Tag Archives: PFIC

IQ and Pediatric Chronic Liver Disease

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DH Leung et al. JPGN: 2022 – Volume 74 – Issue 1 – p 96-103. Neurodevelopmental Outcomes in Children With Inherited Liver Disease and Native Liver

In this longitudinal study, the authors evaluated Full Scale Intelligence Quotient (FSIQ) in children with chronic liver disease (mean age 7.6 yrs). Key finding:

  • Patients with Alagille syndrome (ALGS) are at increased risk of lower FSIQ (with 29% <85), whereas our data suggest A1AT and PFIC are not

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Liver Shorts: PFIC/FIC1, Best Tenofovir, Ascites Practice Guidance

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DBE van Wessel et al. Hepatology 2021; 74: 892-906. Open Access: Impact of Genotype, Serum Bile Acids, and Surgical Biliary Diversion on Native Liver Survival in FIC1 Deficiency

This huge collaborative study with 130 patients provides a great deal of information about familial intrahepatic cholestasis type 1 (FIC1). Key findings:

  • Survival analysis showed an overall native liver survival (NLS) of 44% at age 18 years. NLS was comparable among FIC1-A, FIC1-B, and FIC1-C (% NLS at age 10 years: 67%, 41%, and 59%, respectively; P = 0.12)
  • The number of predicted protein truncating mutations did not correlate with natural history or prognosis

H Toyoda et al. Hepatology 2021; 74: 656-666. Treatment and Renal Outcomes Up to 96 Weeks After Tenofovir Alafenamide Switch From Tenofovir Disoproxil Fumarate in Routine Practice

In this study, the researchers 834 patients with CHB previously treated with TDF for ≥12 months who were switched to TAF in routine practice at 13 US and Asian center. Key findings:

  • “Overall, we observed continued improvement in virologic response, ALT normalization, and no significant changes in eGFR following switch to TAF from TDF.”
  • HBV DNA suppression increased from 88% to 92% at 48 weeks post-switch, and then 95% at 96 weeks postswitch
  • Improved renal function: “By week 96, 21% (55/267) of patients with CKD stage 2 at switch improved to stage 1 and 35% (30/85) of CKD stage 3-5 patients improved to stage 2 and 1.2% (1/85) to stage 1.”

SW Biggins et al. Hepatology 2021; 74: 1014-1048. Open Access. Diagnosis, Evaluation, and Management of Ascites, Spontaneous Bacterial Peritonitis and Hepatorenal Syndrome: 2021 Practice Guidance by the American Association for the Study of Liver Diseases

This practice guidance (with 276 references) is an update from similar guidelines published in 2012.

Key Points For Children:

  • Children with cirrhosis and ascites should be referred for evaluation for LT
  • Children undergoing LVP should receive 25% albumin infusion of 0.5-1.0 g/kg, or 6-8 g per liter of ascites removed.
  • Diagnostic paracentesis should be performed in children with ascites and fever, abdominal pain, or clinical deterioration. The risks and benefits of this procedure for use in all children with new ascites but without these symptoms have not been defined.
Atlanta Beltline Murals

Aspen Webinar 2021 Part 3-IBAT Inhibitors

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This blog entry has abbreviated/summarized this presentation. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well. Another great lecture from Dr. Suchy.

IBAT Inhibitors Frederick Suchy

Key  points:

  • IBAT inhibitors block intestinal absorption of bile acids/disrupt enterohepatic circulation; this leads to augmented bile acid excretion in stools
  • IBAT inhibitors may reduce liver damage in the setting of cholestasis/accumulation of toxic bile acids
  • Potential diseases for IBAT inhibitors include Alagille syndrome and PFIC
  • Van Wessel et al (J Hepatol 2020; 73: 84-93) correlated survival with PFIC1/PFIC2 with bile acid levels and showed improvement in survival in those with surgical biliary diversion
  • Goals for IBAT inhibitor trials: improvement in pruritus, bile acids, reduced ALT, hepatic fibrosis, HCC and need for liver transplantation
  • Marixibat is available for use as an FDA approved breakthrough medication for Alagille and PFIC2 in pediatric patients older than 1 year
  • Odexibat is designated as an orphan drug for Alagille, PFIC, PBC, and biliary atresia
  • Safety appears good with IBAT inhibitors. Fat soluble vitamin monitoring is needed
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Case report: Alejandro Velez Lopez

