When Will MRI Obviate the Need for a Liver Biopsy in Pediatric NAFLD?

Posted on July 14, 2015 by gutsandgrowth

A recent study (JB Schwimmer et al. Hepatology 2015; 1887-95, editorial Vos MB, pages 1779-80) examines the accuracy of magnetic resonance imaging (MRI) compared with liver histology in children with nonalcoholic fatty liver disease.

This prospective validation study enrolled 174 children with a mean age of 14 years. The MRI estimated the liver proton density fat fraction (PDFF).

Key findings:

Liver MRI-PDFF correlated with steatosis grade; the correlation was particularly strong at high and low end values. Thus, a very low MRI-PDFF was highly likely to predict a steatosis grade 0 or 1 while a very high value corresponded to high steatosis levels.
Liver MRI-PDFF was weaker in children with stage 2-4 fibrosis than in children with no fibrosis

The editorial notes that this study “is one of hundreds now published in the literature on MRI and NAFLD…The superiority of MR-based methods…over ultrasound is clear. The question is why are we still ordering abdominal ultrasounds to diagnose NAFLD in children?” The barriers for usage of MRI include cost, potential sedation, and nonuniform methods for MRI usage.

The paper conclude that “MRI is not yet sufficient to replace liver biopsy in children.” The editorial also indicates that the MRI era is fast approaching but not viable today.

Take-home point: Due to the huge numbers of patients with pediatric NAFLD, MRI remains a terrific area for research but remains problematic in clinical practice. Given the expense of MRI, until its use can reduce liver biopsies or improve management, its role is likely to remain limited.

Turner Field

Genetically Modified Humans: Genome Editing 101

Posted on July 13, 2015 by gutsandgrowth

In a review at last year’s NASPGHAN meeting, John Barnard gave a basic science review (Basic Science Year in Review -#NASPGHAN 2014 | gutsandgrowth) that touched on CRISPR-Cas9 for genome engineering (Cell 2014; 157: 1262-78). Reading through a recent editorial (Lander ES. NEJM 2015; 373: 5-7), it seems that the potential for genome editing is not that far from landing into clinical use.

His points:

Genome editing holds great therapeutic promise…

“physicians might edit a patient’s immune cells to delete the CCR5 gene, conferring the resistance to HIV carried by the 1% of the U.S. population.”
“Editing blood stem cells might cure sickle cell anemia and hemophilia.”
Eliminate genes which increase the risk for Alzheimer’s, Huntingdon’s disease and heart attacks

Concerns:

“Genetically modified humans” and true “designer babies”
Technical issues to perform editing with precision.
Unanticipated effects with various edits. “We remain terrible at predicting the consequences of even simple genetic modification.”
Who decides? Future generations cannot consent to their modification.
Is it morally right? “Would the ‘best’ genomes go to the most privileged?”

In the U.S., genome editing would not garner approval from FDA or NIH in the near future. But, given the advancing technical capabilities, it is not too early to begin the discussion about genome editing. At the very least, this technology should spurn a couple great sci-fi movies.

Take-home point: “Authorizing scientists to make permanent changes to the DNA of our species is a decision that should require broad societal understanding and consent…We should exercise great caution before we rewrite” the human genome.

Zoo Atlanta (Kinda looks like a genetically-modified giraffe)

Not Thirsty for Water

Posted on July 12, 2015 by gutsandgrowth

As noted in several previous posts (see below), many kids (and adults) would likely benefit from increased water consumption. The pervasiveness of this problem was recently discussed in a recent (June 11th) USA Today article (“Researchers to kids: drink more water”), though experts disagree on whether mild water deficits are detrimental.

Here’s an excerpt:

The study, published Thursday by the American Journal of Public Health, found 54.5% of children ages 6 to 19 inadequately hydrated, at least by the standard set in the study.

The findings, based on one-time urine samples from more than 4,000 children, do not mean most children are seriously dehydrated…

The researchers considered a child inadequately hydrated if the concentration reached a level other studies have linked to sluggish thinking and mood changes.

