Gastrointestinal

Primary sclerosing cholangitis: workup and surveillance

Clinical Overview and When to Suspect Primary Sclerosing Cholangitis

— Peak incidence age 30–40 years, male predominance (~2:1)

— Strong association with inflammatory bowel disease (IBD) — ~70–80% of PSC patients have IBD, predominantly ulcerative colitis (often pancolitis with rectal sparing and backwash ileitis)

— Conversely, only ~5% of IBD patients develop PSC

— Young to middle-aged adult, often male, with persistently elevated alkaline phosphatase (cholestatic pattern) ± mild AST/ALT elevation

— Known IBD patient with new cholestatic LFTs — screen with imaging even if asymptomatic

— Fatigue, pruritus, intermittent RUQ discomfort, or recurrent cholangitis episodes

— Unexplained elevated GGT with normal imaging of gallbladder

— Jaundice in a patient with UC is PSC until proven otherwise

— Median transplant-free survival from diagnosis ~13–21 years

— Variable course; small-duct PSC has better prognosis than classic large-duct disease

— Disease activity does NOT mirror IBD activity — colectomy does not cure PSC

— Cholangiocarcinoma (CCA) lifetime risk ~10–20%; highest risk in first year after diagnosis

— Gallbladder carcinoma risk elevated

— Colorectal cancer (CRC) risk in PSC-IBD is 4–5× higher than IBD alone

— Hepatocellular carcinoma risk in cirrhotic PSC

Board pearl: Any patient with ulcerative colitis and an unexplained isolated alkaline phosphatase elevation gets an MRCP — this is the highest-yield Step 3 PSC trigger.

Definition: Primary sclerosing cholangitis (PSC) is a chronic, progressive, idiopathic cholestatic liver disease characterized by multifocal stricturing and fibrosis of intrahepatic and/or extrahepatic bile ducts, leading to biliary cirrhosis, portal hypertension, and a markedly elevated risk of hepatobiliary and colorectal malignancy.

Epidemiology and demographics:

When to suspect on Step 3:

Natural history:

Cancer risk (critical for surveillance framing):

Presentation Patterns and Key History

— Routine LFTs in an IBD patient reveal isolated ↑ alkaline phosphatase

— Incidental imaging finding of intrahepatic biliary dilation

— Step 3 stems often present this as a "screening labs" vignette in a UC patient

— Fatigue — most common symptom, often disproportionate to lab abnormalities

— Pruritus — cholestatic; worse at night, on palms/soles; can precede jaundice by years

— Right upper quadrant pain — dull, intermittent

— Jaundice — episodic or progressive; sudden worsening should prompt evaluation for dominant stricture or cholangiocarcinoma

— Recurrent bacterial cholangitis — fever, chills, RUQ pain, jaundice (Charcot triad); suggests dominant stricture

— Weight loss, anorexia — red flag for malignancy

— Late: ascites, variceal bleeding, encephalopathy (decompensated cirrhosis)

— IBD history — type, extent, duration, last colonoscopy; new-onset diarrhea/hematochezia warrants colonoscopy

— Family history — first-degree relatives of PSC patients have ~9–11× increased risk

— Medications: rule out drug-induced cholestasis (anabolic steroids, augmentin, azathioprine)

— Alcohol use, metabolic syndrome features (NAFLD coexists)

— Prior biliary surgery (secondary sclerosing cholangitis mimic)

— Recurrent pancreatitis or sicca symptoms → consider IgG4-related sclerosing cholangitis

— New pruritus + UC → MRCP + cholestatic LFT panel

— Sudden jaundice in known PSC → urgent MRCP/ERCP to evaluate dominant stricture and rule out CCA

— Fever + jaundice → blood cultures, broad-spectrum antibiotics, urgent ERCP

Step 3 management: A PSC patient with new jaundice, weight loss, or rapidly rising bilirubin/CA 19-9 requires prompt MRCP with consideration of ERCP + brush cytology and FISH to evaluate for cholangiocarcinoma — do not attribute to "disease progression" until malignancy is excluded.

Asymptomatic discovery (most common today, ~50%):

Symptomatic presentations:

Critical history elements:

Symptom-to-action mapping:

Physical Exam Findings and Cholestatic Assessment

— Often well-appearing early in disease

— Later: cachexia, muscle wasting, sarcopenia (poor transplant outcome predictor)

— Jaundice — scleral icterus precedes skin; visible when bilirubin >2.5–3 mg/dL

— Excoriations on extremities and trunk from chronic pruritus

— Hepatomegaly — firm, smooth; present in ~40%

— Splenomegaly — suggests portal hypertension

— RUQ tenderness — non-specific; marked tenderness with fever suggests cholangitis

— Ascites, caput medusae, periumbilical venous distention — decompensated cirrhosis

— Murphy sign uncommon (helps distinguish from cholecystitis)

— Spider angiomata, palmar erythema, gynecomastia, testicular atrophy

— Asterixis in hepatic encephalopathy

— Dupuytren contracture (nonspecific)

— Xanthelasmas/xanthomas — chronic cholestasis with hyperlipidemia (more classic for PBC but can occur)

— Pale conjunctivae — anemia of chronic disease or GI blood loss

— Oral aphthae, pyoderma gangrenosum, erythema nodosum, episcleritis — IBD associations

— Sicca symptoms, parotid swelling → consider IgG4-related disease

— Lymphadenopathy → worry about lymphoma or CCA

— Vitals: febrile + tachycardic + hypotensive in cholangitis → sepsis pathway

— Orthostatics if GI bleeding suspected

— Mental status (West Haven grading for HE)

— Volume status — JVP, peripheral edema, ascitic fluid wave

— Baseline weight, MUAC, frailty assessment

— Skin exam at each visit (excoriations, jaundice trend)

— Bone health: kyphosis, height loss (osteoporosis from cholestasis)

Key distinction: PSC patients with fever + jaundice + RUQ pain (Charcot triad) require admission, blood cultures, IV antibiotics covering enteric gram-negatives and anaerobics (piperacillin-tazobactam), and urgent ERCP within 24–48 hours for drainage — do not delay for outpatient MRCP.

