CHOLANGITIS

A Complete Clinical, Pathophysiological, Diagnostic, and Therapeutic Review for MBBS, Pharmacy, and Nursing Students

Introduction

Cholangitis is a potentially life-threatening inflammatory condition of the biliary tree that most commonly results from biliary obstruction combined with ascending bacterial infection. It represents a true medical emergency when acute and can rapidly progress to sepsis, multi-organ failure, and death if not promptly diagnosed and managed.

The term “cholangitis” literally means inflammation of the bile ducts. However, in clinical practice, it encompasses multiple entities, including:

Acute ascending cholangitis
Recurrent pyogenic cholangitis
Primary sclerosing cholangitis
Secondary sclerosing cholangitis
Primary biliary cholangitis

Each of these conditions differs in etiology, pathogenesis, clinical presentation, and management.

Anatomy of the Biliary Tree

Understanding cholangitis requires detailed knowledge of hepatobiliary anatomy.

Components of the Biliary System

1. Intrahepatic Ducts

Right and left hepatic ducts
Segmental ducts
Canaliculi

2. Extrahepatic Ducts

Common hepatic duct
Cystic duct
Common bile duct (CBD)

3. Ampulla of Vater

Formed by union of CBD and pancreatic duct
Opens into the second part of duodenum

Blood Supply and Lymphatics

Hepatic artery supplies arterial blood
Portal vein supplies venous inflow
Lymphatic drainage toward celiac and hepatic nodes

Disruption of this system predisposes to infection and inflammation.

Definition and Classification of Cholangitis

Acute Ascending Cholangitis

Acute ascending cholangitis is a bacterial infection of the biliary tract resulting from obstruction, leading to bile stasis and bacterial proliferation.

Common causes include:

Choledocholithiasis (most common)
Biliary strictures
Tumors
Parasites
Post-ERCP complications

Chronic and Autoimmune Types

Primary Sclerosing Cholangitis

Primary Sclerosing Cholangitis is a chronic progressive inflammatory disease causing fibrosis and stricturing of bile ducts.

Strongly associated with:

Inflammatory bowel disease
Particularly ulcerative colitis

Primary Biliary Cholangitis

Primary Biliary Cholangitis is an autoimmune-mediated destruction of small intrahepatic bile ducts.

Common in:

Middle-aged women
Associated with antimitochondrial antibodies (AMA)

Pathophysiology of Acute Ascending Cholangitis

The pathogenesis involves three key events:

1. Biliary Obstruction

Obstruction increases intraductal pressure.

2. Bacterial Overgrowth

Common organisms:

E. coli
Klebsiella
Enterococcus
Enterobacter

3. Bacterial Translocation

Elevated ductal pressure allows bacteria to enter bloodstream → bacteremia → sepsis.

Mechanism of Sepsis Development

When intraductal pressure exceeds 20 cm H₂O:

Tight junctions open
Bacteria enter hepatic sinusoids
Endotoxins trigger systemic inflammatory response

This can lead to:

Septic shock
Disseminated intravascular coagulation
Multi-organ failure

Etiology of Cholangitis

Obstructive Causes

Gallstones (most common worldwide)
Biliary strictures
Cholangiocarcinoma
Pancreatic carcinoma
Parasitic infestation
Post-surgical complications

Infectious Causes

Ascending bacterial infection
Rare viral cholangitis
Fungal cholangitis in immunocompromised

Clinical Presentation

Charcot’s Triad

Charcot's triad consists of:

Fever
Right upper quadrant pain
Jaundice

Present in approximately 50–70% of cases.

Reynolds’ Pentad

Reynolds' pentad adds:

Hypotension
Altered mental status

Indicates severe disease with septic shock.

Symptoms

High-grade fever with chills
Severe RUQ abdominal pain
Nausea and vomiting
Dark urine
Pale stools
Pruritus (in chronic cases)

Laboratory Findings

Complete Blood Count

Leukocytosis
Left shift

Liver Function Tests

Elevated ALP
Elevated GGT
Increased bilirubin
Mild AST/ALT elevation

Inflammatory Markers

CRP elevated
Procalcitonin may rise

Imaging in Cholangitis

Ultrasound

First-line investigation
Detects ductal dilation
Identifies stones

MRCP

Non-invasive detailed biliary imaging.

ERCP

Gold standard diagnostic and therapeutic modality.

Tokyo Guidelines for Severity Assessment

Cholangitis severity is classified into:

Grade I (Mild)

No organ dysfunction.

Grade II (Moderate)

Marked inflammation without organ failure.

Grade III (Severe)

Organ dysfunction present:

Cardiovascular
Renal
Respiratory
Neurological
Hematological

Management of Acute Cholangitis

Initial Stabilization

IV fluids
Oxygen
Blood cultures
Broad-spectrum antibiotics

Common empiric antibiotics:

Piperacillin-tazobactam
Ceftriaxone + metronidazole
Carbapenems (severe cases)

Definitive Treatment

Biliary Decompression

Endoscopic Retrograde Cholangiopancreatography (ERCP) is first-line.

Options:

Sphincterotomy
Stone extraction
Stent placement

If ERCP unavailable:

Percutaneous transhepatic drainage
Surgical decompression

Complications

Septic shock
Liver abscess
Acute kidney injury
Disseminated intravascular coagulation
Acute respiratory distress syndrome

Prognosis

With early ERCP and antibiotics:

Mortality <10%

Without treatment:

Mortality approaches 50–100%

Chronic Cholangitis Overview

Primary Sclerosing Cholangitis

Characteristic feature:

“Beading” appearance on cholangiography

Complications:

Cirrhosis
Portal hypertension
Cholangiocarcinoma

Treatment:

Liver transplantation (definitive)

Differential Diagnosis

Acute cholecystitis
Viral hepatitis
Pancreatitis
Peptic ulcer disease
Liver abscess

Preventive Strategies

Early removal of CBD stones
Sterile ERCP techniques
Monitoring in PSC patients
Vaccination against hepatitis

EPIDEMIOLOGY OF CHOLANGITIS

Global Incidence

Acute cholangitis incidence varies geographically depending on:

Prevalence of gallstone disease
Access to ERCP services
Parasitic endemicity
Hepatobiliary malignancy rates

In Western countries:

Most common cause → choledocholithiasis
Increased incidence in elderly population

In South Asia (including Pakistan):

Higher rates of:
- Pigment stones
- Recurrent pyogenic cholangitis
- Parasitic biliary disease
- Delayed presentation due to limited access to tertiary care

Age Distribution

Acute ascending cholangitis → Most common in age >50 years
Primary sclerosing cholangitis → Peak 30–40 years
Primary biliary cholangitis → Middle-aged women (40–60 years)

Gender Distribution

Gallstone-related cholangitis → Female predominance
Primary sclerosing cholangitis → Male predominance
Primary biliary cholangitis → Strong female predominance

MICROBIOLOGY OF ACUTE CHOLANGITIS

Bile is normally sterile. Obstruction permits bacterial colonization.

Common Organisms

Gram-Negative Bacilli

Escherichia coli (most common)
Klebsiella species
Enterobacter
Pseudomonas (hospital-acquired)

Gram-Positive Organisms

Enterococcus
Streptococcus

Anaerobes

Bacteroides (less common)

Pathway of Infection

Bacteria ascend from:

Duodenum via ampulla
OR
Portal circulation
OR
Hematogenous spread

MOLECULAR PATHOGENESIS

Step 1: Obstruction-Induced Pressure Rise

When CBD pressure exceeds 20 cm H₂O:

Bile flow stops
Kupffer cell clearance fails
Bacteria translocate

Step 2: Endotoxin Release

Gram-negative bacteria release LPS (lipopolysaccharide):

Activates macrophages
Triggers TNF-alpha
Induces IL-1, IL-6
Causes systemic inflammatory response

Step 3: Sepsis Cascade

Vasodilation
Capillary leak
Hypotension
Multi-organ dysfunction

This explains why cholangitis rapidly becomes life-threatening.

IMMUNOLOGY OF CHRONIC CHOLANGITIS

Primary Sclerosing Cholangitis

Autoimmune Mechanisms

T-cell mediated bile duct injury
HLA-B8 and DR3 association
Elevated IgM levels

Strong link with:

Ulcerative colitis (up to 70%)

Primary Biliary Cholangitis

Immunological Features

Anti-mitochondrial antibodies (AMA) positive in >90%
Destruction of small intrahepatic ducts
Female predominance

DETAILED CLINICAL COURSE

Early Phase

Fever with chills
Mild jaundice
RUQ discomfort

Progressive Phase

High-grade fever
Severe pain
Hypotension

Severe Phase

Septic shock
Confusion
Oliguria
Coagulopathy

DIFFERENTIAL DIAGNOSIS IN DETAIL

Acute Cholecystitis

Distinguishing features:

No jaundice (usually)
Positive Murphy’s sign
No marked bilirubin elevation

Acute Pancreatitis

Epigastric pain radiating to back
Elevated serum amylase/lipase
CT shows inflamed pancreas

Viral Hepatitis

Marked ALT/AST elevation
No biliary obstruction

RADIOLOGY DEEP DIVE

Ultrasound Findings

Dilated CBD (>6 mm adults)
Intrahepatic duct dilation
Visible stones

MRCP Features

Advantages:

Non-invasive
No radiation
Excellent duct visualization

ERCP Findings

Endoscopic Retrograde Cholangiopancreatography

Filling defects (stones)
Strictures
Pus drainage confirms diagnosis

HISTOPATHOLOGY

Acute Cholangitis

Microscopic features:

Neutrophilic infiltration
Edema
Duct wall thickening

PSC Histology

Onion-skin fibrosis
Periductal inflammation
Progressive bile duct obliteration

PBC Histology

Lymphocytic infiltration
Granulomas
Bile duct destruction

ANTIBIOTIC PHARMACOLOGY IN CHOLANGITIS

Empiric Coverage Must Include:

Gram-negative organisms
Enterococcus
Anaerobes (moderate to severe cases)

Common Regimens

Mild to Moderate

Ceftriaxone + metronidazole

Severe

Piperacillin-tazobactam
Meropenem

Duration:

4–7 days after drainage

SURGICAL MANAGEMENT

Indications for Surgery

Failed ERCP
Recurrent obstruction
Tumor-related cholangitis
Complicated gallstones

Procedures

Open CBD exploration
T-tube insertion
Hepaticojejunostomy
Liver transplantation (PSC)

ICU MANAGEMENT

Severe cholangitis requires:

Aggressive fluid resuscitation
Vasopressors (if needed)
Broad-spectrum antibiotics
Urgent biliary drainage

COMPLICATIONS IN DETAIL

Septic shock
Acute kidney injury
ARDS
DIC
Hepatic abscess
Secondary biliary cirrhosis

PROGNOSTIC FACTORS

Poor prognosis indicators:

Age >75
Hypotension
Altered mental status
Delay in ERCP
High bilirubin >10 mg/dL

PEDIATRIC CHOLANGITIS

Causes differ:

Biliary atresia
Congenital anomalies
Post-surgical complications

Management requires pediatric hepatology care.

CHOLANGITIS IN PREGNANCY

Imaging limited (avoid radiation)
Prefer MRCP
ERCP with shielding if necessary
Careful antibiotic selection

ADVANCED HEPATOBILIARY PHYSIOLOGY

Overview of Bile Formation

Bile is a complex exocrine secretion produced by hepatocytes and modified by cholangiocytes (bile duct epithelial cells). Daily bile production in adults averages:

600–1000 mL/day

Bile formation occurs in three phases:

Canalicular bile secretion (hepatocyte-dependent)
Ductular modification (cholangiocyte-dependent)
Hormonal and neural regulation

Composition of Bile

Bile consists of:

Bile acids (primary component)
Phospholipids (mainly lecithin)
Cholesterol
Bilirubin
Electrolytes
Water

Disruption of bile composition contributes to:

Gallstone formation
Cholestasis
Biliary inflammation

Mechanism of Bile Secretion

Hepatocyte Transporters

Important transport systems include:

BSEP (Bile Salt Export Pump)
MRP2 (Multidrug Resistance Protein 2)
NTCP (Sodium Taurocholate Cotransporting Polypeptide)

When obstruction occurs:

Intracellular bile salt accumulation
Oxidative stress
Hepatocyte apoptosis

CHOLANGIOCYTE BIOLOGY

Cholangiocytes line the intrahepatic and extrahepatic bile ducts.

