New Mutations: Achalasia, Pseudoobstruction, & IBD

The ability to use whole exome sequencing and widely available genetic testing is yielding a plethora of new information regarding the genetic causes for many conditions.  In gastroenterology, here are a few recent examples:

  • Shteyer E, et al. “Truncating mutation in the nitric oxide synthase 1 gene is associated with infantile achalasia.” Gastroenterology. 2015 Mar;148(3):533-536.e4. doi: 10.1053/j.gastro.2014.11.044. Epub 2014 Dec 3.
  • Bonora E, et al. “Mutations in RAD21 Disrupt Regulation of APOB in Patients with Chronic Intestinal Pseudo-Obstruction” Gastroenterology 2015; 148: 771-82.  Genetic defect in RAD21 identified in Turkish family with consanguinity; in addition, APOB48 serum levels was identified as a potential biomarker for intestinal pseudo-obstruction and intestinal ganglion numbers.
  • Alonso A, et al. “Identification of Loci for Crohn’s Disease Phenotypes Using a Genome-Wide Association Study.” Gastroenterology 2015; 148: 794-805. Variants in MAG11, CLCA2, 2q24.1, LY75 identified as associated with Crohn’s phenotypes.

For me, I am not sure whether these findings should be considered mundane or amazing. On the one hand, each of the findings helps understand these diseases; yet, I came across all of these articles in the span of 24 hours and from the same journal.

Reaching Consensus on Bariatric Intervention in Children and Adolescents

A recent medical position paper (Nobili V, et al. JPGN 2015; 60: 550-61) provides guidance for bariatric surgery intervention in children and adolescents with and without nonalcoholic fatty liver disease (NAFLD).

While the authors acknowledge that bariatric surgery can “dramatically reduce the risk of adulthood obesity and obesity-related diseases,” they advocate its use in adolescents with the following:

  • BMI >40 kg/m-squared with severe comorbidities: type 2 diabetes mellitus, moderate-to-severe sleep apnea, pseudotumor cerebri, or NASH with advanced fibrosis (ISHAK score >1)
  • BMI >50 kg/m-squared with mild comorbidities: hypertension, dyslipidemia, psychological distress, gastroesophageal reflux, anthropathies, NASH, impairment in activities of daily living, mild obstructive sleep apnea, panniculitis, chronic venous insufficiency, urinary incontinence
  • Additional criteria: have attained 95% of adult stature, failed behavioral/medical treatments, psychological evaluation perioperatively, avoid pregnancy for 1 year after surgery, will adhere to nutritional guidelines after surgery, informed assent from teenager (along with parental consent)

Key points:

  • “There is a lack of randomized controlled trials examining the effects of bariatric surgery on NAFLD or NASH.”  In Table 3, the authors provide a summary of 16 previous studies/outcomes; though none of the studies enrolled more than 60 patients.
  • In an adult prospective study with 381 patients (Mathurin P et al. Gastroenterol 2009; 137: 532-40), there was a significant decline in the severity/prevalence of steatosis and resolution of NASH at 1 and 5 years.
  • Bariatric surgery, in adult studies, have improved diabetes, insulin resistance, hypertension, and dyslipidemia.
  • Patients who have “undergone bariatric surgery show higher suicide rates than the general population.”  Psychological evaluation should be integrated with surgical decision.
  • Type of surgery: Roux-en-Y Gastric Bypass (RYGB) is favored by the authors; they also discuss studies with Laparoscopic Adjustable Gastric Banding (LAGB).  “RYGB and LAGB are the 2 main surgical procedures that have been used in pediatric obesity.  RYGB is considered a safe and effective option for adolescents with extreme obesity, as long as appropriate long-term follow-up is provided. LAGB has not been approved by Food and Drug Administration for use in adolescents, and there should be considered investigational only.”

It is interesting that the authors are so deferential to the Food and Drug Administration.  It is clear from their position paper that LAGB has similar evidence supporting its use in adolescents as RYGB.  They even note that it has potential for reversibility and “an excellent safety profile with a lower risk of postoperative vitamin deficiencies when compared with biliopancreatic diversion and RYGB.”

