Primary Sclerosing Cholangitis [S + DT]

SPEED

Epidemiology

• More common in males
• Western populations: 70% of PSC patients have Inflammatory Bowel Disease (IBD)
• Eastern populations: 25% of PSC patients have IBD
• IBD patients with PSC: 3-5% have PSC
• Asymptomatic cases: 15-40%
• Cholestatic pattern on LFT: Increased ALP (Alkaline Phosphatase)
• Most common symptoms:
  • Abdominal pain > Pruritis > Diarrhea > Jaundice
• Protective factors:
  • Smoking
  • Prior Appendectomy

Diagnosis

Cholestatic Profile:

• Alkaline Phosphatase (ALP): Elevated, though may be normal in some cases
• Bilirubin: Normal in 60% of cases
• AST/ALT: May be elevated (less than 3 times the normal)
• Autoimmune Hepatitis (AIH) and PSC Overlap: AST/ALT levels can be elevated more than 3 times the normal

Radiology:

• Multifocal intrahepatic and/or extrahepatic stricture
• MRCP:
  • Detects multifocal stricturing and beading
  • Involves both extrahepatic and intrahepatic ducts
  • Can be only intrahepatic or extrahepatic as well
  • Small Duct PSC: Normal cholangiogram
  • Pseudodiverticular formations of extrahepatic bile ducts are pathognomonic

Biopsy:

• Not required for routine diagnosis
• Ductular proliferation and periductal fibrosis
• Used to exclude other conditions:
  • Small duct PSC
  • Secondary causes
  • Stage of the disease
• Findings:
  • Paucicellular portal tract inflammation
  • Onion skin fibrosis
  • Ductopenia
  • Granulomas (found in 4% of cases)
  • Ludwig staging

MCQ

Question: Which of the following is not true about the diagnosis of Primary Sclerosing Cholangitis (PSC)?

Options: A) Biopsy is always required

B) Cholangiogram may be normal

C) Stricture in both intrahepatic and extrahepatic ducts

D) Bilirubin is normal in 60% of cases

Explanation:

• MRCP typically shows strictures in both extrahepatic and intrahepatic bile ducts.
• In 5% of cases with Small Duct PSC, the cholangiogram may be normal, necessitating a biopsy.
• Bilirubin is normal in more than 50% of the population. If bilirubin is elevated, it is often due to stones, dominant strictures, or malignancy, indicating a poorer prognosis.

Correct Answer: A) Biopsy is always required

Association of Primary Sclerosing Cholangitis (PSC) and Inflammatory Bowel Disease (IBD)

Epidemiology

• PSC and IBD:
  • 70% of PSC patients in Western countries have IBD; 25% in Eastern countries.
  • IBD diagnosis typically precedes PSC by 8-10 years.
• Risk Factors and Outcomes:
  • Increased risk of recurrent PSC post-liver transplant (LT) if IBD is present and the colon is intact.
  • Pancolitis with rectal sparing is common, with an increased risk of pouchitis.
  • Despite increased risk of pouchitis, IPAA (Ileal Pouch-Anal Anastomosis) is preferred over end ileostomy in IBD cases.
  • No direct correlation between severity of bowel disease and severity of liver disease
  • Mild colitis is typically associated with PSC-IBD compared to IBD alone.
  • Increased risk of colorectal cancer (CRC):
    • 5-fold increased risk.
    • 9% risk at 10 years, 31% at 20 years, and 50% at 25 years. [-2%-5%--10% @ (10,20,25 years) without PSC]
    • Screening for CRC should start at 8 years post-diagnosis (earlier than typical screening = 14-15 years).

Other Implications of PSC:

• Gallbladder:
  • Increased risk of gallbladder polyps and cancer.
  • Cholecystectomy is recommended regardless of polyp size.
  • Acalculous cholecystitis: Diffuse lymphoplasmacytic infiltrate is noted.
• Post-ERCP Complications:
  • Increased risk of bacterial cholangitis.
• Stones:
  • Secondary stones are common in PSC patients.

Treatment of PSC:

• Medical Therapy:
  • Ursodeoxycholic Acid (UDCA):
    • Intermediate dose (17-23 mg/kg/day) is beneficial, while high doses (28-30 mg/kg/day) do not offer additional benefits.
  • Chemoprevention for colon cancer.
  • Cytoprotection and antioxidant benefits.
• Liver Transplant:
  • The only curative treatment for PSC.

MCQ

Question: Which of the following is not true about the association of PSC and IBD?

Options: A) Risk of CRC is 9% after 10 years of disease duration

B) Presence of IBD and intact colon increases the risk of recurrent PSC post LT

C) IBD with PSC is characterized by pancolitis with rectal sparing and increased risk of pouchitis

D) PSC-IBD is characterized by severe colitis compared to IBD alone

Explanation:

• PSC and IBD association includes a 5-fold increased risk of CRC, with a 9% risk at 10 years.
• The presence of IBD and an intact colon increases the risk of recurrent PSC post-LT.
• PSC-IBD is characterized by pancolitis with rectal sparing and an increased risk of pouchitis.
• However, PSC-IBD typically presents with milder colitis compared to IBD alone, not more severe colitis.

Correct Answer: D) PSC-IBD is characterized by severe colitis compared to IBD alone

Risk Factors for Recurrent Primary Sclerosing Cholangitis (PSC) Post Liver Transplant (LT)

• IBD with intact colon: Increases the risk of recurrent PSC.
• Deceased Donor Liver Transplant (DDLT): Risk of recurrent PSC is 34%.
• Living Donor Liver Transplant (LDLT): Higher risk at 67%.
• CMV infection: Associated with increased risk of recurrent PSC.
• Prolonged ischemic time: Contributes to the risk.
• Acute cellular rejection: A known risk factor for recurrent PSC.
• Lymphotoxic cross-match: Also associated with increased risk.

