Category Archives: Pediatric Gastroenterology Liver Disease

What is the role for preventing variceal bleeding in Biliary Atresia?

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During medical school, I read a book called “The House of God”  (The House of God – Wikipedia, the free encyclopedia.  One of this cynical book’s premises is that doing more diagnostic tests and treatments to help patients actually harms them.

A recent study of children with biliary atresia reminded me of this premise (Gastroenterol 2013; 145: 801-7, eidtorial 719-22).   In this retrospective study, there were 66 children with endoscopic evidence of portal hypertension who underwent endoscopic therapy for either primary (n=36, mean age 22 months) or secondary (n=30, mean age 24 months) treatment of esophageal varices biliary atresia (2001-2011).  These children were at high risk for bleeding; they had a mean bilirubin of >10 mg/dL and 20% had ascites.

Results:

Primary prophylaxis group: mean of 4.2 sessions were needed to eradicate varices.  Varices reappeared in 37%; there was no breakthrough bleeding.  97% survived for 3 years.  All of these patients had varices grade 2 or higher and 94% had red wale markings.

Secondary prophylaxis group (after previous bleeding): mean of 4.6 sessions to eradicate varices.  Varices reappeared in 45% and 10% had breakthrough bleeding.  84% survived for 3 years.

Treatment:

  • For bleeding group, sclerotherapy was used in 73%, banding in 17%, and both in 10%.
  •  For prophylaxis group, sclerotherapy was used in 44%, banding in 41%, and both in 14%.
  • By the end of the study, sclerotherapy was mainly used in patients weighing less than 8 kg.
  • Each endoscopy session had the same endoscopist, used octreotide (2 mcg/kg/hr) an 1 hour before and then for 2-3 days afterwards.
  • With bleeding patients, these sessions occurred after the patient was stabilized, with a mean of 10 days afterwards.
  • Patients had an average of four 3-day hospitalizations.
  • Within an average of 14 months, more than half of the primary prophylaxis group had undergone transplantation

The authors interpret their data as follows:  “primary or secondary prophylaxis of bleeding is well tolerated and greatly reduces the risks of variceal bleeding in children with biliary atresia and high-risk gastroesophageal varices.  The results support the active detection of these signs by endoscopic procedures.”

In contrast, the editorial is much less supportive of primary prophylaxis.  “We need to weigh the risks and benefits of multiple procedures in a nonbleeding child who may not bleed for years, when varices have a high chance of recurring and transplant is sometimes imminent. Because mortality from gastrointestinal bleeding in children is quite low (zero in this small study), we may need to consider a ‘wait and see’ approach.”

Bottomline: A failed Kasai is an indication for transplantation which is a much more definitive treatment for portal hypertension.

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Pediatric Fatty Liver Disease -in the news

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An excerpt from The Wall Street Journal, Fatty Liver Disease: More Prevalent in Children (also covered by this blog previously: Increasing prevalence of pediatric NAFLD | gutsandgrowth):

A type of liver disease once thought to afflict primarily adult alcoholics appears to be rampant in children.

image

Some 1 in 10 children in the U.S., or more than 7 million, are thought to have the disease, according to recent studies.

The condition, in which the normally rust-colored organ becomes bloated and discolored by yellowish fat cells, has become so common in non-drinkers that it has been dubbed nonalcoholic fatty liver disease.

The disease’s prevalence is alarming doctors who worry about its progression to nonalcoholic steatohepatitis, or NASH, when the fatty liver becomes inflamed and cells are damaged. That leads to the end stage of cirrhosis, when the liver forms scar tissue and ultimately stops working.

Organ Damage

Some facts about nonalcoholic fatty liver disease:

  • About 10% of children in the U.S. are thought to have the condition.
  • Several factors likely contribute, including genetics, obesity, diet and insulin resistance.
  • It has no detectable symptoms.
  • Weight loss is the standard treatment for earlier stages of liver disease.