Bottomline: Given the continuation of the obesity epidemic, additional pediatric medical expertise will be needed to help evaluate adolescents for bariatric surgery and to follow them postoperatively.

Related blog posts:

The Costs of Unnecessary Care –What’s Wrong with “I want everything ruled out?”

A great article for understanding a lot of what needs to be improved in our health care system –“America’s Epidemic of Unnecessary Care” from Atul Gawande & The New Yorker (Thanks to Kayla Lewis for this reference).  Here are some excerpts:

Well, as a doctor, I am far more concerned about doing too little than doing too much. It’s the scan, the test, the operation that I should have done that sticks with me—sometimes for years…It is different, however, when I think about my experience as a patient or a family member.

 

Dr. Gawande describes several anecdotes:

  • He relates how his mother had unnecessary testing done and only afterwards was a history and physical completed that would have obviated the need for any testing.
  • He relates a story about his friend Bruce. Bruce’s father had a stroke during cardiac surgery. However, the likelihood of that surgery helping Bruce’s father was much lower than the risk of surgery.
  • Ray from Car Talk: Even reputable professionals with the best intentions tend toward overkill, he said. To illustrate the point, he, too, had a medical story to tell. Eight months earlier, he’d torn a meniscus in his knee doing lunges…Ray went for a second opinion, to a physical therapist, who, of course, favored physical therapy, just as the surgeon favored surgery. Ray chose physical therapy.  What Ray recommended to his car-owning listeners was the approach that he adopted as a patient—caveat emptor. He did his research. He made informed choices. He tried to be a virtuous patient.

Other Important Points:

  • The virtuous patient is up against long odds, however. One major problem is what economists call information asymmetry. In 1963, Kenneth Arrow, who went on to win the Nobel Prize in Economics, demonstrated the severe disadvantages that buyers have when they know less about a good than the seller does.
  • The United States is a country of three hundred million people who annually undergo around fifteen million nuclear medicine scans, a hundred million CT and MRI scans, and almost ten billion laboratory tests. Often, these are fishing expeditions, and since no one is perfectly normal you tend to find a lot of fish.
  • What’s more, the value of any test depends on how likely you are to be having a significant problem in the first place…Experts recommend against doing electrocardiograms on healthy people, but millions are done each year, anyway.
  • Overtesting has also created a new, unanticipated problem: overdiagnosis. This isn’t misdiagnosis—the erroneous diagnosis of a disease. This is the correct diagnosis of a disease that is never going to bother you in your lifetime. 

Dr. Gawande explains how some conditions (including cancers) are more like turtles and some are more like rabbits. Diagnosing a turtle results in increased risk, increased cost and little likelihood of benefit.

  • With regard to cost, he updates the situation in McAllen, Tx: Six years ago, in “The Cost Conundrum,” I compared McAllen with another Texas border town, El Paso. They had the same demographics—the same levels of severe poverty, poor health, illegal immigration—but El Paso had half the per-capita Medicare costs and the same or better results…McAllen, in large part because of changes led by primary-care doctors, has gone from a cautionary tale to something more hopeful.

Take-home point (from article): Right now, we’re so wildly over the boundary line in the other direction that it’s hard to see how we could accept leaving health care the way it is. Waste is not just consuming a third of health-care spending; it’s costing people’s lives. As long as a more thoughtful, more measured style of medicine keeps improving outcomes, change should be easy to cheer for. Still, when it’s your turn to sit across from a doctor, in the white glare of a clinic, with your back aching, or your head throbbing, or a scan showing some small possible abnormality, what are you going to fear more—the prospect of doing too little or of doing too much?

Related blog posts:

Weight Loss Improves NASH

A recent study (http://dx.doi.org/10.1053/j.gastro.2015.04.005) helps confirm the notion that the most effective therapy for nonalcoholic steatohepatitis is weight loss. (From Rohit Kohli twitter feed).

Abstract:

Background & Aims

It is not clear how weight loss affects histologic features of liver in patients with nonalcoholic steatohepatitis (NASH). We examined the association between the magnitude of weight loss through lifestyle modifications and changes in histologic features of NASH.

