Primary Biliary Cirrhosis
Primary biliary cirrhosis (PBC) is an auto-immune
disease of the liver that results in chronic injury to the intrahepatic bile
duct epithelium. The gradual destruction of the bile ducts causes cholestasis
with the sub-sequent retention of toxins, inciting further hepatic injury and
resulting in fibrosis, cirrhosis, and eventual liver failure. Early detection
is optimal, before significant liver injury has occurred.
PBC primarily affects middle-aged women. The ratio
of affected women to men has been reported to be as high as 9:1.
The most common presenting symptoms include
pruritis and fatigue. While pruritis can be severe, there is marked
improve-ment by medications such as ursodiol. Fatigue on the other hand causes
signifi-cant disability, as there are no medications that can provide relief.
Other findings may include hyperlipidemia and osteo-porosis. In addition,
patients may have concurrent autoimmune diseases, which include but are not
limited to Sjögren’s syndrome and scleroderma. Patients with more advanced
disease may present with symptoms commonly seen with other chronic liver
diseases such as ascites, por-tal hypertension, and esophageal varices. An
increased incidence of HCC in patients with longstanding advanced disease has
been described.
The diagnostic criteria for PBC include an
elevation in liver enzymes (most nota-bly alkaline phosphatase) for a duration
of six or more months, histologic findings, and the presence of
antimitochondrial antibodies in the serum. The presence of two criteria is
highly suggestive of the disease while a definite diagnosis requires all three.
Involvement of the liver is heteroge-neous, so a
biopsy may demonstrate dif-ferent stages of disease. In such instances, the
disease is assigned the most advanced stage. Stage I is characterized by portal
inflammation comprised of predomi-nantly lymphoplasmacytic infiltrates. The
pathognomonic lesion of PBC, the florid duct lesion, represents focal duct
oblitera-tion by granuloma formation. In stage II there is extension of
inflammation to the periportal areas. There is formation of fibrous septa that
link adjacent portal tri-ads and bile duct loss (ductopenia) in stage III.
Finally, stage IV is defined by frank cirrhosis.
The targets of the antimitochondrial antibodies
belong to the family of 2-oxo-acid dehydrogenase enzyme complexes located in
the inner mitochondrial mem-brane. The major autoantigen is the E2 subunit of
the pyruvate dehydrogenase complex (PDC-E2). Given that 90 to 95 percent of
patients with PBC have anti-mitochondrial antibodies, some of which are
asymptomatic, serologic detection has allowed for earlier diagnosis of disease
and improvement in prognosis.
Molecular mimicry is the most widely proposed
explanation as to the induction of autoimmunity in PBC. Briefly, a host is
infected with a microorganism that con-tains antigens similar to antigens present
in the host. These microbial antigens induce an immunologic response when
presented to the immune system of the host. As a result, what began as a
pathogen-specific response then cross-reacts with the host antigens and results
in tissue injury and disease. This mechanism has also been associated with
other autoimmune dis-eases of the liver such as primary scleros-ing cholangitis
(PSC) and autoimmune hepatitis (AIH).
Bacteria such as Escherichia coli have been implicated due to the reported high
incidence of urinary tract infec-tions in patients with PBC. Antibodies against
human pyruvate dehydrogenase in PBC patients react well against the E. coli
pyruvate dehydrogenase complex. More
recently, a Gram-negative aerobe,
Novosphingobium
aromaticivorans has been demonstrated to have an even higher degree of homology with the
immunodominant epitope on human PDC-E2 than E.
coli. The titers of antibodies in PBC patients against pyruvate
dehydrogenase in N. aromaticiv-orans are
as much as 1,000 times higher than
the titers of antibody against E. coli.
Other potential infectious triggers include
Chlamydia
pneumoniae and lactobacilli.
The exact
mechanism of biliary destruc-tion is not entirely clear, as it appears that the
autoantibodies do not have a direct cytotoxic effect. This is supported by a
lack of correlation between antibody titer and extent of hepatic involvement,
the lack of immediate recurrence despite the persis-tence of antibodies status
post-liver trans-plantation, and the absence of antibodies in about 5–10
percent of patients with histo-logically confirmed PBC.
The
involvement of inflammatory cells in the pathogenesis of PBC is supported by
several findings. The epitopes recognized by portal CD4+ helper and
CD8+ cyto-toxic T cells overlap on the lipoyl domain of PDC-E2. In
patients with PBC, studies have demonstrated that the frequency of autoreactive
CD4+ T cells is higher in the hepatic lymph nodes than in the
circula-tion. In addition, CD8+ T cells and B cells that are
reactive with PDC-E2 are higher in the liver than in the circulation. A
decrease in CD4+ CD25-high regulatory (Treg) cells may also
contribute to an acceleration of autoimmunity in PBC. Bile duct destruc-tion
secondary to the accumulation of bile acids is thought to play a role in
dis-ease progression. Cholestasis increases the expression of HLA class I
antigens in hepa-tocytes in PBC. The implication here is that there is
increased presentation of antigens to cytotoxic cells.
Some
puzzling observations are that the autoantibodies are specifically directed
against the mitochondria in bile duct epi-thelial cells despite the fact that
nucle-ated cells are ubiquitous in the body. One proposed theory is that the
altered state of apoptotic biliary epithelial cells predis-poses them to having
antibodies devel-oped against them. It is thought that the blockage of glutathione attachment to the
lysine-lipoyl moiety of the E2 protein during biliary epithelial cell apoptosis
ren-ders the PDC-E2 susceptible to recognition by autoantibodies. When compared
with PSC, the injury is limited to the intrahepatic ducts in PBC. The
extrahepatic ducts often remain intact even at the cirrhotic stage. This
selectivity for cholangiocytes may be attributed to inherent genetic
differences (observed in mice) present in intra- and extrahepatic
cholangiocytes.
Recently,
studies have identified three murine models that spontaneously develop PBC.
These models include the NOD.c3c4 mouse, a mouse with the domi-nant negative
form of tTGF-β receptor
II (dnTGFβ RII),
and the IL-2Rα knockout
mouse. In all three models, the target of the antimitochondrial antibodies is
PDC-E2 and the immunodominant epitope is the lipoyl domain. In addition, they
all dem-onstrate lymphocyte infiltration around the portal tracts accompanied
by chol-angiocyte injury. These animal models could help elucidate many
unanswered questions.
Medical
therapy is geared toward both symptomatic improvement and treatment of
underlying disease. Cholestyramine and rifampin are common agents used to treat
the pruritis. Ursodiol (ursodeoxycho-lic acid) is the only medical treatment
for PBC that has received approval by the U.S. Food and Drug Administration.
Ursodiol has been found to cause a normalization of enzymes and improve histologic
find-ings in approximately 25 to 30 percent of patients with PBC. In addition,
at least 20 percent of patients treated with ursodiol have no histologic
progression over four years. Its effects are thought to be mul-tifactorial. It
promotes both endogenous bile acid secretion and membrane stabilization. This
compound is also associated with reduced aberrant HLA type 1 expres-sion on
hepatocytes and a fall in cytokine production. Colchicine and methotrexate are
also commonly utilized if there is inad-equate response to ursodeoxycholic
acid. PBC still remains one of the top five indica-tions for liver
transplantation. The survival rates are 92 percent and 85 percent at one and
five years, respectively. PBC recurs in 15 percent of patients at three years
and 30 percent at ten years.
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