The condition’s rise is tied to the obesity epidemic—about 40% of obese children have it—but isn’t caused solely by being overweight. The disease appears to be growing among normal-weight children too, experts say.

And even though obesity rates are starting to level off, the prevalence of fatty liver disease continues to rise, they say.

It also has no symptoms, which means a person could have it for decades without knowing. 

Full link:

Fatty Liver Disease: More Prevalent in Children

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Reference for Mitochondrial Hepatopathies

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This morning’s blog discussed mitochondrial liver disease.

Another useful reference:

The Journal of Pediatrics Volume 163, Issue 4 , Pages 942-948, October 2013  Mitochondrial Hepatopathies: Advances in Genetics, Therapeutic Approaches, and Outcomes  Way Seah Lee, MD and Ronald J. Sokol, MD

NASPGHAN Preview

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I had a few free minutes so I decided to take a look at a bunch of upcoming lectures from the 2013 NASPGHAN upcoming meeting.  With electronic media, it is easy to take a quick glance.  Here’s the master link to all of the following talks:

Annual Meeting page.

Some of the power point lectures that I’ve seen so far:

  • Is my PPI dangerous for me? Eric Hassall MBChB, University of British Columbia One point in his slides that I had not seen much about was a hypothesis that PPI use may predispose to the development of eosinophilic esophagitis by allowing food proteins to be more intact ( attributed to Merwat, Spechler. Am J Gastro ’09).  He explains that “acid reflux” is a clever marketing term and has a slide with Madmen actors.  If there is “acid,” one must need acid suppression.
  • My child doesn’t go to school Lynne Walker MD, Vanderbilt University.  Lynne shows an interesting fax from a parent that asks if the problem is physical, how will she help? And, if it is psychological, how can this be remedied?  She outlines a lot of pain theory and indicates that parents need to become health coaches, avoid catastrophizing (?spelling), and encourages mental health evaluation.  Use the parents words ‘I’m going to refer xxx for relaxation and stress management.’
  • My child’s H. pylori will not go away – (the resistant bug) Benjamin Gold MD, Children’s Center for Digestive Healthcare. Ben manages to stuff so much information into his talk.  His talk is like one of those clown cars where more and more people keep coming out.  He has slides with worldwide resistance maps, slides with treatment regimens and algorithms, and the reasons for treatment failure. Perhaps I can convince him to give a live preview.
  • Administrative/executive functioning Richard Colletti MD, Fletcher Allen Healthcare. Offers personal and pragmatic advice for career advancement.  His slides indicate that he started his GI fellowship at age 40.  One of his quotes, “80% of success is showing up” (Woody Allen) is definitely true.  It’s pretty much akin to what I learned about success in medical school.  You need the three As: availability, affability, and ability.  My mentor said the first was what people needed most.
  • The changing face of intestinal transplantation
    Simon Horslen MD, Seattle Children’s Hospital.  Lecture notes that number of intestinal transplants have decreased dramatically, particularly in children. In 2012, only about 100 intestinal transplants were performed whereas it had peaked at nearly 200.  Much of the credit is due to intestinal rehabilitation work and adjustments in parenteral nutrition (eg. lipid minimization, line care).  Two most common reasons for intestinal transplantation at this time are gastroschisis and volvulus.
  •  Gluten sensitivity: Fact or fiction Alessio Fasano MD, MassGeneral Hospital for Children. This blog has covered a lot of the same material, but Alessio’s slides are pretty impressive.  Also, I was not aware that Lady Gaga consumes a gluten-free diet
  • Controversies in parenteral nutrition Christopher Duggan MD, Boston Children’s Hospital.  This lecture provides a timely update on nutrient deficiencies due to component shortages and discusses lipid minimization compared with fish oil-based lipid emulsions.
  • Vitamin D and immunity James Heubi MD, Cincinnati Children’s Hospital and Medical Center.  In the beginning of the slides, Jim provides a very user-friendly definition of an expert and a suitable picture.  He indicates that in 2011 there were 3746 vitamin D publications but inexplicably only chooses to review a tiny fraction.

