Category Archives: Gastroenterology

EPT for Achalasia

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EPT or esophageal pressure topography (using high-resolution manometry) can help predict outcomes for achalasia (Gastroenterol 2013; 144: 718-25, editorial 681-83).

Background:  Patients with achalasia often present with dysphagia, chest pain, and regurgitation.  These symptoms result from impaired lower esophageal sphincter relaxation and aperistalsis.  While the main treatment has focused on disruption of the sphincter, esophageal body pressures may be important in long-term outcomes.

Three patterns of esophageal body pressures with achalasia:

  • type 1 absence of peristalsis and minimal pressurization
  • type 2 absence of peristalsis with panesophageal pressurization (≥30 mm Hg)
  • type 3 evidence of spasm

According to the cited study which reviewed data from 176 patients in the European achalasia trial (time period: 2003-2008, 18-75 year old), success rates were better with type 2 achalasia (96%, n=114) compared with type 1 (81%, n=44) or type 3 (66%, n=18).

In addition, the EPT findings may influence treatment selection.  Pneumatic dilation (PD) was more successful than Heller myotomy (HM) for type 2 patients (100% vs. 93%, p < 0.05).  However, HM was considered successful more frequently for patients with type 3 achalasia (86% vs. 40% –though not statistically significant due to small numbers).  For type 1, no significant difference was noted between HM and PD at 2 year followup, 81% vs. 85% respectively.

The commentary discusses some of the pertinent issues.   For example, HM may be better than PD among type 1 patients; the exclusion of patients with severe dilatation of esophagus.

Take-home message (from editorial) “The task at hand is to determine whether these distinct categories truly matter in clinical practice…it seems that the subtypes of achalasia do have prognostic value…we …need to determine…whether subtypes can inform treatment options.”

Hemorrhoids and asstronauts

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A recent review on hemorrhoids (Clin Gastroenterol Hepatol 2013; 11: 593-603) had a few useful quotes:

“Why are hemorrhoids called hemorrhoids and asteroids called asteroids? Wouldn’t it make more sense if it was the other way around? But if that were true, then a proctologist would be an astronaut.”  Robert Schimmel

“My troubles are all behind me” George Brett (on returning to World Series after treatment for a thrombosed external hemorrhoid)

Besides the quotes, the review article provides a concise approach to the epidemiology, anatomy, pathophysiology, diagnosis, and management of hemorrhoids.

Specific points:

  • The word ‘Hemorrhoid’ is derived from the Greek words “haima” meaning blood and “rhoos” meaning flow.  The word “pile” is derived from the Latin word “pila” meaning a ball.
  • Conservative treatment: increasing fiber, avoidance of straining/minimizing time on toilet, and sitz baths several times per day.
  • “Well-designed studies have found no evidence to support the use of any of the myriad of over-the-counter topical preparations that contain low-dose local anesthetics, corticosteroids, keratolytics, protectants, or antiseptics.”  “Long-term use of these products, particularly steroid preparations, …should be discouraged.”
  • Rubber band ligation: “highly effective…in a meta-analysis of 18 prospective, randomized trials, RBL was overall superior to injection sclerotherapy or infrared coagulation in the treatment of grades I, II, and III (internal) hemorrhoids.”  “Risk of complications is low <1-3%, including pain, bleeding, and vasovagal symptoms.” Higher rates of pain are reported in some studies and may be dependent on location of RBL.
  • Cryosurgery and Lord’s procedure ..”have lost favor in the United States.”
  • Surgical treatment: “Nonsurgical approaches are successful in 80-99% of patients.” “Surgical hemorrhoidectomy is more effective than RBL in the treatment of grade III hemorrhoids but incurs additional complications, pain, and disability.”  Complications have included urinary retention, bleeding, infection, anal stenosis, and incontinence (2-12%)–Ouch!

Barrett’s Esophagus –refer to cardiology?

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According to a study which examined cause-specific mortality, patients with Barrett’s esophagus may be better off following up with a cardiologist than a gastroenterologist (Gastroenterol 2013; 144: 1375-83).

