Obstetrica }i Ginecologia 51

Obstetrica }i Ginecologia LXVI (2018) 51- 56 Case Report

CORESPONDENCE: Monica G. H@}m@}anu, e-mail:monica.hasmasanu@gmail.comKEY WORDS: neonatal hemochromatosis, GALD, renal failure, hepatic failure, coagulopathy, ferritin

A RARE CASE OF GASTROINTESTINAL BLEEDING: NEONATALHEMOCHROMATOSIS

Gabriela Zaharie1,a, D. Muresan2,a, S. Andreica1,a, Anamaria Hosu3,a, D. Boitor2,a, AdelinaStaicu2,a, Monica Hasmasanu1,a,*, Ioana Ighian3,a, E.C. Botan3, Andrada R. Trif3,

Melinda Matyas1,a

1Iuliu Haţieganu University of Medicine and Pharmacy, Department of Neonatology, Cluj-Napoca, Romania.2Iuliu Haţieganu University of Medicine and Pharmacy, Department of Obstetrics anGynecology, Cluj-Napoca, Romania.3County Clinical Emergency Hospital, Cluj-Napoca, Romania

a The authors have the same contribution

AbstractNeonatal hemochromatosis is a rare disease with a prevalence of <1/1.000.000, of probable alloimmune

etiology marked by severe hepatic dysfunction occurring in utero or in the early neonatal period. Its outcome isoften fatal. We report a case of a female neonate who presented shortly after birth coffee ground vomiting andgradual liver and renal failure. Neonatal hemochromatosis was confirmed postmortem.

Acute liver failure is a relatively rare condition in neonates, and early diagnosis and treatment are crucialfor the treatable conditions. Early diagnosis and proper managements may help to improve the survival rate.

Rezumat: Un caz rar de sângerare gastrointestinală: hemocromatoză neonatală

Hemocromatoza neonatală este o boală rară cu o prevalenţă de <1/1.000.000, cel mai probabil de etiologieautoimună, în care se evidenţiază disfuncţie hepatică severă, debutată in utero sau in perioada neonatală precoce.Consecinţele sunt, de obicei, fatale. Vă vom descrie cazul unui nou-născut de sex feminin care, la puţin timp dupănaştere, a prezentat vărsături în zaţ de cafea şi insuficienţă renală şi hepatică cu agravare progresivă. Hemocromatozaneonatală a fost confirmată postmortem.

Insuficienţa hepatică acută este o situaţie rar întâlnită la nou-născuţi, iar diagnosticarea şi tratamentulprecoce sunt cruciale. Diagnosticarea precoce şi tratamentul adecvat ar putea contribui la îmbunătăţirea şanselorde supravieţuire.

Cuvinte cheie: hemocromatoză neonatală, GALD, insuficienţă renală, coagulopatie, feritină

Introduction

Neonatal hemochromatosis (NH) is a raredisease with a prevalence of <1/1.000.000(ORPHA:446), but the most common causes of liverfailure in the neonatal period. In 2010 it wasdiscovered that gestational alloimmune liver disease

(GALD) is the cause of fetal liver injury leading tonearly all cases of NH and to the conclusion thatwhile NH is both congenital and familial, it is notheritable (1). NH represents a form of secondaryiron overload in which severe fetal liver disease

52 Obstetrica }i Ginecologia

disturbs maternofetal iron homeostasis and in fact isa phenotypic expression of severe fetal liver disease(2). Maternal antibodies of the IgG class are activelytransported across the placenta to the fetus from aboutthe 18th week of gestation. In NH-sensitized mothers,transplacental passage of maternal IgG to the fetusis accompanied by movement of anti-fetal liverantigen IgG to the fetal circulation, where it binds tothe liver antigen and results in immune injury of thefetal liver (3). Clinically, NH infants are unique inthat they have evidence of fetal insult and neonatalliver failure accompanied by extrahepatic siderosis.GALD can present anytime from 18 weeks ofgestation to 3 months post-delivery. Neonates withGALD often present hypoglycemia, coagulopathy,hypoalbuminemia, jaundice, edema with or withoutascites, oliguria. Studies have shown high levels ofalpha-fetoprotein, hypersaturation of availabletransferrin and hyperferritinemia (4, 5).

