CHAPTER IINTRODUCTION

Thalassemia is an inherited disorder of autosomal recessive gene disorder caused by impaired synthesis of one or more globin chains. The impairment alters production of hemoglobin (Hb) (Ridolfi et al., 2002). Thalassemia causes varying degrees of anemia, which can range from significant to life threatening. People of Mediterranean, Middle Eastern, African, and Southeast Asian descent are at higher risk of carrying the genes for thalassemia (Weatherall, 1997). These hereditary anemias are caused by mutations that decrease hemoglobin synthesis and red cell survival. These hereditary anemia caused by decreased or absent production of one type of globin chain either or globin chain. These hematologic disorders range from asymptomatic to severe anemia that can cause significant morbidity and mortality. It was first recognized clinically in 1925 by Dr. Thomas Cooley, who described a syndrome of anemia with microcytic erythrocytes. Then it was called Cooleys anemia. Later Wipple and Bradford renamed this disease as Thalassemia. Because it was found in the region of the Mediterranean Sea (thalasa is an old Greek word for sea) (Cooley, 1946). Thalassemias can cause significant problems because these are inherited disorders, newborn screening and prenatal diagnosis are important in management of patients.1Thalassemia major (TM) originated in Mediterranean, Middle Eastern, and Asian regions. However, because of migration, this diseases now occur globally and represent a growing health problem in many countries.2 Thalassemia is the most common hematologic genetic disease in Southeast Asia. The prevalences of alpha-thalassemia, beta-thalassemia, and HbE genes in our population are 2030, 39, and 14%, respectively.3 In Indonesia,6-10% people are carriers of thalassemia gene.4 The -globin gene families are clustered on chromosome 11 and are arranged over approximately 60,000 nucleotide bases. -thalassemia is a quantitative deficiency of -globin production, and are usually due to DNA mutations of the b-globin gene cluster and result from mutations affecting gene transcription, RNA processing, alter splice junctions or splice consensus sequences, mutations within exons and introns that create an alternative splice site. Majority of the mutations are point mutations and unlike a-thalassemia deletion mutations are relatively less frequent. About the 3 % of the worlds population carries the thalassemia gene. The bulk of this disorder is reported from Mediterranean, African and south-east Asian populations where the incidence of gene carriage may be as high as 10 %.5CHAPTER IILITERATURE REVIEW

2.1. DefinitionThe thalassemias are a group of congenital anemias that have in common deficient synthesis of one or more of the globin subunits of the normal human hemoglobins (Hbs). The primary defect is usually quantitative, consisting of the reduced or absent synthesis of normal globin chains, but there are mutations resulting in structural variants produced at reduced rate (e.g., HbE, Hb Lepore) and mutations producing hyperunstable hemoglobin variants with a thalassemia phenotype (thalassemic hemoglobinopathies). Therefore, a rigid differentiation from the qualitative changes of hemoglobin structure that characterize the hemoglobinopathies is no longer appropriate. According to the chain whose synthesis is impaired, the most common thalassemias are called -, -, -, or -thalassemias. These subgroups have in common an imbalanced globin synthesis, with the consequence that the globin produced in excess is responsible for ineffective erythropoiesis (intramedullary destruction of erythroid precursors) and hemolysis (peripheral destruction of red cells). In the last few years, the advances of DNA analysis have permitted understanding the basic aspects of gene structure and function and the characterization of the molecular basis for deficient globin synthesis. The thalassemias result from the effect of a large number of different molecular defects, which may interact, leading to a variety of clinical and hematologic phenotypes.6

2.2. Epidemiology 7,82.2.1 Occurrence in the United StatesThe frequency of beta thalassemia varies widely, depending on the ethnic population. The disease is reported most commonly in Mediterranean, African, and Southeast Asian populations.2.2.2 International occurrenceThe disease is found most commonly in the Mediterranean region, Africa, and Southeast Asia, presumably as an adaptive association to endemic malaria. The incidence may be as high as 10% in these areas.2.2.3 Race-related demographicsBeta thalassemia genes are reported throughout the world, although more frequently in Mediterranean, African, and Southeast Asian populations. Patients of Mediterranean extraction are more likely to be anemic with thalassemia trait than Africans because they tend to have beta-zero thalassemia rather than beta-plus thalassemia.

Figure 2.1. Possible Outcome of Thalassemia Major

The genetic defect in Mediterranean populations is caused most commonly by (1) a mutation creating an abnormal splicing site or (2) a mutation creating a premature translation termination codon. Southeast Asian populations also have a significant prevalence of Hb E and alpha thalassemia. African populations more commonly have genetic defects leading to alpha thalassemia.2.2.4 Age-related demographicsThe manifestations of the disease may not be apparent until a complete switch from fetal to adult Hb synthesis occurs. This switch typically is completed by the sixth month after birth.

