thalassemia iap

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Introduction Thalassemia is a heterogeneous group of genetic disorders in which the productio n of normal hemoglobin is partly or completely suppressed because of defective synthesis of one or more gl obin chains. Based on the genetic structure, -thalassemia can be divided into: 0 -thalassemia in which there is no globin chain synthesis + -thalassemia where there is reduced b-globin chain synthesis Incidence It is the commonest single gene disorder. In 1996, it was estimated that there a re 36 million carriers in India. An ICMR study (1984-88) implied the following regarding the carrier statu s of beta thalassemia in India (1): Carrier status varied from 3 17%. Prevalence low in Kerala (0.6%) Higher carrier rates in Sindhis, Lohanas and Bhanusalis PGI study of 2000 voluntary blood donors of Punjabi origin found prevalence of b eta thalassemia trait in 3.5% of the population. Diagnosis Beta-Thalassemia Various clinical phenotypes include (2): Silent carrier -Thalassemia trait Thalassemia intermedia Severe -thalassemia (-thalassemia major) The above types are affected by the pattern of inheritance, type of mutation, an d presence of other mutations affecting the output of -globin genes. Beta-Thalassemia Major Clinical features The major clinical features of patients with homozygous -thalassemia are anemia w ith hepatomegaly and splenomegaly. The major clinical features are: Management of Thalassemia IAP Guidelines 2006 OnIAP National Guidelines 2006 170 Hematological manifestations: The infants are normal at birth, and anemia develo ps by about 5-6 months of age. Unless supported by regular blood transfusions hemoglobin may ran ge form 2-8 g/dl. Other reasons for worsening of anemia are rapid splenomegaly and hypersplenism. Progressive hepatosplenomegaly: this is a result of extramedullary hematopoeisis . However, it is not severe in adequately transfused patients. Facioskeletal changes and osteoporosis: Characteristic bony changes occur in poo rly transfused thalassaemics secondary to erythroid hyperplasia with intramedullary exapansion, cortical bone thinning, endocrinopathy, iron overload, and secondary osteoporosis. Frontal bos sing and zygomatic prominence give rise to typical hemolytic facies . Musculoskeletal problems may occ ur due to anatomic proximity of bones and joints to active centers of hematopoesis, these include (3):

Pathological fractures Premature epiphyseal fusions Thalassaemic osteoarthropathy Side effects of the iron chelator drug- deferiprone. Skin changes and leg ulcers: Leg ulcers may be seen especially around the medial malleoli. Diffuse elastic tissue defects resembling inherited pseudolymphoma elasticum may occur. Xanthomatous lesions tend to involve the skin and the eyes. This is probably related to tissu e hypoxia and disturbances in elastic metabolism (4). Infections: Thalassaemic children are immunocompromised; hence have a greater su sceptibility to various infections. These include upper respiratory tract infections, gastroente ritis, cutaneous abscesses, gingivitis, septicemia, pneumonia, UTI s, salmonellosis, and biliary tr act infections. Thromboembolic events: Thromboembolic episodes may involve CNS causing headaches , seizures, and hemiparesis. The risk factors include diabetes, complex cardiopulmonary abno rmalities, hypothyroidism, liver dysfunction, and postsplenectomy thrombocytosis. Sometimes deep vein thrombosis may also occur. Spinal cord compression: It is rare and may occur due to epidural extramedullary hematopoeisis or due to vertebral fractures. Transfusion transmitted infections: Stringent blood screening reduces the risk o f these infections. Psychosomatic illness: Thalassemia causes a major psychosocial impact causing de pression, poor self image, low mean IQ scores, etc. Lab features RBC s show marked anisopoikilocytosis with hypochromia. Nucleated RBC s are also pre sent on the peripheral blood smear. Bone marrow shows though not indicated will show marked erythroid hyperplasia with a erythroid:myeloid ratio of 20:1. - Thalassemia Minor The heterozygous states for the bO or b+ gene constitute the most common genotype for thalassemia minor. The features include: Mild anemia with reduced MCV and MCH Electrophoresis reveals: Predominance of HbA Increased HbA2 (3.5-8%) Minimally increased HbFIAP National Guidelines 2006 171 It s important to note that though thalassemia minor does not need iron therapy, b ut this entity may coexist with iron-deficiency anemia. Thalassemia Intermedia These patients are homozygous for b thalassemia genes but maintain hemoglobin of 6 to 8 g/dl without regular transfusions. They also have associated splenomegaly. The major differen ces between three types of b thalassemia syndromes are: Parameter Major Intermediate Minor Hemoglobin (g/dl) 9

