Diagnosing biliary atresia earlier

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Biliary atresia (BA) is often suspected among infants with prolonged jaundice. In fact, efforts have been underway for a long time to encourage fractionation of the bilirubin values to look for conjugated hyperbilirubinemia, especially in infants that remain jaundiced at three weeks of life.  While this is still good advice, given the lack of success in implementation, there is good evidence that obtaining a fractionated bilirubin at any time point can help identify cholestasis associated with BA.

A recent article by Karpen et al (Pediatrics 2011; 128:. e1428 -e1433) indicates that direct bilirubin values are elevated beginning within the first one to two days in patients with BA.  In their cohort of 61 BA subjects, 56% had newborn fractionated bilirubin values.  Every BA patient had elevated direct bilirubin, on average 1.4 ± 0.43 mg/dL (normal <0.5) (compared with control patients:  0.19 ± 0.075 mg/dL, P < .0001).  Also, another important finding was that early on the ratio of direct bilirubin to total bilirubin was normal in 79%; normally this ratios is ≤0.2.  As such, all patients with increased direct bilirubin need to be followed closely.

Related blog entries:

Outcomes of Biliary Atresia

MicroRNAs and biliary atresia

Bleeding due to vitamin K deficiency

Diarrhea, GC-C and guanylin

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During my fellowship, I participated in research studying the effects of guanylin and its interaction with the receptor, guanylate cyclase C (GC-C).  So whenever clinical articles demonstrate clinical significance, I am interested.  This month there is evidence that some cases of familial diarrhea are due to mutations which activate the GC-C receptor (NEJM 2012; 366: 1586-95).

The authors describe a novel dominant disease in 32 members of a Norwegian family due  to a mutation in the sequence of GUCYC which encodes GC-C.  Exposure of this mutant receptor to its ligands results in increased cyclic guanosine monophosphate (cGMP).  This in turn likely causes hyperactivation of the cystic fibrosis transmembrance regulator (CFTR)  resulting in diarrhea.  Individuals with this mutation tended to have mild chronic diarrhea with an early onset as well as a susceptibility to inflammatory bowel disease and small bowel obstruction.

While this mutation is rare, there is a larger role for GC-C.  Heat-stable enterotoxins form E. coli bind to this receptor starting a cascade which results in diarrhea.  Since there had to be a role for GC-C other than facilitating development of diarrhea after exposure to pathogens (Why would our body create a receptor for a pathogen?), researchers discovered an endogenous ligand for GC-C, guanylin.   Guanylin acts as an agonist of  GC-C and regulates electrolyte and water transport in intestinal and renal epithelia.  In addition, guanylin and GC-C serve as a model for intestinal gene regulation.  Also, GC-C has been investigated as a predictive marker for colorectal cancer and for a role in renal electrolyte transport in humans; in animals, GC-C and its ligands have been shown to have effects on behavior and satiety.  

Additional references:

  • -Steinbrecher KA, Cohen MB. Transmembrane guanylate cylase in intestinal pathophysiology. Curr Opin Gastroenterol 2011; 27: 139-45.
  • -Gastroenterology 2010; 138: 886.  Linaclotide -a guanylin analog –use for constipation.
  • -Hochman JA, Sciaky D, Whittaker T, Hawkins JA, Witte DP, Cohen MB. “HNF-1 Regulates the Transcriptional Activation of Guanylin” Am. J.  Physiol. 273 (Gastrointest. Liver Physiol. 36): G833-G841, 1997.
  • It’s often elemental  Previous post discusses protracted diarrhea of infancy

Oley: Check it out

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Recently, I received a post from Oley Foundation (Linda May) asking me whether I was going to its convention.  While I am not, I did want to share that link:

http://www.oley.org/annualconf.html
The conference is in lovely Redono Beach, CA, right on the beach. We have miles of running paths, beautiful beaches, on site tennis courts, and swimming pool . To quote other MDs, “the Oley Annual conference is the most important clinical conference I attend all year…”

Also, Oley website is a good link for patients with enteral tubes, ostomies, and central lines. http://oley.org/

Many questions and how-to advice available.  For example, look at this link if interested in advice about swimming with central line, or enteral tube: http://www.oley.org/Swimming.html

One for the PPI team

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While this blog in previous posts has pointed out some shortcomings of proton pump inhibitors (PPIs), at the same time this class of medications remains a crucial part of pediatric gastroenterology practice.  In most patients, the benefits of these medications far outweigh the potential risks.