General appearance:

Abdominal exam:

Stigmata of chronic liver disease:

Extrahepatic clues:

Hemodynamic and decompensation assessment:

Documentation for Step 3 longitudinal care:

Diagnostic Workup — Initial Labs and Imaging

— Liver chemistries: hallmark is cholestatic pattern — ALP often 3–10× ULN, GGT elevated (confirms hepatic origin of ALP), AST/ALT mildly elevated (<300, usually <5× ULN)

— Total and direct bilirubin — may be normal early; rising bilirubin = progression or dominant stricture

— Albumin, PT/INR — synthetic function; abnormal in advanced disease

— CBC — anemia, thrombocytopenia (hypersplenism)

— Lipid panel — chronic cholestasis causes hyperlipidemia (often non-atherogenic)

— p-ANCA (atypical/perinuclear) — positive in ~65–80% of PSC; nonspecific

— ANA, ASMA — may be positive; if markedly elevated, consider PSC-autoimmune hepatitis overlap

— AMA — should be negative; if positive, reconsider PBC

— IgG4 level — critical to obtain; elevated → IgG4-related sclerosing cholangitis (steroid-responsive, mimicker)

— Total IgG, IgM — IgM often elevated in PBC, helps differentiate

— Hepatitis B/C serologies, HIV — exclude viral

— Ceruloplasmin (if <40), ferritin/iron studies, alpha-1 antitrypsin in young patients

— CA 19-9 — baseline; surveillance marker for cholangiocarcinoma (not diagnostic alone — elevated in cholangitis, biliary obstruction)

— Non-invasive, no contrast/radiation risk to bile ducts

— Findings: multifocal short strictures alternating with normal/dilated segments → "beaded" appearance, pruning of intrahepatic ducts, mural irregularity

— Sensitivity ~85–90%, specificity >90% — sufficient for diagnosis without ERCP in most cases

— Also evaluates parenchyma (cirrhosis), gallbladder (polyps, mass), and vasculature

— RUQ ultrasound — usually obtained first; may show duct wall thickening, but often nonspecific; evaluates gallbladder

— Transient elastography (FibroScan) — noninvasive fibrosis staging; LSM >14.4 kPa suggests advanced fibrosis

Board pearl: Diagnosis of PSC requires: (1) cholestatic biochemistry, (2) characteristic MRCP/cholangiographic findings, AND (3) exclusion of secondary causes (prior biliary surgery, ischemic cholangiopathy, IgG4 disease, recurrent choledocholithiasis, AIDS cholangiopathy). Liver biopsy is not required when MRCP is diagnostic.

Initial laboratory panel:

Autoimmune/serologic workup (to characterize and exclude mimics):

First-line imaging — MRCP (test of choice):

Other initial imaging:

Diagnostic Workup — Advanced and Confirmatory Studies

— Historic gold standard but now reserved for therapeutic intervention (dilation/stenting of dominant strictures) or when MRCP is non-diagnostic and suspicion remains high

— Carries 5–10% risk of post-ERCP pancreatitis, cholangitis, perforation, bleeding — avoid for diagnosis alone

— Allows brush cytology, biopsy, and FISH (fluorescence in situ hybridization) for cholangiocarcinoma evaluation of dominant strictures

— Indications: dominant stricture with worsening jaundice/cholangitis, suspicion for CCA, planned therapeutic intervention

— Not needed to diagnose classic large-duct PSC

— Indications:

— Suspected small-duct PSC (normal MRCP but persistent cholestasis)

— Suspected overlap with autoimmune hepatitis (elevated transaminases >5× ULN, high IgG)

— Disproportionate clinical-radiographic discordance

— Classic finding: "onion-skin" periductal concentric fibrosis around bile ducts — pathognomonic but seen in <40% of biopsies

— MRI/MRCP with contrast — first-line for mass-forming CCA

— CA 19-9 — >129 U/mL has ~75% sensitivity, ~80% specificity in PSC; can be falsely elevated by cholangitis

— ERCP with brushings + FISH polysomy — increases sensitivity over cytology alone

— Cholangioscopy (SpyGlass) — direct visualization with targeted biopsy

— PET-CT — adjunctive; not first-line

— Endoscopic ultrasound for hilar/distal lesions

— All newly diagnosed PSC patients require full colonoscopy with biopsies regardless of GI symptoms — to detect occult IBD

— If IBD found → enroll in annual surveillance from PSC diagnosis (not from IBD diagnosis)

— Baseline at diagnosis — high osteoporosis prevalence from chronic cholestasis

Step 3 management: When a known PSC patient develops a new dominant stricture, the workup sequence is: MRI/MRCP first → ERCP with brushings + FISH + cholangioscopy if needed. Do not place a stent across a stricture before obtaining cytology samples — it complicates transplant candidacy assessment.

