| Case Presentation | No. 03-2017 | A 48 year old male with and exertional chest pain Mohammad Mizanur Rahman, Md. Monirul Islam, Susane Giti, Mimi Parvin, Arif Ahmed Khan and Debashish Saha

Article Info Presentation of Case cardiac centre of a tertiary care military hospital, Dhaka on 4th May, 2017. The attending Departet of Heatolog, Ared Dr. Md. Monirul Islam: A 48 year old male atten- physician took detailed history of the patient, re Fores Istitute of Patholog, Dhaka Catoet, Dhaka, Bagladesh MMR, ded the cardiac outpatient department with the -examined and evaluated the results of all MMI; Departet of Patholog, Co- complaints of chest pain on exertion. Two years investigations so far done. Here, the history ied Militar Hospital, Chittagog, back, he developed chest pain on exertion. The also unveiled that he is a smoker, taking indige- Bagladesh SG; Departet of Chei- pain was retrosternal, dull in nature, non- nous cigarettes (Biri), about 10 sticks per day, al Patholog, Ared Fores Istitute of Patholog, Dhaka Catoet, Dhaka, radiating, aggravated on exertion and relieved non-diabetic and also suffering from the peptic Bagladesh MP, DS; Departet of by rest. There was no relation with food intake ulcer disease for which he is regularly taking H2 Miroiolog, Ared Fores Istitute of and not relieved by taking H2 blocker. The blocker and also had family history of coronary Patholog, Dhaka Catoet, Dhaka, patient was a known case of hypertension for artery disease. On general examination, all Bagladesh AAK the last 10 years. He was on antihypertensive parameters were within normal limits inclu- medication and his blood pressure was ding blood pressure (130/60 mm Hg) except controlled with therapy. There was no history mild and jaundice. Systemic examina- of respiratory distress and cough. With these tion revealed no abnormality. He also advised For Correspondene: Mohaad Mizaur Raha complaints, he at first attended to a nearby to repeat all previous investigations including iza@ahoo.o Government medical college hospital in Barisal coronary angiogram and requested to do some (South central division of Bangladesh). In that more additional investigations such as peri- Reeied: Septeer hospital, the patient was diagnosed as coronary pheral examination, reticulocyte Aepted: Otoer Aailale Olie: Noeer artery disease after performing first line investi- count, electrophoresis and renal gations and referred to the capital city for function tests including eGFR as well as thyroid further evaluation and management. function tests to resolve the problem of hyper- ISSN: - Olie bilirubinemia as well as to see the anesthetic - Prit In a private clinic in Dhaka, he underwent nece- and operation fitness. On the basis of history, ssary routine and special investigations inclu- DOI: ./suj.i. physical findings and results of previous inves- ding full blood count, random blood sugar, tigations carried out in a private clinic. The liver function tests, hepatitis viral profile (anti- attending cardiac surgeon made the provisional HAV, anti-HEV, HBsAg, anti-HCV, anti- HIV, diagnosis. coagulation testing such as bleeding time, Cite this artile: Raha MM, Isla MM, Giti S, Pari clotting time, prothrombin time and activated M, Kha AA, Saha D. A ears old ale partial thromboplastin time, VDRL, TPHA, X- ith jaudie ad eertioal hest pai. ray chest and KUB region, ultrasonogram of Provisional Diagnosis Bagaadhu Sheikh Muji Med Ui J. whole abdomen and coronary angiogram. ; : -. Double vessel coronary artery disease with Results of all investigations revealed mildly hyperbilirubinemia reduced hemoglobin (11.0 g/dL) and mildly Copyright: raised serum (3.4 mg/dL). Coronary The opright of this artile is retaited angiogram detected double vessel coronary - the authors [Atriutio CC B .] artery disease. After analyzing the history, Differential Diagnosis clinical findings and the results of all investi- Dr. Mohammad Mizanur Rahman: This patient Availale at: gation, the patient was diagnosed as a case of reported to the hospital for a problem related to .aglajol.ifo double vessel coronary artery disease with mild cardiovascular system and after investigations, jaundice. As the prime problem of the patient A Joural of Bagaadhu Sheikh Muji his diagnosis was almost confirmed as double was related to the cardiovascular system, so the Medial Uiersit, Dhaka, Bagladesh vessel coronary artery disease. But mild hyper- treating physician focused on double vessel bilirubinemia with mild anemia in this patient coronary artery disease and decided to perform indicated the presence of a second pathology coronary artery bypass graft operation. other than the liver disease and was taken into The brother in law of the patient has been consideration for differential diagnosis in this serving in Bangladesh Military, so the patient is present case presentation. Therefore, I would entitled to get treatment in military hospital. like to focus on the following differential Therefore, the patient got admitted into the diagnoses related to mild hyperbilirubinemia 228 BSMMU J 2017; 10: 227-233

