Category Archives: Pediatric Gastroenterology Liver Disease

Liver Update -January 2015

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Briefly noted:

1. Gastroenterology 2014; 147: 1327-37 (editorial 1216-18).  “Probiotic VSL#3 reduces liver disease severity and hospitalization in patients with cirrhosis: a randomized, controlled trial.” 66 patients received VSL#3 (9 x 10 to the 11th bacteria), 64 patients received placebo -both groups studied for 6 months. Treatment with lactulose and rifaximin were withdrawn a week prior to study entry. Key findings: ‘fewer hospitalizations for severe encephalopathy, better quality of life, and decreases in Child-Turcotte-Pugh class and Model for End-Stage Liver Disease.’  Hazard ratio for preventing hospitalization with VSL#3 was 0.52. However, the findings did not show that VSL#3 reached a statistically-significant reduction in recurrence rate for hepatic encephalopathy. No adverse events were noted.

2. NY Times: Gilead sued over cost of Sovaldi.

3. N Engl J Med 2014; 371:2375-2382.  Link to abstract: Interferon-free Antiviral Regimen for HCV after Liver Transplantation:  “Treatment with the multitargeted regimen of ombitasvir–ABT-450/r and dasabuvir with ribavirin was associated with a low rate of serious adverse events and a high rate of sustained virologic response among liver-transplant recipients with recurrent HCV genotype 1 infection, a historically difficult-to-treat population.”

4. “Transplantation Traffic –Geography as Destiny for Transplant Candidates” NEJM 2014; 271: 2450-52.  Describes ongoing geographic inequality in organ distribution and obstacles to improving allocation.

5. Liver Transpl 2015; 21: 57-62. Immediate Extubation After Pediatric Liver Transplantation –feasible in 67% according to this retrospective review.

Local Law Office --Truth in Advertising?

Local Law Office –Truth in Advertising?

Sorting Out Discrepancies in Hepatitis B Testing

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A recent study (J Pediatrics 2014; 165: 773-8) highlighted the clinical problem of discrepant hepatitis B virus (HBV) testing in pregnant women.

Design: The Centers for Disease Control and Prevention analyzed a nonrandom sample of discordant cases of HBV reported by US Perinatal Hepatitis B Prevention Program.  Discordant cases indicated that there were differences between an initial HBsAg result and a subsequent test.  Among 142 cases, 89 had sufficient information to determine accuracy of the initial test.

Key finding: 14 (15.7%) of these cases were true positives, the remainders were false-positives.

How did authors sort out cases?

Negative testing for “total anti-HBc or no detectable HBV DNA result indicating no HBV infection…A positive total anti-HBc indicates current or past HBV infection, is not elicited by vaccination, and usually persists for life.”

Pointers regarding serology:

  • IgM anti-HBc -acute or recent infection and can persist for more than 6 months.
  • HBV DNA confirms active infection and can detect infection at levels below those of HBsAg assays.  This can occur either due to “occult HBV infection” or due to a mutant HBV strain that results in non-reactive test for HBsAg.
  • There were at least 11 HBsAg assays that have been FDA-approved –most but not all of them will confirm results before reporting.

It is important to sort out patients with discrepant HBV serology.  In infants who are not identified with HBV testing (false-negatives), this results in suboptimal post exposure prophylaxis and increased likelihood of chronic HBV.  Whereas, infants with false-positive results, incur unnecessary prophylaxis and costs.  The authors note that “total anti-HBc was the most useful single test to resolve HBsAg discrepancies.

Also noted: J Pediatr 2014; 165: 767-72.  “Factors Affecting the Natural Decay of Hepatitis B Surface Antigen in Children with Chronic Hepatitis B Virus Infection during Long-Term Followup”  This study followed 349 Taiwanese children over 20 years and noted annual HBsAg clearance of 0.58% (42 cleared HBsAg).  Spontaneous clearance was more common in HBeAg-seroconverters, infants with low initial HBsAg level <1000 IU/mL, and to those born to non-HBsAg-carrier mothers.

