PBC Case Closed with Kris V. Kowdley, MD https://www.mycme.com/courses/improving-treatment-for-patients-with-primary-biliary-cholangitis-8951

1. Provided by
Case Closed:
Improving Treatment Outcomes for
Patients with Primary Biliary Cholangitis
Chair
Kris V. Kowdley, MD, FACP, FACG, AGAF, FAASLD
Professor
Elson S. Floyd College of Medicine
Washington State University
Director, Liver Institute Northwest
Seattle, Washington

2. Disclosures
u Kris Kowdley, MD, FACP, FACG, AGAF, FAASLD
discloses the following commercial relationships:
Ø Consultant: 89Bio, CymaBay, Genfit, Gilead, HighTide,
Inipharm, Intercept, Madrigal, Mirum, NGM, and Pfizer
Ø Research: 89Bio, Corcept, CymaBay, Genfit, Gilead,
GSK, Hanmi, Intercept, Madrigal, Mirum, Novo Nordisk,
NGM, Pfizer, Terns, and Viking
Ø Speakers’ Bureau: AbbVie, Gilead, and Intercept
Ø Stock Options: Inipharm

3. Learning Objectives
After participating in all 4 modules, learners will be
able to:
u Assess current PBC treatment guidelines
u Apply guideline recommended treatment
strategies in patients with PBC
u Evaluate efficacy and safety data of emerging
therapies for PBC

4. First-Line Treatment and Monitoring
PBC Case Closed: Case 1

5. Case Study 1
u A 35-year-old Mexican-American woman presents with dry eyes, dry
mouth, and pruritus. Physical exam shows xanthelasmas
u Labs show:
u ALP 500 units per liter
u AST 80 units per liter
u ALT 95 units per liter
u Serum albumin is normal at 4.0
u Total bilirubin is 1.1, and direct bilirubin is 0.3
u PT is normal with an INR of 0.9 seconds
u The patient has a workup that shows an abdominal ultrasound with
the heterogeneous-appearing liver, normal size spleen, no ascites,
and no dilated bile ducts
u Additional workup shows a positive antimitochondrial antibody at
high titer; positive antinuclear antibody at 1:40
ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase; INR, international
normalized ratio; PT, prothrombin time.

6. First-Line Treatment: Poll 1
u Which of the following is the next appropriate test
for this patient?
a) Liver biopsy
b) CT scan of the abdomen
c) Transient elastography
d) EGD
e) DEXA scan
CT, computed tomography; EGD, esophagogastroduodenoscopy ; DEXA, dual X-ray absorptiometry.

7. Case 1: Poll 1 - Rationale
The correct answer is c) Transient elastography
u This patient has features that suggest more advanced disease with
the borderline upper limit bilirubin level, very high alkaline
phosphatase and likely high cholesterol due to the presence of
xanthelasma
u Therefore, the next step is to perform staging of the liver disease
since the diagnosis of PBC is confirmed
u Due to the positive antimitochondrial antibody, transient
elastography can be used to stage the liver disease
u Liver biopsy would only be needed if the AMA is negative or if there
are features of another liver disease such as NASH or autoimmune
hepatitis
u If the elastography suggests cirrhosis, the patient should begin HCC
surveillance with ultrasound and alpha fetoprotein every six months
AMA, antimitochondrial antibody; HCC, hepatocellular carcinoma; NASH, non-alcoholic steatohepatitis.
Lindor et al, 2019; Kowdley et al, 2022.

