COMPLICATIONS OF THALASSEMIA MAJOR

DR GIRISH C BHATTASST

PROF,PEDIATRICSAIIMS, BHOPAL

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)

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

COMPLICATIONSEndocrine and metabolic

abnormalities Cardiac complications Pulmonary complications Renal complicationsAplastic crisisChronic pains

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.

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.

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.

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.

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.

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.

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

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

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.

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.

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.

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

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.

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

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

MANIFESTATIONS OF RENAL DYSFUNCTION IN TM

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

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

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%

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

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.