Liver Shorts November 2018

J Ge et al. Hepatology 2018; 68: 1101-10.  This study reviewed liver donation offers between 2010 to 2014.  This study found that 5.6% of men (293/5202) and 6.2% of women (179/2899) received a pediatric donor as a first offer.  Women, but not men, who received a pediatric first offer had a lower risk of waitlist mortality than with those who received adult organ offers. The authors recommend that “offers of pediatric donor liver be prioritized to women, who are generally shorter stature, once alllocation to the entire…pediatric waitlist pool has occurred.”

CA Chapin et al. Hepatology 2018; 68: 1087-1100.  This study found that patients with indeterminate pediatric acute liver failure (iPALF) have a unique pattern of dense CD8+ T-cell infiltrate that is also perforin-positive adn CD103-positive.  These CD8+ cells are a biomarker for immune dysregulation. These CD8+ dense pattern was found in the 27 of 33 patients with iPALF; 3 had moderate and 3 had minimal staining pattern (per table 2).  The dense CD8+ pattern was seen in 3 of 9 with autoimmune hepatitis and in 1 of 14 with other liver diseases.

E-D Pfister et al. Liver Transplantation 2018; 24: 1186-98.  This study examined patient (n=338) and graft survival in the pediatric population (median age 14.0 years) with Wilson’s disease (1968-2013).  Overall, patient survival was 87% at 1 year, 84% at 5 years, and 81% at 10 years.  Though, the survival was much improved since 2009.

JA Bezzerra et al. Hepatology 2018; 68: 1163-73. This review summarized a research workshop (June 2017) focused on the clinical and research challenges for biliary atresia.

Banff

How Often Is Surgical Treatment for Biliary Atresia Delayed Beyond 60 Days?

It is recognized that there is often a delay in the diagnosis of biliary atresia (BA).  A recent study (MR Townsend et al. J Pediatr 2018; 199: 237-42) indicates that hepatoportoenterostomy (HPE) or Kasai procedure is performed in only 37.7% of patients with BA prior to 60 days of age. The data was obtained from the Agency for Healthcare Research and Quality’s Healthcare Cost and Utilization Project (HCUP) Nationwide Inpatient Sample files from 2000-2011.

  • Risk factors for delayed HPE: This study of 1243 patients with BA found that those with delayed HPE were more often uninsured–all self-pay patients had HPE after 60 days, more often black (aOR 4.22), and less likely at a teaching hospital (aOR 0.27).
  • Delayed HPE was associated with increased adverse perioperative outcomes and increased cost.

My take: We have a long way to go if we are going to consistently identify and treat BA in a timely manner.

Related blog posts:

Time-to-diagnosis of Biliary Atresia

A recent study (S Harpavat et al. JPGN 2018; 66: 850-6) identifies race/ethnicity as a factor affecting the timeliness of diagnosis.

Specifically, non-Hispanic white infants were diagnosed earlier than non-Hispanic black infants and Hispanic infants (P=.007); this was related to the timing of referral from the primary care physician.  The authors speculate that this could be related to three factors:

  • lighter colored skin could help identify jaundice more quickly
  • better access to health care
  • implicit bias leading to uneven treatment

The other finding in the study was that after referral, patients referred after 30 days of life had a more expedited diagnosis than those referred prior to 30 days of life.  The authors caution that the histology in these early cases is similar to those who present later, even if their aminotransferases are normal.  In addition, while physicians and parents want to avoid ‘over testing,’ prompt diagnosis, even prior to 30 days of life, may lead to improved outcomes.  Thus, the authors recommend proceeding with liver biopsy if there is clinical suspicion of biliary atresia.

My take: Obtaining objective evidence of cholestasis in infants that are jaundiced beyond 2 weeks of life is important.  This study highlights some of the reasons why the diagnosis is delayed in so many.

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Will We Still Need Liver Biopsies to Diagnose Biliary Atresia in a Few Years?

