Days of Future Past and Declining Liver Graft Quality

Posted on August 18, 2015 by gutsandgrowth

In the most recent ‘X-men’ movie (Days of Future Past), the disastrous future is averted by having Wolverine go back in time to correct a mistake. Overall, while there are a good number of movies that have used this trick, this particular movie is pretty clever. For whatever reason, this movie came to mind as I was reading a recent study: “Declining Liver Graft Quality Threatens the Future of Liver Transplantation in the United States” (ES Orman et al. Liver Transpl 2015; 21: 1040-50). The authors extrapolate data from UNOS to assess what the liver transplantation (LT) picture may look like in 2030. Their results/conclusion:

“If donor liver utilization practices remain constant, utilization will fall from 78% to 44% by 2030, resulting in 2230 fewer LTs.” “The transplant community will need to accept inferior grafts and potentially worse post transplant outcomes and/or develop new strategies for increasing organ donation.”

The authors note that the national epidemics of diabetes and obesity will result in more cases of NAFLD-related liver failure while at the same time worsen the quality of available grafts. In the associated editorial, (RH Wiesner, pages 1011-12) the author emphasizes that the future is not quite so set.

the prevalence of diabetes and obesity in donors for 2030 might not be as great as feared; in addition, medical/surgical advances may diminish the complications associated with obesity
there will be a marked decrease in transplants due to hepatitis C virus related cirrhosis and hepatocellular cancer

His conclusion: “in the future, we will be using donor livers that we have never used before and will be achieving similar excellent results as we have today.” Which vision of the liver transplantation future is correct?

Bison, Yellowstone

Enteral Autonomy in Pediatric Intestinal Failure

Posted on August 17, 2015 by gutsandgrowth

A recent study (FA Khan et al. J Pediatr 2015; 167: 29-34 -thanks to Mike Hart for forwarding this reference) provides data from a multicenter retrospective cohort of 272 infants. These infants had of IF were defined by requiring >60 days of PN; they were enrolled in the Pediatric Intestinal Failure Consortium. The median followup was 33.5 months. The most common etiologies of IF were necrotizing enterocolitis (NEC), gastroschisis, small bowel atresia, and volvulus. Key findings:

43% achieved enteral autonomy (EA), defined as freedom from PN for >3 months, 13% remained dependent on PN, and 43% had died, undergone intestinal transplantation, or both.
Infants with EA were more likely to have had NEC, preserved ileocecal valve, longer preserved small bowel length, and care at a non-transplant center (with retrospective study, high likelihood of a selection bias).

The associated editorial by Valeria Cohran (pages 6-8) notes that pediatric intestinal transplants peaked in frequency in 2007, but in 2014 there only 56 performed. She also notes that the care of these children with short bowel syndrome in the first year of life is approximately $500,000 ± $250,000! The improved survival is attributed to minimizing cholestasis with new lipid strategies, minimizing blood stream infections with better care and ethanol locks, and the use of autologous bowel reconstruction surgery. Bottomline: This study and several others show that meticulous care and advances in the treatment of intestinal failure improve the likelihood of survival without the need for intestinal transplantation. FULL CITATION: Khan FA et al. Predictors of enteral autonomy in children with intestinal failure: A multicenter cohort study. J Pediatr 2015 Jul; 167:29-34. [Free full-text J Pediatr article PDF | PubMed® abstract] Related blog posts:

These windows were huge -Grand Tetons in background

FODMAPS Advice From Harvard

Posted on August 16, 2015 by gutsandgrowth

A recent post from Harvard Health Publications offers a succinct explanation of a low FODMAPs diet for irritable bowel syndrome.

Here’s the link: Try a FODMAPs diet to manage irritable bowel syndrome

Related blog posts:

“Fat Report Cards” –Do They Help?

Posted on August 15, 2015 by gutsandgrowth

Probably not.

From NY Times: Body Report Cards Aren’t Influencing Arkansas Teenagers, Excerpt:

It is one of the boldest and most controversial tactics in the battle against childhood obesity: A growing number of schools are monitoring their students’ weight and sending updates home, much like report cards.

Ten states, including Ohio, Pennsylvania and Illinois, now require schools to send such notifications, sometimes called “B.M.I. letters,” or less charitably “fat letters.” But a new study of the first state to adopt the practice shows that the letters have had almost no effect, at least on older teenagers…

The Arkansas study by Dr. Gee looked at the B.M.I. results of juniors and seniors who had been evaluated and, after the 2007 legislative changes, those who had not. It found that students whose families had received the letters showed no appreciable improvement in B.M.I. scores after two years, compared with those who had not been screened. Another peer-reviewed study of such letters, a 2011 examination of younger students in California, had similar findings.

