UPDATE IN PRIMARY SCLEROSING CHOLANGITIS: DIAGNOSIS …

UPDATE IN PRIMARY SCLEROSING CHOLANGITIS: DIAGNOSIS AND TREATMENT

David M. Fettig M.D.Assistant Professor of Medicine

UAB Liver CenterComprehensive Transplant Institute

UAB LIVER CENTER and COMPREHENSIVE TRANSPLANT INSTITUTE

I have no disclosures to claim and discuss

Disclosures


1. History of PSC and key points of the disease

2. Diagnosis of PSC

3. Treatments of PSC and new therapeutics

4. Cholangiocarcinoma and transplantation

Educational Objectives


1. Definition: The presence of biliary inflammation leading to multifocal biliary strictures

2. Majority of patients with PSC have Inflammatory Bowel Disease (most with IBD due to not have PSC)

3. History:-1960s: First cases were described in case reports-1970s: ERCP began to be used and further disease was described-1980s: USA, UK, and Norway had three landmark papers with specific definitions to the disease and diagnostic criteria.

History of PSC and Educational Keys


3. History continued:-1960s: First cases were described in case reports-1970s: ERCP began to be used and further disease was described-1980s: USA, UK, and Norway had three landmark papers with specific definitions to the disease and diagnostic criteria.

-1980-1990: Cholangiocarcinoma, IgG-4, Small duct subtypes, Overlap Syndromes

-1983: Liver transplantation was essentially inevitable and only curative option for PSC patients. Recurrence of disease in transplanted grafts was established

History of PSC and Educational Keys


1. USA: -Less than 200,000 people-Incidence rate: 1 per 100,000 per year

2. EU: -Less than 250,000 people-Incidence rate: 1 per 100,000 per year

- Spain, Japan, and Singapore have 10-fold lower incidence rates

- Very low incidence rates in children

- 25% of cases have other affiliated Autoimmune conditions

Epidemiology and Demographics


PSC and IBD:

-60-80% of PSC cases have concurrent IBD (Japan is outlier)

-8% of IBD patients have PSC

-Females tend have subclinical course of PSC when they have IBD

Ig4 Cholangiopathy:

-10% of PSC patients have elevated Ig4 disease

-Overall, very hard to distinguish disease process (HISORt criteria)

Epidemiology and Demographics


Norwegian Study: 322 patients with known IBD for 20 years screened with MRCP -7% had large duct PSC when only 2% had a previous diagnosis-All patients were asymptomatic of PSC-New cases were predominantly female

Key points and challenges to current understanding:-PSC may affect males and females equally, females have more of a quiescent disease-Crohns patients have less disease activity early on then Ulcerative colitis, however long term the disease outcomes may be similar-Subclinical PSC in IBD: Implications of Colon Cancer malignancy screening needed. MRCP screening in all IBD patients ?

Epidemiology and Demographics of IBD


Cholangiocarcinoma (CCA):

-7000 patients: EU study-10% of patients diagnosed with Cholangiocarcinoma

-90% of patients diagnosed within 12 months of CCA diagnosis

-0.5% yearly incidence 10 years from diagnosis

Colorectal Cancer:

-5-fold higher risk in PSC/IBD then IBD alone

-PSC alone is not well established given little amount of patients

(50% of PSC deaths are due to malignancy)

Epidemiology and Demographics of Malignancy


-Multiple findings in PSC: Gallstones, Cholecystitis, Gallbladder cancer-Gallstones occur in about 25% of cases -Gallbladder polyps/Mass occur in about 10% of cases

-75% of these cases are malignant-Cholycystectomy for GB polyps:

-EASL recommends regardless of polyp size-Quality of evidence is low due to low sample and data of polyps are

grouped together (5mm to 3cm)-Surgical risk is higher in this population thus may not translate that all GB

with polyps in PSC should go to surgery.

Epidemiology and Demographics of Gallbladder disease


1. No definitive process is known or accepted

2. Concentric Bile duct fibrosis: Final common pathway of the disease leading to cirrhosis

3. Possible Mechanisms-Defects in mechanisms of protection in bile acid toxicity

-IBD: Passive leakage of microbiom components in portal circulation leading to antigenic triggers

-Gut derived T-Cell recruitment to the liver leading to disease activity

KEY: Adaptive Immune response is most likely (T-cells interactive with cholangiocytes)

Pathogenesis of Disease and Therapeutic Targets


1. Contraindications to current theory:

a. The lack of immunosuppressive drug efficacy in pre-/post-Transplant despite autoimmune etiology.

b. The progression of PSC in the absence of “leaky” gut

c. Bile acid toxicity theory causing PSC despite lack of evidence for Ursodeoxycholic acid (UDCA)

Key: How Cholangiocytes and immune cells interact with stellate cells and fibroblasts to produce fibrosis (onion-skinning) is not understood well, thus therapeutics are lacking.