Figure 2.2. Immigration Trends Impacting Thalassemia(Weatherall, 2012)

2.3. Etiology9Thalassemia are caused by an abnormality in the rate of synthesis of the globin chains. This is in contrast to the true hemoglobinopathies (e.g., Hb S and Hb C) that result from an inherited structural defect in one of the globin chains that produces hemoglobin with abnormal physical or functional characteristics. Inheritance of thalassemia is autosomal; whether it is autosomal dominant or recessive is questionable because heterozygotes are not always symptomatic. Globin structural genes are found on chromosomes 11 and 16. The chain and its embryonic counterpart, the z chain, are located on chromosome 16. Two genes on each homologous chromosome, four per diploid cell, specify the a-globin sequence. Only one gene per chromosome, two per diploid cell, specifies most of the non-a chain on chromosome 11. The g chain is also represented by two sites per chromosome. In terms of the genetic basis of a- and b-thalassemia, this represents an important difference. All thalassemia genes that have been studied to date have been found to contain mutations that directly alter gene structure and subsequently gene function. One of five processes is now believed to be responsible for the genetic defect in thalassemia. These processes are:1. A nonsense mutation leading to early termination of the globin chain synthesis2. A mutation in one of the noncoding intervening sequences of the original globin chain gene, which causes inefficient splicing to mRNA3. A mutation in the promoter area that decreases the rate of gene expression4. A mutation at the termination of the gene that leads to lengthening of the globin chain with additional amino acids; the mRNA becomes unstable and causes a reduction in globin synthesis5. A total or partial depletion of a globin gene, probably as the result of unequal chromosomes crossing over

2.4. PathophysiologyThe biochemical hallmark of -thalassemia is reduced biosynthesis of the -globin subunit of Hb A (22). In -thalassemia heterozygotes, -globin synthesis is about half-normal (/ synthetic ratio 0.50.7). In homozygotes for -thalassemia, who account for approximately one-third of patients, -globin synthesis is absent. -Globin synthesis is reduced to 5% to 30% of normal levels in -thalassemia homozygotes or /-thalassemia compound heterozygotes, who together account for approximately two-thirds of cases.1 Because the synthesis of Hb A (22) is markedly reduced or absent, the red blood cells are hypochromic and microcytic. -Chain synthesis is partially reactivated, so that the hemoglobin of the patient contains a relatively large proportion of Hb F. However, these - chains are quantitatively insufficient to replace -chain production. In heterozygotes (-thalassemia trait), relatively little -globin accumulation occurs. Output from the single normal -globin gene supports substantial Hb A formation, thus preventing harmful accumulation of excess -globin chains. Thus, one encounters hypochromic with microcytosis but relatively little evidence of anemia, hemolysis, or ineffective erythropoiesis. Individuals inheriting two -thalassemia alleles experience a more profound deficit of -chain production. Little or no Hb A is produced; more importantly, the imbalance of - and -globin production is far more severe. The limited capacity of red blood cells to proteolyze the excess -globin chains, a capacity that probably exerts a protective effect in heterozygous -thalassemia, is overwhelmed in homozygotes. Free -globin accumulates, and unpaired -chains aggregate and precipitate to form inclusion bodies, which cause oxidative membrane damage within the red blood cell and destruction of immature developing erythroblasts within the bone marrow (ineffective erythropoiesis). Consequently, relatively few of the erythroid precursors undergoing erythroid maturation in the bone marrow survive long enough to be released into the bloodstream as erythrocytes. The occasional erythrocytes that are formed during erythropoiesis bear a burden of inclusion bodies. The reticuloendothelial cells in the spleen, liver, and bone marrow remove these abnormal cells prematurely, producing a hemolytic anemia.Defective -globin synthesis exerts at least three distinct yet interrelated effects on the generation of oxygen-carrying capacity for the peripheral blood: (a) ineffective erythropoiesis, which impairs production of new red blood cells; (b) hemolytic anemia, which shortens the survival of the few red blood cells produced; and (c) hypochromic with microcytosis, which reduces the oxygen carrying capacity of those few red blood cells that do survive. In the most severe forms of the disorder, these three factors conspire to produce a catastrophic anemia, complicated by the effects of exuberant hemolysis. The profound deficit in the oxygen-carrying capacity of the blood stimulates production of high levels of erythropoietin in an attempt to promote compensatory erythroid hyperplasia. Unfortunately, the ability of the marrow to respond positively is markedly impaired by ineffective erythropoiesis. Massive bone marrow expansion does occur, but very few erythrocytes are actually supplied to the circulation. The marrow becomes packed with immature erythroid precursors, which die from their burden of precipitated -globin chains before they reach the reticulocyte stage. Profound anemia persists, driving erythroid hyperplasia to still higher levels. In some cases, erythropoiesis is so exuberant that masses of extramedullary erythropoietic tissue form in the chest, abdomen, or pelvis.

