GASTROENTEROLOGY 1985;88:108-14
LIVER AND BILIARY TRACT
Comparison of the Clinicopathologic
Features of Primary Sclerosing
Cholangitis and Primary Biliary Cirrhosis
RUSSELL H. WIESNER, NICHOLAS F. LARUSSO,
JURGEN LUDWIG, and E. ROLLAND DICKSON
Department of Medicine, Division of Gastroenterology, and the Department of Pathology, Mayo
Clinic and Foundation, Rochester, Minnesota
Primary sclerosing cholangitis and primary biliary
cirrhosis are chronic cholestatic syndromes that
may be difficult to differentiate clinically, Destruc-
tive cholangitis occurs in both diseases and leads to
similar clinical and biochemical abnormalities.
Therefore, we compared the clinical, biochemical,
immunologic, radiologic, and hepatic histologic fea-
tures of these syndromes in two large groups of
patients prospectively selected by predefined crite-
ria. Primary biliary cirrhosis (n = 258) occurred
predominantly in middle-aged women who were
usually symptomatic with fatigue and pruritus,
commonly had keratoconjunctivitis sicca, and often
were hyperpigmented. Tests for antimitochondrial
antibodies were always positive, usually in very
high titer. Although the extrahepatic bile ducts were
normal radiographically, smooth tapering and nar-
rowing of the intrahepatic bile ducts was occasional-
ly noted. Hepatic histology was diagnostic when a
florid duct lesion was present. In contrast, primary
sclerosing cholangitis (n = 60) occurred primarily in
young men who were usually symptomatic with
fatigue and pruritus and frequently had chronic
ulcerative colitis. Tests for antimitochondrial anti-
bodies were nearly always negative and cholangiog-
raphy demonstrated abnormalities of the extrahe-
Received April 5, 1983. Accepted June 29 , 1984.
Address requests for reprints to: Russell H. Wiesfler, M.D.,
Division of Gastroenterology, Mayo Clinic alid Mayo Foundation,
Rochester, Minnesota 55905.
This research was supported by National Institutes of Health
grants AM19448 and RR585 , by a grant from Merck, Sharp, and
Dohme, and by the Mayo Foundation. Data analysis was per-
formed using the CLINFO Data Analysis System.
Part of this work was published previously in abstract form
(GASTROENTEROLOGY 1982;82 :1250).
The authors thank Dawn Warren for secretarial assistance and
Sandra Beaver and Roberta Jorgensen for serving as project
coordinators for the PSC and PBC projects.
© 1985 by the Mayo Foundation
patic and intrahepatic bile ducts in a11 cases.
Although hepatic histology was often compatible
with the diagnosis, 'it was usually not diagnostic,
and considerable overlap existed with the abnor-
malities seen in primary biliary cirrhosis. Likewise ,
biochemical tests of copper metabolism were similar
in both syndromes. These results call attention to
the differences and similarities in the clinicopatho-
logic features of these two cholestatic syndromes
and provide a basis for a rational diagnostic strate-
gy.
Primary sclerosing cholangitis (PSC) is an uncom-
mon syndrome characterized by inflammation and
fibrosis of the intrahepatic and extrahepatic bile
ducts (1,2). In contrast, primary biliary cirrhosis
(PBC) is a syndrome characterized by inflammatory
destruction of only the septal and interlobular bile
ducts with sparing of the extrahepatic bile ducts (3).
These two cholestatic syndromes have a progressive
course and ultimately lead to biliary cirrhosis, portal
hypertension, and premature death from liver failure
(1,4). The etiology of both syndromes is unknown.
We are observjng a large number of patients with
these syndromes in the context of two controlled
therapeutic trials. During the course of these trials,
we observed striking similarities between these dis-
eases, which occasionally made it difficult to dis tin·
guish them. Therefore , we compared the clinical,
biochemical, immunologic, radiologic, and histolog-
ic findings of these two entities.
Materials and Methods
Patients with PSC and PBC were selected prospec-
tively by strict predefined criteria. Primary sclerosing
Abbreviations used in this paper: IBD, inflammatory bowel
disease; PBC, primary biliary cirrhosis; PSC, primary sclerosing
cholangitis.
January 1985
cholangitis was defined as a cholestatic liver disease of
>6-mo duration associated with a serum alkaline phos-
phatase level more than two times the upper limit of
normal and radiologic demonstration of diffuse narrowing,
irregularity, dilatation , or tortuosity of the extrahepatic
bile ducts with or without involvement of the intrahepatic
biliary system. Liver biopsy findings compatible with the
diagnosis of PSC were also required. Exclusion criteria
included bile duct surgery before the diagnosis of PSC,
documented choledocholithiasis, congenital biliary tract
anomalies, and clinical or radiographic abnormalities sug-
gestive of cholangiocarcinoma.
Primary biliary cirrhosis was defined as a cholestatic
liver disease of >6-mo duration associated with a serum
alkaline phosphatase level more than two times the upper
limit of normal with a positive test for antimitochondrial
