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. Due Casi Clinici: - Caso di bambino con ittero franco a bilirubina indiretta ( diagnosi di Crigler-Najiar di tipo II) - Un caso di bambino pallido con.

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Presentazione sul tema: ". Due Casi Clinici: - Caso di bambino con ittero franco a bilirubina indiretta ( diagnosi di Crigler-Najiar di tipo II) - Un caso di bambino pallido con."— Transcript della presentazione:

1 . Due Casi Clinici: - Caso di bambino con ittero franco a bilirubina indiretta ( diagnosi di Crigler-Najiar di tipo II) - Un caso di bambino pallido con segni di carenza di ferro

2 I1I2 II1 II2 Paziente maschio,11 anni Anamnesi familiare: I.1: Colecistectomia all’età di 34 aa I.2: Iperbilirubinemia indiretta I.3: Anemia di ndd Anamnesi personale: Nato da gravidanza normocondotta, a termine, da parto cesareo Ittero neonatale (bilirubina 18 mg/dl) trattato con fenobarbital I3 Anamnesi infantile: A 5 anni ittero sclerale e cutaneo importante (bilirubina indiretta 8.8 mg/dL)


4 Analisi delle regioni codificanti del gene UGT1A1: Assenza di mutazioni causative Analisi delle regioni non codificanti del gene UGT1A1 Paziente (TA)7/7 Ctrl (TA)6/7Ctrl (TA)7/7Ctrl (TA)6/6

5 Bilirubina Totale:8.28 mg/dL Bilirubina diretta:0.93 mg/dL Bilirubina Indiretta:7.35 mg/dL Albumina: 4.3 g/dL QPE: nella norma AST:24 UI/L ALT:17 UI/L Aptoglobina:<6.56mg/dL LDH: 440 UI/L Analitav.n. RBC4-5.2 *10 6 /uL3.67 Hb13-16 g/dL11.3 Hct36-49 %34.4 MCV80-98 fL93.7 MCH27-31 pg30.8 MCHC32-36 g/dL32.9 RDW11-14%14.1 PLT *10 3 /uL300 Ret %0.5-2 %6.5 Ret abs *10 3 /uL238.5 WBC *10 3 /uL4.37 Ecografia addominale Fegato: ecostruttura nella norma Dimensioni ai limiti sup. Milza: diametro bipolare 15 cm

6  Test di Coombs diretto e indiretto: NEGATIVO  Pink Test: 55% (v.n. <30%)  AGLT50: dimezzamento dopo 1’ (v.n. dimezzamento dopo 3’)  Osservazione dello striscio periferico: presenza di sferociti  Ektacitometria:

7 Erythrocyte Membrane Proteins Horizontal Interaction Vertical Interaction HS HE HPP HSt

8 Source of Bilirubin Metabolism of heme mg/kg/day. (adults 3-4mg/kg/day) –75%: from hemoglobin of old RBCs released from RES. 1gr produces 34mg of bilirubin. –25%: from ineffective erythropoyesis, myoglobine, cytochromes, catalase, peroxidase.

9 Albumin- Bilirubin Endoplasm. Retic. BMG and BDG UDPGA UCB UGT Biliary ducts UCB

10 UGT gene 45 UGT 1 locus mRNA Enzyme UGT 5’5’3’3’ NH 2 COOH Substrate binding UDPGA binding 1*71*61*41* aa246 aa

11 Radioactive PCR of UGT1A promoter 5’5’ 3’3’ Exon (TA) 6 TAA C D bp 98 bp 100 bp (TA) 7 /(TA) 7 (TA) 6 /(TA) 6 (TA) 6 /(TA) 7 (TA) 6 /(TA)

12 Transcriptional evaluation of the UGT promoter by luciferase assay UGT1A1 activity TA6 TA7 TA8

13 UGT1A1 activity during perinatal period


15 Hereditary spherocytosis and Gilbert UGT1 Promoterjaundiced Not jaundiced A(TA)7TAA/A(TA)7TAA29(97%)1(3%) A(TA)7TAA/A(TA)6TAA83(56%)65(44%) A(TA)6TAA/A(TA)6TAA Total 112(63%)66(37%)

16 Gallstones and UGT1A Genotype UGT1A GallstonesNO gallst. (TA)6/(TA)6 (TA)6/(TA)7 8(24%)25(76%) (TA)7/(TA)77 (87,5%)1 (12,5%) Total15 (37%)26 (63%)

