PBC Novel Pathways for Treatment of Cholestatic Liver Disease · pathophysiology of disease •...

TABLE OF CONTENTS

Faculty Biographies

SYMPOSIUM AGENDA

Introduction Kris V. Kowdley, MD

Diagnosis, Stratification of Risk, and Initial Treatment in PBC Gideon Hirschfield, MB Bchir FRCP PhD

Long-Term Management of Liver and Non-Liver Complications in PBC Marlyn Mayo, MD

What Are the Limitations of PBC Standard of Care and How Will Emerging Therapies Improve Patient Outcomes? Kris V. Kowdley, MD

Q&A / Conclusion

This independent CME/CE activity is supported by an educational grant from Intercept Pharmaceuticals, Inc.

At the Intersection ofKnowledge and OutcomesSince 1980

At the Intersection ofKnowledge and OutcomesSince 1980

Education Initiativein Gastroenterology Education Initiativein Gastroenterology ®

Peer Review

PBC Novel Pathways for Treatment of Cholestatic Liver Disease

Chair

Kris V. Kowdley, MD

Director Liver Care Network Swedish Medical Center Seattle, Washington

Kris V. Kowdley, MD, is the director of the Liver Care Network and Organ Care Research at Swedish Medical Center in Seattle, Washington. Dr. Kowdley received his BS in biology and anthropology as a member of the Dean’s List at Columbia University, and his medical

degree from Mount Sinai School of Medicine. He completed his internship and residency at Oregon Health and Science University and a fellowship in gastroenterology and hepatology at Tufts University School of Medicine.

Dr. Kowdley has presented his research in liver diseases at more than 135 national and international medical centers and scientific symposia. He is the author of more than 375 articles, book chapters, reviews, and commentaries in this field and has been published in Annals of Internal Medicine, Archives of Surgery, Gastroenterology, Hepatology, American Journal of Physiology, and New England Journal of Medicine, among other professional publications.


Gideon Hirschfield, MB, BChir FRCP PhD, is a clinician and academic with a special interest in hepatology, particularly autoimmune liver disease. He trained at University of Oxford followed by

University of Cambridge. He completed his clinical training in London and Cambridge. His PhD was awarded after research at the Royal Free Hospital in London. After just more than 4 years at the University of Toronto, where he developed his clinical and research focus on the genetics of autoimmune liver disease, he joined the University of Birmingham in 2012 as a senior lecturer and consultant hepatologist.

Dr. Hirschfield is well published scientifically and clinically in his field, having made important contributions to the understanding and clinical management of diseases, such as primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), autoimmune hepatitis (AIH), and nonalcoholic steatohepatitis (NASH). His papers have been published in Lancet, Gastroenterology, Clinical Liver Disease, Seminars in Liver Disease, Nature Genetics, Hepatology, New England Journal of Medicine, and other prestigious journals. As an invited lecturer, he has delivered presentations on liver diseases at numerous major national and international medical meetings. His goal is to continue to translate scientific advances into new therapies for patients with liver disease, particularly those with currently unmet needs, such as PBC, PSC, AIH, and NASH.

Faculty

Gideon Hirschfield, MB BChir FRCP PhD

Clinical Senior Lecturer University of Birmingham Honorary Consultant Hepatologist Queen Elizabeth Hospital Birmingham, United Kingdom

Marlyn Mayo, MD, received her medical degree from Baylor College of Medicine in Houston, Texas, and completed her internship and residency in internal medicine at University of California,

Irvine. She subsequently completed fellowships in gastroenterology and hepatology at the University of Texas Southwestern Medical Center in Dallas, where she is currently an associate professor in the department of Internal Medicine, Division of Digestive and Liver Diseases.

Dr. Mayo is recognized for her expertise in autoimmune liver diseases, particularly PBC. She has been the recipient of several grants from the National Institutes of Health, American Liver Foundation, and the pharmaceutical industry to study the pathophysiology of PBC and the treatment of its complications. She has published book chapters and multiple original scientific articles and review articles in journals such as Gastroenterology, Hepatology, and Clinical Liver Disease, on the subject of cholestatic liver disease and its complications.

Faculty

Marlyn Mayo, MD

Program Director Gastroenterology Fellowship Program Associate Professor Internal Medicine University of Texas Southwestern Medical Center Dallas, Texas

Faculty Biographies

Introduction

Kris V. Kowdley, MD Director, Liver Care Network

Swedish Medical Center Seattle, Washington

Primary Biliary Cirrhosis— Why It’s Important

•  Primary biliary cirrhosis (PBC) is a chronic, autoimmune, cholestatic liver disease

•  Patients with PBC are at increased risk for

–  Liver-related outcomes, including cirrhosis, liver transplantation, hepatocellular carcinoma, and death

–  Esophageal varices and variceal bleeding, osteoporosis, and a host of other extrahepatic complications

•  Quality of life is impaired by symptoms of fatigue, pruritus, and dry mouth and eyes

•  Standard-of-care therapy has limitations

Primary Biliary Cirrhosis— What’s New and Exciting

•  Increased understanding of the pathophysiology of disease

•  Identification of diagnostic markers

–  Earlier diagnosis has triggered a position paper suggesting the name be changed to “primary biliary cholangitis”1

•  Improved criteria for evaluating and assessing patient response to therapy

•  Emerging therapeutic options based on recent identification of key targets for intervention

1. AASLD. http://www.aasld.org/name-change-pbc-cholangitis-replacing-cirrhosis. Abbreviations: Gastros, gastroenterologists; Heps, hepatologists; PBC, primary biliary cirrhosis. Bodenheimer HC, et al. Presented at: 49th EASL; April 9-13, 2014; London, United Kingdom. Poster 339.

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Regarding the Effect of Untreated/Suboptimally Treated PBC on Disease

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Reasons for Suboptimal Therapy

Suggested Readings

Trivedi PJ, Corpechot C, Pares A, Hirschfield GM. Risk stratification in autoimmune cholestatic liver diseases: Opportunities for clinicians and trialists. Hepatology. 2015 Aug 20. [Epub ahead of print].

Trivedi PJ, Hirschfield GM. Review article: overlap syndromes and autoimmune liver disease. Aliment Pharmacol Ther. 2012;36:517-533.

Trivedi PJ, Hirschfield GM. Treatment of autoimmune liver disease: current and future therapeutic options. Ther Adv Chronic Dis. 2013;4:119-141.

.

Primary biliary cirrhosis (PBC) is the most common of the autoimmune liver diseases. It is best thought of as a chronic, immune-mediated, lymphocytic cholangitis. The consequence of the destructive inflammation is cholestasis with secondary liver injury from bile acids. The cause of disease is not known, but PBC is believed to arise on the background of host genetic risk to autoimmunity, alongside exposure to environmental triggers.

The majority of patients with PBC are women. In fact, 1 in 1000 women over the age of 40 years live with PBC. Although the average age at diagnosis is between 50 and 60 years, a substantial number of younger women are diagnosed with PBC. Women who present when younger than 50 years of age frequently have more treatment-resistant disease.

Inflammation in the liver is characteristically identified by elevation in liver biochemistry values, particularly, chronic elevation of serum alkaline phosphatase values. Associated symptoms of disease, when present, include pruritus and fatigue. Late-stage disease is recognized as a biliary cirrhosis and is associated with development of portal hypertension, liver cancer, and liver failure. Jaundice is a common feature of late-stage disease.

Diagnosis focuses on excluding alternate disease and identifying antimitochondrial antibodies, which are found in over 90% of patients. Patients without mitochondrial antibodies frequently have specific antinuclear antibody immunofluorescent profiles. Elevated serum immunoglobulin M values are frequently recognized in PBC. In most cases, liver biopsy is not needed to confirm a diagnosis, as the combination of cholestatic liver chemistry and antimitochondrial antibodies is very specific for PBC.

At presentation, most patients are noncirrhotic, but after approximately 10 years of disease, as many as 40% will have progressed to advanced fibrosis or cirrhosis. PBC is, therefore, not a benign lymphocytic cholangitis but rather a potentially progressive autoimmune cholestatic liver disease associated with future risk of liver failure and impaired quality of life.

Once a diagnosis is established, treatment with lifelong ursodeoxycholic acid (UDCA), given at a dose of 13 to 15mg/kg/day, should be offered to all patients. Therapy is aimed at ameliorating bile duct inflammation. It is not a cure, however; neither does it treat symptoms. Most patients tolerate UDCA, although some develop side effects that include bloating, diarrhea, weight gain, and hair thinning.

Since PBC is an autoimmune liver disease, it is recognized that a small percentage (<5%) of patients can develop features of autoimmune hepatitis. Making such diagnoses is difficult, however, because patients with PBC frequently have hepatic features, particularly symptomatic younger patients with more aggressive UDCA-resistant disease. As it is very hard to codify such “overlap” or “crossover” syndromes, most experts recommend careful attention to liver histology when doubt arises, with treatment of the predominant disease process first, and addition of immunosuppressive therapy if sufficient features exist histologically, biochemically, and serologically to justify a treatment trial.

