Primary Sclerosing Cholangitis

Definition and Overview

Primary Sclerosing Cholangitis — let's break down the name first: "primary" = arising on its own (not secondary to another identifiable cause), "sclerosing" = scarring/fibrosis (Greek skleros = hard), "cholangitis" = inflammation of the bile ducts (Greek chole = bile, angeion = vessel, -itis = inflammation). So PSC is a primary, idiopathic chronic progressive cholestatic liver disease characterised by inflammation, obliterative fibrosis, and multifocal stricturing of both the intrahepatic and extrahepatic bile ducts, leading eventually to biliary cirrhosis, portal hypertension, and liver failure ^[1][2].

The key pathological hallmark is concentric periductal fibrosis ("onion-skin" fibrosis) around medium and large bile ducts, which progressively narrows and obliterates the lumen. This results in cholestasis (impaired bile flow), recurrent bacterial cholangitis, and ultimately end-stage liver disease. There is no known cure apart from liver transplantation.

The term "primary" distinguishes PSC from secondary sclerosing cholangitis — which has an identifiable cause such as surgical trauma, ischaemia, recurrent choledocholithiasis, IgG4-related disease, or recurrent pyogenic cholangitis ^[1].

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Epidemiology

Incidence and Prevalence

• Incidence: ~0.5–1.3 per 100,000 per year in Northern European and North American populations (highest in Scandinavian countries, consistent with the Northern European "IBD belt") ^[2].
• Prevalence: ~6–16 per 100,000 in Western populations.
• Less primary sclerosing cholangitis with UC in Asian populations — PSC is considerably rarer in East and Southeast Asia, including Hong Kong ^[3][4]. The IBD lecture slides specifically note "Less primary sclerosing cholangitis with UC" and "Fewer extraintestinal manifestations" in Eastern populations compared to Western populations ^[3].

Demographics

• Sex: Male predominance (~2:1, M:F), unlike PBC which overwhelmingly affects women. This is one of the distinguishing epidemiological features.
• Age of onset: Typically diagnosed at age 30–40 years (median ~40), though it can present at any age.
• Earlier onset is seen in patients with concomitant IBD, and in those with PSC-associated cholangiocarcinoma, diagnosis can come as early as the 3rd–4th decade ^[5].

Geographic Variation (Hong Kong Context)

• In Hong Kong, PSC is uncommon compared to recurrent pyogenic cholangitis (RPC), which is the major biliary disease causing stricturing ("Hong Kong disease") ^[6].
• When biliary strictures are encountered in an Asian patient, the differential must prominently include RPC, IgG4-associated cholangitis, and parasitic cholangiopathy (Clonorchis sinensis) alongside PSC ^[2][6].

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Risk Factors

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Anatomy and Function of the Biliary System (Relevant to PSC)

Understanding PSC requires knowing the biliary tree anatomy because the disease involves both intrahepatic and extrahepatic ducts, and the pattern of involvement dictates the clinical presentation and imaging findings.

Hierarchy of the Biliary Tree (from small to large)

1. Bile canaliculi → formed between adjacent hepatocytes; bile is secreted here
2. Canals of Hering (cholangioles) → transitional zone between hepatocytes and bile duct epithelial cells (cholangiocytes); site of hepatic progenitor cells
3. Interlobular bile ducts (small intrahepatic ducts, < 100 μm) → within portal triads; these are the target in PBC
4. Septal bile ducts → medium-sized intrahepatic ducts
5. Segmental bile ducts → drain hepatic segments
6. Right and Left hepatic ducts → converge at the hepatic hilum
7. Common hepatic duct (CHD) → formed by confluence of R and L hepatic ducts
8. Cystic duct → joins from the gallbladder
9. Common bile duct (CBD) → CHD + cystic duct → empties into duodenum at ampulla of Vater

Which Ducts Does PSC Affect?

• PSC characteristically affects medium and large bile ducts — both intrahepatic and extrahepatic.
• The inflammation and fibrosis occur around the ducts (periductal), leading to progressive luminal narrowing and stricture formation.
• This contrasts with PBC, which targets small intrahepatic (interlobular) bile ducts.

A useful mnemonic: PSC = Plumbing (large ducts); PBC = Petite (small ducts).

Functional Significance

• Bile ducts transport bile (containing bile salts, bilirubin, cholesterol, phospholipids) from hepatocytes to the duodenum.
• Cholangiocytes (bile duct epithelial cells) actively modify bile composition by secreting bicarbonate (the "bicarbonate umbrella") and water, and reabsorbing certain solutes.
• When ducts are strictured and scarred → bile stasis → cholestasis → secondary damage to hepatocytes → fibrosis → cirrhosis.
• Bile stasis also predisposes to bacterial cholangitis (ascending infection from duodenum), gallstone formation, and fat-soluble vitamin malabsorption (A, D, E, K).

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Aetiology and Pathophysiology

Aetiology: Unknown, but Immune-Mediated

PSC is considered an immune-mediated disease, but it does not fit neatly into the classic "autoimmune" category because:

1. It has a male predominance (most autoimmune diseases are female-predominant)
2. It does not respond well to immunosuppressive therapy (unlike autoimmune hepatitis or PBC with UDCA)
3. No single autoantibody is pathognomonic

The current model involves a "multi-hit" hypothesis:

Pathophysiological Mechanisms (Explained from First Principles)

1. Gut-Liver Axis — The "Lymphocyte Homing" Hypothesis

This is the leading theory linking IBD to PSC:

• In IBD, activated T-lymphocytes in the gut mucosa express surface receptors including α4β7 integrin and CCR9, which normally home to the gut by binding to MAdCAM-1 (mucosal addressin cell adhesion molecule-1) on gut endothelium.
• In PSC, the hepatic endothelium aberrantly expresses MAdCAM-1 and the chemokine CCL25 (normally a gut-specific chemokine). This "tricks" gut-primed T-cells into migrating to the liver and bile ducts.
• These misdirected lymphocytes then mount an immune attack on cholangiocytes → periductal inflammation.

Why does this matter clinically? It explains why PSC can persist or even develop after colectomy — once the aberrant homing pathway is established, it may be self-perpetuating.

2. Toxic Bile Hypothesis

• Altered gut microbiome (common in IBD) → changes in bile acid metabolism → production of hydrophobic, toxic bile acids
• These toxic bile acids damage cholangiocyte membranes → inflammation → fibrosis
• Normally, cholangiocytes are protected by a "bicarbonate umbrella" — a layer of alkaline secretion on their apical surface. If this is disrupted (genetic polymorphisms in bile acid transporters or chloride channels like CFTR), bile acids can penetrate and damage cells.

3. Genetic Susceptibility

• HLA associations: HLA-B8, HLA-DRB103:01 (DR3), HLA-DRB115:01 (DR2) — these are Class I and Class II MHC molecules that present antigens to T cells; specific alleles may present self-antigens (or cross-reactive microbial antigens) that trigger the immune response.
• Non-HLA genes: polymorphisms in genes related to bile acid transport (e.g., ABCB4), innate immunity, and T-cell regulation have been identified in GWAS studies.

4. Periductal Fibrosis ("Onion-Skin" Lesion)

• The hallmark histological finding: concentric rings of collagen deposited around bile ducts, resembling the layers of an onion.
• This is driven by activated portal fibroblasts and hepatic stellate cells responding to chronic inflammation.
• As fibrosis progresses, the duct lumen narrows → stricture.
• Between strictures, bile backs up → duct dilatation → the classic "beaded" appearance on cholangiography.

