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Update on Microcytic Anaemias

Update on Microcytic Anaemias. Photis Beris, MD Professor of Clinical Haematology Department of Internal Medicine, Geneva University Hospital Geneva, Switzerland Achille Iolascon, MD, PhD
 Medical Genetics Chair
 University Federico II – Naples
 CEINGE - Advanced Biotechnologies Naples, Italy.

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Update on Microcytic Anaemias

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  1. Update on Microcytic Anaemias Photis Beris, MDProfessor of Clinical HaematologyDepartment of Internal Medicine, Geneva University HospitalGeneva, Switzerland Achille Iolascon, MD, PhD
Medical Genetics Chair
University Federico II – Naples
CEINGE - Advanced BiotechnologiesNaples, Italy

  2. Causes of Iron Deficiency Anaemia • Blood loss • Limited supply (poor diet) • Increased requirements • Iron malabsorption Hereditary Acquired

  3. Overview of Microcytic Anaemias and New Hereditary Forms Achille Iolascon, MD, PhD

  4. Inherited Microcytic Anaemias • Heme synthesis • Porphyrias – Erythropoietic porphyria • Sideroblastic anaemias • – X-linked • – X-linked with ataxia • – Autosomal recessive (due to glutaredoxin 5 or to Gly transporter deficiency) • Globin synthesis • Thalassaemias • Haemoglobinopathies • Iron metabolism • Hereditary hypotransferrinaemia • Aceruloplasminaemia • Divalent metal transporter 1 (DMT1) disease • Ferroportin disease • TMPRSS6 deficiency Graphics courtesy of Dr. Achille Iolascon.

  5. Iron Compartments Enterocyte:Transfer Erythroid Precursor:Use Macrophage:Recycling Hepatocyte:Storage Iolascon A, et al. Semin Hematol. 2009;46:358-370.

  6. Divalent Metal Transporter 1(DMT1) Disease

  7. DMT1 Deficiency delCTT intron 4 / R416C Severe microcytic anaemia with high transferrin saturation Severe hypochromia with liver iron overload and normal ferritin levels Graphics A, B, and Table with permission from Iolascon, A. et al. Blood. 2006;107:349-354.Top left graphic courtesy of Dr. Achille Iolascon.

  8. Mutations and Clinical Features of 3 DMT1 Patients Abbreviations: Epo, erythropoietin; Hb, haemoglobin; N, normal values; sTfR, saturated transferrin receptor. Iolascon A, et al. J Pediatr. 2008;152:136-139.

  9. Clinical and Laboratory Findings of DMT1 Mutations1,2 • DMT1 is essential in erythropoiesis • DMT1 is not essential for liver iron uptake • DMT1 is not essential for duodenal iron absorption • – Alternative pathways? • – Heme absorption? • Increased iron absorption occurs in the presence of iron overload because of low hepcidin levels • Partial response of anemia to erythropoietin treatment 1. Iolascon A, et al. Blood. 2006;107:349-354. 2. Iolascon A, et al. J Pediatr. 2008;152:136-139. Graphic courtesy of Dr. Achille Iolascon.

  10. Iron-Refractory Iron-Deficient Anaemia (IRIDA)

  11. Iron-Refractory Iron-Deficiency Anaemia (IRIDA)1-7 P686 fs S623T E522K A118D All patients have high hepcidin levels! 1. Edison ES,et al,Br J Haematol. 2009 Aug 29. [Epub ahead of print].2. Tchou I et al.Eur J Haematol. 2009 Aug 25. [Epub ahead of print]. 3. Guillem F, et al. Blood. 2008;112:2089-2091. 4. Finberg KE, et al. Nat Genet. 2008;40:569-571. 5. Melis MA, et al. Haematologica. 2008;93:1473-1479. 6. Ramsay AJ, et al. Hum Mol Genet. 2009;18:3673-3683. 7. Silvestri L, et al. Blood. 2009;113:5605-5608. Left graphic courtesy of Dr. Achille Iolascon. Right graphic with permission from Silvestri L, et al. Blood. 2009;113:5605-5608.

  12. IRIDA–Effect of Iron IV Administration Abbreviations: Hb, haemoglobin; IV, intravenous; MCH, mean corpuscular haemoglobin; MCV, mean corpuscular volume; sat, saturation. Unpublished data from Iolascon et al. Graphic courtesy of Dr. Achille Iolascon.

  13. The Role of TMPRSS6 in The Hepcidin Regulatory Pathway Proteolytic cleavage BMP s-HJV m-HJV BMPRs P SMAD 1-5-8 complex SMAD 1-5-8 complex TMPRSS6 P SMAD 1-5-8 complex SMAD 4 mRNA HAMP P Abbreviations: BMP, bone morphogenic protein; BMPR, bone morphogenic protein receptor; HJV, haemojuvelin; P, phosphorylation. Silvestri L, et al. Blood. 2009;113:5605-5608. Graphic courtesy of Dr. Achille Iolascon.