Treatment success is based on the patient’s biochemical response to UDCA, with a variety of algorithms available to determine UDCA efficacy and subsequent risk of disease progression. All response criteria focus on improvements in liver biochemistry, and most usually look for a change after 12 months of therapy. For patients who fail to get satisfactory biochemical responses to UDCA, there is currently no second-line therapy approved by the FDA or recommended by treatment guidelines. With the potential approval, for the first time in decades, of second-line therapies for patients with PBC—such as obeticholic acid, a novel farnesoid X receptor agonist—it is important that clinicians become confident in recording the individual risk of disease progression for patients. This is most evident by documenting the biochemical response to UDCA, thereby stratifying patients’ risk of disease progression and their individual need for second-line interventions. The most sophisticated tools for stratifying risk at present include the GLOBE score (http://globalpbc.com/globe) and the UK-PBC risk score (http://www.uk-pbc.com/resources/ tools/riskcalculator/).

Diagnosis, Stratification of Risk, and Initial Treatment in PBCGideon Hirschfield, MB BChir FRCP PhD


Diagnosis, Stratification of Risk, and Initial Treatment in PBC

Gideon Hirschfield, MB BChir FRCP PhD Senior Lecturer/Honorary Consultant Hepatologist

Centre for Liver Research University of Birmingham

Birmingham, United Kingdom

Risk Stratification & Treatment Response Endpoints

Current Standard-of-Care Treatment

Outline

Patient Evaluation for PBC

PBC Diagnostic Markers

Diagnostic Considerations

Spectrum of Autoimmune Liver

Injuries1

•  Autoimmune hepatitis1

•  Primary biliary cirrhosis1

•  Primary sclerosing cholangitis1

•  IgG4-related disease2

Differential for Cholestatic Liver

Biochemistry3

•  Drug-induced liver injury •  Inherited cholestasis •  Idiopathic ductopenia •  Malignant infiltration •  Nonalcoholic fatty liver

disease •  Obstructive biliary lesion •  Primary biliary cirrhosis •  Primary sclerosing

cholangitis •  Sarcoidosis

1. Trivedi PJ, et al. Aliment Pharmacol Ther. 2012;36:517-533. 2. Joshi D, et al. Aliment Pharmacol Ther. 2014;40:1251-1261. 3. Hirschfield GM, et al. Best Pract Res Clin Gastroenterol. 2011;25:701-712.

What Are the Diagnostic Markers in PBC?

•  PBC is the most common adult autoimmune liver disease

•  The overwhelming majority of patients are women in middle age who have circulating antimitochondrial antibodies

•  Cholestasis is usually reflected as a predominant rise in alkaline phosphatase values

•  At presentation, most patients are largely asymptomatic – Over time, however, symptoms such as pruritus

and fatigue are recognized to be associated with significant impact on patient quality of life

•  Usually >45 years Age

•  Female > Male (9:1) Gender

•  AMA in ~95%; disease-specific ANA in ~30%–50%; ASMA may be present Serology

•  IgM typically elevated Immunoglobulin

•  Normal MRCP

•  Lymphocytic infiltrate; inflammatory duct lesion; granuloma may be present Liver Histology

•  Not typical Coexisting IBD

PBC Phenotype

Abbreviations: AMA, antimitochondrial antibody; ANA, antinuclear antibody; ASMA, anti-smooth-muscle antibody; IBD, inflammatory bowel disease; MRCP, magnetic resonance cholangiography; PBC, primary biliary cirrhosis. Trivedi PJ, et al. Aliment Pharmacol Ther. 2012;36:517-533.

Interpretation of AMA, ANA, and Immunoglobulin Testing in PBC

•  AMA –  Positive in >90% of patients with PBC, depending on assay1

–  In the correct context, AMA reactivity, with an elevated ALP and no significant elevation in AST, is associated with a >95% PPV of histologic PBC2

•  ANA –  2 ANA immunofluorescent patterns are specific to PBC: multiple

nuclear dots and perinuclear/rim-like membranous3 –  Automated ANA assays will likely not detect these reactivities –  Laboratories should perform immunofluorescence if ELISA-based

assays for gp210 and sp100 are not available

•  Immunoglobulins –  Elevated IgM is a sensitive but not specific characteristic of PBC1 –  Elevated IgG is primarily observed in AIH1

Abbreviations: AIH, autoimmune hepatitis; ALP, alkaline phosphatase; AMA, antimitochondrial antibody; ANA, antinuclear antibody; AST, aspartate aminotransferase; ELISA, enzyme-linked immunosorbent assay; IgG, immunoglobulin G; IgM, immunoglobulin M; PBC, primary biliary cirrhosis; PPV, positive predictive value; PSC, primary sclerosing cholangitis. 1. Trivedi PJ, et al. Aliment Pharmacol Ther. 2012;36:517-533. 2. Zein CO, et al. Clin Gastroenterol Hepatol. 2003;1:89-95. 3. Zeman MV, Hirschfield GM. Can J Gastroenterol. 2010;24:225–231.

Abbreviations: AIH, autoimmune hepatitis; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AMA, antimitochondrial antibody; ANA, antinuclear antibody; ASMA, anti-smooth-muscle antibody; AST, aspartate aminotransferase; GGT, gamma-glutamyl transferase; IgG, immunoglobulin G; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; ULN, upper limit of normal. Trivedi PJ, et al. Aliment Pharmacol Ther. 2012;36:517-533.

“Overlap” or “Crossover” Scenarios

Immunoserologic Overlap

•  Positive ANA/ASMA titers and elevated IgG in AMA-positive PBC

•  AMA-positive AIH

Biochemical Overlap

•  AST/ALT >5 x ULN in PBC or PSC

•  ALP >3 x ULN in AIH (GGT >5 x ULN in children)

Radiologic Overlap

•  Clinical features of AIH with cholangiographic abnormalities consistent with inflammatory cholangiopathy

Histologic Overlap

•  Lymphoplasmacytic infiltrate and interface hepatitis with bile-duct lesions consistent with either PBC or PSC

Also, varying combinations of the above, including temporal variations: consecutive vs sequential presentations



Outline



Take a Good History •  Symptom burden1,2

–  Pruritus –  Fatigue –  Sicca syndrome: dry eyes/mouth/vagina –  Abdominal pain –  Arthralgias –  Remember: some patients remain asymptomatic

•  Relevant medical history1

–  Autoimmunity (personal or family) –  Smoking –  Recurrent urinary tract infection –  Pruritus during pregnancy

1. Hirschfield GM, et al. Best Pract Res Clin Gastroenterol. 2011;25:701-712. 2. Trivedi PJ, et al. Aliment Pharmacol Ther. 2012;36:517-533.

Cholestatic Profile

ALP/GGT ; ALT/AST <5 x ULN

PBC? PSC?

Hepatic Profile

ALT/AST ; no significant ALP "

"

AIH?

•  Doppler ultrasound •  MRI (MRCP)

Symptoms History

•  Serum immunoglobulins

•  Autoantibodies

•  Exclusion of drug-induced liver injury

•  Exclusion of Wilson’s disease

•  Utility of liver biopsy

AILD is usually entertained after common liver disease (alcohol, viral, metabolic, drug-induced)

is excluded

Autoimmune Liver Disease—Patient Evaluation

Abbreviations: AIH, autoimmune hepatitis; AILD, autoimmune liver disease; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transferase; MRCP, magnetic resonance cholangiography; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; ULN, upper limit of normal. Graphic courtesy of Dr. Gideon Hirschfield.

Evaluation of Patients with Cholestatic Profile

PBC*

− ANA

+** Specific PBC

Non-specific

−*** MRCP

+/- liver biopsy if MRCP non-

diagnostic

+

AMA

*0.5%–1% of healthy individuals are AMA+; **>85% patients with AMA–PBC are ANA+; ***Differential is among PSC, antibody- negative PBC, and alternate ductopenic disorders. Abbreviations: AMA, antimitochondrial antibody; ANA, antinuclear antibody; MRCP, magnetic resonance cholangiography; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis. Hirschfield GM, et al. Best Pract Res Clin Gastroenterol. 2011;25:701-712.

Ultrasound; immunoglobulins; medications; thyroid; celiac screen; lipids; bone density; Sjögren’s screen



Outline



Treatment of PBC

•  Present treatment is restricted to ursodeoxycholic acid at a dose of 13−15 mg/kg/day1

•  Second-line therapies are expected soon – For example, obeticholic acid is a farnesoid X

receptor agonist that has been studied in phase II and III studies2-4

1. Lindor KD, et al. Hepatology. 2009;50:291-308. 2. Kowdley KV, et al. J Hepatol. 2011;54:S13. 3. Hirschfield GM, et al. Gastroenterology. 2015;148:751-761. 4. Nevens F, et al. J Hepatol. 2014;60(suppl):S525-S526.



Outline



PBC is heterogeneous and the risk of progression differs

among patients

What Are Appropriate Baseline Factors and Treatment Endpoints to Assess Risk of Progression in PBC?

•  High confidence and applicability –  Baseline and on-treatment ALP, bilirubin –  Baseline and on-treatment AST/platelet ratio –  On-treatment biochemical response criteria

•  Moderate confidence and applicability –  Presenting age –  Baseline disease-specific ANA –  Baseline and on-treatment transient elastography –  Baseline and on-treatment ELF score

•  Indeterminate confidence and applicability –  Gender and baseline symptom profile –  Baseline and on-treatment novel histologic scores –  On-treatment direct portal pressure measurement

Abbreviations: ALP, alkaline phosphatase; ANA, antinuclear antibody; AST, aspartate aminotransferase; ELF, enhanced liver fibrosis; PBC, primary biliary cirrhosis. Trivedi PJ, et al. Hepatology. 2015 Aug 20. [Epub ahead of print]

Abbreviations: ALP, alkaline phosphatase; AST, aspartate aminotransferase; UDCA, ursodeoxycholic acid; ULN, upper limit of normal. 1. Parés A, et al. Gastroenterology. 2006;130:715-720. 2. Corpechot C, et al. Hepatology. 2008;48:871-877. 3. Kuiper EM, et al. Gastroenterology. 2009;136:1281-1287. 4. Kumagi T, et al. Am J Gastroenterol. 2010;105:2186-2194.

