IFfy outcome

Posted on October 12, 2012 by gutsandgrowth

More long-term data on the outcome of intestinal failure (IF) are available (Squire RH et al. J Pediatr 2012; 161: 723-8).

A retrospective analysis of infants <12 months (n=272) who were receiving parenteral nutrition (PN) for more than 60 days was performed by the Pediatric Intestinal Failure Consortium (PIFCon). This study took place between January 2000-December 2007.

Key findings:

Etiologies: necrotizing enterocolitis (71, 26%), gastroschisis (44, 16%), atresia (27, 10%), volvulus (24, 9%), aganglionosis (11, 4%), other/multiple causes (94, 35%)
Residual small bowel length in 144 patients was 41 cm (25-65.5cm).
Catheter-related blood stream infections: 8.9 per 1000 catheter days. (Newer techniques like antibiotic & ethanol locks were not commonly used during study period.)
Enteral autonomy continued into 5th year after study entry & occurred in 47%. Of the 154 patients who were alive without transplant, 27 remained on PN at the completion of the study period. Of the patients who acheived enteral autonomy, this occurred in 31% of initial cohort at 12 months, 40% by 24 months, 44% by 36 months, and 47% at 60 months.
At 72 months, a high incidence of death, 27%, was noted in this cohort. 58 died without transplantation & 10 deaths occurred in patients after transplant. Sepsis was 2nd leading cause of death (after multisystem organ failure).
At 72 months, cumulative percentage of intestinal transplantation was 26%.

Previous related blog entries:

“It is never boring to be a physician”

Posted on October 11, 2012 by gutsandgrowth

…”because patients are so different. Each has a story to tell.” This is the beginning of an excellent editorial (NEJM 2012; 367: 1350-52). The editorial helps translate a study about “Phenotypic Heterogeneity” due to copy-number variants (NEJM 2012; 367: 1321-31). The study itself involved analyzing 32,587 samples from children with developmental delay. Ultimately, the study focused on 2312 children with 72 copy-number variants.

Both the study and the editorial try to explain why individuals with the same genetic defect have variability in the severity/expression. Some of the factors include environment, chance, and modifier genes. Due to the availability of relatively cheap and quick technology, one can sequence all of the 22,000 human genes. The techonology for this study used microarray-based comparative genomic hybridization to interogate the entire genome.

Copy-number variation refers to changes in the number of genes compared to normal. Typically, two gene copies are present. Thus, a deletion or duplications will result in copy-number variants.

In the aforementioned study, investigators found that large copy-number variants contributed to differences in outcomes. That is, persons with “the same chromosomal abnormality may have very different clinical outcomes” because they a have a second genetic event (copy-number variant elsewhere) that “makes matters worse for them.”

These copy-number variants contribute to learning disabilities. Large copy-number variants occur in less than 1% of the unaffected population but in 8.6% of children with learning disabilities. Males are m much more susceptible to have developmental delay due to these copy-number variants and unaffected women are more likely to transmit these copy-number variants. These gender differences are thought to be due to the fact that males have only a single X chromosome and are more vulnerable to genetic insults as a consequence.

Besides learning disabilities, copy-number variants have been implicated in well-known diseases such as schizophrenia, autism, cardiac disease, and epilepsy. In addition, well-defined syndromes, like Smith-Magenis syndrome, Williams-Beuren syndrome, Sotos syndrome, and MAPT (17q21.31) deletion syndrome, are also well-recognized as being associated with de novo copy-number variants.

It really is an exciting time to be a physician. Widely available genetic tests can finally explain a lot of previously unanswered questions.

Screening for subclinical PSC in IBD?

Posted on October 10, 2012 by gutsandgrowth

In children with IBD, elevated liver enzymes raise the concern for primary sclerosing cholangitis (PSC). PSC is thought to develop in up to 5% of patients with IBD. To look more closely at this issue, a group of investigators examined 73 children (median age 12 years) with IBD with MRCP to look for evidence of PSC (JPGN 2012; 55: 308-13).

The majority of these patients had an MRCP at the time of an MRE; this was ordered independently from specific laboratory or clinical factors. On average, the date for MRCP was about one year after the date of diagnosis. In this group, 49 (67%) had Crohn’s disease (CD), 19 (26%) had indeterminate colitis (IC), and 5 (6.8%) had ulcerative colitis (UC) [In the results section, the authors state a discrepancy from previous: 47 with CD, 18 with IC, and 8 with UC.]