This study derived data from UK’s Clinical Practice Research Datalink.  8448 patients with Barrett’s esophagus were matched with 155,212 controls based on age, sex and general practice.

Key findings:

  • Patients with BE had increased risk of death from esophageal cancer leading to a 10-year risk of 1.9%.  The absolute mortality rate due to esophageal cancer was 1.44 per 1000 person-years.  Compared to the general population, this was a 4.5 fold relative increase.
  • Ischemic heart disease resulted in 168 patient deaths, nearly 4-fold the number that died of esophageal cancer.
  • Overall, individuals with Barrett’s esophagus had a 21% relative increased risk of all causes of death; the majority were not due to esophageal cancer.  32% were related to circulatory disorders, 24% were due to nonesophageal cancer, and 15% were due to respiratory disease.

While this was a large study, there remain several limitations; most of these are due to reliance on electronic records for the diagnosis of Barrett’s.  Also, some individuals with Barrett’s may have been identified due to other high risk conditions such as cirrhosis (endoscopy for varicose) which could contribute to excess mortality.  In addition, many controls likely had undiagnosed Barrett’s.  Even the attribution of the cause of death can be quite difficult, especially with a database study.

Nevertheless, the population-based setting likely means that the results are likely meaningful to a broad population.

Take-home message: While Barrett’s esophagus increases the risk of death from esophageal cancer, it is possible that strategies which focus on nonesophageal causes of death may be more effective than esophageal surveillance for increasing longevity.

Related blog entries:

What to Feed Your Baby

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“What to Feed Your Baby” — is the title of a recent, easy-to-read, practical book written by one of my colleagues, Stan Cohen.  I had the opportunity to read it and recommend it as an excellent resource for parents.  This book is not just for selecting formula and introducing foods, but it also reviews gastroesophageal reflux, colic, stooling problems, poor weight gain, overweight issues, prematurity, and allergies.  In addition, the subtitle, “Cost-Conscious Nutrition for Your Infant,” is an important element throughout the book.

The first few chapters highlight the advantages of breastfeeding but acknowledge that formula-feeding is an acceptable alternative.  Specific advantages that are outlined in Table 2.2 include decreased infections, decreased risk for several illnesses like sudden infant death syndrome (along with many others like diabetes and obesity), protection from allergies, and improved intelligence.  Advantages for the mother, like weight loss and better emotional health, are discussed as well.

Almost any question that a new mother would ask about the logistics of breastfeeding are answered in the 3rd chapter: “How long should each feeding be?” “Should I wake the baby?” “Do I need to stop if I have a cold?” “How long can the breastmilk be stored?”  The latter question has its own table 3.1 and the answer depends on the storage temperature.  At room temperature, covered breastmilk should be durable for 6-8 hours.  In addition, Dr. Cohen explains the need for vitamin D supplementation.

Chapters 4 and 5 help parents understand the highly marketed formulas and to understand a rationale for choosing one formula over another, including cost as a factor.  Dr. Cohen provides data on mean docosahexaenoic acid (DHA) content in breastmilk throughout the world.  In the U.S., the level is relatively low at 0.29 (as a percentage of fatty acids).  The breastmilk DHA level is nearly three times higher in Japan and Artic Canada.  These discrepancies account in part why formula companies may choose different target concentrations for some of their components when trying to mimic breastmilk.

While Dr. Cohen explains that some of the differences between formulas are akin to differences between Coke and Pepsi, he expresses a preference for the current Mead Johnson formula Enfamil Premium due to its higher DHA content –“though the research is not thoroughly established.”  However, he states that the differences probably do not justify a much higher cost.  For a generic brand, the Costco brand, “Kirkland Signature…are reasonable and less expensive, FDA-approved options.”

In addition, these chapters question whether infant organic formulas are truly organic (page 55), explain the issue of burping, and discuss the pragmatic advise regarding cleaning nipples/bottles; “kitchen clean” with soap and a washing with hot water should suffice and sterilization is not needed.