antibody. In addition, liver biopsy findings compatible
with the diagnosis of PBC were required . Exclusion crite-
ria included aspartate transaminase levels more than 10
times the upper limit of normal, a history of exposure to
medications known to cause cholestasis, or radiologic or
histologic evidence of disease involving the extrahepatic
bile ducts .
From 1980 through 1982, we evaluated 129 patients
with PSC, 60 of whom were entered into a double-blind
prospective trial evaluating the efficacy of o-penicilla-
mine. Twenty-two patients were excluded from the trial,
most commonly because of our inability to confidently
exclude a diagnosis of choledocholithiasis or of our inabil-
ity to obtain a satisfactory cholangiogram. Forty-seven
patients elected not to participate in the trial.
From 1977 through 1982, we evaluated 559 patients
with PBC, 258 of whom were entered into a double-blind
prospective trial evaluating the efficacy of o-penicilla-
mine. One hundred seventy patients seen were excluded
by criteria most commonly because of negative antimito-
chondrial antibody or a less than twofold elevation of
serum alkaline phosphatase. In addition, 131 patients
elected not to participate in the trial.
In comparing those patients with PBC or PSC entering
the respective o-penicillamine studies with those not
entering the o-penicillamine trials, no differences were
found with regard to age, sex, associated diseases, his-
tologic stage, or the biochemical parameters of serum
bilirubin or albumin. Thus , the patients entered into their
respective o-penicillamine studies, although perhaps not
representing the universal population of these diseases,
are representative of the spectrum of PBC and PSC patients
referred to the Mayo Clinic.
This comparative study is based on the 258 patients
with PBC and the 60 patients with PSC who were entered
into the clinical trials evaluating the efficacy of o-penicil-
lamine.
All patients with a diagnosis of PSC underwent colonos-
copy with multiple colonic biopsies to document the
presence or absence of inflammatory bowel disease (IBD) .
Primary biliary cirrhosis patients routinely underwent
proctoscopy; colon x-ray or colonoscopy was performed
only if the clinical situation suggested IBD.
Serum total thyroxine, free thyroxine, and thyroid-stim-
ulating hormone levels were performed routinely in all
PRIMARY SCLEROSING CHOLANGITIS AND PBC 109
patients. Those patients found to have either an abnormal
thyroid gland to palpation or abnormal thyroid function
tests were screened with one or more of the following:
antithyroid antibody studies, thyroid scan, and thyroid
biopsy.
All patients with PBC and -50% of patients with PSC
underwent Rose-Bengal testing to document the presence
or absence of keratoconjunctivitis sicca. In addition, a
careful history for arthralgias, arthritis, and renal lithiasis
was obtained in all patients; joint x-rays and tomograms of
the kidneys were obtained when clinically indicated.
All patients were tested for presence of antimitochon-
drial antibodies using a radioimmune diffusion technique
(5). Screening for antinuclear antibodies was carried out in
all patients with PSC and in 64 of the 258 patients with
PBC.
Serum, urine, and hepatic copper levels were obtained
by atomic absorption spectrophotometry, and ceruloplas-
min levels were measured by the enzymatic oxidase meth-
od of Scheinberg et al. (6). The Raji cell assay for detecting
immune complexes in human sera was used as described
by Theofilopoulos et al. (7). Liver biopsy specimens were
interpreted in all instances by a single pathologist who
was unaware of the clinical diagnosis.
Statistical analyses were performed using the unpaired
Student's t-test and the X2 test; p < 0.05 was taken as
evidence of a significant difference .
Results
Clinical Presentation and Associated
Diseases
Although PSC and PBC have been considered
rare cholestatic diseases, the frequency with which
these two syndromes are being diagnosed at Mayo
has markedly increased. In 1976, only 14 cases of
PSC were diagnosed at the Mayo Clinic compared
with 36 and 44 cases, respectively, in 1981 and 1982.
Similarly, in 1976, 55 cases of PBC were diagnosed
compared with 92 and 100 cases in 1981 and 1982,
respectively.
Patients with PSC were younger (mean age 41 yr),
more commonly male (63%), and more frequently
presented with symptoms of fever and cholangitis
(Table 1). Although patients with PSC were more
commonly symptomatic from their liver disease at
the time of diagnosis, this was due primarily to
episodes of cholangitis or the presence of fever, as
the incidence of fatigue and pruritus was not signifi-
cantly different between the two groups (Table 1).
Findings on physical examination revealed that
hyperpigmentation and xanthelasma were signifi-
cantly more common in patients with PBC (Table 2).
Jaundice, hepatomegaly, and splenomegaly were
found with the same frequency in both groups (Table
2).
110 WIESNER ET AL. GASTROENTEROLOGY Vol. 88, No.1, Part 1