Methods

We conducted a prospective study of 293 patients with histologically proven NASH who were encouraged to adopt recommended lifestyle changes to reduce their weight over 52 weeks, from June 2009 through May 2013, at a tertiary medical center in Havana, Cuba. Liver biopsies were collected when the study began and at week 52 of the diet, and analyzed histologically.

Results

Paired liver biopsies were available from 261 patients. Among 293 patients who underwent lifestyle changes for 52 weeks, 72 (25%) achieved resolution of steatohepatitis, 38 (47%) had reductions in NAFLD activity scores (NAS), and 56 (19%) had regression of fibrosis. At week 52, 88 subjects (30%) had lost 5% or more of their weight. Degree of weight loss was independently associated with improvements in all NASH-related histological parameters (odds ratios, 1.1–2.0;P<.01). A higher proportion of subjects with 5% weight loss or more had NASH resolution (51/88, 58%) and a 2-pt reduction in NAS (72/88, 82%) than subjects that lost less than 5% of their weight (P<.001). All patients who lost 10% of their weight or more had reductions NAS, 90% had resolution of NASH, and 45% had regression of fibrosis. All patients who lost 7%−10% of their weight and had few risk factors also had reduced NAS. In patients with baseline characteristics that included female sex, body mass index ≥35, fasting glucose >5.5 mmol/L, and many ballooned cells, NAS scores decreased significantly with weight reductions of 10% or more.

Conclusions

A greater extent of weight loss, induced by lifestyle changes, is associated with the level of improvement in histologic features of NASH. The highest rates of NAS reduction, NASH resolution, and fibrosis regression occurred in patients with weight losses of 10% or more.

Hard-to-Treat Shigella Infections

From the CDC (4/2/15): Multidrug-resistant Shigellosis Spreading in the U.S.

International travelers are bringing a multidrug-resistant intestinal illness to the United States and spreading it to others who have not traveled, according to a report released today by the Centers for Disease Control and Prevention (CDC). Shigella sonnei bacteria resistant to the antibiotic ciprofloxacin sickened 243 people in 32 states and Puerto Rico between May 2014 and February 2015…

In the United States, most Shigella is already resistant to the antibiotics ampicillin and trimethoprim/sulfamethoxazole. Globally, Shigella resistance to Cipro is increasing…

Until recently, Cipro resistance has occurred in just 2 percent of Shigella infections tested in the United States, but was found in 90 percent of samples tested in the recent clusters.

Because Cipro-resistant Shigella is spreading, CDC recommends doctors use lab tests to determine which antibiotics will effectively treat shigellosis. Doctors and patients should consider carefully whether an infection requires antibiotics at all…

For more information on Shigella, please visit: www.cdc.gov/shigella.

Travelers can learn more about food and water precautions to prevent Shigella at: http://wwwnc.cdc.gov/travel/yellowbook/2014/chapter-2-the-pre-travel-consultation/food-and-water-precautions.

To view the full MMWR report, please click here.

Related blog posts:

Sandy Springs

Sandy Springs

Brains and Bowels: Kids with IBD Do Fine in School

Screen Shot 2015-05-04 at 8.11.32 PM

A recent study (Singh H, et al. J Pediatr 2015; 166: 1128-33) showed that overall academic performance was not affected for children with inflammatory bowel disease (IBD).

Study characteristics:

University of Manitoba Database IBD population (n=337) was matched by age, sex, and area of residence to 10 randomly selected controls (n=3093).

Key findings:

  • There were no significant differences in the 2 groups in standardized scores or enrollment in grade 12
  • Lower socioeconomic status and diagnosis with a mental health problem (6-month before or after IBD diagnosis) were independent predictors of worse outcomes

Akin to the quote above, I’ve often felt that it is difficult to think clearly when having severe bowel dysfunction.  At the same time, some of our patients accomplish so much despite their physical setbacks.

Bottomline: This study provides reassurance that children with IBD should be able to complete their course work.

Chicago

Chicago

 

Tackling Crohn’s Perianal Fistulizing Disease

I am fortunate to work closely with several well-qualified pediatric surgeons and colorectal surgeons.  When faced with perianal fistulas, I have discussions with them to help optimize therapy.  Understanding exactly what and why the surgeons do what they do has not always been clear to me.  Four recent articles provide guidelines for the management of Crohn’s perianal disease.  The color figures in the articles make understanding what is done pretty obvious.