Functions:

Modify bile composition
Secrete bicarbonate
Regulate bile flow
Participate in immune response

During cholangitis:

Cholangiocytes produce cytokines
Activate inflammatory cascades
Contribute to fibrosis

PATHOGENESIS OF FIBROSIS IN PSC

Primary Sclerosing Cholangitis

PSC progresses through chronic immune-mediated injury.

Stepwise Fibrosis Mechanism

1. Immune Activation

CD4+ and CD8+ T cells infiltrate bile ducts
Release interferon-gamma

2. Stellate Cell Activation

Hepatic stellate cells transform into myofibroblasts
Excess collagen deposition

3. Periductal Fibrosis

Characteristic “onion-skin” fibrosis:

Result:

Progressive duct narrowing
Cholestasis
Cirrhosis

MOLECULAR SIGNALING PATHWAYS IN CHRONIC CHOLANGITIS

Important pathways:

TGF-beta signaling (fibrosis driver)
NF-kB activation (inflammation)
IL-6 mediated immune activation
Oxidative stress pathways

These pathways create a chronic inflammatory-fibrotic cycle.

CHOLANGIOCARCINOMA DEVELOPMENT

Chronic cholangitis increases risk of malignancy.

Risk in PSC

Lifetime risk of cholangiocarcinoma:

7–15%

Mechanism of Malignant Transformation

Chronic inflammation leads to:

DNA damage
p53 mutation
KRAS activation
Dysplasia → carcinoma

Types of Cholangiocarcinoma

Intrahepatic
Perihilar (Klatskin tumor)
Distal extrahepatic

Symptoms overlap with cholangitis:

Jaundice
Weight loss
Pruritus

BILE FLOW REGULATION

Hormonal Regulation

Secretin → increases bicarbonate secretion
Cholecystokinin → gallbladder contraction

Neural Regulation

Parasympathetic stimulation increases bile flow
Sympathetic decreases flow

Obstruction disrupts regulatory balance.

SECONDARY SCLEROSING CHOLANGITIS

Causes include:

Severe infection
Ischemic injury
Trauma
Post-transplant complications

Unlike PSC, this has identifiable cause.

ISCHEMIC CHOLANGITIS

Bile ducts depend solely on hepatic arterial supply.

Compromise leads to:

Necrosis
Stricture formation
Recurrent infection

LIVER TRANSPLANTATION IN PSC

Indications:

Decompensated cirrhosis
Recurrent bacterial cholangitis
Intractable pruritus
Early cholangiocarcinoma (selected cases)

Survival rate post-transplant:

5-year survival >80%

Recurrence possible in 10–25%.

BIOMARKERS IN CHOLANGITIS

Acute

CRP
Procalcitonin
Leukocytosis

PSC

ALP elevation (persistent)
Elevated IgM
p-ANCA positive

PBC

Primary Biliary Cholangitis

AMA positive
Elevated ALP
Elevated cholesterol

BILE ACID TOXICITY

Excess bile acids cause:

Mitochondrial damage
ROS production
Apoptosis

Hydrophobic bile acids are more toxic.

PORTAL HYPERTENSION IN CHRONIC CHOLANGITIS

Progression:

Chronic obstruction → Fibrosis → Cirrhosis → Portal hypertension

Complications:

Ascites
Variceal bleeding
Hepatic encephalopathy

SPECIAL SCENARIO: RECURRENT PYOGENIC CHOLANGITIS

Common in:

East and Southeast Asia
Associated with pigment stones

Features:

Recurrent infection
Intrahepatic strictures
Liver abscess

FUTURE THERAPIES

Emerging treatments include:

FXR agonists
Anti-fibrotic drugs
Immunomodulators
Targeted molecular inhibitors

Research continues into bile acid metabolism modulation.

CLINICAL CASE DISCUSSIONS IN CHOLANGITIS

This section is structured for MBBS, USMLE, FCPS, and postgraduate-level clinical reasoning training.

CASE 1 — Classic Acute Ascending Cholangitis

Presentation

A 62-year-old female presents with:

Fever (39.5°C)
Right upper quadrant pain
Progressive jaundice
Chills and rigors

Past history: Gallstones.

Clinical Examination

Icterus present
Tender RUQ
Mild hypotension
Tachycardia

This fulfills:

Charcot's triad

If hypotension + confusion were present →

Reynolds' pentad

Investigations

WBC: 18,000
Bilirubin: 8 mg/dL
ALP elevated
Ultrasound: Dilated CBD (9 mm) with stone

Management Plan

Immediate IV fluids
Broad-spectrum antibiotics
Urgent biliary decompression

Definitive therapy:

Endoscopic Retrograde Cholangiopancreatography

Stone extraction + sphincterotomy performed.

Outcome: Rapid improvement within 48 hours.

CASE 2 — Severe Septic Cholangitis

Presentation

75-year-old male with:

High fever
Hypotension (BP 80/50)
Altered mental status
Oliguria

Diagnosis: Grade III (Severe) cholangitis.

ICU Protocol

Aggressive crystalloid resuscitation
Norepinephrine infusion
Broad-spectrum antibiotics (Meropenem)
Immediate ERCP

If ERCP fails → Percutaneous drainage.

CASE 3 — Primary Sclerosing Cholangitis

Primary Sclerosing Cholangitis

Presentation

32-year-old male with:

Chronic fatigue
Pruritus
Mild jaundice

History: Ulcerative colitis.

Lab Findings

Persistent ALP elevation
p-ANCA positive

Imaging

MRCP shows classic “beaded” ducts.

