Category Archives: Pediatric Gastroenterology Liver Disease

Learning a new language for HCV

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There is bad news for those of us finally comfortable with the terms and abbreviations of the hepatitis C virus lexicon, like rapid virological response (RVR) and complete early virological response (cEVR).  A new consensus is emerging that more precise nomenclature is needed in this era of direct-acting antivirals (DAA) (Hepatology 2012; 56: 2398-2403).

The problem is that with the use of DAA, drugs that use a 4-week lead-in have their RVR checked at 8 weeks rather than 4 weeks.  Similar problems are present with the other terminology in current use.

RVR should be reported as W4U-tnd.  W4 indicates week 4, U indicates viremia unquantifiable, tnd indicates whether target HCV RNA was not detected (td indicates detected). If there is a lead-in, then LI-w/d-W8U-tnd.

Other terms:

  • vRVR or very rapid virological response is now W2U-tnd
  • eRVR or extended RVR refers to undetectable HCV RNA at week 4 and 12 and is now W4-12U-tnd
  • cEVR refers to undetectable HCV RNA at 12 weeks is now W12U-tnd
  • pEVR or partial EVR indicates at least 2 log10 decrease in HCV RNA after 12 weeks of treatment.  New lingo: W12[-2]
  • SVR or sustained virological response is now SVR12-tnd (if 12 weeks after Rx) and SVR24-tnd (if undetectable HCV RNA 24 weeks after Rx)
  • LLOQ indicates the  lower limit of quantitation.  A value <LLOQ is not necessarily “undetectable.”

You may need the hepatology ‘rosetta’ stone session before your next meeting with your liver expert.

Related blog entries:

Kawasaki disease –there’s an app for that!

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With the ubiquitous availability of smart phones, point-of-care technology becomes increasingly sophisticated.  Many are familiar with mobile drug information resources (eg. Lexicomp, Epocrates), but now information is increasingly disease-specific.  An example of this and the data supporting this are available in a recent publication with regards to diagnosing Kawasaki disease(KD) (J Pediatr 2013; 162: 183-88).

After simulating a model with a training cohort of 276 patients with KD and 243 febrile control (FC) patients, the authors validated the model with 136 patients with KD and 121 FCs.  Inclusion criteria for KD were based on the American Heart Association guidelines.

The scoring system which combined clinical findings and laboratory findings resulted in “a sensitive (>95% PPV) and specific (>95% NPV) diagnosis of ~60% of FCs and ~75% of patients with KD.”  In essence, the patients with high or low scores for KD were quite reliable.

To check out the web site:

http://translationalmedicine.stanford.edu/cgi-bin/KD/kd.pl

Potential limitation: The personnel involved in the study were very experienced in KD; thus, the model may be less effective when less skilled personnel obtain the clinical information.

While pediatric gastroenterologists do not frequently see KD patients, the bigger issue is developing point-of care tools. In our electronic health record (EHR), one point-of-care tool I developed was a smart phrase to assess hospitalized patient’s with colitis (see bottom of post in blue).  This smart phrase can be pulled up with three key strokes and helps me assess the severity of the patient’s colitis.

Another useful smartphrase in blue  (that was shared with me from Mike Hart), also retrieved with three key strokes,  is the following:

Here is a weblink on youtube for a video on changing Mic-Key buttons:

http://www.youtube.com/watch?v=Mn4ePSBiCTk

I often share this link with parents at the end of my “after visit summary” note.

These types of tools can improve recognition and treatment in a wide range of areas and are only limited by our imagination.

Pediatric UC Activity Index:

1. Abd pain

No pain —0 points, Pain can be ignored —5 points, Pain cannot be ignored—10 points

2. Rectal bleeding

None —0 points, Small amount & in <50% of stools — 10 points, small with most stools —20 Large amount —30 points

3. Stool consistency

Formed — 0 points, partially formed — 5 points, completely unformed —10 points.

