FAMILIAL
INTRAHEPATIC
CHOLESTASIS
WITH
MENTAL
AND
GROWTH
RETARDATION
Richard C. Juberg, M.D., Roxie M. Holland-Moritz, M.D., Keith S. Henley, M.D.,
and Carlos F. Gonzalez, M.D.
-Departments of Human Genetics, Pediatrics, and Internal Medicine (Section of Gastroenterology),
The University of Michigan Medical School, Ann Arbor, and
The St. Clair Clink, St. Clair, Michigan
(Received March 2; accepted for publication June 2, 1966.)
Supported in part by the Children’s Bureau, Department of Health, Education and Welfare (R.C.J.),
by an Institutional Grant to the University of Michigan from the U. S. Public Health Service, by Public Health Service Research Grant 5-MO1-Fr-42-05 from the Division of Research Facilities and Resources to the Clinical Research Unit, University of Michigan, and by a Research Career Development Award of the National Institutes of Health to one of us (K.S.H.).
ADDRESS: (R.C.J.). Department of Pediatrics, West Virginia University, Morgantown, West Virginia
26506-PEDIATRICS, Vol. 38, No. 5, November 1966
819
T
HE purjose of this communication is todescribe a severe form of cholestasis beginning in infancy, apparenfly progres-sive in nature, and resulting in significant impairment of growth and development in four siblings. The evidence which suggests a genetic basis for this disorder is present-ed.
Case 1
CASE REPORTS
The proposita (IV-37 in Fig. 1) was born at
term on March 28, 1956, and weighed 3.3 kg
(7/io lb). During pregnancy the mother did not
receive tranquilizers, antibiotics, or blood
trans-fusions. The mother had never been jaundiced.
Hospital records show no indication of jaundice in the baby in the neonatal period, and when she was
discharged at 3 days of age, normal brown stools
were noted. Urinary color was considered to be normal. The baby was well until between 3 and
4 months of age when the mother noted a large
abdomen, a change in stool color from yellow to light gray, darkening of the urine, and scratching so that excoriations resulted. Although the mother
had not noticed any change in skin color, an
ex-amining physician said the baby was jaundiced. She had had an upper respiratory tract infection for 1 month prior to an episode of vomiting, which
prompted her first hospitalization at 53i months
of age. At admission she was very irritable, there was mucopurulent nasal discharge, and coarse rhonchi were heard bilaterally. The abdomen was
very distended, and, during the examination, a large, foul smelling stool was observed. She ap-peared malnourished and there was evidence of weight loss. Neither liver nor spleen was found to be enlarged. The groin and buttocks were red, and it was evident that the baby was in severe
discomfort with prunitus, particularly in the groin
but also over the entire body. In addition to the values in Table I, the red blood cells (rbc) were
noted to be hypochromic, there was no
eosino-philia, and the urinalysis showed no abnormality. Vhile in the hospital, she developed numerous, dime-sized hemorrhages on her back. A diagnosis of food allergy was made following elimination of some foods, and she was discharged when fin-proved on a soy bean milk formula plus vitamins
C and D.
At 6% months epistaxes and further bruising de-veloped with another upper respiratory infection. This led to admission to another hospital. She ap-peared acutely ill with fever, pallor, epistaxis,
scat-tered bruises, grunting respirations, and marked
abdominal distention. Her weight was slightly
be-low the 3rd percentile ( > 2 SD below the mean).
She was mildly jaundiced and the spleen was felt
1 cm below the left costal margin, but the liver
was not felt at the time of admission (Table II). At
the time the blood was typed as ABO group B and
Rh type C positive, D positive (the Rh typing
was later shown to be incorrect). The direct
Coombs test was negative. The clotting time was 180 minutes; the bleeding time was 1.5 minutes; the prothrombin time was prolonged; and she
was anemic. There was moderate anisocytosis, and
a few target cells were noted on two different
specimens. The bleeding stopped within 24 hours
after transfusion of 200 ml B positive blood and administration of vitamin K1 oxide. Prothrombin time was then normal. A diagnosis of pneumonia
was made, and she was treated with penicillin,
oxytetracycline, and streptomycin.
Mild jaundice continued with frequent scratch-ing. The red blood cell fragility test was normal. Following a subsequent rise in the white blood cell count (WBC) and a fall in the hemoglobin con-centration, she was treated with penicillin, tetra-cycline, and chloramphenicol. Bacillus proteus was
DMale OFemale
O Sex unknown
U Intrahepatic cholestasis with mental
and physical retardation Cholangiolitis and cholangitis
B Normal liver function studies
Miscarriage
t Deceased
KINDRED 9000 HEREDITY CLINIC UNIVERSITY OF MICHIGAN
FIG. 1. Pedigree of the B. family. Dotted line indicates illegitimacy.
Ill
IV
TABLE I
HEMATOLOGICAL, CALCIUM, AND PHOSPHORUS VALUES OF THE FOUR AFFECTED SIBLINGS AND
THEIR MATERNAL AUNT
.
Patient Age gin/1 Hb WBC/mm3
Plateleti 1mm3
Prothrombin Time Sec
Ca ing/100 ml
P ing/100 ml
IV 37
mo
6-84 mo
81--lO4mo
21 mo
3yr
Syr
8yr
9yr
10.8
8.0_1.8*
10.7_13.5*
7.8
10.0
7.0
9.4
8.7
14,400
1,000_9,50*
9,600_19,000*
28,700
8,000
3,750
adequate
496,930
adequate
288,0O0
108 (is)f
11.7(1.8)t
78%
15.4 (13.0)t
11.2 5.6
8.6 7.5
IV-38
7mo 64yr
7yr
74yr
12.4
12.2
12.5
13.4
9,500
adequate
12.4 (13.0)t
13.8(12.0)t 10.5 8.2
IV-41
3 yr
34yr
4yr
13.5
14.0
7,850 adequate 13.1 (13.0)t
13.0(11.5)t 11.8 5.5
IV-42
lSmo
21 mo 2yr
11.5
9.2 10.7
9,850 adequate 15.1(13.0)t
14.2(11.5)t 10.7 7.4
111-27 28 yr 14.7 74%
* Range during hospitalization.
t Control.
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0-* Dr. Jean H. Webster, Petoskey, Michigan, personal communication.