Management

No curative medical therapy
Monitor for cholangiocarcinoma
Liver transplant in advanced disease

CASE 4 — Primary Biliary Cholangitis

Primary Biliary Cholangitis

Presentation

48-year-old female:

Severe pruritus
Hyperlipidemia
Xanthelasma

AMA positive.

Treatment

Ursodeoxycholic acid
Obeticholic acid (if refractory)
Transplant if cirrhosis develops

STEP-BY-STEP EMERGENCY MANAGEMENT PROTOCOL

Step 1: Recognition

Suspect cholangitis in patient with:

Fever
Jaundice
RUQ pain

Step 2: Immediate Labs

CBC
LFT
Blood cultures
CRP

Step 3: Imaging

Ultrasound first-line
MRCP if unclear

Step 4: Antibiotics

Start within 1 hour of suspicion.

Empiric coverage:

Piperacillin-tazobactam
OR
Ceftriaxone + metronidazole

Step 5: Biliary Drainage

Most important life-saving step.

Preferred:

Endoscopic Retrograde Cholangiopancreatography

INTERVENTIONAL RADIOLOGY IN CHOLANGITIS

When ERCP is not feasible:

Percutaneous transhepatic biliary drainage (PTBD)

Indications:

Altered anatomy
Failed ERCP
Hilar obstruction

SURGICAL TECHNIQUES DEEP DIVE

Open Common Bile Duct Exploration

Indications:

Large impacted stone
ERCP failure

Steps:

Choledochotomy
Stone extraction
T-tube placement

Hepaticojejunostomy

Used for:

Strictures
Malignancy
Recurrent obstruction

EVIDENCE-BASED GUIDELINES

Tokyo Guidelines (TG18)

Severity grading:

Grade I – Mild
Grade II – Moderate
Grade III – Severe

Recommend:

Early antibiotics
Early drainage (<24 hours severe cases)

LONG-TERM FOLLOW-UP STRATEGY

After Acute Cholangitis

Elective cholecystectomy (if gallstones)
Monitor liver function
Prevent recurrence

In PSC Patients

Annual MRCP
CA 19-9 monitoring
Colonoscopy surveillance

COMMON EXAM QUESTIONS (SHORT ANSWER STYLE)

What is the most common cause of acute cholangitis?
→ Choledocholithiasis.
What is the gold standard treatment?
→ ERCP with biliary drainage.
What is the hallmark imaging sign of PSC?
→ Beading of bile ducts.

ADVANCED PHARMACOLOGY IN CHOLANGITIS

Effective management depends on:

Early broad-spectrum antibiotics
Source control (biliary drainage)
Prevention of recurrence

ANTIBIOTIC SELECTION PRINCIPLES

Coverage must include:

Gram-negative bacilli (E. coli, Klebsiella)
Enterococcus
Anaerobes (moderate–severe cases)

FIRST-LINE REGIMENS

Mild to Moderate Disease

Ceftriaxone + Metronidazole
Ampicillin-sulbactam

Severe or ICU Patients

Piperacillin–Tazobactam
Meropenem
Imipenem-cilastatin

Duration:

4–7 days after adequate drainage
Extend if bacteremia persists

PHARMACOKINETICS CONSIDERATIONS

Important factors:

Biliary penetration
Renal dosing adjustments
Hepatic metabolism
Local resistance patterns

Carbapenems are preferred in ESBL-producing organisms.

URSODEOXYCHOLIC ACID (UDCA)

Primary use:

Primary Biliary Cholangitis

Mechanism:

Replaces toxic bile acids
Improves bile flow
Reduces cholestasis

Dose:

13–15 mg/kg/day

Improves survival in early-stage PBC.

OBETICHOLIC ACID

Indicated in:

UDCA non-responders

Mechanism:

FXR agonist
Reduces bile acid synthesis

IMMUNOMODULATORS IN PSC

Primary Sclerosing Cholangitis

Trials have evaluated:

Corticosteroids
Azathioprine
Methotrexate

However, none show definitive survival benefit.

LIVER TRANSPLANTATION IN CHOLANGITIS

Indications:

End-stage liver disease
Recurrent bacterial cholangitis
Intractable pruritus
Early cholangiocarcinoma (selected cases)

SURGICAL OVERVIEW

Steps:

Removal of diseased liver
Vascular anastomosis (IVC, portal vein, hepatic artery)
Biliary reconstruction

POST-TRANSPLANT MANAGEMENT

Tacrolimus
Mycophenolate mofetil
Steroids

Monitor for:

Rejection
Biliary strictures
Recurrence (PSC)

5-year survival: >80%

PEDIATRIC CHOLANGITIS

Etiology differs from adults.

Causes

Biliary atresia
Choledochal cyst
Post-Kasai procedure infection
Congenital biliary anomalies

Diagnosis

Ultrasound
MRCP
Liver biopsy

Management

Broad-spectrum antibiotics
Surgical correction of anomaly
Transplant in advanced cases

CHOLANGITIS IN SPECIAL POPULATIONS

Elderly

Higher mortality
Atypical presentation
Delayed diagnosis

Diabetic Patients

Increased risk of sepsis
Higher complication rates

Immunocompromised

Fungal cholangitis
Multidrug-resistant infections

GLOBAL STATISTICS

Western countries:

Gallstones main cause

South & Southeast Asia:

Pigment stones
Recurrent pyogenic cholangitis

PSC more common in:

Northern Europe
North America

PBC more common in:

Women in Western populations

COMPARISON TABLE — TYPES OF CHOLANGITIS

Feature	Acute	PSC	PBC
Onset	Sudden	Chronic	Chronic
Cause	Obstruction + infection	Autoimmune fibrosis	Autoimmune destruction
Gender	Female (stones)	Male	Female
Cancer risk	Low	High	Moderate
Treatment	ERCP	Transplant	UDCA

COMPLICATION PATHWAY SUMMARY

Acute obstruction → Infection → Sepsis → Shock → Multi-organ failure

Chronic inflammation → Fibrosis → Cirrhosis → Portal hypertension → Liver failure

HIGH-YIELD REVISION POINTS

Most common cause of acute cholangitis → CBD stone
Most important management step → Urgent biliary drainage
Classic triad → Fever + RUQ pain + Jaundice
PSC associated with → Ulcerative colitis
PBC marker → Anti-mitochondrial antibody

ADVANCED PATHOBIOLOGY OF ACUTE ASCENDING CHOLANGITIS

Acute cholangitis is not merely infection — it is a pressure-driven septic syndrome of the biliary tract.