Other Considerations in LT for PSC:

• Increased risk of biliary stricture and incidence of rejection.
• Roux-en-Y Hepaticojejunostomy (RYHJ) is often performed.
• Duct-to-duct anastomosis is generally not preferred due to higher complication rates.

MCQ

Question: Which of the following is not a risk factor for recurrent PSC post-liver transplant (LT)?

Options: A) IBD with intact colon

B) DDLT

C) CMV infection

D) Acute cellular rejection

Explanation:

• IBD with intact colon, CMV infection, and acute cellular rejection are all recognized risk factors for recurrent PSC after LT.
• DDLT has a lower risk (34%) compared to LDLT (67%), but it is still a risk factor for recurrence, making it a correct answer as a risk factor.

Correct Answer: B) DDLT (This option is misleading; while DDLT is associated with recurrence, it's at a lower risk than LDLT. Thus, this can be seen as "not as significant" as the others.)

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DOCTUTORIALS

Overview of Primary Sclerosing Cholangitis (PSC)

• Chronic Idiopathic Cholangiopathy: PSC is characterized by peribiliary inflammation and fibrosis.
• Progression: PSC can lead to cirrhosis and is a significant risk factor for hepatobiliary and colonic carcinogenesis.
• Survival: The median liver transplant (LT) free survival time is approximately 15 years.
• Liver Transplantation: LT is currently the only life-extending therapy for end-stage PSC, though it is associated with risks of recurrent PSC and hepatobiliary malignancy post-transplantation.

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Epidemiology

• Gender and Age:
  • PSC affects men more commonly than women with a ratio of 2:1.
  • It typically presents in the fourth decade of life.
• Incidence and Prevalence:
  • Incidence: 1.25 per 100,000 for Caucasian men and 0.54 per 100,000 for Caucasian women in the U.S.
  • Prevalence: Reported as 20.9 per 100,000 for men and 6.3 per 100,000 for women, corresponding to approximately 30,000 cases nationwide.
  • The prevalence is rising in both sexes, with similar trends reported in Canada, Northern Europe, and New Zealand.
• Association with IBD:
  • 70% of PSC patients in Western countries have Inflammatory Bowel Disease (IBD), most commonly Ulcerative Colitis (UC).
  • In contrast, only 3-5% of patients with IBD have PSC.
  • In Far Eastern cohorts, only about one-third of PSC patients have IBD.

Clinical Presentation of PSC

• Asymptomatic Presentation: Up to 40% of patients are asymptomatic at diagnosis, often found incidentally through elevated serum liver enzymes, especially alkaline phosphatase (ALP) and alanine aminotransferase (ALT).
• Symptomatic Patients: When symptoms are present, they include:
  • Fatigue
  • Pruritus
  • Jaundice
  • Right Upper Quadrant (RUQ) Pain
  • Signs of Advanced Liver Disease: Ascites, Gastrointestinal Bleeding from varices, Hepatomegaly, and Splenomegaly.

Diagnosis

• Biochemical Abnormalities:
  • The most common is an elevated alkaline phosphatase (ALP), which reflects chronic cholestasis.
  • ALP levels are typically twofold to threefold higher than the upper limit of normal.
  • Autoantibodies may be present, but they are nonspecific and not diagnostic.
• Imaging:
  • Magnetic Resonance Cholangiopancreatography (MRCP) is the preferred noninvasive imaging modality, showing multifocal strictures and dilations in the bile ducts, leading to a “pruned” biliary tree appearance.
  • Endoscopic Retrograde Cholangiopancreatography (ERCP) is now typically reserved for therapeutic interventions, such as stricture dilation or stenting.
• Liver Biopsy:
  • Not required for diagnosis unless to:
    • Exclude other liver diseases (e.g., Autoimmune Hepatitis).
    • Diagnose small-duct PSC.
    • Determine disease stage.
  • Pathologic features may include chronic cholangitis, ductular proliferation, and periductal fibrosis.

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Differential Diagnosis: Secondary Sclerosing Cholangitis

• Infectious Causes:
  • AIDS cholangiopathy (e.g., Cryptosporidium parvum, CMV)
  • Helminth infection (e.g., Clonorchis, Opisthorchis, Ascaris)
  • Recurrent pyogenic cholangitis (e.g., Oriental cholangiohepatitis)
• Chronic Intrinsic or Extrinsic Compression:
  • Cholangiocarcinoma
  • Diffuse intrahepatic malignancy
  • Portal hypertensive biliopathy
  • Postoperative injury or stricture
• Immunologic Causes:
  • IgG4-associated disease
  • Eosinophilic cholangitis
  • Histiocytosis X
• Ischemic Causes:
  • Post-transplant nonanastomotic strictures
  • Intra-arterial chemotherapy
• Congenital and/or Idiopathic Causes:
  • Choledochal cyst
  • Progressive familial intrahepatic cholestasis

Other Serologic Abnormalities in PSC

• Serum Aminotransferase Levels: Typically modestly elevated (less than three times the upper limit of normal). Marked elevation might suggest PSC-AIH overlap syndrome.
• Serum Bilirubin: Normal in 60% of patients at diagnosis; rises as PSC progresses. A sudden, sustained increase indicates a possible dominant biliary stricture, bile duct stone, or cholangiocarcinoma (CCA).
• Copper and Ceruloplasmin Levels: Often abnormal due to prolonged cholestasis, with hepatic copper levels elevated similarly to Wilson’s disease and primary biliary cirrhosis (PBC).
• Immunoglobulins:
  • Elevated IgM: 45% of patients.
  • Elevated IgE: 40% of patients.
  • Elevated IgG: 25% of patients.
  • Elevated IgA: 10% of patients.
  • Typically, multiple isotypes are elevated concurrently.
• Auto-antibodies: Limited value in PSC, though they may indicate overlap syndromes or associated conditions.

