CME INDIA Case Presentation by Dr Ashutosh Chandan Dubey (Dr Strange), DNB, Med, Hindalco Hospital, Renukut, UP.

CME INDIA Case Study:

Ferritin is more than 1k/ Any Spot Diagnosis?

• Case was referred for splenomegaly on routine USG Abdomen, No symptoms
• Later complained of weakness, pain in left hypochondrium.
• CBC showing low Hb
• PBS showing microcytic hypochromic anaemia.
• Past H/O Blood transfusion.
• Mildly raised Total Bilirubin with normal LFT.
• Normal Reticulocyte count.
• No Hepatomegaly on palpation.
• H/O Anaemia in past for which patient is taking oral Iron since 2009.

Report of Hb Electrophoresis

My Diagnosis

Hb electrophoresis is suggestive of HbD disease – Punjab variant with minor thalassemia.

Need opinion for:

1. Splenectomy, is it required?
2. Use of Oral Iron chelators to reduce iron over load-needed or not?
3. Is it HbD disease (Punjab) with Minor B Thalassemia with secondary Iron overload?

CME INDIA Discussion

Dr Sanjeev Yadav, Asso. Prof of haematology, SGPGI, Lucknow:

• Hb D Panjab are usually asymptomatic
• No need for splenectomy unless transfusion requirements are too high
• Iron chelation only if Serum Ferritin more than 800
• I think diagnosis should be Hb D Panjab homozygous
• Why thal minor A2 is less than 3.5
• To confirm please do parents HPLC.That can only give you the answer otherwise sequencing

Dr Dibyendu Dey, Onco-heamatologist, Balco Medical Centre,Naya Raipur, Chattisgarh

• Its hbD homozygous, which behaves like mild haemolytic anaemia.
• Splenomegaly usually mild, and does not need splenectomy.
• Only occasional transfusion.
• Other cause of splenomegaly must be ruled out also, especially liver disease

CME INDIA Learning Points

• Hemoglobin D (Hb-D) hemoglobinopathy occurs mainly in the northwest India (Punjab), Pakistan, and Iran. Hb-D was first discovered in the early 1950s in a mixed British and American family of Indian origin from the Los Angeles area and hence the original Hb-D was called Hb-D Los Angeles, but it was later found to be identical to the Hb-D Punjab found in India and Pakistan.
• It is interesting to note that hemoglobin D-Punjab is also known as hemoglobin D-Los Angeles. In Brazil, for hemoglobin D-Punjab is the third most common hemoglobin variant.
• It is one of the most common hemoglobin variants worldwide. It is derived from a point mutation in the beta-globin gene (HBB: c.364G>C; rs33946267) prevalent in the Punjab region, North-western Indian
• Hemoglobin D-Punjab can be inherited in heterozygosis with hemoglobin A causing no clinical or hematological alterations, or in homozygosis.
• It is the rarest form of inheritance, a condition that is commonly not related to clinical symptomatology. 
• It can exist in association with other hemoglobinopathies, such as thalassemias; the most noticeable clinical alterations occur when hemoglobin D-Punjab is associated to hemoglobin S.
• Heterozygous Hb D disease is a benign condition with no apparent illness
• Hb D is when associated with Hb S or β-thalassemia, clinical conditions such as sickling disease and moderate hemolytic anemia may be observed.
• Heterozygous Hb D is rare and usually presents with mild hemolytic anemia and mild to moderate splenomegaly
• High performance liquid chromatography (HPLC) methods have been developed for hemoglobin fractionation with high sensitivity and specificity.
• Reverse-phase HPLC (RP-HPLC) of human globin chains has been reported as an important tool for detecting hemoglobinopathies.
• Although all these tests aim to diagnose Hb D-Punjab, they are not considered conclusive because of the large number of hemoglobin variants that are similar to each other.
• It is always recommended to perform molecular analysis for genotype confirmation with PCR-RFLP as an alternative esolution problems.
• When the Hb D variant is not identified by the abovementioned methodologies, sequencing of beta-globin gene or other techniques that discriminate amino acid changes are recommended.
• Compound heterozygosity for Hb D-Punjab [β121(GH4) Glu→Gln, GAA>CAA] /β-thalassemia (β-thal) must be carefully differentiated from homozygous Hb D-Punjab in premarital screening. This is essential when the partner is a carrier of β-thal trait. 
• Hb-D Punjab arises from the substitution of glutamine for glutamic acid in the 121st position of the β chain. Hb-D disease can occur in four different forms, including heterozygous Hb-D trait, Hb-D thalassemia, Hb-SD disease, and very rarely homozygous Hb-D disease.

CME INDIA Tail Piece

• Until the early 1950s, only four types of hemoglobin had been described including adult hemoglobin (Hb A) and two variants (Hb S and Hb C). The fourth identified hemoglobin was Hb D which was first described by Itano in 1951.
• When Itano was analyzing a multiethnic family from the Los-Angeles region with British, American and Indian features, and found a molecule with characteristics different to the other known hemoglobins.
• It is prevalent in Punjab region, Northwest Indian, with an estimated frequency of 2.0%. In western India, more specifically in the Gujarat region, its frequency drops by one half.
• Hb D-Punjab is also common in countries such as Italy, Belgium, Austria and Turkey.
• Hb D-Punjab is the second most common hemoglobin alteration in Turkey; it occurs in 0.2% of the population of Denizli province in south-eastern Turkey, where it is the most common variant.
• Hydroxyurea (HU) administration is a potential therapeutic strategy for sickle cell anemia (Hb SS), showing efficacy in increasing Hb F levels and consequently reducing the number of painful crises, acute chest syndrome, transfusions, and hospitalizations. However, HU therapy for Hb S/D-Punjab has not been established.
• Patel et al. treated Hb S/D-Punjab patients using low doses (10 mg/kg/day) of HU noticed an effective reduction in the incidence of vaso-occlusion and the frequency of blood transfusions. These results suggest that HU is a promising therapy for clinical symptomatology in Hb S/D-Punjab individuals.
• Although not always associated with relevant clinical history, Hb D-Punjab is a relatively common hemoglobin worldwide; it is the third most common hemoglobin variant in Brazil.
• Greater attention is given when the association of Hb D-Punjab with another abnormal hemoglobin or thalassemia leads to clinical symptoms.

Further Readings

1. Torres Lde S, Okumura JV, Silva DG, Bonini-Domingos CR. Hemoglobin D-Punjab: origin, distribution and laboratory diagnosis. Rev Bras Hematol Hemoter. 2015;37(2):120-126. doi:10.1016/j.bjhh.2015.02.007
2. Patel S., Purohit P., Ranjeet S.M., Dehury S., Meher S., Sahoo S. The effect of hydroxyurea on compound heterozygotes for sickle cell-hemoglobin D-Punjab—a single centre experience in eastern India. Pediatr Blood Cancer. 2014;61(8):1341–1346.

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