At the time of this posting, I haven’t had a chance to look through these talks:

 

 

How long does it take the liver to recover from PNALD?

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It takes a long time, even when there is no longer biochemical evidence of parenteral nutrition-associated liver disease (PNALD).  A recent study provides long-term data from a population-based, cross-sectional study on liver histology from pediatric intestinal failure (IF) patients (Hepatology 2013; 58: 729-38).  Patients were followed from 1984-2010.  IF was defined as having either >50% small bowel resection or need for PN >30 days.

The 38 IF participants had a median age of 7.2 years.  16 remained on PN after 74 months (range  2.5-204), 22 had weaned off PN 8.8 years (range 0.3-27) earlier after an average of 35 months of PN exposure.

Key findings:

  • Abnormal liver histology was present in 94% of patients on PN and 77% off PN.
  • Nearly 60% of patients on long-term PN had significant or severe fibrosis (Metavir stage ≥2).
  • Significant liver fibrosis and steatosis persisted after weaning off PN. That is, “liver histology remains abnormal up to 9 years after weaning off PN in the majority of IF patients.”
  • One patient off PN developed esophageal varices.
  • Risk factors for increased fibrosis: extensive small intestinal resection, (P=.002) loss of ileocecal valve (P=.048), and recurrent sepsis (P=.002).

Bottomline: While there have been important clinical advances in the management of IF, the data from this study indicate that many patients who have normal liver biochemistries continue to have abnormal liver histology.  Whether this will have an important clinical impact is not known.

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Growth after Liver Transplantation

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A retrospective chart review of patients from Australia and Japan who underwent liver transplantation between 1985-2004 provides some insight into the growth potential after liver transplantation (J Pediatr 2013; 163: 537-42).  The study included height data from 98 patients and weight data from 104 patients.

Study characteristics:

  • 58% were Australian and 42% were Japanese
  • 76 of 98 patients were transplanted for biliary atresia
  • 47% were younger than 2 years at the time of transplantation
  • Measurements were recorded pre-transplant, 1, 5, 10 and 15 years later

Findings:

  • Height recovery continued for at least 10 years to reach the 26th percentile (Z-score -0.67) 15 years after transplant.  Australian patients had better height recovery, reaching the 47th percentile (Z-score -0.06).
  • Weight recovery was most pronounced in 1st year after transplantation but also continued for 15 years.
  • The median height, weight, and BMI Z-scores are listed in Table II for all time periods
  • Those most malnourished and growth impaired at transplant exhibited the most catchup but remained significantly shorter and smaller 15 years later.

While the Australian patients had better growth in this study, this may be attributable to the fact that nearly all the Japanese in this study were transplanted before 1996 whereas Australian patients were transplanted over the entire period of the study.  Improvements in post-operative management with improved immunosuppressive treatment regimens (eg. reduced steroids) may have played a role.

Take-home message:  Most pediatric liver transplantation patients can expect to be normal-sized adults.  Those who are very malnourished at the time of transplantation, though, are likely to have some reduction in growth potential.

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AASLD Guideline: Long-Term Care for Pediatric Liver Transplantation

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Guidelines for the long-term care of pediatric liver transplantation have been published (Liver Transplantation 2013; 19: 798-625). At the time of this writing, it has not been uploaded to the AASLD website which archives a large number of guidelines related to liver disorders (AASLD: Practice Guidelines).

