Primary Biliary Cirrhosis

Definition

Primary Biliary Cholangitis (PBC) — formerly called Primary Biliary Cirrhosis (the name was changed in 2015 to reflect the fact that most patients are now diagnosed before cirrhosis develops) — is a chronic, progressive, autoimmune cholestatic liver disease characterised by a T-lymphocyte–mediated attack on small intrahepatic (interlobular) bile ducts ^[1][2].

Let's break down the name:

• Primary → the disease arises de novo from autoimmune mechanisms, not secondary to stones, strictures, or external compression.
• Biliary → targets the bile ducts (specifically the small/medium intrahepatic interlobular bile ducts, < 100 µm).
• Cholangitis → "chol-" = bile, "-ang-" = vessel/duct, "-itis" = inflammation. So: inflammation of the bile ducts.

The sustained, granulomatous destruction of these bile ductules leads to progressive cholestasis (impaired bile flow), then biliary fibrosis, and ultimately liver cirrhosis and liver failure if untreated ^[1].

Epidemiology

Incidence and Prevalence

• Global prevalence: approximately 1.9–40.2 per 100,000 population (varies by region; highest in Northern Europe and North America) ^[3].
• Incidence appears to be increasing, partly due to earlier diagnosis from routine liver function testing.
• In Hong Kong and Asia, PBC is less common than in Western populations but is increasingly recognised. In HK, chronic Hepatitis B remains the dominant cause of liver cirrhosis (~90%), with PBC representing a small but important subset of biliary causes of cirrhosis ^[2][4].

Age and Sex

• Extreme female predominance (90–95% female) ^[1][2].
  • Why? The precise reason is unclear, but leading hypotheses include:
    • X-chromosome monosomy: Enhanced X chromosome loss in lymphocytes of PBC patients → disinhibition of X-linked immune regulatory genes.
    • Oestrogen effects on immune regulation: Oestrogen modulates T-cell and B-cell function, potentially promoting loss of tolerance to mitochondrial antigens.
    • Microchimerism: Fetal cells persisting in maternal circulation post-pregnancy may trigger graft-vs-host–like immune reactions against biliary epithelium.
• Age of diagnosis: typically 30–65 years (middle-aged women) ^[1].
• Rarely diagnosed before 25 or after 70.

Geographic Variation

• Highest prevalence in Northern Europe (UK, Scandinavia) and North America.
• Lower prevalence in Asia and Africa, though increasingly diagnosed.
• Clustering in families: first-degree relatives of PBC patients have a ~100-fold increased risk.

Risk Factors

Associated Medical Conditions

PBC is strongly associated with other autoimmune diseases. Think of PBC as part of an "autoimmune constellation" ^[1]:

Anatomy and Function — The Biliary System

To understand PBC, you must understand which bile ducts are targeted and why their destruction matters.

Normal Bile Duct Anatomy

Hepatocytes → Bile canaliculi → Canals of Hering → Cholangioles → 
Interlobular bile ducts (< 100 µm) → Septal bile ducts → 
Intrahepatic bile ducts → Right and Left hepatic ducts → 
Common hepatic duct → (+ cystic duct) → Common bile duct → Ampulla of Vater

PBC targets the small interlobular bile ducts (those within the portal triads, < 100 µm diameter). These are lined by biliary epithelial cells (BECs / cholangiocytes).

Why Does Destroying Small Bile Ducts Cause Disease?

1. Bile formation: Hepatocytes produce bile and secrete it into canaliculi. Bile flows through the duct system to the intestine.
2. Bile duct destruction → bile cannot flow out of the liver → cholestasis (bile stasis within the liver).
3. Retained bile acids are toxic to hepatocytes → ongoing hepatocyte injury → inflammation → fibrosis → cirrhosis.
4. Lack of bile in the intestine → impaired fat emulsification → steatorrhoea → malabsorption of fat-soluble vitamins (A, D, E, K).

The Portal Triad

Each portal triad contains:

• Hepatic artery branch
• Portal vein branch
• Bile duct (interlobular) ← THIS is the target in PBC

The classic histological lesion of PBC — the "florid duct lesion" — shows lymphocytic infiltration and granulomatous destruction centred on these portal triad bile ducts.

Etiology and Pathophysiology

Etiology

PBC is an autoimmune disease of unknown precise aetiology, arising from a combination of:

1. Genetic susceptibility

   • HLA associations: HLA-DRB108 (susceptibility), HLA-DRB111, HLA-DRB1*13 (protective)
   • Non-HLA genes: IL-12A, IL-12RB2, STAT4, IRF5, CTLA-4, TNFSF15
   • Strong familial clustering; ~63% concordance in monozygotic twins

2. Environmental triggers

   • Molecular mimicry (bacterial PDC-E2, especially from E. coli)
   • Xenobiotics (halogenated compounds that modify PDC-E2 → neoantigen)
   • Smoking
   • Possibly hormonal factors (explaining female predominance)

3. Loss of immune tolerance

   • The central autoantigen is PDC-E2 (E2 subunit of the pyruvate dehydrogenase complex), located on the inner mitochondrial membrane
   • In PBC, biliary epithelial cells (BECs) are unique: when BECs undergo apoptosis, PDC-E2 remains immunologically intact on apoptotic blebs (it is not glutathionylated/cleaved as in other cell types)
   • This intact PDC-E2 is presented to the immune system → T-cell and B-cell activation → autoimmune attack specifically on BECs

Pathophysiology — Step by Step

Immunopathology in Detail

1. Humoral immunity:

   • Anti-mitochondrial antibodies (AMA) — specifically AMA-M2 targeting PDC-E2 — are the serological hallmark (present in ~95% of PBC patients) ^[1]
   • AMA are highly specific (~98%) but are NOT directly pathogenic; they are a marker of the underlying autoimmune process
   • Other AMA subtypes (M4, M8, M9) are less commonly tested

2. Cellular immunity (the actual effector mechanism):

   • CD4+ T-helper cells and CD8+ cytotoxic T cells infiltrate the portal tracts and directly attack BECs
   • The granulomatous inflammation around damaged ducts is the hallmark histological feature
   • CD8+ T cells are the primary effectors of BEC destruction

3. Biliary epithelial cell (BEC) biology:

   • BECs in PBC show increased apoptosis
   • Unique failure to cleave PDC-E2 during apoptosis → persistent antigen exposure
   • BECs also express MHC class II molecules and can act as antigen-presenting cells, amplifying the immune response
   • Progressive BEC loss → ductopenia (vanishing bile duct syndrome) → cholestasis

The Cholestatic Cascade

Once bile ducts are destroyed and cholestasis develops:

Classification

Histological Staging (Ludwig / Scheuer Classification)

PBC is classically staged 0–4 based on liver biopsy ^[1][2]:

Clinical Classification

Some clinicians also classify PBC by clinical stage:

1. Pre-clinical — AMA positive, normal LFTs, asymptomatic
2. Asymptomatic — AMA positive, abnormal LFTs (↑ALP), no symptoms
3. Symptomatic — pruritus, fatigue, jaundice
4. Decompensated — cirrhosis with portal hypertension, ascites, variceal bleeding, hepatic encephalopathy

AMA-Negative PBC (~5%)

About 5% of patients have typical clinical, biochemical, and histological features of PBC but are AMA-negative. In these patients:

• PBC-specific ANA patterns (multiple nuclear dots [anti-sp100] or rim-like/membranous [anti-gp210]) are often present
• The disease behaves identically to AMA-positive PBC
• Previously termed "autoimmune cholangitis"

PBC-AIH Overlap Syndrome

~10% of PBC patients have features of both PBC and autoimmune hepatitis (AIH):

• Elevated transaminases (ALT > 5× ULN) in addition to cholestatic pattern
• Interface hepatitis on biopsy
• May be ANA-positive
• Requires combined treatment (UDCA + immunosuppression)

Clinical Features

Asymptomatic at diagnosis in 50–60% of cases ^[1] — often detected incidentally through raised ALP on routine blood tests.