ALP decreased by >40% from baseline or normalized after 1 year UDCA

Barcelona1 (2006)

Established Response Criteria Models

All 3 of the following: ALP ≤3 x ULN; AST ≤2 x ULN; and bilirubin ≤1 mg/dL after 1 year UDCA

Paris-I2 (2008)

Albumin and bilirubin normalization when 1 or both were abnormal at baseline; albumin OR bilirubin normalization when both were abnormal at baseline after 1 year UDCA

Rotterdam3 (2009)

ALP <1.67 x ULN after 2 years UDCA Toronto4 (2010)

Abbreviations: ALP, alkaline phosphatase; AST, aspartate aminotransferase; UDCA, ursodeoxycholic acid; ULN, upper limit of normal. 1. Corpechot C. J Hepatol. 2011;55:1361-1367. 2. Zhang LN, et al. Hepatology. 2013;58:264-272.

Barcelona, Paris-I, or Toronto criteria met at 6 months UDCA

Modifications of Biochemical Response Criteria Models

All 3 of the following: ALP ≤1.5 x ULN; AST ≤1.5 x ULN; and bilirubin ≤1 mg/dL after 1 year UDCA

Paris-II1 (2011)

Early Biochemical Response2 (2013)

Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; APRI, AST/platelet ratio index; AST, aspartate aminotransferase; PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid. 1. Trivedi PJ, et al. J Hepatol. 2014;60:1249-1258. 2. Carbone M, et al. Hepatology. 2015 Jul 29. [Epub ahead of print] 3. Lammers WJ, et al. Gastroenterology. 2015 Aug 7. [Epub ahead of print]

Optimized Response Criteria Models

Biochemical response (Barcelona, Paris-I/II, or Toronto) and APRI ≤0.54 after 1 year UDCA

Biochemical + APRI1 (2014)

Prognostic index comprising baseline albumin and platelet count, plus bilirubin, ALT or AST, and ALP after 1 year UDCA

UK-PBC Risk Score2 (2015)

GLOBE Score3 (2015)

Prognostic index comprising baseline age, and bilirubin, ALP, albumin, and platelet count after 1 year UDCA

Biochemical Response + APRI— Transplant-Free Survival Risk Classification

•  Low risk –  Biochemical responder

+ APRI ≤0.54

•  Intermediate risk –  Biochemical responder

+ APRI >0.54

–  Biochemical nonresponder + APRI ≤0.54

•  High risk –  Biochemical nonresponder

+ APRI >0.54

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10-Year Actuarial Survival in Derivation Cohort with Application of

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Results were paralleled in

validation cohort

Abbreviation: APRI, AST/platelet ratio index. Trivedi PJ, et al. J Hepatol. 2014;60:1249-1258.

UK-PBC Risk Score Calculation •  Score comprising “fractional polynomial terms, baseline

survivor function at 5, 10, and 15 years, and regression coefficients for the best-fitting fractional polynomial model” –  Baseline survivor function = 0.98 at 5 years; 0.941 at 10 years;

and 0.893 at 15 years

•  Liver biochemistry values are after 12 months UDCA: ALP, ALT or AST, and BILI

•  ALB and PLT values are baseline

Abbreviations: ALB, albumin; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BILI, bilirubin; LLN, lower limit of normal; PBC, primary biliary cirrhosis; PLT, platelet; UDCA, ursodeoxycholic acid; ULN, upper limit of normal. Carbone M, et al. Hepatology. 2015 Jul 29. [Epub ahead of print]

1-baseline survival function^exp(.0287854*(ALP12xULN-1.722136304) - .0422873* (((ALTAST12xULN/10)^-1)-8.675729006) +1.4199* (ln(BILI12xULN/10)+2.709607778) -1.960303*(ALBxLLN-1.17673001)- .4161954*(PLTxLLN-1.873564875))

UK-PBC Risk Score—AUC in Validation Cohort Compared with Other Models

Response Criteria Model

5-Year 10-Year 15-Year

UK-PBC Index 0.96 0.95 0.94

Barcelona 0.56 0.61 0.61

Paris-I 0.81 0.81 0.80

Toronto 0.65 0.70 0.70

Paris-II 0.75 0.75 0.74

Abbreviations: AUC, area under the curve; PBC, primary biliary cirrhosis. Carbone M, et al. Hepatology. 2015 Jul 29. [Epub ahead of print]

UK-PBC Risk Score—Downloadable Spreadsheet Calculator

With permission from UK-PBC Risk Calculator. http://www.uk-pbc.com/resources/tools/riskcalculator/.

This tool is provided as an information resource only and is not to be used or relied upon for any diagnostic or treatment purpose.

GLOBE Score Calculation

•  Score comprising age at start of UDCA; beta coefficients of identified variables; natural logarithm transformation of BILI, ALP, ALB, and PLT after 1 year UDCA; and a baseline survival estimate

Abbreviations: ALB, albumin; ALP, alkaline phosphatase; BILI, bilirubin; LLN, lower limit of normal; NL, normal logarithm; PLT, platelet; UDCA, ursodeoxycholic acid; ULN, upper limit of normal. Lammers WJ, et al. Gastroenterology. 2015 Aug 7. [Epub ahead of print]

(0.044378 * age at start of UDCA therapy + 0.93982 * NL(BILIxULN) at 1 year)) + (0.335648 * NL(ALPxULN at 1 year)) – 2.266708 * ALBxLLN at 1 year – 0.002581 * PLT at 1 year) + 1.216865

Predictive Significance of ALP and Bilirubin Values

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Abbreviations: ALP, alkaline phosphatase; ULN, upper limit of normal. Lammers WJ, et al. Gastroenterology. 2014;147:1338-1349.

GLOBE Score—Transplant-Free Survival Threshold

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Transplant-Free Survival Rates for Patients with

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Derivation cohort. Lammers WJ, et al. Gastroenterology. 2015 Aug 7. [Epub ahead of print]

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With permission from GlobalPBC.com. http://www.globalpbc.com/globe.

PBC Follow-up Algorithm—UDCA Nonresponders at 12 Months

ALT/AST >5 x ULN?

No Yes

Woman Man Liver biopsy: assess severity

of interface hepatitis and

consider “overlap” syndrome

If cirrhotic, consider HCC

surveillance

Consider HCC surveillance

Consider earlier assessment of response for patients with phenotype associated with nonresponse: baseline LSM ≥9kPa, presenting age <50 years, or anti-gp210 positive. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; HCC, hepatocellular carcinoma; LSM, liver stiffness measurement; PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid; ULN, upper limit of normal. Trivedi PJ, et al. Hepatology. 2015 Aug 20. [Epub ahead of print]

Consider need for 2nd-line agent/clinical trials

PBC Follow-up Algorithm—UDCA Responders at 12 Months

Man

APRI >0.54 If cirrhotic,

consider HCC surveillance

Consider earlier assessment of response for patients with phenotype associated with nonresponse: baseline LSM ≥9kPa, presenting age <50 years, or anti-gp210 positive. Abbreviations: APRI, AST/platelet ratio index; HCC, hepatocellular carcinoma; LSM, liver stiffness measurement; PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid. Trivedi PJ, et al. Hepatology. 2015 Aug 20. [Epub ahead of print]

Consider need for 2nd-line agent/clinical trials

Woman

Yes No

Follow-up with goals of sustained response, nonprogressive LSM,

and symptom relief

Conclusion •  Primary biliary cirrhosis (PBC) is most common in

middle-aged women

•  Taking a good history is essential

•  Diagnosis can typically be made based on persistent cholestatic liver profile and antimitochondrial antibody positivity after other common liver diseases have been excluded

•  Ursodeoxycholic acid is the only approved PBC treatment

•  On-treatment biochemical response is the most robust endpoint by which to stratify risk of progression

•  Lack of biochemical response is associated with a high risk of progression and a poor outcome

Suggested Readings

European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol. 2009;51:237-267.

Lindor KD, Gershwin ME, Poupon R, et al. Primary biliary cirrhosis. Hepatology. 2009;50:291-308.

Trivedi PJ, Lammers WJ, van Buuren HR, et al. Stratification of hepatocellular carcinoma risk in primary biliary cirrhosis: a multicentre international study. Gut. 2015 Jan 7. [Epub ahead of print]

Ursodeoxycholic acid (UDCA) is currently the only FDA-approved therapy for primary biliary cirrhosis (PBC). However, UDCA has never been demonstrated to have a significant impact on extrahepatic symptoms of PBC, such as fatigue and pruritus. In addition, many patients will not respond biochemically to UDCA, and they are at risk for disease progression and liver-related complication of PBC, such as variceal bleeding or hepatocellular carcinoma (HCC).

Patients with PBC and cirrhosis are particularly at increased risk for developing HCC. Current guidelines recommend screening cirrhotic patients for HCC using ultrasound with or without alpha fetoprotein every 6 to 12 months. Recent data, however, indicate that older male patients, even if not cirrhotic, who do not respond biochemically to UDCA are also at risk for HCC and suggest that they also should be screened. Other cancers, such as breast cancer, appear to be no more common among PBC patients than in the general population.

