Issue 01

Mentoring in IBD is an innovative and successful educational program for Canadian gastroenterologists that includes an annual national meeting, regional satellites in both official languages, www.mentoringinibd.com, an educational newsletter series, and regular electronic communications answering key clinical questions with new research. This issue is based on the presentation made by the contributing editor, Dr Gideon Hirschfield, at the annual national meeting, Mentoring in IBD XIX: The Master Class, held November 2, 2018 in Toronto, Ontario.

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Introduction

Patients living with inflammatory bowel disease (IBD) are at increased risk of co-existing liver disease. The nature and severity of the liver injury can vary substantially, but may become the major determining factor for patient outcomes. When characterizing liver disease in a patient with IBD, a systematic and logical approach to etiology, severity, and risk of progression is needed.

Primary sclerosing cholangitis (PSC) is the classic and most clinically significant hepatobiliary manifestation of IBD. This particular hepatobiliary disorder is the main focus of this review.

Recognizing the Breadth of Hepatobiliary Concerns in Patients with IBD

Hepatobiliary concerns are not rare among patients with IBD. Risk factors for liver injury are indeed quite common in this population, including: advancing age / declining renal function, alcohol consumption, obesity, diabetes, pre-existing liver disease and use of medications with potential for liver effects (e.g., methotrexate, azathioprine). Although IBD medications are generally safe, the possibility of a drug-induced hepatotoxicity should still be kept in mind.

While PSC is the classic and most clinically significant hepatobiliary manifestation of IBD, there are also others that have possible associations with IBD, including autoimmune hepatitis, primary biliary cholangitis or, rarely, IgG4 disease. These are, however, less common than PSC-IBD.(1)

Approaches to Diagnosis and Management

When evaluating hepatobiliary abnormalities in patients with IBD, one must first exclude underlying unrelated liver disease (such as non-alcoholic fatty liver disease), then evaluate the possibility of drug therapy. Tools such as transient elastography, which can evaluate disease severity at baseline and over time, can be helpful. Remember that elastography is not an absolute classifier of fibrosis or steatosis and should only be used as an adjunct to a more comprehensive assessment.

PSC-IBD: A Distinct Entity With a Separate Care Pathway

Epidemiology

In a systematic review of 31 population-based epidemiological studies, the incidence of PSC was estimated to be up to 1.3 per 100,000 population per year among patients with IBD.(2) Its prevalence was estimated to be up to 16.2 per 100,000.(2)

Impact

While relatively infrequent, PSC-IBD is a disease with substantial unmet needs related to the heightened risk of complications (e.g., liver failure, recurrent cholangitis, and malignancy of the hepatobiliary tree and colon).(3) The number of transplants for PSC has steadily increased over the past 25 years, with the median age at transplant being 49 years.(4) In patients younger than 40 years with ulcerative colitis, development of PSC is associated with a 6-fold increase in mortality, and 7-fold increased risk of colorectal cancer,(5) highlighting the profound impact of the diagnosis. Additionally, the symptom burden of PSC (e.g., pain, pruritus, fatigue) requires recognition and management.(6)

Pathophysiology

The pathophysiology of PSC is not fully understood and is thought to involve both genetic susceptibility and environmental influences.(7) A current area of research is the role of the microbiome in PSC-IBD. Researchers have demonstrated that there is a significant difference among individuals with PSC-IBD, those with IBD but no PSC, and healthy controls.(8)

Presentation

PSC-IBD has a heterogeneous presentation across all ages, ranging from mild to very severe liver effects. Progressive and chronic injury occurs in small, medium, and large bile ducts with an inflammatory and obliterative concentric periductal fibrosis that leads to biliary strictures. Cholangiocytes increase expression of adhesion molecules, which perpetuate inflammation and fibrosis. Persistent portal inflammation, bile duct destruction, and periportal fibrosis lead to loss of bile ducts, disorganised ductular proliferation, and cirrhosis.(1) Decompensated cirrhosis is typically the reason for transplant, rather than bile-duct destruction.

