Category Archives: Pediatric Gastroenterology Liver Disease

Emerging Targets for Hepatitis C -Part 1

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The latest advances in hepatitis C are related in several recent publications:

  1. Hepatology 2013; 57: 2143-54.
  2. Hepatology 2013; 57: 2155-63.
  3. Clin Gastroenterol Hepatol 2013; 11: 612-619.

The first two studies provide specific information about the effectiveness of Faldaprevir combined with peginterferon alfa-2a/ribavirin (PEG/RBV) in treatment-naive patients and patients with prior nonresponse respectively.  The third reference provides the big picture regarding all of the emerging treatments.

In the first study, the “SILEN-C1” phase 2 trial, 429 patients without cirrhosis were randomized to several treatment arms.  423 of the 429 patients were genotype 1.  This large study involved 89 centers in 15 countries.  All of the treatment groups received PEG/RBV along with either placebo, faldaprevir 120 mg with lead-in (LI), faldaprevir 240 mg LI and faldaprevir 240 mg without LI.   Faldaprevir is a NS3/4A protease inhibitor which can be administered orally once a day.  Results: SVR achieved in 56% (placebo), 72% (faldaprevir 120mg LI), 72% (faldaprevir 240 mg LI), and 84% (faldaprevir 240 mg without LI).  Discontinuation rates were 1%, 4%, 11%, and 5% for the aforementioned treatment groups.

In the second study, the “SILEN-C2” trial, 290 non cirrhotic genotype 1 patients with either no response or partial response to previous treatment underwent a 48 week treatment trial with a similar design as the SILEN-C1. Results: SVR rates among partial responders were 32% (faldaprevir 240 mg LI), 50% (faldaprevir 240 mg without LI), and 42%(faldaprevir 240 mg BID/LI).  Among null responders, SVR rates were 21% (faldaprevir 240 mg LI), 35% (faldaprevir 240 mg without LI), and 29% (faldaprevir 240 mg BID/LI).  Adverse reactions were higher in those on higher doses and included anemia, rash, indirect hyperbilirubinemia, and nausea. Discontinuation rates were 6%, 4%, and 23% for the aforementioned treatment groups.

The third study provides a landscape of current treatment and emerging treatments.  Given the improvement in SVR among genotype 1 patients, the use of either telaprevir or boceprevir in combination with PEG/RBV is the “new standard of care” among adult patients with HCV.  Studies supporting telaprevir include the ADVANCE study, the REALIZE trial, and the OPTIMIZE study.  For boceprevir, its effectiveness was demonstrated with SPRINT-2, and RESPOND-2.

Both boceprevir and telaprevir, are NS3/4A serine protease inhibitors and are considered direct acting antivirals (DAAs). On the horizon:

  • Simeprevir -NS3/4A protease inhibitor.  Studies: PILLAR, ASPIRE.  SVR: 75-86% in treatment-naive patients. Once daily, no rash or increased anemia.  Hyperbilirubinemia can occur.
  • Faldaprevir -see above studies.
  • Danoprevir -NS3/4A protease inhibitor. Study: DAUPHINE. For genotypes 1 and 4. 100% SVR in genotype 4.  Rates of withdrawal with danoprevir were similar to placebo.
  • Daclatasvir -NS5A replication inhibitor. Study: COMMAND-1. For genotypes 1 and 4.
  • Sofosbuvir -NS5B polymerase inhibitor. Studies: PROTON, ATOMIC. For genotypes 1, 4, and 6.
  • Multiple DAAs in combination. Studies: MATTERHORN, INFORM-SVR, AVIATOR, ELECTRON, SOUND-2

Related blog posts:

Saving Livers and Saving Lives -An Insider’s View

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Pediatric Hepatology hep26580

The link above provides a terrific overview (Hepatology 2013; 58: 458-476) of the development of pediatric hepatology as a subspecialty.  For someone who was incredibly fortunate enough to train in the mid-1990s (right place, right time, right colleagues), I enjoyed finding out more about the decades that preceded my fellowship.  In addition, the article provides insight into the personal background of one of my mentors (thanks for Figure 1) and about a few patients that provided the clinical challenge for furthering the understanding of the pathophysiology of hepatobiliary disorders.