5. Cholestasis and Its Consequences

Once strictures form:

• Bile stasis → impaired excretion of bilirubin (→ jaundice), bile salts (→ pruritus, fat malabsorption), and cholesterol
• Ascending bacterial infection → recurrent cholangitis (because stagnant bile is an excellent culture medium)
• Fat-soluble vitamin deficiency (A, D, E, K) → night blindness, osteoporosis/osteomalacia, neuropathy, coagulopathy
• Hepatocyte injury from retained toxic bile acids → ongoing fibrosis → biliary cirrhosis → portal hypertension → liver failure

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Secondary Sclerosing Cholangitis: Causes to Exclude (Differential for "Sclerosing Cholangitis")

Before diagnosing PSC, you must exclude identifiable causes of a similar cholangiographic and histological picture ^[1]:

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Classification

By Duct Involvement

By Associated Conditions

By Cholangiographic Pattern

• Intrahepatic only (~25%)
• Extrahepatic only (~5%)
• Both intrahepatic and extrahepatic (~70%) — most common pattern

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Clinical Features

Natural History

PSC is insidious. Up to 50% of patients are asymptomatic at diagnosis ^[1], often detected incidentally through abnormal liver function tests (particularly elevated ALP) during evaluation of IBD. The median time from diagnosis to liver transplantation or death is approximately 12–18 years without transplantation.

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Symptoms (with Pathophysiological Basis)

Asymptomatic Presentation

• Asymptomatic at diagnosis = 50% and detected as part of the evaluation of abnormal liver tests in patients with IBD ^[1].
• The typical scenario: a young male with known UC has routine blood work showing a persistently elevated ALP → MRCP → beaded bile ducts → PSC diagnosed.

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Signs (with Pathophysiological Basis)

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Extra-Intestinal Associations and Associated Conditions

PSC doesn't exist in isolation. The associated conditions are high-yield:

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Biochemical Features (Cholestatic Pattern) — Not Yet "Diagnosis," but Part of Clinical Assessment

These lab findings are part of the clinical picture that will lead you toward the diagnosis:

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Summary of Pathophysiology → Clinical Feature Connections

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Active Recall - PSC (Definition, Epidemiology, Pathophysiology, Clinical Features)

1. A 35-year-old male with known ulcerative colitis presents with persistently elevated ALP (4x ULN) and normal ALT. What is the most likely diagnosis and what investigation would you perform first?

Your answer

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Most likely diagnosis: Primary Sclerosing Cholangitis (PSC). First investigation: MRCP (non-invasive, comparable diagnostic accuracy to ERCP). Expected finding: multifocal strictures alternating with dilatation giving a 'beaded' appearance of bile ducts.

2. Explain the gut-liver axis hypothesis that links IBD to PSC. What adhesion molecule is aberrantly expressed?

Your answer

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Gut-primed T-lymphocytes express alpha-4-beta-7 integrin and CCR9. Hepatic endothelium aberrantly expresses MAdCAM-1 (mucosal addressin cell adhesion molecule-1) and CCL25, causing gut-activated lymphocytes to home to the liver and attack bile duct epithelium (cholangiocytes), causing periductal inflammation and fibrosis.

3. How do you distinguish PSC from PBC on the basis of demographics, serology, and duct involvement?

Your answer

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PSC: Male predominance, AMA negative, p-ANCA positive (30-80%), large and medium bile ducts affected (intrahepatic and extrahepatic), associated with UC. PBC: Female predominance (90-95%), AMA positive (>95%), targets small interlobular bile ducts only, associated with Sjogren syndrome and scleroderma.

4. What is the hallmark histological finding in PSC, and why does it cause the characteristic 'beaded' appearance on cholangiography?

Your answer

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Hallmark: Concentric periductal 'onion-skin' fibrosis around medium and large bile ducts. This narrows the lumen causing strictures. Between strictures, bile backs up causing segmental dilatation. The alternating strictures and dilatations produce the 'beaded' appearance on MRCP or ERCP.

5. Name 3 malignancies that PSC patients are at increased risk for, and the recommended surveillance for each.

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1) Cholangiocarcinoma (10-20% lifetime risk) - annual MRCP plus CA 19-9; ERCP with brush cytology for dominant strictures. 2) Colorectal cancer (4-5x increased in PSC-UC) - annual colonoscopy from time of PSC diagnosis. 3) Gallbladder cancer - annual ultrasound; cholecystectomy if polyp >= 8 mm (lower threshold than general population).

6. Why is it critical to check serum IgG4 levels in a patient presenting with biliary strictures? What is the key management difference?

Your answer

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IgG4-associated cholangitis (IAC) can mimic PSC cholangiographically but responds to corticosteroid therapy, whereas PSC does not respond to immunosuppression. IAC is associated with autoimmune pancreatitis (type 1). Elevated serum IgG4 (>135 mg/dL) with dense IgG4-positive plasma cell infiltrate on biopsy supports the diagnosis. Missing IAC means missing a treatable condition.

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References

^[1] Senior notes: felixlai.md (Primary Sclerosing Cholangitis section, felix:756–757) ^[2] Senior notes: maxim.md (Acute cholangitis section, maxim:288) ^[3] Lecture slides: Inflammatory bowel disease.pdf (p5, p9, p52, p56) ^[4] Lecture slides: Inflammatory bowel disease.pdf (p5 — East vs West comparison) ^[5] Senior notes: felixlai.md (Cholangiocarcinoma epidemiology, felix:777) ^[6] Senior notes: maxim.md (Recurrent pyogenic cholangitis, maxim:290) ^[7] Senior notes: felixlai.md (UC risk factors — smoking protective, felix:975) ^[8] Senior notes: maxim.md (Obstructive jaundice section, maxim:251–252) ^[9] Senior notes: felixlai.md (Cholangiocarcinoma risk factors, felix:778) ^[10] Senior notes: felixlai.md (Gallbladder cancer risk factors, felix:801) ^[11] Senior notes: felixlai.md (HCC risk factors — autoimmune liver diseases, felix:682)

Differential Diagnosis of Primary Sclerosing Cholangitis

The Clinical Problem — Why Is the DDx Important?

Before we list the differentials, let's understand the clinical scenario you're actually working with. A patient with PSC typically presents with one or more of the following:

1. Cholestatic liver biochemistry — elevated ALP/GGT out of proportion to transaminases
2. Biliary strictures on imaging — multifocal strictures with segmental dilatation on MRCP/ERCP
3. Clinical cholestasis — jaundice, pruritus, dark urine, pale stools
4. Known IBD with incidental abnormal LFTs

The differential diagnosis therefore needs to address two overlapping clinical questions:

• What else causes a cholestatic biochemical pattern?
• What else causes biliary strictures on cholangiography?

These are not the same list, and the approach differs depending on which "entry point" brought the patient to your attention.

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Systematic Framework for the Differential

I like to organise this by thinking about what level of the biliary tree is affected and what mechanism is causing the damage. This mirrors how you'll actually reason at the bedside.

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Detailed Differential Diagnosis

A. Conditions That Mimic PSC on Cholangiography (Biliary Strictures)

These are the "secondary sclerosing cholangitis" mimics — conditions that produce a cholangiographic picture similar to PSC but have an identifiable cause ^[1][2].

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B. Conditions That Mimic PSC Biochemically (Cholestatic LFT Pattern)

These conditions present with elevated ALP/GGT but may not produce biliary strictures visible on cholangiography.