Reticulocyte % 2-15 2-10 10 > 12 NO Suoer transfusion > 12 > 14 NO It is recommended that we follow the moderate transfusion regimen. What to transfuse? Patients with thalassemia should receive leukoreduced packed red cells. Reductio n of leukocytes to 5x106 is considered the critical threshold for eliminating adverse reactions attribute d to contaminating white cells. The methods of leukocyte depletion are: Centrifugation can remove 70% of leukocytes in 1 unit of blood. Cell washing or use of deglycerolised red cells can remove 95% of contaminated wh ite cells. The older microaggregate filters can remove leukocyte content by approximately 1 to 2 logs (90-93%). (5,6) The third generation leukocyte depletion filters can remove < 4 logs (99.9%) of white cells. This lowers

white cells in a unit of blood from 109 to 105 . International guidelines suggest the number of white blood cells be kept 1000g/L After first 15 20 transfusions. Liver iron concentration >3.2mg per gm dry wt of liver. Goals of iron chelation Disciplined chelation therapy, as it is a slow process Maintain S. Ferritin approx 1000g/L or less (3-6 monthly monitoring) Iron chelators presently available are: Desferrioxamine (Desferal, DFO) Deferiprone (Kelfer, L1) Deferasirox (Exjade, ICL 670) Desferal Therapy How Desferioxamine helps? Several factors suggest its importance as a chelating agent. 1. Adequate therapy has led to survival curves approximately close to the normal population (12,15). 2. Its possible to reverse some complications of iron overload (16). 3. Allergic reactions are rare. 4. Besides the subcutaneous routes, in unwilling patients alternate routes may b e used. 5. Even inadequate doses of DFO arrest the progression of fibrosis of liver. 6. If initiated before the age of 10 years, growth and sexual development are no rmal (17). 7. Adequate chelation reduces the likelihood of the development of pancreatic da mage and diabetes mellitus.IAP National Guidelines 2006 177 Initiation of therapy Starting DFO before the age of 3 years can be hazardous as there have been repor ts of abnormal linear growth and metaphyseal dysplasia (18). However, if liver iron concentration exce eds 7mg/gm dry weight of liver chelation should be initiated. Dosage of DFO Children: 20 40mg/kg/day Adults: up to 50mg/kg/day Adjust dose according to body iron load and age If chelation is started before 3 yrs of age then Therapeutic index = mean daily dose (mg/kg) ferritin (g/L) Mean daily dose = actual dose received on each occasion x doses per week 7 use low dose of DFO carefully monitoring growth and bone development Maintain therapeutic index < 0.025 Route of administration of DFO Standard recommendation is: Slow subcutaneous infusion over 8 12 hrs using an infusion pump Strength of infusion 10% (500mg of DFO in 5ml of water) Site of infusion Anterior abdominal wall Lateral side of thigh and deltoid may be useful additional sites. Regularly rotate sites for injection. Type of needle Butterfly needles: 25 to 27 gauge inserted at 450 to skin surface Thalassemia-set: 8mm vertical needle with transparent built in adhesive strap Preparation of site Local anesthetic cream like EMLA can be used 30 minutes before starting infusion . Local reactions These may range from mild redness to itching, to bruises, pain, rashes and lumps

. There are a number of possible factors that can affect the frequency and severity of these reactions: Infusion strength: if more concentrated than a 10% solution reactions are more c ommon. Increasing the duration of infusion helps in passing a smaller amount of drug th rough the skin at a given moment. Rotating the infusion site is helpful. Certain parts of the body are more sensit ive to infusions than others. This also applies to recently infused sites. Hydrocortisone in the form of topical cream may be applied at the reaction site. In case of severe reactions add 5mg of hydrocortisone to the infusion fluid. Topical anesthetic such as EMLA cream applied two hours before the infusion help s in desensitising the infusion site and reduce pain.IAP National Guidelines 2006 178 If body iron burden is high and subcutaneous route very discomforting, then surg ically implanted venous access such as Port-a-cath device may be used. Use of Vitamin C Increases iron excretion by DFO. Start after DFO therapy in progress for one month. Administration after the start of infusion. Dose: 50mg in children 2500g/L Liver iron >15mg/gm dry weight. Significant cardiac disease Significant cardiac dysrythmias. Evidence of falling ventricular function. If one of the following is present, the indication is strengthened: Inability to use subcutaneous desferrioxamine regularly or poor compliance. Female patients who plan a pregnancy. Patients planning bone marrow transplantation. Patients with active hepatitis C. The recommended dose is 50mg/kg/day. It should be a continuous infusion 7 days a week. Besides continuous infusion intravenous therapy may also be used as supplement to conven tional therapy, but its role in contributing to iron overbalance is limited. Monitoring compliance Long-term compliance with chelation has a significant effect on prognosis and mu st therefore be encouraged in every possible way. One suggested approach is the use of a complia nce index: No. of days of treatment per year Compliance index = No. of days for which treatment is prescribed. The use of such index means that records are kept of the amount of treatment act ually being given. Various approaches for collecting such data are: Record the time of infusion on a calendar.