Figure 2.3. Pathophysiology of severe forms of -thalassemia. The diagnosis outlines the pathogenesis of clinical abnormalities marking from the primary defect in -globin chain synthesis, RBCs, and blood cells.

As described in the following section, massive bone marrow expansion exerts numerous adverse effects on the growth, development, and function of critical organ systems and creates the characteristic facies caused by maxillary marrow hyperplasia and frontal bossing. Hemolytic anemia results in massive splenomegaly and high-output congestive heart failure. In untreated cases, death occurs during the first two decades of life. Treatment with red blood cell transfusions sufficient to maintain hemoglobin levels above 9.0 to 10.0 g/dL improves oxygen delivery, suppresses the excessive ineffective erythropoiesis, and prolongs life. Unfortunately, as discussed in more detail later, complications of chronic transfusion therapy, including iron overload, usually proved to be fatal before 30 years of age. The addition of iron chelation therapy to regular transfusion therapy now prolongs survival and improves the quality of life.10

2.5. Diagnosis112.5.1 Clinical DiagnosisThalassemia major is usually suspected in an infant younger than two years of age with severe microcytic anemia, mild jaundice and hepatosplenomegaly. Thalassemia intermedia presents at a later age with similar but milder clinical findings. Carriers are usually asymptomatic, but sometimes may have mild anemia. 2.5.2 Hematologic DiagnosisRBC indices show microcytic anemia. Thalassemia major is characterized by reduced Hb level ( 50 < 70 fl and mean corpuscolar Hb (MCH) > 12< 20 pg. Thalassemia intermedia is characterized by Hb level between 7 and 10 g/dl, MCV between 50 and 80 fl and MCH between 16 and 24 pg. Thalassemia minor is characterized by reduced MCV and MCH, with increased Hb A2 level. 2.5.3 Peripheral blood smearAffected individuals show RBC morphologic changes [microcytosis, hypochromia, anisocytosis, poikilocytosis (spiculated tear-drop and elongated cells)], and nucleated RBC (i.e., erythroblasts). The number of erythroblasts is related to the degree of anemia and is markedly increased after splenectomy.Carriers have less severe RBC morphologic changes than affected individuals. Erythroblasts are normally not seen.2.5.4 Qualitative and quantitative Hb analysisQualitative and quantitative Hb analysis (by cellulose acetate electrophoresis and DE-52 microchromatography or HPLC) identifies the amount and type of Hb present. The Hb pattern in beta-thalassemia varies according to beta-thalassemia type. In beta0 thalassemia, homozygotes HbA is absent and HbF constitutes the 92-95% of the total Hb. In beta+ thalassemia homozygotes and beta+/ beta0 genetic compounds HbA levels are between 10 and 30% and HbF between 70-90%. HbA2 is variable in beta thalassemia homozygotes and it is enhanced in beta thalassemia minor. Hb electrophoresis and HPLC also detect other hemoglobinopathies (S, C, E, OArab, Lepore) that may interact with beta-thalassemia. 2.5.5 Molecular Genetic AnalysisThe prevalence of a limited number of mutations in each population has greatly facilitated molecular genetic testing. Commonly occurring mutations of the beta globin gene are detected by PCR-based procedures. The most commonly used methods are reverse dot blot analysis or primer-specific amplification, with a set of probes or primers complementary to the most common mutations in the population from which the affected individual originated.If targeted mutation analysis fails to detect the mutation, beta globin gene sequence analysis can be used to detect mutations in the beta globin gene.