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C. Conditions That Overlap with PSC (the "Overlap Syndromes")

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D. Conditions That Cause Obstructive Jaundice at Specific Levels (Anatomical DDx)

This is how surgeons think about it — based on where the obstruction is on imaging ^[8][15]:

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The PSC vs PBC Comparison — High-Yield Table

This comparison comes up in virtually every hepatology exam. Know it cold.

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Differentiating Stone vs Tumour in Obstructive Jaundice

When a PSC patient develops worsening jaundice, you need to determine whether it's from the PSC itself (dominant stricture), a superimposed stone, or — critically — a cholangiocarcinoma. The classic stone vs tumour distinction applies ^[8][15]:

"Painless progressive obstructive jaundice in elderly is malignant biliary obstruction until proven otherwise" ^[8].

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History-Taking Clues to Narrow the Differential

When you're working up a patient and PSC is on your differential, these history points help you narrow down ^[8][15]:

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Approach to the Differential — Putting It All Together

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Active Recall - PSC Differential Diagnosis

1. A 65-year-old male presents with obstructive jaundice and multifocal biliary strictures on MRCP. Serum IgG4 is markedly elevated. What is the most likely diagnosis, and how does management differ from PSC?

Your answer

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IgG4-associated cholangitis (sclerosing cholangitis). Key difference: responds to corticosteroid therapy, whereas PSC does not respond to immunosuppression. Associated with autoimmune pancreatitis type 1. Confirm with tissue biopsy showing dense IgG4-positive plasma cell infiltrate.

2. Compare and contrast PSC and RPC across five features: geography, sex, stone type, duct predilection, and IBD association.

Your answer

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PSC: Western predominance, male 2:1, no primary stones, both intra- and extrahepatic ducts (beaded), strong IBD/UC association (60-80%). RPC: Southeast Asia (Hong Kong disease), equal M:F, intrahepatic brown pigment/calcium bilirubinate stones formed de novo, left intrahepatic duct predominance, no IBD association.

3. A PSC patient develops rapidly progressive jaundice. How do you differentiate disease progression from superimposed cholangiocarcinoma?

Your answer

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Progressive painless jaundice with constitutional symptoms (LOW, LOA) raises suspicion for cholangiocarcinoma. Investigate with ERCP + brush cytology with FISH, CA 19-9 (supportive but non-specific), cross-sectional imaging (CT/MRI). PSC progression alone typically causes fluctuating jaundice. Any dominant stricture (duct diameter 1.5 mm or less in CBD, 1.0 mm or less in hepatic duct) must be biopsied.

4. What is the single most important serological test to differentiate PBC from PSC, and what additional investigation confirms PSC when this test is negative?

Your answer

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Anti-mitochondrial antibody (AMA): positive in PBC (95% or more), typically absent in PSC. When AMA is negative, perform MRCP - multifocal strictures alternating with dilatation (beaded appearance) confirms large-duct PSC. If MRCP is normal but cholestatic LFTs persist, liver biopsy is needed to diagnose small-duct PSC.

5. List 3 conditions that cause biliary strictures at the hilum and explain one distinguishing feature for each.

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1) Klatskin tumour (perihilar cholangiocarcinoma): painless progressive jaundice, CA 19-9 elevated, mass on imaging. 2) PSC: multifocal beaded strictures (not just hilar), young male with UC, AMA negative. 3) Mirizzi syndrome: impacted gallstone in cystic duct/Hartmann pouch causing extrinsic compression of CHD; gallbladder contracted with stone on USG, abrupt change to normal CBD calibre below stone level.

References

^[1] Senior notes: felixlai.md (Primary Sclerosing Cholangitis section, felix:756–757) ^[2] Senior notes: maxim.md (Acute cholangitis section, maxim:288) ^[6] Senior notes: maxim.md (Recurrent pyogenic cholangitis, maxim:290) ^[8] Senior notes: maxim.md (Obstructive jaundice section, maxim:251–252) ^[9] Senior notes: felixlai.md (Cholangiocarcinoma risk factors and pathogenesis, felix:778–779) ^[12] Senior notes: felixlai.md (Recurrent pyogenic cholangitis, felix:752) ^[13] Lecture slides: WCS 064 - A large liver - by Prof R Poon ^[20191108].doc.pdf (p5 — Cholangiocarcinoma) ^[14] Senior notes: maxim.md (Cholangiocarcinoma, maxim:294) ^[15] Senior notes: maxim.md (Obstructive jaundice — stone vs tumour, maxim:252) ^[16] Senior notes: felixlai.md (Primary biliary cholangitis, felix:760)

Diagnostic Criteria for PSC

The Fundamental Challenge

Here's the thing about PSC that makes it different from many other conditions: there is no single pathognomonic test. There is no "AMA for PBC" equivalent. The diagnosis is established by combining clinical, biochemical, cholangiographic, and sometimes histological data — and critically, by excluding secondary causes of sclerosing cholangitis. Think of it as a constructive diagnosis rather than a "one-test rules them all" diagnosis.

EASL/AASLD Diagnostic Criteria (Current Guidelines)

The diagnosis of PSC is established when ALL THREE of the following are met:

Comparison: PSC vs PBC Diagnostic Criteria

Understanding both side-by-side helps cement why the approach differs:

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Diagnostic Algorithm

Here is the step-by-step clinical reasoning pathway. The key principle: start with blood tests → serology → imaging → biopsy only if needed.

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Investigation Modalities — Detailed Breakdown

A. Biochemical Tests (Blood Work)

1. Liver Function Tests (LFT) — Cholestatic Pattern

Clinical Pearl: A cholestatic pattern means ALP/GGT elevated out of proportion to ALT/AST. In PSC, the typical picture is ALP 3–10× ULN with ALT < 2× ULN. If the transaminases dominate, reconsider the diagnosis.

2. Serology and Autoantibodies

3. Tumour Markers

4. Additional Blood Tests

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B. Imaging Modalities

1. Ultrasound (USG) Abdomen — First-Line Screening

USG is typically the first imaging test obtained in a patient with cholestatic LFTs or jaundice. It is not diagnostic for PSC but provides critical screening information.

Limitation: USG has limited sensitivity for detecting intrahepatic strictures and cannot characterise the full extent of biliary disease. It is a screening tool, not a diagnostic one for PSC. The next step is always MRCP.

2. Magnetic Resonance Cholangiopancreatography (MRCP) — The Gold Standard for Diagnosis

MRCP is typically the 1st imaging modality due to non-invasiveness and comparable diagnostic accuracy to ERCP ^[1].

How MRCP works (from first principles): MRCP uses heavily T2-weighted MRI sequences. In T2-weighted imaging, stationary fluid (like bile in the biliary tree) appears bright white against a dark background. This creates a "cholangiogram" without injecting any contrast — the bile itself acts as the contrast agent. Non-contrast, T2-weighted imaging ^[18].

MRCP advantages over ERCP:

• Non-invasive (no sedation, no endoscope, no contrast injection)
• No risk of post-procedure pancreatitis or ascending cholangitis
• Does NOT require contrast injection into ductal system unlike in ERCP and PTC ^[17]
• Superior to ERCP for assessing tumour anatomy and resectability ^[17]
• Can visualise ducts above a complete obstruction (ERCP can only image ducts below the scope)

MRCP limitations:

• Cannot perform therapeutic intervention (stenting, dilatation, brush cytology)
• May miss very early/subtle PSC changes (sensitivity ~80–90% vs ERCP as reference)
• Spatial resolution slightly inferior to ERCP

3. Endoscopic Retrograde Cholangiopancreatography (ERCP)

ERCP is indicated in patients who are unable to undergo MRCP such as those with implanted metal devices or in patients with early PSC changes that may be missed by MRCP ^[1].

