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623
Case Report .:
:
.
Neonatal Ailish
Hemochromatosis:
M. Hayes,1
Neonatal
Diego
Jararnillo,2
hemochromatosis,
Harvey
also known
L. Levy,3
as peninatal
hemo-
seen in infants with liver disease of postnatal onset on in infants who do not have liver disease [2]. Neonatal hemochromatosis is not a variant presentation of human leukocyte antigen-linked (adult onset, hereditary) hemochnomatosis [3] and the two entities differ in many respects [1]. The antemortem diagnosis of neonatal hemochnomatosis is difficult, because neonatal liver failure may be associated Nonetheless,
it is important
::‘
.
,
with MR Imaging
and A. S. Knisely4
myocamdium, thyroid gland, oral mucosa), with sparing of reticuloendothelial cells in the spleen, lymph nodes, and bone marrow [i ]. Extrahepatic sidemosis in this distribution is not
disorders.
#{149}
Diagnosis
chromatosis or neonatal iron storage disease, is characterized by severe and usually fatal idiopathic liver disease of intrauterine onset. It may occur in siblings. Its hallmark is fulminant hepatic failure with siderosis of hepatocytes and of extrahepatic parenchymal cells at a variety of sites (pancreas,
with many
,
to establish
the diagnosis clinically. If it is recognized, plans for liver transplantation, the only effective therapy, can proceed. When neonatal hemochromatosis is suspected, liver biopsy may be hazardous owing to coagulopathy and the poor overall status of the patient. Oral mucosal biopsy, to demonstrate stainable iron in the small submucous glands of the lip, cheek, or tongue [4], has been an alternative in several instances [1 ], but it also is invasive. We hypothesized that MR imaging would be a noninvasive technique for diagnosis of neonatal hemochromatosis if signal intensity could be used to detect tissue iron overload [5]. This February 5, 1992; accepted after revision April 13, 1992. in part at the Third Intemational Conference on Hemochromatosis, This work was supported in part by the Pathology Education and Research I Children’s Service, Massachusetts General Hospital, Boston, MA 02114. 2 Department of Radiology, Children’s Hospital, Boston, MA 02115.
report presents our findings with MR imaging in three neonates with neonatal hemochnomatosis and a fetus whose family history indicated the fetus to be at risk for neonatal hemochromatosis. Case
Report
A singleton term female neonate manifested severe hepatic insufficiency within hours of birth. Her two siblings were well. Evaluation indicated no known heritable metabolic or infective diseases. Results of liver biopsy showed advanced cirrhosis, with large amounts of iron in hepatocytes.
Neonatal
hemochromatosis
possible diagnosis. MR images were obtained 1 .5-T
body
system
(Signa,
coil were
GE
used.
considered
Systems,
Ti -weighted
Milwaukee,
WI)
(600-800/i
7-30
and
3
Neurology
4
Department
AJR 159:623-625,
Service,
Massachusetts
of Pathology, September
General
Children’s 1992
Hospital
Hospital, Boston, MA 02114, of Pittsburgh,
0361-803X/92/1593-0623
3705
a
[TR/
TE]) and T2-weighted (2000-2500/20-80) images were obtained. No specific protocol was followed, and gradient-recalled-echo imaging was not used. The images were evaluated visually for the presence of iron overload according to published parameters [5]. Siderosis was diagnosed when the signal intensity of an organ or tissue on T2weighted showed
images evidence
was less than that of skeletal muscle. The images of marked siderosis of the liver and pancreas but
not of the spleen, consistent with the diagnosis of neonatal hemochromatosis (Fig. 1). The patient had an orthotopic liver transplant when she was 4 weeks old. Findings in the hepatectomy and biopsy specimens were similar.
MR
after
liver
transplantation
showed
evidence
of large
amounts of iron in the pancreas and myocardium but not in the donor liver. An endomyocardial biopsy performed to evaluate poor cardiac
Received
Presented
a
as
when the patient was 3 weeks old. A
Medical
Spin-echo
was
D#{252}sseldorf,Germany, Foundation, Pittsburgh,
and Department
Fifth Ave. at DeSoto
July PA.
of Neurology, St., Pittsburgh,
American Roentgen Ray Society
1991.
Harvard PA 15213.