11 (15%) children had PSC-type lesions identified by MRCP. 6 of these patients had CD, 3 had IC, and 2 had UC. Among the PSC group, 5 had abnormal AST & ALT, 4 had abnormal GGT, and 1 had abnormal bilirubin at time of diagnosis & similar numbers were present at the time of MRCP. A much lower percentage of the non-PSC group (n=62), had abnormal LFTs. Though, at time of MRCP, 9 (14.5%) had abnormal ALT.

An editorial in the same issue (page 238), concludes that “screening for PSC by MRCP in all of the newly diagnosed patients with IBD seems promising.” Really? Given a lack of therapeutic options, I don’t think identifying preclinical PSC makes any sense. An exception would be in patients with persistent liver test abnormalities to avoid attributing this to medication toxicity.

Previous RELATED BLOG ENTRies

Challenges with primary sclerosing cholangitis | gutsandgrowth

Colonic disease and PSC | gutsandgrowth

Additional reference:

-Hepatology 2009; 50: 808-14. High-dose ursodeoxycholic acid not effective for PSC (worsened outcomes noted)

“Immune-tolerant” — a misnomer for HBV infection

Posted on October 9, 2012 by gutsandgrowth

When hepatitis B virus (HBV) infection occurs in the perinatal period, often the result is high levels of HBV DNA yet immune-mediated damage of the infected liver is generally not observed and serum aminotransferases are normal. This phase of infection has been considered “immune-tolerant.” This phase can last for years or even decades. New data indicate that the during this phase, there is preserved T-cell function and there are indications of good immune function (Gastroenterol 2012; 143: 637-45, & editorial 529-32).

The authors of the study isolated T cells from different age groups of patients with chronic HBV infection. Then, they used flow cytometry methods to measure production of numerous cytokines. In addition, markers of T-cell exhaustion or inhibition were examined.

Key Finding: young patients had more specific HBV-specific T cells with the ability to proliferate and produce cytokines than adult patients.

The study itself is highly technical with graphs of cytokine profiles, quantitation of T-cell expressing exhaustion markers, dot plots, etc. Some of the figures are easy to understand like Figure 5 which plots the multifunctionality of HBV-specific response with three separate charts lined up; these correspond to “Immune tolerant,” “Chronic active,” and “Inactive carriers.”

The editorial is essential to understanding this study & restates the other findings:

“the authors found that T cells from CHB patients were more likely to produce TH1 cytokines …compared with those from healthy subjects”
they “found no global differences in this profile between tolerant and active states”
HBV-specific T-cell response: “a PD-1 high/CD127 low ‘exhausted’ phenotype were actually found to increase with age”
“T-cell responses to HBV core, envelope, and X proteins were readily observable in all patients”

The editorial speculates that so-called ‘tolerance’ may occur at a local/hepatic level, largely a ‘matter of sequestration.’ And, concludes that this study has “view-changing” observations. Ultimately, this may lead to therapeutic treatments aimed at the liver microenvironment & may change our opinion of the suitability of treating younger patients.

INSPPIRE for pancreatitis

Posted on October 8, 2012 by gutsandgrowth

While anyone who follows this blog knows that I like acronyms, I must say that many investigators have taken lessons from Krispy Kreme on spelling. INSPPIRE is named for the International Study Group of Pediatric Pancreatitis: In Search for a Cure. A study from this group reports on definitions of pediatric pancreatitis & surveys current practice (JPGN 2012; 55: 261-65).

The literature regarding acute recurrent pancreatitis and chronic pancreatitis in children is limited. This consortium hopes to change this. As a start, the authors assigned subcommittees to establish definitions, reviewed the literature, and assessed current practice.

