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Hepatologist and Liver Transplant | Dr Manas Vaishnav

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Primary Sclerosing Cholangitis (PSC)

Primary sclerosing cholangitis is a chronic disease that affects the bile ducts – the tubes that carry bile from the liver to the gallbladder and intestines. In PSC, for reasons not entirely understood, the bile ducts become inflamed, scarred, and narrowed (a process called “sclerosis”). This impedes the flow of bile, causing bile to back up and damage the liver over time. PSC is an uncommon condition, and it most often affects men in their 20s to 40s, though women can have it too. A distinctive feature is its strong association with inflammatory bowel disease (about 70% of PSC patients have ulcerative colitis or Crohn’s colitis). PSC is a serious condition: it can lead to cirrhosis, liver failure, and is a risk factor for bile duct and gallbladder cancer. Currently, there is no cure except liver transplant.

(For simplicity, we will use MASLD to refer to this condition, in line with the newer terminology, but many doctors and patients may still know it as NAFLD.)

Symptoms

In the early stages, up to half of people with PSC have no symptoms at diagnosis; the disease might be found via abnormal liver tests on routine bloodwork my.clevelandclinic.org . When symptoms do occur, they can include:

  • Fatigue: A general feeling of tiredness is common, even in early PSC.
  • Pruritus (itching): A hallmark symptom. Severe itching of the skin may occur, sometimes even before other symptoms. It is caused by bile acids building up in the bloodstream due to impaired bile flow. The itching can be debilitating and often worse at night.
  • Right upper quadrant pain: A dull discomfort under the right ribs (liver area). Not everyone experiences this.
  • Intermittent fevers or chills: Episodes of cholangitis (bacterial infection of bile ducts) can occur due to bile stasis. These may cause fever, chills, night sweats, and abdominal pain.
  • Jaundice: As PSC progresses and bile ducts narrow further, jaundice (yellowing of eyes/skin) may appear. Early on it may come and go during cholangitis episodes, but later it can be persistent. Dark urine and pale stools often accompany jaundice.
  • Enlarged liver and spleen: The liver may enlarge from inflammation, and later the spleen can also enlarge due to portal hypertension from cirrhosis. This may cause a feeling of fullness in the left upper abdomen.

As the disease advances to cirrhosis, symptoms of liver failure can appear: ascites (fluid in belly), variceal bleeding, etc. But those are late signs.

Additionally, because of the link with ulcerative colitis, some patients will have bowel symptoms (diarrhea, blood in stool) if their colitis is active. Sometimes PSC is discovered when evaluating abnormal liver tests in a known IBD patient, or vice versa.

Causes

The exact cause of PSC remains unknown. It is believed to be an immune-mediated disease (possibly autoimmune in nature), but unlike autoimmune hepatitis, there aren’t typically the same autoantibodies, and immunosuppressive medications have limited effect on PSC. Some factors involved:

  • Immune dysregulation: PSC is often considered an autoimmune-like disease because it commonly coexists with other autoimmune conditions (especially ulcerative colitis). The immune system may mistakenly attack bile duct cells. Many PSC patients also share specific genetic backgrounds (certain HLA types) that predispose them.
  • Genetics: There is likely a genetic predisposition. While PSC is not directly inherited, having a family member with PSC modestly increases risk. Certain immune-related genes occur more frequently in PSC patients.
  • Gut microbiome & “leaky gut” hypothesis: Because PSC is strongly linked with colitis, one theory is that bacterial products or toxins from the inflamed colon enter the portal circulation to the liver and trigger bile duct inflammation. The gut–liver axis and microbiome remain key areas of research.
  • Environment: No single environmental trigger has been confirmed. Infections or toxin exposures have been proposed, but evidence remains inconclusive.
  • No alcohol/drug cause: PSC is unrelated to alcohol use, viral hepatitis, or other common external liver toxins. It is a distinct disease entity.

In summary, PSC likely results from a combination of genetic susceptibility, an aberrant immune response, and possibly environmental triggers (including gut bacteria factors). The immune attack causes chronic inflammation in bile ducts. Over years, this leads to scarring (fibrosis) and strictures in both the intrahepatic and extrahepatic bile ducts.

One notable complication cause: since bile ducts are scarred, bile can get infected (ascending cholangitis) when bacteria from the intestine seed the static bile. So recurrent infections can be both a symptom and a complication, which in turn can worsen scarring.