Medical Address
Schcol, reprint
Boston, requests
MA 02115. to A. S. Knisely.
HAYES
624
ET AL.
AJR:159,
September
1992
Fig. 1.-Neonatal
hemochromatosis pancreas in a 3week-old giri. Axial T2-weighted MR image (2000/80) of upper abdomen shows hypointense liver (L) and pancress (arrow). MR imaging after hepatic transplantation showed no cvidence of signal abnormality in transplanted liver.
Downloaded from www.ajronline.org by 109.161.214.101 on 11/09/15 from IP address 109.161.214.101. Copyright ARRS. For personal use only; all rights reserved
involving
liver
and
Fig. 2.-Neonatal hemochromatosis involving liver and pancreas in an 8day-old giri. Axial T2-weighted image (2000/80) of upper abdomen shows signal intensity of liver is less than that of adjacent muscle. Signal intensity of tail of pancreas (arrow), seen ventral to splenic vessels, also is less, indicating iron deposition.
function that began after transplantation iron within
myocytes,
confirming
matosis. The patient has tolerated difficulty
and is growing
the
showed
diagnosis
abundant
of neonatal
the liver transplant
and developing
normally
stainable hemochro-
without
unusual
at age 2Y2 years
old.
The patient’s sister, who is 2 years younger, manifested hypoglycemia
in the first hours
which
after birth and worsening
hepatic
dysfunction
The parents had refused monitoring of the pregnancy,
thereafter.
continued
to
term
without
complications.
Liver
biopsy
when
the neonate was 6 days old showed advanced cirrhosis, with hepatocellular showed
2)
siderosis, evidence
without siderosis of the spleen. Neonatal hemochromatosis
diagnosed.
Her
hepatic
she is being followed
be
and MR imaging when she was 8 days old siderosis of the liver and pancreas (Fig.
of marked
indicated
dysfunction
stabilized,
up as an outpatient.
if her hepatic
status
was
and at age 6 months, Liver transplantation will
deteriorates.
erosis, as detected with MR in adults [5]. On T2-weighted images, the signal intensity was markedly diminished in the liver and pancreas with more severe
also was low on T2-weighted images. We speculate that the younger sister had no evidence of myocardial siderosis because her illness was less severe. Evidence for myocardial siderosis also was observed in a third neonate with neonatal hemochromatosis in whom MR images were obtained at i 7 days of age (Fig. 3); that case is reported fully elsewhere [6]. Of particular value was the ability of MR images to provide information on the presence of iron overload in several organs (liver, pancreas, and heart) and on the absence of siderosis in the spleen. Histologic examination shows that the neticuloendothelial cells of the splenic cords are not siderotic in
neonatal
hemochnomatosis
for neonatal Discussion
Examination of a neonate with severe hepatic disease requires screening for infective agents and for metabolic disorders known to manifest at this age. Serologic markers of maternal infection, culture techniques, and laboratory analytic
studies
permit
screening
for many
such
disorders.
Although neonatal hemochnomatosis is an acknowledged clinicopathologic entity, it is not clear if neonatal hemochnomatosis
is a single
disorder
on a common
phenotype
due to
fetal liver disease from several causes [1 ]. Accordingly, the diagnosis is based not on laboratory results but on recognition of features of the characteristic phenotype (extrahepatic siderosis) in the appropriate clinical setting (liver failure manifest at birth). To date, this has meant an invasive procedure to obtain tissue for histopathologic examination [4]. Our results indicate that MR imaging can supplement or perhaps replace biopsy for diagnosis of neonatal hemochromatosis. Although MR findings and MR assessment of iron stores have not been reported in neonatal liver disease other than neonatal hemochnomatosis, our findings in these neonates with neonatal hemochromatosis who were examined with MR imaging were consistent with hemochnomatotic sid-
and was normal in the spleen. In the patient disease, the signal intensity from the heart
[1 ], and this diagnostic
hemochnomatosis
is not addressed
criterion
by biopsy
of
oral mucosa. It must be stressed that marked siderosis of the liver is physiologic in the pennate, and that in the absence of extrahepatic siderosis the diagnosis of neonatal hemochnomatosis should not be made [i , 2]. Furthermore, because MR evaluation, particularly comparison of signal strength on Ti - and T2-weighted images at various sites, has not been included before in diagnostic studies of neonates with liver disease, the specificity of the findings in the cases reported here may be questioned. However, extrahepatic siderosis in a hemochromatotic distribution is not seen on histopathologic examination in infants with liver disease of postnatal onset or in infants who do not have liver disease [2], so it is likely that MR evaluation of iron overload at extrahepatic sites will be of specific value. Because neonatal hemochromatosis recurs in sibships, fetuses
of a mother
who
has
had
an infant
with
neonatal
hemochromatosis should be considered at risk for neonatal hemochromatosis [i Although percutaneous sampling of cord blood may provide results that can be used to diagnose neonatal hemochnomatosis in an appropriate clinical setting ].