Keep a record of the empty vials of desferrioxamine returned to the provider at the time new prescription is filled.IAP National Guidelines 2006 179 Intravenous administration of DFO during blood transfusion Saves one prick Intravenous therapy piggy backed into infusion line. Dose of DFO should not be more than 10mg/kg/hr. Never add DFO to blood unit. Storage of desferal Store in a cool and dark area. Discard if reconstituted solution is opaque, cloudy or discolored. Reconstituted solution can be stored for up to 24 hrs. Monitoring Progress: Assessment of Body Iron Burden There is a wide scatter of liver iron concentrations with ferritin levels in the range of 2,000g/L. It is quite possible to have dangerously high levels of iron burdens with serum iron in the safe ranges. Hence measuring liver iron concentration is the best approach. Liver Iron Concentration (Used only for research purposes, not meant for routine purposes as it is an invasive procedure) Liver biopsy should be considered in patients whose serum ferritin levels deviat e from the expected or are on experimental chelation regimens. Serum ferritin: It is an easy test to perform with established efficacy. The tar get recommended is 1000g/L but a level below 2,500g/L reduces the risk of cardiac complications. Howe ver, several factors such as hepatitis, infection, ascorbate status may affect the ferritin l evels and day-to-day variations are marked. Ferritin should ideally be monitored every 3 months. But serum ferritin levels underestimate the level of iron burden (19). It is more important to see the tre nd in the serum ferritin levels rather than a single value while assessing the efficacy of treatment. Blo od sample should be taken when child has no evidence of infection. Desferrioxamine Toxicity Severe sensitivity reaction Rarely patients may have generalised sensitivity reactions to DFO. These compris e of wheezing, tachypnea, tachycardia, hypertension, and occasionally coma. Chronic systemic side-effects Patients receiving doses in excess of 50mg/kg body weight or those receiving sma ller doses in the presence of modestly elevated iron levels experience majority of the side effect s. Various complications include:IAP National Guidelines 2006 180 Toxicity Investigations Frequency Alterations in treatment Ocular manifestations Retinal Yearly; if Interrupt DFO such as cataracts and examination, patient is immediately. retinal damage.(20) EOG, ERG and asymptomatic; If iron burden 3.2Rarely night blindness VER else immediately 7 mg/g dry weight may occur with annular of liver discontinue field loss. Non-reversible DFO for 6 months. fundal pigmentation Repeat retinal examination may occur every 3 months. Ototoxicity comprising Audiogram Yearly or as and Same as above

of high frequency when needed. hearing loss. Abnormalities in linear Determine sitting Yearly Reduce DFO to growth with the and standing 25mg/kg/day x 4 per week. evidence of cartilaginous heights.X-rays of If hepatic iron a / thalassemia > Xmn polymorphismIAP National Guidelines 2006 183 - Infections (HbsAg, Anti HCV, HIV I & II) - S. Ferritin / Cardiac / Endocrine Transfusion therapy Pre transfusion Hb Transfusion date Amount of blood (Blood group Bag No. etc.) Type of filter being used Transfusion reactions Immediate Delayed Monitoring for various transfusion transmitted infections: Hepatitis B Infection HBsAg positive Hepatitis C Infection Anti-HCV reactive HIV Infection (Elisa+) confirm Western Blot. In children > 15 months HIV Elisa i s reactive. Iron Overload monitorimg No. of units transfused per year Serum Ferritin level Liver biopsy and iron load assessment. MRI SQUID Monitoring DFO Treatment Effect on iron overload Porter index = Mean daily DFO dose (mg/kg)/ Serum ferritin (g/l) Maintain index value < 0.025 Initial S Ferritin level Desferal Chelation (Dose / Schedule) Deferiprone Combination ICL670 Vitamin C (50-150 mg/D) DFO Toxicity Short stature Swelling of wrists & knees Genu valgum deformity Rickets like changes Platyspondylosis Genu valgum Deferiprone Side effects Nausea, vomiting, diarrhea, abdominal pain Arthropathy is seen in 10-12% of cases. Agranulocytosis is present in 1%.IAP National Guidelines 2006 184 Growth Retardation (>10 yr) Causes of growth retardation in children less than 10 years of age are: Chronic anemia Folic acid deficiency Hypersplenism Endocrine disorders Chronic liver disease Zinc deficiency DFO toxicity Monitoring growth in thalassaemics Decrease in growth velocity could be due to undertreatment i.e., if a child is u nder transfused or inadequately chelates. Sometimes overtreatment may cause DFO toxicity and hence growth retard ation.