Biliary Atresia More Common in Preterm Infants

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During my fellowship, one of the faculty presented an abstract indicating that 4 out of 40 preterm infants with cholestasis had significant underlying liver disease in addition to parenteral nutrition associated cholestasis (PNAC).  One of these patients had biliary atresia.  The obvious point was not to assume that the cholestasis was due to the usual suspects found with premature infants.

A recent study indicates that biliary atresia (BA) in Taiwan is more common in preterm infants than in term infants (J Pediatr 2013; 163: 100-3).  The authors identified 197 cases (166 term infants) of BA between 2004-2010. This retrospective study used a nationwide screening for BA (the national stool card registry center database) along with reports from surgeons of the Taiwan Biliary Atresia Study Group.

Results:

  • Annual incidence of BA per 10,000 live births was 1.43 and 2.37 for term and preterm infants respectively.
  • Kasai operation before 60 days occurred in 68.7% of term and 44.4% of preterm infants.  Mean age of Kasai was 52.9 days for term infants and 71.8 for preterm infants.
  • Major congenital anomalies along with BA were more common among preterm (18.5%) than term (4.1%).
  • Mean onset of clay-colored stools among preterm infants was 33.6 days compared with 29.6 for term infants.
  • Stool cards had good sensitivity in detecting BA in both preterm and term infants: 96.3% and 92.8% respectively.
  • Jaundice-free at 3 months following Kasai was 62% of term infants and 37% of preterm infants.
  • 18-month survival with native liver was 72.7% in term infants and 50% in preterm infants.

While the authors point out several studies that have shown prematurity is an independent risk factor associated with BA, nevertheless this idea is counter to conventional wisdom that BA patients are typically well-appearing term infants at the time of diagnosis.  The authors also note that despite delayed diagnosis in preterm infants, this was not correlated with an impact on jaundice-free status 3 months following surgery.  This finding, in particular, should be cautiously interpreted as there were only 27 infants in the preterm group.

Related blog posts:

More data on DILI

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Using a population-based cohort, the authors of a recent study from Iceland performed a prospective study, collecting data on 96 individuals with drug-induced liver injury (DILI) from 2010-2011 (Gastroenterol 2013; 144: 1419-25 & editorial 1335-36).  This study benefitted from a centralized medical care system with about 250,000 adults.  Patients with acetaminophen toxicity were excluded.

Results:

  1. DILI occurred in 19 cases per 100,000 persons per year.  This is higher than previous DILI estimates in other populations and may be due to identifying more subclinical cases.
  2. DILI increased markedly with age from 9 per 100,000 among 15-29 year olds to 41 per 100,000 among those >70; however, this paralleled the increase use of medications.
  3. Eight drugs were implicated in more than 1 case with subsequent risk estimates:
  • Augmentin 1 per 2350 users
  • Azathioprine 1 per 133  (mostly anicteric cases)
  • Infliximab 1 per 148
  • Nitrofurantoin 1 per 1369
  • Isotretinoin 1 per 732
  • Atorvastatin 1 per 3693
  • Diclofenac 1 per 9148
  • Doxycycline 1 per 16,339

Some commonly implicated drugs did not show up on the list: fluoroquinolones, macrolide antibiotics, minocycline, valproic acid, and cancer chemotherapeutic agents (except one case due to imatinib).  The editorialist notes that these agents are not commonly used in Iceland.  Also, 16% of cases were due to herbals and dietary supplements.

Consequences of DILI: 27% developed jaundice, 12% required hospitalization, and 1 patient died.  The median time for liver tests to normalize in those that recovered was 64 days.