3 yo presented with fatigue and jaundice, 3 weeks after COVID-19 infection. She was not taking any medications.  Labs:  ALT 939, AST 1321, T bili 5.5, D bili 0.9, INR 2, Plts 174, Hgb 12.8, LDH 1297. remained positive for SARS-CoV2 by PCR. Acetaminophen -no exposure.  Evaluation: LKM 1:1280. Neg ANA, NL Ferritin, NL sIL2r, Other viral studies negative, NL IgG. Developed encephalopathy with NH4 317, INR peaked at 2.8.  Treated with steroids, rifaximin and lactulose.  Liver biopsy showed sub-massive necrosis and fibrosis (indicative of  autoimmune hepatitis, likely triggered or exacerbated by COVID-19).  Patient responded to medical therapy and did not require liver transplantation.

Hypothyroidism with ATP8B1 Deficiency

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A recent study (L Li et al. J Pediatr 2015; 157: 1334-9) indicated that hypothyroidism may be another extrahepatic feature of patients with ATP8B1 deficiency; this mutation’s main manifestation has been intrahepatic cholestasis in either progressive familial intrahepatic cholestasis (PFIC type 1) or benign recurrent intrahepatic cholestasis (BRIC type 1).

In this study, 3/13 were hypothyroid and an additional 2/13 had subclinical hypothyroidism.  These patients were compared with a cohort of children with ABCB11 deficiency (PFIC type 2 or BRIC type 2) in which 0/19 had hypothyroidism.

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Clinical Features of Byler Disease

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A recent article (Morris AL, et al. JPGN 2015; 60: 460-6) provides a detailed analysis of six cases of Byler disease during their first two years of life.  These cases were strictly defined and defined by homozygous c.923G>T mutation of ATP8b1.

Presenting features:

  • 2 with newborn direct hyperbilirubinemia
  • 2 with complications of coagulopathy. “Bleeding diathesis is a particular issue in the Amish community where home delivery is common and vitamin K may not be administered perinatally.”
  • 1 with failure to thrive and rickets
  • 1 was a sibling identified with newborn genetic testing

Key features:

  • Intensive fat-soluble vitamin supplementation was needed. “Vitamin K deficiency can be lethal.”
  • Poor growth was frequent (Figure 2): “growth trajectories were generally at the low end of percentiles and did not reflect parental size.” It was “typically responsive to supplementation with medium-chain triglyceride-based formula. and/or use of 30 cal per ounce formulae.”
  • Elevated serum bile acids and low normal GGT (Υ-glutamyltranspeptidase)
  • Diarrhea was commonly reported
  • Intractable pruritus in 4 of 6 children which developed between 6-12 months of age;  in two patients rifampin therapy was effective.
  • Partial external biliary diversion was used in 4 children during 2nd year of life; there was a “generally favorable response to PEBD.”
  • There were not issues noted with portal hypertension

Bottomline: This report shares some practical experience with this rare disorder.

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BRIC, PFIC, and nasobiliary drainage

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Case reports, when effective, help clinicians understand meaningful differences in disease presentation; in addition, they highlight practical treatment approaches.  An excellent example of one such case report is the following:

  • Zellos A et al.  JPGN 2012; 55: 88-90

These authors present a case with unique features that highlight some of the clinical problems with benign recurrent intrahepatic cholestasis (BRIC) and progressive familial intrahepatic cholestasis (PFIC).  BRIC1 and PFIC1 are associated with mutations in ATP8B1; BRIC2 and PFIC2 are associated with mutations in ABCB11.  The primary difference between BRIC and PFIC is the phenotypic expression.  In BRIC, individuals have episodes of cholestasis; in PFIC, progressive chronic liver disease develops in the first months of life.  PFIC2/ABCB11 mutations cause defective bile salt export pump (BSEP) at the bile-canniculus membrane.

Both ATP8B1 and ABCB11 intrahepatic cholestasis conditions present in a similar fashion with low GGT values.  In this case report, a 5-year-old presented with jaundice, acholic stools and dark urine.  His laboratory values revealed an ALT of 60 U/L, direct bilirubin of 7.6 mg/dL and gamma-glutamyl transpeptidase (GGT) of 10 U/L.  Initially, after exclusion of other liver conditions (eg. NL MRCP, copper studies, α-1 antitrypsin, autoimmune serology, infectious etiologies), the authors suspected ‘a clinicopathologic intergrade between BRIC and PFIC’ likely due to ATP8B1 as there was BSEP expression on liver biopsy immunostaining.  After sequencing did not demonstrate any ATP8B1 mutations, the authors identified two heterozygote mutations in ABCB11.

