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

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.

Related blog posts:

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.”

Related blog posts:

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

Most Popular 2022 Posts

The list of the most viewed gutsandgrowth blog posts in 2022.

Links to Posts:

MMP-7 Helps Sort Out Biliary Atresia from Parenteral Nutrition-Associated Liver Disease

PS Salvi et al. J Pediatrics 2022; 249: 97-100. Open access! Comparing Serum Matrix Metalloproteinase-7 in Parenteral Nutrition-Associated Liver Disease and Biliary Atresia

In this single-center retrospective study with 19 patients, MMP-7 and GGT values were compared in children who were diagnosed with Parenteral Nutrition-Associated Liver Disease (PNALD, n=15) and Biliary atresia (n=4). Key findings:

  • Median MMP-7 values for PNALD patients 37.8 ng/mL was much lower than MMP-7 values for biliary atresia 112.3 ng/mL.
  • GGT values were not statistically significantly different 116 for PNALD vs 248 for biliary atresia
  • In this cohort, a MMP-7 threshold of 52.8 ng/mL had a sensitivity of 100% and specificity of 93.5% for biliary atresia.

My take: MMP-7 values reduce diagnostic uncertainty between PNALD and biliary atresia. However, there are infrequent cases of biliary atresia with lower values of MMP-7.

Related blog posts:

Two Sisters Pierre-August’s Renoir

NASPGHAN22: History of Pediatric GI & Selected Slides from the William F Balistreri Lecture (Part 1)

Shortly before attending medical school, I read a book by Lewis Thomas called The Youngest Science. The narrative explains the evolving of medicine into a sophisticated science. The recent Balistreri lecture (given by Dr. Balistreri himself) provides a similar narrative but focused on our specific subspecialty.

Here are some of the slides:

It was not until 1982 that the role of H pylori was recognized as a causative agent for peptic ulcer disease

Pediatric Drug-Induced Liver Injury

F Monge-Urrea, E Montijo-Barrios. JPGN 2022; 75: 391-395. Drug-induced Liver Injury in Pediatrics

Background: Antibiotics and antiepileptics remain the most frequent causes of DILI. DILI may result in severe outcomes (eg liver transplant) in up to 5% of cases and could result in chronic liver disease in ~20%.

This is a terrific review -Figure 1 is particularly helpful. Figure 1 is an algorithm. Prior to using algorithm, review potential hepatoxcity by searching in NIH Livertox website. Next steps:

  1. Calculate pattern of injury (R score). R= ALT/ULN divided by ALP/ULN (ALP =alkaline phosphatase)
  2. Identify suspect drug. Hepatocellular (R >/=5), Mixed (R=2-5), Cholestatic (R</= 2). Examples of hepatocellular include acetaminophen, NSAIDs, Minocycline. Examples of mixed include azathioprine, and sulfasalazine. Examples of cholestatic include amoxicillin/clavulanate, and TMP/SMX
  3. Exclude alternative causes
  4. Calculate RUCAM Score (detailed in Table 1). This score can also be found at this link (open access): Overview of causality assessment in drug-induced liver injury
  5. Discontinue implicated drug and review specific therapies. For example, N-acetylcysteine for acetaminophen, and carnitine for valproate
  6. Consider liver biopsy only if suspected DILI progresses or fails to resolve on withdrawal of suspect drug (resolution can take 3-4 months)

Drug stop rules are reviewed:

  • ALT or AST values that exceed 8 times the ULN
  • ALT or AST values that exceed 5 times the ULN -hold medication for 2 weeks
  • ALT or AST values >3 times the ULN and Bilirubin >2 times the ULN
  • ALT or AST values that exceed 3 times the ULN with progressive nonspecific symptoms

Related blog posts:

Crow’s Pass Trail, AK

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.

Selected Slides from NASPGHAN 2022 Postgraduate Course (Part 1)

Pediatric Foreign Body Ingestions
Esophageal Strictures
Esophageal Strictures
Imaging for Acute Pancreatitis
Imaging for Acute Pancreatitis
For Acute Liver Failure
For Acute Liver Failure
For 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.

Unfortunate or Unfair Disparities in Liver Transplantation

In medical school, I took additional courses in bioethics and one of the influential lecturers was Tristramm Engelhardt (Right to Health Care).  “According to him, injuries, disabilities, and diseases arising from natural causes are considered unfortunate. On the other hand, those situations become unfair when brought about by the doing of others. Engelhardt also notes that the result of someone’s unfair action should not be attributed to the society as a whole.”

Two recent articles detail the link between socioeconomics and outcomes in liver transplantation. Are these problems unfair or just unfortunate?

NH Ebel et al. Liver Transplantation 2022; 28: 1521-1529. A review of racial, socioeconomic, and geographic disparities in pediatric liver transplantation

Key points:

  • Disparities remain in pediatric liver transplantation at all time points: from access to referral for transplantation, likelihood of living donor transplantation, use of exception narratives, waitlist mortality, and inequitable posttransplant outcomes
  • Black children are less likely to be petitioned for exception scores, have higher waitlist mortality, are less likely to be the recipient of a living donor transplant, and have worse posttransplant outcomes compared with White children.
  • Children living in the most socioeconomically deprived neighborhoods have worse posttransplant outcomes.
  • Children living farther from a transplant center have higher waitlist mortality

KA Mohamed et al. Liver Transplantation 2022; 28: 1441-1453. Open access! Neighborhood poverty is associated with failure to be waitlisted and death during liver transplantation evaluation

Key points:

  • Based on retrospective analysis of 3454 patients (2011-2018), neighborhood poverty was independently associated with waitlisting (odds ratio 0.56, 95% confidence interval [CI] 0.38–0.82) and death during LT evaluation (hazard ratio 1.49, 95% CI 1.09–2.09)
  • Despite use of the objective prioritization with MELD scores in the allocation of organs, disparities in access for LT continues for vulnerable populations

My take: It is unfortunate but not surprising that poverty and socioeconomic factors adversely affect liver transplantation; the outcomes show stark differences. These issues, however, affect every aspect of health care (& beyond). Though they are not easily addressed, efforts to try to level the playing field are important especially with regard to transplantation to assure optimal use of this life-saving resource.

