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VTE with IBD

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In our children’s hospital, work is underway to systematically screen children for risk factors for venous thromboembolism (VTE) and to establish an algorithm to lower the risk of a VTE with either mechanical or pharmacologic treatments. One of the risk factors has been the presence of inflammatory bowel disease (IBD).  The absolute risk of IBD for VTE is not clear.  However, a recent study relates the risk among a large Danish population of adults and children (Gut 2011; 60: 937-43).

The study included 49,799 patients with IBD (14,211 Crohn’s, 35,229 UC) and compared with 477,504 members of the general population.  VTE risk for IBD was increased with HR of 2.0.  The incidence of VTE increased with age; however, the RR was higher in younger patients.  Among those less than 20 years, HR was 6.6 for VTE; HR 6.0 for DVT and 6.4 for PE.  In this age group, “unprovoked” VTE had HR of 4.5.  Unprovoked VTE was defined as event occurring without malignancy, recent surgery, pregnancy or fracture.

Although the relative risk is increased, the authors caution that the absolute risk in younger patients is low.  In those IBD patients less than 20 years, the incidence rate was 8.9 per 10,000 person years.  In contrast, in those IBD patients older than 60, the incidence rate was 54.6 per 10,000 person years.  There did not seem to be a significant difference between Crohn’s disease and ulcerative colitis in absolute or relative risk. The authors conclude that in those IBD patients younger than 20 years without ‘other VTE risk factors or limited mobility, the benefits of prophylaxis may no longer outweigh the risks.”  In older patients (>60 years), even outpatients experiencing flares might benefit from VTE prophylaxis.

Additional references:

  • -NEJM 2012; 366: 860 (letter to editor). Authors emphasize importance of VTE with UC, especially during flares.
  • -Lancet 2010; 375: 657-63. VTE with active IBD and in remission.
  • -Clin Gastroenterol Hepatol 2008; 6: 41-5. Thrombosis with IBD.
  • -Gut 2004; 53: 542-8. IBD -risk factor for VTE?
  • -Gut 2004; 53 (suppl 5): v1-16. IBD guidelines for management.

TNF antagonists and UC

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In my fellowship (15 years ago), the use of thiopurines (eg. azathioprine, 6-mercaptopurine) for ulcerative colitis was debated.  Many physicians urged colectomy rather than using these drugs which could have long-term consequences.  At the time, the risk of thiopurines was less well-understood.  Over time, the use of these agents has become common when mesalamine products were ineffective.  The same issue comes up with TNF antagonists versus colectomy.

A recent study provides more information on the effectiveness of adalimumab for patients with moderate-to-severe UC but does not settle this debate (Gastroenterology 2012; 142: 257-65).  In this study, termed ‘ULTRA-2’ (Ulcerative colitis long-term remission and maintenance with adalimumab 2), the  efficacy of adalimumab for induction & maintenance of remission was studied in 494 patients.  This was a randomized, double-blind, placebo-controlled study; average age was 40 years.

Clinical remission in the adalimumab group were 16.5% at 8 weeks (9.3% placebo).  At 52 weeks, 17.3% in the adalimumab group were in remission (8.5% placebo).  Among patients naive to anti-TNF agents, the response rate was 21.3% at week 8 & 22% at week 52.  Safety overall was similar in both groups; however, in the adalimumab group one patient developed gastric cancer and one developed squamous cell carcinoma.

The authors conclude that adalimumab is safe and more effective than placebo in inducing and maintaining remission among patients with moderate-to-severe UC.

A second study, also published this past month, looks at the use of infliximab for maintenance therapy for UC (Inflamm Bowel Dis 2012; 18: 201-11).  Patients who had achieved benefit from ACT-1 and ACT-2 studies were followed for three years.  Dosage of infliximab could be adjusted.  A total of 229 patients entered the study.  During the study, 70 patients (30.6%) discontinued infliximab due to adverse effects (10.5%), lack of efficacy (4.8%) or other reasons (15.2%); the majority were able to continue infliximab.  The authors indicate that no new safety issues were identified. Yet, there were two deaths among the infliximab group including a 19 year-old nonsmoker who developed lung cancer and a lethal case of histoplasmosis.