From a treatment standpoint, once nasobiliary drainage (NBD) was in place, the patient quickly improved.  This occurred after >6 weeks of failure with urosdeoxycholic acid/conservative measures.  As a precaution, the authors cultured the bile once a week and instituted antibiotic treatment when positive cultures were identified.

One other point alluded to by the authors is that the natural history of BRIC2 is poorly described.  Whether this disorder is truly ‘benign’ as the name suggests is unclear.  In patients with similar mutations who develop PFIC2, there is a high risk of hepatocellular carcinoma (HCC).

Intrahepatic Cholestasis Genes/Disorder (Clin Liver Dis 2006; 10: 27-53.)

Gene: Disorder (protein)
ABCB11: PFIC 2, BRIC 2 (BSEP)
ABCB4: PFIC 3, ICP (MDR3)
CFTR: CF (CFTR)
ATP8B1: PFIC1 -Byler’s (FIC1), BRIC, GFC -Greenland Familial
CLDN1: NISCH (Claudin 1) -neonatal sclerosing cholangitis/icthyosis
VPS33B: ARC syndrome (Vascular protein sorting 33) -arthrogryposis-renal dysfn-cholestasis, low GGT
AKR1D1: BAS: Bile acid synthetic defect: neonatal cholestasis with giant cell hepatitis
(5β-reductase)
HSD3B7: BAS (C27-3β-HSD)
CYP7BI: BAS (CYP7BI)
TJP2: (ZO-2) FHC: Familial hypercholanemia (tight junction protein)
BAAT: FHC (BAAT)
EPHX1: FHC (epoxide hydrolase)
JAG1: Alagille (JAG1) JAG1 is transmembrane cell-surface protein important in regulating cell fate during embryogenesis
PKHD1: ARPKD (fibrocystin -important in ciliary function and tubulogenesis)
PRKCSH: ADPLD (hepatocystin)
ABCC2: Dubin-Johnson syndrome (MRP2)
CIRH1A: NAIC -N Amer Indian childhood cirrhosis (Cirhin)

Additional references for BRIC/low GGT PFIC:

  • -JPGN 2010; 51: 494.  Use of biliary diversion –helpful in 18 PFIC2 cases with long-term f/u.
  • -Liver Transplantation 2010; 16: 856.  6 patients developed recurrent low gamma-glutamyl transpeptidase cholestasis, that mimics BSEP disease, following transplantation. All had documented genetic defects in ABCB11 that were predicted to lead to a congenital absence of BSEP protein.
  • -NEJM 2009; 361: 1359. Recurrence of BSEP deficiency p OLT due to antibodies against BSEP
  • -Hepatology 2010; 51: 1645. n=62 children & clinical course.
  • -Gastroenterol 2008; 134: 1203. Severe BSEP –82 different mutations in 109 families. (n=132 patients)
  • -JPGN 2008; 46: 241. Excellent review. FIC1 caused by mutations in ATP8B1, PFIC 2 caused by mutations in ABCB11 which encodes BSEP – bile salt export pump. Increased risk of HCC in PFIC2 especially.
  • -J Pediatr 2007; 150: 556.  Increase risk of HCC in PFIC2.
  • -Hepatology 2006; 44: 478-486. Cases of pediatric HCC in PFIC-2
  • -Gastroenterol 2006; 130: 908. Review of canalicular transport defects.
  • -Hepatology 2005; 42: 222. summary of cholestasis workshop
  • -Gastroenterol 2004; 126: 322. Review of bile salt transporters.
  • -JPGN 2002; 34: 7A. FTT, diarrhea persist p biliary diversion or transplant.

PFIC3 -High GGT

  • -Gastroenterol 2003; 124: 1037-42. MDR3 mutations causing cholelithiasis, cholestasis, biliary cirrhosis, & pregnancy cholestasis.
  • -Gastroenterol 2001; 120: 1448-1458. n=31 cases. MDR3 mutations. ABCB4 gene
  • -Gastroenterol 2001; 120: 1459-67. Gallbladder stones & chronic cholestasis in 6 MDR3+ pts. Avg age of presentation: 2.9yrs. Avg age of Tx: 7.5yrs.  Sx/S : high ggt cholestasis, pruritus, intrahepatic cholestasis of pregnancy in heterozygotes (& c contraception)
  • -Hepatology 1996; 23: 904-8. MDR3 gene assoc c PFIC