Evaluation is done by: 3 monthly charting of sitting & standing height. X-ray left hand & wrist for bone age once ayear Further evaluation if chronological & bone age difference is more than 2 years X-ray spine for platyspondylosis of vertebral bodies Bone Densitometry (DEXA SCAN) once a year, or as indicated Lumbar spine (L1-L4), Hip & Forearm T Score standard deviation (SD) from estimated mean peak values of young adult. Z Score - SD from the mean BMD of an age matched population. Score > -1 Normal BMD Score -1 to -2.5 Osteopenia Score < -2.5 Osteoporosis Cardiac evaluation should also be carried out regularly at atleast I yearly inte rvals or ideally 6 monthly intervals X-ray chest Echocardiogram Holter (Rhythm) MUGA scan Doppler analyzer MRI Diet regulations High calorie, high protein nutritious diet. Foods rich in iron should be avoided e.g., meat, liver, kidney, egg yolk, green vegetables, jaggery etc. Food should not be cooked in iron pots. Meals should include bread, cereals, milk, moong dal, soya bean etc. to reduce t he iron absorption. Vitamin C rich fruits e.g., citrus fruits should be avoided along with meals. Strong tea/coffee should be taken along with meals. Milk and milk products should be frequently taken.IAP National Guidelines 2006 185 Thalassemia Monitoring Yearly HbSAg Anti HBs Ab HB (DNA) (if HbsAg +) Anti HCV-RNA Bone density Audiogram (If on desferal) Eye check up (If on desferal) Cardiac evaluation Endocrine evaluation (>10yrs) MRI (T-2 images) Thalassemia Monitoring Quarterly Date Height Weight S. Ferritin (ug/L) Total bilirubin (ml/dl) Direct bilirubin SGOT/SGPT/SAP/GGTP Serum creatinine. Serum Ca / Phosphorous Thalassemia Monitoring - Transfusion day Date Blood Transfusion (ml) Pre transfusion (Hb gm/dl) Liver spleen (cm) Deferiprone (dose) Desferal (dose) Combination

Next date Remarks Splenectomy in Thalassemia Indications 1. Annual blood requirement increased to 1.5 times or more of previous years for a patient maintaining a pre-transfusion Hb of 10gm/dl. When transfusion requirement increases to more th an 200 to 220ml/ kg/year of packed cells, splenectomy should be considered if other causes have b een ruled out. Other causes of increased requirement are: Development of new alloantibodies Infections especially HIV infection Change in quality of blood transfused. Folate deficiencyIAP National Guidelines 2006 186 2. Clinically significant leucopenia/neutropenia and/thrombocytopenia due to hyp ersplenism. 3. Splenic enlargement accompanied by symptoms such as upper abdominal pain, ear ly satiety and danger of rupture of spleen. Splenomegaly due to temporary period of under-transfusion is reversible. 4. Splenectomy should be delayed till the age of 5 as there is a greater risk of sepsis. Surgical approaches 1. Total splenectomy, it may be open, laproscopic or hand-assissted. The choice of procedure is dependent on surgeon s expertise and need of the patient. For instance, if gallstones have t o be removed then open procedure is a better choice. 2. Partial splenectomy 3. Splenectomy with auto-transplantation 4. Splenic embolization 5. Splenectomy with splenic slice grafting 6. Partial splenic de-arteriaization Procedure Advantages Disadvantages Comments Open 1. Gallstone evaluation Longer post and cholecystectomy operative stay. possible. 2. Can do appendicectomy. 3. Liver biopsy may be taken. 4. Shorter operation time. Laproscopic 1. Shorter recovery time. 1. Complication rates Hand Assisted 2. No surgical scar are similar to open. Laproscopic Surgery 2. Longer operation (HALS) may be done time. for removing large 3. More risk of bleed. spleens laproscopically. 4. Difficult for large spleens. 5. May miss accessory spleens. 6. Expertise required. Post-splenectomy sepsis Influencing Factors Age of the patient is important as, younger the age more the risk of sepsis. Duration after splenectomy, as soon after splenectomy chances of infection are m ore. Iron overload. Desferrioxamine therapy. Associated G-6-PD deficiency. Parathyroid dysfunction.

Preventive strategies Immunoprophylaxis - Common organisms responsible for sepsis are S. pneumoniae, H. influenzae, N me ningitidis, other organisms are E coli, Klebseilla, Pseudomonas. Vaccination against S. Pneumonaie should be givenIAP National Guidelines 2006 187 in the form of 23valent vaccine 2 weeks before operation. - If child has been vaccinated before 2 yrs age- revaccinate at 2 yrs and then r epeat after 3-5 yrs. - H influenzae, typhoid and N meningitidis vaccines should be given if not recei ved as routine immunization. - All vaccines can be given at the same time using different syringes and differ ent sites Chemoprophylaxis - Oral penicillin in the dose of 250 mg BD should be given for children over 2 y rs and125 mg BD for children below 2 yrs. It is ideally given life-long or at least till 5 years of age or 2 years post-op whichever, is later. - Alternative drugs are: Amoxicillin, erythromycin, Co-trimoxazole. - Importance of compliance should be stressed Education-parents/ patients/ physicians - Compliance to chemo/ immunoprophylaxis should be stressed. - Report all febrile illness and seek medical attention. - Tell attending doctor about splenectomy. Education of physicians: - Knowledge regarding common pathogens is essential. - To evaluate all patients coming with fever by complete physical examination. - Obtain blood and other relevant cultures. - Start treatment with drugs effective against S. pneumoniae, N meningitides. Anti-thrombosis prophylaxis: - Risk more in T. intermedia than T. major - Risk of thrombosis is increased due to: O Thrombocytosis O Increased platelet activity O Pro-coagulant activity of damaged red cells Splenectomised children and adults O Associated diabetes O Associated decreased levels of Protein C, S, AT III O For reactive thrombocytosis: If patients have other risk factors for hypercoagulation, children with severe t hrombocytosis (>9 lacs/mm3 ) should be given prophylaxis with Aspirin 75 mg daily. Complications of Thalassemia Major Common Endocrine Disorders Short stature Delayed/Arrested puberty Hypoparathyroidism Hypothyroidism Diabetes Mellitus Osteopenia/porosis Adrenal insufficiencyIAP National Guidelines 2006 188 Short Stature Short stature is a common endocrine disorder. Besides regular growth charting, w hich should be part and parcel of the protocol of any thalassemia clinic, children who fall below the 3r

