Category Archives: Pediatric Gastroenterology Liver Disease

Vaniprevir for HCV

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Vaniprevir (MK-7009) is a hepatitis C virus (HCV) NS 3/4A protease inhibitor.  A phase II study has shown that vaniprevir can be an effective agent in combination with pegylated interferon alpha-2a (PEG-IFN) and ribavirin (RBV) (Hepatology 2012; 56: 884-93).

This double-blind, placebo-controlled study examined 94 patients with treatment-naive genotype 1 HCV.  In combination with PEG-IFN/RBV, patients received either placebo, vaniprevir 300 mg BID, 600 mg BID, 600 mg QD or 800 mg QD for 28 days & then open-label PEG-IFN/RBV for 44 weeks.  There were 18-20 patients in each group.

With all of these vaniprevir doses, there was a rapid two-phase decline in viral load; the HCV RNA level was approximately 3log10 IU/mL lower in vaniprevir-treated patients than placebo.  Rapid viral response occurred in 68.8-83.3% of vaniprevir-treated patients compared to 5.6% of control patients.  Sustained virologic response was higher but did not reach statistical significance.

Resistance to vaneprevir with variants at R155 and D168 was detected in a small number of patients.  The authors note that treatment outcomes were not related to interleukin-28B genotype.

The potential advantage of vaneprevir over currently available triple therapy agents (eg. telaprevir and boceprevir) would be easier administration, QD or BID, and possibly more favorable side effect profile.

Take home message: more treatment options, including vaneprevir, for HCV are on the horizon.

Related blog posts:

Missing “C”

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Ascertainment rates for pediatric hepatitis C virus (HCV) are as bad as in adults with HCV (J Pediatr 2012; 161: 915-21).

As noted in previous blog entries, it has been recommended by the CDC that adults born between 1945-65 undergo a one time screening for HCV due to the high frequency of undetected cases along with improvements in therapy.  The same rationale may apply to children in the near future as some of these therapies are shown to be safe and effective in the pediatric population.

In the meanwhile, it is apparent that most pediatric HCV cases remain undetected.  In the aforementioned study, the investigators examined statewide data from Florida and data from health departments across the United States.  This was compared with data from NHANES III which reported HCV prevalence of 0.2% in children 6-12 years old and 0.4% of 13-18 year olds.  The absolute prevalence may be higher as NHANES did not capture some populations at high risk, like homeless or incarcerated youth.

Results:

  • From 2000-2009, only 2007 children were identified as HCV-antibody positive in Florida.  During this period, it is estimated that this represents about 12% of the expected number of cases (n=12155).
  • In Dade county which has 13 pediatric gastroenterologists, 100% responded to an online questionnaire.  They reported caring for 31 cases of HCV in 2009 and another 55 in the preceding 5 years.  This indicates that 1.6% of the expected number of HCV-antibody-positive children in this region received care in 2009 and 2.8% over previous 5 years.
  • Nationwide, only two states (VT, MA) identified more than 20% of expected cases.

Related blog entries:

Neonatal cholestasis and Down syndrome

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A retrospective Swedish study adds some useful information on the incidence of neonatal cholestasis with Down syndrome (J Pediatr 2012; 161: 899-902).

In this retrospective study of all neonates born between January 2005-September 2011 in Stockholm , a total of 206 newborns were identified as having Down syndrome.  This represents an incidence of 1 in 880 newborns.

  • 3.9% (n=8) had cholestasis
  • 47% (n=96) had congenital heart disease
  • 11.2% (n=23) had GI disorders: duodenal stenosis (n=7), duodenal atresia (n=4), omphalocele (n=3), Hirschsprung disease (n=2), esophageal atresia/duodenal atresia (n=1), jejunal atresia (n=1), and other conditions (n=5)
  • 3.4% (n=7) had bone marrow diseases including transient abnormal myelopoiesis

All eight children with cholestasis had congenital heart disease.  However, severe cholestasis was only seen in the 3 patients with concomitant bone marrow disease. Two of these patients died and one developed cirrhosis/chronic liver disease. All cholestatic patients had involvement of other organ systems.  As this was a retrospective study, some milder cases of neonatal cholestasis may not have been detected.