  • Schwartz DA et al. Inflamm Bowel Dis 2015; 21: 723-30. Overview.
  • Ong EMW et al. Inflamm Bowel Dis 2015; 21: 731-36. Focus on imaging.
  • Schwartz DA et al. Inflamm Bowel Dis 2015; 21: 737-52. Critical evaluation of Medications
  • Fichera A, Zoccali M. Inflamm Bowel Dis 2015; 21: 753-58. Critical evaluation of Surgical Approaches

The first guideline provides a summary statement combining aspects of both medical and surgical management.  Basic anatomy and classification are reviewed (a color figure similar to reproduction below helps describe the types of fistula).

Simple vs Complex fistula is reviewed.  A “Simple fistula is a superficial, intersphincteric or low transspincteric fistula that has only 1 opening and is not associated with an abscess and/or does not connect to an adjacent structure such as the vagina or bladder.”  All others are complex fistulas.  The MRI classifcation is also reviewed (Figure 5).

Other points:

  • For fistulizing disease, top-down cotherapy (anti-TNF/immunomodulator) therapy is recommended.  Antibiotics are recommended in the short term.
  • Placement of a draining seton (for complex fistulas) helps to maintain fistula drainage until the track becomes inactive on medical treatment.
  • A treatment algorithm (Figure 7) notes that endoscopy, imaging (EUS or MRI) and exam under anesthesia are key first steps.  Decision tree then divides based on whether there is rectal inflammation, and whether fistula is simple or complex.
  • Surgical options include fistulotomy, fibrin glue, fistula plug, seton placement, advancement flaps and proctectomy.

Bottomline: These set of articles should serve as a useful reference when managing perianal disease.

Related blog posts:

 

 

 

Clindamycin or Trimethoprim-Sulfamethoxazole for skin infections?

It turns out that both clindamycin and trimethoprim-sulfamethoxazole are good choices for uncomplicated skin infections (NEJM 2015; 372: 1093-103).

In this prospective, randomized trial with 524 patients (children and adults), outpatients with uncomplicated skin infections (cellulitis and abscesses) were treated with either clindamycin or trimethoprim-sulfamethoxazole (TMP-SMX) for 10 days.  Abscesses underwent initial incision and drainage.  Both groups had a similar rate of MRSA: 31.8% and 31.9% respectively.

Key findings:

  • The proportion of patients cured was similar in both groups.  Among those with adequate followup, 89.5% of clindamycin group were cured compared with 88.2% of TMP-SMX.
  • Adverse effects were similar as well.  Diarrhea was the most common adverse event and occurred in 9.7% and 10.1% respectively.

Limitations: trial excluded patients with serious coexisting conditions, involved only outpatients, and followup was for 1 month.

The associated editorial (pg 1164-65) suggests that the design of the study may obscure the likelihood that TMP-SMX might be preferred for empirical treatment of skin abscess (if I&D alone is insufficient) and that clindamycin might be more effective for cellulitis.

Take-home point: With the changes in skin infections, including MRSA, this trial indicates that both clindamycin and TMP-SMX are good options for treating uncomplicated skin infections.

Commentary from NEJM Journal Watch, by Larry Baddour, Chair, Division of Infectious Diseases at Mayo Clinic College of Medicine:  “For most patients, however, β-lactam antibiotics with activity against β-hemolytic streptococci and S. aureus (e.g., cephalexin or dicloxacillin) remain the first-line empirical treatment options for nonpurulent cellulitis. Epidemiologic and host factors, however, should continue to influence this decision.”

Nutrition Imbalance for Ventilated Children

A recent study documents a high rate of nutritional problems among a prospective cohort of 20 children on home ventilators and documents a metabolic assessment aimed at improving these problems (Martinez EE, et al. J Pediatr 2015; 166: 350-7, ed 228-29).

In these children the authors did careful nutritional assessment with anthropometry, bioelectrical impedance analysis (BIA), actual energy intake (AEI), and indirect calorimetry in the subject’s home. Indirect calorimetry was used to calculate a measured energy expenditure (MEE).

