Aspen Webinar 2021 Part 3-IBAT Inhibitors

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.

NASPGHAN Alagille Syndrome Webinar

​A great and short webinar was recently presented from the ​NASPGHAN Foundation​ with three lectures

Webinar​​: Alagille Syndrome (If this link does not work, the On Demand version of the webinar is now available on LearnOnLine, at  You can also find it by logging into LearnOnline at and entering the Webinars section.)

The first lecture by Dr. Melissa Gilbert was an excellent overview of the genetics of Alagille Syndrome.

Key points:

  • JAG1 mutations account for ~95% of Alagille syndrome mutations and NOTCH2 about 3%
  • Many mutations identified are due to missense mutations which are often variants of unknown clinical significance (VOUS). In these patients, to determine if it is pathogenic, one has to correlate the clinical picture along with specific amino acid change, location of variant, and frequency of variant in normal population. Dr. Gilbert noted that among the ~97% of cases with genetic abnormalities, about 80% have recognized pathogenic mutations and about 17% have VOUS.
  • There is variability of severity of Alagille syndrome in the same family, likely related to genetic modifiers
  • When using genetic panel, if panel uses only single nucleotide variants, this will miss the deletion/duplication variants which account for ~10% of cases

The second lecture by Binita Kamath was a terrific review and compared the differences between Alagille Syndrome with JAG1 mutations and NOTCH2; the latter are much less likely to have cardiac abnormalities and butterfly vertebrae. The liver phenotype/survival is similar.

Key points:

  • Outcomes of Alagille syndrome by 25 years of age including frequent bone fractures and development of portal hypertension.
  • Severe liver disease is common. 75% in a multi-center cohort (CHILDREN) required liver transplantation by age 18 years and 10% died; in contrast, a large GALA cohort of 911 children, 41% survived with their native liver at 18 years.
  • After transplantation, renal sparing strategies are needed due to frequent renal insufficiency; patients with severe cardiac disease may not be candidates for liver transplantation.
  • There is work on an Alagille Syndrome growth curve.
  • Screening for brain vascular malformations/Moyamoya –Dr. Kamath tends to screen after age 8 years of age at baseline (when child does not need sedation for brain imaging) and then every 4-5 years. Also, an MRI/MRA is done prior to major surgery.
  • Hyperlipidemia in Alagille Syndrome is mainly due to lipoprotein X; this is not a risk factor for cardiac health.

The third (& also excellent) lecture by Saul Karpen (who disclosed his potential conflicts of interest) reviewed current treatments and emerging treatments.

Key points:

  • The current medical therapies have not been carefully tested; rifampin for pruritus may relieve cholestasis in about 50% of patients.
  • IBAT inhibitors interrupt enterohepatic circulation. These agents improve pruritus and decrease serum bile acids.
  • Dr. Karpen reminded the audience to follow fat soluble vitamin levels and if treatment is needed, to provide Vitamin D formulations with TPGS.
On the right hadd panel (above), the orange bar represents those with severe pruritus and the effects of PEBD on pruritus.

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Intracranial Hypertension & Papilledema with Alagille Syndrome

NM Rock et al. JPGN 2020; 71: 655-662. Intracranial Hypertension and Papilledema in a Large Cohort of Pediatric Patients With Alagille Syndrome

Key findings:

  • In this retrospective cohort of 69 patients, Nine (13.0%) had papilledema and Five (7.2%) had confirmed or probable intracranial hypertension. All five had undergone liver transplantation.
  • Age (in months) when intracranial hypertension was diagnosed: 35, 43, 55, 62, and 103.

Discussion Points:

  • “Cerbrovascular abnormalities, including moyamoya disease, are increasingly describe in patients with” Alagille syndrome.
  • “Opthalmic complications in relation with papilledema seem to appear mostly after” liver transplantation. This could indicate that LT/immunosuppression exaccerbate underlying disorder, that those who need LT have more severe phenotype or could be related to closer scrutiny (‘follow-up bias”).
  • First line treatment for intracranial hypertension in this group is generally acetazolamide.

My take: I agree with the authors who propose regular eye exams for patients with Alagille syndrome, especially if needing liver transplantation. Further evaluation is recommended for patients who have greater than mild papilledema. This includes MRI and lumbar opening pressure.

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Sunrise -Isle of Palms

#NASPGHAN 17 More Abstracts

This link for the NASPGHAN abstracts :NASPGHAN 2017 Scientific Abstracts

The following slides are from some of the abstract posters. This first poster (next 5 pics) showed that symptom association with meals is not predictive of aspiration among a selected group of children who underwent swallow study evaluations. In the figures, the blue bars are children who passed the swallow study whereas the red bars indicate the children who failed the swallow study.

This next slide demonstrated that a six food diet for EoE could be administered blenderized via a gastrostomy tube.

