Looking Beyond the Headline for Ultra-Short Bowel Syndrome

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A quick glance at a recent study (JPGN 2014; 58: 438-42) suggests a favorable outlook for patients with ultra-short bowel syndrome (U-SBS). U-SBS has been defined as having a residual small bowel length <10 cm distal to the ligament of Treitz.  A more cynical definition by a colleague years ago was that U-SBS was when patients can fart and burp at the same time.

Looking at the details:  This study enrolled 11 patients into a prospective Italian database since 2000 and examined their outcomes.  Inclusion criteria included U-SBS diagnosed in the neonatal period (<28 days) and necessitating home parenteral nutrition at discharge.

The demographics note that these patients were bigger at birth and less premature than typical series of patients with SBS:

  • Only one of the patients had necrotizing enterocolitis as the sole underlying disease and six patients had volvulus.
  • All but two had ≥50% of their colons, with five having their entire colon.
  • All but one of these patients had gestational age ≥32 weeks and only two  patients had documented birth weight less than 2300 gm.

The authors note that these patients currently receive SMOFlipid as outpatients and Omegaven as inpatients.  All patients receive some enteral feedings.  Loperamide is used selectively.

Results:

  • Inpatient hospital care ranged from 23 to 104 days/year, but had improved during the last year of followup.
  • With >5 years of followup, 2 of the 11 patients had died.  One of these patients had severe intestinal failure associated liver disease (IFALD) despite use of Omegaven.
  • One patient underwent isolated intestinal transplantation.
  • No children in this series underwent a bowel-lengthening…”given the shortness of the residual small bowel, the gain of length after any procedure will not significantly improve absorption.”

Given their results, the authors note that despite recommendations for early referral for intestinal transplantation in patients with U-SBS, this may not result in a survival benefit.  They note a study by Pironi et al (Gut 2011; 60: 17-25) that showed that among 80 intestinal transplant candidates, 5-year survival was greater in those who were not transplanted.

Bottomline: This small cohort shows that certain populations of U-SBS may do well clinically for a long time with medical management. Caution should be used in extrapolating these results to SBS patients with different demographics.

Fructose Malabsorption and Recurrent Abdominal Pain

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Even before the popularity of a low FODMAPs diet, most pediatric gastroenterologists were aware that a significant number of children would develop pain if their diet included too much high fructose corn syrup.  A recent study shows that a breath hydrogen test (BHT) for fructose malabsorption may predict patients who will improve with a low-fructose diet (JPGN 2014; 58: 498-501).  Here’s a link to the abstract: 

Design: Retrospective study reviewed a single center experience.  Fructose BHT (1 g/kg fructose to max of 25 g) was administered to 222 patients who presented with recurrent abdominal pain.  An abnormal test was defined by a breath hydrogen >20 ppm over baseline.  If positive, families met with a nutritionist for instruction on a low-fructose diet.

Key result: 121 of 222 (54.5%) had positive BHT.  Of these 121 patients, 93 (77%) reported resolution of symptoms on a low-fructose diet.  Among those with a negative BHT, 54% reported resolution of symptoms without a low-fructose diet.

Take-home message: High fructose corn syrup and fructose malabsorption can contribute to abdominal pain; though, in clinical practice, a BHT is not needed to institute a trial of a low-fructose diet.

 

A Leading Cause of Mortality in U.S….

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Being uninsured.  A recent article in Annals of Intern Medicine (2014; 160: 585-93) explored the reduction in mortality associated with expansion of Medicaid.

Key result: “Reform in Massachusetts was associated with a significant decrease in all-cause mortality compared with the control group (−2.9%; P = 0.003, or an absolute decrease of 8.2 deaths per 100 000 adults).”  The control group consisted of similar patients from other states.

An editorial (advbd.co/1lWHfsu) on this subject (from Atul Gawande retweet), notes the following: “The takeaway: Every 830 additional people who got insurance under Massachusetts’ health reforms prevented roughly one death….

A 2012 Urban Institute report estimated that 15.1 million uninsured adults could gain coverage if every state expanded Medicaid. Using the 830 figure from the Massachusetts study, and acknowledging that the state’s coverage wasn’t exactly equivalent to Medicaid, that would translate to 18,193 deaths prevented per year.

For a sense of comparison—that would make the Medicaid coverage gap the number five leading cause of preventable death in the United States”

1 “Medicaid Coverage Gap” based on 2012 estimate; other causes based on 2010 data.

