Primary Sclerosing Cholangitis

Slide 1 · Primary Sclerosing Cholangitis

Primary Sclerosing Cholangitis

Duct injury · Periductal fibrosis · Cholangiographic strictures

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Define PSC by its affected ducts and characteristic fibrosing lesion.

Explain established associations and proposed immune mechanisms.

Connect duct pathology with cholangiography, manifestations, and complications.

Differentiate PSC from primary biliary, IgG4-related, and secondary cholangitis.

Slide 3 · PSC is a chronic fibrosing cholangiopathy

Inflammation and obliterative fibrosis of major bile ducts

Large intrahepatic and extrahepatic bile ducts are principal targets.

Irregularly preserved duct segments may become dilated.

This combination produces a recognizable obstructive biliary phenotype.

Slide 4 · Anatomical distribution determines the phenotype

Major intrahepatic ducts are affected.

Extrahepatic ducts are also affected.

Small portal-tract ducts may show secondary cholestatic changes rather than the defining large-duct lesion.

SCHEMATIC — major duct anatomy

Intrahepatic branches

Extrahepatic duct

Large ducts: Principal lesions

Slide 5 · Alternating injury creates the beaded duct

Inflammation and fibrosis narrow affected segments.

Relatively preserved segments remain patent or dilate.

Multiple strictures alternating with dilatations explain the characteristic appearance.

SCHEMATIC — alternating diameter

Dilated segment

Fibrotic stricture

Imaging appearance: “beading”

Slide 6 · Injury and scarring are linked but distinct

Inflammatory component

Fibrosing component

Cholangiocyte epithelial damage

Acute neutrophilic activity may coexist with chronic inflammation

Periductal edema may worsen narrowing

Persistent periductal collagen deposition

Concentric scar progressively constricts a duct

End-stage lesions can obliterate the lumen

Slide 7 · Who develops PSC?

Typical presentation occurs from the third through fifth decades.

Male predominance is approximately 2:1.

These are population tendencies, not diagnostic requirements.

CHARACTERISTIC ASSOCIATIONS

Age at presentation

3rd–5th decades

Sex distribution

~2:1 male predominance

IBD / ulcerative colitis

~70% have IBD

Slide 8 · PSC is strongly associated with inflammatory bowel disease

Inflammatory bowel disease is reported in approximately 70% of PSC patients.

Ulcerative colitis is the particularly strong association.

The enteric association is relevant both clinically and mechanistically.

Association is not proof that colitis directly causes PSC.

Slide 9 · The gut–liver association raises a mechanistic question

Why should bowel inflammation accompany bile-duct damage?

Ulcerative colitis provides a setting for mucosal T-cell activation.

A proposed mechanism is migration of gut-activated lymphocytes to the liver.

The putative cross-reactive biliary antigen remains hypothetical.

Slide 10 · Familial clustering suggests genetic susceptibility

First-degree relatives have increased risk of PSC.

This supports a heritable component without specifying a single causative variant.

Disease development is thought to require both genetic and environmental contributions.

Slide 11 · Immunogenetic associations support immune involvement

HLA-B8 and other major histocompatibility complex alleles are associated with PSC.

Circulating autoantibodies and local immune cells provide additional evidence.

Association with immune loci does not identify the complete causal pathway.

Slide 12 · T cells are observed in the periductal stroma

Lymphocytes occur around injured ducts.

Immune-mediated damage is a biologically plausible disease model.

Observed infiltration does not alone establish the initiating event.

SCHEMATIC — duct cross-section

Injured epithelium

Periductal inflammatory cells

Slide 13 · Gut-activated T-cell trafficking: A proposed model

PROPOSED mechanism, not an established sequence

UC-associated mucosal injury

Activation of T cells in gut

Trafficking to liver

Possible biliary antigen recognition

This hypothesis is discussed; Causality remains unproven.

Slide 14 · Microbial or infectious triggers have been proposed

Infection is one hypothesized environmental trigger.

Changes in the intestinal microbiome may influence cholangiocyte biology.

Neither idea currently accounts definitively for all PSC cases in the source discussion.

Slide 15 · PSC pathogenesis is multifactorial

Genetic susceptibility contributes to risk.

Environmental and gut-related factors are proposed triggers.