[7],
noninvasive
Sonography
techniques
also
may show abnormalities
are likely
to be of value.
in the fetal liver or blood-
Downloaded from www.ajronline.org by 109.161.214.101 on 11/09/15 from IP address 109.161.214.101. Copyright ARRS. For personal use only; all rights reserved
AJR:159,
MR
September1992
IN NEONATAL
625
HEMOCHROMATOSIS
Fig. 3.-Neonatal hemochromatosis involving heart in a 17-day-old giri. A and B, Axial Ti-weighted (600/17, A) and T2-weighted (2500/70, B) MR images at level of heart show that signal of atrial and ventricular walls on T2weighted image Is decreased so much that outiine of heart is barely perceptible. Myocardial siderosis was confirmed at autopsy.
flow patterns associated with liver disease, but it will not provide information on sidenosis. We have had the opportunity prospectively to evaluate a pregnancy in a woman whose first two offspring were born prematurely and died of liver failure in the neonatal period. Autopsy in both showed neonatal hemochnomatosis [8]. The parents agreed to intensive monitoring during the subsequent pregnancy. Sonography and MR imaging were performed in the 20th gestational week. Neither showed abnormalities, and no evidence of extrahepatic siderosis was found. In order to exclude liver disease of third-trimester onset, sonography and MR were repeated in the 36th gestational week. The findings again were normal. The neonatal course was unremarkable; thus, neonatal hemochnomatosis was ruled out on clinical grounds. The boy has remained well for 2V2 years, with normal growth and development. We think that MR studies can be used to diagnose neonatal hemochromatosis in the neonate and to exclude neonatal hemochromatosis in the late third-trimester fetus at risk. They also may allow conclusive antenatal diagnosis of neonatal hemochnomatosis. Experience with this technique in monitoring fetuses
at risk
will determine
if it can
be used
for the
diagnosis of neonatal hemochnomatosis so, whether pathognomonic features
gestation
for elective
termination
in the fetus, and, if appear early enough in
of the pregnancy.
REFERENCES 1. Knisely AS. Neonatal hemochromatosis. Adv Pediatr 1992;39:383-404 Witzleben CL, Uri A. Perinatal hemochromatosis: entity or end result? Hum Pathol 1989:20:335-340 3. Hardy L, Hansen J, Kushner JP, Knisely AS. Neonatal hemochromatosis:
2.
4.
5.
6.
7.
genetic analysis of transfemn-receptor, H-apoferritin, and L-apofemtin loci and of the HLA class I region. Am J Pathol i990;137: 149-1 53 Knisely AS, O’Shea PA, Stocks JF, Dimmick JE. Oropharyngeal and upper respiratory mucosal gland siderosis in neonatal hemochromatosis: an approach to biopsy diagnosis. J Pediatr 1988;1 13:871 -874 Siegelman ES, Mitchell DG, Rubin R, et al. Parenchymal versus reticuloendothelial iron overload in the liver: distinction with MR imaging. Radiology 1991:179:361 -366 Knisely AS, Harford JB, Klausner RD, Taylor SR. Neonatal hemochromatosis: the regulation of transfemn-receptor and ferritin synthesis by iron in cultured fibroblastic-line cells. Am J Pathol 1989:134:439-445 de Boissieu D, Checoury A, Barbet P, Francoual C, Rochiccioli F, Badoual J. H#{233}mochromatose p#{233}rinatale.Arch Fr Pediatr 1990:47:23-28
8. Driscoll 5G. Hayes AM, for autosomal recessive 43[Supplj:A232
Levy HL. Neonatal hemochromatosis: transmission (abstr). Am J Hum
evidence Genet 1988;
623
Case Report .:
:
.
