Category Archives: Pediatric Gastroenterology Liver Disease

“Genetic Testing and the Future of Pediatric Gastroenterology”

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Last night, a symposium on “Genetic Testing and the Future of Pediatric Gastroenterology” sponsored by Children’s Healthcare of Atlanta took place.  The speakers included Dr. Ben Gold from our pediatric GI group (GI Care for Kids), Dr. Saul Karpen and Dr. Subra Kugasthasan (Emory), and Dr. Robert Heuckeroth (CHOP).

This blog entry has abbreviated/summarized the presentations. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.  All of the speakers had terrific presentations.

GI Genetic Testing –Subra Kugathasan

Reasons for genetic testing:

  • Predicting prognosis: predicting stricturing/fibrosis in Crohn’s, predicting cancer in ulcerative colitis; BRCA1 in breast cancer
  • Choosing the right medicine: pharmcogenomics
  • Precision medicine: prevention of disease, slowing progression of disease.

Examples in current medicine:

  • Recurrent pancreatitis –novel mutations identified in SPINK1.  Also now hereditary pancreatitis may be due to mutations in CPA1, GGT1, CLDN2, MMP1, MTHFR in addition to CTRC, SPINK1, CFTR, and PRSS1.
  • Inflammatory bowel disease (IBD):IL10 Receptor mutation , TTC7A –>VEO IBD; IPEX gene (can worsen with immunosuppression). Panel testing now available for 40 genes –4 of 22 patients identified with IBD.  Identifying cause of VEO IBD may lead to treatment: bone marrow transplantation.
  • IBD: CLIA/CAP certified Emory Genetics panel ~50 genes (genetics.emory.edu/egl/tests/view.php?testid=4420). Dr. Kugathasan indicated that this testing is likely to be a better 1st step then exome testing. Yield with exome sequencing (in highly selected populations) about 25% at this time but likely to increase. If negative, can proceed with whole exome sequence.  Numerous problems with exome sequencing; for example, exome sequencing may identify genes of unknown significance and identifying genetic problems unrelated to clinical issue.

Who/When to test?

  • Very early onset disease (<10 years), atypical presentation, perhaps treatment-refractory.

Take-home point: “All GI diseases have genetic testing in future.” Testing for highly selected patients for gene defects can be accomplished with gene panel and if negative, whole exome testing.

Related blog posts:

Liver: Cholestatic & Metabolic Diseases of Infants and Children —Saul Karpen

Potential areas for genetic testing:

  • Neonatal cholestasis: PFIC, Metaboic, Biliary Atresia
  • NAFLD
  • Transplant

“Why bother…they all get transplanted anyway…”  According to Dr. Karpen, this view needs to be reconsidered.

Neonatal cholestasis:

  • (Front Pediatr 2014; 2: 65)  41% with biliary atresia, 13% idiopathic, and a lot of others.  N=82. Other etiologies: Genetic disorders; Biliary disease (eg. Caroli), transporter defects (PFICs/BRICs), Metabolic (Niemann-Pick C, tyrosinemia, HFI, Peroxisomal, GSDs, Peroxisomal, Mitochondrial, A1AT). Thus, panels to identify these disorders can be very helpful.
  • Emory Cholestasis 56+ Gene Panel. Testing is cheaper than endoscopy

PFIC: Progressive Familial Intrahepatic Cholestasis

  • PFIC1: ATP8B1 (Byler) –besides cholestasis, patients often with diarrhea, hearing loss, very itchy; can have cirrhosis at 2 years of life
  • PFIC2: ABCB11 (BSEP deficiency) –can have cirrhosis at 6 mo, prone to HCC (as early as 13 mo), very itchy
  •  PFIC3 (high GGT) ABCB4 –can have cirrhosis at 5 mo, can cause problems at later ages as well (eg. intrahepatic cholestasis of pregnancy, gallstones); increase risk for HCC/cholangiocarcinoma.
  • Identifying PFIC (could mimic PSC) and BRIC (Benign Recurrent Intrahepatic Cholestasis)–is helpful in following patients for specific management when symptoms recur and to screen for complications (eg. HCC).