Bottomline: Not having health insurance can be very bad for your health.

Related blog post:

45,000 Unnecessary Deaths Per Year | gutsandgrowth

Parental Immunity (to Education) and Vaccine Decision-Making

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A recent NY Times editorial by the lead author of a provocative study in Pediatrics (Published online March 3, 2014  (doi: 10.1542/peds.2013-2365) argues that educational efforts to inform parents may not improve vaccination rates in children.

Here’s a link: http://nyti.ms/1sq4X2s  and here’s an excerpt:

“we found that parents with mixed or negative feelings toward vaccines actually became less likely to say they would vaccinate a future child after receiving information debunking the myth that vaccines cause autism.

Surprising as this may seem, our finding is consistent with a great deal of research on how people react to their beliefs being challenged. People frequently resist information that contradicts their views, such as corrective information— for example, by bringing to mind reasons to maintain their belief — and in some cases actually end up believing it more strongly as a result….

A more promising approach would require parents to consult with their health care provider, as the Oregon law also allows them to do. Parents name their children’s doctor as their most trusted source of vaccine information. That trust might allow doctors to do what evidence alone cannot: persuade parents to protect their children as well as yours and mine.

Related blog posts:

Emerging Treatment for PFIC-2

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A great example of “bench to bedside” research was recently published (J Pediatr 2014; 164: 1219-27). While this research involved treatment of a rare condition, progressive familial intrahepatic cholestasis type 2 (PFIC2), the way the authors used a series of convincing experiments to determine the effect of a new medication shows how important a single patient can be in advancing medical treatment.  For PFIC2, the implications of this study are more direct since there are no established medications.

Previous experimental evidence has indicated that 4-phenylbutyrate (4PB), a drug used to treat ornithine transcarbamylase deficiency (OTCD), can increase the expression of the bile salt export pump (BSEP). Since BSEP, encoded by ABCB11 gene, is defective in PFIC2, the authors sought to determine whether 4PB would be effective for patients with PFIC2 who showed a reduced (but not absent) BSEP expression.

They identified a jaundiced infant female at 2 months of age with normal GGT who was diagnosed with PFIC2 due to the presence of the c.3692G>A (p.R1231Q) mutation in both alleles of ABCB11.

The authors then treated this infant with 200 mg/kg/day (into 4 doses a day) with 4PB; gradually the dosage was increased to 500 mg/kg/day.  The authors performed elegant in vitro studies from genomic DNA from peripheral leukocytes along with histologic studies from liver biopsy specimens.

Key Findings:

At the 500 mg/kg/day dosage, BSEP expression at the canalicular membrane was partially restored and this coincided with improved liver tests, improved liver histology, and relief of pruritus.

Conclusion: 4PB retards degradation of the canalicular BSEP which resulted in biochemical and histologic improvement.  This study involved only one patient; thus, further studies will be needed.

Related blog post:

BRIC, PFIC, and nasobiliary drainage | gutsandgrowth

Questions and Answers about MERS

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Recently two cases of Middle Eastern Respiratory Syndrome (MERS) have been reported in the U.S.  For more information -the following link (thx to Mike Hart) may be useful:  www.cdc.gov/coronavirus/MERS/index.html<http://www.cdc.gov/coronavirus/MERS/index.html

From the CDC: Middle East Respiratory Syndrome (MERS) is viral respiratory illness first reported in Saudi Arabia in 2012. It is caused by a coronavirus called MERS-CoV. Most people who have been confirmed to have MERS-CoV infection developed severe acute respiratory illness. They had fever, cough, and shortness of breath. About 30% of these people died.

So far, all the cases have been linked to countries in the Arabian Peninsula. This virus has spread from ill people to others through close contact, such as caring for or living with an infected person. However, there is no evidence of sustained spreading in community settings.

Therapeutic Inertia in U.S Neonatal Units (vis-a-vis Probiotics)

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“More than 90% of very low birth weight (VLBW) infants receive substandard care” could be the headline of a recent article/editorial (J Pediatr 2014; 164: 980-5 & 959-60).  Instead they are titled: “Cohort Study of Probiotics in a North American Neonatal Intensive Care Unit” and “Probiotic Supplementation in Preterm Infants: It is Time to Change Practice.”

In the article introduction, the authors state: “In 2011, faced with overwhelming evidence that probiotics could decrease NEC in preterm infants, and because there were no significant risks described in the extensive literature, we decided to introduce probiotics as routine care for the prevention of NEC.”