Symptoms

Signs

Signs in Decompensated PBC (Late Disease / Cirrhosis)

When PBC progresses to cirrhosis, all the general signs of chronic liver disease and portal hypertension may be seen ^[1][2]:

• Ascites — portal hypertension + hypoalbuminaemia
• Variceal bleeding — porto-systemic collaterals (oesophageal varices, rectal varices, caput medusae)
• Hepatic encephalopathy — failure of hepatic ammonia clearance + portosystemic shunting → ammonia and other neurotoxins reach the brain
• Coagulopathy — impaired synthesis of clotting factors + vitamin K malabsorption
• Hepatorenal syndrome — splanchnic vasodilation in cirrhosis → renal hypoperfusion → functional renal failure

Key Differences: PBC vs PSC (High Yield Comparison)

Since PBC and PSC are the two major autoimmune biliary diseases, exam questions frequently test their differentiation:

Summary of Pathophysiology → Clinical Manifestation Connections

References

^[1] Senior notes: felixlai.md (Primary Biliary Cholangitis section, pages 532–539) ^[2] Senior notes: maxim.md (Hepatocellular carcinoma section — PBC as risk factor for cirrhosis/HCC; Acute cholangitis section — PBC as cause of strictures) ^[3] Senior notes: felixlai.md (Primary Sclerosing Cholangitis section, pages 529–532) ^[4] Senior notes: felixlai.md (Liver Cirrhosis section — HBV as most common cause in HK, PBC as biliary cause)

Differential Diagnosis of Primary Biliary Cholangitis

The Clinical Problem You're Actually Solving

Before we list differentials, let's understand what clinical scenario forces you to consider PBC in the first place. There are really two clinical doorways through which PBC enters your differential:

1. The incidental cholestatic LFT pattern: A middle-aged woman with raised ALP/GGT, normal or mildly raised transaminases, and no obvious biliary obstruction on ultrasound. What is this?
2. The symptomatic cholestatic patient: Pruritus ± fatigue ± jaundice, with or without hepatomegaly. What is causing this?

Both scenarios demand the same thought process: systematically exclude other causes of cholestasis — both intrahepatic and extrahepatic — before landing on PBC.

Framework: Differential Diagnosis by Clinical Presentation

The DDx of PBC maps onto three overlapping clinical scenarios. Let's work through each systematically.

Scenario 1: Cholestatic LFT Pattern (↑ ALP/GGT, normal-to-mild ↑ AST/ALT)

This is the most common way PBC presents — often as an incidental finding. Your differential here is essentially "What causes a cholestatic biochemical pattern?"

Scenario 2: Obstructive Jaundice (Must Exclude Extrahepatic Causes)

When PBC progresses to cause frank jaundice, or when a patient presents with jaundice and cholestatic LFTs, you must exclude extrahepatic biliary obstruction ^[1][4][6]. This is the "surgical vs medical jaundice" question.

Types of jaundice ^[6]:

• Pre-hepatic: Haemolysis (spherocytosis, G6PD deficiency, malaria, sickle cell anaemia) ^[6]
• Hepatic: hepatitis, cirrhosis, intrahepatic cholestasis, medications, Gilbert's syndrome ^[6]
• Post-hepatic: obstructive jaundice ^[6]

Extrahepatic (post-hepatic) causes to exclude ^[4]:

Scenario 3: Pruritus + Fatigue in a Middle-Aged Woman

This is the classic symptomatic PBC presentation. The DDx here is narrower but still important:

The Critical Differential: PBC vs PSC vs AIH vs Overlap

This is the highest-yield differential for exams. These three autoimmune liver diseases frequently overlap and must be distinguished:

Differential Diagnosis Algorithm

The following flowchart illustrates the systematic approach to narrowing the DDx when PBC is suspected:

Differential Diagnosis by Physical Examination Findings

Physical Examination findings in obstructive jaundice to guide DDx ^[6]:

HK-Relevant Differential Considerations

In Hong Kong specifically, certain diagnoses are more or less likely ^[2][4][5]:

PBC itself is uncommon in HK compared to Western populations but is increasingly diagnosed. When a middle-aged woman in HK presents with cholestatic LFTs and no biliary obstruction on USS, PBC should still be high on the differential — check AMA.

Summary: The DDx "Cheat Sheet"

When you suspect PBC, you are really asking three questions:

1. Is there extrahepatic obstruction? → USS ± MRCP to exclude stones, strictures, tumours
2. Is this a different intrahepatic cholestatic disease? → Check AMA (PBC), pANCA/MRCP (PSC), IgG4 (IgG4-SC), drug history
3. Is there overlap with AIH? → Check transaminases, IgG, consider biopsy if mixed picture

References

^[1] Senior notes: felixlai.md (Primary Biliary Cholangitis section, pages 532–539) ^[2] Senior notes: maxim.md (Hepatocellular carcinoma section — PBC as risk factor; Acute cholangitis — PBC as cause of strictures) ^[3] Senior notes: felixlai.md (Primary Sclerosing Cholangitis section, pages 529–532) ^[4] Senior notes: felixlai.md (Biliary Obstruction section, pages 499–501; Liver Cirrhosis section, pages 440–442) ^[5] Senior notes: maxim.md (Obstructive Jaundice section; Recurrent Pyogenic Cholangitis section; Jaundice DDx table — stone vs tumour) ^[6] Lecture slides: Malignant biliary obstruction.pdf (p2: Types of jaundice; p6: Physical Examination) ^[7] Senior notes: felixlai.md (Cholangiocarcinoma section, pages 548–549)

Diagnostic Criteria for Primary Biliary Cholangitis

The Logic Before the Criteria

Before memorising criteria, understand the reasoning behind them. PBC is an autoimmune disease that destroys small intrahepatic bile ducts. You cannot see these ducts on imaging (they're microscopic, < 100 µm). So the diagnosis rests on three pillars:

1. Biochemistry — Is there evidence of cholestasis? (↑ ALP)
2. Serology — Is there the autoimmune signature? (AMA)
3. Histology — Can we see the duct destruction directly? (Liver biopsy)

And critically, you must first exclude anything else that could explain the cholestasis — especially extrahepatic biliary obstruction and other liver diseases.

Formal Diagnostic Criteria (AASLD/EASL Guidelines)

Diagnosis of PBC is established if there is no extrahepatic biliary obstruction, no comorbidity affecting the liver, and ≥ 2 of the following 3 criteria are present ^[1]:

When Is Each Criterion Alone Insufficient?