Neonatal Ailish
Hemochromatosis:
M. Hayes,1
Neonatal
Diego
Jararnillo,2
hemochromatosis,
Harvey
also known
L. Levy,3
as peninatal
hemo-
seen in infants with liver disease of postnatal onset on in infants who do not have liver disease [2]. Neonatal hemochromatosis is not a variant presentation of human leukocyte antigen-linked (adult onset, hereditary) hemochnomatosis [3] and the two entities differ in many respects [1]. The antemortem diagnosis of neonatal hemochnomatosis is difficult, because neonatal liver failure may be associated Nonetheless,
it is important
::‘
.
,
with MR Imaging
and A. S. Knisely4
myocamdium, thyroid gland, oral mucosa), with sparing of reticuloendothelial cells in the spleen, lymph nodes, and bone marrow [i ]. Extrahepatic sidemosis in this distribution is not
disorders.
#{149}
Diagnosis
chromatosis or neonatal iron storage disease, is characterized by severe and usually fatal idiopathic liver disease of intrauterine onset. It may occur in siblings. Its hallmark is fulminant hepatic failure with siderosis of hepatocytes and of extrahepatic parenchymal cells at a variety of sites (pancreas,
with many
,
to establish
the diagnosis clinically. If it is recognized, plans for liver transplantation, the only effective therapy, can proceed. When neonatal hemochromatosis is suspected, liver biopsy may be hazardous owing to coagulopathy and the poor overall status of the patient. Oral mucosal biopsy, to demonstrate stainable iron in the small submucous glands of the lip, cheek, or tongue [4], has been an alternative in several instances [1 ], but it also is invasive. We hypothesized that MR imaging would be a noninvasive technique for diagnosis of neonatal hemochromatosis if signal intensity could be used to detect tissue iron overload [5]. This February 5, 1992; accepted after revision April 13, 1992. in part at the Third Intemational Conference on Hemochromatosis, This work was supported in part by the Pathology Education and Research I Children’s Service, Massachusetts General Hospital, Boston, MA 02114. 2 Department of Radiology, Children’s Hospital, Boston, MA 02115.
report presents our findings with MR imaging in three neonates with neonatal hemochnomatosis and a fetus whose family history indicated the fetus to be at risk for neonatal hemochromatosis. Case
Report
A singleton term female neonate manifested severe hepatic insufficiency within hours of birth. Her two siblings were well. Evaluation indicated no known heritable metabolic or infective diseases. Results of liver biopsy showed advanced cirrhosis, with large amounts of iron in hepatocytes.
Neonatal
hemochromatosis
possible diagnosis. MR images were obtained 1 .5-T
body
system
(Signa,
coil were
GE
used.
considered
Systems,
Ti -weighted
Milwaukee,
WI)
(600-800/i
7-30
and
3
Neurology
4
Department
AJR 159:623-625,
Service,
Massachusetts
of Pathology, September
General
Children’s 1992
Hospital
Hospital, Boston, MA 02114, of Pittsburgh,
0361-803X/92/1593-0623
3705
a
[TR/
TE]) and T2-weighted (2000-2500/20-80) images were obtained. No specific protocol was followed, and gradient-recalled-echo imaging was not used. The images were evaluated visually for the presence of iron overload according to published parameters [5]. Siderosis was diagnosed when the signal intensity of an organ or tissue on T2weighted showed
images evidence
was less than that of skeletal muscle. The images of marked siderosis of the liver and pancreas but
not of the spleen, consistent with the diagnosis of neonatal hemochromatosis (Fig. 1). The patient had an orthotopic liver transplant when she was 4 weeks old. Findings in the hepatectomy and biopsy specimens were similar.
MR
after
liver
transplantation
showed
evidence
of large
amounts of iron in the pancreas and myocardium but not in the donor liver. An endomyocardial biopsy performed to evaluate poor cardiac
Received
Presented
a
as
when the patient was 3 weeks old. A
Medical
Spin-echo
was
D#{252}sseldorf,Germany, Foundation, Pittsburgh,
and Department
Fifth Ave. at DeSoto
July PA.
of Neurology, St., Pittsburgh,
American Roentgen Ray Society
1991.
Harvard PA 15213.
Medical Address
Schcol, reprint
Boston, requests
MA 02115. to A. S. Knisely.
