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

1. PBC Case Closed: First-Line Treatment and Monitoring
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Case Closed: Improving Treatment Outcomes for Patients with Primary Biliary
Cholangitis
Module 1: First-Line Treatment and Monitoring
Welcome to Case Closed: Improving Treatment Outcomes for Patients with Primary
Biliary Cholangitis. I'm honored to be the chair of this program. My name is Kris Kowdley,
I'm a Professor at Elson S. Floyd College of Medicine, Washington State University. Here
are my disclosures. Here are the learning objectives for this program: after participating
in all four modules, learners will be able to assess current PBC treatment guidelines,
apply guideline recommended treatment strategies in patients with PBC, and evaluate
efficacy and safety data of emerging therapies for PBC.
So now let's begin with First-Line Treatment and Monitoring, PBC Case Closed: Case 1.
The patient is a 35-year-old Mexican American woman who presents with dry eyes, dry
mouth, and pruritus. A physical exam shows xanthelasmas, and laboratory tests are
remarkable for an alkaline phosphatase of 500 units per liter, an AST of 80 units per liter,
ALT 95 units per liter, and a serum albumin that is normal at 4.0. Total bilirubin is 1.1 and
direct bilirubin is 0.3. Prothrombin time is normal with an INR of 0.9 seconds. The patient
has a workup that shows an abdominal ultrasound with a heterogeneous-appearing
liver, a normal size spleen, no ascites, and no dilated bile ducts. Additional workup
shows a positive antimitochondrial antibody at high titer and a positive antinuclear
antibody at low titer at 1:40.
So here's our first poll question. Which of the following is the next appropriate test for this
patient? Choices are A, liver biopsy, B, CT scan of the abdomen, C, transient
elastography, D, EGD, and E, DEXA scan. Please pick your choice now.
The correct answer is transient elastography. This patient has features that suggest more
advanced disease with the borderline upper limit of normal for bilirubin, very high
alkaline phosphatase levels, and likely a high cholesterol due to the presence of
xanthelasmas. Therefore, the next step is to perform staging of the liver disease since
the diagnosis of PBC is confirmed by the cholestatic pattern of elevated liver tests and
the positive antimitochondrial antibody.
Given the positive antimitochondrial antibody allowing us to confirm the diagnosis of
PBC, transient elastography can be used to stage the liver disease and liver biopsy is
not needed. Liver biopsy would only be needed if the antimitochondrial antibody is
negative or if there are features of another liver disease, such as nonalcoholic
steatohepatitis or autoimmune hepatitis. If the elastography suggests a high number in
liver stiffness suggesting cirrhosis, the patient should then begin cancer surveillance for
hepatocellular carcinoma with ultrasound and alpha fetoprotein testing every six
months.
Fibrosis surveillance is appropriate for patients at all stages of PBC. A staging should be
initially done at baseline and can be done using a combination of imaging based
modalities such as MR elastography or transient elastography, and may require a
biopsy in some cases. But in clinical practice, biopsy is generally not needed. Non-

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invasive discrimination of early and advanced stage disease should be based on
biochemical parameters such as normal versus abnormal albumin and bilirubin. Several
prognostic models are now available for staging the disease and predicting outcomes,
and a common one is the Global PBC Study Group calculation using the GLOBE-PBC
score after one year of UDCA therapy. This requires measuring bilirubin and alkaline
phosphatase at baseline and as part of routine testing. And it is now clear from more
recent data that bilirubin levels at 0.6 times upper limit of normal or elevated alkaline
phosphatase at any level have important prognostic implications with regard to liver
transplant and long-term survival.
A variety of different types of imaging-based tests are also available to predict clinical
outcomes or decompensation of liver disease. These include transient elastography if it
shows a stiffness greater than 10 kilopascals; VCTE, which can be done by vibration-
controlled transient elastography; or by shear wave elastography using ultrasound also
showing an elevation level of greater than 10 kilopascals would suggest higher fibrosis
stage, and MR elastography would suggest advanced stage if the reading is greater
than 4.3 kilopascals.
What is the appropriate initial management for this patient? Ursodeoxycholic acid at a
dose of 13 to 15 milligrams per kilogram per day, ursodeoxycholic acid at a dose of 20
to 25 milligrams per kilogram per day, budesonide at nine milligrams per day,
obeticholic acid at a dose of 10 milligrams per day, or azathioprine at a dose of 50
milligrams per day. Please choose your answer now.
The correct answer is A, ursodeoxycholic acid at a dose of 13 to 15 milligrams per
kilogram per day. The appropriate initial management of a newly diagnosed patient
with PBC based on practice guidelines is ursodeoxycholic acid starting at a dose of a
weight-based 13 to 15 milligrams per kilogram per day.
Module 2: Second-Line Treatment
Let's now talk about second-line treatment, case 2. My name is Kris Kowdley from the
Elson S. Floyd College of Medicine at Washington State University and Liver Institute
Northwest in Seattle, Washington.
This case involves a 55-year-old woman with a history of primary biliary cholangitis and
known stage F2/F3 fibrosis who is referred for further management. The patient was
diagnosed with PBC five years ago and has been on weight-based UDCA 15 milligrams
per kilogram per day. She has typical PBC symptoms, including fatigue, which
fortunately is reported as mild, and intermittent mild pruritus. Review of laboratory tests
show alkaline phosphatase of 240 units per liter, AST of 50, and ALT of 65. All are
elevated, but the alkaline phosphatase is elevated out of proportion to the liver
enzymes or aminotransferases. Serum albumin and bilirubin are normal at 4.0 and 0.8
milligrams per deciliter, respectively.
Here's our first poll question for second-line treatment. Which of the following statements
is correct? The patient needs no additional second line treatment; the patient should
be started on obeticholic acid at a dose of 25 milligrams per kilogram per day; the

