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PH-GI33

Cholestasis

How hepatocytes make bile by pumping bile acids into the canaliculi, why drugs, sepsis, pregnancy, autoimmune duct disease or a blocked duct stop the flow, and how retained bile causes itch, jaundice and fat-soluble vitamin deficiency.

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  • 4 steps · 10 questions
  • 3D anatomy, affected parts marked

By the end, you can

  • Describe how hepatocytes form bile: bile acid uptake and export pumps, the canaliculi, the bile ducts and the enterohepatic circulation.
  • Distinguish intrahepatic from extrahepatic cholestasis, and explain how drugs, sepsis, pregnancy, primary biliary cholangitis and primary sclerosing cholangitis each impair bile flow.
  • Describe bile plugs, feathery degeneration, bile infarcts and the ductular reaction, and why each forms.
  • Relate itch, jaundice, pale stools, steatorrhoea, xanthomas and fat-soluble vitamin deficiency to what bile leaves behind and what fails to reach the gut.
  • Interpret the cholestatic blood test pattern and imaging, and explain how drainage, bile acid treatments, itch treatments and vitamin replacement act on the mechanism.

What it is

Cholestasis is reduced formation or flow of bile, so that substances normally excreted in bile, above all bile acids, conjugated bilirubin and cholesterol, build up in the liver and blood while too little bile reaches the gut. It is intrahepatic when the fault lies in the hepatocytes or the small ducts inside the liver, and extrahepatic when a large duct outside the liver is blocked. Jaundice is common but not essential: cholestasis can show first as itch and a raised alkaline phosphatase.

3 types to tell apart
Intrahepatic: hepatocellular (functional)
The hepatocyte’s export machinery fails while the ducts are intact: sepsis, many drugs, pregnancy, parenteral nutrition and inherited transporter defects.
Intrahepatic: ductular
Small bile ducts inside the liver are destroyed or narrowed: primary biliary cholangitis, small-duct primary sclerosing cholangitis, some drug reactions and graft-versus-host disease.
Extrahepatic (obstructive)
A large duct is blocked or narrowed: bile duct stones, cancer of the head of the pancreas or bile ducts, strictures, large-duct primary sclerosing cholangitis and, in infants, biliary atresia.

Normal function

Hepatocytes pump bile into the canaliculi

Bile is made by . Each has a side facing the , where it takes up bile acids returning from the gut through the transporters NTCP and OATPs, and a side facing a canaliculus, a tiny channel between neighbouring hepatocytes sealed by tight junctions (). ATP-driven pumps in the canalicular membrane push bile components out against a steep gradient: the bile salt export pump (BSEP) for bile acids, MRP2 for conjugated bilirubin and drug conjugates, and MDR3 for phospholipid. This export is the slowest, rate-limiting step of bile formation, and the bile acids draw water and electrolytes after them by osmosis.

Bile flows the opposite way to blood, from round the out to the , where it enters the . The cells lining the ducts (cholangiocytes) add water and bicarbonate, which dilutes the bile and coats their surface in an alkaline layer that protects them from bile acids. Bile then leaves through the hepatic ducts; its storage in the gallbladder is covered in the gallstones lesson.

In the gut, bile acids form micelles that carry fats and the fat-soluble vitamins A, D, E and K into the lining cells. The terminal ileum reabsorbs about nine tenths of the bile acids, which return to the liver in portal blood and are secreted again many times a day: the enterohepatic circulation. A nuclear receptor, FXR, senses bile acids in the hepatocyte and the ileum and holds back new bile acid synthesis from cholesterol when there is plenty.

Point to it on the model
How bile is made and deliveredSchematic
NormalSinusoidal bloodBile acids returning from the gut; bilirubin carried on albumin
  • Uptake: NTCP and OATPs (from Sinusoidal blood to Hepatocyte)
NormalHepatocyteConjugates bilirubin and drugs; makes new bile acids from cholesterol
  • Export pumps: BSEP, MRP2, MDR3 (rate-limiting) (from Hepatocyte to Canaliculus and bile ducts)
NormalCanaliculus and bile ductsBile acids draw water in; cholangiocytes add bicarbonate
  • Bile flows to the duodenum (from Canaliculus and bile ducts to Duodenum and ileum)
NormalDuodenum and ileumMicelles absorb fats and vitamins A, D, E and K

Schematic. About nine tenths of bile acids are reabsorbed in the terminal ileum and return in portal blood to be secreted again (the enterohepatic circulation).