HAYES
624
ET AL.
AJR:159,
September
1992
Fig. 1.-Neonatal
hemochromatosis pancreas in a 3week-old giri. Axial T2-weighted MR image (2000/80) of upper abdomen shows hypointense liver (L) and pancress (arrow). MR imaging after hepatic transplantation showed no cvidence of signal abnormality in transplanted liver.
Downloaded from www.ajronline.org by 109.161.214.101 on 11/09/15 from IP address 109.161.214.101. Copyright ARRS. For personal use only; all rights reserved
involving
liver
and
Fig. 2.-Neonatal hemochromatosis involving liver and pancreas in an 8day-old giri. Axial T2-weighted image (2000/80) of upper abdomen shows signal intensity of liver is less than that of adjacent muscle. Signal intensity of tail of pancreas (arrow), seen ventral to splenic vessels, also is less, indicating iron deposition.
function that began after transplantation iron within
myocytes,
confirming
matosis. The patient has tolerated difficulty
and is growing
the
showed
diagnosis
abundant
of neonatal
the liver transplant
and developing
normally
stainable hemochro-
without
unusual
at age 2Y2 years
old.
The patient’s sister, who is 2 years younger, manifested hypoglycemia
in the first hours
which
after birth and worsening
hepatic
dysfunction
The parents had refused monitoring of the pregnancy,
thereafter.
continued
to
term
without
complications.
Liver
biopsy
when
the neonate was 6 days old showed advanced cirrhosis, with hepatocellular showed
2)
siderosis, evidence
without siderosis of the spleen. Neonatal hemochromatosis
diagnosed.
Her
hepatic
she is being followed
be
and MR imaging when she was 8 days old siderosis of the liver and pancreas (Fig.
of marked
indicated
dysfunction
stabilized,
up as an outpatient.
if her hepatic
status
was
and at age 6 months, Liver transplantation will
deteriorates.
erosis, as detected with MR in adults [5]. On T2-weighted images, the signal intensity was markedly diminished in the liver and pancreas with more severe
also was low on T2-weighted images. We speculate that the younger sister had no evidence of myocardial siderosis because her illness was less severe. Evidence for myocardial siderosis also was observed in a third neonate with neonatal hemochromatosis in whom MR images were obtained at i 7 days of age (Fig. 3); that case is reported fully elsewhere [6]. Of particular value was the ability of MR images to provide information on the presence of iron overload in several organs (liver, pancreas, and heart) and on the absence of siderosis in the spleen. Histologic examination shows that the neticuloendothelial cells of the splenic cords are not siderotic in
neonatal
hemochnomatosis
for neonatal Discussion
Examination of a neonate with severe hepatic disease requires screening for infective agents and for metabolic disorders known to manifest at this age. Serologic markers of maternal infection, culture techniques, and laboratory analytic
studies
permit
screening
for many
such
disorders.
Although neonatal hemochnomatosis is an acknowledged clinicopathologic entity, it is not clear if neonatal hemochnomatosis
is a single
disorder
on a common
phenotype
due to
fetal liver disease from several causes [1 ]. Accordingly, the diagnosis is based not on laboratory results but on recognition of features of the characteristic phenotype (extrahepatic siderosis) in the appropriate clinical setting (liver failure manifest at birth). To date, this has meant an invasive procedure to obtain tissue for histopathologic examination [4]. Our results indicate that MR imaging can supplement or perhaps replace biopsy for diagnosis of neonatal hemochromatosis. Although MR findings and MR assessment of iron stores have not been reported in neonatal liver disease other than neonatal hemochnomatosis, our findings in these neonates with neonatal hemochromatosis who were examined with MR imaging were consistent with hemochnomatotic sid-
and was normal in the spleen. In the patient disease, the signal intensity from the heart
[1 ], and this diagnostic
hemochnomatosis
is not addressed
criterion
by biopsy
of
oral mucosa. It must be stressed that marked siderosis of the liver is physiologic in the pennate, and that in the absence of extrahepatic siderosis the diagnosis of neonatal hemochnomatosis should not be made [i , 2]. Furthermore, because MR evaluation, particularly comparison of signal strength on Ti - and T2-weighted images at various sites, has not been included before in diagnostic studies of neonates with liver disease, the specificity of the findings in the cases reported here may be questioned. However, extrahepatic siderosis in a hemochromatotic distribution is not seen on histopathologic examination in infants with liver disease of postnatal onset or in infants who do not have liver disease [2], so it is likely that MR evaluation of iron overload at extrahepatic sites will be of specific value. Because neonatal hemochromatosis recurs in sibships, fetuses
of a mother
who
has
had
an infant
with
neonatal
hemochromatosis should be considered at risk for neonatal hemochromatosis [i Although percutaneous sampling of cord blood may provide results that can be used to diagnose neonatal hemochnomatosis in an appropriate clinical setting ].