HISTOLOGICAL OBSERVATIONS OF LIVER Biosiics OF THE Fouit AFFECTED SIBLINGS AND THEm MATEIINAL AUNT
Patient Age Type of
Bzop.y findings
IV-37
10 mo
9 yr
Surgical
Needle
Hepatic cells show coarse granulations on a clear backgroun(1. There are mmri-able degrees of pericanalicular brownish green pigmentation and some
caitali-cular plugging. Stains for hemosiderin, lipofuscins, melanin, and ceroi(l are
negative. liOn, fibrous strands, confirmed by Massoifs trichrome stain, ex-tend out from the portal areas and central veins. Focal close approximation of
several triads. Occasional focus of mononuclear infiltrate and fibrosis suggest
repair of necrotic focus. Indistinct interlobular bile ducts, often with
incon-spicuously collapsed lumina and irregularly flattened epithelia.
Diagnosis: Suggestive of congenital hypoplasia in asmall amount of material
Fragmented tissue without representation of portal areas. Bile pigment and
canalicular plugging more prominent than previously. “Feathery
degenera-tion,” multinucleation and cytomnegaly more prominent than previously.
Diagnosis: “Intrahepatic cholestasis.”
IV-38 74 yr Needle
Very adequate biopsy specimen. Normal radial parencilymal architecture of the liver lobule is not present and while central veins are easily found and
dilated, the triads are inconspicuous, and only rare interlohular bile ducts are
found. Intracanalicular bile stasis is accompanied by pigmentation of par-enchymal cells. Cellular unrest and multinucleatiomi of liver cord cells with
occasional megalocytic cells. Focal necrosis in the lobules. Prominent
glyco-gen in the nuclei.
Diagnosis :“Intrahepatic cholestasis.”
IV-41 4 yr Needle
Compared with the three siblings, this patient has the least stasis alid cell
pigmentation. Portal areas less well defined than would be expected for this age. Dearth of bile ducts.
Diagnosis: “Intrahepatic cholestasis.”
IV-42 2 yr Needle
Mild but evident bile stasis in canaliculi. Like the other three siblings, portal spaces are small and compressed with a paucity of interlohular bile ducts.
Pigmentation of parenchymal cells and “cellular unrest.” Absence of normal
radiating lobular architecture and many cord cells assume a pseudoductular
arrangement. Thin fibrous bands traverse and accentuate lobules. Focal
cellular necrosis. Prominent glycogen in nuclei.
Diagnosis: “Intrahepatic cholestasis.”
Summary: Similar changes with variable degrees in all four siblings. Bile stasis in canaliculi seen in all, most evident in IV-37, least in I\’-41. Pigment (bile and lipofuscin) is also seen in all four, least evident in 1\’-41. Cellular unrest with multinucleated (up to 4 and 5 nuclei) cells and some megalocytic parenchymal cells in all, least evident in IV-41. Normal lobular radiation is not seen and interlobular bile ducts are rare to absent.
111-27
I
28 yr“In the liver biopsy specimen the liver cord cells are markedly swollen with
cytoplasmic granules and the sinusoids are compressed. In several irregular areas there are collections of lymphocytes and these appear to be arranged
Needle around small bile ducts. There are three areas where there is some reactive
fibrosis around bile ducts. Lipid vacuolization of liver cords is seen in
approxi-mately 10% of the cells.
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The WBC continued between 12,000 and
22,000/cu mm, the latter associated with
eosino-philia of 14. Examination of the stools for trypsin activity was positive. Escherichia coli was cultured from the pharynx on two occasions. Cytological
examinations of two different urine specimens for
cytomegalic inclusion bodies were negative, but
cultures were not attempted. Acholic stools were never seen, but the urine was consistently
posi-live for bile. The reticulocyte count did not
ex-ceed 3sf. Radiological survey of the long bones was negative. The nonprotein nitrogen was
re-ported between 31 and 40 mg/ 100 ml.
During the 2 months of hospitalization, her
liver size fluctuated from 13i cm to 5 cm below
the right costal margin. Pruritus persisted. She
was also treated with erythromycin and mycosta-tin. Developmentally, she was not able to sit alone at 8 months, but she could roll over and reach for objects. She remained below the 3rd percentile in
weight.
The child was transferred to the University of Michigan Hospital for a liver biopsy, which was
performed on January 15, 1957 (Table III and Fig.
2 and 3). At operation the liver edge was sharp
and located 2 cm below the right costal margin.
The gallbladder contained a small amount of light brown bile. The extrahepatic biliary ducts were found to be normal, and the operative
Fic. 2. IV-37. Masson’s trichrome stain of liver.
Well developed bile duct from surgical biopsy
at 10 months.
Fic. 3. IV-37. H. and E. stain of liver. Chronic inflammatory cell infiltrate in Parc11ckY1a from
surgical biopsy at 10 months.
cholangiogram demonstrated a normal extrahepatic
system with ready spill of contrast material from
the gallbladder into the duodenum. A small lymph node was removed and showed chronic
hvper-plastic lymphadenitis without evidence of a spe-cific chronic infective granuloma. Postoperatively
her course was uneventful, except that she
ap-peared more jaundiced and was febrile for several
days, although the wound did not heal com-pletely for 9 months. Urinalyses were repeatedly
normal except for the presence of bile. Stools
were now clay colored. Bromsulphalein (BSP) in-jected intravenously did not appear in the feces.
Her pruritus (lid not improve with antihistaminic and cholagogic drugs. She was discharged without
a definitive diagnosis.
In the 7 years between the first and second ad-missions to the University Hospital, there were nine hospitalizations for either pneumonia, otitis
media, or furunculosis. On each occasion jaundice
was more evident with the associated infection. In December 1957, at the age of 21 months,
anemia was treated with 250 ml of blood. Sodium concentration of sweat was 22 meq/l. Bleeding from the ear in March 1959 was treated with 5
I
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Fic. 5. IV-42. II. and E. stain of liver. Periportal fibrosis froln I)erc11t1neous biopsy at 23 ears. the right costal margin. The spleen was just
pal-pable. The fingers and hands were short and stubby vith thick, coarse wrinkled skin (Fig. 6).
Nail development of the toes was poor.
Tuberculin and histoplasmin skin tests were negative. Examinations of urine for phenlpsTuvic
acid and acid mucopolvsaccharide were negative.
Hvpochromic anemia with depression of granu-locytes but not of platelets WaS noted. The reti-culocyte count was 2.2i. The radiological bone
age was 3 to 33& s-ears. Ceruloplasmin
concen-tration in the serum was “noniial.” The intelli-gence quotient was 67 by the verbal (Stanford-Binet Form L-M) and the nonverbal (Leiter In-ternational Perforlllance Scale) tests.
