Download 112196 Primary Biliary Cirrhosis

The New England Journal of Medicine
Review Articles
Medical Progress
mation and allow determination of the histologic
stage of disease, an important factor in assessing
prognosis.
P RIMARY B ILIARY C IRRHOSIS
PREVALENCE, EPIDEMIOLOGY,
AND GENETICS
MARSHALL M. KAPLAN, M.D.
Primary biliary cirrhosis affects members of all races and accounts for 0.6 to 2.0 percent of deaths from
cirrhosis worldwide.2 Estimates of its prevalence
range from 19 to 151 cases per million population,
whereas estimates of its incidence range from 3.9 to
15 cases per million population per year.1,3-5 Genetic
factors play a part in the development of the disorder.
However, primary biliary cirrhosis is not inherited in
any simple recessive or dominant pattern. Its prevalence in families with one affected member is estimated to be 1000 times higher than in the general
population.6 Familial occurrences of the disease are
found in sisters,7 brothers,8 brothers and sisters,9 and
parent and child.10 Unaffected family members are
more likely than normal persons to have impaired
T-cell regulation11 and high levels of circulating autoantibodies, although significant increases in antimitochondrial antibodies are not found in healthy
family members if purified recombinant mitochondrial autoantigens are used in the assay.12 There is a
weak association between primary biliary cirrhosis
and haplotype HLA-DR8,13,14 and in some populations there are associations with the DPB1 gene.15,16
P
RIMARY biliary cirrhosis is a chronic, progressive cholestatic liver disease of unknown
cause that usually affects middle-aged women
and eventually leads to liver failure and the need for
liver transplantation. It is diagnosed more frequently
now than it was a decade ago because of its greater
recognition by physicians and the widespread use of
automated blood testing and the antimitochondrialantibody test, which is relatively specific for the disease.1 Important advances have been made in our
understanding of the natural history, pathogenesis,
and treatment of primary biliary cirrhosis since the
subject was last reviewed in the Journal.2 Little has
changed in its pathological features, diagnosis, and
clinical manifestations. For completeness, however,
these topics are also included here.
Primary biliary cirrhosis is characterized by the
destruction of small intraheptic bile ducts, portal inflammation, and progressive scarring. The typical
patient is a middle-aged woman who reports fatigue
and itching or who has no symptoms but has been
found to have unexplained hepatomegaly or an elevated serum alkaline phosphatase concentration. Approximately 95 percent of patients are female. Biochemical tests of liver function typically reveal a
cholestatic pattern — that is, the alkaline phosphatase and g-glutamyltransferase levels are disproportionately higher than the aminotransferase levels.
Antimitochondrial-antibody tests are positive in 95
percent of patients. Demonstrating that the bile
ducts are patent is important and can usually be
done with ultrasonography. If the results of these
tests are equivocal, computed tomographic (CT)
scanning or endoscopic retrograde cholangiopancreatography should be performed. Percutaneous needle biopsy of the liver can provide confirmatory infor-
From the Division of Gastroenterology, New England Medical Center,
750 Washington St., Boston, MA 02111, where reprint requests should be
addressed to Dr. Kaplan.
©1996, Massachusetts Medical Society.
1570 PATHOLOGICAL FEATURES
Gross Findings
The liver in patients with primary biliary cirrhosis
is characteristically enlarged and smooth, and it may
be stained with bile. As the disease progresses, the
liver may enlarge further, become finely nodular, and
eventually appear grossly cirrhotic. The gallbladder
is usually normal, although there is an increased
prevalence of gallstones, by approximately 40 percent.17 Bile ducts are grossly normal. There is an increased prevalence of nodular regenerative hyperplasia in early-stage primary biliary cirrhosis. This may
account for the unexpectedly high prevalence of
portal hypertension and its complications in patients
with clinically and histologically early stages of primary biliary cirrhosis.18 Enlarged lymph nodes are
often seen in the porta hepatis, along the common
bile duct, and less often in unexpected sites, such as
the mesentery and supradiaphragmatic paracardiac
areas.19 The enlargement is due to benign reactive
hyperplasia.17 The spleen is normal early in the
course of the disease, but it enlarges as hepatic fibro-
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MED ICA L PROGRES S
sis and cirrhosis develop. Hypersplenism and evidence of portal hypertension are common in late
stages.
Hepatic Histology
The course of primary biliary cirrhosis has been
divided into four histologic stages.20,21 It is assumed
that liver histology worsens and that the histologic
stage advances over time from stage I to stage IV,
frank cirrhosis. However, staging has inherent problems. Several stages, and occasionally all four, may be
seen in a single biopsy specimen. The determination
of stage is based on the most advanced lesion in the
specimen. The liver may not be affected uniformly,
and advanced lesions may be missed if the biopsy
specimen is small.