Related blog posts:

Celiac hepatopathies

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There has been a longstanding recognition that celiac disease can be associated with elevated liver enzymes.  Two articles provide further information about celiac hepatopathies.

  • JPGN 2013; 56: 663-70
  • JPGN 2013; 56: 671-74

The first study describes a review of nine studies identified in a MEDLINE search for celiac disease and hypertransamminasemia (HTS) or autoimmune hepatitis (AIH). In total 2046 patients were identified.

Key findings:

  • 12% of patients with mild persistent HTS had celiac disease.  Among individuals with HTS, the relative risk for celiac disease was 11.59 compared to general population.
  • 36% of newly diagnosed children with celiac disease, has elevated aminotransferases.  A gluten-free diet normalized transaminases in 77% within 4 to 8 months.
  • Among children with celiac disease, 1.4% had AIH.  Among children with AIH, 6.3% had celiac disease.

While this meta-analysis had many limitations, it is clear that celiac disease needs to be considered in patients presenting with elevated aminotransferases and in patients with AIH.  In addition, other liver conditions like primary biliary cirrhosis and sclerosing cholangitis, which are infrequent in the pediatric population, are more common in patients with celiac disease.

The second study involved both retrospective (1995-2000) and prospective evaluation (2000-2012) of patients followed at a single center.  The authors sought to determine the long-term response to immunosuppressive treatment in children with autoimmune hepatitis (AIH) and celiac disease.

In their cohort of 79 AIH patients, 15 (9%) had celiac disease.  There was a similar frequency of type 1, type 2 and seronegative AIH among the celiac patients (47%, 20%, and 33%) compared with the entire cohort (55%, 34%, and 11%).  All 15 patients responded to treatment with prednisone and azathioprine or cyclosporine, along with a gluten-free diet.  When immunosuppressive treatment was withdrawn in 9 patients, 4 relapsed and 5 were maintained off immunosuppression for a mean period of 89 months. A much lower rate of immunosuppression withdrawal was achieved in those AIH patients without celiac disease.  24 of 64 attempted to stop immunosuppression; 5 (8%) were successful.

Take-home point of second study: All AIH patients should be screened for celiac disease as a gluten-free diet may increase the likelihood of withdrawal of immunosuppression.

Low Ceruloplasmin Levels in Pediatric NAFLD

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Pediatric patients with nonalcoholic fatty liver disease (NAFLD) undergo workup to exclude underlying diseases.  For many patients, this may include screening for Wilson’s disease with a ceruloplasmin level.  In a recent study, lower ceruloplasmin in 100 pediatric patients with NAFLD were associated with more severe NAFLD (JPGN 2013; 56: 370-75).

All patients had measurements of copper, iron, ceruloplasmin, transferrin ferroxidase activity, and ferritin; these assays were from archival serum samples from a cohort with biopsy-proven NAFLD. These patients had undergone testing for other etiologies of liver disease.

The authors were trying to determine if oxidative stress and its association with iron or copper may be playing a role in the severity of NAFLD.  Those with lower severity NAFLD score (< 5) had a mean ceruloplasmin of 36.4 mg/dL (standard deviation 5.3); in contrast,  those with higher severity NAFLD score (≥5) who had a mean ceruloplasmin of 28.1 mg/dL (standard deviation 7.2).  That is, there was an inverse association between ceruloplasmin levels and the severity of NAFLD score.  Lower ceruloplasmin was associated with increased inflammation, more ballooning histology, and more steatosis.

Key point:

Lower ceruloplasmin (<28.6 mg/dL) had a 92% specificity and 76% sensitivity for identifying more severe NAFLD.  Thus, even a borderline-low ceruloplasmin that does not suggest Wilson’s disease may be useful in discriminating children more likely to need a liver biopsy.

Related blog entry:

NAFLD Guidelines 2012 | gutsandgrowth

Foil PNALD with FOLE?