Biliary Atresia:

  • No clear genetics in most
  • Laterality defects in 5-10% -asplenia/polysplenia, cardiac defects
  • GPC1 gene is a susceptibility gene in zebrafish
  • ADD3 gene identified in Han Chinese OR 2.38 –may be a susceptibility gene. (30% of cases, 17% of controls)

NAFLD: Associated with increased mortality compared with matched controls. Patients develop thicker atherosclerotic plaques. PNPLA3 gene identified as a susceptibility gene for NAFLD and is highly prevalent in Hispanic populations.  Similarly, PNPLA3 has been associated with NASH in Italian populations.  If you have this genotype, this increases risk of liver fat in the face of increased sugar consumption.

Transplant medicine: Deoxyguanosine Kinase Deficiency (DGUOK) –rapid sequencing for this gene pretransplant –If positive, should not be transplanted. These individuals have systemic disease that cannot be cured with liver transplantation.

Who/When for genetic testing?: DGUOK in liver failure patients, and in infants without diagnosis after liver biopsy/exclusion of A1AT

Take-home message: Genetic testing has a role in pediatric liver disease and it is affordable.

Related blog posts:

GI –Single Microbes to the Microbiome and GI Disease —Ben Gold

  • Described why changes in our environment can trigger development of disease due to changes in microbiome (eg. immigrants/children with IBD in developed countries at much higher rate than at developing countries)
  • Discussed Helicobacter pylori –‘how a single microbe which may have been good turned bad’
  • Described pathogenesis. What you get exposed to early on may lead to an exaggerated response by T-cells/immune system.  Healthy microbiota is critical to train the immune system via GALT to protect host and decrease the chances for immune overexpression.

Key points:

  • 100 trillion bacteria that live in our GI tract. 10x number of human cells in our body and 100x as many genes as there are in the human genome.  Partnership between humans and their microbiome developed over thousands of years.
  • Vaginal delivery is NOT sterile. Are there consequences to C-section? Food allergy for infant –OR 2.5 if Mom with food allergy delivers vaginally vs OR 7.8 if Mom has food allergy and delivers via C-section. Also, some data indicates increased risk of EoE if born via C-section.  From DAY 1, microbiome can be influence by environmental factors.
  • Influencing microbiome happens mainly during first three years of life.

Why the microbiome is so important/more pointers:

  1. Since 1950, there has been a huge decline in infectious diseases like measles, mumps, hepatitis A, tuberculosis, etc
  2. Coincident with these decreases there has been increased multiple sclerosis, Crohn’s disease, asthma, food allergy, autoimmune diseases
  3. Sanitized food supply, decrease in naturally fermented foods, urban lifestyle, antibiotics, C-section all lead to lower microbial exposure and altered intestinal microbiota. This in turn may lead to an inadequate immune response.
  4. Elie Metchnikoff 1845-1916: suggested ingested bacteria could be healthy. Probiotics/prebiotics are not a new idea!
  5. Obese patients had very high levels of Firmicutes and low Bacteroidetes.
  6. Fecal microbial transplantation (FMT)–reseeding GI microbiome. FMT may be beneficial to many diseases and is being  studied.

Helicobacter pylori -evidence of H pylori as far back as 60,000 years ago and has evolved with humans. H pylori may have helped provided a positive immune response in children and adults.

Bottomline: Human genetic diseases may be heavily influenced by the 300 trillion bacteria and their genes; these bacteria are susceptible to environmental disease.

Related blog posts:

 

Genetic Basis of Motility —Robert Heuckeroth

  • Basic machinery controlling motility described –enteric neurons, muscles, pacemaker cells.
  • Very little clinical overlap between modern genetic testing and applicable motility disorders: achalasia, gastroparesis, pseudoobstruction, Hirschsprung’s or irritable bowel
  • Focused testing for suspected diagnosis is being displaced by broader testing in serious disease, especially since more extensive genetic testing may be more cost-effective. When to do exome sequencing?

