thalassemia : a dreadful disease turned to a chronic condition dimitris loukopoulos, md
DESCRIPTION
THALASSEMIA : A DREADFUL DISEASE TURNED TO A CHRONIC CONDITION Dimitris Loukopoulos, MD University of Athens, Greece. A lecture dedicated to the late Professor Antonio CAO (+2012). Thalassemia. - PowerPoint PPT PresentationTRANSCRIPT
THALASSEMIA : A DREADFUL DISEASE TURNED TO A CHRONIC CONDITION
Dimitris Loukopoulos, MDUniversity of Athens, Greece
A lecture dedicated to the late Professor Antonio CAO (+2012)
● 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
Thalassemia
● 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)
After the WW2; milesones in understanding the basic pathophysiology
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
1. TRANFUSION THERAPY; Improves quality of life
● “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)
● PREVENTION OF FEBRILE REACTIONS by Leucapheresis on collection of
blood, prior to or during transfusion
● MAJOR PROBLEM : Shortage of blood; voluntary donation,dedicated donors; but paid donor in some countries
Progress in Thalassemia Milestones in Clinical Management
Thalassemia; Milestones in Clinical Management
2. IRON CHELATION
● 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.
● 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
LiverFe = 3.7-6.8% d
wt
HeartFe = 0.6 –1.3% d
wt
ThyroidFe = 1.6 – 6.8% d
wt
PancreasFe = 1.4-3.9% d
wt
Adapted from Modell & Berdoukas, 1984
Tissue Iron Concentrations in Transfusion-dependent Thalassemia Patients
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 Total number of transfusions versus versus ferritin levels 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
Normal
Severe IronOverload
Myocardial T2* MR Appearances
LiverLiver
Lack of Correlation: Liver and Cardiac Iron
A. Ejection fraction by MRI versus cardiac T2* in thalassemia
(filled circles) and sickle cell disease (hollow squares) patientsB. 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”
Kaplan-Meier analysis of the survival of 257 consecutive patients with transfusion- dependent 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%).
Survival in Patients with Thalassemia Treated with Deferoxamine
Gabutti and Piga, Acta Hematol, 1996
Various Iron Chelators; established or forgotten
0
1000
2000
3000
4000
5000
6000
Initial Final
Ferr
itin
, m
g/L
11
21
1884
29
36
26162/151
71
N°N°
Hoffbrand AV. et al, Blood-2003
Olivieri et al.Olivieri et al.
Al Refaie et al.Al Refaie et al.
Olivieri et al.Olivieri et al.
Al Refaie et al.Al Refaie et al.
Mazza et al.Mazza et al.
Kersten et al.Kersten et al.
Hoffbrand et al.Hoffbrand et al.
Cohen et al.Cohen et al.
Ceci et al.Ceci et al.
Maggio et al.Maggio et al.
Effect of Deferiprone on Serum Ferritin Levels
Various Iron Chelators; established or forgotten
Deferasirox
Cappellini, M. D. et al. Blood 2006;107:3455-3462
Decrease of ferritin in iron-laden patients treated with varying dosages of :
. Deferasirox
in comparison to patients receiving
iv Desferioxamine
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
Age at death
“OLD” patients died young
“NEW” patients survive longer
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 !