The initial lesion noted in biopsy specimens is
damage to epithelial cells of the bile duct, presumably mediated by lymphocytes that surround and
often infiltrate the duct. Epithelial cells may be vacuolated, shrunken, and pyknotic.20,21 Necrotic bile
ducts are often located at the center of large granuloma-like lesions that consist of histiocytes, lymphocytes, plasma cells, eosinophils, and occasionally true
giant cells21 (Fig. 1A). This is the florid bile-duct lesion in primary biliary cirrhosis. In this stage, inflammation remains confined to the portal triads.
The lymphocytes that infiltrate the ductular epithelial cells directly and presumably destroy them are
CD8 cells (suppressor–cytotoxic cells), but not natural killer cells.22 The majority of lymphocytes in the
portal triads are CD4 cells (helper–inducer cells), although B cells are also seen.22,23 T cells cultured
from triads appear to be clonal.24 Portal T cells express HLA class II antigens, interleukin-2 receptors,
or both, and stain positively for tumor necrosis factor and interferon gamma, indicating that they are
activated.25,26 Damaged bile ducts express intercellular adhesion molecule 1, vascular adhesion molecule,
class II MHC molecules, and a molecule antigenically similar to the E2 subunit of mitochondrial pyruvate dehydrogenase.27,28 Granulomas are most often seen in stage I primary biliary cirrhosis.
As the disease progresses to stage II, many portal
triads become scarred, inflammatory cells spill out of
the triads into the surrounding periportal parenchyma, normal bile ducts cut in cross section disappear,
and atypical, poorly formed, tortuous bile ducts with
no obvious lumens are seen (Fig. 1B). Periportal
hepatocytes become vacuolated and surrounded by
foamy macrophages, a process termed biliary piecemeal necrosis29 (Fig. 1C). In stage III, scarring progresses to the point at which fibrous septa link many
adjoining portal triads (Fig. 1D). Stage IV is frank
cirrhosis (Fig. 1E).
Other histologic features of primary biliary cirrhosis are intracellular hyaline deposits in periportal areas identical to those seen in alcoholic liver dis-
ease30 and increased amounts of stainable copper.31
The accumulation of copper correlates with the serum bilirubin level and with advancing stages of disease.32
IMMUNOLOGIC ABNORMALITIES
Primary biliary cirrhosis has a sex distribution
similar to that of other autoimmune diseases, with
the great majority of patients being women. Abnormalities of both the humoral and cellular immune systems are common.33,34 The immunologic
abnormalities seen in this disorder include increased
levels of serum immunoglobulins, particularly IgM35,36;
a failure to convert from IgM to IgG antibody after
immunization37; the presence of a plethora of circulating autoantibodies; increased turnover of complement38; the presence of activated T cells and B cells
in peripheral blood39; impaired T-cell regulation7;
negative delayed-hypersensitivity skin tests; granulomas in the liver or lymph nodes draining the liver;
and histologic liver lesions that resemble those occurring when hepatic allografts are rejected. There is
an association between primary biliary cirrhosis and
other diseases considered to have an autoimmune
basis.40 Up to 84 percent of patients with primary
biliary cirrhosis may have at least one other autoimmune disease, such as thyroiditis, scleroderma, rheumatoid arthritis, or Sjögren’s syndrome.40
Abnormalities of Humoral Immunity
Some patients have a low-molecular-weight monomeric IgM in their blood and an apparent inability
to synthesize the IgM pentamer.41 Others have increased serum levels of an IgM that is highly immunoreactive and highly cryoprecipitable.35 It spontaneously converts complement factor C3 to C3b and
C3c through the classic pathway, behaves like an immune complex in some assays, and may lead to spuriously high serum IgM levels if the levels are measured by radioimmunodiffusion.42 Conversely, serum
levels of IgE are decreased in some patients.43
Many circulating autoantibodies are found in patients with primary biliary cirrhosis, and the list
is constantly growing. The most important diagnostically and perhaps pathogenetically is antimitochondrial antibody.44,45 Others include antinuclear
antibodies, one of which is specific for nuclear
membranes46; antithyroid antibodies47; lymphocytotoxic antibodies48; anti–acetylcholine-receptor antibodies49; antiplatelet antibodies50; anti–SS-A antibodies (also known as antiribonucleoprotein antigen
Ro antibodies)51; antihistone antibodies52; and anticentromere antibodies.53 There is no increase in circulating immune complexes in patients with primary
biliary cirrhosis.54 Earlier reports to that effect may
reflect the presence of the abnormal IgM in the disease that causes spuriously positive results in some
assays.35
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1571
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A
B
C
D
E
F
Figure 1. Histologic Features of the Liver in Various Stages of Primary Biliary Cirrhosis and of a Healthy Liver.
