Category Archives: Pediatric Gastroenterology Liver Disease

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)

“Immune-tolerant” — a misnomer for HBV infection

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When hepatitis B virus (HBV) infection occurs in the perinatal period, often the result is high levels of  HBV DNA yet immune-mediated damage of the infected liver is generally not observed and serum aminotransferases are normal.  This phase of infection has been considered “immune-tolerant.”  This phase can last for years or even decades.  New data indicate that the during this phase, there is preserved T-cell function and there are indications of good immune function (Gastroenterol 2012; 143: 637-45, & editorial 529-32).

The authors of the study isolated T cells from different age groups of patients with chronic HBV infection.  Then, they used flow cytometry methods to measure production of numerous cytokines.  In addition, markers of T-cell exhaustion or inhibition were examined.

Key Finding: young patients had more specific HBV-specific T cells with the ability to proliferate and produce cytokines than adult patients.

The study itself is highly technical with graphs of cytokine profiles, quantitation of T-cell expressing exhaustion markers, dot plots, etc.  Some of the figures are easy to understand like Figure 5 which plots the multifunctionality of HBV-specific response with three separate charts lined up; these correspond to “Immune tolerant,” “Chronic active,” and “Inactive carriers.”

The editorial is essential to understanding this study & restates the other findings:

  • “the authors found that T cells from CHB patients were more likely to produce TH1 cytokines …compared with those from healthy subjects”
  • they “found no global differences in this profile between tolerant and active states”
  • HBV-specific T-cell response: “a PD-1 high/CD127 low ‘exhausted’ phenotype were actually found to increase with age”
  • “T-cell responses to HBV core, envelope, and X proteins were readily observable in all patients”

The editorial speculates that so-called ‘tolerance’ may occur at a local/hepatic level, largely a ‘matter of sequestration.’  And, concludes that this study has “view-changing” observations.  Ultimately, this may lead to therapeutic treatments aimed at the liver microenvironment & may change our opinion of the suitability of treating younger patients.

Test your knowledge of Hepatitis E

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Typically, Hepatitis E virus (HEV) is not considered a frequent pathogen in the U.S.; however, anti-HEV antibody has been detected in 21% of U.S. in population-based surveys between 1988-94 and the prevalence increases with age. It has been associated with acute-on-chronic liver disease and has been overlooked in some individuals labeled as having drug-induced liver disease.  Thus, HEV is a significant cause of hepatitis and a useful review has been published (NEJM 2012; 367: 1237-44).  As such, see if your knowledge is up to the test.

Questions:

  • 1. True or False: Worldwide, HEV is probably the second most common form of acute hepatitis
  • 2. True or False: The autochthonous form is more common in developed countries and can be present in developing countries.  Extra credit, what does “autochthonous” mean?
  • 3. Best test to order to diagnose acute HEV?
  • 4. Animal(s) most likely associated with the autochthonous form of HEV: shellfish, swine,  or wild game
  • 5. True or False: there are 4 genotypes
  • 6. True or False: antibodies (IgG and IgM) appear at the time of clinical onset, just before elevations in serum aminotransferases and symptoms
  • 7. How long do these antibodies remain detectable?
  • 8. Which population is most prone to fulminant epidemic HEV?  Pregnant women, immunocompromised hosts, or infants
  • 9. Incubation period? a. 1-2 weeks    b. 3-8 weeks    c. 9-12 weeks
  • 10. Case fatality rate? a. 1%    b. 2-4%   c. 5%    d. 7-10%
  • 11. Name extrahepatic manifestations
  • 12. Best treatments for chronic HEV?

Answers:

  • 1. False, probably the most common cause of acute hepatitis
  • 2. True.  Autochthonous refers to locally-acquired or endemic HEV
  • 3. IgM for anti-HEV
  • 4, Swine, but the other two have been associated with cases as well
  • 5. True.  Types 1 and 2 are more common in developing countries and associated with waterborne outbreak/fecal-oral transmission
  • 6. True.
  • 7. IgM anti-HEV for only 3-12 months, IgG anti-HEV persists for “years, if not for life”
  • 8. Pregnant women. Nutritional and immunologic features may increase the risk of fulminant HEV in pregnant women.  Rates of HEV are lower in many immunocompromised groups.  Elderly patients are more at risk for mortality due to endemic form.
  • 9. b.
  • 10. c.
  • 11. Arthritis, pancreatitis, aplastic anemia, Guillain-Barre syndrome, Bell’s palsy, peripheral neuropathy, ataxia, and confusion
  • 12. Ribavirin alone for 12 weeks yields sustained virologic response in at least two-thirds; combination with peginterferon may increase the response.  Both are considered experimental at this time.

Previous quiz blog:

Test your knowledge of Clostridium difficile

Congenital hepatic fibrosis

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In a previous blog entry (Hepatic ciliopathies), I briefly discussed congenital hepatic fibrosis (CHF).  A more detailed review and handy reference: Srinath A, Shneider BL. JPGN 2012; 54: 580-87.

This invited review details information related to 1230 CHF patients from 155 articles (available at http://links.lww.com/MPG/A88).  Median and mean age of diagnosis were 2 and 11.2 years respectively.

Distribution of CHF cases/associated conditions: 118 isolated CHF, 788 autosomal recessive polycystic kidney disease, 315 with Caroli disease/syndrome, 9 with type V choledochal cyst

Clinical problems:

  • Sequelae of portal hypertension in 409 patients: 164 with varices, 74 with bleeding varicose, 81 underwent portosystemic shunting.  Portal hypertension itself was identified in 71-97% depending on the patient subset examined.
  • Cholangitis in 152 patients –often recurrent.  This was fatal in 3 of 23 children after renal transplantation.
  • Malignancy in 21 patients (2%). 19 were cholangiocarcinoma.  Of these cases, 10/19 had Caroli disease/syndrome, 7 had isolated CHF, 1 had ARPKD, and 1 had Type V choledochal cysts. Youngest patient with cholangiocarcinoma was 33 years, all other cases involved patients >40 years.

Transplantation: Isolated kidney 91 (95% in ARPKD), Isolated liver 173 (87% had Caroli), Combined 23.  Three renal patients subsequently had combined transplantation.

Other important points:

  • CHF is not ‘typically associated with progressive hepatic insufficiency.’ Only rarely is hepatic synthetic function compromised
  • Predisposition to cholangitis may affect transplantation decisions and timing