ERCP — selective use only:

Liver biopsy — limited role:

Cholangiocarcinoma evaluation when suspected:

Colonoscopy at diagnosis — mandatory:

Bone densitometry (DEXA):

Risk Stratification and Management Framework

— Mayo PSC risk score — uses age, bilirubin, albumin, AST, variceal bleeding history → predicts 4-year survival

— MELD/MELD-Na — for transplant listing; PSC patients often get MELD exception points for recurrent cholangitis or early CCA

— Amsterdam-Oxford model, UK-PSC score — newer alternatives

— Enhanced liver fibrosis (ELF) test — emerging biomarker

— Low risk: asymptomatic, normal bilirubin, no dominant stricture, no advanced fibrosis

— Intermediate risk: symptomatic, elevated ALP >1.5× ULN persistently, small dominant stricture

— High risk: jaundice, recurrent cholangitis, advanced fibrosis on elastography, elevated CA 19-9, dominant stricture with concerning features

— Low risk: LFTs every 3–6 months, MRCP annually, colonoscopy annually if IBD present

— Intermediate/high: more frequent imaging, lower threshold for ERCP, hepatology co-management

— Hepatobiliary cancer surveillance starts at diagnosis — high-risk window is first year

— Ursodeoxycholic acid (UDCA): controversial; moderate dose 13–20 mg/kg/day may improve biochemistry but no proven survival benefit

— High-dose UDCA (>28 mg/kg/day) is harmful — increases mortality/transplant rates and CRC risk (landmark RCT)

— Current US (AASLD) guidelines: do not routinely recommend UDCA for PSC; may consider moderate dose in selected patients

— European (EASL) guidelines slightly more permissive

— Alcohol minimization, vaccinations (HAV, HBV, pneumococcus, influenza, COVID), nutritional optimization

Board pearl: High-dose UDCA in PSC is a Step 3 trap — it sounds therapeutic but is associated with worse outcomes including increased colorectal neoplasia. The correct exam answer for "best disease-modifying therapy" in PSC is usually none / surveillance and supportive care with transplant as definitive therapy.

No disease-modifying medical therapy exists — PSC management is built on (1) symptom control, (2) complication prevention, (3) cancer surveillance, (4) liver transplant timing.

Prognostic models:

Risk stratification at diagnosis:

Stratification-driven monitoring:

Disease-modifying considerations:

Lifestyle:

Pharmacotherapy — Symptom and Complication Management

— First line: cholestyramine 4 g before breakfast, titrate up to 16 g/day in divided doses

— Bile acid sequestrant; separate from other meds by 4 hours (binds drugs/fat-soluble vitamins)

— Constipation, bloating common

— Second line: rifampin 150–300 mg BID

— Monitor LFTs (hepatotoxicity), CBC, drug interactions (CYP3A4 inducer)

— Third line: naltrexone 50 mg daily (opioid antagonist) — beware withdrawal-like reaction; avoid in active opioid use

— Fourth line: sertraline 75–100 mg daily

— Refractory: nasobiliary drainage, MARS, plasmapheresis, transplant referral

— Check vitamins A, D, E, K annually; bilirubin >2 increases risk

— Vitamin D — most commonly deficient; replace to maintain 25-OH-D >30

— Vitamin K — if INR elevated without synthetic dysfunction

— Calcium 1000–1500 mg/day with vitamin D 1000+ IU

— DEXA at diagnosis, every 2–3 years

— Bisphosphonates for T-score ≤ −2.5 or fragility fracture (oral generally safe; caution with varices/esophagitis)

— Empiric piperacillin-tazobactam or ceftriaxone + metronidazole

— Blood cultures before antibiotics

— ERCP for drainage if obstructive

— Prophylactic antibiotics (e.g., ciprofloxacin) only for recurrent cholangitis — not routine

— Nonselective beta-blockers (propranolol, nadolol, carvedilol) for varices

— Spironolactone ± furosemide for ascites; sodium restriction

— Lactulose ± rifaximin for hepatic encephalopathy

— SBP prophylaxis if prior SBP or high-risk ascites

Step 3 management: A PSC patient with refractory pruritus despite cholestyramine should next receive rifampin with baseline LFTs and CBC at 6 and 12 weeks — discontinue if AST/ALT rise >3× baseline. Do not jump straight to opioids for itch.

Pruritus (most quality-of-life-limiting symptom):

Fat-soluble vitamin deficiencies (cholestasis impairs absorption):

Osteoporosis (prevalence ~15–30%):

Bacterial cholangitis:

Portal hypertension complications:

Avoid: high-dose UDCA, hepatotoxic drugs, NSAIDs in cirrhosis

Procedures — Endoscopic and Surgical Management

— Dominant stricture defined as ≤1.5 mm in CBD or ≤1 mm in hepatic duct

— Occurs in ~50% of PSC patients over disease course

— Triggers: rising bilirubin, recurrent cholangitis, worsening pruritus, intractable RUQ pain

— Endoscopic balloon dilation preferred over stenting for benign-appearing strictures

— Stents reserved for refractory strictures (short-duration plastic, weeks not months)

— Self-expanding metal stents generally avoided in benign disease

— Brush cytology + FISH + cholangioscopy with targeted biopsy at every ERCP for dominant stricture — must exclude CCA

— Periprocedural antibiotic prophylaxis mandatory (ciprofloxacin or piperacillin-tazobactam) to prevent post-ERCP cholangitis

— Indications:

— Decompensated cirrhosis (MELD-based listing, typically ≥15)

— Recurrent bacterial cholangitis unresponsive to medical/endoscopic management (qualifies for MELD exception points)

— Intractable pruritus unresponsive to all medical therapy

— Early-stage perihilar cholangiocarcinoma (selected centers, neoadjuvant chemoradiation protocol — Mayo protocol; tumor ≤3 cm, no metastases)

— Hepatocellular carcinoma meeting Milan criteria

— 5-year post-transplant survival ~85%

— Recurrent PSC in graft ~20–25% at 10 years

— Pre-transplant: full cancer screening (colonoscopy, gallbladder evaluation, chest/abdomen/pelvis imaging)

— Any gallbladder polyp ≥8 mm in PSC → cholecystectomy (much lower threshold than general population due to high gallbladder cancer risk)

— Some experts: cholecystectomy for any polyp in PSC

— Total colectomy for IBD does NOT alter PSC course

— When ERCP fails (altered anatomy, inaccessible intrahepatic strictures)

CCS pearl: For a PSC inpatient admitted with ascending cholangitis — order blood cultures × 2, piperacillin-tazobactam IV, IV fluids, NPO, GI consult for ERCP within 24–48 hours, MRCP if not recently performed, CA 19-9, and advance diet only after clinical improvement and drainage achieved.