Pathogenesis of Disease and Therapeutic Targets


1. Genetics vs Environmental (likely more Environmental factors)2. Innate Immune response vs Adaptive Immune response

a. Innate: Gut “leakage” of LPS engaging Toll-Like Receptorsb. Adaptive: Strong HLA association in PSC; gut derived antigens stimulate T-cells and then

migrate to gut and liver; ANCA associated with PSC thus B-cell playing a role

3. Bile acid toxicity: Cholangiocytes are protected from bile acids by a bicarbonate rich membrane (CFTR).

4. Several immune cells such as macrophages and Neutrophils are found in proximity to the bile duct. Cross talk with these immune cell and activated T-cells

5. Chronic injury converges on stellate cells and portal myofibroblasts causes fibrosis of bile ducts (onion skinning) and cirrhosis

General Pathogenesis


1. Radiologic diagnosis upon exclusion of secondary causesa. Ischemic, sarcoid, HIV, IgG4, Covid-19 cholangiopathy, etc.

2. MRCP vs ERCPa. MRCP sensitivity and specificity around 90%b. ERCP cost effectiveness is poor, and risks increase

3. Labs: Cholestatic patterna. Alkaline phosphatase can be normal as its levels naturally fluctuate

4. IBD in PSC: Typical features are not always clearly seen, and disease may not be as prominent as in IBD alone.

Diagnostic Criteria


1. PSC with elevated IgG4

2. Small duct PSC

3. PSC-AIH Overlap syndrome

Distinct variations of PSC


1. Diagnostic Dilemma: a. IgG 4 levels: Insufficient accuracy and poor cut off valuesb. Biopsy of ampulla, pancreas, or biliary biopsy are low yieldc. HISORt criteria for Autoimmune pancreatitis/IgG4 related disease and Japanese

Diagnostic Criteria of IgG4 cholangiopathy(2012)

IgG4 Cholangiopathy/AIP vs PSC with IgG4 elevation


1. Diffuse or Segmental narrowing of bile ducts along with thickening of bile duct wall

2. Elevated IgG4 in serum (>134)

3. Coexistence of AIP and/or retroperitoneal fibrosis

4. Histology:A. Marked lymphocytes and plasma cells infiltration and fibrosisB. Infiltration of IgG 4 positive plasma cellsC. Storiform fibrosis D. Obliterative phlebitis

Japanese Clinical Diagnostic Criteria for Ig4 cholangiopathy


1. Diagnostic Strategy:a. Start with labs and high clinical suspicion: first do MRCPb. If MRCP normal, get opinion from tertiary center with high volume MRCPc. If MRCP still normal, could consider ERCP only if high index of suspicion for gallstones

or other biliary diseased. Final step is liver biopsy

2. Large duct PSC vs Small duct PSCa. HLA associations with IBD appear very similar so likely same etiology for disease

Small Duct PSC


1. Occurs in less than 7% of PSC cases

2. Diagnosis: Rather complexa. International Autoimmune Hepatitis Group (IAHG): Favors abandoning overlap

terminology and treating each as a separate diagnostic and therapeutic diagnosisb. Issues: IgG and LFTs are elevated in both diseases thus difficult to use scoring

systems c. Biopsy needed to make diagnosis

3. Treatment: Use standard immunosuppressive regimen

4. Outcomes: Generally, Overlap AIH does not respond as well as AIH alone

PSC-AIH Overlap Syndrome


1. Alkaline Phosph and Bilirubin: No data to support

2. Revised Mayo Risk Scorea. components: age, bilirubin, variceal bleeding, albumin, and ASTb. Pros: non-invasive test, shows risk stratification(Survival at 4 years with low, medium,

and high-risk groups)c. Cons: only shows 4-year survival and does not predict adverse outcomes in high dose

URSO

3. MRI: Small study (N=62) showed correlation with Revised Mayo Risk Score.

Prognostic Indices of Disease- Noninvasive


1. Liver biopsy: No data to support (invasive and patchy sampling)

2. Amsterdam Score: based on scoring of stricturing disease by ERCP-Age combined with disease was predictive of survival-Overall issue was how to apply to clinical practice given invasive testing

Prognostic Indices of Disease- Invasive


1. Acute Cholangitis: Standard therapy with antibiotics and treatment of strictures if present.

2. Recurrent Cholangitis: Current guidelines recommend prophylactic antibiotics aimed at Gram-negative coverage. a. Regimen is not well defined b. Largest trial (n=80): Flagyl/URSO vs URSO alone

-Improvement in revised Mayo Risk Score in combined treatment group

-No improvements in histology, imaging, or ERCP findings.