Hirschsprung’s disease:

  • 1:5000 children.
  • 100X higher risk in Down Syndrome.
  • Prenatal testing not helpful at this time. There may be >360 genes that increase risk (variable degree of risk) of Hirschsprung’s disease; hence prenatal testing not that helpful at this time.
  • 30 associated genetic syndromes with Hirschsprung’s, >12 known gene defects.  Hirschsprung’s disease: 25% with RET haploinsufficiency.  RET haploinsufficiency –increases risk of Hirschsprung’s disease >2500-fold risk.
  • Gene environment interactions can increase risk of developing Hirschsprung’s disease –if vitamin A deficient, mice with increased risk.
  • RET gene –>too little RET increases risk of Hirschsprung’s
  • RET gene –>too much RET increases risk of MEN2B, MEN2A.  Though 7.5% of MEN2A have Hirschsprung’s –works out to be 1 in 100 kids with Hirschsprung’s have MEN2A mutations.  ??test for this??

Pseudoobstruction genetic basis– a number of genes identified, including ACTG2 (smooth muscle actin gene).  If you understand etiology, this may lead to prevention and treatment.

Take-home message: Currently biggest problem with genetic testing, especially with motility disorders, is identifying genetic defect of unknown significance.  Thus, testing needs to be done as part of research studies.

Related blog posts:

 

 

 

Link to NASPGHAN Lectures and Postgraduate Course

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Later this week, our national pediatric GI meeting (North American Society for Pediatric Gastroenterology Hepatology and Nutrition) is starting in Atlanta.  Many in my group are involved and presenting.

The following link (with permission from NASPGHAN) is to the website with links to all of these lectures:

NASPGHAN 2014 Atlanta meeting

For those interested only in the Syllabus for the Postgraduate Course:  NASPGHAN 2014 Postgraduate Course.

Topics include in this 200 page (online) book: primary sclerosing cholangitis, jaundiced infant, acute liver failure, “dreaded” endoscopy wake up calls, endoscopy for biliary tract disease, extraesophageal manifestations of gastroesophageal reflux, constipation, eosinophilic esophagitis, motility disorders, FODMAPs diet, nutrition for neurologically impaired, early onset inflammatory bowel disease, “luminitis” due to non-IBD causes, new IBD treatments, and diet-microbiome.

Should be great!

Also, to plan your meeting -go to NASPGHAN home page and use mobile guidebook: NASPGHAN 2014 has gone mobile using Guidebook!

Case Report of Poor Growth, Splenomegaly, and Pneumopathy

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From AGA twitter feed link/Gastroenterology Volume 147, Issue 4, Pages e3–e4, October 2014.:

Question: A 6-year-old Caucasian boy presented with recurrent episodes of fatigue, abdominal pain, and diarrhea. In between these episodes, he had good exercise tolerance. He has never traveled outside Hawaii and Western Europe, had no known allergies, and was not taking any medication. An unexplained splenomegaly had first been discovered 6 months ago.

Clinical examination was unremarkable except for growth below the expected range (Figure A) and splenomegaly with a palpable spleen 4 cm below coastal margin. There was no heart murmur, dyspnea, clubbing, icterus, eczema, or lymphadenopathy. Neurologic development was adequate for age.

Laboratory workup showed no anemia and normal lymphocyte subsets. The thrombocytes were in the low normal range (155 × 109/L) and aspartate transaminase (56 U/L) was mildly elevated. The fecal pancreatic elastase and calprotectin were in the normal range. Ultrasonography revealed enlarged liver and spleen without evidence of portal vein thrombosis or focal lesions. A chest x-ray displayed bilateral interstitial lung disease with a reticulonodular pattern.

What is the most likely diagnosis? 

Here’s the link: Answer and explanation.

Liver Masses -Helpful Reference

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A recent review (Clin Gastroenterol Hepatol 2014; 12: 1414-29) is a good reference for liver masses.

Topics include hepatocellular carcinoma, focal nodular hyperplasia, hepatic adenoma, cholangiocarcoma, hemangioma, hepatic abscess, liver imaging, and management advice.

Expert Recommendations for ARPKD

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A recent article (J Pediatr 2014; 165: 611-17) provides expert recommendations for the diagnosis and management of autosomal recessive polycystic kidney disease (ARPKD).

