Category Archives: Gastroenterology

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.

UVA Links

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My alma mater, the University of Virginia, has a fair amount of useful GI educational material on their website.

Here are a few links:

Low FODMAP Diet

Irritable Bowel Syndrome (IBS) diet

Short Bowel Syndrome Diet (Long Version)

Nutritional Considerations for Patients with Inflammatory Bowel Disease

Fiber (dietary recommendations handout)

Gluten-free Diet

Transfusion strategy in acute GI bleeding

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A recent study shows that holding off on blood transfusions can improve survival with severe acute upper gastrointestingal bleeidng (NEJM 2013; 368: 11-21).  This finding is not unexpected as this has been shown in observational studies.  In addition, in critical care patients without acute GI bleeding, a restrictive approach to transfusions has also been beneficial.

This study which enrolled 921 patients (>18 years) assigned 461 to a restrictive transfusion strategy (transfusion if <7 g/dL or at discretion of physician) and 460 to a “liberal” strategy (transfusion if <9 g/dL).

In additon to fewer transfusions, the restrictive group had improved survival:

  • 225 in the restrictive group did not require a blood transfusion compared with 65 in the liberal group
  • Survival at 6 weeks: 95% in the restrictive group compared with 91% in the liberal group.  Hazard ratio 0.55 (confidence interval 0.33 to 0.92) –a 45% reduction in the relative risk of 45-day mortality.
  • Recurrent bleeding occurred in 10% of the restrictive group compared with 16% of the liberal group.
  • The patients with cirrhosis (and Child-Pugh class A or B) were most likely to benefit from a restrictive approach with hazard ratio of 0.30.  Child-Pugh class C did not have a benefit from a restrictive approach with hazard ratio of 1.04.  With the liberal approach, there was a higher portal-pressure gradient within the first five days.

The reasons for bleeding in this study included peptic ulcers in about 50%, and varices in 24%.  The other causes included Mallory-Weiss tears, erosisve gastritis/esophagitis, and neoplasms.

Why does giving less blood result in better outcomes?

  1. Transfusion may impair hemostasis in several ways.  It may result in abnormalities in coagulation properties.  It may counteract splanchnic vasoconstrictive response.  And, in those with cirrhosis, it can increase portal pressure (even in the presence of somatostatin).  All of these mechanims may increase rebleeding.
  2. In addition, systemic effects from transfusion can include circulatory overload and pulmonary edema.

Also (unrelated to this posting), a thoughtful comment to a recent post on FDA regulations was posted by Ben Gold (Can the FDA prohibit free speech? | gutsandgrowth).

Related blog references:

Belching, Hiccups and Aerophagia

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A useful review (Clin Gastroenterol Hepatol 2013; 11: 6-12) provides information on these clinical problems.

Belching or eructation can be divided into gastric belches which are normal and supragastric belching.  Supragastric belching which is a behavior (not a reflex), is often provoked by stress.  Air does not originate from the stomach or air swallowing (aerophagia).  The most common mechanism: a contraction of the diaphragm causes negative pressure in the chest and allows air to be suctioned into the esophagus.  It is expelled subsequently as a belch.  In some instances, it can occur up to 20 times a minute.  Supragastric belching does not occur during sleep and usually does not occur during speaking.

A clinical diagnosis usually is sufficient, though esophageal impedance can document these events as well.

Management:

  1. Explain physiology to patient
  2. Consider psychiatric evaluation when appropriate
  3. Glottis training by qualified speech therapist –needs to be aware of mechanism (that belching is not due to aerophagia).
  4. Alternative treatment could include cognitive behavior therapy, baclofen, hypnosis or biofeedback

Hiccups (singultus) are abnormal if lasting more than 48 hours.

Hiccups (at least in adults) have more likelihood of underlying pathology than belching.  This review suggests workup including blood tests (CBC, CMP, Amylase/lipase, CRP, Cortisol) and consideration of EKG, CT of chest, Upper endoscopy, MRI of brainstem, and esophageal impedance.

Physical maneuvers have usually been tried and include the following: scaring the patient, rapid drinking, eyeball compression, holding breath, biting a lemon, swallowing sugar, and sniffing vinegar.  A good differential diagnosis is given as well in this review -though many cases are idiopathic.

In the U.S. the only approved drug treatment is chlorpromazine.  Typical starting dose  for adults with this condition is 25 mg 3-4/day.  Potential side effects include drowsiness and rarely tardive dyskinesia.  Potential alternatives include baclofen and gabapentin.  Numerous other agents and even surgical options are listed in this review that have been reported in case studies.

Aerophagia indicates excessive swallowing of air (capable of inducing symptoms like bloating or pain).  No controlled studies have been completed.  Expert opinion suggests using a nasogastric tube and sedatives like lorazepam in severe acute cases.  In more typical chronic cases, advice includes restriction of carbonated beverages and possibly speech therapy.  Agents like simethicone may be helpful.  Laxatives may be helpful in some cases as well.

Related posts:

Treatment for rumination and belching | gutsandgrowth

GI bleeding in Heyde’s syndrome

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This eponym is derived from E.C. Heyde, a general practitioner from Vancouver, Washington who observed in 1958 that patients with calcific aortic stenosis were prone to massive gastrointestinal bleeding.  This clinical observation now has a molecular insight (NEJM 2012; 367: 1954-56).

Submucosal angiodysplasia was identified as the source of GI bleeding.  This in turn was discovered to be related to an acquired von Willebrand’s syndrome.  What’s happening is that elevated shear stress coverts the globular von Willebrand polymer into an elongated asymmetric protein.  This conformational change exposes a site to the protease ADAMTS13 which binds  and cleaves the protein, leaving a less competent smaller von Willebrand factor.

Another observation is that the von Willebrand factor is essential for the role that platelets have in maintaining vascular integrity.  Degradation of von Willebrand factor as in Heyde’s syndrome allows for the development of the angiodysplasia in these patients and it leads to an intrinsic vascular diathesis in young patients with hereditary von Willebrand’s disease.

It is pretty cool to see how the science explains the clinical picture.