What you need to know about inherited hemolytic anemia in an adult with splenomegaly and no stigmata of thalasemia.

You have found an enlarged spleen, a tinge of jaundice and anemia in a twenty year old adult.

What will you look for next? How will you start the discussion in a short case?

You will look for and discuss the stigmata of beta thalassemia major underlined below.

Children have a short stature, frontal bossing, non-aeration of the maxillary sinuses, overriding of the upper jaw, irregular teeth with a narrow mouth, osteoporosis with long bone deformities, vertebrae and ribs become box-like and prone to fractures. Bone masses resembling tumors develop but these masses are non-invasive.

Why does hemolysis occur in thalasemia? The inherited abnormality in the genes which causes the disease results in the unbalanced production of alpha and beta hemoglobin genes. The unpaired chains precipitate out and cause hemolysis. This results in transfusion dependent anemia and the production of hematopoietic masses and in beta thalassemia major a dependence on blood transfusions develops from early life (2 years of age). Iron overload is a major problem naturally but is made worse with recurrent blood transfusions.

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This is a CT scan of a young woman with hematopoietic masses in the paravertebral areas bilaterally.
Your patient has none of these abnormalities, has achieved normal height according to the population he comes from. He has only recently become sufficiently anemic to need blood transfusions over the past one year. His spleen is 18 cm enlarged. His liver is not enlarged and the liver span is normal.
How will you open the discussion?
You can say in my opinion my patient has an inherited a form of hemolytic anemia like beta thalassemia minor or intermedia. I do not have the family history (in a short case) but I would like to ask about the health of his other siblings and whether his parents are first cousins. In a long case give a history of blood transfusions or lack thereof, a family history and a history of consanguinity in the parents.
I do not think it is thalassemia major because of the late onset of transfusion dependency and absence of bone deformity and because of his normal average height. He most probably has beta thalasemia minor or intermedia or an acquired hemolytic anemia or another hemoglobinopathy.
He may have other hemoglobinopathies like Hb H which is inherited as an autosomal recessive gene and sometimes Hb S, sickle cell anemia (uncommon in the Pakistani population) and Hb D (also known as Hb Punjab) which may occur alone or accompany thalasemia.
The other possibility is congenital spherocytosis or elliptocytosis. I would place sickle-cell anemia low in the list of D/D as it is uncommon in the Pakistani population and may be found in people of Makran origin.
Discus the acquired hemoglobinopathies next. See my spot on acquired hemolytic anemias.
Inherited hemoglobinopathies. Questions you are likely to be asked.
What is the composition of the different hemoglobins?
HbA has 2 alpha 2 beta chains, HbA2 has 2 alpha and 2 delta chains and constitutes 2.5% of all hemoglobin, HbF (fetal) has 2 alpha and 2 gamma chains. Hb beta has 4 beta chains and HbBarts has 4 delta.
HbS has 2 alpha 2 beta chains but there is a mutation causing a change from glutamic acid to valine on one beta chain. HbS is resistant to hemolysis by malignant tertian malaria.
HbC and HbE have a change from glutamic acid to lysine but on different beta chains.
HbD has a a change from glutamic acid to glutamine. These changes in their composition makes them liable to hemolysis.
What are the qualities of normal hemoglobin?
It is soluble in the RBC, takes up and releases large quantities of oxygen and acts as a buffer.
Why does hemoglobin S cause a problem?
It has the same oxygen carrying capacity as HbA1 but only 20% of the solubility. It forms long strands which settle in the RBC and change its shape to that of a sickle which is liable to stick inside the capillaries causing micro-infarcts and also causes hemolysis. The lifespan of a sickle cell is 10-20 days hence the anemia. Don’t start your discussion with sickle cell anemia as it is very rare in Pakistan (OR find out if it is common in your area) or if your patient gives a history suggestive of bone or organ infarcts or a suggestive ancestry.
What is Hb SC? 
This is hemoglobin S and hemoglobin C occurring together. The patient has 40% HbS, 40% HbC and 20% HbF in their RBCs.
What is Hb D disease? It is also known as Hb D Punjab.
The variant Hb D can be found as a mild hemolytic disease in North India, Pakistan, Iran and African Americans or in combination. It occurs in 4 forms homozygous Hb D disease, heterozygous Hb D trait, Hb D-thalasemia and Hb D-HbS disease. The homozygotes present as mild hemolytic anemia and moderate splenomegaly.
Hb E disease.
This is the most common hemoglobin abnormality found in the world. It is commonly found in Southeast Asia specially Thailand. It is inherited as an autosomal recessive gene. Presents as asymptomatic mild anemia. Its beta chain synthesises more slowly.
Hb Constant Spring. 
The recessive gene produces a long, unstable alpha chain which has 31 extra molecules. Presents as anemia with a low hemoglobin in RBCs.
Hemoglobin C. (named after Christchurch in New Zealand)