8. Staging and Predicting Outcomes in PBC
u Fibrosis surveillance for patients at all stages of PBC
Ø Staging should be done at baseline
u In clinical practice, biopsy is not needed. Non-invasive
discrimination of early- and advanced-stage disease should be
based on biochemical parameters (normal vs abnormal albumin
and bilirubin)
u Recommended for staging and predicting outcomes:
Ø GLOBE-PBC score after 1 year of UDCA therapy
Ø Serum:
v Bilirubin and ALP at baseline and as part of routine testing
v Bilirubin levels at ≤0.6 mg/dL or abnormal ALP may have important
prognostic implications re: liver transplant and survival at 1 year
Ø Imaging to predict clinical outcomes or decompensation:
v LSM by TE ≥10 kPA
v VCTE ≥10 kPA
v MRE ≥4.3 kPA
ALP, alkaline phosphatase; kPa, kilopascal; LSM, liver stiffness measurement; MRE, magnetic resonance elastography;
PBC, TE, transient elastography; ULN, upper limit of normal; VCTE, vibration-controlled transient elastography.
Kowdley et al, 2022.

9. First-Line Treatment: Poll 2
u What is the appropriate initial management for
this patient?
a) UDCA 13 to 15 mg/kg per day
b) UDCA 20 to 25 mg/kg per day
c) Budesonide 9 mg per day
d) Obeticholic acid 10 mg per day
e) Azathioprine 50 mg per day

10. Case 1: Poll 2 - Rationale
The correct answer is a) UDCA at a dose of 13 to 15 milligrams
per kilogram per day
u The appropriate initial management of a newly diagnosed
patient with PBC is UDCA at a dose of 13 to 15 mg/kg per
day
Lindor et al, 2019; Kowdley et al, 2022.

11. Second-Line Treatment
PBC Case Closed: Case 2

12. Case Study 2
u A 55-year-old woman with a history of PBC and stage
F2/F3 fibrosis is referred for management
u She was diagnosed with PBC five years ago and has
been on weight-based UDCA 15 mg/kg per day
u Her symptoms are mild fatigue and intermittent mild
pruritus
u Laboratory tests show
u ALP 240 units per liter
u AST 50 units per liter
u ALT 65 units per liter
u Serum albumin and bilirubin are normal at 4.0 and 0.8
respectively

13. Second-Line Treatment: Poll 1
u Which of the following statements is correct?
a) The patient needs no additional second line
treatment
b) The patient should be started on obeticholic
acid at a dose 25 mg/kg/day
c) The patient should be referred for liver
transplant evaluation
d) The patient should be started on obeticholic
acid at a dose of 5 mg/day
e) The patient should be started on bezafibrate at
400 mg/day

14. Case 2: Poll 1 - Rationale
The correct answer is d) The patient should be started on
obeticholic acid at a dose of 5 mg/day
u The patient meets criteria for second-line treatment given
that the alkaline phosphatase is greater than twice the
upper limit of normal
u The appropriate second line treatment for PBC is obeticholic
acid starting at a dose of 5 mg/day and can be titrated up
to 10 mg/day based on tolerability and response
u An alternate second-line treatment would be fenofibrate.
Bezafibrate is not available in the USA
Lindor et al, 2019; Kowdley et al, 2022.

15. Recommendations for OCA Use in PBC
POISE trial primary end
point
• ALP < 1.67 x ULN, with a reduction of at least 15% from baseline at 12
mo and bilirubin <ULN at 12 mo
Indications • Incomplete biochemical response to UDCA or intolerance to UDCA
Dose
• Start at 5 mg once a day
• If adequate response is not achieved with 5 mg/d and OCA is well
tolerated, increase to 10 mg/d after 3 mo
Contraindications
• Cirrhosis Child-Pugh class B or C
• Patients with PBC with decompensated cirrhosis, a previous
decompensation event, or with compensated cirrhosis who have
evidence of portal hypertension (ie, thrombocytopenia,
splenomegaly, or esophageal varices)
Caution advised
• Presence of synthetic dysfunction (eg, hypoalbuminemia,
coagulopathy, or hyperbilirubinemia)
• Although in isolation, these findings do not constitute
contraindications to OCA, worsening or new development while on
therapy should prompt drug discontinuation
Suggested monitoring
• Laboratory tests every 3 mo, including CBC, PT/INR, and hepatic
function panel
• TE annual in pts with advanced fibrosis to detect clinically significant
portal hypertension with both liver and spleen stiffness may be useful
ALP, alkaline phosphatase; CBC, complete blood count; INR, international normalized ratio; PT, prothrombin time.
Kowdley et al, 2022.

