Transcript Thalassemia Major

THALASSEMIA : A DREADFUL DISEASE TURNED
TO A CHRONIC CONDITION
A lecture dedicated to the late
Professor Antonio CAO (+2012)
Dimitris Loukopoulos, MD
University of Athens, Greece
Thalassemia
● Probably and “old” disease; sculls with “porotic
osteoporosis” found in Sicily and Sardinia; may denote
other conditions as well
● Von Jacsch,1889 and other scientists :
“anaemia infantum pseudoleucaemica”
could also be leishmaniasis, tuberculosis, other
● Thomas Cooley, 1925 : “A series of cases of
splenomegaly and peculiar bone changes”
● Whipple GH and Bradford WL, 1936.
“Mediterranean disease-Thalassemia
● Caminopetros J, 1936. A familial disease; decreased
osmotic fragility in both parents
After the WW2; milesones in understanding the basic pathophysiology
● The hemoglobin of patients with thalassemia more resistant to alkali
denaturation; same as fetal hemoglobin.
Vecchio (Italy, 1946)
● Micro-drepanocytic disease; the scientific importance of compound
heterozygozity.
Silvestroni+Bianco (Italy, 1944)
● Hb A2 is elevated in heterozygotes
(Kunkel+Wallenius, US,1955)
● HbH disease
(Rigas, US) / Gouttas et al, Greece, 1955)
● Concept of a- and β-thalassemia put forward by Itano, Pauling,
Ingram,Stretton and others (1950-1960)
1960-1970
Thalassemia is not confined in the Mediterranean world;
displays a striking heterogeneity.
is a typical example of ineffective erythropoiesis
results from chain imbalance
ingenuous studies of compound heterozygotes define the
β0, β+, β++ types of thalassemia
(Nathan+Gunn, Fessas, Weatherall+Clegg)
Thalassemia Major; Bone Changes
Thalassemia Major; a protuberant spleen
Thalassemia Major;
the beneficial effect of transfusions
Thalassemia Major;
the beneficial effect of transfusions :
a clear increase in survival
Modell; early years
Progress in Thalassemia
Milestones in Clinical Management
1. TRANFUSION THERAPY; Improves quality of life
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“Hypertransfusion” in an attempt to suppress ineffective erythropoiesis
Neocytes to avoid frequent transfusions
Improved genotyping to avoid allo-immunization
Splenectomy to reduce size of “splenic pool” and hemolysis
Consider : Age, preparation with appropriate vaccines,
chronic penicillin administration etc.
SAFETY : improved control of infections (HIV, HBV, HCV and other
infectious agents)
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PREVENTION OF FEBRILE REACTIONS by Leucapheresis on collection of
blood, prior to or during transfusion
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MAJOR PROBLEM : Shortage of blood; voluntary donation,dedicated
donors; but paid donor in some countries
Thalassemia; Milestones in Clinical Management
2. IRON CHELATION
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Iron accumulation removes all benefits of transfusions because it
causes severe organ damage through production of abundant free
radicals which readily oxidize and destroy various cellular
components.
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Iron accumulates
in the liver (> liver failure)
in the endocrine glands (hypogonadism, hypoparathyroidism,
diabetes, other hormonal deficiencies)
in the heart (heart failure; the major cause of death)
in other organs
Tissue Iron Concentrations in Transfusiondependent Thalassemia Patients
Thyroid
Fe = 1.6 – 6.8% d wt
Heart
Fe = 0.6 –1.3% d wt
Liver
Fe = 3.7-6.8% d wt
Pancreas
Fe = 1.4-3.9% d
wt
Adapted from Modell & Berdoukas, 1984
Thalassemia; Milestones in Clinical Management
3. MEASUREMENT OF THE IRON LOAD
Iron load is reflected in the levels of ferritin in the serum
(exceptions occur, especially in thalassemia intermedia).
Excess iron can also be measured
directly by biochemical methods in liver (and other tissue) specimens, and
indirectly in the liver and other organs including the heart by various
non-invasive techniques, such as
the SQUID , Superconducting Quantum interference device
MRI
, Magnetic Resonance Imaging and
(Τ2 and Τ2*) Modified/Ultrarapid Magnetic Resonance Imaging
Additional important information obtained by measuring the
non-transferrin-bound plasma iron and/or Labile Iron Pool (NTBI/LPI)
Iron accumulation increases in parallel with number of transfusions
Thalassemia Major; transfusional hemosiderosis.
