Primary sclerosing cholangitis

• Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease in which inflammation and fibrosis progressively narrow and obliterate the intrahepatic and extrahepatic bile ducts, leading to multifocal strictures, cholestasis and, eventually, biliary cirrhosis.^[1][3]
• It most often affects young to middle-aged men, and 60 to 80 percent of patients have concomitant inflammatory bowel disease (IBD), above all ulcerative colitis.^[3][1]
• Many patients are found because an alkaline phosphatase is raised on routine testing; others have fatigue, pruritus, jaundice, right upper quadrant pain or episodes of bacterial cholangitis.^[1][3]
• Magnetic resonance cholangiopancreatography (MRCP) is the first imaging test: in classical disease it shows multiple short strictures with intervening normal or slightly dilated segments, giving a "beaded" appearance; ERCP is reserved for unclear cases or therapeutic work.^[1][3]
• There is no proven therapy that stops progression. Ursodeoxycholic acid (UDCA) is not used at high dose; dominant strictures may be dilated endoscopically; liver transplantation is the only definitive treatment, although PSC can recur in the graft.^[2][3]

By the end of this page you should be able to:

1. Define PSC and distinguish large-duct, small-duct and overlap variants from secondary sclerosing cholangitis and IgG4-related disease.
2. Explain why PSC is associated with ulcerative colitis and with HLA risk genes, and give the basic epidemiology.
3. Read a cholestatic liver profile and an MRCP report and say whether they fit PSC.
4. Choose the first investigations, including when liver biopsy is genuinely needed.
5. Outline the medical, endoscopic and transplant management, including pruritus, fat-soluble vitamins and bone density.
6. State the screening programme for IBD and for hepatobiliary, gallbladder and colorectal cancer in these patients.

PSC is best understood as a spectrum of bile-duct injury rather than a single pattern. The following forms are recognised.^[1][3]

• Classic (large-duct) PSC. Multifocal strictures of the larger intrahepatic and/or extrahepatic ducts on cholangiography. This is the commonest form.
• Small-duct PSC. The biochemical picture is cholestatic and the liver biopsy shows PSC-type changes, but cholangiography is normal. Liver biopsy is required to diagnose this variant.^[1][3]
• PSC with autoimmune hepatitis overlap. Coexistence of a cholangiopathy with features of autoimmune hepatitis; suspected when transaminases rise to more than 5 times the upper limit of normal and immunoglobulin G to more than 2 times normal. Overlap occurs in about one third of children with PSC and about 10 percent of affected adults.^[1]
• IgG4-related sclerosing cholangitis (IgG4-SC). A steroid-responsive form of cholangitis that can look identical on imaging but is driven by IgG4-positive plasma cells; it is diagnosed with the HISORt criteria (histology, imaging, serology (raised IgG4), other organ involvement, response to corticosteroids).^[1]
• Secondary sclerosing cholangitis. A cholangiopathy arising from an identifiable cause: choledocholithiasis, prior biliary surgery, ischaemic cholangiopathy (after hepatic artery thrombosis or transplant), recurrent pyogenic cholangitis, portal cholangiopathy, eosinophilic or mast-cell cholangitis, HIV-associated cholangiopathy and others.

PSC is uncommon but its prevalence is rising. Prevalence has been reported to reach up to 31.7 cases per 100,000 individuals, although it varies widely, with the highest rates in northern Europe (especially Scandinavia) and lower rates in southern Europe and the Middle East.^[1] Earlier estimates from North America and Europe ranged from 6 to 16 cases per 100,000.^[3]

• Who is affected. Typically young to middle-aged men, with a median age at diagnosis of about 40 to 41 years.^[2][3] PSC is reported almost exclusively in nonsmokers in the original descriptions.^[3] Women can be affected, but men predominate.
• Geography. Incidence is similar in North America and northern Europe, with lower estimates in Asia and southern Europe.^[3]
• IBD. Between 60 and 80 percent of patients with PSC have concomitant IBD, most commonly ulcerative colitis; the co-occurrence of IBD and PSC may reach up to 80 percent.^[1][3] The prevalence of PSC in IBD is around 2 percent overall and correlates with the extent of colitis, being higher with pancolitis; a meta-analysis reported 2.16 percent in IBD overall, 2.4 percent in ulcerative colitis, 0.9 percent in Crohn disease and 5.0 percent in indeterminate colitis.^[1] Conversely, 60 to 70 percent of patients with PSC will develop IBD.^[3]
• Family history. There is an 11-fold increased risk in first-degree relatives and 23 risk genes have been identified; the HLA complex on chromosome 6p21 contributes many of them.^[2]
• Transplantation. PSC accounts for up to 15 percent of all liver transplantations in some series (4 to 5 percent in others).^[1][3]
• Asymptomatic disease. About 50 percent of patients are asymptomatic at diagnosis and are detected through an abnormal liver test.^[1]