Table 1. Comparison of Clinical Parameters Table 2. Comparison of Findings on Physical

Examination
Pri mary Primary
sclerosing biliary Primary Primary
cholangitis cirrhosis sclerosing biliary
Clinical parameter (n = 60) (n = 258) P cholangi tis cirrhosis
Sign (n = 60) (n = 258) P
Age, yr (mean ± SD) 41 ± 14.0 53 ± 10.2 < 0.01
Sex, MIF 63 %/37% 10%/90% < 0.01 Hyperpigmentation 25% 54% < 0.01
Symptomatic 85% 69% < 0.01 Xanthelasma 3% 19% < 0.01
Cholangitis o 14% 2% < 0.01 Jaundice 43% 41 % NS
Fever 32% 8% < 0 .01 Hepatomegaly 55% 53% NS
Fatigue 73% 77% NS Splenomegaly 33% 28% NS
Pruritus 72% 69% NS
NS , not significant.
NS, not significant. a Defined as episodes of upper abdominal
pain , jaundice, dark urine, and fever .
Raji cell assay, were elevated in 70% of patients with
PSC and in 65% of patients with PBC (8-10). These
Inflammatory bowel disease was present almost particular data must be interpreted cautiously, how-
exclusively in patients with PSC (Table 3); all pa- ever, as others have not been able to confirm these
tients had chronic ulcerative colitis. Only one of 258 results in PBC (11) and no technique of measuring
patients with PBC had concurrent IBD and this circulating immune complexes is currently available
patient had granulomatous colitis. to unequivocally distinguish between antigen-anti-
Keratoconjunctivitis sieca, demonstrated by rose body complexes and immunoglobulin aggregates.
bengal staining, was frequently present in patients Tests of copper metabolism, including serum ceru-
with PBe. Sixty-nine percent of patients with PBC loplasmin levels, 24-h urine copper excretion, and
had symptoms of the sicca complex, which was only hepatic copper content, were abnormal in most pa-
observed in 1 patient with PSC (Table 3). Arthritis tients in both groups but were not significantly
and thyroid disease were significantly more com- different between groups. Mean (±SD) serum cerulo-
mon in PBC, but were also seen in a small number of plasmin levels (nl 23-43 mg/dl) were 60 (±20.6)
patients with PSC. mg/dl in PSC vs. 65.5 (±15.7) mg/dl in PBC; mean
urine copper levels (nl 15-60 J,Lg/24 h) were 133
(±130) J,Lg/24 h in PSC vs. 100 (±91) J,Lg/24 h in PBC;
Laboratory Tests
and mean hepatic copper levels (nl < 35 J,Lg/g dry wt)
Comparison of laboratory data revealed that were 325 (±299) J,Lg/g dry wt in PSC vs. 276 (±70)
mean serum aspartate transaminase levels were sig- J,Lg/g dry wt in PBC.
nificantly higher in patients with PSC compared
with patients with PBC (Table 4). However, there
Cholangiography
was considerable overlap and complete separation of
these values between the two groups was not possi- Cholangiograms were performed in all 60 pa-
ble. Immunoglobulin M levels were elevated in both tients with PSC; endoscopic retrograde cholangiog-
groups of patients but were significantly higher in raphy was performed in 49 patients, transhepatic
patients with PBC. Other laboratory parameters in- cholangiograms were done in 7 patients, and opera-
cluding serum bilirubin, serum alkaline phospha- tive cholangiograms were performed in 4 patients.
tase, serum albumin, y-globulin, and prothrombin Cholangiograms demonstrated diffuse narrowing, ir-
time were not significantly different between pa- regularity, dilatation, or tortuosity of the extrahepat-
tients with PSC and PBe. Immunologic testing re- ic bile ducts, with involvement of the intrahepatic
vealed that antimitochondrial antibodies were pres- bile ducts seen in 85% of patients (Figure 1).
ent in all patients with PBC in a mean titer of
>1: 160. Ninety-seven percent of patients with PBC
had a positive antimitochondrial antibody test in a Table 3. Comparison of Associated Diseases
titer of >1: 20. In contrast, antimitochondrial anti- Primary Primary
bodies were found in only three of the 60 patients sclerosing biliary
with PSC (5%); the titer was :51: 10 in each case. The cholangitis cirrhosis
presence of antinuclear antibodies was found signifi- Disease tn = 60) (n = 258) P
cantly (p < 0.05) more often in PBC (23%) vs. PSC Inflammatory bowel disease 68% 0.04% < 0.001
(6%). Sicca syndrome 2% 69% < 0.01
Finally, as we have previously reported, circulat- Arthritis 7% 19% < 0.01
Thyroid disease 2% 19% < 0.01
ing levels of immune complexes, as measured by the
January 1985 PRIMARY SCLEROSING CHOLANGITIS AND PBC 111

