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Disease Categories > Hematologic Disease

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Hemoglobinopathies

The hemoglobinopathies are a group of common, inherited disorders of hemoglobin caused by mutations in the globin genes resulting in either the synthesis of structurally abnormal globin subunits or reduced synthesis of structurally normal globin subunits (thalassemia). Thalassemias are addressed in a separate ARUP Consult section.

Pathophysiology

Hemoglobin, a tetramer of 2 alpha and 2 beta or beta-like (delta and gamma) proteins found in red blood cells, combines reversibly with oxygen and is the medium by which oxygen is transported within the body
Primary hemoglobin (Hb) in normal adults is Hb A, with small amounts of Hb A2 and Hb F
More than 400 hemoglobin variants have been identified which are the result of alpha, beta, delta or gamma globin gene mutations
- Identification of the hemoglobin variant leads to correct diagnosis, improved treatment and accurate genetic counseling
Hemoglobin variants may produce different phenotypes
- Benign (clinically and/or hematologically insignificant)
- Sickling disease (associated with several genotypes)
- Hemolytic anemia (unstable hemoglobins)
- Methemoglobinemia (M-hemoglobins), associated with heme in oxidized ferri (rather than ferro) state, renders methemoglobin unable to deliver oxygen and causes cyanosis
- Polycythemia (associated with increased oxygen hemoglobin affinity; ie, decreased P50)
- Anemia (associated with decreased oxygen hemoglobin affinity; ie, increased P50)
- Thalassemia phenotype (imbalance of alpha, beta and beta-like chains; ie, Hb E, Hb Constant Spring, Hb Lepore)
  - See the Thalassemias topic in ARUP Consult

Diagnosis

Most hemoglobinopathies can be screened for using electrophoretic or HPLC techniques
- Recommended screening tests for specific phenotypes:
  - Hemoglobin instability test (isopropanol or heat instability test) for unstable hemoglobins causing hemolytic anemia
  - Determination of heme oxygen dissociation curve (P50) for those with polycythemia and decreased oxygen affinity hemoglobin
  - Spectrophotometric techniques for M hemoglobins
Some mutant hemoglobins cannot be readily identified by electrophoretic or HPLC techniques
The definite confirmation of hemoglobin mutant can be always performed by DNA analysis

Sickle Cell Disease

Epidemiology
- Prevalence – among African Americans, 1:10 has sickle cell trait (Hb AS), while 1:600 has sickle cell disease (Hb SS)
- Ethnicity – sickle cell disease occurs most commonly in African descendants; other hemoglobin variants are specific for ethnic and racial groups (including African, Mediterranean, Southeast Asian)
Genetics
- Autosomal recessive
- Sickle cell anemia is characterized by homozygosity for Hb S
- Sickle cell disease refers to the inheritance of Hb S in combination with another beta globin mutation (such as Hb E, Hb C, Hb Lepore or beta thalassemia) to produce a sickling phenotype.
- Sickle cell trait (Hb AS) is the asymptomatic carrier state for sickle cell disease
- Common genotypes associated with sickle cell disease
  - Hb SS – sickle cell anemia
  - Hb S/C
  - Hb S/B0 or Hb S/B+-sickle cell beta thalassemia
  - Hb S/E
  - Hb S/Lepore
  - Hb S/D
  - Hb S/O Arab
- Parental screening for sickle cell trait and interacting hemoglobinopathies can aid in genetic counseling
Clinical Presentation
- Asymptomatic at birth – neonate has not yet switched from fetal to adult hemoglobin (gamma genes to beta genes)
- Severity of disease depends on genotype
- Hemolytic anemia is always present
- Acute painful crises (long bones, chest and back) are common
- Micro and macrovascular damage that affects organs leads to spleen fibrosis, strokes, kidney failure, lungs (acute chest syndrome and pulmonary hypertension), central nevous system and bone infarcts

See Also

Hemolytic Anemias

Hemolytic Disease of the Newborn - Rh Disease

Paroxysmal Nocturnal Hemoglobinuria - PNH

Thalassemias

Unstable Hemoglobinopathies

Test Name and Number	Recommended Use	Limitations
Hemoglobin Evaluation with Reflex to Electrophoresis and/or RBC Solubility 0050610 Method: High Performance Liquid Chromatography/Electrophoresis/RBC Solubility	Rapidly distinguishes many hemoglobin variants when an abnormal hemoglobin is suspected; determines and confirms the presence of hemoglobin S	Some mutants are electrophoretically silent; false-positives may occur for RBC solubility for hemoglobin S
Hemoglobin S, Evaluation with reflex to RBC Solubility 0050520 Method: High Performance Liquid Chromatography	Determines presence of hemoglobin S
Beta Globin Gene Mutations for HbS, HbC, & HbE by PCR 0051421 Method: Polymerase Chain Reaction/Fluorescence Resonance Energy Transfer	Molecular confirmation of Hb C (c.19G>A), Hb S (c.20>T) and Hb E (c.79G>A) variants Detects common hemoglobinopathies, including sickle cell anemia
Beta Globin Gene Mutations for HbS, HbC, & HbE by PCR, Fetal 0051422 Method: Polymerase Chain Reaction/Fluorescence Resonance Energy Transfer	Fetal testing when both parental variants have been identified as Hb C (c.19G>A), Hb S (c.20>T) or Hb E (c.79G>A)

General References

Beutler E. Disorders of Hemoglobin Structure: Sickle Cell Anemia and Related Abnormalities. In Lichtman MA et al. eds. Williams Hematology, 7th ed. New York: McGraw-Hill, 2006. pp. 667-700.

