Primary biliary cirrhosis (PBC) is a chronic cholestatic
liver disease characterized by the destruction of interlobular and septal bile
ducts. The natural history is usually one of gradual progression to cirrhosis
and death. Although ursodeoxycholic acid (UDCA) has been shown to prolong
survival free of liver transplantation, not all patients benefit from this
therapy, and PBC remains an important indication for orthotopic liver
transplantation (OLT). As therapy for end-stage PBC, OLT has been shown to prolong
survival and improve quality of life.Recurrence of PBC after liver
transplantation is not uncommon, yet there is little evidence to date that
recurrent PBC is of major clinical importance.
Symptomatic
Disease
The classic manifestation of PBC is that of a middleaged
woman in whom fatigue and pruritus gradually
develop. Patients with PBC may also have conditions that
affect their energy level, such as depression or sleep disturbance Most patients report more severe symptoms at
nighttime than in daylight hours. Curiously, pruritus tends to gradually resolve with progression
of hepatic disease. tends to gradually resolve with progression of hepatic
disease. As many as 70% of individuals with PBC have coexistent
extrahepatic autoimmune disease states.
Disease Complications
Hypercholesterolemia and hyperlipidemia are present in up to
85% of patients with PBC. In early-stage disease, lipoprotein abnormalities are
commonly found Metabolic bone disease is also common in patients with PBC and
for the most part results from decreased bone mass (osteopenia and
osteoporosis) rather than osteomalacia (defective bone mineralization).
Approximately one third of patients with PBC have osteopenia
(defined as greater than 1.5 SD lower than controls), and 11% have osteoporosis
(lower than 2.5 SD) by lumbar spine bone mineral densitometry.
Hence, many patients
are at an increased risk for bone fractures, which adds to the morbidity and
decreased quality of life. In addition to chronically impaired liver function,
which in general has been associated with osteopenia, the subsequent
cholestasis and predilection for females are thought to underlie the high
prevalence of bone disease in patients with PBC.
The increased occurrence of hepatocellular carcinoma (HCC)
in PBC is increasingly being recognized in the late stages of disease. The
clinical effectiveness of HCC surveillance by abdominal ultrasound and
determination of serum α -fetoprotein levels every 6 to 12 months in end-stage
PBC patients, however, remains unknown. An increased risk for extrahepatic
malignancy such as breast cancer remains controversial
Diagnosis
The diagnosis of PBC is usually based on a clinical syndrome
consisting of chronic cholestasis, including increased alkaline phosphatase,
the presence of AMA, and characteristic histological features of nonsuppurative
inflammation of the bile ducts on liver biopsy. In addition to elevated serum
alkaline phosphatase, modestly increased values of alanine aminotransferase and
aspartate Although histological
confirmation of the diagnosis may not be necessary for a typical patient with
positive AMA, liver biopsy is needed for determining the histological stage of
the disease. aminotransferase are common. Serum total bilirubin levels often
rise during disease progression but are commonly within normal limits at
diagnosis. Serum AMA is found in 95% of patients with PBC.
Natural History and Prognosis :
In the majority of patients with PBC, a progressive clinical
course resulting in fibrosis and eventually cirrhosis is often observed. Estimates of overall
median survival range between 10 and 15 years from the time of diagnosis, whereas
advanced histological disease (stage 3 or 4) imparts a median survival
approaching 8 years.
Elevations in total
bilirubin above 8 to 10 mg/dL have been associated with a median life
expectancy of
2 years.
Medical Treatment of Primary Biliary Cirrhosis
Five randomized controlled trials of adequate size and duration
have provided extensive information regarding the effectiveness of UDCA for PBC
Improvements in symptom and hepatic
biochemical parameters were demonstrated in all five studies. A combined
analysis of three studies using UDCA at doses of 13 to 15 mg/kg/day revealed
improvement in survival free of liver transplantation in patients receiving
active drug.
Long-term (10-year)
survival with UDCA has also been Observed. Although some degree of response is
seen almost universally in PBC patients receiving UDCA therapy, up to two
thirds of patients may be classified as incomplete responders, defined as the
failure to normalize serum hepatic biochemistry or histological progression, or
both, despite treatment with UDCA. Higher levels of serum alkaline phosphatase
and advanced fibrosis at baseline have been associated with incomplete
responses.
A number of agents have been evaluated for further treatment
of PBC, particularly in patients who fail to achieve a complete response. These
agents include immunosuppressants such as corticosteroids, azathioprine, cyclosporine,
and methotrexate; antifibrotic agents such as D -penicillamine; and colchicine
alone or in combination with UDCA.
Liver Transplantation for Primary
Biliary Cirrhosis
As of today, PBC remains among the most common indications
for liver transplantation in the United States. Clearly, the most effective
therapeutic alternative for patients with end-stage PBC is liver
transplantation. Indications for OLT in PBC include complications of portal
hypertension, such as hepatic encephalopathy, refractory ascites, spontaneous
bacterial peritonitis, and hepatorenal syndrome. In addition, intractable pruritus
and disabling fatigue have been considered a justifiable indication for
patients with PBC, although the increasing donor organ shortage has made it
difficult to perform OLT for quality-of-life issues alone.
Outcome
of Orthotopic Liver Transplantation for Primary Biliary Cirrhosis:
As seen in the figure survival after
transplantation has significantly improved after 1990. Pretransplant disease severity has the greatest impact on
short-term outcome because patients with
higher risk scores are likely to have
multisystem dysfunction and be at higher risk for perioperative mortality and
morbidity. Once patients survive the initial insult from the transplant
operation, their longevity may not be greatly affected by the extent of injury
to the replaced liver.
Conclusion
OLT represents a major advance in the care of patients with
PBC. Although there will undoubtedly be more clinical trials to assess the
efficacy of medical therapies, no studies to date have demonstrated that these
therapies ultimately preclude death or the need for OLT. Mathematical models
provide a reliable estimate of a patient’s survival with and without
transplantation. As the trend continues toward progressively more favorable survival
with OLT, the tendency will be to offer transplantation earlier in the course
of the disease. Studies are currently under way to better assess qualityof- life
and cost-effectiveness issues in liver transplantation. Most patients appear to
enjoy extended periods of good health and productive work after transplantation.
Pearls and Pitfalls
• The diagnosis of PBC should be considered
when the following clinical features are present:
• Cholestatic serum liver profile
• Serum AMA positivity
• Liver histology compatible with PBC
• Initial therapy with UDCA at 13 to 15
mg/kg/day for a minimum treatment period of 6 months is
recommended. The treatment goal is to
achieve a reduction in the serum alkaline phosphatase
level that is less than or equal to 1.5
times the upper limit of normal (complete response).
• Survival after liver transplantation
in PBC exceeds 90% at 1 year and 80% at 3 years.
•
Recurrent PBC may occur in up to 25% of patients after liver
transplantation.
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