PSC-IBD appears to have some clinical distinctions from more classical UC; for example, the colitis can be macroscopically more right-sided, but frequently total histologically; it may be more symptomatically mild, often with rectal sparing (no rectal bleeding or inflammation) and characterised by prolonged remissions.(1) PSC-IBD is notable for its elevated colon cancer rates.(1)

Evaluation

A stratified approach to confirming the diagnosis is shown in Figure 1. Importantly, MRI-based cholangiography is a critical diagnostic tool, while endoscopic retrograde cholangiopancreatography (ERCP) is reserved for specific interventions.

The stage of liver disease (i.e. degree of fibrosis) can be estimated, beyond the use of simple blood tests, through transient elastography, enhanced liver fibrosis (ELF) testing, MR elastography and/or biopsy, while severity and risk of disease progression can be quantified by liver biochemistry.

Management

Therapies for patients with PSC-IBD remain very limited, and many patients ultimately require liver transplantation. Strategies for surveillance of the liver and bowel are important. Treatment with ursodeoxycholic acid (UDCA) does not, unfortunately, offer significant benefit. A study involving 150 adult patients with PSC compared high-dose UDCA (28-30 mg/kg/day) vs. placebo, and demonstrated improvement in serum liver tests with UDCA, but no significant impact on survival.(9) The intervention was also associated with higher rates of serious adverse events.(9)

More recently, several other treatments have been evaluated for PSC. A phase 2 study of 24-norursodeoxycholic acid (norUDCA: a homologue of UDCA) showed a dose-dependent reduction in serum alkaline phosphatase (ALP) among 160 patients with PSC, with a side effect profile comparable to placebo.(10) A phase 3 study is recruiting in Europe.

Obeticholic acid (OCA) has also been associated with some biochemical efficacy in a phase 2 study. A placebo-controlled study in 77 patients with PSC showed a statistically significant reduction in ALP vs. placebo at week 24.(11)

NGM282, an FGF19 analogue, has been studied in PSC. Its proposed mechanism is regulation of CYP7A1-mediated bile acid homeostasis.(12) In a phase 2 study of 62 patients with PSC and elevated ALP, there was no difference between NGM282 and placebo in improvement of ALP, which was the primary endpoint.(12) However, the intervention did reduce bile acids and hepatic CYP7A1 activity, as well as ELF scores and Pro-C3 (fibrosis biomarkers that predict transplant-free survival).(12).

Antibiotics may have a role to play in the treatment of PSC. A study investigating vancomycin or metronidazole among 35 patients with PSC showed that vancomycin significantly reduced ALP, while both agents improved serum bilirubin and Mayo PSC risk scores.(13) Before adoption of this approach to care however, longer term randomised controlled trials are clearly needed.

Other interventions have been less successful in PSC. A study involving 34 patients with PSC-IBD demonstrated that vedolizumab did not improve liver biochemistry.(14) However, it remained efficacious for the IBD itself and had a favourable safety profile in this population.(14) These results were mirrored by a second study involving 80 patients with PSC-IBD in which there was no significant benefit on liver biochemistry.(15)

Simtuzumab, a monoclonal antibody directed against lysyl oxidase like-2 (LOXL2), was investigated in a phase 2 study in PSC. LOXL2 is thought to play a central role in fibrogenesis and is elevated in patients with PSC.(16) However, there was no significant impact of simtuzumab on hepatic collagen content (primary endpoint), Ishak fibrosis stage, progression to cirrhosis, or frequency of clinical events.(16)

While no therapy has yet been approved for PSC, ongoing clinical trials offer hope for patients with this disease. PSC can remain relatively mild and stable (fibrosis F0-F1) for up to ten years, but there can then be rapid progression to more advanced stages (F2 to F4 fibrosis).(17) This earlier relative stability offers a window for therapy.

