Nej M CPC 1404334

The
n e w e ng l a n d j o u r na l
of
m e dic i n e
Case Records of the Massachusetts General Hospital

Founded by RichardC. Cabot
EricS. Rosenberg, M.D., Editor
JoAnneO. Shepard, M.D., Associate Editor
SallyH. Ebeling, Assistant Editor
NancyLee Harris, M.D., Editor

AliceM. Cort, M.D., Associate Editor
EmilyK. McDonald, Assistant Editor
Case 20-2015: A Newborn Girl

with Hypotension, Coagulopathy,
Anemia, and Hyperbilirubinemia
Serguei Roumiantsev, M.D., Ph.D., Uzma Shah, M.D., SjirkJ. Westra, M.D.,
and Joseph Misdraji, M.D.
Pr e sen tat ion of C a se

From the Departments of Pediatrics (S.R.,
U.S.), Radiology (S.J.W.), and Pathology
(J.M.), Massachusetts General Hospital,
and the Departments of Pediatrics (S.R.,
U.S.), Radiology (S.J.W.), and Pathology
(J.M.), Harvard Medical School both
in Boston.
N Engl J Med 2015;372:2542-53.
DOI: 10.1056/NEJMcpc1404334
Copyright 2015 Massachusetts Medical Society.
2542
Dr. Emily B. Rubin (Pediatrics): A newborn girl was transferred to the neonatal intensive care unit (NICU) of this hospital on the first day of life because of hypotension, coagulopathy, anemia, and hyperbilirubinemia.
At an affiliated hospital, the infant was born by cesarean section to a 30-yearold primigravida mother at 34 weeks 6 days of gestation, after late-onset oligohydramnios and premature labor occurred and a nonreassuring fetal heart-rate pattern
developed. The membranes were ruptured at delivery, and the baby emerged vigorous, with Apgar scores of 8 and 9 at 1 and 5 minutes, respectively. The weight was
2.15 kg (34th percentile for gestational age), the head circumference 31.5 cm
(54th percentile), and the length 46 cm (64th percentile). The oxygen saturation
was 95% while the baby was breathing ambient air. The initial blood pressure was
40/25 mm Hg (reference range for a premature newborn, 55 to 75 systolic and 35 to
45 diastolic), with a mean arterial pressure of 25 mm Hg; the remainder of the
examination revealed features consistent with those of a late preterm infant.
The standard dose of vitamin K was administered shortly after birth. The infant
was admitted to the special-care nursery. Subsequent blood-pressure recordings reportedly revealed a systolic blood pressure between 30 and 39 mm Hg and a diastolic blood pressure between 10 and 19 mm Hg. Laboratory test results are shown
in Table1. Supplemental oxygen through a nasal cannula and boluses of normal
saline and dextrose were administered, without improvement. Blood oozed at the
site of peripheral punctures, and fresh-frozen plasma was administered. A repeat
hematocrit was 29%, and packed red cells were transfused. A chest radiograph
reportedly showed diffuse, nonspecific pulmonary haziness.
A blood culture was performed, and ampicillin and gentamicin were administered 1 and 2 hours after birth, respectively. Approximately 7.5 hours after birth,
the total serum bilirubin level was 6.4 mg per deciliter (109 mol per liter) and the
direct bilirubin level was 1.5 mg per deciliter (26 mol per liter); phototherapy was
begun. A KleihauerBetke test (hemoglobin F stain) for fetalmaternal hemorrhage
(fetal blood loss across the placenta and into the maternal circulation) was positive
n engl j med 372;26nejm.org June 25, 2015
The New England Journal of Medicine

