Treatment of Neonatal Hemochromatosis with Exchange Transfusion and
Elizabeth B. Rand, MD, Saul J. Karpen, MD, PhD, Susan Kelly, RN, Cara L. Mack, MD, J. Jeffrey Malatack, MD,
Ronald J. Sokol, MD, and Peter F. Whitington, MD
Objective To determine if immunomodulatory treatment including intravenous immunoglobulin (IVIG) can favor-
ably affect survival in neontatal hemochromatosis (NH) diagnosed postnatally because it can effectively prevent
occurrence of NH when applied during gestations at risk.
Study design We treated 16 newborn infants with liver failure due to NH with high-dose IVIG, in combination with
Results The severity of liver disease as estimated by prothrombin time was similar in the subjects receiving ET/
IVIG and the historical controls, and the medical therapy was equivalent with the exception of the ET/IVIG therapy.
Twelvesubjects(75%) hadgood outcome,defined assurvivalwithoutlivertransplantation,whereasgood outcome
was achieved in only 17% (23/131) of historical control patients (P < .001). Four subjects died, 2 without and 2 after
than 1 year are within normal measures for growth, development, and liver function.
Conclusions Immune therapy with ET/IVIG appears to improve the outcome and reduce the need for liver trans-
plantation in patients with NH. (J Pediatr 2009;155:566-71).
being <20%.4-6Orthotopic liver transplantation (OLT) has been applied, but with substantial difficulty in this clinical sce-
nario.7More effective medical therapy is clearly needed for newborns with this devastating disease.
We have hypothesized that many cases of NH are due to maternal alloimmunity directed at the fetal liver.8The principal
evidence suggesting an alloimmune mechanism comes from the observation that the risk of occurrence in a gestation subse-
quent to one ending in an affected baby is as high as 90%.9,10Further, treatment of women at risk for having an affected baby
with high-dose intravenous immunoglobulin (IVIG) reduces the occurrence of having a severely affected baby.10,11This proof
ofconcept thattherapydirectedattheimmune mechanismofNHcanpreventthediseaseinuteroledtothehypothesisthatthe
same approach could alter the course of already established disease postnatally. We therefore treated NH-affected newborn in-
fants with exchange transfusion (ET) and IVIG in an attempt to attenuate immune-mediated liver injury and permit recovery.
We retrospectively reviewed the course and outcome of newborn infants receiving this therapy and compared them with his-
torical controls derived from recently published series.4,6,10,12,14
here is no effective treatment for neonatal hemochromatosis (NH).1-3Beginning as a fetal liver disease, it typically pres-
prenatal insult. Thus, treatment options are limited, and survival rates with medical therapy are generally recorded as
The subjects of the study were 16 newborn infants with a clinical diagnosis of NH and liver failure. The Pediatric Acute Liver
tion accompanied by hepatic-based coagulopathy uncorrectable by parenteral vitamin K administration in the absence of sep-
sis-related disseminated intravascular coagulation.15To meet the diagnostic
criteria for coagulopathy in the absence of encephalopathy, the prothrombin
time must be $20 seconds or an INR $2. NH was diagnosed by demonstration
of extrahepatic siderosis by MRI16,17and/or oral mucosal biopsy,18,19or by a ma-
ternal sibling having been diagnosed with NH by these methods or at autopsy. In
1 subject, the diagnosis was made at the time of open liver biopsy for evaluation
From the Department of Pediatrics (E.B.R.), Children’s
Hospital of Philadelphia, Philadelphia, PA; the
Department of Pediatrics (S.J.K.), Baylor College of
Medicine, Texas Children’s Hospital, Houston, TX;
Children’s Memorial Hospital (S.K.), Chicago, IL; the
Department of Pediatrics (C.L.M., R.J.S.), The Children’s
Hospital, University of Colorado Denver, Aurora, CO; the
Department of Pediatrics (J.J.M.), Alfred I DuPont
Hospital for Children, Wilmington, DE; the Department of
Pediatrics (P.F.W.), Children’s Memorial Hospital,
Northwestern University, Feinberg School of Medicine,
The authors declare no conflicts of interest, real or
0022-3476/$ - see front matter. Copyright ? 2009 Mosby Inc.
All rights reserved. 10.1016/j.jpeds.2009.04.012
Orthotopic liver transplantation
of cholestasis; the histopathology was considered to be char-
acteristic; thus, given the clinical setting, further evaluation
was not performed. None of the subjects’ mothers had re-
ceived IVIG therapy during the affected pregnancy.