Diagnosis

PSC is usually diagnosed through a combination of lab tests and imaging:

  • Liver blood tests: PSC typically shows a cholestatic pattern with elevated alkaline phosphatase (ALP) and gamma-GT, often very high, reflecting bile duct injury. ALT and AST may be mildly elevated but not as high as in autoimmune hepatitis. Bilirubin is usually normal early, but rises as disease progresses or during cholangitis episodes.
  • Cholangiography (bile duct imaging): The key test for diagnosis.
    • MRCP (Magnetic Resonance Cholangiopancreatography): The modern first choice, non-invasive, shows the classic “beading” appearance (multiple strictures and dilatations in intra- and extrahepatic ducts).
    • ERCP (Endoscopic Retrograde Cholangiopancreatography): Used historically, still done if intervention is needed, but less common for initial diagnosis.
    • Small-duct PSC: If imaging is normal but suspicion remains, a biopsy may be needed.
  • Autoimmune markers: No specific antibody exists for PSC.
    • p-ANCA may be positive (also common in ulcerative colitis).
    • ANA and SMA can be weakly positive but are not diagnostic.
  • Liver biopsy: Not always required if imaging is diagnostic. Helpful in cases of:
    • Small-duct PSC suspicion.
    • Staging fibrosis.
    • Checking for AIH-PSC overlap (important because immunosuppressants may help if AIH features exist).
    Classic finding: “onion-skin” fibrosis around bile ducts.
  • Exclude similar diseases: Important to rule out:
    • Primary biliary cholangitis (PBC) – affects only small ducts, AMA antibody positive.
    • Secondary causes – bile duct stones, surgical injury, or cholangiocarcinoma strictures.
    The diffuse “beading” in a young patient with IBD is very characteristic of PSC.

Importantly, whenever PSC is diagnosed, patients undergo colonoscopy if they haven’t already, because of the strong association with ulcerative colitis (and even if no bowel symptoms, about 1 in 3 PSC patients have asymptomatic colitis). And conversely, known ulcerative colitis patients with abnormal liver tests often get checked for PSC.

Treatment

Unfortunately, there is no medicine proven to stop or reverse PSC or the scarring in the bile ducts. Several treatments are used to manage symptoms and complications:

  • Ursodeoxycholic Acid (UDCA):
    • Effective in PBC, tested in PSC with mixed results.
    • Improves liver blood tests and symptoms in some patients.
    • Does not clearly prolong transplant-free survival in PSC.
    • High doses were linked to adverse outcomes.
    • Some doctors use moderate doses (13–15 mg/kg) to improve labs, but it is optional and not a cure.
  • Symptomatic treatments:
    • For itching (pruritus): First-line is cholestyramine. If inadequate: rifampin, naltrexone, or antihistamines.
    • For cholangitis episodes: Treated with antibiotics (e.g., ciprofloxacin). Some patients use rotating or chronic antibiotics for recurrent flares. Prophylactic antibiotics are given before ERCP procedures.
    • Vitamins: Monitor and supplement fat-soluble vitamins (A, D, E, K). Vitamin D and calcium are important for bone health (due to cholestasis and IBD medications).
  • Endoscopic interventions:
    • ERCP can dilate tight dominant strictures and sometimes place temporary stents.
    • This relieves jaundice or recurrent cholangitis, though it doesn’t cure PSC.
    • Dominant strictures are biopsied or brushed during ERCP to exclude cholangiocarcinoma.
  • Liver transplant:
    • The only curative treatment for PSC.
    • Indicated in cirrhosis with liver failure, severe symptoms, or complications.
    • 5-year post-transplant survival is high (~85%+ at experienced centers).
    • PSC can recur in 20–25% of cases, usually milder and not early.
  • Colon cancer surveillance: PSC patients with ulcerative colitis have higher colon cancer risk.
    • Annual or every-other-year colonoscopies with biopsies are recommended, even if colitis is in remission.
  • Experimental approaches:
    • Drugs in trials: nor-UDCA, obeticholic acid, fibrates, antifibrotics, immunosuppressants, and antibiotics (e.g., vancomycin in pediatric PSC).
    • Classic immunosuppressants (like prednisone) are ineffective unless AIH overlap exists.
    • Oral vancomycin shows anecdotal success in pediatric PSC/IBD, possibly via microbiome effects, but is not standard for adults.

FAQs

Unfortunately, no cure exists aside from liver transplant. PSC is a stubborn disease where, so far, no drug has been proven to halt its progression. Ursodeoxycholic acid (a bile acid pill) is used by some doctors to improve liver tests, but it doesn’t clearly change the long-term outcome in a major way. Various other medications (steroids, immunosuppressants) generally have not shown benefit for classic PSC. Researchers are actively trying to find a medical therapy – there are many clinical trials in progress. So, at present, management focuses on dealing with symptoms (itching, infections) and complications, and then transplant when necessary. Liver transplant is highly effective – it can “cure” PSC in that the new liver will have normal bile ducts. However, PSC can sometimes recur in the transplanted liver years later, but not always and usually not immediately.