Panel A shows an acute bile-duct injury in a patient with stage I primary biliary cirrhosis. The bile duct at the center is degenerating
and is infiltrated by lymphocytes and fragments of lymphocytes. The epithelial cells are damaged and are missing from one quadrant of the duct, which has presumably been totally destroyed. The cells surrounding the bile duct are primarily lymphocytes, but
there are also larger mononuclear cells and eosinophils (hematoxylin and eosin, 310). Panel B shows stage II primary biliary
cirrhosis. There is atypical bile-duct hyperplasia. The bile ducts are tortuous, and few are cut in cross section. The inflammatory
cells are primarily lymphocytes (hematoxylin and eosin, 310). Panel C shows foamy degeneration of hepatocytes adjacent to portal triads in a patient with primary biliary cirrhosis. There are collections of hyaline droplets in many of these swollen hepatocytes,
identical to those seen in alcoholic hepatitis (Masson trichrome, 496). Panel D shows stage III primary biliary cirrhosis. Adjacent
portal triads are connected by septa consisting of dense infiltrates of mononuclear cells and strands of connective tissue (Masson
trichrome, 54). Panel E shows stage IV primary biliary cirrhosis. A wedge biopsy was obtained at the time of portacaval anastomosis for bleeding esophageal varices. There is a noncaseating granuloma in the center of a nodule. The portal triads are linked
by bands of connective tissue and inflammatory cells (Masson trichrome, 90). Panel F shows a normal portal tract, containing a
branch of the portal vein, an interlobular bile duct, and small arterioles (Masson trichrome, 250).
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MED ICA L PROGRES S
Abnormalities of Cellular Immunity
There are decreased numbers of circulating
T lymphocytes (both helper and suppressor) in the
blood of patients with primary biliary cirrhosis, as
well as abnormalities in the regulation and function
of these cells.55,56 Sequestration of T lymphocytes
within hepatic portal triads probably accounts for
their decreased numbers in the circulation.57 The
decreased in vitro suppressor function of cells from
some patients may be due to the abnormal activation and suppressor function of CD4 and Leu-8
T cells.58 Peripheral-blood T lymphocytes from patients with primary biliary cirrhosis do not respond
normally to interleukin-2 and produce inadequate
amounts of lymphotoxins, tumor necrosis factor,
and interferon gamma when stimulated by mitogens.59,60 However, both circulating and intrahepatic
T lymphocytes recognize and are stimulated by the
E2 subunits of the mitochondrial oxo-acid dehydrogenase complexes61,62 and by a different bile-duct epithelial-cell antigen.63
Mitochondrial Antigens and Antibodies
A major advance in our understanding of primary
biliary cirrhosis occurred with the identification and
cloning of the antigens against which antimitochondrial antibodies are detected.64 They are the dihydrolipoamide S-acetyltransferase component (E2 subunit) of a functionally related family of enzymes, the
2-oxo-acid dehydrogenases. These are pyruvate dehydrogenase, 3-methyl-2-oxobutanoate dehydrogenase (also known as branched-chain keto-acid dehydrogenase), and oxoglutarate dehydrogenase. Each
may serve as an antigen for antimitochondrial antibodies, but pyruvate dehydrogenase is the most prevalent.45,65 Each catalyzes the reductive transfer of an
acetyl group from its respective substrates to coenzyme A for oxidation in the Krebs cycle. Lipoic acid,
a cofactor in the E2 subunit against which antimitochondrial antibodies are directed, is not an obligate
component of the epitope. Human antimitochondrial antibodies clearly inhibit the enzymatic activity
of these complexes in vitro.65 Thus far, all the mitochondrial autoantigens screened have been targets of
only the anti-M2 antimitochondrial antibodies. Other antimitochondrial antibodies previously described,
anti-M4, anti-M8, and anti-M9, are probably artifacts.66,67
Antimitochondrial antibodies are found in 95 percent of patients with primary biliary cirrhosis, and
they have a specificity of 98 percent for this disease.45 Their role in the pathogenesis of the disorder
is unclear. Their titers differ greatly among patients
and do not correlate with the severity or rate of progression of disease.2 Antimitochondrial antibodies
raised in animals immunized with recombinant human pyruvate dehydrogenase do not damage the
bile duct or cause any recognizable disease.68 Human antimitochondrial antibodies recognize pyruvate dehydrogenase in Escherichia coli and yeast, but
their binding affinities are several orders of magnitude lower than those of human antigens.69
Although the cause of primary biliary cirrhosis is