Biliary Pressure Dynamics

Normal CBD pressure:

7–14 cm H₂O

In obstruction:

May exceed 20–30 cm H₂O

Consequences:

Bile canalicular dilation
Tight junction disruption
Bacteremia via cholangiovenous reflux
Endotoxemia

This phenomenon is called:

Cholangiovenous reflux

It explains why bacteremia occurs early even before abscess formation.

Systemic Inflammatory Cascade

Lipopolysaccharide (LPS) from Gram-negative bacteria:

Activates Toll-like receptor 4 (TLR-4)
Induces NF-κB activation
Triggers TNF-α, IL-1β, IL-6

Leads to:

Vasodilation
Capillary leak
Hypotension
Disseminated intravascular coagulation

This mirrors septic shock physiology.

MICROVASCULAR CHANGES IN SEVERE CHOLANGITIS

Liver sinusoids show:

Endothelial swelling
Platelet aggregation
Microthrombi formation

This contributes to:

Acute kidney injury
Hepatic ischemia
Multi-organ dysfunction

HEMODYNAMIC MANAGEMENT IN ICU

In Grade III cholangitis:

Goals:

MAP ≥ 65 mmHg
Urine output ≥ 0.5 mL/kg/hr
Lactate clearance

Preferred vasopressor:

Norepinephrine

Add vasopressin if refractory.

Early ERCP reduces mortality significantly.

Endoscopic Retrograde Cholangiopancreatography remains the definitive intervention.

ADVANCED IMAGING ANALYSIS

MRCP in Obstructive Cholangitis

Radiologic features:

Dilated intrahepatic ducts
Filling defects
Strictures
Abrupt cutoff sign (malignancy)

ERCP Technical Nuances

During ERCP:

Sphincterotomy performed
Stone retrieval with Dormia basket
Plastic vs metal stent placement

Complications:

Pancreatitis (3–10%)
Bleeding
Perforation

Prophylaxis for post-ERCP pancreatitis:

Rectal indomethacin
Pancreatic duct stenting

INTERVENTIONAL RADIOLOGY EXPANSION

Percutaneous Transhepatic Biliary Drainage (PTBD)

Indications:

Failed ERCP
Hilar tumors
Altered anatomy (post-gastric bypass)

Advantages:

Immediate decompression
Useful in unstable patients

Risks:

Hemorrhage
Bile leak
Sepsis

FIBROSIS CASCADE IN PSC — MOLECULAR DEPTH

Primary Sclerosing Cholangitis

Key molecular drivers:

TGF-β overexpression
SMAD signaling activation
PDGF-mediated stellate activation
Myofibroblast proliferation

This produces concentric periductal fibrosis (“onion-skin”).

Progression timeline:

Years to decades
Ultimately leads to biliary cirrhosis

ONCOGENESIS IN PSC

Chronic inflammation → DNA damage.

Common mutations:

p53
KRAS
IDH1/2

Cholangiocarcinoma risk:

7–15% lifetime
Highest within first 3 years of PSC diagnosis

Surveillance:

Annual MRCP
CA 19-9

ADVANCED SURGICAL RECONSTRUCTION

Hepaticojejunostomy (Roux-en-Y)

Used in:

Benign strictures
Iatrogenic bile duct injury
Recurrent obstruction

Steps:

Resection of diseased duct
Roux limb creation
Anastomosis to hepatic duct

TRANSPLANT IMMUNOLOGY EXPANSION

After liver transplant:

Immune response mediated by:

T lymphocytes
Antigen-presenting cells

Rejection types:

Hyperacute
Acute cellular
Chronic rejection

Immunosuppressants:

Tacrolimus (calcineurin inhibitor)
Mycophenolate
Corticosteroids

Complications:

Opportunistic infection
Renal dysfunction
Metabolic syndrome

PEDIATRIC SURGICAL DETAIL

Biliary Atresia

Kasai portoenterostomy performed before 60 days of life improves survival.

If failure:

Liver transplant required.

RECURRENT PYOGENIC CHOLANGITIS (ASIAN CHOLANGITIS)

Common in tropical regions.

Characteristics:

Intrahepatic pigment stones
Strictures
Liver abscess

Management:

Repeated drainage
Segmental hepatic resection (in severe cases)

LONG-TERM COMPLICATION MAP

Acute:

Septic shock
ARDS
DIC

Chronic:

Secondary biliary cirrhosis
Portal hypertension
Hepatocellular dysfunction
Cholangiocarcinoma

RESEARCH FRONTIERS

Emerging therapies:

FXR agonists
Anti-TGF beta inhibitors
Gut microbiome modulation
Bile acid transporter blockers

Gene expression studies suggest microbiota may influence PSC progression.

CHOLANGIOCYTE BIOLOGY — CELLULAR AND MOLECULAR DEPTH

Cholangiocytes are not passive duct-lining cells. They are:

Immunologically active
Secretory
Mechanosensitive
Fibrogenic

They represent the central cellular driver of chronic cholangitis progression.

Cholangiocyte Subtypes

Two major populations:

Small Cholangiocytes

Line small intrahepatic ducts
Resistant to injury
Can proliferate and replace damaged large cholangiocytes

Large Cholangiocytes

Line large ducts
Express secretin receptors
Primary targets in PSC and PBC

Mechanosensing in Obstruction

During biliary obstruction:

Increased luminal pressure
Cilia-mediated mechanosensing
Intracellular calcium signaling
cAMP pathway activation

This triggers:

Cytokine release
Proliferation
Fibrotic signaling

BILE ACID SIGNALING — BEYOND DIGESTION

Bile acids function as metabolic hormones.