Methods: Prospective cohort study of infants at a single center NICU.  Examined rates of necrotizing enterocolitis (NEC) and death for 17 months before and after introduction of a probiotic (FloraBABY).  This probiotic (0.5 g) was mixed with water and administered just before milk once a day.  It was started at the first feeding and continued until the infant reached 34 weeks postmenstrual age.

Key findings:

  • Probiotics reduced NEC from 9.8% to 5.4% (OR for NEC 0.51)
  • Probiotics reduced combined outcome for NEC or death from 17% to 10.5% (OR 0.56).  Reduction in death by itself did not meet statistical significance.

Why, in 2012, were probiotics only used in 8-9% of VLBW?

Potential profits for probiotics are small which has limited studies of specific strains.  The probiotic, FloraBABY, in this study cost 11 cents per day in amount used; however, since the probiotic came in a tub, the actual cost was $12.79 for a 60-g tub for each patient.  Thus, manufacturers are unlikely to support studies to garner FDA approval.

Yet, there have been 22 randomized controlled trials published which “showed substantial benefits of probiotics and no adverse events.” A recently completed ProPrems trial (Jacob S et al, presented at 2013 PAS Annual Meeting) used a probiotic called ABC Dophilus Probiotic Powder for Infants.  This trial showed “a significant, >50%, reduction in NEC despite an incidence in their control patients of only 4.4%” and despite the fact that >95% of infants received breast milk.

“Good quality control and confirmation of the contents of the preparation are essential…There seems to be no further reason to delay the introduction of this evidence-based therapy in the NICU.”  The adoption of probiotics could avoid 2500 cases of NEC every year in North America.

The editorial notes that the evidence for probiotics is much better than many other therapies used in NICUs.  They note that some have argued that “the evidence that probiotics reduce mortality rates is as conclusive as that for surfactant for respiratory distress syndrome.”  A recent Cochrane review of 17 trials and >4900 VLBW infants showed that the RR of severe NEC for probiotics versus control was 0.41.

If people really understood this issue, there would be outrage over this issue.  In the U.S., there was recently extensive coverage over inaction about a faulty ignition switch which has been linked to at least 13 deaths.  The potential reduction in NEC and deaths with probiotics is likely much greater.

While the editorial recommends involving parent representative groups, I recommend discussing this issue with your neonatology colleagues along with your “quality care” team to find out what they are going to do about it.  Given the enormous costs in most NICUs, it is likely that each unit could self-fund a quality project (with consented patients) to provide probiotics to this vulnerable population.

Bottomline: Probiotics have excellent evidence as prophylaxis for NEC in VLBW infants.  Physicians need to advocate for their usage to “avoid years of therapeutic inertia.”

Related blog post: One More Day Syndrome & Necrotizing Enterocolitis …

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.

Source Article: Methotrexate Safety

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A recent post (Monotherapy or Combination Therapy with Adalimumab) referenced an article indicating some potential concern for malignancy potential with methotrexate (Semin Arthritis Rheum 2014; 43: 489-97). Here’s a link to the source article/abstract:  Comparative cancer risk associated with methotrexate, other…

The authors conducted a comparative effectiveness study with cancer as an outcome in patients with rheumatoid arthritis (RA).  The final sample size was 6806 patients.  The most common drugs examined included methotrexate (n=1566) and TNF antagonists (n=3761). Other disease-modifying anti-rheumatic drugs (DMARDs) included other non-biologics (n=904), rituximab (n=167), and abatacept (n=408).

The authors note that with “the advent of newer DMARDs and combination therapy (this) has allowed more RA patients to lead more functional lives.  With this improvement in therapy, more attention is focused on the comparative risks and benefits of treatment.”

Key findings/discussion:

  • TNF antagonists were associated “with a reduced overall cancer risk versus methotrexate.” (HR 0.29).  Figure 2B, shows a plot with specific HR for various malignancies.  TNF antagonists had a HR of 0.15 for lymphoma.
  • Oncogenic potential of methotrexate was described almost 20 years ago, however, “its obvious clinical benefits have overshadowed malignancy concerns.”
  • “Our findings suggest that when examining the cancer risk associated with other DMARDs, combined methotrexate use must be factor into adjusted analyses.”

How does this translate to inflammatory bowel disease (IBD)?  While RA and IBD patients may have different risks for malignancy, this study suggests that patients receiving methotrexate therapy may have a low risk of malignancy.  The potential benefits of methotrexate therapy along with alternatives need to be weighed against this possible risk. Perhaps, this article may help reduce the concerns regarding anti-TNF therapy with regard to relative risk.

