History

Fact Explanation
Symptoms of anemia (lethargy/ poor exercise tolerance) Most commonly seen in alpha thalassemia intermedia (Hemoglobin H disease) where 3 of the 4 genes that produce alpha globin chains on chromosome 16 are deleted [1]. Abnormal Hb H is formed consisting of 4 beta chains, which is relatively unstable and oxidized to form precipitates that accumulate within circulating red cells causing cell membrane damage and increased haemolysis leading to anemia. Less often, ineffective erythropoiesis contributes to anemia when the precipitates are within the erythroblasts [2]. Persons with alpha thalassemia trait (deletion of 2 genes) may have borderline anemia [3], though they are usually asymptomatic [1].
Features of iron overload Patients with Hb H disease may complaint of features of cirrhosis (body swelling, jaundice, itching)/ heart failure (body sweeling, poor exercise tolerance, dyspnea, orthopnea, paroxysmal nocturnal dyspnea)/ diabetes mellitus (loss of weight, polydypsia & polyuria) resulted by iron overload due to increased iron absorption secondary to increased erythropoiesis caused by anemia & hypoxia [4].
Obstetric complications in the mother carrying a fetus with alpha thalassemia major Presentation can be with early gestational miscarriage due to non-immune hydrops fetalis, features of pre-eclampsia (visual disturbances, epigastric pain, headache) or bleeding per vagina (ante partum hemorrhage). All 4 genes are deleted in alpha thalassemia major, producing Hb Barts ( gamma tetromere) in the fetus which has very high affinity to oxygen causing poor delivery of oxygen to tissues. Fetus develops severe anemia & hypoxia which leads to the formation of massively enlarged placenta resulting in pre-eclampsia & ante partum hemorrhage, and early fetal demise [5].
Family history Asking about family history of thelassemia can be useful as some patients may have relatives with the disease.
References
  1. MUNCIE HL JR, CAMPBELL J. Alpha and beta thalassemia. Am Fam Physician [online] 2009 Aug 15, 80(4):339-44 [viewed 17 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/19678601
  2. YUAN J, BUNYARATVEJ A, FUCHAROEN S, FUNG C, SHINAR E, SCHRIER SL. The instability of the membrane skeleton in thalassemic red blood cells. Blood [online] 1995 Nov 15, 86(10):3945-50 [viewed 17 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/7579365
  3. CHUI D. H. K.. Hemoglobin H disease: not necessarily a benign disorder. [online] December, 101(3):791-800 [viewed 17 August 2014] Available from: doi:10.1182/blood-2002-07-1975
  4. LIN CHUNG-KING, LIN JEONG-SHI, JIANG MEI-LANG. Letter to the editor: Iron absorption is increased in hemoglobin H diseases. Am. J. Hematol. [online] 1992 May, 40(1):74-75 [viewed 17 August 2014] Available from: doi:10.1002/ajh.2830400119
  5. CHUI DH, WAYE JS. Hydrops fetalis caused by alpha-thalassemia: an emerging health care problem. Blood [online] 1998 Apr 1, 91(7):2213-22 [viewed 17 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/9516118

Examination

Fact Explanation
Pallor Seen mostly in Hb H disease due to anemia caused by increased hemolysis [1].
Hepatosplenomegaly Seen mostly in Hb H disease due to increased hamopoiesis [1]. Note: acquired form of alpha thalassemia is seen in myeloproliferative disorders [2]. These patients also may present with hepatosplenomegaly.
Features of fatal hydrops fetalis seen in the mother High blood pressure caused by the massively enlarged placenta, increased liquor/ large for gestational age abdomen suggestive of polyhydramnios are the common findings in the mother [3].
Features of hydrops fetalis seen in the new born Pallor, oedema and congenital malformations are seen in the baby [4]. Common congenital malformations involve hypospadias [4] & limb malformations [3].
References
  1. CHUI D. H. K.. Hemoglobin H disease: not necessarily a benign disorder. [online] December, 101(3):791-800 [viewed 17 August 2014] Available from: doi:10.1182/blood-2002-07-1975
  2. STEENSMA D. P.. Acquired -thalassemia in association with myelodysplastic syndrome and other hematologic malignancies. Blood [online] 2005 January, 105(2):443-452 [viewed 18 August 2014] Available from: doi:10.1182/blood-2004-07-2792
  3. CHUI DH, WAYE JS. Hydrops fetalis caused by alpha-thalassemia: an emerging health care problem. Blood [online] 1998 Apr 1, 91(7):2213-22 [viewed 18 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/9516118
  4. VICHINSKY E. P.. Alpha thalassemia major--new mutations, intrauterine management, and outcomes. Hematology [online] December, 2009(1):35-41 [viewed 18 August 2014] Available from: doi:10.1182/asheducation-2009.1.35