Downloaded from nejm.org by GUSTAVO BAUMANN PINTO on October 28, 2016. For personal use only. No other uses without permission.
Copyright 2015 Massachusetts Medical Society. All rights reserved.
Case Records of the Massachuset ts Gener al Hospital
4 hours after birth. Fresh-frozen plasma was transfused 14 hours after birth. Blood samples were
obtained on the first day of life, before the transfusions were performed, and sent to the New
England Newborn Screening Program; the results
were reportedly indeterminate, and a requested
follow-up sample could not be definitively interpreted because blood products had been administered.
Hypotension persisted. Dopamine was administered intravenously, and the blood pressure rose
to 64/24 mm Hg, with a mean arterial pressure of
36 mm Hg. Anuria developed. The patient was
transferred to this hospital by the neonatal transport team, arriving 16 hours after birth.
The patients mother had a history of genital
herpes and had been treated during the pregnancy
with valacyclovir; she had no active lesions at delivery. She had received prenatal care and was immune to rubella; tests for hepatitis B surface antigen and syphilis were negative. Her ABO blood
type was O, Rh positive, and screening for antibodies to red cells was negative. Results of testing for group B streptococcus were not known.
She reported no history of alcohol, tobacco, or
illicit-drug use. She had emigrated from eastern
Europe 12 years earlier, lived with the infants
father, and worked in an office.
On examination, the infant was nondysmorphic, with pink skin, a normal cry, and normal
activity. The blood pressure was 58/28 mm Hg
(with a mean arterial pressure of 38 mm Hg),
the pulse 168 beats per minute, the respiratory
rate 30 to 49 breaths per minute, and the temperature 36.8C. A harsh systolic murmur, grade 2/6,
was loudest at the left lower sternal border, and
there were mild respiratory retractions and coarse
breath sounds. The umbilical-cord stump oozed
blood; bruising was present around sites of intravenous-catheter insertion, and there was a small
caf au lait spot on the left side of the chest.
Muscle tone was slightly decreased, and the remainder of the examination was normal. The
blood levels of phosphorus and calcium were
normal; other test results are shown in Table1.
Radiographs of the chest and abdomen revealed
clear lungs and a normal bowel-gas pattern. Infusions of glucose and dopamine were continued;
acyclovir, phytonadione (vitamin K), ampicillin,
cefotaxime, and oxygen (through a nasal cannula)
were administered. Cryoprecipitate (1 unit) and
fresh-frozen plasma (1 unit) were transfused. Over-
night, generalized edema increased, and ecchymoses and bleeding at the venipuncture sites and
crackling breaths sounds developed.
On the second day of life, urine output remained minimal. Results of screening for partialthromboplastin timelupus anticoagulant were
interpreted as negative. Additional laboratory test
results were obtained (Table1). A transthoracic
echocardiogram showed a patent foramen ovale
with trace left-to-right shunting, a patent ductus
arteriosus (2 mm in diameter), dilatation of the
ascending aorta, trace aortic insufficiency, elevated pulmonary resistance, slight right ventricular
dilatation, and normal left ventricular function
(estimated ejection fraction, 65%). Oxygen saturation decreased to 89 to 91%. Midazolam and
fentanyl were administered, the trachea was intubated, mechanical ventilation was initiated, and a
central venous catheter was placed.
Magnetic resonance imaging (MRI) was performed without the administration of gadolinium.
T2-weighted imaging showed a diffuse hypointense signal in the liver and pancreas, a moderate
amount of ascites, and anasarca. The kidneys appeared to be normal. Vecuronium, vancomycin,
calcium gluconate, furosemide, famotidine, vitamin E, total parenteral nutrition, and additional
doses of acyclovir, cefotaxime, ampicillin, and vitamin K were administered, and infusions of glucose and dopamine were continued. Additional
fresh-frozen plasma, packed red cells, platelets,
and albumin were transfused. A rectal culture for
vancomycin-resistant enterococcus, a nasal culture for methicillin-resistant Staphylococcus aureus,
and a blood culture were negative.
The next day, ultrasonography of the abdomen
revealed ascites and normal kidneys; intrarenal
arterial Doppler ultrasonography revealed an absence of diastolic flow, which was most likely
caused by vasopressor treatment, and no evidence
of renal-artery stenosis or renal-vein thrombosis.
Dopamine was tapered and discontinued, and a
mean arterial pressure above 40 mm Hg was
maintained without the use of pressors.
Additional diagnostic procedures were performed.
Differ en t i a l Di agnosis
Dr. Serguei Roumiantsev: All discussants are aware
of the diagnosis in this case. This newborn girl,
born at 34 weeks of gestation, initially presented

2543
The
of
m e dic i n e
Table 1. Laboratory Data.*
Variable
Hematocrit (%)
White-cell count (per mm3)
Differential count (%)

Neutrophils
Band forms
Lymphocytes
Monocytes
Eosinophils
Nucleated red-cell count
(per 100 white cells)
Platelet count (per mm3)
Reference Range,
Age-Adjusted
42.060.0
940034,000
5362
0.54.0 Hr
after Birth,
Other Hospital
12 Hr
after Birth,
Other Hospital
17.321.0 Hr
after Birth,
This Hospital
2nd Day
of Life,
This Hospital
31.5
(repeat, 29.0)
23,000
33.1
33.0
(manual)
20,500
(adjusted for
nucleated
red cells)
26.0
44,800
34
1
55
2134
411
08
0
107
150,000450,000
58,000
54
46,000 (after
transfusion)
Peripheral-blood smear
Reticulocytes (%)
ABO blood type
Antibody screening
Direct antiglobulin test
Fibrinogen (mg/dl)
d-Dimer (ng/ml)
Activated partial-thromboplastin
time (sec)
Prothrombin time (sec)
Prothrombin-time international
normalized ratio
Sodium (mmol/liter)
Potassium (mmol/liter)
Chloride (mmol/liter)
Carbon dioxide (mmol/liter)
Glucose (mg/dl)
Bilirubin (mg/dl)
Total
Direct
Urea nitrogen (mg/dl)
Creatinine (mg/dl)
Cortisol (g/dl)
Aspartate aminotransferase (U/liter)

Alanine aminotransferase (U/liter)
Alkaline phosphatase (U/liter)
24
19
3
88
28
77,000
63,000
3+ anisocytosis,
2+ polychromasia,
2+ hypochromasia,
3+ macrocytosis
6.6
O, Rh positive
Negative
Negative
54
0.52.5
Negative
Negative
150400
<350, negative;
350399,
borderline;
400, positive
25.348.3
18,500
(adjusted for
nucleated
red cells)
840
>150
>150
67.2
60.0
10.115.4
80
>9
>80
>9.8
28.3 (icteric)
2.7
24.3
2.2
135145
4.05.6
100108
23.031.9
60100
149
4.3
119
16
42
132
4.6
105
19
128
3.7
98
19.2
53
128
3.7
92
19.4
46
2.015.0
0.53.5
520
0.301.00
Morning,
4.322.4; after
noon, 3.116.7
47150
730
4.2
0.8
6.7
1.6
7
1.1
8
6.5
2.0
5
1.27
10.4
3.1
7
1.77
206
34
157
27
122
32
197
194
15350
Protein (g/dl)
2544