still unknown, most data suggest that it is due to
some inherited abnormality of immunoregulation
whose precise nature is unknown.34 The fact that
only one of two identical twins had the disease suggests that an additional factor, such as a triggering
event that damages the epithelial cells of the bile
duct, is also required in genetically susceptible persons.70 Potential triggers include treatment with interferon alfa and toxic effects on the liver from
chlorpromazine, factors that may have initiated the
development of primary biliary cirrhosis in two
women.71,72
Such putative damage to bile-duct epithelial cells
could then unmask a new antigen, such as pyruvate
dehydrogenase complex E2, that is recognized by
both hepatic and peripheral-blood T lymphocytes in
primary biliary cirrhosis.61,62 A molecule that shares
some antigenic determinants with the E2 subunit of
pyruvate dehydrogenase is found on the luminal surface of biliary epithelial cells in patients with primary
biliary cirrhosis early in their disease.28,73 Expression
of this autoantigen on the luminal surface of biliary
epithelial cells may provoke antibody-mediated attack by IgA antibodies, the antibodies present in
bile.28 Alternatively, this E2-like antigen, together
with the appropriate class II MHC molecules and
another molecule required for antigen presentation,
BB1/B7, could be the target of activated CD8
lymphocytes. All these molecules are found in and
around damaged bile ducts in patients with primary
biliary cirrhosis.73 The E2 component appears in
damaged bile ducts before the class II MHC molecules and BB1/B7 appear. This sequence suggests
that the E2 component may have a pathogenetic
role. The histology of primary biliary cirrhosis is also
consistent with T-lymphocyte–mediated cytotoxicity, as is the fact that the E2 antigens stimulate the
production of interleukin-2 by cloned T cells isolated from liver tissue.60
In addition to the destruction of small bile ducts
mediated by T lymphocytes, secondary damage to
hepatocytes may result from the accumulation in the
liver of increased concentrations of substances normally secreted into bile, such as bile acids. The foamy
degeneration of hepatocytes in primary biliary cirrhosis has been attributed to the noxious effects of
bile acids (Fig. 1C).29 Cholestasis in itself causes increased expression of HLA class I antigens on hepatocytes and renders them better targets for an
immunologically mediated attack. Treatment with
ursodiol reduces the expression of HLA class I antigens by hepatocytes, in addition to mitigating the
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toxic effects of naturally occurring bile acids, such as
cholic acid and chenodeoxycholic acid.74,75
CLINICAL FEATURES
Symptoms and Physical Examination
The onset of primary biliary cirrhosis typically
occurs between the ages of 30 and 65, but I have
seen and others have described women as young as
22 and as old as 93 at the time of diagnosis.76,77 Fatigue and pruritus are the usual presenting symptoms, with fatigue noted in up to 78 percent of patients.78 As many as 48 to 60 percent of patients may
be asymptomatic.78,79 Pruritus may first occur during
pregnancy and may be mistaken for the pruritus of
pregnancy. However, the pruritus of pregnancy resolves in the postpartum period, whereas that due to
primary biliary cirrhosis persists. Once pruritus occurs in a patient with biliary cirrhosis, it is unusual
for the itching to disappear spontaneously. The same
is true of jaundice. Itching is worse at night; under
constricting, coarse garments; in association with
dry skin; and in hot, humid weather. Pruritus is often not recognized as a sign of cholestasis, and many
patients are referred to dermatologists.
The cause of the pruritus in patients with primary
biliary cirrhosis is unknown. It is not due to the retention of bile acids and their sequestration in skin80
but does respond to treatment with bile-acid–binding agents, such as cholestyramine resin. Increased
opiodergic tone (that is, increased concentrations of
endogenous opioid peptides and up-regulation of
endogenous opioid receptors) related to chronic
cholestasis has been suggested as a potential cause
of the pruritus.81 Unexplained right-upper-quadrant
discomfort was reported in 8 percent of patients
in one study.82 In rare cases patients present with
advanced disease that includes hemorrhage from
esophageal varices, ascites, or hepatic encephalopathy.76,83
The findings on physical examination vary widely
and depend on the stage of the disease at the time
of presentation. The physical examination is often
normal in asymptomatic patients. The skin is initially normal, but excoriations severe enough to
cause bleeding may occur as the disease progresses.