with mild anemia. Palestinians and people of Palestinian descent and Asians. In the world, the incidence of beta globin Chronic chain defect with a carrier rate of 18% of the The history of man and malaria is thought to be population in Maldives is found and the evaluated educed together. A number of genetic conditions frequency is 15% in people from , 1% in such as hemoglobin C and red cell Duffy negativity Thailand and 3–7% in populations from Bangla- provide some form of defense or resistance to desh, China, India, Malaysia and Pakistan.9 Plasmodium falciparum and P. vivax respectively and Symptoms of beta can vary and may be these conditions are more prevalent in West Africa completely asymptomatic to the signs and symp- and West and Central Africa indicating the original toms of mild anemia (e.g., feeling tired and pale root of malaria in these regions.1 skin) as well as mild jaundice and dark urine. Individuals with beta thalassemia minor may have It is difficult to define chronic malaria as there is some shield against malaria and such phenomenon differences of opinion about its definition. How- explains its high incidence in areas of the world ever, in semi-immune individuals without fever or where plasmodium infections exist.10 Beta thalasse- any other symptoms pertaining to malaria persis- mia heterozygosity is associated with a reduced risk ting for a considerable period may be the features of against advanced coronary artery disease. Indivi- chronic malaria but some authors argues that duals with beta thalassemia have such lipoproteins asymptomatic or chronic malaria does not exist.2, 3 and blood rheology profile that may be the under- Chronic presence of malarial parasites is the cause lying causes of this safeguard effect.11 There is a of mild leading to asymptomatic anemia possibility of this patient is being thalassemic as and inclines the affected individuals to other mild anemia and jaundice are present but early infections.4 Patient with malaria may present with development of coronary artery disease is against mild jaundice which is frequently missed clinically. heterozygous beta thalassemia because it has mild Such jaundice is quite common and may be protective effect against coronary artery disease. detected in 20–40% of the cases. Severe P. falciparum malaria is usually associated with deeper jaundice This patient, presented with mild anemia and and serum bilirubin level may be more than 3 mg/ jaundice, favors the diagnosis of inherited hemo- dL and is consociated with anemia, hyperparasite- lytic anemia that may be hemoglobin, red cell mia and malarial hepatitis with elevated serum membrane or enzyme disorders. But age of the enzymes. In all cases of mild jaundice, malaria must patient and absent family history of inherited be considered as a differential diagnosis, preferably hemolytic disorders are the possible points against in a malarious zone.5 In this patient, mild anemia the diagnosis of inherited . and jaundice favor the diagnosis of chronic malaria but absence of , previous history of : A single point in beta () malaria and residing in non-malarious zone are globin chain at position 26 causing substitution of against the diagnosis of malaria. glutamic acid to lysine results in the formation of an abnormal hemoglobin called HbE. HbE is most Inherited Hemolytic prevalent among peoples of South Asian countries 12 Mild hyperbilirubinemia is caused by an increased including Bangladesh. Among hemoglobin- rate of hemolysis. The prime cause of unconjugated pathies and , HbE is in the second hyperbilirubinemia is the escalated position in terms of its frequency among hemo- destruction and accumulation of such bilirubin into globin disorders in the world and also common in 13 various tissues can lead to yellowish or jaundiced Bangladesh. HbE is the most common in mainland appearance. Certain genetic red cell disorders, such Southeast Asia (Thailand, Myanmar, Cambodia, as thalassemia and , spherocy- Laos and Vietnam). In Northeast India, the carrier tosis as well as red cell enzyme defects like pyru- rate of HbE reach approximately 60% of the vate kinase and glucose 6-phosphate dehydroge- population. Its incidence is also very high in 14 nase deficiency can lead to mild hyperbilirubine- Bangladesh. Individual with homozygous HbE mia.6, 7 In the perspective of Bangladesh, beta thala- allele may have the features of mild hemolytic ssemia trait, HbE disease and hereditary sphero- anemia such as mild anemia but the jaundice