Category Archives: Gastroenterology

What is the risk of colon cancer in IBD?

Posted on by

Some recent studies have shown that colorectal cancer complicating IBD may not be as common as previously thought or may be decreasing in incidence (Gastroenterology 2012; 143: 375-81 & Gastroenterology 2012; 143: 382-89 ).

The first study used a nationwide cohort of 47,374 Danish patients with IBD over a 30-year period.  During a 178 million person-years of follow-up evaluation, 268 patients with ulcerative colitis (UC) and 70 patients with Crohn’s disease (CD) developed colorectal cancer (CRC).  The risk was comparable to the general population (RR 1.07)!  Furthermore, the relative risk for CRC decreased over sequential time periods: 1.34  (1979-88) to 0.57 (1999-2008).

Increased risk:

  • UC diagnosed in childhood or adolescence
  • longer disease duration
  • patients with primary sclerosing cholangitis

Their conclusion, ‘the overall risk of CRC in patients with UC has decreased markedly over time and no longer exceeds that of the general population, at least in the first decade after diagnosis.”  And, based on their data, patients with Crohn’s disease are not at increased risk for CRC.

The second study from California used a large Kaiser Permanente database from 1998-June 2010.  29 cancers were identified in CD (n=5603) and 53 in UC (n=10,895) patients.  The incidence per 100,000 for CRC was 75 for CD, 76 for UC, and 47 for general population.

These authors conclude that there is an increased risk of CRC in a community-based IBD population between 1998-2010 despite advances in medical treatment.

To understand the discrepancy of these reports, the same issue provides an editorial (page 288).  My take is that the current incidence of CRC is lower than in previous reports but that the risk factors identified in the Danish cohort (see above) likely remain important.

Additional references:

  • -Gastroenterol 2009; 136: 718. 22% of cancers occurred before recommended surveillance in adults (only 9% if exclusion of patients who had IBD and cancers diagnosed at same time).
  • Colon Cancer Survival Calculator http://www.mayoclinic.com/calcs-Gastro 2010; 138: 207-2177 (entire issue)
  • -JAMA 2009; 302: 649. Aspirin use likely increases survival after dx of colon cancer. Commentary-Gastro 2010;138: 2012.
  • -NEJM 2009; 361: 2449. molecular basis of colorectal cancer
  • -Gut 2008; 57: 1246. IBD and colon cancer
  • -IBD 2007; 4: 367. 5ASA Rx did not reduce rate of cancer in large study of UC/CD -review of 18,000 colorectal cancer cases. IBD increased risk of CRC 6-7-fold..
  • -Clin Gastro & Hep 2006; 4: 1346. aminosalicylates reduce CRC.
  • -Gastroenterol 2006; 130: 1030, 1039, 1350. 600 patients followed for 35 yrs: CRC by colitis duration: 2.5% @ 20yrs, 7.6% @ 30yrs, 10.8% @ 40yrs. 5 year survival was 73% among those with cancer. 2nd study showed main CRC risk in UC pts is among those with extensive colitis.
  • -Clin Gastro & Hepatol 2004; 2: 1088. Lower cancer risk in this cohort, n=1460. CRC 0.4 @10yrs, 1.1% @ 20yrs, 2.1% @ 30yrs. Lower CRC may be due to more surgery in Rx failures & use of 5-ASA.
  • -Clinical perspectives in Gastro 1999; 2: 9 & 25. (review) surveillance/ overview take 4 bx q10cm. start p 8yrs in pancolitis & 15yrs for left-sided dz. Cancer risk: ~5% at 20yrs + 1%/yr p 20yrs in pancolitis.
  • -Gastroenterol 2003; 125: 1311. Advancement of dysplasia to cancer in UC.

Why didn’t patient with documented reflux get better with PPI?

Posted on by

There are numerous problems with pH studies; many of these problems have been alluded to in previous blog entries (see below).  Another problem is that these studies are not highly predictive of response to therapy (Gut 2012; 61: 501-506).

This French study from three centers examined 100 consecutive patients (58 females) with an average age of 50 years.  All patients had reflux symptoms, namely regurgitation and/or heartburn.  PPI dosage was not standardized and reflux symptoms were quantified with recall questionnaires.

The authors note that up to 40% of patients with reflux symptoms have inadequate symptom relief with a 4-week course of single dose proton pump inhibitor (PPI) therapy; the aim of their study was to investigate which factors on pH probe-impedance (pH-MII) would predict a response to therapy.