Related blog posts:

Portage Pass Trail (near Whittier AK) with views of Portage glacier

Autoimmune Hepatitis: Safety of Low Dose Steroids and Utility of Aminotransferases

K Manwani et al. JPGN 2022; 75: 252-256. Long-Term Growth in Children and Young People with Autoimmune Liver Disease Treated with Daily Steroids

This retrospective study of patients (n=74) diagnosed with autoimmune hepatitis (AH) prior to 16 years of age examined the safety of low dose steroids. Median age of patients with 12.8 yrs and median followup was 12.6 years. Typically, after induction, patients were tapered over ~2 months to 5 mg per day (& 2.5 mg per day if <12 years). Key findings:

  • Growth of patients with AILD on a daily maintenance dose of steroids remains stable and within normal range during long-term follow up.  At all time-points, the mean z-scores for weight, height and BMI were within the normal range, indicating normal nutritional status. 
  • Small, daily doses are effective in maintaining disease control and minimize the need for high-dose steroid pulses during relapses.
  • In this cohort, there were 14 patients in which prednisolone was utilized as monotherapy; the majority received cotherapy with azathioprine (n=44), mycophenolate (n=12); triple-therapy was utilized tacrolimus (n=4).
  • Prednisolone was stopped in 17 patients (23%) after a median time of 9.5 years (range 3 years-14 years)

M Biewenga et al. Clin Gastroenterol Hepatol 2022; 20: 1776-1783. Open access! Aminotransferases During Treatment Predict Long-Term Survival in Patients With Autoimmune Hepatitis Type 1: A Landmark Analysis

In this multicenter cohort study (n=301), it was shown that higher aminotransferases during treatment were independent of baseline risk factors associated with liver transplantation–free survival in patients with AIH type 1. Median followup was 99 months. Key finding:

  • During follow-up, 15 patients required liver transplantation and 33 patients died
  • In multivariate analysis AST at 12 months (HR, 2.13; P < .001) was predictive for survival independent of age, AST at diagnosis and cirrhosis, while IgG was not associated with survival (HR, 1.30; P = .53)
  • There was a trend toward a worse survival in patients with mildly elevated aminotransferases (1–1.5× upper limit of normal) compared with patients with normal aminotransferases (P = .097)

My take: Normalization of AST (aminotransferases), especially during the first year of treatment, is associated with better long-term outcomes. The study by Manwani et al suggest that long-term low dose steroids are associated with low risks.

Also: Y Li et al.Hepatology 2022; 76: 564-575. Genome-wide meta-analysis identifies susceptibility loci for autoimmune hepatitis type 1 This study with 1622 Chinese patients identified two novel loci (CD28/CTLA4/ICOS and SYNPR) and may provide potential targets for additional treatments.

Related blog posts:

AST Values and Cumulative Live Transplant-Free Survival

Liver Briefs: Hep C Undertreated, Mystery Hepatitis Pediatric Cases, & AAP Hyperbilirubinemia Guidelines

Yesterday’s link to a funny 2 minute eulogy did not work right and has been fixed. Here is the updated link and it should work: Humor: Eulogy

In response to this video, Steven Liu sent me a link to a a Weird Al Yankovic:YouTube: Word Crimes. This link would probably be helpful for those reviewing a poorly-written journal submission when providing feedback (& hopefully not sent to anyone trying to provide information via a GI blog).

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USA Today (8/9/22): Fewer than a third of insured Americans with hepatitis C receive timely treatment, CDC study shows

“More than 95% of people infected with hepatitis C can be cured with a simple course of antivirals…[the CDC] looked at nearly 50,000 insured patients diagnosed with hepatitis C between January 2019 and October 2020 and found less than one-third received treatment within a year of their diagnosis, according to the study published Tuesday in the Morbidity and Mortality Weekly Report...Treatment was lowest among patients who had state-administered Medicaid plans, with about 23% receiving it. About 28% people covered by Medicare and 35% with private insurance received treatment within the year.”

“Cases of hepatitis C rates have skyrocketed as the opioid epidemic worsens, jumping from an estimated 2,700 infections in 2011 to 57,500 infections in 2019, according to the CDC.”

NY Times (7/26/22): Viral Infections and Gene Variant Are Linked to Child Hepatitis Cases

“Two small studies…suggest a possible explanation for the hepatitis cases: In a small subset of children with this particular gene variant, dual infections with A.A.V.2. (adeno-associated virus 2) and a helper virus, often an adenovirus, trigger an abnormal immune response that damages the liver….As of July 8, 1,010 probable cases had been reported from 35 countries, according to the World Health Organization”

AR Kemper et al. Pediatrics 2022; https://doi.org/10.1542/peds.2022-058859. Open Access: Clinical Practice Guideline Revision: Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation

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.