Culture of the peripheral blood revealed that the chromosome nulliber was 46 in 26 cells
cx-aniined. Five cells ere selected for detailed an-alvsis and studs-. Each of these cells contained 16 chromosomes in Group C (6-12-X) and 4
chromosomes in Group G (21-22-Y), which is
nor-ma! for a female. There was no evidence of structural abnormality (such as, translocation or
deletion). No structural variation, which might
be considered a marker and thus followed in the family, was found.
In September 1964 she s-as admitted to a local
FIG. 4. IV-37. II. and E. stain of liver. Bile throm- hospital because of a urinary tract infection. The bus and accumulation of bile pigment from per- stools were positive to guaiac, but
roentgenologi-cutaneous biopsy at 9 years.
The stools, which had been bulks’ and loose, im-1roved in consistency on a low fat diet.
At 4 years when admitted to another hospital,
she was just recovering from “3-day measles” and had signs of an upper respiratory tract infection.
She was jaundiced, and her skin was excoriated
from scratching. The liver was palpated 5 cm
be-low the right costal margin, and the spleen was
again felt just below the left costal margin. Warty
growths were present on the vulva and in the perianal region, which were large enough to inter-fere with defecation. Examinations of the urine
for bile remained positive.
At 5 years, she was operated upon for an
in-cisional hernia and an abscess at the site of the original biopsy.
\Vhen readmitted to the University hospital in
May 1964, her weight and height were both
mark-edly less than the 3rd percelltile. The head
circurn-ference was 48.5 cm (19.1 in.) and the chest cir-cumfercnce was 60 cm (23.6 in.). She presented an unusual facial appearance because of a small,
round head, round face, prominent bulging eyes,
and slightly bulging cheeks. She could only walk
slowly, often needing support, and she could not
run. Iler gait was widely based, and she showed
genu recurvaturn. Her hair was -er fine and light
FIG. 6. IV-37. Hands at 9 years showing short, stubby appearance with thickened skin and convex
nails.
I
ARTICLES
cal examination of the esophagus for varices was reported to be negative.
In May 1965 she was admitted to the Clinical Research Unit of the University Hospital. She was
just over 9 ears of age, and recently six per-manent incisor teeth had erupted. The heart was questionably enlarged by percussion, and a systolic
murmur (grade 1 of 4) was heard along the lower
left sternal border and considered to be func-tional. The liver was palpated 63i cm below the
right costal margin and the spleen was palpated 23i cm below the left costal margin. The gallblad-der did not visualize following ingestion of Tele-paque. BSP retention increased from 13.5 at 45
minutes to 25% at 120 minutes. This raises the
possibility that sonic conjugated BSP was released
from the liver into the blood stream rather than
being excreted in the biliary system. A percutan-eous liver biopsy was performed (Fig. 4). The
child was discharged on a regime of oral iron,
water soluble vitamins, and cholestvramine (% teaspoonful three times per day which was
in-creased to 3i and then 1 teaspoonful three times per day). The latter drug was stopped after 1 month because the mother noted no diminution
ilL scratching. Subsequent experience with other children suggests that the starting dose aS too small. Response to the iron therapy was nOt
evalu-ated.
\Vhen last seen at the age of 9I2 years, she could not stand without support, although she was attending school in an ungraded class. The
liver was palpable 5 Clii below the right costal margin and the sl)leen was palpable 4 cm below
the left costal margin. The photographs of Figures 7 and 8 were taken at this age and show the proposita and her three affected siblings, to be described, compared with their three normal siblings.
Case 2
IV-38 (Fig. 1), a sister of the proposita, was born on October 13, 1957, after 63 months of
-
-
-4--.
‘1, ---. 2
FIG. 7. B. sibship. From the left, the proposita (IV-37) at 91#{176}jvr, affected sister (IV-38) at 8 yr,
nor-mal brother (IV-39) at 73 yr, normal sister (IV-43) at vr, normal brother (IV-40) at 6h yr, affected
Fic. 8. B. sibship. Same order as in Figure 7. Note leaning stance of the proposita.
gestation and weighed 1.36 kg (3 ib). The mother had ingested no drugs. Icterus was noted at age
48 hours, at which time she was having normal
meconium stools. On this same date, a papular
rash was noted over her trunk which disappeared
within 48 hours. She received penicillin for 4 days and ox-gen for 7 days. When 9 days old, because
of increased jaundice, increased lethargy, and
reddened umbilicus, she was given oxytetracycine.
The total bilirubin was 11 mg/100 ml, and blood
culture showed hemolytic staphylococcus, coagu-lase positive. There was no major blood group incompatibility, and the direct Coombs test was negative. She received a total of 70 ml blood after
the hemoglobin concentration decreased to 6.7 gm/100 ml at 5 weeks of age. There was no
nota-tion of jaundice after 11 days of age, normal
brown stools were noted, and urine color was normal.
The history of her illness is similar to her older
sister’s. Pruritus appeared at 4 months, and she
also scratched until she bled. Her urine had been
noted to be unusually deep yellow, but the stools were not light colored. Her abdomen was noted to
be large. The parents became concerned when she failed to gain weight, and an intravenous
pyelo-gram (IVP) at age 7 months was normal. She did
not appear jaundiced (Tables I and II). Four
urinalyses were examined specifically for inclusion bodies, but none were seen. She had rubella at 18 months.
She was hospitalized elsewhere at 21 months to investigate the severe growth retardation. She weighed 4.8 kg (1019i6 lb). She had sat unsup-ported at 14 months, and by 21 months she was
able to pull herself up to stand but could not walk. There was Inarked wasting of the face, ex-tremities, and buttocks with a distended abdomen
and prominent superficial abdominal veins. There was no intra-abdominal fluid and no
hepato-splenomegaly.
There was no retardation in bone age. Hilar calcifications were seen in the roentgenogram of
the chest, but tuberculin and histoplasmin skin
tests were negative. Sodium concentration of sweat was 36.4 meq/l. Blood urea nitrogen (BUN) was 13 mg/100 ml. A trace of bile was reported in
the urine on one occasion. An oral glucose
toler-ance test showed a maximum increase of 40 mgI
100 ml above the fasting level at 2 hours. A
827
found to be low and she was treated with a
modified celiac diet, vitamins, and pancreatin. By 2% years she weighed 6.8 kg (15 lb) The
color of her skin was sallow with scattered ex-coriations. The abdomen was protuberant, the
liver was palpable 3 cm below the right costal
margin, but the spleen was not felt. Warty growths were noted in the perineum and, especially, in the perianal region. By this time she walked with
support but did not talk. She learned to walk
Un-aided at 3li years. At this time she was reported to have loose stools, which were light in color, and
her urine was darker than normal.