Xanthomas are a late manifestation. Striking hepatic
enlargement is often found, occasionally in asymptomatic patients. Hepatomegaly becomes more common with progressive disease and is found eventually
in approximately 70 percent of patients.77 Splenomegaly is present in 35 percent of patients at presentation but becomes more common as the disease
progresses. Jaundice is a later manifestation of the
disease, but in some patients it may be seen at presentation. Spider nevi, temporal and proximal-limb
muscle wasting, ascites, and edema are all late manifestations of disease and suggest cirrhosis. Kayser–
1574 Fleischer rings are a very rare manifestation and result from the retention of copper.84
Laboratory Tests
The serum alkaline phosphatase concentration is
invariably elevated in patients with primary biliary
cirrhosis, often to striking levels, and the enzyme is
of hepatic origin. The level tends to reach a plateau
early in the disease and usually fluctuates within 20
percent of that value.83 The serum levels of 5-nucleotidase and g-glutamyltransferase parallel those of
alkaline phosphatase. The serum levels of alanine
and aspartate aminotransferase may be normal or
slightly elevated, rarely more than five times the upper limit of the normal value. They tend to fluctuate
within a relatively narrow range and have no prognostic importance.85 The serum bilirubin level is
usually normal early in the course of the disease, but
it becomes elevated in 60 percent of patients as the
disease progresses. Both the direct and indirect fractions are increased. An elevated serum bilirubin level
is a sign of a poor prognosis.85
Serum lipids may be strikingly elevated in primary
biliary cirrhosis. Serum cholesterol levels are elevated
in at least half of patients76 and may exceed 1000 mg
per deciliter in patients with xanthomas.86,87 Patients
with early-stage primary biliary cirrhosis have mild
elevations of low-density lipoprotein cholesterol and
very-low-density lipoprotein cholesterol and marked
elevations of high-density lipoprotein cholesterol.88
This may explain why patients with primary biliary
cirrhosis have striking hypercholesterolemia but are
not at increased risk for death from atherosclerosis.89
Another protective factor is their low serum levels of
Lp(a) lipoprotein, an independent risk factor for coronary artery disease.90 Patients with advanced disease
have striking elevations of low-density lipoprotein
cholesterol, decreased levels of high-density lipoprotein cholesterol, and detectable levels of lipoprotein
X, an abnormal lipoprotein seen in patients with
chronic cholestasis.91 Other biochemical abnormalities include elevated serum ceruloplasmin levels,
striking elevations of serum bile acids,92 and elevations of serum hyaluronate.93 Rising hyaluronate
levels correlate with serum bilirubin levels and worsening histologic features.93 A previous report of impairment of sulfoxidation in primary biliary cirrhosis94 could not be confirmed.95
Diagnosis
Primary biliary cirrhosis should be suspected in a
patient who reports unexplained itching, fatigue,
jaundice, or unexplained weight loss, with discomfort in the right upper quadrant and an unaccountable elevation of serum alkaline phosphatase. If the
diagnosis is suspected, the patient should be questioned about symptoms frequently associated with
it, such as dry eyes, dry mouth, arthritis, and Ray-
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MED ICA L PROGRES S
naud’s phenomenon. It is important to question patients about the use of medications, because some
drugs may cause cholestasis similar to that associated
with primary biliary cirrhosis.
If the alkaline phosphatase and serum IgM levels
are both elevated and the antimitochondrial-antibody test is positive, primary biliary cirrhosis is likely. Slight increases in aminotransferases, to as much
as four times the normal level, and elevations of serum cholesterol are corroborative data. The serum
albumin level and the prothrombin time are typically
normal at the time of diagnosis. Striking elevations
of serum bile acids are characteristic, but this test is
not commonly available.
The diagnosis should be confirmed by a percutaneous liver biopsy, which will also provide information about the disease stage and the prognosis. The
more portal triads there are in the specimen, the
more likely it is that florid bile-duct lesions and granulomas will be found.21 If the history, physical findings, results of blood tests, and liver-biopsy findings
are consistent, neither imaging nor cholangiography
is needed.
Associated Disorders
Steatorrhea occurs primarily in patients with jaundice who have advanced disease. It is due to the decreased biliary secretion of bile acids and the resulting
low concentration of bile acids in the small intestine
— often lower than the critical micellar concentration.96,97 Pancreatic insufficiency may contribute to
this condition.96,97 A diet low in neutral triglycerides
and supplemented with medium-chain triglycerides
and, when indicated, pancreatic extract will decrease
the steatorrhea and improve nutritional status.