Table 1. (Continued.)
Variable
Reference Range,
Age-Adjusted
Total
Albumin
Globulin
Magnesium (mg/dl)
Lactate dehydrogenase (U/liter)
Alpha-fetoprotein (nonmaternal)
(ng/ml)
Iron (g/dl)
Iron-binding capacity (g/dl)
6.08.3
3.35.0
2.34.1
1.72.4
110210
Not available for
newborns
30160
230404
Ferritin (ng/ml)
Lactate (mmol/liter)
Ammonia (mol/liter)
Uric acid (mg/dl)
-Glutamyl transferase (U/liter)
Factor V (%)
Factor VII (%)
Factor VIII (%)
Antithrombin III (%)
Functional
Antigen
Protein C (%)
Functional
Antigen
Activated protein C resistance
screening assay
Protein S (functional) (%)
Arterial blood gases
Fraction of inspired oxygen
(ml/min)
pH
Partial pressure of carbon
dioxide (mm Hg)
Partial pressure of oxygen
(mm Hg)
Bicarbonate (mmol/liter)
10200
0.52.2
1248
2.36.6
536
34108
28104
50178
0.54.0 Hr
after Birth,
Other Hospital
12 Hr
after Birth,
Other Hospital
17.321.0 Hr
after Birth,
This Hospital
2nd Day
of Life,
This Hospital
2.5
1.3
1.2
1.6
2.9
1.7
1.2
1370
72,260
161
Unable to
perform
2527
3.9
71
7.2
10
26
5
285
3988
3988
18
22.0
1754
1754
>2.0
13
11
2.3
1261
44
1.0 (400 ml)
1.0 (800 ml)
7.357.45
3035
7.12
61
7.37
36
6080
76
71
1922
Base excess (mmol/liter)
19
21
10.4
4.2
* To convert the values for glucose to millimoles per liter, multiply by 0.05551. To convert the values for bilirubin to micromoles per liter,
multiply by 17.1. To convert the values for urea nitrogen to millimoles per liter, multiply by 0.357. To convert the values for creatinine to mi
cromoles per liter, multiply by 88.4. To convert the values for magnesium to millimoles per liter, multiply by 0.4114. To convert the values
for iron and iron-binding capacity to micromoles per liter, multiply by 0.1791. To convert the values for uric acid to micromoles per liter,
multiply by 59.48.
Reference values are affected by many variables, including the patient population and the laboratory methods used. The ranges used at
Massachusetts General Hospital are age-adjusted for patients who are not pregnant and do not have medical conditions that could affect
the results. They may therefore not be appropriate for all patients.
The reference ranges for activated partial-thromboplastin time and prothrombin time for newborns and infants are estimates derived from
published normal ranges for these age groups and were not determined at Massachusetts General Hospital.
The reference range for cortisol is for adults and is used at the other hospital.
Laboratory interpretation indicated that the result of testing for iron-binding capacity caused suspicion for occupied binding sites or the
presence of interference.
The value for the activated protein C resistance screening assay is the ratio of activated partial-thromboplastin time with activated protein C
to activated partial-thromboplastin time without activated protein C after dilution in factor Vdeficient plasma.

2545
The
with problems commonly associated with late

preterm birth, including mild respiratory distress
and hypoglycemia. During the first 24 hours of
life, unexpected clinical deterioration occurred,
with the development of multiorgan failure, including coagulopathy, hypotension, worsening
respiratory distress, hyperbilirubinemia, anuria,
anemia, and thrombocytopenia. Critically ill neonates with signs of cardiopulmonary collapse
are commonly admitted to the NICU. The degree
of respiratory distress, including respiratory failure and hypotension, frequently indicates the
severity of the illness but is not always helpful in
establishing the diagnosis. Careful clinical evaluation often allows us to narrow the differential
diagnosis (see Fig. S1 in the Supplementary Appendix, available with the full text of this article
at NEJM.org).
In this patient, coagulopathy that was difficult
to correct, direct hyperbilirubinemia, and hypoalbuminemia suggest a loss of metabolic or synthetic liver function (or both) and raise the possibility of acute neonatal liver failure.1 The differential
diagnosis of this uncommon condition includes
five major entities: intrauterine insult, bacterial or
viral sepsis, hematologic disorders, inborn errors
of metabolism, and primary liver disease.2,3
Intrauterine Insult
Hypoxicischemic injury and fetalmaternal hemorrhage are two intrauterine insults that commonly cause multiorgan failure in newborns. Criteria for the diagnosis of hypoxicischemic injury
are an acute intrapartum event, low Apgar scores,
the need for resuscitation in the delivery room,
and the development of neurologic symptoms
later in the disease course.4,5 The absence of these
criteria in this patient makes this diagnosis unlikely.
Fetalmaternal hemorrhage is common. Fortunately, almost 99% of cases are associated with
fetal blood loss of less than 15 ml, which does
not result in an adverse neonatal outcome. Fetal
blood loss of 20 ml per kilogram has been associated with an increased risk of admission to the
NICU, a need for blood transfusion, and other
complications; blood loss of greater than 40 ml
per kilogram leads to a dramatic increase in morbidity and mortality.6 In this case, a Kleihauer
Betke test suggested fetal blood loss of approximately 15 ml, confirming the presence of
fetalmaternal hemorrhage. Neonatal anemia is
2546
of
m e dic i n e
the most frequent symptom of fetalmaternal

hemorrhage, and in this patient, the hematocrit
on admission was abnormally low (31%). In an
otherwise asymptomatic infant, a hematocrit of
31% does not require treatment and is associated
with a high rate of spontaneous recovery. The degree of fetalmaternal hemorrhage seen in this
case would not result in multiorgan or liver failure.
Sepsis
Sepsis in critically ill neonates occurs at an estimated rate of 2 per 1000 newborns.7 The manifestations include hypotension, respiratory distress, and coagulopathy, all of which were seen in
this patient. Liver failure can develop as a part of
multiorgan failure. Prematurity, low birth weight,
and preterm labor are risk factors for neonatal
infection. Approximately 80% of cases of neonatal
sepsis have a bacterial cause, and group B alphahemolytic streptococcus is the most common;
gram-negative organisms, such as Escherichia coli
and klebsiella, have become more prevalent causes
than they were in the past, because of the universal prophylactic treatment of pregnant women for group B streptococcus.8 Herpes simplex
virus and enterovirus are the two most common
viral causes of sepsis in neonates.
Infants with suspected sepsis are treated empirically with broad-spectrum antibiotic agents
and acyclovir before the results of microbiologic
testing are available, as was the case with this
patient. Although an extensive evaluation of this
infant for infection (Table2) was negative, an
estimated 40% of cases of neonatal sepsis are
culture-negative. The absence of signs of acute
inflammation and the disproportionally low aminotransferase levels at the point of liver failure
make neonatal sepsis an unlikely diagnosis in
this patient.
Hematologic Disorders
Hemophagocytic lymphohistiocytosis is a lifethreatening condition that results from excessive

