neonatal haemochromatosis and gestational …...neonatal liver cirrhosis without iron overload...

03/09/2015

1

Neonatal haemochromatosis and

gestational alloimmune liver disease

XXXVII IPPA Course

Fontainebleau France

September 2015

Dr Sophie COLLARDEAU-FRACHON, MD PhD

Department of pathology

Children and Mothers Hospital

CHU de Lyon, France

[email protected]

1

NH: definition

• rare disease

• fetus and neonate

• H Cottier 1957

• hepatic and extrahepatic siderosis sparing the

reticuloendothelial system

• and severe liver disease

S Collardeau-Frachon, IPPA course, September 2015 2

NH is a phenotype : several etiologies2001

2004

Peter Whitington’s group

Chicago’s Northwestern

University

An alloimmune-mediated

mechanism

S Collardeau-Frachon, IPPA course, September 20153

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2

Alloimmune NH

Hypothesis based on:

• recurrence rate > 80%– similar to rhesus incompatibility

– too high for an inheritance explanation

• no mutations in genes of hereditary haemochromatosis

• affects maternal half-siblings but not paternal half-siblings

• intravenous immunoglobulin (IV-Ig) therapy – during pregnancy reduces the severity and the recurrence rate

of the diseaseHigh-dose immunoglobulin during pregnancy for recurrent neonatal haemochromatosis. Whitington PF, Hibbard JU.Lancet 2004;364:1690–98.

– in neonates: improvements in outcomeTreatment of neonatal hemochromatosis with exchange transfusion and intravenous immunoglobulin. Rand EB, Karpen SJ, Kelly S, et al. J Pediatr 2009;155:566–71.

Whitington PF, Malladi P. Neonatal hemochromatosis: is it an

alloimmune disease? J Pediatr Gastroenterol Nutr 2005;40:544–49.


Alloimmune NH mechanisms

• maternal sensitization

to a fetal hepatocyte

antigen?

• Production of maternal

IgG antibodies directed

against this Ag

• activation of fetal complement via

the classic pathway

• formation of membrane attack

complex on hepatocytes (MAC or

TCC or C5b9)

• Hepatocyte injury and death

transplacental passage of the

IgG antibodies occur in the

subsequent pregnancy

IgG

Hepatocytes

IgG

fetal complement is produced

by the fetus ∼12 WGnature of the fetal hepatocyte

antigen is currently still unknown


GALD

• gestational alloimmune liver disease (GALD)-

associated NH (GALD-NH)

• for each case GALD complement-mediated

hepatocyte injury can be demonstrated

• Positive C5b-9 immunostaining on the

hepatocytes

• GALD is considered to be the most common

cause of NH (>95% of cases)


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Cb9 immunostaining on hepatocytes� Pan X, Kelly S, Melin-Aldana H, Malladi P, Whitington PF. Novel mechanism of fetal

hepatocyte injury in congenital alloimmune hepatitis involves the terminal complement cascade. Hepatology 2010;51:2061-68.

� Whitington PF, Pan X, Kelly S, Melin-Aldana H, Malladi P. Gestational alloimmune liver disease in cases of fetal death. J Pediatr. 2011 Oct;159(4):612–6.

Immunohistochemistry for TCC neoantigen in typical cases of NH

with subacute and chronic liver injuryImmunohistochemistry for TCC neoantigen in cases of

NH with acute liver injury

S Collardeau-Frachon, IPPA course,

September 20157

GALD : mechanisms of iron overload

• Complement-mediated liver injury is the primary

event

• It is not a primary iron overload disease

• MAC-mediated cell lysis

• Fetal/neonatal iron overload and siderosis of

extrahepatic tissues result from fetal liver dysfunction


Proteins involved in iron homeostasis

Iron homeostasis.

Step 1 represents DMT1-mediated iron

absorption into mature enterocytes. Step 2

indicates ferroportin-mediated movement of

iron from enterocytes (and macrophages)

into the circulation. Step 3 illustrates

movement of iron from the circulation into

hepatocytes and duodenal enterocytes

fostered by the complex of Transferrin

receptor 2 and the HFE protein.

Step 4 indicates hepatocyte production and

excretion of hepcidin into the circulation.