The noxious effect of transfusions.
Ferritin levels and liver iron content
increase with number of transfusions
Total number of transfusions
versus
ferritin levels
Total number of transfusions
versus
liver iron content
Shortened survival in relation to iron overload;
High ferritin levels predict early death
Ladis et al, 2005
Correlation of LIC with Liver T2*
Voskaridou et al, 2005
Myocardial T2* MR Appearances
Normal
Severe Iron
Overload
Lack of Correlation: Liver and Cardiac Iron
Liver
Liver
A. Ejection fraction by MRI versus cardiac T2* in thalassemia
(filled circles) and sickle cell disease (hollow squares) patients
B. Cardiac T2* as a function of transfusion duration. Sickle cell
disease patients were predominantly transfused for less than 13
years (13/17),
Wood et al. Blood, 2003:
Various Iron Chelators; established or forgotten
Various types of “infusors”
The “pumps”
Survival in Patients with Thalassemia Treated
with Deferoxamine
Kaplan-Meier analysis of the survival of 257 consecutive patients with transfusiondependent thalassemia, according to chelation patterns.
Well chelated. DFO infusions>250/year; n=149; age 17.8+6.5 years; deaths 3 (2%)
Poorly chelated.DFO infusions<250/year; n=108; age 19.7+5.9 years; deaths,58 (54%).
Gabutti and Piga, Acta Hematol, 1996
Various Iron Chelators; established or forgotten
Effect of Deferiprone on Serum Ferritin Levels
6000
5000
N°
21
11
Ferritin, mg/L
18
4000
84
Olivieri et al.
29
Al Refaie et al.
36
3000
2000
Olivieri et al.
26
162/151
Al Refaie et al.
71
Mazza et al.
Kersten et al.
Hoffbrand et al.
1000
Cohen et al.
Ceci et al.
0
Maggio et al.
Initial
Final
Hoffbrand AV. et al, Blood-2003
Various Iron Chelators; established or forgotten
Deferasirox
Decrease of ferritin in iron-laden patients treated with
varying dosages of :
.
Deferasirox
in comparison to patients
receiving
iv Desferioxamine
Cappellini, M. D. et al. Blood 2006;107:3455-3462
Effects of combined therapy (desferioxamine/deferiprone) in heavily
iron laden patients after 12 months of continuous therapy;
Note gradual decrease of ferritin levels (left) and clear increase of
left ventricular ejection fraction (right)
Effects of combined therapy (desferioxamine/deferiprone) in
heavily iron laden patients after 12 months of continuous therapy;
Note gradual increase of Heart (left) and liver (right) T2* values
Thalassemia; Milestones in Clinical Management
4. ADDITIONAL MEASURES
Correction of endocrine deficiencies;
Normal Growth. Improvement of gonadal function.
Pregnancy is now possible.
Re-mineralization of bones; biphosphonates.
Bone Marrow Transplantation. May offer cure to patients having a
HLA-compatible sibling
The future
Re-induction of γ-chain (HbF) synthesis by
selective recruitment of F-erythroid progenitors,
de-repressing γ gene repressors or
inducing the gene promoters and enhancers across the DNA sequence
Gene therapy. So far one successful case. Others on the way.
look forward to the next meeting !!!
Improvement of survival depicted according
to year of birth in the UK based patients
Patients born
after
“NEW” patients
survive longer
“OLD” patients
died young
Age at death
Modell et al, 2010
Thalassemia;
A dreadful Disease turned to a Chronic Condition !
CONTRIBUTORY FACTORS
.
The Patients. Through their steady insistence that something
be done, their patience and their collaboration in several clinical
trials and tests
The medical and paramedical-nursing staff. Through their steady
dedication to treating a chronic condition, with stubborn observance
of the rules of good medical practice; through their kind approach
to the patients and their endless patience.
The success of the prevention programs wherever these were
applied. Unless prevention were effective, the continuous addition
of new patients would never allow the allocation of the available
resources to the optimization of the care of the patients actually
surviving.
Professor
Antonio Cao
A leader in thalassemia research,
A productive scientist,
An excellent clinician,
An efficient organizer, and
A good friend !