Various complications of Thalassemia Major

1. COMPLICATIONS OF
THALASSEMIA MAJOR
DR GIRISH C BHATT
ASST PROF,PEDIATRICS
AIIMS, BHOPAL

2. Β-THALASSEMIA MAJOR
Point mutations in genes present on
chromosome 11
Severity depends on the β chain
deletions
Overproduction of α-globulin
( Normal ratio of of α to non-α is 1.00
±0.05)

3. 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

4. COMPLICATIONS
Endocrine and metabolic abnormalities
Cardiac complications
Pulmonary complications
Renal complications
Aplastic crisis
Chronic pains

5. ENDOCRINE AND METABOLIC
ABNORMALITIES
o In two studies comprising of 800 patients
with transfusion dependent thal,
o Hypogonadism – 40 to 55 percent
o Growth failure – 33 percent
o Diabetes – 6 to 13 percent
o Hypothyroidism – 10 to 11 percent
o Chelation therapy can arrest
the progression of these endocrine
abnormalities Br J Haematol 2006; 135:574.

6. ENDOCRINE AND METABOLIC
ABNORMALITIES
Growth 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.

7. 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.

9.  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.

10.  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.

11. 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.

12. CARDIAC COMPLICATIONS
Cardiac 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

13. Untreated children
 Cardiomegaly
 Non-specific electrocardiographic
changes (eg, bradycardia, repolarization
abnormalities), and
 Atrial as well as left ventricular dysfunction
End-stage cardiomyopathy
Transfused patient
 cardiac hemodiderosis is the most feared
complication

14. 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.

15.  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.

16. 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.

17. 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

18. 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.

19. 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 overload
 Pain management in thalassaemia-
inadequate.
 Pain appears to be under-treated
 with 25% of participants reporting no
relief with pain treatment

20. 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

21. MANIFESTATIONS OF RENAL
DYSFUNCTION IN TM

22. TUBULAR DYSFUNCTION
Study 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 pts
 Aminoaciduria-33.3%, 100%-Low molecular
weight proteinuria

23.  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

24. 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%

25. 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/creatinine
 Urinary protein creatinine ratio
 Urinalysis
Am J Blood Res 2014;4(1):1-6

26. 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.