Evaluation of Splenomegaly


The spleen is a secondary lymphoid organ that lies in intraperitoneally in the left hypochondrium, abuting the diaphragm. It spans from the 9th to 11th rib and weighs between 150-200g. Spleen is supplied by the splenic artery and drains into portal circulation via the splenic vein. It is a part of reticuloendothelial system, immune system and is a site of in utero haematopoiesis. The spleen is enlarged in a diverse set of disease of the above mentioned  systems and in portal hypertension.

Normal Functions of the Spleen

The normal functions of the spleen include

  1. Reticuloendothelial functions: The spleen as a component of the reticuloendothelial system is involved in clearing the blood of ageing or damaged erythrocytes, antibody coated cells and opsonised bacteria. It also removes particles from red cells. The spleen ensures that the red cell in circulation have adequate deformability for passage through microcirculation.
  2. Immune Functions: The spleen is a part of the immune system and plays a role in mounting the immune response . Splenectomy increases the risk of infections particularly with capsulated organisms (see Overwhelming Post-Splenectomy Infection (OPSI)).
  3. Haematopoiesis: Spleen is the site for haematopoiesis in utero. In extrauterine life spleen can become a site of haematopoiesis in disease.

Palpating the Spleen

  1. Palpation of the spleen should start from the right iliac fossa. If this is not done there is a risk of missing a massively enlarged spleen.
  2. Move towards the left costal margin in a direction perpendicular to the margin. Move with each breath. At every position ask the patient to take a deep breath. The tip of the spleen will hit your palpating finger.
  3. If the spleen does not hit your finger move your palpating finger to a position closer to coastal margin, ask the patient to take a deep breath and repeat the procedure described above till your finger hits the costal margin.
  4. If the spleen is felt measure the perpendicular distance between the tip and the left coastal margin. Also note the texture and presence of tenderness.
  5. If the spleen is not felt repeat the procedure with patients lying on right side.
  6. Large spleen can rupture with aggressive palpation. The spleen lies directly under the anterior abdominal wall. One does not need to be aggressive.

Causes of Splenomegaly

The spleen enlarges from the left coastal margin in the direction of the umbilicus. It needs to enlarge 2-3 times before it is palpable. Splenomegaly may be caused be increase in portal venous pressure, infiltrative conditions or when the spleen function needs to increase. Clinically it is useful to classify splenomegaly by size. Massive splenomegaly is enlargement of the spleen beyond the umbilicus. The causes of massive splenomegaly include

  1. Malignant: Chronic myeloid leukaemia, Idiopathic myelofibrois, hairy cell leukaemia, splenic marginal zone lymphoma, chronic lymphocytic leukaemia, prolymphocytic leukaemia
  2. Infections: Tropical splenomegaly, AIDS with Mycobacterium avium complex infections, Kala-azar (visceral leishmaniasis)
  3. Others: β-Thalassaemia major and intermedia, Extrahepatic portal venous obstructions,megaloblastic anaemia, diffuse splenic haemagiosis

The causes of splenomegaly include the above and the following

  1. Portal Hypertension: Cirrhosis, Budd-Chairy syndrome, splenic vein thosmbosis, congestive heart failure, hepatic schistosomiasis
  2. Increased splenic function:
    1. Increased functional demands: Haemolytic anaemia commonly hereditary spherocytosis, autoimmune haemolytic anaemia, β-thalassaemia, early sickle cell anaemia, sickle cell β-thalassaemia,
    2. Infections:
      1. Bacterial: Septicaemia, bacterial endocarditis, splenic abscess, brucellosis, tuberculosis, AIDS with Mycobacterium avium complex infections, secondary syphilis
      2. Viral: Viral hepatitis, infectious mononucleosis, cytomegalovirus,
      3. Parasitic: Malaria , Kala-azar (visceral leishmaniasis), Trypanosomiasis,
      4. Fungal: Histoplasmosis
    3. Immune Disorders:
      1. Autoimmune diseases: Rhumatoid arthritis (Felty’s syndrome), systemic lupus erythrmatosis
      2. Other immune disorders: Immune haemolytic anaemia, immune neutropenia, drug reaction, serum sickness, sarcoidosis
      3. Haemophgocytic lymphohistiocytosis
  3. Infiltrations
    1. Haematological Malignancy:
      1. Myeloid: Chronic myeloid leukaemia, myeloproliferative disease, idiopathic myelofibrosis, polycythaemia vera
      2. Lymphoid: Acute lymphoblastic leukaemia, hairy cell leukaemia, chronic lymphocytic leukaemia, prolymphocytic leukaemia, splenic marginal zone lymphoma, angioimmnoblastic T cell lymphoma
      3. Other: Histiocytosis X, eosinophilic granuloma
    2. Storage disorders:Gaucher disease, Niemann-Pick, Tangier disease, mucopolysachroidosis
    3. Other Infiltrations: Amyloid
  4. Others: Iron deficiency anaemia