Empire State Building

Hepatitis C : New and Newer Treatments

Posted on August 14, 2015 by gutsandgrowth

A recent study (KR Reddy et al. Hepatology 2015; 62: 79-86) shows that the combination of ledipasvir/sofosbuvir is a safe, effective therapy for patients with genotype 1 Hepatitis C (HCV) and compensated cirrhosis.

The authors performed a post-hoc analysis of seven clinical trials in 513 treatment-naive and previously treated patients; 69% were previously treated. Key findings:

Overall, 493 (96%) achieved an SVR12; 98% of treatment-naive patients achieved an SVR12.
However, many patients in this analysis had received ribavirin. In those treated without ribavirin (ledipasvir/sofosbuvir alone), the SVR12 was 90%.
Most common adverse effects included headache (23%), fatigue (16-19%), and asthenia (14-16%).

Bottomline: While ledipasvir/sofosbuvir was effective in this population, the 90% SVR12 is not as good as 96%. This leads to the question of whether ribavirin is needed as well.

Related & briefly noted: SA Alqahtani et al. Hepatology 2015; 62: 25-30. Ledipasvir/sofosbuvir treatment (8-24 weeks) resulted in SVR of 97% (with or without ribavirin) among the 1952 patients treated in the ION-1, ION-2, and ION-3 studies.

Related blog posts:

From FDA (July 24th): FDA approves new treatment for chronic hepatitis C genotype 3 infections

“The U.S. Food and Drug Administration today approved Daklinza (daclatasvir) for use with sofosbuvir to treat hepatitis C virus (HCV) genotype 3 infections. Daklinza is the first drug that has demonstrated safety and efficacy to treat genotype 3 HCV infections without the need for co-administration of interferon or ribavirin, two FDA-approved drugs also used to treat HCV infection….

The safety and efficacy of Daklinza in combination with sofosbuvir were evaluated in a clinical trial of 152 treatment-naive and treatment-experienced participants with chronic HCV genotype 3 infection. Participants received Daklinza 60 mg plus sofosbuvir 400 mg once daily for 12 weeks and were monitored for 24 weeks post treatment. The studies were designed to measure whether a participant’s hepatitis C virus was no longer detected in the blood 12 weeks after finishing treatment (sustained virologic response), suggesting a participant’s infection had been cured.

Results showed that 98 percent of the treatment-naive participants with no cirrhosis of the liver and 58 percent of the treatment-naive participants with cirrhosis achieved sustained virologic response. Of the participants who were treatment-experienced, 92 percent with no cirrhosis of the liver and 69 percent with cirrhosis achieved sustained virologic response. Daklinza labeling carries a Limitations of Use statement to inform prescribers that sustained virologic response rates are reduced in HCV genotype 3 infected patients with cirrhosis.”

From FDA (July 24th): FDA approves Technivie for treatment of chronic hepatitis C genotype 4

“The U.S. Food and Drug Administration today approved Technivie (ombitasvir, paritaprevir and ritonavir) for use in combination with ribavirin for the treatment of hepatitis C virus (HCV) genotype 4 infections in patients without scarring and poor liver function (cirrhosis).

Technivie in combination with ribavirin is the first drug that has demonstrated safety and efficacy to treat genotype 4 HCV infections without the need for co-administration of interferon, an FDA-approved drug also used to treat HCV infection…

The safety and efficacy of Technivie with ribavirin were evaluated in a clinical trial of 135 participants with chronic HCV genotype 4 infections without cirrhosis. Ninety-one participants received Technivie with ribavirin once daily for 12 weeks. Forty-four participants received Technivie once daily without ribavirin for 12 weeks. The studies were designed to measure whether a participant’s hepatitis C virus was no longer detected in the blood 12 weeks after finishing treatment (sustained virologic response), suggesting a participant’s infection had been cured.

Results showed that 100 percent of the participants who received Technivie with ribavirin achieved a sustained virologic response. Of those who received Technivie without ribavirin, 91 percent achieved sustained virologic response.”

Garden of the Gods, Colorado Springs

What is Driving Racial Disparities in Access to Living Donor Liver Transplants

Posted on August 13, 2015 by gutsandgrowth

Recent articles highlight a huge gap in the availability of living donor liver transplants (LDLTs) when examined based on racial/ethnic background.

YR Nobel et al. Liver Transpl 2015; 21: 904-13.
A Doyle et al. Liver Transpl 2015; 21: 897-903.

What is the reason for this inequality?

The first study examined UNOS data from 2002-2014 among adult liver transplant recipients. Of 35,401 recipients, 2171 (6.1%) received a LDLT.