16. Second-Line Treatment: Poll 2
u What is the optimal duration after starting UDCA
to assess alkaline phosphatase response?
a) 24 months
b) 18 months
c) 6 months
d) 48 months
e) 36 months

17. Case 2: Poll 2 - Rationale
The correct answer is c) 6 months
u Although the Practice Guidelines suggest that response to
UDCA should be assessed after 12 months of treatment, a
recent study suggests that on treatment response after six
months of UDCA therapy can predict patients who are
unlikely to meet biochemical response criteria after one
year; consequently, six months can also be used as a time
point to determine whether additional treatment is required
Murillo et al, 2023; Kowdley et al, 2022.

18. Reducing Symptom Burden
PBC Case Closed: Cases 3a and 3b

19. Case Study 3a
u A 37-year-old woman with a history of PBC establishes care as a new
patient. She reports that she has had moderate to severe pruritus for
at least 5 years; she has been prescribed cholestyramine which she
did not tolerate due to cramps and constipation
u She has attempted both over the counter as well as prescription
antihistamines which have exacerbated chronic dry eyes, dry
mouth, and worsened fatigue
u She's frustrated because although her previous doctors have
focused on laboratory results and long-term prognosis, there has not
been adequate attention paid to her symptoms of pruritus
u She has also attempted topical therapies with little success. Her
local gastroenterologist suggested rifampicin, but she's concerned
about taking this medication because she heard it is toxic to the
liver

20. Symptom Burden: Poll 1
u Which of the following therapies have been
recommended as possible treatment options for
pruritus associated with PBC in the outpatient
setting?
a) Naloxone
b) Naltrexone
c) Topical corticosteroids
d) Systemic corticosteroids
e) H2 receptor antagonists

21. Symptom Burden: Poll 1 - Rationale
The correct answer is b) Naltrexone
u Only naltrexone has been recommended as a possible
therapy for pruritus associated with PBC
u Naloxone is a short acting opiate antagonist which is
administered by SQ or IV or IM injection
u Oral opiate antagonists (naltrexone and nalmefene) listed as
as third-line therapy as they can reduce the sensation of
itching
u Naltrexone should be started at a low dose to avoid opiate
withdrawal-like symptoms in the first few days of treatment.
Long-term use may be limited by altered pain threshold or
opiate-withdrawal type symptoms
IM, intramuscular; IV, intravenous; SQ, subcutaneous.
Wolfhagen et al, 1997; Terg et al, 2002; EASL, 2017.

22. Case Study 3b
u A 45-year-old woman with PBC is in the clinic for follow up
u She is very worried about her prognosis given that she has
progressive incapacitating fatigue. She states that her
fatigue gets worse over the course of the day and limits
her from performing any pleasurable or leisure activities
u She's increasingly unable to do any housework or other
chores and other than going to work in an office as a
travel agent, she has very limited energy for any other
activities
u She is concerned that her worsening fatigue is the sign of
cirrhosis and progressive liver disease

23. Symptom Burden: Poll 2
u Which of the following statements is true about
fatigue related to PBC?
a) It is correlated with severity of histologic stage
b) Hypothyroidism, anemia, or sleep disturbances
may exacerbate fatigue
c) Patients do not have excessive daytime
sleepiness
d) Serotonin-neurotransmitter pathways may be
involved
e) Intractable fatigue is an indication for liver
transplantation

24. Symptom Burden: Poll 2 - Rationale
The correct answer is b) Hypothyroidism, anemia, or sleep
disturbances may exacerbate fatigue
u Hypothyroidism anemia or sleep disorders may exacerbate
fatigue in PBC and should be explored and treated
appropriately
u Fatigue and PBC have been linked to altered
neurotransmitter pathways although treatment with SSRIs has
not shown obvious benefit
u Fatigue is also unrelated to severity of histologic disease,
often associated with daytime sleepiness, and not an
indication for liver transplantation since fatigue may persist
after liver transplantation
Kowdley et al, 2022; Sivakumar et al, 2021; EASL, 2017.