One of the risks has been a low rate of increased infections due to lowering gastric acid which provides some protection against enteric infections.  More information about PPIs show that these medications are not likely to increase the risk of small intestinal bacterial overgrowth (SIBO) (Am J Gastroenterol 2012; 107: 730-35 –thanks to Ben Gold for showing me this article).

In this retrospective study from 2004-2010, 1191 patients were included with 566 receiving PPI therapy.  Mean age: 63 years for PPI users and 59 years for nonusers. Glucose breath hydrogen testing (GBHT) for bacterial overgrowth did not differ significantly between PPI users and nonusers.  The authors acknowledge that there have been conflicting reports previously between the use of PPIs and the development of SIBO (see Table 5 of article); interestingly, SIBO with PPIs has occurred predominantly in studies from Europe.  The authors note that while achlorhydria leads to SIBO, the intermittent surges of acid production with PPIs should be sufficient to prevent SIBO.

Additional references/previous blog posts:

  • Proton pump inhibitors–infection risk with cirrhosis
  • The Medical Pendulum and Gastroesophageal Reflux
  • -Gastroenterol Hepatol 2011; 7: 10-2.  Risk of infections with PPIs.
  • -Gut 2007; 56: 802-8.  SIBO with IBS.
  • -NEJM 2010; 363: 2114. large Denmark study. 5082 fetuses with PPI exposure (out of 840,968 live births. Risk of birth defects NOT increased with exposure during 1st trimester. Possible slight increase with preconception use except with omeprazole.
  • -Gastroenterol 2010; 139: 1115. Review of safety of PPIs.
  • -Gastroenterol 2010; 139: 93. n=167,000. PPIs associated with hip fracture risk, OR 1.3, in patients with other risk factors.
  • -Gastroenterol 2010; 138: 896-904. 5 yrs of PPI -no increase risk in hip/spine fx.
  • -Arch Intern Med 2010; 170: 765-71, 747 (ed). PPI not related to hip fx (n=161,806) women 50-79. INCREASE risk of spine fx, hazard risk 1.47
  • -Arch Intern Med 2010; 170: 772-8. PPIs increase risk of CDT (hazard ratio 1.42 –42% increase in risk), n=1166.
  • -Arch Intern Med 2010; 170: 784-90. n=101,796.  Risk of nosocomial infection: OR 1.74 for daily PPI, OR 2.36 if BID Rx; thus ~70% increase risk of nosocomial infection.

Improve Care Now

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Several years ago, “ImproveCareNow” Network was established with a goal of improving the quality of care children with inflammatory bowel disease. https://improvecarenow.org/ (http://www.youtube.com/watch?v=beG2eMROWqg)

Documentation of some outcomes of this effort have now been published (Pediatrics 2012; 129: e1030-e1041).  In this study from six U.S. centers, data from 843 children with Crohn’s disease and Ulcerative Colitis were available.  Centers were eligible to participate if they did not have extensive quality improvement (QI) experience and if they were able to enroll >75% of their IBD patients.  During the course of the study (2007-2010), there were increases in the proportion of patients with measurement of thiopurine methyltransferase (TPMT) before initiation of thiopurines, increased percentage of individuals receiving an appropriate thiopurine dosage, and an increased percentage of patients with inactive disease.  In Crohn’s disease, the number with inactive disease changed from 55% to 68%; in ulcerative colitis, the number increased from 61% to 72%.  

This study shows significant progress in these patients and the potential benefit of a more-structured approach.  However, some of the improvements in these outcomes may not be to process improvements. 

