Clinical Case: Hereditary
Haemochromatosis
Pierre Brissot, MD
Professor of Medicine
Liver Disease Department
University Hospital Pontchaillou
Rennes, France
Slide 1 of 50
Patient Presentation
Male, Age 55 Years
Background
• Hypertension
(treated)
• Increased weight
(BMI 26.6)
• High cholesterol
(untreated)
History
• Fatigue (1 year)
• Arthralgias of 2nd
and 3rd metacarpophalangeal joints
(8 months)
Lab Values
• Ferritin 2500 µg/L
• Transferrin saturation
95%
• Hyperglycaemia
(1.25 g/L)
• No alcoholism
• No tobacco
Slide 2 of 50
Diagnosis?
Polymetabolic Syndrome
Hypertension
Increased weight
High cholesterol
Hyperglycaemia
Could explain
Could not explain
• Fatigue
• Hyperferritinaemia
• This type of arthropathy
• Such high ferritin level
• Elevated transferrin
saturation
Slide 3 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 4 of 50
Diagnostic Grid
Slide 5 of 50
Diagnostic Grid
Slide 6 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 7 of 50
Search for Visceral Complications
Degree of Body Iron Excess: Beware Ferritin Interpretation
Organ
Test/Finding
Liver
LIC (MRI): 9 mg/g dw (N <2mg/g dw)
ALT/AST: normal
Ultrasound: hyperechoic
Liver biopsy?
Abbreviations: ALT, alanine aminotransaminase; AST, aspartate aminotransaminase; DW, dry weight;
ECG, electrocardiogram; LIC, liver iron concentration.
Slide 8 of 50
Diagnostic Grid
Slide 9 of 50
Search for Visceral Complications
Degree of Body Iron Excess: Beware Ferritin Interpretation
Organ
Test/Finding
Liver
LIC (MRI): 9 mg/g dw (N <2mg/g dw)
ALT/AST: normal
Ultrasound: hyperechoic
Liver biopsy?
Pancreas
Hyperglycaemia
Joints/bones
X-ray: arthropathy
Bone mineral density: normal
Gonads
Testosterone: normal
Heart
ECG, ultrasound: normal
Abbreviations: ALT, alanine aminotransaminase; AST, aspartate aminotransaminase; DW, dry weight;
ECG, electrocardiogram; LIC, liver iron concentration.
Slide 10 of 50
Haemochromatosis Grade
4
Type 1 haemochromatosis, grade 3
0
3
Lifed
2
Quality
of lifec
Quality
of lifec
1
Ferritinb
Ferritinb
Ferritinb
T Sata
T Sata
T Sata
T Sata
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.
Brissot P, et al. Hematology. 2006;1:36-41.
Slide 11 of 50
Final Diagnosis
Polymetabolic Syndrome
+
Type 1 Haemochromatosis, Grade 3
Accounting for: ferritin overexpression as compared
with liver iron concentration
Contributing to: hyperglycaemia
Slide 12 of 50
Treatment
Metabolic syndrome
Diet
Exercise
Haemochromatosis
Phlebotomies
(7 mL/kg/wk)
Beware ferritinaemia interpretation!
50 µg/L: not an appropriate goal in this case
Slide 13 of 50
Diagnostic Grid
Slide 14 of 50
Family Study
Patient
Sister, age 52 y
T
Sat:
30%
Ferritin: 40 µg/L
no C282Y
Brother, age 48 y
T
Sat:
37%
Ferritin: 95 µg/L
C282Y heterozygote
Spouse, age 53 y
T Sat: 29%
Ferritin: 50 µg/L
C282Y heterozygote
Daughter, age 31 y
T Sat: 32%
Ferritin: 45 µg/L
C282Y heterozygote
Son, age 28 y
T Sat: 75%
Ferritin: 450 µg/L
C282Y homozygote
Slide 15 of 50
Conclusions
In type 1 haemochromatosis
• 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
Slide 16 of 50
Clinical Case: Myelodysplastic
Syndromes (MDS)
Aristoteles A. N. Giagounidis, MD
Medizinische Klinik II
St. Johannes Hospital
Duisburg, Germany
Slide 17 of 50
The Diagnostic Challenge of MDS
CDA
Megaloblastic
anaemia
AA
Immune
cytopaenias
(AIHA/ITP)
Myelodysplastic
syndromes
Bone marrow infiltration
(NHL, solid tumors)
AML
TTP
HUS
AIDS
Anaemia of
chronic
disease
Nutritive and
pharmacologic
toxins
Hypersplenism
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 18 of 50
Cumulative Survival of 1806
Untreated Patients with Primary MDS
(Düsseldorf MDS Registry, 1970–2003)
Cumulative Survival
1.0
0.8
0.6
0.4
0.2
0.0
0
2
Courtesy of Dr. U. Germing.