d percentile, or those who fall behind in growth across 2 major percentiles of the growth chart, irrespective of the percentile, should undergo a complete evaluation. Management Management of the short stature has to patient bases after a comprehensive evalu ation of the cause: EtiologyTreatment Etiology Treatment Chronic anemia Keep pre-transfusion hemoglobin above 9g/dl to ensure normal grow th. Hypersplenism If blood consumption exceeds 200ml/kg/year then splenectomy should be planned. Nutritional deficiencies a. Folate deficiency may be seen in malnourished, irreg ularly transfused children. Folic acid in the dose of 1-2 mg daily is sufficient. b. Zinc deficiency results from chelation with desferrioxamine. They also have skin disorders. Oral Zinc sulphate in the dose of 200-220mg should be given daily (25) Endocrine disorders- a. It occurs in poorly chelated patients. Initially TSH is high a. Hypothyroidism with normal T3 and T4 . Later T3 and T4 also become low. b. Delayed puberty/ L-thyroxine in the dose of 100g/m2 may be given daily. hypogonadism b. Manage as per the cause. c. Abnormalities of GH secretion c. In GH deficient patients GH in the dose of 0 .5-1 IU/kg/ week may be given (26,27). In non-GH deficient individuals, GH therapy may cause a rise in growth velocity, probably due to secondary GH insensitivity. Desferrioxamine toxicity Reduce the dose of DFO to 20-25mg/kg, if serum ferritin is below 1000 ng/ml.In case of hypersensitivity discontinue DFO.Oral Zinc supplements Delayed puberty Sexual Development and Fertility Management Improved care of patients with thalassemia has led to issues such as normal pube rty, sexual development and ultimately fertility. Hypogonadism leading to delayed puberty is a common pr oblem of children with thalassemia major.IAP National Guidelines 2006 189 In boys delayed puberty is defined as absence of pubertal changes till the age o f 14 years, and for the girls it is defined as13 years. The pituitary and hypothalamus are very sensitive to iron damage, and hypogonado trophic hypogonadism is a frequent complication (28). It is supported by the fact that this type of hypo gonadism responds to GnRH therapy. Some studies support the role of primary gonadal failure as evidenced b y interstitial fibrosis of the testis, small seminiferous tubules, and absence of Leydig cells (29). Hemosidero sis damages pituitary gland. Management of gonadal dysfunction 1. Adequate transfusion and early and effective chelation regimen.

2. If pubertal changes fail to occur then hormonal replacement therapy. 3. In boys long acting testosterone may be given keeping the bone age in mind. 4. In girls cyclic administration of estrogen and progesterone is required. 5. Treatment of associated endocrinopathies especially hypothyroidism, hypogonad ism is also required. 6. Management of nutritional deficiencies. Fertility and Management of Pregnancy Key interventions (30) Optimum iron chelation since childhood better fertility. If pubertal delay, or hormonal disturbance- consult Endocrinologist. Counseling to be done regarding the risk of a hemoglobinopthy in the baby, partn er should be screened for any trait. Discuss the risks of pregnancy, and assess cardiac status. General pregnancy issues to be discussed. Couples may be infertile for reasons unrelated to thalassemia, discuss the issue s. Induction of ovulation or spermatogenesis to be done. During pregnancy her obstetrician, cardiologist, and hematologist should closely monitor woman. Transfusion requirements are likely to increase. Withhold medications like bisphosphonates, and ACE inhibitors. Ideally desferrioxamine should be withheld during pregnancy, but its toxicity is reduced in the 2nd and 3rd trimester, so women who need iron chelation may be considered (31). Foli c acid is important in pre- and early pregnancy. Penicillin prophylaxis should be continued in those splenectomised. Calcium and vitamin D supplements to be given. Discuss and plan mode of delivery. Deferrioxamine may be resumed after pregnancy, but deferiprone not to be given d uring breast-feeding. Hypoparathyroidism Hypoparathyroidism in thalassemia usually occurs due to destruction of parathyro id gland by iron deposition. As signs and symptoms do not appear immediately, hence regular scree ning of thalassaemic patients for hypoparathyroidism is important. The screening involves:IAP Nationa l Guidelines 2006 190 Samples to be drawn When How Inference Serum Ca, PO4 , 6 monthly in Fasting samples. Low Ca, high PO4 Alkaline phosphatase poorly chelated, with normal alkaline phosphataseannually i n well hypoparathyroidism. chelated Magnesium levels May be the cause of hypoparathyroidism. PTH levels After assessing Low or lower limit of normal above levels. suggest hypoparathyroidism. S.Ferritin Regularly, Direct co-relation with depending on hypoparathyroidism. Higher the how well patient serum ferritin level lesser the is chelated. parathyroid levels (32) Management Acute hypoparathyroidism: The presentation is of tetany and seizures. Slow intravenous injection of 10% calcium gluconate 1to2 ml/kg every 6 to 8 hour s. Chronic hypoparathyroidism