The association of scleroderma, Sjögren’s syndrome, arthropathy, and the CREST syndrome (calcinosis cutis, Raynaud’s phenomenon, esophageal
dysmotility, sclerodactyly, and telangiectasia) is well
known.98,99 The scleroderma associated with primary
biliary cirrhosis is rarely fatal.99 When specific testing
for lacrimation was performed in one study, approximately 86 percent of patients had keratoconjunctivitis sicca, xerostomia, or both.100
Approximately 20 percent of patients have hypothyroidism,47 which may predate the onset of primary biliary cirrhosis or occur during its course. The
prevalence of antithyroglobulin antibodies was 20
percent, and that of antimicrosomal antibodies 34
percent.47 Serum levels of thyroid-hormone–binding proteins are increased. The most accurate test
for hypothyroidism is the test for serum thyroidstimulating hormone.101 Renal tubular acidosis occurs frequently but is usually subclinical.102 It is related to the deposition of copper in the kidney.
About 40 percent of patients with primary biliary
cirrhosis have defective urinary acidification after
acid loading, but symptoms of acidosis are rare.
Earlier reports of an increased prevalence of hepatocellular carcinoma and breast cancer in patients
with primary biliary cirrhosis have not been confirmed in more recent, larger studies.103,104 I have
also not found an increased prevalence of these cancers in 630 patients with primary biliary cirrhosis
whom I have followed during the past 20 years.
There is an increased prevalence of both asymptomatic bacteriuria and acute cystitis in patients with
primary biliary cirrhosis.105 Antibiotic treatment appears to have little effect in asymptomatic patients.
Bacteriuria spontaneously resolves in most asymptomatic patients, and eventually they become reinfected with different organisms.
Osteoporosis is the bone disorder most often seen
in patients with primary biliary cirrhosis.106 Osteomalacia occurs rarely. Symptomatic osteoporosis is
seen less often, now that patients are referred for liver transplantation before the complications of longstanding cholestasis occur. The osteoporosis is not
related to vitamin D deficiency,107 but its severity
does correlate with the intensity and duration of
jaundice,106 and unconjugated bilirubin inhibits the
formation and function of osteoblasts in in vitro
models of bone growth.108 There is no proved treatment for the osteoporosis other than liver transplantation, and improvement is first noted 6 to 12
months after surgery. Treatments with 25-hydroxyvitamin D plus calcium,106,109 ursodiol,110 and calcitonin111 have been ineffective. Fluoride (50 mg per
day orally) was reported to prevent bone loss in seven patients followed for two years.112
Clinically important deficiencies of the fat-soluble
vitamins A, K, and E are uncommon, except in patients with jaundice who have advanced primary biliary cirrhosis.113 Oral replacement therapy is usually
adequate.
Natural History and Prognosis
Primary biliary cirrhosis progresses in most cases,
but the rate of progression varies greatly among individual patients. Asymptomatic patients have substantially longer life expectancies than symptomatic
ones, but their survival is still less than that of
healthy patients matched for age and sex.78,114 The
median survival of asymptomatic patients was 10
and 16 years in two large cohorts followed for up to
24 years.78,114 The median survival of symptomatic
patients is approximately seven years.114,115 Symptoms
develop in two to four years in most asymptomatic
patients,78 but one third may remain symptom-free
for many years.114 Neither the presence of antimitochondrial antibodies nor their titer affects survival.
Some investigators have considered antimitochondrial-antibody–negative patients who have either antinuclear antibodies or antibodies to smooth muscle
as having a separate disease, autoimmune cholangitis.116 However, these patients are identical to
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patients with primary biliary cirrhosis in all other
ways — for example, in histologic stage, results of
biochemical tests, survival, and response to treatment.116
Prognosis and hence management decisions vary
considerably depending on the clinical status of the
patient. Whether to treat an asymptomatic patient is
a difficult question. There is no reliable way to predict which such patients will have symptoms, nor
is any therapy generally accepted as effective. If an
asymptomatic patient has other diseases, such as thyroiditis, sicca syndrome, and scleroderma, survival is
more likely to be decreased117 and cirrhosis more
likely to be present.118 Granulomas are associated
with better survival.119 The only laboratory measures
of prognostic value — the serum bilirubin level, the
serum albumin level, and the prothrombin time —
are usually normal in asymptomatic patients. What is
needed is a quantitative test of liver function that
can identify asymptomatic patients who have decreased hepatic reserve.