Some of the recommendations relevant to hepatologists:

  • Congenital hepatic fibrosis (CHF) “is presumed when portal HTN [hypertension] is present.”  Portal HTN is defined by splenomegaly (i.e.. spleen >2 cm below the left costal margin or >1 cm larger than ULN for age) and thrombocytopenia with a value of <150 mm3.  Other evidence of portal HTN includes varicose, ascites or hepatopulmonary syndrome.
  • “Liver biochemistries are not typically informative…one should monitor for associated neutropenia and thrombocytopenia.”
  • “Cholangitis may be difficult to diagnose definitively…should be considerd in any child with ARPKD with unexplained fever.” “Routine antibiotic prophylaxis is not indicated…antibiotic prophylaxis for 6-12 weeks after a cholangitis episode..may be considered.”
  • The “use of ursodeoxycholic acid as a choleric cannot be recommended.”
  • Hepatobiliary cancer is not a feature of ARPKD in children
  • “Limiting contact activities in individuals with a palpable spleen is highly controversial and not guided by evidence, but more by common sense.”
  • Recommends annual CBC, ultrasound at five years of age, and then follow-up ultrasound every 2-3 years.

Related blog post:

Outcome of “Successful” Biliary Atresia Patients

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A recent publication (J Pediatr 2014; 165: 539-546) from the Childhood Liver Disease Research and Education Network (CHiLDREN) provides a strong rationale for close followup of biliary atresia (BA) patients with their native livers.  The Biliary Atresia Study of Infants and Children (BASIC) is one of the ongoing longitudinal studies within CHiLDREN.

Among a cross-sectional study BASIC cohort of 219 children (median age 9.7 years) who survived with their native livers for at least 5 years, they had the following findings:

  • In preceding 12 months, cholangitis occurred in 17%, and 62% had experienced cholangitis at least once following hepatoportoenterostomy (HPE) (also called Kasai procedure.  The authors note wide discrepancy in usage of prophylactic antibiotics; some stop at 2 years following HPE and some never stop antibiotic prophylaxis.
  • In preceding 12 months, bone fractures occurred in 5.5%.  Overall, 15% had had at least one bone fracture at some point, which is higher than the general population. Only 14.6% of entire cohort were receiving vitamin D supplementation.
  • Portal hypertension: clinically detectable splenomegaly, thrombocytopenia, ascites, and variceal hemorrhage were seen in 56%, 43%, 17%, and 9% of patients in this cohort.
  • Health-related quality of life was reported as normal in 53%
  • Mean height and weight z-scores were normal in this cohort.
  • Over 98% had clinical or biochemical evidence of chronic liver disease.

Full-text Link

Bottomline: This BASIC study shows the need for careful followup of “successful” biliary atresia patients and provides more accurate data regarding risks of specific complications.

Briefly noted: J Pediatr 2014; 165: 547-55.  In this study with same first author (Vicky Ng), the investigators develop and validate a pediatric liver transplantation (LT) quality of live instrument for LT patients aged 8-18 years.

Related blog posts:

Understanding the Costs and Benefits of HCV Treatment

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A useful editorial in JAMA (available free online –) provides a useful overview of HCV treatments in terms of costs and strategies for using new therapies.

A couple of useful points

  • Given the cost of medications, many are using the newer therapies in those who absolutely need treatment now and waiting for costs to improve in others
  • “The ultimate approach to cost will be lower prices, which will occur as more products create competition.”
  • “This fall, an oral combination of sofosbuvir and ledipasvir will be introduced that inhibits both the NS5B polymerase and NS5A polymerase and has been shown to reduce treatment to an 8-week course with cure rates of more than 95%.2 Now, a chronic disease that affects millions of Americans can be cured by well-tolerated oral medications.”
  • Because of the large number of potential patients, “the simple math is that treatment of patients with HCV could add $200 to $300 per year to every insured American’s health insurance premium for each of the next 5 years.”

Related blog posts:

Cognitive Outcomes after Liver Transplantation

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An important measure of liver transplantation (LT) is cognitive/academic outcomes. Previous studies have indicated increased intellectual deficits but were not optimally-designed.  A recent study (J Pediatr 2014; 165: 65-72) overcomes many of the limitations of previous studies.