Development of varices and variceal bleeding may occur in patients with PBC prior to the onset of cirrhosis. In most instances, however, variceal bleeding occurs in the setting of portal hypertension due to cirrhosis. Thus, screening for varices is recommended only in patients suspected of having cirrhosis. Management is the same as for other etiologies of cirrhosis with varices.

Osteoporosis is more common in patients with cholestatic liver diseases, including PBC, and should be actively sought through screening with bone densitometry every 2 to 3 years. Supplemental calcium and vitamin D should be administered. Recent data suggest that the best dose for calcium is 1200 mg per day and vitamin D supplements should be targeted to achieve a serum level of 33 ng/mL. Bisphosphonates, such as alendronate, have been demonstrated to be safe and to improve bone density in PBC, but studies with newer drugs are lacking.

All fat-soluble vitamins (A, D, E, and K) may have difficulty being absorbed from the intestine when bile acids are not present in sufficient quantity. Vitamin A often becomes deficient early in patients with PBC, so levels should be followed as well and replaced as needed.

Fatigue and pruritus are the two most common and most vexing symptoms of PBC. There is no proven pharmacologic therapy for fatigue in PBC. Modafinil has been used successfully in some patients, but placebo-controlled trials are needed because fatigue in other diseases often responds very well to placebo. Modafinil is also poorly tolerated in approximately half of patients.

Pruritus is characteristically intermittent but progressive. Typical features include diurnal variation in severity, exacerbation by heat, and involvement of the palms and soles. Although patients are often prescribed antihistamines by their clinicians, there are no data to support that these are effective or that histamine is involved in the pathophysiology of itch in PBC. No single therapy works for all patients. A “step-up” approach to therapy of itch is usually recommended, beginning with lifestyle modifications and bile acid binding resins, then progressing to rifampicin, naltrexone, or sertraline if itch persists. Farnesoid X receptor agonists, such as obeticholic acid, an emerging therapy for PBC, may be associated with itching, so learning to manage pruritus effectively is timely and important.

Sicca syndrome (dry eyes, dry mouth) is present in the vast majority (80%) of patients with PBC. Often overlooked by physicians, it may lead to discomfort and early caries. Therapy begins with moisture replacement, but cholinergic stimulants and immunosuppression with topical calcineurin inhibitors may be needed to control symptoms.

Lastly, a variety of extrahepatic diseases have been associated with PBC in the literature, and the practicing physician should be aware of these associations in order to recognize the symptom complexes when they arise. Common associations include thyroid disease, gallstones, renal disease, and arthritis. Some of the uncommon associations include lichen planus, ulcerative colitis, and autoimmune anemias.

Management of the patient with PBC involves attention to the myriad of associated symptoms, diseases, and complications, which are often not responsive to therapy with UDCA.

Long-Term Management of Liver and Non-Liver Complications in PBCMarlyn Mayo, MD


Long-Term Management of Liver and Non-Liver

Complications in PBC

Marlyn Mayo, MD Associate Professor

Department of Internal Medicine Digestive and Liver Diseases

University of Texas Southwestern Medical Center, Dallas, Texas

Overall Management of PBC

•  Start UDCA and assess response1

•  Determine stage of disease1 –  Institute HCC and variceal screening for cirrhotics

•  Assess and address1 –  Osteoporosis –  Fat-soluble vitamin deficiency –  Fatigue –  Pruritus –  Sicca syndrome

•  Be aware of these extrahepatic manifestations –  Common: thyroid disease, gallstones, renal disease,

arthritis –  Uncommon: lichen planus, ulcerative colitis, anemias

Abbreviations: HCC, hepatocellular carcinoma; PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid. 1. Lindor KD, et al. Hepatology. 2009;50:291-308.

Abbreviations: HCC, hepatocellular carcinoma; PBC, primary biliary cirrhosis. Liang Y, et al. Hepatology. 2012;56:1409-1417.

PBC and Cancer Risk— Meta-Analysis of 17 Studies

HCC 18.80 (10.81–26.79)

(n = 13,576)

Breast 0.90 (0.58–1.23)

(n = 5945)

Kidney 2.06 (−1.36–5.48)

(n = 3221)

Colon 1.10 (0.81–1.40)

(n = 8466)

Lung 1.10 (0.43–1.76)

(n = 3880)

Uterine 0.71 (−0.70–2.13)

(n = 2679)

Cervical 3.81 (−4.85–12.47)

(n = 420)

Prostate 0.27 (−1.25–1.79)

(n = 2679)

Surveillance for HCC in Patients with PBC

•  AASLD PBC guidelines –  Patients with cirrhosis should be screened every

6−12 months using ultrasound with (or without) alpha fetoprotein1,2

•  Beware the older male nonresponder, even if not cirrhotic!3

Abbreviations: AASLD, American Association for the Study of Liver Diseases; HCC, hepatocellular carcinoma; PBC, primary biliary cirrhosis. 1. Lindor KD, et al. Hepatology. 2009;50:291-308. 2. Bruix J, et al. Hepatology. 2010:1-35. http://www.aasld.org/sites/default/files/guideline_documents/HCCUpdate2010.pdf. 3. Trivedi PJ, et al. Gut. 2015 Jan 7. [Epub ahead of print]

Abbreviations: HCC, hepatocellular carcinoma; PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid. Trivedi PJ, et al. Gut. 2015 Jan 7. [Epub ahead of print]

Factors Associated with HCC Risk in UDCA-Treated PBC Patients—

Multivariate Analysis (N = 4565)

3.42 (P <.0001) Paris-I not fulfilled

2.41 (P <.0001) Male

1.42 (P <.0001) Thrombocytopenia (per 50 x 103/mm3 decline)

1.31 (P = .009) Age (per 10 years)

Surveillance for Varices

•  Patients with cirrhosis should be screened every 1−3 years using EGD1

–  Interval based on decompensation2

•  Varices with bleeding may occur in noncirrhotic PBC patients3

Abbreviation: EGD, esophagogastroduodenoscopy; PBC, primary biliary cirrhosis. 1. Lindor KD, et al. Hepatology. 2009;50:291-308. 2. Garcia-Tsao G, et al. Hepatology. 2007;46:922-938. 3. Vlachogiannakos J, et al. Eur J Gastroenterol Hepatol. 2009;21:701-707.

AASLD Levy et al

Angulo et al

MABPT

Criteria

Cirrhotic (stage IV)

PBC

Mayo risk score ≥4.5

and/or platelets ≤140,000

Mayo risk score ≥4

Male sex, ALB <3.5 g/dL,

BILI ≥1.2 mg/dL, and/or PT ≥12.9 sec

Sensitivity 53% 90% 93% 95%

Specificity 85% 56% 32% 47%

Abbreviations: AASLD, American Association for the Study of Liver Diseases; ALB, albumin; BILI, bilirubin; MABPT, Male sex, low ALB (<3.5 g/dL), elevated BILII level (≥1.2 mg/dL), and/or prolonged PT (≥12.9 s); PBC, primary biliary cirrhosis; PT, prothrombin time. Ali AH, et al. J Clin Gastroenterol. 2011;45:e66-e71.

Effectiveness of Screening for Esophageal Varices in Patients with Early-Stage PBC

•  Retrospective chart review of PBC patients, N = 325

•  8/127 (6%) had esophageal varices when stage I or II

*Total from diet plus supplement. Abbreviations: AASLD, American Association for the Study of Liver Diseases; DEXA, dual-energy X-ray absorptiometry; EGD, esophagogastroduodenoscopy; GERD, gastroesophageal reflux disease; PBC, primary biliary cirrhosis; WHO, World Health Organization. 1. Lindor KD, et al. Hepatology. 2009;50:291-308. 2. Cosman F, et al. Osteoporos Int. 2014;25:2359-2381. 3. Carmel AS, et al. Osteoporos Int. 2012;23:2479-2487. 4. Diab DL, et al. Ther Adv Musculoskelet Dis. 2013;5:107-111. 5. Fosamax [PI]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp.; 2015.

Surveillance for and Managing Risk of Osteoporosis in Patients with PBC

AASLD Guidelines1

DEXA every 2–3 y

Calcium 1000–1500 mg/d*

Vitamin D 1000 IU/d*

Vitamin D level yearly

Alendronate 70 mg/wk if osteopenic

Savvy Patient

Radiation?

Cardiovascular risk?

Effective? Necessary?

Jaw necrosis? Esophageal cancer?

Savvy Clinician

WHO FRAX algorithm2

Calcium 1200 mg/d*2

Vitamin D ≥33 ng/mL3

3–5 y on (or longer based on risk assessment),

1–2 y off;4 EGD if GERD5

Rate of Nonresponse to Bisphosphonate Stratified by 25-Hydroxy Vitamin D Level

•  Real-world setting, postmenopausal women with low BMD (N = 210)

•  Patients with a mean 25(OH)D ≥33 ng/mL (predetermined cutoff level) were approximately 4.5-fold more likely to achieve favorable response (P <.0001)

Abbreviation: 25(OH)D, 25-hydroxy vitamin D; BMD, bone mineral density. Carmel AS, et al. Osteoporos Int. 2012;23:2479-2487. Graphic courtesy of NIH Osteoporosis and Related Bone Diseases National Resource Center.