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patient should be referred for liver transplant evaluation; the patient should be started
on obeticholic acid at a dose of 5 milligrams per day; or the patient should be started
on bezafibrate at 400 milligrams per day. Please make your choices now.
The correct answer is D. The patient should be started on obeticholic acid at a dose of
5 milligrams per day. This is the recommended starting dose of obeticholic acid for
second-line treatment in PBC or in patients who are UDCA intolerant. The patient meets
criteria for second line treatment given that the alkaline phosphatase is greater than
twice the upper limit of normal. The appropriate second-line treatment for PBC is
obeticholic acid starting at a dose of 5 milligrams per day and can be titrated up to 10
milligrams per day based on tolerability and response. Higher doses of obeticholic acid
are not studied in PBC and not approved for treatment of PBC. An alternate second-
line treatment would be fenofibrate since bezafibrate is not available in the US.
Here are the recommendations for OCA use in primary biliary cholangitis. The POISE
clinical trial was the phase 3 trial that led to approval of obeticholic acid as second-line
treatment for PBC. The primary end point of the POISE trial was an alkaline phosphatase
less than 1.67 times upper limit of normal with a reduction of at least 15% from baseline
at 12 months and bilirubin less than upper limit of normal at 12 months. Indications
include an incomplete biochemical response to UDCA or intolerance to UDCA. The
starting dose should be 5 milligrams once a day. If adequate response is not achieved
with 5 milligrams per day and obeticholic acid is well tolerated, an increase to 10
milligrams per day after three months is appropriate.
Contraindications to use of obeticholic acid in PBC include Child-Pugh class B or C
cirrhosis, patients with decompensated liver disease, a prior decompensation event or
evidence of clinically significant portal hypertension, such as thrombocytopenia with
splenomegaly or esophageal varices. Obeticholic acid should not be used in these
patients. Caution is advised in the presence of synthetic dysfunction, such as low
albumin, coagulopathy, or hyperbilirubinemia. Although in isolation these findings do
not constitute contraindications to OCA, worsening or new development while on
therapy should prompt discontinuation of the medication. Suggested monitoring
schedule includes laboratory tests every three months, including complete blood
count, prothrombin time/INR, and liver function panel. Transient elastography or some
other staging modality annually is appropriate in patients with advanced fibrosis to
detect clinically significant portal hypertension and liver and spleen stiffness, which is
now available, may be useful.
Here's our poll question for second-line treatment. 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; and E, 36 months? Please make your selection now.
The correct answer is C, 6 months. Although the practice guidelines have historically
suggested that response to UDCA should be assessed after 12 months of treatment, a
recent study suggests that an on-treatment response after 6 months of UDCA therapy
can predict which patients are unlikely to meet biochemical response criteria after one
year. Consequently, 6 months can also be used as a time point to determine whether