They found boys and black children were more likely than girls and children of other races to have highly concentrated urine…

But … some experts …say most people can judge their fluid needs by thirst alone – and that fluids can come from any drink and many foods…

The study showed 22% of children drank no water.

Related blog posts:

Will Infliximab Worsen Flare-ups Associated with Cytomegalovirus Infection?

Posted on July 11, 2015 by gutsandgrowth

Another look (Pillet S, et al. Inflamm Bowel Dis 2015; 21: 1580-86) at Cytomegalovirus (CMV) infection in patients with ulcerative colitis (UC) examines 109 flareups in 73 patients who were receiving maintenance therapy with anti-TNF therapy.

This was a single-center prospective observational study. CMV load was determined with PCR based on a pair of biopsies. DNA load was either undetectable, mild (10-250 copies/mg of tissue) or high (>250 copies/mg of tissue). 69 patients with anti-TNF therapy were compared with 40 patients receiving azathioprine. Key findings:

CMV reactivation was noted in 35% of anti-TNF therapy patients and 38% in azathioprine patients.
Among 45 patients requiring infliximab optimization, clinical remission was not significantly impacted by the presence of CMV reactivation.
17 of 20 who had repeat biopsies 8 weeks later had stable or decreased CMV load.

Bottomline: This prospective, small study shows that “in patients with moderate-to-severe UC, treatment with anti-TNF mab does not increase the risk of colonic CMV infection.” In addition, “no adverse influence of CMV colonic infection was observed in patients with flare-up treated by anti-TNF mabs.”

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.

Zoo Atlanta

Utility of Antiviral Therapy for Cytomegalovirus in the Setting of Inflammatory Bowel Disease

Posted on July 10, 2015 by gutsandgrowth

According to a recent study (Jones A et al. Clin Gastroenterol Hepatol 2015; 13: 949-55), the tissue density of cytomegalovirus (CMV) is an important determinant of antiviral response in patients with inflammatory bowel disease (IBD).

In this case-control study, the authors identified 68 samples from 1111 patients with IBD that were found to contain CMV. Adequate data was available for 50, including 16 with high-grade CMV (all treated) and 34 with low-grade CMV (20 treated). High-grade CMV was defined as biopsies with 5 or more inclusions. Treatment included ganciclovir, valganciclovir or both; 33 of 36 treated patients received at least 21 days of therapy.

Key findings:

Patients with high-grade CMV showed significant benefit from treatment: they had the best outcomes with “only 33% undergoing surgery by 1 year after biopsy.”
All patients with low-grade CMV, treated or not, were more likely to undergo surgery than those with high-grade CMV, with HR of 2.13. However, the treated low-grade CMV had a lower risk of surgery (HR 0.39) compared with the untreated group. 73% of the untreated low-grade CMV group had undergone resection by 1 year after biopsy.

The authors note the many limitations of the study. Requests to rule out CMV were not done uniformly but “usually reflected refractoriness of steroids or failure to respond to escalation of therapy.”

Bottomline: In those with high-grade CMV, the likelihood of responding to antiviral therapy was much higher than in patients with low-grade CMV; however, treatment in all patients with CMV inclusions was associated with improved outcomes.

Another Way of Preventing Recurrent Clostridium Difficile

Posted on July 9, 2015 by gutsandgrowth

I frequently tell families that Clostridium difficile is the ‘Forrest Gump’ of bacteria; it tends to do well when its competitors are decimated. One of the problems with Clostridium difficile infection (CDI) has been recurrence. This occurs in part because after treatment of CDI the microbiota of the host remains vulnerable to recurrence. This has been one of the rationales behind the use of probiotics. However, probiotics have not been very effective. As such, more research has been directed in this area. This includes a recent study (Gerding DN et al. JAMA 2015; 313: 1719-27) which showed that administration of spores of nontoxigenic Clostridium difficile can prevent recurrent CDI.