immune activation and tissue damage. Affected
patients present with fever, hepatosplenomegaly,
abnormal results on liver-function tests, a high
serum ferritin level, an elevated triglyceride level,
hypofibrinogenemia, and cytopenias. Both primary (familial) and secondary (sporadic or idiopathic) hemophagocytic lymphohistiocytosis are
triggered by infections or other immune-activating
events. In the absence of a defining gene muta-

tion (at PRF1 [encoding perforin], UNC13D [encoding Munc13-4], STX11 [encoding syntaxin 11],
or STXBP2 [encoding Munc18-2]), the diagnosis
of hemophagocytic lymphohistiocytosis requires
the presence of five out of eight clinical criteria.9
This patient had only three criteria: an elevated
ferritin level, an elevated level of soluble interleukin-2 receptor, and decreased natural killer cell
activity. The absence of the other criteria fever,
hepatosplenomegaly, cytopenias, hypertriglyceridemia, and hemophagocytosis make this diagnosis unlikely.
Inborn Errors of Metabolism
An acute neonatal illness and liver failure without evidence of acute inflammation might indicate a congenital metabolic disorder.10 Inborn
errors of metabolism can be divided into two
groups.
The first group is characterized by multiorgan
failure and clinical collapse and is associated
with major metabolic disturbances, such as acidosis, alkalosis, and hyperammonemia. This group
includes organic acidemias, urea-cycle defects,
disorders of amino acid metabolism, and primary
lactic acidoses. No related findings were seen in
this patient.
The second group is characterized by liver failure as a leading clinical symptom and includes
metabolic disorders, such galactosemia, hereditary
fructose intolerance, type I tyrosinemia, and mitochondrial respiratory-chain disorders. Mildly increased or normal aminotransferase levels and
elevated alpha-fetoprotein and ferritin levels, together with a gradual clinical decline, are common features. The absence of reducing substances
and succinylacetone in this infants urine allows
us to rule out galactosemia, hereditary fructose
intolerance, and type I tyrosinemia.11 Testing for
most of these metabolic conditions is currently
included in the New England Newborn Screening Program.12 Although results of the newborn
screening in this case were affected by the timing and transfusion of multiple blood products,
no abnormalities consistent with these disorders
were detected. Mitochondrial respiratory-chain
disorders are a rapidly expanding group of disorders, and affected patients often present with
multiorgan involvement of variable acuity and
nonspecific findings. Several mutations (at DGUOK,
MPV17, SUCLG1, POLG1, and C10orf2) have been
identified as causes of mitochondrial hepatopa-
Table 2. Evaluation for Suspected Infection.

Bacterial blood culture
General viral culture
Screening for hepatitis B antigen, core IgM antibodies, and IgG antibodies
Screening for hepatitis C antibodies
Culture and polymerase-chain-reaction assay for herpes simplex virus
Shell-vial assay for cytomegalovirus and screening for cytomegalovirus IgG
and IgM antibodies
Polymerase-chain-reaction assay for parvovirus and screening for parvovirus
IgG and IgM antibodies
Screening for EpsteinBarr virusspecific viral capsid antigen, IgG and IgM
antibodies, and nuclear antigen
Screening for antibodies to human immunodeficiency virus types 1 and 2
thy.13,14 Hypoglycemia, coagulopathy, and direct

hyperbilirubinemia, in conjunction with hypotonia, abnormal results of a neurologic examination,
and renal tubulopathy, should alert clinicians to
the possibility of this diagnosis. The absence of
lactic acidosis, neurologic findings, and renal tubulopathy in this patient makes this diagnosis
unlikely.
Primary Liver Disease
Neonatal hemochromatosis is the most common

cause of neonatal liver failure and the leading
indication for liver transplantation in infants. Also
known as gestational alloimmune liver disease,
neonatal hemochromatosis is now recognized to
be a congenital alloimmune hepatitis15 and is defined as the association of severe neonatal liver
disease with iron deposition (siderosis) in extrahepatic tissue. It is characterized by progressive
iron deposition during the fetal period, predominantly targeting the liver, pancreas, heart, and
thyroid and salivary glands but sparing the reticuloendothelial system.16 Extensive liver injury
is typically present at birth, and some signs
such as placental edema, oligohydramnios, intrauterine growth retardation, prematurity, and
stillbirth can be detected antenatally. Hypoalbuminemia, hypoglycemia, coagulopathy, a low
fibrinogen level, thrombocytopenia, and eventual
multiorgan failure are the hallmarks of the disease. Low aminotransferase levels at birth are
consistent with a long-standing antenatal process.
The elevated levels of ferritin, alpha-fetoprotein, and free iron and the increased saturation
of iron-binding capacity in this patient are suggestive of neonatal hemochromatosis. T1-weight-