In children with concomitant bone marrow disease, neonatal cholestasis may forebode an increased risk for severe disease.  While all 3 of the newborns with severe disease also had congenital heart disease, most infants with combined congenital heart disease/cholestasis (n=5) did not have a severe case.

Related blog posts

Working on biomarkers for Biliary Atresia

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Two studies have tried to identify biomarkers to facilitate the diagnosis of biliary atresia (BA).

  • JPGN 2012; 55: 366-69
  • JPGN 2012; 55: 370-75

The first study looks at the serum of 24 patients with BA & 24 cholestatic controls.  Several circulating microRNAs (miRNAs) were associated with BA.  The miR-200b/429 cluster could correctly classify up to 85% of patients.

The second study took serum samples from 42 infants with BA, 38 infants with non-BA cholestasis, and 36 healthy controls.  Using mass spectrometry and enzyme-linked immunosorbent assays, they identified a candidate biomarker, Apo C-II, which was down-regulated in BA samples compared to healthy controls, but relatively upregulated compared with cholestatic non-BA samples.  The sensitivity of this model was 94% and the specificity was 92%.

Given the consequence of a missed diagnosis of BA, further work to identify biomarkers with even better sensitivity/specificity will be necessary to change current diagnostic algorithms.

Previous related blog entries:

Looking ‘Sily’ taking this herb?

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Taking milk thistle (silymarin) does not seem to improve disease status or symptoms with chronic hepatitis C (JAMA 2012; 308: 274-82).

This multicenter, randomized, double-blind, placebo-controlled study examined 154 patients with chronic hepatitis C (HCV).  Mean age was 54 years (71% male).  The study required participants to have an ALT ≥ 65 U/L and all patients had been previously unsuccessfully treated with interferon-based therapy.

Silymarin (Silybum marianum) is an extract of milk thistle.  In the HALT-C trial, 33% of patients with chronic HCV and cirrhosis reported current or past use of silymarin.  It has been shown to have anti-inflammatory and immunomodulator properties via inhibition of NG-κB; in addition, it may have direct effects on HCV replication.

Of the 154 patients, 52 received placebo, 50 received 420-mg silymarin dose, and 52 received 700-mg dose. The trial name was ‘Silymarin in NASH and C Hepatitis’ or SyNCH.  All patients were instructed to take medication three times a day. Only 2 patients in each group (~4%) met the primary outcome of an ALT ≤ 45 U/L.  In addition, HCV RNA levels remained unchanged and were similar between placebo-treated patients and silymarin-treated patients.

In addition, there were no significant changes in physical or mental health components of quality-of-life scores: CES-D (Center for Epidemiologic Studies-Depression), CLDQ (Chronic Liver Disease Questionnaire), and SF-36 (Short-Form 36).

Adverse effects were similar, though silymarin-treated patients had increased GI adverse effects,12% vs 5% among placebo-treated patients.   Though, the study was not powered to detect significant differences with respect to adverse effects.

The major limitation of the study was the patient selection; that is, patients not responsive to interferon may not be representative of all patients with chronic HCV.  While newer HCV therapies have become much more effective, due to their expense, effective less-costly therapies would be helpful.

Unfortunately, milk thistle/silymarin is not likely therapeutic for HCV and thus not cost-effective either.

Related blog entries:

Don’t forget the liver for APC patients

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A recent case report serves a useful reminder that patients with APC gene mutation are at risk for hepatoblastoma (JPGN 2012; 55: 334-36).  A comprehensive review on this subject and APC gene disorders in general (along with related disorders) can be found at the following link: (APC-Associated Polyposis Conditions – GeneReviews™ – NCBI …)

One of the authors of the online link is a well-established expert in the field (Randall W Burt, MD) and updated the link in October 2011.