17 Genotype Phenotype Monogenic diseases Modifier genes ? Environment

18 I1I2 II1 Femmina, 7 aa Anamnesi familiare: Negativa per anemia Negata consanguineità Anamnesi personale: All’età di 3 aa osservato pallore Anemia microcitica associata a riduzione dell’indice di saturazione della transferrina

19 Analitav.n. RBC4-5.2 *10 6 /uL2.9 Hb13-16 g/dL6.7 Hct36-49 %20 MCV80-98 fL65 Ferritina ng/mL25 Sideremia ug/dL14 Transferrina mg/dL290 IS transferrina15-45%3.7 Elettroforesi dell’Hb: assenza di Hb patologiche HbF e HbA2: non elevate Sangue occulto nelle feci: negativo Calprotectina fecale: nella norma EGDS: nulla da segnalare

20 Prima del trattamento Hb6.7 MCV65 Ferritina25 Sideremia14 Transferrina290 IS transferrina3.7 Dopo il trattamento

21 Prima del trattamento RBC2.9 Hb6.7 MCV65 Ferritina25 Sideremia14 Transferrina290 IS transferrina3.7 Dopo il trattamento

22 Analisi delle regioni codificanti del gene TMPRRS6 * c.749T>C p.I212T * c.926G>A p.R271Q * *

23 (Andrews, NEJM, 1999) Ironmetabolism Iron metabolism The total body iron content of an average male adult is about 4 g; Total iron: –Red cell mass as haemoglobin – 65%- 75% –Muscles as myoglobin – 10% –Storage as ferritin - 10% Bone marrow Reticulo-endothelial cells Liver (0.5-1 g) –Other Haem proteins - 5% Cytochromes, others –In Serum - 0.1% Iron balance is maintained by the meticulous regulation of iron absorption from the intestine because there is no regulated pathway for iron excretion

24 1kg body weight= 50 mg Fe Newborn (3,300 Kg) Children(35 Kg)Adult (75 Kg) Total iron mg1,5 – 2 g3 -4 g HB 132 – 137,5 mg (55%) 1 – 1,4 g (68%) 2,04 – 2,72 g (68%) Ferritin 101 – 105 mg (42%) 400 – 500 mg (27%) 0,81 -1,08 g (27%) Myoglobin 7 -7,5 mg (3%) 60 – 80 mg (4%)120 – 160 mg (4%) Enzyme9 – 12 mg (0,6%)18 – 24 mg (0,6%) Transferrin15 – 20 mg (0,1%)3 – 4 mg (0,1%) Iron content in the body in different age Iolascon A et al.,2013

25 Transport Use Recycling Storage Ferritin Erythroid precursors Iolascon A, De Falco L Semin Hematol Oct;46(4): Absorption and metabolism of iron

26 Sistemic regulation- Hepcidin, a key regulator of iron homeostasis Nemeth et al., Science 2004 The liver peptide hepcidin is the main regulator of systemic iron homeostasis, since it influences the macrophages and in duodenal activity of the iron exporter ferroportin though its internalization and degradation. C. Beaumont

27 Iron deficiency and iron deficiency anemia Iron deficiency and iron deficiency anemia Iolascon A et al.,2013

28 Peripheral blood smear Characters of this story Normal values ​​ for age AgeMCV (fl) At born months years years78-95 >12 years RBC: Microcytosis hypochromia reduced size and reduced Hb content of red blood cells, as inferred by erythrocyte indexes MCH: <26 pg (n.v 27-30) MCHC: <30 g/dl (n.v.31-37)

29 Characters of this story RDW: red cell distribution width (measure of anysocytosis, e.g. dual populations) HRC: % hypochromic red cells CHr: reticulocyte Hb content Serum iron Transferrin Transferrin saturation Serum ferritin Soluble transferiin receptor Hepcidin assay

30 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 –Hemoglobinopathies Iron metabolism –Hereditary hypotransferrinaemia –Aceruloplasminaemia –Divalent metal transporter 1 (DMT1) disease –Ferroportin disease –TMPRSS6 deficiency Microcytic anemias: Classification Iolascon A et al.,2013

31 Hereditary haemochromatosis Iron-loading Anaemias Anaemia of Inflammation Iron-refractory iron-deficiency anaemia Hepcidin-secreting tumors HepcidinIron Normal homeostasis Ganz T. J Am Soc Nephol. 2007;18: Ganz T, Nemeth E. Am J Physiol Gastrointest Liver Physiol. 2006;290:G199-G203. Courtesy of Tomas Ganz, PhD, MD. Diseases of Hepcidin Dysregulation Iron deficiency anemia