2547
The
ed and T2-weighted MRI images can be helpful

in detecting iron deposits in the liver, pancreas,
and thyroid glands. The presence of iron deposits in the biopsy specimens of affected organs has
become the standard in establishing the diagnosis. Since marked coagulopathy makes a liver biopsy exceedingly difficult to perform, biopsy of
the minor salivary gland offers an excellent alternative and was performed in this case.17,18
Dr . Serguei Roumi a n t se v s
Di agnosis
Neonatal hemochromatosis (gestational alloimmune liver disease).
Im aging S t udie s
Dr. Sjirk J. Westra: On coronal T2-weighted images,
the signal intensity of the liver was lower than
that of the spleen and adjacent skeletal muscle,
a finding that is consistent with abnormal iron
storage in the liver (Fig.1A). A moderate amount
of ascites and edema were present in the soft
tissues. All newborns have a relatively large
amount of iron deposited in the liver because of
prenatal maternal transfer19; therefore, to make
the diagnosis of neonatal hemochromatosis, abnormal iron storage in the pancreas, which is
not seen in healthy newborns, must also be established. As compared with regular T2-weighted
images (Fig.1B), gradient-echo images (Fig.1C
and 1D) are obtained using a technique that is
more sensitive to the paramagnetic shortening
of proton relaxation times, which is caused by abnormal iron deposition.20 On out-of-phase gradient-echo images (Fig.1D), which are acquired with
a longer echo time than that used to acquire inphase images (Fig.1C), the signal intensity of the
pancreas drops when abnormal iron storage is
present.
Gradient-echo MRI has become the standard
noninvasive diagnostic procedure for neonatal
hemochromatosis.18,20,21 Reliable quantitative methods, independent of the make and model of the
scanner, have been developed for the assessment
of iron levels in the liver,22 obviating the need for
liver biopsy, which less than a decade ago was
considered essential for establishing the diagnosis of neonatal hemochromatosis23; such methods
can also be used for monitoring treatment re-
2548
of
m e dic i n e
sults.20 Since neonatal hemochromatosis is associated with a high risk of recurrence in subsequent pregnancies, fetal MRI may be helpful in
monitoring such pregnancies.24
Pathol o gic a l Discussion

Dr. Joseph Misdraji: Examination of the placenta
revealed that it was heavy and somewhat immature. Microscopic examination revealed erythroblasts inside fetal capillaries in villi. No hemophagocytosis by macrophages was identified.
Erythroblastosis is indicative of fetal hypoxia or
anemia.
The biopsy specimen of the lower lip contained tissue of the minor salivary gland; Prussian blue staining of the tissue revealed an iron
level of 2+ (range, 1+ to 4+) (Fig.2A), confirming the presence of extrahepatic hemosiderosis.
Biopsy of the minor salivary gland is a useful
method for detecting evidence of extrahepatic
hemosiderosis and is a highly sensitive and specific test for neonatal hemochromatosis.17 Often,
the amount of iron is small, as it was in this case.
False negatives can occur, particularly in premature infants, possibly because not enough iron
has accumulated for detection on histochemical
stains.17
Examination of liver-biopsy specimens from
patients with neonatal hemochromatosis often
reveals evidence of subacute or chronic liver injury with marked hepatocyte loss and can reveal
evidence of neonatal cirrhosis.15 Alternatively, if
fetal death occurs, the liver can show extensive
necrosis with little evidence of chronic damage.25 Examination of residual hepatic tissue reveals evidence of variable acinar transformation
and giant-cell transformation of hepatocytes, bile
in canaliculi, and pigment (Fig.2B and 2C).15 Iron
staining frequently reveals iron in hepatocytes
and sometimes in bile ducts, with sparing of the
reticuloendothelial system (Fig.2D). The pattern
of iron deposition is similar to that associated
with HFE-related hemochromatosis in adults.
Although these histologic features, together with
the presence of extrahepatic siderosis, are highly
characteristic of neonatal hemochromatosis, this
phenotype has been described in patients with
other conditions, including tyrosinemia, mitochondrial DNA depletion syndromes, inborn errors
of metabolism, and hematopoietic disorders.26

L
S
L
S
Figure 1. MRI Scans of the Liver.

On a coronal T2weighted image (Panel A), the signal intensity of the liver (L) is slightly lower than that of the spleen
(S). Ascites (A) and a generalized increased T2weighted signal are present in the soft tissues of the chest and ab
dominal wall; these findings are indicative of anasarca. On an axial T2weighted image (Panel B), the signal intensity
of the tail of the pancreas (arrow) is similar to that of the spleen, and thus the presence of abnormal iron storage in
the pancreas is indeterminate. However, axial inphase (Panel C) and outofphase (Panel D) gradientecho images
were obtained; on the outofphase image, which is acquired with a longer echo time than that used to acquire the
inphase image, the signal intensity of the pancreas (Panel D, arrow) is lower than that of the spleen. The gradient
echo images (Panels C and D) also show that the signal intensity of the liver is lower than that of the spleen; the
signal intensity of the liver drops further on the outofphase image (Panel D).
Discussion of M a nagemen t
Dr. Uzma Shah: Although some infants with neonatal hemochromatosis may present with mild
antenatal liver disease, most present with acute
liver failure, as was seen in this patient. Neonatal
hemochromatosis is associated with a high recurrence rate (80 to 92%) in subsequent pregnancies, a pattern that cannot be explained by
genetic inheritance but is consistent with an alloimmune pathogenesis.27 The disease is unrelated
to adult or juvenile hemochromatosis, primary or
secondary hepcidin deficiencies, and hepcidin resistance.26 The final pathway seems to be complement-mediated tissue injury.
n engl j med 372;26
How did neonatal hemochromatosis result in

increased iron deposition in fetal tissues in this
case? The maternal-to-fetal transfer of iron across
the syncytiotrophoblast by ferroportin is thought
to be controlled by fetal hepcidin. Neonatal hemochromatosis leads to hepcidin deficiency, dysregulation of placental iron transport, accumulation
of fetal nontransferrin-bound iron, and low
serum transferrin levels.28 Iron overload in extrahepatic tissue, which was seen in this case, may
be related to ZIP14, a zinc transporter with an
inverse relationship with ferroportin.28 Neonatal
liver failure with clinically significant hepatic and
extrahepatic iron overload (which was seen in this
case) is not unique to neonatal hemochromato-
nejm.org
June 25, 2015