25(OH)D Serum Concentration

Nonresponse

<30 ng/mL 79% (52/66)

≥30 to <40 ng/mL 50% (34/68)

≥40 ng/mL 33% (25/76) Normal

Bone Osteoporotic

Bone

Surveillance for Fat-Soluble Vitamin Deficiencies in Patients with PBC

•  Decreased bile acid secretion may lead to impaired absorption of fat-soluble vitamins ADEK1

•  Monitoring guidelines –  AASLD: no specific recommendation2

–  Medicare: no more than once annually3

•  Reasonable practice: annual vitamin A, D, PT (surrogate marker for K)

•  May need to increase frequency of surveillance with new bile acid pool-lowering therapies

Abbreviations: AASLD, American Association for the Study of Liver Diseases; ADEK, vitamins A, D, E, and K; PBC, primary biliary cirrhosis; PT, prothrombin time. 1. Phillips JR, et al. Am J Gastroenterol. 2001;96:2745-2750. 2. Lindor KD, et al. Hepatology. 2009;50:291-308. 3. https://www.cms.gov/medicare-coverage-database/details/lcd-details.aspx?LCDId=29510&ContrId=269&ver=38&ContrVer=1&Date=08%2f04%2f2014&DocID=L29510&bc=AAAAAAgAAAAAAA%3d%3d&

Vitamin

Proportion of PBC Patients

with Deficiency1

(N = 180)

A 33.5%

D 13.2%

E 1.9%

K 7.8%

Fatigue in Patients with PBC •  Loss of capacity to recover from

acidosis1

•  Associated with autonomic dysfunction, loss of sleep, and cognitive impairment2

•  Role of modafinil for fatigue –  Produces significant and sustained

reduction of ESS3 –  Some patients relapse3 –  >50% of patients don’t tolerate

side effects3 •  Dizziness and GI upset are

common reasons to discontinue

–  Worsening of migraines4

Abbreviation: ESS, Epworth Sleepiness Score; GI, gastrointestinal. 1. Hollingsworth KG, et al. J Hepatol. 2010;53:155-161. 2. Griffiths L, et al. Dig Dis. 2014;32:615-625. 3. Hardy T, et al. Liver Int. 2010;30:1551-1552. 4. Ian Gan S, et al. Dig Dis Sci. 2009;54:2242-2246.

Reduction in Fatigue Score After Modafinil for 12 Weeks in Patients with PBC

Abbreviation: PBC, primary biliary cirrhosis. Silveira M, et al. Hepatology. 2011;54(4suppl):1211A-1212A.

Change from Baseline

Modafinil 200 mg (n = 20)

Placebo (n = 20)

P-Value

Fisk Fatigue Impact Score

-1.5 -3.5 0.91

Fatigue Severity Score

-13 -3 0.36

PBC-40 fatigue domain

-8 -4 0.87

Pruritus in Patients with PBC

•  Occurs early in cholestatic diseases,1 later in hepatocellular diseases

•  Localized vs generalized

–  Palms and soles

•  No primary rash1

•  Exacerbated by –  Pressure

–  Heat1

•  Circadian rhythm (worse in evenings)1,2

•  Periodic exacerbations and improvements2

1. Rishe E, et al. Acta Derm Venereol. 2008;88:34-37. 2. Mayo MJ, et al. Primary biliary cirrhosis. In: Yamada T, ed. Textbook of Gastroenterology, 4th ed. Oxford, UK: Lippincott Williams & Wilkins; 2003.

Behavioral Modifications for Pruritus in Patients with PBC

•  Loose, absorbent clothes

•  Cool (not dry) environment

•  Frequent use of cool emollients

•  Avoid pruritogenic medications (narcotics)

•  Trim nails

•  Controlled sun/ultraviolet exposure

Management of Pruritus—EASL Guidelines

Cholestyramine up to 4g x 4/d

Rifampicin 150 mg/d

Increase up to 600 mg/d EOW

Naltrexone up to 50 mg/d

Sertraline up to 100 mg/d

Consider experimental approach

Consider transplantation Abbreviation: EASL, European Association for the Study of the Liver. EASL. J Hepatol. 2009;51:237-267.

Sicca Syndrome Management—Dry Mouth

•  Professional dental cleaning every

6 months

•  Sugar-free

candies/gum

•  Rinsing with water

•  Saliva substitutes

•  Pilocarpine or cevimeline if refractory to all of the above

Lindor KD, et al. Hepatology. 2009;50:291-308. Graphic courtesy of National Institutes of Health.

Sicca Syndrome Management— Dry Eyes

•  Artificial tears

•  Pilocarpine or cevimeline if refractory to artificial tears

•  Cyclosporine eye drops if refractory to all of the above

•  Tear duct plugs

Lindor KD, et al. Hepatology. 2009;50:291-308. Graphic courtesy of National Institutes of Health.

Be Aware of Extrahepatic Associations

Bacteriuria 11%–35%

Hypothyroidism 11%–32% Graves’ disease 3%–6%

Raynaud’s 7%–14%

CREST, including esophageal dysmotility 3%–6%

Autoimmune anemias 1%–2%

Gallstones 30%–50%

Low DLC02 40%–50%

Arthropathy 4%–38% Rheumatoid arthritis 3%–26%

Lichen planus 0.5%–6% Psoriasis 1%–13%

Ulcerative colitis 0.5%–1%

Renal tubular acidosis 20%–33%

Abbreviation: DLCO2, diffusing capacity for carbon dioxide. Mayo MJ, et al. Primary biliary cirrhosis. In: Yamada T, ed. Textbook of Gastroenterology, 4th ed. Oxford, UK: Lippincott Williams & Wilkins; 2003. Human body graphic from: Lambert TS. Human Anatomy, Physiology and Hygiene. Hartford, CT: Brockett, Hutchinson & Co.;1854.

Conclusion •  Management of PBC patients requires a comprehensive

approach

•  Screening for HCC and varices in cirrhotic patients − Highest risk in men who do not respond to UDCA

•  Surveillance and management of osteoporosis

•  Surveillance and management of fat-soluble vitamin deficiencies

•  Management of pruritus and fatigue

•  Symptomatic and preventative management of sicca syndrome

•  Awareness of multiple extrahepatic associations

Suggested Readings

Hirschfield GM, Mason A, Luketic V, et al. Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology. 2015;148:751-761.

Hosonuma K, Sato K, Yamazaki Y, et al. A prospective randomized controlled study of long-term combination therapy using ursodeoxycholic acid and bezafibrate in patients with primary biliary cirrhosis and dyslipidemia. Am J Gastroenterol. 2015;110:423-431.

Luo J, Ko B, Elliott M, et al. A nontumorigenic variant of FGF19 treats cholestatic liver diseases. Sci Transl Med. 2014;6:247ra100.

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease that predominantly affects middle-aged women. The diagnosis of PBC is straightforward and can be made by the presence of a positive antimitochondrial antibody (AMA) and cholestatic liver test abnormalities in the absence of known drug-induced liver injury or biliary tract obstruction.

Several exciting, new developments have recently taken place in the diagnosis, staging, and treatment of PBC. A position paper has suggested the name of this condition should be changed to “primary biliary cholangitis,” given the fact that most patients are now diagnosed prior to the development of cirrhosis. The role of biopsy has been called into question, as prognostic models have been refined to provide useful information about the natural history of the disease and the role of biochemical response with ursodeoxycholic acid (UDCA) treatment on natural history. These models have increasingly replaced liver biopsy for the purpose of staging and predicting outcome, emphasizing instead the value of alkaline phosphatase level along with serum bilirubin in predicting complications over time.

UDCA has been the mainstay of PBC therapy for more than 20 years and has been shown to reduce the likelihood of liver disease complications and need for liver transplantation or death. While the role of UDCA as an effective therapy has continued to be debated, it is increasingly clear that a biochemical response to UDCA portends a good prognosis. Two new prognostic models—the “GLOBE Score” and the “UK-PBC Risk Score”—have further refined the model using common laboratory tests and are available for clinical practice.

Several novel agents have been studied for PBC. The furthest along in development is obeticholic acid, which has been studied in phase II and III studies, both as monotherapy and in combination with UDCA. Compared with placebo, significant reductions in serum alkaline phosphatase were shown in patients receiving obeticholic acid alone as well as in patients receiving the combination therapy. The current dose of obeticholic acid being used in phase III clinical trials has been 5 and 10 mg, although doses up to 50 mg were studied in the monotherapy studies. The main adverse effect of obeticholic acid is pruritus, which is dose-related and generally responsive to bile acid sequestrants or dose reduction. Obeticholic acid is also associated with changes in serum lipid profiles, although the clinical significance of these changes in patients with PBC is currently unclear. Long-term studies examining the safety and efficacy of obeticholic acid in PBC are underway.

Other agents under investigation for PBC include bezafibrate and fenofibrate, peroxisome proliferator-activated receptor alpha agonists, and NGM282, a fibroblast growth factor 19 agonist. A recent long-term study showed bezafibrate in addition to UDCA was more effective in lowering serum alkaline phosphatase than UDCA alone. However, renal dysfunction was a concerning adverse effect associated with the combination therapy. Fenofibrate is contraindicated in patients with hepatic or severe renal dysfunction, including PBC. Preliminary phase II findings of NGM282 monotherapy showed significant reductions in serum alkaline phosphatase and transaminases relative to placebo, with mild adverse effects.

What Are the Limitations of PBC Standard of Care and How Will Emerging Therapies Improve Patient Outcomes?Kris V. Kowdley, MD


What Are the Limitations of PBC Standard of Care and How

Will Emerging Therapies Improve Patient Outcomes?