Affected neonates received therapy with ET and/or IVIG.
ET was performed per local clinical protocol as used for the
treatment of hyperbilirubinemia using blood bank compo-
nents: packed RBCs reconstituted with fresh frozen plasma
to a hematocrit of 40% to 50%. The recommended volume
of ET was twice the calculated blood volume of the subject.
The recommended dose of IVIG was 1 g per kg body weight.
Various standard commercial preparations of IVIG were
used, depending on local availability. Collection of data was
approved by the IRB of Children’s Memorial Hospital (Chi-
cago, Illinois) and submission of data by the local center’s
IRB where required.
The significance of differences of continuous variables mea-
sured in the subjects at different times was determined by
Student t test for paired samples. Repeated-measures AN-
OVA was used to determine the significance of change over
time for group variables. Fisher exact test was used to deter-
mine differences in outcome of the current therapy versus
that of conventional therapy as extracted from the literature.
Data are presented as mean ? standard deviation.
The 16 subjects were enrolled between 2004 and 2008 in 7
institutions in the United States and 1 each in The Nether-
lands and Australia. Table I provides basic clinical data in-
cluding the results of laboratory testing and the clinical
evidence of liver failure in the subjects. The gestational
ages of the subjects ranged from 25 to 41 (median, 35)
weeks and birth weights from 0.57 to 3.73 (median, 2.28)
kg. The degree of coagulopathy qualified all subjects for
the diagnosis of liver failure: the initial prothrombin time
for 15 subjects was 41.0 ? 16.9 seconds (range, 25 to 79
seconds). One subject (patient 15) was considered to
have liver failure on clinical grounds and received IVIG
on day 1 and day 8 of life: a prothrombin time was mea-
sured on day 13, when it was 23.4 seconds. Seven subjects
required prolonged mechanical ventilation. Ten were re-
ported to be hypoglycemic to the degree that they required
increased glucose infusion rates to maintain adequate
blood glucose concentrations. Six subjects showed signifi-
cant ascites either clinically or by imaging, two in associa-
tion with anasarca (hydrops).
Thirteen subjectsreceived some constituentsof the combina-
tion of chelating agents and antioxidants that has been used
for treating NH4,6: 10 received vitamin E; 10 N-acetylcys-
teine; 9 deferoxamine; 7 selenium; and 4 PGE-1. Fifteen sub-
jects received some support for coagulation: 13 received
continuous or repeated infusions of FFP; 8 received cryopre-
cipitate; and 3 received recombinant factor VII infusions.
Eight subjects received pressors to maintain blood pressure.
Five subjects developed severe bacterial infection (sepsis or
peritonitis), 3 while the subject was receiving deferoxamine,
which can impair neutrophil function.20No significant im-
provement in the clinical status of the patients was observed
up to the point of ET/IVIG treatment. Although the pro-
thrombin times recorded immediately before this treatment
in 15 subjects (30.1 ? 7.5 seconds) were somewhat improved
relative to those initially recorded (41.0 ? 16.9 seconds; P =
.04), most of the subjects were receiving intravenous support
to have had no beneficial effects.
This therapy was initiated on day of life 1 through 30 (15.1 ?
9.0 days). There was no difference in the day of initiation of
Table I. Subject characteristics and findings defining liver failure associated with NH
Patient No.Gestational age (wk)Birth weight (kg)NH diagnosis* Initial PT (s)Ferritin (ng/mL)ALT IU/L Hypoglycemia Ascites
*NH diagnosis established by history in sibling (Sib), MRI, oral mucosal biopsy (OMB), or open liver biopsy (OLB). Prothrombin time (PT) obtained within the first week of life. ALT and ferritin values
obtained when the diagnosis of NH was first considered, all within the first 4 weeks of life.
†Received IVIG before the PT was measured, with PT peaking at 23.4 sec on day of life 13.
Vol. 155, No. 4 ?
therapy between the 12 survivors (14.4 ? 9.8 days) and the 4
nonsurvivors (17.2 ? 7.0 days) (P = .6). ET was performed in
13 subjects (Table II): 7 received full double-volume ex-
change and 6 received less (1 to 1.6 volumes). No complica-
tions of ET were recorded. All subjects received IVIG: 13
received a single dose of 1 g/kg, 1 (patient 10) received 2
15) received 2 partial doses 1 week apart, totaling 875 mg/kg.
