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
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
OBJECTIVES 1. Iron deficiency anemia Utility of hepcidin determination in diagnosing IRIDA 2. Porphyrias Overview of porphyrias Appropriate tests for the diagnose of porphyrias
1. IRON DEFICIENCY ANEMIA 1.1. Introduction Iron multiple functions Absolute iron deficiency body iron stores exhausted Prevalence (Lopez A et al, Lancet 2015)
1. IRON DEFICIENCY ANEMIA Iron homeostasis: Pietrangelo A, N Engl J Med 2004
1. IRON DEFICIENCY ANEMIA Hepcidin: main regulator of systemic iron metabolism Controlled iron absorption Controlled recycling Controlled storage Ganz T, Physiol Rev 2013
1. IRON DEFICIENCY ANEMIA Stimuli affecting hepcidin transcription Polin V et al, Dig Liv Dis 2013
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
1. IRON DEFICIENCY ANEMIA Iron status and hepcidin regulation In IDA Ferritin Rischi G et al, 2015
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
1. IRON DEFICIENCY ANEMIA 1.3. Causes Increased needs Decreased absorption Increased losses
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
1. IRON DEFICIENCY ANEMIA 1.4. Iron refractory iron deficiency anemia (IRIDA) Rare autosomal disorder (estimated prevalence <1/1.000.000) Less than 1% of the case of IDA seen in medical practice Mutations of TMPRSS6 encoding for matriptase 2 Folgueras A, Blood 2008
1. IRON DEFICIENCY ANEMIA 1.4. Iron refractory iron deficiency anemia (IRIDA) Pathophysiology Cui Y, Kidney Int 2009
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
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
2.1 Introduction http://www.porphyria-europe.com http://www.porphyriafoundation.com Heme synthesis: 80% erythropoietic cells 15% liver parenchymal cells Eight metabolic disorders of the heme biosynthesis pathway Karim Z et al, 2015
+++ Drugs, stress, steroids Bissell et al, 2015
Autosomal dominant Autosomal recessive X-linked Most often sporadic
2.2 Types of porphyrias Acute porphyrias cutaneous porphyrias Karim Z et al, 2015
Prevalence according the Porphyria Consortium (Rare Clinical Disease Research Network) Type of porphyria ADP Prevalence 10 cases reported in the literature AIP 1/20.000 VP Variable* (South Africa: 3/1000) HCP 1/500.000 PCT 1/10.000 CEP Several hundred cases reported in the literature EPP/XLP 1/200.000 * Prevalence much lower in other countries
Diagnosis specific tests on appropriate specimen d-ala Uroporphyrin III PBG Coproporphyrin III Protoporphyrin IX Solubility Urine Urine/Stool Stool/red blood cells
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
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
2.3. Acute porphyrias treatments Supportive: Analgesia Management of fluid balance Avoiding any precipitating factors http://www.drugs-porphyria.org Specific Heme complexed with arginine (Normosang ) Liver transplantation (severest forms) Ventura P et al, 2014
2.4. Cutaneous porphyrias 2.4.1. 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
2.4.1. Porphyria cutanea tarda (PCT) Biochemical tests Urinary porphyrins analysis: spectrophotometric test and HPLC fractionation 2.0 1.8 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 Screening urinaire positif: 1171 nmol/l (V.R. < 300) (Porphyrie Cutanée Tardive) 350 370 390 410 430 450 Stool porphyrins analysis, plasmatic fluorescence
2.4.1. Porphyria cutanea tarda (PCT) Treatments Avoiding risk factors Phlebotomies Low-dose regimen chloroquine
2.4.2. Erythropoietic protoporphyria (EPP) EPP autosomic recessive XLP-X-linked form (5% of EPP cases) Skin photosensitivity (childhood) Liver disease Balwani M et al, 2012
2.4.2. Erythropoietic proptoporphyria (EPP) Biochemical tests Porphyrins in erythrocytes: Free protoporphyrin Zn protoporphyrin Plasmatic fluorescence Stool porphyrins analysis
2.4.2. Erythropoietic proptoporphyria (EPP) Treatments Avoid sunlight exposure Oral β-carotene (limited effects) Αlpha-melanocyte-stimulating hormone Harms J et al, 2009
2.4.3. Congenital erythropoietic porphyria (CEP) Decrease of URO-synthase activity Severe cutaneous photosensitivity (Childhood) Hypertrichosis-erythrodontia Severe hemolytic anemia Balwani M et al, 2012
2.4.3. Congenital erythropoietic porphyria (CEP) Biochemical tests Urine and stool porphyrins analysis 2.4.3. Congenital erythropoietic porphyria (CEP) Treatment Avoiding sun exposure Repeated transfusions Bone marrow transplantation Tezcan I et al, 1998
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
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