The cause of PSC is unknown. It is regarded as an immune-mediated disease in a genetically predisposed person, with the gut-liver axis as the most plausible driver.^[2] The following are well-recognised associations:

• Genetic predisposition. HLA associations on chromosome 6p21 and 23 additional risk genes affecting immune regulation and bile acid homeostasis.^[2]
• IBD, particularly ulcerative colitis. The shared risk with IBD, the gut-homing of mucosal lymphocytes into the liver, and the consistent finding of gut dysbiosis all support this link.^[2]
• Male sex and northern European ancestry.^[1][3]
• Other immune-mediated diseases in the same patient or family.^[1]

No modifiable risk factor is established. IBD can be diagnosed before, at the same time as, or years after PSC, including after colectomy or after liver transplantation.^[3]

Understanding why each symptom and test result occurs makes PSC easier to reason about.

1. Trigger. Bacterial components and other luminal antigens cross a more permeable intestinal epithelium and reach the liver through the portal circulation; gut dysbiosis is consistently present.^[2]
2. Immune activation. Toll-like receptors and CD14 on hepatic cells activate innate immunity; gut-specific lymphocytes bearing α4β7 and CCR9 home to the liver and attack the biliary epithelium.^[2]
3. Genetic susceptibility. HLA and non-HLA variants (those involving interleukin-2, IL-21, CD28, CTLA4 and bile acid transporters) determine who is affected.^[2]
4. Bile acid injury. Disruption of the protective bicarbonate-rich layer over the biliary epithelium exposes the ducts to toxic bile acids ("toxic bile" hypothesis). Mouse models of defective biliary transport develop biliary inflammation and stricturing resembling human PSC.^[2]
5. Fibrosis. Cholangiocytes, portal myofibroblasts and hepatic stellate cells cooperate to lay down concentric periductal collagen, producing the "onion-skin" fibrosis that narrows the lumen; bile stasis follows.
6. Progression. Repeated cycles of obstruction, infection and cholestasis lead to biliary cirrhosis, portal hypertension and liver failure.

• Gross. The bile ducts are thickened and narrowed with fibrotic stenoses; the intervening segments may be slightly dilated, explaining the beaded cholangiogram.
• Microscopic. Concentric ("onion-skin") periductal fibrosis around the bile ducts within portal tracts, with bile duct proliferation, chronic periportal inflammation and, in advanced cases, secondary biliary cirrhosis. The classic onion-skin lesion can be absent, especially in small-duct PSC.^[1][3]
• Why biopsy is limited. Percutaneous biopsy samples the peripheral small portal tracts, so it often shows only indirect features of large-duct obstruction or appears normal; conversely, large ducts are not sampled.^[1]

• Fatigue and pruritus, which can be severe enough to dominate quality of life.^[3]
• Right upper quadrant discomfort.
• Jaundice and dark urine when strictures obstruct bile flow.
• Episodes of fever, rigors and right upper quadrant pain — acute bacterial cholangitis, usually from an obstructing stricture.^[3][1]
• Weight loss and malabsorption in advanced disease.
• Asymptomatic, discovered through an abnormal liver test in roughly half of patients.^[1]

• Jaundice and, in advanced disease, spider naevi, palmar erythema and signs of portal hypertension.
• Hepatomegaly and/or splenomegaly.
• Excoriations from scratching; in prolonged cholestasis, xanthomas and xanthelasma.
• Fever and right upper quadrant tenderness during cholangitis.
• There are no specific examination findings that distinguish PSC from other cholestatic diseases; the diagnosis rests on biochemistry and imaging.