Before her admission to the University of
Michi-gan Hospital for the first time in May 1964,
treat-ment with bile salts was reported to have in-creased the color of her stools. The urine was said
to be brown intermittently. For the first time,
she was noted to be jaundiced by the parents.
At 63i years she was noted to be constantly scratching, and the skin showed many
excoria-tions (Table I). Her weight and height were less
than the 3rd percentile. The abdomen was en-larged, and the liver was palpable 3 cm below the right costal margin. Slight clubbing was present.
Her posture was lordotic.
Tuberculin and histoplasmin skin tests were negative. There was no defect of urinary concen-trating ability and no albuminuria. Urine tests
for phenylpyruvic acid and acid
mucopolysac-charide were negative. The bone age was less than 2 years. Bone marrow morphology was normal. By
the verbal and nonverbal tests, her I.Q. was 62.
At 73 years her eyes were less prominent. A
cardiac murmur was considered to be functional. The spleen was not palpable, and the liver was
difficult to define. Her stool, the darkest in color of the four affected children, was negative to
Fouchet’s reagent for bile pigments. There was faint visualization of the gallbladder by oral
chole-cystography. Following ingestion of fat, the
shadow was denser but still faint. The BSP
re-tention was 15.5% at 45 minutes and 16.% at 120 minutes. Percutaneous liver biopsy was per-formed. She was discharged on a regime of choles-tyramine (li teaspoonful three times per day which
was increased to 3i and then 1 teaspoonful three
times per day) and water soluble vitamins. The former was discontinued after 1 month, and the mother reported no diminution in scratching.
When last seen at the age of 8% years, the liver
margin was indistinct, and the spleen was not
palpated. She did not have the ambulatory diffi-culties of her sister. She had not been experienc-ing much pruritus, but she has not been as con-sistently jaundiced as her older sister. She has not been frequently ill like her sister, and she has not required hospitalization for other than investigational purposes. She was attending school
in a special education class.
Case 3
The only affected male (IV-41, Fig. 1) was born on April 26, 1961, at term and weighed 3.24 kg
(731s Ib). The mother had received an injection
of an unknown material for threatened abortion at 2 months’ gestation. She took approximately 12 red and grey capsules for relief of headache throughout the pregnancy. Throughout this and
the subsequent tsvo pregnancies she also took
vitamins. He was not noted to be jaundiced in
the neonatal period; the hospital record stated that
the stools changed from meconium to brown to
yellow prior to discharge, and no note was made
about color of urine. This boy had operations for bilateral inguinal hernias at 6 and 10 weeks of age.
He developed pruritus at about 4 months but
the stools were not acholic and the urine was not
dark. He bled readily from scratching, especially
around the ears. He gained weight satisfactorily
until he was about 2 years old. He was at that
time noted to have a large abdomen and frequent
stools which were loose and sometimes floated.
They were improved on a gluten-free diet with
added skimmed milk. He was never thought to
be jaundiced. His appetite was good.
His development was considered about the same
as that of his male siblings except that he did
not walk alone until 19 months. He sat unsup-ported at 8 months, said simple sentences at 18
months, and was toilet trained at 2% years. On admission to University Hospital in May 1964 his weight was found to be at the 10th percentile (within 2 SD of the mean) while his
height was less than the 3rd percentile. The skin was excoriated with multiple patches of erythe-matous, scaly lesions over the trunk and extensor
surfaces of the extremities. The heart was
ques-tionably enlarged; a cardiac murmur ( grade 1 of
4) was considered to be functional. The liver was questionably felt 1% cm below the right costal
margin, but the spleen could not be felt. His
hands were short and stubby with broad fingers
and presented the appearance of clubbing. His
bone age was 2% years. The peripheral eosinophil count was 6%. There was no albuminuria,
galac-tosuria, or glycosuria, and urine specific gravity was 1.025. Tests on the urine for phenylpyruvic acid and acid mucopolysaccharide were negative.
Old tuberculin and histoplasmin skin tests were
negative (Tables I and II).
During the next year he appeared quite well;
but, he was noted to have rhinorrhea most of the time, he developed epistaxis occasionally, and he occasionally complained of abdominal pain.
He was admitted for percutaneous liver biopsy
to the Clinical Research Unit of University Hos-pital in May 1965 at the age of 4 years. The
828
the chest circumference was 59.5 cm (23.5 in.).
He was a chubby boy who did not appear jaun-diced. His facial outline was square rather than
round like that of the affected sisters. The liver
was palpable Ui cm below the right costa! mar-gin. The spleen was not enlarged to palpation or
percussion. The skin was rough, thick and
ex-coriated. The nails of the fingers were convex while those of the toes were flat.
At this time his eosinophilia had risen to 18%,
which could not be accounted for on the basis of
pica. Further inquiries revealed that the family kept a dog. An oral cholecystogram showed nor-ma! opacification of the gallbladder. He showed
11% BSP retention at 45 minutes and 13% at 120 minutes. A percutaneous liver biopsy was
per-formed. He too was discharged on a regime of cholestyramine (3i teaspoonful three times per day which was increased to ii and then 1
tea-spoonful three times per day) and water soluble
vitamins. The cholestyramine was discontinued by
the mother after 1 month.
When he was last examined in January 1966 at the age of 4% years, he was not jaundiced and his
skin did not show evidence of recent scratching. The liver was palpable 5 cm below the right
costal margin, and the tip of the spleen could be
felt. He has always appeared less severely and less
frequently jaundiced and more robust than the two older affected sisters, even though he is small
in comparison with other children his age. His urine has never been very dark. His most
trouble-some smptom has been pruritus, and his abdomen
has always been unusually large.
Case 4
IV-42 (Fig. 1), a full-term, infant girl was born
on February 2, 1963. Birth weight was 3.24 kg
(7%’i Ib) and she was a breech presentation. On
the third clay she was noted to be slightly
jaun-diced, but she was discharged the following day.