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As noted on previous blog entries (see below), there has been significant enthusiasm for fish oil based lipid emulsion (FOLE) despite a lack of data showing superiority compared with standard soy-based lipid emulsions at similar dosing.  More data for FOLE helping infants with cholestasis are available (J Pediatr 2013; 162: 793-8).

Design: Single center, prospective observational study of 57 infants with parenteral nutrition-associated liver disease (PNALD) which  took place between 2007-2011.  All infants were between 2 weeks and 6 months of age at enrollment.  At enrollment, FOLE (Omegaven) at a dose of 1 g/kg/d was infused over 24 hrs.  FOLE which is not FDA-approved is available on a compassionate use protocol.

Infant characteristics: Median gestational age: 28 weeks. 47 of 57 were long-term survivors.  The median time at initiation of FOLE was 39.3 weeks post-menstrual age.

Results:

  • Median conjugated bilirubin at initiation of FOLE therapy was 7.5 mg/dL.
  • Resolution of cholestasis occurred at a median of 35 days (range 7-129) after starting FOLE.  Longer times for resolution were noted in those with higher initial bilirubin.
  • Time to resolution was inversely proportional to gestational age at birth (p=0.02) and directly to time to receive 100% calories enterally (p=0.03)

The authors note that none of the infants who died had liver failure; most deaths were due to multi-organ failure and sepsis.

In the discussion, the authors state “the most significant finding from this study is the effectiveness of FOLE in resolving cholestasis irrespective of the initial serum bilirubin values.”  I take issue with this statement primarily because the design of the study does not allow such attribution.  Without a randomized trial comparing FOLE to standard intralipids, this statement overstates any conclusion that can be drawn from this study.  Given the fact that resolution was correlated with advancement of enteral feedings, it is plausible that a similar result would occur with standard intralipids.

The authors make a number of other speculations about the potential superiority of FOLE over standard soy-based lipid emulsions, but concede that “our study was not adequately equipped to address” the association of reduced intralipid with improvement in cholestasis.  Despite this concession, the authors boldly proclaim in the concluding paragraph: “while awaiting the more general availability of FOLE, infants at high risk should be identified early and referred to centers that provide the option of FOLE…in which families are fully informed of both the potential benefits and limited current data.”

A recent media report also promotes the effectiveness of FOLE: http://nbcnews.to/11vbL2E 

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LIU Score

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The LIU acronym interested me in part because I work with Steven Liu. The LIU score refers to a Liver Injury Unit scoring system which is used to predict survival in pediatric acute liver failure (J Pediatr 2013; 162: 1010-6).

The LIU score and admission value LIU (aLIU) were examined in individuals enrolled in the Pediatric Acute Liver Failure (PALF) Study group.  LIU score was determined in 461 patients and aLIU in 579 patients.

  • LIU =[3.584 x peak total bilirubin (mg/dL)] + [1.809 x peak prothrombin time (PT) (sec)] + [0.307 x peak ammonia (μmold/L)]

or alternatively, using INR instead of PT:

  • LIU =[3.507 x peak total bilirubin (mg/dL)] + [45.51  x peak INR] + [0.254 x peak ammonia (μmold/L)]

Results: The LIU score was shown to be strongly predictive of transplant-free survival with a c-index 0.81.  The aLIU score was less predictive with a c-index of 0.76.  In this population, the LIU score predicted the likelihood of receiving a liver transplant better than the risk of death.

Bottom-line: The LIU score may have similar utility as a MELD/PELD score but is easier to calculate.

Liver Injury from Anti-TNF Agents

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While anti-TNF agents have been associated with drug-induced liver injury (DILI), it has been difficult to get a handle on how much importance to place on this.  A recent study provides more data and some reassurance (Clin Gastroenterol Hepatol 2013; 11: 558-64).