Definition: Nonresponders were patients who had more than 2 days of mild symptoms per week while receiving a standard or double dose of PPI treatment for 4 weeks

Results:

  • No reflux pattern on pH-MII was associated with a response to PPIs. Table 2 in the study looked at multiple factors including SI, SAP, time for acid exposure, and number of reflux events.
  • Lower BMI (≤ 25 kg/m-squared), non-erosive reflux, and normal pH study were associated with poor PPI response
  • Other factors associated with poor PPI response: female gender, irritable bowel syndrome (IBS), and functional dyspepsia.
  • Response rates: 58% of individuals with BMI >25, 71% with esophagitis, 23% with functional dyspepsia, 30% with IBS
  • Among responders, 77% were receiving a single dose PPI

Some of the poor response may be related to the study population.  Only 35% had abnormal acid exposure.  In total, 67% were determined to have abnormal pH studies, though this was due to a large fraction having a positive symptom-reflux association analysis.

However, this study population likely reflects a typical clinical group of patients diagnosed with GERD and demonstrates some of the shortcomings of pH-MII in clinical practice.  Even patients with abnormal pH-MII studies, the presence of functional dyspepsia and IBS were strongly associated with PPI failure.

Previous related blog entries:

HEROES trial

Impedance recommendations from PIG

Gastroesophageal Reflux: I know it when I see it

Treating reflux does not help asthma

Unexplained chest pain

ELEVATE study

Posted on by

Another clever acronym for the following:  Eltrombopag Evaluated for Its Ability to Overcome Thrombocyopenia and Enable Procedures (NEJM 2012; 367: 716-24).

Eltrombopag is an oral thrombopoietin-receptor agonist which is approved for use in chronic immune thrombocytopenia.

This double-blind, placebo-controlled trial evaluated whether eltrombopag increased platelet counts and reduced platelet transfusions in patients with chronic liver disease & platelet counts less than 50,000 per cubic millimeter.  145 patients received eltrombopag (75 mg once a day) and 147 received placebo.  Patients received therapy for 14 days. Elective procedures were scheduled no more than 5 days after the final dose of study medication (days 15 to 19).

Key findings:

  • Transfusions of platelets were reduced in the treatment group: 28% of patients compared with 81% in placebo group.
  • No differences in significant bleeding episodes noted.
  • Portal venous thrombosis was increased in treatment group with 6 patients compared with 1 patient in placebo group.

Study limitation: no standard practice with regard to use of platelet transfusions for thrombocytopenia (especially with platelet counts between 50,000-80,000)

Platelet transfusions can be problematic with cirrhosis.  Platelet transfusions have a short duration of efficacy, reactions to transfusions can occur, and multiple transfusions can result in antiplatelet antibodies. Nevertheless, the conclusions from this study: ‘until better identification of risk factors for the development of thrombosis…have been conducted, eltrombopag is not recommended as an alternative to platelet transfusion.’

Epidemic of Prescription Drug Overdoses

Posted on by

More information on the epidemic of drug overdoses: MMWR 2012: 61: 10-13.

In 2007, in U.S. one death due to unintentional drug overdose occurred every 19 minutes (27,000 cases), primarily due to opioid analgesics.  In addition, for every death, there were nine persons admitted for drug treatment, and 35 emergency room visits.

The escalating drug use can be quantified.  In 1997, drug distribution through pharmacies delivered the equivalent of 96 mg of morphine per person whereas in 2007 the amount was 700 mg per person; 700 mg is enough for every person in U.S. to receive a three-week course of Vicodin (hydrocodone/acetaminophen 5mg q4 hours).

Only 10% of these patients were seeking care from multiple doctors; yet this 10% accounted for 40% of the cases of overdosage.

Prevention strategies:

  • Prescription data to prevent doctor shopping & reduce inappropriate use of opioids/selling excessive opioid prescriptions
  • Enforcing laws against ‘pill mills’
  • Improve medical practice in prescribing opioids

Additional references/previous blog entries:

Epidemic: Responding to America’s Prescription Drug Abuse Crisis  Whitehouse plan

Pediatric pharmaceutical poisoning

Deadly consequences of pain management

Why “therapeutic dose” of codeine can kill

Abatacept for IBD?

Posted on by

Doesn’t work (Gastroenterology 2012; 143: 62-69).  While this study indicates that Abatacept was not effect for either Crohn’s disease (CD) or ulcerative colitis (UC), it was useful nevertheless.

In brief, the study examined four placebo-controlled trials of abatacept for induction and maintenance therapy in both CD and UC.  The induction studies included 451 CD patients and 490 UC patients.  The maintenance studies had 90 CD and 131 UC patients.