While fecal microbiota transplantation (FMT) has been very effective in treating CDI, there is definitely a yuck factor. In addition, more targeted therapy is desirable. In this study, the authors enrolled 173 patients (157 completed treatment) at 44 study centers as part of a phase 2, randomized, double-blind placebo-controlled, dose-ranging study. After completion of antibiotics (metronidazole or vancomycin), participants received 1 of 4 treatments with a nontoxigenic C difficile strain M3 (NTCD-M3).

Key findings:

Recurrence of CDI were reported in 14 (11%) of NTCD-M3 patients compared with 13 (30%) placebo patients.
69% of NTCD-M3 patients were colonized. Recurrence in this group (n=86) occurred in 2 (2%) compared with 12 (31%) of NTCD-M3 non-colonized patients.
Fewer adverse events were noted in NTCD-M3 group compared with placebo patients with serious events occurring in 3% and 7% respectively.

Bottomline: These nontoxigenic oral spores of NCTD-M3 were well-tolerated and significantly reduced the risk of recurrent CDI.

Related blog posts:

Dollars for Doctors

Posted on July 8, 2015 by gutsandgrowth

A recent NPR report, Industry Payments To Doctors Are Ingrained, Federal Data Show, provides a link detailing payments by drug and device companies to U.S. doctors and teaching hospitals. Doctors may be paid for promotional speaking, consulting, travel expenses, and meals.

If you want to see how much is reported for each doctor, check out the ProPublica Dollars for Doctors database.

Here’s a screenshot:

The article notes that the a close relationship between doctors and pharmaceutical companies is important. “Collaboration between physicians and biopharmaceutical professionals is critical to improving the health and quality of life of patients.”

Take-home point: Some financial relationships between doctors and pharmaceutical companies lead to important improvements in drug (or device) development; other relationships may alter prescribing habits without apparent patient benefit. Will this information empower patients to ask why their physicians has close ties to the pharmaceutical industry?

Related blog post:

Marketing to Doctors -Informative Satire | gutsandgrowth

Point of Care -Mobile, Anywhere, Cheap EKGs

Posted on July 7, 2015 by gutsandgrowth

Note: This blog and author do not have any financial disclosures or receive any support from any companies.

Using a smartphone app, AliveCor has developed the technology to obtain a limited EKG (ECG) for a minimal cost; after an initial investment of $74.99, this technology can function similar to a standard EKG machine but only provides one lead (V1).

From the AliveCor website (thanks to Larry Saripkin for showing me this):

The FDA-cleared AliveCor Mobile ECG wirelessly communicates with the free AliveECG app, available in the U.S. App Store and Google Play Store. ECGs are stored in the app and on secure, encrypted servers that can be viewed anytime, anywhere. ECGs can also be printed or e-mailed directly from your smartphone or tablet, and you can grant access to your physician.

Do I have to attach the Mobile ECG to my smartphone or tablet? That is our recommendation, however, you may use the Mobile ECG within 12 inches of your smartphone or tablet if you’d like….

Simply rest it on your fingers or chest to record an ECG in just 30 seconds. Know right away when your ECG is normal and if atrial fibrillation is detected.

Potential Uses:

Detect atrial fibrillation
Correlate symptoms like palpitations and shortness of breath
Accurately assess heart rate
?Assess for QT interval -this could be particularly useful to pediatric gastroenterologists

While many of the uses may be self-evident, the website offers ECG review by a U.S. board-certified Cardiologist, with an average turnaround time of 24 hours. The current price of this service is $12.

Bottomline: This is another example of how new technology improves clinical information and at the same time should be less expensive and more timely.

Related blog posts:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) and use of new technology 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.

Sign at Children’s Healthcare of Atlanta

Generation R Study: Insights into the Effects of Anti-Tissue Transglutaminase Antibody Positivity

Posted on July 6, 2015 by gutsandgrowth

In a study from Rotterdam (Jansen MAE, et al. Clin Gastroenterol Hepatol 2015; 13: 913-20), the authors show that positivity for anti-tissue transglutaminase IgA antibodies (TTG) is associated with lower growth trajectories and bone mineral density.