Liver Disease Associated with Inflammatory Bowel Disease

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A useful review on the hepatobiliary manifestations of inflammatory bowel disease (IBD): Inflamm Bowel Dis 2014; 1655-67.

A few topics/comments from review:

Primary sclerosing cholangitis (PSC):

  • “among those with PSC, about 70% to 80% have UC and 15% to 20% have CD.  Those IBD patients with PSC are more likely to develop malignant complications and to require liver transplantation. Conversely, only about 0.4% to 7.5% of patients with IBD will develop PSC.”
  • “Currently, no medical treatment has been proven to decrease the progression of PSC.”
  • “At the time of diagnosis of PSC, IBD must be ruled out and a complete colonoscopy with multiple segmental biopsies of the mucosa needs to be performed.”  Among PSC-IBD patients, “annual surveillance colonoscopy is recommended.”
  • Further surveillance recommendations (eg. annual imaging/CA 19-9 annually) discussed in Table 2.

Cholelithiasis: Gallstones are reported in 13% to 24% of all patients with CD.  In UC, the risk of cholelithiasis “does not seem to be increased.”

Drug-induced liver disease: (see liver tox website)

  • Thiopurines
  • Methotrexate
  • Sulfasalazine/mesalamine
  • Biologic agents

Viral hepatitis in immunosuppressed IBD patients:

Hepatitis B reactivation -algorithm for screening/management of latent hepatitis B provided in Figure 3

Other liver problems seen in IBD patients:

  • Portal Vein Thrombosis
  • Nonalcoholic Fatty Liver Disease
  • Secondary amyloidosis
  • Hepatic abscess

Related blog posts:

Exceptions for Valproate-Associated Liver Failure

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Recent guidelines (AASLD/NASPGHAN 2014 Guidelines for Evaluation of Pediatric …) have included valproate-associated acute liver failure (VPA-ALF) as an absolute contraindication to liver transplantation.  The reason is that most of these VPA-ALF patients have Alpers-Huttenlocher syndrome (AS) and have done poorly after transplantation due to progressive neurological decline.

AS in turn has been recognized as secondary to mutations in DNA polymerase subunit gamma (POLG1).  This gene product’s role is to maintain the integrity of mitochondrial DNA (mtDNA).

New data (Liver Transplantation 2014; 20: 1402-14, editorial 1287-89) suggests that there are exceptions for some cases of VPA-ALF.  In this report, 4 VPA-ALF patients with POLG1 mutations underwent successful liver transplantation.  Three are alive at followup 4-19 years later and one died suddenly 2 years after transplantation.

Key findings:

  • These cases had mutations in POLG1 associated with later onset and milder disease.
  • In the three long-term survivors, VPA was introduced at 14, 20 , and 21 years of life.

Take-home points:

  • For children less than 10 years of age, “VPA-ALF should remain an absolute contraindication to LT because neurological progression is almost inevitable.”  Supportive treatment, including N-acetylcysteine and carnitine should continue.
  • There is a “strong case for screening for POLG1 mutations before VPA use…even a single mutation should be seen as a contraindication to VPA.”

Related blog posts:

Also, I added a link on yesterday’s post regarding measles to a story on NPR which explores the most recent increase in cases and provides background information.  For example: “Before a vaccine was developed in the 1960s, measles caused more than 2 million deaths per year.”  And worldwide, even now, “nearly 400 kids die from measles each day. In 2013, more than 70 percent of measles deaths were confined to six countries: the Democratic Republic of Congo (DRC), Ethiopia, India, Indonesia, Nigeria and Pakistan.”

Lysosomal Acid Lipase Deficiency -Another Needle in a Haystack

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A recent article (Atherosclerosis 2014; 235: 21-30) reviews lysosomal acid lipase deficiency (LAL-D) and how this rare disease needs to be considered by pediatric hepatologists.

