This retrospective study analyzed data from 11,965 infants who had fractionated bilirubin obtained in the nursery (2016-2019). Key findings:
DB of 0.6 mg/dL was chosen as the cut-off based on a high sensitivity (100%) and specificity (99%) for screening newborns for CLD
Out of 60 infants who met criteria for DB ≥0.6 mg/dL, only 15 (25%) had a repeat level drawn after nursery discharge; 3 (5%) were eventually diagnosed with CLD (2 with BA and 1 with Alagille syndrome)
It is fairly easy to get fractionated bilirubins on infants. Many need to get a bilirubin check and in many centers, a fractionated bilirubin is automatically generated at no additional costs. The hard part is making sure that those with abnormal values receive timely followup.
My take: It is a mistake to get fractionated bilirubins in newborns unless one has developed a plan/infrastructure to make sure those with abnormal values receive appropriate followup.
Ten males [mean 15.1 years, standard deviation (SD) 2.2] with NASH were randomized to once daily treatment with Elafibranor: 80 mg (n = 5) or 120 mg (n = 5). Elafibranor, a dual peroxisome proliferator-activated receptor α/δ agonist, has been proposed as a treatment for nonalcoholic steatohepatitis (NASH, aka Metabolic dysfunction-associated steatohepatitis (MASH)). Key findings:
End of treatment mean ALT was 52 U/L (SD 20) for the 120 mg group, with a relative mean ALT change from baseline of −37.4% (SD 23.8%) at 12 weeks.
Elafibranor was rapidly absorbed and well tolerated.
My take: I think we are on the verge of identifying medications which will be able to improve outcomes for those with steatotic liver disease.
This retrospective study (2005-2019) used an administrative data from a large integrated healthcare network in Utah to identify newborns with abnormal fractionated bilirubins. since 2005, all newborns at this healthcare system had a fractionated bilirubin measured.
Key findings:
There were 252 892 newborns with fractionated bilirubin assessed, including 26 of those subsequently confirmed to have biliary atresia (BA).
Conjugated or direct bilirubin was elevated in all 26 infants with BA and an additional 3246 newborns (1.3%) without BA. The lowest direct bilirubin in the BA group was 0.6, just above cutoff value of 0.5 mg/dL. The conjugated bilirubin cutoff value wa 0.2 mg/dL.
The 15-year crude birth prevalence of BA was 0.68 per 10,000 births in this cohort
Median time to Kasai HPE was 69.5 days
This study found that all infants with BA have elevated conjugated or direct bilirubin at birth. The authors estimate that a healthcare system with about 30,000 deliveries per year, would have between 450 and 630 newborns that would require a second screen. In this group, 96 per 100,000 screened newborns (~1 in 1000) will have a positive second screen at 2-week well check and need further evaluation.
What I don’t understand about this paper is how the authors omit a discussion of the age of Kasai HPE. How is it that all of these newborns received a fractionated bilirubin and the age of Kasai HPE is not improved compared to other U.S locations that have not implemented universal testing? (Previous data from 15 ChiLDReN sites indicate age of Kasai HPE 65-70 days and unchanged over past 30 years, see blog post: Online Aspen Webinar (Part 5) -Biliary Atresia Diagnosis and Screening).
The authors note that implementation of screening could be improved with newer tests (eg. MMP-7) but that more analysis is needed to determine if screening is cost-effective and avoids harm (eg. subjecting healthy newborns to invasive testing).
My take: If universal screening is implemented, it is imperative to show that it helps and to set up the needed infrastructure to arrange appropriate followup. The first surrogate marker of this effort would be improving the age of surgical intervention.
As an aside, I find the new page numbering by The Journal of Pediatrics to be quite annoying. When you are going through the hard copy of the Journal, it is more difficult to find the articles that are listed in the table of contents because the articles are not ordered by lowest to highest numbered page. Each article is given a single page number like 113339 in this article but inside the article it is numbered page 1–10 (or however long the pages). The article prior could be a lower or higher page number. Until hard copies are eliminated, it would be an improvement if the articles could at least be ordered such that the next article would not have a lower page reference than the preceding article.
In this study, serum was assessed from 32 biliary atresia (BA) patients and 27 controls.