The most inciteful comments, in my opinion, are in chapter 5:

  • Lactose-free formulas: “Mead Johnson pulled its product from the market because lactose sensitivity is rare, rare, rare in infants…Abbott, in a shrewd marketing move, renamed its formula, originally called Lactofree, to Similac Sensitive, and that labeling has convinced an enormous number of mothers that this formula makes a difference.”  Similac Sensitive accounts for >10% of formula market.  A similar product is Gerber (previously Nestle) Good Start Soothe.
  • Elemental formulas: “cost as much as a monthly Porsche payment.”  Monthly costs of each type of formula are detailed in Table 5.3.  Routine cow’s milk based formula $149.88, soy-based $153.56, cow’s milk with rice starch $159.39, hydrolyzed (broken down protein) formula (e.g.. Alimentum, Nutramagen) $223.56, and elemental amino acid based $511.83.
  • Among extensively hydrolyzed formulas, Dr. Cohen indicates a preference for Alimentum (from Abbott) over its competitors due to better acceptance by infants.
  • The rationale for not switching from contracted WIC products is explained.  When changing from a contracted product to a non-contract product, the costs are much greater and among the same type of formula there is not a scientific rationale.
  • Reasons why goat’s milk are not a good choice and “dangerous” for infants are detailed.  “The protein content is over three times higher than cow’s milk…additionally, goat’s milk is deficient in folate and vitamin B6.”

As noted above, the book covers a variety of pediatric gastroenterology problems in the newborn.  As part of the chapter on undernutrition, additives to increase calories are detailed (pg 136).  For example, a tablespoon of polycose adds 23 cal, a tablespoon of rice cereal 15 cal, and  a tablespoon of vegetable oil 124 cal.

The last few chapters provide ample advice on transitioning to solid foods, reviews nutrients and mineral oils.  In addition, he provides growth charts (for full term, premature infants, and infants with Down syndrome) as well as tables on infant formula contents.

Take-home message: this is a terrific resource for parents to help understand the what, why and when of feeding their infant.  At the same time, the book provides advice on the most common pediatric gastroenterology problems of infancy like reflux, colic, stooling difficulties, allergies, and poor weight gain.

Book’s website and how to purchase:

http://www.what2feedyourbaby.com

To purchase the book:

Here is the link:

Reviews:

Other favorable reviews (http://what2feedyourbaby.com/reviews/) have come from influential pediatricians like Jay Berkelhammer and pediatric gastroenterologists like Jeff Hyams and Allan Walker.

“In this book, Dr. Stanley Cohen, a pediatric gastroenterologist and nutritionist with longstanding interest in infant nutrition, provides a practical and pragmatic approach to a major concern for new mothers, namely What to Feed Your Baby. ”

— Allan Walker, M.D., director, Division of Nutrition, Conrad Taff professor of pediatrics and nutrition, Harvard Medical School

Related blog entries:

Early Surgery for Acute Uncomplicated Cholecystitis

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Data in adults suggests that early surgery is the best approach for acute uncomplicated cholecystitis:

From the following link: Early cholecystectomy beats delayed in acute cholecystitis : Internal …: Acute cholecystitis patients fared significantly better with early rather than delayed laparoscopic cholecystectomy in the largest-ever randomized trial addressing surgical timing for this common condition.

Patients assigned to early cholecystectomy – that is, surgery within 24 hours of presentation to the hospital – had one-third the morbidity, markedly shorter hospital lengths of stay, and correspondingly lower hospital costs compared with patients who underwent surgery on day 7-45, according to Dr. Markus W. Buchler of Heidelberg (Ger.) University….

The optimal timing of surgical intervention in acute cholecystitis is a subject of long-standing controversy. The ACDC trial was conducted because in a Cochrane review of five smaller randomized trials totaling 451 acute cholecystitis patients, researchers concluded there was insufficient evidence to say which surgical strategy was best (Cochrane Database Syst. Rev. 2006 Oct 18;4:CD005440).

Dr. Buchler noted that surveys indicate many American surgeons prefer to delay laparoscopic cholecystectomy, while in Germany the surgical preference is for immediate surgery in patients with uncomplicated acute cholecystitis.