4. #Stools/24hrs

0-2 —0 points, 3-5 —5 points, 6-8 — 10 points, > 8 15 points

5. Nocturnal Stools

No —0 points, Yes —10 points

6. Activity Level

No limitation —0 points, Occasional limitation —5 points, Severe limitations —10 points

 

Total Score: *** @TD@ 

 

Interpretation: 

Remission <10, Mild dz 10-30, Mod dz 31-64, Severe dz >65

 

References: 

1. Gastroenterology 2010; 138: 2282-2291.  PUCAI helps predict IV steroid failure in hospitalized pediatric colitis pts. n=128.  37 failed IV steroids (29%)

Score >45 (on day 3) indicates pts likely to fail IV steroids: Pos PPV 43%, Neg PPV 94%

Score >70 (on day 5) indicates need for alternate rx (+PPV100%) 

25/33 steroid failures responded to IFX.  Colectomy rate 9% initial, & 19% at 1 year.

2. Gastroeterology 2007; 133: 423-32.  Turner et al.

Related blog entry:

Cholestatic Kawasaki Disease | gutsandgrowth

Augmentin Hepatotoxicity

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Augmentin (amoxicillin-clavulanic acid) hepatotoxicity is common, anywhere from 1 in 1000 prescriptions to 1 in 78,000 prescriptions.  Despite its frequent use in pediatrics, there is limited data on augmentin hepatotoxicity in this population.  A recent study adds some information (JPGN 2012; 55: 663-67).

As part of a prospective observational study involving 8 Spanish hospitals from 2008 to 2011, 11 patients, ages 1 to 11 years, with augmentin hepatotoxicity were identified.  Drug-induced hepatotoxicity was suspected in the presence of augmentin therapy if ALT was >2 time ULN, conjugated bilirubin was >2 times ULN, or if other liver biochemistries (AST/GGT or bilirubin) were >2 times ULN.  Causality criteria relied on the Council for International Organizations of Medical Sciences (CIOMS) scale.

According to CIOMS scale, 3 cases were highly probable for augmentin hepatotoxicity, 3 cases were probable, and 5 cases were possible.  In this study, the patient’s details and labs are given in Table 1.  Most cases were mild.  The most common symptom was vomiting. Only one had a bilirubin >1 mg/dL.  Two had very high ALT values (one 52 times normal). Viral serology (measured at least 2 determinations) and autoimmune titers were negative in all patients.

Resolution of the hepatotoxicity occurred over a 4 to 16 week period.  No cases required a biopsy.  The authors note that many more cases of milder disease likely go undetected.

Related blog entry:

Reference:

  • -Curr Drug Saf 2010; 5: 212-22.  Antibiotic-induced liver toxicity –clinical features/causality.
  • -JPGN 2008; 47: 395-405.  Drug-related hepatotoxicity/liver failure
  • -J Pediatr 2000; 136: 121.  Augmentin & cholestasis. 1.7 cases per 10,000 prescriptions.

Expert advice on portal hypertension

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A consensus report on portal hypertension has helpful advice on a broad range of management issues and should be kept in mind as a handy reference (Pediatr Transplantation 2012; 16: 426-37).  The report is concise and full of bullet points.  It is based on a meeting of pediatric experts to modify adult guidelines (Baveno V) for pediatrics.

In many instances, the experts indicate that there is not enough pediatric data. Specific subjects include the following (along with some points):

  • Treatment options for portal hypertension -consider screening for varices if thrombocytopenia and splenomegaly.  ‘No indication to use beta-blockers to prevent varices.’
  • Prevention of first bleeding episode -in the presence of varices (grade II or III), variceal ligation reasonable in selected children and/or within context of defined research protocols. Grade I varices can be flattened with insufflation, and grade III varices are confluent around circumference of esophagus (per Japanese Research Society for Portal HTN analysis)
  • Role of hepatic venous pressure gradient measurement (HVPG) -‘panel was undecided as to whether HVPG measurements in children’ should be ‘part of specialized clinical practice or’ a research tool.
  • Blood volume restitution -suggests use of platelets in cases of bleeding with profound thrombocytopenia (<20,000).
  • Antibiotic prophylaxis -unclear whether empiric antibiotics in children are needed in the presence of variceal bleeding.
  • Management of treatment failures -can retry endoscopy and if fails, consider transjugular intrahepatic portosystemic shunting (TIPS)
  • Management of gastric varices -only case reports in children, thus no evidence-based recommendations.
  • Prevention of rebleeding -variceal ligation (EVL) preferred in patients with cirrhosis.  EVL should be performed every 2-4 weeks up to five sessions to eradicate varices after 1st bleed.
  • Treatment of portal vein obstruction -diagnosis, natural history, anticoagulation, use of MesoRex bypass procedure, associated portal biliopathy -diagnosis and treatment.  With regard to MesoRex, ‘controversy exists as to the appropriateness of ..this procedure in an asymptomatic child.’ Surveillance endoscopy may assist in decision-making.
  • Hypersplenism with portal vein obstruction-in the presence of platelet count <50,000 and portal vein obstruction, strong consideration should be given to MesoRex procedure.
  • Portopulmonary hypertension and hepatopulmonary syndrome -important to monitor oxygen saturation in patients with portal vein obstruction/other causes of portal hypertension. If <97%, additional investigation may be needed.  Portopulmonary hypertension is best characterized with cardiac catheterization and hepatopulmonary syndrome with saline echocardiography.
  • Other topics: Prevention of hepatic encephalopathy, managing bleeding episodes, endoscopic treatment

