Transcript Slide 1 - ABOUT - Iron Metabolism & Related Disorders

Epidemiology and
Disease Pathophysiology:
Other Anaemias
Ali T. Taher, MD
Professor
Department of Internal Medicine
American University of Beirut Medical Center
Beirut, Lebanon
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Rare Anemias
• Types
–
–
–
–
Diamond Blackfan anaemia
Fanconi’s anaemia
Sideroblastic anaemia
Congenital dyserythropoietic anaemia
• Epidemiology
– Incidence, prevalence, epidemiologic data
• Differentiation
• Diagnosis
– Clinical manifestations
– Complications
– Prognosis and management
• Factors contributing to iron overload in these populations
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Diamond Blackfan Anaemia
• Diamond Blackfan anaemia (DBA) is a blood
condition resulting from a failure within the bone
marrow
• The hallmark of this rare anaemia is the inability
to produce red blood cells
• The majority of DBA cases are diagnosed
between 4 months–2 years of age
• This extremely rare condition affects 600–700
individuals worldwide
DBA-UK, the UK Diamond Blackfan Anaemia Support Group. 2007. Available at:
http://www.diamondblackfan.org.uk
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Diamond Blackfan Anaemia
• Exact pathogenic mechanisms have not been
elucidated; however, DBA seems to be characterized by
a fault in 1 of the early steps of red blood cell
production.1
– 25% of affected children have gene defect called small
ribosomal protein 19 (RPS 19)2
• Condition is named for 2 doctors who first documented
cases in the 1930s1
– Dr. Louis Diamond (founder of the Haematology/Oncology
branch at Children's Hospital in Boston, USA)
– Dr. Kenneth D. Blackfan (Chief of the Paediatric Department).
1. DBA-UK, the UK Diamond Blackfan Anaemia Support Group. 2007. Available at:
http://www.diamondblackfan.org.uk
2. Draptchinskaia N et al. Nat Genet. 1999 Feb;21:169.
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Diamond Blackfan Anaemia
Physical Examination
30%–50% of patients with DBA have
associated congenital abnormalities
• Craniofacial abnormalities
• Neck anomalies
• Thumb abnormalities
• Genitourinary malformations
• Pre- and postnatal growth failure
Halperin DS; Freedman MH. Am J Pediatr Hematol Oncol. 1989;11:380.
Reprinted from Hoffbrand V, Pettit JE. Atlas of Clinical Hematology. 3rd ed. Mosby; 2000, with permission
from Elsevier.
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Diamond Blackfan Anaemia
• Children are reported to have typical
facies with tow-colored hair, snub nose,
wide set eyes, thick upper lip and an
intelligent expression, although facies with
different appearances have been reported
in other children1
• Physical anomalies are more common in males2
• Growth retardation occurs in 30% of affected patients2
– Often associated with other congenital abnormalities and the need
for ongoing therapy
1. Freedman MH. In: Hoffman R, et al (eds). Hematology: Basic Principles and Practice. Philadelphia,
PA: Churchill Livingstone, 2005. 2. Ball SE, et al. Br J Haematol. 1996;94:645.
Reprinted from Hoffbrand V, Pettit JE. Atlas of Clinical Hematology. 3rd ed. Mosby; 2000, with permission
from Elsevier.
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Diamond Blackfan Anaemia
Treatment
• The mainstays of therapy of DBA are corticosteroids and
blood transfusion1
– However, 1 study reported remissions in 22% of patients2
• Transfusion therapy is the mainstay of treatment for patients
in whom steroid therapy is ineffective or in whom
corticosteroid toxicity is prohibitive2
• Bone marrow transplantation has been employed with
success in steroid refractory patients2
• Prognosis is dependent on transfusion dependence and
subsequent complications of iron overload2
1. Freedman MH. In: Hoffman R, et al (eds). Hematology: Basic Principles and Practice. Philadelphia,
PA: Churchill Livingstone, 2005. 2. Willig TN, et al. Pediatr Res. 1999;46:553.
