Assoc Prof Dr Norsarwany Mohamad

USM
 Transfusion dependent (TDT)
 Non-transfusion dependent (NTDT)
 Ineffective erythropoiesis
 Chronic haemolytic anaemia
 Compensatory hemopoietic expansion
 Increased intestinal iron absorption
 Iron overload from repeated blood
transfusions
 Remains the primary cause of mortality in
TDT, less frequently in NTDT

Cardiac dysfunction
Arrhythmias
 Cardiac iron overload  Causes due to:
due to multiple blood  Pulmonary
transfusions hypertension
 Iron deposition in  thrombosis

ventricles, epicardium
 Free labile iron
interacts with calcium
channelsimpaired
myocardial contractility

TDT NTDT
 Myocardial iron overload-patient
asymptomatic for a long time
 Once myocardial dysfunction develops,
symptoms are related to degree of ventricular
impairment
 In more advanced stages, CF equivalent to
any severe heart failure
 ECG, ECG recording for 24 hours,
echocardiography, cardiac MRI (MRI T2*)
Grade of Iron deposition Cardiac T2* (ms)
Severe <10
Moderate 10-15
Mild 15-20
Normal >20
 Heart involvement due to pulmonary
hypertension & thrombosis

Chronic anaemia/hypoxia ↑ Cardiac Output

 ↑ Pulmonary hypertension

 HbF’s increased oxygen affinity, dilatation of

vessel due to elastic tissue injury↑CO
 Intramedullary & extramedullary
erythropoiesis↑CO
 ↑CO, ↑PVR, ↑ Pulmonary hypertensionR
sided heart failure & arrhythmia

 Endothelial injury,recurrent respiratory

infection, chest wall deformities ↑PVR
 Iron overload play added role
 Complication of disease progression

 In TDT as high as 66%, emphasizing impact

of long term hypoxia

 NTDT 5 times more likely to develop

Pulmonary hypertension than TDT
 Iron overload affect conduction
 AF is the most commonly encountered
arrhythmia

MRI T2*-a good tool for arrhythmia prediction

 One of major complications
 Liver damage is multifactorial
 Due to iron overload , HCV and HBV

Iron over load, HCV hepatic fibrosis

 R2*MRI quantify organ iron excess/LIC

 Iron enters hepatocytes & generate reactive-
oxygen speciesdamage to lipids, proteins,
DNA, subcellular organelles ( lysosomes,
mitochondria)
 Result in cellular dysfunction, apoptosis and
necrosis
 HCC, because of above  more common in
NTDT because of severe iron overload in
which some remains untreated
 Iron overload:
◦ -toxic free radicals
◦ -damages tumour suppressor genes
◦ -damages DNA repair genes
◦ -profibrogenicaccelerates liver cirrhosis

Iron overload also maybe associated with HCC in

the absence of cirrhosis
Hep C second key factor/synergy with iron overload
Hep B: no established role in hepatic carcinogenics
 Screening is necessary for close observation
 R2* MRI is favoured over liver biopsy
 Serum ferritin is still heavily used

NTDT: HCV infection, HBV infection, se ferritin >1000ng/ml, LIC

> 5mg Fe/g dry weight, or advanced cirrhosis
recommendation: biannual hepatic USG for HCC screening
 Hepatitis C is more common than Hepatitis B

 Malaysia seroprevalence rate 22.4% for Hep C

& 1.2% Hep B ( Jamal et al., 1998)

 Hep C 2.2-44%, Hep B 1.2-7.4% HIV 0-9% ( Al-

Sheyyab et al 2001)
 Investigation: regular blood testing for Hep
B,C
 Most of alive patients >30 yrs of age have
endocrine problem due to poor iron chelation
in their first decade of life (De Sanctis V et al, 2016)
 Anterior pituitary gland is particularly
sensitive, even a low amount of deposition
during childhood interfere with its function
in older age
 Hypogonadotropic Hypogonadism
 Growth Hormone Deficiency
 Hypothyroidism
 Diabetes
 Hypoparathyroidism
 Adrenal Insufficiency
 Endocrinopathies are more prevalent in TDT