[7],
noninvasive
Sonography
techniques
also
may show abnormalities
are likely
to be of value.
in the fetal liver or blood-
Downloaded from www.ajronline.org by 109.161.214.101 on 11/09/15 from IP address 109.161.214.101. Copyright ARRS. For personal use only; all rights reserved
AJR:159,
MR
September1992
IN NEONATAL
625
HEMOCHROMATOSIS
Fig. 3.-Neonatal hemochromatosis involving heart in a 17-day-old giri. A and B, Axial Ti-weighted (600/17, A) and T2-weighted (2500/70, B) MR images at level of heart show that signal of atrial and ventricular walls on T2weighted image Is decreased so much that outiine of heart is barely perceptible. Myocardial siderosis was confirmed at autopsy.
flow patterns associated with liver disease, but it will not provide information on sidenosis. We have had the opportunity prospectively to evaluate a pregnancy in a woman whose first two offspring were born prematurely and died of liver failure in the neonatal period. Autopsy in both showed neonatal hemochnomatosis [8]. The parents agreed to intensive monitoring during the subsequent pregnancy. Sonography and MR imaging were performed in the 20th gestational week. Neither showed abnormalities, and no evidence of extrahepatic siderosis was found. In order to exclude liver disease of third-trimester onset, sonography and MR were repeated in the 36th gestational week. The findings again were normal. The neonatal course was unremarkable; thus, neonatal hemochnomatosis was ruled out on clinical grounds. The boy has remained well for 2V2 years, with normal growth and development. We think that MR studies can be used to diagnose neonatal hemochromatosis in the neonate and to exclude neonatal hemochromatosis in the late third-trimester fetus at risk. They also may allow conclusive antenatal diagnosis of neonatal hemochnomatosis. Experience with this technique in monitoring fetuses
at risk
will determine
if it can
be used
for the
diagnosis of neonatal hemochnomatosis so, whether pathognomonic features
gestation
for elective
termination
in the fetus, and, if appear early enough in
of the pregnancy.
REFERENCES 1. Knisely AS. Neonatal hemochromatosis. Adv Pediatr 1992;39:383-404 Witzleben CL, Uri A. Perinatal hemochromatosis: entity or end result? Hum Pathol 1989:20:335-340 3. Hardy L, Hansen J, Kushner JP, Knisely AS. Neonatal hemochromatosis:
2.
4.
5.
6.
7.
genetic analysis of transfemn-receptor, H-apoferritin, and L-apofemtin loci and of the HLA class I region. Am J Pathol i990;137: 149-1 53 Knisely AS, O’Shea PA, Stocks JF, Dimmick JE. Oropharyngeal and upper respiratory mucosal gland siderosis in neonatal hemochromatosis: an approach to biopsy diagnosis. J Pediatr 1988;1 13:871 -874 Siegelman ES, Mitchell DG, Rubin R, et al. Parenchymal versus reticuloendothelial iron overload in the liver: distinction with MR imaging. Radiology 1991:179:361 -366 Knisely AS, Harford JB, Klausner RD, Taylor SR. Neonatal hemochromatosis: the regulation of transfemn-receptor and ferritin synthesis by iron in cultured fibroblastic-line cells. Am J Pathol 1989:134:439-445 de Boissieu D, Checoury A, Barbet P, Francoual C, Rochiccioli F, Badoual J. H#{233}mochromatose p#{233}rinatale.Arch Fr Pediatr 1990:47:23-28
8. Driscoll 5G. Hayes AM, for autosomal recessive 43[Supplj:A232
Levy HL. Neonatal hemochromatosis: transmission (abstr). Am J Hum
evidence Genet 1988;