Results for induction:

  • CD: Clinical response: 17%, 10%, 15% for abatacept dosing of 30, 10, and 3 mg/kg.  Placebo 14%
  • UC: 21%, 19%, 20%  for abatacept dosing of 30, 10, and 3 mg/kg.  Placebo 29.5%

Results for maintenance:

  • CD: 24% abatacept vs 11% placebo
  • UC: 12.5% vs 14% placebo

The premise of this study was that T-cell activation requires co-stimulatory signaling via T cell CD28 and CD80 or CD86 on the antigen-presenting cell.  Abatacept (CTLA4-Ig) which is effective for psoriasis, rheumatoid arthritis, and juvenile idiopathic arthritis was thought to have potential; it blocks costimulation pathways involved in T-cell activation which was shown to be helpful in animal model of colitis.

So why did it not work?  The editorial in the same volume (pages 13-16) suggests the following possibilities:

  • Abatacept would be more likely to work when naive T cells are actively recruited into inflammation rather than memory T cells which are predominant in IBD
  • CD28-related pathways may not be important in IBD pathogenesis
  • Abatacept may have impeded Treg function in addition to preventing T-cell activation (explained in Fig 1D)
  • Blockade of CD28 pathways could have resulted in unfavorable changes in cytokine profiles from T-cell differentiation (Th1 vs Th2)

The implication of this study is that not all T-cell mediated inflammatory disease respond to the same treatment approaches.  The complexity of intestinal immune responses necessitates ongoing clinical studies to determine which promising therapies will be useful.

Pregnancy after Liver Transplantation

Posted on by

As there are about 14,000 women of reproductive age in the U.S. who have undergone liver transplantation (LT), data about the outcomes of pregnancy are important for counseling.  A review and meta-analysis (Liver Transpl 2012; 18: 621-29) provides some information; going forward the National Transplantation Pregnancy Registry (NTPR) which was established in 1991 offers the promise of additional insight.

In the current review, Deshpande et al found 8 of 578 studies which met inclusion criteria; in total 450 pregnancies in 306 LT recipients were examined.  While healthy live births were the most common outcome, there were several pertinent risks identified.  The main concerns were development of preeclampsia, rejection/graft loss as well as the potential for birth defects.  While miscarriage rates were similar to the general population (15.6% compared with 17.1%), the following were much higher:

  • preeclampsia 21.9% vs. 3.8% in general population
  • cesarean section delivery 44.6% vs. 31.9% in general population
  • preterm birth 39.4% vs. 12.5% in general population

While rates of rejection and graft loss are not given for the entire cohort, specific study results were discussed.  In one study, rates of acute rejection ranged from 2% to 8% and loss of graft within two years of pregnancy occurred in 6-11%.

Similar to rejection data, the data for birth defects was not uniformly reported.  Specific study results were discussed and included several birth defects: 1 patient with total anomalous pulmonary venous return, 1 with pyloric stenosis, 2 with hypospadias, 1 with tracheoesophageal fistula, 1 with unilateral cystic kidney, and 2 with ventricular septal defects.

Take-home message:

Liver transplant recipients can have successful pregnancies but should be considered high risk.  Active reporting to established registries can give more accurate and up-to-date information.

Related post:

Alive and well? 10 years after liver transplantation

Fish intake may reduce liver cancer

Posted on by

In a large Japanese adult population (n=90,296), the consumption of n-3 fatty acids and fish was associated with reduced risk for hepatocellular cancer (HCC) (Gastroenterology 2012; 142: 1468-75 and editorial 1411-12).

HCC ranks fifth among cancer incidence and third for mortality worldwide.  Many factors contributing to HCC cannot be modified.  The main factors subject to modification include diet and avoidance of viral hepatitis.  Dietary studies are methodologically-challenging due to difficulties assessing diet and due to the complex nature of diets.  Without going into any significant detail, this study shows an inverse relationship between fish intake and incidence of HCC.  The hazard ratio for the highest quintiles compared to the lowest were 0.56-0.64 depending on the specific dietary agent.  The specific n-3 polyunsaturated fatty acids (PUFA) examined included eicosapentaenoic acid (EPA), docosapentaenoic adic (DPA), and docosahexaenoic acid (DHA).

HCC Established Risk Factors:

Age, males, family history of HCC, HCV/HBV infection, alcohol, cirrhosis, tobacco, aflatoxin exposure, Hereditary Hemochromatosis, α-1 antitrypsin deficiency, primary biliary cirrhosis

Likely Risk Factors:

Diabetes, obesity, NAFLD

Possible Risk Factors:

Red meat, saturated fat, fructose, oral contraceptives

Possible Protective Factors:

Coffee, micronutrients (vitamin D, vitamin E, selenium), white meat (fish, poultry), and n-3 fatty acids

Related blog posts:

Looking for trouble

Live longer -drink more coffee

Drink Up!