 

History and Physical Examination

  1. Fever: Fever is a feature of splenomegaly due to infections, inflammations or malignancy, particularly haematological malignancy. Usually the fever is low grade. High grade fever suggests splenic abscess.
  2. Painful splenemegaly: The nature of pain associated with splenomegaly varies with the cause of splenomegaly.
    1. An enlargement spleen from any cause can cause a dragging pain in the left upper quadrant.
    2. Acute pain left upper quadrant pain is a feature of is a feature of splenic infarct and splenic abscess. Sickle Cell anaemia is associated with small fibrotic spleen because of repeated splenic infarcts. Early in disease the spleen enlarges. Patients may present with acute pain from splenic infarcts. Enlarged spleen from any cause is predisposed to infarction. Acute pain in the left upper quadrant is also a feature of acute splenic abscess.
    3. Splenic vein thrombosis can cause splenomegly and pain in left upper quadrant or epigastric region. It may also cause generalised abdominal pain.
    4. Pancreatitis presents with abdominal pain and can cause painful splenomegaly secondary to splenic vein thrombosis.
    5. Alcohol induced pain is an uncommon but unique feature of Hodgkin lymphoma. Spleen is a common site of involvement by Hodgkin lymphoma. Such patients may have alcohol induced pain in an enlarged spleen.
  3. Pallor: Pallor in a patient with splenomegaly suggests a diagnosis of haemolytic anaemia, haemolymphatic malignancy and infective endocarditis.
  4. Clubbing: Clubbing with splenomegaly is a feature of infective endocarditis and cirrhosis of the liver.
  5. Skin rash: Skin rash in a patient with splenomegaly is seen in systemic lupus erthomatosis, infective endocarditis, lymphoma (angioimmuniblastic T Cell lymphoma, mycosis fungiodes, skin involvement with lymphoma) and drug reaction.  Each of these conditions have a distinct type of rash.
  6. Skin Pigmentation: Hyperpigmantation suggests be seen in hemachromatosis or megaloblastic anaemia. The patients with megaloblastic anaemia may also have knuckle pigmentation.
  7. Jaundice: Jaundice with enlarged spleen is a feature of haemolytic anaemia. The jaundice is usually achloruric. Patients with haemolytic anaemia are predisposed to gallstones. Obstruction of the biliary system from a calculus dislodged from the gall bladder can cause obstructive jaundice with abdominal pain and signs of acute inflammation. Splenomegaly with jaundice is a feature of advanced cirrhosis. Patients with advanced cirrhosis almost always have ascites.
  8. Lymphadenopathy: The enlargement of lymph nodes and spleen is a feature of lymphoid malignancies or diseases that stimulate the lymphoid systems viz. infections and autoimmune diseases and lymphoid malignancy.
  9. Joint symptoms: Arthropathy with splenomegaly suggests the diagnosis of rheumatoid arthritis, systemic lypus erythrmatosis or haematochromatosis.
  10. Oral symptoms: infectious mononucleosis is charecterized by pharyngitis and generalised lymphadenopathy. Bleeding gums and/or gum hypertrophy suggests a diagnosis of leukaemia. Lymphoma can cause tomsillar enlargement. Amyloid is charectetized by macroglossia.
  11. Evidence of Portal Hypertension and Liver Cell Failure: Patients with portal hypertension often have history of haemetemesis. Examination may reveal periumbilical veins (capital medusae), anterior abdominal or flank veins. Patients with evidence liver cell failures with portal hypertension (e.g. jaundice, ascites, spider angiomas, asterxis etc. see Portal Hypertension) have cirrhosis. When the jugular venous pressure is high a diagnosis of congestive cardiac failure should be considered.

Laboratory Evaluation

Haemogram; The haemogram is the most important laboratory test in evaluating a patient with splenomegaly. The significance of findings on haemogram is described in the table below.