Study limitations:

  • The study does not document the rate of inactive disease in non-participating centers; thus there is not an adequate control population.  Given more widespread use of biologic therapies, this may account for much of the improvement in outcomes.   In fact, the study does not describe the percentage of patients receiving thiopurines or biologic agents.
  • The use of the physician global assessment (PGA) as indicative of disease activity.  The authors acknowledge that “PGA ….is a relatively subjective measure.”  A more reliable measure of disease activity like a stool calprotectin, endoscopy, or imaging study improvement would have been helpful.  
  • Better documentation or better outcomes? It is not clear whether some of the improvement reflects better documentation or improved care delivery.

Despite the limitations of this study, it is a good starting point.  The goal of improving the care of patients is shared by almost all physicians.  One way to start making a difference is measuring specific outcomes and targeting specific goals/checklists. Going forward with QI there are many QI hurdles: 

  • Defining optimal care is nearly impossible, there are few trials comparing efficacy & difficult to judge risk/benefit ratio of many therapies.
  • Difficulty selecting appropriate outcome measures -indications for hospitalization and surgery are not clear-cut in many cases.  Surgery may be an appropriate treatment rather than a negative outcome. 
  • Risk adjustment is an imperfect science.

Goals with Quality Improvement:

  • Plan-Do-Study-Act cycles.
  • Learning from high-performing centers -benchmarking

Warranted vs unwarranted variations:
Unwarranted: selecting inadequate dosing of medications, failure to check for TB before remicade/biologics, failure to consider drug interactions, failure to discuss options with families
Warranted: variation due to differences in disease (eg budesonide for ileitis but not pancolitis), variation driven by patient preferences (eg. using NG instead of corticosteroids)

“When you can measure what you are speaking about and express it in numbers, you know something about it; but when you cannot express it in numbers, your knowledge is of a meagre and unsatisfactory kind” –Lord Kelvin 1883

“Not everything that counts can be counted, and not everything that can be counted counts.” –Albert Einstein

Additional references on quality improvement:

  • Free Self Management Handbook endorsed by ImproveCareNow:

https://improvecarenow.org/patients/self-management-handbook

  • -JPGN 2009; 49: 272.  Review of quality measures/history.
  • -Kohn LT, et al. To Err is Human: Building Safer Health System.  Nat’l Academy Press; 2000
  • -Crossing the quality chasm.  Wash DC: Nat’l Academy Press; 2001.
  • -Clin Gastro & Hep 2010; 8: 709.  Quality indicator sets in cirrhosis.
  • -J Pediatr 2005; 146: 744-50.  Bucuvalas JC et al.  Adjusting calcinerin inhibitor dosing
  • -IBD guidelines: www.cincinnatichildrens.org/svc/alpha/health-policy/ev-based/ibd.htm
  • -JPGN 2009; 49: 297.  Variation in care in pediatric Crohn disease. (Our center participated in this study)
  • -J Pediatr 2009; 154: 582.  Ventilator assoc pneumonia reduced w bundle of hand hygiene, elevated HOB, not changing ventilator circuits except when soiled & mouth care
  • -“The Learning Curve”(Atul Gawande) in The Best American Essays 2003 -some CF ctrs outperform, extending life expectancy ~14yrs.
  • -” A Surgeons Notes on Performance-Atul Gawande
    -NEJM 2007; 357: 2652.  Nice editorial.
  • www.icsi.org
  • www.qualityforum.org
  • www.ambulatoryqualityalliance.org
  • www.ncqa.org
  • www.cms.hhs.gov/hospitalqualityinit

Comments from lead author forwarded to blog:

Thanks for including our recent paper in your blog.  I agree with the study limitations as you mentioned, but wanted to put a couple of things in context.  We actually thought very hard about the issue of a control group, and specifically how to determine what the remission rate would be without the intervention.  We could not come up with a reasonable comparator (very few people/groups outside of ICN even know what the remission rate of their population is).  One very rough measure (which we did not feel was legitimate to include) is the rate of remission for new sites as they are joining the collaborative.  Established sites with complete participation have better outcomes than newer sites or sites that participate less fully, suggesting that at least a significant portion of the effect is due to the QI intervention rather than secular trend.  As far as the objective measures for outcomes, I know you realize that we are not able to mandate specific objective evaluations for a QI/observational research study, so we may never be able to use mucosal healing (for example) as our measure of remission.  However you probably noticed in the paper that we did demonstrate improvements in objective measures including sPCDAI, PUCAI and use of corticosteroids.  Certainly improvements in process measures may have been due in part to better documentation, but it is unlikely that objective outcome measures improved due to documentation. Thanks again for sharing our work with your audience.