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Fanconi’s Anaemia
• Fanconi’s anaemia (FA) represents 1 of the inherited
anaemias that leads to bone marrow failure; these are
also known as aplastic anaemias1
• Recessive disorder2
– A child whose parents both carry a mutation in the same FA
gene has a 25% chance of inheriting the defective gene from
both parents, causing him or her to have FA
• At least 13 FA genes have been identified: A, B, C, D1
(BRCA2), D2, E, F, G, I, J, L, M, and N2
– Mutations in these genes account for almost all cases of
Fanconi’s anaemia
1. Alter, BP. In: Nathan DG, et al (eds). Hematology of Infancy and Childhood. W.B. Saunders;
Philadelphia 2003. 2. Fanconi Anemia Research Fund. About Fanconi anemia. 2007. Available at:
http://www.fanconi.org/aboutfa/AboutFAHead.htm
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Fanconi’s Anaemia
• Clinical manifestations
• Most children with FA are diagnosed between 6
to 9 years of age; the median age for boys is 6.5
years and for girls is 8 years
• Approximately 4% of cases are recognized
between birth and 1 year of age and 9%
diagnosed after 16 years of age
Alter, BP. In: Nathan DG, et al (eds). Hematology of Infancy and Childhood. W.B. Saunders; Philadelphia,
2003.
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Fanconi’s Anaemia
Common physical anomalies in
children with Fanconi’s Anaemia
Anomaly
Frequency %
Skin — hypopigmented or hyperpigmented areas; large freckles,
café-au-lait spots
55%
Short stature, delicate features
51%
Upper limbs — absent of hypoplastic thumb, supernumerary, bifid,
clinodactyly
43%
Gonads — hypogenitalia, undescended/absent testes, bicornuate uterus
30%
Head — microcephaly, bird face, flat forehead, Sprengel's deformity of
neck
26%
Eyes — micro-ophthalmia, ptosis, epicanthal folds, strabismus
23%
Kidney — abnormal, ectopic, or hypoplastic kidney, hydronephrosis
21%
Ears — hearing
9%
Developmental delay
11%
Alter BP, Young NS. In: Nathan DG, Orkin SH (eds). Hematology of Infancy and Childhood. W.B.
Saunders; Philadelphia, 1998.
Reprinted from Hoffbrand V, Pettit JE. Atlas of Clinical Hematology. 3rd ed. Mosby; 2000, with permission
from Elsevier.
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Fanconi’s Anaemia
Testing for FA
• The chromosome breakage test is regarded as the
definitive test for FA
• Any infant born with characteristic thumb and arm
abnormalities should receive testing for FA
• Regardless of whether other defects are present, all
patients developing aplastic anaemia at any age should
be tested for FA; this may be the only abnormality
present in many patients with FA
• Testing for FA prior to contemplating bone marrow
transplantation for aplastic anaemia is considered
essential
Fanconi Anemia Research Fund. About Fanconi anemia. 2007. Available at:
http://www.fanconi.org/aboutfa/AboutFAHead.htm
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Fanconi’s Anaemia
Carrier Frequency
• Worldwide, the total number of FA patients has
not been reported
• Researchers estimate that carrier frequency for
FA ranges between 1 per 600 and 1 per 100
• Case data on more than 3000 patients is
maintained at the International Fanconi Anemia
Registry at The Rockefeller University in New
York, NY
Fanconi Anemia Research Fund. About Fanconi anemia. 2007. Available at:
http://www.fanconi.org/aboutfa/AboutFAHead.htm
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Fanconi’s Anaemia
Treatment
• Androgens
– For > 40 years, have been used to treat patients with FA, with
~ 50% response rate
– Stimulate the production of red blood cells, and potentially platelets
– Treatment may be effective for many years, but eventually most patients
fail to respond
• Growth factors
– Acting to stimulate the production of white blood cells, G-CSF appears
to be effective in the treatment of patients with FA
• Bone marrow transplantation
– While this is the only potentially curative treatment for FA, substantial
risks are associated with this procedure; FA patients have high
sensitivity to chemotherapy and radiation.
Fanconi Anemia Research Fund. About Fanconi anemia. 2007. Available at:
http://www.fanconi.org/aboutfa/AboutFAHead.htm. Freedman MH. In: Hoffman R, et al (eds).
Hematology: Basic Principles and Practice. Philadelphia, PA; Churchill Livingstone; 2005.
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Fanconi’s Anaemia
Prognosis and Complications
• Approximately 25% of patients will develop a malignancy1
– Myelodysplastic syndromes (MDS)
– Acute myelocytic leukemia (AML)
– Squamous cell carcinoma of the head and neck
• The presence of clonal chromosomal changes may be a risk factor
for malignancy in patients with FA2
• Malignancy may be the first manifestation of FA, so the diagnosis of
FA should be considered in patients presenting with cancers at an
unusually young age3
1. Kutler DI, et al. Blood. 2003;101:1249.
2. Tonnies H. Blood. 2003;101:3872.
3. Alter BP, Young NS. In: Nathan DG, Orkin SH (eds). Hematology of Infancy and Childhood. WB
Saunders; Philadelphia, PA; 1998.
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Sideroblastic Anaemia
• With all sideroblastic anaemias, principal clinical
features are those of an indolent or progressive
anaemia
• Laboratory results, combined with patient history and
clinical findings, usually permit accurate diagnosis of
the various forms of sideroblastic anaemia
• In several hereditary forms of sideroblastic anaemia,
and in some patients with idiopathic acquired
sideroblastic anaemia, molecular defects can be
identified
Bottomley S. Clinical aspects, diagnosis, and treatment of the sideroblastic anemias. May 2007.
Available at: http://patients.uptodate.com
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Different Forms of Sideroblastic Anaemia
Hereditary
X-linked
X-linked with ataxia
Autosomal
Sporadic congenital
Associated with thiamine-responsive megaloblastic anaemia (Rogers syndrome)
Associated with mitochondrial cytopathy (Pearson syndrome)
Associated with mitochondrial myopathy and lactic acidosis
Acquired idiopathic
Pure sideroblastic anaemia
Refractory anaemia with ring sideroblasts (RARS)
Reversible
Alcoholism
Drugs (isoniazid, chloramphenicol)
Copper deficiency (zinc toxicity)
Hypothermia
Bottomley, SS. In: Greer JP, et al (eds). Wintrobe's Clinical Hematology. 11th Ed. Lippincott, Williams
and Wilkins; Philadelphia, PA. 2004.
Reprinted from Bottomley SS. Sideroblastic anemias. In: Greer JP, Foerster J, et al, eds. Wintrobe's
Clinical Hematology, 11th ed. Philadelphia, Penn: Lippincott, Williams and Wilkins; 2004:1011, with
permission from Lippincott, Williams and Wilkins.
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Sideroblastic Anaemia
• Anaemia generally remains stable over many years in hereditary
forms of the sideroblastic anaemias resulting from X-linked or
autosomal inheritance, or in association with sporadic congenital
defects
• In some individuals there is progression of anaemia over time,
which may be in part the result of the following factors:
– Prior intake of pyridoxine
– Lyonization, or progressive skewing of X inactivation patterns
associated with aging, in women with X-linked sideroblastic anaemia
– Iron overload toxicity
Bottomley, et al. Am J Hum Genet. 1998;63:A352. Bottomley S. Clinical aspects, diagnosis, and
treatment of the sideroblastic anemias. May 2007. Available at: http://patients.uptodate.com
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Sideroblastic Anaemia
Diagnosis
• Complete blood count
– Erythrocyte hypochromia and microcytosis
the degree of which roughly parallels the
severity of the anaemia
– In more anaemic patients, marked variation in
RBC size and shape and occasional
siderocytes are prominent
• Iron studies
– Increased serum transferrin saturation
– Reduced transferrin
– Increased serum ferritin levels
– Increase in marrow reticuloendothelial iron
Bottomley S. Clinical aspects, diagnosis, and treatment of the sideroblastic anemias. May 2007.
Available at: http://patients.uptodate.com
Reproduced with permission from: Bottomley S. Clinical aspects, diagnosis, and treatment of the
sideroblastic anemias. In: UpToDate, Rose BD, ed, UpToDate, Waltham, MA, 2007. Copyright 2007
UpToDate, Inc. For more information visit www.uptodate.com.
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Sideroblastic Anaemia
Diagnosis
Bone marrow examination
• Prominent at the late, nondividing erythroblast stage, ring
sideroblasts are considered the
diagnostic hallmark of
sideroblastic anaemia
• There is also a significant
increase of iron in bone marrow
macrophages, the result of
ineffective erythropoiesis
(intramedullary haemolysis)
Bottomley S. Clinical aspects, diagnosis, and treatment of the sideroblastic anaemias. May 2007.
Available at: http://patients.uptodate.com
Reproduced with permission from: Bottomley S. Clinical aspects, diagnosis, and treatment of the
sideroblastic anemias. In: UpToDate, Rose BD, ed, UpToDate, Waltham, MA, 2007. Copyright 2007
UpToDate, Inc. For more information visit www.uptodate.com.
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Sideroblastic Anaemia
Diagnosis
• Free erythrocyte protoporphyrin (FEP)
– Levels are reduced in X-linked sideroblastic anaemia, as defective
ALAS2 enzymatic activity results in reduced protoporphyrin
production
• Molecular studies
– X-linked form of hereditary sideroblastic anaemia
 Mutations common in erythroid-specific 5-aminolevulinate synthase
(ALAS2) gene
– X-linked sideroblastic anaemia with ataxia
 Mutations found in ABC7 transporter gene
– Thiamine-responsive megaloblastic anaemia syndrome
 Mutations in SLC19A2 gene
– Mitochondrial myopathy and sideroblastic anaemia disorder
 Mutations in PUS1 gene
Bottomley S. Clinical aspects, diagnosis, and treatment of the sideroblastic anemias.
Available at: http://patients.uptodate.com
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Sideroblastic Anaemia
Treatment
The treatment of sideroblastic anaemia varies according to its cause
•
Acquired sideroblastic anaemia should be treated by the removal of the
offending agent; anaemia may subsequently resolve
•
Underlying inflammatory conditions, such as rheumatoid arthritis, should be
treated
•
Vitamin B6 (pyridoxine) 50–200 mg/day may reverse anaemia
– Response to pyridoxine therapy has been documented in hereditary, acquired,
and idiopathic anaemias
– Pregnant women and nursing mothers may wish to limit pyridoxine to 100 mg/day,
later resuming a higher B6 dosage
•
Whole red blood cell transfusion may be required in extreme cases of
anaemia
Iron Disorders Institute. Sideroblastic anemia. Available at:
http://www.irondisorders.org/Disorders/Sideroblastic.asp
Accessed October 23, 2007.
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Sideroblastic Anaemia
Prognosis and Complications
• Iron overload accompanies sideroblastic anaemia
– When repeated whole red blood cell transfusion is needed to
treat anaemia, it exacerbates existing iron burden
– Patients will probably require chelation therapy
• In patients with acquired sideroblastic anaemia,
leukaemia (eg, acute granulocytic leukaemia) may
develop
– In the early preleukaemic stages of disease, myelodysplastic
syndromes are typically observed
Iron Disorders Institute. Sideroblastic anemia. Available at:
http://www.irondisorders.org/Disorders/Sideroblastic.asp
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Congenital Dyserythropoietic Anaemia
(CDA)
• The CDAs (types I, II, III, and IV) form a rare group of disorders that
result in anaemia caused by ineffective erythropoiesis and may
present in childhood1
• Loci of the genes for types I, II, and III have been identified but only
1 gene, associated with type I CDA, has thus far been identified.
This gene has been termed codanin-1, and may be involved in
nuclear envelope integrity2
• In one retrospective study of 98 subjects with CDA type II3
– Mean age at presentation was 5 years (range: 1 month–25 years),
although the mean age at the time of correct diagnosis was 16 years
(range: 4 months–65 years)3
– Anaemia and jaundice were present in 66% and 53% of subjects,
respectively
1. Wickramasinghe SN. Curr Opin Hematol. 2000;7:71.
2. Dgany O, et al. Am J Hum Genet. 2002;71:1467.
3. Iolascon A. Blood. 2001;98:1258.
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Congenital Dyserythropoietic Anaemia
In a second study of 48 patients with type II CDA
• Majority of patients had splenomegaly within the first 3 decades of
life
• Absence of splenomegaly in an adolescent should raise doubts
regarding the diagnosis
• Gallstones were found in 22 of 39 patients before the age of 40
years, appearing during childhood or adolescence a small
percentage of the time; cholecystectomy was performed at a median
age of 26 years
• In a patient with congenital haemolytic anaemia, inadequate
reticulocyte response suggests this diagnosis, while the presence of
binucleated normoblasts on the peripheral blood smear is noted as
being highly specific
Heimpel H, et al. Blood. 2003;102:4576.
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Congenital Dyserythropoietic Anaemia
• These disorders have pathognomonic
cytopathologic findings consisting of
nuclear abnormalities in bone marrow
erythroid precursors1
• Families with variants of CDA that do
not fall into the outlined types have
also been reported2
• An X-linked form is caused by a
mutation in the gene for GATA-1, a
transcription factor that contributes to
the regulation of erythropoiesis3
1. Marks PW and Mitus AJ. Am J Hematol. 1996;51:55.
2. Wickramasinghe SN, Wood WG. Br J Haematol. 2005;131:431.
3. Mehaffey M, et al. Blood. 2001;98:2681.
Graphic reprinted from Hoffbrand V, Pettit JE. Atlas of Clinical Hematology. 3rd ed. Mosby; 2000, with
permission from Elsevier.