25. Symptoms and Manifestations of PBC
Extrahepatic
manifestations:
• Sicca syndrome
• Thyroid disorders
• Systemic sclerosis
• Hyperlipidemia
• Metabolic bone
disease
• Fat-soluble vitamin
deficiency
• Autoimmune
conditions (eg,
Raynaud’s,
scleroderma)
Hepatic manifestations:
• Cirrhosis and related
complications, eg:
• Esophageal
varices
• Hepatic
encephalopathy
• Hepatocellular
carcinoma
Symptoms reported
by PBC patients:
• Restless leg
syndrome
• Cognitive
impairment
• Bone and joint pain
• Impaired QoL
attributed to
fatigue, cognitive
symptoms,
social/emotional
dysfunction, sleep
disturbance, and
depression
Symptoms directly
associated with PBC:
• Fatigue
• Pruritus
Kowdley et al, 2022.

26. Emerging Data
PBC Case Closed: Case 4

27. Case Study 4
u A 64-year-old woman with PBC seeks a second opinion
for additional therapeutic options
u She has stage 3 disease and has been on UDCA for 10
years
u Her laboratory results show:
Ø ALP 280 units/liter
Ø ALT and AST are 60 and 50 units per liter, respectively
Ø Total bilirubin is 0.7 mg/dL
u She states that she tried obeticholic acid but did not
tolerate because of pruritus

28. Emerging Data: Poll 1
u All of the following therapies have shown promise
as second-line treatment for patients with PBC
unresponsive to UDCA except:
a) Bezafibrate
b) Elafibranor
c) Seladelpar
d) Saroglitazar
e) Cholestyramine

29. Emerging Data: Poll 1 - Rationale
The correct answer is e) Cholestyramine
u Bezafibrate is a fibrate with pan-PPAR activity
Ø This agent was shown in a randomized controlled trial to significantly reduce
liver biochemical tests and achieve alkaline phosphatase normalization in a
minority of patients
u Elafibranor, and seladelpar have both shown promising results in
phase 2 studies and have completed phase 3 trials and results are
pending
u Saroglitazar has also been studied in a phase 2 trial with
encouraging results and a phase 2b/3 trial is underway
u Cholestyramine is used to treat pruritus in PBC but does not have
the ability to modify the disease and has not been shown to
improve serum ALP levels
Sohal et al, 2023; Kowdley et al, 2022.

30. Emerging Data: Poll 2
u Which of the following statements is true about
IBAT inhibitors in treating PBC?
a) They block ileal bile acid reabsorption in the
terminal ileum and disrupt the enterohepatic
circulation
b) They are not effective in relieving pruritus
c) They lower serum ALP levels
d) The main side effect is constipation
e) They are contraindicated in patients with PBC

31. Emerging Data: Poll 2 - Rationale
The correct answer is a) They block ileal bile acid reabsorption
in the terminal ileum and disrupt the enterohepatic circulation
u Ileal bile acid transport inhibitors block reabsorption of bile
acids in the terminal ilium and therefore disrupt enteropathic
circulation allowing bile acids to be excreted in the stool
u They are being developed as a therapy for pruritus
associated with cholestasis
u A phase 2 trial showed efficacy of linerixibat in treating PBC
patients with moderate to severe pruritus, and a phase 3 trial
is currently underway
Levy et al, 2023.