Her stools were recorded as meconium in the
newborn nursery, and there was no note about
urine color. A right inguinal hernia was repaired at the age of 6 weeks. Pruritus was noted at 5
months, and the mother noted intermittent dark urine, light stools, and jaundice. The child was
hospitalized at 11 months for diarrhea and an enlarged liver was found. She was treated with intravenous fluids but did not receive blood. She was considered to have the same disease as her
three siblings.
She crawled at 12 months but did not sit un-supported until she was 13 months. She was said to speak clearly in sentences at 18 months but did
not walk until 26 months.
When admitted to the University Hospital in
Mw 1964, the anterior fontanelle had remained open. She had received vitamin supplementation for many months. Both her height and weight
were in the 10th percentile. The skin showed
many small excoriated lesions widely scattered
over the body with evidence of bleeding. The
liver was palpable 6% cm below the right costa! margin, and their was an umbilical hernia. Her
hands were noted to be stubby.
Her maximum urine concentration was 1.020, there was no albuminuria or glycosuria, and tests
for phenylpyruvic acid and acid mucopolysac-charide were negative. Old tuberculin and histo-plasmin skin tests were negative. Her bone age was 12 months (Tables I and II).
When admitted to the Clinical Research Unit
at 2% years for liver biopsy, her height was at the
3rd percentile, while her weight was still at the
10th percentile. The head circumference was 47
cm (18.5 inches) and the chest circumference 52 cm (20.5 inches). Her face appeared round with bulging cheeks, a depressed nasal bridge, and bilateral inner epicanthal folds. The heart was
questionably enlarged to percussion, and a mur (grade 1 of 4) was considered to be
func-tional. The abdomen was protuberant, the liver was palpable 33i cm below the right costa! mar-gin, and the spleen could not be felt. The skin
color was bronze, and it was thick and rough.
There was excoriation and bleeding. Nails of the
fingers were more convex than normal. Her fin-gers appeared short and stubby.
The gallbladder did not visualize with a total of 3 gm of Telepaque. Her BSP retention was 16% at 45 minutes and 27% at 120 minutes. A per-cutaneous biopsy of the liver was performed (Fig. 5). She received the same medications as did IV-38 and IV-41 at the time of discharge.
Eight months later, at the age of 3 years, she appeared more jaundiced than her siblings. She was constantly scratching. The liver was palpable 6 cm below the right costal margin, and the tip
of the spleen could be felt. Her jaundice has fre-quently appeared as intense and sometimes more intense than that of her oldest sister.
In summary, similar symptoms first ap-peared at approximately the same age in each of the four siblings. The male has ap-peared to be the least affected. The
pre-senting manifestation has been pruritus at 3 to 5 months and, in the females, enlarge-ment of the abdomen, pallor of the stools, darkening of the urine, and jaundice have
occurred. The most prominent manifesta-tions in the male have been pruritus and abdominal enlargement. Their development
has been slow, and their growth has been
marked by relatively more retardation in
GiRL ‘S PHYSICAL OEVELOPMENT - I TO 18 YEARS
AGE IN YEARS
829
FIG. 9. Growth of the three affected females of the B. sibship.
Physically, they have each consistently had a moderately enlarged liver, an
incon-sistently enlarged spleen, protuberant ab-domen, short fingers and toes, prominent
eyes, and rough, thickened skin.
Figures 9 and 10 reveal their growth re-tardation. In contrast, the older normal brother is in the 50 to 75th percentile
(with-in 1 SD from the mean) for height and on
the 90th percentile for weight (within 2 SD
from the mean); the younger normal
broth-er is in the 10 to 25th percentile (within
2 SD from the mean) for height, and the 50
to 75th percentile for weight. The younger, unaffected sister at 10 months of age is 80
cm (31.5 in.) in length and 10.4 kg (23 ib) in weight.
A 28-year-old married female ( 111-27, Fig. 1),
maternal aunt of the proposita, is the only relative on eIther side of the family who is known to have had any form of liver disease. She was admitted to the Burns Clinic, Petoskey, Michigan, on January
29, 1965, because of right lower quadrant pain. She had been under observation because of obesity
but had not responded to dietary restrictions. Past history revealed that in May 1956 she had undergone an exploratory abdominal operation
elsewhere, performed because of recurrent, crampy,
right upper quadrant pain and suspected ectopic
pregnancy. Adhesions were found in the right lower quadrant in the region of a previous ap-pendectomy, but the liver appeared normal. The
0
0
C 2
AGE IN YEARS
830 FAMILIAL CHOLESTASIS
U) I 4-) 2
BOY ‘S PHYSICAL DEVELOPMENT - I TO 18 YEARS
FIG. 10. Growth of the affected male of the B. sibship.
gallbladder emptied easily with pressure and
con-tamed several faceted stones. Then in August 1959 she underwent a cholecystectomy. A small fibrotic gallbladder with thickened wall and one ovoid stone measuring almost 2.5 cm in diameter was found, but there were no signs of acute infiamma-tion. The liver again was reported to be normal. There was no preoperative jaundice.
The physical examination was within normal
limits, except for obesity.
Laboratory sttIdies during the 1965 admission,
in addition to those in Tables I and II, included: complete blood cell count, veneral disease re-search laboratories test for syphilis, catheterized
urine, pregnancy test, and urine for porphyrins
were all within normal limits, as were the BUN,
creatinine, calcium, phosphorous, fasting blood sugar, and uric acid determinations. The serum
gamma globulin was slightly elevated at 1.73 gm/ 100 ml. An IVP showed blending of the right midrenal calyx, and there was non-filling of the
left lower pole calyces. A retrograde pyelogram
showed evidence of extrinsic pressure on the
dome of the urinary bladder. Barium enema ex-amination showed a normal large bowel and ter-minal ileum. Upper gastrointestinal examination showed abnormal motility. A roentgenogram of the chest was normal. The abnormal BSP reten-tion was interpreted to be secondary to
overadmin-istration of the dye as a result of the patient’s
marked obesity.
ARTICLES 831
Bio-Science Laboratories, Los Angeles. California 91403.
data are recorded in Table III. Subsequenfly, she is reported to have remained in good health and
to have lost weight.
Biochemical Characterization
In all the siblings studied elevation of total bilirubin has usually been moderate, the highest recorded value in any of the
four siblings was 12.8 mg/100 ml in the youngest affected, and two normal values have been obtained-one in IV-38 and one in IV-41. The proportion of the total as con-jugated has generally been three fourths. The oldest sibling has been more
consis-tently hyperbilirubinemic as well as clini-cally jaundiced than the three younger sib-lings, but she has not shown progression in the total level nor in the proportion of con-jugated bilirubin. The maternal aunt has not been hyperbilirubinemic.