Hepcidin downregulates activity of

ferroportin, predominantly in duodenal

enterocytes and macrophages (step 2).


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GALD: mechanisms of iron overload

• Ferroportin is highly expressed in placental

cells

• Hepcidin is produced by the fetal liver and is

the main regulator of iron efflux from the

placenta

• reduced hepatocyte mass in GALD

– ↘ hepcidin production

– impair the feedback control of placental iron flux


Proposed pathophysiology of neonatal hemochromatosis.

(Left panel) Iron transport across the normal placenta, where maternal transferrin bound iron is taken up through transferrin medicated endocytosis at

the apical (maternal) membrane of the syncytiotrophoblast, which is released at the basolateral membrane by ferroportin and binds to fetal transferrin.

Iron release is controlled by the fetus through fetal hepcidin, which inhibits ferroportin.

(Right panel) Iron transport across the placenta of a fetus with neonatal hemochromatosis. Reduced fetal hepcidin and reduced transferrin concentration

are proposed to result in dysregulated transplacental iron transfer and increased non-transferrin bound iron, which is toxic and primarily stored in tissues

with high expression of the transition metal transport protein ZIP14 and low expression of the iron export protein ferroportin.


September 201511

GALD : extrahepatic hemosiderosis

determined by the tissue’s capacity for

importing non-transferrin-bound iron (NTBI)

ZIP14 facilitates the uptake of NTBI into various cells


September 201512

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GALD : a spectrum

• fetal acute liver failure and fetal death with or without iron overload

• neonatal liver failure with liver and extrahepatic siderosis

• antenatal cirrhosis and mild neonatal liver disease without hepatic siderosis

• mild neonatal liver disease (anomalies of LFT)

Inter and intrafamilial variability

individual sensitivity to alloimmune injury?

begins in utero in all cases (midgestation) S Collardeau-Frachon, IPPA course, September 2015 13

GALD : clinical presentation

Neonatal Liver Cirrhosis Without Iron Overload Caused by Gestational Alloimmune Liver Disease

Debray FG, de Halleux V, Guidi O, Detrembleur N, Gaillez S, Rausin L, Goyens P, Pan X, Whitington PF.

Pediatrics. 2012 Apr;129(4):e1076-9

2 sets of twins (1 set without pregnancy immunotherapy): 1 infant with liver failure

and the other nearly unaffected (elevated serum AFP and/or ferritin levels)

34.5 weeks of gestation

no liver or extrahepatic siderosis (liver biopsy and MRI)

But antiplatelet antibodies in the mother’s serum→ fetal alloimmune thrombopeniaS Collardeau-Frachon, IPPA course,

September 201514

GALD : clinical presentation• panethnic distribution

• sexe ratio ≈1

• Mother: previous fetal or neonatal loss

• No consanguinity

• Antenatal manifestations: in late second or third trimester

– IUGR, oligohydramnios, hydrops, hepatomegaly, ascites

→ fetal death, stillbirth and prematurity

• Neonatal manifestations:

– Liver failure usually within the first hours of life →

multiorgan failure→ death

• Without treatment: very poor prognosis


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GALD: Laboratory tests

• Liver failure

– severe coagulopathy :↑ INR (normal range in newborns: 0.8–1.5)

– hyperammonemia (>95 umol/L)

– hypoglycemia

– hypoalbuminemia

• Liver function test

– Transaminases and γGT: N or mildly ↑

– ↑ AFP >100 000 ng/mL (normal values in term newborns <80 000 ng/mL)

– ↑direct and indirect bilirubin

• Iron overload

– ↑ ferritin (normal values 40–775 ng/mL)

– hypersaturation (up to 95–100%) of the available transferrin

• Severe thrombocytopenia (platelet count <50 000 μL) +/- anemia


• nonspecific and may mimic – viral or bacterial infections but negative infectious work-up

– perinatal asphyxia : low Apgar scores +respiratory distress syndrome + premature neonates , tachypnea, pulmonary hypertension, pulmonary hemorrhage

– disseminated intravascular coagulopathy (DIC):consumption of clotting factors and platelets+ schistocytes + severe bleeding

– haemolytic-uraemic syndrome( HUS): acute oligo-anuric renal failure + anemia with fragmented red blood cells (schistocytes )+ thrombocytopenia