Indirect calorimetry allows measurement of energy expenditure: (From NASPGHAN Foundation N2U Course 2012, Praveen Goday: “Energy and Protein Metabolism”)

  • “When carbohydrate, protein, and fat are oxidized, oxygen is consumed and carbon dioxide is produced.”
  • “If oxygen consumption and carbon dioxide production can be measured, the energy released in the course of the utilization of these gases (or the energy expenditure can be determined.”
  • “The techniques is referred to as indirect, because gas exchange does not actually measure heat production.”

Key findings:

  • 13 were either underfed (AEI:MEE <90%) or overfed (AEI:MEE >110%)
  • 11 of 19 had suboptimal protein intake
  • 15 subjects were hypo or hypermetabolic

The authors conclude that a “majority of children on home ventilation are characterized by malnutrition, altered metabolic status, and suboptimal macronutrient intake” (especially low protein intake).  The discussion lists many of the study limitations: small number, discrepancies between some of their measuring tools, lack of long-term followup, lack of widespread availability of mobile indirect calorimetry, diverse comorbidities, and reliance of 3-day food records. In addition, the indirect calorimetry must be properly calibrated, performed when patient at baseline state, and feedings held (if on bolus feeds).

Although I think this study makes some important points, I think the ‘high-tech’ approach is overemphasized.  It would be interesting to see how (if at all) these interventions would improve a child who is followed closely by a nutritionist and a GI physician.  While precise measurement of resting energy expenditure, when performed properly, is informative, I think this information is much less helpful than serial basic measurements.

At the same time, there are many limitations on optimal nutrition in these children.  The mobility problems of many kids on home ventilators can make gaining weight problematic for care providers.  It is not practical for all caregivers to manage a 60 kg adolescent.

Recent advice from N2U () regarding children who were tube-fed/wheelchair-bound:

  • In children older than 10 years, if they are receiving 6 cans/day of commercial formula product, they are likely receiving adequate nutrients.
  • In children younger than 10 years, if if they are receiving 4 cans/day of commercial formula product, they are likely receiving adequate nutrients.
  • The newer reduced calorie formulas make it easier to provide adequate nutrients without excessive calories
  • Avoid obesity in these children.  Losing weight can be very difficult in this population.

Bottomline: Children on ventilators often are too heavy or too thin and need to be followed closely.  Whether indirect calorimetry is useful in this regard is not clear to me.

Briefly noted: A high nutrient diet appears to help treat fatigue (Nutrients 20157(3), 1965-1977).  From abstract (thanks to Kipp Ellsworth): A group of 98 children (2–18 years old) with unexplained symptoms of fatigue was examined. Children in the intervention group were asked to follow the diet for three months, whereas the control-group followed their normal diet.  The dietary modifications consisted of green vegetables, beef, whole milk and full-fat butter.

From NPR: Empathy Cards “Please Let Me Be the First to Punch the Next Person Who Says Everything Happens for a Reason”

What’s More Important: Improving Mortality Rate or Survival Rate? (Hint: It is not a trick question)

A recent commentary by Aaron E. Carroll in the NY Times explains “Why Survival Rate is Not the Best Way to Judge Cancer Spending.”  If you don’t understand the difference between survival rate and mortality rate, then it is worth a quick read; it explains the concept of “lead-time bias” and “overdiagnosis bias.” Here’s an excerpt:

Mortality rates are determined by taking the number of people who die of a certain cause in a year and dividing it by the total number of people in a population…

Survival rates describe the number of people who live a certain length of time after a diagnosis…

Let’s consider a hypothetical illness, thumb cancer. We have no method to detect the disease other than feeling a lump. From that moment, everyone lives about four years with our best therapy. Therefore, the five-year survival rate for thumb cancer is effectively zero, because within five years of detection, everyone dies.

Now, let’s assume that we develop a new scanner that can detect thumb cancer five years earlier. We prevent no more deaths, mind you, because our therapy hasn’t improved. Everyone now dies nine years after detection instead of four. The five-year survival rate is now 100 percent.