Kris V. Kowdley, MD Director, Liver Care Network

Swedish Medical Center Seattle, Washington

Efficacy and Safety of Emerging Therapies

Targets for New Therapeutic Interventions

Outline

Management of Suboptimal Response

Limitations of Current Standard of Care

Considering Patients for Emerging Therapies

UDCA—Current Standard-of-Care PBC Therapy

•  UDCA is the only FDA-approved PBC therapy

•  Recommended adult dosage is 13−15 mg/kg/day

•  Typically administered in 2 divided doses

Abbreviations: FDA, Food and Drug Administration; PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid. Lindor KD, et al. Hepatology. 2009;50:291-308.

Effect of UDCA on Mortality and Liver Transplantation Risk

Endpoint RR (95% CI)

P-value

Death or OLT1

0.32 (0.14−0.74)

.005

OLT-free survival2

1.92 (1.30−2.82)

<.001

•  Long-term UDCA reduces death and OLT1,2

•  UDCA normalizes survival rates when given at early stages of PBC3

•  However, survival in patients with late-stage disease is reduced3

Abbreviations: OLT, orthotopic liver transplantation; PBC, primary biliary cirrhosis; RR, relative risk; UDCA, ursodeoxycholic acid. 1. Poupon RE, et al. N Engl J Med. 1994;330:1342-1347. 2. Poupon RE, et al. Gastroenterology. 1997;113:884-890. 3. Corpechot C, et al. Gastroenterology. 2005;128:297-303.


Optimized PBC Response Criteria Models



Prognostic index comprising baseline albumin and platelet count, plus bilirubin, ALT, AST, and ALP after 1 year UDCA


GLOBE Score3 (2015)


The Other Point of View—Findings from Cochrane Review

Endpoint RR (95% CI)

All-cause mortality

0.97 (0.67−1.42)

All-cause mortality or liver transplantation

0.96 (0.74−1.25)

•  Meta-analysis of 16 trials

•  No significant differences in effect between UDCA and placebo or “no intervention”

•  UDCA showed beneficial effect on liver biochemistry measures and histologic progression

Abbreviations: RR, relative risk; UDCA, ursodeoxycholic acid. Rudic JS, et al. Cochrane Database Syst Rev. 2012; DOI: 10.1002/14651858.CD000551.pub3.



Outline




Study Treatment Failure (%)

Pells et al, 20131 (UK-PBC group)

•  60% of patients presenting at age <40 years

•  10% of patients presenting at age >70 years

Corpechot et al, 20112 13%–37%*

Kuiper et al, 20093 34%–38%*

Corpechot et al, 20084 35%–39%*

Reported Incidence of UDCA Treatment Failure

*Depending on criteria used. Abbreviation: UDCA, ursodeoxycholic acid. 1. Pells G, et al. J Hepatol. 2013;59:67-73. 2. Corpechot C, et al. J Hepatol. 2011;55:1361-1367. 3. Kuiper EM, et al. Gastroenterology. 2009;136:1281-1287. 4. Corpechot C, et al. Hepatology. 2008;48:871-877.

What Can Clinicians Do Next for Patients with Suboptimal Response to UDCA?

Abbreviation: UDCA, ursodeoxycholic acid. 1. Lindor KD, et al. Hepatology. 2009;50:291-308. 2. Angulo P, et al. Am J Gastroenterol. 2001;96:3152-3157.

•  No clear, proven choices •  Query patient for adherence1

–  Barriers to adherence: weight gain, loose stools, hair loss

•  Confirm UDCA dosage 13–15 mg/kg1 –  Doubling UDCA dose has not shown benefit2

•  Check for comorbid liver disease1 •  Avoid coadministration of bile acid sequestrant1

•  Refer patient to clinical trial –  Many promising drugs being investigated



Outline




PBC Investigational Targets

FXR

PPAR-α

FGF19

Abbreviations: FGF, fibroblast growth factor; FXR, farnesoid X receptor; PBC, primary biliary cirrhosis; PPAR, peroxisome proliferator-activated receptor.

Farnesoid X Receptor Signaling

Abbreviations: BSEP, bile salt export pump; FXR, farnesoid X receptor; MRP 2/3/4, multidrug resistant protein 2/3/4; NTCP, sodium/taurocholate cotransporting polypeptide; OATP, organic anion transporting polypeptide; OST α/β, organic soluble transporter α/β. Neuschwander-Tetri BA. Curr Gastroenterol Rep. 2012;14:55-62.

Bile Acids (Primary ligands

for FXR)

↓ Bile Acid

Synthesis and

Uptake

↑ Gene Expression

(BSEP, MDR3, MRP 2/3/4, OST α/β)

↓ Gene Expression

(CYP7A1, NTCP, OATP)

FXR (Hepatocytes, biliary

epithelium, small bowel enterocytes, renal tubular cells,

adrenal cells, adipocytes, beta

cells)

Binding

Direct Effects

Indirect Effects

↑ Bile Acid

Efflux

Peroxisome Proliferator-Activated Receptor Alpha Activity

•  Regulates bile acid synthesis and detoxification

•  Modulates phospholipid secretion, which helps protect bile duct epithelium by formation of micelles

Zollner G, Trauner M. Br J Pharmacol. 2009;156:7-27.

Fibroblast Growth Factor 19 Signaling

•  Fibroblast growth factor 19 (FGF19) is an endocrine hormone that helps regulate bile acids, and carbohydrate, lipid, and energy metabolism

•  It also has a role in regulating hepatic cell proliferation –  FGF19-FGFR4 signaling is associated with hepatocellular

tumorigenesis

•  An engineered FGF19 variant has been shown to be capable of targeting the bile acid homestasis function, but not the proliferative function, by suppressing hepatic Cyp7a1 expression

Luo J, et al. Sci Transl Med. 2014;6:247ra100.



Outline




Target/Class Drug Phase

Farnesoid X receptor (FXR) agonist

Obeticholic acid

III, completed

Peroxisome proliferator-activated receptor alpha agonist

Bezafibrate III, ongoing

Fenofibrate II

Fibroblast growth factor 19 analog

NGM282 II

Drugs in Phase II/III Testing for PBC

OCA—Phase II Monotherapy and Combination Therapy Trial Designs

Placebo

OCA 10 mg

OCA 25 mg

OCA 50 mg

Baseline Follow-up

12-week double-blind

treatment

ALP x 1.5 ULN

Placebo

OCA 10 mg

OCA 50 mg

Baseline Follow-up


treatment

ALP x 1.5 ULN

OCA Monotherapy Trial1 OCA + UDCA Combination Therapy Trial2

Abbreviations: ALP, alkaline phosphatase; OCA, obeticholic acid; UDCA, ursodeoxycholic acid; ULN, upper limit of normal. 1. Kowdley KV, et al. J Hepatol. 2011;54:S13. 2. Hirschfield GM, et al. Gastroenterology. 2015;148:751-761. Graphic courtesy of Kris V. Kowdley, MD.

Primary endpoint: Percent change in serum

ALP from baseline to end of study

OCA—Phase III POISE Trial Design

Positive response: ALP <1.67 x ULN and bilirubin WNL, and ≥15% ALP reduction

M9 Screening

1−8 weeks

Continue prestudy UDCA

OCA 10 mg (n = 73)

Placebo (n = 73)

12 Months

M12 M6 W2 0

OCA 5 mg

M3

OCA 10 mg (n = 33)

Entry: ALP ≥1.67 x ULN

and/or bilirubin >ULN but <2 x ULN

Abbreviations: ALP, alkaline phosphatase; OCA, obeticholic acid; UDCA, ursodeoxycholic acid; ULN, upper limit of normal; WNL, within normal limits. With permission from Nevens F, et al. Paper presented at: 49th EASL; April 9-13, 2014; London, UK. Abstract 0168.

OCA 5 mg (n = 36)

Abbreviations: ALP, alkaline phosphatase; OCA, obeticholic acid; ULN, upper limit of normal. With permission from Nevens F, et al. Paper presented at: 49th EASL; April 9-13, 2014; London, UK. Abstract 0168.

R e s p o n d e rs (% )

0

2 0

4 0

6 0P la c e b o (n = 7 3 )

T it ra te d O C A (n = 7 0 )

1 0 m g O C A (n = 7 3 )

1 2 m o n th s6 m o n th s

*

***

Primary endpoint = Proportion of subjects achieving ALP <1.67 x ULN with bilirubin ≤ULN and ≥15% reduction in ALP

OCA—Phase III POISE Trial Primary Endpoint

*P <.0001 vs placebo

Abbreviations: LS, least squares; OCA, obeticholic acid; SE, standard error. With permission from Nevens F, et al. Paper presented at: 49th EASL; April 9-13, 2014; London, UK. Abstract 0168.

OCA—Phase III POISE Trial Change in Direct Bilirubin

*P <.05 vs placebo

OCA—Analysis of Phase II and III International Trials

•  Hepatobiliary injury1

–  Increased plasma ALP and bilirubin correlate with disease progression

–  ALP <1.67 x ULN and normal bilirubin after 1 year of UDCA predicted improved outcomes

•  This analysis evaluated the phase II monotherapy and phase II combination therapy, and phase III POISE studies for2:

–  The POISE primary composite endpoint: ALP <1.67 x ULN + ≥15% reduction and normal bilirubin, shown to correlate with survival

–  Change from baseline in ALP, bilirubin, GGT, ALT, AST

–  Safety and tolerability Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transferase; OCA, obeticholic acid; UDCA, ursodeoxycholic acid; ULN, upper limit of normal. 1. Lammers WJ, et al. Gastroenterology. 2014;147:1338-1349. 2. Kowdley K, et al. Paper presented at: DDW 2015; May 16-19, 2015; Washington, DC; Abstract 657.