Differential Diagnoses

Fact Explanation
Iron deficiency anemia Blood picture shows hypochromic microcytic cells similar to alpha thalassemia. However, the mean corpuscular volume (MCV) value will not be less than 80 fl as opposed to alpha thalassemia where the MCV will be less than 70 fl. Elavated red cell distribution width (RDW) will be seen in about 90% of patients with iron deficiency, whereas it is seen only in 50% of patients with alpha thalassemia [1].
Sideroblastic anemia This will also show hypochromic microcytic cells in the blood picture, but absence of ring sideroblasts in the smear or the bone marrow aspirate helps in excluding the diagnosis as well as elevated RDW [1].
Lead poisoning This will also show hypochromic microcytic cells in the blood picture but normal serum lead level helps in excluding the diagnosis [1].
References
  1. MUNCIE HL JR, CAMPBELL J. Alpha and beta thalassemia. Am Fam Physician [online] 2009 Aug 15, 80(4):339-44 [viewed 17 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/19678601

Investigations - for Diagnosis

Fact Explanation
Full blood count Hb H disease will show microcytic anemia with MCV less than 75 fl. Thalassemia trait may have mild microcytic anemia [1].
Blood picture Hb H disease will show microcytic hypochromic cells [2]. In acquired alpha thalassemia associated with myelodysplastic syndromes & other hematological malignancy, other cell lines will also be affected showing specific features of each disease [3].
Detection of abnormal Hb by Hb electrophoresis / iso electric focusing/ high performance liquid chromatography (HPLC) Presence of Hb Barts / Hb H aids in confirming the diagnosis of Hb H disease and Hb Barts disease. This is usually normal in alpha thalassemia trait [1]. HPLC is considered to be the method of choice for diagnosis of thalassemia [4].
Serum ferritin level A normal serum ferritin level helps to exclude the diagnosis of iron deficiency anemia as iron stores will be low in iron deficiency anemia [1].
Serum lead level This can be done when there is a diagnostic uncertainty with lead poisoning [1].
Bone marrow aspiration & biopsy This may help in acquired alpha thalassemia in identifying the associated condition (myelodysplastic syndrome/hematological malignancy).
DNA based genotyping (southern blotting/ PCR) This is used in the prenatal diagnosis of alpha thalassemia. Fetal DNA is obtained by either chorionic villous sampling or amniocentesis [5]. This is important in patients with alpha thalassemia trait as Hb Barts increases the risk of toxemia and post partum bleeding [1]. DNA testing can also be used to screen the partner and other family members of patients with Hb H disease [2].
Ultra sound scan measurements of the fetus Doppler ultrasonography of the middle cerebral artery aids in the diagnosis and measuring the severity of anemia [4]. Placentomegaly and increased placental thickness, increased cardiothoracic ratio, ascites and hepatomegaly in the fetus aids in the diagnosis [6].
References
  1. MUNCIE HL JR, CAMPBELL J. Alpha and beta thalassemia. Am Fam Physician [online] 2009 Aug 15, 80(4):339-44 [viewed 17 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/19678601
  2. CHUI D. H. K.. Hemoglobin H disease: not necessarily a benign disorder. [online] December, 101(3):791-800 [viewed 17 August 2014] Available from: doi:10.1182/blood-2002-07-1975
  3. STEENSMA D. P.. Acquired -thalassemia in association with myelodysplastic syndrome and other hematologic malignancies. Blood [online] 2005 January, 105(2):443-452 [viewed 18 August 2014] Available from: doi:10.1182/blood-2004-07-2792
  4. COLAH R. B., SURVE R., SAWANT P., D’SOUZA E., ITALIA K., PHANASGAONKAR S., NADKARNI A. H., GORAKSHAKAR A. C.. HPLC studies in hemoglobinopathies. Indian J Pediatr [online] December, 74(7):657-662 [viewed 19 August 2014] Available from: doi:10.1007/s12098-007-0117-8
  5. VICHINSKY E. P.. Alpha thalassemia major--new mutations, intrauterine management, and outcomes. Hematology [online] December, 2009(1):35-41 [viewed 18 August 2014] Available from: doi:10.1182/asheducation-2009.1.35
  6. LEUNG W. C., OEPKES D., SEAWARD G., RYAN G.. Serial sonographic findings of four fetuses with homozygous alpha-thalassemia-1 from 21 weeks onwards. Ultrasound Obstet Gynecol [online] 2002 January, 19(1):56-59 [viewed 18 August 2014] Available from: doi:10.1046/j.0960-7692.2001.00498.x