Definitions:

Acute pancreatitis (AP): requires at least 2 of 3 criteria:

Abdominal pain consistent with AP
Serum amylase and/or lipase activity at least 3 times ULN
Imaging findings compatible with AP

Acute recurrent pancreatitis (ARP): requires at least two episodes of AP along with

Complete resolution of pain (≥ 1-month pain-free interval) OR complete normalization of pancreatic enzyme levels along with resolution of pain (can be shorter interval than 1 month)

Chronic pancreatitis (CP): requires one of the following:

Abdominal pain and imaging suggestive of chronic pancreatic damage
Exocrine pancreatic insufficiency and imaging suggestive of chronic pancreatic damage
Endocrine pancreatic insufficiency and imaging suggestive of chronic pancreatic damage
Surgical/histologic specimen consistent with chronic pancreatitis

Managing pancreatitis:

Typical tests for these three conditions are shown in figure 2 and vary widely. For AP, most respondents (63%) routinely checked liver enzymes, triglycerides, calcium and abdominal ultrasound. For ARP and CP, most respondents (69%) obtained additional imaging modalities (eg. MRCP), genetic testing, and sweat chloride. If ERCP was needed, 88% of practices relied on adult gastroenterology colleagues.

Related blog posts:

Recurrent pancreatitis and genetic underpinnings | gutsandgrowth

Does pancreas divisum cause pancreatitis? | gutsandgrowth

How helpful are antioxidants for chronic pancreatitis pain …

Coming soon –Fibroscan?

Posted on October 7, 2012 by gutsandgrowth

Transient elastography as measured by the Fibroscan device is used throughout the world, except notably in the U.S. That may change soon as an application is under review by the FDA (Gastroenterology & Hepatology 2012; 8: 605-7).

Fibroscan works by measuring shear wave velocity with a 50-MHz wave that is “passed into the liver from a small transducer on the end of an ultrasound probe.”
“The technology measures the velocity of the sound wave passing through the liver and then converts that measurement into a liver stiffness measurement.”
Takes 5-7 minutes to perform
Fibroscan is particularly reliable when showing either no fibrosis or advanced fibrosis. Less accuracy is noted with moderate fibrosis.
Technology can be augmented with noninvasive biomarkers of fibrosis
Not reliable in several groups: morbidly obese & patients with ascites

Additional references:

Am J Gastroenterol 2011; 106: 2121-22. Staging liver fibrosis for HCV
Gastroenterol 2005; 128: 343-50. Comparison of elastography, biomarkers, and liver biopsy for staging fibrosis

Preventing Type 2 Diabetes

Posted on October 6, 2012 by gutsandgrowth

A ‘perspective’ article reviews data from several studies that show the efficacy of medical treatments aimed at preventing type 2 diabetes (NEJM 2012; 367: 1177-79).

The Diabetes Prevention Program (DPP) was a comparative effectiveness trial of 3234 overweight or obese adults with impaired glucose tolerance (prediabetes). Findings from this study (published in 2002) showed that lifestyle intervention (attempts at weight loss through diet and exercise) reduced conversion to diabetes by 58% over 3 years, whereas metformin reduced this conversion by 31% over 2 years. Lifestyle intervention worked best in patients ≥ 60 years.

Subsequently, 88% of these subjects were enrolled in the 10-year outcome study (DPPOS). The lifestyle intervention group had a 31% 10-year reduction in diabetes compared with 18% for metformin.

The editorial points out that there have been efforts to expand these results across the country through CDC-sponsored programs in cooperation with the YMCA and UnitedHealth.

Potential roadblocks remain:

Most payers do not cover these preventive services.
US Preventive Services Task Force (USPSTF) has not issued a recommendation on these services. this affects both public and private insurance coverage.
Metformin which may be useful in younger populations does not have a specific indication for diabetes prevention from the FDA (off-label use only).

Whether prevention is ‘worth a pound of cure’ may be hard to discern with prediabetes. Since the peak incidence of diabetes is between 50 and 60 years and complications often emerge more than a decade later, the benefits of preventing diabetes may not be fully apparent for quite a long time.

Related blog entries:

Treating diabetes with surgery | gutsandgrowth

Lower leptin with physical activity | gutsandgrowth

Staggering cost of obesity | gutsandgrowth

Eliminating sweetened beverages to help obesity

Posted on October 5, 2012 by gutsandgrowth

For every difficult problem there’s a solution that’s simple, neat and wrong.–HL Mencken

Two studies from the New England Journal of Medicine, thus far (at the time of writing) published only online, shed some light on the difficult problem of consumption of sugar-sweetened beverages and its relationship to obesity:

A Trial of Sugar-free or Sugar-Sweetened Beverages and Body Weight in Children. Janne C. de Ruyter, M.Sc., et al. September 21, 2012DOI: 10.1056/NEJMoa1203034
A Randomized Trial of Sugar-Sweetened Beverages and Adolescent Body Weight. Cara B. Ebbeling, Ph.D., et al, September 21, 2012DOI: 10.1056/NEJMoa1203388

