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Slide 1 of 50
Clinical Case: Hereditary Haemochromatosis
Pierre Brissot, MDProfessor of Medicine
Liver Disease DepartmentUniversity Hospital Pontchaillou
Rennes, France
Slide 2 of 50
Patient PresentationMale, Age 55 Years
Background
• Hypertension(treated)
• Increased weight(BMI 26.6)
• High cholesterol (untreated)
• Hyperglycaemia (1.25 g/L)
• No alcoholism
• No tobacco
History
• Fatigue (1 year)
• Arthralgias of 2nd and 3rd metacarpo-phalangeal joints(8 months)
Lab Values• Ferritin 2500 µg/L• Transferrin saturation
95%
Slide 3 of 50
Diagnosis?
Polymetabolic Syndrome
Hypertension
Increased weight
High cholesterol
Hyperglycaemia
Could explain• Fatigue• Hyperferritinaemia
Could not explain• This type of arthropathy• Such high ferritin level• Elevated transferrin
saturation
Slide 4 of 50
Diagnosis?
Polymetabolic Syndrome + Hereditary Haemochromatosis
Could explain1,2
• This type of arthropathy• Elevated transferrin
saturation• High ferritin level
1. Brissot P, et al. Blood Rev. 2008;22:195-210. 2. Aguilar-Martinez P, et al. Am J Gastroenterol. 2005;100:1185-1194.
Slide 7 of 50
Diagnosis?
Polymetabolic Syndrome + Hereditary Haemochromatosis
HFE is Key Test
C282Y/C282Y = type 1 haemochromatosis
Brissot P, et al. Blood Rev. 2008;22:195-210.
Slide 8 of 50
Search for Visceral ComplicationsDegree of Body Iron Excess: Beware Ferritin Interpretation
Abbreviations: ALT, alanine aminotransaminase; AST, aspartate aminotransaminase; DW, dry weight;ECG, electrocardiogram; LIC, liver iron concentration.
LIC (MRI): 9 mg/g dw (N <2mg/g dw)
ALT/AST: normalUltrasound: hyperechoicLiver biopsy?
Liver
Test/FindingOrgan
Slide 10 of 50
Search for Visceral ComplicationsDegree of Body Iron Excess: Beware Ferritin Interpretation
ECG, ultrasound: normalHeart
Testosterone: normalGonads
X-ray: arthropathyBone mineral density: normal
Joints/bones
HyperglycaemiaPancreas
Abbreviations: ALT, alanine aminotransaminase; AST, aspartate aminotransaminase; DW, dry weight; ECG, electrocardiogram; LIC, liver iron concentration.
LIC (MRI): 9 mg/g dw (N <2mg/g dw)
ALT/AST: normalUltrasound: hyperechoicLiver biopsy?
Liver
Test/FindingOrgan
Slide 11 of 50
Haemochromatosis Grade
Brissot P, et al. Hematology. 2006;1:36-41.
Type 1 haemochromatosis, grade 3
aT Sat, transferrin saturation >45%; bFerritin, >300 µg/L in men and >200 µg/L in women; csymptoms such as fatigue, impotence, arthropathies; dconditions of vital risk, such as cirrhosis or cardiomyopathy.
0
2
3
1
4
Ferritinb Ferritinb
Quality of lifec
T Sata T Sata T Sata
Ferritinb
Quality of lifec
Lifed
T Sata
Slide 12 of 50
ferritin overexpression as compared with liver iron concentration
Accounting for:
Contributing to: hyperglycaemia
Final Diagnosis
Polymetabolic Syndrome
+
Type 1 Haemochromatosis, Grade 3
Slide 13 of 50
Beware ferritinaemia interpretation!
Treatment
Metabolic syndromeDiet
Exercise
Haemochromatosis Phlebotomies (7 mL/kg/wk)
50 µg/L: not an appropriate goal in this case
Slide 15 of 50
Sister, age 52 yT Sat: 30%Ferritin: 40 µg/Lno C282Y
Patient
Family Study
Brother, age 48 yT Sat: 37%Ferritin: 95 µg/LC282Y heterozygote
Son, age 28 yT Sat: 75% Ferritin: 450 µg/LC282Y homozygote
Spouse, age 53 yT Sat: 29% Ferritin: 50 µg/LC282Y heterozygote
Daughter, age 31 yT Sat: 32%Ferritin: 45 µg/LC282Y heterozygote
Slide 16 of 50
Conclusions
• Increased plasma transferrin saturation is a key diagnostic parameter
• Beware confounding associated condition, which can increase ferritinaemia (eg, polymetabolic syndrome)
• In presence of confounding associated conditions– Quantify hepatic iron load by MRI– Carefully monitor Hb levels when treating iron overload
• It is essential to perform a family study
In type 1 haemochromatosis
Slide 17 of 50
Clinical Case: Myelodysplastic Syndromes (MDS)
Aristoteles A. N. Giagounidis, MDMedizinische Klinik IISt. Johannes HospitalDuisburg, Germany
Slide 18 of 50
The Diagnostic Challenge of MDS
Megaloblasticanaemia
Myelo-dysplasticsyndromes
AA
CDAImmune
cytopaenias(AIHA/ITP)
TTPHUS
Anaemia ofchronic disease
HypersplenismAML
Bone marrow infiltration(NHL, solid tumors)
AIDS
Nutritive and pharmacologic
toxins
Abbreviations: AA, aplastic anaemia; AIDS, acquired immune deficiency syndrome; AIHA, autoimmune haemolytic anaemia; AML, acute myelocytic leukaemia; CDA, congenital dyserythropoietic anaemia; HUS, haemolytic uremic syndrome; ITP, immune thrombocytopaenic purpura; PNH, paroxysmal nocturnal haemoglobinuria; TTP, thrombotic thrombocytopaenic purpura. Graphic courtesy of Dr. A.A.N. Giagounidis.
Slide 19 of 50
Cumulative Survival of 1806 Untreated Patients with Primary MDS
(Düsseldorf MDS Registry, 1970–2003)
YearsCourtesy of Dr. U. Germing.
20
0.6
0.4
0.2
0.0
0.8
1.0
4 6 8 10 12 14 16 18 20
Cu
mu
lati
ve S
urv
ival
Slide 20 of 50
Subtype Blood Marrow
Refractory cytopaenia
Anaemia, thrombocytopaenia, neutropaenia
Anaemia
Blasts ≤1%
Dyserythropoiesis only
Blasts <5%
Ring sideroblasts <15%
Refractory anaemia with ring sideroblasts
Anaemia
Blasts ≤1%
Dyserythropoiesis only
Blasts <5%
Ring sideroblasts >15%
Refractory cytopaenia with multilineage dysplasia with or without ring sideroblasts
Cytopaenia
Blasts ≤1%
No Auer rods
Monocytes <1000/mL
Dyserythropoiesis in >10% of othercell lines
Blasts <5%
No Auer rods
MDS with isolated del(5q) Anaemia
Platelets, normal orelevated
Blasts <5%
No Auer rods
Megakaryocytes with hypolobulatednuclei
MDS, unclassifiable Cytopaenia Dysplasia of noneyrthroid line
2008 WHO Proposals for the Classification of MDS
Swerdlow SH, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Geneva, Switzerland: World Health Organization; 2008. Table courtesy of Dr. A.A.N. Giagounidis.
Abbreviation: WHO, World Health Organization.
Slide 21 of 50
Subtype Blood Marrow
Refractory anaemia with excess blasts I
CytopaeniaBlasts <5% No Auer rodsMonocytes <2000/mL
Unilineage or multilineageDysplasiaBlasts 5%–9% No Auer rods
Refractory anaemia with excess blasts II
CytopaeniaBlasts <19%Auer rods possible
Unilineage or multilineageDysplasiaBlasts 10%–19% Auer rods possible
2008 WHO Proposals for the Classification of MDS
Swerdlow SH, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Geneva, Switzerland: World Health Organization; 2008.
Courtesy of Dr. A.A.N. Giagounidis.
Slide 22 of 50
Patient Case Presentation
Symptoms
• Exertional dyspnoea
• Fatigue
• No changes in bowel habits
• No melaena
• No overt blood loss or haematuria
• No hepatosplenomegaly or lymph node enlargement
Laboratory values
• Haemoglobin 8.9 g/dL
• Platelets 278,000 cells/µL (normal range: 150,000–350,000/µL)
• White blood cell count 4300 cells/µL (normal range: 4000–10,000 cells/µL)
• Absolute neutrophil count 2600 cells/µL (normal range: 1800–7000 cells/µL)
• Mean corpuscular volume 92 fL (normal range: 80–95 fL)
77-year-old woman, admitted to hospital in January 2007
Slide 23 of 50
Patient History
• Interventions had been unsuccessful in correcting anaemia
– Administration of iron, folic acid, vitamin B12 and B6
– Transfusions with 2 units of packed red blood cells every 4 weeks during the last 4 months
• Imaging studies had not revealed any pathology– Gastroscopy
– Colonoscopy
– CT scans of thorax and abdomen
Abbreviation: CT, computed tomography.
Slide 24 of 50
Anaemia Testing
• Ferritin 1140 ng/mL (normal range: 15–350 ng/mL)
• Transferrin 172 mg/dL (normal range: 200–400 mg/dL)
• Transferrin saturation 87%
• Vitamin B12 and folic acid within normal range
• Lactate dehydrogenase 225 U/L (normal range: <240 U/L)
• Erythropoietin 149 U/L
• Direct and indirect bilirubin not elevated
• Coombs test negative
• Haptoglobin within normal limits
Slide 25 of 50
Bone Marrow Aspirate and Core Biopsy
• Trilineage dysplastic changes
• Blast count 3%
• Cytogenetics 46,XX,del(20q)
Diagnosis: refractory cytopaenia with multilineage dysplasia
Slide 26 of 50
Treatment Options in Myelodysplastic Syndromes
Low riskIntermediate 1
Intermediate 2High risk
Risk stratification according to IPSSa
Abbreviation: IPSS, International Prognostic Scoring System.
a Greenberg P, et al. Blood. 1997;89:2079-2088.
Slide 27 of 50
Decision-Making Process
• Low-risk myelodysplastic syndrome
• Relatively long life expectancy
• Good quality of life
• Isolated anaemia with transfusion dependency
What is the best treatment for this patient?
Slide 28 of 50
EPO ± G-CSF Lenalidomide
Therapeutic Options for Myelodysplastic Syndromes
ATG/CSA Ironchelation
Transfusions
Low riskIntermediate 1
Risk stratification according to IPSS
Abbreviations: ATG, antithymocyte globulin; CSA, cyclosporin A; EPO, erythropoietin; G-CSF, granulocyte colony-stimulating factor.
Slide 29 of 50
• Trial with erythropoietin resulted in 12 months of transfusion independence
• Relapse occurred in January 2008
• Regular blood transfusions (2 units/4 weeks)
When to start iron chelation?
Therapy
Slide 30 of 50
• Ferritin 1630 ng/mL
• Transferrin saturation 89%
• Substantial iron overload in liver MRI
• Low cardiac iron deposits– Cardiac T2* MRI 28 ms
Decision: commencement of iron chelation to prevent damage to liver and heart (ie, to
maintain good quality of life)
Iron Chelation Diagnostics
Slide 32 of 50
Conclusions
• MDS are heterogeneous and have a broad differential diagnosis– Morphologic expertise needed for correct classification
• Low-risk MDS have a relatively favourable overall survival– Supportive care is a sensible treatment option
• Iron overload is a continuous threat to patients with MDS who are transfusion-dependent
• Evaluating iron overload includes laboratory testing of ferritin, transferrin, and transferrin saturation levels– To assess organ-specific iron deposits, MRI techniques
are valuable
Slide 33 of 50
Clinical Case:Thalassaemia Major
Ali T. Taher, MDProfessor
Department of Internal MedicineAmerican University of Beirut
Medical CenterBeirut, Lebanon
Slide 34 of 50
Patient Presentation
• 12-year-old boy of Mediterranean origin
• Previously diagnosed with– β-thalassaemia major at age 6 months
– Hepatitis C virus infection at age 4 years
• Splenectomized at the age of 6 years
• Received ~45 packed red blood cell transfusions in his childhood
• Never received iron chelation therapy
• Presenting for assessment of iron overload
Slide 35 of 50
Relevant Laboratory Value
Serum ferritin level = 7200 ng/mL
How reliable is serum ferritin for the assessment of iron overload in this case?
