Scleroderma and primary biliary cirrhosis.
ABSTRACT Two cases of scleroderma and primary biliary cirrhosis are described. One had systemic sclerosis with primary biliary cirrhosis of six years' duration at the stage of ductular proliferation. The other had the C.R.S.T. syndrome (calcinosis, Raynaud's phenomenon, sclerodactyly, and telangiectases) with primary biliary cirrhosis at the florid stage. Several similar cases were found in a review of other reports, and it is suggested that the association may be due to a common "autoimmune" process.
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ABSTRACT: Primary biliary cirrhosis (PBC) can be complicated by systemic sclerosis (SSc) and more specifically, limited cutaneous SSc (lcSSc), which was previously called CREST syndrome. Moreover, combined PBC and SSc has been described in many case reports. Although neither the etiology of PBC nor that of SSc has been elucidated, some genetic and immunological factors are known to be shared. Both disorders are autoimmune fibrotic diseases characterized by increased levels of pro-fibrotic cytokines transforming growth factor β (TGFβ) and IL-6, which have recently been suggested to influence Th17 cells and regulatory T cells involved in acquired immunity. LcSSc is accompanied by CREST symptoms, although complete CREST cases are rare, with relatively high prevalence of Raynaud's phenomenon, sclerodactyly and telangiectasia, and lower prevalence of calcinosis and esophageal dysmotility. Because patients with anti-centromere antibody-positive PBC-SSc are at a high risk of developing portal hypertension, particular attention should be paid to the management of gastroesophageal varices. In addition, the management of SSc-related non-hepatic disorders, such as pulmonary fibrosis, pulmonary hypertension, heart disorder, infection and malignancy, is also important for improved outcomes. Since PBC is often complicated by rheumatic disease, hepatologists should keep the possibility of systemic disorder in mind when examining PBC patients.Hepatology Research 12/2013; · 2.07 Impact Factor
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ABSTRACT: Primary biliary cirrhosis (PBC) is an autoimmune disease of the liver characterised by biochemical evidence of cholestasis, elevated alkaline phosphatase levels and the presence of the highly disease specific anti-mitochondrial autoantibodies. Extra-hepatic autoimmune manifestations are common, including rheumatic disorders, such as systemic sclerosis (SSc). Notably, PBC is the most frequent autoimmune liver disease in SSc patients. Based on skin lesion extension, two major SSc disease subgroups are recognised: limited cutaneous SSc (lSSc) and diffuse cutaneous SSc. Anti-centromere antibody (ACA) positivity is highly characteristic of SSc, with up to 90% prevalence in lSSc patients. ACA has also been found in up to 30% of PBC patients and 80% of patients with a PBC/SSc overlap syndrome. The diagnostic and clinical significance of ACA positivity in patients with PBC without SSc has recently been under investigation, with several studies highlighting links to severe bile duct injury and portal hypertension. This review discusses the diagnostic and clinical relevance of ACA in patients with PBC, with or without SSc.Gastroentérologie Clinique et Biologique 07/2013; · 0.80 Impact Factor
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ABSTRACT: OBJECTIVE: To investigate the prevalence of primary biliary cirrhosis (PBC) and PBC-associated autoantibodies in Japanese systemic sclerosis (SSc) patients. METHODS: Clinical data from 225 Japanese SSc patients were retrospectively obtained. Serum samples from these patients were examined for PBC-associated autoantibodies, anti-mitochondrial M2 antibodies (AMA), anti-sp100 antibodies (anti-sp100), and anti-gp210 antibodies (anti-gp210) by enzyme-linked immunosorbent assay. RESULTS: Of 225 patients, 37 (16.4%) had AMA, 13 (5.8%) had anti-sp100, and 3 (1.3%) had anti-gp210. Three patients were positive for both AMA and anti-sp100, and 2 were positive for both AMA and anti-gp210. PBC was found in 22 (9.8%) patients positive for AMA with or without anti-sp100 or anti-gp210, but not in those with anti-sp100 or anti-gp210 without AMA. Furthermore, 13 patients lacking these three antibodies were diagnosed with or suspected of PBC by liver biopsy and/or their clinical manifestation. Multivariable analysis revealed that AMA and anti-centromere antibodies were independently associated with PBC in SSc patients, while anti-sp100 and anti-gp210 were not. CONCLUSIONS: This study has demonstrated even higher prevalence of both PBC-associated autoantibodies and PBC in the Japanese SSc population than in the Caucasian SSc population. AMA and anti-centromere antibodies are likely to indicate increasing risk of PBC in SSc patients.Modern Rheumatology 02/2012; · 1.72 Impact Factor
1 AIkugust 1970
Scleroderma and Primary Biliary Cirrhosis
I. M. MURRAY-LYON,* M.B., B.SC., M.R.C.P. (LOND., ED.)
I. D. ANSELL,4 M.A., M.R.C.PATH.
; R. P. H. THOMPSON,t D.M., M.R.C.P.
