I recently attended an online lecture which reviewed Alagille Syndrome and the emergence of an IBAT inhibitor for the management of cholestatic pruritus. Selected slides from Mirum Pharmaceutical Lecture: “Updates in the Treatment of Cholestatic Pruritus in Patients With Alagille Syndrome.” *I have no financial disclosures or conflict of interests in this medication or company.
The severe itching which is seen in most patients with Alagille is often quite detrimental to quality of life. It impacts sleep, causes irritability, skin damage, and physical distcomfort
Typically, the first week of receiving the medication, it is started at1/2 the maintenance dose.
Monitoring response can be done with the ItchCheck App, Itch score or Clinical scratch score
Monitoring hepatic blood tests and periodic monitoring of fat soluble vitamins is recommended
My take: Though Alagille syndrome is a multisystem disease, improvement in pruritus due to cholestasis with an oral daily medication is an important advance/option. There is little systemic absorption and thus far a reassuring safety profile.
Pediatric Foreign Body IngestionsEsophageal StricturesEsophageal StricturesImaging for Acute PancreatitisImaging for Acute PancreatitisFor Acute Liver FailureFor Acute Liver FailureFor Acute Liver Failure
Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician. Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure. 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.
JM Boster et al. Liver Transplantation 2022; 28: 483-492. Malnutrition in Biliary Atresia: Assessment, Management, and Outcomes Good review article. Malnutrition and sarcopenia negatively impact pretransplant, peritransplant, and posttransplant outcomes and survival in children with BA.
E Alexander et al. JPGN 2022; 74: 333-337. Clinical Implications for Children Developing Direct Hyperbilirubinemia on Extracorporeal Membrane Oxygenation Key findings: 36/106 (34%) children developed direct hyperbilirubinemia (DHB) on ECMO. Illness acuity scores were significantly higher in the DHB group on ECMO day 2 (P = 0.046) and day 7 (P = 0.01). Mortality rate was higher in the DHB group 72%, versus 29% in the control group (P < 0.001).
Compared with the patients who underwent transplantation a age >1 year (n = 35), those who did so at age <1 year (n = 30) had a lower FSIQ (87.1 ± 12.6 vs 96.6 ± 13.8; P = .005) and lower verbal comprehension index (87.3 ± 13.8 vs 95.4 ± 13.0; P = .020).
Transfusion of >80 mL/kg (P = .004; adjusted for age at transplantation: P = .046) was also associated with detrimental effects on FSIQ.
No difference in IQ between tests was found in those patients tested more than once, indicating no significant improvement with more time after transplantation (first testing was at median of 4.1 years after transplantation and the second testing was at a median age of 6.7 years after transplantation)
“Our findings indicate that transplantation at early age has a pronounced effect on later neurocognitive impairment, and that this effect is separate from and more pronounced than the effect of cholestasis before transplantation.”
This study, using a rat animal model, demonstrated how gastro-resistant mixed micelles (MMs) could be used to overcome the limitations of current prophylactic vitamin K formulations which are associated with failures in newborns with unrecognized cholestatic liver diseases (1:2,500 live births).
Key findings:
Under cholestatic conditions, gastro-resistant formulations greatly improved vitamin K absorption.
Pathophysiology: “Our data provide an explanation why: unstabilized MMs will aggregate during gastric passage, once aggregated vitamin K will not be sufficiently resolubilized upon a subsequent pH increase”
My take: It is likely that these gastro-resistant MMs would be effective in pediatric patients. If proven in clinical trials, this would reduce bleeding events in infants and lower bleeding risks in those with chronic liver disease while obviating the need for parenteral Vitamin K.
Between February 2016 and December 2017, 2171 results were reported. Median turnaround time was 21 days.
583 pathogenic (P) variants, 79 likely pathogenic (LP) variants, and 3117 VOUS; 166 P/LP variants and 415 VOUS were novel.
The panel’s overall diagnostic yield was 12% (n = 265/2171) representing 32 genes with mutations identified (the panel tested up to 66 genes).
The top five genetic diagnoses for the group, in order: JAG1 + NOTCH2 (Alagille syndrome), ABCB11, SERPINA1, ABCB4, and POLG. (Table 3 lists all of the findings)
Other reports in the same issue describe a normal-GGT cholestasis due to USP53 deficiency
S Kemme et al. JPGN 2021; 72: 194-201. Outcomes of Severe Seronegative Hepatitis-associated Aplastic Anemia: A Pediatric Case Series This small case series (n=4) with HAAA found that this condition was poorly responsive to steroids, azathioprine and tacrolimus; however, Anti-Thymocyte Globulin (ATG) was associated with sustained biochemical remission of the hepatitis. Two patients underwent hematopoietic stem cell transplantation. All patients had extensive investigations. All had evidence of systemic hyperinflammation (with markedly-elevated ferritin and soluble IL-2 R levels) and CD8+ T cell predominant liver tissue infiltration.
