Hemoglobinopathies: Clinical Manifestations, Diagnosis, and Treatment

With approximately 7% of the worldwide population being carriers, hemoglobinopathies are the most common monogenic diseases and one of the world’s major health problems (1, 2, e1, e2). They were originally found mainly in the Mediterranean area and large parts of Asia and Africa (3). International migration has spread them from those areas all over the world. In many parts of Europe today, hemoglobin (Hb) defects are classified as endemic diseases (3) (Table 1 gif ppt).

Germany is one of the countries in which hemoglobinopathies have increased in recent years (4–7). There are no epidemiological studies on their frequency. The following statements can be made regarding gene carriers: prevalence among the 9 million immigrants from countries with a high risk of hemoglobinopathies as a whole is 4.5%, giving a figure of 400 000 for the number of hemoglobinopathy gene carriers (6). The total number of patients diagnosed with these diseases in the author’s laboratory from 1970 to 2010 is 5831.

This review article should be considered an extension of the original article “Hemoglobinopathies in Germany—a longitudinal study over four decades,” also published in Deutsches Ärzteblatt International (6). It aims to provide a brief summary of the most important clinical pictures and indicate the features that can be used to identify those with these diseases with low-level symptoms, but not gene carriers in good health, in general practice (Tables 2, 3). Topical grounds for the publication of this article are the increase in the number of people affected, which has implications for care provision, and the fact that optimum treatment can give patients a steadily-increasing projected life span. As a result, medical treatment is becoming more and more part of adult medicine, rather than pediatrics alone.

Indications for hemoglobin testing

Hemoglobin testing is particularly indicated in the following situations (8, 9):

• Microcytic hypochromic anemia after iron deficiency has been ruled out
• Chronic hemolytic anemia
• Vascular obliteration crises of unclear etiology in patients from areas in which HbS and/or HbC is widespread
• Drug-induced anemia
• Erythrocytosis and/or cyanosis caused by hematological factors
• Hydrops fetalis of unclear etiology
• Prevention (testing of family members, diagnosis of partners for genetic counseling)
• Prenatal diagnosis.

Generalized hemoglobin electrophoresis for all cases of anemia cannot be justified on the basis of expediency or financial considerations, particularly in those with no background of migration.

Diagnosis

Hemoglobinopathy diagnosis in routine practice involves a red blood cell (RBC) count with erythrocyte indices, and a hemoglobin test (hemoglobin electrophoresis and/or chromatography) (Tables 2, 3). Specialized tests in facilities qualified for the purpose are often required (6, 9, 11, e3, e4). The eFigure (gif ppt) shows a testing plan for step-by-step diagnosis and also includes indications for DNA testing.

Basic types of hemoglobinopathy

The umbrella term “hemoglobinopathy” includes all genetic hemoglobin disorders. These are divided into two main groups as follows:

• Thalassemia syndromes
• Structural hemoglobin variants (abnormal hemoglobins).

Both are caused by mutations and/or deletions in the α- or β-globin genes. When gene defects cause Hb synthesis disorders, this gives rise to thalassemia. Hemoglobin structure in these cases is normal. When they cause changes in Hb structure, this gives rise to abnormal hemoglobin (5, 6, 11). There are also many mixed forms that combine features of both groups, e.g. β⁰/β⁺-thalassemias, HbSC disease and HbE α-thalassemias. The common features of the pathophysiology and various disease patterns are limited, and as a result so are the possibilities for summarizing them.

Thalassemia syndromes

This term includes all thalassemic Hb synthesis disorders (Table 2 gif ppt). These are autosomal recessive conditions. α- and β-thalassemias have the greatest clinical significance (5, 11, 12).

Heterozygous thalassemia carriers are not completely healthy: they always have symptoms that require clarification with mild, iron-refractory, microcytic hypochromic anemia. Homozygous major forms are accompanied by serious, hypochromic hemolytic anemias and complex diseases.

α-thalassemias

α-thalassemias are caused by an α-globin chain synthesis defect. At the molecular level, they result from partial (α⁺) or total (α⁰) deletions, or more rarely mutations, of one or more of the four α-globin genes (αα/αα). They occur mainly in Africa, Arab nations, and, more frequently, South-East Asia (5).