Table 4. Comparison of Results of Laboratory Tests findings are also shown in Table 5. Nonobliterative
Primary Primary
fibrous cholangitis, periductal lymphoid aggregates,
sclerosing biliary absence of bile ducts, periportal cholestasis with
Laboratory tests cholangitis cirrhosis feathery degeneration of hepatocytes, and copper
(normal) (n = 60) (n = 258) P deposition were among the histologic findings
Aspartate transaminase 93 ± 50.1 82 ± 38.0 <0.05 shared by PSC and PBC and were thus not useful in
«31 U/L) distinguishing these two syndromes.
Immunoglobulin M 2.3 ± 1.29 6.2 ± 4.43 <0.001 Ultrastructurally, specimens from patients with
(0.2-1.4 mg/ml)
PSC and PBC showed an increase in the number of
Bilirubin 4.5 ± 6.4 3.4 ± 4.8 NS
«1.1 mg/dl) lysosomelike vesicles that were clustered around
Alkaline phosphatase 1366 ± 806 1515 ± 822 NS hepatocellular nuclei. The use of x-ray microanaly-
«250 U/L) sis showed the presence of copper in these vesicles
y-Globulin 1.73 ± 0.55 1.90 ± 0.83 NS and, to a lesser degree, in the nonlysosomal areas of
(0.7-1.6 g/dl)
the cell (13,15). Thus, it appears that the perinuclear
Albumin 3.34 ± 0.44 3.51 ± 0.42 NS
(3.5-5.0 g/dl)
accumulation of lysosomelike vesicles and the se-
Prothrombin time 10.7 ± 1.3 10.8 ± 1.3 NS questration of copper in these structures is shared by
«11.8 s) both PSC and PBC.
Mean ± SD. NS, not significant.
Discussion
Cholangiograms were performed in 117 of the 258 The main finding recorded in this manuscript
patients with PBC. Cholangiographically, the extra- concerns the clinicopathologic features of two im-
hepatic biliary ductal system was normal in all 117 portant chronic cholestatic syndromes, PSC and
PBC patients. The intrahepatic ducts, however, were PBC. By prospectively and systematically selecting
abnormal in 9% of PBC patients revealing mild patients with these syndromes using strict, prede-
tapering, narrowing, and irregularity (Figure 2). fined criteria, we have been able to compare and
contrast their clinical, biochemical, radiologic, and
hepatic histologic features.
Hepatic Histology
Liver biopsy specimens were taken from each
patient on entry into each trial and at yearly inter-
vals. These specimens were analyzed for histologic
characteristics that would separate these two choles-
tatic syndromes. Biopsy specimens were classified
and staged according to the criteria established by
Ludwig et al. for PSC and PBC (12,13). Distribution
of histologic stage was as follows: PSC-stage 1,
13%; stage 2, 15%; stage 3, 30%; stage 4, 42%; PBC-
stage 1, 6%, stage 2, 19%; stage 3, 43%; stage 4,32%.
Histologic examination allowed a reliable distinc-
tion between PSC and PBC in 90 of the 318 patients
(28%) who had one of these two syndromes. The
fibrous-obliterative cholangitis lesion in PSC (Figure
3) and the granulomatous cholangitis lesion in PBC
(florid duct lesion) (Figure 4) were the only two
findings that were diagnostic and allowed distinc-
tion of PSC from PBC (Table 5) (14). It should be
noted that the chances of finding such a diagnostic
lesion in a single liver biopsy specimen are consider-
ably less than the figures in Table 5 may seem to
indicate (see footnote in Table 5). For instance, when
only one liver biopsy specimen from each of 100
consecutive patients with PBC was examined, a
Figure 1. Endoscopic cholangiogram demonstrating typical dif-
florid duct lesion was identified in only nine in- fuse narrowing and irregularity of the extra- and intra-
stances (9%). hepatic biliary system in primary sclerosing cholangi-
The incidence of other important liver biopsy tis.
112 WIESNER ET AL. GASTROENTEROLOGY Vol. 88, No.1, Part 1

