complications of thalassemia major
TRANSCRIPT
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COMPLICATIONS OF THALASSEMIA MAJOR
DR GIRISH C BHATTASST
PROF,PEDIATRICSAIIMS, BHOPAL
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Β-THALASSEMIA MAJORPoint mutations in genes present on
chromosome 11Severity depends on the β chain
deletionsOverproduction of α-globulin ( Normal ratio of of α to non-α is 1.00
±0.05)
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WHY COMPLICATIONS OCCUR?Direct effects of thalassemia major:
Deleterious effects of profound anemia
Intramedullary and extramedullary expansion
Rapid Iron turnover
Tissue deposition of excess iron
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COMPLICATIONSEndocrine and metabolic
abnormalities Cardiac complications Pulmonary complications Renal complicationsAplastic crisisChronic pains
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ENDOCRINE AND METABOLIC ABNORMALITIES
o In two studies comprising of 800 patients with transfusion dependent thal,o Hypogonadism – 40 to 55 percento Growth failure – 33 percento Diabetes – 6 to 13 percento Hypothyroidism – 10 to 11 percent
o Chelation therapy can arrest the progression of these endocrine abnormalities
Br J Haematol 2006; 135:574.
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ENDOCRINE AND METABOLIC
ABNORMALITIESGrowth retardation-
Diversion of caloric resources for erythropoiesis
Anemia hypertransfusion frequently restores growth rates to normal
However, the adolescent growth spurt is often delayed, even in children who are hypertransfused, unless intensive iron chelation therapy is instituted early in life.
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DELAYED PUBERTY/HYPOGONADISM
Girls:Menarche is delayed, Breast development is poor, patients are frequently
oligomenorrheic or amenorrheic, even if menarche occurs.
Boys: no or sparse facial and body hair tend to have decreased libido, even
if sperm production does occur.
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Approximately 25 percent of children and adults, regardless of their thalassemia syndrome, had short stature.
Patients with beta thalassemia major had higher rates of multiple endocrinopathies, worse hyperglycemia, subclinical hypoparathyroidism, and hypercalciuria.
All were found to correlate with higher ferritin concentrations.
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Hypogonadism, the most frequent endocrinopathy (14.4% girls vs 25.5% males<20 years), was frequently undertreated (25% females/56% males).
Among hypogonadal girls, menarche was delayed to 17 years.
Low levels of vitamin D were common, especially among adolescents
Br J Haematol 2009; 146:546.
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DIABETES MELLITUS(6-14%) Abnormal carbohydrate metabolism Usually develops during the 2nd decade of life,
even though baseline blood sugar levels are frequently normal
The early lesion appears to be related more to insulin resistance
Defective insulin production occurs only in late phase of hemosiderosis
More effective iron chelation appears to improve glucose intolerance
Br J Haematol 2006; 134:438.
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CARDIAC COMPLICATIONSCardiac malfunction, including heart
failure and fatal arrhythmias, are frequent causes of death
Cardiac dilatation sec to anaemia is universal
Approximately 70-80% of thalassaemic patients die from this cause
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Untreated childrenCardiomegaly Non-specific electrocardiographic changes (eg, bradycardia, repolarization
abnormalities), andAtrial as well as left ventricular
dysfunction
End-stage cardiomyopathyTransfused patient
cardiac hemodiderosis is the most feared complication
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Delayed institution of iron chelation therapy:Sterile pericarditis, Arrhythmias (both supraventricular
and ventricular), poor exercise performance
Am Heart J 2001; 141:428.
Am J Hematol 2012; 87:1079.
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Fatal ventricular arrhythmias are a frequent cause of death.
Cardiovascular MRI- "gold standard" for measurement of all left and right ventricular indices
Myocardial iron deposition can be quantified reproducibly with myocardial T2.
Am Heart J 2001; 141:428.
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PULMONARY COMPLICATIONS Abnormalities of pulmonary function
Restrictive and small airway obstructive defects Hyperinflation Decreased maximal oxygen uptake Abnormal anaerobic thresholds
These abnormalities are not corrected by transfusion do not correlate with somatic iron burden, blood
counts, or hemolysis
Haematol 2011;155:102.
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APLASTIC CRISIS Parvovirus B19 infects erythroid precursor
stem cells In normal children- mild transient
erythrocytopenia because the impairment of marrow function is transitory and normal 120-day survival of normal red blood cells
In TM- extremely shortened red cell survival, as the effect is far more profound
In: Hematology: Basic Principles and Practice, 3rd ed
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CHRONIC PAINS A multicenter prospective study of 258
thalassemia patients (mean age 29; range 12 to 71) receiving care at 12 Thalassemia Clinical Research Network sites 81 percent reported having pain for ≥1 Yr 31 percent reported pain for ≥5 Yrs
31% of pediatric patients had pain as compared to 72% of patients aged 18 years and older (P < 0·001)Br J Haematol 2013; 160:680.
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Regression analysis- significant correlation of increased age with increased pain, irrespective of the type of thalassemia, transfusion status, gender, bone density, chelator type, or degree of iron overloadPain management in thalassaemia-
inadequate. Pain appears to be under-treatedwith 25% of participants reporting no
relief with pain treatment
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RENAL COMPLICATIONS Historically, renal diseases have not been a major
issue Because survival was limited by severe cardiac iron
loading Simply patients did not live long enough to develop
conditions linked to kidney dysfunction Mechanism of renal disease in thalassemia major:
Include shortened red cell life span Rapid iron turnover, and tissue deposition of excess iron The uses of specific iron chelators are not without
harm to the kidney
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MANIFESTATIONS OF RENAL DYSFUNCTION IN TM
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TUBULAR DYSFUNCTIONStudy from Iran(n=166) TM children
Hypercalciuria (12.9%), proteinuria (8.6%), phosphaturia (9.2%), magnesiumuria (8.6%) and hyperuricosuria (38%)
Another study-Thailand, n=104 TM ptsAminoaciduria-33.3%, 100%-Low molecular
weight proteinuria
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Two studies in thalassemia -increased urinary excretion of N-acetyl-D-glucosaminidase (NAG) beta-2 microglobulin.
Another study from thailand (n=29 children who underwent HSCT) showed that the secretion of such markers was significantly reduced after HSCT
Pediatr Nephrol 2009; 24: 183-187
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GLOMERULAR DYSFUNCTION Mean values of creatinine clearance and GFR are
higher than normal in patients with β-TM Hamed et al.(n=69;34 on DFO, 35-No chelation ,
children with TM)
Ital J Pediatr 2010; 36: 39
With chelation therapy
Without chelation therapy
GFR (< 90 mL/minute/1.73 m2
58.8% 45.7%
Proteinuria 47.1% 45.7%
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ACUTE KIDNEY INJURY AKI requiring dialysis have been
reported due to overdose of chelators. Several cases of AKI have also been
reported in post-marketing surveillance of the oral chelator deferasirox
Monitoring:3 monthly Urea/creatinineUrinary protein creatinine ratioUrinalysis Am J Blood Res 2014;4(1):1-
6
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CONCLUSION Associated with complications Optimal therapy with transfusion and
chelation therapy reduces these complication rates
Hypogonadism/chronic pains remains undertreated in these pts
High risk group for glomerulopathy/tubulopathy should be evaluated appropriately.
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