In the PSC context, ERCP has shifted from a primary diagnostic tool to a problem-solving and therapeutic tool.

ERCP findings in PSC:

• Multiple short annular strictures with intervening normal or dilated segments
• "Band-like" strictures — short, sharp, concentric narrowings
• Diffuse involvement — both intrahepatic and extrahepatic tree
• Diverticulum-like outpouchings — representing ectasia between strictured segments

ERCP risks (important because PSC patients may need multiple ERCPs over their lifetime):

• Post-ERCP pancreatitis (~3–5%)
• Ascending cholangitis — involves injection of contrast into bile duct and hence risk for ascending cholangitis in cases of impaired biliary drainage ^[17]
• Perforation (~0.5%)
• Haemorrhage (from sphincterotomy)
• Bacteraemia (thus antibiotic prophylaxis required) ^[18]

4. Percutaneous Transhepatic Cholangiography (PTC)

PTC is preferred to ERCP in stricture/obstruction at or above the level of confluence of hepatic ducts ^[18] — i.e., hilar-level disease where ERCP cannot access above the obstruction.

Complications: Bacteraemia (thus antibiotic prophylaxis required), haemobilia ^[18].

5. CT Abdomen (with Contrast)

CT is not the primary diagnostic modality for PSC but plays important supporting roles:

6. Liver Elastography (FibroScan / MR Elastography)

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C. Histological Examination (Liver Biopsy)

Percutaneous liver biopsy may support diagnosis of PSC but is rarely diagnostic and is not routinely recommended ^[1].

When Is Biopsy Indicated?

Histological Findings

Why is biopsy rarely diagnostic? Because the hallmark onion-skin fibrosis is found in only ~30–40% of biopsy specimens due to sampling error — PSC is patchy and predominantly affects larger ducts that may not be captured in a needle biopsy of the liver parenchyma. This is why cholangiography (MRCP/ERCP) is superior to biopsy for diagnosing large-duct PSC.

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D. Colonoscopy — Mandatory in All PSC Patients

This deserves its own section because it's frequently overlooked:

• All patients diagnosed with PSC should undergo colonoscopy with biopsies to screen for IBD, even if they have no GI symptoms ^[1].
• Why? Because ~60–80% of PSC patients have UC, and the colitis in PSC-IBD is often subclinical (pancolitis with rectal sparing and minimal symptoms).
• Primary sclerosing cholangitis → yearly surveillance colonoscopy ^[3] — if IBD is confirmed, annual colonoscopy is mandated from the time of PSC diagnosis because of the markedly elevated CRC risk.
• If no IBD is found on initial colonoscopy, repeat colonoscopy every 5 years (because IBD can develop later).

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E. Bone Densitometry (DEXA Scan)

• Chronic cholestasis → vitamin D malabsorption → osteoporosis/osteomalacia
• DEXA scan at diagnosis and every 2–3 years to monitor bone mineral density
• Treat with calcium + vitamin D supplementation; bisphosphonates if T-score ≤ −2.5

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Summary: Complete Investigation Panel for Suspected PSC

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Active Recall - PSC Diagnostic Criteria, Algorithm and Investigations

1. What are the 3 criteria required to diagnose PSC? Which single criterion is the cornerstone of diagnosis?

Your answer

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1) Cholestatic biochemistry (ALP > 1.5x ULN for > 6 months). 2) Characteristic cholangiographic findings (multifocal strictures alternating with dilatation - 'beaded' pattern on MRCP or ERCP). 3) Exclusion of secondary causes of sclerosing cholangitis. The cornerstone is the cholangiographic findings on MRCP.

2. Why is MRCP preferred over ERCP as the first-line imaging modality for diagnosing PSC? Name 2 situations where ERCP is still indicated.

Your answer

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MRCP is non-invasive, does not require contrast injection into the ductal system (uses T2-weighted sequences where bile itself appears bright), has comparable diagnostic accuracy, and avoids ERCP complications (pancreatitis, cholangitis, perforation). ERCP indicated for: 1) Dominant stricture evaluation with brush cytology to exclude cholangiocarcinoma. 2) Therapeutic intervention - balloon dilatation or stenting of symptomatic strictures. Also indicated when MRCP is contraindicated (ferromagnetic implants) or when early PSC changes may be missed by MRCP.

3. A patient with suspected PSC has a completely normal MRCP. What is your next diagnostic step and what histological finding would confirm the diagnosis?

Your answer

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Next step: Liver biopsy (percutaneous). This is one of the few indications for biopsy in PSC - suspected small-duct PSC. Histological hallmark: concentric periductal 'onion-skin' fibrosis around medium-sized bile ducts. Also check AMA is negative to exclude PBC, and exclude drug-induced cholestasis and sarcoidosis.

4. What mandatory non-hepatobiliary investigation must ALL patients with newly diagnosed PSC undergo, and why?

Your answer

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Colonoscopy with biopsies to screen for inflammatory bowel disease (IBD), even if the patient has no GI symptoms. Reason: 60-80% of PSC patients have underlying UC which is often subclinical (pancolitis with rectal sparing, minimal symptoms). If IBD confirmed, annual surveillance colonoscopy is required due to 4-5x increased CRC risk. If no IBD found, repeat colonoscopy every 5 years.

5. How do you use serum IgG4 levels in the diagnostic workup of PSC? What is the clinical significance of an elevated IgG4?

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IgG4 is checked to exclude IgG4-associated cholangitis (IAC), which mimics PSC cholangiographically but responds to corticosteroids. About 9-15% of PSC patients have mildly elevated IgG4 without true IgG4-SC. Markedly elevated IgG4 (> 4x ULN) with features of autoimmune pancreatitis and dense IgG4-positive plasma cell infiltrate on biopsy = IgG4-SC. Mildly elevated IgG4 in a typical PSC picture with IBD = still PSC with incidental IgG4 elevation.

6. List 5 components of the annual surveillance programme for a patient with established PSC and concurrent UC.

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1) Annual colonoscopy with biopsies for CRC surveillance. 2) Annual MRCP for cholangiocarcinoma surveillance. 3) Annual CA 19-9 for cholangiocarcinoma monitoring. 4) Annual USG abdomen for gallbladder polyps and cancer. 5) Bone densitometry (DEXA) every 2-3 years for osteoporosis. Also: fat-soluble vitamin levels, LFTs for disease progression.

