Liver Shorts -March 2021. Neonatal liver disease, Hepatitis-Associated Aplastic Anemia & Two

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.

C Potter. JPGN Reports 2021; 1: e031. doi: 10.1097/PG9.0000000000000031. Full text: The Role of a NICU Hepatology Consult Service in Assessing Liver Dysfunction in the Premature Infant This was a retrospective observational study of 157 consecutive babies were evaluated by a single hepatologist. The approach outlined by this study:

  1. 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.
  2. 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.”
  3. Sepsis: Babies with sudden increase in DB and ALT should be evaluated for sepsis (including urosepsis) and CMV.
  4. Nutritional support: Infants should be “supported with MCT and vitamin supplementation.”
  5. 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.”
  6. Liver biopsy: “Liver biopsy should be pursued in babies whose cholestasis is not improving and the diagnosis is unclear.”
  7. 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.

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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.”

W-M Choi et al. Clin Gastroenterol Hepatol 2021; 19: 246-258. Effects of Tenofovir vs Entecavir on Risk of Hepatocellular Carcinoma in Patients With Chronic HBV Infection: A Systematic Review and Meta-analysis “In a meta-analysis of studies of patients with chronic HBV infection, we found that TDF treatment was associated with a significantly lower (20%) risk of HCC than entecavir treatment. Randomized trials are needed to support this finding.” This analysis comprised 15 studies (61,787 patients; 16,101 patients given TDF and 45,686 given entecavir).

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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.

Online Aspen Webinar (Part 5) -Biliary Atresia Diagnosis and Screening

Online Webinar –Annual Aspen Conference  —July 14, 2000

Below I’ve included a few slides and some notes; my notes may have errors of omission or transcription.

Biliary Atresia -Prompt Diagnosis and Screening Ronald Sokol

Key Points:

  • We have NOT improved age of diagnosis in biliary atresia in the past 30 years
  • Uniform screening of fractionated bilirubin has been effective in Texas:  Diagnostic Yield of Newborn Screening for Biliary Atresia Using Direct or Conjugated Bilirubin Measurements S Harpavat et al. JAMA 2020; 323: 1141-50
  • Pale stools are usually NOT due to biliary atresia but should prompt investigation (eg. fractionated bilirubin)
  • MMP-7 may improve diagnostic approach; unclear if MMP-7 performs well in all populations (eg. prematurity)
  • Outcome key factors: age at diagnosis (goal less than 30-45 days) and surgeon/center

 

Related blog posts:

Online Aspen Webinar (Part 1)

Online Webinar –Annual Aspen Conference  —July 14, 2000

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

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Not part of webinar:

Elevated Bilirubin in Newborns with Down Syndrome

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.

Related blog post: Neonatal cholestasis and Down syndrome

Island Ford Nat’l Recreation Area/Chattahoochee River, Sandy Springs

Double-Blind Randomized SMOFLipid Study

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.

Sandy Springs

Favorable Fish Oil Outcomes in High Risk Preterm Infants

Briefly noted: M Sorrell et al. JPGN 2017; 64: 783-88. In this small study with 13 infants (mean gestational age of 28 weeks) who had short bowel syndrome or severe dysmotility and direct bilirubin ≥4 mg/dL (mean 9.8 at enrollment), patients received a fish oil-based lipid emulsion (1 g/kg/d). They were compared with 119 GA-matched controls.

Overall, the authors found the fish oil supplement to be safe.  All patients had resolution of cholestasis. They note the difficulty of proving effectiveness and performing studies in this population.  “Neonatologists…find themselves faced with …a growing body of uncontrolled data that suggests benefits of an unapproved treatment…An attempt to perform a randomized controlled comparison of a plant-based lipid emulsion to FishLE in preventing PNALD in infants at risk was terminated early after an interim analysis revealed much lower than expected incidence of PNALD…[making] trials ethically problematic.”

My take: The data remain incomplete and make it difficult to use a therapy like Omegaven that is quite expensive (not covered) and not FDA approved.  The availability of SMOFlipid is likely to result in less usage of plant-based soy products.

Related blog posts:

Rodin Museum

Nutrition Week (Day1) Downside on Lipid Reduction

Recently I gave a lecture on parenteral nutrition associated liver disease (PNALD), though the term intestinal failure associated liver disease (IFALD) is probably more popular at this time.  The day afterwards, I read an important study (L Beauport et al. J Pediatr 2017; 181: 29-36) reiterating one of the concerns in the lecture.

This study showed that higher lipid intake in a cohort of neonates born at <30 weeks during the first 2 weeks after birth was associated with a lower incidence of brain lesions and dysmaturation when examined by MRI at term equivalent age (TEA).