Alkaline phosphatase levels in serum have been elevated, the higher values have been obtained in the younger siblings and at younger ages. One normal value has been recorded for the eldest. Alkaline
phos-phatase activities in the serum of the
mater-nal aunt have been normal.
Glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT)
activities in serum have been moderately
elevated in the four siblings, but the values
for the aunt were markedly increased.
Cholesterol values in serum for the four
siblings have been slightly elevated.
While total serum protein values have been either normal or slightly low, the dis-tribution of components has generally been
altered because of diminution in the
albu-men portion with increases in the alpha-i, alpha-2, and beta globulin portions. The percent of total proteins recorded as gamma globulin has been normal. While this is true for the four siblings, in contrast, the maternal aunt showed a slight elevation in the gamma globulin portion as the only
abnormality.
Retention of BSP at 45 minutes has
been elevated, and 2-hour determinations
showed the same or slightly more retention
in the four siblings. The maternal aunt
showed marked retention. It is apparent, then, that the maternal aunt has not shown
the same biochemical abnormalities as the
four affected siblings.
As the metabolism of bilirubin in the liver involves, successively, uptake, conju-gallon, and excretion, and as most of the
bilirubin in the serum was conjugated, this
suggests that the final step of excretion is impaired in these children. This is support-ed by the grossly elevated levels of bile acids in the serum in all four affected sib-lings and the uniformly increased ratio of the trihydroxy to dihydroxy acids (Table IV). This suggests a defect in the excretory mechanism located between the sites of conjugation and the lumen of the bile duc-tule, rather than severe parenchymatous, hepatocellular failure. The mechanism of excretory failure may be functional, me-chanical, or both. The histological evidence does not support the presence of a mechan-ical defect, as bile ducts were identified both at operation in the proposita and in the liver biopsy specimens (Fig. 2 and 5). Par-enchymatous hepatocellular damage was further suggested by the presence of slight, but persistent, elevations of the
transami-nases of the serum of the affected children. This is more striking because the commonly accepted upper limits of normal for these estimations are regarded by some as too high.5 The changes in the alkaline phospha-tase are those frequenfly seen in cholestasis.
On the other hand, the concentrations of
the serum proteins were less strikingly
ab-TABLE IV
SERUM BILE ACIDS OF THE FOUR AFFECTED SIBLINGS
Patient
Dihyd cozy
Bile Acids
5g/m.l
Trihydrozy
Bile Acids
pg/mt
Trihydrozy
-Dihydrozy
AdultNorrntI
IV-37
IV-38
IV-41 IV-42
0-I .9 as
chenodesoxy-cholic acid
27
16
23 20
0-3.5 as
cholic acid
54
66
66
79
<I .0
2.0
4.12 2.87
normal and characterized by an elevation
in the concentrations of and globulins in the serum. This differentiates this condition biochemically from cirrhosis of uncertain origin (postnecrotic cirrhosis, multilobular cirrhosis, etc.) in which increases in the gamma-globulin concentration in serum are usually found.
FAMILY INVESTIGATION
The pedigree of the family is illustrated
in Figure 1. There is no consanguinity,
al-though both families come from the same
area in the northern part of Michigan’s lower peninsula. Including the sibship of the father, his family has lived in the same
area for four generations and is thought to have originated from France and Germany. Including the sibship of the mother, her family has lived in the same area for three
generations, but their origin is not known.
Aside from the maternal aunt there was no
one with a history of jaundice or liver dis-ease. The father is a cement worker and has always been healthy. The mother has been a housewife since her marriage at age 17 and has never been employed outside the
home. The maternal grandfather was killed in World War II.
One paternal uncle and one of his Sons
have diabetes mellitus. Several members of both families apparently consume moderate quantities of alcohol. Both families tend to
shortness; the father’s height is 168 cm (66
in.), the paternal grandfather’s is 173 cm (68
in.), and the paternal grandmother’s is 157
cm (62 in.). The mother’s height is 152 cm (60 in.), the maternal grandfather’s was 183
cm (72 in.), and the maternal grandmother’s
is 165 cm (65 in.).
Blood was obtained from the only four living great-grandparents, three living grandparents, parents, normal siblings, and all 15 living uncles, half-uncles and aunts,
except for one paternal aunt who was in a mental institution. (The results of these studies are summarized in Table V, which appears in the reprints only.) The only ab-normalities discovered were those for the maternal aunt (111-27) who had developed
symptoms and was hospitalized shortly
af-terwards (see Case Report).
COMMENT
Although presenting with jaundice, the children described by us have none of the clinical and biochemical features of the un-conjugated hyperbilirubinemias discussed and elucidated by Arias.6 The presence of severe and apparently progressive histolog-ical abnormalities shown in the liver
biop-sies as well as the preponderance of conju-gated bilirubin distinguish these cases from the group of conditions sometimes referred to as “Gilbert’s disease” and from the
Cri-gler-Najjar syndrome, both of which are characterized by increased levels of circu-lating unconjugated bilirubin.
Because of the nature of the histological abnormalities, our patients are distin-guished from the syndrome described by
Rotor, Manahan, and Florentin,7 the case of Schiff, Bffling, and Oikawa,8 the siblings presented by Davis and Young,9 the syndrome reported by Haverback and Wirtschafter,1#{176} and the case of Vest, Kauf-mann, and Fritz. Our patients are also
different from those reported by Dubin and
J
ohnson who have shown infiltration of the liver with an incompletely identifiedpig-ment as the sole histological abnormality.12
There are, however, some apparent simi-larities between the patients reported here
and various forms of familial or apparently familial recurrent jaundice manifesting an “obstructive” pattern. Summerskill and
abnor-malities during remissions, and there were no irreversible sequelae.
Tygstrup in 1960 described two cases of
intermittent jaundice which first appeared at ages 1 and 2.16 Though not
demon-strated, the patients “were probably re-lated.” Liver biopsy indicated intrahepatic cholestasis. Serum bilirubin levels were higher and both GOT and GPT activities in serum were lower than in the cases of the present report. Although symptoms were severe during periods of jaundice, the con-dition seemed to be completely reversible. There is no evidence of reversibility in our
cases, indeed progression is apparent,
pos-sibly to hepatic cirrhosis.