2549
The
of
m e dic i n e
Figure 2. Biopsy Specimens.

Prussian blue staining of a biopsy specimen of the minor salivary gland (Panel A) shows iron deposition (stained
blue) in the glandular cells, a finding confirming the presence of extrahepatic siderosis. Hematoxylin and eosin
staining of a liverbiopsy specimen from another infant with neonatal hemochromatosis (Panel B) shows marked
damage, including lobular alterations and disarray; the clusters of cells (arrowheads) represent extramedullary he
matopoiesis, which is normal in a neonate. At a higher magnification, the same liverbiopsy specimen (Panel C)
shows giantcell transformation of hepatocytes (arrows) and bile in canaliculi that were formed from hepatocytes
that had undergone acinar transformation (arrowheads). Prussian blue staining of the other infants liverbiopsy
specimen (Panel D) shows iron in hepatocytes (stained blue, left) and in the bileduct epithelium (stained blue,
right), a finding typical of neonatal hemochromatosis.
sis and may be seen in patients with mitochondrial DNA depletion syndromes or the transient
myeloproliferative disorder associated with Downs
syndrome, neither of which was evident in this
case. Therapy for neonatal hemochromatosis includes treatment for liver failure with antioxidant cocktails (including vitamin E, N-acetylcysteine, prostaglandins, and selenium), fresh-frozen
plasma, and cryoprecipitate. Infusions of intravenous immune globulin (IVIG) and exchange
transfusion have also been suggested.
Exchange transfusion is performed to remove
any maternal alloantibodies remaining in the fetal
circulation, and IVIG is administered to displace
specific reactive IgG antibodies that are bound
2550
n engl j med 372;26
to target antigens and to bind with circulating

complement. Favorable outcomes among patients
with neonatal hemochromatosis have been described29; however, the prognosis remains seriously guarded, and the disease is associated with
an overall survival of 36%. In a large case series,
the survival rate was 51% among patients who
had undergone liver transplantation and 22%
among those who had not undergone transplantation.30 Both IVIG and exchange transfusion
were recommended for this patient.29
Dr. Roumiantsev: Double-volume exchange transfusion was performed on the 3rd day of life. IVIG
(at a dose of 1 g per kilogram of body weight)
was administered twice, on the 3rd day of life
nejm.org
June 25, 2015

Figure 3. Ultrasound Images and T2-Weighted MRI Scans.

Coronal and left parasagittal ultrasound images (Panels A and B, respectively) show intraventricular hyperecho
genicity, and coronal and midsagittal T2weighted images (Panels C and D, respectively) show low T2weighted sig
nals with horizontal fluid levels (known as the hematocrit effect) that are indicative of the presence of hemosiderin
containing blood products in severely dilated ventricles; these findings are consistent with severe intraventricular
hemorrhage (arrows).
and the 8th day of life. Despite these interventions, the infant had persistent coagulopathy and
required daily replacement therapy with freshfrozen plasma, platelets, and cryoprecipitate. She
was listed as a candidate for liver transplantation. Cranial intraventricular hemorrhage developed on the 15th day of life (Fig. 3), along with
components of obstructive hydrocephalus. Despite administration of factor VIIa to control the
intracranial bleeding and surgical placement of
an extraventricular drain, the patients condition
continued to deteriorate, with further extension
n engl j med 372;26
of the bleeding and seizures. After a discussion

among the family and multidisciplinary care team,
the patients treatment was transitioned to comfort measures only, and she died peacefully in
her parents arms.
Five months later, the patients mother was
seen by Dr. William Barth (Maternal and Fetal
Medicine) with a naturally conceived pregnancy
at 10 weeks 5 days of gestation. There was a high
risk of recurrence of neonatal hemochromatosis,
and thus, in consultation with Dr. Annemarie
Fogerty (Hematology), IVIG therapy (1 g per ki-
nejm.org
June 25, 2015

2551
The
logram) was begun at 14 weeks of gestation; it

was initially administered every other week and
then administered weekly beginning at 18 weeks
of gestation.31 A healthy, premature female infant was delivered by cesarean section at 31 weeks
6 days of gestation because of a suspected placental abruption. The infant was admitted to the
NICU because of prematurity. She was monitored closely for evidence of neonatal hemochromatosis. Coagulation status and levels of ferritin,
total iron-binding capacity, and bilirubin remained
normal throughout the NICU course, which was
complicated by late-onset bacteremia. The patient was discharged home at 36 weeks 2 days of
corrected gestational age.
Dr. Nancy Lee Harris (Pathology): Has there been
any progress on finding out what antigen is responsible for neonatal hemochromatosis?
Dr. Shah: No, not yet.
Dr. Roumiantsev: I want to add some important
historical information. Neonatal hemochromatosis was considered for decades to be part of
the hemochromatosis family and to have a genetic cause. Despite multiple attempts, no candidate genes were identified. Dr. Peter Whitington
noticed that the distribution of neonatal hemochromatosis in offspring was not consistent with
any genetic diseases but was consistent with alloimmune diseases, in particular Rh(D) hemolytic disease of the newborn.32 On the basis of
this premise, he used known treatment for Rh(D)
hemolytic disease, first in mothers and then in
affected infants, with great success.
References
1. Squires RH Jr, Shneider BL, Bucuvalas
J, et al. Acute liver failure in children: the
first 348 patients in the Pediatric Acute
Liver Failure study group. J Pediatr 2006;
148:652-8.
2. Sundaram SS, Alonso EM, Narkewicz
MR, Zhang S, Squires RH. Characterization and outcomes of young infants with
acute liver failure. J Pediatr 2011;159:8138.
3. Shanmugam NP, Bansal S, Greenough
A, Verma A, Dhawan A. Neonatal liver
failure: aetiologies and management
state of the art. Eur J Pediatr 2011;170:
573-81.
4. American College of Obstetricians
and Gynecologists Task Force on Neonatal Encephalopathy. Executive summary:
neonatal encephalopathy and neurologic
outcome, second edition. Obstet Gynecol
2014;123:896-901.
5. Socol ML, Garcia PM, Riter S. De-
2552
of
m e dic i n e
Dr. Harris: A discussion by Dr. Nancy Andrews