may cytosis are the potential candidates to be considered or may not be present. Mild splenomegaly may be 15 in the differential diagnosis. present. Presence of mild anemia and jaundice favors the diagnosis of HbE disease but absence of Beta thalassemia trait: Thalassemias are inherited family history of hemoglobinopathies and thalasse- genetic blood disorders transmitted in an autosomal mias as well as splenomegaly are against the recessive pattern from one generation to next - diagnosis of HbE disease. ration. Mainly two types of thalassemia exist– alpha thalassemia and beta thalassemia.8 Beta thalasse- Spherocytosis: and auto- mias are more prevalent among the peoples of immune hemolytic anemia are characterized by the Mediterranean origin, Arabian Peninsula such as presence of spherocytes which are sphere-shaped BSMMU J 2017; 10: 227-233 229

and lack of central pallor in the peripheral blood. mean platelet volume are reduced. The increased Hereditary spherocytosis is inherited as autosomal levels of bilirubin and decreased levels of mean dominant fashion and results from the defects of platelet volume and C-reactive in patients cytoskeleton of red cells. Clinically patients with with Gilbert’s syndrome may have an effect to slow hereditary spherocytosis presented with mild to down the atherosclerotic process.22 This patient moderate anemia, mild jaundice and splenomegaly presented with mild jaundice which was detected and also in some cases gall stone formation.16 Due incidentally and the patient was unwary about the to the presence of mild anemia and jaundice, here- symptoms which were in favor of the diagnosis of ditary spherocytosis may be one of the differential Gilbert’s syndrome. But presence of mild anemia diagnoses in this patient but negative family and coronary artery disease in early age is the history, non-palpable and absence of points against Gilbert’s syndrome. cholelithiasis are against the diagnosis of hereditary Dr. Mohammed Kamruzzaman: After three days I elliptocytosis. Autoimmune hemolytic anemia received the results of all the investigations which occurs when anti-bodies are formed against the were sent after getting admitted into the cardiac person’s own red cells and make them susceptible centre. Again I have evaluated all the reports. to lyse leading to hemolysis and development of Coronary angiogram revealed triple vessel coronary severe anemia, jaundice and splenomegaly.17 artery disease. Blood film showed numerous Autoimmune hemolytic anemia is an uncommon elliptical red cells suggesting hereditary elliptocyto- condition, occurs in one to three people per 100,000 sis and advised to carry out family screening, per year. In about 50% of cases, autoimmune osmotic fragility test and red cell membrane protein hemolytic anemia is secondary to many other ill- analysis. Hemoglobin electrophoresis was normal. nesses.18 This patient had mild anemia and absence Indirect (unconjugated) serum bilirubin was 2.0 of splenomegaly which disfavor the diagnosis of mg/dL and direct (conjugated) 0.6 mg/dL, confir- autoimmune hemolytic anemia but jaundice is in ming the presence of unconjugated hyperbilirubi- favor of autoimmune hemolytic anemia. nemia. Cardiac specific troponin I (cTr) was Gilbert’s Syndrome negative. But his serum TSH was found raised though the serum FT3 and FT4 were within normal Among the abnormal bilirubin metabolism of limit. Reticulocyte count was at the upper limit of genetic nature, Gilbert’s syndrome is one of the normal range. Blood film of the only son of the common types of unconjugated hyperbilirubinemia, patient also revealed elliptocytosis but his only accounting 5% of the population. A considerable daughter could not come for family screening. number of people are asymptomatic but many Osmotic fragility of the patient and his son were patients with Gilbert’s syndrome may present with also normal. Results of all investigations and blood mild jaundice. Genetic mutation in the UGT1A1 film of the index case and his son are shown in gene results in reduced activity of the bilirubin Table I, Figure 1 and Figure 2. In the cardiac center, uridine diphosphate glucoronyltransferase enzyme. we all specialists discussed the detailed of the case Occasionally patients with and decided to refer the case to gastroenterologist Gilbert’s syndrome may also Table I and endocrinologist for the opinion about unconju- have tiredness, weakness and gated hyperbilirubinemia and raised serum TSH. abdominal pain.19 Many studies Hematological and biochemical pa- on Gilbert’s syndrome have Dr. S. M. Mizanur Rahman: I reviewed the case and rameters shown that a significantly found that the patient is a diagnosed case of triple diminished risk of coronary Patient Son vessel coronary artery disease with unconjugated artery