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Imaging Modalities in PSC

• MRI/MRCP:
  • Gold standard for diagnosing large-duct PSC.
  • Noninvasive with diagnostic accuracy comparable to ERCP.
  • MRCP is recommended as the initial imaging technique by the International PSC Study Group.
• ERCP:
  • Reserved for complex cases (e.g., unexplained hepatobiliary symptoms, dominant strictures, or suspected malignancy).
  • Higher risk of complications in PSC patients (e.g., acute cholangitis).
• Ultrasound and CT:
  • Useful for monitoring complications such as biliary stones and hepatobiliary malignancy.
• Percutaneous Cholangiography (PTC): Employed when ERCP is not feasible.

• PET/CT:

  • High sensitivity for detecting cholangiocarcinoma (CCA) within a dominant stricture.
  • Often used alongside brush cytology for monitoring.

  

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Histopathology in PSC

• Classic Findings:
  • Mixed, nonsuppurative portal tract inflammation.
  • Cholangitis (with or without ductopenia).
  • Periductal fibrosis, often with a characteristic “onion skin” appearance.
• Differential Diagnosis:
  • Important to differentiate PSC from conditions such as PBC, mechanical bile duct obstruction, ductopenic rejection post-liver transplant, and AIDS-related cholangiopathy.

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Staging of PSC (Ludwig System)

• Stage I (Portal):
  • Portal edema, inflammation, and ductular proliferation.
  • Abnormalities confined to the limiting plate.
• Stage II (Periportal):
  • Periportal fibrosis and inflammation, in addition to Stage I features.
• Stage III (Septal):
  • Septal fibrosis or bridging necrosis, with potential piecemeal necrosis.
  • Features of Stage I and II present.
• Stage IV (Cirrhotic):
  • Development of biliary cirrhosis.
  • Potential for ductopenia.

Etiopathogenesis of Primary Sclerosing Cholangitis (PSC)

Pathogenesis:

• Cholangiocytes: Central in PSC, these bile duct cells produce proinflammatory cytokines (e.g., TNF-α, IL-6) in response to stimuli like infections, leading to immune cell recruitment and peribiliary inflammation.

Key Hypotheses:

1. PSC-Microbiota Hypothesis:
   • Leaky Gut: Increased circulation of gut-derived microbial molecules to the liver, possibly due to compromised intestinal barriers, may trigger PSC.
   • Microbial Dysbiosis: Altered gut microbiota in PSC patients may provoke abnormal cholangiocyte responses, driving inflammation.
2. Gut Lymphocyte Homing Hypothesis:
   • T Cells: Intestinally-activated T cells, marked by integrin α4β7 and CCR9, may migrate to the liver, where they contribute to inflammation and cholangiocyte damage.

Genetic Factors:

• Family Risk: Higher incidence of PSC in relatives suggests genetic susceptibility.
• HLA Genes: Strongest genetic risk factor identified through studies.
• Other Genes: MMP1, MMP3, and ICAM1 also implicated in PSC pathogenesis.

Animal Models:

• Mdr2-/- Mouse: Mimics several PSC features but lacks full replication of human disease, especially the link with IBD and CCA.

Natural History of PSC

Disease Progression:

• Chronic Condition: PSC typically progresses to end-stage liver disease, even in asymptomatic patients. Median LT-free survival is around 20 years.

Prognostic Models:

• Revised Mayo PSC Risk Score:
  • Uses age, bilirubin, albumin, AST, and variceal bleeding history to predict outcomes.
• MELD/MELD-Na: Indicators for LT allocation in PSC patients.
• ALP Normalization: Potential biomarker for better outcomes, though still under investigation.

Small-Duct PSC:

• Prognosis: Patients with small-duct PSC have a better prognosis compared to classic PSC, with longer LT-free survival and a lower risk of CCA unless disease progresses to large-duct PSC.

Associated Diseases with Primary Sclerosing Cholangitis (PSC)

1. Inflammatory Bowel Disease (IBD) and Colorectal Cancer:

• Prevalence:
  • Approximately 70% of Western PSC patients have IBD.
  • The majority of these patients (~80%) have ulcerative colitis (UC), while the remainder have Crohn’s disease or indeterminate colitis.
• Disease Characteristics:
  • PSC-IBD typically presents with pancolitis (inflammation affecting the entire colon), often characterized by rectal sparing and backwash ileitis.
  • Colitis in PSC-IBD tends to be milder but more extensive than in patients with IBD alone.
  • PSC is not typically associated with small bowel-only Crohn’s disease, although ileal pouchitis is more common post-colectomy for PSC-IBD patients.
• Prognosis:
  • The presence and duration of IBD are associated with greater PSC-related morbidity and mortality.
  • The presence and activity of IBD, as well as an intact colon before liver transplantation (LT), are predictors of recurrent PSC post-LT.
  • Colorectal Cancer Risk:
    • PSC-IBD confers nearly a fivefold increased risk of colorectal cancer compared with IBD alone.
    • In a Swedish study, the absolute cumulative risk of developing colorectal dysplasia or carcinoma in patients with PSC-UC was:
      • 9% after 10 years,
      • 31% after 20 years,
      • 50% after 25 years.
    • In comparison, the cumulative risk in patients with UC alone was:
      • 2% after 10 years,
      • 5% after 20 years,
      • 10% after 25 years.
• Surveillance Recommendations:
  • Societal guidelines recommend that colonoscopy surveillance (with extensive random mucosal biopsies) be performed:
    • Annually from the time of PSC diagnosis in patients with IBD.
    • Approximately every five years in patients with PSC alone.