Details: This prospective cohort study examined energy/lipid intake in the first 2 weeks of life. Eligible patients were neonates ≤30 weeks.  Group 1 with 27 patients had birth weight median of 900 gm compared with Group 2 with 15 patients had median weight of 844 gm. During the first year of the study, participants received a soybean emulsion whereas in the last year of the study, the neonates received a mixture of soybean and olive oil (Clinoleic).

Key finding: After adjusting for clinical risk scores and sepsis, the authors found that the higher energy/lipid intakes resulted in improved brain MRIs in group 1. A “10 Kcal/kg/day increase in energy of 0.7 g/kg/day increase in lipids intake would reduce the risk of having more severely abnormal MRI at TEA by >60%.”

Here are some slides from my talk relevant to this topic and to parenteral nutrition associated liver disease (PNALD):

screenshot-102 screenshot-103

Explaining Differences in Disease Severity for Alagille Syndrome

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

Sertraline and Liver Disease

A recent case report (MA Conrad, HC Lin. J Pediatr 2016; 169: 313-5) on sertraline-associated cholestasis provided a good reason to take a quick review on the NIH Liver Toxicity website:

Hepatotoxicity with sertraline (zoloft)

Liver test abnormalities have been reported to occur in up to 1% of patients on sertraline, but elevations are usually modest and infrequently require dose modification or discontinuation.  Rare instances of acute, clinically apparent episodes of liver injury with marked liver enzyme elevations with or without jaundice have been reported in patients on sertraline.  The onset of injury is usually within 2 to 24 weeks and the pattern of serum enzyme elevations has varied from hepatocellular to mixed and cholestatic.  Autoimmune (autoantibodies) and immunoallergic features (rash, fever, eosinophilia) are uncommon.  Actue liver failure due to sertraline has been described but is very rare.

The case report describes a 15 yo who developed jaundice (peak bilirubin 33.7 mg/dL with a direct fraction of 29.2 mg/dL) after 6 months of treatment with 75 mg per day.  After negative blood tests, he had a liver biopsy which was notable for rare bile ducts.  A jaundice chip was negative for underlying disorders like Alagille syndrome.  Urine bile acids were negative as well.  His laboratories normalized completely four months after cessation of sertraline.

It is interesting to note that sertraline has been used therapeutically for patients with pruritus due to cholestasis (Understanding Cholestatic Pruritus | gutsandgrowth)

My take: This case report describes bile duct paucity (vanishing bile ducts) as a result of sertraline therapy.  For practitioners, the bottom line is that SSRIs rarely cause liver toxicity; however, for patients with persistently-abnormal liver chemistries on SSRI therapy, discontinuation and identification of a safe alternative medication may be warranted.

Castillo San Felipe del Morro

Castillo San Felipe del Morro

Parenteral Lipids & Cholestasis –a Little More Data

A recent publication in JPGN indicates that resuming low dose soy-based parenteral lipid can be effective in patients (n=7) whose cholestasis had resolved on a fish oil-based parenteral lipid. It does not resolve the larger question of whether fish oil-based parenteral lipids are truly more effective than soy-based parenteral lipids (see previous blog links below).

Here’s the abstract:

Objectives: Intestinal failure associated liver disease (IFALD) contributes to significant morbidity in pediatric intestinal failure (IF) patients. However, the use of parenteral nutrition (PN) with a fish oil-based IV emulsion (FO) has been associated with biochemical reversal of cholestasis and improved outcomes. Unfortunately, FO increases the complexity of care: as it can only be administered under FDA compassionate use protocols requiring special monitoring, is not available as a 3-in-1 solution and is more expensive than comparable soy-based lipid formulation (SO). Due to these pragmatic constraints a series of patient families were switched to low-dose (1 g/kg/day) SO following biochemical resolution of cholestasis. This study examines if reversal of cholestasis and somatic growth are maintained following this transition.

Methods: Chart review of all children with IFALD who switched from FO to SO following resolution of cholestasis. Variables are presented as medians (interquartile ranges). Comparisons performed using Wilcoxon signed-rank test.

Results: 7 patients aged 25.9 (16.2,43.2) months were transitioned to SO following reversal of cholestasis using FO. At a median follow up 13.9 (4.3,50.1) months there were no significant differences between pre- and post-transition serum alanine and aspartate aminotransferases, direct bilirubin, and weight-for-age z-scores. Due to recurrence of cholestasis, one patient was restarted on FO after four months on SO.

Conclusions: Biochemical reversal of IFALD and growth were preserved after transition from FO to SO in 6/7 (86%) patients. Given the challenges associated with the use of FO, SO may be a viable alternative in select home PN patients.

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