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Congenital Dyserythropoietic Anaemia
Treatment
Therapy depends on the type, and may include
• Splenectomy (effective in type II CDA but not in type I)1
• Interferon α (effective in most patients with type I)2
• Transfusion in symptomatic patients2
1. Marks PW and Mitus AJ. Am J Hematol. 1996;51:55.
2. Wickramasinghe SN, Wood WG. Br J Haematol. 2005;131:431.
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Congenital Dyserythropoietic Anaemia
Prognosis and Complications
• Haemosiderosis, caused by multiple RBC
transfusions and increased absorption of
intestinal iron, is a problem for patients with all
types of CDA
• Iron chelation may be used in the treatment of
the iron overload state in these patients. Iron
therapy is almost always contraindicated in
these patients because of their predisposition to
develop iron overload.
Marks PW; Mitus AJ. SOAm J Hematol. 1996;51:55.
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Iron Overload in Rare Anaemias
• Iron overload
– Accompanies all transfusion-dependent anaemia
– Repeated whole red blood cell (RBC) transfusion will contribute
significantly to this existing iron burden and likely require chelation
therapy
• Haemosiderosis, caused by multiple RBC transfusions and
increased absorption of intestinal iron, is a problem for
patients with all types of transfusion-dependent anaemia
• Iron chelation may be used in the treatment of the iron
overload state in these patients
• Iron therapy is almost always contraindicated in these patients
because of their predisposition to develop iron overload
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Study 0108—Phase II Single-Arm Trial
-Thalassaemia and Other Anaemias
Study Design
• 1-year trial
– 85 patients with β-thalassaemia
– 99 patients with rare anaemia
• Patients treated with deferasirox for 1 year
• LIC assessed by liver biopsy or SQUID
• Ongoing safety and serum ferritin
monitoring
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Study 0108—Phase II Single-Arm Trial
-Thalassaemia and Other Anaemias
Disease
Number of Patients
-thalassaemia
1
Thalassaemia intermedia
1
Fanconi's anaemia
1
Chronic autoimmune haemolytic anaemia
1
Congenital dyserythropoietic anaemia
1
Pyruvate kinase deficiency
2
Myelofibrosis
3
Pure red cell aplasia
3
Aplastic anaemia
4
Congenital sideroblastic anaemia
5
Unknown/other
9
Diamond Blackfan anaemia
26
MDS
47
Thalassaemia
84
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Deferasirox is Effective Across a Range of
Transfusion-Dependent Anaemias
β-thalassaemia (n = 83)
Other anaemias, eg, DBA, MDS (n = 80)
5000
15
Mean ± SD Change in
Sserum Ferritin (μg/L)
Mean ± SD Change in LIC
(mg Fe/g dw)
LIC
10
5
0
-5
-10
-15
-20
Serum ferritin
4000
3000
2000
1000
0
-1000
-2000
-3000
-4000
5
10
20
30
Deferasirox Dose (mg/kg/d)
5
10
20
30
Deferasirox Dose (mg/kg/d)
Porter J, et al. Blood. 2004;104:abstr 3193.
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Summary*
Diamond
Blackfan
Fanconi’s
Anaemia
Sideroblastic
Anaemia
Congenital
Dyserythropoietic
Anaemia
Red cell aplasia
Inherited anaemia
leading to bone
marrow failure
Enzyme disorder
3 forms have been
described
Prevalence/
incidence
5–10 per 1 million
births
Unknown
?
< 1 per 100,000 births
Mutation
25% of affected
children have gene
defect called
RPS19
FA genes (A, B, C,
D1 (BRCA2), D2, E,
F, G, I, J, L, M, and
N
Carrier frequency
estimated between
1/600 and 1/100
Hereditary,
acquired due to
prolonged exposure
to toxins or
idiopathic
X-linked recessive
Codanin-1 associated with
CDA-I
2 months
3–12 years of age
Treatment
Bone marrow
transplantation
Bone marrow
transplantation
Androgens
Pyridoxine B6 blood
transfusion
Symptomatic and includes
blood transfusion
Complications
Transfusional
haemosiderosis
Transfusional
haemosiderosis
Myelodysplasia
Transfusional
haemosiderosis
Leukaemia
Myelodysplasia
Transfusional
haemosiderosis
Features
Pathophysiology
Age of presentation
5 years
*Sources as in previous slides.
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