2. Autoimmune Hepatitis (AIH):

• Overlap Syndrome:
  • The overlap syndrome between PSC and AIH is recognized and seen in:
    • Up to 35% of pediatric patients with PSC.
    • Approximately 5% of adult patients with PSC.
  • Cases of PSC-AIH overlap syndrome typically fulfill criteria for both diseases, including:
    • Elevated serum ALP and cholangiographic abnormalities,
    • Elevated serum aminotransferases (more than three times the upper limit of normal),
    • Elevated serum IgG, and the presence of antinuclear and/or anti-smooth muscle antibody titers.
• Clinical Presentation:
  • Patients may present with:
    • A patient with AIH who does not respond completely to immunosuppressive therapy and subsequently develops a cholestatic serum liver profile.
    • A patient who has features of PSC but also aminotransferase level elevations that are beyond what would be expected of PSC alone (i.e., more than three times the upper limit of normal).
• Management:
  • Immunosuppressive therapy is recommended, particularly for those in whom AIH seems to be the “dominant” disease.
• Prognosis:
  • Patients with PSC-AIH overlap syndrome have increased mortality and are more likely to require liver transplantation compared to patients with AIH alone or PBC-AIH overlap.

Complications of Primary Sclerosing Cholangitis (PSC)

1. Gallbladder Disorders and Choledocholithiasis

• Prevalence:
  • Approximately 30% of patients with PSC will have calculi in the gallbladder or biliary tree.
  • 26% of PSC patients have gallstones, with half being pigment stones.
  • 10-20% of PSC patients develop gallbladder masses.
• Risks:
  • PSC patients are at an increased risk for gallbladder malignancy.
  • Gallbladder masses in PSC warrant annual surveillance.
  • Management recommendations for gallbladder masses vary, with cholecystectomy recommended for lesions >8 mm by the American College of Gastroenterology.
• Choledocholithiasis:
  • Present in ~8% of PSC patients.
  • Associated with bacterial infection; ERCP with sphincterotomy and/or stent placement is indicated for duct clearance.

2. Dominant Strictures

• Prevalence:
  • Occurs in ~45% of PSC patients.
• Characteristics:
  • Defined as stenosis with a diameter of ≤1.5 mm in the common bile duct or ≤1 mm in the hepatic duct.
  • Strictures typically present with jaundice, pruritus, cholangitis, and right upper quadrant pain.
  • Requires cholangiography (preferably ERCP) for evaluation and therapeutic dilation.

3. Cholangiocarcinoma (CCA)

• Incidence:
  • Annual incidence of 1% and a lifetime risk of 15%.
  • Accounts for ~30% of all-cause mortality in PSC patients.
• Diagnosis:
  • Challenging due to overlap of symptoms with PSC.
  • CA 19-9 is the primary biomarker, with sensitivity ranging from 13-79% and specificity from 99-100% depending on the cutoff.
  • Annual CA 19-9 testing is recommended for CCA surveillance.
• Surveillance:
  • Routine CCA surveillance can lead to earlier diagnosis and improved survival.

4. Cirrhosis and Portal Hypertension

• Complications:
  • Development of esophageal varices, ascites, and hepatocellular carcinoma.
  • Managed similarly to cirrhosis from other causes.

5. Pruritus

• Prevalence:
  • Affects ≥33% of PSC patients.
• Management:
  • Treated with stepwise use of cholestyramine, rifampicin, naltrexone, and/or sertraline.
  • Antihistamines and UDCA may provide symptomatic relief.
  • Severe cases may require extracorporeal albumin dialysis or liver transplantation (LT) for intractable pruritus.

6. Fatigue

• Etiology:
  • Fatigue does not correlate with liver disease severity but is associated with depression and poor quality of life.
  • Important to rule out other causes such as AIH overlap syndrome, clinical depression, sleep disturbance, hypothyroidism, and autonomic dysfunction.

7. Fat-Soluble Vitamin Deficiency and Steatorrhea

• Prevalence:
  • Deficiencies of vitamins A, D, and E found in 82%, 57%, and 43% of PSC patients undergoing LT evaluation, respectively.
• Management:
  • Oral supplementation of fat-soluble vitamins is recommended.
  • Evaluation for celiac disease and pancreatic exocrine insufficiency if steatorrhea is present.

8. Hepatic Osteodystrophy

• Incidence:
  • Osteoporosis in 4-10% of PSC patients.
  • Up to 50% of patients have bone mineral density below the fracture threshold.
• Management:
  • Screen for hepatic osteodystrophy every 2-3 years.
  • Treat with calcium, vitamin D, and possibly bisphosphonates.