2.6. Differential Diagnosis11 Few conditions share similarities with homozygous beta thalassemia: The genetically-determined sideroblastic anemias are easily differentiated because of ring sideroblasts in the bone marrow and variably elevated serum concentration of erythrocyte protoporphyrin. Most sideroblastic anemias are associated with defects in the heme biosynthetic pathway, especially delta-aminolevulinic acid synthase. Congenital dyserythropoietic anemias do not have high HbF and do have other distinctive features, such as multinuclearity of the red blood cell precursors. A few acquired conditions associated with high HbF (juvenile chronic myelomonocytic leukemia with normal kariotype, aplastic anemia both congenital and acquired during the recovery phase) may be mistaken for beta-thalassemia, even though they have very characteristic clinical and hematological features.Typical beta-thalassemia carriers are identified by analysis of RBC indices, which shows microcytosis (low MCV) and reduced content of Hb per red cell (low MCH), and by qualitative and quantitative Hb analysis, which displays the increase of HbA2. Pitfalls in carrier identification by hematologic testing are: Coinheritance of alpha-thalassemia, which may normalize the RBC indices. However, in alpha/beta double heterozygotes, the HbA2 concentration remains in the beta-thalassemia carrier range and thus is diagnostic. Therefore, HbA2 determination should always be performed for betathalassemia carrier identification. Coinheritance of delta-thalassemia, which may reduce to normal the increased Hb A2 levels typical of the beta-thalassemia carrier state. Double heterozygosity for delta- and betathalassemia can be distinguished from the most common alpha-thalassemia carrier state by globin chain synthesis or globin gene analysis. Silent mutations, i.e., very mild mutations associated with consistent residual output of Hb beta chains and with normal RBC indices and normal or borderline HbA2. The above reported groups of carriers are referred to as atypical carriers. When the hematologic analysis is abnormal, molecular genetic testing of beta globin gene is performed to identify the disease-causing mutation.

2.7. Treatment12Some aspects of the management of thalassemia major, particularly transfusion therapy, how to manage transfusion complications other than iron overload and other supportive therapies, endocrinopathies and their treatment, osteoporosis, fertility, assisted reproduction and management of pregnancy. Transfusion therapyThe goals of transfusion therapy are the correction of anemia, suppression of erythropoiesis and inhibition of gastrointestinal iron absorption, which occurs in transfused patients as a consequence of increased, although ineffective, erythropoiesis.The decision to start transfusion in patients with a confirmed diagnosis of thalassemia should be based on the presence of severe anemia (Hb < 7 g/dL on 2 occasions, more than two weeks apart, excluding all other contributory causes such as infections). However, even in patients with hemoglobin > 7 g/dL, other factors should be considered, including age at presentation of first symptoms, facial changes, poor growth, evidence of bony expansion and increasing splenomegaly. The decision to start regular transfusions should not be delayed until after the third year, as the risk of developing multiple red cell antibodies increases, with subsequent difficulty in finding suitable blood units. Several different regimens have been proposed over the years, but at present the majority of centers choose to transfuse at a pre-transfusion Hb level of 9 to 10 g/dL, and to reach a post-transfusion level of 13 to 14 g/dL. This prevents growth impairment, organ damage and bone deformities, allowing normal activity and quality of life, and is associated with relatively low rates of blood requirement and of iron accumulationThe frequency of transfusion is usually every two to five weeks. The amount of blood to be transfused depends on several factors including the weight of the patient, and the target increase in Hb level. In general, the amount of transfused RBC should not exceed 15 to 20 mL/kg/day, infused at a maximum rate of 5 mL/kg/hour to avoid a fast increase in blood volume.Evaluation of transfusion therapy should be recorded by some indices at each transfusion, including pre- and post-transfusion Hb, amount and Hematocrit (Hct) of the unit, daily Hb fall, and interval between transfusions. These measurements enable red cell requirement and iron intake parameters to be calculated. Dedicated computerized programs are available to monitor transfused thalassemia patients. If the annual red cell requirement exceeds 1.5 times that of splenectomised patients splenectomy should be considered, provided that other reasons for increased consumption, such as hemolytic reactions (see below), have been excluded. For patients maintaining a pretransfusion Hb of 9.5 g/dL, the increase in transfusion requirement is represented by a consumption of more than 200 mL of RBC/kg/year (assuming that the Hct of the unit of red cells is 75%).Table 2.1 Indications for splenectomy

Blood consumption > 200-220 mL/kg/year

Symptoms of splenic enlargemen

Leukopenia and/or thrombocytopenia

Increasing iron stores despite good chelation

Growth deficiency and endocrinopathies Around 30% of patients with thalassemia major are affected by growth disorders. Growth is usually normal until the age of 9 and afterwards there is a decrease of growth rate which leads to a final height lower than that expected on a genetic basis. The factors contributing to stunted growth are not completely understood but include chronic anemia, hypersplenism, folate deficiency, direct iron toxicity, endocrine disorders such as hypogonadism, hypothyroidism and growth hormone (GH) insufficiency, chronic liver disease and deferoxamine toxicity. In regularly transfused and well-chelated patients, deferoxamine at high doses or at therapeutic doses in patients with hypersensitivity, can be toxic to osteogenesis, collagen synthesis and bone turnover, leading to reduced growth (especially of the trunk), protrusion of the sternum, valgus deformity of knees and elbows, swelling of wrists and knees and sliding of the femoral head. Radiologically, platyspondylisis and rachitic-like lesions in the metaphyses of the long bones are present (Figure 2.4).The effective treatment of growth disorders depends on an accurate assessment of their cause. Studies evaluating the secretion of GH have yielded contradictory results, limiting the therapeutic use of GH to those patients proven to have GH deficiency, the only ones to show a satisfactory response to treatment. In the case of signs of deferoxamine toxicity, a reduction in deferoxamine dose or its substitution with an oral chelator, can prevent progression of bone lesions and improve growth. In the most severe cases, surgery can be necessary to correct valgus deformity of the knees or sliding of the femoral head.Figure 2.4. Abnormalities of metaphyseal growth and platospondylisis in patients with thalassemia major