Because the improvement compared to placebo is modest with both of these agents, the question about whether to use these medications or proceed to surgery in UC patients is unanswered.

Additional references:

  • -Aliment Pharmacol Ther. 2008 Oct 15;28(8):966-72. Epub 2008 Jul 24.  Long-term outcome of adalimumab therapy for ulcerative colitis with intolerance or lost response to infliximab: a single-centre experience.
  • -Am J Gastroenterol (Oussalah A et al) 2010; 105: 2617-25. Multicenter study of IFX for UC
  • -Gastroenterology 2010; 138: 2282. Severe pediatric UC. 25/33 responded to IFX. colectomy rate 19% at 1 year.
  • -Gastroenterology 2009; 137: 1204 (ed), 1250. lower colectomy rates at 54wks in IFX vs placebo (+concomitant meds): 10% vs. 17%.
  • -Clin Gastro & Hep 2008; 6: 1112. Do NOT use CYA post infliximab and vice versa. n=19. 1 death due to sepsis. Remission rates occur in ~1/3rd but are of short duration.
  • -NEJM 2005; 2462. 69% clinical response @ 8 weeks (vs. 37% placebo) & 45% at week 54 (vs. 20% placebo).
  • -JPGN 2004; 38: 298. 82% short-term response, 63% sustained response; n=16.

Methotrexate and liver toxicity

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There are drawbacks with all of the therapies for inflammatory bowel disease; however, usually the inflammatory bowel disease is worse than any of the medications. One of the therapies that  has started to see increased usage in Crohn’s disease is methotrexate (MTX), both as an alternative to thiopurines and as an adjunct to Remicade.  There are a number of side effects; a patient handout is available at the following: http://www.ccdhc.org/diseases/MethotrexateLetter.pdf

One of the concerns with MTX has been liver toxicity, in part because of descriptions in the rheumatology literature with long-term usage.  In Crohn’s disease patients, it appears that the risk is much lower (Inflamm Bowel Dis 2012; 18: 359-67).  This study found 13 trials for their meta-analysis.  A total of 632 participants were included: 373 MTX, 131 thiopurines, 128 placebo.  In the MTX group, elevated hepatic aminotransferases occurred in 1.4 per 100 person-months.  The rate of elevation more than 2-fold the upper limit of normal was 0.9 per 100 person-months.  Thus, of the initial 373 patients, 39 had an abnormal aminotransferase.  26 of these 39 had spontaneous resolution, 3 improved with dose reduction & 10 withdrew from MTX treatment (0.8 per 100 person-months).  Seven of these withdrawals were from one of the earlier studies (Feagan et al. NEJM 1995; 332: 292-97). Besides the low likelihood of needing to stop MTX due to liver toxicity, the other observation was that the liver toxicity was mostly dependent on the dose; therefore, dosage reduction would likely be effective if needed.

In my practice, when considering MTX treatment, I usually recommend the following:

  • Monitoring: Baseline: CXR, CBC, Amylase, Renal, LFTs, urine HCG & then Q2-4 weeks initially, then Q3months
  • Give Folate during therapy.
  • Use zofran if needed for nausea
  • Avoid NSAIDs during treatment due to renal toxicity
  • Contraindicated with pregnancy (MTX=teratogen) -females should see gynecology
  • Families warned in writing that this medication is given once a week; more often can be deadly

Additional references:

  • -IBD 2011; 17: 2521. ~25% remission at 1yr, 16% at 2yrs.. n=93.
  • -JPGN 2011;53: 389. n=64. Supports use of zofran for 1st few months to prevent nausea.
  • -JPGN 2010; 51: 714. Use of MTX after thiopurines. n=27. 48% in remission at 6 months.
  • -JPGN 2009; 48: 526. Use in pediatric CD, n=25. 64% response
  • -JPGN 2009; 48 suppl 2: S111. MTX may be effective for UC.
  • -NEJM 2008; 359: 2790. Similar safety of AZA and MTX in vasculitis patients. AZA may be safer.
  • -IBD 2008; 14: 756. MTX in Crohn’s. n=39. 71% remission (20% steroid-free).
  • -J Clin Pharm & Therapeutics 2007; 32: 327-31.
  • -Am J Health Syst Pharm 2004; 61: 1380-84. review of MTX errors -FDA reported
  • http://www.npsa.nhs.uk/patientsafety/alerrts-and-directives/alerts/oral-methotrexate/
  • -Am J Gastro 2007; 102: 2804-2812. n=60 pediatric patients. ~42% in remission with MTX & ~50% improved. 13% (8) had to stop due to increased LFTs or sepsis.
  • -IBD 2006; 12: 1053. n=61. MTX for AZA nonresponders/breakthroughs: 80% with improvement/ 45% with long-term response; 10% discontinued due to side effects. Steroids stopped in 36.
  • -JPGN 2005; 40: 445. Oral MTX works as well as IM/SC.
  • -JPGN 2003; 37: 392 (194A) 0.4 mg/kg/weekly. 91% response at 2 mo, most still needed remicade
  • -Gastroenterology 2003; 124: suppl 1, A-41 (305) 11/12 responded – able to stop remicade
  • -Feagan et al. NEJM 1995; 332: 292-97.
  • -J Pediatr 1999: 134: 47. Hepatotoxic risk factors. (enzymes & obesity). Consider bx if serial enzymes increased >40% of the time over 1 year
  • -Arthritis Rheum 1997; 40: 2226.

More imaging needed?

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With new tools at our disposal in diagnosing inflammatory bowel disease, we need to decide how and when to use them.  Potential new modalities include stool inflammatory markers, video capsule endoscopy, CT enterography (CTE), and MR enterography (MRE).  Several studies have shown that the information that these studies yield may change management. The latest of these studies (Inflamm Bowel Dis 2012; 18: 219-25) looked at how the knowledge of CTE effected management and physician confidence with Crohn’s disease.

The authors prospectively assessed 273 patients with established or suspected Crohn’s disease.  In their analysis, 70 patients (48%) of established cases had altered management because of CTE and 69 (54%) of suspected cases.  These changes were considered to be  independent of clinical, serological or histologic findings.  Changes included medication modification in 45 (16.2%), excluding Crohn’s disease in 46 (16.8%), surgery referral in 10 (3.7%), alternate diagnosis established in 9 (3.2%), & canceling surgery in 7 (2.6%).  The authors considered excluding active small disease as an important management plan change; this occurred in 18 patients (6.6%).

The authors state that their current practice is to use MRE for serial imaging rather than CTE, to minimize risks from radiation; though CTE is often the initial imaging.

My take on this article is that information from imaging often increases the certainty about the diagnosis and gives a more complete picture of the severity.  It is likely that more information leads to more aggressive therapy.  At the same time, in pediatric gastroenterology, the trend towards using more effective therapy earlier in the course of the disease has developed even in the absence of extensive imaging (see previous: Only one chance to make first impression).  Whether more imaging in pediatric patients would be worthwhile is not known.

Additional references:

  • -JPGN 2008; 47: 31.  Capsule endoscopy may reclassify pediatric IBD
  • -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.
  • -Clin Gastro 2008; 6:283. Use of CT enterography.
  • -JPGN 2010; 51: 603.  MRE for suspected IBD.  Useful in Crohn’s disease.
  • -IBD 2004;10: 278-285.  WCE for Crohn’s (review)  Capsule can help differentiate UC from Crohn’s.

Food as medicine

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Two recent articles add some useful information regarding enteral therapy for Crohn’s disease (Inflamm Bowel Dis 2012; 18: 246-53 & JPGN 2012; 54: 298-305).