9. Peristomal Varices and Pouchitis After Proctocolectomy

• Risks:
  • 26% of PSC-UC patients with an ileostomy develop peristomal varices.
  • PSC-UC patients have a 60% risk of acute pouchitis at 10 years post-IPAA compared to 15% in UC alone.
• Management:
  • IPAA is recommended over end ileostomy due to the risk of life-threatening peristomal varices.
  • Advances include microcoils injected under EUS and fluoroscopic guidance for less invasive treatment.

Treatment of Primary Sclerosing Cholangitis (PSC)

Pharmacotherapy

• Overview: Despite extensive research, no specific medical therapy has been definitively recommended for PSC. Multiple pharmacologic agents, including immunosuppressants, antifibrotics, antiinflammatories, and oral antibiotics, have been studied, but none have shown consistent benefit in altering the disease course.
• Ursodeoxycholic Acid (UDCA):
  • Mechanism: UDCA is a hydrophilic bile acid thought to exert beneficial effects by protecting cholangiocytes and hepatocytes against hydrophobic bile acids, stimulating bile acid excretion, and promoting bicarbonate-rich choleresis.
  • Clinical Trials:
    • Low-dose UDCA (10–15 mg/kg/day): Initial studies showed significant improvements in liver biochemistry but failed to impact "hard endpoints" such as cholangiocarcinoma (CCA), liver transplantation (LT), or death.
    • Intermediate-dose UDCA (17–23 mg/kg/day): This dose has shown the most promise with improvements in liver biochemistry, fibrosis stage, and cholangiographic findings. A large trial reported a 22% relative reduction in CCA, 34% reduction in the need for LT, and 31% reduction in mortality, though these results did not reach statistical significance.
    • High-dose UDCA (28–30 mg/kg/day): Associated with a two-fold increase in serious adverse events, likely due to toxic metabolites from supratherapeutic levels of UDCA.
  • Current Guidelines: Due to inconsistent evidence, societal guidelines generally recommend against or do not endorse the routine use of UDCA for PSC.
• Emerging Therapies:
  • Vedolizumab: Targets the integrin α4β7 to treat IBD and was hypothesized to reduce lymphocyte infiltration into the liver. However, a large trial showed no significant biochemical response in PSC, although it remains effective and safe for treating IBD in PSC patients.
  • Ongoing Trials:
    • NorUDCA and Cilofexor (a farnesoid X receptor [FXR] antagonist): Both are bile acid–based therapies under investigation.
    • Peroxisome Proliferator-Activated Receptor (PPAR) Agonists: Aimed at modulating liver inflammation and fibrosis.
    • Gut Microbiota Modulation: Exploring the role of gut-liver axis in PSC.
    • Immune-Modulating Therapy: Targeting inflammatory pathways involved in PSC pathogenesis.

Surgical Therapy

• Resection of Cholangiocarcinoma (CCA):
  • Challenges in PSC Patients:
    • Multifocal Disease: CCA in PSC is often multifocal, making complete resection difficult.
    • Underlying Liver Disease: Hepatic fibrosis and cirrhosis in PSC reduce the liver's ability to regenerate post-surgery, increasing surgical risk.
    • High Recurrence Rate: More than 90% of patients experience recurrence post-resection.
  • Outcomes: Five-year survival post-resection is approximately 25%, significantly lower than in patients without PSC.
• Orthotopic Liver Transplantation (LT):
  • Indications: PSC is the fifth most common indication for LT in the US and the leading indication in Nordic countries. LT offers the best outcomes for PSC patients with end-stage liver disease or complications unresponsive to medical therapy.
  • Survival Rates:
    • 1-Year Survival: Over 90%.
    • 5-Year Survival: Over 80%.
  • Recurrent PSC Post-LT:
    • Incidence: Occurs in up to 34% of deceased donor LTs and 67% of living-related donor LTs.
    • Risk Factors:
      • IBD with Intact Colon: Pre-LT colectomy may reduce recurrence risk.
      • Prolonged Ischemic Time: Longer periods without blood supply during surgery increase the risk.
      • Acute Cellular Rejection: Episodes post-LT are associated with higher recurrence.
      • Cytomegalovirus (CMV) Infection: Linked to a higher risk of recurrent PSC.
      • Donor Age: Older donor age correlates with a higher risk of recurrence.
      • INR at Transplant: Higher INR at the time of transplant is a risk factor.
    • Survival Without Redo-LT: Estimated median survival is approximately four years after recurrent PSC diagnosis.
• CCA and LT:
  • Traditional View: CCA has historically been a contraindication for LT due to high recurrence rates and poor outcomes.
  • Neoadjuvant Therapy: New protocols involving neoadjuvant chemotherapy and radiotherapy, followed by LT, have shown promising outcomes in early-stage hilar CCA.
  • Outcomes:
    • 5-Year Recurrence-Free Survival: 65% in patients following the specialized neoadjuvant and LT protocol.
    • Incidental CCA: Patients with incidental CCA found at LT (tumors <1 cm discovered during pathology) have a 5-year survival rate of ~80%.

Question:

Explanation:

• More common in men: This is true. PSC has a male predominance with a male-to-female ratio of approximately 2:1.
• Most common sign is hepatosplenomegaly: While hepatomegaly and splenomegaly are common physical findings in PSC, many patients are asymptomatic and present primarily with elevated ALP. Therefore, hepatosplenomegaly is not necessarily the most common sign.
• Asymptomatic rise in ALP: This is true. Many patients with PSC are asymptomatic at diagnosis and have an elevated serum ALP level, which is often the first clue leading to further evaluation.
• PSC with IBD is less common than IBD with PSC: This statement is incorrect. The correct understanding is that while approximately 70% of patients with PSC have IBD (most commonly ulcerative colitis), only about 3-5% of patients with IBD develop PSC. Therefore, PSC with IBD is more common than IBD with PSC.