The first study was an 18-month double-blind, randomized, controlled trial with 641 primarily normal-weight children between 4-12 years of age; patients were recruited from elementary schools. Patients either received a sugar-free artificially sweetened beverage or a similar sugar-containing beverage, 8 oz per day at school. At 18 months, 74% continued consuming these beverages; among those remaining in the program, on average, they consumed 83% of the assigned 7 cans each week. Another marker of adherence was increased urinary sucralose in the sugar-free group (6.7 mg/L compared with 0.1 mg/L in the sugar group). Weight gain was less in the sugar-free group: 6.35 kg compared with 7.37 kg. Other measures of weight gain were less as well, including skinfold-thickness, waist-to-height ratio, and fat mass. It is also noted that in the U.S. the average consumption of sweetened beverages is three times the amount noted in this Dutch study.

The second study examined 224 overweight and obese adolescents who were randomly assigned into experimental and control groups. The experimental group received a 1-year intervention designed to decrease consumption of sugar-sweetened beverages; they were followed for an additional year afterwards. Retention rates were good: 93% at 2 years. To support the experimental group, sugar-free beverages were delivered to the house and the families received monthly motivational calls. In addition, patients had three check-in visits and written materials. The consumption of sugar-sweetened beverages declined in the experimental group from a baseline of 1.7 servings per day to nearly 0 at 1 year & remained lower at 2 years than the control group. The primary outcome, BMI, did not differ significantly between the two groups at 2 years nor did change in body fat percentage. (BMI did improve at 1 year, -0.57.) In the small number of Hispanic participants (n=27 in experimental group), there was a significant change in BMI at both 1 and 2 years.

While consumption of sugar-sweetened beverages have been considered to be more fattening than solid foods because they do not lead to a sense of satiety, it appears that restriction of these beverages by itself will not make a major dent in the problem of obesity.

Related blog posts:

NAFLD Guidelines 2012

Treating diabetes with surgery

Lower leptin with physical activity

Staggering cost of obesity

Psychology of obesity and food addiction

Weight of the Nation

Cardiovascular disease for the entire family

TODAY is worrisome for a lot of tomorrows

How helpful are antioxidants for chronic pancreatitis pain?

Posted on October 4, 2012 by gutsandgrowth

The ‘ANTICiPaTE’ study shows that antioxidants are not helpful in the typical patient with chronic pancreatitis (Gastroenterol 2012: 143: 655-63). While chronic pancreatitis is a rare problem for the pediatric population, I was drawn to this study because I had to see what the acronym stood for: ANTI-oxidant therapy for painful Chronic Pancreatitis Therapy Evaluation.

In brief, this study was a double-blind placebo-controlled single-center randomized trila of Antox version 1.2 in patients with painful chronic pancreatitis. The ingredients of this antioxidant included selenium, ascorbic acid, d-α-tocopherol and multiple secondary ingredients. Antioxidant levels were measured as well and did increase on study medication.

Results: after 6 months, pain scores were reduced by 1.97 from baseline in placebo group and 2.33 in the antioxidant group. The -0.36 difference was within the 95% confidence interval (-1.44 to 0.72). Quality of life measures were similar as well.

The discussion points out that the largest randomized study (Bhardwaj et al) found that antioxidants were effective in relieving pain in chronic pancreatitis. So why the discrepancy? Possible reasons:

1. Different populations: Bhardwaj study had a younger population: 31 years compared with 50 years in current study
2. Different etiologies: The Bhardwaj study had only 31% with alcoholic etiology for chronic pancreatitits compared with 72% in current study
3. Comorbid conditions: The Bhardwaj study had 28% smokers compared with 80% in current study
4. Antioxidant constituents differed
5. Chance

Take-home message: While there are notable differences between this study and the Bhardwaj study, the present study is more indicative of typical chronic pancreatitis patients in the U.S. and indicates that antioxidants are not effective in this population. For the pediatric population, the Bhardwaj study has more applicability; however, the present study diminishes optimism that antioxidants will be effective.

What are the alternatives? Both surgical and endoscopic treatments can be considered for chronic pancreatitis, though neither has consistently been effective at reducing pain.