– metabolic disorders

– congenital hepatic arteriovenous malformation: patent ductus venosus + DIC

• liver failure and hyperferritinemia are not pathognomonic for NH

present in other causes of fulminant liver


GALD : clinical & biological

presentation

Doppler ultrasound : patent ductus venosus

• in the setting of portal hypertension

• mistaken for a congenital hepatic arteriovenous shunt


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GALD: pathological findingsacute hepatocyte injury

• fetal acute liver failure and fetal death

• Small proportion of GALD cases

• with or without iron overload: extrahepatic siderosismight not have time to develop

• Liver injury:– Global panlobular hepatocyte necrosis

– no or minimal fibrosis

– no viable hepatocytes

– only ‘‘ghosts’’ remained

– Absent hepatic cords

– # postmortem hepatocyte autolysis in which cords remain

Whitington PF, Pan X, Kelly S, et al. Gestational alloimmune liver

disease in cases of fetal death. J Pediatr 2011;159:612–16


GALD : pathological findings

acute hepatocyte injury


Abortion at 33WG

Fetal and placental Hydrops at 27WG

Massive necrosis

no viable hepatocytes

Liver : Perls score 4

Extrahepatic iron: duodenum & stomach

glands only

subacute or chronic liver disease

• in most cases, the process moves more slowly

• starting in midgestation: fetus and neonates

• extrahepatic siderosis present

• Liver injury: – extensive fibrosis with mild inflammation

– loss of hepatocytes

– surviving cells show • giant cell

• or pseudoglandular transformation and varying degrees of cholestasis

• tubular forms devoid of bile, similar to “ductular reaction” neoductules or neocholangioles

– focal nodular regeneration

– most of the iron deposition in the hepatocytes


GALD: pathological findings

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GALD : pathological findingssubacute/chronic hepatocyte injury

Heterogeneous

Areas with extensive fibrosis and variable nodules


panlobular fibrosis

loss of hepatocytes

mild inflammation

Pseudoglandular

formations

with bile plug

giant cell


neoductules

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Nodular formation: focal nodular regeneration or areas of preserved hepatocytes?

surrounded by fibrosis

Sometimes entirely necrotic


Liver iron overload

Inside the hepatocytes , giant cells, pseudoacinar formation, neoductules

Some macrophages can be stained

27

1 2

3 4

Liver iron overload: Perls semiquantitative score

< 25%25%–50%,

50%–75% > 75%


Perls score is inversely proportional to fibrosis progression

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10


Birth 33GW, died at 6 days

TOP at 33 WG


Birth : 30GW

Died at 5 days

Extrahepatic iron overload

• acinar cells of the pancreas

• acinar cells of minor salivary glands

• proximal renal tubules

• thyroid follicles

• adrenal cortex

• myocardium

• parathyroid

• pituitary gland


September 201530

Extrahepatic iron storage is only seen

after Perls staining

localization varied:

• depending on the age

• within the same sibship

Sometimes:

• only seen in a few organs

• with a mild intensity (high-power

magnification is required)

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In fetuses: more frequent in thyroid than in pancreas

In neonates: more frequent in pancreas than in thyroid


September 201532

Usually within a few proximal tubules

Extrahepatic iron overload

in GALD and non GALD cases


Neonatal hemochromatosis phenotype: a multicentric retrospective study

of 72 cases with characterization of hepatic and extrahepatic iron overload.

Béatrice Nadaud, Estelle Dubruc, Sophie Collardeau-Frachon

32 GALD cases

40 non GALD cases

thyroid pancreas kidneys

GALD fetuses: 10 GALD neonates: 22 Non GALD fetuses:13 Non GALD neonates: 27

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myocardium Paratracheal glands

parathyroid Thymus: Hassal corpuscles

GALD: other lesionsHypoperfusion & ischemic lesions

Renal tubular dysgenesis : 30% of our series

– reduced hepatocyte mass

– ↘ hepatic angiotensinogen

– proximal renal tubular development

Other renal ischemic lesions:

• collapse of glomerular tufts with enlargement of the urinary

space often associated with renal tubular dysgenesis


September 201535

• Bonilla SF, Melin-Aldana H, Whitington PF. Relationship of proximal renal tubular dysgenesis

and fetal liver injury in neonatal hemochromatosis. Pediatr Res 2010;67:188–193.