; ROGER WILLIAMS,§ M.D., F.R.C.P.
BritishMedical_Journal, 1970, 3, 258-259
sclerosis with primary biliary cirrhosis of six year' dura-
tion at the stage of ductular prolifetion. The odte
the C.R.S.T. syndrome (calcinis, Raynaud's phenome-
biliary cirrhosis at the florid stage. Several similar cases
were found in a review
of other reports, and
suggested that the association may be due to a common
of scieroderma and primary
described. One had systemc
Though there are reports, dating from 1934, of liver disease
occuring in patients with scieroderma few are given in suf-
ficient detail to allow a valid assessment of the type of invol-
vement. Two of the cases described by Bartholomew et al.
(1964), however, had features suggestive of primary biliary
cirrhosis and Reynolds et al. (1970) drew attention to this
association. In this paper we describe the cases of two patients
with scleroderma who have the distinctive immunological and
histological picture of primary biliary cirrhosis, and discuss
the possible mechanisms involved.
In 1963 a 64-year-old woman with mild Raynaud's phenomenon
was found to have hepatosplenomegaly. In 1965 she complained of
generalized itching, and telangiectases of face and arms were noted.
In 1966 bone radiographs revealed an unusual patchy osteoporosis,
but a biopsy specimen from the right radius showed normal his-
tology. It was followed by a fracture, and the skin of the right
tongue, and lips. They were bluish red and blanched on pressure,
but had no central arteriole. No bleeding occurred, and there was
no family history of bleeding or telangiectases.
oesophagus with absence of peristalsis, and radiographs of the
hands showed acrolysis of the terminal phalgeal bones. Liver
function tests fluctuated, but changed little overall in three years:
plasma bilirubin 1-6-3*5 mg./100 ml., alkalin
units/100 ml., serum cholesterol 225-370 mg./100 ml. Serum IgA
immunoglobulin (300 mg./100 mL) was raised and IgM (185) and
IgG (1,300) fractions were normal. Immunofluorescent and com-
plement fixing antibodies to mitochondria had been present in low
titre since 1966 and smooth muscle antibodies and antinuclear
factor had developed in the past year (Dr. Deborah Donmach).
Needle liver biopsy specimens taken in 1966 and 1969 were
similar and showed considerable ductular proliferation
with portal fibrosis and early septum formation in the later biopsy
lymphocytes, neutrophil polymorphs, and plasma cells and there
was piecemeal necrosis, pronounced in the second biopsy speci-
men. The features were those of primary biliary cirrhosis
stage of ductular proliferation.
so. Macular telangiectases were present on the face, arms,
*Senior Registrar in Medicine.
tM.R.C. Clinical Research Fellow and Honorary Registrar.
Lecturer in Morbid Anatomy.
Physician and Director of Liver Research Unit.
Kng's College Hospital, London S.E.5.
FIG. l.-Case 1. Portal tract with ductular proliferation and piecemeal
necrosis. (haematoxylin and eosin.
A62-year-old woman with Raynaud's phenomenon had noted
telangiectases for 10 years. There were sclerodermatous changes
in the fingers with small pitted
Telangiectases were present on the hands, lips, tongue, and feet,
and there was pronounced hepatosplenomegaly. There was no
relevant family history and examination
Investigations.-Serum bilirubin 0 7 mg./100 ml., aspartate trans-
aminase 190 units/100 ml. (normal
alkaline phosphatase 44 K.A. units/100 ml., serum cholesterol
236 mg./100 ml. Serum IgG (1,850 mg./100 ml.) and IgM
(560 mg./100 ml.) were raised and IgA was normal. Mitochondrial
antibodies and the sensitized sheep cell test were positive at a
titre of 1/256, and smooth muscle antibodies and
factor were weakly positive. (Dr. Deborah Doniach). Radiographs
of the hands showed acrolysis of the terminal phalanges with soft
tissue calcfication and the barium swallow diminished peristalsis.
A needle liver biopsy specimen showed retention of normal
scars and areas of calcinosis.
110 units/100 ml.),
FIG 2.-Case 2. Portal tract showing dense infiltrate of lymphocytes
parenchyma is normaL (H. & E. X 170)
1 August 1970
Scleroderma and Primary Biliary Cirrhosis-Murray-Lyon et al.
irregularity of the limiting cell plates with piecemeal necrosis.
