Clinical Practice Guidelines

clinical practice guidelines on the management of primary biliary cholangitis
The guidelines were published in full in the July 2017 issue of the Journal of Hepatology
The full publication can be downloaded from the Clinical Practice Guidelines section of the EASL website
Please cite the published article as: EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis. J Hepatol 2017;67:145–72
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These slides are intended for use as an educational resource and should not be used in isolation to make patient management decisions. All information included should be verified before treating patients or using any therapies described in these materials

Ulrich Beuers, Christophe Corpechot, Pietro Invernizzi, David Jones, Marco Marzioni, Christoph Schramm
Reviewers
Kirsten M Boberg, Annarosa Floreani, Raoul Poupon

CPG PBC. J Hepatol 2017;67:145–72

Grading is adapted from the GRADE system1

disease
Mainly >40 years
Does not present in childhood
Global: Estimated 1 in 1,000 women over the age of 40 years old living with PBC
Europe: Estimated incidence 1–2 per 100,000 population per year
Incidence range: 0.3–5.8 per 100,000
Prevalence range: 1.9–40.2 per 100,000

essential for adequate hepatic detoxification and is integral to digestive function
PBC reflects the consequences of immune and cellular injury to biliary epithelial cells, resulting in cholestasis and progressive liver fibrosis

1)
EASL CPG PBC. J Hepatol 2017;67:145–72

Patients can progress to end-stage liver disease
Average survival (historical) among those untreated is 9–10 years
Symptoms associated with PBC impact on QoL, and include:
Pruritus
Sicca complex
Abdominal discomfort
Jaundice
Fatigue
Restless legs
Insomnia
Depression
Cognitive dysfunction

Life-long care that is
structured and
individualized
is required

Goal is to
prevent end-stage complications of liver disease and manage associated symptoms*
that reduce QoL

PBC
Stratification of risk in PBC
Defining inadequate response to treatment
Prognostic tools for PBC in practice: guidance
Treatment: therapies to slow disease progression
Special settings: pregnancy
PBC with features of autoimmune hepatitis
Management of symptoms
Management of complications of liver disease
Organisation of clinical care delivery

Click on a topic to skip to that section

approach to diagnosis of PBC is recommended

J Hepatol 2017;67:145–72

Elevated serum ALP/GGT
and/or conjugated bilirubin
(HBsAg and anti-HCV negative)

History, physical examination, abdominal US

AMA, ANA
(anti-sp100, anti-gp210)

Extended imaging
MRCP (± EUS)

Liver biopsy

Genetics

Observation/re-evaluation

No abnormalities

No abnormalities

No abnormalities

Negative and no specific drug history

DIAGNOSIS
ESTABLISHED
(with/without additional specific diagnostic measures)

Suspicion of DILI
Focal lesions; dilated bile ducts

Serum antibodies

Stenoses (sclerosing cholangitis)

Parenchymal damage
Biliary lesions

Gene mutations

be suspected in patients with persistent cholestatic serum liver tests or symptoms
Including pruritus and fatigue

2017;67:145–72

Elevated ALP is typical of PBC

Except in patients with ductopenic non-cirrhotic variant
EASL CPG PBC. J Hepatol 2017;67:145–72

Elevated ALP is typical of PBC

not generally required to diagnose PBC
Essential when:
PBC-specific antibodies are absent
Co-existent AIH or NASH is suspected
With other systemic/extrahepatic co-morbidities

2017;67:145–72

Liver biopsy is not generally required to diagnose PBC
Essential when:
PBC-specific antibodies are absent
Co-existent AIH or NASH is suspected
With other systemic/extrahepatic co-morbidities

Florid duct lesion showing a dense periductal inflammatory infiltrate associated with disruption of bile duct epithelium*

with immunoperoxidase
EASL CPG PBC. J Hepatol 2017;67:145–72

Liver biopsy is not generally required to diagnose PBC
Essential when:
PBC-specific antibodies are absent
Co-existent AIH or NASH is suspected
With other systemic/extrahepatic co-morbidities

Expanded portal tract contains arterial branches without accompanying bile ducts Marginal ductular reaction associated with loose fibrosis (biliary interface activity)* Absence of properly formed bile ducts/presence of prominent marginal ductular reaction†