Key findings:
Median MMP-7 was higher in BA (96.4 vs 35 ng/mL; P < 0.0001) with an optimal cut-off value of 69 ng/mL. Sensitivity and specificity was 68% and 93%, respectively [negative predictive value (NPV) = 71%]
Median osteopontin (OPN) was higher in BA (1952 vs 1457 ng/mL; P = 0.0001) and an optimal cut-off of 1611 ng/mL. Sensitivity and specificity was 84% and 78%, respectively (NPV = 81%)
The authors note that numerous studies from Asian countries have shown very high sensitivity and specificity for MMP-7. These studies used different cut-offs based on the testing kit. One limitation of this study was that samples were stored for a median of 12 years and perhaps this affected the results (some prior studies also used banked specimens).
My take: When these levels are very elevated, they are highly suggestive of BA. This study serves as a caution to note that the sensitivity at typical cut off values could be suboptimal
Using NHANES data for 12-19 year olds, the authors examined rates of elevated ALT. Elevated ALT was defined as >22 U/L (females) and >26 U/L (males) Key findings:
Prevalence of elevated ALT in adolescents was 16.5% overall and 39.5% among those with obesity
For White (W), Hispanic (H), and Asian (A) adolescents, prevalence of elevated ALT was 15.8%, 21.8%, and 16.5% overall. In overweight adolescents, 12.8% (W), 17.7% (H), and 27.0% (A), and in those with obesity, 43.0% (W), 43.5% (H), and 43.1% (A) in those with obesity, respectively
Prevalence was much lower in Black adolescents (10.7% overall, 8.4% for overweight, 20.7% for obesity)
Prevalence ofALT at 2X-ULN was 6.6% in adolescents with obesity
Hispanic ethnicity, age, male sex, and higher BMI were independent predictors of elevated ALT
My take: It is hard to get very excited about a mildly elevated ALT value when 1 in 6 adolescents has this as well as ~40% of adolescents with obesity.
Background: Waitlist (WL) mortality is highest in children under the age of 1 year (12.5 deaths/100 WL years).2 It is thought that TVG (technical variant grafts) [including living donor (LD) and deceased donor split/partial grafts] improve outcomes.
Methods: The authors, in this retrospective study, analyzed Organ Procurement and Transplantation Network (OPTN) data on first-time LT or liver-kidney pediatric candidates listed at centers that performed >10 LTs during the study period, 2004–2020.
Key findings:
Sixty-four centers performed 7842 LTs; 657 children died on the WL
Death from listing was significantly lower with increased center TVG usage (HR = 0.611) and LT volume (HR = 0.995)
Recipients of LD transplants (HR = 0.637) had significantly increased survival from transplant compared with other graft types, and recipients of deceased donor TVGs (HR = 1.066) had statistically similar outcomes compared with whole graft recipients
My take (borrowed from authors): “LD partial grafts and overall volume performed by the center in the preceding 3 years was significantly associated with increased post-LT survival. Deceased donor graft type (DD TVG vs. DD Whole) was not a predictor of post-LT survival after accounting for patient diagnosis, center volume, and other significant factors that were predictive of survival. DD TVG should not be considered an inferior graft option in experienced centers…LD grafts are associated with a survival advantage.”
“While outcomes have improved, with current 1- and 5-year patient survival >97% and 94%, respectively, many children continue to die on the waitlist (WL) or are removed because they are too sick.1,2“
“As expected, these children were younger, smaller, sicker (more status 1 listings), and remained on the WL longer than children who received a transplant during the same time period…These small infants are particularly at risk because of the difficulty of obtaining an appropriately sized-matched graft. Data indicate that this problem can be solved largely by increasing the use of technical variant grafts (TVGs), which includes living donor (LD) grafts and split/reduced grafts from deceased donors (DDs).4,5“
“This manuscript obliquely touches on another pressing issue within the pediatric LT community, namely, the core skill set of a pediatric LT surgeon. Currently, there is no such distinct designation in the North American training environment, and therefore, no training requirements exist. To provide the full spectrum of surgical care, the technical skill set should include LD hepatectomies and graft implantations, DD graft reduction/splitting, the reduction or hyper-reduction of left lateral segment grafts, and staged abdominal closure.”
My take: Where a patient is listed is a very important variable in outcomes. Choosing a low volume center without availability to perform TVG increases the risk of lethal outcomes. This information should be disclosed to families at all centers.
Health care resource utilization and costs associated with pediatric LT were retrospectively assessed using insurance claims data from the US IBM MarketScan Commercial and Medicaid databases collected between October 2015 and December 2019. Study cohort: 53 commercially insured and 100 Medicaid-insured children
Key findings: Commercially insured and Medicaid-insured patients averaged US $512,124 and $211,863 in medical costs and $26,998 and $15,704 in pharmacy costs, respectively
A total of 236 panelists from 56 countries participated in four online surveys and two hybrid meetings.