disease in individuals hyperbilirubinemia. Laboratory investigations re- Hb (g/dL) 11.2 13.5 with Gilbert’s syndrome was vealed that unconjugated serum bilirubin was 2.0 found. Importantly, people with mg/dL. Blood film was suggestive of hereditary RBC count (x109/L) 3.8 4.9 mildly increased levels of biliru- elliptocytosis which was also almost confirmed by MCV (fL) 88.0 80.9 bin were at lower risk for coro- family screening and osmotic fragility test, though MCH (pg) 29.8 27.7 nary artery disease as well as polyacrylamide gel electrophoresis of red cell future heart disease. Bilirubin MCHC (g/dL) 33.8 34.2 membrane protein is required for full confirmation IX, which is recognized as an RDW (%) 15.6 13.8 of hereditary spherocytosis. Therefore, the cause of effective antioxidant was thou- unconjugated hyperbilirubinemia is hereditary HbA 97.6 97.7 ght to have beneficial effect elliptocytosis and I advised to consult with hemato- against coronary artery dis- HbA2 2.4 2.3 logist. ease.20 Long-term data from Reticulocyte count (%) 2.5 1.0 Framingham Heart Study also Dr. Mohammed Mosleh Uddin: After evaluating the Osmotic fragility test (%) 0.4 0.4 supported such association.21 patient and all other investigations, especially the Serum bilirubin (mg/dL) 2.8 1.0 Patients with Gilbert’s syn- blood film, reticulocyte count, osmotic fragility test Serum (ng/mL) 668.1 63.0 drome due to unknown and hemoglobin electrophoresis, my impression is mechanism, platelet count and hereditary elliptocytosis and I prescribed tablet folic 230 BSMMU J 2017; 10: 227-233

Dr. Islam’s Diagnosis Hereditary elliptocytosis with triple vessel coronary artery disease and subclinical .

Discussion

Dr. Mohammad Mizanur Rahman: Hereditary ellipto- cytosis is inherited as an autosomal dominant manner.23 In normal healthy individuals, elliptical red cells are often seen as many as 10% of the red cells. Slightly increased number of elliptocytes is often seen in iron deficiency, thalassemias, and myelodysplastic syndrome.24 Incidence varies from region to region and is not exactly known because of its asymptomatic nature. In USA, the approximate frequency of hereditary elliptocytosis is between 1 in 1000 to 1 in 5000. No racial or ethnic group is spared but it confers Figure 1: Blood film of the index case showing about 82% elliptocytes resistance to malaria.25 Hereditary elliptocytosis is caused by numbers of different of affecting red cell cytoskeleton and membrane protein integrity. Most of the mutations found in hereditary elliptocytosis occurs in the -spectrin, - spectrin and protein 4.1 genes. These mutations are due to single nucleotide substitutions, insertions, deletions and defective RNA processing. Most patients are symptomless with heterozygous form of hereditary elliptocytosis, although some may have splenomegaly and features of hemolysis.26 Diagnosis of hereditary elliptocytosis is usually made by positive family history of the condition and presence of at least 25% elliptocytes of the red cell on a blood smear.27 If there is doubt about the diagnosis, definitive diagnosis can involve osmotic fragility test, an autohemolysis test and direct red cell membrane protein assay by poly acrylamide gel electrophoresis.28 Hereditary elliptocytosis is a rare inherited single gene autosomal dominant Mende- lian disorder which was first identified by Dresbach in 1904 and hereditary nature in 1932 by Hunter.29 It is much more common among blacks and in areas Figure 2: Blood film of son of the index case showing about 67% elliptocytes where malaria is endemic. In Malayan aborigines, the incidence of hereditary elliptocytosis is high, acid 5 mg daily continuously. I also empha-sized about 30%, which may explain the resistance of that for the operative treatment of triple vessel hereditary elliptocytes to invasion by malarial para- coronary artery disease, hereditary elliptocytosis is sites.30 In more than 60% of patients with hereditary not a contraindication. elliptocytosis, –spectrin mutation is mainly res- Dr. Md. Anwarul Kabir: This patient was referred for ponsible for the development of the condition.31 high serum TSH level to me. I evaluated the patient Hereditary elliptocytosis is most commonly diag- and enquired about the thyroid problems. The nosed by chance from a blood film or the presence patient did not have any signs and symptoms of marginally raised bilirubin.32 In this index case, relating to hypothyroidism. As the serum TSH level the blood film showed 82% elliptocytes with was repeatedly high, so my clinical impression was hemoglobin level 11.20 g/dL along with normal subclinical hypothyroidism. I opined that the car- mean corpuscular fragility, normal hemoglobin diac surgeons may perform the operative treatment electrophoresis and slightly raised serum bilirubin. of the patient without thyroid hormone replace- Reticulocyte count was at the upper limit of the ment. normal range but serum ferritin was raised indica- BSMMU J 2017; 10: 227-233 231