The first article enrolled 34 children with newly-diagnosed Crohn’s disease.  Patients were divided into elemental and polymeric formula groups and followed in a prospective, double-blind randomized controlled trial for two years.  Measures of improvement included the PCDAI as well as fecal calprotectin and fatty acids.  Both groups of patients responded clinically.  93% (14/15) of the elemental formula group achieved remission based on PCDAI scores (<11) and 79% (15/19) of the polymeric formula group.  The initial treatment was use of formula (along with only clears) either by NG or oral for 6 weeks.  All patients had NG placed at time of endoscopy and if sufficient oral intake was demonstrated (for 2 days), NG was removed.  All subjects had small bowel and colonic disease.  Although calprotectin levels decreased, they remained very elevated.  In the EF group, the median calprotectin dropped from 2023 μ/g to 1113 μ/g, though only one patient had a level below 400; similarly in the PF group the calprotectin dropped from 1929 μ/g to 1134 μ/g, and only two patients had a level below 400.  Some to the reasons why changes in diet may be useful have been alluded to in a previous post: Eat your veggies…if you don’t want to get sick.

The second reference is a clinical guideline on the use of exclusive enteral nutrition EEN).  The introduction notes that 65% of European pediatric gastroenterologists use EEN compared to 4% for North American pediatric gastroenterologists.  In pediatric trials, EEN and corticosteroids were considered ‘equally effective’ in a pediatric meta-analysis which included five randomized controlled trials (n=147).  However, a Cochrane review favored corticosteroid treatment over EEN in a meta-analysis that included adult and pediatric patients (n=192 EEN, n=160 corticosteroids).  According to the authors, small studies have demonstrated other potential advantages of EEN including higher rates of mucosal healing and better linear growth.  With regard to mucosal healing, the initial cited study casts with ongoing elevated calprotectin indicates that this does not occur in the majority of children with EEN therapy.  Other caveats:

  • Disease location: some evidence favors small bowel disease rather than colonic disease
  • Formula composition: does not seem to matter whether elemental or polymeric
  • Duration of therapy: majority treat for 6-8 weeks of EEN.  The authors recommend at least 8 weeks
  • Time for response: Inflammatory markers improve in a little as a week, remission typically 2-4 weeks
  • Concomitant medications: many places initiate immunomodulator treatment; others cycle EEN
  • Start with goal 120% of ‘maintenance’ nutrient needs.  On 1st day, authors recommend starting at 1/2 goal volume and gradually increase over 1-2 days
  • Partial enteral nutrition (PEN) (eg. overnight feedings & normal daytime diet) has been helpful in improving growth and may improve remission rates.
Why not EEN or PEN? Potential barriers include cost, difficulty changing diet, fear of tube feedings, and more acceptable alternatives.  At the same time, some of these barriers could be overcome.  Quality of life measures have improved in children receiving enteral nutrition.

The use of more top-down therapy may affect all of the above considerations (Only one chance to make first impression).

Additional references:

  • -Cochrane Database Syst Rev 2007; CD000542.  Enteral nutritional therapy vs corticosteroids to induce remission in Crohn’s disease.
  • -Gastroenterology 2011; 141: 742. AGA guidelines on use of enteral nutrition in wide variety of conditions.
  • -Gastroenterology 2008; 135 : 1005. omega-3 fatty acids ineffective in Crohn’s dz for maintaining remission.
  • -Pediatr Res 2007; 61: 356-60.  Enteral nutrition effect on protein turnover in adolescents with Crohn’s disease.
  • -J Pediatr 2000; 136: 285-91. Nutritional Rx w polymeric diet is effective w/in 8 weeks in 32/37.
  • -Scand J Gastro 2001; 36: 383-8. Elemental & polymeric diets successful in maintaining remission in ~43% of adults with complete steroid withdrawal
  • -JPEN 1992; 16: 499. improved wt,ht, decreased prednisone, decreased CDAI
  • -JPGN 2000; 31 (supp 2) A291. Polymeric vs elemental diet.
  • -JPGN 2002; 35: 339-40. Lactase deficiency – same prevalence in IBD as in RAP.
  • -JPGN 2000; 31: 3 & 8. EN about as effective as steroids for primary Rx.