Immune-cell recruitment and bile-duct injury lead to a fibrosing response.

SCHEMATIC — structural progression

Epithelial injury + edema

Fibrosis and luminal narrowing

Concentric scar ± obliteration

Chronic cholestasis → cirrhosis

Slide 16 · PANCA is common but not disease-specific

Perinuclear antineutrophil cytoplasmic antibodies occur in approximately 65% of patients.

The source describes reactivity to a nuclear-envelope protein.

PSC lacks the characteristic autoantibody signature seen in PBC.

A serologic association is not interchangeable with a diagnostic test.

Slide 17 · Autoantibodies: PSC and PBC are not equivalent

Primary sclerosing cholangitis

Primary biliary cholangitis

PANCA commonly detectable

No highly characteristic PSC-specific antibody profile

Antimitochondrial antibody generally absent

Antimitochondrial antibody is a central association

PDC-E2 is the key mitochondrial antigen

Antibody profile is much more disease-characteristic

Slide 18 · Large ducts show epithelial injury

Injured biliary lining is the initiating morphologic compartment.

Luminal integrity and bile passage are affected.

Inflammation is centered on the bile duct wall and adjacent stroma.

SCHEMATIC — morphologic triad

Injury

Epithelial damage

Inflammation

Chronic ± neutrophils

Repair/scarring

Concentric fibrosis

Slide 19 · Acute and chronic inflammation can coexist

Neutrophilic infiltrates may be superimposed on chronic inflammation.

The mixed response is described in the large intrahepatic and extrahepatic ducts.

The inflammatory tissue changes contribute to narrowing before fixed fibrosis dominates.

Slide 20 · Edema can constrict a bile duct

Inflammation produces mural and periductal edema.

Swelling reduces the available luminal diameter.

Subsequent fibrosis may convert reversible narrowing into a fixed stricture.

SCHEMATIC — duct cross-section

Injured epithelium

Periductal inflammatory cells

Slide 21 · Progressive periductal fibrosis causes stricture

Periductal collagen accumulates during chronic injury.

The residual lumen is increasingly narrow.

Multiple fibrotic segments interrupt biliary drainage at different levels.

SCHEMATIC — concentric periductal fibrosis

Concentric scar

Atrophic duct lumen

Slide 22 · Duct dilatation coexists with strictures

Segments that remain patent can become expanded.

This creates an irregular rather than uniformly narrow biliary tree.

The combined appearance is the basis of cholangiographic beading.

SCHEMATIC — alternating diameter

Dilated segment

Fibrotic stricture

Imaging appearance: “beading”

Slide 23 · Lithiasis can complicate dilated ducts

Stones may develop within dilated biliary segments.

The coexistence of strictures and lithiasis complicates bile drainage.

Biliary obstruction can contribute to episodes of ascending cholangitis.

Stones in PSC are a consequence of distorted duct architecture.

Slide 24 · “Onion-skin” fibrosis: The signature microscopic pattern

Concentric rings of periductal fibrosis encircle an injured duct.

The ductal epithelium progressively degenerates.

The residual lumen may be severely narrowed.

SCHEMATIC — concentric periductal fibrosis

Concentric scar

Atrophic duct lumen

Slide 25 · Duct atrophy follows concentric scarring

Repeated injury and fibrosis reduce residual duct caliber.

Ducts may become increasingly atrophic within a fibrotic cuff.

The morphologic process advances toward duct obliteration.

SCHEMATIC — concentric periductal fibrosis

Concentric scar

Atrophic duct lumen

Slide 26 · The “tombstone” scar is an end-stage duct lesion

A bile duct may be replaced by a solid fibrous scar

Progressive periductal fibrosis can completely obliterate a lumen.

The resulting scar reflects chronic duct loss rather than simple acute edema.

Recognizing a vanished duct depends on adequate tissue context.

Slide 27 · Routine biopsy may miss the principal PSC lesion

Needle biopsy preferentially samples peripheral, smaller portal tracts.

The defining large-duct inflammatory lesion may lie outside the sampled tissue.

Therefore, secondary cholestatic changes can predominate in a biopsy.

SCHEMATIC — major duct anatomy

Intrahepatic branches

Extrahepatic duct

Large ducts: Principal lesions

Slide 28 · Smaller bile ducts often show indirect injury

Small intrahepatic ducts are not the principal directly inflamed structures in classic PSC.