Diagnostic criteria and cardinal symptoms: there are four clinical pictures of α-thalassemia, according to the number of genes affected by loss of function (5, 12). All of them become manifest perinatally (Table 2):

• Clinically inapparent α-thalassemia minima (heterozygous α⁺-thalassemia, -α/αα). This can be identified on the basis of mild hypochromia revealed in a blood count, with a barely measurable reduction in Hb values.
• α-thalassemia minor (heterozygous α⁰-thalassemia, --/αα, or homozygous α⁺-thalassemia, -α/-α) with mild anemia, hypochromia, microcytosis.
• HbH disease (compound heterozygous α⁺/α⁰-thalassemia with three inactive α-genes, --/-α), moderate hypochromic hemolytic anemia with splenomegaly. Anemic crises are caused by viral infections and oxidants (drugs). Complications include cardiac problems, gallstones, lower leg ulcers, and folic acid deficiency.
• Hb Bart’s hydrops fetalis (homozygous α⁰-thalassemia) with very serious hemolytic anemia already present in utero and marked by a lack of any α-globin chain synthesis (--/--), with hydrops and ascites. This is fatal if not treated.

β-thalassemias

β-thalassemia syndromes (Table 2) are the result of insufficient (β⁺) or absent (β⁰) production of β-globin chains. Their molecular causes are β-globin gene mutations. Most patients come from Mediterranean countries, South-East Europe, Arab nations, and Asia. Hematological changes become manifest from between the ages of three months and six months onwards (5, 6, 13).

Diagnostic criteria and cardinal symptoms:

• Thalassemia minor (heterozygous β-thalassemia) with mild, microcytic hypochromic anemia (2)
• Thalassemia intermedia (mild homozygous or mixed heterozygous β-thalassemia) of moderate severity and with a varying need for transfusions; typical complications are skeletal deformities and tumorous masses as a result of massive hyperplastic erythropoiesis (2)
• Thalassemia major (severe homozygous or mixed heterozygous β-thalassemia) (13) with long-term, transfusion-dependent anemia (Table 4 gif ppt); untreated children die before the age of 10. Thalassemia major entails a risk of iron overload and multiorgan involvement. As a result of treatment, the full clinical picture is no longer seen in Germany (2, 13). Optimally treated patients have a projected life span of 50 to 60 years.

Abnormal hemoglobins

This group of autosomal dominant inherited hemoglobin disorders is caused by structural defects resulting from an altered amino acid sequence in the α or β chains (3, 10, 14). Clinicians must distinguish between clinically harmless Hb abnormalities and those that cause illness (Table 3 gif ppt). These latter are divided into the following four well-defined groups:

• Variants with a tendency to aggregate and with sickle cell formation, e.g. the sickle syndromes (14)
• Variants with abnormal hemoglobin synthesis, e.g. HbE (2, 10)
• Variants with a tendency to precipitate and with hemolysis (unstable hemoglobins), e.g. Hb Köln (15)
• Variants with abnormal oxygen transportation and congenital polycythemia, e.g. Hb Johnstown (16, 17), or with congenital cyanosis (abnormal methemoglobins, HbM abnormalities, e.g. M Iwate) (2).

The forms in the third and fourth groups cause serious illness when heterozygous. When homozygous, they are fatal.

The main Hb abnormalities, both worldwide and among immigrants living in Germany, are HbS, HbC, and HbE. The large groups of rare Hb abnormalities that occur only in isolated cases all over the world should also be monitored. These are often accompanied by hemolysis, polycythemia, and/or cyanosis. Identifying these is an important part of differential diagnosis of hematological diseases where other efforts towards diagnosis have proved inconclusive (3, 6, 10, 11).

HbS and sickle-cell disease

The term “sickle-cell disease” includes all manifestations of abnormal HbS levels (proportion of HbS >50%). These include homozygous sickle-cell disease (HbSS) and a range of mixed heterozygous hemoglobinopathies (HbS/β-thalassemia, HbSC disease, and other combinations) (14).

According to the International Nomenclature, the previously commonly-used term “sickle-cell anemia” should not be used, as the dominant aspects of the disease are vascular obliterations and the organ damage they cause, not anemia.

HbS is the most dangerous of all hemoglobinopathies. The sickle cells caused by a lack of oxygen lead to vascular obliterations, so infarctions with tissue death can occur in almost all organs (skin, liver, spleen, bone, kidneys, retina, CNS). Chronic hemolytic anemia can usually be well tolerated (14). Aplastic crises are seen with severe anemia following viral infections (2).

Diagnostic criteria and cardinal symptoms: Symptoms begin before the age of one, with chronic hemolytic anemia and developmental disorders (Table 3). The main problems are pain crises (sickle-cell crises) that can affect the back, extremities, thorax, abdomen, and CNS in particular. Patients are also dangerously susceptible to infection, particularly by pneumococci, hemophilus, salmonellae, klebsiellae, and mycoplasmae. Sepsis, osteomyelitis, and meningeal events, sometimes with cardiac involvement, frequently result in death. Spleen crises, acute thoracic syndrome (ATS), and strokes are also fatal in more than a few cases. These issues cause serious organ damage.