Special Diagnostic Scenarios

AMA-Negative PBC (~5% of cases)

About 5% of patients have classic PBC clinically and histologically but are AMA-negative. In these patients:

• Check for PBC-specific ANA patterns ^[1]:
  • Multiple nuclear dots pattern (anti-sp100 antibodies)
  • Rim-like / membranous pattern (anti-gp210 antibodies)
• These ANA patterns have high specificity for PBC
• Liver biopsy becomes essential in AMA-negative suspected PBC to confirm histological features ^[1]
• The disease behaves identically to AMA-positive PBC

Suspected PBC-AIH Overlap

Liver biopsy is indicated in patients if the diagnosis is in doubt, patient has evidence of autoimmune hepatitis, or if patient is not responding optimally with ursodeoxycholic acid ^[1].

Features suggesting overlap ^[1]:

• ALT > 5× ULN
• IgG > 2× ULN or positive anti-SMA
• Interface hepatitis on biopsy (moderate to severe)

The Paris criteria for PBC-AIH overlap require ≥ 2 of 3 PBC features AND ≥ 2 of 3 AIH features:

Diagnostic Algorithm

The following algorithm represents the systematic approach from initial suspicion to confirmed diagnosis:

Investigation Modalities — Detailed Breakdown

1. Biochemical Tests

A. Liver Function Tests (LFT)

B. Complete Blood Count (CBC)

CBC with differentials ^[1]:

• Pancytopenia ^[1] in advanced disease — reflects hypersplenism from portal hypertension
  • Patients with PBC may have iron deficiency anaemia due to GI blood loss related to portal hypertension ^[1] — oesophageal or rectal variceal bleeding
  • Patients with liver cirrhosis may develop leukopenia and thrombocytopenia ^[1] — sequestration in enlarged spleen + decreased thrombopoietin production by diseased liver

C. Lipid Profile

Serum lipids may be strikingly elevated in PBC ^[1]:

• Patients with early PBC often have mild elevations in LDL and VLDL and striking elevations in HDL ^[1]
• Why? Bile is the major route for cholesterol excretion. Cholestasis → cholesterol retention. Additionally, lipoprotein-X (Lp-X) — an abnormal lipoprotein — accumulates in cholestasis and is measured as "LDL" by some assays, artefactually inflating it.
• Increase in HDL explains why patients with PBC despite with striking hypercholesterolaemia do not appear to be at increased risk of death from atherosclerosis ^[1]
• Clinical pearl: Don't reflexively start statins for high cholesterol in PBC — the lipid profile is not atherogenic.

D. Clotting Profile

• PT / INR may be prolonged in two settings:
  1. Early — Vitamin K malabsorption from cholestasis → reduced synthesis of factors II, VII, IX, X (correctable with parenteral vitamin K)
  2. Late — Hepatic synthetic failure in cirrhosis → reduced production of ALL clotting factors (NOT correctable with vitamin K alone)
• Differentiating these two: give 10 mg IV vitamin K. If PT corrects → malabsorption. If PT does NOT correct → synthetic failure.

E. Immunoglobulins

2. Serological / Autoantibody Tests

A. Anti-Mitochondrial Antibody (AMA)

Serological hallmark of PBC — 95% of patients are positive for AMA ^[1].

B. Anti-Nuclear Antibodies (ANA)

Occurs in 70% of patients ^[1].

• Two immunofluorescence patterns are considered PBC-specific ^[1]:
  1. Multiple nuclear dots pattern — targeting anti-sp100 (a nuclear body protein)
  2. Rim-like or membranous pattern — targeting anti-gp210 (a nuclear pore glycoprotein)
• These patterns are distinct from the homogeneous or speckled ANA patterns seen in AIH or SLE
• Presence of ANA can cause confusion with autoimmune hepatitis or overlap syndrome ^[1]
• Presence of ANA is associated with more rapid progression of disease and a poorer prognosis ^[1]
• Anti-gp210 specifically is associated with hepatic failure phenotype (progressive jaundice)
• Anti-sp100 is more specific for PBC but has lower sensitivity

C. Other Autoantibodies to Check

3. Radiological Tests

A. Ultrasound (USS) Abdomen — FIRST-LINE Imaging

USG abdomen — imaging to exclude extrahepatic biliary obstruction or space-occupying lesion in the liver ^[1].

The maxim notes describe the jaundice investigation flowchart ^[5]: cholestatic pattern on LFTs → abdominal USS → if bile ducts normal → "Intrahepatic cholestasis — PBC/PSC, Drugs → AMA, P-ANCA, MRCP, Liver biopsy" ^[5]. If bile ducts dilated → "Extrahepatic cholestasis → Visualise bile duct" ^[5].

B. Magnetic Resonance Cholangiopancreatography (MRCP)

MRCP — imaging to exclude extrahepatic biliary obstruction ^[1].

C. ERCP (Endoscopic Retrograde Cholangiopancreatography)

• NOT routinely indicated in PBC diagnosis — PBC is a small-duct disease; ERCP visualises large ducts
• Indicated in patients who are unable to undergo MRCP (e.g., implanted metal devices) or in patients with early PSC changes that may be missed by MRCP ^[3]
• ERCP carries procedural risks (pancreatitis, perforation, cholangitis) and should only be performed when therapeutic intervention (stone removal, stent placement) is anticipated

D. Transient Elastography (FibroScan)

• Non-invasive assessment of liver fibrosis — measures liver stiffness using ultrasound-based shear wave velocity ^[8]
• Increasingly used to stage fibrosis in PBC without biopsy
• Liver stiffness values:
  • < 7.1 kPa → minimal fibrosis (F0-F1)
  • 7.1–9.5 kPa → significant fibrosis (F2)
  • 9.5–12.5 kPa → advanced fibrosis (F3)
  • > 12.5 kPa → cirrhosis (F4)
• Advantages: non-invasive, repeatable, good for monitoring progression
• Limitations: unreliable in obesity, ascites, acute hepatitis (inflammation falsely elevates stiffness)

4. Liver Biopsy

Liver biopsy is often NOT required to establish the diagnosis of PBC but can provide useful information with regard to staging and prognosis ^[1].

Indications for Biopsy in PBC

Indicated in patients if ^[1]:

1. The diagnosis is in doubt (e.g., AMA-negative, atypical features)
2. Patient has evidence of autoimmune hepatitis (elevated ALT/IgG → need to confirm/exclude overlap)
3. Patient is not responding optimally with ursodeoxycholic acid (to reassess staging and look for other pathology)
4. Need to assess fibrosis stage when non-invasive methods are inconclusive

Histological Findings and Staging

Histological findings in PBC are staged on a scale of 0–4 ^[1]:

The hallmark lesion — the "florid duct lesion" — is pathognomonic:

• A medium-sized interlobular bile duct is surrounded by a dense lymphocytic infiltrate
• Epithelioid granulomata may be seen around the damaged duct
• The duct epithelium shows degenerative changes (vacuolation, nuclear irregularity, eosinophilic change)
• "Non-suppurative" = NO neutrophils (this is immune-mediated destruction, not infection)

5. Additional Investigations for Screening and Staging

Once PBC is diagnosed, additional tests are needed to assess disease complications and associated conditions:

6. Prognostic Markers and Risk Stratification

Factors associated with a poorer prognosis ^[1]:

Assessing UDCA Response (at 12 months)

Multiple criteria exist to define "UDCA response" — all assess whether the biochemistry has improved after 1 year of UDCA:

Non-responders require second-line therapy (obeticholic acid, bezafibrate) or transplant referral.