32. Conclusion & Key Takeaways
u PBC is a chronic autoimmune liver disease characterized by immune
mediated attack to the small bile ducts within the liver. Over time,
patients may develop cirrhosis and complications of end-stage liver
disease
u First-line therapy is UDCA at a dose of 13 to 15 mg/kg per day
u Obeticholic acid was approved in 2016 as a second line treatment
u The AASLD practice guidelines were updated in 2021 to include fibrates
as an alternate second-line treatment for PBC for patients with an
inadequate response to UDCA measured by the effect on serum
bilirubin and ALP after six months of treatment

33. Conclusion & Key Takeaways (cont.)
u Several new therapies are currently in late-stage development for PBC
as second-line treatments including PPAR agonists, both fibrates as well
as specific PPAR agonists targeting alpha, delta, and gamma
receptors
u These therapies appear to lead to greater reduction in alkaline
phosphatase than with obeticholic acid and may also have favorable
effects on serum lipids and pruritus
u In addition, IBAT inhibitors are being developed to treat pruritus in PBC
u It is important for clinicians to be aware of new prognostic models that
predict long-term survival in PBC and identify patients who may benefit
from second-line treatments

34. Conclusion & Key Takeaways (cont.)
u It is also important for clinicians to focus on the symptom burden in PBC
which can be quite severe and for which there remain suboptimal
therapeutic options
u Liver biopsy is no longer required for diagnosis but staging of the
disease remains important
u Transient elastography has emerged as an important office-based tool
to stage patients based on liver stiffness measurement and is useful for
staging and long-term follow up

35. Thank You for Joining Us!
u We are excited to see the impact of this
educational activity on patient care in PBC!
u In 4 weeks, you will receive a follow-up survey to
see if you’ve been able to implement any of your
intended changes as a result of what you learned
u Keep an eye out for the survey and feel free to
send us an email if you have any questions:
contact@cmespark.com

36. References
u European Association for the Study of the Liver (2017). EASL Clinical Practice Guidelines: The diagnosis and
management of patients with primary biliary cholangitis. J Hepatol. 67(1):145-172.
DOIi:10.1016/j.jhep.2017.03.022
u Kowdley KV, Bowlus CL, Levy C, et al (2023). Application of the Latest Advances in Evidence-Based Medicine
in Primary Biliary Cholangitis. Am J Gastroenterol. 118(2):232-242. DOI:10.14309/ajg.0000000000002070
u Levy C, Kendrick S, Bowlus CL, et al (2023). GLIMMER: A Randomized Phase 2b Dose-Ranging Trial of
Linerixibat in Primary Biliary Cholangitis Patients With Pruritus. Clin Gastroenterol Hepatol. 21(7):1902-1912.e13.
DOI:10.1016/j.cgh.2022.10.032
u Lindor KD, Bowlus CL, Boyer J, et al (2019). Primary Biliary Cholangitis: 2018 Practice Guidance from the
American Association for the Study of Liver Diseases. Hepatology. 69(1):394-419. DOI:10.1002/hep.30145.
u Murillo Perez CF, Ioannou S, Hassanally I, et al (2023). Optimizing therapy in primary biliary cholangitis: Alkaline
phosphatase at six months identifies one-year non-responders and predicts survival. Liver Int. 43(7):1497-1506.
DOI:10.1111/liv.15592
u Sivakumar T & Kowdley KV (2021). Anxiety and Depression in Patients with Primary Biliary Cholangitis: Current
Insights and Impact on Quality of Life. Hepat Med. 13:83-92. DOI:10.2147/HMER.S256692
u Sohal A & Kowdley KV (2023). Primary Biliary Cholangitis: Promising Emerging Innovative Therapies and Their
Impact on GLOBE Scores. Hepat Med. 15:63-77. DOI:10.2147/HMER.S361077
Terg R, Coronel E, Sorda J, et al (2002). Efficacy and safety of oral naltrexone treatment for pruritus of
cholestasis, a crossover, double blind, placebo-controlled study. J Hepatol. 37:717–722.
u Wolfhagen FHJ, Sternieri E, Hop WCJ, et al (1997). Oral naltrexone for cholestatic pruritus-a double-blind,
placebo-controlled study. Gastroenterology. 113:1264–1269.