Primary biliary cholangitis

Definitions & Key takeaways

Primary biliary cirrhosis (PBC), also referred to as primary biliary cholangitis, is a chronic autoimmune disease that affects the liver. It is characterized by the progressive destruction of the small bile ducts in the liver, which leads to inflammation, fibrosis, and ultimately cirrhosis (scarring) of the liver. Symptoms may not appear until the later stages of the disease but can include fatigue, itching, jaundice, and abdominal pain. Treatment involves drugs like ursodeoxycholic acid (UDCA) and cholestyramine, which slow the progression of the disease and improve symptoms. In advanced cases, liver transplantation may be necessary.

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Introduction0:00–0:55

. With primary biliary cholangitis or PBC, biliary refers to the bile ducts, cholangitis refers to the inflammation of these ducts, while primary indicates that this inflammation occurs on its own, not as a complication of another condition.
The condition was previously called primary biliary cirrhosis, however, the name was updated because cirrhosis is a late complication of the condition, and many individuals don't reach that stage thanks to early diagnosis and effective treatment.
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 components include bile salts, phospholipids, cholesterol, and conjugated bilirubin. Once they produce bile, hepatocytes drain it into tiny intrahepatic channels called bile canalliuli.

Causes0:55–1:21

These canaliculi merge to form progressively larger intrahepatic 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.

Pathology1:21–4:37

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 bileproduct in the intestine helps digest fats and absorb fat-soluble vitamins A, D, E, and K. However, in PBC 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 small and medium sized intrahepatic bile ducts.
First, let's focus on genetic factors. PBC tends to run in families and predominantly affects biological females.
If a person has PBC their first degree relative carries a higher risk. Some of these individuals carry specific HLA molecules like HLADR8, which shape how immune cells present antigens.
In this case, the combination of HLADR8 plus an environmental trigger can cause the immune system to mistake normal proteins on cholangiocytes for foreign ones.
This breakdown of the immune system's ability to recognize the body's own cells as self is called loss of immune tolerance.
Think of it like the immune system is misreading a self ID badge as if it belongs to an intruder. Once immune tolerance is lost, autoreactive T cells begin attacking cholangiocytes, kicking off the inflammatory response.
As cholangiocytes come under attack, many of them undergo apoptosis or programmed cell death. Normally the contents of dying cells are broken down quietly, so the immune system never sees them, but in PBC that cleanup process isn't complete.
One key mitochondrial enzyme, the E2 subunit of the pyruvate dehydrogenase complex, or PDCE2, is not broken down. Instead, it pops up on the surface of dying cholangiocytes.
Since immune cells have never seen the PDCE2 before, They mistake it for a foreign invader. In response, the immune system activates B cells to mature into plasma cells that produce anti-mitochondrial antibodies, or AMA for short.
These antibodies bind PDCE2 on cholangiocytes, further inducing inflammation. Together, infiltration of T cells into the walls of small and medium intrahepatic bile ducts, along with plasma cells, results in lymphoplasma cytic inflammation.

Symptoms4:37–5:35

As the inflammation intensifies, macrophages join the fight. Together with T cells, they can cause granulomatous destruction of bile ducts, known as florid duct lesion, which is a hallmark of PVC.
But here's the thing, inflammation doesn't affect every duct. Instead, it follows a patchy pattern, where one bile duct might be under attack, while another several millimeters away, looks perfectly fine.
Over time, some of these affected ducts are completely destroyed, which is known as ductopenia. With fewer ducts to drain bile, the bile 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.
This attempt to reroute bile drainage is called a ductular reaction. Meanwhile, hepatocytes can't get rid of their bile salts, which act like tiny detergents, damaging cell membranes and letting water in.

Diagnosis5:35–6:08

Ultimately this results in hepatocyte swelling and destruction of the internal components, creating a pale streaky appearance called feathery degeneration.
At this point, the liver can take one of two paths. The first is called nodular regenerative hyperplasia.
In this case, hepatocytes try to compensate for lost neighbors by dividing and forming small regenerative nodules. Here there is little to no scar tissue, just clusters of hepatocytes reshaping the liver's architecture, which can distort blood flow through the liver and eventually lead to portal hypertension.

Treatment6:08–6:33

The second path is more destructive and more common. In this case, as hepatocytes die, the liver tries to repair itself by laying down collagen, which leads to progressive perioral fibrosis.

Review6:33–10:54

Over time, this fibrosis spreads outwards, creating bridging fibrosis that links adjacent portal tracts, and if left untreated, fibrosis progresses to biliary cirrhosis.
PBC typically affects biological females between the ages of 40 and 60. The early symptoms tend to be non-specific.
One of the first signs are fatigue and itching or pruritus. Itching happens when bile salts enter the blood stream and build up in the skin.
As PBC progresses, more bile ducts are lost, so bile flow becomes obstructed, which allows bilirubin to build up in the blood.
Once bilirubin levels rise enough, the skin and eyes turn yellow, which is known as jaundice. And because bile normally helps eliminate cholesterol, reduced bile flow traps cholesterol in the bloodstream.
Over time, cholesterol can deposit in the skin, forming soft yellowish plaques around the eyes, known as xantholasma. On top of that, less bile reaching the intestines results in malabsorption of fat and fat-soluble vitamins, fatty stools, and weight loss.
Next, some individuals might report discomfort in the right upper abdomen, but fever is uncommon. That's because in PBC large extrahepatic bile ducts, which are usually involved in acute infections like cholangitis, remain unaffected.
Finally, as cirrhosis develops, you'll notice signs of portal hypertension, including splenomegaly and ascites. Beyond the liver, PBC often comes with other autoimmune conditions, such as Sjogren's syndrome, scleroderma, and thyroid conditions.
Diagnosis of PBC usually starts with lab tests, which typically reveal elevated alkaline phosphatase and GGT levels, suggesting biliary damage, along with mildly elevated AST and ALT levels indicating hepatocyte injury.
Early on, bilirubin levels can be normal because enough ducts remain open to drain bile, but as damage progresses and more ducts are lost, bilirubin levels begin to rise.
Next comes immunology testing. The hallmark of PBC is the presence of AMA.
Keep in mind that imaging like MRCP is usually normal because PVC affects small intrahepatic ducts, which are too tiny to visualize.
If the diagnosis remains unclear, proceed with a liver biopsy. Fortunately, PBC has effective treatments.
Ursodeoxycholic acid is a hydrophilic bile acid that enters the bile acid pool and pushes out the more toxic bile acids, protecting cholangiocytes from further damage.
If ursodeoxycholic acid is not enough, other options include fibrates like besafibrate, which help reduce cholestasis. In advanced stages when cirrhosis develops, the definitive treatment is liver transplantation.
All right, as a quick recap, PBC is an autoimmune condition in which the immune system attacks small and medium sized intrahepatic bile ducts.
It typically affects biological females between the ages of 40 and 60. Genetic predisposition triggers T cells and anti-mitochondrial antibodies to target cholangiocytes, causing inflammation and destruction.
Biopsy shows lymphoplasmacytic inflammation, florid duct lesions, and ductopenia, along with hallmarks of cholestatic injury such as ductular reaction and feathery degeneration of