ERCP for dominant strictures:

Liver transplantation — definitive therapy:

Cholecystectomy:

Percutaneous transhepatic cholangiography (PTC):

Special Populations — Elderly and Renal/Hepatic Impairment

— New PSC diagnosis after age 65 is uncommon — strongly consider mimics: IgG4-related sclerosing cholangitis (steroid-responsive), ischemic cholangiopathy, cholangiocarcinoma masquerading as PSC, post-surgical strictures

— Always check IgG4 level in older new-onset cholestasis

— Transplant candidacy assessment more stringent: cardiac evaluation (stress testing), pulmonary, frailty/sarcopenia indices, cognitive screening

— Polypharmacy reconciliation — bile acid sequestrants bind levothyroxine, warfarin, digoxin, statins

— Higher baseline osteoporosis and fall risk — aggressive bone health management

— Procedural risk: ERCP complications increase with age; consider risk-benefit carefully

— Hepatorenal syndrome (HRS) in decompensated PSC — terlipressin (now FDA-approved), albumin, midodrine + octreotide

— Avoid nephrotoxins: NSAIDs, aminoglycosides, IV contrast in advanced disease

— Dose adjustments:

— Rifampin — generally safe but monitor

— Naltrexone — caution; reduce in severe renal disease

— Cholestyramine — no renal adjustment

— Pre-ERCP: hydration to reduce post-ERCP pancreatitis and contrast nephropathy risk

— Avoid acetaminophen >2 g/day in cirrhosis; NSAIDs contraindicated (renal failure, variceal bleeding, ascites)

— Benzodiazepines and opioids precipitate encephalopathy — use lowest effective dose

— Statins generally safe in compensated cirrhosis and may improve outcomes

— Rifampin for pruritus — avoid or use cautiously in bilirubin >3 or decompensation

— Lactulose-titrate to 2–3 soft stools/day; add rifaximin if breakthrough HE

— Annual HCC screening with ultrasound ± AFP every 6 months once cirrhotic

— INR is unreliable for bleeding risk — viscoelastic testing (TEG/ROTEM) where available

— Platelet transfusion threshold: <50K for major procedures

Board pearl: New-onset "PSC" in a man >60 with elevated serum IgG4 and steroid-responsive cholestasis is IgG4-related sclerosing cholangitis, not PSC — treat with prednisone 40 mg/day taper, often with dramatic biochemical improvement. Missing this diagnosis denies an effective therapy.

Elderly PSC patients (>65):

Renal impairment:

Hepatic impairment / cirrhosis-specific considerations:

Pre-procedure prep in cirrhosis:

Special Populations — Pregnancy, Pediatrics, and Overlap Syndromes

— PSC and pregnancy is uncommon (female PSC patients fewer, and PSC may impair fertility in advanced disease)

— Cholestasis often worsens during pregnancy — pruritus, ALP rise (note: ALP physiologically rises from placenta — interpret with caution; use GGT and bile acids)

— Serum bile acids > 40 µmol/L associated with fetal complications (preterm birth, stillbirth) — overlap with intrahepatic cholestasis of pregnancy management

— UDCA is safe and effective for symptomatic cholestasis in pregnancy (even though not routinely used in non-pregnant PSC)

— Cholestyramine safe but worsens fat-soluble vitamin deficiency — supplement vitamin K

— Rifampin — limited data; generally avoid in first trimester

— Imaging: MRCP without gadolinium acceptable; avoid ERCP except for cholangitis/obstruction

— Delivery planning: multidisciplinary; varices screen with EGD in second trimester if cirrhotic; consider elective C-section if large varices

— Often presents with autoimmune sclerosing cholangitis (overlap with AIH) — high IgG, positive ANA/ASMA

— Responds partially to immunosuppression (prednisone + azathioprine) unlike adult PSC

— Higher rate of IBD association (~80%)

— Worse long-term outcomes; earlier transplant consideration

— Suspect when: AST/ALT >5× ULN, IgG markedly elevated, interface hepatitis on biopsy, positive ANA/ASMA

— Treat the AIH component: prednisone ± azathioprine

— Improves biochemistry; does not arrest bile duct disease

— Older men, often with autoimmune pancreatitis (sausage-shaped pancreas), salivary gland involvement, retroperitoneal fibrosis

— Elevated serum IgG4 (>135 mg/dL; >2× ULN more specific)

— Biopsy: storiform fibrosis, obliterative phlebitis, IgG4+ plasma cell infiltrate (>10/HPF)

— Treatment: corticosteroids — dramatic response distinguishes from PSC

— ~5% of cases; normal cholangiogram, cholestatic LFTs, biopsy shows PSC features

— Better prognosis; ~25% progress to large-duct disease

Key distinction: AIH-overlap responds to immunosuppression; classic PSC does not. Pediatric and young adult patients with markedly elevated transaminases + IgG warrant liver biopsy to identify treatable overlap before assuming uniform PSC course.