2.8. Complications of Transfusion12,13Although red cell transfusions are lifesavers for patients with thalassemia, they are responsible for a series of complications and expose the patients to a variety of risks. Adverse events associated with red cell transfusions are iron overload, infections, and immunisations (allergic reactions, alloimmunisation). 2.8.1 Iron overloadIron overload is the most relevant complication associated with transfusion therapy. The timing of appearance of signs or symptoms depends on the rate of iron overload. In severe conditions such as thalassemia major, they may appear in childhood, with skin hyperpigmentation, growth impairment, delayed puberty, cardiac arrhythmias and the onset of overt organ dysfunction, including congestive heart failure or diabetes. Otherwise, as in genetic hemochromatosis, signs and symptoms may be very late and non-specific: weakness, fatigue, loss of libido, and/or arthralgia. If the iron burden progresses and is not treated, all the clinical features may become manifest, with heart disease, diabetes, hypothyroidism, hypoparathyroidism, hypogonadism, and cirrhosis. A clear association with the risk of developing hepatocellular carcinoma has been established, at least for thalassemia.Serum ferritin is the most widely used and the least expensive parameter for assessing iron status. A positive correlation exists between serum ferritin concentration and iron stores, but independent conditions may falsely elevate ferritin levels (cancer, hepatitis, inflammation, hemolysis, vitamin C deficiency). Furthermore, the accuracy diminishes at high ferritin values and the correlation may have different slopes in different hematological conditions such as thalassemia intermediate where serum ferritin values notably underestimate iron overload. Therefore serial assessments are recommended. Transferrin saturation (TS) is usually extremely high in regularly transfused patients and its level may suggest the site of iron accumulation (reticuloendothelial iron overload alone is associated with normal TS, whereas parenchymal iron overload leads to a high TS value).Treatments of iron overload are phlebotomy, iron chelation therapy, Phlebotomy is the reference treatment for iron overload in genetic hemochromatosis. It may be applied also to patients after successful bone marrow transplantation for thalassemia and other conditions, as indicated previously.The aims of iron chelation are the prevention of iron-related complications, the maintenance of safe tissue iron levels and the reversal of iron-related complications. DeferoxamineA single excellent drug, deferoxamine (DFO) has been available for many years. DFO displays a strong and specific affinity for iron with a theoretically capability of binding 8.5 mg ferric iron every 100 mg of DFO. The subcutaneous slow infusion has been the standard iron chelation choice since the end of the seventies. In thalassemia major, the regular use of DFO resulted in an impressive improvement in life expectancy and a reduction in the prevalence and severity of iron-related clinical complications. With experience and skill it is possible to limit side effects and optimize compliance in most patients. The standard prescription is a slow subcutaneous infusion over 8-12 hours of a 10% DFO solution by an infusion pump at a standard dose of 20-40 mg/kg for children and up to 50-60 mg/kg for adults. Alternatives in treatment modalities, such as s.c. bolus injection or i.v. continuous infusion enable DFO to be used in a wide range of conditions and special needs. Symptomatic heart disease can be reversed by high dose intravenous treatment. Recent data show that a significant proportion of patients on long-term s.c. DFO still have evidence of cardiac iron load despite low serum ferritin levels. With a single i.v. infusion it is possible to obtain a significant iron excretion lasting up to several days, with limited side effects. Oral iron chelatorsDuring the past few years the body of advances on iron chelation research has been impressive, leading to the development of new oral chelators. Deferiprone (DFP) (Apotex, Toronto, ON, Canada) also known as L1, CP20, Ferriprox and Kelfer, is a 1,2 dimethyl-3hydroxypyrid-4-one, was initially synthesised in 1982, but its development did not follow a systematic design.Recent data on patients with beta-thalassemia demonstrate that daily through levels of DFX suppress LPI for 24 hours. In regularly transfused MDS patients, DFX is also efficient in reducing LIC. In this condition there is a higher rate of adverse events and more frequent discontinuation of therapy. Indications are only based on an expert consensus, additional data are required for a better definition of patients with the best risk-benefit ratio. In a recent study on MDS patients DFX may reduce transfusion requirement. The hypothesis that there is a direct effect of DFX on the neoplastic clone is under investigation. At high doses DFX shows a positive effect on heart iron. A systematic review on DFX analyses also its economic aspects. Table 2.2. shows the properties of available iron chelators.