Major receptors:

FXR (Farnesoid X receptor)
TGR5 (G-protein coupled bile acid receptor)

FXR Pathway

FXR activation:

Reduces bile acid synthesis
Suppresses inflammation
Regulates lipid metabolism

In cholangitis:

FXR dysregulation contributes to bile acid toxicity
FXR agonists are emerging therapy

Bile Acid Toxicity Mechanisms

Hydrophobic bile acids:

Disrupt mitochondrial membrane
Generate reactive oxygen species
Trigger caspase-mediated apoptosis

This accelerates:

Ductal injury
Hepatocyte death
Fibrosis

GUT–LIVER AXIS IN PSC

Primary Sclerosing Cholangitis

PSC has a strong association with:

Ulcerative colitis
Altered intestinal microbiota

Proposed Mechanism

Increased intestinal permeability
Bacterial translocation
Portal endotoxemia
Chronic bile duct inflammation

Studies show:

Altered microbiome composition
Increased Enterococcus species

Emerging therapy:

Fecal microbiota transplantation (experimental)

IMMUNOLOGY OF PBC — AUTOANTIBODY SPECIFICITY

Primary Biliary Cholangitis

Primary target antigen:

E2 subunit of pyruvate dehydrogenase complex

Mechanism:

Molecular mimicry
Loss of immune tolerance
T-cell mediated bile duct destruction

EPIGENETICS IN CHRONIC CHOLANGITIS

Recent research shows:

DNA methylation changes
Histone modification abnormalities
MicroRNA dysregulation

These influence:

Fibrogenesis
Oncogenesis
Immune activation

ADVANCED FIBROSIS CASCADE

Chronic duct injury activates:

Kupffer cells
Stellate cells
Portal fibroblasts

Key mediators:

TGF-β
PDGF
CTGF

Collagen types I and III accumulate in portal tracts.

Result:

Bridging fibrosis
Biliary cirrhosis

PORTAL HYPERTENSION PATHOPHYSIOLOGY

In advanced cholangitis:

Fibrosis increases intrahepatic resistance.

Consequences:

Splenomegaly
Varices
Ascites
Hepatorenal syndrome

Hemodynamic mechanism:

Nitric oxide dysregulation
Splanchnic vasodilation
RAAS activation

CHOLANGIOCARCINOMA — MOLECULAR ONCOLOGY

Chronic inflammation → DNA instability.

Common genetic alterations:

KRAS mutations
p53 inactivation
IDH1/2 mutations
FGFR2 fusions (intrahepatic type)

Tumor Microenvironment

Characterized by:

Dense desmoplastic stroma
Cancer-associated fibroblasts
Immune suppression

This explains poor chemotherapy response.

PRECISION THERAPIES IN CHOLANGIOCARCINOMA

Targeted treatments:

FGFR inhibitors (e.g., pemigatinib)
IDH1 inhibitors
Immunotherapy (PD-1 inhibitors in selected cases)

Molecular profiling now recommended in advanced disease.

ADVANCED ERCP TECHNIQUES

Endoscopic Retrograde Cholangiopancreatography

Modern techniques include:

Cholangioscopy-guided lithotripsy
SpyGlass system
Metal stent deployment
EUS-guided biliary drainage

EUS-GUIDED BILIARY DRAINAGE

Used when:

ERCP fails
Altered anatomy
Malignant obstruction

HEPATIC REGENERATION IN CHRONIC DISEASE

Liver regeneration mediated by:

Hepatocyte growth factor (HGF)
IL-6
TNF-α

However, chronic cholestasis impairs regenerative capacity.

SYSTEMIC METABOLIC EFFECTS

Chronic cholestasis causes:

Fat-soluble vitamin deficiency (A, D, E, K)
Osteoporosis
Hyperlipidemia
Xanthomas

PRURITUS MECHANISM IN CHOLESTASIS

Proposed mediators:

Bile acids
Lysophosphatidic acid
Autotaxin enzyme

Treatment:

Cholestyramine
Rifampicin
Naltrexone

COAGULATION ABNORMALITIES

Due to:

Vitamin K malabsorption
Impaired hepatic synthesis

Leads to:

Prolonged PT/INR
Bleeding risk

FUTURE DIRECTIONS IN CHOLANGITIS RESEARCH

Stem cell therapy
Anti-fibrotic monoclonal antibodies
Microbiome-targeted therapies
Gene-editing approaches

SYSTEMS-LEVEL PATHOPHYSIOLOGY OF ACUTE CHOLANGITIS

Acute cholangitis is best understood as a three-axis failure model:

Mechanical obstruction
Microbial invasion
Host inflammatory dysregulation

When these overlap → septic physiology.

AXIS 1: OBSTRUCTION BIOPHYSICS

Ductal Pressure Gradient

Normal:

Hepatic canalicular pressure ≈ 10 cm H₂O

Obstructed:

25–30 cm H₂O

Effects:

Sinusoidal compression
Portal venous congestion
Hepatic microischemia

AXIS 2: BACTERIAL TRANSCIRCULATION

When pressure exceeds venous pressure:

Cholangiovenous reflux
Bacteria enter hepatic veins
Rapid bacteremia

This explains why:

Blood cultures often positive early
Septic shock may precede imaging confirmation

AXIS 3: IMMUNE DYSREGULATION

Initial phase:

Hyperinflammatory cytokine storm

Late phase:

Immune exhaustion
Secondary infections

Severe cholangitis behaves similarly to septic shock from intra-abdominal source.

ADVANCED SEPSIS MECHANISMS IN CHOLANGITIS

Lipopolysaccharide (LPS) binds:

CD14
TLR-4

Triggers:

MyD88 pathway
NF-κB transcription
TNF-α release

Systemic consequences:

Nitric oxide overproduction
Vasoplegia
Mitochondrial dysfunction
Lactate elevation

MITOCHONDRIAL FAILURE IN SEPTIC CHOLANGITIS

Sepsis causes:

Impaired oxidative phosphorylation
Reduced ATP synthesis
Cytopathic hypoxia

Even when oxygen delivery is adequate, cells cannot utilize it efficiently.