Opportunities for Clinical Trials

New insights into basic pathophysiology are driving early phase trials, and a dedicated PSC-IBD program at the University of Toronto is focused on delivering integrated, research-driven, trial-focused, holistic and life-long care. The key themes of this integrated care are shown in Figure 2.

Conclusions

Patients with IBD are at risk of hepatobiliary complications. PSC is the most clinically significant of these, with a highly deleterious impact on morbidity and mortality. While there remains no effective therapy for PSC, substantial research is being conducted with promising observations. Early diagnosis of PSC and referral to a centre with expertise in this area (and access to clinical trials) should be considered a priority for these patients.

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Clinical Case

Tara is a 26-year-old female with newly diagnosed Crohn’s disease (CD). Colonoscopy three weeks ago showed scattered aphthous ulceration in the right colon, and a distorted ileocecal valve with normal ileum. Her medical history includes a previous vaginal hysterectomy for fibroids, a diagnosis of Gilbert’s syndrome in her teens, and moderate obesity. Her weight is 102 kg and her examination is otherwise normal. There is no visible icterus.

Bloodwork drawn on the day of her colonoscopy shows:

• White blood cell (WBC) count: 6.4 x10⁹/L
• Hemoglobin (Hb): 109 g/L
• Mean corpuscular volume (MCV): 84.2 fL
• Platelets: 422 x10⁹/L
• C-reactive protein (CRP): 12.4 mg/L
• Alanine aminotransferase (ALT): 85 U/L
• Alkaline phosphatase: 120 U/L
• Gamma-glutamyl transpeptidase (GGT): 87 U/L
• Total bilirubin: 12 μmol/L

Commentary

Patients living with IBD are frequently at risk of co-existing liver disease—approximately 5% of adults with IBD develop chronic liver disease.(19,20)

The nature and severity of the liver injury can vary substantially in both UC and CD, but may become the major determining factor for patient outcomes.(19,21)

The most associated hepatobiliary manifestation is primary sclerosing cholangitis (PSC), particularly in UC.(19,22) Other less frequent IBD-associated hepatobiliary disorders include cholelithiasis, steatosis, hepatic amyloidosis, granulomatous hepatitis, portal vein thrombosis, liver abscess and primary biliary cirrhosis (PBC).

For IBD patients presenting with abnormal liver testing, the possibility of PSC or other liver pathologies should be considered.

Case Evolution

Her additional bloodwork reveals anti-smooth muscle antibodies and a positive ANA (titre 1/80). However, quantitative immunoglobulins are normal and there are no anti-mitochondrial antibodies. Repeat ALT has fallen to 45 U/L. Repeat GGT has fallen to 60 U/L. Ultrasound suggests moderate hepatic steatosis but is otherwise normal.

Tara is started on ileal-release budesonide 9 mg PO OD and methotrexate 25 mg SC weekly. Her bloodwork is repeated monthly. Her liver enzymes rise gradually. After six months, alkaline phosphatase has risen to 157 U/L and ALT to 65 U/L. On questioning, she acknowledges drinking two or three glasses of wine each evening.

Commentary

Methotrexate is associated with cumulative dose-dependent hepatotoxicity. It may cause steatosis, liver fibrosis and cirrhosis.(19)

In a meta-analysis of clinical trials in IBD patients, the rate of abnormal aminotransferase serum levels (defined as up to a two-fold elevation over the upper limit of the normal [ULN]) in patients treated with methotrexate was 1.4 per 100 person-months, while the incidence of hepatotoxicity (defined as greater than a two-fold over ULN) was 0.9 per 100 person-months.(19,23)

Supplementation with folic acid is recommended for patients taking methotrexate to help reduce the risk of hepatotoxicity.(19,24)

Obesity, alcohol and diabetes mellitus are considered risk factors for liver injury by methotrexate, and so, alcohol should be strictly avoided.(19,25)