Pregnancy:

Pediatric PSC:

PSC-AIH overlap syndrome:

IgG4-related sclerosing cholangitis (key mimic):

Small-duct PSC:

Complications and Adverse Outcomes

— Cholangiocarcinoma (CCA): 10–20% lifetime risk; ~1.5% annual incidence; highest risk in first year after diagnosis

— Often perihilar (Klatskin)

— Red flags: rapid bilirubin rise, weight loss, new dominant stricture, CA 19-9 >129

— Gallbladder cancer: prevalence ~3–14%; any gallbladder polyp warrants cholecystectomy

— Hepatocellular carcinoma: in cirrhotic patients; surveillance with US ± AFP q6 months

— Pancreatic cancer: modestly increased risk

— 4–5× higher risk than IBD without PSC

— Right-sided predominance, often flat lesions — emphasizes chromoendoscopy

— Annual surveillance colonoscopy from PSC diagnosis, regardless of IBD duration

— Multifactorial: dominant strictures, biliary stasis, prior instrumentation

— Cumulative episodes drive transplant listing; qualifies for MELD exception points

— Varices (screen every 1–3 years), ascites, SBP, hepatic encephalopathy, hepatorenal syndrome, hepatopulmonary syndrome

— Hepatic osteodystrophy — osteoporosis ± osteomalacia from cholestasis, vitamin D malabsorption, hypogonadism

— Fragility fractures even with mild disease

— A (night blindness), D (osteomalacia), E (neuropathy, ataxia), K (coagulopathy)

— From bile salt deficiency or coexistent pancreatic insufficiency (especially IgG4-related)

— Disabling fatigue, depression, chronic pruritus — screen at every visit

— Post-ERCP pancreatitis (5–10%), cholangitis, perforation, bleeding

Step 3 management: Any PSC patient with new or worsening jaundice, weight loss, or CA 19-9 doubling requires expedited workup for cholangiocarcinoma — MRCP + ERCP with brushings/FISH + cross-sectional imaging within 1–2 weeks, not at the next routine visit. Delay costs curative options.

Hepatobiliary malignancies (defining feature of PSC):

Colorectal cancer in PSC-IBD:

Recurrent bacterial cholangitis:

Portal hypertension / decompensated cirrhosis:

Metabolic bone disease:

Fat-soluble vitamin deficiencies:

Steatorrhea:

Quality of life:

Procedural complications:

When to Escalate — ICU, Consults, and Inpatient Triage

— Severe cholangitis with sepsis — hypotension, altered mental status, lactate >2, organ dysfunction → ICU, broad-spectrum antibiotics, vasopressors, urgent ERCP

— Variceal hemorrhage — ICU, transfuse to Hgb 7, IV octreotide, ceftriaxone prophylaxis, EGD within 12 hours

— Hepatic encephalopathy grade III–IV — airway protection, lactulose, identify precipitant

— Acute kidney injury / HRS — terlipressin + albumin, hold diuretics/nephrotoxins

— Acute on chronic liver failure (ACLF) — transplant center transfer

— Cholangitis without sepsis but unable to tolerate POs / requires IV antibiotics

— New jaundice with rapid bilirubin rise pending malignancy workup

— Decompensation: new ascites, SBP, refractory pruritus

— Suspected dominant stricture requiring inpatient ERCP

— Hepatology — at diagnosis and at every escalation

— Advanced endoscopy / interventional GI — for ERCP, dominant strictures, brushings

— Transplant hepatology — refer when MELD ≥10–15, recurrent cholangitis, decompensation, or suspected early CCA

— Surgical oncology / HPB surgery — confirmed CCA

— GI (luminal) — for IBD management and surveillance colonoscopy

— Interventional radiology — PTC when ERCP fails

— Nutrition — sarcopenia, vitamin deficiencies

— Palliative care — advanced disease, symptom burden, goals of care

— MELD ≥10

— Recurrent bacterial cholangitis (≥2 episodes/year)

— Intractable pruritus

— Progressive cholestasis with bilirubin >4 sustained

— Suspected early hilar CCA at center with neoadjuvant protocol

— HCC within Milan criteria

CCS pearl: On a CCS case, a PSC patient with fever 39°C, BP 88/50, bilirubin 8, and WBC 18K → orders should include IV access ×2, NS bolus 30 mL/kg, blood cultures ×2, lactate, CBC/CMP/coags, piperacillin-tazobactam IV, GI consult STAT for ERCP, ICU admission, MRCP, with reassessment of hemodynamics every 30 minutes.

Immediate admission and ICU triage criteria:

Routine hospital admission indications:

Consultations:

Transplant referral triggers (refer early, do not wait):

Key Differentials — Other Cholestatic and Biliary Diseases

— Middle-aged women (90%), AMA-positive (95%), elevated IgM, intrahepatic small duct destruction

— Normal MRCP (no large duct strictures)

— Treat with UDCA 13–15 mg/kg/day (proven survival benefit, unlike PSC)

— Obeticholic acid for non-responders (caution in cirrhosis)

— Older men; elevated serum IgG4; autoimmune pancreatitis association

— Storiform fibrosis on biopsy; IgG4+ plasma cells

— Steroid-responsive — diagnostic and therapeutic

— Critical to distinguish before labeling as PSC

— Recurrent choledocholithiasis with chronic obstruction

— Ischemic cholangiopathy — post liver transplant (hepatic artery thrombosis), critically ill patients ("post-ICU cholangiopathy"), intra-arterial chemotherapy

— AIDS cholangiopathy — CD4 <100, often Cryptosporidium/CMV; treat opportunistic infection + ART

— Post-surgical biliary injury — cholecystectomy bile duct injury, Roux-en-Y anatomy

— Recurrent pyogenic cholangitis — Asian populations, parasitic

— Caroli disease — congenital intrahepatic duct dilation

— Eosinophilic cholangitis, mast cell cholangitis — rare

— Diffuse infiltrative CCA can mimic PSC radiographically

— Especially consider in older adults with new "PSC" diagnosis

— Bile duct dilation, cholangitis episodes — distinguished by stone visualization, response to clearance

— Hepatocellular pattern (transaminases dominant), elevated IgG, ANA/ASMA, interface hepatitis on biopsy

— Normal MRCP

— Responds dramatically to prednisone ± azathioprine

Key distinction: PBC vs. PSC — PBC is AMA-positive, female-predominant, intrahepatic small ducts, normal MRCP, treat with UDCA; PSC is ANCA-associated, male-predominant, large duct strictures on MRCP, no proven medical therapy, associated with IBD. The AMA status and MRCP findings are the discriminators most commonly tested.