• Azar D, Bonilla S, Amaro D, Whitington P, Krous H. Reduced angiotensinogen in neonatal

hemochromatosis leads to impaired development of proximal renal tubules and

compensatory glomerular changes. Lab Invest 2011;91:357A.

CD10EMA

Renal tubular dysgenesis : absence or paucity of proximal tubules


03/09/2015

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Renal tubular dysgenesis and collapse of glomerular tufts

• Significant glyceroluria might be the reflect of

proximal renal tubular dysgenesis?

• 2 siblings

– 1 died of sepsis (E Coli)

– 1 with increased excretion of lactate and pyruvate

• extensive liver siderosis and injury and C5b9+

• siderosis of heart, pancreas, thyroid and renal tubule

• DTR


• Hypoperfusion & ischemic lesions

– hypocalvaria

– microcephaly

– with cerebral ischemia


GALD: other lesions

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Chronic fetal distress

thymic hypoplasia

Oligohydramnios sequence

pulmonary hypoplasia

arthrogryposis

facial dysmorphism

Portal hypertension

splenomegaly

patent ductus venosus

Extrahepatic hematopoiesis due to liver failure


September 201540

GALD: other lesions

Myofibroma: 3 cases reported in the litterature


GALD: other lesions

Aksoy F, Go¨ksel S, Ilvan S, Dervis¸og˘lu S, Ramazanog˘lu R. Congenital generalized infantile

myofibromatosis and neonatal hemochromatosis: an autopsy case report. Turk J Pediatr

2000;42:334–337.

Dalhoj J, Kiaer H, Wiggers P, Grady RW, Jones RL, Knisely AS. Iron storage disease in parents and sibs

of infants with neonatal hemochromatosis: 30-year follow-up. Am J Med Genet 1990;37: 342–345.

Collardeau-Frachon S, Heissat S, Bouvier R, Fabre M, et al. French retrospective multicentric study of

neonatal hemochromatosis: importance of autopsy and autoimmune maternal manifestations.

Pediatr Dev Pathol. 2012;15:450-70.

lung heart


GALD: other lesions: placentaChronic histiocytic intervillositis

CD68

Chronic villitis, some avascular villi, perivillous fibrin deposition

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should be suspected :

• in all neonates with antenatal or postnatal

signs of severe liver disease

– growth restricted

– born prematurely

• unexplained fetal demise

– unexpected intrauterine fetal death in the late-

second and third trimester

GALD: diagnosis


September 201543

Based on :

• demonstration of extrahepatic siderosis

– biopsy of oral mucosal salivary glands: Perls staining

– T2-weighed MRI : low signal intensity in pancreas (heart and adrenal glands) compared to spleen

• Immunohistochemical study with antiC5b9: positive staining on and or hepatocytes >75%

GALD: diagnosis


September 201544


MRI-T2: d ecreased T2 signal intensity of the hepatic

parenchyma (long arrows) and pancreas (short arrow)

GALD: diagnosis

iron in oral mucosal salivary glands

Hepatocytes C5b9+

03/09/2015

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GALD: diagnosis and management


Comments

1/Extrahepatic iron overload is not specific of GALD

Iron in oral mucosal salivary glands

- is not always present in GALD cases

- can be present in non GALD cases

2/ Be careful with C5b9 immunohistochemistry

-specially on liver biopsy sample

- is not specific of GALD

3/ Always think about other differential diagnoses– importance of autopsy

– importance of liver histological examination

– Intravenous immunoglobulin therapy • is very expensive ( average cost of a treatment course > USD 100,000 / France 65000

euros/ pregnancy)

• and may have side-effects


September 201547

comments

1/Extrahepatic iron overload is not specific of GALDNH is a phenotype: several diseases can present with hepatic

+/- extrahepatic siderosis

Association

with GALD


myofibromatosis

Can be secundary to chronic fetal distress

Infections

• Parvovirus B19: 5*

• CMV:3*

• HSV:3*

• Echovirus

• Adenovirus

• Enterovirus:2*

• Orthomyxovirus A or B

• Respiratory syncytial virus

• Rubella

• Chlamidya psittaci

• Coxiella burnetii

• Mycoplasma pneumoniae

• S aureus

• Toxoplasma gondii:1*

• E Coli:1**Neonatal hemochromatosis phenotype: a multicentric retrospective study