With regard to hepatoblastoma:

“The risk for hepatoblastoma in FAP is 750 to 7500 times higher than in the general population, although the absolute risk is estimated at less than 2%. The majority of hepatoblastomas occur prior to age three years.”

Screening for hepatoblastoma in FAP?

“Efficacy in individuals with FAP is unclear. Screening protocols in Beckwith-Wiedemann syndrome, in which the risk for hepatoblastoma is also increased, often include frequent (every 2-3 months) abdominal ultrasound examinations and measurement of serum alpha-fetoprotein concentrations and have resulted in early detection of hepatoblastomas. Screening for hepatoblastoma in FAP using the same protocol may be considered from infancy to age five years. However, the optimal interval for hepatoblastoma screening in FAP is not known, although it has been recommended that screening should occur at least every three months.”

Additional references:

  • -Liver Tx 2008; 14: 1545.  Reviews predisposing conditions to hepatoblastoma & HCC, screening & Rx.  Disorders include Beckwith-Wiedeman, FAP, tyrosinemia, GSD type II, PFIC type 2, Alagille, EHBA, HBV, TPN-cholestasis/extreme prematurity.
  • -J Pediatr 2005; 146: 204.  Review of Cincy experience and algorithm for hepatoblastoma management.
  • -H F A Vasen, G M G Möslein, A Alonso, et al. Guidelines for the clinical management of Familial adenomatous polyposis (FAP) Gut 2008 57: 704-713
  • -Polymnia Galiatsatos, ,William D. Foulkes. Familial Adenomatous Polyposis Am J Gastroenterol 2006;101:385–398
  • -Gastroenterol 2001; 121: 195-197 &198-213. Guidelines & technical review of genetic testing for FAP & HNPCC.

Vision and persistence in developing liver transplantation

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A concise perspective article examines the history and challenges of developing liver transplantation into an accepted treatment for end-stage liver disease (NEJM 2012; 367: 1483-86).

Key points:

  • Thomas Starzl 1st attempted liver transplant in 1963.  The 3-year-old boy with biliary atresia did not survive the operation; the next 5 attempts were failures as well with the longest survivor lasting only 23 days.  A moratorium of nearly 4 years was placed after these initial failures.
  • Improvements in immunosuppression were a key advance, including antilymphocyte serum in 1966.  During the 1970s, 70% of liver-allograft recipients died shortly after surgery.
  • Brain death concept, accepted in 1968, allowed for better donor organs (less ischemia)
  • Key immunosuppression advance was in 1979 when Roy Calne (Cambridge) reported the use of cyclosporin for organ transplantation.  Between 1980-81, 70% (n=40) of Starzl’s patients survived more than one year.
  • In 1983, National Institutes of Health at a consensus conference concluded that liver transplantation should be considered a ‘clinically applicable, lifesaving procedure.’
  • Other improvements, such as better organ procurement protocols and preservation along with further improvements in immunosuppression have helped improve 1-year and 5-year survival rates to climb, >85% and >70% respectively in 2010.
  • In 2010, 6291 patients underwent liver transplantation.
  • Remaining challenges include inadequate organ supply, recurrent primary hepatic disease (eg. hepatitis C), adverse drug effects, and post-transplantation complications.

The persistence and vision of Starzl and Calne has been recognized with the Lasker-Debakey Award (Lasker-DeBakey Clinical Medical Research Award – Wikipedia, the …).

Cholestatic Kawasaki Disease

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Periodically, Kawasaki disease (KD) will present with fever and cholestasis (JPGN 2012; 55: 380-83).

The authors of this study which took place between 2003-2010 reviewed the presentation of children less than 16 years of age who presented with fever on admission (>38.5), total bilirubin >3 mg/dL and elevated ALT values.  In all 24 patients who met criteria for review; 5 (21%) had KD.  Patients with KD ranged in age between 1-10 years.

The other causes included viral hepatitis in 13 (EBV, HAV, CMV, Adenovirus, HSV), 4 had drug-induced cholestasis, 1 with cholelithiasis, and 1 with a choledochal cyst.