In the past, treatment consisted in a cocktailof antioxidants and an iron chelator, with a successrate of 10% to 20% (6). Nowadays, treatmentemploys the combination of double-volume exchangetransfusion to remove existing reactive antibody andadministration of high-dose IVIG (1 g/kg) to blockantibody action (2). In case of severe acute liver failureand in non-responders, liver transplantation is thestate-of-the-art therapy (survival rates of 50%) (7).

We report a case of a female neonate whopresented shortly after birth with coffee groundvomiting and gradual liver and renal failure. Neonatalhemochromatosis was confirmed postmortem.

CASE DESCRIPTION

A female Caucasian neonate was born at 37weeks gestation from a secundigesta, secundiparousmother by caesarian section due to oligohydramniosand severe intrauterine growth restriction. HerAPGAR Scores were 8 at 1 minute and 9 at 5minutes. Birth weight was 2300 g (10 th to 25th

percentile), length 50cm (75th percentile), and headcircumference 31 cm (10 th to 25th percentile).Umbilical-cord blood gas analysis was within normal

parameters. The newborn had some urinarydischarge in the delivery room.

The mother’s personal history revealed onevaginal birth at term with a healthy, eutrophic child,no exposure to teratogenic drugs or infections duringpregnancy. Also, there were no family history ofchronic liver diseases or metabolic disorders and noconsanguinity between the parents. The motherdenied any consumption of alcohol during pregnancy.Furthermore, routine genetic screening and blood testswere not remarkable. The mother’s was type Bpositive.

Prenatal ultrasound demonstrated a single,live hypotrophyc foetus with normal morphology,without any, serous effusions with a biometrycorresponded to 13 percentile, normal middle cerebralto umbilical artery Doppler ratio, no notching on theuterine artery, but a constant slightly tachycardicfoetal heart rate.

A worrying thing during pregnancy was theonset of idiopathic oligohydramnios starting with 35weeks of gestation.

The newborn was admitted in the neonatalunit. Upon arrival the neonate had a good generalappearance, with normal skin tone, a respiratory rateof 50 breaths/minute, lungs clear to auscultation,without rales or diminished breath sounds, normalheart sounds with a regular rhythm, no murmurs,capillary refill less than 3 seconds, pulse 150b/min,abdomen was soft, nondistended, nontender, goodmuscle tone, physiological reflexes, anterior fontanel1/1cm, normotensive. The infant was provided withprotection from heat loss in an incubator, prophylaxisfor hemorrhagic disease of the newborn, oral feedingand glucose levels were monitored.

Gradually the general appearancedeteriorated and, at 12 hours of life, the newbornpresents with coffee ground vomiting, oliguria, axialhypotonia, jaundice which resulted in admission in theneonatal intensive care unit. The baby rapidlydeveloped respiratory distress, severe renal failurewith anuria and liver failure with ascites.

Ultrasound showed fluid in the abdomen,hepatosplenomegaly, gall bladder edema with bilesludge, low bowel peristalsis, acute kidney injury(Fig.1 a, b).

A rare case of gastrointestinal bleeding: neonatal hemochromatosis

Obstetrica }i Ginecologia 53

Laboratory tests revealed liver failure (limitedcytolysis: CK 7359 U/L, CK-MB 222 U/L, LDH 2820U/L), high ASAT,ALAT - Fig. 2; hypoalbuminemia(1,32 g/dL) with subsequent altered coagulation tests(APTT 81 sec, fibrinogen 42,5 mg/dl, PT 49,9 sec,INR 5,59, IP 15,8%), renal impairment (Fig. 3),cholestasis (Fig. 4), persistent anemia (HGB 9 g/dl,

HCT 25,1%), thrombocytopenia (46 10^9/L),hypocalcemia, high ferritin levels (652 ng/ml), normaliron levels (116mg/dl). Inflammatory markers wereconstantly negative.

Patient’s blood group was O Rh positive.Direct Coombs test was negative.

Fig. 1 a and b Liver and kidney ultrasound

Fig. 2. ASAT and ALAT levels (mg/dl)

Fig. 3 Creatinine and urea levels (mg/dl)

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54 Obstetrica }i Ginecologia

As the patient’s health rapidly declined weprovided life support measures: intubation andmechanical ventilation, positive inotropic treatment(Dopamine, Dobutamine, and Adrenaline), diuretic(Furosemide).