Biochemical Features

Laboratory testing revealed a significantly

higher level of serum aspartate transaminase in PSC
and a significantly higher level of serum immuno-
globulin M in PBe. However, again because of con-
siderable overlap, these differences did not permit
reliable differentiation. Other laboratory studies in-
cluding serum bilirubin, alkaline phosphatase, se-
rum proteins, and prothrombin time were not differ-
ent.
Immunologic testing revealed that antimitochon-
drial antibodies were present in all PBC patients,
usually in high titer. In contrast, only 3 of 60 patients
with PSC had anitimitochondrial antibodies, all oc-
curring in very low titer. Thus, the presence of
antimitochondrial antibodies, especially in high ti-
ter, strongly supports the diagnosis of PBC. It should
be noted that a positive antimitochondrial antibody
Figure 2. Endoscopic cholangiogram demonstrating smooth ta- was required for entry into our PBC trial; in other
pering, decreased branching, and narrowing of the studies, 7%-33% of PBC patients were noted to be
intrahepatic biliary system seen in -9% of patients antimitochondrial antibody-negative (16,17). The re-
with primary biliary cirrhosis.
cent development of a radioimmunoassay that de-
tects specific antibodies against one mitochondrial
determinant, namely the PBC antigen (Mz-antigen),
Clinical Features
promises to be of further help in distinguishing PBC
The increased frequency of diagnosis of PSC from other cholestatic diseases (18).
and PBC at the Mayo Clinic most likely reflects
several factors, including increased clinical aware-
ness and increased referrals because of our ongoing
therapeutic trials. A true increase in the frequency of
these two diseases seems less likely, although data
on the incidence of PSC and PBC are scant and
further epidemiologic and demographic data are
badly needed.
Although PSC usually occurs in young men,
whereas PBC is found most commonly in middle-
aged women, considerable overlap exists so that age
and sex alone do not reliably differentiate these two
syndromes. Both entities usually present with simi-
lar symptoms, namely, features of progressive cho-
lestasis, which may include fatigue, pruritus, and
jaundice. Fever and cholangitis were experienced in
both groups but significantly more often in PSC
patients. Patients with PBC were hyperpigmented
significantly more often than patients with PSC; in
addition, xanthelasma were more common in PBe.
Other findings on physical examination were similar
and not helpful in distinguishing these two entities.
Both PSC and PBC were frequently accompanied
by other diseases. Inflammatory bowel disease oc-
curred in 68% of PSC patients in the form of chronic
ulcerative colitis. In contrast, only 1 of 258 patients
Figure 3. Interlobular bile ducts showing fibrous-obliterative cho-
with PBC had IBD. On the other hand, 69% of PBC langitis characteristic of primary sclerosing cholangitis.
patients had symptomatic keratoconjunctivitis sicca, Note remnants of epithelium on the bottom and com-
an association found in only 1 patient with PSe. plete obliteration of the duct on the top.
January 1985 PRIMARY SCLEROSING CHOLANGITIS AND PBC 113

copper metabolism, nq significant differences were

noted between the two groups.