The next slide showed that irritable bowel syndrome was more frequent (overall hazard ratio of 1.52) following a urinary tract infection in the first year of life.

The next pictures are from a poster discussing high rates of recurrent C difficile infection following fecal microbial transplantation in pediatric patients with inflammatory bowel disease (mainly ulcerative colitis).  An inference from this study would be that many cases of C difficile that were attributed as causing symptoms could in fact have been from a flare up of their IBD.  More details about the diagnosis of C difficile (based on PCR or ELISA) would be helpful

The next poster provides data from CHOP experience with Ustekinumab.  Overall, in this highly-selected (refrcactory) population the long term improvement was low; while one-third had steroid-free remission at week 8, this was not maintained at week 16 and week 24.  In addition, among the 22 patients, one developed transverse myelitis.

This study that follows (next two pics) documented the relative safety of liver biopsies (mainly percutaneous without interventional radiology) in the post-transplant period.  The two most serious adverse events, cholangitis and bile leak, helped identify biliary strictures.

The following collaborative study examined the neurocognitive status of children with Alagille syndrome.  Overall, this study shows that children with Alagille syndrome are at increased risk of low IQ compared to children with other cholestatic diseases.



Explaining Differences in Disease Severity for Alagille Syndrome

A recent study (DOI: has shown a gene which may help explain the difference in disease severity in Alagille syndrome.

Here’s a link to full text: THBS2 is a Candidate Modifier of Liver Disease Severity in Alagille Syndrome

Here’s the abstract:

Background & Aims

Alagille syndrome is an autosomal-dominant, multisystem disorder caused primarily by mutations in JAG1, resulting in bile duct paucity, cholestasis, cardiac disease, and other features. Liver disease severity in Alagille syndrome is highly variable, however, factors influencing the hepatic phenotype are unknown. We hypothesized that genetic modifiers may contribute to the variable expressivity of this disorder.


We performed a genome-wide association study in a cohort of Caucasian subjects with known pathogenic JAG1 mutations, comparing patients with mild vs severe liver disease, followed by functional characterization of a candidate locus.


We identified a locus that reached suggestive genome-level significance upstream of the thrombospondin 2 (THBS2) gene. THBS2 codes for a secreted matricellular protein that regulates cell proliferation, apoptosis, and angiogenesis, and has been shown to affect Notch signaling. By using a reporter mouse line, we detected thrombospondin 2 expression in bile ducts and periportal regions of the mouse liver. Examination of Thbs2-null mouse livers showed increased microvessels in the portal regions of adult mice. We also showed that thrombospondin 2 interacts with NOTCH1 and NOTCH2 and can inhibit JAG1–NOTCH2 interactions.


Based on the genome-wide association study results, thrombospondin 2 localization within bile ducts, and demonstration of interactions of thrombospondin 2 with JAG1 and NOTCH2, we propose that changes in thrombospondin 2 expression may further perturb JAG1–NOTCH2 signaling in patients harboring a JAG1mutation and lead to a more severe liver phenotype. These results implicate THBS2 as a plausible candidate genetic modifier of liver disease severity in Alagille syndrome.

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World Congress 2016 Postgraduate Course

I’ve attached (with permission) the syllabus from the World Congress 2016 Postgraduate Course: 2016-world-congress-postgraduate-course-syllabus



One lecture that I will highlight with a few slides is from Dr. Martin Martin (pg 53-62) which emphasizes a new model for evaluating neonatal intestinal failure/congenital diarrhea by using whole exome sequencing –see slides below.

Other pointers:

  • Pg 82.  Breastmilk associated with shorter duration of TPN dependence in short bowel syndrome
  • Pg 137. Look for vasculopathy (MRI/MRA) and renal disease in Alagille syndrome
  • Pg 152. Lactated ringer’s likely better in acute pancreatitis than normal saline.
  • Pg 171. If constipation at less than 1 year is untreated, >60% have issues with constipation at age 3.

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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Solitary Hepatic Nodule and Alagille Syndrome

A retrospective study (A Alhammad et al. JPGN 2016; 62: 226-32) of 55 children from 1999-2014 examined the frequency of a solitary hepatic nodule adjacent to the right portal vein as a potential diagnostic finding for Alagille syndrome.  Only 39 had appropriate imaging to examine.

Key findings:

  • In 12 (of 39) focal hepatic lesions were evident (11 were solitary).
  • The median diameter was 8.1 cm.
  • In those with pathology review, the cases were suggestive of a regenerative nodule.
  • In all but one case, the alpha-fetoprotein levels were normal.
  • 10 of these lesions were adjacent to the right portal vein.

One other point from the discussion:

  • ~21% of patients with Alagille require liver transplantation, primarily for unremitting cholestasis and pruritus

My take: Recognition of this entity will help avoid mistaking this lesion for hepatocellular carcinoma.