References

^[1] Senior notes: felixlai.md (Primary Sclerosing Cholangitis section, felix:756–757) ^[2] Senior notes: maxim.md (Acute cholangitis section, maxim:288) ^[3] Lecture slides: Inflammatory bowel disease.pdf (p52, p56 — CRC surveillance in PSC) ^[6] Senior notes: maxim.md (Recurrent pyogenic cholangitis, maxim:290) ^[8] Senior notes: maxim.md (Obstructive jaundice section, maxim:251–252) ^[13] Lecture slides: WCS 064 - A large liver - by Prof R Poon ^[20191108].doc.pdf (p5 — Cholangiocarcinoma diagnosis) ^[16] Senior notes: felixlai.md (Primary biliary cholangitis, felix:760–761) ^[17] Senior notes: felixlai.md (Cholangiocarcinoma diagnosis, felix:780–782; MBO investigations, felix:723) ^[18] Senior notes: maxim.md (HBP investigations — MRCP, PTC, ERCP, maxim:250–251) ^[19] Senior notes: maxim.md (Gallbladder polyps management in PSC, maxim:292)

Management of Primary Sclerosing Cholangitis

The Harsh Reality — Setting the Scene

Let me be upfront about this: PSC is one of the most frustrating diseases in hepatology to manage. Why? Because:

1. There is no proven medical therapy that alters the natural history of the disease
2. NONE of the following agents are proven to alter the natural history of the disorder — Glucocorticoid, Cyclosporine, Methotrexate, Azathioprine, Tacrolimus ^[1]
3. UDCA is NOT generally recommended in PSC due to uncertain benefits ^[1]
4. The only definitive treatment is liver transplantation for advanced disease ^[1]

So the management of PSC is fundamentally about: (a) managing symptoms, (b) treating complications as they arise, (c) surveillance for malignancy, and (d) knowing when to refer for transplantation. Think of it as chronic disease management with serial troubleshooting, not curative treatment.

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Management Algorithm — Overview

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A. Medical Management

1. Ursodeoxycholic Acid (UDCA) — The Controversial One

Let's break down the name: "urso" = bear (Latin ursus), "deoxy" = oxygen removed, "cholic acid" = a bile acid. UDCA was originally isolated from bear bile — it is a hydrophilic bile acid that constitutes only ~3% of the human bile acid pool.

Mechanism of action (theoretical in PSC):

• Replaces toxic hydrophobic bile acids in the bile acid pool → protects cholangiocytes from bile acid–mediated injury
• Stimulates biliary secretion (choleresis) → improves bile flow
• Has anti-inflammatory and immunomodulatory properties (reduces HLA class I expression on hepatocytes)
• Stabilises the "bicarbonate umbrella" on cholangiocyte apical membranes

The evidence problem:

2. Immunosuppressive Therapy — Why It Doesn't Work in PSC

This seems counterintuitive for an immune-mediated disease, so let me explain why:

• PSC is driven primarily by innate immune mechanisms and fibrosis rather than classic adaptive autoimmunity
• The periductal fibrosis, once established, is self-perpetuating — suppressing the immune system doesn't reverse scar tissue
• The gut-liver axis (aberrant lymphocyte homing via MAdCAM-1) is not effectively targeted by conventional immunosuppressants
• Unlike AIH, where interface hepatitis responds to steroids, the biliary-targeted injury in PSC follows a different pathway

NONE of the following agents are proven to alter the natural history of the disorder — Glucocorticoid, Cyclosporine, Methotrexate, Azathioprine, Tacrolimus ^[1].

3. Emerging / Investigational Therapies (2024–2026)

While no agent has achieved regulatory approval specifically for PSC as of 2026, several are in advanced clinical trials and worth knowing:

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B. Endoscopic Management — Dominant Stricture Management

This is where the real procedural action happens in PSC management. Patients with dominant stricture or cholangitis should undergo endoscopic therapy to dilate or stent the stricture to relief jaundice and pruritus ^[1].

What Is a Dominant Stricture?

A dominant stricture is a stenosis with luminal diameter ≤ 1.5 mm in the CBD or ≤ 1.0 mm in a hepatic duct. It occurs in ~50% of PSC patients during their disease course and represents a critical management inflection point because:

1. It causes clinically significant cholestasis (worsening jaundice, pruritus)
2. It predisposes to recurrent bacterial cholangitis
3. It must be investigated to exclude cholangiocarcinoma (10–20% lifetime risk)

Endoscopic Approach

Role of PTC (Percutaneous Transhepatic Cholangiography/Drainage)

PTC is preferred to ERCP in stricture/obstruction at or above the level of confluence of hepatic ducts ^[18] — i.e., when the dominant stricture is at the hilum and ERCP cannot access above it.

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C. Management of Acute Cholangitis in PSC

PSC patients are prone to recurrent bacterial cholangitis because strictured, stagnant bile is an excellent culture medium. The management follows the same principles as acute cholangitis from any cause — RAD: Resuscitation, Antibiotics, Drainage ^[2].

Management of cholangitis: Resuscitation → Treat sepsis with intravenous antibiotic → Decompression of biliary system (Endoscopic vs percutaneous) → Definitive management ^[22].

Key point for PSC-specific cholangitis: The "definitive management" step differs from stone-related cholangitis. In choledocholithiasis, you remove the stone. In PSC, you dilate the stricture — but the underlying disease persists, so cholangitis tends to recur. Prophylactic antibiotics (e.g., ciprofloxacin) may be considered for patients with frequent episodes.

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D. Management of Symptoms

1. Pruritus — Stepwise Approach

Pruritus in cholestasis is one of the most debilitating symptoms and the most common reason patients seek help. The itch is not caused by bile salts directly depositing in skin (an old theory) but by autotaxin-generated lysophosphatidic acid (LPA) acting on neural itch pathways.

Mnemonic for pruritus stepladder: Come Running Now Sir → Cholestyramine → Rifampicin → Naltrexone → Sertraline

2. Fatigue

• Most difficult symptom to treat — no specific effective therapy
• Exclude and treat contributing factors: anaemia, hypothyroidism, depression, sleep disruption from pruritus
• General measures: exercise, sleep hygiene, caffeine management
• Modafinil has been tried anecdotally but not evidence-based

3. Fat-Soluble Vitamin Deficiency

4. Steatorrhoea

• Symptomatic steatorrhoea due to bile acid insufficiency can be partially corrected by restricting dietary fat ^[20]
• Medium-chain triglycerides (MCTs) do not require bile acids for absorption — they are absorbed by passive diffusion directly into portal circulation without requiring micellar formation ^[20]
• Pancreatic enzyme supplementation if concurrent pancreatic insufficiency

5. Metabolic Bone Disease

• Osteoporosis is more common than osteomalacia in PSC
• DEXA scan at diagnosis → repeat every 2–3 years
• Management: Calcium + Vitamin D supplementation → bisphosphonates (alendronate/risedronate) if T-score ≤ −2.5
• Weight-bearing exercise; fall prevention

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E. Liver Transplantation — The Definitive Treatment

Liver transplantation is the treatment of choice for patients with advanced liver disease due to PSC ^[1].

Indications for Liver Transplantation in PSC

Transplant Outcomes in PSC

• 5-year survival: ~85% (excellent — among the best outcomes for any transplant indication)
• 10-year survival: ~70%
• Recurrent PSC post-transplant: Occurs in ~20–25% of cases; the disease can recur in the allograft, typically 3–5 years post-transplant. This confirms the immunological basis of the disease (it follows the patient, not the liver)

Contraindications

Pre-Transplant Considerations Specific to PSC

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F. Surgical Management (Non-Transplant)

Historically, biliary reconstructive surgery (e.g., hepaticojejunostomy) was attempted for PSC but is now largely abandoned because:

• It makes subsequent liver transplantation technically much more difficult (adhesions, altered anatomy)
• It does not alter disease progression
• It carries significant operative morbidity (bile leaks, stricture recurrence, cholangitis)

The only non-transplant surgical indication in PSC is cholecystectomy for:

• Gallbladder mass or polyp ≥ 8 mm — adenomatous polyps ≥ 1cm (or 8 mm if underlying PSC) ^[19]
• Gallbladder carcinoma
• Symptomatic cholelithiasis

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G. Cancer Surveillance — An Integral Part of Management

This is not optional — it is core management. PSC patients carry increased risk of cholangiocarcinoma, CRC, gallbladder carcinoma, and HCC.

