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

Table 1 Genotype, phenotype and histopathological differentiation of the various types of progressive familial intrahepatic cholestasis

	PFIC1	PFIC2	PFIC 3
Locus/gene/protein	18q21-22/ATP8B1/FIC1	2q24/ABCB11/BSEP	7q21/ABCB4/MDR3
Known mutations (n)1	50	200	300
Clinical profile
Onset	Early onset	Early onset	Second decade
Age of presentation pruritus	60% by 3 mo	72% by 3 mo	2-3 yr
Jaundice	Severe	Severe	Mild to none
Cirrhosis	Severe; By end of first decade	Severe; Majority within first 2 yr of life	Mild to moderate; By end of first decade
Growth failure	Present 90%	Present 59%
Others	Diarrhea 61%; Pneumonia 13%; Pancreatitis 12%; Deafness 31%	Gall stones in 32%	Delayed puberty
Progression	Moderate rate of progression	Rapidly progressive	Highly variable rate of progression
Associations with other cholestatic presentations	BRIC; ICP	BRIC, DIC; ICP, HCC	DIC, LPAC; ICP
Laboratory profile
TBA	High	Very high	High
GGT	Low to normal	Low to normal	High
AST/ALT	Mild elevation	Moderate elevation	Mild elevation
AFP	Normal	High	Normal
Histopathology	As disease progresses, periportal & pericentrilobular fibrosis develops; Leads to bridging fibrosis and micronodular cirrhosis	Canalicular cholestasis, lobular/portal fibrosis and inflammation with giant cells; Severe hepatocellular necrosis	Portal inflammation, portal fibrosis, cholestasis, ductular proliferation
Immunohistochemistry	Canalicular BSEP is normal or faint and MDR3 is normal bland intralobular cholestasis	BSEP expression decreased to absent in the canalicular membrane	MDR3 decreased to absent in the canalicular membrane

¹Medline genetics. BRIC: Benign recurrent intrahepatic cholestasis; BSEP: Bile salt exporter pump; ICP: Intrahepatic cholestasis of pregnancy; HCC: Hepatocellular carcinoma; DIC: Drug induced cholestasis; FIC1: Familial Intrahepatic Cholesatsis-1; LPAC: Low-phospholipid-associated cholelithiasis; MDR3: Multidrug resistant protein-3; PFIC: Progressive familial intrahepatic cholestasis; ABCB: ATP-binding cassette subfamily B.

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.

Table 3 Recent studies describing outcome and complications with biliary diversion surgeries in progressive familial intrahepatic cholestasis

Study	Type of biliary diversion	No of patients	Median follow up	Outcome	Adverse events
Yang et al[54] (2009)	PEBD	14 (11-PFIC)	3.1 yr (2-5.7)	Resolution of pruritus: 50%; Decrease in pruritus: 21%; Decrease in serum bile acids; Improvement in growth; Improved quality of life; No response in 2 patients with advanced fibrosis; 21.4% were listed for LT at mean follow-up 3.2 yr (all had advanced fibrosis pre-PEBD)	3 developed stoma prolapse; Post-op bleed and wound dehiscence in 1 each
Schukfeh et al[55] (2012)	PEBD	24	9.8 yr (1.6-14.3)	Resolution of pruritus with normalization of bile acids in 54%; 37.5% received LT at mean 1.9 yr; All of them had failed PEBD & 78% of them had cirrhosis pre-PEBD	Stomal prolapse in 2; Cholangitis, dyselectrolytemia, GI bleed and intestinal obstruction in 1 each
Wang et al[50] (2017)	PEBD; IE; PIBD	39; 11; 7; (38 PFIC & 20 alagillesyndrome)	24 mopostsurgery	Decrease in severe pruritus-54% in PFIC1 and 30% in PFIC2; Trend towards decreased pruritus after IE and PIBD; PEBD but not IE led to decrease in bilirubin and ALT in PFIC1; 23.7% of PFIC underwent LT post diversion	PEBD: Dehydration/dyselectrolytemia in 4; Stoma prolapse in 3; Intestinal ischemia & bowel obstruction in 1 each; IE; Dyselectrolytemia-2; PIBD: Dyselectrolytemia in 2, intestinal ischemia & intussusception-1 each
Cielecka-Kuszyk et al[47] (2019)	PEBD	4 (all PFIC2)	> 10 yr	Resolved cholestasis in 3; Reversal of fibrosis in 2
Bull et al[48](2018)	PEBD; IE	57; 6		Sustained improvement in pruritus: PFIC1-57%; PFIC2 (D482G/E297G mutations)-76%; PFIC2 other mutations-33%; Improvement in bilirubin and bile acids; Improvement in growth; 27% of PFIC1 & 31% of PFIC2 were listed or received LT (less often in D482G/E297G)	Dehydration/dyselectrolytemia due to high stoma output seen in 6 patients (1 died); Cholangitis in 3; Bile stagnation in 2; Stoma bleed in 1
Van Wessel et al[20] (2020)	PEBD; IE; PIBD	47; 13; 1; (all PFIC2)	8.4 yr (1.6-12)	Relief in pruritus – sustained: 54%; Transient: 17%; None: 29%; Relief in pruritus more common in BSEP1 mutations (66%) vs BSEP2 (36%) & BSEP3 (0%); Decrease in serum bile acids, bilirubin, AST & ALT; A 75% reduction in bile acids or decrease to a level < 102 µmol/L post diversion predicts long term NLS of > 15 yr; Biliary diversion associated with higher NLS: HR 0.51; 95%CI: 0.29-0.91, P = 0.02
Bjørnland et al[49] (2021)	PEBD	33; (25 PFIC)	10 yr (0.6-25.2)	Decrease in bile acids 1 wk post-op predictive of successful drainage; 39% received LT or were listed LT at a median follow up of 10 yr	42% early post op complications; Long term stoma related complications in 55%-20% secondary surgeries
Van Vaisberg et al[51] (2020)	IE	11	5 yr	Significant relief in pruritus: 8 (72.7%); 2/11 (18.2%) progressed to ESLD within a year and were listed for LT	Intussusception in 1; No diarrhoea
Foroutan et al[53] (2020)	PIBD	44	54 mo (10-105)	Significant decrease in jaundice and pruritus	Ascending cholangitis in 19.2%; No difference in cholangitis between standard procedure and PIBD with anti-reflux valve
Chen et al[52](2018)	PIBD	34; (PFIC1-10, PFIC2-14, PFIC3-5)	-	Decreased bilirubin and bile acids; Improved growth; 2 (5.9%) underwent LT at 20 & 39 mo post PIBD	Dyselectrolytemia/dehydration in 2; Relapse of symptoms in 4
Agarwal et al[38] (2016)	PIBD; PEBD	3; 1	2 yr (1-2)	PIBD: Decrease in pruritus score, improved growth & decreased serum bile acids; PEBD: Failed; One with failed PEBD needed LT in 7 yr; Rest all survived with native liver at mean follow up 8 yr	No complications with PIBD
Bull et al[48](2018)	PEBD; IE	57; 6		Sustained improvement in pruritus: PFIC1-57%; PFIC2 (D482G/E297G mutations)-76%; PFIC2 other mutations-33%; Improvement in bilirubin and bile acids; Improvement in growth; 27% of PFIC1 & 31% of PFIC2 were listed or received LT (less often in D482G/E297G)	Dehydration/dyselectrolytemia due to high stoma output seen in 6 patients (1 died); Cholangitis in 3; Bile stagnation in 2; Stoma bleed in 1