Optimally treated patients can have a projected life span of 50 to 60 years.

Heterozygous HbS gene carriers are not affected clinically or hematologically (18).

HbC abnormality and HbC disease

HbC homozygosity, or HbC disease, progresses in a similar way to sickle-cell disease, but is less serious (2, 3). Variable hemolytic anemia is the most dominant form. Heterozygous HbC gene carriers enjoy complete clinical health (Table 3).

HbE abnormality and HbE disease

HbE is an extremely common Hb variant native to South-East Asia. Its disease pattern is similar to that of β-thalassemias. Hb is also unstable, which means that hemolysis can be caused by viral infections and medications (Table 3). HbE is often combined with thalassemias, which may result in serious major-form hemoglobinopathies (2, 3, 10).

HbE homozygosity (HbE disease): Typically, this is moderate, microcytic hypochromic anemia with possible hemolysis due to exogenous causes.

HbE heterozygosity: Patients have variable hypochromic anemia similar to that found in β-thalassemia minor.

Treatment for β-thalassemias

β-thalassemia major

After being diagnosed, patients should be referred to a hematology center for counseling and to decide on treatment, and, if appropriate, for regular diagnosis appraisal (Table 4).

The current international standard treatment (18–20) is based on the results of studies conducted at large sites in England (5) and the USA (3) and is stated in available child and adolescent medicine guidelines (20) (AWMF/II/025–017.htm).

Curative treatment: Hematopoietic stem-cell transplantation is the first-line treatment if a donor can be found (21).

Supportive treatment: Supportive treatment for thalassemia major includes lifelong regular transfusions combined with effective iron removal (20). Hemosiderosis-related organ damage requires specific treatment (22, 23).

• Transfusion therapy: Repeat hemoglobin concentration levels of less than 8 g/dL are an indication for beginning transfusion therapy. The target baseline hemoglobin level is 9 to 10.5 g/dL. The recommended frequency of transfusions is usually one every three weeks. Transfusion volume is usually 12 to 14 mg/kg body weight (BW) with an RBC concentrate hematocrit of 60%. Target Hb levels are 13 to 13.5 g/dL.
• Drug treatment to remove iron (chelation therapy): Iron removal is indicated when serum ferritin concentration repeatedly exceeds 1000 ng/mL (20).

  – Iron removal using deferoxamine: Standard deferoxamine treatment is a daily subcutaneous infusion (over several hours) at a dose of (20) – 40 – (50) mg/kg BW, 5 to 7 days per week. Dose adjustment is based on monthly testing of serum ferritin concentration. Patients must be closely monitored for potential side effects of deferoxamine (reduced growth, bone damage, high-frequency hearing loss, retinal damage) (20).

  – Iron removal with deferasirox: Deferasirox is a well-tolerated iron chelator in tablet form and has taken on a central role in iron removal therapy (22, 23). However, this is a relatively new drug of which no long-term studies have been conducted. A standard dose of 20 mg/kg BW/day is recommended for patients with β-thalassemia major who are receiving long-term transfusion therapy. This dose must be adjusted on the basis of monthly measuring of ferritin levels. The main side effects (close monitoring required!) are kidney failure, agranulocytosis, and liver failure (22, 23). Liver iron levels must be measured every two years (Table 4).

• Splenectomy is indicated for tumorous enlargement of the spleen with increased need for transfusions and hypersplenism.

β-thalassemia intermedia

Transfusion therapy is indicated for patients with complications as a result of major increases in erythropoiesis, and patients with anemia and an inability to maintain stable hemoglobin levels of more than 8 g/dL. In such cases, lifelong continuous transfusion therapy should be considered, rather than transfusions at intervals, combined with appropriate chelation therapy (24).

β-thalassemia minor

For severe anemia, folic acid supplements (0.5 mg/day orally) may be considered (2). Iron supplements are contraindicated unless there is simultaneous iron deficiency.

Treatment for α-thalassemias

α-thalassemia minima and minor do not require treatment. Iron supplements are contraindicated (except in cases of iron deficiency) (20).

Treatment for HbH disease depends on the severity of the clinical picture, which can vary widely. Transfusions are rarely indicated. Anemia requires regular substitution with folic acid (e.g. 5 mg/week) (2, 20). Iron supplements are contraindicated (unless there is simultaneous iron deficiency).

For Hb Bart’s syndrome, transfusions are required in utero and continuously after birth. Where possible, stem-cell transplantation is performed (12, 20).