A cure for satiety

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A safe cure for excessive appetite is a holy grail in pharmacology.  Although gluttony is a much more pervasive problem that poor appetite, an effective cure for satiety is also needed.  In the clinical setting, poor appetite remains a common problem with and without underlying problems.  Treatments to this point, such as cyproheptadine or megestrol, may be useful in some patients.  Better treatments are needed.  One drug of interest is ghrelin (Cancer 2012; DOI: 10.1002/cncr.27430).

The introduction summarizes ghrelin’s biologic activity: “Ghrelin is an endogenous ligand for the growth hormone (GH) secretagogue receptor and is secreted predominantly by gastric endocrine cells.  It induces dose-dependent, GH-releasing activity; stimulates appetite and food intake; and triggers a positive energy balance through a central mechanism involving hypothalamic neuropeptides.”

Plasma ghrelin levels decrease after gastric resection, helping to maintain weight loss. Therefore, the stomach may act as endocrine organ to maintain appropriate weight. Exogenous administration may increase appetite.

This cited article reports a prospective randomized placebo-controlled phase 2 study in which ghrelin was administered to 21 patients with esophageal cancer, receiving cisplatin-based chemotherapy; the dosage was 3 μcg/kg twice daily for 1 week.  A placebo group  (n=20) received saline.  The ghrelin group consumed 18.2 kcal/kg/day compared with 12.7 kcal/kg/day.  A measure of appetite, an appetite visual analog score, was also higher in the ghrelin-treated patients, 6.2 vs 4.1.  Patients in the ghrelin group had fewer adverse effects of chemotherapy related to anorexia and nausea than patients in the control group.  One patient receiving ghrelin stopped therapy because of excessive diaphoresis.

Although this medication is being studied in adult chemotherapy patients, down the road ghrelin and potential analogs may have a role in pediatric patients with a variety of disorders which inhibit their appetite.

Additional references:

  • -Adachi S, Takiguchi S, Okada K, et al. Effects of ghrelin administration after total gastrectomy: a prospective, randomized, placebo- controlled phase II study. Gastroenterology. 2010;138:1312-1320.
  • -NEJM 2002; 346: 1623-30, 1662. Plasma ghrelin levels decrease after gastric resection.   Therefore, stomach may act as endocrine organ to maintain appropriate weight. However, ghrelin levels are reduced in obesity; so it is not clear that further reduction of these levels is clinically important.
  • -Gastroenterology 2003; 125: 1492. Review of ghrelin.
  • -Yamamoto K, Takiguchi S, Miyata H, et al. Randomized phase II study of clinical effects of ghrelin after esophagectomy with gastric tube reconstruction. Surgery. 2010;141:31-38.
  • -Nakazato M, Murakami N, Date Y, et al. A role for ghrelin in the central regulation of feeding. Nature. 2001;409:194-198.
  • -Kojima M, Hosoda H, Date Y, et al. Ghrelin is a growth-hormone- releasing acylated peptide from stomach. Nature. 1999; 402:656- 660.
  • http://www.surgjournal.com/article/S0039-6060(09)00784-3/abstract
  • http://pennmedicine.adam.com/content.aspx?productId=16&pid=16&gid=50495 Review of cited article.

The undiscovered country

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The title of this blog is derived from a Star Trek movie.  I think that when we see patients with eosinophilic esophagitis that we are often seeing something new and poorly characterized.

Despite so many unanswered questions, particularly on an individual basis, this topic has seen a lot of interest and there are many advances in both bedside and basic research.  The review article  (Allergy 2012; DOI: 10: 10.1111/j.1398-9995.2012.02787.x) focuses on many of the similarities and differences between pediatric and adult patients.  Is it the same disease? (Probably yes)

With regard to medical history, the article reminds clinicians to ask about coping strategies:

  • do you wash food down with liquid?
  • are you the last one to finish your food?
  • do you chew your food a long time?
  • do you avoid foods like meats or breads?

Clinical features –main difference is greater presentation variety in children.  Adults almost always have long-standing dysphagia.  In pediatrics, painful symptoms, reflux symptoms, and feeding refusal are often seen in early stages.  In both populations, other atopic diseases are very common.

