#NASPGHAN19 Liver Symposium Notes (Part 1)

Although I was unable to attend this year’s liver symposium at NASPGHAN19, I reviewed the lecture notes.  There is some terrific content.  Here are some of the slides (borrowed with permission from NASPGHAN).

Link to complete NASPGHAN Chronic Liver Disease Symposium 2019

Session I

How do I best evaluate a cholestatic infant? Sanjiv Harpavat MD Texas Children’s Hospital 

Related blog post: What is the evidence that biliary atresia starts in utero?

As for this algorithm, in my opinion, the 1st step needs to be to exclude emergencies associated with infantile cholestasis: coagulopathy, hypoglycemia, sepsis, and checking urine for reducing substances (cow’s milk formula can worsen liver disease if galactosemia is present). Subsequently, evaluation needs to proceed quickly to determine the etiology.

How do I interpret genetic results?  Saul J. Karpen MD, PhD, Emory University School of Medicine/Children’s Healthcare of Atlanta

What do abnormal liver enzyme levels mean in a tween?  William F. Balistreri MD, Cincinnati Children’s Hospital Medical Center

What do I do with this abnormal radiology finding? Jean Molleston MD, Riley Children’s Hospital

I have not selected slides from Dr. Molleston’s handout –the images are terrific.  For most of the problems that are presented, the lecture notes do not provide specific recommendations for management.

Disclaimer: NASPGHAN/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. The discussion, views, and recommendations as to medical procedures, choice of drugs and drug dosages herein are the sole responsibility of the authors. Because of rapid advances in the medical sciences, the Society 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. Some of the slides reproduced in this syllabus contain animation in the power point version. This cannot be seen in the printed version.

 

 

30 -Year Outcomes with Biliary Atresia

M Fanna et al. JPGN 2019; 69: 416-24. In this retrospective 30-year study (1986-2015) from France, patients were examined in 4 time cohorts: 1986-96, 1997-2002, 2003-9, and 2010-5.

  • Age at Kasai operation remained stable throughout the study period -median 59 days.
  • Early Kasai was associated with a reduced need for liver transplantation. 25-year survival with native liver was 38%, 27%, 22%, and 19% for patients operated in first, second, third months or later respectively.
  • Clearance of jaundice (total bilirubin ≤20 micromol/L) after Kasai did not change appreciably in the time cohorts and was 38.8%.
  • 753 (of 1428 in cohort) patients underwent liver transplantation.
  • Overall survival of entire cohort was 87% (including all levels of followup).
  • Survival after LT was 79% at 28 years.
  • Five-year patient survival after LT was 76%, 91%, 88%, and 92% in the cohorts, indicating better survival more recently.
  • 22% of patients reached age 30 years without transplantation.

The authors note that better outcomes were noted in a long-term study from Japan where there are lower rates of LT needed for biliary atresia. IN Japan 20-year survival with native liver and overall patient survival was 48% and 89%, compared to 26% and 76% in France.

My take: This study indicates that the majority of patients with BA will require liver transplantation and that earlier Kasai operation is associated with a better chance of survival with native liver.  It is likely that data in the U.S. would be more similar to France than Japan based on prior publications.

Related blog posts:

Ecola State Park, OR

Liver Briefs -October 2019

Briefly noted:

M Mouzaki et al. JPGN 2019; 69: 339-43. In a cohort of 228 patients with 17 (8%) who were receiving psychotropic medications, the use of psychotropic medications was associated with increased nonalcoholic fatty liver disease (NAFLD) severity.  These patients were more likely to be receiving metformin (53% vs 18%) and antihypertensive medications (29% vs 8%).

S Honigbaum et al. JPGN 2019; 69: 344-50. Among 20 infants with biliary atresia, tissue had abundantly expressed lysly oxidase-like 2 (LOXL2) compared to controls.  LOXL2 is an extracellular matrix enzyme that catalyzed cross-linking of collagen and elastin; LOXL2 likely contributes to fibrosis.

What Is The Evidence That Biliary Atresia Starts in Utero?

A good read: KR Mysore, BL Shneider, S Harpavat. JPGN 2019; 69: 396-403.

This review dissects the evidence that biliary atresia (BA) most often begins in utero.

Key points:

  • Infants with BA have elevated conjugated/direct bilirbuin at birth.
  • Infants with BA have biliary abnormalities on fetal ultrasound (eg. gallbladder abnormalities, biliary cysts).
  • Infants with BA have abnormal gamma-glutamyl transferase levels in their amniotic fluid with low levels noted at gestational age 18-19 weeks.  This finding is not specific for BA as other conditions that affect biliary tree (eg. cystic fibrosis, trisomy 21) can have low levels as well.
  • BA is more common in premature infants.
  • Early recognition is important. In U.S (from 1976-89), transplant-free survival rates were 63% for Kasai when done in 1st 30 days, 44% for 30-60 days, 40% for 60-90 days, and 29% if >90 days.
  • A diagnostic approach is given in Figure 2 but is already out of date due to the availability of MMP-7 testing (article received by JPGN in January 2019).