No complications or side effects of IVIG administration were
Treatment had only modest immediate beneficial effect on
liver function as estimated by the coagulation profile
(Figure). Prothrombin time measured in 11survivorsimme-
diately before treatment was 30.7 ? 9.1 seconds and fell to
as compared with 1 day after treatment, survivors showed no
significant improvement on days 3 (25.1 ? 6.5 versus 25.0 ?
7.1, P = .9) and 7 (22.6 ? 7.7, P = .3). By day 14, some im-
provement was observed (19.6 ? 5.7, P = .05), and by day
28 after treatment, prothrombin time fell to 17.1 ? 5.0 sec-
onds without the need for coagulation support (P = .002 ver-
sus 1 day after treatment). Analysis by repeated-measures
ANOVA showed significant improvement over the 4 weeks
after treatment (P < .0002).
Treatment appeared to have an immediate effect on glu-
cose homeostasis in survivors. Hypoglycemia resolved within
1 day of treatment in 8 of 10 subjects reported to have hypo-
glycemia before treatment. Two nonsurvivors (subjects 1 and
11) had persistent or intermittent hypoglycemia throughout
the hospital course.
Twelve subjects had good outcome, defined as survival with-
out OLT (Table II). The age at discharge ranged from 18 to
101 (median, 46) days, 6 to 90 (median, 35) days after initial
ET/IVIG therapy. Five subjects have been followed for more
than 1 year (Table II). At last follow-up, all were within nor-
mal measures for height, weight, and development, and
none had residual clinical liver disease (ie, no hepatospleno-
megaly and no evidence of portal hypertension) or dysfunc-
tion (ie, normal bilirubin, coagulation and liver enzymes).
Poor outcome was defined as death or receipt of OLT.
Two subjects received OLT (2 and 3 days after treatment);
both died. Two subjects died without receiving OLT:
1 died of aspergillus infection and pulmonary hemorrhage
20 days after treatment, and 1 of multi-organ failure
17 days after treatment.
Comparison with Historical Controls
Table III (available at www.jpeds.com) summarizes the pub-
lished data4-6,10,12-14used to establish historical controls. The
patients included in the analysis of these series were not re-
dundant (ie, did not appear in more than 1 series). The
131 patients included were accrued from 1985 to 2008. Of
these, 94 did not undergo OLT, of whom 23 survived
(24%), and 37 received OLT, of whom 19 survived (51%).
The overall survival was 32%. Good outcome as defined by
survival without OLT was 23/131 (17%). Eighty-four of the
131 patients received chelation-antioxidant therapy, 15
(17%) of whom survived without OLT. Survival with or
without OLT was no greater in those receiving chelation-an-
tioxidant therapy than in those who did not. In summary,
outcome of conventional medical therapy for NH was
poor, with only 17% of patients surviving without OLT,
and antioxidant-chelation therapy did not appear to affect
Table II. Treatment of NH and outcome of subjects
Figure. The prothrombin times of 11 subjects with good
outcome after ET/IVIG therapy are plotted against time
expressed as the days after treatment. The zero time point is
the value obtained immediately before treatment.
Coagulation improved somewhat immediately after treat-
ment, but prothrombin times did show further improvement
until 4 weeks after treatment, probably reflecting the need for
the liver to recover from severe insult. The central horizontal
line = median; box = 25 - 75th percentile range; capped
bars = maximum and minimum values.
*Denotes significant difference from values recorded on day
this analysis because a prothrombin time was not performed
before initiating treatment.
THE JOURNAL OF PEDIATRICS
Vol. 155, No. 4
Rand et al
Comparison of the prothrombin times between the cur-
rent series of patients and the historical controls where avail-
able shows no significant difference in the degree of
coagulopathy. Therefore, it can be said that the current series
of patients and the historical controls are comparable in
terms of degree of liver dysfunction, and the medical care
they were provided was similar with the exception of the
ET/IVIG therapy. The comparison of outcomes with the cur-
rent ET/IVIG therapy versus that of conventional therapy
drawn from published literature is provided in Table IV.
Using the Fisher exact test, the current therapy significantly
improved outcome (P < .001).