Due to the extensive nature of the guidelines, I will not try to summarize them, though I think having this reference is useful.  To see how familiar you are with current recommendations, you may want to take the following quiz:

1. Which of the following are not part of routine liver transplantation care, according to the authors?

  • a. Assessment of school functioning
  • b. Assessment for hearing loss
  • c. Protocol liver biopsy at 1 year
  • d. Resumption of full physical activity by 12 weeks after LT

2. Which of these vaccines should be given (if age appropriate) before LT but not afterwards?

  • a. Measles, Mumps, Rubella
  • b. Varicella
  • c. Rotavirus
  • d. Human papillomavirus

3. True/False: Tattoos and piercings are acceptable if the child has received the hepatitis B vaccine.

4. Options for treating chronic rejection, which is a major cause of late graft loss, include all of the following except:

  • a. Give rituximab
  • b. Switch to mycophenolate
  • c. Switch to rapamycin
  • d. Higher doses of tacrolimus

5. Target level for tacrolimus trough for patients more than 1 year after transplantation?

  • a. 10-12 ng/mL
  • b. <10 ng/mL
  • c. 8-10 ng/mL
  • d. <8 ng/mL
  • e. <6 ng/mL

6. True statements regarding cytomegalovirus infection include all of the following except

  • a. Prophylactic intravenous ganciclovir is indicated for CMV donor-positive/recipient negative but not for CMV donor-negative/recipient-negative
  • b. Second-line treatments include foscarnet, acyclovir, and cidofovir
  • c. Genotypic testing for mutations can be done to determine if CMV is resistant to ganciclovir
  • d. Ganciclovir resistance should be considered in patients with rising CMV loads despite at least 14 days of therapy

7. Minimal recommended time for Pneumocystis jirovecii prophylaxis, according to the authors:

  • a. 0 months
  • b. 3 months
  • c. 6 months
  • d. 12 months
  • e. 3 years

Answers:

1. C, 2. D, 3. True, 4. A, 5. E, 6. B, 7. C

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We still see this

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Despite a number of previous studies regarding transient benign hyperphospatasemia which date back to 1954, pediatric gastroenterologists still see kids referred for this.  A new study analyzes 142 previous reports which included 813 cases (JPGN 2013; 57: 167-71).

Most of the alkaline phosphatase is produced in the liver and bone. “Sometimes a marked increase in alkaline phosphatase values is found in infants and toddlers without evidence of liver or bone disease…The temporary increase in alkaline phosphatase resolves without intervention within 16 weeks…is termed transient benign hyperphosphatasemia.”  With this disorder, the alkaline phosphatase is commonly ≥ 5 times the upper reference range.

Findings:

  • 733 cases were in patients <19 years of age; 80 cases were in those ≥ 19 years
  • Among infants and toddlers, the prevalence may be between 1.1% and 3.5%
  • The duration of elevation was ≤4 months in 80%
  • A preceding infection often preceded the reported cases
  • Our analysis “indicates that isoenzyme studies are not useful.” In about 50% the most prevalent isoform is from bone, though this may reflect poor clearance from the circulation.

Evaluation recommended by authors: aminotransferases, bilirubin, γ-glutamyl transferase, calcium, phosphorus, urea, and creatinine (eg. CMP, phosphorus, & GGT) –though they indicate that these may be waived by many experienced clinicians.

Bottom-line: Transient benign hyperphosphatasemia is likely the most common cause of elevated alkaline phosphatase in healthy infants and toddlers.  Sometimes this occurs in older children and adults. Recognition of this disorder may help avoid unnecessary investigation.

Severe Pruritus with Alagille Syndrome

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A recent study reviews the King’s College experience for managing pruritus associated with cholestasis in patients with Alagille syndrome (AGS) (JPGN 2013; 57: 149-54).

This retrospective study examined 62 patients (1995-2010). 82% (n=51) had pruritus.  Most common treatments:

  • Ursodeoxycholic acid in 40 patients. 1st line Rx in 31. Efficacy was rated as good in 20% and some efficacy in 67.5%.
  • Rifampicin in 39 patients. 1st line Rx in 8. Efficacy was rated as very good/good in 49% and some efficacy in 46%.
  • Cholestyramine in 18 patients. 1st line Rx in 9. Efficacy was rated as  very good in 17% and some efficacy in 67%.
  • Naltrexone in 14 patients. Efficacy was rated as good in 43% and some efficacy in 36%.
  • Alimemazine in 13 patients
  • Nonsedating antihistamines in 7 patients
  • Ondansetron in 5 patients
  • Phenobarbital in 1 patient.