Buchanan GR, DeBaun MR, Quinn CT, Steinberg MH. Sickle cell disease. Hematology (Am Soc Hematol Educ Program ). 2004;35-47. (Link to PubMed)

Clark BE, Thein SL. Molecular diagnosis of haemoglobin disorders. Clin Lab Haematol. 2004;26(3):159-176. (Link to PubMed)

Delaunay J. The molecular basis of hereditary red cell membrane disorders. Blood Rev. 2007;21(1):1-20. (Link to PubMed)

Dhaliwal G, Cornett PA, Tierney LM Jr. Hemolytic anemia. Am Fam Physician. 2004;69(11):2599-2606. (Link to PubMed)

Fixler J, Styles L. Sickle cell disease. Pediatr Clin North Am. 2002;49(6):1193-210, vi. (Link to PubMed)

Gregg XT and Prchal JT. Red Cell Enzymopathies. In Hoffman R et al. Hematology: Basic Principles and Practice, 4th ed. Philadelphia: Churchill Livingstone, 2004. pp. 653-660.

Meremikwu M. Sickle cell disease. Clin Evid. 2005;(14):15-28. (Link to PubMed)

Prchal JT and Gregg XT. Hemoglobinopathies: Methemoblobinemias, Polycythemias and Unstable Hemoglobins. In Goldman L and Ausiello D, eds. Cecil Textbook of Medicine, 22nd ed. Philadelphia: WB Saunders, 2004.

Schnog JB, Duits AJ, Muskiet FA, ten Cate H, Rojer RA, Brandjes DP. Sickle cell disease; a general overview. Neth J Med. 2004;62(10):364-374. (Link to PubMed)

Stuart MJ, Nagel RL. Sickle-cell disease. Lancet. 2004;364(9442):1343-1360. (Link to PubMed)

References from the ARUP Institute for Clinical and Experimental Pathology®

Agarwal N, Kutlar F, Mojica-Henshaw MP, Ou CN, Gaikwad A, Reading NS, Bailey L, Kutlar A, Prchal JT. Missense mutation of the last nucleotide of exon 1 (G->C) of beta globin gene not only leads to undetectable mutant peptide and transcript but also interferes with the expression of wild allele. Haematologica. 2007;92(12):1715-1716. (Link to PubMed)

Herrmann MG, Durtschi JD, Bromley LK, Wittwer CT, Voelkerding KV. Amplicon DNA melting analysis for mutation scanning and genotyping: cross-platform comparison of instruments and dyes. Clin Chem. 2006;52(3):494-503. (Link to PubMed)

Herrmann MG, Durtschi JD, Wittwer CT, Voelkerding KV. Expanded instrument comparison of amplicon DNA melting analysis for mutation scanning and genotyping. Clin Chem. 2007;53(8):1544-1548. (Link to PubMed)

Little RR, Vesper H, Rohlfing CL, Ospina M, Safar-Pour S, Roberts WL. Validation by a mass spectrometric reference method of use of boronate affinity chromatography to measure glycohemoglobin in the presence of hemoglobin S and C traits. Clin Chem. 2005;51(1):264-265. (Link to PubMed)

Nussenzveig RH, Lingam HB, Gaikwad A, Zhu Q, Jing N, Prchal JT. A novel mutation of the cytochrome-b5 reductase gene in an Indian patient: the molecular basis of type I methemoglobinemia. Haematologica. 2006;91(11):1542-1545. (Link to PubMed)

Pont-Kingdon G, Chou LS, Damjanovich K, Sumner K, Herrmann M, Erali M, Lyon E. Multiplex genotyping by melting analysis of loci-spanning probes: beta-globin as an example. Biotechniques. 2007;42(2):193-197. (Link to PubMed)

Roberts WL, De BK, Brown D, Hanbury CM, Hoyer JD, John WG, Lambert TL, Lundell RB, Rohlfing C, Little RR. Effects of hemoglobin C and S traits on eight glycohemoglobin methods. Clin Chem. 2002;48(2):383-385. (Link to PubMed)

Roberts WL, Safar-Pour S, De BK, Rohlfing CL, Weykamp CW, Little RR. Effects of hemoglobin C and S traits on glycohemoglobin measurements by eleven methods. Clin Chem. 2005;51(4):776-778. (Link to PubMed)

Reviewed by

Hill, Harry R., M.D. Group Medical Director, Laboratory of Immunology, ARUP Laboratories, and Executive Director of the ARUP Institute for Clinical and Experimental Pathology; Professor and Division Head, Clinical Pathology, University of Utah

Lyon, Elaine, Ph.D. Medical Director, Molecular Genetics at ARUP Laboratories; Associate Professor, Pathology, University of Utah

Prchal, Josef T., M.D. Medical Director, Hematology at ARUP Laboratories; Professor, Hematology, Pathology and Genetics, University of Utah

Reading, N. Scott , Ph.D. Scientist II, Special Genetics at ARUP Laboratories

Comprehensive Review: March 2008
Last Update: May 2008

Hemoglobinopathies

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