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Clinical Case: Hereditary Haemochromatosis

Clinical Case: Hereditary Haemochromatosis . Pierre Brissot, MD Professor of Medicine Liver Disease Department University Hospital Pontchaillou Rennes, France. Background Hypertension (treated) Increased weight (BMI 26.6) High cholesterol (untreated) Hyperglycaemia (1.25 g/L)

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Clinical Case: Hereditary Haemochromatosis

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  1. Clinical Case: Hereditary Haemochromatosis Pierre Brissot, MD Professor of Medicine Liver Disease Department University Hospital Pontchaillou Rennes, France

  2. 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) Patient PresentationMale, Age 55 Years • Lab Values • Ferritin 2500 µg/L • Transferrin saturation 95%

  3. 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

  4. 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. Diagnosis? Polymetabolic Syndrome + Hereditary Haemochromatosis

  5. Diagnostic Grid

  6. Diagnostic Grid

  7. HFE is Key Test C282Y/C282Y = type 1 haemochromatosis Brissot P, et al. Blood Rev. 2008;22:195-210. Diagnosis? Polymetabolic Syndrome + Hereditary Haemochromatosis

  8. Organ Test/Finding LIC (MRI): 9 mg/g dw (N <2mg/g dw) ALT/AST: normalUltrasound: hyperechoicLiver biopsy? Abbreviations: ALT, alanine aminotransaminase; AST, aspartate aminotransaminase; DW, dry weight;ECG, electrocardiogram; LIC, liver iron concentration. Search for Visceral Complications Degree of Body Iron Excess: Beware Ferritin Interpretation Liver

  9. Diagnostic Grid

  10. Organ Test/Finding LIC (MRI): 9 mg/g dw (N <2mg/g dw) ALT/AST: normalUltrasound: hyperechoicLiver biopsy? Abbreviations: ALT, alanine aminotransaminase; AST, aspartate aminotransaminase; DW, dry weight; ECG, electrocardiogram; LIC, liver iron concentration. Search for Visceral Complications Degree of Body Iron Excess: Beware Ferritin Interpretation Liver Pancreas Hyperglycaemia Joints/bones X-ray: arthropathyBone mineral density: normal Gonads Testosterone: normal Heart ECG, ultrasound: normal

  11. 4 3 Lifed Quality of lifec Quality of lifec 2 1 Ferritinb Ferritinb Ferritinb 0 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. Haemochromatosis Grade Type 1 haemochromatosis, grade 3 Brissot P, et al. Hematology. 2006;1:36-41.

  12. Final Diagnosis Polymetabolic Syndrome + Type 1 Haemochromatosis, Grade 3 Accounting for: ferritin overexpression as compared with liver iron concentration Contributing to: hyperglycaemia

  13. Diet Exercise Phlebotomies (7 mL/kg/wk) Treatment Metabolic syndrome Haemochromatosis Beware ferritinaemia interpretation! 50 µg/L: not an appropriate goal in this case

  14. Diagnostic Grid

  15. Patient Spouse, age 53 yT Sat: 29% Ferritin: 50 µg/LC282Y heterozygote Sister, age 52 yT Sat: 30%Ferritin: 40 µg/Lno C282Y Daughter, age 31 yT Sat: 32%Ferritin: 45 µg/LC282Y heterozygote Brother, age 48 yT Sat: 37%Ferritin: 95 µg/LC282Y heterozygote Son, age 28 yT Sat: 75% Ferritin: 450 µg/LC282Y homozygote Family Study

  16. 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

  17. Clinical Case: Myelodysplastic Syndromes (MDS) Aristoteles A. N. Giagounidis, MDMedizinische Klinik IISt. Johannes HospitalDuisburg, Germany

  18. The Diagnostic Challenge of MDS Immune cytopaenias (AIHA/ITP) CDA Megaloblastic anaemia TTP HUS Myelo-dysplastic syndromes AIDS AA Anaemia of chronic disease PNH Nutritive and pharmacologic toxins Bone marrow infiltration (NHL, solid tumors) Hypersplenism AML 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.