32 Nutritional deficiency Deficit of absorption Thalassemia heterozygotes ACD ACD+iron deficiency Hb - - = / MCV GR RDW = = = / + + Reticulocytes - - = / + = / + / - IS - / -- = = / - - Ferritin = / - = / + = = = / - FEP = / + = = sTfR = = / + CHr - - = / Oral responseYESNO Not to be expected Partial Iv responseYES NO Not to be expected Partial InheritanceAcquired Acquired / multifactorial ARMultifactorial Suggested therapy Oral iron Etiological therapy / iv injection if severe anemia Not required Etiological therap yif possible (EPO, iv iron) Etiological therap + oral iron Differential diagnosis of the most common forms of microcytosis Iolascon A et al.,2013

33 Differential diagnosis of the less common forms of microcytosis IRIDA Erythropoietic protoporphyria Sideroblastic anemia X- linked Sideroblastic anemia X- linked with ataxia Microcytic anemia sideroblastic-like (GLRX5) Deficiency of DMT1 Hypotransferri nemia Acerulopla sminemia Deficiency of Steap3 Hb - / (età dipendente) MCV GR RDW = = = = = = = = = Reticulocytes SI -- / % + ++ Ferritin = / - = = = = + = FEP = / - = + = = + Oral responseNO YESNO Iv response YES, not long- lasting NO YESNO InheritanceARAD/ARX- linked AR AR/ADAR Suggested therapy not possible  -carotene Vit B6 Iron chelationEPO Plasma / apotransferrin Iron chelation EPO, iron chelation Iolascon A et al.,2013


35 Defective iron transport or utilization DMT1 deficiency, Hypo-transferrinemia Defects of iron absorption IRIDA (Iron-Refractory Iron Deficiency Anemia) Defects of mitochondrial iron utilization Inherited (and acquired) Sideroblastic Anemias Defects of iron recycling usually normocytic-normochromic anemias Aceruloplasmina, ACD (some cases) Defects of iron Metabolism

36 BMPRs BMP TMPRSS6 SMAD complex SMAD 4 m-HJV SMAD complex P SMAD complex P P mRNA HAMP s-HJV Adapted from Silvestri L, et al. Blood. 2009;113: The role of TMPRSS6 in the hepcidin regulatory pathway

37 CN TMCUB L LL SERINE PROTEASE ATG STOP I212T Y141C S304L R271Q Q229fs L166fs W247fs S561X SEA C510S S570fs Iolascon et al.2010 TMPRSS6 gene and protein N:.amino-terminusC1r/C1s, urchin embryonic growth factor and bone morphogenic protein 1 domain C: carboxy-terminusL: low density lipoprotein receptor clas A domain (LDLR) TM: transmembrane domainSerine Protease: serine protease domain SEA: sea urchin sperm protein, enteropeptidase agrinBlack oval: cleavage activation site CUB: complement protein subcomponents

38 MCV47-60 fL Serum Iron- Tf saturation- sTfR++ BM sideroblasts- FEP+ Liver Ironn Neonatal appearance+/- Effect oral /iv Fe+/- Serum or urinary Hepcidin + InheritanceAR Therapy- Laboratory findings of IRIDA-TMPRSS6 mutations Iolascon A et al.,2013

39 Aknowledgements: my coworkers at CEINGE, Naples

40 Prevalence of Iron Deficiency and Iron Deficiency Anemia Iron nutrition and iron status changes in Italian in infants in the last decade (ISS), % 2% 59% 36% 20% 10% 28% 16% USA Côte-d'Ivoire Asie du Sud-Est Philippine Islands UK 7% 2% 8% 2% France ? 20.7% 5% 1983

41 Breastfeeding and Iron The initiation of solid food should not be delayed 4-6 months after birth (Boyce at al, 2011) Weaning food should be initiated 4 months after birth for infants without risk for atopic dermatitis (Schoetzau et al, 2002) Children need at least 1 month to adapt to solid food (Kang et al, 2006) When nutrition is provided only by breastfeeding for more than 6 months iron intake is insufficient (Hyung etal,2013) Birth 4 months 6 months Weaning food (low risk) Weaning food (lhigh risk) ID if only breastfeeding

42 Red Meat: -beef, horse, heep, duck… White Meat: - rabbit, chicken, turkey, pig… Meat and Iron Iron content Horse3.2 mg/100g Turkey2.5 mg/100g Beef2.1 mg/100g Pig1.5 mg/100g Chicken1.5 mg/100g meat products red meat poultry meat sausages Chi l d Adolescent Adult Indagine INRAN-SCAI

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