Investigations - Followup

Fact Explanation
Fetal blood sampling Serial monitoring of fetal Hb is needed after the first intrauterine blood transfusion to asses the degree of anemia [1], as the the sensitivity of Doppler measurement falls following blood transfusion [2].
Serum ferritin level This is needed to monitor iron overload and to prevent associated complications in adults [3].
Tests to screen for organomegaly ( USS abdomen/ cardiac echogram) This is needed to monitor for complications associated with iron overload in the adults [3].
References
  1. VICHINSKY E. P.. Alpha thalassemia major--new mutations, intrauterine management, and outcomes. Hematology [online] December, 2009(1):35-41 [viewed 18 August 2014] Available from: doi:10.1182/asheducation-2009.1.35
  2. ZIMMERMANN ROLAND, DURIG PETER, CARPENTER ROBERT J., MARI GIANCARLO. Longitudinal measurement of peak systolic velocity in the fetal middle cerebral artery for monitoring pregnancies complicated by red cell alloimmunisation: a prospective multicentre trial with intention-to-treat. BJOG: An Internal Journal of Obs Gyn [online] 2002 July, 109(7):746-752 [viewed 18 August 2014] Available from: doi:10.1111/j.1471-0528.2002.01314.x
  3. CHEN FREDERICK E., OOI CLARA, HA SAU YIN, CHEUNG BERNARD M.Y., TODD DAVID, LIANG RAYMOND, CHAN TAI KWONG, CHAN VIVIAN. Genetic and Clinical Features of Hemoglobin H Disease in Chinese Patients. N Engl J Med [online] 2000 August, 343(8):544-550 [viewed 18 August 2014] Available from: doi:10.1056/NEJM200008243430804

Investigations - Screening/Staging

Fact Explanation
Full blood count Hypochromic myicrocytosis in the full blood count is used for population screening.
References

Management - General Measures

Fact Explanation
Folic acid supplementation Supportive care is the primary mode of treatment in Hb H disease. Folic acid supplementation helps in enhancing erythropoiesis [1].
Avoidance of oxidative medication and compounds This helps in reducing haemolysis [1].
Prompt treatment of infections This is important to prevent hemolytic crisis. Patients should be educated about possible hemolytic crisis and advised to seek medical care at the earliest sign of infection [1].
Blood transfusion therapy This is usually not required unless hemolytic crisis occurs causing severe anemia secondary to pyrexia, infection, oxidative stress, hypersplenism & pregnancy. Important: anemia should be well addressed and properly treated during pregnancy as it may cause poor outcome for both the mother and the fetus [1].
Intra uterine transfusion therapy for Hb Barts This has shown positive results in reducing complications in fetuses with good neurological function. Drawbacks are the need for lifetime transfusion and chelation therapy for most patients [2].
Monitoring for iron overload This is required in adults for early identification of complications associated with iron overload. Serum ferritin level, ultra sound scan tests are useful to look for iron stores and organomegaly [1].
Iron chelation therapy This is required in those who need regular blood transfusions [1].
Splenectomy This can have a significant positive effect on those with splenomegaly and hypersplenism and improve their outcome [3].
References
  1. CHUI D. H. K.. Hemoglobin H disease: not necessarily a benign disorder. [online] December, 101(3):791-800 [viewed 17 August 2014] Available from: doi:10.1182/blood-2002-07-1975
  2. VICHINSKY E. P.. Alpha thalassemia major--new mutations, intrauterine management, and outcomes. Hematology [online] December, 2009(1):35-41 [viewed 18 August 2014] Available from: doi:10.1182/asheducation-2009.1.35
  3. KANAVAKIS E., TRAEGER-SYNODINOS J., PAPASOTIRIOU I., VRETTOU C., METAXOTOU-MAVROMATI A., STAMOULAKATOU A., LAGONA E., KATTAMIS C.. The interaction of alphao thalassaemia with Hb Icaria: three unusual cases of haemoglobinopathy H. Br J Haematol [online] 1996 January, 92(2):332-335 [viewed 18 August 2014] Available from: doi:10.1046/j.1365-2141.1996.d01-1487.x

Management - Specific Treatments

Fact Explanation
Prenatal diagnosis, screening & genetic counseling Important in prevention of alpha thalassemia. Prenatal diagnosis is recommended in patients with alpha thalassemia trait, as Hb Barts increases the risk of toxemia and post partum bleeding [1]. DNA testing can also be used to screen the partner and other family members of patients with Hb H disease, followed by genetic counseling [1].
Stem cell therapy The role of this on curing the disease is yet to be established.
References
  1. CHUI D. H. K.. Hemoglobin H disease: not necessarily a benign disorder. [online] December, 101(3):791-800 [viewed 17 August 2014] Available from: doi:10.1182/blood-2002-07-1975