Slide 37 of 50
Measuring and InterpretingSerum Ferritin1-3
Advantages Disadvantages
• Easy to evaluate
• Inexpensive
• Serial measures to monitor chelation therapy
• Positively correlates with morbidity and mortality
• Allows longitudinal follow-up of patients
• Indirectly measures iron burden
• Fluctuates in response to inflammation, abnormal liver function, ascorbate deficiencies
• Individual measures may not accurately reflect iron levels and response to chelation therapy
Serial measurement of serum ferritin is a simple, reliable, indirect measure of total body iron
1. Taher A, et al. Semin Hematol. 2007;44(suppl 3):S2-S6. 2. TIF. Guidelines for the clinical management of thalassaemia. 2nd ed. Nicosia, Cyprus; 2008. 3. Brittenham GM, et al. Blood. 2003;101:15-19.
Slide 38 of 50
Serum Ferritin Underestimates Iron Burden in Thalassaemia Intermedia
Patients
1000
2000
3000
4000
5000
6000
7000
8000
9000
10,000
0 5 10 15 20 25 30 35 40 45 50
Liver Iron Concentration (LIC) (mg Fe/g dry weight)
Ser
um
Fer
riti
n L
evel
(n
g/m
L) Thalassaemia intermedia (TI)
Thalassaemia major (TM)
Linear (TI)
Linear (TM)
With permission from Taher A, et al. Haematologica. 2008;93:1584-1586.
0
Serum ferritin correlates with LIC in patients with TM and TI. However, for the same LIC, patients with TI had lower ferritin levels than corresponding patients with TM.
Slide 39 of 50
Case Continues—Liver Biopsy
• A liver biopsy was recommended– To determine the liver iron concentration
– To evaluate histopathologic changes secondaryto hepatitis C infection
• Patient’s mother refused due to concerns about the associated risks of invasive intervention
Slide 40 of 50
Measuring LIC by Liver Biopsy1,2
Advantages Disadvantages
• Directly measures LIC (quantitative, specific, sensitive)
• Validated reference standard
• Measures nonheme storage iron
• Evaluates liver histology/pathology
• Positively correlates with morbidity and mortality
• Invasive, painful, and potentially serious complications (eg, bleeding)
• Sampling error risk, especially in patients with cirrhosis
• Inadequate standardization between laboratories
• Difficult to follow up
1. Taher A, et al. Semin Hematol. 2007;44(suppl 3):S2-S6. 2. TIF. Guidelines for the clinical management of thalassaemia. 2nd ed. Nicosia, Cyprus; 2008.
Slide 41 of 50
Case Continues—Assessing Liver Iron
Patient underwent R2 MRI of the liver = 16 mg/g dry weight
How well does liver R2 MRI correlate with liver biopsy?
Slide 42 of 50
Correlation Between R2 MRI and Liver Biopsy
With permission from St. Pierre TG, et al. Blood. 2005;105:855-861.