The authors searched the U.S. DILI Network database from 2003 to 2011 and describe 6 cases of anti-TNF DILI; in addition, they searched PubMed for articles related to anti-TNF agent associated hepatotoxicity and identified an additional 28 cases. Other causes of liver disease were excluded in these patients, including reactivation of hepatitis B, and acute viral hepatitis (eg. hepatitis C, hepatitis E).

Results of anti-TNF hepatotoxicity:

  • 26 cases due to infliximab, 4 cases due to etanercept, and 4 due to adalimumab.
  • Based on scoring system, the anti-TNF agent was considered a definite cause of DILI in 1 (3%), very likely in 21 (62%) and probable in 12 (35%).
  • Median latency (duration of therapy before onset of DILI) was 13 weeks with a range of 2-104 weeks.
  • 22 (67%) had positive anti-nuclear and/or smooth muscle antibodies.  15 of 17 of these patients had liver biopsy features consistent with autoimmunity.
  • Among those 22 with autoimmune features, there was a higher peak alanine aminotransferase compared with the 12 without these features (784 vs 528 U/L)
  • Favorable outcome: all but one patient improved after discontinuation of the implicated drug; 12 received corticosteroids. One patient with underlying cirrhosis underwent liver transplantation after infliximab-induced liver injury.

While the authors note the potential for a class effect of anti-TNF agents, in studies from patients with psoriasis, there was a lack of cross-toxicity between etanercept and infliximab.

Take-home messages:

The risk of hepatocellular injury from anti-TNF agents is very low.  DILI due to anti-TNFs often have autoimmune features. The prognosis is favorable, and alternative anti-TNFs can be given after resolution.

Related blog links:

From theory to bedside practice

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“That’s fine in practice, but how does it work in theory?”

I heard this quote while visiting the University of Chicago. A recent (really cool) study reminded me of this quote because of the interplay between predictions of the effects of a genetic defect in bile acid conjugation and the actual clinical presentation of 10 pediatric patients  (Gastroenterol 2013; 144: 945-55).

Background: Bile acid synthesis from cholesterol requires 17 enzymatic reactions in different cellular compartments of the hepatocyte.  These steps are tightly regulated.  All of the steps are vulnerable to genetic defects, some of which have been recognized for a long time.  The final step occurs in the peroxisome and is 2-part mediated by bile acid-CoA ligase enzyme (SLC27A5) and bile acid-CoA:amino acid N-acyltransferase (BAAT). This latest study examines the final step of primary bile acid synthesis in which there is conjugation with amino acids. Conjugation of bile acids improves absorption of lipids including fat-soluble vitamins.

Results: Ten patients with severe fat-soluble vitamin deficiency (five with rickets) were carefully analyzed. Levels of urinary bile acids showed increased unconjugated forms (79%).  In addition, there was an absence of glycine and taurine conjugates in the urine, bile, and serum. In the 8 patients with duodenal bile analysis, >95% of bile acids were unconjugated which was too low for efficient lipid absorption. Typically, glycine and taurine conjugates account for >95% of bile acids secreted in bile.  On mass spectrometry, there was a marked presence of a dominant ion at m/z 407 which represents cholic acid.  The investigators also performed molecular analysis and identified mutations in BAAT in 7 of 8 who had available DNA.

Clinical features:

  • Hepatomegaly in 3 of 10
  • Age at diagnosis: 3mo-14 years
  • Elevated aminotransferase: 4 of 10
  • Low GGT
  • Liver failure/transplant in one patient
  • All 10 had fat-soluble vitamin deficiency
  • None had diarrhea (which had been theorized)

Thus, patients had variable liver disease ranging from none to severe.

Take-home message(s):

Specific genetic defects have been identified in the final steps of bile acid production. Abnormal urine mass spectrometry may increase the suspicion for mutations in BAAT (or SLC27A5).  Breakdown in any of these bile acid synthesis steps can lead to fat-soluble vitamin deficiency.  Potential treatment with primary conjugated bile acids (e.g.. glycocholic acid) should improve fat-soluble vitamin absorption in these patients.

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