Key points:
Steatotic liver disease (SLD) was chosen as an overarching term to encompass the various “aetiologies” of steatosis.
The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease (MASLD). There was consensus to change the definition to include the presence of at least one of five cardiometabolic risk factors (see 2nd figure).
The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. Metabolic dysfunction-associated steatohepatitis (MASH) is the replacement term for NASH.
Those with no metabolic parameters and no known cause were deemed to have cryptogenic SLD.
A new category, outside pure MASLD, termed MetALD was selected to describe those with MASLD who consume greater amounts of alcohol per week (140 to 350 g/week and 210 to 420 g/week for females and males respectively).
AASLD News Digest: “MASLD, formerly known as NAFLD, is the most common chronic liver disease around the world, affecting more than 30% of global population. This was why it was vital that the global liver community coalesce around an affirmative, non-stigmatizing name and diagnosis. Ultimately, the global members of the Nomenclature Development Initiative were focused on ensuring the global community had better nomenclature that could be used around the world so that the research and funding could be better directed to save more people’s lives.”
My take: NAFLD is now MASLD –time to update patient handouts (hopefully someone at GIKids.org is on top of this). Aslo, if you have really bad disease, should it be called the ‘monster MASH’ ?
Methods: This population study assessed all confirmed cases of BA, from January 2020 to December 2021 across the 3 UK pediatric liver centers originating from England and Wales. Data was then compared to the incidence of confirmed BA cases from January to December 2017, 2018, and 2019.
Key findings -BA cases:
2017: 16
2018: 13
2019: 18
2020: 8
2021: 12
This difference was significant in a two-sided t test for 2020 (P = 0.035) but not for 2021 (P = 0.385)
The authors note that new BA diagnoses were reduce among Danish centers as well. In their discussion, the authors discuss the possibility of missed diagnosis versus an actual drop in BA cases. The later is intriguing due to concerns that perinatal infections could trigger BA.
My take: This study provides a piece of a puzzle regarding the etiology of BA, indicating a good likelihood of environmental/infectious etiologies as a trigger.
This prospective study with 27 term infants (<7 days) with mild unconjugated hyperbilirubinemia (total bilirubin 6-12 mg/dL) (to convert to micromol/L multiple by 17.1) and with sepsis. Free bilirubin concentrations were measured by the peroxidase method using a UB analyzer and a Zone Fluidics device before (baseline) and 15 minutes after (follow-up) IV ceftriaxone administration on postnatal days 4 to 6.
Key findings:
The mean free bilirubin (μg/dL) at follow-up was not different from that at baseline when measured by the UB analyzer (P = .78). The mean free bilirubin was significantly lower at follow-up compared with baseline when measured by the Zone Fluidics device (P = .02). The ratio of a free bilirubin with and without ceftriaxone, an index of displacing effect, was 1.02 (95% CI 0.89-1.14) using the UB analyzer and 0.58 (95% CI 0.30-0.86) using the Zone Fluidics device.
Ceftriaxone has been considered contraindicated in the presence of neonatal unconjugated hyperbilirubinemia due to concern of bilirubin displacement from albumin, resulting in elevated serum free bilirubin (& risk of kernicterus). However, “most of the evidence for the bilirubin-displacing effect of IV ceftriaxone has been derived from in vitro studies.”
My take: This study indicates that there is no significant effect of ceftriaxone in increasing free bilirubin in term infants with mild unconjugated hyperbilirubin
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This is a very helpful review. Table 1 lists treatment indications by group. For example, AASLD recommendations:
Table 3 compares the effectiveness of current treatments
Table 4 describes the large number (~50) of antiviral agents in development and their mechanism of action
The authors recommend HCC surveillance in those with cirrhosis every 6 months with ultrasound with or without serum AFP
“Although current therapy is associated with improved clinical outcome, it is not curative because of a lack of effect on cccDNA and integrated HBV DNA. Stopping therapy in the absence of HBsAg loss usually leads to relapse to active disease in most patients and thus treatment must be administered long term.”
“Many challenges remain, the sheer breadth of therapeutic approaches in development holds great promise for curing and eliminating chronic HBV infection”
My take: While it is likely that newer medications will help many with chronic hepatitis B, the best hope for eliminating HBV continues to be with prevention and vaccination.
Key finding: In this study with more than 30 years of prospective followup (n=214): n a multivariate analysis, both an HBsAg titer >4.44 log10 IU/mL at 15 years of age and HBV genotype C were predictors of advanced fibrosis (odds ratios, 15.43 and 4.77; P = .01 and P = .02, respectively).
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