OCA International Trials—Subjects Achieving Composite Endpoint

Su

bje

cts

(%)

3 months 3 months 3 months 6 months 12 months

Phase II OCA

Phase II OCA + UDCA

Phase III OCA ± UDCA

Abbreviations: ALP, alkaline phosphatase; OCA, obeticholic acid; UDCA, ursodeoxycholic acid; ULN, upper limit of normal. Kowdley K, et al. Paper presented at: DDW 2015; May 16-19, 2015; Washington, DC. Abstract 657. Graphic courtesy of Kris V. Kowdley, MD.

Primary Endpoint: Composite endpoint of ALP <1.67 x ULN, ≥15% ALP reduction, normal bilirubin

Placebo (n = 134)

OCA Titrated (n = 70)

OCA 10 mg (n = 131)

*P <.05 **P <.01 ***P <.0001

Phase II OCA

Phase II UDCA + OCA

Phase III UDCA ± OCA

AL

P C

han

ge

fro

m

Bas

elin

e (

U/N

)

3 months 3 months 3 months 6 months 12 months

Abbreviations: ALP, alkaline phosphatase; OCA, obeticholic acid; UDCA, ursodeoxycholic acid. Kowdley K, et al. Paper presented at: DDW 2015; May 16-19, 2015; Washington, DC. Abstract 657. Graphic courtesy of Kris V. Kowdley, MD.

OCA International Trials—Change in Alkaline Phosphatase

***P<.0001; values are least squares mean ± standard error

Placebo (n = 134)


OCA 10 mg (n = 131)

OCA International Trials—Changes in Serum Liver Biochemical Tests

ALT (U/L) AST (U/L)

P II OCA

P II UDCA + OCA

P III ± UDCA + OCA

Ch

ang

e fr

om

Bas

elin

e

3 mo 3 mo 3 mo 6 mo 12 mo 3 mo 3 mo 3 mo 6 mo 12 mo

*P<.05, **P<.01, ***P<.0001; values are least squares mean ± standard error. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transferase; OCA, obeticholic acid; UDCA, ursodeoxycholic acid. Kowdley K, et al. Paper presented at: DDW 2015; May 16-19, 2015; Washington, DC. Abstract 657. Graphic courtesy of Kris V. Kowdley, MD.

Placebo (n = 134)


OCA 10 mg (n = 131)

P II OCA

P II UDCA + OCA

P III ± UDCA + OCA

Phase II OCA

Phase II OCA + UDCA

Phase III OCA ± UDCA

Placebo (n = 23)

OCA 10 mg

(n = 20) Placebo (n = 38)

OCA 10 mg

(n = 38) Placebo (n = 73)

Titration OCA

(n = 70)

OCA 10 mg (n = 73)

LDL-C (mg/dL) -3.1 3.9 3.5 9.7 1.4 3.5 -1.9

HDL-C (mg/dL) -1.5 -12.7 3.5 -9.7 -3.5 -11.2 -16.6

Triglyceride (mg/dL) -1.8 -2.7 -8.9 -2.7 4.4 -5.3 -14.2

OCA International Trials—Absolute Change in Lipid Levels from Baseline

Abbreviations: C, cholesterol; HDL, high-density lipoprotein; LDL, low-density lipoprotein; OCA, obeticholic acid; UDCA, ursodeoxycholic acid. Kowdley K, et al. Paper presented at: DDW 2015; May 16-19, 2015; Washington, DC. Abstract 657. Graphic courtesy of Kris V. Kowdley, MD.

•  Treatment with OCA has been associated with increase in LDL-C and decrease in HDL-C and triglycerides

•  Clinical significance is unclear –  Absolute differences are small –  Patients had high HDL-C at baseline, typical for PBC patients

OCA International Trials—Summary of Adverse Effects

•  5 placebo patients (4%) and 8 OCA 10 mg patients (6%) reported at least 1 treatment-emergent serious adverse effect –  None in OCA 10 mg were considered drug-related

•  Pruritus was the most common adverse effect reported across all treatment groups –  Most pruritus treatment-emergent adverse effects

were mild or moderate in severity –  Uptitrating OCA dose from 5 mg−10 mg at 6 months

mitigated the incidence of pruritus and improved tolerability as assessed by patient discontinuation rate dues to pruritus: 1% in titration group vs 9% in 10-mg group

Abbreviation: OCA, obeticholic acid. Kowdley K, et al. Paper presented at: DDW 2015; May 16-19, 2015; Washington, DC. Abstract 657.

Primary endpoint: Percent change in serum ALP from baseline to end of study

OCA—5-Year Phase II Monotherapy Extension Trial

Placebo

OCA 10 mg

OCA 50 mg

Baseline


treatment

ALP x 1.5 ULN

Double-Blind Phase1

N = 59

*8 patients added UDCA during the extension phase. Abbreviations: ALP, alkaline phosphatase; OCA, obeticholic acid; UDCA, ursodeoxycholic acid; ULN, upper limit of normal. 1. Kowdley KV, et al. J Hepatol. 2011;54:S13. 2. Kowdley KV et al. Hepatology. 2015;62(1 suppl):521A.

OCA initiated at double-blind dose;

10-mg dose titrated up to 50 mg based on tolerability

and efficacy*

Open-Label Long-Term Safety Extension Phase2

N = 28

Open-ended duration Clinic visits every 3 months

OCA Monotherapy—Biochemical Reductions from Baseline Through Year 5

All Patients, Mean Reduction (SD)

n = 18

Patients with No Added UDCA, Mean

Reduction (SD) n = 11

ALP (U/L) -269 (322) P = .0025

-182 (187) P = .0009

GGT (U/L) -350 (382) P = .0012

-260 (274) P = .0104

ALT (U/L) -41 (39) P = .0003

-33 (27) P = .0021

AST (U/L) -23 (29)

P = .0033

-16 (18) P = .0178

Total Bilirubin (µmol/L)

-2 (7) P = .1708

1 (4) P = .6397

Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transferase; OCA, obeticholic acid; UDCA, ursodeoxycholic acid Kowdley KV et al. Hepatology. 2015;62(1 suppl):521A. Paper presented at: AASLD 2015; November 13–17, 2015; San Francisco, CA. Abstract 628.

OCA Monotherapy—Alkaline Phosphatase Reductions Through Year 5

Abbreviations: ALP, alkaline phosphatase; OCA, obeticholic acid; UDCA, ursodeoxycholic acid Kowdley KV et al. Hepatology. 2015;62(1 suppl):521A. Paper presented at: AASLD 2015; November 13–17, 2015; San Francisco, CA. Abstract 628. Graphic courtesy of Kris V. Kowdley, MD.

T i m e ( Y )

Ch

an

ge

in A

LP

(IU

/L)

- 6 0 0

- 4 0 0

- 2 0 0

0

1 2 3

A l l s u b j e c t s ( N = 1 8 ) N o U D C A u s e ( N = 1 1 )

4 5

AL

P C

han

ge

fro

m B

asel

ine

(U/L

)

Year ALP reduction was significant by Month 3 and

remained significant throughout treatment (P <.05).

All Patients (n = 18)

Patients with No UDCA (n = 11)

Bezafibrate + UDCA—Long-term Outcome in UDCA Nonresponders with Dyslipidemia

•  Prospective, randomized, controlled, multicenter study (N = 27)

•  Continued administration of UDCA vs bezafibrate add-on to UDCA after ≥24 weeks; therapy continued through 8 years

•  Primary endpoints –  ALP levels –  Mayo risk score –  Total bilirubin, AST, albumin

•  Other endpoints –  Overall survival –  HCC incidence –  Creatinine – safety endpoint

Abbreviations: ALP, alkaline phosphatase; AST, aspartate aminotransferase; HCC, hepatocellular carcinoma; UDCA, ursodeoxycholic acid. Hosonuma K, et al. Am J Gastroenterol. 2015;110:423-431.

•  Mayo risk score significantly lower in patients who received bezafibrate + UDCA compared with patients who received only UDCA –  0.91 vs 1.42 (P <.05)

•  Mortality rate and incidence of HCC were not significantly different between the 2 groups

•  Creatinine levels were significantly higher with combination therapy vs UDCA only –  0.94 vs 0.56 (P <.05)

•  “We should pay close attention to adverse events during this long-term combination therapy”

Bezafibrate + UDCA— Key Long-term Outcomes at 8 Years

Abbreviations: HCC, hepatocellular carcinoma; UDCA, ursodeoxycholic acid. Hosonuma K, et al. Am J Gastroenterol. 2015;110:423-431.

Fenofibrate—Phase II Findings in Patients with PBC and Incomplete Response to UDCA

•  Open-label study (n = 20)1 •  ALP levels decreased

significantly1 •  Rebound in ALP levels

occurred following fenofibrate discontinuation1

•  Fenofibrate is contraindicated in patients with hepatic or severe renal dysfunction, including PBC2

Abbreviations: ALP, alkaline phosphatase; PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid. 1. Levy C, et al. Aliment Pharmacol Ther. 2011;33:235-242. 2. Tricor [PI]. North Chicago, IL: Abbott Laboratories; 2013.