Despite these medications, pruritus was controlled by medication in 41% (n=21).  16 patients were referred for liver transplantation and 11 of these patients have been transplanted.  These 11 patients make up 55% of those who had permanent resolution of their pruritus.

The authors proposed an algorithm for treatment:

  • 1st line: ursodeoxycholic acid 10-20 mg/kg/day divided in 2 doses or cholestyramine 240 mg/kg/day divided into 3 doses
  • 2nd line: (if needed) Add/substitute rifampicin 5-10 mg/kg/day divided into 2 doses (max 600 mg/day)
  • 3rd line: (if needed) Add/substitute naltrexone 0.25-0.5 mg/kg/day (max 50 mg/day)
  • 4th line: (if needed) Add/substitute ondansetron max 8 mg/day divided into 2 doses per day (or phenobarbital 5-10 mg/kg/day divided into 2 doses.
  • If none of these are helpful, options could include MARS (molecular adsorbent recirculation system), partial external biliary diversion, or liver transplantation.

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Staying current with PSC

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A recent article provides a useful review for primary sclerosing cholangitis (PSC) (Clin Gastroenterol Hepatol 2013; 11: 898-907).

This blog has previously discussed PSC (links below); however, the above reference is succinct and covers the key issues.  A couple of points that I found particularly helpful:

Cancer surveillance:

  • Cholangiocarcinoma (CCA): recommends “consider annual imaging (MRCP or Ultrasound) along with serum CA19-9 levels” to monitor for cholangiocarcinoma.  If there is a dominant stricture, proceed with ERCP with brushings. In pediatrics, the age to start screening is less clear, usually not presenting until beyond the late teen years, though CCA has been diagnosed in one case report at 14 years of age (NEJM 2003; 348: 1464).
  • Gallbladder cancer (30-40-fold higher risk than general population): If gallbladder polyp identified that is ≥0.8 cm, recommends cholecystectomy.  If smaller, may also want to remove if normal synthetic function; otherwise repeat imaging in 3-6 months.
  • Colon cancer: colonoscopy every 1-2 years in those with coexistent IBD (70% of patients with PSC have IBD).

Diagnosis: 44-56% of patients are asymptomatic at time of diagnosis, picked up due to abnormal serum liver tests or on cross-sectional imaging.

Small-duct PSC: occurs in the setting of features of PSC (histology, biochemistry) without abnormal cholangiogram.  This represents 11-17% of PSC patients and is difficult to identify in patients without IBD. Over time, 25% will develop large-duct PSC. Small-duct PSC does not appear to result in increased risk of CCA.

Overlap syndrome with autoimmune hepatitis: patients with typical PSC but with 5- to 10-fold aminotransferase elevations should be suspected of having an overlap syndrome and may benefit from treatments directed at autoimmune hepatitis.  Other features often include histology with an interface hepatitis and the presence of auto-antibodies. This situation is more common in children and young adults.

Immunoglobulin G4-Related sclerosing cholangitis: this occurs most commonly in conjunction with autoimmune pancreatitis.  Since steroids can be effective, IgG4 levels should “be tested in all patients with suspected PSC, and, if elevated to consider an evaluation for IgG4-related disease.”

Medical management: “to date, there are no medical therapies that have been proven to alter the natural course of PSC.”  The discussion notes that standard doses of ursodeoxycholic acid (UDCA) may have protective effects against colorectal cancer in patients with coexisting IBD.  Higher doses of UDCA have been associated with a 2-fold risk of increased disease progression. Specific treatments for dominant strictures, pruritus, metabolic bone disease, and malabsorption are discussed.  In patients with cholestasis, monitoring fat-soluble vitamins is important.

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