Primary biliary cholangitis (PBC):

IgG4-related sclerosing cholangitis (IgG4-SC):

Secondary sclerosing cholangitis:

Cholangiocarcinoma masquerading as PSC:

Choledocholithiasis with chronic inflammation:

Autoimmune hepatitis (pure):

Key Differentials — Other-Category Mimics

— Anabolic steroids, oral contraceptives, augmentin, azathioprine, erythromycin, chlorpromazine, total parenteral nutrition

— Pattern: pure cholestasis (bland) or cholestatic hepatitis

— Resolves on drug discontinuation

— RUCAM scoring system to assess causality

— Normal MRCP

— Inpatients with bacteremia (especially gram-negative) → conjugated hyperbilirubinemia from cytokine-mediated cholestasis

— No biliary obstruction on imaging

— Resolves with sepsis source control

— Sarcoidosis — granulomatous cholangitis, elevated ALP, hilar lymphadenopathy, elevated ACE; biopsy shows non-caseating granulomas

— Amyloidosis — hepatomegaly, ALP elevation

— Lymphoma — hepatic infiltration

— Drug-induced, immune-mediated, or post-transplant rejection

— Progressive ductopenia on biopsy

— HCC, metastatic disease (colorectal, pancreatic, breast)

— Imaging reveals mass

— Elevated ALP, mild bilirubin rise; "nutmeg liver" appearance on imaging

— Hepatic venous distention, elevated JVP

— Younger patients; ceruloplasmin low, urinary copper elevated, Kayser-Fleischer rings, hemolytic anemia + acute hepatitis pattern

— Predominantly hepatocellular, but cholestatic forms exist

— Phenotype PiZZ; emphysema + liver disease; PAS-positive globules on biopsy

— Mild ALP elevation (mostly bone); rule out with TSH

— Fractionate ALP or check GGT — if GGT normal with elevated ALP, source is bone (Paget, fracture healing, growth), pregnancy (placental), or rarely intestinal — not liver. Prevents unnecessary hepatobiliary workup.

Board pearl: Always check GGT alongside ALP — an isolated ALP elevation with normal GGT in a young patient may be bone in origin, not hepatic. Conversely, ALP + GGT both elevated → hepatobiliary source → pursue MRCP.

Drug-induced cholestasis (DILI):

Sepsis-associated cholestasis:

Infiltrative liver diseases:

Vanishing bile duct syndrome:

Hepatic neoplasms causing biliary obstruction:

Right-sided heart failure / congestive hepatopathy:

Wilson disease:

Alpha-1 antitrypsin deficiency:

Hyperthyroidism:

Bone source of ALP:

Long-Term Plan — Surveillance and Secondary Prevention

— MRI/MRCP + CA 19-9 every 6–12 months (AASLD/EASL) for cholangiocarcinoma surveillance starting at diagnosis

— Rising CA 19-9 trend more significant than absolute value; new mass-forming lesion → urgent ERCP with brushings/FISH ± cholangioscopy

— Gallbladder ultrasound annually (often combined with MRI); any polyp → strong cholecystectomy consideration; ≥8 mm = cholecystectomy

— HCC surveillance with US ± AFP every 6 months once cirrhotic

— Annual colonoscopy with chromoendoscopy or high-definition white light + biopsies from PSC diagnosis

— Continues even after liver transplantation (risk persists/may increase)

— All PSC patients without known IBD: colonoscopy every 5 years to detect occult IBD

— DEXA every 2–3 years

— Calcium 1000–1500 mg/day, vitamin D to maintain >30 ng/mL

— Bisphosphonates for osteoporosis (caution with varices)

— Weight-bearing exercise; fall prevention

— Hepatitis A and B at diagnosis (check titers, vaccinate if non-immune)

— Annual influenza, pneumococcal (PCV20 or PCV15+PPSV23), COVID-19 boosters

— Zoster (Shingrix) at age 50+

— Avoid live vaccines if immunosuppressed (overlap AIH treatment, post-transplant)

— Statin not contraindicated in compensated cirrhosis; may be beneficial in PSC

— Lipid abnormalities of cholestasis often non-atherogenic — assess true CV risk

— Complete oral antibiotic course (typically 10–14 days total)

— Schedule repeat ERCP if stent placed (removal/exchange in 4–8 weeks)

— Hepatology follow-up within 2–4 weeks

— Trend LFTs at 2 weeks post-discharge

Step 3 management: A newly diagnosed PSC patient leaves the first clinic visit with: MRI/MRCP scheduled, colonoscopy ordered, DEXA scan, hepatitis A/B serologies, vitamin D level, CA 19-9 baseline, vaccinations updated, hepatology referral, and patient education on red-flag symptoms (jaundice, fever, weight loss). This is the canonical Step 3 "comprehensive ambulatory plan" answer.

