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.

Probiotics for Crohn’s Disease –No Beneficial Effects Noted

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With all the buzz regarding how a patient’s microbiome seems to affect everything from metabolic syndrome and colic to autoimmune diseases and inflammatory bowel disease, more attention has been paid in attempts to alter the microbiome for therapeutic benefits.  In Crohn’s disease (CD), the fact that antibiotics have shown beneficial effects have led to a number of studies of probiotics.  A recent study, like previous ones, did not demostrate any benefit with Saccharomyces boulardii (Clin Gastroenterol Hepatol 2013; 11: 982-87).

In this prospective double-blind, placebo-controlled study of 165 patients who achieved remission after steroids or salicylates, subjects were randomly assigned to groups given S boulardii (1 gram per day) or placebo for 52 weeks.

Results:

  • CD relapse occurred in 80 patients: 38 (47.5%) in the probiotic group  and 42 (53.2%) in the placebo group
  • Time to relapse did not differ significantly: 40.7 weeks in probiotic group vs 39 weeks in placebo group
  • No differences were seen in disease activity scores or serum inflammatory markers
  • In post hoc analysis, nonsmokers given S boulardii were less likely to experience a relapse compared with nonsmoker control patients (34.5 % vs. 72%)

One important limitation of this study was not examining the effects of the probiotic on the microbiome of these patients.  Perhaps, other probiotics would be more effective in restoring a “healthy” flora.

Based on these results, and others, the accompanying editorial (pg 988-89), advocates use of probiotics only for prevention of antibiotic-associated diarrhea, prevention of recurrent Clostridium difficile, and treatment/prevention of pouchitis.

Bottom-line: Probiotics have not been demonstrated to be helpful for Crohn’s disease.

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“Too many vaccines and autism” is debunked

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Based on false science, many parents think that refusing or delaying vaccinations will be safer for their children and decrease the risk of autism.  While the scientific underpinnings for such a concept have no basis (Pediatrics 2004; 114: 793-804, and Institute of Medicine. Immunization safety review: vaccines and autism. Washington, DC: National Academies Press; 2004), lingering concerns persist.  Into this background, another rigorous study (J Pediatr 2013; 163: 561-7) has concluded that there is “no association between exposure to antigens from vaccines during infancy and the development of autism spectrum disorder (ASD),” autism, or ASD with regression.

So how did the authors reach this conclusion?

Using a case-control study from three managed care organizations (MCOs) of 256 children with ASD and 752 control children, the authors examined exposure to total antibody stimulating proteins and polysaccharides from vaccines.  They utilized vaccine registries and medical records.  The children in this study were born between 1994-1999 and were aged 6-13 years at the time of data collection.

The results showed that with each 25-unit increase in total antigen exposure, the adjusted odds ratio (aOR) for ASD was 0.999 for cumulative exposure to age 3 months. The aOR stayed the same at 7 months and 2 years.  When autism or autism with regression were examined, similarly there was no increased risk.

One of the strengths of this study was that members of these MCOs have routine immunizations as a covered benefit; this helps minimize socioeconomic factors which could influence results.  A small number of ASD cases (5%) and controls (2%) had an older sibling with autism; results were unchanged when these children were excluded.

In many ways, this finding is completely anticipated and in agreement with the Institute of Medicines most recent 2013 report on immunizations (The Childhood Immunization Schedule and Safety: Stakeholder …).  As the authors note in their discussion, “beginning at birth, an infant is exposed to hundreds of viruses and other antigens, and it has been estimated that an infant theoretically could respond to thousands of vaccines at once.”

Bottom-line: Vaccines prevent disease without causing autism.  Vaccine refusal increases the risk of disease for those who refuse and creates collateral damage as well.

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An Unexpected Twist for “Gluten Sensitivity”

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While the concept of gluten sensitivity without celiac disease has been recognized since 1980 (Gastroenterol 1980; 79: 801-06), a recent study indicates that gluten may not be the main culprit in inducing these symptoms (Gastroenterol 2013; 145: 320-28; editorial 276-79).

The authors of this double-blind crossover study were the same investigators who popularized the concept of nonceliac gluten sensitivity (NCGS) two years ago (Am J Gastroenterol 2011; 106: 508-14).  In this current study, they demonstrate that in NCGS patients consuming a low FODMAPs diet (see previous post links below) gluten reintroduction did not cause specific or reproducible symptoms.

Methods: In this study, they enrolled 37 subjects with NCGS who fulfilled Rome III criteria for IBS and improved on a gluten-free diet (GFD).  All participants continued their GFD and after a 1-week baseline, started on a low FODMAP diet for a 2-week run in period.  Subsequently, patients were randomly assigned to 3 study arms: high gluten (16 g gluten/day), low gluten (2 g gluten & 14 g whey per day) or control (16 g whey/day).  Each participant took this diet for 1 week, had a 2-week washout, then crossed over to each arm.  In addition, at least 8 months, 22 subjects underwent another brief crossover study (high-gluten, whey only, or control with no additional protein).  As part of the study, clinical, serological, and immunologic parameters were monitored during all aspects of the rechallenges.