about a case of neonatal hemochromatosis was
held at these grand rounds in 2004 and was
published in 2005.23 At the time, there was little
understanding of the cause of this entity. It is
remarkable how far our understanding has come
in the subsequent 10 years. However, it is curious
that, unlike with neonatal alloimmune thrombocytopenia, there has apparently been no progress in finding the alloantigen responsible for
neonatal hemochromatosis.
Dr. Westra: Is there a role for fetal MRI in the
diagnosis of this condition in the next pregnancy?
Dr. Shah: Iron deposition may vary. Imaging
studies that show evidence of iron deposition may
be helpful in making a diagnosis. However, the
absence of such evidence on imaging does not rule
out neonatal hemochromatosis.
A nat omic a l Di agnosis

Neonatal hemochromatosis (gestational alloimmune liver disease), with erythroblastosis of the
placenta and siderosis of the minor salivary gland.
This case was presented at Pediatric Grand Rounds.

No potential conflict of interest relevant to this article was
reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank Drs. Hasan Merali and Mohammad Aslam (Pediatrics) for assistance with organizing the conference, Dr. Richard
E. Wilker (Pediatrics) for assistance with preparing the case history, and Drs. Eric Grabowski (Pediatric Hematology) and Amita
Sharma (Pediatric Nephrology) and members of the Pediatric
Neurology, Neurosurgery, and Palliative Care teams for assistance with the care of the infant.
pressed Apgar scores, acid-base status,

and neurologic outcome. Am J Obstet Gynecol 1994;170:991-8.
6. Rubod C, Deruelle P, Le Goueff F,
Tunez V, Fournier M, Subtil D. Long-term
prognosis for infants after massive fetomaternal hemorrhage. Obstet Gynecol
2007;110:256-60.
7. Remington JS, Klein J, Wilson C,
Nizet V, Maldonado Y. Infectious diseases
of the fetus and newborn infant. 7th ed.
Philadelphia:Saunders Elsevier, 2011.
8. Weston EJ, Pondo T, Lewis MM. The
burden of invasive early-onset neonatal
sepsis in the United States, 20052008.
Pediatr Infect Dis J 2011;30:937-41.
9. Henter JI, Horne A, Aric M, et al.
HLH-2004: Diagnostic and therapeutic
guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007;
48:124-31.
10. Leonard JV, Morris AA. Diagnosis and
early management of inborn errors of metabolism presenting around the time of

birth. Acta Paediatr 2006;95:6-14.
11. Ogier de Baulny H. Management and
emergency treatments of neonates with a
suspicion of inborn errors of metabolism.
Semin Neonatol 2002;7:17-26.
12. Levy PA. An overview of newborn
screening. J Dev Behav Pediatr 2010;31:
622-31.
13. Fellman V, Kotarsky H. Mitochondrial
hepatopathies in the newborn period. Semin Fetal Neonatal Med 2011;16:222-8.
14. Lee WS, Sokol RJ. Mitochondrial hepatopathies: advances in genetics and pathogenesis. Hepatology 2007;45:1555-65.
15. Whitington PF. Neonatal hemochromatosis: a congenital alloimmune hepatitis. Semin Liver Dis 2007;27:243-50.
16. Cottier H. A hemochromatosis similar disease in newborn. Schweiz Med
Wochenschr 1957;87:39-43. (In German.)

17. Smith SR, Shneider BL, Magid M,
Martin G, Rothschild M. Minor salivary

gland biopsy in neonatal hemochromatosis. Arch Otolaryngol Head Neck Surg
2004;130:760-3.
18. Udell IW, Barshes NR, Voloyiannis T,
et al. Neonatal hemochromatosis: radiographical and histological signs. Liver
Transpl 2005;11:998-1000.
19. Williams H, McKiernan P, Kelly D,
Baumann U. Magnetic resonance imaging in neonatal hemochromatosis are
we there yet? Liver Transpl 2006;12:1725.
20. Queiroz-Andrade M, Blasbalg R, Ortega CD, et al. MR imaging findings of iron
overload. Radiographics 2009;29:157589.
21. Hayes AM, Jaramillo D, Levy HL,
Knisely AS. Neonatal hemochromatosis:
diagnosis with MR imaging. AJR Am J
Roentgenol 1992;159:623-5.
22. St Pierre TG, El-Beshlawy A, Elalfy M,
et al. Multicenter validation of spin-density projection-assisted R2-MRI for the
noninvasive measurement of liver iron