The ACDC trial involved 618 patients with uncomplicated acute cholecystitis who were placed on the same antibiotic – moxifloxacin – and randomized to early laparoscopic cholecystectomy or to delayed surgery on day 7-45. Pregnant patients were excluded from the trial, which was conducted at 35 European hospitals, including seven German university medical centers. All participating hospitals were staffed by surgical teams experienced in performing difficult laparoscopic cholecystectomies.

The primary endpoint was total morbidity within 75 days. This included cholangitis, pancreatitis, biliary leak, stroke, myocardial infarction, abscess, bleeding, peritonitis, infection, and renal failure. The rate was 11.6% in the early cholecystectomy group compared with 31.3% with delayed surgery. Among less challenging patients with an ASA score of 2 or less, the rates were 9.7% and 28.6%, respectively. Patients with an ASA score above 2 had an overall morbidity rate of 20% with early surgery compared with 47% with delayed laparoscopic cholecystectomy.

The rate of conversion to open surgery was 9.9% in the early laparoscopic cholecystectomy group and similar at 11.9% in the delayed surgery group…Total hospital stays averaged 5.4 days in the early surgery group compared with 10.0 days with delayed surgery. Mean total hospital costs calculated via the German DRG system were 2,919 euro in the early cholecystectomy group and 4,261 euro with delayed surgery.

Discussant Dr. Andrew L. Warshaw…“There’s no doubt in my mind that immediate cholecystectomy is superior in this patient population,” said Dr. Warshaw, professor and chairman of the department of surgery at Harvard Medical School, Boston.

Why Eliminating Gluten May Help Irritable Bowel Syndrome

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As noted in previous posts, gluten-free diets (GFDs) have become commonplace for individuals without celiac disease.  Clinically, subgroups of patients with irritable bowel syndrome (IBS) were noted to have gluten sensitivity.  But, these subgroups were difficult to define and the mechanisms of improvement with a GFD were purely speculative.  A new study identifies changes in the frequency of bowel habits and mucosal permeability associated with a GFD among diarrhea-predominant IBS patients (Gastroenterol 2013; 144: 903-11).

While the investigators conducted a trial of short duration (4 weeks) and only enrolled 45 patients, they completed a number of sophisticated studies.

Design: 45 patients were randomized into either a gluten-containing diet (GCD, n=22) or GFD (n=23).  In each group, there were 11 patients who were HLA-DQ2/8 positive.

Measurements:

  • Daily bowel frequency
  • Small bowel and colonic transit
  • Mucosal permeability using lactulose/mannitol excretion.  Lactulose is normally not absorbed except with increased permeability. Mannitol is passively absorbed throughout intestine.  Higher lactulose:mannitol ratio in urine reflects intestinal permeability.
  • Cytokine production
  • Rectosigmoid biopsies (from 28 patients) to analyze messenger RNA for tight junction proteins and immunohistochemical staining

Key Results:

  • Fewer bowel habits were noted in patients receiving GFD.  In this group, bowel habits decreased from ~2.6/day to 2/day.  This was significant compared with GCD group.  Furthermore, this effect was more pronounced among patients positive for HLA-DQ2 or HLA-DQ8.
  • There was no significant change in stool form or ease of passage between GFD and GCD groups.
  • GCD had increased small bowel permeability as shown by mannitol excretion and lactulose-to-mannitol ratio (specific #s Table 1). Again, this effect was more pronounced among patients positive for HLA-DQ2 or HLA-DQ8.
  • GCD group had a reduced mRNA expression of mucosal tight junction proteins.
  • GCD was not associated with significant effects on colonic transit, immunocyte activation, or altered histology (eg. increased intraepithelial lymphocytes, change in crypt:villus ratio).

The increased changes in HLA-DQ2/HLA-DQ8 suggest a role for adaptive immune response in mediating GCD effects on barrier function.

Conclusion: “our data provide mechanistic explanations for the observation that gluten withdrawal may improve patient symptoms in IBS.”