In almost 20% of KD patients, the presentation does not meet all of the diagnostic criteria: at least 5 days of fever and 4 of 5 following conditions: bilateral nonpurulent conjunctival injection, oral mucosal changes, peripheral extremity changes (edema/erythema of palms/soles, desquamation of fingers/toes), rash, cervical lymphadenopathy (unilateral, >1.5 cm).

Also, for those who did not receive yesterday’s blog on NASPGHAN postgraduate course, check out the following link:

NASPGHAN Postgraduate Course 2012 | gutsandgrowth

Additional references:

  • Kawasaki disease – Wikipedia, the free encyclopedia

  • -J Pediatr 2011; 158: 644.  Infliximab may work better than IVIG for Kawasaki.
  • -J Pediatr 2009; 155: 695.  Reviews recent experience & criteria for Kawasaki.
  • -Pediatrics 2004; 114: 1708. guidelines from AAP for Kawasaki.

NASPGHAN Postgraduate Course 2012

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Postgraduate course syllabus: naspghn.informz.net/

So far I’ve looked at the first few talks from the postgraduate course syllabus (see link above), including CVS slides by B Li.  Several good pointers are given.  For example, for abortive therapy, he recommends use of Zofran 0.3 mg/kg/dose.  Page 17 of course book details preventative measures.  Also, with regard to amitriptyline, he recommends starting at 0.3 mg/kg and titrating as needed up to 1-1.5 mg/kg/day.  Mitochondrial-type support often helpful as well (eg. CoQ10 10 mg/kg/day divided BID).

At the end of this lecture are a couple of questions –see how you do:

  1. Which NASPGHAN Consensus diagnostic criteria for CVS is the most specific?
    1. positive family history of migraine
    2. vomiting at least 4 times/hour at peak
    3. well between episodes of vomiting
    4. each attack resembles the others
    5. associated pallor and listlessness
  2. All of the potential mechanisms below have been implicated in CVS except:
    1. HPA axis activation
    2. migraine vascular changes
    3. autonomic nervous dysfunction
    4. mitochondrial dysfunction
    5. serotonin receptor polymorphisms

page22image7408 page22image7568

3. NASPGHAN recommended evaluation of a child with episodic vomiting:

  1. a. electrolytes, BUN, Cr
  1. electrolytes, BUN, Cr & UGI
  2. electrolytes, BUN, Cr, UGI & ultrasound
  3. electrolytes, BUN, Cr, UGI, ultrasound & endoscopy
  4. electrolytes, BUN, Cr, UGI, ultrasound, endoscopy & MRI
  1. Which is the best initial approach to the 11 year old child with CVS who has failed multiple medications and missed 4 weeks of school?
    1. consult psychology for anxiety and stressors
    2. redo all laboratory and radiographic testing
    3. consider induced sleep in the PICU
    4. hospitalize and observe teenager in episode
    5. add a second prophylactic medication
  2. Which statement best applies to the preventative approach to CVS?
    1. step‐wise increases in medicines are rarely required
    2. life style modifications are not recommended
    3. after anti‐migraine agents, anticonvulsants are used
    4. toddlers should receive propranolol first line
    5. topirimate does not cause cognitive dysfunction

    Answers: 1. d;2.e;3.b;4.a;5.c

Foreign body talk: if object >2cm or longer than 5 cm, may have difficulty passing.

Also a link to the meeting notes and abstracts:
naspghan.org/wmspage.cfm?parm1=723 …

NASPGHAN POSTGRADUATE COURSE Table of Contents

MODULE A: WHAT GOES IN, MUST COME OUT: CLINICAL GASTROINTESTINAL ISSUES

FROM PROPRANOLOL TO INDUCING COMA: CARING FOR A CHILD WITH INTRACTABLE CYCLIC VOMITING SYNDROME (CVS)………………………13 INCONTINENCE WITHOUT FECAL IMPACTION    …………………………….23 ELIMINATION DIETS: RISKS AND BENEFITS……………………………………..37