Kuhn in 1963 reported intrahepatic cho-lestasis in two brothers.17 The elder brother had experienced recurrent attacks of jaun-dice from the age of 14 years, the serum
bi-lirubin reaching 22 mg/100 ml. Alkaline
phosphatase activity in serum never
ex-ceeded 28.5 King-Armstrong units, and other “liver function tests” were normal. It
was thought that this represented
progres-sion to primary biliary cirrhosis. The younger brother’s illness began at the age of 17 s-ears and was similar. Liver biopsy
showed intracellular and intercellular bile
thrombi, and there was no evidence of he-patitis nor of any other pigment. The au-thor suggested that the new syndrome be called “familial jaundice due to intrahepatic cholestasis.” However, the onset was much later than in the present cases, and the manifestations were considerably milder.
Ahrens, Harris, and MacMahon
de-scribed four non-related cases of atresia of
the intrahepatic interlobular bile ducts in
1951.15 Three of the four also had
abnor-malities of the extrahepatic bile ducts,
which may have been acquired. The course of the disease was characterized by a rela-tively long life span in comparison with the common situation in extrahepatic bile duct
atresia. The patients had extensive general-ized skin xanthomatosis associated with marked and characteristic elevation of serum lipids. The siblings of the present re-port have not had xanthomatosis and have
not had comparable serum cholesterol ele-vations. The presence of intrahepatic bile ducts in all four siblings studied by us dis-tinguishes our patients from those de-scribed by Ahrens, et al.8 The possibility that these bile ducts may disappear later in the course of the disease remains open.
“Byler’s Disease : Fatal Familial
Intra-hepatic Cholestasis in an Amish Kindred” was reported in six members of four
sib-ships by Clayton, et al. in 1965.19 The time
of onset, development of the disease, and biochemical characterization are similar to those in the family of the present report. However, in four of the six, death occurred
between 17 months and 8 years, and there
was no mention of mental retardation. The conclusion was that the syndrome was probably due to autosomal recessive inheri-tance and was the result of an error in bile salt metabolism. Apparently, clinically simi-lax cases have been observed by others but not in a family with as many affected off-spring as in the family we have investi-gated.1#{176}
With the possible exception of the report
by Clayton, et al.,19 we do not believe that the present cases are sufficiently like any previously described to be included with them at this time.
Before a genetic etiology can be seriously considered for a disease in an individual family, other possible causes must be elimi-nated as conclusively as possible. After ex-haustive questioning, we have been unable to find a drug, with or without known hepa-to-toxic properties, which all four affected children have ingested at a sufficiently early age to account for the early onset of symp-toms. There have been no unusual foods consumed prior to the onset of symptoms, and their diets have been the same as those of their healthy siblings and appeared ade-quate. The family has not travelled outside
the state of Michigan.
834
TABLE VI
BLOOD Gitoucs OF THE B. FAMILY
Position in
Pedigree
Relation ABO Rh MNSs P Kell Kji’ K1P Fr Jka a LeP
IlI-4 IIl-3 IV-37 IV-38 IV-39 IV-40 IV-41 IV-4Z IV-43 Mother Father Proposita Sister (affected) Brother Brother Brother (affected) Sister (atteeted) Sister B 0 B 0 0 B B B 0 cDE/cde eI)E/cde cde/cde cl)E/cde cDE/cde cDE/cDE cde/cde cDE/cDE cde/cde MNs MNSs MNSs MNs MSs Ns MNs MNs MNs + + + + + + + + + -+ + -+ -+ + + + + + + + + + + + + + + -+ + + + + + -+ + + + + + + -+ + -+ + -+ + + -+ -+
-A specific maternal influence is possible,
either by deficiency or by ingestion. The
course of the pregnancies was not unusual,
and the mother’s diet has apparently been
adequate. Drug ingestion, specifically of tranquilizers, has been repeatedly denied. She has not had any infections or severe fe-brile illnesses during the gestations.
The onset of the jaundice in the middle
third of the first year is unlike that due to blood group incompatibility. The blood groups of the four affected and three healthy siblings do not reveal blood group genes consistently characteristic of the four affected children (Table VI). The direct
Coombs test has been negative on several
occasions.
Genetic determination of neonatal
hepati-tis has been suggested, at least in some families. Analysis by the Weinberg sib
method showed the trait to be consistent
with an autosomal recessive mode of
inheri-tance in the analysis by Hsia, et al.2#{176} Cassa-dy, et a!. in 1964 reported a family with “giant-cell hepatitis” and suggested that genetic factors appeared to be significant in the causation of the syndrome.21 Two
dis-tinguishing factors indicate that the cases of the present family do not represent the cat-egory of “neonatal hepatitis:” (1) all four
affected children were normal during the
neonatal period and did not begin to be
symptomatic until the middle third of the first year; (2) the histological picture is
different, because even the early biopsies of the present family do not show the multinu-cleated giant cells which are typically seen in neonatal hepatitis.
Four criteria are commonly used for the assessment of the role of genetic factors in the etiology of a given trait.’#{176}These are customarily employed after the description of numerous cases whose identity is reason-ably well assured. They are generally map-plicable in the evaluation of an individual
family, but they may be supportive. The conclusion that genetic factors are responsi-ble for a trait in a single family is tentative and usually reached by the reasonable ex-clusion of all other possible causative fac-tors.
The first criterion is the occurrence of the disease in definite numerical proportions among individuals related by descent. Since there are no previous cases reported in the literature which are sufficienfly similar to those in the present family, even a limited analysis is not possible. In the present family, of the six children born after the proposita, three are affected.
The second criterion is the failure of the
disease to spread to nonrelated individuals. There is no evidence that the disease in this family has been communicated to anyone
in the area in which the family has lived. The two older affected siblings have had a limited school experience, without apparent
The third criterion is the onset of the dis-ease at a characteristic age without a known precipitating event. This has been observed four times in this family. The time of onset has been similar as well as the de-velopment of the clinical manifestations, especially in the affected females. No
pre-cipitating event has been identified even
after extensive questioning.
The fourth criterion is the greater concor-dance of the disease in monozygotic than in dizygotic twins. To our knowledge there are no reports of a similar disease picture in
twins.
If a disease is determined by genetic fac-tors, three questions arise. (1) Is a single locus responsible or is it polygenic or
possi-bly polyfactorial? (2) How is the mutant
gene related to its normal allele? (3) Is there an identifiable simple protein altera-tion?