At the other end of the spectrum are patients with
clinically advanced disease. Here, the major consideration is the timing of liver transplantation. There
are more than five prognostic models for predicting
survival, most based on Cox multiple-regression analysis.118-123 The only variable common to all five is the
serum bilirubin level. These models are helpful in
the timing of liver transplantation, but they are useful only for patients with advanced disease. All depend on variables that are primarily manifestations
of the failing liver — namely, elevated serum bilirubin levels, decreased serum albumin levels, prolonged prothrombin time, fluid retention, and hemorrhage from esophageal varices. Patients with any
of these negative prognostic indicators probably
have both cirrhosis and irreversible, medically untreatable disease. Even if medical treatment is attempted in such patients, they should be evaluated
for liver transplantation.
TREATMENT OF SYMPTOMS
The most common symptom that is relatively specific for primary biliary cirrhosis is pruritus. Cholestyramine resin (4 g three times per day orally) will
relieve pruritus in most patients. The dose of this
nonabsorbed resin must be adjusted in individual
patients, and it takes one to four days from the initiation of treatment for the itching to remit. Antihistamines are helpful only early in the course of the
disease, when itching is not severe. Another ammonium resin, colestipol hydrochloride, is as effective as
cholestyramine. Rifampin,120 ursodiol,121 and naloxone81 control itching in some patients who are unresponsive to cholestyramine. Large-volume plasmapheresis relieves the symptom in the rare patient
who does not respond to any of these medications.122 Individual patients have responded to pho1576 totherapy with ultraviolet B light, methyltestosterone, cimetidine, phenobarbital, and prednisone.
The complications of primary biliary cirrhosis, except for symptomatic osteoporosis and hemorrhage
from esophageal varices in patients with early-stage
disease, are similar to those in patients with other
types of cirrhosis and are not reviewed here. The
management of osteoporosis has already been discussed. Unlike patients with other types of cirrhosis,
those with primary biliary cirrhosis may have bleeding from esophageal varices early in the course of the
disease, before there is jaundice123 or true cirrhosis.124 Distal splenorenal shunting is the preferred
treatment.125 Survival is not adversely affected and is
similar to that predicted by the Mayo prognostic
model.123,125,126
TREATMENT OF UNDERLYING DISEASE
There is no generally accepted treatment for the
underlying disease process in primary biliary cirrhosis, but the results with ursodiol, colchicine, and
methotrexate are encouraging. Glucocorticoids do
not appear to improve the course of the disease and
may worsen osteoporosis. In one prospective trial of
low-dose prednisolone, the only significant effect after three years was a decrease in serum immunoglobulins and alkaline phosphatase activity.127 Azathioprine has limited efficacy and is no longer used.118
Penicillamine, an agent that induces cupriuria and
has some antiinflammatory actions, is ineffective and
caused side effects in more than 25 percent of patients in one study.115
Ursodiol
Ursodiol has been evaluated in four randomized,
prospective, double-blind trials.121,128-130 The appropriate dose is 12 to 15 mg per kilogram of body
weight per day, given either in divided doses or as
one dose at bedtime. It is safe and well tolerated. Diarrhea occurs in less than 2 percent of patients. Ursodiol lowers the serum levels of bilirubin, alkaline
phosphatase, g-glutamyltransferase, alanine and aspartate aminotransferase, and IgM. It relieves pruritus in some patients, although it may exacerbate that
symptom during the first two weeks of treatment.
Its effect on liver histology is uncertain. Ursodiol
decreased hepatic inflammation in one study,121 but
not in the others.128-130
Ursodiol extended the time before a patient died
or was referred for liver transplantation, as compared
with placebo, in studies that continued for four
years.121 When the data from three of these studies
were combined and analyzed, ursodiol slightly prolonged the time before liver transplantation was indicated, as compared with placebo (3.66 vs. 3.45
years, P0.014), and decreased the likelihood of
liver transplantation or death by 32 percent.131 Ursodiol appears to be more effective in patients with
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MED ICA L PROGRES S
early disease than in those with later disease stages.132 In one trial, the results of biochemical tests became completely normal in 12 of 65 patients after
two years of treatment. As compared with the other
patients, these 12 patients had less advanced histologic stages of disease and lesser elevations of serum
bilirubin and alkaline phosphatase at the time that
ursodiol was given.