She repeated gastrointestinal hemorrhages,which required multiple fresh frozen plasma, red bloodcell and platelet transfusions, recombinant factor VIIaadministration and total parenteral nutrition.

The combination of oligohydramnios, smallbirth weight, elevated ferr itin levels,thrombocytopenia, liver and renal failure, made thediagnosis of NH most likely. IVIG treatment (1g/kg)was started on th 5th day of life but unfortunately anuncontrolled pulmonary hemorrhage occurred and thepatient died on the same day. Due to the fulminantevolution of the case, no MRI nor biopsy of the oralmucosa were performed.

Postmortem studies depicted severe hepaticlesions with cirrhosis. Histopathology showed

deposition of iron in the hepatocytes, Kupffer cells(Fig. 5), pancreatic (Fig. 6) and kidney cells. Basedon the findings, the diagnostic of neonatalhemochromatosis was established.

The pathological examination of the placentarevealed multiple calcifications, hypertrophic placenta(90th percentile) and an area of 2/1 cm of infarction.

Discussion

Neonatal hemochromatosis should besuspected in all neonates with antenatal or postnatalsigns of severe liver disease. The diagnosis remainsa challenge in early stages, therefore in severe casesit is made postmortem.

In the early stages of our case we had aseemingly well newborn baby, with little to no healthissues, who started developing symptoms of whatappeared to be either hemorrhagic disease of the

Fig. 4 Total bilirubin and direct bilirubin levels (mg/dl)

Fig. 5 Images of hepatic parenchyma with iron overload of the hepatocytes and Kupffer cells (left panel:H&E stained section, magnification 20x; right panel: Perls’ stained section, magnification 40x)

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Fig. 6 Pancreatic parenchyma with iron overload in the acinar cells (Perls’ stained section, magnification40x)

newborn or had simply swallowed some blood duringbirth which were treated as such. Afterwards, whenthe general appearance worsened and the infant wasadmitted to the neonatal intensive care unit, theexcessive severity of symptoms did not match therelatively mild alterations on the diagnostic tests. Themajority of the abnormal test results could beexplained by perinatal hypoxia (elevated levels ofcreatinine, urea and transaminases, cytolysis,thrombocytopenia). As the newborn developed morecomplications, these were followed by anemia, alteredcoagulation panel which were treated with bloodtransfusions and coagulation factor. This was thoughtto be an acute surgical abdomen but was dismissedby the surgical consult.

Most affected live-born babies showevidence of fetal insult (intrauterine growth restriction,oligohydramnios). Liver insult usually presents withinhours after birth often associated with multiorganfailure (1, 8, 9). However, in our case, liver damagebecame only slightly apparent and only after the firsttwo days of life, which led to a significant delay inreaching the correct diagnosis.

The oligohydramnios installed during theprenatal period may be explained by the renalhypoplasia with dysgenesis of proximal tubules andpaucity of peripheral glomeruli which has beendescribed in patients with NH. This is due to the injuryof the hepatocites starting from week 24 of gestation,which leads to a reduced angiotensinogen productionand defective renal development (1, 10).

Although liver damage begins in the prenatalperiod, hemochromatosis prenatal diagnosis is verydifficult due to the lack of specific call signs.

The obstetr ician should consider thediagnostic of hemochromatosis if there are signs offetal liver damage e.g fetal anemia (considering thatduring this period hematopoiesis occurs mostly in theliver), which in severe forms can lead to non-immunehidrops or idiopathic oligohydramnios.

In these cases, fetal blood sampling for thedirect determination of fetal hemoglobin, hematocritbut also hepatic enzymes, albuminemia, bilirubinemiaor the Betke-Kleinhauer test can be considered forthe elucidation of the diagnosis, thus only earlyrecognition of this disease can provide a survivalchance for these children.

Only the knowledge of the disease entityallows antenatal diagnosis and rational perinatalmanagement.

In the case of our newborn it was whenrepeated hemorrhages occurred on an underlyingrenal and hepatic failure that we started to considerthe diagnosis of NH. Then we identified elevatedferritin and serum iron levels, confirming ourhypothesis, and started treatment with IVIG.

