Primary sclerosing cholangitis

Definitions & Key takeaways

Primary sclerosing cholangitis (PSC) is a disease of the bile ducts that causes inflammation and obliterative fibrosis of bile ducts inside and/or outside of the liver. This results in scarring of the biliary tree, which impedes the flow of bile to the intestines and can ultimately lead to cirrhosis of the liver, liver failure, and liver cancer. Symptoms of PSC can include fatigue, itching, jaundice, abdominal pain, and weight loss. If left untreated, PSC can lead to liver failure. Definitive treatment is liver transplant, but ursodeoxycholic acid (UDCA help to slow disease progression and alleviate symptoms.

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Introduction0:00–1:09

. With primary sclerosing cholangitis or PSC, cholangitis refers to the inflammation of the bile ducts.
Sclerosing refers to scarring that hardens the duct, while primary indicates that this inflammation occurs on its own, not as a complication of another condition.
So in PSC chronic inflammation of the bile ducts triggers progressive fibrosis that makes the bile ducts stiffer and narrower, which can eventually block the normal flow of bile.
But before we proceed, first let's focus on the bile ducts. Everything starts with hepatocytes, which carefully mix several ingredients to create bile.
These include bile salts, phospholipids, cholesterol, and conjugated bilirubin. Once they produce bile, hepatocytes drain it into tiny intrahepatic channels called bile canaliculi.
These canaliculi merge to form progressively larger hepatic bile ducts, which combine to create the right and left hepatic ducts.
Eventually, these two join to create the common hepatic duct, marking the beginning of the extrahepatic biliary system. The common hepatic duct then meets the cystic duct from the gallbladder to form the common bile duct, which empties into the duodenum.

Causes and pathology1:09–3:23

But what hepatocytes produce is not the final product that reaches the intestine. That's because intrahepatic and extrahepatic bile ducts are lined with cholangiocytes that fine tune the composition of bile as it flows toward the intestine.
The ultimate bile product in the intestine helps digest fats and absorb fat soluble vitamins A, D, E, and K. However, in PSC something goes wrong and the biliary system comes under attack.
The exact cause remains unknown, but it seems to occur when genetic and environmental factors spark a misfiring immune response that damages the intrahepatic and extrahepatic bile ducts.
First, let's focus on genetic factors. PSC tends to run in families and predominantly affects biological males.
If a person has PSC their first degree relative carries a higher risk. Some of these individuals carry specific HLA molecules like HLAB8, which shape how immune cells present antigens.
HLAB8 increases the risk that the immune system will mistake normal cholangiocyte proteins for foreign ones. Think of it like the immune system is misreading a self ID badge as if it belongs to an intruder.
This process is called molecular mimicry. Because of this misidentification, T cells begin attacking cholangiocytes, kicking off the inflammatory response.
Another important genetic link is ulcerative colitis, which appears in about 70% of cases. In ulcerative colitis, the immune system overreacts to bacteria in the colon, causing mucosal inflammation and making the intestinal barrier leaky.
This allows bacterial fragments and antigens to slip into the bloodstream and reach the liver. The extra exposure to foreign substances increases the risk that T cells will misidentify cholangiocytes as targets.

Symptoms3:23–3:52

Additionally, activated T cells can slip into the bloodstream and travel from the intestines to the liver, spreading inflammation to the bile ducts.
Then there are environmental factors such as infections or changes in the intestinal bacteria. These factors can activate cholangiocytes to sound the alarm and trigger inflammation.
Normally this is protective, but when things go too far, the inflammation ends up harming the bile ducts instead of protecting them.

Diagnosis3:52–5:28

Now, depending on which bile ducts are affected, PSC comes in two main forms. Large duct PSC, also called classic PSC, is the more common type.
In this case, the immune system targets extrahepatic and large intrahepatic bile ducts. Sending immune cells to infiltrate their walls.
The pattern of injury is actually similar to what we see in ulcerative colitis. In other words, there is inflammation and injury of the bile duct epithelium in combination with neutrophilic infiltration.
Over time, in extrahepatic bile ducts, inflammation gradually progresses to fibrosis and eventually sclerosis. The ducts start narrowing in some areas and widening in others, creating the classic pattern of strictures and dilations.
These changes slow the flow of bile, setting the stage for bile stasis and stone formation. Meanwhile, in the large intrahepatic bile ducts, ongoing inflammation triggers fibrosis that forms the onion skin fibrosis.
Layers of fibrous tissue wrap concentrically around the duct just like the layers of an onion. But here's the twist.
The immune system typically spares small intrahepatic ducts. However, as the larger ducts become blocked, bile has nowhere to go and starts backing up in the liver.
This backup stretches the tiny intrahepatic ducts, causing them to proliferate in an attempt to find new drainage routes.