Ursodiol is ineffective in patients with advanced
disease and may worsen symptoms and blood-test
results in some patients.73 Because ursodiol may lower serum bilirubin levels in patients with clinically
and histologically progressive disease, treatment with
the drug may take away the predictive value of bilirubin in the timing of liver transplantation.93
Cyclosporine
Cyclosporine has been evaluated prospectively in
two short-term double-blind studies and one sixyear study.133,134 In 29 patients with precirrhotic primary biliary cirrhosis, cyclosporine (4 mg per kilogram per day orally) stabilized fatigue and itching
and decreased serum levels of bilirubin, alanine aminotransferase, alkaline phosphatase, gamma globulin, and antimitochondrial antibody.133 Most patients had hypertension and renal toxic effects. In
the largest treatment trial to date, 349 patients were
randomly assigned to receive 3 mg per kilogram per
day of cyclosporine or placebo and were followed for
up to six years.134 The cyclosporine-treated patients
had slight but significant improvements in levels of
albumin, alkaline phosphatase, serum bilirubin, and
alanine aminotransferase, but worsening in serum
creatinine levels. Survival was not improved except
when a Cox proportional-hazards model was used
to correct for the fact that the patients who received
cyclosporine were sicker. Pruritus was improved, but
not fatigue or histology. The limited efficacy of
cyclosporine is counterbalanced by its predictable
toxicity.
Colchicine
Colchicine (0.6 mg twice daily) significantly improved serum levels of bilirubin, albumin, alkaline
phosphatase, cholesterol, and the aminotransferases
after two years of follow-up and significantly improved survival after four years in one prospective,
double-blind trial.135 There was lesser improvement
in these variables in two similar studies.136,137 Histology and symptoms did not improve in any of these
trials. Patients in one study were followed for up to
eight years, at which time the results of biochemical
tests were stable but there was no survival benefit.138
One placebo-controlled trial of 90 patients compared colchicine with ursodiol.139 Both drugs improved pruritus. Colchicine improved the biochemical values slightly, whereas ursodiol reduced serum
alkaline phosphatase and aminotransferase activities
significantly as compared with placebo or colchicine
and also lowered serum bilirubin levels. Ursodiol
and colchicine were synergistic when they were used
in combination in 12 patients followed for two
years.140
Methotrexate
Methotrexate (15 mg per week orally) decreased
serum levels of alkaline phosphatase, alanine and aspartate aminotransferase, cholesterol, and bilirubin
in a pilot study of nine patients followed for two
years.141 All the patients had improvement or resolution of their fatigue, their itching, or both. Most patients had transient increases in aminotransferase
levels two to eight weeks after treatment with methotrexate began, followed by decreases in the levels
and often a return to normal values. Serum biochemical values became normal in five of these patients with prolonged treatment (60 months), and
their mean histologic stage decreased from 2.5 to
1.0.142 Methotrexate did not benefit patients with
advanced cirrhosis or decompensated liver disease.141
The response to methotrexate is slower than the
response to ursodiol, and improvements in biochemical values with methotrexate may continue
slowly for up to four years.142 In an interim (24
month) analysis of a randomized, double-blind trial
comparing methotrexate with colchicine in 89 patients, enzyme measurements improved significantly
in both groups, but the decrease in alkaline phosphatase and the aminotransferases was significantly
greater with methotrexate.143 Pruritus and liver histology improved significantly in the methotrexate
group.143,144 In both treatment groups, the synthesis
of interleukin-1b by cultured peripheral-blood
monocytes increased significantly over the two-year
period.145
The effects of methotrexate and ursodiol appear
to be additive.146 Methotrexate improved symptoms
and biochemical values in one study of eight patients who had only partial responses to ursodiol.147
However, in another study of 32 patients who received methotrexate and ursodiol together, no additive effect was observed when these patients were
compared with patients from an earlier study of ursodiol alone.148 Interstitial pneumonitis is a serious
problem in patients with primary biliary cirrhosis
who are treated with methotrexate.149 That condition occurred in 14 percent of patients in one study
but responded promptly when methotrexate therapy was discontinued and glucocorticoids were instituted.
Liver Transplantation
The only treatment that clearly improves the natural history of primary biliary cirrhosis is liver transplantation.150 There is 85 to 90 percent survival at
one year, and survival rates thereafter resemble those
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1577
The New England Journal of Medicine
of healthy persons matched for age and sex. For all
practical purposes, primary biliary cirrhosis does not
recur after liver transplantation if appropriate immunosuppression is used.151 However, a minority of patients may have minor histologic lesions that resemble those in early primary biliary cirrhosis, although
the patients are asymptomatic and have normal biochemical values.152 There are close clinical and histologic similarities between patients with primary biliary cirrhosis and patients in whom transplanted
livers are rejected. Regimens in which immunosuppressive agents are combined effectively prevent such
rejection. Therefore, future treatments for primary
biliary cirrhosis will probably use combinations of
drugs.153
I am indebted to Jane Bankoff-Popkin and Drs. Andrew Leiter
and Arthur Rabson for their assistance in the preparation of the
manuscript.
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