03/09/2015

17

comments

1/Extrahepatic iron overload is not specific of GALDNH is a phenotype: several diseases can present with hepatic

+/- extrahepatic siderosis

Association

with GALD

• Mitochondrial cytopathies

• DGUOK mutations

• GRACILE syndrome

• Pearson syndrome

• Transaldolase deficiency

• Familial Hemophagocytic

lymphohistiocytosis (FHL)

• Martinez-Frias syndrome

• 16p duplication

• CDG1a (PMM2)

• Mitochondrial cytopathies

• DGUOK mutations

• GRACILE syndrome

• Pearson syndrome

• Transaldolase deficiency

• Familial Hemophagocytic

lymphohistiocytosis (FHL)

• Martinez-Frias syndrome

• 16p duplication

• CDG1a (PMM2)

Personal cases

• Congenital leukemia & chromosomal

breakage syndrome (Bloom syndrome)

• Congenital dyserythropoietic anemia

type I (CDA I)S Collardeau-Frachon, IPPA course, September 2015

49

myofibromatosis


Mol Genet Metab 2010;101:253-7

GRACILE syndrome

Growth Retardation, Aminoaciduria, Cholestasis, Iron overload, Lactacidosis, Early death

Diseases with NH phenotype13 groups of etiology

Alloimmune diseasesGALD

anti-red cells (Rhesus or private antigens)

anti-platelets

Mitochondrial cytopathies

DGUOK, Gracile, Pearson

Chromosomal anomalies

T21, T18, 16p

Neonatal anemia

Congenital

dyserythropoietic

anemia

Congenital heart disease

Infections

Metabolic disorders

TALDO

Zellweger

Tyrosinemia

CDG1a

Neonatal diabetes

Marinez-Frias

Donohue

Neonatal cholestasis

Delta 4-3 oxo

Congenital proliferation

Leukemia

FHL

Maternal autoimmune disorders

Neonatal lupus

Tricho-hepato-enteric syndrome

Exogeneous

Transfusions

Toxic agentsS Collardeau-Frachon, IPPA course,

September 201551

03/09/2015

18


and NH


dysimmunity manifestations in half of the mothers

5 mothers : personal history of autoimmune disease:

• systemic erythematous lupus (1 case)

• hypothyroidism (2 cases)

• peripheral vascular disease (1 case)

• autoimmune hepatitis (1 case)

9 mothers without clinical autoimmune disorder:

antinuclear autoantibodies at time of delivery

Characterization of the autoantibodies in 4 cases:

• anti-Ro/SSa and anti RLa/SSB in 1 case

• anti-mitochondria and anti-phospholipid in 2

cases

• and anti-cardiolipid in 1 case

Indirect immunofluorescence study :nuclear

staining of hepatocytes and endothelial cells


2013

Some NH cases could be a possible consequence of autoimmune disorders in the

mothers with transfer of autoantibodies through the placenta


and NH

Schoenlebe J, Buyon JP, Zitelli BJ, Friedman D, Greco MA, Knisely AS. Neonatal

hemochromatosis associated with maternal autoantibodies against Ro/SS-A and

La/SS-B ribonucleoproteins. Am J Dis Child 1993;147:1072–1075.

1 case

2 / 8 mothers with anti-Ro/SSa and

anti R-La/SSB antibody

AMA in the mother& the child

Diseases with NH phenotype



anti-platelets




T21, T18, 16p

Neonatal anemia

Congenital

dyserythropoietic

anemia


Infections

Metabolic disorders

TALDO

Zellweger

CDG1a

tyrosinemia

Neonatal diabetes

Martinez-Frias

Donohue


Delta 4-3 oxo


Leukemia

FHL



Exogeneous

Transfusions

Toxic agents

Fetus or

at birth


September 2015

54

03/09/2015

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Diseases with NH phenotypeExtrahepatic iron overload