At one time, liver biopsy was proposed before the initiation of methotrexate treatment and a second biopsy later (e.g., after a cumulative dose of 1.5–2g). However, this is no longer recommended, as experience (in the rheumatoid arthritis field, where methotrexate is recommended as the standard backbone disease-modifying antirheumatic drug) has taught that the rate of liver disease with chronic methotrexate treatment was too low to justify this practice routinely.(19,26)

Case Evolution

Tara agrees to stop drinking and you discontinue her methotrexate. Over the next three months her alkaline phosphatase rises to 228 U/L with ALT 102 U/L. You arrange a Magnetic Resonance Cholangiopancreatography (MRCP), which notes minor intrahepatic duct dilation in a single liver segment.

• Hb: 87 g/L
• CRP: 90 mg/L
• Albumin: 30 g/L

Commentary

As previously noted, PSC is the most common liver disease encountered in IBD.(19)

Clinical presentation is variable; most patients with PSC are asymptomatic at diagnosis. The diagnosis of PSC is a combination of biochemical profile and cholangiography.

Alkaline phosphatase (ALP) is usually elevated and is the most frequent biochemical abnormality; however, ALP in the normal range does not exclude PSC.(19)

Serum aminotransferase levels are usually increased.(19,27)

Autoantibodies may also be detected in PSC (e.g., anti-nuclear antibodies [ANAs; 24-53% of patients], smooth muscle antibodies [SMAs; 13-20%] and anti-perinuclear antibody [pANCA; 65-88%].(19,28)

Characteristic findings on cholangiography are bile duct changes, such as strictures and dilations of intra- and extra-hepatic bile ducts.(19)

Endoscopic retrograde cholangiopancreatography (ERCP) is a more accurate diagnostic method than magnetic resonance cholangiography (MRCP), but MRCP is always recommended as the initial diagnostic modality because ERCP is associated with serious complications, such as pancreatitis and bacterial cholangitis.(19,29)

The MRCP findings in this case, together with the biochemical findings, are consistent with PSC.

Case Evolution

A liver biopsy, arranged under ultrasound guidance, shows a lymphoplasmacytic periportal infiltrate with interface hepatitis and a few poorly formed granulomas. Unfortunately, her bowel habit has worsened since stopping methotrexate, with five loose stools per day and intermittent crampy abdominal pain. Her fecal calprotectin is 1230 mcg/g.

Commentary

Granulomas on liver histology in patients with IBD are described in less than 1% and can be an extraintestinal manifestation of IBD or have infectious or malignant etiologies.(19,30,31)

Treatment of PSC is limited; symptom control and management of complications are currently the main goals of management.(19)

Treatment with ursodeoxycholic acid does not, unfortunately, offer significant benefit.(19,32) Nor do infliximab, budesonide, cyclosporine or azathioprine, which have all been evaluated for PSC.(19,33)

Liver transplantation is the only effective treatment for these patients once they have reached end-stage liver disease; the 5- and 10-year survival rates are approximately 85% and 70%, respectively. Additionally, recurrent PSC can be expected in approximately 20% of patients post-transplant.(19,34)

Consequently, many new insights from basic pathophysiology studies are driving early phase trials and there is a dedicated PSC-IBD programme at the University of Toronto focused on delivering integrated liver and GI research-driven, clinical-trial focused, whole-patient, life-long care. This focused approach is justified; while it is relatively infrequent, PSC-IBD is a disease with substantial unmet needs related to the heightened risk of events and complications (e.g., liver failure, recurrent cholangitis, recurrent disease in the liver graft, and elevated malignancy risk in the hepatobiliary tree and colon). Additionally, the symptom burden for patients (e.g., pain, pruritus, fatigue) is an added axis of clinical disease that requires recognition and management.

Tara’s worsening CD requires a change of approach. A biologic, with or without steroid therapy, may be considered at this point after she has already had a course of methotrexate and inadequate response to budesonide.