  14. How to Recognize an Atypical Microcytosis • Refractory (or partially refractory) to IV iron • Noncongruent iron parameters: microcytosis + • High transferrin saturation and high serum ferritin • Low transferrin saturation and high serum ferritin • Ringed sideroblasts (any percentage) • Familial cases • High hepcidin (TMPRSS6 mutations)

  15. Faculty Discussion

  16. Unexplained or Refractory Acquired Iron-Deficiency Anaemia Photis Beris, MD

  17. Unexplained or Refractory Acquired Iron-Deficiency Anaemia (IDA) • Helicobacter pylori • Celiac disease • Autoimmune atrophic gastritis

  18. Helicobacter pylori Infection • In recent years, H. pylori has been implicated in several studies as a cause of IDA refractory to oral iron treatment1 • – Favorable response to H. pylori eradication • Mechanisms: Occult GI bleeding? Alterations in intragastric pH and ascorbic acid concentration? Induction of IL-1β and TNF-α, (inhibitors of parietal cell function)? Induction of parietal cell apoptosis?2 • Diagnosis: IgG antibody screening, urease breath test1 1. Hershko C, et al. Semin Hematol. 2009;46:339-350.2. Hershko C, et al. Blood Cells Mol Dis. 2007;38:45-53.

  19. Celiac Disease • Celiac disease is a common nonbleeding gastrointestinal condition that may result in refractory IDA1 • – Celiac disease accounts for 5%–6% of unexplained IDA cases • – Approximately 50% of patients with subclinical celiac disease develop IDA • Diagnosis: Anti-tissue transglutaminase antibodies and/or anti-endomysial antibodies Hershko C, et al. Semin Hematol. 2009;46:339-350.

  20. Autoimmune Atrophic Gastritis • Autoimmune atrophic gastritis, or atrophic body gastritis, is associated with chronic idiopathic IDA with no evidence of gastrointestinal blood loss • Iron deficiency may develop many years before the depletion of vitamin B12 stores • Possible role of H. pylori in the pathogenesis of autoimmune gastritis due to antigenic mimicry of H+K+-ATPase • Diagnosis: Serum gastrin, parietal cell antibodies Hershko C, et al. Semin Hematol. 2009;46:339-350.

  21. Unexplained or Refractory Acquired IDA 300 Patients with IDAMean age 39 ± 18 y; 251/300 (84%) women of reproductive age H. pylori Adult Celiac Disease Autoimmune Atrophic Gastritis 18 cases (6%); refractoriness 100% 77 cases (26%); 39/77 (51%) also had H. pylori;refractoriness 69% 57 cases (19%); coexisting in 165/300 (55%);refractoriness 68% Hershko C, et al. Blood Cells Mol Dis. 2007;39:178-183. Graphic courtesy of Dr. Photis Beris.

  22. Effect of Age on Autoimmune Gastritis1,2 As age from 20 to 60 years and vitamin B12 levels and H. pylori prevalence Gastrin levels • With increasing age from <20 to >60 years, gastrin progressively increases and B12 decreases1 • HP infection decreases from 87.5% at age <20 years to 12.5% at age >60 years1 1. Hershko C, et al. Blood. 2006;107:1673-1679. 2. Hershko C, et al. Blood Cells Mol Dis. 2007;39:178-183.

  23. Treatment • Cure the underlying disease • In many cases, H. pylori eradication will cure the anaemia without iron therapy • IV iron therapy is indicated in autoimmune atrophic gastritis due to malabsorption • When IV iron is used, always calculate the precise amount of iron needed to correct anaemia and to replenish iron stores Hershko C, et al. Semin Hematol. 2009;46:339-350.

  24. Recommendations for the Diagnostic Work-Up of Unexplained or Refractory Acquired IDA Screening for celiac disease, autoimmune atrophic gastritis and for H. pylori should be performed in the following populations: • Males and postmenopausal females with IDA and negative endoscopic and radiologic studies • Fertile females and children/adolescents refractory to oral iron treatment Hershko C. In: Disorders of Iron Homeostasis, Erythrocytes, Erythropoiesis. Forum service editore: Genoa, Italy; 2006.

  25. Acquired IDA—Conclusions • Blood loss, insufficient dietary iron intake, and increased iron requirements are the main causes of iron deficiency anaemia. • Acquired decreased iron absorption has recently been recognized in patients with unexplained or refractory IDA • Celiac disease, autoimmune atrophic gastritis, and H. pylori infection are increasingly diagnosed in such patients • In some cases, H. pylori may be directly implicated in the genesis of autoimmune gastritis • We strongly recommend a diagnostic work-up for these conditions in case of acquired refractory or obscure IDA

  26. Faculty Discussion Part of the information given in the answers to the questions was taken from the electronic edition of “Up to-date” chapter “pathogenesis, epidemiology, and clinical manifestations of celiac disease in adults” written by Detlef Schuppan MD, PhD, and Walburga Dieterich, PhD, version 17.2 January 27, 2009.

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