What is Wrong with the Glimmer of “Precision Medicine”

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Several thought leaders, including Francis Collins, have heralded the age of “precision medicine.” A recent commentary provides compelling arguments why “enthusiasm is premature.”

The greatest problems we face in improving health care do not require precision medicine.

“In 2013, the National Research Council (NRC) and the Institute of Medicine (IOM) issued a bleak report on life expectancy and well-being in the United States.  Shorter Lives, Poorer Health documented the extent to which Americans were at a disadvantage at every stage of life compared with their counterparts in peer countries.”  Americans fared worse in all of the following:

  • Birth outcomes
  • Heart disease
  • Motor vehicle accidents
  • Violence
  • Sexually transmitted disease
  • Chronic lung disease

The NRC notes that “health is determined by far more than health care.”

Other points:

  • While the U.S. may have the most advanced healthcare in the world, the “whiz-bang technology just cannot fix what ails us.” (NY T-inequality-is-costing-the-us-on-social issues.html)
  • “Precision medicine itself may ultimately make critical contributions to a narrow set of conditions, but the challenge we face…entails…willingness to address certain persistent social realities”
  • “Our public investments in broad, cross-sectional efforts to minimize…foundational drivers of poor health as poverty…are pitifully few in comparison with those of other countries.”
  • Take-home message from authors: “We worry that an unstinting focus on precision medicine by trusted spokespeople for health is a mistake — and a distraction from the goal of producing a healthier population.”

My view: The challenges posed by the authors do seem monumentally greater than those facing the development of precision medicine.

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Here's a Book Where the Title May Be Misinterpreted

Here’s a Book Where the Title May Be Misinterpreted

 

Is It a Good Idea for Pregnant Mothers to Take Probiotics?

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A previous study has indicated that maternal probiotic administration was associated with a lower rate of atopic dermatitis.  The overall quality of evidence supporting this association is considered low.

A recent study (CK Dotterud et al. JPGN 2015; 61: 200-7) examined the effect on the intestinal microbiota in both mother and child following maternal perinatal probiotic supplementation. This randomized, double-blind trial examined the effect of probiotic administration (or placebo) from 36 weeks of gestation up to 3 months postnatally while breastfeeding. Stool microbiome was examined in both mother and child.

Key findings:

  • The changes in the infants microbiome were quite limited. “Only the Lactobacillus rhamnosus GG bacteria colonized the children at 10 days and at 3 months of age. There were no significant differences in the abundance of administered probiotic bacteria between the groups at 1 and 2 years of age.”

My take: We know very little about probiotics and their effects on the GI tract. We often do not even the basics: which strains? which dosage?  optimal timing/when to use?  Given the lack of persistent change in the infant’s microbiome, does administration to pregnant mothers really make any sense (outside of research endeavors)?

Disaccharidase Deficiencies in Recurrent Abdominal Pain

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Question for pediatric gastroenterologists (first poll I’ve placed in this blog): Do you think disaccharidases are needed routinely for patients with abdominal pain in the absence of bloating, or diarrhea?

A recent report indicated a high rate of disaccharidase deficiencies among children with recurrent abdominal pain. Here’s the abstract link: Disaccharidase Deficiencies in Children With Chronic Abdominal Pain (K El-Chammas, SE Williams, A Miranda. Published online before print July 9, 2015, doi: 10.1177/0148607115594675JPEN J Parenter Enteral Nutr July 9, 2015 0148607115594675).  Thanks to Kipp Ellsworth for this reference.

Here’s an excerpt:

Data on disaccharidase activity and histology of endoscopic biopsies were collected retrospectively. Only patients with normal histology were included in the study.

Results: A total of 203 pediatric patients with CAP were included. The mean (SD) age was 11.5 (3.1) years, and 32.5% were male. The percentages of abnormally low disaccharidase levels using the standard laboratory cutoffs were lactase, 37%; sucrase, 21%; glucoamylase, 25%; and palatinase, 8%. Thirty-nine percent of the patients with low lactase also had low sucrase, and 67% of the patients with low sucrase had low lactase…Also, no association was found between stool consistency, stool frequency, or location of pain and low disaccharidase activity.

My take: I am highly skeptical regarding these findings–see Twyman’s Law | gutsandgrowth. For sucrase deficiency, for example, this report represents an extraordinarily high rate of deficiency compared with previous reports. In addition, there are numerous errors which can occur in the handling of tissue specimens.  With regard to lactase deficiency, of course, this is common but having lactose intolerance does not prove causality with regard to abdominal pain.  Many physicians encourage families to see if there is a link between milk ingestion and GI symptoms to help determine if lactose intolerance is a likely contributor to stomach pain (before endoscopy). Stomach pain in the absence of milk ingestion is not due to lactose intolerance.

Before accepting these high rates, improved methodology (eg. control group and duplicating results) would be helpful.

Related blog post: Congenital Sucrase Isomaltase Deficiency

 

Lipid Testing: Why Screen and Fail to Act?