Putting It All Together — Investigation Summary Table

References

^[1] Senior notes: felixlai.md (Primary Biliary Cholangitis section, pages 532–539) ^[3] Senior notes: felixlai.md (Primary Sclerosing Cholangitis section, pages 529–532) ^[5] Senior notes: maxim.md (Obstructive Jaundice section — jaundice investigation flowchart; intrahepatic vs extrahepatic cholestasis algorithm) ^[8] Senior notes: felixlai.md (Liver Cirrhosis — Diagnosis section, pages 442–446)

Management of Primary Biliary Cholangitis

Management Philosophy — First Principles

Before diving into individual treatments, understand the management framework. PBC is a chronic autoimmune disease that destroys bile ducts. You cannot regenerate destroyed bile ducts. So the management strategy is:

1. Slow/halt disease progression — UDCA and second-line agents to protect remaining ducts and reduce cholestatic injury
2. Manage symptoms — pruritus, fatigue, sicca symptoms
3. Prevent and treat complications — fat-soluble vitamin deficiency, osteoporosis, portal hypertension
4. Replace the liver when it fails — liver transplantation as definitive treatment for end-stage disease

The good news: with UDCA, patients who respond biochemically have a near-normal life expectancy. The challenge: ~40% do not adequately respond to UDCA and need escalation.

Management Algorithm

1. Disease-Modifying Therapy

A. Ursodeoxycholic Acid (UDCA) — FIRST-LINE

Ursodeoxycholic acid (UDCA) is the cornerstone and 1st line therapy in treatment of PBC ^[1].

Let's break down the name: "urso-" = bear (originally isolated from bear bile — Ursus species), "deoxy-" = removal of an oxygen/hydroxyl group, "cholic acid" = bile acid. UDCA is a naturally occurring hydrophilic bile acid that constitutes only ~3% of the normal human bile acid pool.

Mechanisms of UDCA — explained from first principles:

The problem in PBC is that toxic hydrophobic bile acids (chenodeoxycholic acid, lithocholic acid) accumulate in the liver due to cholestasis → these damage hepatocyte membranes and bile duct epithelium → worsen inflammation and fibrosis.

UDCA works by:

1. Displacing toxic bile acids — UDCA is hydrophilic ("water-loving"). When you flood the bile acid pool with UDCA (it becomes ~40–60% of the pool), it displaces hydrophobic toxic bile acids → reduced hepatocyte injury. Think of it as diluting poison with a harmless substance.

2. Choleretic effect — UDCA stimulates bicarbonate secretion by cholangiocytes (the "bicarbonate umbrella") → protects bile duct epithelium from bile acid toxicity → slows duct destruction.

3. Anti-apoptotic — UDCA inhibits mitochondrial membrane permeabilisation → reduces hepatocyte apoptosis triggered by toxic bile acids.

4. Immunomodulatory — UDCA reduces aberrant HLA class I expression on hepatocytes, reducing immune-mediated attack. It also decreases production of pro-inflammatory cytokines (IL-2, IL-4, IFN-γ).

5. Stimulates biliary secretion — Enhances canalicular transporter expression (BSEP, MRP2) → promotes bile acid excretion → reduces intracellular bile acid toxicity.

Clinical significance ^[1]:

• Decreases pruritus and improves LFT (bilirubin/ALP/GGT) ^[1]
• Increases survival, delays progression to end-stage liver disease and delays liver transplantation ^[1]
• UDCA responders have survival rates comparable to the age- and sex-matched general population
• Does NOT reverse established cirrhosis — it slows progression and may reverse early fibrosis

Adverse effects ^[1]:

• GI upset is the most common including abdominal pain and diarrhoea ^[1]
• Weight gain (~3 kg in first year)
• Very rarely: hair thinning
• Overall, UDCA is remarkably well-tolerated

Contraindications:

• Complete biliary obstruction (bile acid cannot reach the bile duct if there's complete blockage)
• Known hypersensitivity to UDCA or bile acids
• Caution in patients with calcified gallstones (theoretical risk of stone dissolution → complications, though this is more relevant to gallstone dissolution therapy)

B. Assessing UDCA Response — The 12-Month Decision Point

After 12 months of UDCA at adequate dose, you must assess whether the patient has responded. This is THE critical management decision in PBC — it determines prognosis and need for second-line therapy.

Why assess at 12 months? UDCA takes time to reach steady-state effect on the bile acid pool and cholangiocyte protection. Assessing too early leads to false non-response.

What proportion respond? Approximately 60% of PBC patients show adequate biochemical response to UDCA. The remaining ~40% are "inadequate responders" who need escalation.

C. Obeticholic Acid (OCA) — SECOND-LINE

Obeticholic acid — indicated in patients with an inadequate response to UDCA defined as ALP level > 2× upper limit of normal after 1 year of UDCA ^[1].

Let's break down the name: "obe-" = from obese/bile acid research, "ti-" = modification, "cholic acid" = bile acid. OCA is a semi-synthetic derivative of chenodeoxycholic acid, modified to be a potent FXR agonist.

D. Fibrates — EMERGING SECOND-LINE (Now Guideline-Recommended)

Bezafibrate and fenofibrate are PPARα agonists that have shown significant benefit in PBC:

E. Elafibranor — NEWEST APPROVED AGENT (2024)

Elafibranor ("ela" = selective, "fibr" = fibrate-like, "anor" = novel modulator) is a dual PPARα/δ agonist approved by the FDA in June 2024 for PBC patients with inadequate UDCA response.

F. Seladelpar — Another PPAR-δ Selective Agonist

Seladelpar was approved by the FDA in August 2024 — a selective PPARδ agonist:

• 10 mg orally once daily
• ENHANCE trial showed significant biochemical response
• Well tolerated; may improve pruritus
• Now included in updated AASLD guidelines as second-line option

Summary: Disease-Modifying Therapy Decision Tree

2. Symptom Management

A. Pruritus — Stepwise Approach

Pruritus is often the most debilitating symptom and can be present even before jaundice develops. Management follows a stepladder approach ^[1]:

Step 1: Cholestyramine (First-line for pruritus)

Cholestyramine ^[1]:

• Pharmacological category: Resins ^[1] (bile acid sequestrant)
• Mechanism: ↑ Excretion of bile acids in jejunum and ileum by chelating bile salts ^[1]. Cholestyramine is a positively-charged anion-exchange resin that binds negatively-charged bile acids in the intestinal lumen → prevents their enterohepatic recirculation → reduces serum bile acid levels → less pruritogen delivery to skin. Think of it as a "bile acid sponge" in the gut.
• Dosage: 4 g before and after breakfast (timing matters: give 4 hours apart from UDCA because cholestyramine will also bind UDCA and reduce its absorption)
• Adverse effects include dyspepsia, bloating, diarrhoea and constipation ^[1]
• Also reduces absorption of fat-soluble vitamins (A, D, E, K) — supplement as needed
• Can interfere with absorption of other medications (thyroid hormones, warfarin, digoxin) — take other drugs 1 hour before or 4–6 hours after cholestyramine

Step 2: Rifampicin (Second-line for pruritus)

Rifampicin ^[1]:

• Category: Enzyme-inducing antibiotic ^[1]
• Mechanism: Improves pruritus in cholestasis ^[1] through multiple mechanisms:
  • Induces hepatic microsomal enzymes (CYP3A4, CYP2C) → enhanced metabolism and detoxification of pruritogens
  • Activates PXR (pregnane X receptor) → upregulates bile acid export pumps (MRP2) → enhanced biliary excretion of pruritogens
  • May reduce serum autotaxin activity (the enzyme producing lysophosphatidic acid, a key pruritogen)
• Dosage: 150–300 mg/day (start low)
• Potentially hepatotoxic ^[1] — monitor LFTs every 2–4 weeks for the first 3 months; discontinue if transaminases rise significantly
• Also causes orange discolouration of urine, tears, sweat (warn patients)
• Drug interactions: potent CYP inducer → reduces efficacy of many drugs (OCP, warfarin, immunosuppressants)

Step 3: Opioid Antagonists (Third-line for pruritus)

Naloxone/Naltrexone/Nalmefene ^[1]:

• Opioid antagonists ^[1]
• Mechanism: Cholestatic pruritus involves upregulation of endogenous opioid tone. Bile acids stimulate opioid receptor pathways → itch. Opioid antagonists block μ-opioid receptors → reduce itch signal transmission.
• Naloxone is given IV whereas naltrexone and nalmefene are given orally ^[1]
• Dosage: Naltrexone 25–50 mg/day orally (start at 12.5 mg to avoid opioid withdrawal-like reaction)
• Side effects: Initial opioid withdrawal-like syndrome (nausea, anxiety, dysphoria) — start at very low dose and titrate slowly; also potential hepatotoxicity
• Not first-line because of withdrawal reaction and limited efficacy data

Step 4: IBAT Inhibitors / Other Agents (Fourth-line)

• Linerixibat / Maralixibat — ileal bile acid transporter (IBAT) inhibitors. Block bile acid reabsorption in terminal ileum → increased faecal bile acid excretion → reduced enterohepatic circulation → less pruritogen load. Linerixibat showed benefit in the GLIMMER trial (2023).
• Sertraline (SSRI) — 75–100 mg/day; may modulate serotonergic itch pathways; modest evidence
• UV-B phototherapy — unclear mechanism; may alter cutaneous nerve fibres
• Plasmapheresis / albumin dialysis (MARS) — for severe refractory pruritus as bridge to transplant
• Nasobiliary drainage — temporary measure to physically divert bile in extreme cases

Step 5: Liver Transplantation (Definitive for intractable pruritus)

When pruritus is so severe that quality of life is unacceptable despite all medical therapy, this alone can be an indication for transplant listing.

B. Fatigue

Fatigue in PBC is multifactorial and unfortunately does NOT correlate with disease severity and often does NOT improve after transplantation:

• Exclude and treat contributing causes: anaemia, hypothyroidism (check TFTs), depression, sleep disturbance from pruritus, adrenal insufficiency
• No specific effective treatment for PBC-related fatigue
• Supportive measures: regular exercise (shown to improve fatigue and quality of life), sleep hygiene, psychological support
• Modafinil has been trialled with limited benefit

C. Sicca Symptoms (Dry Eyes / Dry Mouth)

From associated Sjögren's syndrome (40–65%):

• Artificial tears (preservative-free) for dry eyes
• Pilocarpine (muscarinic agonist) — stimulates residual salivary gland function
• Saliva substitutes (methylcellulose-based) for dry mouth
• Regular dental check-ups (dry mouth → increased caries risk)
• Avoid anticholinergic medications (worsen dryness)

3. Dietary Modification and Nutritional Support

Medium chain triglycerides (MCT) ^[1]:

• Symptomatic steatorrhoea due to bile acid insufficiency can be partially corrected by restricting dietary fat ^[1]
• MCTs are added or used for cooking if caloric supplementation is required to maintain body weight ^[1]
• MCT does not require bile acids for absorption to enterocytes and hence can be digested and absorbed into circulation despite low bile acid concentration ^[1]
• MCT is absorbed by diffusion and does not require micellar formation ^[1]

Why does this work from first principles?

• Normal dietary fats are long-chain triglycerides (LCTs, C14–C20) → require bile acid-dependent micellar solubilisation → absorbed via lymphatics → chylomicrons
• MCTs (C6–C12 fatty acids) are smaller → directly absorbed across enterocyte membrane by passive diffusion → enter portal circulation directly (NOT lymphatics)
• So when bile acids are deficient (as in PBC cholestasis), MCTs bypass the impaired step entirely

Vitamin supplementation ^[1]:

• Vitamin A — oral supplement to compensate for deficiency ^[1]
• Vitamin D — prescribed to treat the hepatic osteodystrophy ^[1]
• Vitamin A and D deficiency are more common requiring supplementation ^[1]
• Measurement of serum vitamin A and calcidiol is required ^[1]
• Vitamin K — oral or parenteral if coagulopathy present (check PT/INR)
• Vitamin E — supplement if neurological symptoms or very low levels

4. Management of Hepatic Osteodystrophy

Hepatic osteodystrophy (Osteopenia/Osteoporosis/Osteomalacia) ^[1]:

• Metabolic bone disease includes osteopenia and osteoporosis or rarely osteomalacia ^[1]
• Characteristic bone disorder in PBC reflects the inhibitory effect of a retained toxin on the osteoblast which prevents it from functioning normally ^[1]

Treatment ^[1]:

• Calcium and vitamin D supplementation ^[1] — 1000–1200 mg calcium + 800–2000 IU vitamin D daily
• Bisphosphonates ^[1] — Example: Alendronate ^[1]
  • Mechanism: bisphosphonates ("bis" = two, "phosphonate" = phosphorus-containing) bind to hydroxyapatite in bone → taken up by osteoclasts → inhibit farnesyl pyrophosphate synthase (in the mevalonate pathway) → osteoclast apoptosis → reduced bone resorption
  • Indicated when T-score ≤ −2.5 (osteoporosis) or ≤ −1.5 with additional risk factors
  • Concern in PBC: oesophageal varices are a relative contraindication to oral bisphosphonates (risk of oesophageal ulceration) → use IV zoledronic acid instead if varices present
• Regular weight-bearing exercise
• DEXA scan every 2–3 years to monitor

5. Management of Hyperlipidaemia

Hyperlipidaemia ^[1]:

• Increased cholesterol level in PBC does not increase atherosclerotic risk ^[1]
• Majority are elevation of HDL and lipoprotein-X which are anti-atherogenic ^[1]
• Treatment is not always needed and is indicated only if familial or other known risk factors are present ^[1]

Practical approach:

• Do NOT routinely start statins for elevated cholesterol in PBC
• If patient has additional cardiovascular risk factors (family history, diabetes, smoking, hypertension) → treat per standard lipid guidelines
• If statin indicated, use with caution (cholestasis can alter statin metabolism)

6. Surgical Treatment — Liver Transplantation

Liver transplantation — indicated in patients with ^[1]:

• Serum bilirubin > 6 mg/dL ^[1] (reflects severe ductopenia with very poor prognosis)
• Decompensated liver cirrhosis ^[1]
• Anticipated death within a year due to ^[1]:
  • Treatment-resistant ascites and spontaneous bacterial peritonitis ^[1]
  • Recurrent variceal bleeding ^[1]
  • Hepatic encephalopathy ^[1]
  • HCC ^[1] (within Milan criteria: single lesion ≤ 5 cm OR up to 3 lesions each ≤ 3 cm)
• Intractable pruritus unresponsive to all medical therapy (quality of life indication)