Hepatobiliary cancer surveillance:

Colorectal cancer surveillance in PSC-IBD:

Bone health:

Vaccinations:

Cardiovascular and metabolic:

Discharge/transition medications after cholangitis admission:

Follow-Up, Monitoring, and Counseling

— Stable, asymptomatic, no cirrhosis: hepatology every 6 months

— Symptomatic, cirrhotic, or post-ERCP: every 3 months

— Transplant-listed: every 1–3 months with MELD updates

— CMP with LFTs every 3–6 months (ALP, AST/ALT, bilirubin, albumin, INR)

— CBC every 6 months

— Vitamin A, D, E, K (PT) annually if bilirubin >2 or steatorrhea

— Lipids, TSH, A1c annually

— CA 19-9 every 6–12 months with imaging

— MRI/MRCP every 12 months (some centers every 6 months in high-risk)

— Variceal screening EGD every 1–3 years if cirrhotic (or per Baveno criteria using platelets/elastography)

— Abdominal US ± AFP every 6 months once cirrhotic

— Fever, RUQ pain, jaundice (cholangitis)

— New or worsening jaundice

— Unintentional weight loss

— Severe pruritus

— Hematemesis, melena (varices)

— Confusion, sleep-wake disturbance (encephalopathy)

— Abdominal distention, leg swelling

— Alcohol abstinence (especially with cirrhosis)

— Tobacco cessation — independent CCA risk factor

— Healthy weight, Mediterranean-style diet, salt restriction if ascites

— Regular weight-bearing exercise

— Sun protection (Vitamin D paradox — still supplement)

— Screen for depression and anxiety annually — chronic disease, pruritus, fatigue, uncertainty

— Refer to support groups (PSC Partners Seeking a Cure)

— Sleep hygiene; melatonin for pruritus-related insomnia

— Subclinical encephalopathy impairs driving — assess before clearance

— Occupational counseling if cognitive symptoms

— First-degree relatives at increased risk but routine screening not recommended in absence of symptoms; counsel to evaluate any cholestatic symptoms or IBD

Board pearl: Trending alkaline phosphatase decrease >40% from baseline at 12 months has been associated with improved long-term outcomes in PSC, regardless of cause — making ALP a useful longitudinal biomarker even though no therapy reliably modifies it.

Visit cadence:

Lab monitoring schedule:

Imaging cadence:

Patient counseling — red flags to call:

Lifestyle counseling:

Mental health and QoL:

Driving/work counseling:

Family screening:

Ethical, Legal, and Patient Safety Considerations

— Discuss 5–10% post-ERCP pancreatitis risk, cholangitis, perforation, bleeding before each procedure

— Document explicit understanding that ERCP is therapeutic, not diagnostic in most PSC cases — avoid "routine surveillance ERCP" requests

— For dominant stricture: explain that brushings have ~40% sensitivity for CCA — negative cytology does not exclude malignancy; serial imaging needed

— Equitable access — MELD-based allocation; PSC patients often disadvantaged by lower MELD relative to symptom burden, hence MELD exception petitions for recurrent cholangitis or early CCA (Mayo protocol)

— Discuss organ availability, regional disparities, living donor options

— Substance use, psychosocial readiness — discuss center-specific listing criteria with transparency

— Re-listing after recurrent PSC requires careful discussion

— Annual colonoscopy, biannual MRI, lab monitoring — high lifetime healthcare exposure

— Use shared decision-making aids; discuss false-positive rates and downstream procedure risks

— In elderly or transplant-ineligible patients, deintensify surveillance if it won't change management

— Familial clustering exists but no single gene; routine genetic testing not indicated; counsel that risk to relatives is modestly elevated

— Patient discharged after cholangitis: stent removal/exchange must be scheduled before discharge — retained plastic stents cause recurrent cholangitis

— Ensure outpatient hepatology appointment within 2–4 weeks; medication reconciliation (antibiotic course, beta-blocker, lactulose dosing)

— Send discharge summary to all involved clinicians; explicit handoff of CA 19-9 results pending

— Structured transition program at age 18–21; PSC-AIH overlap patients especially vulnerable to immunosuppression nonadherence

— Advance directives, healthcare proxy documentation by time of transplant evaluation

— For non-transplant candidates with advanced disease: early palliative care; address itch, fatigue, depression, hospice when prognosis <6 months

— Reporting if patient with overt encephalopathy continues to drive — state-specific DMV reporting laws

Step 3 management: When a PSC patient is discharged after ERCP with a plastic biliary stent placed, the stent removal/exchange appointment must be scheduled within 4–8 weeks before the patient leaves the hospital — failure to do so is a recognized transition-of-care safety failure leading to occluded stent cholangitis and avoidable readmission.

Informed consent — ERCP risk-benefit:

Transplant listing ethics:

Surveillance burden and shared decision-making:

Genetic counseling:

Transitions of care — Step 3 high-yield safety issue:

Pediatric-to-adult transition:

End-of-life:

Mandatory considerations:

High-Yield Associations and Rapid-Fire Facts

— Cholangiocarcinoma (highest in year 1)

— Gallbladder cancer (any polyp = surgery)

— Colorectal cancer (annual surveillance from PSC diagnosis)

Board pearl: The single most tested PSC-associated cancer relationship is PSC + UC + colon cancer — annual colonoscopy from PSC diagnosis, not from IBD diagnosis duration; this is the most common Step 3 trap when the question asks about CRC screening intervals.

PSC + ulcerative colitis: ~70–80% have UC, often pancolitis with rectal sparing, backwash ileitis, mild course — paradoxically increases CRC risk

High-yield serology: p-ANCA atypical positive ~65–80%; AMA negative; IgG4 must be checked to exclude mimic

Imaging signature: "Beaded" or "string of pearls" appearance on MRCP — multifocal short strictures alternating with normal/dilated segments

Biopsy hallmark (when obtained): "Onion-skin" concentric periductal fibrosis — pathognomonic but only present ~30–40%

Cancer triad to remember:

CA 19-9 caveat: Falsely elevated in cholangitis; ~7% of population is Lewis-negative and cannot produce CA 19-9 (false negative)

High-dose UDCA (>28 mg/kg/day): HARMFUL — increases mortality and colorectal neoplasia (Lindor trial)

Dominant stricture management: Balloon dilation > stenting; obtain brushings/FISH at every ERCP

Pruritus ladder: Cholestyramine → rifampin → naltrexone → sertraline → transplant

Mayo Protocol CCA + transplant: Early hilar CCA ≤3 cm, no metastasis, neoadjuvant chemoradiation → liver transplant with ~65% 5-year survival