The correct answer is d) PSC with IBD is less common than IBD with PSC.

ERCP we see prune tree appearance.

Mimics and Overlap Syndromes in Primary Sclerosing Cholangitis (PSC)

Differentiating PSC from IgG4-Related Disease:

• IgG4-Related Disease: IgG4-related disease is a systemic fibroinflammatory condition that can involve multiple organ systems, including the biliary tree. Differentiating it from PSC is crucial as it may respond well to corticosteroid therapy.
• Novel Diagnostic Tools:
  • qPCR Quantification of IgG4/IgG RNA Ratio: This test measures the ratio of IgG4 to IgG RNA in the blood, which is elevated in patients with IgG4-related disease.
  • Next-Generation Sequencing: This technique identifies dominant IgG4+ B-cell receptor clones, which are a hallmark of IgG4-related disease. These tools can aid in distinguishing IgG4-related disease from PSC.

PSC-AIH Overlap Syndrome:

• Elevated Aminotransferase Levels: In PSC patients with significantly elevated aminotransferase levels (greater than three times the upper limit of normal), there may be features suggesting an overlap with Autoimmune Hepatitis (AIH).
• Overlap Syndrome Features:
  • Serologic and Histologic Markers: These patients may exhibit serologic markers (e.g., elevated IgG levels, autoantibodies) and histologic features (e.g., interface hepatitis) consistent with AIH, in addition to the cholangiographic findings typical of PSC.
  • Management Consideration: In cases where AIH is suspected to overlap with PSC, immunosuppressive therapy may be warranted, as AIH might be the "dominant" disease in these patients.

Abrupt Raise of Bilirubin in PSC Patients - Key Considerations

Correct Answer:

c) Exacerbation of associated IBD

Explanation:

• Dominant Stricture: A common cause of an abrupt increase in bilirubin in PSC patients. It represents a significant narrowing in the bile ducts, leading to obstruction.
• CBD Stone (Choledocholithiasis): The presence of stones in the common bile duct can obstruct bile flow, causing a rapid rise in bilirubin.
• Cholangiocarcinoma (CCA): A severe complication of PSC, CCA can obstruct bile ducts and cause a sudden increase in bilirubin.
• Exacerbation of Associated IBD: While IBD can exacerbate the course of PSC, it typically does not directly cause an abrupt increase in bilirubin levels. The correct answer is C because the exacerbation of IBD itself does not directly lead to a rise in bilirubin.

Criteria Not Included in the Mayo PSC Risk Score

Correct Answer:

c) ALT (AST is included, not ALT)

Disease Not Associated with PSC

Correct Answer:

b) Type II DM

Comment:

Primary sclerosing cholangitis (PSC) is strongly associated with inflammatory bowel diseases (IBD) such as Crohn's disease and ulcerative colitis, as well as with other autoimmune conditions like celiac disease and autoimmune hemolytic anemia. However, Type II diabetes mellitus (DM) is a metabolic disorder and is not commonly associated with PSC. The presence of Type II DM in a patient with PSC would likely be incidental rather than part of the disease's autoimmune spectrum. it is associated with TYPE I DM.

IBD Associated with PSC: Not True

Correct Answer:

d) Less incidence of malignancy

Comment:

Inflammatory Bowel Disease (IBD) associated with Primary Sclerosing Cholangitis (PSC) typically presents with a distinct phenotype characterized by pancolitis with rectal sparing and backwash ileitis (option a), and generally, the colitis is less severe (option b) compared to IBD alone. PSC-associated IBD is not associated with small bowel-only Crohn's disease (option c). However, the presence of PSC significantly increases the risk of colorectal cancer in patients with IBD, making option d incorrect. Therefore, the statement that PSC-associated IBD has a "less incidence of malignancy" is not true, as the incidence of colorectal cancer is actually higher in these patients compared to those with IBD alone.

PSC Recurrence After Liver Transplantation in IBD Patients

Key Points:

• Increased Morbidity and Mortality: The presence and duration of Inflammatory Bowel Disease (IBD), irrespective of its severity, are linked with greater morbidity and mortality in Primary Sclerosing Cholangitis (PSC) patients.
• Predictors of Recurrence Post-LT: Factors such as the presence and activity of IBD and an intact colon before Liver Transplantation (LT) are significant predictors of PSC recurrence post-LT.
• Risk of Colorectal Cancer: Despite being associated with milder colitis, PSC-IBD significantly increases the risk of colorectal cancer, with a nearly fivefold increase compared to IBD alone.

Impact of PSC on IBD:

• Pan Colitis with Rectal Sparing and Backwash Ileitis: PSC is associated with a unique phenotype of IBD characterized by pan colitis with rectal sparing and backwash ileitis.
• Milder Colitis: Colitis in PSC-IBD patients tends to be milder compared to IBD alone.
• Increased Risk of Colorectal Cancer (CRC): PSC-IBD patients have an increased risk of CRC.
• Crohn's Disease: When associated with PSC, small bowel-only Crohn's disease is rare.

Impact of IBD on PSC:

• Colon Presence Increases PSC Recurrence: The presence of the colon or even part of it, irrespective of the symptoms and duration of colitis, increases the risk of PSC recurrence post-LT.
• Cholangiocarcinoma Risk: IBD also heightens the risk of cholangiocarcinoma in PSC patients.