This was a population-based prospective cohort study which examined children born from 2002-2006 (median age 6 years). 4249 children with TTG <7 U/mL were compared with 57 children with TTG >7 U/mL. The authors specifically looked at those >70 U/mL as well. Children with a previous diagnosis of celiac disease were excluded.

Key findings:

Positive TTG serology was associated with reduced weight gain 0.05 standard deviation score (SDS) per year and less linear growth 0.02 SDS/year.
Children with positive TTG were shorter 0.29 SDS and weighed less 0.38 SDS.
Children with positive TTG had lower bone mineral density (BMD) 0.26 SDS less.
Children with positive TTG did not have increased gastrointestinal symptoms compared with control children.

The authors note that the majority of these effects (poor growth, shortness, lower BMD) were mostly present in children with TTG >10 times upper limit of normal.

Bottomline: Subclinical or potential celiac disease is associated with reduced growth and bone mineral density.

Briefly noted: Emilsson L, et al. Clin Gastroenterol Hepatol 2015; 13: 921-27. Using a Norwegian cohort study with 95,200 women and 114,500 children (199-2008), the authors showed that development of celiac disease was associated with maternal celiac disease and type 1 diabetes. There was no significant association noted with intrauterine growth, or mode of delivery.

Related blog posts:

Cumberland Island

Critique of the 21st Century Cures Act

Posted on July 5, 2015 by gutsandgrowth

The most compelling article (Avorn J, Kesselheim AS. NEJM 2015; 372: 2473-5) in a recent edition of the NEJM delved into the 21st Century Cures Act which was recently introduced in the U.S. House of Representatives; it was approved 51 to 0 in committee but continues to be debated.

One of the underlying premises of the bill is accelerate approval for new products. Key features:

Increase in National Institutes of Health (NIH) of about 3% per year for 3 years. And, additional $2 billion per year for 5 years to create an “NIH Innovation Fund”
Instructs FDA to consider nontraditional study designs for clinical trials. This is aimed at shorter, smaller and less expensive studies. This could allow FDA to rely on “observational studies” and “clinical experience.”
The bill encourages the FDA to rely more on surrogate end points
The bill would allow informed consent to be bypassed if the “proposed testing poses no more than minimal risk.”

Critiques for each point, point by point:

1. The funding increases largely counterbalance stagnating funds at the NIH secondary to sequestration and budget cuts.

2. The premise that the FDA is inefficient is not accurate.

“A third of new drugs are currently approved on the basis of a single pivotal trial” with a median of 760 patients.
Most drugs are approved based on studies with a duration of 6 months or less, even medications taken for a lifetime.
Evaluation of nearly all new drug applications is completed within 6 to 10 months.

3. Surrogate markers often overestimate the potential benefit of medications. The FDA “already uses surrogate end points in about half of new drug approvals.” Specific examples:

Bevacizumab has been shown to delay tumor progression in breast cancer “but was shown not to benefit patients.
Rosiglitazone “lowered glycated hemoglobin levels in patients with diabetes even as it increased their risk of myocardial infarction.”
One new tuberculosis drug improved bacterial counts in the sputum but “the treatment group had a death rate four times that in the comparison group.”

4. Informed consent has been “sacrosanct, with exceptions made only when consent is impossible or contrary to a patient’s best interests.” With this new proposal, “it is not clear who gets to determine whether a given trial of a new drug poses “minimal risk.”

Bottomline (from authors): The 21st Century Cures Act’s call for increased NIH funding may prove to be its most useful component. But political forces…could lead to the approval of drugs and devices that are less safe or effective than existing criteria would permit.”

Audio interview with Jerry Avorn: nej.md/1TPy6Ta

Some pictures from yesterday’s Peachtree Road Race:

Coveted T-shirt -2015 Edition

Rainy Day for a 10K

Largest 10K in the World