Haemogram Finding Conditions
Pancytopenia Hypersplenism, Lymphoma (splenic marginal zone lymphoma), Hairy cell leukaemia, Myelofibrosis, systemic lupus erythrmotosis
Neutrophilic Leucocytosis Acute infections, inflammation
Leucocytosis with premature white cells Chronic myeloid leumaemia, Myeloproliferative disease, Myeloproliferative/Myelodysplastic overlap, Acute lymphoblastic leukaemia
Leucoerythroblastic anaemia Idiopathic myelofibrosis, Bone marrow infiltration
Polycythaemia Polycythaemia vera
Atypical Lymphocytes Infectious mononucleosis
Thrombocytosis Myeloproliferative disease (Chronic myeloid leukaemia, idiopathic myelofibrosis, polycythaemia vera), chronic infections like tuberculosis
Parasites Malaria, bartonelosizs, babesiosis

Other investigations are dictated by the clinical presentations. Commonly performed investigations include biochemistry, microbiology, echocardiography, endoscopy and biopsy of any lymph node or any other mass. Other investigation may be performed as indicated

Imaging

Imaging is an important aspect of evaluation of the spleen but is beyond the scope of this article. Several good reviews exist e.g Singapore Med J 56(3):133-144.

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Sickle β-Thalassaemia


Sickle cell anaemia and β-thalassaemia are two common haemoglobinopathies. Co-inheritance of the two is called sickle β-thalassaemia. Sickle β-thalassaemia seen in Africa, throughout the  Mediterranean, Arabian Peninsula and sporadically in india. It has heterogeneous clinical presentation. The severity depends on the severity of the thalassaemia allele and the extent to which the impaired haemoglobin synthesis is compensated by foetal haemoglobin synthesis.

Pathophysiology

With a very few exceptions (Blood 1989; 74: 1817-22) the sickle cell and the thalassaemia gene are arranged in trans i.e on different chromosomes (βsthal). One allele is inherited from the mother and one from the father. One parent carries the a β-thalassaemia trait the other parent has a sickle cell disease that may be sickle cell anaemia, sickle β-thalassaemia or a trait. Sickle β-thalassaemia in Africa and India/Arabia is mild whereas the patients from the Mediterranean region have severe disease. As mentioned above the differences in severity have to do with severity of the β-thalassaemia and the degree to which the impaired haemoglobin A synthesis is compensated by HbF. Weatherall suggested that patients with HbA <15% follow a course similar to severe HbA and those with HbA 20-30% follow a mild course.

  1. African sickle β-thalassaemia: African patients have a mild β-thalassaemia resulting in a relatively higher HbA level and a lower risk of sickling. These patients run a mild clinical course.
  2. Arab/Indian sickle β-thalassaemia: Patients from India and the Arabian peninsula have a sickle cell haplotype that is associated with a high HbF production. The HbF retards sickling. High levels of HbF attenuate symptoms. Patients carrying this haplotype have mild symptoms even when the inherit a severe β- chain defect. Another reason of a mild phenotype in India is the interaction with α thalassaemia.
  3. Mediterranean sickle β-thalassaemia: Mediterranean patients usually inherit a severe form of  β-thalassaemia. These patients have severe sickling because there is very little HbA or HbF to offset inhibit the crystallisation of HbS. Despite only one chromosome carrying HbS the phenotype of these patients resembles sickle cell anaemia.

Clinical Picture of Sickle-β Thalassaemia

The features of sickle-β thalassaemia resemble those of other sickling disease. It is a chronic haemolytic anaemia the course of which is interrupted by acute exacerbations known as crisis. The manifestations include haemolytic anaemia, painful and other crisis, leg ulcers, priapism and complications of pregnancy. The severity of symptoms is variable. One end of the spectrum are patients, usually of origin Mediterranean descent, whose presentation is indistinguishable from sickle cell anaemia. These patients have inherit severe forms of β (β0) chain defects. Those with sickle cell-β+ thalassaemia have milder symptoms. These patients are typically of African ancestory. Unlike patients with sickle cell anaemia patients with sickle-β thalassaemia may have splenomegaly that is more prominent patients with sickle cell-β+ thalassaemia. The spleen is usually moderately enlarged but massive splenomegaly that may be associated hypersplenism neccesisating splenectomy has been reported. The effect of co-inheritance of α-thalassaemia is small. A decrease in the frequency of acute chest syndrome and leg ulcers and a higher persistence of splenomegaly is seen. Co-inheritance of α thalassemia is one of the reasons that sickle-β thalassaemia runs a milder course in India (the other being the high HbF due to the Arab-Indian haplotype of HbS).

Diagnosis

The haematological findings vary with severity. More severe phenotypes shows greater anaemia, lower MCHC, higher reticulocytes, HbF and HbA2. A variable number of sickle cells may be found. Unlike sickle cell anaemia both forms of sickle cell-β thalassaemia have an elevated HbA2. The distribution of HbA2 is very similar to heterozygous β thalassaemia. The levels of HbF are variable. High levels are found in patients with the Arab-Indian and Senegal haplotype of HbS.

Sickle cell-β0 thalassaemia needs to be differentiated from sickle cell anaemia. The presentation of both may be identical. However an offspring of a sickle cell-β0 thalassaemia patients and a carrier of β-thalassamia trait has a 25% risk of suffering from β-thalassaemia major. The offspring of a patients with sickle cell anaemia and a carrier of β thalassaemia trait does not carry the risk of β thalassaemia major. Though sickle cell-β0 thalassaemia is characterised by an elevated HbA2 and splenomegaly this can not be relied upon to differentiate between the two conditions. Family and DNA studies are needed. If the studies show one parent to be heterozygous for HbS and the other a carrier of β thalassaemia trait no further studies are needed. If any of the parent has a phenotype of sickle cell anaemia DNA studies may be the only way to make the diagnosis.

Sickle Cell β thalassaemia in cis

Almost all patients with sickle-β thalassaemia have the disorder in trans i.e. the one β globin gene is thalassaemic and the other has a the sickle mutation. Patients with HbS and thalassaemia gene in cis have been described. These patients have a mild hemolysis, HbA2 levels were 6%–7%, HbF approximately 3% and HbS of 10%–11%.

Treatment

The symptoms of sickle-β thalassaemia are due to sickling need to be treated accordingly.

Heterozygous β-Thalassaemia 


β-Thalassaemia is an inherited disease characterised by an imbalance between production of α and β globin chains of haemoglobin resulting from impaired production of β chains. The genes responsible for β-thalassaemia carry mutations in areas coding for the β globin gene or regions regulating the expression of this gene. Patients who are homozygous of compound heterozygous for the gene are symptomatic. They manifest as thalassaemia major. Thalassaemia major is a fatal illness where patients suffer the consequences of anaemia, bone marrow hyperplasia and iron overload. Iron overload that results from increased iron absorption and repeated transfusion is the cause of death. The treatment consists of lifelong transfusion with iron chelation or in those who have a matched donor, allogeneic bone marrow transplantation.

Thalassaemia Inheritance

The risk of inheritance of β-thalassaemia in offsprings when both parents are heterozygous is shown on the left. There is a 25% risk of thalassaemia major, 50% risk of heterozygous β-thalassaemia and 25% of the offsprings will be normal. If one of the parents does not carry the thalassaemia gene there is a 50% risk of the offspring carrying heterozygous β-thalassaemia and 50% of the offsprings will be normal.

As opposed to homologous or compound heterozygous β-thalassaemia, heterozygous the β-thalassaemia is asymptomatic. The condition is also known as β-thalassaemia minor (see classification of β-thalassaemia). The terminology reflecting the asymptomatic nature of the disease. Though β-thalassaemia is an asymptomatic disease the diagnosis has clinical implications. These include:

  1. Risk of β-thalassaemia in children: β-Thalassaemia major is inherited in an autosomal recessive manner. If both the parents are heterozygous for β-thalassaemia there is a 25% risk of the child suffering from thalassaemia major (see figure above, left). The most effective way to prevent β-thalassaemia major is to ensure that at least one parents does not carry the β-thalassaemia gene (see figure above, right). Diagnosis of an index case of heterozygous β-thalassaemia should initiate a search for all individuals carrying the β-thalassaemia gene in the family. Patients with heterozygous β-thalassaemia should be discouraged from choosing another heterozygous β-thalassaemia as a life partner. Those who make this choice despite counselling or those who already married should be explained the importance of prenatal diagnosis of β-thalassaemia major on conception and encouraged to undergo the same.
  2. Prevention of unnecessary iron therapy: Iron deficiency anaemia, like thalassaemia, is microcytic and hypochromic. Iron therapy alleviates the anaemia of thalassaemia only if iron deficiency co-exists. Iron therapy is associated with gastrointestinal adverse effects. Some patients with heterozygous β-thalassaemia have increased iron absorption and there have been reports of iron overload in β-thalassaemia trait (Br J Haematol). Diagnosis of heterozygous β-thalassaemia spares the patient unnecessary and sometimes dangerous iron therapy.

Pathophysiology of Heterozygous β-Thalassaemia

Heterozygous β-thalassaemia minor is characterised by an imbalance between the α and β globin chains because of decreased production of β-chains. The clinical manifestations of thalassaemia depend on the degree on imbalance between α chains and non-α (β+γ) chains. Thalassaemia minor, the phenotype of heterozygous β-thalassaemia results when the ratio of α to non-α chains is 2:1 (Cold Spring Harb Perspect Med 2012;2:a011726).

Clinical Features

Patients of heterozygous thalassaemia are asymptomatic. The clinical presentations is that of thalassaemia minor. Diagnosis is usually made incidentally when

  1. A haemogram is performed for another reason or
  2. Screening is performed following detection of a β-thalassaemia patient in the family
  3. Evaluation of anaemia of pregnancy

Though traditionally heterozygous β-thalassaemia are considered to be asymptomatic recent studies have found these patients to have symptoms of mild anaemia. Heterozygous β-thalassaemia may become symptomatic

  1. In pregnancy:The third trimester of pregnancy sees a plasma volume expansion accompanied by an increased production of red cells. In normal women the volume expansion is more than the increase in the number of red cells. Women become anaemic in the third trimester as a result of this discrepancy. Patients with β-thalassaemia trait show a plasma volume expansion but are not able to increase the number of red cells like normal women do. As a consequence women with heterozygous β-thalassaemia become more anaemic than normal women. This anaemia is usually mild and haemoglobin values lower than 8-9g/dL should prompt a search for another cause of anaemia. Iron deficiency anaemia is the commonest anaemia in pregnancy and it mimics thalassaemia. Serum iron and iron binding capacity may not be reliable in pregnancy and a serum ferritin must be performed for diagnosing iron deficiency.
  2. In case of autosomal dominant β-thalassaemia: Some forms of deletion β-thalassaemia result in the formation of an unstable β chain that forms inclusions. These inclusions cause ineffective erythropoietin and a thalassaemia like syndrome. Such patients are said to have a dominant β-thalassaemia and have the clinical picture of thalassaemia intermedia even when heterozygous.
  3. If the co-inherit an overdose of α thalassaemia genes: Manifestations of β-thalassaemia depend on the ratio of α to non-α chains. Thalassaemia minor results when the ration is 1.5-2.5:1 and intermedia when the ratio is about 4:1. Thalassaemia major is seen with higher rations. Some patients have three or even four α globin genes (ααα or αααα). These patients produce more α globin chains. Increase in α chains can push up the ratio of α to non-α chains and result in manifestations of thalassaemia intermedia in heterozygous β-thalassaemia. Similarly co-inheritance of α and β thalassaemias can attenuate the manifestations of thalassaemia.

Laboratory Features

  1. Haemogram: Heterozygous β-thalassaemia is characterised by anaemia, low MCH and low MCV. The MCHC is usually normal. The erythrocytes count is high and there may be a slight increase in the reticulocyte count. The peripheral smear shows microcytosis, hypochromia, poikilocytosis, basophilic strippling and target cells. Co-inheritance of α-thalassaemia attenuates the findings. The red cell indices are normal at birth. Changes associated with heterozygous β-thalassaemia become apparent by 3 months. By 6 months thalassaemic changes are firmly established.
  2. Haemoglobin A2: Haemoglobin A2 (HbA2) is in the range of 3.5-7%. Iron deficiency causes a disproportionate fall in HbA2 in patients with heterozygous β-thalassaemia but does not push the HbA2 levels in the normal range. Heterozygous β-thalassaemia with normal HbA2 is discussed below.
  3. Bone Marrow: The bone marrow shows erythroid hyperplasia with pyknotic normoblasts dominating. There is ineffective erythropoiesis mainly due to destruction of haemoglobinized precursors. Studies have shown approximately 25% decrease in efficiency of erythropoiesis.
  4. Iron Metabolism: Rate of iron absorption is slightly increased. Some cases of iron overload have been reported. Iron deficiency may co-exist the heterozygous β-thalassaemia particularly in pregnancy. Serum ferritin estimations should be performed to diagnose iron deficiency.
  5. Osmotic Fragility: Osmotic fragility is increased particularly after 24 hours of sterile incubation of erhthrocytes. It has been suggested that this be used as a screening test for heterozygous β-thalassaemia but has not gained widespread acceptability.
  6. Globin Chain Synthesis: Heterozygous β-thalassaemia is associated with a α:β ratio of 1.5-2.5:1.