Related blog entries:

One year later

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It has been one year and 300 posts since I’ve started this blog.  I’ve enjoyed putting together my thoughts about recent articles.  In addition, I like being able to search for previous blogs for information that I find helpful.

Currently there are close to ~35 hits per day in addition to the email/wordpress followers (about 30).  This number has been increasing and it is fascinating to see that people from all over the world will sometimes stumble across this blog.

If you have suggestions for topics, articles or other ways to improve this pediatric GI blog, please send me an email at jjhochman@gmail.com.

Learning a lot from ChiLDREN (part 2)

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As noted in previous post (Learning a lot from ChiLDREN (part 1) | gutsandgrowth), several recent studies highlight the benefits of multisite collaboration to study infrequent pediatric liver problems.  In these studies, the Childhood Liver Disease Research and Education Network (ChiLDREN) has collected prospective longitudinal observational date from multiple centers; data from 10 centers provides useful information on the frequency of portal hypertension (PHT) in young adults with biliary atresia (BA) (JPGN 2012; 55: 57-73).

163 subjects were enrolled between May 2006 and December 2009.  Seven patients were excluded due to the presence of polysplenia which interferes with the assessment of PHT.

Demographics: subjects ranged in age from 1 to 25 years with a mean of 9.2 years.  56% were female, 75% were caucasian.

PHT was considered definite if there was either a history of a PHT complication (variceal bleeding, ascites) or if there were clinical findings c/w PHT (both splenomegaly and thrombocytopenia).  PHT was considered “possible” if either splenomegaly or thrombocytopenia was present and “absent” if no criteria were met.

  • PHT: definite in 80 (49%), possible in 27 (17%) and absent in 56 (34%)
  • 43 subjects had a history of PHT complications: 32 with esophageal variceal (EV) bleeding, 14 with ascites, and 8 with hepatopulmonary syndrome.
  • Of the patients with EV, only 3 had normal platelet count and normal spleen size.

Teaching points:

  1. One-third of subjects with EV bleeding survived with their native liver for at least 5 years.
  2. EV age of onset was highly variable; 7 had bleeding in the first two years of life.
  3. Growth parameters were fairly unremarkable in those with definite PHT.
  4. Long-term followup will be needed to identify factors which predict progression of PHT and the development of adverse outcomes.

Previous related blog posts:

HBV in the Joseon Dynasty

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Investigators have found evidence of Hepatitis B virus (HBV) in the mummified remains of a Korean child from the 16th century (Hepatology 2012; 56: 1671-80).

There are at least 10 HBV genotypes (A-J) and several sub genotypes; each have a specific geographical distribution.  Genotypes are defined by an >8% sequence divergence whereas as sub genotypes have 4-8% sequence divergence.  The HBV in this study corresponds to C2 clade.

While the technical aspects are fascinating, the other important contribution of this article is to the understanding of the evolutionary history of HBV.   There are two theories with regard to the origin of HBV, which may have occurred 100,000 years ago.  One suggests a primate origin with subsequent cross-species transmission.  Another theory suggests a common ancestor of HBV for primates and humans.

In this study, the mummy-derived HBV has the same genotype C which is currently predominant in Korea (>95%); and C2 sub genotype is the most common sub genotype.

The studies conclusions regarding the identification of the subtype is supported by the process of testing the samples in three independent laboratories.  The genetic diversity noted in the sample is likely related to natural evolutionary processes.

Additional references:

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