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gastroesophageal varices and variceal hemorrhage in cirrhosis in patients with PBC
follows the guidelines published by the American Association for the Study of Liver
Disease (AASLD)[364].Salient points of those recommendations include a screen-
ing upper endoscopy when the diagnosis of cirrhosis is made[364]. The published
report from the Single Topic conference of portal hypertension sponsored by the
AASLD[365] stated that a platelet count of 140,000/mm
3
correlated with the pres-
ence of varices hence, an indication of upper endoscopy; this number has been
changed to 150,000/mm
3
in the most recent guidance [364]. However, apublished
retrospective review of data from 236 patients, 79 of whom had PBC suggested that
a platelet count of less than 200,000/mm
3
, a serum albumin concentration of less
than 4.0g/dl, or serum bilirubin greater than 1.7mg/dl predicted the presence of
esophageal varices on upper endoscopy [366]in patients with PBC, suggesting that
screening upper endoscopies may need to be done earlier in these patients than in
patients with liver disease from other etiologies. If no varices are documented at the
index endoscopy, it is recommended in the guidelines that the procedure be repeated
in2 years [364]. The management of variceal bleeding in patients with cirrhosis
secondary to PBC also follows the gastroesophageal varices and variceal hemor-
rhage in cirrhosis guidelines published by theAASLD [364]. Variceal bleeding that
does not respond to pharmacological and endoscopic therapy in patients with PBC
in the pre-cirrhotic stage poses a specic challenge, as orthotopic liver transplanta-
tion is not desirable in patients with good synthetic liver function [367]. In this
context, a transjugular intrahepatic portosystemic shunt (TIPS) or a distal splenore-
nal shunt, which does not deprive the liver of its blood supply, can betherapeutic
alternative[368]. This type of shunt was not associated with accelerated liver failure
in patients with PBC who underwent surgery to treat variceal bleeding[368].
Bleeding from esophageal varices in patients with PBC whose bilirubin was less
than 2 mg/dl had better survival than patients with advanced disease, especially
those of a certain age, who had ascites and hepatic encephalopathy, as expected
[369]. The general approach to patients with portal hypertension is described in
Chap. 15 of this book.
Hepatocellular Carcinoma
The incidence of hepatocellular carcinoma (HHC) was reported to range from 0.7 to
3.8% in patients with PBC, and more commonly in patients who did not respond to
treatment with UDCA, from a total of 375 after a median follow-up of 9.7years [370];
advanced stage was associated with an increase in the risk for HCC, with an odds
ratio of 5.8, with a condence interval of 2.34–14.38in an analysis from patients
from Italy and Spain[371]. Portal hypertension and history of blood transfusions
were identied as risk factors for the development of hepatocellular carcinoma in
patients with PBC, in a retrospective study, identifying these features as potentially
useful in developing some scoring system to develop screening guidelines
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specically for PBC[372]. For now, all cirrhotic patients should be surveyed for
HCC every 6months with a liver sonogram and alpha fetoprotein.
Hepatic Synthetic Dysfunction
Liver failure from PBC is an indication for liver transplantation. As reported in
2007, analysis from the United Network for Organ Sharing database throughout
1995 to 2006 indicated that there is a decrease in the number of liver transplants
done in the USA because of PBC, with a reported decrease by ve per year[373];
also, the indication for liver transplantation for PBC in 2008 according to the United
Network for Organ Sharing database was 5%. According to the European Liver
Transplant Registry report from 2008, liver transplantation for PBC comprised 10%
of those operations, in contrast to over 50% in the initial years of implementing this
practice. The experience from Europe is similar with a reported decrease in liver
transplantation for PBC over the years of 1988 to 2006; this is likely a reection of
the reported change in the natural history of the disease in association with UDCA
or the fact that patients are being diagnosed earlier than in the past, and, as years go
by before patients meet transplantation criteria, there will be a lag between the need
for transplant to the procedure itself. In regards to the timing for transplantation,
bilirubin is the most important prognostic factor in PBC.In a landmark publication,
it was reported that serum bilirubin over 2mg/dl 6 months apart dened the late
phase of the disease, which was characterized by a period of a rapid increase in this
marker[374]. If the serum bilirubin reached 6mg/dl, the survival time was calcu-
lated to be 25months, and if it was 10g/dl in two successive 6month periods, the
survival time was 17months. The rapidity with which the bilirubin increases was
identied as prognostic, with a rise of 2.5mg/dl/year in the patients who died [374].