In this family with intrahepatic
cholesta-sis the remarkable similarity of the process, particularly of the three females, suggests the role of a similar, perhaps single etio-logic factor.
The possibility of sex modifying the course of the disease exists because of the
slightly milder course of the male. In order
to be substantiated, this would require the identification and study of further families.
If two assumptions can be accepted, i.e., that all four siblings are similarly affected and that this is due to genetic factors, then the question of the mode of inheritance de-pends, first upon the state of health of the parents, and second, on that of all other rel-atives, since there is no consanguinity.
The parents are not clinically affected. This is equally true for all three living grandparents and presumably also for the fourth who was fit for military service at the time of death. The disease could be de-termined by a dominant gene if sporadic mutation occurred four times in one sib-ship. Since the rate of spontaneous muta-tion in man is of the order of i0, the likeli-hood of this event is (10#{176}),and, therefore, this possibility is highly unlikely. Alterna-tively, the disease could also be determined
by a dominant gene if one of the parents is
a gonosomal mosaic, a significant portion of a gonad having experienced a mutation at a very early stage in its development. This
argument can be employed for a disease which appears in families but which does not conform to the usual modes of inheri-tance. On the other hand, at the present
time it can neither be proven nor dispro-yen. A recessive mode of inheritance, auto-somal (since the father is unaffected) is the most acceptable explanation. Each parent is a carrier of the mutant gene, presumably derived from one grandparent, and some of the aunts and uncles should also be hetero-zygous at this locus.
In this case the aunt with cholangiolitis and cholangitis could be considered as a manifest heterozygote for the gene which is then incompletely recessive. In the event that the aunt’s disease is unrelated to that of the four siblings, this hypothesis would be unnecessary. Her clinical presentation and biochemical characterization are con-siderably different from that of the four sib-lings, and we, therefore, conclude that her disease is probably not related.
For the disease in this sibship we suggest the term of familial intrahepatic cholestasis
with mental and growth retardation. In this family autosomal recessive inheritance ap-pears as the most likely etiology. The path-ogenetic mechanism, which may not be pri-manly hepatic, remains to be identified.
SUMMARY
Four siblings have been described with similar onset and progression of
intrahepat-ic cholestasis. Pruritus at 3 to 5 months was the presenting manifestation and was
ac-companied by jaundice, an enlarged
abdo-men, bilirubinuria, and occasional light stools. Liver enlargement, retarded growth, and mild mental retardation have been present in all.
836
pattern of the proteins, with elevation of the and globulin fractions.
Liver biopsies have been characterized by bile stasis in the presence of bile ducts. Two of the children show hepatic fibrosis which appears to be progressive and irre-versible.
Aside from one aunt with cholangitis and cholangiolitis, there are no family members with liver disease. Autosomal recessive in-heritance is suggested.
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2. Pearson, S., Stern, S., and McGavock, T. H.:
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Anal. Chem., 25:813, 1953.
3. Carey, J. B., Jr. : The serum
trihydroxy-dihy-droxy bile acid ratio in liver and biliary
tract disease. J. Clin. Invest., 37:1494, 1958.
4. Osbom, E. C., Wootton, I. D. P., Da Silva, L. C., and Sherlock, S. : Serum-bile-acid
levels in liver disease. Lancet, 2:1049,
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5. Henley, K. S., Schmidt, E., and Schmidt, F.
\V. : Enzymes In Serum. Their Use in
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6. Arias, I. M. : Chronic unconjugated
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7. Rotor, A. B., Manahan, L., and Florentin, A.: Familial non-hemolytic jaundice with di-rect van den Bergh reaction. Acta Med. Philipp., 5:37, 1948.
8. Schiff, L., Billing, B. H., and Oikawa, Y.:
Familial nonhemolytic jaundice with
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J.
Med., 260:1315, 1959.9. Davis, \V. D., Jr., and Young, P. C.: An
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bromsulphalein retention and microscopic-ally normal liver. Gastroenterology, 37:206,
1959.
10. Haverback, B. J., and Wirtschafter, S. K.: Familial nonhemolytic jaundice with
nor-ma! liver histology and conjugated
biliru-bin. New Eng. J. Med., 262:113, 1960.
11. Vest, M. F., Kaufmann, H. J., and Fritz, E.: Chronic non-haemolytic jaundice with con-jugated bilirubin in the serum and normal
liver histology: a case study. Arch. Dis.
Child., 35:600, 1960.
12. Dubin, I. N. : Chronic idiopathic jaundice: a
review of fifty cases. Amer. J. Med., 24:
268, 1958.
13. Summerskill, W. H. J., and Waishe, J. M.: Benign recurrent intrahepatic “obstructive”
jaundice. Lancet, 2:686, 1959.
14. Summerskill, W. H. J.: The syndrome of be-nign recurrent cholestasis. Amer. J. Med., 38:298, 1965.
15. Neel, J. V., and Schull, W. J.: Human He-redity, Chicago: The University of Chi-cago Press, p. 285, 1954.
16. Tygstrup, N. : Intermittent possibly familial
intrahepatic cholestatic jaundice. Lancet, 1:1171, 1960.
17. Kuhn, H. A. : Intrahepatic cholestasis in two
brothers. German Med. Monthly, 8:185,
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18. Ahrens, E. H., Jr., Harris, R. C., and
Mac-Mahon, H. E. : Atresia of the intrahepatic bile ducts. PEDIATRICS, 8:628, 1951.
19. Clayton, R. J., Iber, F. L., Ruebner, B. H., and McKusick, V. A. : Byler’s disease:
Fa-tal familial intrahepatic cholestasis in an Amish kindred. J. Pediat., 67:1025, 1965. 20. Hsia, D. Y.-Y., Boggs, J. D., Driscoll, S. G.,
and Gellis, S. S.: Prolonged obstructive
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21. Cassady, C., Morrison, A. B., and Cohen, M. M. : Familial “giant-cell hepatitis” in infancy. Amer. J. Dis. Child., 107:456,
1964.
Acknowledgment
This study was made possible by the
coopera-tion of Dr. Joanne E. Mertz, who referred the
original patient and supplied detailed information
regarding the early course of the three older chil-dren, and that of Dr. Gustav A. Uhlich, both of the Burns Clinic, Petoskey, Michigan, who
pro-vided the information concerning the maternal
aunt. The blood group determinations were