Not True Regarding AIH-PSC Overlap Syndrome

Question:

Answer:

c) Incidence: Adult- 35%%, Pediatric- 5%

Comment:

The correct answer is c because the incidence percentages provided in this option are incorrect:

• AIH-PSC Overlap Syndrome is more common in the pediatric population than in adults. The correct incidence rates are approximately 35% in pediatric patients and around 5% in adult patients.
• AST > three times normal in PSC: This is true in AIH-PSC overlap syndrome, where aminotransferase levels (like AST) can be significantly elevated beyond what is typical in isolated PSC.
• AIH - having cholestasis despite immunosuppression: This is a defining feature of the overlap syndrome. When a patient diagnosed with AIH presents with persistent cholestasis despite adequate immunosuppressive therapy, it suggests the presence of PSC.
• More likelihood to land in LTP: Patients with AIH-PSC overlap syndrome are indeed more likely to progress to liver transplantation (LTP) compared to those with AIH or PSC alone due to the increased severity and complications associated with the overlap syndrome.

Not True Regarding Biliary Complications in PSC

Question:

Answer:

d) They invariably require surgery despite successful ERC and dilatation

Comment:

The correct answer is d because it is not true that patients with dominant strictures invariably require surgery despite successful endoscopic retrograde cholangiography (ERC) and dilatation. Here’s why:

• Small GB polyps carry risk of malignancy: This is true. In patients with PSC, gallbladder (GB) polyps, even small ones, are associated with an increased risk of malignancy, particularly cholangiocarcinoma, which warrants regular surveillance and possibly prophylactic cholecystectomy depending on the polyp size.
• 45% of patients develop dominant strictures: This is accurate. Approximately 45% of patients with PSC will develop dominant strictures, which are significant stenoses within the biliary tree that can lead to complications such as recurrent cholangitis or obstructive jaundice.
• Stenosis of CBD 1.5 mm and RHD 1 mm is criteria for defining dominant stricture: This is true. Dominant strictures in PSC are defined by specific criteria, including a stenosis diameter of up to 1.5 mm in the common bile duct (CBD) and up to 1 mm in the right hepatic duct (RHD).
• They invariably require surgery despite successful ERC and dilatation: This is false. Many patients with PSC and dominant strictures can be successfully managed with endoscopic treatments, such as ERC and dilation, without the need for surgery. Surgery is typically reserved for cases where endoscopic management fails, or complications arise that cannot be addressed through less invasive means.

True Regarding Cholangiocarcinoma in PSC

Question:

Answer:

c) CA 19-9 though not specific, is done in annual surveillance

Comment:

The correct answer is c because it accurately reflects the current understanding of cholangiocarcinoma (CCA) surveillance in patients with PSC. Here's a breakdown of why each option is true or false:

• a) Longer duration of PSC: This is false. The risk of developing cholangiocarcinoma (CCA) in PSC does not necessarily correlate with the duration of the disease. While PSC is a premalignant condition, CCA can develop at any time during the course of the disease, and its occurrence is not directly linked to how long the patient has had PSC.
• b) Perihilar lymphadenopathy is specific: This is false. Perihilar lymphadenopathy is common in PSC but is not specific for cholangiocarcinoma. It can occur due to the chronic inflammation associated with PSC and does not reliably distinguish between benign and malignant conditions.
• c) CA 19-9 though not specific, is done in annual surveillance: This is true. CA 19-9 is a tumor marker used in the surveillance of cholangiocarcinoma in PSC patients. Although it lacks specificity and can be elevated in other conditions, it is still recommended as part of annual surveillance due to its potential to indicate CCA when levels are markedly elevated.
• d) FISH does not add to brush cytology: This is false. Fluorescence in situ hybridization (FISH) does add significant value to brush cytology in the detection of CCA. FISH can identify chromosomal abnormalities that are indicative of malignancy, thereby improving the sensitivity of brush cytology when used together.

Not a Risk Factor for Recurrent PSC Post-LTP

Question:

Answer:

d) Chronic cellular rejection

Comment:

The correct answer is d) Chronic cellular rejection because this option does not accurately represent the known risk factors for recurrent PSC after liver transplantation (LTP). Here's an explanation for each option:

• a) IBD with colon intact: This is a known risk factor. Patients with PSC who have inflammatory bowel disease (IBD) and retain their colon (intact colon) are at an increased risk for recurrent PSC post-LTP. The presence of an intact colon, regardless of the severity or duration of colitis, is associated with a higher likelihood of PSC recurrence after transplantation.
• b) CMV infection: Cytomegalovirus (CMV) infection has been identified as a potential risk factor for recurrent PSC. CMV infection can lead to increased inflammation and immune responses that might contribute to the recurrence of PSC after liver transplantation.
• c) Lymphotoxic cross match: A positive lymphotoxic cross match is considered a risk factor for recurrent PSC. This test identifies the presence of antibodies in the recipient that can react against the donor's lymphocytes, potentially leading to increased immunologic challenges post-transplant and a higher likelihood of PSC recurrence.
• d) Chronic cellular rejection: This is not typically listed as a risk factor for recurrent PSC. While chronic cellular rejection can affect graft function and overall outcomes post-transplant, it is not specifically associated with the recurrence of PSC. The recurrence of PSC is more closely related to the Acute cellular Rejection

Biliary Stricture Due to Chronic Calcific Pancreatitis

Question:

Answer:

d) Occurs exclusively in alcohol-related CCP

Comment:

The correct answer is d) Occurs exclusively in alcohol-related CCP because this statement is false.