Any of the currently indicated biologics can be considered for Tara at this time (anti-TNF, ustekinumab or vedolizumab).(35-38)

Case Evolution

You decide to treat Tara with ustekinumab and prednisone. Pre-biologic workup reveals no detectable hepatitis B surface antigen but also no detectable hepatitis B surface antibody. She is sure she was vaccinated as a teenager.

Commentary

With respect to vaccination, the 2017 ACG guidelines on preventive care in IBD have the following recommendations relevant to this case:(39)

All adult patients with IBD should undergo annual vaccination against influenza.

• Those on immunosuppressive therapies and their household contacts should receive the non-live trivalent inactivated influenza vaccine, but not the live inhaled influenza vaccine.
• Adult patients with IBD receiving immunosuppressive therapy should receive pneumococcal vaccination with both the PCV13 and PPSV23, in accordance with national guidelines.
• Adults with IBD should be assessed for prior exposure to varicella and vaccinated if naive before initiation of immunosuppressive therapy when possible.
• Household members of immunosuppressed patients can receive live vaccines with certain precautions.
• Adults with IBD should receive age-appropriate vaccinations before initiation of immune suppression when possible.
• Vaccination against Tdap, HAV, HBV, and HPV should be administered as per Advisory Committee on Immunization Practice guidelines.

Patients with IBD can receive all inactive vaccines, regardless of their level of immunosuppression.(40) However, live vaccines—such as the measles, mumps, and rubella vaccine; the varicella zoster (chickenpox) vaccine; and the herpes zoster (shingles) vaccine should be used with caution in patients who are on high-level immunosuppression.(39)

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3. Jiang X, Karlsen TH. Genetics of primary sclerosing cholangitis and pathophysiological implications. Nat Rev Gastroenterol Hepatol. 2017;14(5):279–95.
4. Webb GJ, Rana A, Hodson J, et al. Twenty-Year Comparative Analysis of Patients With Autoimmune Liver Diseases on Transplant Waitlists. Clin Gastroenterol Hepatol. 2018;16(2):278–87.
5. Trivedi P, Mytton J, Evison F, et al. Nationwide population-based evaluation of mortality and cancer-risk in young patients with ulcerative colitis/primary sclerosing cholangitis [abstract OWE-012]. Gut. 2018;67(Suppl 1):A103–A104.
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Editor-in-Chief

John K. Marshall, MD MSc FRCPC AGAF
Director, Division of Gastroenterology
Professor, Department of Medicine
McMaster University, Hamilton, ON

Contributing Editor

Gideon Hirschfield, MA MB BChir FRCP PhD
Lily and Terry Horner Chair in Autoimmune Liver Disease, University of Toronto
Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, ON

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Mentoring in IBD Curriculum Steering Committee

Alain Bitton, MD FRCPC, McGill University, Montreal, QC
Brian Bressler, MD MS FRCPC, University of British Columbia, Vancouver, BC
Anne M. Griffiths, MC FRCPC, University of Toronto, Toronto, ON
Steven E. Gruchy, MD MSc FRCPC, Dalhousie University, Halifax, NS
Remo Panaccione, MD FRCPC, University of Calgary, Calgary, AB
Craig Render, MD FRPCP, University of British Columbia, University of Alberta, Kelowna, BC
Hillary Steinhart, MD MSc FRCPC, University of Toronto, Toronto, ON
Jennifer Stretton, ACNP MN BScN, St. Joseph’s Healthcare, Hamilton, ON

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IBD Dialogue 2019·Volume 15 is made possible by unrestricted educational grants from…

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Published by Catrile & Associates Ltd., 1B-391 Berkeley Street, Toronto, ON M5A 2X8

(c) Catrile & Associates Ltd., 2019. All rights reserved. None of the contents may be reproduced in any form without prior written permission from the publisher. The opinions expressed in this paper are those of the authors and do not necessarily reflect the opinions or recommendations of the sponsors, the grantor, or the publisher.