The approach to treating NH presented herein represents
a major change from current care. Historically, NH has
been difficult to treat, given the early onset of liver failure
andthegenerallypoorconditionofaffected infants. Nomed-
ical therapy has proven effective, and data from recently pub-
lished series suggest that only the application of liver
est of these series, among 19 children with NH treated at
King’s College London, the overall survival was 36%: 5 of
10 children receiving liver transplants survived, whereas
only 2 of 9 (22%) not receiving liver transplant survived.5
apy can improve the outcome of severe NH without need for
liver transplantation. Although not the intent of the study,
the data show improved survival with the current therapy
(12 of 14 patients not receiving OLT) compared with OLT
(19 of 37 historical controls plus 0 of 2 in the current series;
Fisher exact test, P < .05). In addition, several of the patients
in the current series were too small to receive OLT, further
arguing for the use of ET/IVIG therapy in this circumstance.
This was not a randomized, controlled trial; however, it is
unclear how such a treatment trial could ever be performed
in the setting of severe NH. The lack of any effective medical
therapy against which to compare a new therapy makes a de-
sign in equipoise impossible. Randomization between medi-
cal therapy and transplantation is likewise difficult. Even
though the severity of liver disease as estimated by the degree
of coagulopathy was similar in the current series and histor-
ical controls, the latter may have received different neonatal
care compared with the study infants. For example, all pa-
tients receiving ET/IVIG therapy did so since 2004, making
it possible that other improvements in medical care might
have affected outcome. However, the literature contains no
evidence that improved general medical care of these infants
overtime has affectedoutcome.Thus, thedramatic improve-
ment in clinical outcome demonstrated in this study, not
generally observed in NH in the same timeframe, suggests
that the ET/IVIG therapy is responsible.
A potential confounder in this study stems from the fact
lation-antioxidant combination that has been used to treat
NH. Since its original description,21the chelation-antioxi-
dant combination has been the mainstay of medical therapy
for this disease.4,6,22However, the cumulative information in
the literature reporting the use of the chelation-antioxidant
combination therapy shows it to be of little benefit.4,6,23In
this study, it remained at the discretion of the clinicians car-
ing for the individual patients to decide whether to apply the
standard chelation-antioxidant combination therapy or part
of it. The concomitant use of chelation-antioxidant therapy
could have affected the outcome of these subjects. We, how-
historical controls. Currently, we believe it prudent to retain
the elements of the chelation-antioxidant combination that
may benefit a patient with NH and have little risk associated
with their use. Acetylcysteine and vitamin E are considered
safe and easily administered and may have potential benefit
in the setting of NH as in other forms of acute liver fail-
ure.24,25In contrast, the use of deferoxamine can be poten-
tially harmful because of its inhibitory effect on neutrophil
function.20PGE-1 and selenium have no proven benefit in
a setting of established liver disease such as NH.
The ET/IVIG therapeutic strategy seeks to limit any ongo-
ing liver injury mediated by maternally derived IgG. ET is in-
tended to remove maternal alloantibody remaining in the
neonate’s circulation. High-dose IVIG has many beneficial
effects in IgG mediated injury,26including displacing specific
reactive IgG already bound to target antigen and binding to
circulating complement, thus preventing or blunting the
IVIG can interfere with the mechanisms of cell death that re-
sult from the formation of membrane attack complexes,
namely caspase-dependent apoptosis and calpain-dependent
oncosis (death by swelling).27The precise mechanisms by
which IVIG functions in prevention and treatment of NH
are yet tobe determined. Three patientsin this series received
no ET and several received less than full double-volume ET,
yet had good outcomes. Thus,one must consider whetherET
is an essential component of the treatment paradigm, or
whether IVIG alone would be effective. ET, in addition to re-
moving specific reactive antibody, adds nonreactive IgG in
the amount normally found in plasma. However, the recom-
mended 1 g/kg dose of IVIG is expected to raise the plasma
IgG concentration by about 1400 mg/dL, or 2 to 5 times
the normal concentration found in the plasma of normal
newborn infants. Whether this level of IgG is required for
optimal effect is not known.
In most cases of NH, liver disease will be well established at
the time of birth. The typical case of NH is characterized by
Table IV. Comparison of outcome with ET/IVIG
therapy versus conventional therapy in historical
Outcome / Treatment Y
Fisher exact test, P < .001 for improved outcome with ET/IVIG therapy.