Immunopathogenesis (same in pediatrics and adults):  Th2-type inflammatory response; not just eosinophils but also IL-5-expressing T-cells, B cells, and IgE-bearing mast cells.  A break-down of all the types of quantified cells from a large number of studies is detailed (Table 2).

Allergic profile –main difference is much higher aeroallergen sensitization in adolescent & adult patients than in pediatric patients.  In children, top four allergens: milk, wheat, egg, and soy.  In older patients/adults, nuts are frequent food allergens.

Treatment strategies –basic question of whether to treat for symptomatic relief or histologic response is still debated.  Three goals of treatment are the same:

  • improve quality of life
  • reduce the risk of severe esophageal injury
  • prevent esophageal damage

3 D’s of treatment drugs, diet, dilatation:

Drugs: topical steroids (fluticasone, budesonide) are effective in ~50% of children & these agents may reverse subepithelial fibrosis, PPIs -small percentage have EoE PPI-responsive disease, & systemic steroids.  Lower doses of budesonide may be effective as maintenance treatment (0.25mg BID).  Interestingly, infliximab has not been effective clinically or histologically despite the high amounts of TNF.  Azathioprine (or 6-MP) was effective in three steroid-dependent patients in a pilot study.

Diet –review does not cover new territory (see previous blog: Eosinophilic Esophagitis -Six Food Group Diet).  States that elemental diets are not practical in adults.  Discusses the fact that food allergy identification is difficult & remains a pressing research need.

Dilatation –can provide long-lasting symptom relief.  Dilatation is infrequently utilized in pediatrics and virtually never in absence of other therapies.

On a side note, in my training I was taught that there were 3D’s to treating every patient: diet, drugs, and demeanor — a good attitude goes a long way, particularly in an uncertain world.

Additional references:

  • -Gastroenterology 2011; 141: 1593.  anti-IL-5.  partially effective for EoE.
  • -JPGN 2010; 51: 723. n=91.  Incidental gastric eosinophils does not predict a worse response to fluticasone then isolated EoE.
  • -Clin Gastro & Hepatology 2011; 9: 400 (editorial 370). Budesonide at dose of 0.25mg BID was partially effective in adult cohort of n=28.
  • -Aceves SS et al. Allergy 2010; 65: 109-116. 3 month course of budesonide can lead to resolution of esophageal remodeling. Lamina propria fibrosis resolution correlates with response to topical steroids. Examined effect on lamina propria after 3 months of Rx.
  • -Gastroenterology 2010; 139: 1526. n=36. (summary pg 1429) 15 day course of budesonide (1mg BID). 13/18 in Rx group had improved dysphagia, 72% wiht histologic remission, 92% reduction in eosinophil count. Did not seem to matter if “allergic” or not. 3 pts developed mild candida.
  • -Gastroenterology 2010; 139: 418. Randomized placebo study showed effectiveness.n=15 Rx (n=9 placebo). 87% of Rx group responded.  2ml of water with 0.5gm pulmicort and mixed it with 4-5 packets of splenda.
  • -JPGN 2007; 45: 281/370/319. Review/research symposium/subepithelial fibrosis associated with EoE & dysphagia.
  • -JPGN 2007; 45: 22-31. Th2 Immunity w Eotaxin-3/ C-C chemokine receptor in EoE.
  • -Gastroenterology 2006; 131: 1381-1391. Randomized double-blind, placebo-controlled trial of fluticasone for EoE: 880mcg divided bid; n=21 Rx, n=15 placebo. 50% (vs 9% controls) achieved histologic remission; Rx more effective in those w/o detectable food allergies. 67% (vs. 27% controls) resolution of vomiting.
  • -Clin Gastro & Hep 2007; 5: xxiv. EoE causing Boerhaave’s syndrome (spontaneous rupture)
  • INCREASED FRAGILITY: -Gastrointest Endosc 2003; 57: 407-12. -Clin Gastro Hepatolo 2003; 1: 433-37.
  • -Clin Gastro & Hep 2006; 4: 1328. absolute eosinophilia (AEC 440 vs 140 controls), eosinophil-derived neurotoxin, and eotaxin-3 act as biomarkers of EE activity.
  • -Gastroenterology2006; 131: 2018 (-J Clin Invest 2006; 116: 536-547. ) Eostaxin-3/EcE transcript signature.
  • -J Pediatr 2005; 147: 540 Picture of ringed esophagitis.
  • -JPGN 2004; 39: S8 [abstract 0005]. CHOP experience in 250 pts. NG elemental diet was most effective. ~6% of pts presenting with GER. Strict avoidance of allergens needed.