Related post:

A Lack of $2.17 Can Cost Thousands More

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An interesting article in the NY Times explains a couple situations in which patients reluctantly admit their lack of financial resources and how this impacts their care.  The article underscores the message that doctors need to find a careful way to find out if patients can afford their medications.

Here’s the link: http://nyti.ms/1fVPzDx  and here’s an excerpt:

His protuberant belly was actually a sign of serious liver disease that had quickly worsened…

“I know how to take the pills, but I can’t buy them,” he said, his eyes refusing to meet mine as he stared at a spot on the hospital’s beige floor…The medicines were crucial to helping him avoid landing in the hospital again, so I went down to the pharmacy to see what the problem might be. “The co-pay is $2.17,” the pharmacist told me matter-of-factly, referring to a white paper bag with a few pill-filled bottles inside…The medications cost less than a subway ticket, but were still more than my patient could afford. If he ended up in the hospital again because he couldn’t take them, the medical costs would be thousands of times greater than $2.17…

A recent report in The American Journal of Medicine that found that one-third of Americans suffering from a chronic illness such as diabetes or high blood pressure said they had trouble affording medications, food or both…

The standard co-payment was $20, the doctor told her, and then gently asked if it would be a problem to pay.  The mother shook her head, but tears were welling up in her eyes. “But we can’t come back in a few months,” she blurted out. “It’s just too expensive.”

Tears rolled down her cheeks, and she looked away as her cheeks flushed. Her daughters sat silently on the exam table, their thin legs swinging back and forth.

I felt the family’s shame and embarrassment, and in retrospect, it seems obvious they lacked enough to eat. Yet we wouldn’t have known they were pressed for funds if our patient hadn’t brought up the issue at the last minute. The pediatrician was able to waive the co-payment, but it was just another short-term fix to a longer-term problem.

Neither doctors nor medical students can solve a patient’s financial problems on the spot. Yet any one of us can be the first to detect a problem. If we’ve done the research, we can help patients get the assistance they need, or at least direct them to social workers, pharmacists and other members of the health care team who can. What we cannot do is fail to ask.

Marriage, Divorce and Separation with Anti-TNF Therapy

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This review article (Inflamm Bowel Dis 2014; 20: 757-66) examines the question of whether and when anti-tumor necrosis factor (anti-TNF) agents can be stopped in Crohn’s disease (CD) patients in remission.  This topic is particularly helpful since this comes up frequently in clinical practice.

As recently as a few years ago, one expert advised me that starting an anti-TNF agent (like infliximab or adalimumab) was like getting married.  Once you committed, you stayed in that relationship indefinitely.  Of course, it is well-known that individuals get divorced.  In medical terms, I guess that would be the equivalent of developing antibodies to the anti-TNF agent or other adverse reactions.  Switching from one anti-TNF to another would be equivalent to marital infidelity.

So what does this review article say about all of this?  The article examines nine studies with a little more than 500 patients.  “Current evidence suggests that a group of CD patients, possibly 30% to 40% in clinical remission while on IM (immunomodulators) and infliximab can stop the latter and maintain clinical remission for a relatively long interval.  It seems that, if followed long enough, virtually all patients (including those on IM) will eventually develop clinical recurrence.”

If tempted to separate but not divorce anti-TNF therapy, the authors recommend, in addition to clinical remission, “normal colonoscopy (and/or normal surrogate markers of disease activity) should be adopted as a criterion when stopping therapy and during follow-up….As of today, many authors do not recommend to routinely stop anti-TNF agents in patients responding to this therapy and in the absence of other issues.  Others propose to stop them after a minimum of 2 years of clinical and endoscopic remission or longer if only clinical remission can be documented…

If costs or other issues are present, we suggest to cautiously stop anti-TNF agents only in patients on combination therapy with profound (clinical, biochemical, and endoscopic) and long lasting (>1 year) remission and continuing the IM.  Such patients should be closely followed by serial determinations of fecal calprotectin and inflammatory indices, and the medication immediately restarted in the presence of a flare. When in doubt, colonoscopy should be performed.”

Take-home message: Most patients are better off staying married to their anti-TNF therapy.

Also noted: Inflamm Bowel Dis 2014; 20: 742-56.  Clinical Utility of Fecal Biomarkers for the Diagnosis and Management of Inflammatory Bowel Disease.  This is a useful review with 103 references.