Calciferol sterols may be started in a dose of 25 to50 ng/kg/day and then titrat ed according to serum calcium levels. Start Calcitriol in a dose of 0.25g daily. Calcium supplements. Serum calcium levels may normalise in a weeks time, however , phosphorous levels may take up to 6 weeks. Bone Problems Various reasons contribute to the bone disorders: Inadequate transfusion therapy. They develop characteristic deformities of the skull and face. They are suscepti ble to fractures following minor trauma, develop dental deformities, dental malocclusions, and re current sinusitis due to inadequate drainage. These problems occur due to erythroid expansion. Desferrioxamine toxicity. It leads to cartilaginous dysplasia of the long bones and spine, giving rise to shortening of trunk and a pseudo-rickets appearance. Hypoparathyroidism. Asian children are susceptible to rickets and vitamin D defi ciency. Hypogonadism Osteoporosis. Transfusion dependent thalassaemics show a high rate of osteoporosis and osteope nia(33) . Bone density is reduced in well chelated and transfused patients as well due to increased bone resorption relative to formation.(34) Back pain is common in such patients. It c ould be due to OsteoporosisIAP National Guidelines 2006 191 Crush fractures Mild degree of bone loss Disc disease due to long-term desferrioxamine toxicity. Extramedullary hematopoeitic masses. These patients need to be evaluated by a team of orthopedic surgeon, rheumatolog ist, physiotherapist, and chronic pain specialist. Key interventions Optimal transfusion to prevent excessive bone expansion. Diet rich in calcium. Moderate exercise. Optimum dose of desferrioxamine. Regular growth charting with radiological investigations. Hormone replacement therapy for hypogonadism. Measure bone mineral density in hip and spine every 18-24 months. In established osteoporosis i.e., Z-score of 126 Post Prandial (mg/dl) 140-200 >200 Screening for diabetes All patients above 10 years of age should be routinely screened for diabetes.

Screening is done by performing an oral glucose tolerance test (GTT). GTT is performed by: Drawing a fasting sample for blood glucose. Oral glucose is given in a dose of 1.75g/kg, up to a maximum of 75 gms. Blood glucose level is measured 2 hours after oral glucose. Improved chelation may lower the risk of developing diabetes Routine screening is important to identify the pre-diabetic and asymptomatic dia betic children, so that diabetic complications can be prevented. Cardiac Complications in a Poorly Chelated patient Following features raise the suspicions of heart failure in a poorly chelated pa tient: A decline in exercise tolerance with recent increase in dyspnea. Persistent recent increase in heart rate (when other causes have been ruled out) . Pansystolic murmurs. Increase in cardiomegaly. Increase in intensity of S3 gallop.IAP National Guidelines 2006 192 Pulmonary arterial hypertension may occur in these patients due to: Left heart failure and pulmonary venous hypertension. Secondary to lung disease. Thrombocytosis due to microvascular occlusion of pulmonary vascular bed. ECG of the patient may reveal any of the following: Sinus tachycardia always seen. Tachyarrhythmias are more common than bradyarrhythmias. Frequent ventricular ectopics. Non-sustained ventricular tachycardia. Atrial ectopics. Atrial fibrillation. Biventricular hypertrophy may cause left or right bundle branch block. Echocardiography (Echo) It is inexpensive, non-invasive, and easily available but needs a skilled techni cian to carry out the procedure. ECHO findings reflect the following: High cardiac output state Increased left ventricular volume, stroke volume, and cardiac index. Decrease in systemic vascular resistance Dilated cardiomyopathy A restrictive pattern of transmitral flow may be seen. Overt heart failure Progressive decrease in LV and RV contractile functions. Thi s is followed by progressive dilatation of all 4 chambers. Stress Echo After a baseline Echo patients are made to exercise on a treadmill and repeat Ec ho is done after 15 minutes. This modality helps in identifying patients at risk of heart failure but needs a skillful operator and low sensitivity. 24 hour Holter Monitoring This is needed when arrhythmia is suspected. Blunted heart rate disease is used as variability for cardiac disease in thalassemia. Magnetic Resonance Imaging (36) It is an expensive but useful modality to assess iron load in heart and lungs. I ron load causes signal loss in tissues. It is measured by T2. T2 less than 20 msec represents abnormal myocardi al load. Radionuclide Studies The multigated scan provides a highly reproducible quantification of LVEF. It ca n be used to follow patients prospectively. Comparatve to stress Echo there is a fall in left and right ventr