Larger portal tracts contained focal deposits of lymphocytes and
plasma cells in association with damaged bile ducts (Fig. 2). There
was no ductular proliferation or cholestasis and the histological
features were those of primary biliary cirrhosis at the florid duct
a minor degree of septal fibrosis and
The first patient has systemic sclerosis with oesophageal
involvement. The skin changes became more pronounced in
the right arm after the fracture, as they did in the patient of
Copeman and Medd (1967) after a fracture of the humerus.
The second patient has the characteristic C.R.S.T. syndrome
(calcinosis, Raynaud's phenomenon, sclerodactyly, and telan-
variant of scleroderma. The telangiectases of scleroderma are
microscopically and macroscopically identical with those of
the Osler-Weber-Rendu syndrome, though they are said to
occur later in life and are less likely to bleed (Winterbauer,
1964). There was, however, no family history in our cases,
nor apparently in the cases described by Reynolds
the Osler-Weber-Rendu syndrome
though these authors put forward this view. Four of the five
patients they described with chronic intrahepatic cholestasis
and skin telangiectasis had sclerodactyly, and three of these
the C.R.S.T. syndrome. All five patients had mitochondrial
antibodies in high titre and in four the liver histology was
compatible with primary biliary cirrhosis.
The histological appearances in the two present cases are
also typical of primary biliary cirrhosis, in Case 1 at the stage
of ductular proliferati,on (stage II) and in Case 2 at the florid
antibodies were present in the serum of both cases and are
almost invariable in primary biliary cirrhosis (Doniach et al.,
commonly present in the serum in both primary biliary cir-
rhosis and scleroderma (Bouchier et al., 1964; McGiven et al.,
1968). Though the pattern of immunoglobulin disturbance is
not constant enough to be of great diagnostic help, a high
IgM is often found in primary biliary cirrhosis as in Case 2.
appeared in the literature. Hepatomegaly (Rivelis, 1963) and
hepatosplenomegaly (Milbradt, 1934; Boyd et al., 1954; Mas-
simo, 1954) have been noted, as well as cirrhosis (Piper and
Helwig, 1955; Calvert et al., 1958; Perez and Barbieri, 1959)
and "chronic biliary cirrhosis" (Goetz, 1945). Striking cal-
cification of the liver and spleen has been recorded once
(Harvier and Bonduelle, 1947). Disturbed liver function with
raised levels of plasma bilirubin, alkaline phosphatase, and
serum aspartate transaminase were noted in some cases bv
Barnett and Coventry (1969) and in one case of the C.R.S.T.
syndrome (Dellipiani and George, 1967), but no histoloptical
details were given. Involvement of the extrahepatic biliary
tree with fibr.osis of the gall bladder (CoTeman and Medd,
1967) and mucosal ulceration causing extrahepatic obstructive
jaundice has also been found (Wildenthal et al., 1968). Brief
reports on hepatic histology include focal necrosis (Piner and
Helwig, 1955), lymphoid cell infiltration (Ormea and Apra,
More detailed histological and biochemical data are avail-
able in a few cases. In the descriptions and photographs of
the hepatic histology in five cases reported by Bartholomew
et al. (1964) infiltration with lymphocytes, disruption of the
limiting cell plates, and ductular proliferation were prominent
features. In two patients the histological description of the
interlobular bile duct damage and the high serum alkaline
phosphatase levels are very suggestive of primary biliary cir-
rhosis, and this diagnosis also closely fits the description of a
case by Grilliat et al. (1967). The five cases described by
Reynolds et al. (1970) have already been mentioned. MacKay
and Wood (1962) found that one of their 22 patients with
lupoid hepatitis also had scleroderma.
however, to distinguish the early stages of primary biliary cir-
rhosis from lupoid (or chronic aggressive hepatitis), particu-
larly on a needle biopsy specimen, and the later stage of the
condition may be indistinguishable from the end stages of cir-
rhosis from other causes.
Though these two cases have been seen over a three-year
period, liver disease of all varieties would appear to be rare
in systemic sclerosis. From the records of 727 cases only
seven with cirrhosis were found (Tuffanelli and Winkelmann,
1961). The aetiology of scleroderma is unknown, but because
of the presence of antinuclear factor and other antibodies in
rheumatoid arthritis, and Sjogren's syndrome (Tuffanelli and
Similarly, the histological appearances
and serological abnormalities in primary biliary cirrhosis also
suggest an autoimmune aetiology. There seems to be little
doubt, from the literature reviewed and the present two cases,
of a link between scleroderma and primary biliary cirrhosis,
and it is hoped that this report will stimulate study of possible
common immunological abnormalities.
It may be difficult,
is often considered to have an autoimmune
It may also occur in association with other "auto-
We are grateful to Professor J. Anderson for details of the early
history of the
permission to publish the second case.
first patient and to Dr.
J. R. R. Spurrell for
Australia, 1, 1040.
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