anti-platelets




T21, T18, 16p

Neonatal anemia

Congenital

dyserythropoietic

anemia


Infections

Parvo

CMV

HSV

E.Coli

Metabolic disorders

TALDO

Zellweger

Tyrosinemia

CDG1a

Neonatal diabetes

Martinez-Frias

Donohue


Delta 4-3 oxo


Leukemia

FHL



Exogeneous

Transfusions

Toxic agents





September 201555

Diseases with NH phenotypeReticuloendothelial system not spared



anti-platelets




T21, T18, 16p

Neonatal anemia

Congenital

dyserythropoietic

anemia


Infections

Parvo

CMV

HSV2

E.Coli

Metabolic disorders

TALDO

Zellweger

Tyrosinemia

CDG1A

Neonatal diabetes

Martinez-Frias

Donohue


Delta 4-3 oxo


Leukemia

FHL



Exogeneous

Transfusions

Toxic agents





September 201556

Iron in oral mucosal salivary glands

and/or pancreas T2 low signal intensity on MRI

can lack in GALD


“Siderosis of the buccal glands and other extrahepatic tissues is not seen in neonatal

diseases other than NH/GALD” (Whitington PF. Fetal and infantile hemochromatosis.

Hepatology 2006;43:654–60.): not true

Perls +

- 30% of GALD

- HSV2, T18, enterovirus,CDA1

Pancreas low signal intensity

50% of GALD



Béatrice Nadaud, Estelle Dubruc, Sophie Collardeau-FrachonLittérature

• T21

• DGUOK

• Lupus

• 16p

• Delta 4-3 oxo

03/09/2015

20

2/comments

C5b9 immunohistochemistry

Non GALD cases : 37 (31 liver biopsies)– 13 biliary atresia

– 3 PFIC1

– 3 PFIC2

– 3 D4-oxosteroid reductase deficiency

– 3 cases of total parenteral nutrition-associated cholestasis afterbowel resection

– 3 Alagille

– 2 alpha-1-antitrypsin deficiency (PiZZ genotype)

– 2 tyrosinemia type 1

– 1 abetalipoproteinemia

– 1 glycogen storage disease type 1

– 1 inspissated bile syndrome after cardiac surgery

– 1 tricho-hepato-enteric syndrome

– 1 herpes simplex 1

10.8% à 12.5% (range 0%-45%) of hepatocytesexpressed C5b9

2 studies: 41 GALD cases with >75% of hepatic parenchyma stained with anti-C5b9

� Pan X, Kelly S, Melin-Aldana H, Malladi P, Whitington PF. Novel mechanism of fetal hepatocyte injury in

congenital alloimmune hepatitis involves the terminal complement cascade. Hepatology 2010;51:2061-68

9 cases in the upper

quartile of values: 3 PFIC1,

1 D4-3oxo, 1 Alagille, 1

tyrosinemia , 1tricho-

hepato-enteric syndrome,

2 biliary atresia


33 GALD cases (27 autopsy and 6 liver explants)

Whitington PF, Pan X, Kelly S, Melin-Aldana H, Malladi P. Gestational alloimmune liver disease in

cases of fetal death. J Pediatr. 2011 Oct;159(4):612–6: 8 cases

1+ = <25%, 2+ = 25%-50%, 3+ = 50%-75%, 4+ = >75% positive hepatocytes


2/comments


Non GALD cases with NH phenotype: 40 cases

• 2/5 parvo: 5%

• 3 / 4 CMV: <5%

• 1 HSV1: 90%

• 1/2 HSV2: 80%

• 1 /2 Enterovirus:90%

• 1/3 DGUOK: 80%

• 3 /3 Allo-imm anti Red B cells: 80%

• 2/2 T18 < 5%

• 1/3 T21: 90%

• 3/5 heart: 5%

• 1Taldo : 20%

• 1D4-3oxo: 90%

• 2: leukemia <5%

• 1 GRACILE<5%

• 1CDA I

• 1 Martinez-Frias

• 1CDG1a

• 2 FLH

• 1 E coli

32 cases of NH alloimmune type

C5b9 on 20 cases (still available blocks):

anti-C5b9 neoantigen, Quidel, San Diego,CA

dilution: 1/150

expressed in all cases but

>75% in 40%

<75% in 60%

Average: 64%

Non GALD cases without siderosis: 10 cases

• 1 Giant cell hepatitis with autoimmune hemolytic

anemia: 90%

• 1Gaucher : 80%

• 2 BA: 0%

• 2 Alagille: 0%

• 1 A1AT: 0%

• 1PFIC1: 20%

• 1 PFIC2:0%

• 1Tyrosinemia: 0%

Relevance of C5b9 immunostaining in the diagnosis of neonatal

hemochromatosis : a retrospective multicenter study.

Estelle Dubruc, Beatrice Nadaud, Sophie Collardeau-Frachon.S Collardeau-Frachon, IPPA course, September 2015 60

2/comments


03/09/2015

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HES Perls C5b9

Co

ntr

ol c

ase

sa

me

ag

eG

ALD

ca

se


hemochromatosis : a retrospective multicenter study ;

Estelle Dubruc, Beatrice Nadaud, Sophie Collardeau-Frachon.S Collardeau-Frachon, IPPA course, September 2015

61

HES Perls C5b9

x200

x40


hemochromatosis : a retrospective multicenter study

Estelle Dubruc, Beatrice Nadaud, Sophie Collardeau-Frachon.

G

A

L

D

C

A

S

E

S

Influence of :

→ fixation : formalin (old cases, different

centers)

→ type of sample: liver biopsy or autopsy

→ Age : neonate (77,5%)/ fetus (62%)

→ Perls : no

→ immune factors ?


September 2015 62

34GW

died at35days

100%

38GW

died at 45days

100%

32GW

died at 3 days

50%

Born at 32GW died at 5days

40%

F 27 GW

70%

F 29GW

20%

F 32GW

50%

Born at 32GW died at

3 days

50%

F 26 GW

75%

GA

LD ca

ses

03/09/2015

22


HSV2

Delta4-3 oxoGaucher Giant cell hepatitis Coombs+

DGUOK parvo

No

n G

ALD

case

s

Definitive diagnosis of GALD

• Still remains difficult

– Heterogeneity of liver hemosiderosis & C5b9

expression

• Often a diagnosis of exclusion

• Importance of correlations

– clinical, biological, radiological and pathological

findings

• Easier on autopsy


September 201565

• 1st pregnancy? Previous cases of child or fetal loss

• Mother auto-immunity?

• Consanguinity?

• Dysmorphism, malformations?

• Onset of symtoms? Immediately after birth or not?

• Karyotype?

• Infections?

• Lactate/pyruvate ratio >20→ mitochondrial respiratorychain disorders

• LFT: low GGT → delta 4-3 oxo


September 201566


Importance of clinical & biological data

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• All organs can be examined and sampled

– Look for other macroscopic and microscopic malformations

– Don’t forget to take bone marrow sample

– Placenta : signs of infections or dysimmunity

• Renal tubular dysgenesis: more frequent in GALD cases?

• Allows to do Perls staining on multiple organs

– extrahepatic iron overload is not limited to pancreas and labial salivary

glands

– must be systematic on liver, thyroid, pancreas , kidneys, spleen +/-

lymph nodes and bone marrow

• Allows to take samples for biochemical, genetic, molecular

investigations

– Frozen samples : thymus (lymphocytes), liver, muscle, kidneys, lungs,

placenta

– skin biopsy: fiboblasts cultureS Collardeau-Frachon, IPPA course, September 2015 67


autopsy is very hellpful

Acute fetal liver failure:

• parvovirus B19 +++:

– inclusion sometimes difficult to see /macerated

fetus→ immunostaining

• transaldolase deficiency (autosomal recessive) :

– dysmorphism & malformations may lack in fetus

– polyols urinary analysis

– TALDO1 gene


September 201568

Similar liver lesions than GALD

Subacute/ chronic liver failure:

• DGUOK:

– steatosis might be focal, oncocytic cells not always present

• Congenital dyserythopoietic anemia 1 (autosomal recessive)

– pseudo-tumoral multivisceral hematopoiesis

– Bone marrow: bi-, tri- or tetra-nucleated polychromatic

erythroblasts and internuclear chromatin bridges in some

erythroblasts

– CDAN1 gene

• FHL (autosomal recessive): 5 genes

– carefully look for activated macrophages (sometimes few

in the liver)S Collardeau-Frachon, IPPA course,

September 201569

Similar liver lesions than GALD

03/09/2015

24

Thank you!


neonatal haemochromatosis and gestational …...neonatal liver cirrhosis without iron overload...

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