icular ejection fractions on exercise (37). An absolute LVEF of 45% or less or fall in LVEF by more than 10% over previous value is taken as evidence of excess iron in the heart.(38)IAP National Guidelines 2006 193 Cardiac Involvement in Thalassemia Intermedia (39) Post patients with thalassemia intermedia develop abnormalities only in adulthoo d. About 5-6% develop congestive heart failure in the fourth decade of life. They have a hyperdynamic circulatory state secondary to anemia. Echo shows multiple minor abnormalities. Some may show LVH/RVH. Valvu lar abnormalities of minor leaflet thickening may be seen in up to 50% of the cases. The most important abnormality is pulmonary arterial hypertension, secondary to elevated pulmonary vascular resistance. As the patient grows older PAH leads to right ventricular h ypertrophy and later right heart failure. It is probably related to the consequence of thalassemia intermed ia rather than blood transfusions. Management (40,41) Management largely depends on the stage of disease. It has to be individualised to the patient. Phase of illness Management Diet: avoid table salt. Subclinical Lifestyle: no major modifications needed except regular physical exercise. Chelation: to be stepped up with regular monitoring Early heart disease Diet: mild modifications, low salt. Lifestyle: mild exercises and non-competetive sports allowed. Upper body weight lifting not allowed. Chelation: intensify chelation with desferrioxamine and or deferiprone. ACE inhibitors such as Captopril, Enalpril or Losartan potassium may be used. Diuretics: small doses of frusemide may suffice. Carvedilol for excessive tachycardia may be used. Hb should be maintained at 10gb/dl, by giving small frequent transfusions. Advanced heart disease Dietary restrictions No exercise allowed, if need be then hospitalization and cardiac consultation. Chelation: Initiate intravenous continuous desferrioxamine and continue oral deferiprone. ACE inhibitors in low doses. IV diuretcs to reduce fluid overload (thiazide diuretic+ frusemide+aldactone). Digoxin may be used in atrial fibrillation and late stages of heart failure. Antiarrhythmic therapy: for supraventricular tachycardias use Verapamil or Diltiazem. Management of ventricular ectopics and tachycardia by Amiodarone.IAP National Guidelines 2006 194 Bone Marrow Transplantation (BMT) for Thalassemia Bone marrow transplantation can offer a complete cure to patients with thalassem ia major (42) BMT was started in 1981, at Seattle (43). What is Bone Marrow Transplant? Bone marrow transplant involves harvesting bone marrow from a healthy donor to t he recipient. The

patient s marrow is first ablated by drugs and or irradiation, a process called co nditioning. Thereafter, the healthy marrow is given to the patient in the form of intravenous transfusion. I n about 2 to 3 weeks donor s cells start producing normal marrow. This procedure is associated with significant risks of infection, regimen relate d toxicity, graft versus host response and relapse especially in those patients who because of inadequate treatment and poo r chelation have developed hepatomegaly and hepatic fibrosis (44). The risk stratification is based on the following criteria: Class I Well chelated, no hepatomegaly, no hepatic fibrosis. Class II One to two adverse risk factors. Class III All three adverse risk factors. The decision of a bone marrow transplant is dependent on the family and the thal assaemic child, whether they wish to continue transfusion chelation therapy or are willing to take the r isk of bone marrow transplantation. Following options may be evaluated for a match: A histocompatible sibling is a must for bone marrow transplant. If a sibling is not available, then extended (parents or cousins) family can be surveyed for a match. The probability of finding such a donor is rare except in cases of consanguineous ma rriages. In case the couple have one child and are planning another one then an antenatal diagnosis should be performed at 10 weeks of age and if normal or carrier, pregnancy may be allowed to continue. HLA typing can be performed on the DNA sample available form chorionic villus sampli ng. When the baby is born cord blood transplant (45) may be done or a bone marrow transplant can be d one when they baby is 2 years old. The HLA need not be fully matched. Complications (46,47,48) The major complications of BMT are: Graft versus host disease Acute: if it occurs within first 100 days. It is most devastating. Most affected organs are skin, liver and intestines. - Occurs in 30-70 percent of the patients transplanted with HLA identical marrow . - May cause death in 20-40%. Chronic: if it continues or develops after 100 days. May be caused by cytomegalo virus infection. The standard treatment protocol for prevention of GVHD is cyclosporine with meth otrexate. Once GVHD develops then corticosteroids may be added.IAP National Guidelines 2006 195 Infection Mechanism: after transplantation due to profound neutropenia and disruption of t he anatomic barriers are most important risk factors for bacterial and disseminated fungal i nfections. At earliest sign of fever intravenous antibiotics, a cephalosporin along with am inoglycosides is started. At times Vancomycin and Imipenam may be used. Prophylaxis: - Antifungals like fluconazole and Amphotericin B are given to prevent fungal in fections in the immunocompromised host.