Table 2.2. Comparison of iron chelators

Side effects of iron chelation Most of the side effects of iron chelation are caused by the iron subtraction from iron-dependent physiological pathways. Age, high doses of chelator and low level of iron overload are the main risk factors, whereas certain side effects are characteristic of each drug. For detecting early iron chelation toxicity and minimising its consequences, a close monitoring schedule should be individually tailored. This may include: auxological assessment (weight, body fat, standing and sitting height, pubertal stages, radiological assessment of bone age and the main metaphyses), bone densitometry, liver function tests, ophthalmological examination, audiometry, plasma zinc, rheumatological assessment are recommended. For DFO specific attention must be paid to early signs of infection for diagnosis and treatment of iron related complications as Yersinia enterocolitica septicaemia. For DFP weekly check of absolute neutrophil count is required. For DFX regular renal function monitoring is recommended. Table 2.3. shows a comparison of side effects of available iron chelators.

Table 2.3. Comparison of iron chelators side effects

2.8.2 InfectionsThe risk of infections is one of the most relevant potential complications of blood transfusion. Blood-borne infections can be viral, bacterial or protozoa. The hepatotropic viruses include hepatitis B virus (HBV), hepatitis C virus (HCV) and hepatitis G virus. Transmission of these viruses in multitransfused patients varies widely in different parts of the world and is directly correlated with their frequency in each population. Administration of recombinant HBV vaccine is recommended for all non-infected patients.The prevalence of HIV positivity in patients from Mediterranean countries is 1.6%. The implementation of nucleic acid testing (NAT) together with the existing antigen/antibody-based assays for donor screening has further reduced the residual risk of recipients viral infection by shortening the window period that is the temporal gap spanning from the time of infection to seroconversion.Fever, shivers, nausea, vomiting, dyspnoea and hypotension are the most common symptoms occurring during or shortly after transfusion. Differential diagnosis includes haemolytic and non-haemolytic reactions. Supportive and antibiotic therapy should be initiated as required. In US death from transfusion-transmitted infections is the second leading cause of death. In countries where it is endemic, malaria can be acquired from transfusions.

CHAPTER IIICASE REPORT3.1 ObjectiveThe objective of this paper is to report a case of 10 years old girl with a diagnosis of Thalassemia Major + Moderate Mitral Regurgitation + Mitral Prolapse.

3.2 CaseVR, a 10 years old girl, with 10 kg of BW and 118 cm of BH, is a new patient of non-infection unit in PediatricDepartment in Central Public Hospital Haji Adam Malik Medan on May 5th 2015 at 17.30. Her chiefcomplaint was pale.History of disease: VR, a girl, 10 years old, came to Haji Adam Malik Hospital at May, 5th 2015 with pale as the chief complaint. The pale symptom have been experienced by patient since a month ago, and become paler in recent week. The patient has no history of spontaneous bleeding, nosebleed, melena, and fever. Urination and defecation of the patient within normal limits.History of previous illness: The patient is an old patient of Hematology Unit with Thalassemia and got routine transfusions.History of medication:Vitamins : C 1x1 tab, E 1x1 tab; Folic acid 1x1 tab; Exjade 2x1 tab.History of family:No family history of thalassemia and other diseases.History of parents medication: unclearHistory of pregnancy:The gestation age was 36 weeks. No history of complication, neonate and maternal problem.History of birth: Birth assisted by midwife spontaneously. The baby was bornparavaginalandshe cried immediately. Bluish was not found. Body weight 3500 gram, body length 50 cm, and head circumference wasnot measured.History of feeding:6 months of breast feeding, additional food since 7 months old.History of immunization: BCG, Polio 4 times, Hepatitis B3 times, DPT 3 times,and Measles.History of growth and development:Face down: 4 months old, Sit down: 6 months old, Crawl: 8 months old, Stand up: 10 months old, Walk: 13 months old, Talk: 12 months old.Physical Examination: Present status: Level of consciousness: compos mentis, GSC 15 (E4V6M5). Body temperature: 36.4C, BP: 90/50 mmHg, HR: 110 bpm, RR: 26 bpm, BW: 20 kg, BH: 118 cm, BW/A: %, BL/A: %, BW/BL: % (), anemic (+/+), icteric (-), dyspnea (-), cyanosis (-), edema (-). Localized status: Head: Eyes: Light reflex +/+, isochoric pupil, pale was found in inferior conjunctiva palpebral.Ears:within normal rangeNose:within normal rangeMouth:within normal range Neck:Lymph node enlargement (-) Thorax:Symmetrical fusiform, retraction (-), Cor S1,S2 regulerHR: 111bpm, regular, murmur (-)RR: 26 bpm, regular, wheezing (-/-), rhonchi (-/-) Abdomen : Supple, normal peristaltic, liver was palpated3 cm below the right costal arches and spleen was palpable (Schuffner II). Extremities : pulse 111 bpm regular, p/v adequate, warm acral, CRT < 3, clubbing finger(-). Working diagnosis: Thalassemia Major Laboratory findingComplete blood analysis (May 5th, 2015)TestResultUnitReferral