Mild epithelial injury may nevertheless occur.

A prominent ductular reaction reflects chronic cholestatic stress.

Slide 29 · Ductular reaction signals impaired bile drainage

Duct narrowing impedes normal passage of bile.

Intrahepatic bile retention accompanies chronic obstructive cholangiopathy.

Smaller portal areas may react even when the most conspicuous strictures are proximal.

SCHEMATIC — consequence chain

Irregular large-duct strictures

Impaired bile flow

Biliary retention / cholestasis

Ductular reaction, chronic injury

Slide 30 · Structural disease evolves toward biliary cirrhosis

SCHEMATIC — structural progression

Epithelial injury + edema

Fibrosis and luminal narrowing

Concentric scar ± obliteration

Chronic cholestasis → cirrhosis

This is a conceptual sequence; Individual rates of progression vary.

Slide 31 · Biliary cirrhosis is the major fibrotic endpoint

Long-standing duct injury sustains cholestatic hepatocellular stress.

Fibrosis can extend and eventually remodel the liver.

End-stage biliary cirrhosis contributes to transplant indications.

Slide 32 · Chronic epithelial injury creates a neoplastic risk

Biliary intraepithelial neoplasia may develop.

Dysplastic epithelial change can precede cholangiocarcinoma.

Risk assessment must consider malignancy, not fibrosis alone.

SCHEMATIC — disease-linked pathways

Chronic duct injury

Biliary epithelial neoplasia

Cholangiocarcinoma

The sequence is a biologic concept, not a claim that all lesions progress.

Slide 33 · Cholangiocarcinoma is a feared complication

A lifetime cholangiocarcinoma risk of 20%

The figure is a textbook estimate, not a personalized prediction.

Persistent biliary epithelial injury is the relevant pathologic context.

Malignancy may complicate the protracted natural history.

Slide 34 · Cholangiography reveals the main duct abnormality

Irregular strictures alternate with preserved or dilated segments.

Large intrahepatic and extrahepatic branches can be involved.

This imaging pattern supplies the main diagnostic visualization.

SCHEMATIC — alternating diameter

Dilated segment

Fibrotic stricture

Imaging appearance: “beading”

Slide 35 · Why cholangiography looks “beaded”

SCHEMATIC — alternating diameter

Dilated segment

Fibrotic stricture

Imaging appearance: “beading”

This figure is an editable schematic, not a patient cholangiogram.

Slide 36 · MRCP and ERCP visualize the ductal pattern

Magnetic resonance cholangiopancreatography (MRCP) delineates biliary architecture.

Endoscopic retrograde cholangiopancreatography (ERCP) can also demonstrate strictures and dilatations.

The Robbins account emphasizes characteristic morphology on duct imaging.

The source excerpt does not compare procedural indications or safety.

Slide 37 · Large-duct PSC involves both biliary compartments

Intrahepatic large ducts may contain multiple narrow segments.

Extrahepatic duct strictures may coexist.

Their combined involvement distinguishes classic disease from small-duct PSC.

SCHEMATIC — major duct anatomy

Intrahepatic branches

Extrahepatic duct

Large ducts: Principal lesions

Slide 38 · Small-duct PSC can have normal cholangiography

A subset has disease confined to smaller intrahepatic ducts.

The large-duct imaging examination may appear normal.

An accompanying history of inflammatory bowel disease is common in the source description.

SCHEMATIC — different anatomical targets

LARGE-DUCT PSC

Inflammation → fibrosis → visible strictures

SMALL-DUCT PSC

Small ducts only; Cholangiography normal

Slide 39 · Small-duct disease may evolve to large-duct PSC

Small-duct PSC is not synonymous with a permanently isolated process.

Some patients subsequently develop the characteristic large-duct phenotype.

Disease subtype and evolution need to be distinguished.

Slide 40 · PSC may be detected before symptoms

Nearly half of patients are reported asymptomatic when first identified.

Persistently increased alkaline phosphatase is a common detection route.

Routine monitoring in ulcerative colitis can lead to discovery.