One more cause of rectal bleeding

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Two articles in this month’s JPGN, along with the editorials, make it clear that when patients are having rectal bleeding, we should ask if they are spending an inordinate amount of time straining on the toilet.  (JPGN 2012: 54: 263-65, 266-70, 167-68, 169-70).  This question may help uncover Solitary Rectal Ulcer Syndrome (SRUS).

This syndrome which is often a misnomer because many cases have erythema rather than ulcers; and, lesions can be ulcerative or polypoid.  They can be single or multiple involving the distal rectum.  SRUS often has a delayed diagnosis, 1.7 years and 3.2 years respectively in the two studies.  The differential diagnosis includes polyps, infections, IBD, abuse, and rectal manipulation.  Histology features include muscularinization of lamina propia, mixed inflammatory infiltrate, thickened muscularis mucosa, and epithelial hyperplastic changes.

Treatment includes avoidance of straining/behavior modification, use of laxatives, and perhaps topical mesalamine.

Additional references:

  • -Gastroenterol Clin North Am 2008; 37: 645-68. Rectal disorders/SRUS -review.
  • -Gastrointest Endosc 2005; 5: 755-62,
  • -Eur J Gastroenterol Hepatol 2008; 2: 89-92. SRUS in children.
  • -Gut 2004; 53: 368-70.  Biofeedback for SRUS.
  • -Pediatrics 2002; 110: e79.
  • -Clinical Perspectives in Gastroenterology 1999; 2: 190.

Think twice about checking thyroid

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Hypothyroidism is not a frequent cause of constipation in children (JPGN 2012; 54: 285-87).  According to this study, the yield on checking for hypothyroidism in pediatric patients with constipation is no greater than in the general population.

This retrospective study examined the records of 873 patients who underwent thyroid testing ordered by pediatric gastroenterology; 443 (51%) had isolated constipation.  In all, 56 had abnormal thyroid function testing though 40 were normal on repeat testing. Of these 16 remaining cases, 7 were known to have hypothyroidism.  Of the nine remaining “new” cases, 3 had slow growth (2 without constipation), 3 had trisomy 21, and 2 were taking medications which affect thyroid function.  This leaves only 1 patient who presented with constipation without a clear risk factor or other indication for testing.

The authors state that 1/443 (0.2%) is quite similar to background incidence of hypothyroidism (0.3%).  The costs of identifying this case would exceed $18,000 but could be considered much higher (~$200,000) when all of the costs of false-positives are considered (eg. endocrinology consultations, followup testing).  In patients with slow growth (with or without constipation), about 2.5% had hypothyroidism.

In short, think twice about checking thyroid status in patients with isolated constipation.

Additional references:

  • -JPGN 2011; 53: S2. 49, 55. ‘Rarely do children with constipation need w/u’–only if alarming features: Delayed meconium, bilious vomiting, bloody stools, fever, bladder disorders, poor growth, NO RESPONSE to conventional treatment, abnormal exam. 25% of functional constipation problems may persist into adulthood.
  • -JPGN 2010; 51: 155. Lack of utility of AXR -suggested only in uncooperative pts, concerns about abuse/concerns about psychologic impact of exam
  • -J Pediatr 2010; 156: 461-5. MRI in children with chronic constipation or not-retentive soiling (n=130, n=28) -MRI showed lumbar sacral abnormalities in 3% –none required neurosurgery (1 w spina bifida occulta, 3 w terminal filum lipomas). Prospective study.
  • JPGN 2006; 43: e1Ye13.  http://www.naspghan.org/user-assets/Documents/pdf/PositionPapers/constipation.guideline.2006.pdf  Guidelines suggest checking thyroid, calcium, celiac and lead if not responding to therapy.