351

175

0

50

100

150

200

250

300

350

400

AL

P L

evel

U/L

Baseline

Week 48

Comparison of ALP at Baseline and On-Treatment Week 48

NGM282—Phase II Findings of Engineered Variant FGF19 in PBC

•  Double-blind, placebo-controlled trial in patients with PBC and incomplete response to UDCA (n = 45)

•  Preliminary findings –  ALP, ALT, and AST levels

decreased significantly

–  Pruritus not exacerbated

–  AEs mild; most common being headache and lower GI symptoms

Abbreviations: AE, adverse effect; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; FGF, fibroblast growth factor; GI, gastrointestinal; PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid. Globe Newswire. March 24, 2015. http://globenewswire.com/news-release/2015/03/24/718185/10126091/en/NGM-Biopharmaceuticals-Announces-Positive-Phase-2-Clinical-Data-in-Primary-Biliary-Cirrhosis-Patients-for-NGM282-a-First-in-Class-Investigational-Medicine.html.

-15.8 -19.2

-30

-20

-10

0

10

Red

uct

ion

in A

LP

Lev

el

fro

m B

asel

ine

(%)

NGM282 0.3 mg

NGM282 3.0 mg

Comparison of ALP Reduction from Baseline at On-Treatment Day 28

P = .003 vs placebo

P = .009 vs placebo

Drugs in Early Investigation for Efficacy in PBC Disease Activity

•  Prednisolone and azathioprine in combination with UDCA1

•  LJN4522

Abbreviations: PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid. 1.  Fang YQ, et al. Medicine (Baltimore). 2014;93:e104. 2. ClinicalTrials.gov. https://www.clinicaltrials.gov/ct2/show/NCT02516605.

Role of Emerging Therapies


Outline




Which Patients Should Be Considered for a Clinical Trial?

•  Patients with a partial response or no response to ursodeoxycholic acid (UDCA)

•  Patients who are intolerant of UDCA – Diarrhea, abdominal pain

– Worsening pruritus

•  Patients with evidence of progressive disease

Actions Needed to Reach the Goal of Improved Care of PBC Patients

•  Improve community, patient, and PCP awareness of the disease and its presentations

•  Improve physician awareness of the need for therapy with UDCA and assessment of response

•  Use a systematic approach to management with built-in triage for high-risk/nonresponding patients

•  Apply a systematic approach to the evaluation of second-line therapy and implementation into stratified management pathways

•  Improve awareness, assessment, and treatment of symptoms in PBC using systematic approaches

Abbreviations: PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid.

Conclusions

•  PBC is a slowly progressive disease that is associated with morbidity and mortality

•  UDCA has been a mainstay of therapy

•  Additional treatment options needed

•  Fatigue and pruritus limit health-related quality of life

•  OCA is in late-stage development

•  Other therapies are being studied

Abbreviations: OCA, obeticholic acid; PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid.

Personalizing PBC Therapy: Case-Based Panel Discussion

Faculty Panel

Patient Presentation

•  Mrs. F is a 44-year-old woman who presented to her PCP for fatigue

•  Past medical history was notable for hypothyroidism

•  Physical examination showed no spider angiomas, xantholasmas, or xanthomas

•  Liver and spleen were normal in size and there was no muscle wasting

Laboratory Evaluation

Analyte Value Reference Range

ALT 230 U/L 9–46 U/L

AST 180 U/L 10–40 U/L

ALP 440 U/L 40–125 U/L

Bilirubin, total 0.8 mg/dL 0.3–1.0 mg/dL

Albumin 4.5 g/dL 3.6–5.1 g/dL

Prothrombin time 13.2 seconds 12.0–15.5 seconds

Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Hepatology Referral •  The patient was referred to a hepatologist

•  Additional testing showed: –  ANA positive at 1:320

–  AMA positive at 1:80

–  SPEP showed a elevated gamma globulin fraction (>1.5 x ULN)

•  Liver biopsy showed: –  Florid bile duct lesions and multiple non-caseating

granulomas

–  Interface hepatitis with an intense plasma cell infiltrate

–  Portal and periportal fibrosis (Stage 2)

Abbreviations: AMA, anti-mitochondrial antibody; ANA, anti-nuclear antibody, SPEP, serum protein electrophoresis.

Diagnosis

Overlap syndrome with

primary biliary cirrhosis and autoimmune hepatitis

The diagnosis was based on a mixed pattern of both hepatocellular and

cholestatic liver enzyme elevation and liver biopsy findings

What Should We Do Next?

Initial Treatment

•  Patients who have overlap syndrome with PBC and AIH may need to be treated for both PBC and AIH

•  Budesonide 9 mg per day –  Preferred therapy for AIH in the absence of cirrhosis

•  Ursodeoxycholic acid at a dose of 13–15 mg/kg/day in 2 doses with meals –  Approved therapy for PBC

•  Re-evaluate in 3 months

Abbreviations: AIH, autoimmune hepatitis; PBC, primary biliary cirrhosis.

On-Treatment Laboratory Monitoring

•  *At 6 months the patient subsequently expressed an interest in a steroid-sparing regimen with lower cost than budesonide

•  TMPT genotyping was done and the patient was negative for “slow metabolizer” alleles

•  She was started on azathioprine at a dose of 75 mg per day (1.0 mg/kg) and 3 months later budesonide was discontinued

Analyte Value Reference

Range 3 months 6 months* 12 months

ALT 65 U/L 30 U/L 20 U/L 9–46 U/L

AST 50 U/L 27 U/L 22 U/L 10–40 U/L

ALP 175 U/L 155 U/L 124 U/L 40–125 U/L

Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Case Conclusions

•  The patient had a complete biochemical remission

•  Given the patient’s absence of cirrhosis at baseline and a complete response to treatment, she has an excellent prognosis

•  Repeat liver biopsy is not needed as long as the patient remains in a biochemical remission

•  This case demonstrates that there is a spectrum of autoimmune liver diseases that range from PBC to AIH; some patients may have an overlap syndrome

•  When overlap syndrome with PBC and AIH is present, both PBC and AIH must be treated

Abbreviations: AIH, autoimmune hepatitis; PBC, primary biliary cirrhosis.

Case 2—Patient Presentation

•  Ms. E is a 58-year-Caucasian woman who presented with fatigue and mild pruritus

•  Past medical history –  Hypothyroidism

–  Mild osteopenia •  Physical exam

–  No xanthelasmas

–  Mild hyperpigmentation

–  No ascites, jaundice

–  Hepatomegaly

Case 2—Laboratory Evaluation


ALT 92 U/L 9–46 U/L

AST 89 U/L 10–40 U/L

ALP 640 U/L 40–125 U/L




Platelet count 135,000/mm3 150,000–350,000/mm3

CBC Normal but for platelets –

ANA Negative Negative

AMA Positive; 1:640 Negative

Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AMA, antimitochondrial antibody; ANA, antinuclear antibody; AST, aspartate aminotransferase; CBC, complete blood count.

Ultrasound Findings

•  Nodular liver

•  Borderline splenomegaly

Diagnosis

Primary biliary cirrhosis

Initial Treatment

•  Ursodeoxycholic acid at a dose of 15 mg/kg/day in 2 doses with meals –  Approved therapy for PBC

•  Re-evaluate in 6 months

•  EGD for variceal screening

Abbreviations: PBC, primary biliary cirrhosis.

Case 2—On-Treatment Laboratory Evaluation at 6 Months


ALT 52 U/L 9–46 U/L

AST 50 U/L 10–40 U/L

ALP 460 U/L 40–125 U/L




Platelet count 125,000/mm3 150,000–350,000/mm3

CBC Normal but for platelets –

Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AMA, antimitochondrial antibody; ANA, antinuclear antibody; AST, aspartate aminotransferase; CBC, complete blood count.

On-Treatment Ultrasound and FibroScan Findings at 6 Months

•  Ultrasound: –  Unchanged from baseline

•  FibroScan: •  14 kPa; median interquartile range 12%

Questions

•  Should you perform liver biopsy?

•  What do you advise the patient about natural history of PBC?

•  Should you add colchicine or methotrexate?

•  Should you consider overlap syndrome?

•  Would the patient be a candidate for an OCA clinical trial?

Abbreviations: OCA, obeticholic acid; PBC, primary biliary cirrhosis.

In UDCA nonresponders, consideration should be given to include patients in

clinical trials, including OCA trials.

Conclusion

Hepatocellular

Carcinoma

Sicca/Sjögren’s Syndrome

Osteoporosis and Other

Extrahepatic Complications

Cirrhosis, Transplantation,

Liver-Related Death

Esophageal Varices/

Variceal Bleeding

Symptoms: Fatigue Pruritus

Primary Biliary Cirrhosis

Evaluation of Patients with Cholestatic Profile

PBC*

− ANA

+** Specific PBC

Non-specific

−*** MRCP

+/- Liver biopsy if MRCP non-

diagnostic

+

AMA

*0.5–1% of healthy individuals are AMA+; **>85% patients with AMA– PBC are ANA+; ***Differential rests between PSC, antibody negative PBC, and alternate ductopenic disorders. Abbreviations: AMA, antimitochondrial antibody; ANA, antinuclear antibody; MRCP, magnetic resonance cholangiography; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis. Hirschfield GM, et al. Best Pract Res Clin Gastroenterol. 2011;25:701-712.

Ultrasound; immunoglobulins; medications; thyroid; celiac screen; lipids; bone density; Sjögren’s screen


Optimized Response Criteria Models



Prognostic index comprising baseline albumin and platelet count, plus bilirubin, ALT or AST, and ALP after 1 year UDCA


GLOBE Score3 (2015)


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