4
6
8
10
Years
12
14
16
18
20
Slide 19 of 50
2008 WHO Proposals for the
Classification of MDS
Subtype
Blood
Marrow
Refractory cytopaenia
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 other
cell lines
MDS with isolated del(5q)
Anaemia
Blasts <5%
No Auer rods
Anaemia, thrombocytopaenia,
neutropaenia
Platelets, normal or
elevated
MDS, unclassifiable
Cytopaenia
Blasts <5%
No Auer rods
Megakaryocytes with hypolobulated
nuclei
Dysplasia of noneyrthroid line
Abbreviation: WHO, World Health Organization.
Swerdlow SH, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Geneva,
Slide 20 of 50
Switzerland: World Health Organization; 2008. Table courtesy of Dr. A.A.N. Giagounidis.
2008 WHO Proposals for the
Classification of MDS
Subtype
Blood
Marrow
Refractory anaemia with
excess blasts I
Cytopaenia
Blasts <5%
No Auer rods
Monocytes <2000/mL
Unilineage or multilineage
Dysplasia
Blasts 5%–9%
No Auer rods
Refractory anaemia with
excess blasts II
Cytopaenia
Blasts <19%
Auer rods possible
Unilineage or multilineage
Dysplasia
Blasts 10%–19%
Auer rods possible
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 21 of 50
Patient Case Presentation
77-year-old woman, admitted to hospital in January 2007
Symptoms
Laboratory values
•
Exertional dyspnoea
•
Haemoglobin 8.9 g/dL
•
Fatigue
•
•
Platelets 278,000 cells/µL
(normal range: 150,000–350,000/µL)
No changes in bowel habits
•
White blood cell count 4300 cells/µL
(normal range: 4000–10,000 cells/µL)
•
No melaena
•
No overt blood loss or haematuria •
•
No hepatosplenomegaly or lymph
node enlargement
•
Absolute neutrophil count
2600 cells/µL
(normal range: 1800–7000 cells/µL)
Mean corpuscular volume 92 fL
(normal range: 80–95 fL)
Slide 22 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 23 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 24 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 25 of 50
Treatment Options in Myelodysplastic
Syndromes
Risk stratification according to IPSS
Low risk
Intermediate 1
a
Intermediate 2
High risk
Abbreviation: IPSS, International Prognostic Scoring System.
a
Greenberg P, et al. Blood. 1997;89:2079-2088.
Slide 26 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 27 of 50
Therapeutic Options for
Myelodysplastic Syndromes
Risk stratification according to IPSS
Low risk
Intermediate 1
EPO ± G-CSF
Iron
chelation
Transfusions
Lenalidomide
Abbreviations: ATG, antithymocyte globulin; CSA, cyclosporin A; EPO, erythropoietin;
G-CSF, granulocyte colony-stimulating factor.
ATG/CSA
Slide 28 of 50
Therapy
• 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?
Slide 29 of 50
Iron Chelation Diagnostics
• 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)
Slide 30 of 50
Diagnostic Grid
Slide 31 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 32 of 50
Clinical Case:
Thalassaemia Major
Ali T. Taher, MD
Professor
Department of Internal Medicine
American University of Beirut
Medical Center
Beirut, Lebanon
Slide 33 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 34 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 35 of 50
Diagnostic Grid
Slide 36 of 50
Measuring and Interpreting
Serum Ferritin1-3
Advantages
Disadvantages
• Easy to evaluate
• Indirectly measures iron burden
• Inexpensive
• Fluctuates in response to
inflammation, abnormal liver
function, ascorbate deficiencies
• Serial measures to monitor chelation
therapy
• Positively correlates with morbidity
and mortality
• Individual measures may not
accurately reflect iron levels and
response to chelation therapy
• Allows longitudinal follow-up of
patients
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 37 of 50
Serum Ferritin Level (ng/mL)
Serum Ferritin Underestimates Iron Burden
in Thalassaemia Intermedia Patients
Thalassaemia intermedia (TI)
Linear (TI)
10,000
9000
Thalassaemia major (TM)
Linear (TM)
8000
7000
6000
5000
4000
3000
2000
1000
0
0
5
10
15
20
25
30
35
40
45
50
Liver Iron Concentration (LIC) (mg Fe/g dry weight)
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 38 of 50
With permission from Taher A, et al. Haematologica. 2008;93:1584-1586.