2017;67:145–72

Liver biopsy is not generally required to diagnose PBC
Essential when:
PBC-specific antibodies are absent
Co-existent AIH or NASH is suspected
With other systemic/extrahepatic co-morbidities

In the presence of prominent interface hepatitis associated with ballooning, rosetting and entrapment of periportal hepatocytes, additional autoimmune hepatitis should be considered. Focal lymphocyte emperipolesis is also present*

biopsy is not generally required to diagnose PBC
Essential when:
PBC-specific antibodies are absent
Co-existent AIH or NASH is suspected
With other systemic/extrahepatic co-morbidities

Established cirrhosis with broad fibrous septa surrounding small hepatocyte nodules
Septa have narrow peripheral ‘halo zones’ of loose fibrosis characteristic of chronic biliary disease*

of recommendation 1)
EASL CPG PBC. J Hepatol 2017;67:145–72

Even when treated, PBC can remain a progressive disease
Risk of liver-related complications
Risk of death
All patients should be evaluated for their risk of developing progressive PBC*
Consequently, their potential need for additional treatments

High- and low-risk disease defined by:
Evaluation of response to first-line agent UDCA

Greatest risk of disease complications identified by:
​Age at onset
​Sex (male)
​Stage at presentation
Selected biochemical/ serological indices pre- and post-therapy with UDCA

2017;67:145–72

PBC. J Hepatol 2017;67:145–72

Treatment failure must be defined on validated surrogate endpoints
To account for the slow progression of disease
Qualitative biochemical response to UDCA assessed using binary definitions or continuous scoring

biopsy, absent or mild vs. bridging fibrosis or cirrhosis; Elastography, LSM ≤9.6 kPa vs. >9.6 kPa; Serum bilirubin and albumin, both normal vs. ≥1 elevated)
EASL CPG PBC. J Hepatol 2017;67:145–72

Prognostic tools allow:
Selection of patients for second-line therapies
Risk stratification in clinical trials to account for prognostic disparity

2017;67:145–72

Ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) approved in PBC
Heterogeneity of treatment efficacy in clinical trials may be due to:
Variable inclusion criteria without reference to disease risk or stage

of women diagnosed with PBC are of reproductive age
UDCA is safe during conception, pregnancy and post-partum according to expert clinical opinion

a diagnosis can be made in a patient with PBC with at least two of the following: 1. ALP >2x ULN or GGT >5x ULN. 2. AMA >1:40. 3. Florid bile duct lesion on histology AND two of the following three features:1. ALT >5x ULN. 2. IgG serum levels >2x ULN or smooth muscle autoantibody positive. 3. Moderate or severe interface hepatitis on histology EASL CPG PBC. J Hepatol 2017;67:145–72

~8–10% of patients with PBC have features characteristic of AIH
‘AIH−PBC overlap syndrome’, ‘hepatitic form of PBC’, or ‘PBC with secondary AIH’
With non-response to UDCA after 6−12 months additional AIH features should be investigated
Paris criteria used most commonly†

initial use (after 6 and 12 weeks) and after dose increase. Stop if hepatotoxicity observed EASL CPG PBC. J Hepatol 2017;67:145–72

Symptoms associated with PBC have a significant impact on QoL

2017;67:145–72

Osteoporosis is a common complication in PBC

J Hepatol 2017;67:145–72

Fat soluble vitamin malabsorption can occur in PBC

Serum lipids can be elevated in up to 80% of patients with PBC
Underlying mechanism is different to that of other conditions
No substantial evidence to support an elevated CV risk

J Hepatol 2017;67:145–72

Patients with PBC may develop portal hypertension as a result of biliary cirrhosis
Associated with a poor prognosis

HCC is one of the most serious complications of PBC
Incidence of HCC in those with diagnosed PBC is 0.36 per 100 person years

Hepatol 2017;67:145–72

PBC as an indication for liver transplant is declining
Despite increasing prevalence of PBC
Outcome post-liver transplant is usually favourable and better for most other liver transplant indications
5-year survival of 80−85%

of stratified therapy has increased the complexity of managing patients with PBC
Optimal care models must be flexible
Effectively manage high-risk patients/those with a high symptom burden
Avoid over-management of low-risk asymptomatic patients