PSC usually progresses, but slowly and unpredictably. The rate of biochemical worsening, the presence of dominant strictures, and the fibrosis score all predict outcome; validated prognostic models (Mayo risk score, PREsTo, UK-PSC score, Amsterdam-Oxford model, ELF score, liver stiffness measurement) are used, particularly in trials.^[2]

1. Liver biochemistry.

   • Cholestatic pattern: alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) raised. A total of 25 percent of cases have normal liver tests, so normal bloods do not exclude PSC.^[1]
   • Serum bilirubin is normal in most early patients and tends to rise as the disease progresses; it is elevated in 28 to 40 percent of cases.^[1][3]
   • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are usually mildly raised (AST predominance can suggest cirrhosis).^[1]
   • Immunoglobulin M may be elevated.^[1]
   • An overlap with autoimmune hepatitis should be suspected when transaminases rise more than 5 times the upper limit of normal with immunoglobulin G more than 2 times normal.^[1]

2. Serology.

   • p-ANCA (atypical, also called p-ANNA) is positive in up to 70 percent of patients with PSC, but it is not disease-specific (it targets antigens at the nuclear periphery and is usually negative on MPO- and PR3-specific assays). A negative result therefore does not exclude PSC, and a positive one is only supportive.^[1]
   • Anti-Saccharomyces cerevisiae antibodies (ASCA) are positive in about 30 to 53 percent of PSC patients in some studies but are not specific.^[1]
   • Antinuclear, antimitochondrial and smooth-muscle antibodies may be present but are nonspecific.^[3]
   • IgG4 must be measured to assess IgG4-related disease, alongside total immunoglobulins.^[1][3]
   • Human immunodeficiency virus serology and other differential tests are taken according to the clinical picture.

3. Imaging: MRCP first.

   • MRCP is the imaging modality of choice: it is non-invasive, avoids contrast- and procedure-related complications, and has reported sensitivity 0.86 and specificity 0.94 for PSC-related biliary changes.^[1][3]
   • Classical picture: multiple short annular strictures with alternating normal or slightly dilated segments, producing a "beaded" appearance in the intra- and/or extrahepatic ducts.^[1][3]
   • MRCP cannot reliably separate PSC from IgG4-SC or cholangiocarcinoma; clinical and serological correlation is essential.^[1]
   • MRCP-based severity scores (ANALI, DiStrict) and elastography are used for risk stratification, especially in trials.^[1][2]

4. ERCP is reserved for inconclusive MRCP, strong clinical suspicion with a normal MRCP (particularly in IBD), symptomatic dominant strictures or tissue sampling:

   • ERCP allows brushing cytology, biopsy, FISH, and therapeutic balloon dilation.^[1][3]
   • Post-ERCP pancreatitis occurs in 4.2 percent (bleeding 0.3 percent, perforation 0.7 percent) in patients with PSC, so ERCP should not be used for routine surveillance of disease or cancer.^[1]

5. Liver biopsy is not needed for classical PSC and is not used for fibrosis staging. It is valuable for:

   • Small-duct PSC.
   • Overlap with autoimmune hepatitis.
   • An unclear diagnosis.
   • Clinical trial endpoints and, increasingly, mechanistic assessment of new drugs. Serious adverse events occur in less than 0.5 percent.^[1][2][3]

6. ELF score and liver stiffness measurement predict transplant-free survival and can stage fibrosis non-invasively; a liver stiffness of 9.5 kPa or more supports advanced fibrosis in compensated patients without major biliary obstruction.^[1][2]

There is no single diagnostic test. A reasonable summary is:

• Raised ALP or GGT (cholestatic profile), plus
• Typical cholangiographic findings on MRCP (or ERCP), after
• Exclusion of secondary sclerosing cholangitis, IgG4-SC and cholangiocarcinoma.^[1]

AASLD 2022/2023 definitions differ slightly from older European terminology.^[4][5][1]

• Possible dominant stricture (International PSC Study Group): narrowing of major ducts on MRI/ERCP with obstructive symptoms and a rise in bilirubin and ALP, or worsening biochemistry alone over six months.^[1]
• Definitive dominant stricture: the above plus difficulty passing a catheter larger than 5 Fr, or symptomatic and biochemical improvement after dilation or stenting.^[1]
• Clinically relevant stricture (AASLD 2022/2023): a stenosis of the common hepatic duct or its first-order branches with obstructive symptoms or bacterial cholangitis. This is confirmed only after ERCP.^[1][4]

Dominant strictures merit investigation (including brushing and FISH) because cholangiocarcinoma often arises at the site of a stricture (see Management).^[1][4]

