene, while the minus sign (−) symbolizes a dysfunctional gene. The absence of a functional globin gene may be due to simple deletion or to the Saudi polyadenylation mutation described in the text.
† Hemoglobin A2 molecule contains 2 α globin chains and 2 δ chains and normally represents 2.0% to 3.3% of the total hemoglobin. Hemoglobin H consists of 4 β globin chains and is unstable and inefficient at carrying oxygen to tissues. Hemoglobin Bart's represents 4 γ chains and is almost completely ineffective at delivering oxygen.
The α-thalassemias are most often the result of simple deletions of α globin genes. There may be deletion of 1 or 2 α globin genes on a single allele of chromosome 16. Deletion of 3 or 4 of the α globin genes is quite uncommon in Middle Eastern populations. This is because individuals in this region commonly have the “α–” gene haplotype (ie, 1 α gene deletion on 1 allele of chromosome 16) and only rarely carry the “– –” gene haplotype (2 α gene deletions on the same allele of chromosome 16). Inheritance of the latter is usually necessary to develop the 2 most serious forms of α-thalassemia.
However, hemoglobin H disease due to dysfunctional α globin genes occurs with some frequency in eastern Saudi Arabia. This is because of a polyadenylation signal mutation found in the region that renders 1 copy of the α globin gene nonfunctional; the other allele on the same chromosome may be deleted.
Individuals inherit 1 × globin gene from each parent, so only 4 general genetic patterns are possible: 2 normal genes; 1 normal gene and 1 abnormal gene (simple heterozygous state); 2 different abnormal genes (compound heterozygous state); or 2 copies of the same abnormal gene (homozygous state). However, at the genetic level, there are many different × globin mutations leading to thalassemia. In contrast to α-thalassemia, simple deletions are rare in ×-thalassemia; instead, messenger RNA splicing errors, promoter lesions, and nonsense mutations leading to premature chain termination are frequent.
This genotypic heterogeneity leads to a very diverse set of phenotypes, compounded by the coinheritance of other genes affecting globin synthesis or its consequences. Because of this, the clinical manifestations seen in patients who have identical × globin gene mutations (eg, siblings) may be quite different.
The majority of Middle Eastern patients with ×-thalassemia detected incidentally on medical visits to the West are simple heterozygotes, ie, they have ×-thalassemia trait. More severe thalassemia is inevitably detected early in life.
The major danger of an undetected minor thalassemia mutation is that it may be mistaken for iron deficiency. Numerous cases have been reported of patients who were prescribed long-term iron supplementation for presumed iron deficiency who instead had thalassemia; a few of these patients have developed complications of iron overload, including liver failure and diabetes.
Patients with thalassemia trait have also been subject to unnecessary endoscopic evaluations in search of a gastrointestinal bleeding source. The use of various “discriminant functions” based on RBC indices may help exclude iron deficiency,
but specificity and sensitivity are low. In addition, iron deficiency and thalassemia mutations often coexist, compounding the difficulty. Careful analysis of iron studies (especially measurement of the serum ferritin concentration), RBC indices, and hemoglobin electrophoresis results is critical. A low serum ferritin concentration is diagnostic of iron deficiency but does not rule out concomitant thalassemia. A brief trial of iron therapy followed by retesting or direct genetic analysis of globin genes may be required for definitive diagnosis.
No treatment is usually required for the milder thalassemias. The more severe forms often require aggressive management with RBC transfusions, chelation of excess iron, other supportive care, and occasionally bone marrow transplantation.
Such care may be best coordinated within the context of a long-term relationship with a physician who has expertise in treating severe hemoglobinopathies. Lack of access to a safe blood supply and modern medical care is associated with severe morbidity among thalassemia patients in some parts of the world.
The sickle cell syndromes are most common in patients of Central and West African descent. However, 2 other areas of the world have a high prevalence of the sickle mutation (hemoglobin S): the Arabian Peninsula and the Indian subcontinent. The mutation also occurs throughout the Mediterranean littoral. Haplotype analysis has shown that the mutation found commonly in Saudi Arabia arose separately from the African mutations.
The clinical manifestations of Arabic patients with homozygous hemoglobin S are usually milder than those in patients with African hemoglobin S mutations, but cases with severe manifestations do exist.
Nonetheless, sickle cell anemia causes much morbidity in affected Arabic patients.
There are several compound heterozygous conditions in which hemoglobin S is coinherited with another abnormal hemoglobin gene. Hemoglobin S C disease, for instance, is seen particularly in North Africa and results from inheritance of hemoglobin C from one parent and hemoglobin S from the other.
Hemoglobin S ×-thalassemia has a wide variety of clinical presentations, depending on the level of synthesis of the thalassemic × globin chain. The severity ranges from moderate to severe. Hemoglobin S O Arab disease, despite its name, is rarely found in Middle Eastern patients.
Some homozygous patients such as those with a very high level of fetal hemoglobin may need little more than long-term folate supplementation, but others may have a catastrophic course and require aggressive supportive care, frequent hospitalizations, generous use of narcotics for pain relief, and transfusions. Pulmonary symptoms in particular must be addressed urgently and aggressively, as the acute chest syndrome remains a major cause of death in this group.
As with the severe thalassemia syndromes, the care of these patients may best be coordinated within the context of a long-term relationship with a physician who has expertise in treating severe hemoglobinopathies.
RBC MEMBRANE DISORDERS
The RBC membrane disorders are uncommon in the Middle East. The major inherited RBC membrane abnormalities worldwide are hereditary spherocytosis and hereditary elliptocytosis. Quite rare are hereditary pyropoikilocytosis (which is biochemically related to hereditary elliptocytosis and is sometimes seen in the same families) and hereditary stomatocytosis.
Hereditary elliptocytosis is found at a low level in all ethnic groups. Hereditary pyropoikilocytosis is most common in persons of sub-Saharan African descent and is rare in other ethnic groups. Occasional cases have been seen in the Middle East.
Hereditary stomatocytosis and hereditary xerocytosis are quite rare and have been seen in individuals in many different populations.
OTHER HEMOGLOBIN DISORDERS
Although many other hemoglobin disorders have been reported in patients from the Middle East, most are found in very small groups of patients or single families and are likely to be of no consequence for primary care physicians. One possible exception is hemoglobin C, which is seen occasionally throughout the Mediterranean littoral. The heterozygous state for hemoglobin C is clinically silent (unless it is coinherited with hemoglobin S), and the homozygous state typically causes a mild chronic hemolytic anemia. The name of 1 abnormal hemoglobin, hemoglobin O Arab, suggests a Middle Eastern predominance, but this is misleading. Although it was first identified in an Egyptian and in a Palestinian, hemoglobin O Arab has been seen with frequency only in Eastern Europe. Its highest prevalence is among Bulgarians, and it is actually uncommon in Arab individuals.
It is important for Western clinicians to be aware of RBC disorders in Middle Eastern patients. G6PD deficiency and the thalassemias (especially heterozygous ×-thalassemia) are quite common in this group and must always be considered. Sickle cell disease is not limited to Central and West African populations but also occurs in the Arabian Peninsula. Erythrocyte membrane disorders, in contrast, are not a major concern in the Middle East.
If a hemoglobinopathy or thalassemia is suspected, hemoglobin electrophoresis or chromatography is the test of choice. Known oxidative drugs should be avoided unless G6PD deficiency has been ruled out. By keeping these principles in mind, unnecessary complications and unfruitful diagnostic evaluations may be avoided.
A Syllabus of Human Hemoglobin Variants. Sickle Cell Anemia Foundation,