Hemoglobin5.30g%12.0-14.4

Erythrocyte2.29106/mm34.40-4.48

Leucocyte12.98103/mm34.5-13.5

Thrombocyte157103/mm3150-450

Hematocrite17.30%37-41

Eosinophil2.40%1-6

Basophil1.200%0-1

Neutrophil46.20%37-80

Lymphocyte42.40%20-40

Monocyte7.80%2-8

Neutrophil absolute6.00103/L2.4-7.3

Lymphocyte absolute5.51103/L1.7-5.1

Monocyte absolute1.01103/L0.2-0.6

Eosinophyl absolute0.31103/L0.10-0.30

Basophyl absolute0.15103/L0-0.1

MCV75.50fL81-95

MCH23.10pg25-29

MCHC30.60g%29-31

RDW26.40%11.6-14.8

Morphology:Erythrocyte:Hypochromic microsite, Anisopoikilocytosis (Basophilic stippling, target cells).Leukocyte: normalTrombocyte: normalClinical ChemistryTestResultUnitReferral

Carbohydrate Metabolism

Blood Glucose119.00mg/dL< 200

Electrolite

Natrium131mEq/L135-155

Kalium3.8mEq/L3.6-5.5

Cloride107mEq/L96-106

Other Test

Therapy:1. Exjade 2x1 tab2. Vit.C 1x1 tab3. Vit.E 1x1 tab4. Folic acid 1x1 mg5. Calorie needed= RDA x Ideal body weight= 3000 kkalCalorie needed 50% of total calorie needed = 1500 kkalDiet 1500 kkal such as :Breakfast = 20% . 1500 kkal Carbohidrate = 300 kkal = 75 grSnack = 10% . 1500 kkal KH = 150 kkal = 37,5 grLunch = 25% . 1500 kkal KH = 375 kkal = 93,7 grSnack = 10% . 1500 kkal KH = 150 kkal = 37,5 grDinner = 25% . 1500 kkal KH = 375 kkal = 93,7 grSnack = 10% . 1500 kkal KH = 150 kkal = 37,5 gr

Planning Assesment: Hand bone age (May 6th, 2015) PRC Transfusion =PRC needed= (Hb target Hb actual) x Constants x BW= (12 5,3) x 4 x 20 = 536 cc 540 ccPRC capability = 20 x 5 cc = 100 cc

Follow Up06 May 2015

SPale(+)

OSensorium: Compos Mentis, Temp: 36,7oC.Head : Eye : light refleks (+/+), isochoric pupil, pale was found in inferior conjunctiva palpebral(+/+) Ear : within normal range Nose : within normal range Mouth : pale mucous +/+Thorax : symmetrical fusiform, retraction (-) HR: 111 bpm, reguler, murmur (-) RR : 26 bpm, reguler, wheezing (-/-), rhonchi (-/-) Abdominal : supple, peristaltic (+)N, liver was palpated 3 cm below the right costal arches and spleen was palpable (Schuffner II)Extremities : pulse 111 bpm, reguler, p/v adequate, warm acral, CRT < 3

AThalassemia Mayor

PExjade 2x1 tabVit C 1x1 tabVit E 1x1 tabFolic acid 1x1 tabR/ TransfusionR/ Echocardiography

7 May 2015

SPale(+)

OSensorium: Compos Mentis, Temp: 36,7oC.Head : Eye : light refleks (+/+), isochoric pupil, pale was found in inferior conjunctiva palpebral(+/+) Ear : within normal range Nose : within normal range Mouth : pale mucous +/+Thorax : symmetrical fusiform, retraction (-) HR: 110 bpm, reguler, murmur (-) RR : 26 bpm, reguler, wheezing (-/-) Abdominal : supple, peristaltic (+)N, liver was palpated 3 cm below the right costal arches and spleen was palpable (Schuffner II)Extremities : pulse 110 bpm, reguler, p/v adequate, warm acral, CRT < 3

AThalassemia Mayor

PExjade 2x1 tabVit C 1x1 tabVit E 1x1 tabFolic acid 1x1 tab

EchocardiographyMitral Valve Prolapse; Moderate MRHand bone age (Left manus)Retarded girls [norm. range bone age: 8-12 y.o.; actual bone age: 7 years 10 months]

