intrahepatic%20cholestasis
INTRAHEPATIC CHOLESTASIS
Cholestasis is bile formation &/or bile flow impairment that manifests as fatigue, pruritus and jaundice.
It can be classified into intrahepatic or extrahepatic cholestasis.
Extrahepatic cholestasis develops from mechanical blockage in the duct system or hepatocellular defects.
Intrahepatic cholestasis may be due to functional defects hepatocellularly or from obstructive lesions of the intrahepatic biliary tract distal from the bile canaliculi.

Pharmacotherapy

Ursodeoxycholic acid (UDCA)

  • A hydrophilic, dihydroxy bile acid
  • Recommended treatment for intrahepatic cholestasis of pregnancy
    • May improve pruritus & serum liver tests based on evidence obtained from randomized clinical trials
  • An effective treatment for primary sclerosing cholangitis
    • Study shows that it improves serum liver tests & surrogate markers of prognosis, but does not reveal a proven benefit on survival or a delay in the need for liver transplantation
    • Thought to exert its effects in cholestatic conditions via protection of cholangiocytes against cytotoxic hydrophobic bile acids, stimulation of hepatobiliary secretion, protection of hepatocytes against bile
      acid-induced apoptosis, & induction of antioxidants
    • Some guidelines do not recommend the use of UDCA in the treatment of PSC due to inadequate proven efficacy on results such as death or liver transplantation for low- or intermediate-dose UDCA & the worse outcomes described in a randomized controlled trial of high-dose UDCA
    • Although standard dose of UDCA has not been associated w/ adverse outcomes, UDCA cannot be recommended routinely until further data on efficacy & safety are available

Corticosteroids

  • Regarded as initial treatment of choice for immunoglobulin G4-associated cholangitis
    • Azathioprine at doses of up to 2 mg/kg/day should be considered in those w/ proximal & intrahepatic stenoses & those after relapse during/after corticosteroid therapy 
  • They have not demonstrated improvement in disease activity or outcome of PSC
  • Dexamethasone has been studied in small clinical trials for intrahepatic cholestasis of pregnancy but is not recommended due to adverse neurological effects in the fetus/neonate
    • Promotes fetal lung maturity, but is ineffective in reducing pruritus & ALT levels in patients w/ ICP

Immunosuppressants

  • Immunosuppressive treatment has been shown to exert a marked effect on inflammatory activity of IAC, & complete long-term remission after 3 months of treatment has been reported
    • However, the extent of disease may affect the long-term response, & a retrospective analysis showed that patients w/ alterations of proximal extrahepatic & intrahepatic bile ducts are prone to a higher risk of relapse after stopping of treatment than patients w/ distal bile duct strictures only

Bile Acids Sequestrants

  • Eg, Cholestyramine, antihistamines & opioid antagonists have been used to alleviate the pruritus in ICP
  • Cholestyramine is an exchange resin that binds bile acids & other anions in the intestine & increases their fecal excretion
    • It does not improve biochemical parameters or fetal outcomes in ICP

Other Drugs

  • Eg, Ademetionine, Phospholipid, Silymarin
  • Ademetionine is a naturally occurring molecule found in virtually all body tissues & fluids that was found in some studies to have caused clinical improvement in patients w/ intrahepatic cholestasis including that associated w/ pregnancy
  • Phospholipids are naturally occurring lipids that some studies show have therapeutic effect for hepatic disorders although more controlled clinical trials are required to determine its benefits
  • Silymarin is a fruit extract from the plant milk thistle that is claimed to be a free radical scavenger & to have hepatoprotectant properties; it has been used in various liver disorders

Non-Pharmacological Therapy

Primary Sclerosing Chlolangitis (PSC)

  • Biliary dilatation is the recommended treatment in patients w/ PSC that has dominant bile duct strictures w/ significant cholestasis
    • If there are unsatisfactory stricture dilatation & biliary drainage, biliary stent insertion should be done
  • Liver transplantation is recommended in patients w/ late-stage PSC & may be considered in patients w/ evidence of cholangiocyte dysplasia or severe recurrent bacterial cholangitis

Intrahepatic Cholestatis of Pregnancy (ICP)

  • There is no strong evidence that early delivery (at 27 weeks gestation) for pregnant women w/ high levels of bile acids can treat ICP
    • Although this strategy is still used in some practices

Drug-induced Cholestatic Liver Disease (DILI)

  • Withdrawal of the drug is the only effective treatment of drug-induced cholestasis
  • Prevention & early detection of abnormal serum liver tests, together w/ prompt withdrawal of the suspected drug, are crucial to avoid serious liver injury
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