• Mayo risk score: uses age, bilirubin, AST, albumin and prior variceal bleeding to predict four-year mortality; performs best in late-stage disease.^[1][2]
• PREsTo (primary sclerosing cholangitis risk estimate tool): uses bilirubin, albumin, ALP (x upper limit of normal), platelets, AST, haemoglobin, sodium, age and years since diagnosis to predict hepatic decompensation.^[1]
• UK-PSC score and Amsterdam-Oxford model: predict transplant or PSC-related death at 2 and 10 years using age, bilirubin, ALP, albumin, platelets and disease features.^[1][2]
• Enhanced liver fibrosis (ELF) score: hyaluronic acid, TIMP-1 and procollagen III propeptide; higher scores predict shorter survival and are more stable than ALP.^[1][2]
• Normal and reduced ALP values are associated with a better prognosis (Lindstrom data: a fall of 40 percent or more, or normalisation, predicts longer survival).^[3]

• There is no proven disease-modifying drug for PSC. The honest position, repeated by every guideline and review, is that no medical therapy has been shown to slow progression, prevent transplant or reduce hepatobiliary cancer. Management centres on complications, symptoms and transplantation.^[1][2][3]
• UDCA (ursodeoxycholic acid) remains the most studied drug, and controversy is real:
  • Low to moderate doses (10 to 15 mg/kg/day in early trials; current guidance 15 to 20 mg/kg/day under EASL; 13 to 23 mg/kg/day under AASLD) improve ALP and other liver tests and can improve surrogate markers of prognosis.^[2][4][5][6]
  • AASLD (updated after 2011) and EASL (2022) now accept moderate-dose UDCA for this biochemical benefit, provided it is continued only if ALP or symptoms improve within a year.^[2][4]
  • High-dose UDCA (28 to 30 mg/kg/day) is not recommended: in a randomised trial patients had improved liver tests but more hepatic decompensation, transplantation and death.^[2][3]
  • UDCA is not used as a chemopreventive agent against colorectal cancer: evidence is conflicting, and high doses have even been associated with increased colorectal neoplasia risk.^[2]
  • Withdrawal of UDCA leads to biochemical deterioration for most patients.^[3]
• Immunosuppression has no routine role in classical PSC. Corticosteroids, azathioprine, tacrolimus and biologics have not altered progression. Corticosteroids or other immunosuppression are reserved for documented autoimmune hepatitis overlap or for IgG4-SC (which is steroid-responsive).^[2][3]
• Antibiotics (vancomycin, metronidazole and tetracyclines) have been studied, with small trials showing reductions in ALP or bilirubin; they are not standard PSC therapy, although they are useful for acute cholangitis.^[3][2]
• Norursodeoxycholic acid (norUDCA), FXR agonists, PPAR agonists, bile acid transporter inhibitors, and FGF19 analogues are investigational; norUDCA in particular has shown dose-dependent biochemical improvement and is in phase III trials.^[2]

• Acute cholangitis should be treated with intravenous antibiotics and biliary decompression without delay; antibiotic choice should follow local microbiology advice, but regimens must cover the organisms typical of cholangitis.^[3]
• Dominant or clinically relevant strictures are treated when symptomatic (cholangitis, jaundice, pruritus, right upper quadrant pain, worsening biochemistry) by:
  • Balloon dilation first — safer than stenting with equivalent clinical benefit.^[2][3]
  • Stenting reserved for refractory or rapidly recurring strictures; both are performed during ERCP.^[2]
  • Brushing and/or biopsy (with FISH where available) before any therapy to exclude cholangiocarcinoma, as AASLD recommends for suspected perihilar or distal disease.^[3][4]
  • AASLD advises that initial suspicious cytology warrants repeat ERCP within three months regardless of FISH.^[4]
• AASLD restricts these therapeutic procedures to patients with symptoms or rising biochemistry.^[3] ERCP complications in PSC are not trivial (pancreatitis 4.2 percent, bleeding 0.3 percent, perforation 0.7 percent).^[1]

Pruritus can devastate quality of life, causing sleep loss, depression and excoriations; rarely it is an indication for transplantation.^[3] Step up treatment:

1. Emollients and antihistamines for mild disease.
2. Cholestyramine (bile acid sequestrant) for more severe pruritus.^[3]
3. Rifampicin (beware hepatotoxicity), naltrexone or naloxone, sertraline, or phenobarbital if cholestyramine fails or is not tolerated.^[3]
4. In unresponsive or intractable cases, or where a dominant stricture is contributing, treat the stricture (and, ultimately, transplant).^[3]