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H. Management of Concurrent IBD

The IBD in PSC-UC has unique features and requires specific attention:

• Colitis may be quiescent despite significant liver disease — don't be falsely reassured
• 5-ASA (mesalazine) is the mainstay for mild-to-moderate UC; some evidence suggests it may also be chemopreventive for CRC in PSC-UC
• Immunosuppressants (azathioprine, biologics) for moderate-to-severe IBD follow standard IBD protocols
• Elective surgery for debilitating extra-intestinal manifestations, except those independent of colitis activity — sacroiliitis, hepatobiliary complications ^[23] — meaning PSC itself is NOT an indication for colectomy (it doesn't improve after colectomy; it can even present after colectomy)
• Post-transplant: IBD can worsen (immunosuppressive regimens differ from IBD-specific ones); close monitoring needed

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Summary Table: Management at a Glance

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Active Recall - PSC Management

1. A patient with PSC asks whether ursodeoxycholic acid will help prevent disease progression. What do you tell them, and how does this differ from PBC?

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UDCA is NOT generally recommended in PSC as it has not been proven to improve transplant-free survival, prevent cirrhosis, or reduce cholangiocarcinoma risk despite improving biochemistry. High-dose UDCA (28-30 mg/kg/day) is actually harmful. This contrasts with PBC where UDCA at 13-15 mg/kg/day is first-line therapy with proven survival benefit, delaying progression to end-stage liver disease and need for transplant.

2. Describe the endoscopic management approach for a dominant stricture in PSC, including the critical investigation that must be performed.

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ERCP with brush cytology plus or minus FISH to exclude cholangiocarcinoma (sensitivity improved from 40-60% with cytology alone to 60-70% with FISH). If cytology negative: balloon dilatation of the stricture. If dilatation alone does not achieve adequate drainage: short-term plastic stent (2-4 weeks only, then scheduled removal). Avoid long-term stenting as indwelling stent serves as nidus for infection and worsens strictures.

3. List the stepwise approach to managing cholestatic pruritus in PSC. For each agent, briefly explain its mechanism.

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Step 1: Cholestyramine - bile acid sequestrant, binds bile salts in gut preventing enterohepatic recirculation. Step 2: Rifampicin - induces hepatic CYP enzymes enhancing metabolism and excretion of pruritogens. Step 3: Naltrexone - opioid antagonist, blocks endogenous opioid-mediated pruritus pathway. Step 4: Sertraline - SSRI, modulates central serotonergic itch processing. Refractory: plasmapheresis or liver transplantation.

4. What are the indications for liver transplantation in PSC, and what is the expected 5-year survival?

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Indications: 1) Decompensated cirrhosis (ascites, encephalopathy, variceal bleeding). 2) MELD score 15 or above. 3) Recurrent bacterial cholangitis uncontrollable by endoscopic means. 4) Intractable pruritus refractory to medical therapy. 5) Selected cholangiocarcinoma (Mayo Protocol with neoadjuvant chemoradiation). 6) HCC within transplant criteria. Expected 5-year survival approximately 85%. Note: PSC recurs in the allograft in approximately 20-25% of cases.

5. Why does immunosuppressive therapy fail in PSC but succeed in PSC-AIH overlap? What specific immunosuppressive regimen is used in the overlap syndrome?

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PSC is driven by innate immune mechanisms and established periductal fibrosis that is self-perpetuating. Conventional immunosuppressants cannot reverse scar tissue and do not effectively target the gut-liver axis (MAdCAM-1 mediated lymphocyte homing). PSC-AIH overlap has a superimposed adaptive autoimmune component (interface hepatitis) that responds to immunosuppression. Regimen: Prednisolone for induction plus Azathioprine for maintenance, same as standard AIH treatment.

References

^[1] Senior notes: felixlai.md (PSC Treatment section, felix:758) ^[2] Senior notes: maxim.md (Acute cholangitis management — RAD, maxim:288–289) ^[3] Lecture slides: Inflammatory bowel disease.pdf (p52, p56 — CRC surveillance in PSC; yearly colonoscopy) ^[8] Senior notes: maxim.md (Obstructive jaundice — biliary obstruction consequences, maxim:251) ^[9] Senior notes: felixlai.md (Cholangiocarcinoma risk factors — PSC association, felix:778) ^[18] Senior notes: maxim.md (HBP investigations — PTC preferred for hilar obstruction, maxim:250–251) ^[19] Senior notes: maxim.md (Gallbladder polyps management — 8 mm threshold in PSC, maxim:292) ^[20] Senior notes: felixlai.md (PBC treatment — UDCA, vitamin supplementation, liver transplant, felix:763; maxim liver transplant criteria, maxim:268) ^[21] Lecture slides: GC 200. RUQ pain, jaundice and fever Cholecytitis and cholangitis Imaging of GI system.pdf (p14 — ERCP contraindications) ^[22] Lecture slides: Malignant biliary obstruction.pdf (p15, p17 — Management of cholangitis and biliary obstruction) ^[23] Senior notes: maxim.md (IBD surgical indications — EIM independent of colitis, maxim:190)

Complications of Primary Sclerosing Cholangitis

The Big Picture — Why PSC Is a Disease of Complications

PSC itself progresses silently in many patients for years. The morbidity and mortality come overwhelmingly from the complications of the disease rather than the primary pathology per se. Think of PSC as a slow-burning fire in the biliary tree: the strictures form quietly, but the consequences — cholestasis, cirrhosis, infection, and cancer — are what kill or debilitate patients.

Let's organise the complications into a logical framework that follows the pathophysiological cascade:

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I. Complications of Cholestasis

These complications arise because bile cannot flow properly through the strictured biliary tree. The retained bile and its constituents cause systemic damage.

1. Steatorrhoea and Fat Malabsorption

Steatorrhoea and vitamin deficiency result from decreased biliary secretion of bile acids ^[1][24].

From first principles: Bile salts are essential for the emulsification and absorption of dietary fats. They form mixed micelles with fatty acids and monoglycerides in the duodenal lumen, which are then absorbed across the enterocyte brush border. When bile salt delivery to the duodenum is reduced (because strictures impair bile flow), fat remains undigested in the gut lumen → steatorrhoea (greasy, foul-smelling, floating stools that are pale because of absent stercobilin).

• Fat malabsorption leads to caloric loss and weight loss
• The degree of steatorrhoea correlates with the severity of cholestasis

2. Fat-Soluble Vitamin Deficiency (A, D, E, K)

Leads to decreased absorption of fat-soluble vitamins A, D, E, K. Vitamin A and D deficiency are more common requiring supplementation ^[24].

Fat-soluble vitamins (mnemonic: ADEK) require bile salt-mediated micellar solubilisation for intestinal absorption. When bile salt delivery fails:

3. Hepatic Osteodystrophy

Metabolic bone disease includes osteopenia and osteoporosis or rarely osteomalacia. Characteristic bone disorder which reflects the inhibitory effect of a retained toxin on the osteoblast ^[24].