- Prophylaxis with penicillin or Trimethoprim sulpha in the first year post-tran splant reduces the risk of sepsis. - Ganciclovir and Acyclovir are administered to high risk patients to reduce the incidence of CMV infection. Interstitial pneumonia may be seen in 30 percent of the patients when irradiatio n is used for conditioning. It is largely due to CMV infection. Regimen related toxicity Busulphan and Cyclophosphamide can cause significant problems. Veno-occlusive disease of the liver may occur. It causes hepatomegaly and ascite s. It appears within first week of transplant and resolves by the third week. Cyclophosphamide may cause hemorrhagic cystitis. Treatment comprises of plenty o f fluids and Mesna. In iron overloaded patients cardiac failure and acute cardiac tamponade may occu r. Post-transplant Care Following need to be given to a bone marrow transplant patient To prevent GVHD Cyclosporine for 6 months at full dose, followed by tapering ove r next 6 months. Pneumocystis prophylaxis for 1 year. Folic acid supplement for 1 year. Oral penicillin for 1 year to reduce the incidence of gram positive infection. May return to normal activities after 6 months. After Care The bone marrow transplant patient needs to be monitored carefully for: Re-vaccinate the patient to facilitate development of antibodies by the new immu ne system. Remove iron by chelation or venesection to prevent late iron related side effect s such as hepatocellular carcinoma. Ensure growth and gonadal development. Treat hepatitis viruses with interferon and ribavarin. Prevention by Pre-natal Diagnosis of -Thalassemia. The success of a prenatal diagnosis program is outlined below: 1. Ensure that both partners are carriers. 2. Molecular studies in the affected child and the parents to identify the mutat ions in the -globin gene that cause the disease. 3. Choose an appropriate obstetric technique to obtain fetal tissue. 4. Extract DNA from the fetal tissue and carry out molecular studies. 5. Keep in mind sources of error. 6. Verify the result after birth or abortion.IAP National Guidelines 2006 196 Methods of Obtaining Fetal Tissue Chorionic Villus Sampling When to be done Can be done in the first trimester Ideally performed at 10-12 weeks of pregnancy. Advantages Results available in early pregnancy Technical advantage is that using phase contrast microscope fetal placental tissue can be separated from maternal deciduas. It reduces the risk of misdiagnosis due to maternal contamination, as DNA is prepared from single villus. Adequate DNA can be obtained from a CVS sample. Method Performed under ultrasound guidance Transvaginal approach for low lying or posterior placenta, or transabdominal approach for fundal or anteriorly located placenta. Give Rho (D) Immune globulin 300mg to unsensitised Rh negative mothers. Assess adequacy of sample immediately.

20-30mg of villi is ideal, but minimum of 10mg villi are needed for diagnosis. Amniocentesis Indications When Chorionic Villus sampling is contraindicated. Patient comes late Time At 16 weeks of pregnancy when fetal cells are adequate in the tissue. Method Real time ultrasound before the procedure to assess fetal cardiac motion, gestational age and placental position. Give Rho (D) to unsensitised Rh negative mothers. DNA can be prepared from amniotic fluid directly or after culture. Method Real time ultrasound before the procedure to assess fetal cardiac motion, gestational age and placental position. Give Rho (D) to unsensitised Rh negative mothers. DNA can be prepared from amniotic fluid directly or after culture. Disadvantages Processing from culture leads to delay of testing as it may take a bout 2 to 3 weeks to get sufficient cells. A blood obtained AF sample has the risk of maternal cell contamination. At times the amount of DNA obtained may be inadequate to carry out, maternal contamination analysis.IAP National Guidelines 2006 197 Percutaneous Umblical Blood Sampling Indications To sort out unidentified mutations Method Blood sample is obtained by percutaneous umbilical vein sampling. It is done with ultrasound guidance using a 23- or 25- gauge needle in the umbilical cord vein, near the site of cord insertion in to the placenta. Purity of sample is assessed by red cell indicies, as determined by electronic cell counter, as well as Kleihaeur s test followed by molecular genetic maternal contamination tests (49) Advantages Procedure related fetal loss rates are only 1 % HPLC analysis can be carried out to provide prenatal diagnosis. Disadvantages High risk of maternal blood contamination Results are obtained late in pregnancy (around 18 weeks), hence abortion may become a difficult option. Various Methods for the Pre-natal Diagnosis Analysis of Globin Chain Synthesis 1. Diagnosis was as follows: Thalassemia diagnosed by ratio of /? chain synthesis. The results were interprete d as: Ratio of 0.02-0.07 (? 2-7% HbA), meant heterozygous or normal fetus Ratio