Tag Archives: Alagille syndrome

GALA: Alagille Study

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SM Vandriel et al. Hepatology 2023; 77: 512-529. Open Access! Natural history of liver disease in a large international cohort of children with Alagille syndrome: Results from the GALA study

This was a very large retrospective study (with more than 90 authors) with 1433 children.

Key findings:

  • Only 40.3% of children reach adulthood with their native liver; 54.4% had their native liver at 10 years of life
  • “It is noteworthy that bile duct paucity was reported in only 65% of liver biopsies performed during the first 3 months of life, the period during which there are diagnostic challenges with distinguishing ALGS from syndromic BA.” Thus, with a liver biopsy, there is a significant risk of misdiagnosis
  • The all‐cause mortality rate was 8.5%
  • The total bilirubin level between 6-12 months of life had significant predictive value. In the associated editorial: “The authors reported that 79% of patients with median TB of <5.0 mg/dL..reached adulthood with their native livers, whereas only 31.6% and 18.2% of patients with median TB levels between” 5-10 and >10 mg/dL survived into adulthood with their native livers.
  • The editorial makes the point that this data will be helpful and ongoing studies will be needed to determine the effectiveness of novel treatments (e.g. IBAT inhibitors)

My take: This is a very useful study in understanding the long term outcomes of Alagille syndrome.

Related blog posts:

Sandy Springs, GA

Liver Briefs: HLH in Infancy, Maralixibat for Alagille Syndrome, Liver Disease Due to Inborn Errors of Immunity

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N Hadzic et al. J Pediatr 2022; 250: 67-74. High Prevalence of Hemophagocytic Lymphohistiocytosis in Acute Liver Failure of Infancy In this retrospective study of pediatric acute liver failure (PALF, n=78) in children <24 months of age: Thirty of the 78 children had the HLH phenotype and underwent genetic assessment, which demonstrated positive findings in 19 (63.3%), including 9 (30%) with biallelic primary HLH mutations and 10 (33.3%) with heterozygous mutations and/or polymorphisms. The mortality in this group was 33% (n=10). The authors conclude that targeted genetic analysis (ie perforin, SIAP, XIAP, and GRA) or whole exome sequencing should become a standard part of PALF workup.

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BM Kamath et al. J Pediaatr 2023; 252: 68-75. Open Access! Maralixibat Treatment Response in Alagille Syndrome is Associated with Improved Health-Related Quality of Life. Twenty of the 27 patients (74%), all with moderate-to-severe pruritus at enrollment, achieved an Itch-Reported Outcome (Observer) treatment response at week 48. “The significant improvements in pruritus seen with maralixibat at week 48 of the ICONIC study are clinically meaningful and are associated with improved HRQoL.”

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D Sharma et al. Hepatology 2022; 76: 1845-1861. Tip of the iceberg: A comprehensive review of liver disease in Inborn errors of immunity This articles reviews inborn errors of immunity (IEI) and their liver manifestations. This includes the following:

  • T-cell/B-cell deficiency: SCID, CD40 ligand deficiency, DOCK8 deficiency, IL-21R deficiency, and Activated P13K delta syndrome
  • Antibody deficiency: CVID, X-linked aggamoglobulinemia
  • Phagocytic disorders: CGD
  • Primary Immune Regulatory Disorders: STAT1 GOF, STAT3 GOF, IPEX, APECED
  • Others: Wiskott-Aldrich syndrome, Immunodeficiency-centromeric instability-facial anomalies syndrome, Hepatic veno-occlusive disease with immunodeficiency, STAT3-deficient hyper IgE syndrome

In patients with IEIs with liver abnormalities, one needs to consider infectious etiologies (eg. HAV, HBV, HCV, HEV, CMV, EBV, HSV, cryptosporidium, liver abscess), autoimmune disorders (eg. AIH), drug-induced liver disease, and sclerosing cholangitis

Royal Terns at Siesta Key, FL

Favorite Posts of 2021

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I am happy to say that this is the last nightcall that I will have this year!

Today, I’ve compiled some of my favorite posts from the past year. I started this blog a little more than 10 years ago. I am grateful for the encouragement/suggestions from many people to help make this blog better. Also, I want to wish everyone a Happy New Year.

GI:

IBD:

LIVER:

Nutrition:

Other Topics:

Thanks to Jennifer

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.

NASPGHAN Alagille Syndrome Webinar

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​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 https://learnonline.naspghan.org/products/on-demand-advances-in-diagnosis-and-treatment-of-alagille-syndrome.  You can also find it by logging into LearnOnline at https://learnonline.naspghan.org/ 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

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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

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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

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A recent study (DOI: http://dx.doi.org/10.1016/j.jcmgh.2016.05.013) 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.

Methods

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.

Results

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.

Conclusions

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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alagille-cover

World Congress 2016 Postgraduate Course

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

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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

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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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HeavenHellBillMurray