LAL-D is a rare lysosomal storage disease which encompasses a rapidly progressive disease in infants (previously referred to as Wolman disease) as well as a later-onset condition called cholesteryl ester storage disease (CESD).  Both of these diseases are caused by mutations in the LIPA gene and share the same pathophysiology related to deficiency of LAL. The disease prevalence estimates vary widely (1 in 40,000 to 1 in 300,000) and depend on ethnicity and location.  Jewish, Iraqi, and Iranian infants appear to be at highest risk.

According to the review algorithm, patients with three or more of the following should be considered for screening:

  • ALT >1.5 ULN
  • Hepatomegaly (may be mild)
  • HDL <50 mg/dL
  • Low BMI (in adults <30 kg/m2)
  • Liver biopsy with microvesicular steatosis; grossly the liver may appear orange

Thus, the potential target patients:

  1. Non-obese individuals with persistent increases in LFTs –usually with LDL >160 and low HDL <50
  2. Non-obese NAFLD/microvesicular steatosis

Given the potential for treatment with recombinant sebelipase alfa (Synageva Biopharma) and the widely available testing, looking for LAL-D makes sense in selected patients; though, even in highly selected patients, finding cases may truly be like finding the so-called ‘needle in a haystack’ given the huge numbers of individuals with elevated ALTs who do not have LAL-D.

Note: many of the review’s authors received research grants from Synageva.  (I do not have any financial conflicts to disclose.)

Esophageal Varices and Primary Prophylaxis

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

One of the topics debated at this year’s meeting was the issue of whether it is worthwhile for patients with esophageal varices to undergo primary prophylaxis.

Here’s a summary:

Esophageal Banding: Proactive vs Expectant Waiting Maureen Jonas (Boston Children’s) and Karen Murray (Seattle Children’s)

Reviewed definitions of portal hypertension. Hepatic venous portal gradient (HVPG) >12 associated with variceal bleeding is the standard in adult medicine.

Management issues: primary prophylaxis, treatment of acute bleeding, and secondary prophylaxis.

Adult Data/Guidelines:

  • 1-year rate of first bleeding 5% for small varices and 15% for large varices
  • 1-year recurrent variceal bleeding ~60%
  • Compensated cirrhotics with small high-risk varices (or mod-large varices): consider treatment with beta-blocker (and/or EVL for mod-large varices).
  • Beta-blockers and EVL –similar efficacy and survival in adults.
  • Lowering HVPG by 20% lowers risk of complications
  • Beta-blockers stopped in ~20% of adults due to side effects like fatigue or shortness of breath.

Pediatrics and Beta-Blockers:

  • Beta-blockers have good safety in children in a wide range of conditions –cardiomyopathy, migraines, others. HVPG is used in adults but is very invasive.
  • Pediatric HVPG correlation to variceal development is not yet established.
  • Bleeding from varices –17-29% in biliary atresia (BA) patients over 10 years. Yearly rates: 2-9%.
  • Mortality in pediatrics from bleeding varices: 2-5% with BA, 0-2% with portal vein thrombosis.

Non-Selective Beta-blockers.

  • There are adverse effects: hypotension, bronchospasm, hypoglycemia. Am Gastroenterol 2014; 27: 20-6.  In infants/pediatric patients with shock, tachycardia is the primary response. Beta-blockers interfere with this.
  • In pediatric studies, bleeding risk has not been proven to be reduced with non-selective Beta-Blockers.

Risks of primary prophylaxis with banding or sclerotherapy:

  • Adverse effects: could convert a child not prone to bleeding into one prone to bleeding. Stricture possible.
  • Efficacy? Limited data.  Study on prophylactic sclerotherapy if grade 2/3. Median followup was only 1.7 years. JPGN 2012; 55:574
  • Sometimes cannot eradicate varices and/or recur quickly. Gastroenterol 2013; 145: 801.