Workup: In the well and stable premature with elevated DB, “aminotransferases, AP, GGT, glucose, T4, TSH, UC, urine CMV PCR, and US with Doppler evaluation should be obtained…Coagulation studies in well babies with other evidence of good synthetic function are not necessary.” Empiric ursodeoxycholic acid may be given with weekly evaluation.
Genetic testing: “Genetic panels are indicated in babies with no obvious risk factors after the first tier of studies…In critically ill babies with multisystem disease, critical whole exome sequencing (WES) is faster and provides broader results.”
Sepsis: Babies with sudden increase in DB and ALT should be evaluated for sepsis (including urosepsis) and CMV.
Nutritional support: Infants should be “supported with MCT and vitamin supplementation.”
Severe liver disease: “Babies with coagulopathy and marked elevation of aminotransferases who have multiorgan failure in the first few days of life need to be evaluated for perinatal complications, severe metabolic disease, and gestational alloimmune liver disease (GALD). In this period, ischemic shock or infectious disease is much more common than primary liver disease, but the presentations can overlap.”
Liver biopsy: “Liver biopsy should be pursued in babies whose cholestasis is not improving and the diagnosis is unclear.”
Etiology: Infection, genetic disease, cardiac dysfunction, large heme loads, and hypothyroidism are common causes of liver dysfunction in the NICU. Common findings included trisomy 21-associated liver dysfunction (n=12), and thyroid disease. 6 patients had type 2 Abenathy shunts -only one required closure. Two patients had biliary atresia. Other liver diseases identified included GALD (n=2), PFIC2, Alagille, Alpha-one-antitrypsin, Cystic Fibrosis, and Niemann-Pick.
Wahid N et al. AASLD 2020, Abstract 153. Summary from GI & Hepatology News: Liver-related deaths decline after Medicaid-expansion under ACA. “Beginning around 2015, liver-related deaths began to decline in expansion states by a mean of –0.6%, while they continued on an upward trajectory in the nonexpansion states…“It’s a no-brainer that the lack of insurance accessibility for the most vulnerable people in the United States meant that they were dying of cirrhosis instead of being transplanted,” said Elliot Benjamin Tapper, MD, of the University of Michigan, Ann Arbor.”
Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician. Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure. 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.
Below I’ve included a few slides and some notes; my notes may have errors of omission or transcription.
Can We Skip Liver Biopsies in Infants with Cholestasis? Jim Squires
Key points:
Data suggest that cholestasis in infants needs to be defined as direct bilirubin/conjugated bilirubin >0.3 (if TB <5) or 10% if TB >5.
Identifying cholestasis is challenging as cholestasis occurs in ~1 in 2500 whereas jaundice occurs in 15% of all infants
Genetic testing (eg. Cholestasis Panel, or exome) needs to be moved up earlier in diagnostic algorithm, after ultrasound completed and after A1AT & biliary atresia considered
Elevated bilirubin in newborns with Down syndrome has been previously reported but the frequency has not been well-described. A recent retrospective report (TM Bahr J Pediatr 2020; 219; 140-5) compared 357 neonates with Down syndrome to 377,368 controls.
Key findings:
Compared with control subjects, neonates with Down syndrome had 4.7 times the risk of having an initial total serum bilirubin exceeding the 95th percentile (23.5% vs 5.0%), 8.9 times the need for phototherapy (62.2% vs 7.0%) and 3.6 times the readmission rate for jaundice (17.4 vs 4.8 per 1000 live births).
The authors note that the basis for the increased risk of hyperbilirubinemia may be early hemolysis related to “neocytolysis” which is due to destruction of RBCs following a change from low to high oxygen exposure. Other factors could include slower bilirubin conjugation/elimination and poor feeding.
My take: This study indicates that infants with Down syndrome have a substantial risk of hyperbilirubinemia. And, while you are checking a bilirubin, it is worthwhile to obtain a direct bilirubin as cholestasis is increased in infants with Down syndrome too; the latter is often transient and/or associated with other organ involvement.
A recent double-blind randomized study (A Repa et al. J Pediatr 2018; 194: 87-93) compared a mixed lipid emulsion (SMOFlipid) to a soybean-oil lipid in 223 extremely low birth weight infants. Median time on parenteral nutrition was ~23 days.
Key findings:
The primary outcome of parenteral nutrition associated cholestasis (PNAC) was NOT significantly different in the two groups: 10.1% for SMOF and 15.9% for control group (P=.20).
No other outcome measures were affected, including ROP, BPD and growth.
The authors note that even the control group had less cholestasis than previous cohorts and indicated that the use of probiotics and possibly more aggressive enteral feeds were at work.
My take (borrowed in part from authors): These results “cannot be generalized to infants with substantially longer time on PN.” However, this study shows that SMOFlipid alone will not prevent cholestasis, which is well-known to be multifactorial.
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