Demonstration of extrahepatic siderosis isnecessary to make the diagnosis of NH. In livingbabies, an oral mucosa biopsy to obtain glandulartissue or a magnetic resonance imaging (MRI) todocument siderosis of various tissues (particularly theliver and the pancreas) can be made (1, 11, 12). In

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56 Obstetrica }i Ginecologia

the case of our newborn, the fulminant evolution andthe somewhat misleading results of the laboratorytests prevented us from establishing a preliminarydiagnosis of NH earlier, and thus the infant had exitedbefore we could run the appropriate tests.

When presented with an infant in liver failure,it is recommended that one dose of IV IG should begiven, while NH is being considered. Regardless theetiology of the disease, one dose of IG poses littlerisk for the neonate. If NH is proven and the infanthas not shown significant clinical improvement, thenexchange transfusion can be performed followed bya second dose of IVIG (2). NH is a frequent indicationfor liver transplantation in the first 3 months of life asstudies have shown that iron does not redeposit aftertransplantation.

Accumulating experience indicates thatsevere NH can be prevented by treatment duringgestation .The current guideline for treatment consistsof IVIG administered at a dose of 1 g/kg body weightat 14 weeks, 16 weeks, and weekly from the 18thweek until the end of gestation. It should be notedthat without gestational treatment, the rate ofrecurrence of lethal disease is >90 % (2).

Conclusion

Acute liver failure is a relatively rarecondition in neonates, and early diagnosis andtreatment are crucial for the treatable conditions. Anynewborn with liver failure and no identifiable othercause should be considered to have GALD andtreated accordingly. Early diagnosis, prevention andproper arrangements may help to improve the survivalrate.

AUTRHOR DISCLOSUREThe authors have disclosed no financial

relationships relevant to this article. This commentarydoes not contain a discussion of an unapproved/investigative use of a commercial product/device.

ABBREVIATIONSGALD - Gestational Alloimmune Liver

DiseaseNH - Neonatal HemochromatosisIgG- Immunglobulin GIVIG – Intravenous ImmunglobulinMRI – Magnetic Resonance Imaging

References

1.Feldman AG, Whitington PF. Neonatal Hemochromatosis.Journal of Clinical and Experimental Hepatology2013;3(4):313-3202.Whitington PF. Gestational alloimmune liver disease andneonatal hemochromatosis. In: Murray KF, Horslen S, eds,Diseases of the Liver in Children: Evaluation andManagement. New York: Springer 2014: 215-2263.Whitington PF. Neonatal Hemochromatosis: ACongenital Alloimmune Hepatitis. Seminars in Liver Disease2007;27(3):243-2504.Knisely AS, Mieli-Vergani G, Whitington PF. Neonatalhemochromatosis. Gastroenterology Clinics of NorthAmerica 2003;32(3):877-889, vi-vii5.Lee WS, McKiernan PJ, Kelly DA. Serum ferritin level inneonatal fulminant liverfailure. Archives of Disease inChildhood Fetal and Neonatal Edition 2001, 85(3):F2266.Rogrigues F, Kallas M, Nash R, Cheeseman P, D’AntigaL, Rela M et al. Neonatal hemochromatosis- medicaltreatment vs transplantation: the king’s experience. LiverTranspl 2005;11(11):1417-14247.F. Babor, B Hadzik, H Stannigel, E Mayatepek, T Hoehn.Succesful management of neonatal hemochromatosis byexchange transfusion and immunoglobulin: a case report.Journal of Perinatology, 2013,33(1):83-858.Durand P, Debray D, Mandel R, Baujard C, BranchereauS, Gauthier F, et al. Acute liver failure in infancy: a 14-yearexperience of a pediatric liver transplantation center.JPediatr.2001;139(6):871–876.9.Knisely A.S. Iron and pediatric liver disease. Semin LiverDis.1994;14(3):229–23510.Whitington P.F. Fetal and infantile hemochromatosis.Hepatology. 2006;43(4):654–66011.Knisely AS, O’Shea PA, Stocks JF, Dimmick JE.Oropharyngeal and upper respiratory tract mucosal-glandsiderosis in neonatal hemochromatosis: an approach tobiopsy diagnosis. J Pediatr. 1988;113(5):871–87412.Smith SR, Shneider BL, Magid M, Martin G, RothschildM. Minor salivary gland biopsy in neonatalhemochromatosis. Arch Otolaryngol Head Neck Surg.2004;130(6):760–763.

A rare case of gastrointestinal bleeding: neonatal hemochromatosis