-Fungal infections have poor prognosis

Bacterial Cholangitis


1. Definition: Stenosis of extrahepatic duct with following criteriaa. Stenosis of <1.5mm in CBDb. Stenosis of <1mm in the hepatic duct within 2cm of the hilumc. Not validated for MRCP, only ERCP

2. Labs: a. Cholestatic elevation does not appear in definitionb. Retrospective data: Shows about half of patients regardless of dominant stricture

present have similar labs at two months and one year evaluation, however patients with dominant strictures have decreased survival/poor prognosis.

Dominant Strictures


3. Treatment:a. Antibiotics: Pre-procedural antibiotics recommendedb. Stenting vs balloon dilation:

-Balloon dilation appears to be preferred method-Short term plastic stenting is acceptable (1-2 weeks)

c. UDCA combined with stenting has shown survival benefit when predicated by Mayo risk model, however, does not prevent stricture development

Dominant Strictures


Multicenter randomized trial comparing short-term stenting versus balloon dilatation for dominant strictures in primary sclerosing cholangitis

-N=80

-Randomized to stenting vs balloon dilatation

-Primary Outcome: Recurrence free patency of dominant stricture

-Results: Stenting was not superior to balloon dilatation. Stenting had higher rates of pancreatitis and cholangitis.

Dominant Strictures


1. Imaging with CT or MR is preferred if symptoms change/increase or changes in labs

2. Dominant strictures should be sampled for Cholangiocarcinoma upon initial ERCP

3. Balloon dilation should be done over short-term stenting when able.

Dominant Strictures Recommendations


1. Genetics vs Environmental (likely more Environmental factors)2. Innate Immune response vs Adaptive Immune response

a. Innate: Gut “leakage” of LPS engaging Toll-Like Receptorsb. Adaptive: Strong HLA association in PSC; gut derived antigens stimulate T-cells and then

migrate to gut and liver; ANCA associated with PSC thus B-cell playing a role

3. Bile acid toxicity: Cholangiocytes are protected by bile acids by a bicarbonate rich membrane (CFTR).

4. Several immune cells such as macrophages and Neutrophils are found in proximity to the bile duct. Cross talk with these immune cell and activated T-cells

5. Chronic injury converges on stellate cells and portal myofibroblasts causes fibrosis of bile ducts (onion skinning) and cirrhosis

General Pathogenesis- REVIEW


1. Aim of Drug therapy:a. Therapy targeting bile acid composition: Ursodeoxycholic Acid and 24-norURSOb. Bile receptor /Farensoid X receptor agonist: Obeticholic Acidc. Fatty acid-activated receptorsd. Vitamin D and Vitamin A receptor agonistse. Therapy targeting gut-liver axis (IBD): Given association of PSC/IBDf. Antifibrotic agents: Simtuzumab

Medical Treatment


1. Variable clinical presentation-Large Duct vs small duct vs other-Disease heterogeneity with emerging sub-types and overlap syndromes

2. Variable presence of IBD

3. Risk of malignancy

-Need to treat as a pre-malignant condition

Medical Treatment- Issues


UDCA Clinical Trials


1. Currently no established data to support usea. UDCA at 15-20mg/kg/day does improve labs but not survival benefit. b. Higher doses have been shown to cause poor outcomes

2. EASL:a. No formal recommendation but open to useb. Consideration of use in PSC-IBD for chemoprevention in high-risk groups

3. AASLD:a. Advise against useb. Does not recommend use in PSC-IBD for chemoprevention

UDCA


1. Start UDCA at 10-15mg/kg/day

2. Monitor enzymes for 3-6 months and if improvement by labs and Mayo risk model then continue

3. If no improvement, could consider stopping and switching to other medications such as fenofibrate

Rationale: Prospective Evaluation of Ursodeoxycholic Acid Withdrawal in patients with PSC. Hepatology 2014

UDCA-My practice


-UDCA homologue that resists amidation in biliary system

-Key Aspect: undergo cholehepatic shunting(stimulation in canalicular bile flow and biliary bicarbonate excretion) thereby flushing biliary system with bicarbonate enriched bile, thus reducing toxic formulation of bile and reducing hepatic injury

-Multiple studies in animal models has shown to reduce and prevent biliary strictures.