Additional references:

-Bhardwaj P, et al. Gastroenterology 2009; 136: 149-59. Antioxidants for chronic pancreatitis pain. antioxidant included 600mcg selenium, 0.54g ascorbic acid
-Gastroenterol 2011; 141: 1690. Surgical Rx outperformed medical Rx. n=79. Only 5% of surgical pts needed more Rx. 47% of endoscopic pts eventually needed surgery, 68% of endoscopic pts had repeated procedures.
-NASPGHAN Postgraduate Course 2011: Exercise helpful in reducing pain/depression, coffee/green tea may help. Surgery (eg Puestow) -most commonly for pain —>75-80% good outcome. Rarely Frey procedure & investigational pancreatectomy (harvesting islet cells) -n=24 in Minnesota. May benefit from dual sphincterotomy -bilary/pancreatitic (33% improve) but increased complications (pancreatitis, cholangitis, restenosis)
-Am J Gastro 2010 105: 1884. –cleaning out ducts w ERCP-1/3rdimprove (some worsen)
-Clinical Gastro & Hep 2011; 9: 541. steatorrhea (w pancreatitis) typical adult dosing of pancreatic enzymes: 40,000-50,000 IU lipase/meal & 1/2 dose for snacks.
-Gastroenterol 2011; 141: 536. Pregabalin reduces pain in chronic pancreatitis -randomized control trial.

Related blog entries:

Does pancreas divisum cause pancreatitis?

Recurrent pancreatitis and genetic underpinnings

Pain changes brain

Picking the right diet for EoE

Posted on October 3, 2012 by gutsandgrowth

A study from Philadelphia/CHOP offers more insight into food selection diets for eosinophilic esophagitis (EoE) (Spergel JM, et al, J Allergy Clin Immunol 2012; 130: 461-7) –thanks to Seth Marcus for forwarding this article to my attention.

For this study, the authors examined their database of 1187 patients. While the data was collected prospectively, this was a retrospective study. Of this 1187, the authors excluded patients with proton pump inhibitor-responsive EoE (n=191) along with patients with more extensive eosinophilic GI diseases (n=55).

Among the remaining 941, the male-to-female ratio was 2.8:1 and the average age was 6.4 years. Concurrent atopic disorders were common: 64% had rhinitis, 50% had asthma, and 24% had atopic dermatitis. Only 18% had no atopic disorders.

The actual number for the study though was 319. Among the 941 noted above, 148 were receiving medications (n=130 for topical steroids), and causative foods were not identified in 474. In some of these patients, families were content to stick with a multiple food elimination without determining with certainty which foods were truly necessary.

In less than 5% of patients, a strict elemental diet was used. In this group, the population was younger (average 2.8 years). Biopsy improvement was noted in “upward of 98%.”

Key findings:

Elimination of foods based on combined skin prick tests (SPT)/atopy patch tests (APT) had an identical response to the six food group diet –53%. The allergy testing group had less eliminated foods (average 3.2 foods) compared with 8 food groups in SFED.
Elimination of milk with SPT/APT testing resulted in 77% response. Authors note that there was a “particularly high false-negative rate (34%)” with milk testing (SPT/APT).
Elimination of top 8 allergens: milk, soy, egg, wheat, and meats [chicken, turkey, pork, beef] had an identical response of 77%.
Elimination of milk, egg, and wheat had a success rate of 48%. Milk only elimination had a 30% response rate.
Most common foods by biopsy: milk (35%), egg (13%), wheat (12%), soy (9%), corn (6%)
Most common foods by symptoms: milk (19%), egg (11%), wheat (9%), soy (10%), beef (8%)
IgE-mediated foods: milk (10%), egg (17%), soy (4%), peanut (22%)

Additional useful information in the addendum of methods notes their technique for APT testing (which is not standardized across centers). The authors use 2 g of dry foods in 2 mL of isotonic saline solution for most foods; for milk, they use 3 g of powdered milk with 1 mL of isotonic saline. Then these mixtures are placed in aluminum cups (6- or 12-mm Finn chambers on Scanpore). These cups are placed on patient’s backs and removed at 48 hours and read at 72 hours.

In addition, for each food, their tables list predictive values (positive predictive value, negative predictive value, sensitivity, and specificity) for SPTs, and for APTs. Overall, the predictive values are quite variable and much different from the general population. For example, in the general population, the negative predictive value is essentially 100% for combination of SPT/APT.

Previous related blog entries: