Infections in Hb SD Disease

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13th Oct 2017 Health Reference this

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Case Report

HBSD Disease, a compound heterozygote condition presentation with stroke

Dr. Hasnain Afzal 1 Dr. Syed Farrukh Umair 2

Abstract

Haemoglobin SD βSD is a rare compound heterozygous Haemoglobinopathy which presents as severe disease similar to homozygous sickle cell anemia(1). The patient being reported is a 8 yr old girl, Kiran who is a resident of Larkana, presented with complains of fever and headache for 15 days which progressed to generalized tonic clonic seizures and acute loss of consciousness while being treated in Larkana. After the child was stabilized, a thorough history, physical examination was done; initial laboratory tests, lumbar puncture, and MRI were performed. Treatment was started on the lines of acute meningoencephalitis on clinical suspicion. On peripheral blood film, sickle shaped cells, target cells, poikilocytosis, anisocytosis were noted and Hb Electrophoresis was sent which showed compound heterozygous state for Hb S/ Hb D. The lumbar puncture was negative for CSF infection and an alternate diagnosis was sought

Introduction

The adult hemoglobin HbA molecule consists of two α chains coded by 4 genes on chromosome 16 and two beta chains coded by 2 genes in the β gene cluster on chromosome 11(2). Sickle Hemoglobulin Hb S is a beta chain variant which occurs when valine is substituted for glutamic acid on the surface of the Hb S molecule in the sixth codon of the beta globin chain whereas the most common subtype of HbD i.e HbD Punjab also known as Haemoglobulin D Los Angeles (after the city where it was first discovered) is also a beta chain variant caused by a glutamic acid to glutamine substitution at codon 121 of the beta globin gene. HbS is associated with a number of compound heterozygous syndromes with other mutant beta globin which include Hemoglobin SC disease, Sickle beta+thalassemia, Sickle beta0thalassemia, Sickle alpha thalassemia, Sickle hereditary persistence of HbF (sickle HPFH), Other less common sickle cell syndrome variants (eg, delta beta0thalassemia, Hb Lepore, HbD, HbO Arab, HbE). HbSD presents as mild to moderate hemolytic anemia unlike HbD homogyzous and simple hetrozygotes which are usually asymptomatic.(3)

Discussion

A study done on abnormal hemoglobin variants among the major ethnic groups of Karachi in 2002 showed that 60% had iron-deficiency anemia and 40% had hemolytic anemia, of which 20.6 % was due to thalassemia major, 13% thalassemia trait, 5.1% sickle cell disease, 0.76% hemoglobin D Punjab (HbD Punjab), 0.32% hemoglobin C (HbC), and 0.22% hereditary persistence of fetal hemoglobin (HPFH) (4).Hb S is the most common Hb variant, its clinical outcome is severe in homozygous or when associated with other hemoglobinopathies, such as beta-thalassemia, Hb C or Hb D. (5). A number of studies have been done on Hb S and Hb C but Hb D is still poorly studied especially in Pakistan. Hemoglobin D has several varients such as HbD Punjab (Los Angeles), Hb D Iran, Hb D Ibadan and Hb D Bushman but the most common variant is HbD-Los Angeles (also called HbD-Punjab). High performance liquid chromatography (HPLC) can be used to separate hemoglobin polypeptide chains in the laboratory. High performance liquid chromatography (HPLC) employs ion exchange method to identify and exchange various fractions of Hb.Hb D can be also distinguished from Hb S by acid electrophoresis or isoelectric focusing (IEF) (separation according to isoelectric points). On alkali electrophoresis (cellulose acetate) Hb D Punjab migrates slower than Hb A which is similar to HbS but its migration under acid electrophoresis (agarose gel) is similar to Hb A (6) In HbSD disease, HbD does not take part in the sickling process, as patients homozygous for HbD do not sickle but mild hemolytic anemia, mild to moderate splenomegaly may occur (7,8). Studies has indicated that although HbD itself does not polymerize, it increases the hydrophobic interaction between Hb S molecules and facilitates the polymerization of HbS thus enhancing the severity of the disease. (9) HbD heterozygotes with normal HbA have no clinical or hematologic alterations. (6) Table 1.1: Hb Electrophoresis : Test Done on high performance liquid chromatography (HPLC)

Haemoglobin

Test Percentage

Normal Percentage

Haemoglobin A

20.7%

(98-100)

Haemoglobin A2

2.6%

(1.5-3.5)

Haemoglobin F

13%

(1-2) <7 months

Haemoglobin D

37.9%

(0.0-0.0)

Haemoglobin S

25.8%

(0.0-0.0)

Interpretation

A+F+D+S+A2

Case Report

8 yr old, 16 kg, Kiran resident of Larkana district, presented to us on 7th April, 2015 with acute loss of consciousness and recurrent episodes of seizures for 3 days. Patient’s father reported that she was in a usual state of health 15 days back when she developed high grade intermittent fever and constant severe headache associated nausea, vomiting and neck stiffness. She was taken to a primary care hospital in Larkana and treated on the lines of viral/bacterial meningoencephalitis. During her hospital stay in Larkana she developed recurrent episodes of generalized tonic clonic seizures which were controlled by multiple antiepileptic agents. First Lumbar pucture was done on 31ST March, 2015 and CSF DR showed 21mg/dl Protein, 68 mg/dl Glucose, CSF TLC 17 and 2-3 RBC/HPF. CT was done on 31st March, 2015 showed generalized brain edema. Upon arrival in ICU Patel Hospital the patient was in a comatose condition with GCS 5/10, bilateral upgoing planters and flexor response to pain(decorticate) Patient was febrile 103F, other vitals were BP 130/90, Pulse 100, RR 28. After the child was stabilized, a thorough history, physical examination was done; initial laboratory tests, lumbar puncture, and MRI were performed. CBC showed normocytic anemia and peripheral film showed target cells, sickle cells, anisocystosis, poikilocytosis, polychromasia & diamorphic picture. Hb Electrophoresis was sent on hematologist advice. Patient was started on mannitol to decrease intracranial pressure and multiple antiepileptic agents for seizure prevention. ATT, bacterial and viral meningitis cover was given and CSF DR was sent on 9th April, 2015 which showed 27 mg/dl Protein, 71 mg/dl Glucose, Chloride 123 mg/dl, TLC 04 and 17 RBC/HPF. CSF fluid gram stain, culture were initially negative. AFB Culture report to follow in 6 weeks. MRI done on 8th April, 2015 showed widespread abnormal signal intensity area involving bilateral frontal and parietal lobes. Few focal hyperintense signals were identified on bilateral occipital region which may represent areas of ischemic infarction. An alternate diagnosis such as cerebral ischemia due to small infarcts/ vasculitis involving bilateral frontal and parietal lobes was sought secondary to Hb SD disease. Patient had significant improvement in GCS 10/15 with spontaneous eye opening, withdrawal on pain and few incomprehensible sounds and was shifted out of the ICU due to financial constraints.

Graph 1.1 High Performance Liquid Chromatography

Conclusion

The case demonstrates increase susceptibility to infections in Hb SD disease. Studies are seldom on Hb D in Pakistan. Genetic counceling is of pivotal role in hereditary hemoglobinopathies and hospitals should consider it as an important management strategy and employ in hospital genetic counceling facilities. Hydroxyurea used to increase Hb F levels in Homozygous Sickle Cell Disease Hb SS disease has shown efficacy by reducing the complications, frequency of transfusions and hospitalization but its role in Hb SD Punjab is not well established. A recent study in India showed reduction in incidence of vaso-occlution and frequency blood transfusions in Hb SD Punjab disease which is encouraging and more studies should be done on the management of Hb SC compound heterozygous disease. (10)

References

Case Report

HBSD Disease, a compound heterozygote condition presentation with stroke

Dr. Hasnain Afzal 1 Dr. Syed Farrukh Umair 2

Abstract

Haemoglobin SD βSD is a rare compound heterozygous Haemoglobinopathy which presents as severe disease similar to homozygous sickle cell anemia(1). The patient being reported is a 8 yr old girl, Kiran who is a resident of Larkana, presented with complains of fever and headache for 15 days which progressed to generalized tonic clonic seizures and acute loss of consciousness while being treated in Larkana. After the child was stabilized, a thorough history, physical examination was done; initial laboratory tests, lumbar puncture, and MRI were performed. Treatment was started on the lines of acute meningoencephalitis on clinical suspicion. On peripheral blood film, sickle shaped cells, target cells, poikilocytosis, anisocytosis were noted and Hb Electrophoresis was sent which showed compound heterozygous state for Hb S/ Hb D. The lumbar puncture was negative for CSF infection and an alternate diagnosis was sought