Bleeding due to vitamin K deficiency

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With cholestasis in infancy, Bill Balistreri taught me that there were four potential emergencies:

  • Bleeding due to vitamin K deficiency or coagulopathy
  • Hypoglycemia
  • Sepsis
  • Metabolic poisoning with formula (in patients with galactosemia)

Once these issues have been considered, then it is appropriate to start investigating the etiology of the cholestasis.

One of the more dramatic complications is intracranial hemorrhage (ICH). While ICH is a well-recognized complication of cholestasis in infancy, the long-term outcomes are not well-characterized. A report from Japan adds some insight (JPGN 2012; 54: 552-57).

Among a retrospective review of 83 infants with biliary atresia (BA) between 1979 to 2009, ICH occurred in 8% despite oral vitamin K prophylaxis (2 mg).  The onset of ICH was between 47-76 days after birth and was prior to surgery.  Coagulopathy was noted in all cases, which improved with vitamin K intravenously.  Two infants required craniotomy.  In 5 of 7 cases, neurologic sequelae were noted including developmental delay in three, epilepsy in one, and mild hemiparesis in two.

Additional references:

  • Blood Rev 2009; 23: 49-59.  Review of vitamin K deficiency.
  • Pediatrics 2008; 121:e857.  Vitamin K deficiency common in cholestatic breastfed babies.  Can be prevented with 1mg po each week or single IM dose of 2mg.
  • Eur J Pediatr Surg 2005; 15: 295-9.  Bleeding disorder as 1st symptom of BA.
  • Pediatr Neurosurg 2006; 42: 362-7.  ICH due to vitamin K deficiency.
  • Pediatrics 2006; 118: e1657.  dose of 0.2mg effective for median of 25days (w/o toxicity/accumulation of K1O) in infants <32weeks gestation.

Pierre Robin and what else?

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In a large pediatric center, patients with Pierre Robin Sequence (PRS) are routinely seen by genetics and for good reason.  Underlying syndromic features were present in 60% of a recent retrospective review (J Pediatr 2012; 160: 645-50).

Most common syndromes with PRS include the following:

  • Stickler syndrome (22% pf all cases)
  • 22q11.2 deletion syndrome/velocardiofacial syndrome
  • Marshall syndrome
  • Moebious syndrome
  • Cornelia de Lange syndrome
  • Treacher Collins syndrome
  • Fetal alcohol syndrome
  • Van der Woude syndrome
  • Oculo-auricular-vertebral spectrum

For gastroenterologists, the article notes that 43% of the San Diego cohort required tube feeding whereas 79% of the Cleveland cohort needed tube feedings.  Overall, average was 52% needing tube feeds.

Additional references:

  • -J Pediatr 2011; 159: 887.  Feeding problems common in UAO/Robin-like phenotype.
  • -Burstein FD, Williams JK.  Mandibular distraction. Plast Reconstr Surg 2005; 115: 61-7.
  • www.vcfsef.org
  • www.sticklers.org
  • -J Pediatr 2002; 140: 719.  Frequent upper esophageal/oral motor dysfxn (24/28)
  • -J Pediatr 2001; 139: 588. n=117.  descriptive study.  35% c syndrome, 48% isolated, 17% c associated anomalies.
  • -JPGN 2001; 32: 297.  Frequent oroesophageal motor disorders in these patients.  86% required prolonged NG feeds.

Increased ferritin predicts poor response in Hepatitis C

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Serum ferritin levels were independently shown to be a risk factor for poor response to treatment in hepatitis C virus (HCV) infection (Hepatology 2012; 55: 1038-47).  This article adds additional information to previous work which has shown that increased iron can be a comorbid factor in chronic viral hepatitis and other liver diseases.

