Copyright ©The Author(s) 2021.
World J Hepatol. Dec 27, 2021; 13(12): 2024-2038
Published online Dec 27, 2021. doi: 10.4254/wjh.v13.i12.2024
Table 1 Clinical characteristics and outcome in patients with TJP2 mutation
Age at onset of symptoms
Other symptoms
Liver transplant
Sambrotta et al[5]121 wk-3 moNC-12/12Chronic respiratory disease-1, recurrent unexplained hematoma-1UDCA, PEBD-29/12 cases at the age of 1.5-10 yrPost-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 moNC-6/7, pruritus at 7 mo-1/7Gallstones 2/7Response to UDCA, cholestyramineNoneResolved cholestasis (n = 6) over 7-26 mo; Persisting icterus-1
Ge et al[46]1 (F)6moJaundice, pruritus, FTT-Responded to medical treatmentNoneResolved cholestasis
Mirza et al[47]1 (M)4 yrJaundice, pruritus-Medical treatmentNoneCirrhosis, PHT with variceal bleed at 15 yr
Wei et al[24]Index case (M) with multiple affected family members119 yrCirrhosis, PHT with variceal bleed, HCC at 22 yr-Medical treatment including EVL23 yrWell in post-transplant period
Table 2 Clinical characteristics and outcome in patients with NR1H4 mutation
Age at onset of symptoms
Age at initial evaluation
Lab parameters
Age at LTx
INR (at onset)
AFP ng/mL
Gomez-Ospina et al[6], 2016All cases had homozygous mutations
1Patient 1F2 wk20 moJ, FTT532716Cirrhosis22 mo10 yr4
1Patient 2M2 wk7 wkJ, FTT452146000Fibrosis4.4 mo15 mo4
2Patient 3F6 wk6 wkJ591.413900FibrosisNDDied 8 mo
2Patient 4MBirthBirthJ, ascites, pleural effusion, ICB--FibrosisNDDied at 4 wk
Himes et al[7], 2020Patient 5 and 7 had homozygous mutations
Patient 5M16 mo17 moJ, ascites811.99610Cirrhosis20 moAlive at 8 yr of age, no graft steatosis
3Patient 6M3 wk1 moJ, FTT, hydrothorax----NDDied at 8 mo, liver failure
3Patient 7F1 wk4 moJ, FTT, hydrothorax--> 100000-NDDied at 7 mo, liver failure
Chen et al[27], 2019Patient had compound heterozygote mutation
Patient 8N/A3 moJ, splenomegaly3.0> 80000-NDDied at 5 mo
Table 3 MYO5B mutation clinical characteristics and outcome

Age at onset of symptom
Age at initial evaluation
Lab parameters
Qiu et al[20], 2017n = 10, M-8, F-2, 4 had affected siblings2 d-19 mo1 mo-10 yrJaundice and pruritus; No diarrheaUDCA, cholestyramine9-9924-25541-432Recurrent-3, persistent-2, transient cholestasis-2, lost to follow-3, listed for LT -1 (died)
Cockar et al[19], 2020n = 6, M-3, F-3-6 mo-15 yrPruritus with pale stools-6, Jaundice-3; FTT-3; Diarrhea-2, (intractable and settled at 3 yr and 7 yr), gallstone-1Antipruritic medications-6; PIBD-1; PIBD followed by PEBD-1; ENBD followed by PEBD-110-22-15-1771-LT for poor QOL and pruritus; 5-Partial response with mild pruritus while on medications
Gonzales et al[8], 2017n = 5, M-4, F-1-7-15 moPruritus-5; Jaundice-5; Pale stools-5 hepatomegaly-5; Language delay-1 episodes of severe diarrhea before 3 yr of age-1UDCA and rifampicin-5; PEBD-17-1131-17057-207Followed 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], 2014n = 8/28 MVID, patients with cholestasis M-5, F-33-60 moJaundice, pruritus, hepatomegaly-8; Pre Int Tx-5, post Int Tx-3Antipruritic medications-8; PIBD followed by PEBD-1; PIBD-1; PEBD-1; Combined liver and Int Tx-18-4251-12452-121Follow 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
Table 4 Comparison of clinical features, laboratory profile and outcome in progressive familial intrahepatic cholestasis 4, 5 and 6

Gene mutationTJP2/Zona occludens-2 located in 9q21.11NR1H4/FXR-located in 12q23.1MYO5B located in 18q21.1
Clinical features
Clinical featuresCholestatic jaundice with pruritusRapidly progressive neonatal-onset cholestasis with uncorrectable coagulopathyCholestasis with pruritus, with/without transient, recurrent or progressive diarrhea (association with MVID)
Extrahepatic featuresNeurological and respiratory symptoms--
ICPYesYes (uncommon)No
Laboratory parameters
AST/ALTElevatedModerate elevationMild to moderate elevation
GGTNormal or mild elevationNormalNormal
Alpha fetoproteinNormal, elevated in cases with HCCElevatedNormal
S. Bile acidsElevatedElevatedElevated
Canalicular cholestasisYesYesYes
Portal/lobular fibrosisYesYesYes
Giant-cell transformationYesDiffuseSparse
Ductular reactionNoYesYes
Hepatocyte necrosisYes--
CirrhosisYesYesLess common
BSEPPresentAbsent BSEP staining on bile canaliculusAbnormally thick, irregular and granular positivity that overflows into subcanalicular area
MDR3PresentPresentThickened canalicular staining granular and patchy pattern overflows into subcanalicular area
TJP2Absent expression in canalicular membranePresentPresent
Claudin1Absent or reduced staining on bile canaliculiPresentPresent
FXRNormalAbsent staining on bile canaliculusNormal
MYO5B/RAB11NormalNormalIntense, granular staining pattern in hepatocyte cytoplasm, and weak/loss of canalicular expression
ProgressionRapidVery rapidSlow
ComplicationsHepatocellular carcinomaPost-transplant graft steatosis similar to PFIC1Worsening of cholestasis post intestinal transplant
Medical managementUDCA, RifampicinMinimal roleUDCA, rifampin, cholestyramine
Biliary diversionPEBD some roleNot triedCholestasis subsides after BD in MVID patients with cholestasis
Liver transplantYesYesYes. Combined liver intestinal transplant in children with MVID and ongoing cholestasis