Key findings:

Cholestatic liver disease: When compared with white patients, the odds ratios of receiving LDLT were 0.35 for African American, 0.58 for Hispanic, and 0.11 for Asian.
Noncholestatic liver disease: When compared with white patients, the odds ratios of receiving LDLT were 0.53 for African American, 0.78 for Hispanic, and 0.45 for Asian.
LDLT recipients were more likely to have private insurance

The second study did not look at racial/ethnic background but instead focused on other recipient factors. Using a retrospective cohort of 491 consecutive patients, they determined that all of the following resulted in a lower likelihood of LDLT:

Single — OR 0.34
Divorced –OR 0.53
Immigrant — OR 0.38
Low income quintile — OR 0.44

Together these studies allow speculation on why there is such a disparity.

Financial costs, including lost wages, could preclude those with lower socioeconomic status from being available as donors
Distrust of donation system and/or fear of surgery

Bottomline: Racial/ethnic differences and financial resources are associated with significant access inequality to living donor liver transplantation.

Related blog posts:

Cascade Canyon, Grand Tetons

Low FODMAPs Diet in Pediatric Irritable Bowel

Posted on August 12, 2015 by gutsandgrowth

A low FODMAPs diet has been associated with clinical improvement in adults with irritable bowel syndrome and “gluten sensitivity” (see links below). Now, there is more data that this diet can be effective in the pediatric population (Chumpitazi BP, et al. Aliment Pharm Ther DOI: 10.1111/apt.13286. Article first published online: 24 JUN 2015 -Thanks to KT Park for this reference). In addition, this small study (n=33) tries to correlate changes in symptoms with changes in the gut microbiome. Interestingly, the dietary trials were only 48 hours.

From the methods: Following a 7-day baseline period, “we employed a randomised, double-blind, crossover study design. Subjects received either a low FODMAP or typical American childhood diet (TACD) for 48 h. After 48 h on the first assigned diet, they returned to their habitual diet for 5 days. Following this 5-day washout period, they were crossed over to the other intervention diet for 48 h.”

Here is the abstract and a link to the full text: Randomised clinical trial: gut microbiome biomarkers are associated with clinical response to a low FODMAP diet in children with the irritable bowel syndrome

Abstract:

Background

A low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) diet can ameliorate symptoms in adult irritable bowel syndrome (IBS) within 48 h.

Aim

To determine the efficacy of a low FODMAP diet in childhood IBS and whether gut microbial composition and/or metabolic capacity are associated with its efficacy.

Methods

In a double-blind, crossover trial, children with Rome III IBS completed a 1-week baseline period. They then were randomised to a low FODMAP diet or typical American childhood diet (TACD), followed by a 5-day washout period before crossing over to the other diet. GI symptoms were assessed with abdominal pain frequency being the primary outcome. Baseline gut microbial composition (16S rRNA sequencing) and metabolic capacity (PICRUSt) were determined. Metagenomic biomarker discovery (LEfSe) compared Responders (≥50% decrease in abdominal pain frequency on low FODMAP diet only) vs. Nonresponders (no improvement during either intervention).

Results

Thirty-three children completed the study. Less abdominal pain occurred during the low FODMAP diet vs. TACD [1.1 ± 0.2 (SEM) episodes/day vs. 1.7 ± 0.4, P < 0.05]. Compared to baseline (1.4 ± 0.2), children had fewer daily abdominal pain episodes during the low FODMAP diet (P < 0.01) but more episodes during the TACD (P < 0.01). Responders were enriched at baseline in taxa with known greater saccharolytic metabolic capacity (e.g. Bacteroides, Ruminococcaceae, Faecalibacterium prausnitzii) and three Kyoto Encyclopedia of Genes and Genomes orthologues, of which two relate to carbohydrate metabolism.

Conclusions

In childhood IBS, a low FODMAP diet decreases abdominal pain frequency. Gut microbiome biomarkers may be associated with low FODMAP diet efficacy.

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Baseball Broadcast with a Sense of Humor

Selective Data Mining: Reflux and Bronchopulmonary Dysplasia

Posted on August 11, 2015 by gutsandgrowth

With some studies, the abstract may suggest a more compelling result than is truly evident. That’s how I feel about a recent report (Nobile S, et al. J Pediatr 2015; 167: 279-85).

Here’s the conclusion (verbatim) from the abstract: “The increased number of (and sensitivity for) pH-only events among infants with BPD may be explained by several factors, including lower milk intake, impaired esophageal motility, and a peculiar autonomic nervous system response pattern.”

To me, it sounds like this prospective study of pH-multichannel intraluminal impedance (pH-MII) of 46 infants born ≤32 weeks gestation (12 with bronchopulmonary dysplasia (BPD) and 34 without BPD) must have identified something important linking gastroesophageal reflux disease (GERD) and BPD. But, the real findings, in my view, are that this is a negative study. Period.