ting mild hemolysis and deposition of iron in the cytosis has three major forms: common hereditary body. elliptocytosis, spherocytic elliptocytosis and South- east Asian ovalocytosis. This patient has been The blood film of the son revealed 67% elliptocytes recognized as having common hereditary ellipto- with normal hemoglobin level and all other labora- cytosis which is the least severe form and here it tory investigations including reticulocyte count, was diagnosed incidentally.31 hemoglobin electrophoresis, serum bilirubin and serum ferritin were within reference range indica- Dr. Mimi Parvin: Why did serum bilirubin elevated ting the absence of hemolysis. Though in both the in this patient? cases red cell membrane protein assay was not done but basing on family screening and blood film Dr. Lutfunnahar Khan: Though the patient is finding, it can be concluded that both have been asymptomatic but he is suffering from mild chronic suffering from hereditary elliptocytosis. Pedigree hemolysis which results in unconjugated hyperbili- chart of the index case is shown in Figure 3. rubinemia.31 Dr. Mohammad Shahidul Islam: Is there any relation- Dr. Parvin: HbA1c is 3.3% in this patient. How will ship between hypothyroidism and hereditary ellip- you explain this? tocytosis? Dr. Islam: Low HbA1c in this patient may be due to Dr. Islam: There is no association between hypothy- low hemoglobin level (11.2 g/dL) and shortened roidism and hereditary elliptocytosis. Clinical fea- red cell survival.34 tures of hypothyroidism are completely distinctive Dr. Rukhsana Khanum: How will you explain normal from hereditary elliptocytosis. Blood film findings osmotic fragility test in this patient? also differ from each other. In hypothyroidism, round macrocytes are usually seen but in hereditary Dr. Rahman: In general a change in the osmotic elliptocytosis, elliptical cells are found.33 fragility test is less marked in hereditary ellipto- Dr. Debashish Saha: Is there any cut off count of cytosis than hereditary spherocytosis. Abnormal elliptical cells in the blood film for diagnosing osmotic fragility usually correlates with severity of hereditary elliptocytosis? hemolysis, osmotic fragility is usually normal in non-hemolytic hereditary elliptocytosis.35 I think Dr. Rahman: For diagnosing hereditary elliptocyto- this patient belongs to non-hemolytic hereditary sis, there should be more than 25% elliptocytes in elliptocytosis or there is mild hemolysis that could the blood film as well as a positive family history.27 not interfere the osmotic fragility. Dr. Mehedi Hasan Shourov: Do you think that there is Dr. Arif Ahmed Khan: How will confirm your diag- relationship between hereditary elliptocytosis and nosis? coronary artery disease? Dr. Monwar Tarek: Red cell membrane protein Dr. Islam: No data is available regarding the associa- analysis and DNA-based assays to detect mutations tion between hereditary elliptocytosis and coronary within genes for the red cell membrane are artery disease. It was found that people with mildly the most specific tests for membrane defects but elevated levels of bilirubin are at lower risk for these are not routinely done. Osmotic fragility test coronary artery disease and future heart disease. and family screening are usually sufficient for This advantageous sequel is due diagnosing hereditary elliptocytosis.32 to bilirubin IX which is Unavailable recognized as a powerful anti- Dr. Md. Monirul Islam: What are the complications oxidant.20 of hereditary elliptocytosis and life expectancy of Dr. Dildar Alam: What are the patients with hereditary elliptocytosis? conditions where we may get Dr. Rahman: Patients with hereditary elliptocytosis elliptocytes in the blood film? have mildly increased risk of developing . Dr. Rahman: Slightly increased Life expectancy is usually normal but those with number of elliptocytes is often very severe disease have a shortened life expec- Index case seen in iron deficiency, thalasse- tancy.27 mias, sickle cell disease and Dr. Rahman: How will you differentiate morpholo- 24 myelodysplastic syndrome. gically between elongated/elliptical cells of iron Dr. Wasim Selimul Hoque: What deficiency anemia and of hereditary elliptocytosis? type of hereditary elliptocytosis Affected son Dr. Khan: Elliptocytes in iron deficiency anemia did this patient inherit? have hypochromia but elliptocytes in hereditary Figure 3: Pedigree chart of the index case Dr. Rahman: Hereditary ellipto- elliptocytosis do not have any hypochromia. 232 BSMMU J 2017; 10: 227-233

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