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second line treatment is required. And of the choices given for this question, 6 months
was the most suitable answer.
Module 3: Reducing Symptom Burden
Our next cases are focused on reducing symptom burden in PBC. My name is Kris
Kowdley from Liver Institute Northwest and Elson S. Floyd College of Medicine,
Washington State University, Seattle, Washington.
Here's our case study 3a: a 37-year-old woman with a history of PBC establishes care as
a new patient. She reports she has had moderate to severe pruritus for at least five
years. She has been prescribed cholestyramine, which she did not tolerate due to
cramps and constipation. She has attempted both over the counter as well as
prescription antihistamines, which have exacerbated chronic dry eyes, dry mouth, and
worsening fatigue. 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. She has attempted topical therapies as well
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.
So here's our poll. Which of the following therapies have been recommended as
possible treatment options for pruritus as associated with PBC in the outpatient setting?
A, Naloxone, B, Naltrexone, C, Topical corticosteroids, D, Systemic corticosteroids, and
E, H2 receptor antagonists. Please make your selections now.
The correct answer here is B Naltrexone. Only naltrexone has been recommended as a
possible therapy for pruritus associated with PBC, and opiate antagonists have shown
some rationale for mitigating the symptoms of pruritus. Naltrexone can be given orally.
Naloxone is a short-acting opiate antagonist, which is administered intravenously or can
be given subcutaneously or intramuscular. And this is used predominantly to reverse
overdose from opiates. Oral opiate antagonists such as naltrexone or nalmefene are
listed as third-line therapy and they can reduce the sensation of itching and can be
quite effective for some patients. Naltrexone should be started at a low dose to avoid
opiate withdrawal like symptoms in the first few days of treatment, and long-term use
may be limited by altered pain threshold or opiate withdrawal symptoms.
And here's our case study 3b: a 45-year-old woman with PBC is in the clinic for follow-
up. She's very worried about her prognosis given that she has progressive and fairly
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.
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.
She's concerned that her worsening fatigue is the sign of cirrhosis and progressive liver
disease.
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 day daytime

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sleepiness. D, serotonin neurotransmitter pathways may be involved. And E, intractable
fatigue is an indication for liver transplantation. Please make your choices now.
The correct answer is B, hypothyroidism, anemia, or sleep disturbances may exacerbate
fatigue. Hypothyroidism in particular is very important to look for in assessing fatigue in a
patient with PBC since 30% to 40% of patients with PBC also have hypothyroidism, and
this obviously could be an important confounder in the symptom of fatigue. Sometimes
anemia may play a role and sleep disorders may also exacerbate fatigue in PBC and
should be explored and treated appropriately. Fatigue and PBC have been linked to
altered neurotransmitter pathways. However, treatment with SSRIs has not shown
obvious benefit, and that's why that choice was not correct. Fatigue is also unrelated to
severity of histologic disease. It is often associated with daytime sleepiness, but not an
indication for liver transplantation since fatigue may persist after liver transplantation.
This slide reviews the symptoms and manifestations of PBC. So fatigue and pruritus are
the symptoms that are directly associated with PBC and frequently present. Patients
may also have symptoms related to hepatic manifestations or complications of liver
disease, such as complications from portal hypertension, including esophageal varices,
hepatic encephalopathy from systemic shunting, and in patients with cirrhosis, there is
always an increased risk of hepatocellular carcinoma.
Several other hepatic manifestations may accompany PBC due to the concomitant
autoimmune disorders. Keratoconjunctivitis sicca or sicca syndrome is present in 40% of
patients with PBC. Thyroid disorders, as we have mentioned, are also commonly
associated with PBC. Systemic sclerosis may be seen in some patients. Hyperlipidemia is
very commonly seen in PBC and hallmark of the hyperlipidemia of PBC is often
associated with very high HDL levels and therefore not necessarily associated with an
atherogenic profile. Metabolic bone disease may be common, and particularly in post-
menopausal women. Osteoporosis and accelerated osteoporosis can sometimes be a
concern and this should be monitored and evaluated, particularly in the older patient.
Fat-soluble vitamin deficiency can be seen, and in one study we published many years
ago, 25% of patients with PBC were found to be deficient in vitamin K. Other
concomitant autoimmune conditions such as Raynaud, et cetera, may also lead to
symptoms of those diseases.
In addition, a whole range of other symptoms have been reported by PBC patients and
we need to take those symptoms into account and try and do what we can to mitigate
them, including restless leg syndrome, cognitive impairment—sometimes called brain
fog by patients, not necessarily related to hepatic encephalopathy—bone and joint
pain, impaired quality of life due to fatigue, cognitive symptoms. And these may lead
to social and emotional dysfunction and particularly social isolation, which can
exacerbate many of these symptoms and lead to depression and sleep disturbances.
So a holistic, comprehensive approach is necessary in allowing our PBC patients to
achieve the maximum quality of life that they can, given the condition they have.
Module 4: Emerging Data