Recurrent PSC post-transplant: ~20–25% at 10 years

MELD exception: Recurrent bacterial cholangitis (≥2 episodes) and early CCA qualify for exception points

Pediatric overlap: PSC-AIH overlap responds to immunosuppression; classic adult PSC does not

Small-duct PSC: Normal MRCP, biopsy-diagnosed, better prognosis, ~25% progress to large-duct

IgG4-SC: Older men, autoimmune pancreatitis, steroid-responsive — always check IgG4

Family risk: First-degree relatives have ~9–11× increased PSC risk

Charcot triad: Fever, jaundice, RUQ pain = cholangitis → IV antibiotics + urgent ERCP

Reynolds pentad: Charcot + hypotension + altered mental status = suppurative cholangitis → ICU

Bone disease: DEXA at diagnosis; hepatic osteodystrophy from chronic cholestasis

Fat-soluble vitamins: A/D/E/K — check annually if bilirubin >2

Board Question Stem Patterns

— "A 32-year-old man with ulcerative colitis on mesalamine has routine labs: ALP 412, AST 58, ALT 64, bilirubin 0.9. What is the next best step?"

— Answer: MRCP

— Distractors: liver biopsy (premature), ERCP (invasive), AMA (PBC workup), increase mesalamine

— Cholestatic LFTs in a young male with UC, MRCP shows multifocal strictures with beaded appearance

— Answer: Primary sclerosing cholangitis — no further confirmation needed; start surveillance plan

— Older man, painless jaundice, elevated ALP, MRCP with strictures, autoimmune pancreatitis on CT, elevated IgG4

— Answer: IgG4-related sclerosing cholangitis → prednisone 40 mg/day

— Known PSC, new jaundice with bilirubin from 1.5 → 6, weight loss, CA 19-9 rising

— Answer: ERCP with brushings, FISH, cholangioscopy to evaluate for cholangiocarcinoma

— PSC patient, fever 39°C, RUQ pain, jaundice, BP 88/52

— Answer: Blood cultures, IV piperacillin-tazobactam, urgent ERCP for drainage, ICU monitoring

— Newly diagnosed PSC, no known IBD, asymptomatic

— Answer: Colonoscopy now (to detect occult IBD)

— If IBD present → annual colonoscopy from PSC diagnosis

— Refractory pruritus despite cholestyramine 16 g/day

— Answer: Rifampin with LFT monitoring

— "Which therapy improves survival in PSC?"

— Answer: Liver transplantation (not UDCA at any dose)

— PSC patient, US shows 9-mm gallbladder polyp

— Answer: Cholecystectomy

— PSC patient with AST/ALT 400s, IgG markedly elevated, positive ASMA

— Answer: Liver biopsy to confirm PSC-AIH overlap; treat with prednisone + azathioprine

— Recurrent cholangitis (3 episodes in 1 year) despite optimal management

— Answer: Refer for liver transplant evaluation; eligible for MELD exception points

— PSC patient pregnant with worsening pruritus and bile acids 65 µmol/L

— Answer: UDCA initiation (safe and effective in pregnancy-associated cholestasis)

Key distinction: When the stem features female + AMA-positive + normal MRCP, answer is PBC; when it's male + UC + beaded MRCP, answer is PSC; when it's older male + IgG4 elevated + pancreatic mass, answer is IgG4-SC.

Pattern 1 — The screening trigger:

Pattern 2 — The diagnostic confirmation:

Pattern 3 — The mimic:

Pattern 4 — The complication / dominant stricture:

Pattern 5 — The acute cholangitis:

Pattern 6 — The surveillance question:

Pattern 7 — The pruritus ladder:

Pattern 8 — The therapy trap:

Pattern 9 — The gallbladder polyp:

Pattern 10 — The overlap syndrome:

Pattern 11 — The transplant trigger:

Pattern 12 — Pregnancy:

One-Line Recap

Primary sclerosing cholangitis is a progressive, idiopathic large-duct cholestatic liver disease — diagnosed by cholestatic biochemistry plus a "beaded" multifocal stricturing pattern on MRCP after excluding mimics — that has no proven disease-modifying medical therapy and demands lifelong cancer surveillance (cholangiocarcinoma, gallbladder, colorectal) with liver transplantation as definitive treatment.

Board pearl: The three most testable PSC associations are PSC + UC + colon cancer (annual colonoscopy from PSC dx), PSC + dominant stricture + cholangiocarcinoma (ERCP + brushings + FISH + CA 19-9), and PSC mimicked by IgG4-SC (older male + IgG4 elevated → steroid-responsive) — mastering these three patterns will resolve the overwhelming majority of Step 3 PSC vignettes.

Diagnose: Cholestatic LFTs (↑ALP, ↑GGT) + characteristic MRCP findings + exclude IgG4-SC, PBC, secondary causes; liver biopsy only for small-duct disease or suspected AIH overlap.

Surveil: MRI/MRCP + CA 19-9 every 6–12 months for cholangiocarcinoma from diagnosis; annual colonoscopy from PSC diagnosis if IBD; gallbladder polyp ≥8 mm → cholecystectomy; DEXA every 2–3 years; HCC screening once cirrhotic.

Manage: No high-dose UDCA (harmful); treat pruritus with cholestyramine → rifampin → naltrexone; ERCP with balloon dilation + brushings for dominant strictures; vaccinate (HAV, HBV, pneumococcal, influenza); supplement fat-soluble vitamins; treat cholangitis with IV piperacillin-tazobactam + urgent ERCP drainage.

Escalate: Refer to transplant when MELD ≥10, recurrent cholangitis (≥2/year), intractable pruritus, decompensation, or early hilar CCA eligible for Mayo neoadjuvant protocol — and recognize that 5-year post-transplant survival is ~85% with ~20–25% PSC recurrence at 10 years.