This study used the Swiss Hepatitis C Cohort Study (SCCS) (n=3648).  In this group, the success of treatment with pegylated interferon alpha and ribavirin were correlated with clinical and histological features.

Ferritin levels ≥ the sex-specific median values was one of the strongest pretreatment predictors of treatment failure (OR 0.45). It had a similar predictive effect as the IL28B genotype.  In addition, higher ferritin levels were associated with severe liver fibrosis (OR 2.67) and steatosis (OR 2.29).  For women the sex-specific median for ferritin level was 85 μg/L and for men it was 203 μg/L.  The authors note that these cutoffs are quite close to the upper limits of normal of the general population (150 and 300 respectively).

Mechanistically, HCV interferes with the host’s iron metabolism leading to iron accumulation in the liver.  Part of this is explained by down-regulation of hepcidin (Help with hepcidin).  Part is due to ferritin acting as an acute phase reactant to inflammation.  Ultimately, excess iron promotes liver inflammation, oxidative stress and mitochondrial dysfunction.

How important ferritin will be with newer therapies is not clear.  It is likely that patients that are less responsive to dual therapy (pegylated interferon/ribavirin) will have poorer response as well to triple or quadruple therapies.

Additional references/previous related posts:

Recurrent pancreatitis and genetic underpinnings

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While the absolute number of patients with genetic causes of pancreatitis is small, due to frequent hospitalizations, this remains a significant problem.  This month additional information on genetic predisposition for pancreatitis is available (JPGN 2012; 54: 645-50).

Sultan et al (Milwaukee, WI) reviewed the charts of children <18 years with recurrent acute pancreatitis (RAP) and patients with chronic pancreatitis (CP) from 2000-2009.   RAP was considered if patient had a minimum of two distinct episodes of acute pancreatitis.  Acute pancreatitis was considered the diagnosis if patient had typical symptoms associated with 3-fold elevation of amylase or lipase or imaging changes consistent with acute pancreatitis. CP was defined as a minimum of 2 episodes of acute pancreatitis associated with pancreatic duct abnormalities or pancreatic insufficiency.

Among this cohort of 29 children, 23 (79%) had mutations which have been associated with genetic pancreatitis (GP).  Family history was positive in only five patients.

  • CFTR mutation in 14 (48%): two had homozygous mutations, six heterozygous, and four had 5 T variants.  The importance of a single CFTR mutation in contributing towards pancreatitis is unclear.  However, the Wisconsin population has a carrier frequency of 1:32; the striking difference in frequency  indicates that even a single mutation may be important in the pathogenesis of RAP.
  • SPINK1 (serine protease inhibitor Kazal type 1) in 8 (27%).  SPINK1 mutations occur in 1-3% of the general population.  It is often a modifying factor rather than an isolated causal factor in the development of RAP.  Four of the patients with SPINK1 mutations also had a CFTR mutation.
  • PRSS1 (cationic trypsinogen gene) in 7 (24%).  Individuals with these mutations are considered to have hereditary pancreatitis, an autosomal disease with incomplete penetrance.
  • Only one patient was tested for chymotrypsin C gene (CTRC) –tested negative.

Seven patients with RAP did not undergo genetic testing & were excluded from the study.  These patients had other known causes of RAP: 3 had gallstones, 2 had pancreas divisum, 1 had a metabolic disorder, and 1 had a medication-induced pancreatitis.  The authors note, however, that patients with pancreas divisum have had genetic mutations identified in other studies.