A recent study (C Lertudomphonwanit, R Moura, L Fei, Y Zhang, S Gutta, L Yang, KE Bove, P Shivakumar, JA Bezerra. Sci Transl Med. 2017; 9: eaan8462) may change how we diagnose biliary atresia (BA) and provides an insight into potential pathogenesis. Link to studyLarge-scale proteomics identifies MMP-7 as a sentinel of epithelial injury and of biliary atresia

Using large-scale proteomics, the authors screened 1129 proteins in a discovery cohort (n=70) of patients with BA.  They identified several proteins that were increased with BA. Matrix metalloproteinase-7 (MMP-7) was the lead biomarker.  Subsequently, they used two additional validation cohorts.  Human subjects were infants in enrolled in the Prospective Database of Infants with Cholestasis (PROBE) which is part of the NIDDK-funded ChiLDRen (www.childrennetwork.org).

Key findings:

  • 76 proteins were significantly overexpressed or underexpressed in BA compared with children with intrahepatic cholestasis (IHC).
  • MMP-7 was more accurate than gamma glutamyltranspeptidase (GGT).  The combination of MMP-7 and GGT had a AUROC of 0.94 in validation cohorts.
  • The authors further studied the role of MMP-7 by immunostaining and found it primarily was detected in cholangiocytes of intrahepatic bile ducts in infants with BA.  It was also identified in a few hematopoietic cells.
  • MMP-7 expression in the liver did not correlate with fibrosis.
  • MMP-7 serum levels increased in neonatal mice after bile duct epithelial injury induced by intraperitoneal rotavirus administration.
  • Using a mice model, they found that a MMP-7 inhibitor (batimastat) could block the development of BA in a mouse model (in 86% of cases) compared with 0% in control mice.
  • Overall, the authors note that coupled with GGT, MMP-7 serum levels result in “sensitivity and specificity of 97 and 94% respectively, at optimal cutoff, which provided positive and negative predictive values of 85 and 99% respectively, if one considers the prevalence of BA of 25.9% among infants with conjugated hyperbilirubinemia.”

My take: More work is needed.  However, these values suggest that MMP-7 and GGT combined may be more accurate than a liver biopsy in the diagnosis of BA.

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South Kaibab Trail, Grand Canyon

Liver Articles: Short Takes

DBE van Wessel et al. JPGN 2017; 65: 370-74.  This retrospective study showed an increase in biliary atresia incidence in preterm infants compared with full-term: 1.06 per 10,000 compared with 0.52/10,000. In addition, 4-year transplant-free survival rates were significantly worse at 21%, whereas 4-year survival rates was 61%. Clearance of jaundice (with Kasai) was achieved in only 23%.

Related post: Biliary Atresia More Common in Preterm Infants

ES Björnsson et al. Clin Gastroenterol Hepatol 2017; 15: 1635-36. This study examined response to steroids in 18 patients with drug-induced autoimmune hepatitisKey findings: 14 patients had elevated antinuclear antibodies & there were none with elevated smooth muscle antibodies. Infliximab was most frequent agent (n=11) and nitrofurantoin was other frequent agent (n=3).  Overall, 40% improved after discontinuation of medication, the remainder had prompt responses to corticosteroids.  Relapse did not occur when corticosteroids were discontinued.  Among the infliximab group, there was no evidence of liver injury after transitioning to alternative tumor necrosis factor-α inhibitor.

M Balwani et al. Hepatology 2017; 66: 1314-22. Acute Hepatic Porphyrias -Review. Current recommendations include gene sequencing to confirm all biochemical cases. Biochemical tests are spot urine testing of porphobilinogen (PBG), 5-aminolevulinic acid (ALA), and porphyrins. A normal urine PBG in symptomatic patients “excludes the three most common acute hepatic porphyrias.”  For those with abnormal studies, this reference is a handy.

S Wirth et al. Hepatology 2017; 66: 1102-10.  This study examined the effectiveness of sofosbuvir and weigh-based ribavirin dosing in 12-17 year olds with genotype 2 & 3 Hepatitis C infection.  Duration of treatment was 12 weeks for genotype 2 and 24 weeks for type 3.  Overall, SVR12 was achieved in 51 of 52 (98%); one patient with genotype 3 did not achieve SVR12.

Related post: New HCV Treatment Effective in Adolescents (Genotype 1 study)

F Kanwal et al. Gastroenterol 2017; 153: 996-1005. This study, a retrospective cohort of 22,500 VA patients treated for hepatitis C infection, showed that direct-acting antivirals (DAAs) lowered, but did not eliminate, the risk of hepatocellular carcinoma (HCC). Among the 87% who achieved an SVR, the adjusted hazard ratio for HCC was 0.28.  This was true as well as among patients with cirrhosis.. Hazard ratio for those with compensated cirrhosis was 0.32 compared with 0.18 among those without cirrhosis.

