Newer variants of progressive familial intrahepatic cholestasis

Table 1 Clinical characteristics and outcome in patients with TJP2 mutation

Ref.	n	Age at onset of symptoms	Symptoms	Other symptoms	Treatment	Liver transplant	Outcome
Sambrotta et al[5]	12	1 wk-3 mo	NC-12/12	Chronic respiratory disease-1, recurrent unexplained hematoma-1	UDCA, PEBD-2	9/12 cases at the age of 1.5-10 yr	Post-transplant-9 (doing well, no disease recurrence); Stable liver disease with PHT-2; Mortality-1 at 13 mo age
Zhang et al[22]	7 (M = 6, F = 1)	3 d-2 mo	NC-6/7, pruritus at 7 mo-1/7	Gallstones 2/7	Response to UDCA, cholestyramine	None	Resolved cholestasis (n = 6) over 7-26 mo; Persisting icterus-1
Ge et al[46]	1 (F)	6mo	Jaundice, pruritus, FTT	-	Responded to medical treatment	None	Resolved cholestasis
Mirza et al[47]	1 (M)	4 yr	Jaundice, pruritus	-	Medical treatment	None	Cirrhosis, PHT with variceal bleed at 15 yr
Wei et al[24]	Index case (M) with multiple affected family members1	19 yr	Cirrhosis, PHT with variceal bleed, HCC at 22 yr	-	Medical treatment including EVL	23 yr	Well in post-transplant period

¹Variable severity of liver disease: Cholestatic liver disease requiring transplant, cholestatic liver disease and intrahepatic cholestasis of pregnancy in other affected members.

EVL: Endoscopic variceal ligation; F: Female; FTT: Failure to thrive; HCC: Hepatocellular carcinoma; M: Male; NC: Neonatal cholestasis; PEBD: Partial external biliary diversion; PHT: Portal hypertension; UDCA: Ursodeoxycholic acid.

Table 2 Clinical characteristics and outcome in patients with NR1H4 mutation

Ref.		Sex	Age at onset of symptoms	Age at initial evaluation	Symptoms	Lab parameters			Histology/IHC	Age at LTx	Outcome
						GGT	INR (at onset)	AFP ng/mL
Gomez-Ospina et al[6], 2016	All cases had homozygous mutations
	1Patient 1	F	2 wk	20 mo	J, FTT	53	2	716	Cirrhosis	22 mo	10 yr4
	1Patient 2	M	2 wk	7 wk	J, FTT	45	2	146000	Fibrosis	4.4 mo	15 mo4
	2Patient 3	F	6 wk	6 wk	J	59	1.4	13900	Fibrosis	ND	Died 8 mo
	2Patient 4	M	Birth	Birth	J, ascites, pleural effusion, ICB		-	-	Fibrosis	ND	Died at 4 wk
Himes et al[7], 2020	Patient 5 and 7 had homozygous mutations
	Patient 5	M	16 mo	17 mo	J, ascites	81	1.9	9610	Cirrhosis	20 mo	Alive at 8 yr of age, no graft steatosis
	3Patient 6	M	3 wk	1 mo	J, FTT, hydrothorax	-	-	-	-	ND	Died at 8 mo, liver failure
	3Patient 7	F	1 wk	4 mo	J, FTT, hydrothorax	-	-	> 100000	-	ND	Died at 7 mo, liver failure
Chen et al[27], 2019	Patient had compound heterozygote mutation
	Patient 8		N/A	3 mo	J, splenomegaly		3.0	> 80000	-	ND	Died at 5 mo

¹Family 1.

²Family 2.

³Family 3.

⁴Post transplant both cases have hepatic steatosis and liver function test abnormalities.

AFP: Alpha fetoprotein; BSEP: Bile salt export pump; F: Female; FTT: Failure to thrive; FXR: Farnesoid X receptor; GGT: Gamma-glutamyltransferase; ICB: Intracranial bleed; IHC: Immunohistochemistry; INR: International normalized ratio; J: Jaundice; LTx: Liver transplantation; MDR3: Multidrug resistance protein 3; M: Male; N/A: Not applicable; ND: Not done.