This is a specific and important complication of chronic cholestatic liver disease (both PSC and PBC):

• Osteoporosis (reduced bone density, normal mineralisation) is more common than osteomalacia in PSC
  • Mechanism: retained bile constituents (e.g., bilirubin, lithocholic acid) directly inhibit osteoblast function → reduced bone formation. Additionally, vitamin D deficiency impairs calcium absorption → secondary hyperparathyroidism → bone resorption
• Osteomalacia (defective mineralisation of osteoid) is less common
  • Mechanism: severe vitamin D deficiency → insufficient calcium and phosphate incorporation into bone matrix
• Clinical significance: Vertebral compression fractures, pathological fractures, chronic back pain
• Management: DEXA scan at diagnosis and every 2–3 years; calcium + vitamin D supplementation; bisphosphonates if T-score ≤ −2.5; weight-bearing exercise

4. Pruritus

Already discussed in the management section, but worth listing as a complication because it can be severely debilitating:

• Chronic pruritus → excoriations → skin infections → sleep deprivation → depression → markedly impaired quality of life
• Can be the primary reason for liver transplant referral even in the absence of advanced cirrhosis
• Mechanism: autotaxin-generated lysophosphatidic acid (LPA) rather than bile salt deposition in skin (old theory)

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II. Complications of Biliary Strictures

The strictures are the defining anatomical lesion of PSC, and they generate their own cascade of problems.

1. Dominant Strictures

Up to 60% of patients may develop a dominant stricture in intrahepatic or extrahepatic biliary tree ^[24].

A dominant stricture is defined as a luminal diameter ≤ 1.5 mm in the CBD or ≤ 1.0 mm in a hepatic duct. Why does this matter?

• Causes acute worsening of jaundice (increased bilirubin due to near-complete obstruction)
• Predisposes to recurrent bacterial cholangitis (bile stasis → bacterial overgrowth)
• Must be investigated to exclude cholangiocarcinoma — any new dominant stricture requires ERCP with brush cytology ± FISH
• Management: ERCP balloon dilatation ± short-term plastic stent

2. Choledocholithiasis and Cholelithiasis

Choledocholithiasis and cholelithiasis due to cholesterol or pigment stones ^[24].

Why do PSC patients develop gallstones?

• Bile stasis → supersaturation of bile with cholesterol → cholesterol stone nucleation
• Altered bile composition (reduced bile salt:cholesterol ratio) → lithogenic bile
• Pigment stones can also form from bilirubin precipitation in the setting of chronic biliary inflammation
• Stones can form within the gallbladder (cholelithiasis) or within the bile ducts themselves (choledocholithiasis)
• Bilirubin may fluctuate substantially, possibly indicating transient blockage of strictured bile ducts by biliary sludge or small stones ^[1]

3. Recurrent Bacterial Cholangitis

Cholangitis develops spontaneously in patients with bile duct stones or obstructing strictures or in patients after undergoing endoscopic or surgical manipulation ^[24].

From first principles: Normal bile is sterile. The sphincter of Oddi acts as a barrier preventing duodenal bacteria from ascending into the biliary tree. In PSC:

• Strictures cause bile stasis → stagnant bile is an excellent culture medium
• Endoscopic interventions (ERCP, stenting) disrupt the sphincter barrier → bacterial access
• Biliary stent in-situ serves as a nidus for infection ^[2]
• Pathogens: GNR (E. coli, Klebsiella) > Enterococcus; Pseudomonas if stent present ^[2]

Clinical presentation:

• Charcot's triad (50–70%): Fever, RUQ pain, jaundice ^[2]
• Reynolds pentad ( < 10%): Charcot's triad + shock + altered mental state ^[2] — this represents suppurative cholangitis with sepsis, a surgical emergency

Why is recurrent cholangitis so dangerous in PSC?

• Each episode causes further inflammation → additional scarring → worsening strictures → more stasis → more cholangitis → a vicious cycle
• Biliary sepsis with endotoxaemia, impaired reticuloendothelial function, and impaired cell-mediated immunity ^[8]
• Can precipitate acute hepatic decompensation

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III. Complications of Cirrhosis and Portal Hypertension

As PSC progresses, periductal fibrosis extends into the parenchyma → bridging fibrosis → regenerative nodules → biliary cirrhosis. Once cirrhosis is established, PSC patients develop the same complications as any cirrhotic patient:

Liver cirrhosis is characterised by bridging fibrosis, distortion of hepatic architecture and formation of regenerative nodules ^[25].

1. Portal Hypertension and Its Consequences

Signs and symptoms of hepatic decompensation: abdominal distension from ascites, confusion from hepatic encephalopathy, haematemesis from oesophageal variceal bleeding ^[1].

Risk factors for decompensation of cirrhosis include bleeding, dehydration, infection, obesity, alcoholism, and medications ^[25].

2. Hepatocellular Carcinoma (HCC)

Patients with PSC and cirrhosis are at increased risk of HCC ^[1][24].

• HCC develops on the background of cirrhosis from any cause — PSC is no exception
• Any cause of cirrhosis — infection (HBV, HCV), metabolic (ALD, NAFLD, Wilson's disease), immune (PBC, PSC) — can lead to HCC ^[11][26]
• However, the HCC risk in PSC-cirrhosis is lower than in HBV/HCV-related cirrhosis
• Surveillance: USG + AFP every 6 months once cirrhosis is established (standard protocol)

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IV. Malignant Complications — The Cancers of PSC

This is arguably the most important section on complications because malignancy is the leading cause of death in PSC patients.

1. Cholangiocarcinoma (CCA)

Strong association with cholangiocarcinoma especially perihilar disease ^[9].

Lifetime risk: 10–20% (some studies report up to 25%). This makes PSC the single strongest risk factor for cholangiocarcinoma worldwide.

Why does chronic biliary inflammation lead to cholangiocarcinoma?

• Chronic inflammation → repeated cycles of cholangiocyte injury and regeneration → accumulation of genetic mutations (similar to the inflammation → dysplasia → carcinoma sequence seen in UC-CRC)
• Bile stasis → prolonged exposure of cholangiocytes to toxic bile constituents → DNA damage
• Cholangiocarcinoma is characterised by slow growth, high rate of local invasion, mucin production and tendency to invade perineural sheath and spread along nerves ^[9]
• Association with ulcerative colitis (common in Westerners) and recurrent pyogenic cholangitis (common in Orientals) ^[13]

Key clinical features in PSC-associated CCA:

• Often occurs early in the disease course — ~50% of CCAs in PSC are diagnosed within the first 1–2 years of PSC diagnosis (sometimes simultaneously)
• Mostly occurs in patients > 50 years ^[13], but PSC-associated CCA can present earlier
• Typically perihilar (Klatskin tumour) — obstruction to just left or right hepatic duct alone will not cause obstructive jaundice ^[20]; obstruction at the bifurcation blocks both systems
• Presents as a new dominant stricture with rapidly progressive jaundice, weight loss, and rising CA 19-9

Surveillance and detection:

• Annual MRCP + serum CA 19-9
• Any new dominant stricture → ERCP with brush cytology ± FISH
• Tumour markers: CEA, CA 19-9 (may or may not be elevated, nonspecific) ^[13]
• FNAC or Trucut biopsy ONLY for unresectable cases ^[13]

Prognosis: Dismal. PSC-associated CCA has a worse prognosis than sporadic CCA. Most are unresectable at diagnosis. Hepatic resection is the treatment of choice (resectability rate about 20%) ^[13]. For selected patients with perihilar CCA arising in PSC, the Mayo Protocol (neoadjuvant chemoradiation + liver transplantation) offers 5-year survival of ~60–70%.