Study design: Prospective, multicenter longitudinal cohort of neurocognitive functioning after pediatric liver transplantation.  144 participants, ≥2 years after liver transplantation -recruited through Studies of Pediatric Liver Transplantation (SPLIT).  Tested with multiple cognitive test at two separate time points.

Key findings:

  • At the time 2, 29% had full scale IQ (FSIQ) between 71-85 (compared to 14% expected); 7% had FSIQ <71 (compared with 2% expected)
  • 42% received special education.
  • Pretransplant markers of nutritional status and operative complications predicted intellectual outcome
  • Having a primary care provider with a college education was a protective factor.

One limitation of the study was that only 55% of those approached to participate were enrolled; however, the authors noted similar demographics between those who enrolled and those who did not.

Understanding Cholestatic Pruritus

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A recent review (Hepatology 2014; 60: 399-407) sorts out “facts and fiction” with regard to pruritus in cholestasis.

The authors note that for more than 2000 years there has been a search for the potential pruritogen in cholestasis, “when Aretaeus the Cappadocian (2nd century B.C.) stated that ‘pruritus in jaundiced patients is caused by prickly bilious particles.'”

Key points of review:

Pruritus affects a large number of hepatobiliary diseases

  • Hepatocellular cholestasis: intrahepatic cholestasis of pregnancy (ICP), benign recurrent intrahepatic cholestasis (BRIC), progressive familial intrahepatic cholestasis (PFIC1, PFIC2), Hepatitis C
  • Biliary-liver diseases: primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), PFIC3, Alagille, Drug-induced diseases
  • Obstructive cholestasis: gallstones, IgG4-associated cholangitis, biliary atresia, and other causes

Most recently lysophosphatidic acid LPA) and autotaxin (ATX) have been shown to be important pruritogen candidates in cholestasis

  • “ATX is the main source of circulating LPA levels…In cholestasis, serum ATX activity, but not other putative markers of itch such as serum bile salt levels or serum μ-opiod activity, were correlated with itch intensity.”
  • “Rifampicin was found to reduce ATX expression at the transcriptional level.”  This may explain rifampicin’s efficacy for pruritus in cholestasis.
  • “When the enterohepatic circulation is interrupted by nasobiliary drainage, circulating levels of ATX rapidly dropped concomitant with relief of pruritus.”  So, while ATX is not secreted into bile, other substances in bile, like steroid hormones, like play a role in the induction of ATX.

Current therapeutic recommendations (dosing recommendations provided by authors in Table 3)

  • 1st line: Cholestyramine (except in ICP in which ursodeoxycholic acid is considered 1st line)
  • 2nd line: Rifampicin
  • 3rd line: naltrexone
  • 4th line: sertraline
  • Experimental: ondansetron, phenobarbitol, propranolol, lidocaine, dronabinol, butorphanol, phototherapy, nasobiliary drainage, plasmapharesis (and similar treatments), biliary diversion
  • Liver transplantation

Related blog posts:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Understanding Breast Milk Jaundice

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A recent study of 170 Japanese infants with breast milk jaundice (BMJ) demonstrated that 52% had a homozygous mutation: UGT1A1*6 (J Pediatr 2014; 165: 36-41).  The study included 55 controls without BMJ.

Defects in UGT1A1 have been associated with a number of hereditary unconjugated hyperbilirubinemias including Crigler-Najjar type 1 in which there is complete deficiency of the enzyme Crigler-Najjar type 2 in which there is limited activity of the enzyme, and Gilbert syndrome in which there is moderate activity of the enzyme (but less than general population).

In this study, none of the control population had the UGT1A1*6 homozygous mutation.  The authors note that “the components of breast milk clearly contribute to the onset of neonatal jaundice. Our in vitro investigation showed the inhibitory effect of 5α-pregnane-3α, 20β-diol on UGT1A1 activity.”  Thus, this may help explain why cessation of breastfeeding for a short period can improve BMJ.

Take-home message: In this Japanese population, the UGT1A1*6 homozygous mutation is an important reason for BMJ.  Yet, for about half of all infants another, yet unidentified mechanism(s), is responsible.