There’s a strong link. About 70% of people with PSC also have ulcerative colitis (UC) or sometimes Crohn’s colitismy.clevelandclinic.org. Conversely, about 3-7% of people with UC might develop PSC. They seem to be related autoimmune processes. Interestingly, treating the colitis (even removing the colon by surgery) does not cure PSC – the liver disease can progress independently. But having both conditions affects management: PSC patients with IBD need more frequent colonoscopies because they have a higher risk of colon cancer than IBD patients without PSC. Also, if an IBD patient shows unusual liver enzyme elevations, doctors will consider PSC. The reason for the association isn’t fully understood – possibly genetic factors or immune responses in the gut triggering liver inflammation. But in practical terms: if you have PSC, you’ll likely undergo colonoscopy to check for colitis, even if you have no bowel symptoms. If you have UC and abnormal liver tests, your doctor will check for PSC.

 PSC progression can vary widely. Some people have a very slow course over many years with minimal symptoms (especially those diagnosed young and asymptomatic initially), while others progress faster. On average, from diagnosis to advanced liver disease might be on the order of 10-15 years, but that’s very variable. There’s a scoring system (Mayo PSC risk score) that helps estimate prognosis based on age, bilirubin, etc. Many patients will eventually require a liver transplant, but some mild cases might never reach that point or only after several decades. It’s important to have regular follow-ups and monitoring. Also, complications like cholangiocarcinoma (bile duct cancer) can sometimes occur even before end-stage liver failure – about 10-15% of PSC patients might develop cholangiocarcinoma in their lifetime. So, progression isn’t always a straight line to cirrhosis; there are specific risks along the way. In short: PSC is generally slowly progressive, but unpredictable. Staying in touch with a hepatologist to monitor labs and imaging periodically is key. If things worsen (e.g., rising bilirubin, frequent cholangitis, etc.), then it’s time to consider transplant evaluation.

The itching (pruritus) in PSC is due to the build-up of bile acids and other substances that would normally be excreted, but aren’t flowing well because of bile duct blockagesmy.clevelandclinic.org. These substances deposit in the skin or affect nerves, causing intense itch. It can be one of the most distressing symptoms, sometimes even leading to sleep loss and reduced quality of life. To manage it:
– Cholestyramine (Questran) is often the first option. It’s a powder you drink that binds bile acids in your gut so they don’t get reabsorbed. It can help a lot, though some find it inconvenient or don’t like the taste. Take it spaced from other meds because it can bind them too.
– Rifampin: This antibiotic, oddly enough, can reduce itching by an unclear mechanism (perhaps by inducing liver enzymes that process pruritogens). Even low doses can help if cholestyramine isn’t enough.
– Antihistamines: They might take a little edge off, especially at night to help sleep (e.g., hydroxyzine or diphenhydramine). They don’t fix the cause, but sedation can help with nighttime relief.
– Naltrexone: An opioid blocker – it can be effective in some patients with cholestatic itch, though mechanism is complex (itch in cholestasis might involve opioid receptors). If cholestyramine and rifampin fail, some doctors try naltrexone.
– UV light (phototherapy): In resistant cases, controlled exposure to UVB light (like a tanning light) can relieve itch.
– Plasmapheresis: In extreme refractory cases, filtering the blood can remove itch-inducing substances temporarily.
– Ultimately, relief often comes after transplant because the new liver’s working bile ducts clear the bile properly. Many PSC patients say one of the best parts post-transplant was “the itch is gone.”
In summary, don’t suffer in silence – let your doctor know how bad the itch is. It’s a known PSC symptom and there’s a stepwise approach to treat it.

Not always, but PSC does carry an elevated risk of certain cancers. The most notorious is cholangiocarcinoma, which is cancer of the bile ducts. About 5-15% of PSC patients might develop cholangiocarcinoma over their lifetime, often within the first few years of PSC diagnosis (though it can happen later too). Signs might be sudden worsening of cholestatic labs or a stricture that looks suspicious on imaging. That’s why any “dominant stricture” found on ERCP is usually brushed for cytology to check for cancer cells. The risk of gallbladder cancer is also higher, so PSC patients who develop even small polyps in the gallbladder might be recommended to have the gallbladder removed prophylactically. And as mentioned, colon cancer risk is higher in those PSC patients who have ulcerative colitis, hence annual colonoscopies. Liver cancer (hepatocellular carcinoma) can occur once cirrhosis is present (as with any cirrhosis, risk is elevated), but cholangiocarcinoma is the hallmark PSC-associated malignancy. So while cancer is not inevitable, PSC patients are closely surveilled for it. Many will never get cancer, especially if they undergo transplant before that can happen. Adhering to surveillance recommendations (like regular imaging, tumor marker checks, colonoscopies) improves the chances of catching any malignancy early.