The importance of serum bilirubin was conrmed in the era of UCDA[375],and it
should continue to be interpreted as an invaluable prognostic factor. In an analysis
from a group of over 500 patients who had participated in clinical trials, survival
without liver transplantation was estimated to be increased in association with nor-
malization of serum bilirubin in the group of patients that took UDCA for at least
6months, as compared to the group that took the placebo. Survival without liver
transplantation was estimated to be not signicantly different in the group that took
UDCA, and that normalized the serum bilirubin versus the group that took the pla-
cebo and that had had normal serum bilirubin at baseline. The relative risk of death
or liver transplantation was 6 for the group of patients that had taken UDCA and 5.7
for the group that had taken the placebo[375]. Various models have been developed
to predict survival and the need for liver transplantation, including that of patients
with PBC[376–378]. The Mayo Model predicts survival[379–381]. The variables
are the patient’s age, total serum bilirubin and serum albumin concentrations, pro-
thrombin time, and severity of edema. The prognostic index R is calculated by the
followingequation: R=0.871×log e (bilirubin[mg/dl]−2.53×log e (albumin[g/
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dl]) + 0.039× age (years)+ 2.38 × log e (prothrombin time[s]) +0.859 edema
(0=no edema, no diuretic therapy, 0.5=edema, no diuretic therapy or no edema,
diuretic therapy; 1 = edema and diuretic therapy); the application of this model
predicted survival intra and extramurally from the developing institution[379–381].
The initial experience with the Mayo Model suggested that the risk of death after
liver transplantation was high when the score reached 7.8 and suggested this num-
ber to be the optimal time for the operation. In association with the development of
the Mayo score, patients were transplanted at an earlier stage than prior to the avail-
ability of the model; post transplantation, the probability of survival was 93, 90, and
88 percentages at 1, 2, and 5 years. At present, the Model for End Stage Liver
Disease (MELD) score is used to determine priority for liver transplantation, includ-
ing patients with PBC[382, 383]. A MELD score of 15 is an indication for referral
to liver transplantation; however, the referral can be made when the score is greater
than 10 to allow for relationships to develop with the transplant team. For PBC, in
general, recommendations to refer to liver transplantation are[383]:
1. plasma bilirubin concentration is greater than 5mg/dL and is increasing
2. the serum albumin concentration is below 2.8g/dL (28g/L) and is decreasing
3. signs of decompensation or portal hypertension develop, such as ascites, variceal
bleeding, coagulopathy malnutrition, or encephalopathy
4. the patient has intractable pruritus
5. the patient has recurrent, debilitating, nontraumatic bone fractures
Survival after liver transplantation for PBC has been reported to be 88% at 5years
in a large center from the USA [384] and 80% from a comparable large experience
in England [385]. Death after liver transplantation was reported to be 25.5%; 60%
of patients died within 6months from sepsis and multisystem organ failure [385].
The number of liver transplantations for PBC has declined over the past 30years,
with the proportion of liver transplantations signicantly decreasing from 20% in
1986 to 4% in 2015 from a study conducted in Europe [383].
Acute rejection occurs in 46% to 50% of patients with PBC post liver transplan-
tation; it usually responds to immunosuppression. Chronic rejection has been
reported to occur in 2–9% of patients, being more common when cyclosporine was
used instead of tacrolimus[386].
Liver transplantation is associated with signicant improvement in the quality of
life in patients with PBC, although aspects of physical activity remain impaired as
compared to control subjects[387].
PBC recurs in the graft at a reported rate from 9% to 35%[388, 389]. The diag-
nosis is made by histology, as AMA persist in the serum after transplantation, and
liver prole may not be normal after liver transplantation, making it difcult to use
the criteria for probable disease [2]. HLA mismatches do not seem to be associated
with recurrence [390]. The use of cyclosporine and azathioprine has been reported
to be associated with protection from recurrence of disease in the graft [391].
Disease recurrence has been reported to increase in association with a graft with
brosis and fat[392]. The natural history of recurrent PBC seems to be character-
ized by slow progression and infrequent loss of graft[391].
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In summary, PBC is a rare disease; however, clinicians evaluating patients with
a liver prole suggestive of cholestasis must generate a liver disease workup to
exclude this disease, to identify it early. The treatment of PBC is UDCA, and
obeticholic acid as an added treatment, in patients who have not responded opti-
mally to the former, if the patient has compensated disease; however, other options
must be explored as there is no cure for the disease. The frequency of follow- up
depends on the severity of the disease. Referral for liver transplantation when the
bilirubin is 2mg/dl on two occasions, 6months apart, is a good practice. A MELD
score of 15 is an indication for referral to liver transplantation.
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