Rebuttal:

  • Sometimes we have to extrapolate from adult data
  • Currently about half of pediatric GIs use primary prophylaxis in these cases (JPGN 2011; 52: 751)

Take-home message: insufficient data to demonstrate efficacy of primary prophylaxis as well as to demonstrate adverse effects of primary prophylaxis.

Related blog posts:

Parenteral Lipids & Cholestasis –a Little More Data

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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.

Related blog posts:

 

Basic Science Year in Review –#NASPGHAN 2014

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John Barnard –Basic Science Year in Review

“Emerging Trends and Provocative Findings in Basic Science”

This blog entry has abbreviated/summarized this terrific presentation. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.  To minimize these issues, I have placed a link to most of Dr. Barnard’s slides which he shared:

2014 John Barnard Slides

“Big Data” –big increase in “big data” cited in pubmed over past year.

  • Good read on this subject: Foreign Affairs: The Rise of Big Data Kenneth Cukier

Scientific fraud –more attention to this issue this past year. Two papers in Nature were retracted. One researcher committed suicide and one arrested. Scientific fraud undermines important messages & ruins credibility of other important advances.

CRISPR-Cas9: Gene editing.  CRISPRs –“RNA guides”  Cas9: “molecular scissors” (endonucleases)

“Genome editing has never been easier.”  Examples:

  • Cell Stem Cell 2013: 13: 653-58. “Functional repair of CFTR by CRISPR-Cas9”
  • Also, genome editing has been used in mouse model of tyrosinemia.

Liver regeneration in zebrafish. Implication: Liver cells will be regenerated in humans. Gastroenterol 2014; 146: 789.

Microbiome Big Data:

  • J Clin Invest 2014; 124: 3617. This was a very important and complex study.  The slides explaining this study start at slide 35.
  • Pediatric Crohn disease exhibit specific ileal transcriptome and microbiome signature.
  • RISK study (CCFA). Treatment-naïve, 28 sites.
  • 1281 ileal host genes in ileocolonic Crohn’s, 1055 in Colonic Crohn’s had ileal host genes =82% similar, 232 host genes in ulcerative colitis –18% similar to ileocolonic Crohn’s.
  • Tissue microbiomes are where changes are noted; changes are not evident in luminal microbiome.
  • Antibiotics worsen dysbiosis.
  • Microbiome at diagnosis strongly correlates with Crohn’s disease.

Microbiome –affects the entire body:

  • J Clin Invest 2014; 124: 3391. Incorporation of microbes with genetically-engineered E coli can prevent obesity in mice

Recommended Reading by Dr. Barnard: “Missing Microbes” How the overuse of antibiotics is fueling our modern plagues. Martin Blaser

 

NASPGHAN Postgraduate Course 2014 -Liver Module

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This blog entry has abbreviated/summarized the presentations. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.  I’ve attached the course syllabus as well:

PG Course Syllabus – FINAL

Primary Sclerosing Cholangitis –Dennis Black (Le Bonheur Children’s Hospital)

  • Up-to-date review provided
  • GWAS (genome-wide association study) identified 16 significant risk loci which account for only 7.3% of overall risk; environmental influences need to be worked out
  • Pediatric studies –total of 328 patients reported to date

Is pediatric disease the same disease as in adults?

  • Incidence in pediatrics: 0.23/100,000 incidence vs 1.1/100,000 in adults
  • Mean age at diagnosis 13 years in pediatrics.
  • 30% of pediatric patients have overlap with autoimmune hepatitis which is higher than in adult patients.

Other pointers:

  •  Discussed “Autoimmune cholangitis.” Imaging needed in autoimmune hepatitis to look for primary sclerosing cholangitis.
  • IBD Association with PSC: IBD occurs in about 55% of PSC patients. If PSC diagnosed first, usually with right-sided colitis.  If IBD diagnosed first, than pancolitis is more commonly noted.
  • Add IgG4 as part of workup to rule out IgG4 cholangiopathy (sensitive to immunosuppression).