Additional References:

  • www.uni-leipzig.de/pancreasmutation. This link will take you to the hereditary pancreatitis database where you can search for the specific mutation you identified and find articles dealing with a variety of aspects of that particular mutation.
  • 2011 Naspghan Postgraduate Course:
    Pancreatitis Workup
    -1st bout, check U/S, trig
    -if 2nd bout, suggested to check MRI, genetics (SPINK1, PRSS1, CFTR), sweat test, fecal elastase, possibly IgG4/ANA
  • OMIM#167800/276000
  • -Gastroenterology 2006; 131: 1844.  Mouse model w R122H Trypsiongen expression.
  • -Whitcomb DC. Gut 2004; 53: 1710-17. test for PRSS1 (cationic trypsinogen), SPINK1 (Serine protease inhibitor, Kazal Type 1), and CFTR gene.
  • -JPGN 2002; 34: 1A pg 444. n=108 with hereditary or idiopathic pancreatitis. (28% had + fhx)  12 c PRSS1 mutation, 24 c SPINK1 (21 s fhx); 22 had + CFTR mutation.
    -Pancreatology 2001; 1: 405-415.  Consensus guidelines for testing for H. Pancreatitis. PRSS1 gene -cationic trypsinogen
    http://www.pancreas.org/assets/pdfs/Pancreatology/HPgeneTestConsensus.pdf
  •  David Whitcomb’s laboratory at the University of Pittsburgh. The test is commercially available there. Their web site for the forms is:
    http://www.pitt.edu/~whitcomb/HPINFO/MolGenTest.html
  • -JPGN 2011; 52: 262. Review.
  • -J Pediatrics 2011; 158: 612.  Acute pancreatitis can result in diabetes.
  • -Clin Gastro & Hep 2010; 8: 410-416, 417. REVIEW of acute pancreatitis.  Rec NJ generally over TPN.
  • -Clin Gastro Hep 2010; 8: xxii.  Anomalous pancreatobiliary jxn as a cause.
  • -JPGN 2009; 49: 137.  Pancreatitis assoc w celiac
  • -Clin Gastro & Hep 2009; 7: 702.  Harmless Acute pancreatitis score.  Nonsevere when NL hgb, NL creatitine, and no rebound tenderness/guarding
  • -Alim Pharm Ther 2008; 28: 777-781.  Use of a low fat diet helped shorten hospital stay among adult pts with acute pancreatitis.
  • -Clin Gastro & Hep 2008; 6: 1070, 1077.   Fluids and imaging in acute pancreatitis.  With imaging, CT probably best.
  • – J Pediatrics 2008; 152: 106.  Acute pancreatitis in young children

Related blog entry:

Indomethacin to prevent post-ERCP pancreatitis

How much radiation from your CT scanner?

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Our children’s hospital, along with many others, has made a concerted effort to reduce radiation exposure by adjusting CT scan settings.  Even a single abdominal CT scan may confer a small but real risk of developing cancer.  The trade-off with low-dose CT techniques has been a concern about poor image quality.  New research indicates that low-dose CT scan is not inferior to standard-dose CT with respect to detecting appendicitis (NEJM 2012; 366: 1596-605).

This single-center study examined 441 patients assigned in a single-blind fashion to low-dose CT (median dose: 116 mGy-cm) in comparison to 447 patients receiving a standard-dose CT (median dose: 521 mGy-cm).  All patients had CT for suspected appendicitis.  The negative appendectomy rate was 3.5% in the low-dose group and 3.2% in the standard-dose group.  There was no significant difference in appendiceal perforation rate or proportion of patients needing more imaging.

How much radiation do your patients receive with a CT scan?

Related newspaper article:

FDA issues guidelines to lower radiation exposure in children:

http://www.ajc.com/health/child-sizing-radiation-doses-1434081.html

Related posts:

Magnetic resonance enterography for Crohn’s disease

More imaging needed?

Additional references:

  • -NEJM 2010; 363: 1, 4. Safety of CT.  Can have overdose of radiation and even standard doses could cause complications.  Also, a big issue is downstream unnecessary testing due to incidental findings.
  • -JPGN 2011; 52: 280. Documents high exposure to radiation in large IBD pediatric cohort.
  • -J Clin Gastroenterol 2011; 45: 34-39. High levels of ionizing radiation thru CT scan in pts with IBD.
  • -Pediatr Radiology 2002; 32: 217-313. Minimizing radiation exposure, risk/benefit of CT. Proceedings from conference.
  • -Pediatr Radiology 2002; 32: 700-706. Risk of CT for young child: ~ 1 in 1000 risk of fatal cancer later in life.