This review also lists numerous current investigative therapies which include probiotic, steroids, desflurane/sevoflurane (anesthetics), pentoifyline, IVIG, vancomycin, meloxicam, GCSF, Bone marrow stem cells, N-acetylcysteine, and obeticholic acid.

My take: This article shows that the clock on liver injury begins in utero in most cases of BA and this will have implications on pathogenesis and management.

Related blog posts:

Cannon Beach, OR from Ecola State Park

Liver Briefs -September 2019

P Rosenthal et al. Hepatology 2019; 69: 2326-37.  This study examined the efficacy and safety of combined entecavir and Peginterferon for immune-tolerant chronic hepatitis B-infected children (n=60). 48 weeks after completing treatment (week 96), 2 children (3%) achieved the primary outcome of undetectable HBeAg with HBV DNA levels <1000 IU/mL.  These two children were also HBsAg negative/anti-HBs positive. In the other children (55 completed study), the ALT and HBV DNA levels were similar to baseline.  37 children experienced adverse events.  My take: Entecavir/peginterferon is not very effective in immune-tolerant children infected with chronic HBV.

DL Thomas. NEJM 2019; 380: 2041-50. This article reviews the pathway to the global elimination of chronic hepatitis.  Currently, it is estimated that hepatitis C virus (HCV) and hepatitis B virus (HBV) kill more than 1 million persons each year. “In fact, by 2040, deaths from chronic hepatitis are projected to exceed the combined mortality associated with HIV infection, tuberculosis, and malaria.”

JR Dillman et al. J Pediatr 2019; 212: 60-5. This study with 41 patients and 13 patients with biliary atresia prospectively assessed ultrasound shear wave elastography (SWE). The authors found that SWE with a cut-off value of >1.84 m/s had 92% sensitivity and 79% specificity.  Also, in their cohort, GGT >320 had a sensitivity of 100% and specificity of 78%.

Z Younossi et al. Hepatology 2019; 69: 2672-82.  This review provides a global perspective of NAFLD.  25% of the world’s population is currently thought to have NAFLD with highest prevalence in South America at 30.45% and lowest in Africa at 13.5%. This article usggest North America to have 24.1% prevalence rate.

Briefly Noted: Alpha-Fetoprotein Norms for Beckwith-Wiedeman Spectrum

Alpha-fetoprotein (AFP) levels are increased in >95% of patients with hepatoblastoma.  These levels have to be interpreted carefully in infants as these levels typically are elevated in the first 6-12 months of life.

For patients with Beckwith-Wiedeman Spectrum (BWS), the relative risk of hepatoblastoma has been estimated to be 2280 times greater than the general population.  In addition, in patients with BWS, AFP levels are known to be elevated compared to the general population in the absence of hepatoblastoma as well.

A recent study (KA Duffy et al. J Pediatr 2019; 212: 195-200) obtained 1372 AFP levels from 147 patients to establish normative values.

Table 2 -will be a useful reference. The authors found that AFP values were significantly higher in premature infants with BWS compared to full term and gradually approached normal levels around 12 months of life.

Some example AFP (95% CI) values from the entire cohort:

  • 1 week 5364 (3554-8095)
  • 4 weeks 3134 (2136-4597)
  • 12 weeks 849 (613-1176)
  • 6 months 134 (102-177)
  • 12 months 13.8 (11.1-17.3)

My take: This article will be very useful when monitoring for the risk of hepatoblastoma in patients with BWS

 

 

SMOFlipid vs. Intralipid for Intestinal Failure Patients

A recent study (C Belza et al. JPEN 2019; https://doi.org/10.1002/jpen.1692) showed that SMOFlipid reduced the frequency of cholestasis in intestinal failure patients. Thanks to Kipp Ellsworth for reference.

An Observational Study of Smoflipid vs Intralipid on the Evolution of Intestinal Failure–Associated Liver Disease in Infants With Intestinal Failure. From Abstract:

Methods

This was a retrospective cohort study of infants with IF with a minimum follow‐up of 12 months in 2008–2016. Patients were stratified into 2 groups: group 1 received SMOFlipid; group 2 was a historical cohort who received Intralipid. The primary outcome was liver function evaluated using conjugated bilirubin (CB) levels…

Results

Thirty‐seven patients were evaluated (17 = SMOFlipid, 20 = Intralipid). SMOFlipid patients were less likely to reach CB of 34 (24% vs 55%, P = 0.05), 50 µmol/L (11.8% vs 45%; P = 0.028), and did not require Omegaven (0% vs 30%; P = 0.014). CB level at 3 months after initiation of parenteral nutrition (PN) was lower in patients receiving SMOFlipid (0 vs 36 µmol/L; P = 0.01). Weight z‐scores were improved for patients receiving SMOFlipid at 3 months (−0.932 vs −2.092; P = 0.028) and 6 months (−0.633 vs −1.614; P = 0.018).

Related blog posts:

Crater Lake, OR