About 5 to 10 percent of patients have severe pruritus refractory to medical therapy.^[3] Metronidazole has also been shown to reduce pruritic symptoms in a pilot study.^[3]

• Nutrition and the vitamins A, D, E and K that need bile to be absorbed: cholestasis reduces absorption; monitor and supplement as needed, especially after bile drainage procedures.
• Bone density: hepatic osteodystrophy is common. DEXA T-scores define osteopenia (1 to 2.5 standard deviations below normal) and osteoporosis (more than 2.5). Incidence of osteoporosis in PSC is 4 to 10 percent, rising with age, duration of disease and low body mass index.^[3]
  • Calcium and vitamin D for osteopenia; add a bisphosphonate for osteoporosis; consider parenteral bisphosphonates if oesophageal varices are present, because oral bisphosphonates can ulcerate the oesophagus.^[3]
• Treat coincidental conditions that worsen fatigue (anaemia, hypothyroidism, sleep disorders, adrenal insufficiency, depression). Safe screening tests should be chosen; there is no drug therapy recommended specifically for fatigue in PSC.^[3]

Transplantation is the only definitive treatment for end-stage PSC.^[2]

• Indications: end-stage cirrhosis with portal hypertension; recurrent bacterial cholangitis; intractable pruritus unresponsive to all therapy; (in some jurisdictions) advanced dysplasia.^[1][3]
• Outcomes: one-year survival exceeds 90 percent; five-year survival for deceased-donor grafts is about 85 percent.^[3]
• Technique: Roux-en-Y choledochojejunostomy is the usual biliary reconstruction.^[3]
• Recurrence: PSC recurs in 20 to 25 percent of recipients over 10 years (and approximately one quarter within the first ten years). Colectomy before transplant may protect (hazard ratio 0.65), while active IBD (HR 1.73), prior cholangiocarcinoma (HR 2.42) and older age at transplant increase risk.^[1][3]
• Retransplant can succeed when recurrence leads to graft failure.^[3]

• Liver tests including ALP (normalisation or marked improvement predicts better outcome).^[3]
• Imaging surveillance for strictures, gallbladder and cholangiocarcinoma (see Prevention and screening).
• Non-invasive fibrosis assessment with elastography/ELF as disease progresses.^[1][2]
• Standard care for cirrhosis complications (portal hypertension, varices) where indicated.

• Dominant strictures recollect; repeated episodes of cholangitis, jaundice, rising biochemistry.^[3]
• Biliary cirrhosis and portal hypertension: variceal bleeding, ascites and hepatic encephalopathy.
• Recurrent bacterial cholangitis with risk of sepsis.
• Cholangiocarcinoma: lifetime risk 5 to 20 percent depending on series (5 to 10 percent in older series; up to 20 percent cumulative in newer); annual incidence 0.5 to 1.5 percent after the first year, but up to 50 percent of cases are diagnosed within the first year of PSC diagnosis. Five-year survival after diagnosis is less than 10 percent.^[1][3]
• Gallbladder cancer — risk roughly 10 times that of the general population.^[3]
• Hepatocellular carcinoma — about 2.4 percent over a median 10 years of follow-up; ultrasound surveillance every 6 months if cirrhotic.^[1]
• Colorectal neoplasia (in PSC with concomitant IBD) — adenomatous and "flat" mucosal dysplasia in the right colon that is often missed without careful colonoscopy.^[1][3]
• Hepatic osteodystrophy (osteopenia/osteoporosis) and fat-soluble vitamin deficiency.^[3]
• Nutritional failure (fat-soluble vitamin deficiency, malabsorption).
• Recurrence after transplantation (see above).

Prognosis is variable. Classical PSC in adults without treatment progresses over years to decades; most patients eventually develop cirrhosis and require transplantation. Survival is better when ALP improves or normalises, with worse outcomes when bilirubin rises early. Risk scores (Mayo, PREsTo, UK-PSC, Amsterdam-Oxford, ELF, LSM) stratify patients and are increasingly used in trial endpoints rather than treatment decisions alone.^[1][2][3] Because alcohol, obesity and metabolic syndrome can independently worsen liver disease, minimising them is worthwhile general advice even though it is not PSC-specific.