concentration. Magn Reson Med 2014;71:
2215-23.
23. Case Records of the Massachusetts
General Hospital (Case 21-2005). N Engl J
Med 2005;353:189-98.
24. Hill BJ, Joe BN, Qayyum A, Yeh BM,
Goldstein R, Coakley FV. Supplemental
value of MRI in fetal abdominal disease
detected on prenatal sonography: preliminary experience. AJR Am J Roentgenol
2005;184:993-8.
25. Whitington PF, Pan X, Kelly S, MelinAldana H, Malladi P. Gestational alloimmune liver disease in cases of fetal death.
J Pediatr 2011;159:612-6.
26. Zoller H, Knisely AS. Control of iron
metabolism lessons from neonatal hemochromatosis. J Hepatol 2012;56:12269.
27. Whitington PF, Hibbard JU. Highdose immunoglobulin during pregnancy
for recurrent neonatal haemochromatosis. Lancet 2004;364:1690-8.
28. Bonilla S, Prozialeck JD, Malladi P, et
al. Neonatal iron overload and tissue siderosis due to gestational alloimmune liver
disease. J Hepatol 2012;56:1351-5.
29. Rand EB, Karpen SJ, Kelly S, et al.
Treatment of neonatal hemochromatosis
with exchange transfusion and intravenous immunoglobulin. J Pediatr 2009;
155:566-71.
30. Rodrigues F, Kallas M, Nash R, et al.
Neonatal hemochromatosis medical
treatment vs. transplantation: the kings
experience. Liver Transpl 2005;
11:
141724.
31. Whitington PF, Kelly S. Outcome of
pregnancies at risk for neonatal hemochromatosis is improved by treatment
with high-dose intravenous immunoglobulin. Pediatrics 2008;121(6):e1615-e1621.
32. Whitington PF, Hibbard JU. Highdose immunoglobulin during pregnancy
for recurrent neonatal haemochromatosis. Lancet 2004;364:1690-8.
Copyright 2015 Massachusetts Medical Society.
Lantern Slides Updated: Complete PowerPoint Slide Sets from the Clinicopathological Conferences
Any reader of the Journal who uses the Case Records of the Massachusetts General Hospital as a teaching exercise or reference
material is now eligible to receive a complete set of PowerPoint slides, including digital images, with identifying legends,
shown at the live Clinicopathological Conference (CPC) that is the basis of the Case Record. This slide set contains all of the
images from the CPC, not only those published in the Journal. Radiographic, neurologic, and cardiac studies, gross specimens,
and photomicrographs, as well as unpublished text slides, tables, and diagrams, are included. Every year 40 sets are produced,
averaging 50-60 slides per set. Each set is supplied on a compact disc and is mailed to coincide with the publication of the
Case Record.
The cost of an annual subscription is $600, or individual sets may be purchased for $50 each. Application forms for the current
subscription year, which began in January, may be obtained from the Lantern Slides Service, Department of Pathology,
Massachusetts General Hospital, Boston, MA 02114 (telephone 617-726-2974) or e-mail Pathphotoslides@partners.org.

2553

Nej M CPC 1404334

Diunggah oleh

Informasi Dokumen

Judul Asli

Hak Cipta

Format Tersedia

Bagikan dokumen Ini

Bagikan atau Tanam Dokumen

Opsi Berbagi

Apakah menurut Anda dokumen ini bermanfaat?

Apakah konten ini tidak pantas?

Hak Cipta:

Format Tersedia

Nej M CPC 1404334

Diunggah oleh

Hak Cipta:

Format Tersedia

The

Case Records of the Massachusetts General Hospital

NancyLee Harris, M.D., Editor

Case 20-2015: A Newborn Girl

Pr e sen tat ion of C a se

The New England Journal of Medicine

Case Records of the Massachuset ts Gener al Hospital

n engl j med 372;26nejm.org June 25, 2015

The New England Journal of Medicine

Table 1. Laboratory Data.*

Differential count (%)

Aspartate aminotransferase (U/liter)

n engl j med 372;26nejm.org June 25, 2015

The New England Journal of Medicine

Case Records of the Massachuset ts Gener al Hospital

1.0 (800 ml)

Base excess (mmol/liter)

n engl j med 372;26nejm.org June 25, 2015

The New England Journal of Medicine

with problems commonly associated with late

the most frequent symptom of fetalmaternal

Hemophagocytic lymphohistiocytosis is a lifethreatening condition that results from excessive

n engl j med 372;26nejm.org June 25, 2015

The New England Journal of Medicine

Case Records of the Massachuset ts Gener al Hospital

Table 2. Evaluation for Suspected Infection.

thy.13,14 Hypoglycemia, coagulopathy, and direct

Neonatal hemochromatosis is the most common

n engl j med 372;26nejm.org June 25, 2015

The New England Journal of Medicine

ed and T2-weighted MRI images can be helpful

Pathol o gic a l Discussion

n engl j med 372;26nejm.org June 25, 2015

The New England Journal of Medicine

Case Records of the Massachuset ts Gener al Hospital

Figure 1. MRI Scans of the Liver.

How did neonatal hemochromatosis result in

June 25, 2015

The New England Journal of Medicine

Figure 2. Biopsy Specimens.

n engl j med 372;26

to target antigens and to bind with circulating

June 25, 2015

The New England Journal of Medicine

Case Records of the Massachuset ts Gener al Hospital

Figure 3. Ultrasound Images and T2-Weighted MRI Scans.

of the bleeding and seizures. After a discussion

June 25, 2015

The New England Journal of Medicine

logram) was begun at 14 weeks of gestation; it

Dr. Harris: A discussion by Dr. Nancy Andrews

A nat omic a l Di agnosis

This case was presented at Pediatric Grand Rounds.

pressed Apgar scores, acid-base status,

early management of inborn errors of metabolism presenting around the time of

n engl j med 372;26nejm.org June 25, 2015

The New England Journal of Medicine

Case Records of the Massachuset ts Gener al Hospital

17. Smith SR, Shneider BL, Magid M,

Martin G, Rothschild M. Minor salivary

noninvasive measurement of liver iron

28. Bonilla S, Prozialeck JD, Malladi P, et

n engl j med 372;26nejm.org June 25, 2015