Recent updates on progressive familial intrahepatic cholestasis types 1, 2 and 3: Outcome and therapeutic strategies

Table 2 Drugs used for control of pruritus in progressive familial intrahepatic cholestasis: Mechanism of action, dose, adverse effects

Drug	Mechanism of action	Dose	Adverse effects
Ursodeoxycholic acid	Protection of cholangiocytes from the hydrophobic bile acids; Choleretic action through both bile acid dependent (cholehepatic shunt) and independent pathway; Protection of hepatocytes from bile acid induced apoptosis; Direct membrane stabilizing effect in cholangiocytes; Up-regulate synthesis, apical insertion & activation of BSEP & Mrp2 via Ca2+ and PKC-dependent mechanisms or via activation of p38 MAPK and Erk-1/2–dependent mechanisms in animal models	10-30 mg/kg/d	Adverse effects rare: Severe vomiting or diarrhoea
Rifampicin	Activates pregnane X receptor leading to decrease in autotoxin level thus leading to decrease in lysophosphatidic acid synthesis and down-regulation of TRP vanilloid 1; Upregulates multidrug-resistance protein 2; Activates enzymes UDP-glucuronosyltransferase-1A and cytochrome P450-3A4 and stimulates 6α-hydroxylation of bile acids, promoting urinary excretion of dihydroxy and monohydroxy bile acids	5-10 mg/kg/d	Adverse effects rare: Hepatotoxicity, vomiting
Bile acid sequestrants: Cholestyramine, colestipol, colesevelam	Non-absorbable anion exchange resins that bind bile acids, cholesterols and other compounds in the intestinal lumen and prevent their enterohepatic circulation	240-500 mg/kg/d; Usually administered mixed with juice	Palatability, steatorrhoea, constipation, intestinal obstruction from inspissations, hyperchloremic metabolic acidosis; Growth failure; Decreased absorption of other drugs (e.g., UDCA) if not spaced; Need to be spaced from food
Opioid antagonists: Naltrexone	Reduces central opioidergic tone, believed to be raised in patients with cholestatic pruritus; Decreasing plasma levels of endogenous opioids like enkephalins	Gradually increment starting at 12.5 mg/d increasing every 3-7 d till pruritus reduces	Opioid withdrawal-like symptoms including abdominal pain, tachycardia and hypertension
Selective serotonin reuptake inhibitors: Sertraline	Exact mechanism of action not elucidated; Mediates its effect through serotonergic signals in the central nervous system that provide inhibitory signals to the itch pathways; Neuropharmacologic inhibition of stress	Adults: 75-100 mg/d; Children: 2.2 mg/kg/d	Adverse effects: Allergic reaction, behavioural issues, diarrhoea, insomnia, dizziness, high first pass metabolism-risk of hepatotoxicity

BSEP: Bile salt export pump; PKC: Protein kinase C; MAPK: Mitogen-activated protein kinase; TRP: Transient receptor potential; UDP: Uridine diphosphate; UDCA: Ursodeoxycholic acid.