Treatment for sickle-cell disease

Following diagnosis, patients should be referred to a hematology center for counseling and to decide on treatment, and, if appropriate, for regular diagnosis appraisal (Table 5 gif ppt). The current standard treatment (18) is based on the results of studies conducted at large sites in England (5, e6, e7) and the USA (14) and is stated in available guidelines (18) (AWMF/II/025–016.htm).

Curative treatment

Allogeneic stem-cell transplantation may be used for children under 16 (21, e9). Indications are CNS infarction, particularly severe, frequent pain crises, or frequent occurence of acute thoracic syndromes. For older patients, transplantation is usually not an option due to a lack of donors and the high risks of transplantation.

Symptomatic treatment

• Analgesics: first-line treatment for pain crises consists of sufficient administration of fluids and analgesics appropriate to the level of pain (paracetamol, metamizol, possibly also codeine or tramal, or even morphine).
• With proteinuria above 0.5 g/24 hours, ACE inhibitors can inhibit progression of glomerulonephritis or glomerulosclerosis.
• Antibiotics are also administered, particularly for pneumococcal infection with suspected sepsis and for salmonella infection with suspected osteomyelitis.
• Hydroxyurea (18, e7, e8) is the only substance to date that can reduce the number and severity of pain crises (in 70% to 75% of patients) and decrease the number of episodes of acute thoracic syndrome and mortality. The initial dose of 15 mg/kg/day can be increased to 35 mg/kg/day. Due to severe side effects (18), sickle-cell patients may only be treated with hydroxyurea when it is strictly indicated, following patient education, if birth control is used (for women of reproductive age), with regular blood counts (initially every two weeks and then monthly), and with careful documentation of side effects. Side effects include cytopenia revealed in a blood count, hyperpigmentation, weight gain, opportunistic infections, azoospermia in approximately 80% of men (even years after the end of treatment), and marked hypomagnesemia. It is also believed that there is a teratogenic effect (18).
• Transfusion therapy is subject to strict indications (18). Unfortunately, these rules are often broken. Single transfusions are indicated for major splenic sequestration, aplastic crises, and acute thoracic syndrome, as well as before major surgery (Hb must be increased to 10 g/dL!). Partial exchange transfusions to reduce the proportion of HbS are indicated for acute organ failure or vascular occlusions, but rarely for refractory pain crises.
• The main indication for long-term transfusion programs (to maintain low proportions of HbS in the blood long-term) is a CNS infarction. Sickle-cell patients receiving frequent transfusions must receive chelation therapy.
• Splenectomy: homozygous sickle-cell diseases lead to spleen sclerosis and functional asplenia even in childhood. Patients with HbS β-thalassemia undergo splenectomy following splenic sequestrations or in the event of hypersplenism.

Prevention

Affected children must receive all vaccinations recommended by STIKO, Germany’s Standing Vaccination Commission, and 7-valent pneumococcal vaccinations from the age of two months onwards (also see guidelines).

Prophylactic penicillin must also be administered from the age of three months onwards, for at least five years.

The most important guidelines for psychosocial treatment are stated in the eTable (gif ppt).

Evidence available on treatment for hemoglobinopathies

The evidence available in the literature is consistent and ranges from meta-analyses of controlled studies to field reports (5, 7, 13, 14). The evidence supports stem-cell transplantation (21), transfusion therapy (5, 7), and treatment for secondary hemosiderosis (22, 23) to treat thalassemias; and symptomatic treatment as a whole, including hydroxyurea treatment, to treat sickle-cell disease (8, 14, 25).

Conclusion

The projected life span and quality of life of patients with severe hemoglobin disorders can be significantly improved using advanced treatment methods. In contrast to other European countries, in Germany there is unfortunately still no comprehensive overall approach to optimum diagnosis and treatment strategies. One problem that has barely been addressed is continued treatment after patients have moved from pediatric or adolescent care to adult care. It would be particularly desirable to establish hemoglobinopathy care centers at which interdisciplinary teams care for patients, as happens in neighboring countries (25).

Conflict of interest statement
The author declares that no conflict of interest exists.

Manuscript received on 15 April 2010, revised version accepted on
10 August 2010.

Translated from the original German by Caroline Devitt, MA.

Corresponding author
Prof. Dr. med. Elisabeth Kohne
Hämoglobinlabor Universitätsklinikum Ulm
Klinik für Kinder- und Jugendmedizin
Eythstr. 24
89075 Ulm, Germany
elisabeth.kohne@uniklinik-ulm.de

@For eReferences please refer to:
www.aerzteblatt-international.de/ref3111

eFigure, eTable:
www.aerzteblatt-international.de/11m532