Here are the results reported in the abstract:

“Infants with BPD…had increased numbers of pH-only events (median number 21 v 9) and a higher symptom symptom sensitivity index for pH-only events (9% vs. 4.9%)”
They also state: “the number and characteristics of acid, weakly acid, nonacid and gas gastroesophageal reflux events, acid exposure, esophageal clearance, and recorded symptoms did not significantly differ between the 2 groups.”

Here’s a little more data –not in the abstract:

The P value for the difference in pH-only events was .360
The authors could just have easily pointed out (in the abstract) that infants without BPD had increased acid exposure: 40.5 min compared with 27.0 min (P = .599)

What should have been in the abstract conclusion? Perhaps, the first line of their discussion: “Infants with BPD did not have significantly higher GER features compared with infants without BPD as measured by esophageal pH-MII monitoring, except for higher occurrence of pH-only events and higher SSI for pH-only events.”

The authors try to explain the differences in the BPD patients by highlighting some of the potential mechanisms of reflux and/or autonomic dysfunction. I think the limitations of this study deserve careful scrutiny. This was a small study with only 12 BPD infants. There was a significant selection bias -only ‘symptomatic’ infants were included. Some of the factors affecting BPD directly could have an indirect effect on reflux (eg. caffeine).

The authors make one other point: “we believe pharmacologic treatment for GER should be initiated only after the demonstration of pathologic pH-MII monitoring to avoid unnecessary drug therapy, adverse events, and costs.”

Related blog posts:

Grand Prismatic Spring, Yellowstone

“Negative Externality,” Splitting Checks, and Feeding Psychology

Posted on August 10, 2015 by gutsandgrowth

If you have a great psychology book that you recommend, please let me know. As frequent readers of this blog know, I am fascinated with psychology experiments.

In a recent blog from fivethirtyeight.com, the author tackles the question of whether people eat more when they know they are splitting a dinner check. Does it Make Sense to Split The Check at a Restaurant?

Here’s an excerpt:

In 2004, a study in The Economic Journal, a publication of the Royal Economic Society, …the researchers told four groups of diners (always three men and three women) to split the bill equally among them. They told another four groups to pay for what they had ordered. Lastly, they told two lucky groups that they would get their meals for free…

Those who were getting a free meal spent the most … Those who were splitting the bill spent less, and those who were paying individually spent the least…

Any time you make a decision that affects someone else without considering how it might affect that person, whether positively or negatively, you create an externality — it’s basically a fancy way of saying “indirect effect.” There are positive externalities (e.g. when you decide to get a flu shot, other people benefit) and negative externalities (e.g. when you decide to fart, other people suffer).

The unscrupulous diner’s dilemma reveals how negative externalities — and even the mere threat of negative externalities — affect our behavior. Participants in the bill-splitting experiment expected the others to order more, so they tried to maximize what they could get out of the situation by ordering more themselves.

Bottomline: It is fascinating to me how something as simple as splitting a bill may encourage someone to order a lot more.

Related blog posts:

How the Trans-Pacific Partnership Could Affect Health Outcomes

Posted on August 9, 2015 by gutsandgrowth

Generally, trade agreements are not something I scrutinize and typically have little to do with the medical field. Recently, I was surprised to learn that the Trans-Pacific Partnership (TPP) has language in its intellectual property chapter that could impact the lives of millions (A Kapczynski. NEJM 2015; 373: 201-3). The background for this story is that pharmaceutical companies want to have patent protection for their medications for as long as possible. This has a substantial impact on pricing. “For example, patents increase the annual cost of antiretroviral therapy from around $100 per person to $10,000 per person.”

Some countries, like India, have undermined patent protections. “India allows patents on new drugs but not on new uses of old drugs or new forms of known drugs that do not increase therapeutic efficacy.” Other countries have been following India’s lead. Even in the U.S., there are efforts to decrease data exclusivity, which prevents regulatory agencies like the FDA from registering a generic version of a drug.

“President Barack Obama’s fiscal year 2016 budget proposes rolling back the data exclusivity period for biologic drugs in the United States to 7 years from 12 years, yielding a projected savings of more than $4 billion over the next decade. In the TPP negotiations, however, the United States is proposing a 12-year term of exclusivity.”

Other potential concerns include both the elimination of a provision to use “competitive market-derived prices” and the potential for promoting foreign companies to sue TPP countries for millions of dollars in damages due to loss of profits.

Currently there are escalating drug prices, both with innovative new medications and well-established treatments. Even lifesaving cures are being rationed in the United States. While the TPP has not been finalized, there are provisions that could limit the United States from regulating “critical aspects of health policy for years to come.”

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Cascade Canyon, Grand Tetons