Here's an explanation for each option:

• a) Present in 30% of CCP: This is true. Biliary strictures occur in a significant proportion of patients with Chronic Calcific Pancreatitis (CCP), approximately 30%. These strictures are often due to the fibrotic changes and calcifications associated with CCP, which can compress or obstruct the bile duct.
• b) Pain is similar to biliary colic: This is true. The pain associated with biliary strictures in CCP can be similar to that of biliary colic. It typically presents as severe, episodic pain in the upper abdomen, often radiating to the back, which is characteristic of biliary colic.
• c) Cholangitis and fever are less common: This is true. Although biliary strictures can lead to cholestasis, the occurrence of acute cholangitis (with fever, jaundice, and abdominal pain) is less common in CCP-related strictures compared to other causes of biliary obstruction, such as choledocholithiasis.
• d) Occurs exclusively in alcohol-related CCP: This is false. Biliary strictures in CCP can occur in various forms of chronic pancreatitis, not just those related to alcohol. While alcohol-related chronic pancreatitis is a common cause, strictures can also develop in other forms of CCP, including those caused by genetic factors, autoimmune pancreatitis, and idiopathic cases.

IgG4 Systemic Disease and Sclerosing Cholangitis

Overview:

• Prevalence: IgG4 sclerosing cholangitis is a rare biliary manifestation of IgG4 systemic disease, with an estimated prevalence of 1.8 per 100,000 individuals and an incidence of 0.5 per 100,000.
• Male Predominance: There is a strong male predominance in this condition.
• Histological Features: The disease is characterized by lymphoplasmacytic infiltration, storiform fibrosis, and obliterative phlebitis. These morphological features can mimic hilar cholangiocarcinoma (CCA) and primary sclerosing cholangitis (PSC).
• Association with Autoimmune Pancreatitis: IgG4 sclerosing cholangitis is often associated with type I autoimmune pancreatitis, and patients may also have other extrapancreatobiliary manifestations like sialadenitis, renal infiltrates, interstitial lung disease, ocular disturbances, and hypopituitarism.

Diagnosis:

• Serum IgG4 Levels: An elevated serum IgG4 level (>135 mg/dL) aids in diagnosis, but 10% to 40% of patients may have normal levels.
• Biliary Tract Imaging: Complete biliary imaging is necessary, with stricture patterns offering diagnostic clues.
• Biliary Tract Biopsy: While useful, biopsy may not entirely rule out CCA due to the potential for malignancy to induce reactive changes mimicking IgG4 sclerosing cholangitis.

Treatment:

• Steroids: The mainstay of treatment is steroids, which often lead to dramatic improvements, sometimes eliminating the need for procedural or surgical intervention. A short course of steroids followed by imaging to confirm resolution can help confirm the diagnosis.

Differentiation from Malignancy:

• Differentiation from biliary tract malignancy requires a combination of serum IgG4 levels, evaluation for other systemic manifestations, cholangiogram findings, bile duct cytology and biopsy review, and careful clinical monitoring.

IgG4-Related Sclerosing Cholangitis

Question:

Answer:

b) Biopsy helps in ruling out CCA

Comment:

The correct answer is b) Biopsy helps in ruling out CCA because this statement is false.

Here's a breakdown of each option:

• a) Male preponderance: This is true. IgG4-related sclerosing cholangitis (IgG4-SC) shows a male predominance, similar to other conditions within the IgG4-related disease spectrum.
• b) Biopsy helps in ruling out CCA: This is false. While biopsy is important in the diagnosis of IgG4-SC, it does not definitively rule out cholangiocarcinoma (CCA). The histopathological findings in IgG4-SC can be similar to those seen in CCA, and in some cases, CCA may coexist with IgG4-SC. Therefore, a biopsy alone is not always sufficient to rule out malignancy, and additional diagnostic modalities are often required.
• c) Mimics CCA/PSC: This is true. IgG4-SC often mimics cholangiocarcinoma (CCA) and primary sclerosing cholangitis (PSC) both clinically and radiologically, which can complicate the diagnostic process. The similarities in imaging and presentation can lead to challenges in distinguishing these conditions.
• d) Associated with other organ involvement: This is true. IgG4-SC is often associated with other manifestations of IgG4-related disease, including involvement of organs such as the pancreas (autoimmune pancreatitis), retroperitoneum (retroperitoneal fibrosis), kidneys, salivary glands, and others.

Ampullary Stenosis Associated with Roux-en-Y Gastric Bypass

Overview:

• Association: Benign distal common bile duct stricture at the ampulla has been reported in patients post-Roux-en-Y gastric bypass (RYGB) for morbid obesity.
• Demographics: Affected patients are predominantly female with a mean age of 54 years, and symptoms can range from abdominal pain to severe cholangitis.
• Time to Diagnosis: Ampullary stenosis typically presents a mean of 7.5 years post-RYGB.
• Imaging: Diagnosis is aided by biliary imaging techniques such as MRCP or PTC.

Treatment:

• Initial Approach: The current treatment approach has shifted from open ampullectomy or biliary bypass to less invasive techniques like laparoscopic transgastric ERCP with sphincterotomy.
• Surgical Intervention: More invasive surgical options are considered if sphincterotomy fails, restenosis occurs, or if malignancy is strongly suspected.

Pathophysiology:

• The exact mechanism is unclear, but possible contributing factors include autoimmune conditions, chronic opioid use, and gastrointestinal regulatory hormonal changes post-RYGB.

Conclusion:

• While ampullary stenosis post-RYGB appears to be benign, malignancy must still be ruled out during patient evaluation.