Iron deficiency anemia and porphyrias

Transcription

1 Iron deficiency anemia and porphyrias Fleur Wolff¹, Frédéric Cotton¹, Axelle Gilles² ¹Department of clinical chemistry, Hôpital Erasme, ULB ²Department of hematology, Hôpital Erasme, ULB BHS, November 2015

2 PLAN 1. Iron deficiency anemia 1.1. Introduction 1.2. Biochemical markers 1.3. Causes 1.4. IRIDA 1.5. Take home message 2. Porphyrias 2.1. Introduction 2.2. Type of porphyrias 2.3. Acute porphyrias 2.4. Cutaneous porphyrias 2.5. Take home message

3 OBJECTIVES 1. Iron deficiency anemia Utility of hepcidin determination in diagnosing IRIDA 2. Porphyrias Overview of porphyrias Appropriate tests for the diagnose of porphyrias

4 1. IRON DEFICIENCY ANEMIA 1.1. Introduction Iron multiple functions Absolute iron deficiency body iron stores exhausted Prevalence (Lopez A et al, Lancet 2015)

5 1. IRON DEFICIENCY ANEMIA Iron homeostasis: Pietrangelo A, N Engl J Med 2004

6 1. IRON DEFICIENCY ANEMIA Hepcidin: main regulator of systemic iron metabolism Controlled iron absorption Controlled recycling Controlled storage Ganz T, Physiol Rev 2013

7 1. IRON DEFICIENCY ANEMIA Stimuli affecting hepcidin transcription Polin V et al, Dig Liv Dis 2013

8 1. IRON DEFICIENCY ANEMIA Iron status and hepcidin regulation Regulation by circulating iron and by iron stores In case of iron overload TfS Ferritin Rischi G et al, 2015

9 1. IRON DEFICIENCY ANEMIA Iron status and hepcidin regulation In IDA Ferritin Rischi G et al, 2015

10 1. IRON DEFICIENCY ANEMIA 1.2. Biochemical parameters Ferritin: <30ng/mL ; sensitivity of 98% and specificity of 92% for ID (Mast et al, 1998) Acute phase protein Hepatic cytolysis Soluble receptor of transferrin stfr (stfr/log ferritin): Not affected by inflammation Concentration raised with increased erythropoiesis Absence of standardized cut-offs

11 1. IRON DEFICIENCY ANEMIA 1.3. Causes Increased needs Decreased absorption Increased losses

12 1. IRON DEFICIENCY ANEMIA 1.3. Causes (Camaschella C, N Engl J Med 2015) Refractory : No hematological response (delta Hb<1g/dL) after 4 weeks of oral iron treatment

13 1. IRON DEFICIENCY ANEMIA 1.4. Iron refractory iron deficiency anemia (IRIDA) Rare autosomal disorder (estimated prevalence <1/ ) Less than 1% of the case of IDA seen in medical practice Mutations of TMPRSS6 encoding for matriptase 2 Folgueras A, Blood 2008

14 1. IRON DEFICIENCY ANEMIA 1.4. Iron refractory iron deficiency anemia (IRIDA) Pathophysiology Cui Y, Kidney Int 2009

15 1. IRON DEFICIENCY ANEMIA 1.4. Iron refractory iron deficiency anemia (IRIDA) Microcytic hypochromic anemia, TfS, ferritin levels to Normal or high hepcidin levels Absence of hematologic response after oral iron administration Slow and partial response to intravenous iron injections De Falco, Haematologica 2013

16 1. IRON DEFICIENCY ANEMIA 1.5. Take home message: IRIDA -hepcidin -IRIDA nutritional iron deficiency other genetic causes -Most of the cases diagnosed in childhood -Sequencing of the TMPRSS6 gene

17 2.1 Introduction Heme synthesis: 80% erythropoietic cells 15% liver parenchymal cells Eight metabolic disorders of the heme biosynthesis pathway Karim Z et al, 2015

18 +++ Drugs, stress, steroids Bissell et al, 2015

19 Autosomal dominant Autosomal recessive X-linked Most often sporadic

20 2.2 Types of porphyrias Acute porphyrias cutaneous porphyrias Karim Z et al, 2015

21 Prevalence according the Porphyria Consortium (Rare Clinical Disease Research Network) Type of porphyria ADP Prevalence 10 cases reported in the literature AIP 1/ VP Variable* (South Africa: 3/1000) HCP 1/ PCT 1/ CEP Several hundred cases reported in the literature EPP/XLP 1/ * Prevalence much lower in other countries

22 Diagnosis specific tests on appropriate specimen d-ala Uroporphyrin III PBG Coproporphyrin III Protoporphyrin IX Solubility Urine Urine/Stool Stool/red blood cells

23 2.3. Acute porphyrias - Types Include acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HC), ALA-dehydratase deficient porphyria (ADP) Most common: AIP low penetrance Triggering factors Women +++ (third and fourth decades) Ventura P et al, 2014

24 2.3. Acute porphyrias Biochemicals test First-line urine porphobilinogen (PBG) and delta-aminolevulinic acid (d-ala) Second-line urine and stool porphyrin isomers fractionation plasmatic fluorescence Deacon AC et al, 2001

25 2.3. Acute porphyrias treatments Supportive: Analgesia Management of fluid balance Avoiding any precipitating factors Specific Heme complexed with arginine (Normosang ) Liver transplantation (severest forms) Ventura P et al, 2014

26 2.4. Cutaneous porphyrias Porphyria cutanea tarda (PCT) Sporadic (80%) or familial (20%) Decrease activity of URO-decarboxylase Cutaneous manifestations in adulthood Triggering factors: iron overload, HCV, alcohol abuse Karim Z et al, 2015

27 Porphyria cutanea tarda (PCT) Biochemical tests Urinary porphyrins analysis: spectrophotometric test and HPLC fractionation Screening urinaire positif: 1171 nmol/l (V.R. < 300) (Porphyrie Cutanée Tardive) Stool porphyrins analysis, plasmatic fluorescence

28 Porphyria cutanea tarda (PCT) Treatments Avoiding risk factors Phlebotomies Low-dose regimen chloroquine

29 Erythropoietic protoporphyria (EPP) EPP autosomic recessive XLP-X-linked form (5% of EPP cases) Skin photosensitivity (childhood) Liver disease Balwani M et al, 2012

30 Erythropoietic proptoporphyria (EPP) Biochemical tests Porphyrins in erythrocytes: Free protoporphyrin Zn protoporphyrin Plasmatic fluorescence Stool porphyrins analysis

31 Erythropoietic proptoporphyria (EPP) Treatments Avoid sunlight exposure Oral β-carotene (limited effects) Αlpha-melanocyte-stimulating hormone Harms J et al, 2009

32 Congenital erythropoietic porphyria (CEP) Decrease of URO-synthase activity Severe cutaneous photosensitivity (Childhood) Hypertrichosis-erythrodontia Severe hemolytic anemia Balwani M et al, 2012

33 Congenital erythropoietic porphyria (CEP) Biochemical tests Urine and stool porphyrins analysis Congenital erythropoietic porphyria (CEP) Treatment Avoiding sun exposure Repeated transfusions Bone marrow transplantation Tezcan I et al, 1998

34 2.5. Take home message Neurovisceral crisis Urine PGB and d-ala (Spot urine protected from light) Photosensitivity (bullous lesions in adulthood) Total urinary porphyrins and isomers fractionation (Spot urine protected from light) Photosensitivity (oedematous erythema in childhood) Erythrocyte protoporphyrins (whole blood protected from light) Balwani M et al, 2012

35 Thank you for your attention