Case Continues—Liver Biopsy
• A liver biopsy was recommended
– To determine the liver iron concentration
– To evaluate histopathologic changes secondary
to hepatitis C infection
• Patient’s mother refused due to concerns about
the associated risks of invasive intervention
Slide 39 of 50
Measuring LIC by Liver Biopsy1,2
Advantages
Disadvantages
• Directly measures LIC (quantitative, • Invasive, painful, and
specific, sensitive)
potentially serious
complications (eg, bleeding)
• Validated reference standard
• Sampling error risk, especially
• Measures nonheme storage iron
in patients with cirrhosis
• Evaluates liver histology/pathology
• Inadequate standardization
• Positively correlates with morbidity
between laboratories
and mortality
• 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 40 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 41 of 50
Mean Transverse Relaxation Rate <R2> (s-1)
Correlation Between R2 MRI and
Liver Biopsy
300
250
Hereditary
haemochromatosis
200
β-thalassaemia
150
β-thalassaemia/
haemoglobin E
50
100
40
Hepatitis
30
50
20
0.5
1.0
1.5
2.0
0
0
10
20
30
40
50
Biopsy Iron Concentration (mg/g-1 dry weight)
R2 MRI is a validated and standardized technique approved by the Australia Therapeutic
Goods Administration, FDA, and European Medicines Agency
With permission from St. Pierre TG, et al. Blood. 2005;105:855-861.
Slide 42 of 50
Measuring LIC with MRI1,2
Advantages
Disadvantages
• Estimates iron content throughout
the liver
• Indirectly measures LIC
• Increasingly available worldwide
• Status of liver and heart can be
assessed in parallel
• Validated relationship with LIC
• Requires MRI imager with
dedicated imaging method
• Children younger than age 7
years require a general
anaesthetic
• Allows longitudinal patient followup
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 43 of 50
Diagnostic Grid
Slide 44 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 45 of 50
Left Ventricular Ejection Fraction (LVEF) (%)
T2* MRI—Emerging New Standard for Cardiac
Iron Assessment in TM Patients
90
80
70
60
50
Cardiac T2* value of
37 in a normal heart
40
30
20
10
0
0
10
20
30
40
50
60
70
80
90
100
Heart T2* (ms)
Myocardial T2* values <20 ms are associated with
progressive and significant decline in LVEF
With permission from Anderson LJ, et al. Eur Heart J. 2001;22:2171-2179.
Photos courtesy of Maria D. Cappellini, MD.
Cardiac T2* value of 4
in a significantly iron
overloaded heart
Slide 46 of 50
T2* and Left Ventricular Ejection
Fraction (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 47 of 50
Measuring Cardiac Iron with MRI1,2
Advantages
Disadvantages
• Rapidly assesses iron content in
the septum of heart
• Indirectly measures cardiac iron
• Relative iron burden can be
estimated reproducibly
• Requires MRI imager with
dedicated imaging method
• Functional parameters can be
examined concurrently
• Iron status of liver and heart can be
assessed in parallel
• Allows longitudinal follow-up
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 48 of 50
Thresholds for Parameters Used to
Evaluate Iron Overload
Iron Overload State
Parameter
LIC (mg Fe/g dw)1
Serum ferritin
(ng/mL)2,3
Cardiac T2* (ms)4
Normal
Range
Mild
Moderate
Severe
<1.2
3–7
>7
>15
<300, male
<200, female
>20
>1000 to <2500
14–20
8–14
>2500
<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 49 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
Slide 50 of 50