Genotype Phenotype Co-relations

There is a continuous spectrum of changes with mild alleles having less pronounced effect on haematological parameters. Severe alleles have higher HbA2 values. Mild thalassaemia with high HbA2 suggest a promoter mutation.

Interaction between Heterozygous β-thalassaemia and other Haemoglobinopathies

Heterozygous β-thalassaemia is a common disorder and a chance associations may be seen with other haemoglobinopathies or inherited disorders of erythrocytes. Fortunately no deleterious association has been found with most disorders these include glucose-6-phosphate dehydrogenase deficiency, hereditary spherocytosis  and pyruvate kinase deficiency.

α-Thalassaemia

α-Thalasaemia tends to reduce the α:β globin ratio. The amount of free α globin chain reduces attenuating the manifestations of heterozygous β-thalassaemia.

Sickle Cell Disease

β-Thalassaemia and sickle-cell diseases are common genetic diseases. Co-inheritance of the two is found in Africa, Mediterranean and sporadically through India. The symptoms depend on the relative amounts of HbS and HbA. HbA polymerises less than HbS. High levels of HbA reduce symptoms of sickling.  HbF is excluded from and protects against sickling. The clinical manifestations of patients co-inhereting sickle-cell and β-thalassaemia depend on the type of thalassaemia allele inherited and the HbF levels.

  1. Sickle β-thalassaemia with β0 or severe β+ alleles: Mediterranean forms of β-thalassaemia trait are either β0 severe β+. Patients from this region have severe sickling symptoms and HbA levels <15%.
  2. Sickle β-thalassaemia with mild β+ alleles: African patients of sickle β-thalassaemia inherit mild β+ alleles.  These patients have haemoglobin levels in the range of 20-30%  and mild symptoms . Many do not have symptoms. Diagnosis in some may be made incidentally.
  3. Sickle β-thalassaemia with high HbF: Patients from Indian and Saudi Arabia have mild symptoms despite inheriting severe β alleles because of high levels of HbF.

Treatment of Heterozygous β-Thalassaemia

Heterozygous β-thalassaemia does not need any treatment. A family screening should be carried out to detect other members carrying the thalassaemic β globin gene. Iron therapy should not be administered to patients empirically. Some patient have an increase iron absorption and iron overload has been reported. Iron studies should guide iron therapy. Anaemia can worsen during pregnancy. Folate and iron supplementation may be needed.

 

 

Classification of β-Thalassaemia


β-Thalassaemia is a term applied to describe heterozygous group of diseases that are characterised by a decrease in the production of β globin  chain. Over 200 mutations in the β-globin gene and promoter regions that cause β-thalassaemia have been recognised. Thalassaemic alleles that produce no β-chain are designated β0 and those producing some β chain are designated as β+.  Before the genetic basis of thalassaemia was understood the disease was classified according to the clinical presentation and natural history of the disease. The genetic defects need to be determined for prenatal diagnosis but the clinical patterns remains relevant for clinical management of β-thalassaemia.

Based of the severity of disease three patterns of disease have been identified, thalassaemia major, thalassaemia minor and thalassaemias intermedia

  1. Thalassaemia Major: Thalasaemia major is a transfusion dependent anaemia that usually appears early in life, often in the first year. Anaemia is associated with splenomegaly, skeletal deformities and growth retardation. Iron overload develops by the end of second decade unless chelation is used. Unless treated with blood transfusion and chelation or allogeneic stem cell transplant, it is a fatal illness. There is a severe impairment of β-chain synthesis. Genetically these patients may be β0β0, β0β+ or β+β+.
  2. Thalassaemia Minor: patients with thalassaemia minor are asymptomatic. They are diagnosed when a complete haemogram is performed as a part of antenatal care or as a pert of investigations of another illness. Genetically they me be β0β or β+β.
  3. Thalassaemia Intermedia: Thalassaemia intermedia has a clinical presentation between that of thalassaemia major and thalassaemia minor. It is a very heterogeneous condition. The patient is not transfusion dependent but anaemic with a low and stable haemoglobin. Transfusion may be needed during periods of stress like infection and pregnancy. Advancing age is also associated with transfusion requirement. This may in part be due to hyperplenism associated with splenomegaly. The genetics of thalassaemia intermedia are complex. It may result from a mild β chain defect or because of interaction of β chain defects with other defects of haemoglobin synthesis