This is the commonest hemoglobin variant found in the USA. This mutation reduces the normal plasticity of host erythrocytes. Hb C crystallizes in the RBC, due to decreased solubility. RBCs become more rigid, often fragment (microspherocytes form) as they attempt to transverse microvasculature. RBC life-span is 30-35 days. Hb composition:- Hb C >90%, Hb F <10%Prevalence. The Hb C mutant allele is common in West Africa; found in I%of African Americans.  Genetic compounds (heterozygotes for both HbS and C or thalassemia) are not infrequent, due to significant geographic overlap. Clinical Symptoms: splenomegaly (from sequestration of rigid cells), mild-to-moderate normocytic, normochromic anemia(Hb level 8-12 g/dL). In homozygotes, nearly all Hb is in the Hb C form, resulting in moderate normocytic normochromic anemia. In those who are heterozygous for the mutation, about 28-44% of total Hb is Hb C and anemia does not develop(it is considered a benign condition)
Thalasemia.
This is an autosomal recessive gene found in Cyprus 16%, Thailand 3-14%, 3-8% in India, Pakistan, Bangladesh and China and also Southeast Asia and Africa. When the abnormality is in the production of the alpha gene it is called alpha thalasemia and when in the beta chain it is called beta thalasemia. The mutation slows down the production of the affected chain so tetramers of the healthy chain form Beta 4, alpha 4 or gamma-4. These accumulate in the nucleus and stop cell division. Many cells die in the bone marrow, those released into the circulation sequester in the spleen.
Patients do not become symptomatic while they are producing fetal hemoglobin that is upto the age of 2 years when the adult type of hemoglobin is phased in.
Complex thalasemia is fortunately, much less common. Involves large deletions from the beta-globin gene cluster.  If at least one of the gamma genes is still intact, Hb F will persist after birth.
Hereditary Persistence of Fetal Hemoglobin.
Fetal Hb (Hb F) is the main oxygen transport protein in the fetus during the last 7 months of development. Hb F binds oxygen with greater affinity than the adult form. Hb F is nearly completely replaced by Hb A by approximately the 12th week of postnatal life. Decreased~-globin chain synthesis is compensated for by the production of gamma-globin. Homozygotes have 100% Hb F.  Heterozygotes have 70 % Hb A and 30 % Hb F.
Your patient may also have an acquired hemoglobinopathy. This will be discussed in another post.
Would you consider splenectomy in this patient?
If the survival of transfused RBCs is short so that he develops anemia soon after a blood transfusion and progressive worsening of the anemia along with other cytopenias  are indications that hypersplenism has developed and that it may be appropriate to evaluate the patient for splenectomy.
What other treatment would you consider to make this patient free of transfusions and prevent him from suffering the consequences of iron overload?
I would consider hematopoietic bone marrow transplant. A two haplotype HLA matching preferably sibling donor will be required. The cost is prohibitive about 4 million rupees are required. The major problems encountered in a bone marrow transplant are the difficulty in finding a matching donor as parents are not suitable as they are only one haplotype match, the occurrence of graft versus host disease and the prohibitive cost.
Why do normal RBCs die eventually? Remember they have a lifespan of 120 days only.
They encounter oxidative trauma from oxygen and its products, shear pressure while traveling through the splenic cords and aortic valves, osmotic changes encountered repeatedly in the lungs (hypo-osmolarity) and kidneys hyperosmolarity), loss of enzymes and slow development of a spherical shape with age.
How do you assess the severity of on going hemolysis?
Historically radiolabelling of RBCs with CR 51 and differential agglutination and
The evidence of persisting hemolysis are : a high retic count of >6 at any time or persistent retic count of 10, or a low haptoglobin levels and if the LDH levels and serum bilirubin (indirect) are high. The Hb will be low and the MCV low around 65 ftl.
Why does iron overload develop even when the patient has minimal or no blood transfusion requirement?
Persistent inadequate hematopoiesis and continual breakdown of RBCs releases iron into the circulation causing it to be stored in parenchymal sites such as the liver and spleen.
What vitamin and metal deficiencies may occur in thalassemia?
The patient requires folate, B12, zinc supplements.
Can you measure RBC life span?

Yes but the techniques are not used clinically. Labelling RBCs with Biotin and radio active chromium 51 have been used to determine the site of RBC destruction and their life span in research. Another method is differential aggregation of a cohort of RBCs. It is possible to calculate RBC life span from the formula:

RBC survival (days)  ≈  100  ÷  [Reticulocytes (percent)  ÷  RLS (days)].

RLS is reticulocyte survival and is approximately 4 days; 3 days in the bone marrow and one day in the circulation

Alpha thalasemia major is severe and causes hydrops fetalis and despite in utero blood transfusion death usually occurs in utero or soon after birth.

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shaheenmoin

I am a Professor of Medicine and a Nephrologist. Having served in the Army Medical College, Pakistan Army for 27 years I eventually became the Dean and Principal of the Bahria University Medical and Dental College Karachi from where I retired in 2016. My passion is teaching and mentoring young doctors. I am associated with the College of Physicians and Surgeons Pakistan as a Fellow and an examiner. I find that many young doctors make mistakes because they do not understand how they should answer questions; basically they do not understand why a question is being asked. My aim is to help them process the information they acquire as part of their education to answer questions, pass examinations and to best take care of patients without supervision of a consultant. Read my blog, interact and ask questions so that I can help you more.

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