Introduction

The adult hemoglobin HbA molecule consists of two α chains coded by 4 genes on chromosome 16 and two beta chains coded by 2 genes in the β gene cluster on chromosome 11(2). Sickle Hemoglobulin Hb S is a beta chain variant which occurs when valine is substituted for glutamic acid on the surface of the Hb S molecule in the sixth codon of the beta globin chain whereas the most common subtype of HbD i.e HbD Punjab also known as Haemoglobulin D Los Angeles (after the city where it was first discovered) is also a beta chain variant caused by a glutamic acid to glutamine substitution at codon 121 of the beta globin gene. HbS is associated with a number of compound heterozygous syndromes with other mutant beta globin which include Hemoglobin SC disease, Sickle beta+thalassemia, Sickle beta0thalassemia, Sickle alpha thalassemia, Sickle hereditary persistence of HbF (sickle HPFH), Other less common sickle cell syndrome variants (eg, delta beta0thalassemia, Hb Lepore, HbD, HbO Arab, HbE). HbSD presents as mild to moderate hemolytic anemia unlike HbD homogyzous and simple hetrozygotes which are usually asymptomatic.(3)

Discussion

A study done on abnormal hemoglobin variants among the major ethnic groups of Karachi in 2002 showed that 60% had iron-deficiency anemia and 40% had hemolytic anemia, of which 20.6 % was due to thalassemia major, 13% thalassemia trait, 5.1% sickle cell disease, 0.76% hemoglobin D Punjab (HbD Punjab), 0.32% hemoglobin C (HbC), and 0.22% hereditary persistence of fetal hemoglobin (HPFH) (4).Hb S is the most common Hb variant, its clinical outcome is severe in homozygous or when associated with other hemoglobinopathies, such as beta-thalassemia, Hb C or Hb D. (5). A number of studies have been done on Hb S and Hb C but Hb D is still poorly studied especially in Pakistan. Hemoglobin D has several varients such as HbD Punjab (Los Angeles), Hb D Iran, Hb D Ibadan and Hb D Bushman but the most common variant is HbD-Los Angeles (also called HbD-Punjab). High performance liquid chromatography (HPLC) can be used to separate hemoglobin polypeptide chains in the laboratory. High performance liquid chromatography (HPLC) employs ion exchange method to identify and exchange various fractions of Hb.Hb D can be also distinguished from Hb S by acid electrophoresis or isoelectric focusing (IEF) (separation according to isoelectric points). On alkali electrophoresis (cellulose acetate) Hb D Punjab migrates slower than Hb A which is similar to HbS but its migration under acid electrophoresis (agarose gel) is similar to Hb A (6) In HbSD disease, HbD does not take part in the sickling process, as patients homozygous for HbD do not sickle but mild hemolytic anemia, mild to moderate splenomegaly may occur (7,8). Studies has indicated that although HbD itself does not polymerize, it increases the hydrophobic interaction between Hb S molecules and facilitates the polymerization of HbS thus enhancing the severity of the disease. (9) HbD heterozygotes with normal HbA have no clinical or hematologic alterations. (6) Table 1.1: Hb Electrophoresis : Test Done on high performance liquid chromatography (HPLC)

Haemoglobin

Test Percentage

Normal Percentage

Haemoglobin A

20.7%

(98-100)

Haemoglobin A2

2.6%

(1.5-3.5)

Haemoglobin F

13%

(1-2) <7 months

Haemoglobin D

37.9%

(0.0-0.0)

Haemoglobin S

25.8%

(0.0-0.0)