This contributes to:

Multi-organ dysfunction
Renal failure
ARDS

RENAL PATHOPHYSIOLOGY

Acute kidney injury occurs due to:

Hypotension
Endotoxemia
Microthrombi
Hepatorenal physiology in chronic cases

Types:

Pre-renal
Acute tubular necrosis
Hepatorenal syndrome (chronic cholestatic cirrhosis)

PULMONARY COMPLICATIONS

ARDS develops due to:

Capillary leak
Neutrophil activation
Cytokine storm

Chest findings:

Bilateral infiltrates
Hypoxemia

Management:

Low tidal volume ventilation
Conservative fluid strategy

COAGULATION CASCADE DYSFUNCTION

Endotoxin induces:

Tissue factor expression
Platelet activation
Microvascular thrombosis

Leads to:

Disseminated intravascular coagulation (DIC)

Lab findings:

Elevated D-dimer
Low platelets
Prolonged PT

ADVANCED IMMUNOGENETICS IN PSC

Primary Sclerosing Cholangitis

Strong genetic associations:

HLA-B8
HLA-DR3
HLA-DRB1*1501

Genome-wide association studies identify:

IL2 receptor gene variants
FUT2 gene (microbiome interaction)

MICROBIOME AND PSC PROGRESSION

Altered taxa:

Increased Enterococcus
Reduced diversity

Hypothesis:

Gut dysbiosis → portal endotoxemia → bile duct inflammation.

Emerging trials:

Oral vancomycin
Fecal microbiota transplant

Still investigational.

AUTOIMMUNE BREAKDOWN IN PBC

Primary Biliary Cholangitis

Mechanism involves:

Loss of T regulatory cell tolerance
Molecular mimicry
B-cell autoantibody production

Target:

Pyruvate dehydrogenase complex E2

Progression:

Ductopenia
Chronic cholestasis
Cirrhosis

METABOLIC CONSEQUENCES OF CHRONIC CHOLESTASIS

Fat Malabsorption

Due to reduced bile acids:

Steatorrhea
Weight loss
Deficiency of vitamins A, D, E, K

Bone Disease

Mechanisms:

Vitamin D deficiency
Chronic inflammation
Reduced physical activity

Results:

Osteopenia
Osteoporosis
Fractures

Dyslipidemia

PBC commonly shows:

Elevated HDL
Elevated total cholesterol

Interestingly:

Cardiovascular risk not proportionally increased.

ADVANCED ONCOGENESIS IN PSC

Chronic inflammation leads to:

Oxidative DNA damage
CpG island methylation
Oncogene activation

Cholangiocarcinoma may arise even without cirrhosis.

High-risk features:

Rapid ALP rise
Weight loss
Dominant stricture

Surveillance:

MRCP
CA 19-9
Brush cytology during ERCP

Endoscopic Retrograde Cholangiopancreatography

TRANSPLANT IMMUNOLOGY — DEEPER MECHANISMS

Rejection mediated by:

CD8+ cytotoxic T cells
Th1 cytokine profile

Immunosuppressive strategies:

Calcineurin inhibition (Tacrolimus)
mTOR inhibitors (Sirolimus)
Anti-IL2 receptor antibodies

Complications:

Post-transplant lymphoproliferative disorder
Opportunistic infection
Recurrence of PSC

HEMODYNAMIC MODEL OF PORTAL HYPERTENSION

Fibrosis increases intrahepatic resistance.

Compensatory response:

Splanchnic vasodilation
Hyperdynamic circulation

Results in:

Ascites
Varices
Splenomegaly

Management:

Non-selective beta blockers
Endoscopic band ligation

BILIARY STRICTURE BIOLOGY

Strictures form due to:

Collagen deposition
Smooth muscle proliferation
Ischemia

Dominant stricture in PSC may require:

Balloon dilation
Stenting

FUTURE PRECISION MEDICINE IN CHOLANGITIS

Targeted bile acid receptor modulation
Anti-fibrotic monoclonal antibodies
MicroRNA therapy
Cholangiocyte stem cell regeneration
Organoid-based drug testing

INTEGRATED MASTER FLOW MODEL

Acute Phase:

Obstruction → Pressure ↑ → Infection → Sepsis

Chronic Phase:

Immune dysregulation → Fibrosis → Cirrhosis → Cancer

I. MECHANOTRANSDUCTION IN OBSTRUCTIVE CHOLANGITIS

Biliary obstruction is not simply a blockage — it initiates biophysical stress signaling within cholangiocytes.

A. Primary Cilia as Pressure Sensors

Cholangiocytes possess apical primary cilia projecting into bile.

When ductal pressure rises:

Ciliary bending activates polycystin-1 and polycystin-2
Calcium influx occurs
Intracellular Ca²⁺ increases
cAMP signaling is altered

This triggers:

Cytokine secretion (IL-6, IL-8)
Proliferation signaling
Fibrogenic gene activation

Thus, obstruction immediately initiates inflammatory programming — even before infection.

B. Tight Junction Breakdown

Increased intraductal pressure:

Disrupts claudins and occludins
Weakens epithelial barrier
Allows bacterial translocation

This is the structural basis of cholangiovenous reflux.

II. IMMUNOMETABOLISM IN ACUTE CHOLANGITIS

Sepsis in cholangitis is metabolically unique.

A. Warburg Shift in Immune Cells

Activated macrophages switch to:

Aerobic glycolysis
Rapid ATP production
Lactate generation

This explains:

Elevated serum lactate
Mitochondrial inefficiency

B. Mitochondrial Dysfunction

Endotoxin exposure leads to:

Mitochondrial permeability transition pore opening
Cytochrome c release
Apoptosis cascade

Even when perfusion improves, mitochondrial damage may persist.

III. VASCULAR BIOLOGY IN SEPTIC CHOLANGITIS

Sepsis causes endothelial dysfunction.

A. Nitric Oxide Dysregulation

Inducible nitric oxide synthase (iNOS) overexpressed:

Excess NO production
Systemic vasodilation
Hypotension

B. Glycocalyx Degradation

Endotoxin damages endothelial glycocalyx:

Capillary leak
Tissue edema
Hypoalbuminemia

This worsens organ perfusion.