Treatment of Neonatal Hemochromatosis with Exchange Transfusion and Intravenous Immunoglobulin
severe liver injury with extensive loss of hepatocyte mass and
fibrosis.1,28This is a pattern of injury that typifies subacute
hepatic failure in which injury has taken place over a time
frame of weeks to months.1,29One cannot say if a similar de-
gree of pathophysiology was present in all of these cases.
However, the severe coagulopathy at onset attests to the se-
verity of the liver injury. As acute hepatic necrosis (hepato-
cyte death in the absence of fibrosis) has never been
recorded in NH, it is highly likely that most of these cases
had well-established necro-inflammatory liver disease at
birth. Furthermore, 2 of the survivors had liver biopsies
showing cirrhosis, and the liver explant pathology of the 2
who underwent transplant showed histopathology typical
of severe NH. Thus, to benefit patients with NH, a therapy
should limit or eliminate ongoing hepatocyte injury to per-
mit survival and ultimately recovery. Any disease-specific
therapy should be applied as soon as the disease is diagnosed.
In this case series, the therapy was applied from 1 to 30 days
after birth, which was entirely dependent on when NH was
diagnosed in the individual cases. The diagnosis of NH is of-
ten delayed mainly because of unfamiliarity with the disease
and lack of suspicion for it in sick neonates. In this series,
there was minimal delay in establishing the diagnosis and
initiating ET/IVIG therapy once the patient was transferred
to the centers involved. It is not clear if outcome would
in this series was not associated with earlier treatment in that
the day of life that survivors and nonsurvivors started treat-
ment was not different. It is intuitive that earlier use of a ben-
eficial therapy is likely to lead to better results. In the case of
IVIG, it could be used in any infant with liver failure without
significant risk and with potential benefit in NH and infec-
tious disease. Perhaps the outcome of NH could be further
improved by universally applying such a strategy.
The question arises as to whether IVIG might have some
negative effect when used to treat NH. The 2 subjects who re-
ceived liver transplants both died, whereas 51% of the histor-
ical controls receiving transplants survived. IVIG is routinely
used in transplants involving chronic viral hepatitis with ben-
eficial effect. Indeed, IVIG has been shown to be a powerful
immunomodulator and to reduce allograft rejection.30It
seems, therefore, that administering IVIG to an infant who
may receive a liver transplant does no harm. Some of the in-
fants in this study received more than 1 dose of IVIG, spaced
on the initiative of the local clinicians to perhaps gain some
istration of high-dose IVIG appears to be very small in other
conditions in which it is used such as autoimmune disease.
ET/IVIG therapy resulted in minimal immediate or short-
term improvement incoagulation orotherobjectivemeasure
of liver function. This probably is because these patients had
severely injured livers, which must recover before improve-
ment in typical measures of function would occur. The pro-
thrombin time in surviving patients showed only mild
improvement for weeks after therapy; however, it may have
prevented progressive worsening of hepatic synthetic func-
tion. Importantly, other clinical features improved shortly
after IVIG, such as resolution of hypoglycemia. Regardless
of the mechanisms involved, it is clear that ET/IVIG treat-
ment had a significant positive impact on the medical status
of the patients who recovered. The long-term follow-up in
thecurrent series suggeststhat patientswhose initial recovery
how sick they were initially.
In conclusion, ET/IVIG therapy appears to improve the
outcome of NH associated acute liver failure and should be
considered as early as possible for treatment of this serious
condition. Further studies will be needed to more clearly de-
fine the role of ET and/or IVIG for this disease and if some
components of the antioxidant/chelation combination pro-
vide added benefit. n
The authors thank Stokes Houck, MD, Lourens R. Pistorius, MD, Rene
Romero, MD, and Shikha S. Sundaram, MD, for assistance in prepar-
ing the manuscript.
Submitted for publication Nov 25, 2008; last revision received Jan 27, 2009;
accepted Apr 8, 2009.
Reprint requests: Dr Peter F. Whitington, 2300 N Children’s Plaza, Box 57,
Chicago, IL 60614. E-mail: email@example.com.
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Treatment of Neonatal Hemochromatosis with Exchange Transfusion and Intravenous Immunoglobulin
Table III. Summary of literature regarding outcome of treatment for NH Download full-text
17-40 s 25 ? 8 s
30 – 120 s 75 ? 37 s
22 – 58 s 34 ? 12 s
0-31% 12.5 ? 16%
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