Complications5:28–6:14

This attempt to reroute bile drainage is called a ductular reaction. But things don't stop there.
As bile backs up in these tiny intrahepatic ducts, it starts damaging hepatocytes. As hepatocytes die, the liver tries to repair itself by laying down collagen, which leads to progressive paraportal fibrosis.
Over time, this fibrosis spreads outwards, creating bridging fibrosis that links adjacent portal tracts. And if left untreated, fibrosis progresses to biliary cirrhosis.
Additionally, chronic inflammation of cholangiocytes can progress to pre-cancerous lesions called biliary intraepithelial neoplasia, which can eventually turn into cholangiocarcinoma.

Treatment6:14–10:11

On the other hand, small duct PSC is rare. In this case, the immune system primarily attacks small and medium intrahepatic bile ducts.
Affected ducts develop onion skin fibrosis, eventually obliterating the lumen and leaving a tombstone scar. Like large duct PSC, bile accumulation damages hepatocytes, triggering fibrosis that can progress to cirrhosis over time.
PSE typically affects biological males between the ages of 30 and 40. The early symptoms tend to be non-specific symptoms, including right upper quadrant abdominal pain and fatigue.
Since the liver cannot drain properly, the bile backs up, enabling bilirubin to enter the bloodstream. Once bilirubin levels rise enough, the skin and eyes turn yellow, which is known as jaundice.
In PSC, jaundice is intermittent because bile flow can fluctuate depending on the severity of strictures. In addition, bile salts from the bloodstream accumulate in the skin, causing pruritis.
On top of that, less bile reaching the intestines results in malabsorption of fat and fat soluble vitamins, fatty stools, and weight loss.
Finally, as cirrhosis develops, you will notice signs of portal hypertension, including splenomegaly and ascites. Beyond the liver, PSC often comes with other autoimmune conditions, such as autoimmune pancreatitis and IgG-4 related fibrosing disease.
Often, PSE is diagnosed incidentally, especially in individuals with ulcerative colitis. Labs typically reveal elevated alkaline phosphatase and GGT levels, suggesting biliary damage.
Bilirubin can be normal or elevated depending on whether the bioflow is blocked at that time. Next comes immunology testing.
The hallmark of PSC is the presence of pernuclear ineutrophil cytoplasmic antibodies. However, this finding is not diagnostic for PSC because these antibodies are also found in other autoimmune conditions.
On top of that, serum anti-nuclear and anti-smooth muscle antibodies could also be present. Definitive diagnosis relies on magnetic resonance cholangiopancreatography, which helps visualize the bile ducts.
In large duct PSC, the imaging reveals the beating pattern of alternating strictures and dilations along the biliary tree.
If imaging findings look normal, which happens in small duct PSC, the definitive diagnosis comes from a liver biopsy. Unfortunately, there is no cure for PSC.
Treatment focuses on relieving symptoms and managing complications. If someone develops severe strictures or blockages in the extrahepatic bile ducts, endoscopic balloon dilation can open the ducts and restore bile flow.
In advanced stages, when cirrhosis develops, the definitive treatment is liver transplantation. All right, as a quick recap, PSC is a chronic condition characterized by inflammation and fibrosis of intrahepatic and extrahepatic bile ducts.
It typically affects biological males between the ages of 30 and 40. In large duct PSC, the inflammation of large extrahepatic ducts progresses to fibrosis, which leads to strictures and dilation, while in the medium sized bile ducts, fibrosis creates the classic onion skin fibrosis.
Finally, in small duct PSC the immune system attacks smaller intrahepatic ones, creating characteristic onion skin fibrosis and obliterating the lumen, leaving a tombstone