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Clinical Case: Hereditary Haemochromatosis

Pierre Brissot, MDProfessor of Medicine

Liver Disease DepartmentUniversity Hospital Pontchaillou

Rennes, France

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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%

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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

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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.

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Diagnostic Grid

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Diagnostic Grid

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Diagnosis?

Polymetabolic Syndrome + Hereditary Haemochromatosis

HFE is Key Test

C282Y/C282Y = type 1 haemochromatosis

Brissot P, et al. Blood Rev. 2008;22:195-210.

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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

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Diagnostic Grid

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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

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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

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ferritin overexpression as compared with liver iron concentration

Accounting for:

Contributing to: hyperglycaemia

Final Diagnosis

Polymetabolic Syndrome

+

Type 1 Haemochromatosis, Grade 3

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Beware ferritinaemia interpretation!

Treatment

Metabolic syndromeDiet

Exercise

Haemochromatosis Phlebotomies (7 mL/kg/wk)

50 µg/L: not an appropriate goal in this case

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Diagnostic Grid

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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

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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

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Clinical Case: Myelodysplastic Syndromes (MDS)

Aristoteles A. N. Giagounidis, MDMedizinische Klinik IISt. Johannes HospitalDuisburg, Germany

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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.

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Cumulative Survival of 1806 Untreated Patients with Primary MDS

(Düsseldorf MDS Registry, 1970–2003)

YearsCourtesy of Dr. U. Germing.

20

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0.4

0.2

0.0

0.8

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4 6 8 10 12 14 16 18 20

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ival

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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.

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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.

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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

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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.

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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

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Bone Marrow Aspirate and Core Biopsy

• Trilineage dysplastic changes

• Blast count 3%

• Cytogenetics 46,XX,del(20q)

Diagnosis: refractory cytopaenia with multilineage dysplasia

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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.

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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?

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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.

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• 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

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• 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

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Diagnostic Grid

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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

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Clinical Case:Thalassaemia Major

Ali T. Taher, MDProfessor

Department of Internal MedicineAmerican University of Beirut

Medical CenterBeirut, Lebanon

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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

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Relevant Laboratory Value

Serum ferritin level = 7200 ng/mL

How reliable is serum ferritin for the assessment of iron overload in this case?

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Diagnostic Grid

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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.

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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.

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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

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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.

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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?

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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

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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.

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Diagnostic Grid

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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?

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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

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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.

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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.

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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.

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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