Related blog posts:

There must be a reason for intractable vomiting

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There are cases when patients are clearly ill and the potential explanations are quite unsatisfactory.  Most patients with intractable nausea and vomiting have a specific etiology for this.  A disorder, rarely seen by gastroenterologists, has been identified that provides a detailed reason for a few patients with an “idiopathic vomiting” diagnosis (Clin Gastroenterol Hepatol 2013; 11: 240-5).

The authors examined a database of patients who presented with vomiting for autoantibodies to aquaporin-4 (AQP4).

Background: These autoantibodies are sensitive and specific for neuromyelitis optica (NMO).  In fact, finding these autoantibodies in serum or spinal fluid allows distinction of NMO spectrum disorders (NMOSDs) from multiple sclerosis.

In patients with NMOSDs, there are typical brain MRI findings in AQP4-enriched areas, including the fourth ventricle floor which contains the chemosenisitve nausea and vomiting center (area postrema).  AQP4 is the principal water channel in the central nervous system.

Design: The authors reviewed their database of 70 NMOSD patients to determine how many presented with vomiting.  In addition, they tested serum samples from patients who presented with idiopathic nausea and vomiting for AQP4-IgG from the gastroparesis research registry.  This included 318 patients with gastroparesis and 117 patients without gastroparesis.

Results:  Ten patients (14% of NMOSD database) presented with intractable vomiting. The youngest patient in this group was 26 years old.  All of these patients had a noncyclic pattern of vomiting.  Four had associated hiccups.  No control patients from the gastroparesis database was identified as having AQP4-IgG.

Why this is important: Early diagnosis allows initiation of immunosuppressant therapy which may modify the disease course. AQP4-IgG positivity predicts a high likelihood of relapsing attacks of optic neuritis and transverse myelitis.

And the Best Prep is…

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A meta-analysis has concluded that a 4-Liter split-dose polyethylene glycol prep is best (Clin Gastroenterol Hepatol 2012; 10: 1225-1231).  This is an expected finding and has been discussed previously on this blog (see below).

What is unexpected is the tremendous heterogeneity in studies of bowel preparations. For this study, the investigators identified 1123 potentially relevant references.  Almost all of these were excluded due to criteria which required 1) randomized control trial, 2) English-based language, and 3) specific study design issues.  Thus 9 studies with 2477 patients met inclusion criteria.  Mean age of patients in these studies were 52-59 years.

The pooled odds for excellent or good bowel prep quality for 4-L split-dose PEG was 3.46 compared with other methods.  The comparison regimens included non-split dose PEG, 2-L split-dose PEG, 3-L split dose PEG, Miralax preps (64 oz split dose with or without stimulants).

While the prep results were generally more favorable, there were no differences in other adverse effects, such as cramping, compliance, or overall experience.

Related blog entry:

  • split-dose PEG | gutsandgrowth This blog entry discusses a specific prep, describes the Ottawa scale, and provides additional references. In addition, includes a link to Dave Barry’s column on colonoscopy.

AGA Constipation Guidelines

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Constipation is a ubiquitous problem.  Updated guidelines and a technical review for adults with constipation have been published (Gastroenterol 2013; 144: 211-17, Gastroenterol 2013; 144: 218-38). AGA Institute Policy and Position Statements – Gastroenterology …

For pediatric gastroenterologists, the 2006 NASPGHAN guidelines (Evaluation and Treatment of Constipation – North American Soci) are more useful.  Nevertheless, these AGA guidelines offer some helpful insights.

Definition: “physicians often regard constipation to be synonymous with infrequent bowel movements, typically fewer than 3 per week, patients have a broader set of symptoms” that are considered constipation including hard stools, abdominal discomfort, incomplete evacuation, and excessive straining.  Rome  III criteria: “symptoms for ≥ 6 months and ≥ 2 of the following symptoms for more than one-fourth of defecations during the past 3 months: straining, lumpy or hard stools, sensation of incomplete evacuation, sensation of anorectal obstruction, manual maneuvers to facilitate defecations; ❤ defecations/wk, loose stools are not present and there are insufficient criteria for IBS”

In adults, medical testing:

  • “In the absence of other symptoms and signs, only a complete blood count is necessary.”  Not needed unless other features: TSH, calcium, colonoscopy
  • Anorectal manometry and rectal balloon expulsion should be performed in patients who fail to respond to laxatives.  Defocography should be considered subsequently.  Colonic transit should be evaluated if anorectal test results do not show a defecatory disorder.