PEBD: Partial external biliary diversion; PIBD: Partial internal biliary diversion; PFIC: Progressive Familial Intrahepatic Cholestasis; IE: Ileal Exclusion; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; TBD: Total biliary diversion; LT: Liver transplantation; NLS: Native Liver Survival; BSEP: Bile salt exporter pump; ESLD: End stage liver disease.

Table 4 Potential novel therapeutic drugs for treatment of progressive familial intrahepatic cholestasis

Drug	Mechanism of action	Clinical trials and current status	Notes
Maralixibat/LUM001	Apical sodium-dependent bile acid transporter inhibitor	NCT04185363: Open label phase III trial; Recruiting patients; NCT03905330: MARCH-PFIC trial; Randomized controlled trial, recruiting patients; NCT04729751: RISE trial in infants; Open label phase II safety study; NCT04168385: Long term safety study; NCT02057718; Open label phase II trial; Completed	Orphan drug designation by FDA; Breakthrough therapy for PFIC2
Odevixibat/A4250	Selective inhibitor of ileal bile acid transporter	NCT03566238: PEDFIC 1 study; Phase III, open label, randomized controlled trial; Ongoing; NCT04483531: Expanded access study including patients not enrolled in PEDFIC 1 study	Orphan drug designation by FDA; Fast track designation for PFIC
4-PB/GPA	Prolongs degradation rate & increases cell surface expression of BSEP & functions as a chemical chaperone to correct the misfolded proteins	Leads to long term reduction in serum BA, improvement in liver biochemistry as well as relief of pruritus; Increased canalicular localization of E297G and D482G BSEP mutants; GPA more palatable, has lower sodium, doesn’t interact with rifampicin; Doses: 4-PB: 500 mg/kg/d; GPA: 8 g/m2/d	4-PB FDA approved for urea cycle defect
Ivacaftor	Rescues the function of missense mutations in the nucleotide binding domains of BSEP & MDR3	In vitro correction of binding domain missense mutation (T463I) of BSEP; Improved phospholipid secretion activity in mutant ABCB4	In vitro studies; Animal studies
Oxcarbazepine	Nerve stabilizing effect; Enzyme inducer – possible role in potentiating action of 4-PB	Single case report on its combined use with 4-PB and maralixibat
Gentamicin	Induce readthrough in nonsense mutation	In vitro increased readthrough in 6 common nonsense mutation of BSEP leading to increased canalicular expression of bile salt transporter
FXR agonist (Obeticholic acid)	Farsenoid X receptor agonist	No trials in PFIC; Safe and efficacious in treatment of PSC and non-alcoholic steatohepatitis	FDA approved for PSC
Nor-UDCA	Side-chain-shortened derivative of UDCA; Increases cholehepatic shunt	No trials in PFIC; NCT03872921: Ongoing phase III randomized controlled trial in PSC
Steroids	Possible upregulation of BSEP transporter? Up-regulation of sodium taurocholate copeptide transporterproviding increased gradient for BSEP	Only case reports and animal studies
NGM282	FGF19 analogue	NGM282 inhibited bile acid synthesis and decreased fibrosis markers, without change in alkaline phosphatise level
Bezafibrate	Peroxisome proliferator activated receptor agonist	Bezafibrate reduced pruritus and cholestasis in 2 out of 3 children with PFIC1 and improved lipid profile in all

PFIC: Progressive familial intrahepatic cholestasis; BSEP: Bile salt export pump; FGF: Fibroblast growth factor; NGM282: Codename of drug which is an engineered analogue of fibroblast growth factor - 19; UDCA: Ursodeoxycholic acid; PSC: Primary sclerosing cholangitis; FDA: Food and drug administration; PB: Phenyl-butyrate; MDR3: Multidrug-resistant type 3; ABCB: ATP-binding cassette subfamily B; GPA: Glycerol phenylbutyrate; BA: Bile acids.