Cholangiographic Features
Cholangiography was the most useful proce-
dure in distinguishing patients with PSC from those
with PBC. All 60 patients with PSC showed radio-
graphic abnormalities of the extrahepatic bile ducts.
In contrast, the extrahepatic bile ducts were radio-
logically normal in all 17 patients with PBC in whom
cholangiography was performed. The intrahepatic
ducts were, however, radiographically abnormal in
9% of patients with PBC showing decreased branch-
ing and narrowing. Although these changes tended
to occur more often in the advanced histologic stages
of PBC, the changes were occasionally noted even in
histologic stage 1 and 2 disease; this observation
suggests that these radiologic abnormalities are prob-
a
ably not simply manifestation of underlying cirrho-
sis, as has previously been proposed (20,21).

Hepatic Histologic Features

Figure 4.
Tests of copper metabolism were also markedly
abnormal in both syndromes. Ninety-one percent of
patients with PSC and 97% of patients with PBC had
elevated hepatic copper levels, generally in the range
reported for patients with Wilson's disease (19).
Likewise, urine copper excretion was increased in
68% of PSC patients and 80% of PBC patients.
Despite these marked biochemical abnormalities in
Our results indicate that liver histology in
these two syndromes is often strikingly similar. The
presence of granulomatous cholangitis (i.e., florid
duct lesion), however, is highly suggestive of PBC. In
contrast, the presence of ,fibrous obliterative cholan-
gitis appears to be highly specific for PSC. The
presence of granulomas at sites not associated with
cholangitis is more characteristic of PBC occurring
in 71% of PBC patients but in only 8% of PSC
patients. Other histologic findings including the
presence of cholestasis, positive copper staining,
decreased number of bile ducts, and the occurrence
of nongranulomatous, nonobliterative, peri ductal fi-
brosis and inflammation were common and were not
helpful in distinguishing these two cholestatic syn-

Table 5. Liver Biopsy Findings in Primary Sclerosing Cholangitis and Primary Biliary Cirrhosis
Primary sclerosing
cholangitis Primary biliary cirrhosis
(n = 60) (n = 258)
Histologic abnormalities" No, % No. % p
Granulomatous cholangitis (florid duct lesion) a a 83 32 < 0.01
Fibrous-obliterative cholangitis 7 12 a a < 0,01
Granulomas at any site, not associated with 5 8 183 71 < 0,01
cholangitis
Cholestasis 28 47 65 25 < 0.01
Positive copper stain 41 69 207 80 < 0.05
Nongranulomatous and nonobliterative peri ductal 13 22 39 15 NS
fibrosis and inflammation
Decreased number of ducts or absence of ducts 49 82 219 85 NS
" Most figures represent the results of more than one biopsy per patient (No. = number of patients) . The findings would be lower if only
one specimen from each patient would have been studied. (See text.)
114 WIESNER ET AL.
dromes. We acknowledge that becaus!'l of referrral
practices, our study populations may be skewed to
the more advanced histologic stages of each disease.
Nevertheless, all four histologic stages of each syn-
drome were well represented in our study.
Summary and Conclusions
We have prospectively identified and charac-
terized similarities and differences in clinical fea-
tures, hepatic chemistries, cholangiographic find-
ings, and hepatic histology in two large groups of
patients with pse and PBe selected by strict, uni-
form criteria. Our results show that although there is
considerable overlap in the clinical and biochemical
features of these cholestatic syndromes, age, sex, and
the presence or absence of antimitochondrial anti-
bodies, IBD, or keratoconjunctivitis sicca are helpful
in distinguishing these two entities. When present,
the histologic findings of fibrous-obliterative cholan-
gitis or of granulomatous cholangitis (florid duct
lesions) allow reliable distinction of PSC and PBe. In
most cases, however, distinguishing histologic ab-
normalities are not found in liver biopsy specimens
from these patients. The most useful diagnostic
procedure is cholangiographic visualization of the
intrahepatic and extrahepatic bile ducts that allows
confident distinction of pse from PBC in all cases.
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