Recommended Treatment:

  • Start with increased fiber and laxatives (e.g. PEG, milk of magnesia, bisacodyl).  Newer pharmaceutical agents (e.g. lubiprostone and linaclotide) can be considered if no improvement.
  • Both “normal transit constipation and slow transit constipation can be safely managed with long-term use of laxatives.” (strong recommendation, moderate-quality evidence).  “Contrary to earlier studies, stimulant laxatives (senna, bisacodyl) do not appear to damage the enteric nervous system.  Neurologic damage might just as readily be the cause, not the result.”
  • Pelvic floor retraining by biofeedback rather than laxatives is recommended for defecatory disorders
  • Additional workup in those who do not respond.  Surgical treatment of slow transit constipation (subtotal colectomy or colectomy with ileorectal anastomosis) only when well-documented failure of aggressive prolonged laxatives/prokinetics

The technical review has a table that lists medications associated with constipation, describes pathophysiology in detail, lists the conditions associated with constipation, and explains the testing/medical management in-depth.

Related blog entries:

PEG vs. Fiber for constipation | gutsandgrowth
Stimulants for constipation | gutsandgrowth
It’s worth the cost | gutsandgrowth
ACE report -10 year effectiveness | gutsandgrowth
Linaclotide –not for kids | gutsandgrowth
Clues about constipation and more than 2.5 million … – gutsandgrowth

T-cell therapy for Crohn’s disease

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Data from the Crohn’s and Treg Cells Study (CATS1) are very preliminary but indicate that administration of antigen-specific T-regulatory cells (Tregs) to refractory Crohn’s disease (CD) patients could be effective (Gastroenterol 2012; 143: 1207-17).  Tregs are specialized subpopulations of T-cells.

In this study, the investigators, performed a 12-week open-label multicenter single injections study of 20 patients with refractory CD.  After withdrawing blood from patients, mononuclear cells were isolated and cultured.  Subsequently, T cells were cloned.  A specific subset with high IL-10/IL-13 production and low IL-4 production were selected.

Key findings:

  • 8 of 20 (40%) patients had a CDAI reponse at 5 and 8 weeks.  This was associated with a reduction in serum CRP and a trend of decreasing fecal calprotectin.
  • Remission was noted in 3 patients at week 5 and in 2 patients at week 8.
  • Overall, regardless of dose used, the safety profile was “in line” with severe active refractory CD.  Gastrointestinal adverse events were common.  7 patients had CD flares. One patient died due to suicide.

To understand this study more fully, an accompanying editorial is in the same issue (pages 1135-38).  A more complete discussion of the function of Treg cells is given, included their physiologic role of patrolling the gut lamina propia for antigens ‘derived from food and commensal flora.’  Circulating Treg cells may be deficient in IBD patients and thus contribute to the pathogenesis.

While injecting Treg cells may become a useful therapy, other ways of boosting Treg cells may be enhanced as an alternative.  Currently, granulocyte colony-stimulating factor (GCSF), anti-TNFα agents, and IL-2 all have the potential to enhance Treg cell function.  This supports the editorial’s conclusion that ‘Treg cells are rapidly moving from the bench to the bedside.’

Given the experimentation with stem cell therapy and bone marrow transplantation for CD, Treg cells show promise of a much more targeted effect on the immune system.

Additional references:

  • -Blood 2010; 116:6123-32.  Autologus stem cell transplantation in patients with refractory CD.
  • -Gut 2008; 57: 211-17.  Autologus stem cell transplantation for refractory CD.
  • -Gut 2010; 59: 1662-69.  Mesenchymal stromal cell treatment for luminal Crohn’s.