30
20
40
50
0.5 1.0 1.5 2.0
Biopsy Iron Concentration (mg/g-1 dry weight)
0
100
200
50
150
250
300
0 10 20 30 40 50
R2 MRI is a validated and standardized technique approved by the Australia Therapeutic Goods Administration, FDA, and European Medicines Agency
Hereditary haemochromatosis
Hepatitis
β-thalassaemia
β-thalassaemia/ haemoglobin E
Mea
n T
rans
vers
e R
elax
atio
n R
ate
<R
2> (
s-1)
Slide 43 of 50
Measuring LIC with MRI1,2
Advantages Disadvantages
• Estimates iron content throughout the liver
• Increasingly available worldwide
• Status of liver and heart can be assessed in parallel
• Validated relationship with LIC
• Allows longitudinal patient follow-up
• Indirectly measures LIC
• Requires MRI imager with dedicated imaging method
• Children younger than age 7 years require a general anaesthetic
1. Taher A, et al. Semin Hematol. 2007;44(suppl 3):S2-S6. 2. TIF. Guidelines for the clinical management of thalassaemia. 2nd ed. Nicosia, Cyprus; 2008.
Slide 45 of 50
Case Continues—Assessing Cardiac Iron
The patient underwent myocardial T2* MRI = 16 ms
Can cardiac dysfunction be predicted on the basis of this value alone?
Slide 46 of 50
T2* MRI—Emerging New Standard for Cardiac Iron Assessment in TM Patients
Lef
t V
entr
icu
lar
Eje
ctio
n F
rac
tio
n (
LV
EF
) (%
)
0
50
70
40
30
20
10
60
80
90
0 20 40 60 9080 10010 30 50 70
Heart T2* (ms)
Cardiac T2* value of 37 in a normal heart
Cardiac T2* value of 4in a significantly iron
overloaded heart
With permission from Anderson LJ, et al. Eur Heart J. 2001;22:2171-2179.Photos courtesy of Maria D. Cappellini, MD.
Myocardial T2* values <20 ms are associated with progressive and significant decline in LVEF
Slide 47 of 50
T2* and Left Ventricular EjectionFraction (LVEF)
A shortening of myocardial T2* to <20 ms (ie, increased myocardial iron) is associated with an increased chance of decreased LVEF
T2* Value (ms)
Chance of Decreased
LVEF
>20 Low chance
10–20 10%
8–10 18%
6 38%
4 70%
TIF. Guidelines for the clinical management of thalassaemia. 2nd ed. Nicosia, Cyprus; 2008.
Slide 48 of 50
Measuring Cardiac Iron with MRI1,2
Advantages Disadvantages• Rapidly assesses iron content in
the septum of heart
• Relative iron burden can be estimated reproducibly
• Functional parameters can be examined concurrently
• Iron status of liver and heart can be assessed in parallel
• Allows longitudinal follow-up
• Indirectly measures cardiac iron
• Requires MRI imager with dedicated imaging method
MRI is a nonvalidated method to rapidly and effectively assess cardiac iron
1. Taher A, et al. Semin Hematol. 2007;44(suppl 3):S2-S6. 2. TIF. Guidelines for the clinical management of thalassaemia. 2nd ed. Nicosia, Cyprus; 2008.
Slide 49 of 50
Thresholds for Parameters Used to Evaluate Iron Overload
Parameter Normal
Range
Iron Overload State
Mild Moderate Severe
LIC (mg Fe/g dw)1 <1.2 3–7 >7 >15
Serum ferritin (ng/mL)2,3
<300, male
<200, female>1000 to <2500 >2500
Cardiac T2* (ms)4 >20 14–20 8–14 <8
1. Wood JC, et al. Blood. 2005;106:1460-1465. 2. Taher A, et al. Semin Hematol. 2007;44(suppl 3):S2-S6. 3. Brissot P, et al. Blood Rev. 2008;22:195-210. 4. Anderson LJ, et al. Eur Heart J. 2001;22:2171-2179.
Slide 50 of 50
Conclusions
• Assessment of iron overload is essential in the clinical management of patients with thalassaemia because it guides chelation therapy
• Historically, serum ferritin and liver biopsy have been the diagnostic methods of choice– However, limitations to the reliability of the first and invasiveness
of the latter call for novel noninvasive approaches
• Liver R2 MRI and cardiac MRI T2* are becoming highly sought methods for the diagnosis of iron overload and monitoring of chelation therapy
Recommended