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There has been controversy regarding the American Academy of Pediatric recommendations on lipid screening and treatment, mainly because the guidelines propose earlier screening and more aggressive treatment than other guidelines, including guidelines from the American College of Cardiology and the American Heart Association.  However, according to a recent article (N Joyce et al. J Pediatr 2015; 167: 113-9), it does not appear that many children (8-20 years) are actually being treated.

The authors used commercial health plan data between 2004-2010 and collected data from more than 13 million children.  Only 665 were initiated on lipid lowering therapy which equates to an incidence rate of 2.6/100,000 person-years.

Rates of lipid lowering therapy were higher in those ≥15 years with odds ratio of 2.9 and much higher in those with a familial hypercholesterolemia (OR 165.2).

Take home message from authors: “our findings suggest lipid lowering therapy is underutilized in this population.”   It is likely that many who have undergone testing and who have abnormal lipids are not being treated.  If so, why bother testing?

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Helpful Review on Biliary Atresia

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Biliary atresia (BA) remains the leading cause of pediatric liver transplantation and a frequent cause of cholestasis in newborns.  A recent review (AG Feldman, CL Mack. JPGN 2015; 61: 167-75) provides a helpful update. The article begins with a review on pathogenesis, though this remains unknown and continues to be an area of speculation.

The section on evaluation includes a suggested diagnostic algorithm for neonatal cholestasis.  In short, for a 2 week old with jaundice , the authors recommend (STEP 1) fractionating the bilirubin.  The infant is considered cholestasis if the direct bilirubin is ≥1 mg/dL (if total bilirubin is <5 mg/dL) or if direct bilirubin ≥20% of total bilirubin (if total bilirubin is >5 mg/dL).

Among cholestatic infants, the authors recommend (STEP 2) next checking ultrasound and alpha-one antitrypsin (A1AT) (level & phenotype).  The text implies that the authors would check a GGTP.  While this is not in their algorithm, many would suggest checking urine reducing substances, coags, serum glucose, and consideration of sepsis evaluation; these tests can identify issues that are more urgent than identifying biliary atresia.

STEP 3: If U/S and A1AT, are not diagnostic, consider urine culture, urine reducing substances, urine succinylacetone, and additional infectious studies.

STEP 4: Proceed with liver biopsy. If findings of biliary atresia (eg. bile plugs, bile duct proliferation, portal fibrosis), proceed with intraoperative cholangiogram.

Other points:

  • “It is rare for an infant with BA to have a GGTP level <200 U/L.” If low GGTP, consider PFIC, inborn error of bile acid metabolism, and panhypopituitarism.
  • Extensive differential diagnosis table given ((Table 1)
  • “Late diagnosis of BA remains a problem in the United States. The average age of HPE [hepatoportoenterostomy] is 61 days and 44% of patients still undergo HPE after 60 days of life.”  The authors indicate a goal for HPE of taking place  at <45 days of life.
  • Successful HPE can occur even with late diagnosis. 10% to 20% of children who undergo HPE after 100 to 120 days of life still have success in restoring bile flow.”
  • Early/successful HPE is helpful in increasing 10-year transplant-free rate.  Early on, 3 months after HPE, those with a total bilirubin <2 mg/dL compared with those with a total bilirubin of >6 mg/dL have a much lower likelihood of liver transplantation by 2 years of age: 84% vs. 16%.
  • Recommends checking a pulse oximetry at routine followup visits following HPE to look for the possibility of hepatopulmonary syndrome.
  • The article reviews complications including ascites, portal hypertension/GI bleeding, cholangitis, malignancy, and hepatopulmonary syndrome/portopulmonary hypertension.
  • Outcomes: With HPE, “up to two-thirds of patients with BA have short-term clearance of jaundice.” Yet, “80% of patients with biliary atresia will require liver transplantation during childhood.”

Also noted:

“Biliary Atresia is Associated with Hypertension” JPGN 2015; 61: 182-86.

“Pathogenesis of biliary atresia: defining biology to understand clinical phenotypes” A Asai, A Miethke, JA Bezerra. Nat Rev Gastroenterol Hepatol 2015; 12: 343-52.  This review provides in-depth review examines more precise phenotyping, influencing factors (eg. cytomegalovirus), and potential mechanisms.

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From Mt Washburn, Yellowstone

From Mt Washburn, Yellowstone

Days of Future Past and Declining Liver Graft Quality

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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?

Related blog post: AASLD/NASPGHAN 2014 Guidelines for Evaluation of Pediatric …

Bison, Yellowstone

Bison, Yellowstone

Enteral Autonomy in Pediatric Intestinal Failure

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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

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FODMAPS Advice From Harvard

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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

 

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“Fat Report Cards” –Do They Help?

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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

Empire State Building

Hepatitis C : New and Newer Treatments

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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.

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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

Garden of the Gods, Colorado Springs