NASPGHAN Postgraduate Course 2017 (Part 3): Biliary Atresia, NAFLD, SMOFlipid, Pancreatic Pain

This blog entry has abbreviated/summarized these presentations. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.

Here is a link to postgraduate course syllabus: NASPGHAN PG Syllabus – 2017

Biliary Atresia: Update on diagnostic and prognostic biomarkers and therapeutic interventions

Cara Mack    Children’s Hospital of Colorado

Key points:

  • 84% of biliary atresia is isolated; 16% are syndromic with other defects
  • Direct bilirubin is (mildly) elevated at birth in patients with biliary atresia
  • Total bilirubin 3 months after Kasai predicts outcome. If <2 mg/dL, then unlikely to need a transplant in the first 2 years of life.
  • Reviewed biomarkers including Th1, Autotaxin, IL-8

Therapeutic interventions:

  • Nutritional support. Better nutrition improves outcomes after liver transplantation.
  • Fat soluble vitamin supplementation
  • Cholangitis prevention. Some studies have shown that prophylactic antibiotics may reduce incidence of cholangitis.
  • No therapeutic interventions that delay progression of this disease

 

 

CHILDREN Cohort Mgt of Vitamin Supplementation

Steroids are not helpful after Kasai procedure

Diagnosis and Management of Pediatric NAFLD 2017

Stavra Xanthokos   Cincinnati Children’s Hospital Medical Center

Key points:

  • NAFLD is #2 cause of liver transplantation in adults and on its way to becoming #1
  • ALT is still the best screening tool; NASPGHAN guidelines recommends screening overweight/obese children 9-11 years of age
  • Ultrasound has poor sensitivity and specificity for NAFLD; it is helpful for detecting gallbladder disease
  • Bariatric surgery has been effective for NAFLD

 

SMOFlipid and the Pediatric Patient

Peter Wales  Hospital for Sick Children (Toronto)

Slides are not available in syllabus

Key points:

  • Improving outcomes noted in the intestinal failure population
  • Dr. Wales reviewed proposed improvements with Omega-3 lipids -less cholestasis, less hepatitis, and less fibrosis
  • Compared improvements with lipid minimization (1 g/kg/day) compared to newer agents: omegaven and SMOFlipid. Additional studies are needed due to limitations of previous studies
  • Discussed SMOFlipid vs. Intralipid trial at 5 centers in Canada. N=24.
  • At SickKids: SMOFlipid for all preterms at admission & for term infants after 2 weeks of PN. Dosing 2-2.5 g/kg & now accounts for 85% of lipid usage at institution
  • None of the lipid products were designed for preterm infants. Intralipid has a pediatric indication and other products are used off label
  • Lipid restriction probably affects brain size/development; thus, a lipid agent that allows for higher doses likely will be beneficial for developmental outcomes.  The retina can be used as a biomarker of the brain affects of lipids.

Painful Chronic Pancreatitis: Management/therapeutic interventions

Vikesh Singh  Johns Hopkins University School of Medicine

Slides are not available in syllabus

 

 

Updated Biliary Atresia Epidemiology

A recent retrospective study (PC Hopkins, N Yazigi, CM Nylund. J Pediatr 2017; 187: 253-7) provides an update on the recent incidence of biliary atresia in the US from 1997-2012. This study relied on coding for biliary atresia or Kasai hepatoportoenterostomy to identify cases using HCUP-KID database.  This database provides a nationally representative sample of pediatric hospitalizations and captures ~96% of pediatric hospitalizations in the US.

Key findings:

  • Incidence of biliary atresia (BA) was 4.47 per 100,000 (1 in 22,371 infants)
  • BA was more common in females (RR 1.43), Asian/Pacific Islanders (RR 1.89), and blacks (RR 1.30)
  • Median age at the time of the Kasai procedure was 63 days with no improvement over the course of the study period.  More than 50% of all children underwent the Kasai procedure after the optimal window of 60 days of life

My take: In my view, at this time, obtaining a blood test for direct bilirubin in the first two weeks of life will need to be adopted broadly if we are going to diagnose biliary atresia at an earlier age.

Related blog posts:

Dry Falls, Highlands NC

Dry Falls, Highlands NC