Nor-UDCA


Overview of Novel Therapies


1. Targeting Bile Acid Synthesis

2. Targeting Gut-Liver Axis (PSC)

3. Targeting fibrotic activity

Goals of Future Therapy


Cholangiocarcinoma

• Peri-Hilar/Hilar- 60%

• Intrahepatic- 10%

• Disease is increasing• Diagnosis is challenging

• Surgical resection is the main treatment for disease


1. Second most common primary liver tumor

2. Incidence of Intrahepatic is rising (accuracy of imaging improving)

3. Extrahepatic Incidence (perihilar and distal): stable

Incidence of Cholangiocarcinoma


1. Patients with PSC have a 400-fold increased risk of CCA compared to the general population

-1-2% yearly incidence, 30-year incidence of 20%

2. Yearly screening with imaging and CA 19-9

Cholangiocarcinoma in PSC


1. Imaging: CT (good for vascular involvement) and MR (ductal and vascular disease).

2. EUS: Helpful for nodal disease. KEY: Do NOT biopsy main tumor as this will rule out patient for transplant

3. ERCP: evaluation of strictures that are concerning for CCA

4. Labs: Elevated CA 19-9

Diagnosis of Cholangiocarcinoma


-Sensitivity and specificity of CA 19-9 >130U/L in setting of PSC and the absence of bacterial cholangitis are 79% and 98% respectively

-Patients without PSC, CA 19-9 > 100 has a sensitivity of 76%

- 10% of patients may be Lewis Ag negative thus not secrete CA 19-9

CA 19-9 role in Diagnosis in PSC


1. Sensitivity: 46%-Low sensitivity because tumor is very desmoplastic or dense fibrous connective tissue in the tumor; very inflammatory-FISH improves to 65% (helps identify multiple copies of same chromosome)

2. Specificity: 97%-FISH preserves specificity

Brushing and Cytology


1. Most present with Unresectable disease

2. The potentially resectable disease: some are aborted once disease is noticed intraoperatively that make them unresectable

3. Key: Imaging pitfall is that given small tumor and location in hilum can make distinguishing resectable vs unresectable challenging.

-Margin negative/R0: 5 year survival is 35%

-Lymph node negative: 5 year survival is 45%

Resection of Peri-Hilar/Hilar CCA


1. Penn I: Surgery 110:726, 1991-207 patients with hilar cholangiocarcinoma underwent transplant alone. Survival was very poor. 2-year survival was 20% and 5-year survival was 5%-Key point: Transplant ALONE was not a good option.

History of Peri-Hilar/Hilar CCA resection


1. Resectable:a. Resection with removal of extrahepatic ducts, regional lymph node resection with

Right or Left hepatectomy

2. Unresectable: includes PSCa. Proceed with liver transplant protocol

Peri-Hilar/Hilar Gold standard


1. Bilateral ductal extension

2. Encasement of main portal vein

3. Unilateral ductal extension with contralateral vascular encasement

4. PSC

Criteria for unresectable CCA


1. Unresectable perihilar cholangiocarcinoma

2. Less than 3cm diameter

3. No evidence of lymph node metastasis

4. No previous transperitoneal biopsy of primary tumor

5. Diagnosis-Positive Cytology, CA 19-9 >100 with malignant appearing stricture or mass lesion

Transplant protocol for Cholangiocarcinoma Eligibility


Transplant protocol for Cholangiocarcinoma


1. 5 Year survival: 68%

2. 5 year survival in PSC: 76%

3. Suspect that PSC is better survival vs De Novo given that likely PSC has good response to radiation therapy and diagnosis likely earlier.

Survival in Transplant for Cholangiocarcinoma


1. History of PSC and Key Points of the disease

2. Diagnosis of PSC

3. Treatments of PSC and new therapeutics

4. Cholangiocarcinoma and Transplantation

Educational Objectives and Summary


Questions UAB LIVER CENTER and COMPREHENSIVE TRANSPLANT INSTITUTE

1. Karlsen, T et al. Primary Sclerosing cholangitis: A comprehensive Review; Journal of hepatology 2017 Vol 67 1298-1323

2. Zein, C. Primary Sclerosing Cholangitis. Clinical Liver Disease 17 (2013) 211-227

3. Halilbasick E. Therpay of Primary Sclerosing Cholaongitis- Today and Tommorrow. Digestive Disease 2015; 33 149-163

4. Chapman, R. AASLD guidelines. Diagnosis and management of PSC. Hepatology 2010

5. Lindor, K. High dose URSO for the treatment of PSC. Hepatology, 2009 Vol 50 No3

6. Chapman, H. British Society of Gastroenterology and UK-PSC guidelines for diagnosis and management of PSC. Gut 2019; 68, 1356-1378.

7. Heimbach, J. AASLD hepatology board review. Cholangiocarcinoma presenation 2018, Dallas Tx.

8. Cannon, R. UAB slide deck provided to me for review.

References


UPDATE IN PRIMARY SCLEROSING CHOLANGITIS: DIAGNOSIS …

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