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Let's move on and talk about emerging data, and our next case will focus on new
therapies. My name is Kris Kowdley. I'm Director at Liver Institute Northwest and Professor
at Elson S. Floyd College of Medicine, Washington State University in Seattle.
This patient is a 64-year-old woman with PBC who seeks a second opinion for additional
therapeutic options. She has advanced fibrosis with stage 3 disease and has been on
ursodeoxycholic acid for 10 years. Laboratory tests show alkaline phosphatase that is
elevated at a level of 280 units per liter. Aminotransferases are also elevated with ALT
and AST of 60 and 50 respectively. Total bilirubin is 0.7 milligrams per deciliter, just above
the threshold associated with increased risk of adverse outcomes of 0.6 milligrams per
deciliter. She states that she tried obeticholic acid, but she did not tolerate it because
of pruritus.
Here's our poll. All of the following therapies have shown promise as second-line
treatment for PBC patients unresponsive to ursodeoxycholic acid except: bezafibrate,
elafibranor, seladelpar, saroglitazar, and cholestyramine.
The correct answer is cholestyramine. All the others have shown promise as potential
second-line treatment options for PBC. Bezafibrate is a fibrate with pan-PPAR activity.
This agent was originally studied in Japan and has been shown to significantly reduce
liver biochemical tests and achieve alkaline phosphatase normalization in a minority of
patients, based on the BEZURSO study. Long-term studies from Japan have suggested
that in fact, use of bezafibrate may reduce liver-related death, liver-related
complications, and possibly improve overall survival. These are from population
databases. Both elafibranor and seladelpar, which are PPAR agonists—elafibranor
targeting alpha delta and seladelpar targeting delta—have both shown promising
results in phase 2 studies and have completed phase 3 trials and results are pending.
Saroglitazar is an alpha gamma dual agonist to the PPAR and has also been studied in
a phase 2 trial with encouraging results and a phase 2b/3 trial is underway. Now,
cholestyramine, which is a bile acid binding resin and binds bile acids in the intestine
and allows them to be excreted in the stool, 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
alkaline phosphatase levels.
Here's our second poll question. Which of the following statements is true about IBAT
inhibitors in treating PBC? IBAT inhibitors are ileal bile acid transport inhibitors, and the
choices are A, they block ileal bile acid reabsorption in the terminal ileum and disrupt
the enterohepatic circulation; B, they're not effective in relieving pruritus; C, they lower
serum alkaline phosphatase levels; D, the main side effect is constipation; and E, they
are contraindicated in patients with PBC.
The correct answer is A, they block bile acid reabsorption in the terminal ileum and
disrupt enterohepatic circulation. Ileal bile acid transport inhibitors work in the terminal
ileum. They specifically target the active reabsorption site of bile acids for the
enterohepatic circulation and by blocking reabsorption, they disrupt enterohepatic
circulation, allowing bile acids to be excreted in the stool. These are being developed
as a therapy for pruritus associated with cholestasis. A phase 2 trial showed efficacy of

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linerixibat in treating PBC patients with moderate to severe pruritus, and a phase 3 trial is
currently underway.
Our conclusions and key takeaways for this program are: 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. First-line therapy is ursodeoxycholic acid at a dose of 13 to 15 milligrams per
kilogram per day. Obeticholic acid was approved in 2016 as a second-line treatment.
The AASLD practice guidelines were updated in 2021 to include fibrates as an
alternative second-line treatment for PBC for those patients with an inadequate
response to UDCA measured by the effect on serum bilirubin and alkaline phosphatase
after six months of treatment.
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. 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 symptoms of pruritus. In addition, IBAT
inhibitors are being developed to treat pruritus in PBC. It is important for clinicians to be
aware of new prognostic models that predict long-term survival in PBC, such as the
GLOPE-PBC score or the UK PBC score, and identify patients who may benefit from
second-line treatments.
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. Liver biopsy is
no longer required for diagnosis of PBC, but staging of the disease remains important.
However, transient elastography has now emerged as an important office-based tool
to classify patients into different histologic stages based on liver stiffness measurement
and is both useful for staging as well as for long-term follow-up and may predict future
clinical events.
Thank you for joining us. We are excited to see the impact of this educational activity
on patient care and PBC. In four weeks, you will receive a follow-up survey to see if
you've been able to implement any of our intended changes as a result of what you
learned. Please keep an eye out for the survey and feel free to send us an email if you
have any questions at contact@cmespark.com. Thank you for your attention.