8 May 2015

SPale(+)

OSensorium: Compos Mentis, Temp: 36,7oC.Head : Eye : light refleks (+/+), isochoric pupil, pale was found in inferior conjunctiva palpebral(+/+) Ear : within normal range Nose : within normal range Mouth : pale mucous +/+Thorax : symmetrical fusiform, retraction (-) HR: 110 bpm, reguler, murmur (-) RR : 26 bpm, reguler, wheezing (-/-) Abdominal : supple, peristaltic (+)N, liver was palpated 3 cm below the right costal arches and spleen was palpable (Schuffner II)Extremities : pulse 110 bpm, reguler, p/v adequate, warm acral, CRT < 3

AThalassemia Mayor + Moderate MR + Mitral Valve Prolaps

PExjade 2x1 tabVit C 1x1 tabVit E 1x1 tabFolic acid 1x1 tab

9 May 2015

SPale (-)

OSensorium: Compos Mentis, Temp: 37oC, BW: 20 kg, Head : Eye : light refleks (+/+), isochoric pupil, pale inferior conjungtiva palpebra (+/+) Ear : within normal range Nose : within normal range Mouth :within normal range Thorax : symmetrical fusiform, retraction (-) HR: 92 bpm, reguler, murmur (-) RR : 22 bpm, reguler, wheezing (-/-) Abdominal : supple, peristaltic (+)N,liver was palpated 3 cm below the right costal arches and spleen was palpable (Schuffner II)Extremities : pulse 92 bpm, reguler, p/v adequate, warm acral, CRT < 3

AThalassemia Mayor + Moderate MR + Mitral Valve Prolaps

PExjade 2x1 tabVit C 1x1 tabVit E 1x1 tabFolic acid 1x1 tab

Laboratory finding (May 9th 2015)Hb/Ht/L/T = 13/4.94/8.51/39MCV/MCH/MCHC/RDW = 78.9/26.5/33.6/21.0Difftel = N/L/M/E/B = 35.4/49.1/10.2/4.2/1.10

R/outpatient

CHAPTER IVDISCUSSION CaseTheory

Patients mother had a history of diabetes mellitus

Type 1 DM is the result of interactions of genetic, environmental, and immunologic factors that ultimately lead to the destruction of the pancreatic beta cells and insulin deficiency.

Patient was admitted to the hospital with a chief complaint history of unconsiousnes after an injection of Novorapid.Natural history of Type 1 DM is marked by partial/total remission which is known as honeymoon period. Features of diabetes do not become evident until a majority of beta cells are destroyed (~80%). At this point, residual functional beta cells still exist but are insufficient in number to maintain glucose tolerance. Clinically, the evident of this phase should be accounted if type 1 diabetes mellitus patient often experiencing hypoglicemia so that insulin doses should be reduced.

Patient had blurred vision, poliuria, polidipsy and eneuresis nocturnal.Clinical signs and symptoms of type 1 diabetes mellitus polyuria, polydipsia, and polyphagia, along with lassitude, nausea, and blurred vision, all of which result from the hyperglycemia itself. Polyuria is caused by osmotic dieresis secondary to hyperglycemia. Severe nocturnal enuresis secondary to polyuria can be an indication of onset of diabetes in young children. Thirst is a response to the hyperosmolar state and dehydration. Blurred vision results from the effect of the hyperosmolar state on the lens and vitreous humor. Glucose and its metabolites cause osmotic swollen of the lens, altering its normal focal length.

Calori needed = RDA x Ideal body weight = (50 60) x 35 kg = 1750 2100 2000 kkal Carbohidrate needed 50% x 2000 kkal = 1000 kkal = 250 gr Diet 1500 kkal such as :Breakfast = 20% . 1000 kkal KH = 200 kkal = 50 grSnack = 10% . 1000 kkal KH = 100 kkal = 25 grLunch = 25% . 1000 kkal KH = 250 kkal = 62,5 grSnack = 10% . 1000 kkal KH = 100 kkal = 25 grDinner = 25% . 1000 kkal KH = 250 kkal = 62,5 grSnack = 10% . 1000 kkal KH = 100 kkal = 25 gr

Optimal calorie is needed to control growth and development of type 1 diabetes mellitus children. Daily total calorie count based by ideal body weight, age, sex, height and actual body weight. Total calorie divided to 50-60% carbohydrate, 15-20% protein and 30% fat. Food portion divided to appropriate daily dose: 20% breakfast, 10% morning snack, 25% lunch, 10% snack lunch, 25% dinner, and 10% snack night.

CHAPTER VSUMMARY

REFERENCES

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