 NTDT eventhough experience late puberty,

normal sexual development and usually
fertile
 Pregnancy in NTDT complicated by high risk
of abortions, thromboembolic events & IUGR
in more than half of cases
 Pathogenesis of growth failure is
multifactorial : chronic anemia, iron overload,
chelation toxicity, other endocrinopathies,
chronic liver disease, malnutrition
 GH stimulation test can detect growth
hormone deficiency
 Prevalence 8-75%
 In Malaysia, TDT 54.5% ( Hamidah et al, 2001)
 Truncal shortening was also seen in majority
of patients
 High prevalence of defective growth hormone
secretion, mainly due to iron overload
 Strongly correlated with anemia & iron
overload
 Not frequent in NTDT
 Regular thyroid function test
 20-30% of adult patients with β-thalassemia
worldwide
 Chern et al , 2001: prevalence 5.4% -19.5%;
impaired glucose tolerance in 7.9-86%.
 Strongly associated with iron overload, HCV
 Risk factors: poor compliance , late initiation
of chelation therapy, family predisposition
 Hemoglobin (Hb)A1c cannot be used because
of alterations in Hb balance

 Instead fructosamine-evaluation of glucose

metabolism over the last 2-3 weeks
 One of less frequent endocrinopathies in
thalassemia patients
 Related to iron overload & hormonal
suppression induced by increased bone
reabsorption consequent to chronic anemia
 Often signs absent, paresthesia, Chvostek &
Trousseau signs, QT prolongation
 Investigationss: hypocalcemia,
hyperphosphatemia, low parathyroid
hormone & 1,25 dihydroxy calcifediol
 Hypothalamic-pituitary-adrenal axis:
infrequent target of chronic iron toxicity
 High ACTH-direct damage to adrenal gland
 Lower ACTH suggest adrenal insufficiency
due to pituitary iron deposition
 ? Combined
 Symptoms may develop gradually
 Can present with acute life threatening crisis

 Investigations: ACTH & cortisol basal levels

 Chronic anaemia/hypoxiainduce activation
of fibroblasts & damage to tubular &
endothelial cells in the kidneys.
 Results in interstitial fibrosis & proximal
tubular cell dysfunction
 Anaemia ↓systemic vascular resistance,
trigger compensatory glomerular
hyperfiltration
 Lead to progressive renal damage
 Iron overloadtubular & glomerular
dysfunction
 Anaemia & Iron overload end-stage kidney
disease
 Osteopenia & osteoporosis↑ risk of fractures
 Both TDT & NTDT,can be more severe in NTDT
 Prevalence 39-67% ( Chan et al, 2001), 84%
unpublished data in Malaysia among TDT
 Direct iron toxicity on osteoblasts & endocrine
disease
 NTDT-chronic anaemia impacting bone
metabolism
-ineffective erythropoiesis marrow
expansion & thinning of cortical bone
 Iron deposition in bones impair maturation of
osteoid & mineralisation of bone
 Vit D-deficient state, hypercalciurialow
bone mass
 Deferoxamine block DNA synthesis, hence
osteoblastic & fibroplastic proliferation

 Gold standard is bone mineral density using

bone densitometry
 DVT, portal vein thrombosis, pulmonary
thromboembolism, cerebral thrombosis,
recurrent arterial thrombosis
 Ischaemic strokes-thromboembolic disease
linked to cardiac valvular lesion (elastic tissue
defects) or AF
 Silent thrombosissubclinical thrombi in
lung & brain
 Silent cerebral infarcts in TI in 27-60%, white
matter lesions
 Hypercoagulable status , especially NTDT,
splenectomised patients
 Up to 20% in NTDT compared to 1% in TDT
 Contributing factors:
advanced age, Hb<9g/dL,
Se Ferritin ≥1000ng/mL,
history of thrombotic event before,
elevated platelet > 500 X 109/L
& nucleated blood cell > 300 X 106/L
 Ineffective erythropoiesis expansion of
hematopoietic tissue
 -more common in NTDT, prevalence 20% in
compared with <1% inTDT
 -almost all body sites
 Paraspinal involvement spinal cord
compression
 High degree of ineffective
erythropoiesischronic peripheral
hemolysis cholelithiasis

 USG is the most helpful tool to monitor

 GB should always be inspected during
splenectomy
 GIT symptoms, hence some also undergo
removal GB
 Although rare, more common in NTDT,
especially poorly controlled disease
 Risk factors: advancing age, extremities skin
more thin , reduced tissue oxygenation,
elevated venous pressure & fragile
subcutaneous tissue
 Venous pressure elevated due to liver injury
or RHF
 Typically at medial & lateral malleoli
 Mostly seen during the second decade of life
 1. Clinical Complications and Their
Management. Alessia Marcon, Irene Motta, Ali
Taher & Maria Domenica Cappellini. Hematol
Oncol Clin N Am, 2017.

 2.Non- Transfusion-Dependent
Thalassaemia: An Update on Complications
and Management. Joseph Sleiman, Maria
Domenica Cappellini & Ali T.Taher. Int J. Mol.
Sci.2018
Thank You