MODULE B: LIVER BEYOND VIRUS, METABOLIC, STORAGE, TUMORS

METABOLIC LIVER DISEASE: WORKING THROUGH THE MAZE ……………….51 UPDATE ON ALPHA‐1‐ANTITRYPSIN DEFICIENCY         ……………………………61 THERE IS A LIVER MASS ON THE ULTRASOUND: WHERE DO YOU GO FROM HERE? ….75

MODULE C: THE INFLAMED INTESTINE

GI INFLAMMATION, IMMUNE FUNCTION AND IBD          ………………………………87 MY STOMACH IS BUGGING ME!: THE MICROBIOME IN IRRITABLE BOWEL SYNDROME ……………………………………………………………………………………………101                                                                                                THE SORE BOTTOM: PERIANAL INFLAMMATORY BOWEL DISEASE         ……111 RESCUE ME FROM MY IBD: UPDATES ON INFLAMMATORY BOWEL DISEASE THERAPY ………………………………………………………………………………………………125

MODULE D: IMAGING AND ACCESSING THE TUBES

LOOKING DEEPLY INTO THE NOT SO SMALL INTESTINE ……………………………..137 PUTTING TUBES WITHIN TUBES: ENTERAL THERAPEUTIC ACCESS    ………….151 IMAGING THE PANCREATO‐BILIARY TREE                …………………………………….169 UPDATE ON CRITICAL FOREIGN BODY INGESTIONS  ………………………………….189

MODULE E: WHEN ALL ELSE FAILS: LIVER, INTESTINE AND POUCH

THE KID IS ON THE LIST: KEEPING COMPLICATIONS AT BAY FOR THE
NON‐TRANSPLANT HEPATOLOGIST ……………………………………………………201 TRICKS OF THE TRADE FOR INTESTINAL FAILURE ……………………………….213 GASTROINTESTINAL AND LIVER COMPLICATIONS OF BONE MARROW TRANSPLANT                                                                    …………………………225 POUCH DYSFUNCTION AND SURVEILLANCE: WHAT ARE MY OPTIONS? .235

Screening for subclinical PSC in IBD?

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In children with IBD, elevated liver enzymes raise the concern for primary sclerosing cholangitis (PSC).  PSC is thought to develop in up to 5% of patients with IBD.  To look more closely at this issue, a group of investigators examined 73 children (median age 12 years) with IBD with MRCP to look for evidence of PSC (JPGN 2012; 55: 308-13).

The majority of these patients had an MRCP at the time of an MRE; this was ordered independently from specific laboratory or clinical factors.  On average, the date for MRCP was about one year after the date of diagnosis.  In this group, 49 (67%) had Crohn’s disease (CD), 19 (26%) had indeterminate colitis (IC), and 5 (6.8%) had ulcerative colitis (UC) [In the results section, the authors state a discrepancy from previous: 47 with CD, 18 with IC, and 8 with UC.]

11 (15%) children had PSC-type lesions identified by MRCP.  6 of these patients had CD, 3 had IC, and 2 had UC.  Among the PSC group, 5 had abnormal AST & ALT, 4 had abnormal GGT, and 1 had abnormal bilirubin at time of diagnosis & similar numbers were present at the time of MRCP.  A much lower percentage of the non-PSC group (n=62), had abnormal LFTs.  Though, at time of MRCP, 9 (14.5%) had abnormal ALT.

An editorial in the same issue (page 238), concludes that “screening for PSC by MRCP in all of the newly diagnosed patients with IBD seems promising.”  Really?  Given a lack of therapeutic options, I don’t think identifying preclinical PSC makes any sense.  An exception would be in patients with persistent liver test abnormalities to avoid attributing this to medication toxicity.

Previous RELATED BLOG ENTRies

Challenges with primary sclerosing cholangitis | gutsandgrowth

Colonic disease and PSC | gutsandgrowth

Additional reference:

-Hepatology 2009; 50: 808-14.  High-dose ursodeoxycholic acid not effective for PSC (worsened outcomes noted)