Results: “Gastrointestinal symptoms consistently and significantly improved during reduced FODMAP intake, but significantly worsened to a similar degree when their diets included gluten or whey protein.” There were no changes in any serological or immunologic parameters between the dietary challenges.

There were several limitations to this study of this highly-selected cohort which are well-described in their discussion.

Bottom-line: Gluten might not be a specific trigger once dietary FODMAPs are reduced.

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Don’t forget HLH

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A recent clinical challenge (Gastroenterol 2013; 145: 289, 489) regarding a a 78-year-old with a 12-year history of ulcerative colitis serves as a good reminder to remember hemophagocytic lymphohistiocytosis (HLH) in inflammatory bowel disease patients with high fever, even in the presence of recognized viral infections like cytomegalovirus and Epstein-Barr virus which can trigger HLH.  Patients receiving immunosuppressive medications are at risk.

Other clinical points:

  • Consider HLH when cytopenias are present in addition to fever
  • Ferritin values >10,000 mcg/L serves as a good screen

Take-home point: HLH has a significant mortality rate.  Quick recognition can improve outcome.

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Diagnosing hemophagocytic lymphohistiocytosis … – gutsandgrowth

Noninvasive prenatal testing and why statistics matter

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New assays for detecting chromosomal abnormalities with prenatal testing are being adopted clinically without enough data to allow appropriate interpretation (NEJM 2013; 369: 499-501).

The assays are cell-free DNA (cfDNA) tests which can be performed as early as 9 weeks and require only a maternal blood sample.  The potential advantages also include avoiding invasive testing, like amniocentesis or chorionic villus sampling, which can result infrequently in miscarriage.  The tests are reported to have high sensitivity and high specificity for detecting abnormalities.

The problem is that these assays have not been tested adequately in more general populations and the manufacturers have not provided positive predictive values (PPV) for these tests.

Here’s why the statistics matter:

If you perform testing with samples that have a chromosomal abnormality prevalence of 1 in 8 with sensitivity/specificity of 99.9% and 99.7% respectively, then you derive a PPV of 98% and negative predictive value of 99.99% which are excellent.  However, when one uses the exact same sensitivity/specificity, then when the prevalence drops to 1 in 200, the PPV drops to 62.6%.

As a result, professional organizations like the American Congress of Obstetricians and Gynecologists have recommended cfDNA only for “high-risk” pregnancies and to confirm positive results through invasive testing.  These recommendations negate much of the potential benefits of early screening and avoidance of invasive testing.  In addition, the costs of these tests range from $795 to more than $2000 (though some discounts or “introductory pricing” are available).

Ultimately, cfDNA may prove to be extremely useful.  Until more data are available in the general population, this remains unproven.

NASPGHAN: Enteral Nutrition for Crohn’s Remission

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A new document from NASPGHAN highlights the potential for enteric formulas (oral and nasogastric) as an alternative 1st line therapy for Crohn’s disease remission.  The following is a link with specific case examples along with background information and practical advice:

http://goo.gl/p19o0z 

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Rest easy with enteral nutrition | gutsandgrowth

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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Extensive Workup Not Needed for IBS

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Another study has shown that an extensive workup is not needed for IBS (Clin Gastro Hepatol 2013; 11 956-62).

In this study from Denmark, the authors enrolled 302 patients aged 18-50 from a primary care setting with suspected IBS.  250 patients completed the entire study including a 1-year followup.  These patients fulfilled Rome III criteria and had no alarm signals which were the following:

  • Unexplained weight loss >3 kg
  • Rectal bleeding
  • Unexplained fever or anemia
  • Family history of inflammatory bowel disease (IBD) or colorectal cancer (CRC)
  • Abnormal physical exam

Patients were randomly assigned to either an extensive diagnostic group which included blood tests (including celiac screen & lactase gene test), stool exams, and sigmoidoscopy or to a “positive strategy” which involved testing only with a blood count (CBC/diff) and C-reactive protein.

The group which underwent a more extensive workup had no cases of serious disease, like IBD or CRC identified.  11 patients were identified with lactose intolerance, 1 patient had a rectal adenoma, 1 patient had a benign polyp, and 1 patient had giardiasis.

Overall, the authors and the accompanying editorial (pgs 963-964) conclude that the positive strategy was noninferior to the more extensive evaluation.  One limitation of this study was that patients had carried symptoms compatible with IBS for an average of 7 years before enrollment.

Take-home message: this study “adds to the growing body of evidence in favor of a relatively minimal symptom-based approach to diagnosing IBS.”

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