SCHEMATIC — interpretation framework

Cholestatic presentation / raised ALP

Characteristic duct strictures and dilations

Assess PSC and relevant mimics

Slide 41 · Persistent alkaline phosphatase elevation is a clue

A biochemical cholestatic pattern can prompt further evaluation.

Alkaline phosphatase elevation does not by itself diagnose PSC.

The decisive source-described pattern is ductal alteration on imaging.

Slide 42 · Three clinical complaints recur

Fatigue is a common presentation.

Pruritus reflects symptomatic cholestatic disease.

Jaundice may indicate clinically evident impaired bile excretion.

SCHEMATIC — clinicopathologic links

Duct narrowing

Cholestasis

Ongoing injury

Fibrosis / cirrhosis

Duct obstruction

Ascending cholangitis

Slide 43 · Pruritus accompanies chronic cholestasis

PSC-associated duct narrowing reduces effective biliary flow.

Cholestatic disease can produce substantial itching.

Symptomatic control is distinct from correction of the underlying duct injury.

Slide 44 · Jaundice links duct disease to bile retention

Strictures restrict movement of bile through the tree.

Retention becomes clinically manifest in some patients.

Jaundice has to be interpreted alongside the broader cholestatic presentation.

SCHEMATIC — consequence chain

Irregular large-duct strictures

Impaired bile flow

Biliary retention / cholestasis

Ductular reaction, chronic injury

Slide 45 · Ascending cholangitis may be the first presentation

Infected or inflamed obstructed ducts can create an acute clinical episode.

Ascending cholangitis may reveal previously unrecognized PSC.

It must be recognized as a complication rather than the defining chronic lesion.

Slide 46 · Biliary-associated disease extends beyond the liver

Chronic cholecystitis can accompany PSC.

Chronic pancreatitis is also described in association with duct involvement.

Pancreatic and gallbladder findings may influence the differential diagnosis.

Slide 47 · Case: Biochemical detection in ulcerative colitis

A patient with ulcerative colitis has persistently elevated alkaline phosphatase but no jaundice.

What cholangiographic pattern would make PSC likely?

Which duct compartments would you assess?

Why is the absence of symptoms not reassuring?

Slide 48 · Case interpretation: Characteristic duct architecture

Multiple irregular biliary strictures alternating with dilatations suggest classic PSC.

Disease can be present before the classical symptoms develop.

Large-duct imaging is central to the source-described diagnostic approach.

A normal study raises a different question: Could this be small-duct PSC?

Slide 49 · PSC and PBC: Compare the major clinical patterns

Feature

Primary sclerosing cholangitis

Primary biliary cholangitis

Typical sex

~70% male

~90% female

Median age

~30 years

~50 years

Common association

Inflammatory bowel disease

Sjögren syndrome; autoimmune disorders

Characteristic serology

pANCA may be present; AMA typically negative

AMA frequently positive

Ductal imaging

Large-duct beading / strictures

Usually normal large ducts

Slide 50 · The principal duct targets separate PSC from PBC

PSC: Predominantly large intrahepatic and extrahepatic ducts.

PBC: Small- and medium-sized intrahepatic ducts.

The different targets explain why large-duct imaging separates the conditions.

SCHEMATIC — primary duct targets

PBC

PSC

Small intrahepatic bile ducts

Large intrahepatic and extrahepatic ducts

Florid duct lesions

Periductal concentric fibrosis

Slide 51 · Morphology: Concentric sclerosis or florid duct lesion

PSC morphology

PBC morphology

Large-duct epithelial injury and periductal concentric fibrosis

Progressive narrowing and duct obliteration

Secondary ductular reaction in smaller portal tracts

Inflammatory destruction of small intrahepatic ducts

Granulomatous florid duct lesions

Progressive small-duct loss / ductopenia

Slide 52 · IgG4-related sclerosing cholangitis is a key mimic

The biliary picture may resemble classic PSC.

It is often associated with pancreatitis.

It by responsiveness to corticosteroids.

CLINICAL DIFFERENTIAL — editable teaching schema

Sclerosing cholangiographic changes

Primary PSC?

IgG4-related disease

Secondary injury / obstruction

Small-duct disease when imaging normal

Slide 53 · PSC may overlap with autoimmune hepatitis

Concomitant autoimmune hepatitis in 5%–10% of PSC cases.