Treatment:

  • Supportive care for cholestasis (vitamins, pruritus management, etc
  • Monitoring for complications (rare cases of cholangiocarcinoma in pediatric population).  14 drugs tested to date –mainly in adults.  “All without proven positive impact on long-term outcome.”
  • Ursodeoxycholic acid –widely used but controversial because higher doses associated with worsened outcomes in adult study (Lindor et al).  Ongoing study in pediatric population with ursodeoxycholic acid.
  • Vancomycin (Aliment Pharm 37: 2013; 604.  Adults n=35). Both Flagyl and Vanc seemed to be helpful. Uncontrolled pediatric studies with vancomycin reviewed. Vancomycin study in the works for pediatric/adults.
  • No prospective randomized controlled trials in children and very little data in adults. Hard endpoints –very difficult in children/not practical in children (eg. portal hypertension, transplant, death).

PSC and Transplantation: PSC 2.6% of total transplants –long-term outcome is similar.

Related Blog Posts:

The Jaundiced Infant –Saul Karpen (Emory)

  •  “We don’t estimate jaundice very well… Our eyes do an awful job.”
  • Breastmilk Jaundice: Archives of Disease in Childhood 1978; 53: 506-16.  Only 12 of 853 had jaundice beyond 3 weeks of life.
  • Cholestasis. One of the best studies looking at etiology was recently published:  Hoerning A, et al Front Pediatr. 2014; 2: 65. N=82.  Only 1 patient had CMV.  41% had biliary atresia.

Biliary atresia (BA):

  • Reviewed study indicating that liver biopsy was most accurate means of making diagnosis of biliary atresia (blog comment: this study result may not be accurate in all settings as the interpretation relies on the ability/reliability of pathologist).  High utility of stool pigment & ultrasound (including flow).
  • In retrospective study (Pediatrics 2011; 128 e1428-33), all the BA patients had elevated direct bilirubin by 24-48 hrs of life.
  • Genetic panels and whole exome sequencing (~$4-7K) are happening now. Cost-effective.

Take-home message: Molecular understanding possible for conjugated/unconjugated hyperbilirubinemias. Direct bilirubin >1 is abnormal

Related blog posts:

Acute Liver Failure –Estella Alonso (Children’s Hospital of Chicago) (pg 43)

Points:

  • Few patients receive a full diagnostic workup (J Pediatr 2009;155:801‐6)–especially with regard to metabolic and autoimmune disorders.
  • Reviewed etiologies –most frequently “indeterminant” especially in younger patients.  Acetaminophen is most frequent etiology in teenagers and adults.
  • Systemic inflammation is common in acute liver failure (Bucuvalas, J JPGN 2013;56: 311–315). Soluble IL2 receptor alpha –significantly higher in patients that died.  Immune regulation important aspect regarding survival. Should steroids be used in cases with high inflammation?

Prognosis: Squires et al. J Pediatr 2006;148:652-8, Lee et al. JPGN 2005;40:575-81, Baliga et al. Liver Transpl 2004;10:1364-71

  • 33% ‐53% survival with native liver
  • 61% survival including LT
  • 70%‐80% after LT
  • Multiorgan failure is most common etiology of death. Bleeding is “a rare cause of mortality.”

Management:

  • Reviewed including coagulopathy/bleeding, cardiovascular collapse, hepatic encephalopathy/cerebral edema
  • Pediatric N-acetylcysteine Trial Squires, et al Hepatology 2013;57:1542‐9 N=182.  Patients with NAC seemed to do worse, but not statistically proven.  This study has stopped the widespread use of NAC in acute liver failure.
  • Discussed approach to neurological complications in ALF. Hussain et al, JPGN 2014;58:449‐56. Retrospective study (n=18). Early EEGs obtained. Hypertonic saline may be more effective than mannitol.  Hypothermia may be helpful adjunct.
  • Timing of Transplantation discussed (pg 54 in syllabus). Difficult to predict spontaneous survival.

Related blog posts:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  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.

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This Year’s Pumpkin