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Clearing Out My Desk

These articles have been sitting on my desk or my email and worth a quick mention:

“Proton Pump Inhibitors Alter Specific Taxa in the Human Gastrointestinal Microbiome: A Crossover Trial” DE Freedberg et al. Gastroenterol 2015; 149: 883-85. In this study of 12 healthy volunteers over 12 weeks, the study’s major finding (according to associated commentary) “is the absence of any significant changes in microbial diversity with proton pump inhibitors.” However, there was “an increase in bacterial taxa associated with C difficile infection.”

“Quality of Life and Its Determinants in a Multicenter Cohort of Children with Alagille Syndrome” BM Kamath et al. J Pediatr 2015; 167: 390-6.  Quality of life is impaired in Alagille compared to healthy children and children with alpha-one antitrypsin; it is associated with growth failure which may be modifiable.

“Baseline Ultrasound and Clinical Correlates in Children with Cystic Fibrosis” DH Leung et al. J Pediatr 2015; 167: 862-68.  In this prospective study of children (n=719) from age 3-12 years, unsuspected cirrhosis was seen in 3.3% of patients and a heterogeneous liver echotexture was identified in 8.9%.

Case report of phlegmonous gastritis associated with ulcerative colitis (with good pictures): J Cordova, R Gokhale, B Kirschner. Gastroenterol 2015; 149: 867-69.

“High Prevalence of Idiopathic Bile Acid Diarrhea Among Patients with Diarrhea-Predominant Irritable Bowel Syndrome Based on Rome III Criteria” I Aziz et al. Clin Gastroenterol Hepatol 2015; 13: 1650-55.

Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study” The Lancet. DOI: (Reference from Sana Syed)

Severe Pruritus with Alagille Syndrome

A recent study reviews the King’s College experience for managing pruritus associated with cholestasis in patients with Alagille syndrome (AGS) (JPGN 2013; 57: 149-54).

This retrospective study examined 62 patients (1995-2010). 82% (n=51) had pruritus.  Most common treatments:

  • Ursodeoxycholic acid in 40 patients. 1st line Rx in 31. Efficacy was rated as good in 20% and some efficacy in 67.5%.
  • Rifampicin in 39 patients. 1st line Rx in 8. Efficacy was rated as very good/good in 49% and some efficacy in 46%.
  • Cholestyramine in 18 patients. 1st line Rx in 9. Efficacy was rated as  very good in 17% and some efficacy in 67%.
  • Naltrexone in 14 patients. Efficacy was rated as good in 43% and some efficacy in 36%.
  • Alimemazine in 13 patients
  • Nonsedating antihistamines in 7 patients
  • Ondansetron in 5 patients
  • Phenobarbital in 1 patient.

Despite these medications, pruritus was controlled by medication in 41% (n=21).  16 patients were referred for liver transplantation and 11 of these patients have been transplanted.  These 11 patients make up 55% of those who had permanent resolution of their pruritus.

The authors proposed an algorithm for treatment:

  • 1st line: ursodeoxycholic acid 10-20 mg/kg/day divided in 2 doses or cholestyramine 240 mg/kg/day divided into 3 doses
  • 2nd line: (if needed) Add/substitute rifampicin 5-10 mg/kg/day divided into 2 doses (max 600 mg/day)
  • 3rd line: (if needed) Add/substitute naltrexone 0.25-0.5 mg/kg/day (max 50 mg/day)
  • 4th line: (if needed) Add/substitute ondansetron max 8 mg/day divided into 2 doses per day (or phenobarbital 5-10 mg/kg/day divided into 2 doses.
  • If none of these are helpful, options could include MARS (molecular adsorbent recirculation system), partial external biliary diversion, or liver transplantation.

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Learning a lot from ChiLDREN (part 1)

Several recent studies highlight the benefits of multisite collaboration to study infrequent pediatric liver problems.  In one of these, it is shown that pancreatic insufficiency (PI) is not a common problem for patients with Alagille syndrome (JPGN 2012; 55: 612-614).

In these studies, the Childhood Liver Disease Research and Education Network (ChiLDREN) collected prospective longitudinal observational date from multiple centers, 16 in this study.

150 subjects who met criteria for Alagille syndrome were enrolled between December 2007 to September 2010.  42 had fecal elastase results available.  Elastase results were characterized as normal if >200 μg/g, indeterminant if 100-200 μg/g, and pancreatic insufficient if <100 μg/g.

  • 40/42 (95%) had normal results
  • 2/40 (5%) were indeterminant

The collaborative study provides a few teaching points:

  1. Fecal elastase is a very reliable tool for detecting exocrine PI with a 99% negative predictive value for ruling out PI.
  2. Previous results suggesting that PI was common in Alagille syndrome were flawed due to the fallibility of previous secretin stimulation testing and due to the occurrence of steatorrhea induced by impaired bile salt secretion

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