  19. Cumulative Survival of 1806 Untreated Patients with Primary MDS(Düsseldorf MDS Registry, 1970–2003) 1.0 0.8 0.6 Cumulative Survival 0.4 0.2 0.0 0 20 2 4 6 8 10 14 16 18 12 Years Courtesy of Dr. U. Germing.

  20. 2008 WHO Proposals for the Classification of MDS Abbreviation: WHO, World Health Organization. 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.

  21. 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.

  22. 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

  23. 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.

  24. 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

  25. Bone Marrow Aspirate and Core Biopsy Trilineage dysplastic changes Blast count 3% Cytogenetics 46,XX,del(20q) Diagnosis: refractory cytopaenia with multilineage dysplasia

  26. Treatment Options in Myelodysplastic Syndromes Risk stratification according to IPSSa Low risk Intermediate 1 Intermediate 2 High risk Abbreviation: IPSS, International Prognostic Scoring System. a Greenberg P, et al. Blood. 1997;89:2079-2088.

  27. Decision-Making Process What is the best treatment for this patient? Low-risk myelodysplastic syndrome Relatively long life expectancy Good quality of life Isolated anaemia with transfusion dependency

  28. Therapeutic Options for Myelodysplastic Syndromes Risk stratification according to IPSS Low risk Intermediate 1 Transfusions Ironchelation EPO ± G-CSF Lenalidomide ATG/CSA Abbreviations: ATG, antithymocyte globulin; CSA, cyclosporin A; EPO, erythropoietin; G-CSF, granulocyte colony-stimulating factor.

  29. Trial with erythropoietin resulted in 12 months of transfusion independence Relapse occurred in January 2008 Regular blood transfusions (2 units/4 weeks) Therapy When to start iron chelation?

  30. Iron Chelation Diagnostics Decision: commencement of iron chelation to prevent damage to liver and heart (ie, to maintain good quality of life) • Ferritin 1630 ng/mL • Transferrin saturation 89% • Substantial iron overload in liver MRI • Low cardiac iron deposits • Cardiac T2* MRI 28 ms

  31. Diagnostic Grid

  32. 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 techniquesare valuable

  33. Clinical Case:Thalassaemia Major Ali T. Taher, MDProfessorDepartment of Internal MedicineAmerican University of BeirutMedical CenterBeirut, Lebanon

  34. 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

  35. Relevant Laboratory Value Serum ferritin level = 7200 ng/mL How reliable is serum ferritin for the assessment of iron overload in this case?

  36. Diagnostic Grid

  37. Measuring and InterpretingSerum Ferritin1-3 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.

  38. Serum Ferritin Underestimates Iron Burden in Thalassaemia Intermedia Patients Thalassaemia intermedia (TI) Linear (TI) 10,000 9000 Thalassaemia major (TM) Linear (TM) 8000 7000 Serum Ferritin Level (ng/mL) 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. With permission from Taher A, et al. Haematologica. 2008;93:1584-1586.

  39. 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

  40. Measuring LIC by Liver Biopsy1,2 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.

  41. 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?

  42. Correlation Between R2 MRI and Liver Biopsy 300 250 Hereditary haemochromatosis 200 β-thalassaemia Mean Transverse Relaxation Rate <R2> (s-1) 150 β-thalassaemia/ haemoglobin E 50 100 40 Hepatitis 30 50 20 0.5 1.0 1.5 2.0 0 50 0 10 20 30 40 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.

  43. Measuring LIC with MRI1,2 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.

  44. Diagnostic Grid

  45. 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?

  46. T2* MRI—Emerging New Standard for Cardiac Iron Assessment in TM Patients 90 80 70 60 50 Left Ventricular Ejection Fraction (LVEF) (%) 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) Cardiac T2* value of 4in a significantly iron overloaded heart 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.

  47. 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 TIF. Guidelines for the clinical management of thalassaemia. 2nd ed. Nicosia, Cyprus; 2008.

  48. Measuring Cardiac Iron with MRI1,2 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.

  49. Thresholds for Parameters Used to Evaluate Iron Overload 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.

  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

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