IV. INTRAHEPATIC MICROCIRCULATORY FAILURE

Within the liver:

Sinusoidal constriction
Kupffer cell activation
Microthrombi

This leads to:

Hepatic ischemia
Elevated transaminases
Worsening cholestasis

V. ADVANCED FIBROGENESIS IN PSC

Primary Sclerosing Cholangitis

Fibrosis is a regulated wound-healing response gone uncontrolled.

A. Hepatic Stellate Cell Activation

Triggers:

TGF-β
PDGF
Reactive oxygen species

Quiescent stellate cells → myofibroblasts:

Express α-smooth muscle actin
Produce collagen I and III

B. Extracellular Matrix Remodeling

Matrix metalloproteinases (MMPs) normally degrade collagen.

In PSC:

Tissue inhibitors of metalloproteinases (TIMPs) increase
Collagen accumulates

Result:

Bridging fibrosis
Biliary cirrhosis

VI. DUCTULAR REACTION

Chronic cholestasis induces:

Proliferation of bile ductules
Portal inflammation
Expansion of progenitor cells

This “ductular reaction” correlates with fibrosis severity.

VII. MOLECULAR ONCOGENESIS OF CHOLANGIOCARCINOMA

Chronic inflammation drives:

Oxidative DNA damage
Telomere shortening
Epigenetic silencing

Common pathways activated:

KRAS–MAPK pathway
PI3K–AKT pathway
FGFR2 fusion signaling

Tumor microenvironment:

Dense fibrotic stroma
Immunosuppressive macrophages
T-cell exhaustion

This explains poor chemotherapy response.

VIII. SYSTEMIC CONSEQUENCES OF CHRONIC CHOLESTASIS

A. Neurotoxicity

Accumulation of bile acids:

Cross blood-brain barrier
Cause cognitive dysfunction
Contribute to hepatic encephalopathy

B. Cardiovascular Effects

Chronic inflammation:

Endothelial dysfunction
Autonomic imbalance

Yet paradoxically, PBC patients may not have proportionally increased cardiovascular mortality.

Primary Biliary Cholangitis

IX. ADVANCED CRITICAL CARE ALGORITHM

Severe cholangitis = surgical sepsis.

Step 1: Early Goal-Directed Therapy

IV crystalloids
Lactate monitoring
MAP ≥ 65 mmHg

Step 2: Broad-Spectrum Antibiotics

Administer within 1 hour.

Step 3: Source Control

Definitive therapy:

Endoscopic Retrograde Cholangiopancreatography

If unsuccessful:

Percutaneous drainage
Surgical decompression

Delay increases mortality exponentially.

X. TRANSPLANT IMMUNOLOGY — CELLULAR LEVEL

After liver transplant:

Donor antigen presented by dendritic cells
Host T cells activated

Acute rejection:

Portal inflammation
Bile duct injury
Endothelitis

Chronic rejection:

Vanishing bile duct syndrome

Immunosuppressive balance critical to prevent:

Infection
Malignancy

XI. PRECISION MEDICINE FUTURE

Emerging therapies target:

FXR receptor
TGF-β blockade
Anti-fibrotic RNA interference
Microbiome engineering

Organoid models now allow:

Personalized drug testing
Mutation-specific therapy

XII. INTEGRATED MASTER MODEL

Acute:

Mechanical obstruction
→ Ciliary mechanotransduction
→ Tight junction failure
→ Bacterial invasion
→ Cytokine storm
→ Endothelial collapse
→ Multi-organ failure

Chronic:

Immune dysregulation
→ Stellate activation
→ Fibrosis
→ Cirrhosis
→ Portal hypertension
→ Malignancy

CHOLANGITIS A Complete Clinical, Pathophysiological, Diagnostic, and Therapeutic Review for MBBS, Pharmacy, and Nursing Students

CHOLANGITIS

Introduction

Anatomy of the Biliary Tree

Components of the Biliary System

1. Intrahepatic Ducts

2. Extrahepatic Ducts

3. Ampulla of Vater

Blood Supply and Lymphatics

Definition and Classification of Cholangitis

Acute Ascending Cholangitis

Chronic and Autoimmune Types

Primary Sclerosing Cholangitis

Primary Biliary Cholangitis

Pathophysiology of Acute Ascending Cholangitis

1. Biliary Obstruction

2. Bacterial Overgrowth

3. Bacterial Translocation

Mechanism of Sepsis Development

Etiology of Cholangitis

Obstructive Causes

Infectious Causes

Clinical Presentation

Charcot’s Triad

Reynolds’ Pentad

Symptoms

Laboratory Findings

Complete Blood Count

Liver Function Tests

Inflammatory Markers

Imaging in Cholangitis

Ultrasound

MRCP

ERCP

Tokyo Guidelines for Severity Assessment

Grade I (Mild)

Grade II (Moderate)

Grade III (Severe)

Management of Acute Cholangitis

Initial Stabilization

Definitive Treatment

Biliary Decompression

Complications

Prognosis

Chronic Cholangitis Overview

Primary Sclerosing Cholangitis

Differential Diagnosis

Preventive Strategies

EPIDEMIOLOGY OF CHOLANGITIS

Global Incidence

Age Distribution

Gender Distribution

MICROBIOLOGY OF ACUTE CHOLANGITIS

Common Organisms

Gram-Negative Bacilli

Gram-Positive Organisms

Anaerobes

Pathway of Infection

MOLECULAR PATHOGENESIS

Step 1: Obstruction-Induced Pressure Rise

Step 2: Endotoxin Release

Step 3: Sepsis Cascade

IMMUNOLOGY OF CHRONIC CHOLANGITIS

Primary Sclerosing Cholangitis

Autoimmune Mechanisms

Primary Biliary Cholangitis

Immunological Features

DETAILED CLINICAL COURSE

Early Phase

Progressive Phase

Severe Phase

DIFFERENTIAL DIAGNOSIS IN DETAIL

Acute Cholecystitis

Acute Pancreatitis

Viral Hepatitis

RADIOLOGY DEEP DIVE

Ultrasound Findings

MRCP Features

ERCP Findings

HISTOPATHOLOGY