• Full colonoscopy with multiple biopsies at the time of PSC diagnosis, to confirm or exclude IBD (including right-sided and "flat" dysplasia).^[3][1]
• If IBD is present: colonoscopic surveillance every 1 to 2 years thereafter, and AASLD recommends that surveillance begin at age 15 years.^[1][3][4]
• If no IBD: colonoscopy at diagnosis and every 5 years thereafter.^[1][3]
• Colectomy does not abolish PSC risk, and PSC can develop after colectomy; surveillance should continue after liver transplantation.^[3]

Practice differs between guidelines, and this is stated honestly:^[1][3][4]

• EASL (2022) recommends ultrasound and/or MRI/MRCP surveillance for cholangiocarcinoma and gallbladder malignancy at least yearly in large-duct PSC regardless of disease stage, and every 6 months when cirrhosis is present; EASL specifically does not recommend CA 19-9 for surveillance.^[1][6][6]
• EASL also recommends contrast-enhanced ultrasound assessment of smaller gallbladder polyps, with cholecystectomy if they enhance.^[4]
• AASLD (2010-era statement cited in 2016 reviews) advised CA 19-9 and annual MR imaging/MRCP or ultrasound where clinically indicated and did not recommend routine surveillance for hepatobiliary cancer; newer AASLD 2022/2023 guidance recommends FISH in all patients with suspected perihilar or distal CCA.^[3][4]
• Routine structured monitoring is associated with markedly better outcomes (one cohort reported 68 percent five-year survival with surveillance versus 20 percent without).^[1]
• CA 19-9 above 130 U/L is 79 percent sensitive and 98 percent specific for cholangiocarcinoma in the absence of bacterial cholangitis; it should be interpreted only in context, because false positives occur in cholangitis and obstruction.^[3]

• Gallbladder cancer risk is about 10 times higher than in the general population; male sex and age under 60 years are additional risk factors.^[3]
• Annual abdominal ultrasound to detect gallbladder abnormalities/masses.^[3]
• Polyp management thresholds differ between guidelines (say which values come from which source): greater than 8 mm (AASLD 2022/2023) for considering cholecystectomy, 8 mm or more (EASL), greater than 6 mm in the older ESGAR 2017 guidance, and no malignant changes in polyps under 8 mm in one series.^[4][3]
• Where cirrhosis is also present, HCC surveillance is ultrasound every 6 months.^[1]

• Children. Autoimmune hepatitis overlap occurs in about one third of children with PSC, a much larger share than in adults (about 10 percent). Small-duct PSC and overlapping disease should be biopsied.^[1]
• Pregnancy. Pregnancy is not an indication to defer surveillance or delivery planning by obstetrics; decisions about cholangitis, strictures and endoscopy in pregnancy should be made jointly by hepatology, gastroenterology and obstetrics. The evidence base for PSC in pregnancy is limited and centres should follow local high-risk pregnancy pathways.
• Older adults. Age itself increases hepatobiliary and gallbladder cancer risk and osteoporosis risk; screening practices still apply, tailored to fitness.

When MRI, ERCP and transplantation are unavailable, a practical approach is:

• Use the cholestatic profile (ALP, GGT) plus clinical picture to suspect PSC; many patients can be diagnosed clinically with supportive imaging later.
• Ultrasound (widely available) still detects secondary causes and gallbladder disease and can screen for cholangiocarcinoma and gallbladder polyps; a focused right-upper-quadrant examination is cheap and valuable.^[3]
• Colonoscopy is essential at diagnosis even when scarce: prioritise this single examination to detect IBD and rule out cancer; repeat it in the highest-risk patients (documented IBD and dysplasia).^[3][1]
• Antibiotics for suspected cholangitis should be started promptly and directed against enteric organisms; oral regimens may be used for milder disease while arranging referral.
• Pruritus management (emollients, cholestyramine where available, rifampicin with hepatotoxicity monitoring) is low-cost and improves quality of life.^[3]
• Bones and vitamins: daily calcium and vitamin D for anyone with chronic cholestasis; bisphosphonates where DEXA is available and osteoporosis is confirmed.^[3]
• Refer early for any suspected cholangiocarcinoma or dominant stricture that needs therapeutic endoscopy; transplants are usually not available locally, and early referral matters.
• Send every excised gallbladder for histology where polyps or wall thickening are found.

Inflammatory bowel disease (above all ulcerative colitis), autoimmune hepatitis, IgG4-related disease, cholangiocarcinoma, gallbladder cancer, hepato-osteodystrophy, chronic cholestasis and jaundice, cirrhosis and portal hypertension, liver transplantation, acute cholangitis.