2. Gallbladder Carcinoma

Gallbladder cancer is an under-appreciated complication of PSC ^[24].

• PSC patients have a higher prevalence of gallbladder mass lesions — both benign (polyps, adenomyomatosis) and malignant
• Primary sclerosing cholangitis is a risk factor for gallbladder carcinoma ^[10][19]
• The threshold for cholecystectomy in PSC patients is lower: adenomatous polyps ≥ 1 cm (or 8 mm if underlying PSC) ^[19] — compared to 10 mm in the general population
• Surveillance: Annual USG abdomen to monitor gallbladder
• Any gallbladder mass lesion in a PSC patient should prompt cholecystectomy regardless of size

3. Colorectal Cancer (CRC)

This is a complication of the PSC-IBD association rather than PSC directly, but it is one of the most clinically significant:

PSC is a patient-specific risk factor for IBD-associated colorectal neoplasia ^[3].

Why does PSC increase CRC risk above and beyond UC alone?

• The prevailing hypothesis: altered bile acid metabolism in PSC → increased concentration of secondary bile acids (deoxycholic acid) in the colon → direct mitogenic and DNA-damaging effects on colonic epithelium → accelerated dysplasia-carcinoma sequence
• PSC-UC patients have a 4–5× higher CRC risk than UC patients without PSC
• The colitis in PSC-UC is often pancolitis (extensive involvement), which itself is a CRC risk factor

Surveillance: Primary sclerosing cholangitis: yearly surveillance colonoscopy ^[3]. This is more frequent than standard IBD surveillance:

Ideally, surveillance colonoscopy should be performed when the disease is in remission ^[3].

• UDCA and 5-ASA (mesalazine) may have chemopreventive effects against CRC in PSC-UC, though evidence is not definitive
• If high-grade dysplasia or CRC is found → colectomy (total proctocolectomy with ileal pouch-anal anastomosis for UC; segmental resection may be considered in CD)

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V. Complications Related to PSC-IBD Interaction

PSC doesn't just coexist with IBD — it modifies the behaviour of IBD and vice versa:

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VI. Recurrence After Liver Transplantation

Even after definitive treatment (transplantation), PSC has a significant recurrence rate:

• Recurrent PSC in the allograft: ~20–25% at 5–10 years post-transplant
• Manifests as new biliary strictures in the transplanted liver with cholangiographic features identical to original PSC
• Must be distinguished from other causes of biliary strictures post-transplant: hepatic artery thrombosis (ischaemic cholangiopathy), chronic ductopenic rejection, ABO-incompatible graft
• Recurrence is more common in patients with concurrent IBD (supporting the gut-liver axis hypothesis)
• Recurrent PSC can lead to graft loss requiring re-transplantation

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Summary Table: All Complications at a Glance

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Active Recall - PSC Complications

1. List the 4 fat-soluble vitamins deficient in PSC and one clinical consequence of each. Explain the shared mechanism of deficiency.

Your answer

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Vitamin A: night blindness. Vitamin D: osteoporosis/osteomalacia. Vitamin E: peripheral neuropathy. Vitamin K: coagulopathy (prolonged PT/INR). Shared mechanism: bile salt delivery to duodenum is reduced due to biliary strictures causing cholestasis. Fat-soluble vitamins require bile salt-mediated micellar solubilisation for intestinal absorption, so they cannot be absorbed.

2. A PSC patient presents with rapidly progressive jaundice, weight loss, and a rising CA 19-9. What complication do you suspect, what is the investigation of choice, and what is the lifetime risk?

Your answer

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Suspect cholangiocarcinoma (CCA), most likely perihilar. Investigation: ERCP with brush cytology plus FISH (fluorescence in situ hybridization) of the dominant stricture. Cross-sectional imaging (CT/MRI) for staging. Lifetime risk of CCA in PSC is 10-20%. Approximately 50% are diagnosed within the first 1-2 years of PSC diagnosis.

3. Why is the CRC surveillance protocol different for PSC-UC patients compared to UC patients without PSC? State the recommended intervals.

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PSC-UC patients have 4-5x higher CRC risk than UC alone, likely due to altered bile acid metabolism increasing secondary bile acids (deoxycholic acid) in the colon causing direct mutagenic effects. PSC-UC: yearly colonoscopy from time of PSC diagnosis. UC without PSC: screening starts at maximum 8 years after diagnosis, then every 1-3 years depending on risk factors.

4. A PSC patient has a prolonged PT/INR. How do you determine whether this is due to vitamin K malabsorption or hepatic synthetic failure, and why does this distinction matter?

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Give IV vitamin K 10 mg and recheck INR in 24-48 hours. If INR corrects: vitamin K malabsorption from cholestasis (treatable with supplementation). If INR does not correct: hepatic synthetic failure (hepatocytes too damaged to synthesise clotting factors even with adequate substrate). This distinction matters because synthetic failure indicates advanced cirrhosis and need for liver transplant assessment, while malabsorption is manageable with replacement.

5. Describe the vicious cycle of complications that biliary strictures create in PSC. Why does each episode of cholangitis worsen the long-term prognosis?

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Strictures cause bile stasis, which provides a culture medium for ascending bacteria leading to cholangitis. Each episode of cholangitis causes further biliary inflammation, which heals with additional fibrosis, creating tighter or new strictures. Tighter strictures cause worse bile stasis, predisposing to more cholangitis. This vicious cycle (stricture, stasis, infection, inflammation, more stricture) accelerates progression to biliary cirrhosis and also increases the cumulative risk of malignant transformation to cholangiocarcinoma.

6. What is the rate of PSC recurrence after liver transplantation, and what must it be distinguished from?

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Recurrent PSC in the allograft occurs in approximately 20-25% of patients at 5-10 years post-transplant. It manifests as new biliary strictures with cholangiographic features identical to original PSC. Must be distinguished from: (1) hepatic artery thrombosis causing ischaemic cholangiopathy, (2) chronic ductopenic rejection, (3) ABO-incompatible graft complications. Recurrence is more common in patients with concurrent IBD, supporting the gut-liver axis hypothesis.

References

^[1] Senior notes: felixlai.md (PSC Complications section, felix:758–759) ^[2] Senior notes: maxim.md (Acute cholangitis — clinical features and management, maxim:288) ^[3] Lecture slides: Inflammatory bowel disease.pdf (p52 — CRC risk factors in IBD; p56 — surveillance intervals) ^[8] Senior notes: maxim.md (Obstructive jaundice — pathophysiological disturbances, maxim:251) ^[9] Senior notes: felixlai.md (Cholangiocarcinoma risk factors — PSC, felix:778–779) ^[10] Senior notes: felixlai.md (Gallbladder cancer risk factors — PSC, felix:801) ^[11] Senior notes: felixlai.md (HCC risk factors — autoimmune liver diseases including PSC, felix:682) ^[13] Lecture slides: WCS 064 - A large liver - by Prof R Poon ^[20191108].doc.pdf (p5 — Cholangiocarcinoma) ^[19] Senior notes: maxim.md (Gallbladder polyps management — 8 mm threshold in PSC, maxim:292) ^[20] Senior notes: felixlai.md (Cholangiocarcinoma — biliary obstruction causing jaundice, felix:720) ^[24] Senior notes: felixlai.md (PSC specific complications — detailed, felix:759) ^[25] Senior notes: felixlai.md (Liver cirrhosis overview and causes, felix:636) ^[26] Senior notes: maxim.md (HCC risk factors — any cause of cirrhosis including PSC, maxim:260)