Table 3 MYO5B mutation clinical characteristics and outcome

Ref.		Age at onset of symptom	Age at initial evaluation	Symptoms	Treatment	Lab parameters			Outcome
						GGT (IU/L)	AST (IU/L)	ALT (IU/L)
Qiu et al[20], 2017	n = 10, M-8, F-2, 4 had affected siblings	2 d-19 mo	1 mo-10 yr	Jaundice and pruritus; No diarrhea	UDCA, cholestyramine	9-99	24-255	41-432	Recurrent-3, persistent-2, transient cholestasis-2, lost to follow-3, listed for LT -1 (died)
Cockar et al[19], 2020	n = 6, M-3, F-3	-	6 mo-15 yr	Pruritus with pale stools-6, Jaundice-3; FTT-3; Diarrhea-2, (intractable and settled at 3 yr and 7 yr), gallstone-1	Antipruritic medications-6; PIBD-1; PIBD followed by PEBD-1; ENBD followed by PEBD-1	10-22	-	15-177	1-LT for poor QOL and pruritus; 5-Partial response with mild pruritus while on medications
Gonzales et al[8], 2017	n = 5, M-4, F-1	-	7-15 mo	Pruritus-5; Jaundice-5; Pale stools-5 hepatomegaly-5; Language delay-1 episodes of severe diarrhea before 3 yr of age-1	UDCA and rifampicin-5; PEBD-1	7-11	31-170	57-207	Followed till 3.5-13.5 yr of age; Fluctuating cholestasis-4; Cholestasis resolved after 1 mo of PEBD, well till 7 yr of age
Girard et al[17], 2014	n = 8/28 MVID, patients with cholestasis M-5, F-3	3-60 mo		Jaundice, pruritus, hepatomegaly-8; Pre Int Tx-5, post Int Tx-3	Antipruritic medications-8; PIBD followed by PEBD-1; PIBD-1; PEBD-1; Combined liver and Int Tx-1	8-42	51-124	52-121	Follow up till 2.8-14 yr of age, remission-6, partial remission-2; Removal of small bowel graft due to acute rejection in 2 cases improved cholestasis

AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; ENBD: Endonasal biliary drainage; F: Female; FTT: Failure to thrive; GGT: Gamma glutamyl transferase; Int Tx: Intestinal transplant; LT: Liver transplantation; M: Male; MVID: Microvillus inclusion disease; PEBD: Partial external biliary drainage; PIBD: Partial internal biliary drainage; QOL: Quality of life; UDCA: Ursodeoxycholic acid.

Table 4 Comparison of clinical features, laboratory profile and outcome in progressive familial intrahepatic cholestasis 4, 5 and 6

	PFIC 4	PFIC 5	PFIC 6
Gene mutation	TJP2/Zona occludens-2 located in 9q21.11	NR1H4/FXR-located in 12q23.1	MYO5B located in 18q21.1
Clinical features
Clinical features	Cholestatic jaundice with pruritus	Rapidly progressive neonatal-onset cholestasis with uncorrectable coagulopathy	Cholestasis with pruritus, with/without transient, recurrent or progressive diarrhea (association with MVID)
Extrahepatic features	Neurological and respiratory symptoms	-	-
ICP	Yes	Yes (uncommon)	No
Laboratory parameters
AST/ALT	Elevated	Moderate elevation	Mild to moderate elevation
GGT	Normal or mild elevation	Normal	Normal
Coagulopathy	Late-onset	Early-onset	Late-onset
Alpha fetoprotein	Normal, elevated in cases with HCC	Elevated	Normal
S. Bile acids	Elevated	Elevated	Elevated
Histopathology
Canalicular cholestasis	Yes	Yes	Yes
Portal/lobular fibrosis	Yes	Yes	Yes
Giant-cell transformation	Yes	Diffuse	Sparse
Ductular reaction	No	Yes	Yes
Hepatocyte necrosis	Yes	-	-
Cirrhosis	Yes	Yes	Less common
Immunohistochemistry
BSEP	Present	Absent BSEP staining on bile canaliculus	Abnormally thick, irregular and granular positivity that overflows into subcanalicular area
MDR3	Present	Present	Thickened canalicular staining granular and patchy pattern overflows into subcanalicular area
TJP2	Absent expression in canalicular membrane	Present	Present
Claudin1	Absent or reduced staining on bile canaliculi	Present	Present
FXR	Normal	Absent staining on bile canaliculus	Normal
MYO5B/RAB11	Normal	Normal	Intense, granular staining pattern in hepatocyte cytoplasm, and weak/loss of canalicular expression
Progression	Rapid	Very rapid	Slow
Complications	Hepatocellular carcinoma	Post-transplant graft steatosis similar to PFIC1	Worsening of cholestasis post intestinal transplant
Treatment
Medical management	UDCA, Rifampicin	Minimal role	UDCA, rifampin, cholestyramine
Biliary diversion	PEBD some role	Not tried	Cholestasis subsides after BD in MVID patients with cholestasis
Liver transplant	Yes	Yes	Yes. Combined liver intestinal transplant in children with MVID and ongoing cholestasis

ALT: Alanine aminotransferase; ASBT: Apical sodium-dependent bile acid transporter; AST: Aspartate aminotransferase; BD: Biliary diversion; BSEP: Bile salt export pump; FXR: Farnesoid X receptor; GGT: Gamma-glutamyl transferase; HCC: Hepatocellular carcinoma; MDR3: Multidrug resistance class 3 glyco-protein; ICP: Intrahepatic cholestasis of pregnancy; MVID: Microvillus inclusion disease; MYO5B: Myosin-5b; NBD: Nasobiliary drainage; PEBD: Partial external biliary drainage; PFIC1Progressive familial intrahepatic cholestasis-1; RAB11: RAS-related GTP-binding protein-11; TJP2: Tight junction protein-2; UDCA: Ursodeoxycholic acid.