Unexplained chest pain

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Not surprisingly -unexplained pediatric chest pain has a high association with anxiety/psychiatric disorders (J Pediatr 2012; 160: 320).  In this study, the authors compared patients (8-17 years) with chest pain (n=100) to a cohort referred with innocent heart murmur (n=80).  In addition to cardiology evaluation, patients had a structured interview and a child health questionnaire to assess for psychiatric disorders; also, the investigators interviewed the parent(s).

Based on DSM-IV criteria, 70% of chest pain patients had an anxiety disorder and 9% had depression.  In contrast, 33% of heart murmur patients had an anxiety disorder and none were depressed.  Among the chest pain subjects, 26% had abdominal pain and 26% had headaches -both higher than the control group, 9% and 10% respectively.  Also, 90% of patients with chest pain had psychiatric disorders which preceded the chest pain.

For pediatric gastroenterologists, a take home message from this article is that chest pain is quite similar to abdominal pain (see references below); it might be interesting to discuss with cardiologists.

  • Do cardiologists experience the same reluctance from families to seek help from mental health?
  • How much testing is required before a functional diagnosis is accepted?
  • Do they follow patients with functional chest pain or send back promptly to primary care physician?

This article does not examine parental mental health issues.  This would be interesting.  In functional abdominal pain, maternal anxiety has been ascribed as the most consistent predictor of outcome (Acta Paediatr 2007; 96: 697-701).  Another factor that would be of interest would be level of activity; exercise helps reduce symptoms of irritable bowel/abdominal pain.

At the same time, the issue of reflux is not addressed by this article and not infrequently the issue of whether reflux is causing chest pain needs to be considered.  An article (Gut 2011; 60: 1473-78) regarding chest pain in adults indicates that patients with pH-probe (or endoscopic) proven GERD often respond partially (>50% reduction in symptoms) to PPI use.  This study reviewed RCTs involving chest pain and PPIs -six met inclusion criteria.  The RR of therapeutic gain for PPI usage was 4.3 for those with proven reflux and 0.4 for those with pH-probe (or endoscopic) negative chest pain.  Interestingly, in this study, heartburn was not predictive of whether chest pain was due to GERD on pH study.

Additional references:

  • -Pediatr Emerg Care 2010; 26: 830-6.  Psychopathology among children presenting to ER with unexplained chest pain.
  • -Clin Gastro 2008; 6: 329-32.  Depressive symptoms common in RAP -45%
  • -Pediatrics 2004; 113: 817.  Anxiety & depression commonly associated with RAP.  anxiety in ~79%, depression ~43%; anxiety often precedes RAP.
  • -JPGN 2011; 53: 200. n=98. 79% of FAP responded to low dose tricyclics
  • -Gastroenterology 2009; 137: 1261, 1207– Editorial.  Amitriptyline helped in 66% vs 58% with placebo. n=90. dose 10mg <35kg, 20mg >35kg. 89% had failed Rx prior to study. ‘Inability to use placebo.. in practice may justify amitriptyline’ Rx. Consider hypnotherapy/CBT first.
  • -Gut 2011; 60: 1473-78. PPI use in unexplained chest pain.
  • -Pain 2006; 122: 43-52. (Walker LS et al), J Pain 2006; 7: 319-26.  Distraction/ignoring important.
  • -J Pediatr 2009; 154: 313 (editorial), 322. Prospective school study. n=237. Weekly prevalence of abd pain was 38%. 18% with persistence for >12 weeks.
  • -Clin Gastro Hepatol 2008; 6: 329-32.  FAP persists into adulthood in 1/3 to 1/2 of cases.
  • -Gastroenterol 2006; 130: 1459-1465.  Functional esophageal d/o.
  • -Clin Gastro & Hep 2006; 4: 558. Review.
  • -Ann Heart J 2000; 40: 367-372.  Sertraline decreased chest pain independent of mood alteration/psychological scores.