This is an overlap context, not the usual phenotype of isolated PSC.

Its presence complicates clinicopathologic interpretation.

Slide 54 · Secondary sclerosing cholangitis must be considered

A PSC-like sclerosing duct pattern is not necessarily primary.

Long-standing obstruction and ischemic injury are alternative causes.

A focused causal assessment prevents erroneous attribution to PSC.

CLINICAL DIFFERENTIAL — editable teaching schema

Sclerosing cholangiographic changes

Primary PSC?

IgG4-related disease

Secondary injury / obstruction

Small-duct disease when imaging normal

Slide 55 · Drug injury and infection may mimic PSC

Ketamine is an example of a drug linked with secondary sclerosing injury.

CMV, HIV, and COVID-19 are among infections discussed as causes.

The mechanism and context differ from primary disease.

Slide 56 · Transporter defects belong in the secondary differential

Late-onset bile transporter defects can produce a PSC-like biliary phenotype.

MDR3 deficiency is the example named.

The existence of a phenocopy means imaging must be interpreted in context.

Slide 57 · A careful differential begins with disease context

Exclude obstructive or ischemic causes.

Consider IgG4-related sclerosing disease and pancreatic findings.

Recognize small-duct PSC when classic imaging changes are absent.

CLINICAL DIFFERENTIAL — editable teaching schema

Sclerosing cholangiographic changes

Primary PSC?

IgG4-related disease

Secondary injury / obstruction

Small-duct disease when imaging normal

Slide 58 · The clinical course can be prolonged and progressive

The source describes a course extending approximately 10–15 years toward cirrhosis.

This is a general natural-history summary, not a fixed time for an individual.

Fibrosis, cholestatic symptoms, and malignant complications can all affect outcomes.

SCHEMATIC — long-term course

Duct injury

Fibrosis + cholestasis

Biliary cirrhosis

Transplant assessment

Slide 59 · Management addresses distinct clinical problems

Cholestyramine is used to relieve pruritus.

Endoscopic dilation or stenting may relieve biliary obstruction.

Liver transplantation is used for end-stage disease.

SCHEMATIC — management target, not cure

Pruritus

Bile-acid binding resin

Focal duct obstruction

Dilation or stenting

End-stage liver disease

Transplantation

Slide 60 · A medical cure is not established account

No established medical therapy that reverses PSC.

Ursodeoxycholic acid is discussed in relation to clinical trials.

Relief of symptoms or strictures does not imply elimination of underlying disease.

This slide reflects the supplied textbook, not an independently updated treatment guideline.

Slide 61 · Case: Progressive strictures and cholangitis

A patient with established PSC develops jaundice and episodes of ascending cholangitis.

What duct-level process may explain deterioration?

Which intervention directly addresses an obstructed segment?

Why does management also require long-term risk assessment?

Slide 62 · Case interpretation: Injury, obstruction, consequence

Worsening stricture can impair drainage, while chronic injury continues.

Endoscopic dilation or stenting may address obstruction.

Repeated injury can sustain fibrosis and eventually biliary cirrhosis.

Cholangiocarcinoma remains a significant associated long-term risk.

Slide 63 · Integrating the disease in one causal map

Susceptibility and uncertain environmental triggers are associated with immune injury.

Large-duct inflammation and concentric fibrosis produce irregular strictures.

Cholestasis, complications, and biliary cirrhosis follow downstream.

SCHEMATIC — structural progression

Epithelial injury + edema

Fibrosis and luminal narrowing

Concentric scar ± obliteration

Chronic cholestasis → cirrhosis

Slide 64 · Four high-yield distinctions

PSC primarily injures large intrahepatic and extrahepatic ducts.

“Onion-skin” periductal fibrosis and cholangiographic beading are characteristic.

Ulcerative colitis is a strong association; PANCA is not a specific diagnostic signature.

Always consider IgG4-related and secondary sclerosing conditions, plus cholangiocarcinoma risk.

Slide 65 · Principal reference

Robbins, Cotran & Kumar: Pathologic Basis of Disease. 11th edition (2026).

Source section: primary sclerosing cholangitis within autoimmune cholangiopathies.

All native diagrams are conceptual schematics, not clinical images or microscopic specimens.

Management and numerical risk estimates reflect the supplied textbook account.