7. Management of Complications of Cirrhosis in PBC

When PBC progresses to cirrhosis, management of complications is the same as for cirrhosis of any cause:

A. Ascites

• First-line: Sodium restriction (< 2 g/day = < 88 mmol/day) + Spironolactone (100–400 mg/day) ± Furosemide (40–160 mg/day)
• Refractory: Large-volume paracentesis (LVP) with albumin replacement (6–8 g albumin per litre drained), TIPS
• Mechanism: Portal hypertension → splanchnic vasodilation → reduced effective arterial blood volume → RAAS activation → sodium and water retention → ascites

B. Hepatic Encephalopathy

Hepatic encephalopathy management ^[1]:

• IV Dextrose drip — provide adequate calorie intake to prevent protein breakdown ^[1]
• Oral Lactulose — as an enema with the aim of inducing bowel movements 2–4 times per day ^[1]
• No protein diet ^[1] (short-term; long-term moderate protein restriction 1–1.5 g/kg/day is preferred over complete restriction)
• Any treatable precipitating factor should be identified and treated ^[1]

Lactulose mechanism ^[1]:

• Non-absorbable disaccharide ^[1]
• Acts as an osmotic diarrheal agent ^[1]
• Acted upon by lactobacilli in colon to form H₂ and CO₂ ^[1]
• Acidic pH buffers NH₃ from gut-derived bacteria and in blood to form NH₄⁺ ^[1]
  • NH₃ (ammonia) is lipophilic and crosses the blood-brain barrier → neurotoxic
  • NH₄⁺ (ammonium) is charged/hydrophilic and CANNOT cross → trapped in gut lumen → excreted in faeces
• Side effects: Flatulence, dehydration (from excessive diarrhoea), aversion to sweet taste ^[1]

Rifaximin (non-absorbable antibiotic) is added for secondary prophylaxis of encephalopathy.

Precipitating factors for hepatic encephalopathy ^[1]:

• ↑ Protein intake ^[1]
• GI bleeding (↑ protein from blood in gut + ↓ liver blood supply) ^[1]
• Constipation ^[1]
• Infection (especially spontaneous bacterial peritonitis) ^[1]
• Over-diuresis (dehydration and electrolyte disturbance) ^[1]
• Inappropriate paracentesis without adequate albumin infusion ^[1]
• Shunting procedures including TIPS ^[1]
• Drugs — hypnotics ^[1]

C. Variceal Bleeding

• Primary prophylaxis: Non-selective beta-blockers (propranolol, carvedilol) or endoscopic band ligation
• Acute bleeding: Resuscitation → IV terlipressin + antibiotics → emergency OGD with band ligation → TIPS if refractory
• Secondary prophylaxis: Band ligation + non-selective beta-blocker

D. HCC Surveillance

Patients with PBC and cirrhosis are at increased risk of HCC ^[1]:

• AFP + USS every 6 months
• CT/MRI if suspicious lesion identified

Management Summary Table

References

^[1] Senior notes: felixlai.md (Primary Biliary Cholangitis — Treatment section, pages 535–539; Case study and Q&A, pages 538–540) ^[3] Senior notes: felixlai.md (Primary Sclerosing Cholangitis — Treatment section, pages 531–532) ^[8] Senior notes: felixlai.md (Liver Cirrhosis section — causes, complications, pages 440–446)

Complications of Primary Biliary Cholangitis

Organising Framework

Complications of PBC fall into two categories, exactly as the exam expects you to present them ^[1]:

1. General complications of cirrhosis — these occur once PBC has progressed to Stage 4 (cirrhosis) and are identical to complications of cirrhosis from any aetiology
2. Specific complications of PBC — unique to the cholestatic and autoimmune nature of PBC itself, and can occur before cirrhosis develops

Understanding this distinction is important because it tells you when to expect each complication and how to monitor for it. A patient with early PBC (Stage 1–2) may have severe pruritus and fat-soluble vitamin deficiency but will NOT have ascites or varices. A patient with PBC cirrhosis (Stage 4) can have ALL complications.

Part A: General Complications of Cirrhosis

These occur when PBC progresses to Stage 4 (cirrhosis) ^[1]. The pathophysiology is the same as cirrhosis from any cause — the key driver is architectural distortion of the liver causing increased intrahepatic vascular resistance → portal hypertension → a cascade of downstream consequences, combined with hepatocellular failure → reduced synthetic and metabolic function.

1. Portal Hypertension

Portal hypertension is the haemodynamic consequence of cirrhosis and is the root cause of most cirrhotic complications.

Why does PBC cause portal hypertension?

• Progressive fibrosis → regenerative nodules compress sinusoids and hepatic venules → increased intrahepatic vascular resistance
• Activated hepatic stellate cells contract around sinusoids → further increases resistance
• Portal pressure gradient > 5 mmHg = portal hypertension; > 10 mmHg = clinically significant (varices form); > 12 mmHg = variceal bleeding risk

a. Ascites

Abdominal distension from ascites ^[1]

• Pathophysiology: Portal hypertension → splanchnic vasodilation (NO-mediated) → reduced effective arterial blood volume → RAAS activation + ADH secretion → sodium and water retention → fluid transudation into peritoneal cavity. Simultaneously, hypoalbuminaemia (reduced hepatic synthesis) reduces plasma oncotic pressure → further fluid shift.
• Clinical correlation: The case study patient had progressive abdominal swelling, which was only partially controlled by diuretics ^[1], requiring repeated hospital admission for paracentesis ^[1] — this represents refractory ascites, a transplant indication.
• Complications of ascites: Spontaneous bacterial peritonitis (SBP), abdominal discomfort, respiratory compromise, umbilical hernia
• Management: Sodium restriction, spironolactone ± furosemide, large-volume paracentesis with albumin replacement, TIPS for refractory cases, transplant

b. Variceal Bleeding

Haematemesis from oesophageal variceal bleeding ^[1]

• Pathophysiology: Portal hypertension → blood seeks alternative routes to bypass the liver → portosystemic collaterals develop at sites of portal-systemic anastomosis:
  • Oesophageal/gastric varices (left gastric vein → oesophageal veins → azygos system)
  • Rectal varices (superior rectal → middle/inferior rectal veins)
  • Caput medusae (recanalised umbilical vein → epigastric veins)
  • Retroperitoneal collaterals
• Oesophageal varices are thin-walled and under high pressure → rupture → massive UGIB → haematemesis and/or melaena
• Mortality: 15–20% per bleeding episode, even with modern treatment
• Surveillance: OGD screening when cirrhosis diagnosed; repeat 1–3 yearly
• Management: Non-selective beta-blockers (propranolol/carvedilol) for primary prophylaxis; endoscopic band ligation + terlipressin for acute bleeding; TIPS if refractory

c. Splenomegaly and Hypersplenism

• Pathophysiology: Portal hypertension → congestion of splenic vein → splenic engorgement → splenomegaly → excessive sequestration and destruction of blood cells in the enlarged spleen → pancytopenia (thrombocytopenia most prominent, then leukopenia, then anaemia)
• Reduced thrombopoietin production by the diseased liver also contributes to thrombocytopenia

2. Hepatic Encephalopathy

Confusion from hepatic encephalopathy ^[1]

Pathophysiology: Two mechanisms work in concert:

1. Hepatocellular failure → liver cannot metabolise ammonia (via urea cycle) → hyperammonaemia
2. Portosystemic shunting → gut-derived toxins (ammonia, mercaptans, short-chain fatty acids, GABA-like substances) bypass the liver entirely via collaterals → reach the systemic circulation and cross the blood-brain barrier

Ammonia (NH₃) is lipophilic → crosses BBB → converted to glutamine by astrocytes → osmotic astrocyte swelling → cerebral oedema → impaired neurotransmission

Clinical features ^[1]:

• Drowsy to comatose ^[1]
• Flapping tremor (asterixis) ^[1] — caused by sudden involuntary loss of muscle tone during sustained posture; reflects impaired motor neuron function from neurotoxins
• Fetor hepaticus ^[1] — sweet, musty odour on breath from dimethyl sulphide, a mercaptan that is normally metabolised by the liver
• Constructional apraxia, day-night reversal, personality change (early)

Grading (West Haven criteria):

• Grade 0: Subclinical (detectable only on psychometric testing)
• Grade 1: Mild confusion, altered sleep
• Grade 2: Drowsy, inappropriate behaviour, asterixis
• Grade 3: Somnolent but arousable, gross disorientation
• Grade 4: Coma

Precipitating factors ^[1]:

• ↑ Protein intake ^[1]
• GI bleeding ^[1] — provides a massive protein (haemoglobin) load to the gut
• Constipation ^[1] — prolongs ammonia absorption from gut
• Infection (especially SBP) ^[1]
• Over-diuresis ^[1] — hypovolaemia, hypokalaemia, metabolic alkalosis (alkalotic pH favours NH₃ over NH₄⁺ → more ammonia crosses BBB)
• Inappropriate paracentesis without adequate albumin infusion ^[1]
• Shunting procedures including TIPS ^[1]
• Drugs — hypnotics ^[1]

The case study illustrates this perfectly: the patient became drowsy after celebrating her daughter's marriage ^[1] — likely precipitated by increased protein intake at the celebration → diagnosed with "liver coma" ^[1] → managed with low protein diet and laxatives (lactulose) ^[1].

Management ^[1]:

• IV Dextrose drip — provide adequate calorie intake to prevent protein breakdown ^[1]
• Oral Lactulose — inducing bowel movements 2–4 times per day ^[1]
• Lactulose mechanism: Non-absorbable disaccharide → osmotic laxative → acidifies colonic pH → converts NH₃ to NH₄⁺ (trapped, non-absorbable) → faecal excretion ^[1]
• Rifaximin (non-absorbable antibiotic) — reduces ammonia-producing gut bacteria; used for secondary prophylaxis
• Identify and treat precipitating factor ^[1]

3. Hepatorenal Syndrome (HRS)

• Pathophysiology: Advanced cirrhosis → severe splanchnic vasodilation → arterial underfilling → intense renal vasoconstriction (RAAS, sympathetic nervous system, ADH) → functional renal failure with structurally normal kidneys
• Type 1 (HRS-AKI): Rapid deterioration (doubling of creatinine in < 2 weeks); often triggered by SBP; very poor prognosis without transplant
• Type 2 (HRS-CKD): Slower progression; associated with refractory ascites
• Management: IV albumin + terlipressin (splanchnic vasoconstrictor → reverses the underfilling); definitive treatment is transplant

4. Coagulopathy

• Pathophysiology: The liver synthesises virtually ALL coagulation factors (except vWF, which is endothelial, and factor VIII). In cirrhosis:
  • Reduced synthesis of factors II, V, VII, IX, X, fibrinogen
  • Reduced synthesis of natural anticoagulants (protein C, protein S, antithrombin) — so cirrhosis is actually a rebalanced haemostatic state, not simply "anticoagulated"
  • Vitamin K malabsorption (from cholestasis) further reduces factors II, VII, IX, X specifically
  • Thrombocytopenia from hypersplenism
• Clinical manifestation: Easy bruising, prolonged PT/INR, increased bleeding risk from procedures

5. Hepatocellular Carcinoma (HCC)

Patients with PBC and cirrhosis are at increased risk of HCC ^[1][2].

• Pathophysiology: Cirrhosis of any cause creates a pro-carcinogenic environment — chronic inflammation → regenerative nodules → dysplastic nodules → hepatocellular carcinoma. The cycle of cell death, inflammation, and regeneration → accumulation of somatic mutations → malignant transformation.
• PBC is listed as an autoimmune cause of cirrhosis leading to HCC, alongside AIH and PSC ^[2][9].
• Any cause of cirrhosis: infection (HBV, HCV), metabolic (ALD, NAFLD, Wilson's disease), immune (PBC, PSC) ^[2] can lead to HCC.
• Risk: Lower than HBV/HCV-related cirrhosis (~4% lifetime in PBC cirrhosis vs ~20–30% in HBV cirrhosis), but still significant enough to warrant surveillance
• Surveillance: AFP + USS every 6 months in all PBC patients with established cirrhosis
• HCC in PBC tends to present later in the disease course (only after cirrhosis is established), unlike HBV where HCC can occur without cirrhosis

6. Spontaneous Bacterial Peritonitis (SBP)

• Pathophysiology: Ascites provides a culture medium for bacteria. In cirrhosis, gut barrier function is impaired (portal hypertensive enteropathy) + immune dysfunction (reduced complement, opsonisation defects) → bacterial translocation from gut to ascitic fluid → SBP
• Organisms: Most commonly E. coli, Klebsiella, Streptococcus pneumoniae (monomicrobial)
• Diagnosis: Ascitic fluid PMN count ≥ 250/mm³
• Treatment: IV ceftriaxone or cefotaxime + IV albumin
• SBP is a precipitant of hepatic encephalopathy ^[1] and a transplant indication ^[1]

Part B: PBC-Specific Complications

These are complications that arise from the cholestatic nature of PBC itself and can occur at any stage, including before cirrhosis develops. They are unique to PBC (and other cholestatic diseases) rather than being generic cirrhotic complications.

1. Pruritus

Pruritus ^[1]

• Pathophysiology: Cholestasis → accumulation of pruritogens in blood and skin. The key mediators are now understood to include:
  • Lysophosphatidic acid (LPA) — produced by the enzyme autotaxin (ATX); serum ATX levels correlate best with itch severity
  • Bile acids — activate TGR5 receptors on cutaneous sensory nerve fibres → itch signalling
  • Endogenous opioids — cholestasis upregulates opioidergic tone → opioid-mediated itch (explains why opioid antagonists help)
  • Histamine — may play a minor role, but antihistamines are generally ineffective in cholestatic pruritus (this is NOT histamine-mediated itch)
• Clinical features: Worst at night, can precede jaundice by months to years, may be so severe as to cause excoriations and sleep deprivation → quality of life impairment that alone can justify transplant listing
• Management: Stepwise — cholestyramine → rifampicin → naltrexone → IBAT inhibitors → transplant (covered in detail in the Management section)

2. Steatorrhoea and Fat-Soluble Vitamin Deficiency

Steatorrhoea (malabsorption of dietary fat) and vitamin deficiency ^[1]

Pathophysiology — trace this from first principles:

1. PBC destroys bile ducts → cholestasis → reduced bile acid secretion into duodenum
2. Bile acids are essential for micellar solubilisation of dietary fat (long-chain triglycerides and fat-soluble vitamins)
3. Without micelles → fat cannot be absorbed across the intestinal epithelium → steatorrhoea (pale, bulky, foul-smelling, floating stools)
4. Fat-soluble vitamins (A, D, E, K) are co-absorbed with fat in micelles → malabsorption of all four fat-soluble vitamins

Lipid malabsorption — result of decreased biliary secretion of bile acids ^[1]

Fat-soluble vitamins A, D, E, K deficiency ^[1]:

• Vitamin A and D deficiency are more common requiring supplementation ^[1]
• Measurement of serum vitamin A and calcidiol is required ^[1]

Mnemonic — Fat-soluble vitamins: "A, D, E, K" — "A Dark, Empty Kitchen" (A = vision/dark adaptation, D = bones, E = nerves, K = Koagulation)

3. Hepatic Osteodystrophy

Hepatic osteodystrophy (Osteopenia/Osteoporosis/Osteomalacia) ^[1]

Metabolic bone disease includes osteopenia and osteoporosis or rarely osteomalacia ^[1]

Pathophysiology — this is a "double hit" mechanism:

1. Osteoporosis (reduced bone formation): Characteristic bone disorder in primary biliary cirrhosis which reflects the inhibitory effect of a retained toxin on the osteoblast which prevents it from functioning normally ^[1]. Retained bile acids, bilirubin, and other cholestatic toxins directly inhibit osteoblast activity → reduced bone formation → osteoporosis. This is the dominant mechanism in PBC.

2. Osteomalacia (defective mineralisation): Vitamin D malabsorption → reduced calcium absorption from gut → inadequate mineralisation of osteoid → soft bones. This is less common because most patients receive vitamin D supplementation, but it can occur if supplementation is inadequate.

Clinical consequences: Vertebral compression fractures, hip fractures, chronic bone pain, kyphosis Prevalence: Osteoporosis occurs in 20–45% of PBC patients; increases with disease duration Risk factors for worse bone disease: Post-menopausal women (oestrogen withdrawal + PBC effects = compounded risk), advanced cholestasis, low BMI, smoking, corticosteroid use (if overlap syndrome)

Management ^[1]:

• DEXA scan at diagnosis and every 2–3 years
• Calcium and vitamin D supplementation ^[1]
• Bisphosphonates — example: Alendronate ^[1] (if T-score ≤ −2.5 or fracture history)
• IV zoledronic acid if oesophageal varices contraindicate oral bisphosphonates
• Weight-bearing exercise, falls prevention

4. Hyperlipidaemia

Hyperlipidaemia ^[1]

Increased cholesterol level in PBC do not increase atherosclerotic risk ^[1]

Pathophysiology:

• Bile is the major excretory route for cholesterol. Cholestasis → impaired cholesterol excretion → accumulation in blood
• Additionally, lipoprotein metabolism is altered: increased HDL, appearance of lipoprotein-X (Lp-X) — an abnormal lipoprotein unique to cholestasis
• Lp-X is measured by some assays as "LDL" but is NOT atherogenic
• Majority are elevation of HDL and lipoprotein-X which are anti-atherogenic ^[1]

Clinical features: Xanthelasma (yellowish periorbital plaques), xanthomata (lipid deposits in tendons, skin creases), grossly elevated total cholesterol (sometimes > 15 mmol/L)

Treatment is not always needed and is indicated only if familial or other known risk factors are present ^[1]

5. Biliary Strictures

Biliary strictures — up to 60% of patients may develop a dominant stricture in intrahepatic or extrahepatic biliary tree ^[9]

• Pathophysiology: Chronic periductal inflammation and fibrosis → narrowing of bile ducts → stricture formation. Although PBC primarily affects small ducts, progressive disease can lead to fibrotic changes affecting larger ducts as well.
• Clinical significance: Strictures worsen cholestasis, predispose to stone formation and cholangitis, and can mimic malignant obstruction
• Management: MRCP to delineate anatomy; endoscopic dilatation/stenting if symptomatic; always exclude cholangiocarcinoma as the cause of a new dominant stricture

6. Choledocholithiasis and Cholelithiasis

Choledocholithiasis and cholelithiasis — due to cholesterol or pigment stones ^[9]

• Pathophysiology:
  • Cholesterol stones: Cholestasis alters bile composition → supersaturation of bile with cholesterol (reduced bile acid secretion tips the cholesterol saturation index)
  • Pigment stones: Altered bilirubin metabolism in chronic liver disease → increased unconjugated bilirubin in bile → calcium bilirubinate precipitation
• Gallstones occur in ~30–40% of PBC patients (higher than general population)
• Can cause biliary colic, acute cholecystitis, or choledocholithiasis → obstructive jaundice (confusing the picture with worsening PBC cholestasis)

7. Cholangitis

Cholangitis — develops spontaneously in patients with bile duct stones or obstructing strictures or in patients after undergoing endoscopic or surgical manipulation ^[9]

• Pathophysiology: Bile duct obstruction (from stones or strictures) → bile stasis → bacterial colonisation (ascending infection from duodenum) → acute cholangitis
• Clinical features: Charcot's triad (fever, RUQ pain, jaundice) or Reynolds' pentad (+ shock + confusion in suppurative cholangitis)
• Organisms: E. coli, Klebsiella, Enterococcus
• Management: IV antibiotics, biliary drainage (ERCP ± sphincterotomy for stone removal)

8. Cholangiocarcinoma and Gallbladder Cancer

Cholangiocarcinoma — high incidence necessitates screening including USG or MRCP with a measurement of serum CA19-9 ^[9]

Gallbladder cancer ^[9]

• Pathophysiology: Chronic biliary inflammation → epithelial metaplasia → dysplasia → carcinoma. The same chronic inflammatory milieu that drives duct destruction in PBC also creates a pro-carcinogenic environment in the biliary epithelium.
• Risk: Lower than in PSC (where cholangiocarcinoma risk is 10–15% lifetime), but still elevated compared to general population
• Screening: Regular USS or MRCP + serum CA 19-9 (though CA 19-9 is non-specific and can be elevated in any cholestatic state)
• Suspect malignancy if: Sudden clinical deterioration, rapidly rising bilirubin disproportionate to disease stage, new dominant stricture, rapid weight loss

Part C: Complications Related to Associated Autoimmune Diseases

Because PBC clusters with other autoimmune diseases, complications of these associations should also be considered:

Prognosis

Factors associated with a poorer prognosis ^[1]:

Natural history without treatment: Median survival from symptom onset to death or transplant was ~10–15 years before UDCA era. With UDCA, responders have survival comparable to general population. Non-responders still face progressive disease, but newer second-line agents (bezafibrate, elafibranor, seladelpar) are improving outcomes.

Complications Summary Table

References

^[1] Senior notes: felixlai.md (Primary Biliary Cholangitis — Complications section, pages 536–540; Case study Q2-Q7, pages 538–540; Prognosis section, page 537) ^[2] Senior notes: maxim.md (Hepatocellular carcinoma — Risk factors section: PBC listed as immune cause of cirrhosis leading to HCC) ^[8] Senior notes: felixlai.md (Liver Cirrhosis — Overview, Etiology, Complications sections, pages 440–446) ^[9] Senior notes: felixlai.md (Primary Sclerosing Cholangitis — Complications section, pages 531–532; shared cholestatic complications listed under both PSC and PBC)