Interpretation

A+F+D+S+A2

Case Report

8 yr old, 16 kg, Kiran resident of Larkana district, presented to us on 7th April, 2015 with acute loss of consciousness and recurrent episodes of seizures for 3 days. Patient’s father reported that she was in a usual state of health 15 days back when she developed high grade intermittent fever and constant severe headache associated nausea, vomiting and neck stiffness. She was taken to a primary care hospital in Larkana and treated on the lines of viral/bacterial meningoencephalitis. During her hospital stay in Larkana she developed recurrent episodes of generalized tonic clonic seizures which were controlled by multiple antiepileptic agents. First Lumbar pucture was done on 31ST March, 2015 and CSF DR showed 21mg/dl Protein, 68 mg/dl Glucose, CSF TLC 17 and 2-3 RBC/HPF. CT was done on 31st March, 2015 showed generalized brain edema. Upon arrival in ICU Patel Hospital the patient was in a comatose condition with GCS 5/10, bilateral upgoing planters and flexor response to pain(decorticate) Patient was febrile 103F, other vitals were BP 130/90, Pulse 100, RR 28. After the child was stabilized, a thorough history, physical examination was done; initial laboratory tests, lumbar puncture, and MRI were performed. CBC showed normocytic anemia and peripheral film showed target cells, sickle cells, anisocystosis, poikilocytosis, polychromasia & diamorphic picture. Hb Electrophoresis was sent on hematologist advice. Patient was started on mannitol to decrease intracranial pressure and multiple antiepileptic agents for seizure prevention. ATT, bacterial and viral meningitis cover was given and CSF DR was sent on 9th April, 2015 which showed 27 mg/dl Protein, 71 mg/dl Glucose, Chloride 123 mg/dl, TLC 04 and 17 RBC/HPF. CSF fluid gram stain, culture were initially negative. AFB Culture report to follow in 6 weeks. MRI done on 8th April, 2015 showed widespread abnormal signal intensity area involving bilateral frontal and parietal lobes. Few focal hyperintense signals were identified on bilateral occipital region which may represent areas of ischemic infarction. An alternate diagnosis such as cerebral ischemia due to small infarcts/ vasculitis involving bilateral frontal and parietal lobes was sought secondary to Hb SD disease. Patient had significant improvement in GCS 10/15 with spontaneous eye opening, withdrawal on pain and few incomprehensible sounds and was shifted out of the ICU due to financial constraints.

Graph 1.1 High Performance Liquid Chromatography

Conclusion

The case demonstrates increase susceptibility to infections in Hb SD disease. Studies are seldom on Hb D in Pakistan. Genetic counceling is of pivotal role in hereditary hemoglobinopathies and hospitals should consider it as an important management strategy and employ in hospital genetic counceling facilities. Hydroxyurea used to increase Hb F levels in Homozygous Sickle Cell Disease Hb SS disease has shown efficacy by reducing the complications, frequency of transfusions and hospitalization but its role in Hb SD Punjab is not well established. A recent study in India showed reduction in incidence of vaso-occlution and frequency blood transfusions in Hb SD Punjab disease which is encouraging and more studies should be done on the management of Hb SC compound heterozygous disease. (10)

References

  1. Rahimah A, Syahira Lazira O, Siti Hida HM, Faidatul Syazlin AH, Nur Aisyah A, Nik Hafidzah NM, Zubaidah Z. Haemoglobin sickle d punjab: – a case report. Med J Malaysia. 2014 Feb;69(1):42-3.
  2. Birol G, Abdullah C, Cagatay U4, Sule MY, Ferda TT, Sevcan TB. β-Globin chain abnormalities with coexisting α-thalassemia mutations. Arch Med Sci 2012; 8, 4: 644-649.
  3. El-Kalla S, Mathews A R. HbD Punjab in the United Arab Emirates. Hemoglobin 1997;21:369-75.
  4. Ghani R,Manji MA,Ahmed N. Hemoglobinopathies among five major ethnic groups in Karachi, Pakistan. Southeast Asian J Trop Med Public Health.2002 Dec;33(4):855-61.
  5. Thom CS, Dickson CF, Gell DA, Weiss MJ. Hemoglobin variants: biochemical properties and clinical correlates. ColdSpring Harb Perspect Med. 2013;3(3):a011858.4.
  6. Torres Lde S,Okumura JV,Silva DG,Bonini-Domingos CR. Hemoglobin D-Punjab:origin,distributionand laboratory diagnosis. Rev Bras Hematol Hemoter.2015 Mar-Apr;37(2):120-6. doi: 10.1016/j.bjhh.2015.02.007. Epub 2015 Feb 23.
  7. Adekile A, Muah-AlI A, Akar NA. Does elevated hemoglobin Fmodulate the phenotype in Hb SD-Los Angeles? ActaHaematol. 2010;123(3):135–9.
  8. Taghavi Basmanj M, Karimipoor M, Amirian A, Jafarinejad M,Katouzian L, Valaei A, et al. Co-inheritance of hemoglobin D and thalassemia traits in three families: clinical relevance.Arch Iran Med. 2011;14(1):61–3.
  9. Winford CW, John NL. Wintrobe’s Clinical Hematology, 11th edn. Philadephia; 2004. pp. 1347-81.
  10. Patel S, Purohit P, Ranjeet SM, Dehury S, Meher S, Sahoo S,et al. The effect of hydroxyurea on compound heterozygotesfor sickle cell-hemoglobin D-Punjab—a single centreexperience in eastern India. Pediatr Blood Cancer.2014;61(8):1341–6.32.

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