More about coffee

One for the PPI team

Posted on by

While this blog in previous posts has pointed out some shortcomings of proton pump inhibitors (PPIs), at the same time this class of medications remains a crucial part of pediatric gastroenterology practice.  In most patients, the benefits of these medications far outweigh the potential risks.

One of the risks has been a low rate of increased infections due to lowering gastric acid which provides some protection against enteric infections.  More information about PPIs show that these medications are not likely to increase the risk of small intestinal bacterial overgrowth (SIBO) (Am J Gastroenterol 2012; 107: 730-35 –thanks to Ben Gold for showing me this article).

In this retrospective study from 2004-2010, 1191 patients were included with 566 receiving PPI therapy.  Mean age: 63 years for PPI users and 59 years for nonusers. Glucose breath hydrogen testing (GBHT) for bacterial overgrowth did not differ significantly between PPI users and nonusers.  The authors acknowledge that there have been conflicting reports previously between the use of PPIs and the development of SIBO (see Table 5 of article); interestingly, SIBO with PPIs has occurred predominantly in studies from Europe.  The authors note that while achlorhydria leads to SIBO, the intermittent surges of acid production with PPIs should be sufficient to prevent SIBO.

Additional references/previous blog posts:

  • Proton pump inhibitors–infection risk with cirrhosis
  • The Medical Pendulum and Gastroesophageal Reflux
  • -Gastroenterol Hepatol 2011; 7: 10-2.  Risk of infections with PPIs.
  • -Gut 2007; 56: 802-8.  SIBO with IBS.
  • -NEJM 2010; 363: 2114. large Denmark study. 5082 fetuses with PPI exposure (out of 840,968 live births. Risk of birth defects NOT increased with exposure during 1st trimester. Possible slight increase with preconception use except with omeprazole.
  • -Gastroenterol 2010; 139: 1115. Review of safety of PPIs.
  • -Gastroenterol 2010; 139: 93. n=167,000. PPIs associated with hip fracture risk, OR 1.3, in patients with other risk factors.
  • -Gastroenterol 2010; 138: 896-904. 5 yrs of PPI -no increase risk in hip/spine fx.
  • -Arch Intern Med 2010; 170: 765-71, 747 (ed). PPI not related to hip fx (n=161,806) women 50-79. INCREASE risk of spine fx, hazard risk 1.47
  • -Arch Intern Med 2010; 170: 772-8. PPIs increase risk of CDT (hazard ratio 1.42 –42% increase in risk), n=1166.
  • -Arch Intern Med 2010; 170: 784-90. n=101,796.  Risk of nosocomial infection: OR 1.74 for daily PPI, OR 2.36 if BID Rx; thus ~70% increase risk of nosocomial infection.

Aspirin prophylaxis for colorectal cancer?

Posted on by

A recent article in The Lancet has provided additional information about the use of aspirin for cancer prevention, especially colorectal cancer (Rothwell PM et al. Lancet 2012; published online March 21. DOI: 10: 1016/S0140-6736 (11)61720-0).  In the commentary on this article (DOI: 10: 1016/S0140-6736 (11)61654-1), the potential benefits of aspirin are placed into context and previous studies are reviewed.  In short, the data from a number of studies suggest that aspirin lowers the risk of cancer.

In Rothwell’s study, which pooled data from 51 randomized trials, aspirin at any dose reduced the risk of non-vascular death by 12% and cancer death by 15%.   Benefit was seen within 3 years for high-dose (>300 mg/day) and after 5 years for low doses (<300 mg).  The cumulative numbers of patients in the reviewed studies was approximately 40,000 in each arm.  These studies were divided and examined under separate categories to assess primary prevention for vascular events and to assess effects on cancer deaths.

Yet, these encouraging results though have not been seen in several large randomized trials; the editorial notes that “the Women’s Health Study (WHS) of 39,876 women treated with alternated day 100 mg aspirin over 10 years and the Physicians’ Health Study (PHS) of 22,071 men treated with alternate-day 325 mg aspirin for 5 years.  After 10-12 years of folllow-up, aspirin was not associated with reduced risk of colorectal cancer.”  In addition, as noted in previous post, ( Who needs aspirin?/Arch Intern Med 2012; 119: 112-8) a large study with over 100,000 patients also did not show reduction in mortality from vascular or non-vascular events.

Whether alternate-day dosing of aspirin (in WHS and PHS studies) undermines its efficacy in preventing cancer is not clear.  Until more data are available, aspirin for chemoprevention is best-suited for those with increased cancer risk (eg. history of colorectal cancer & hereditary cancer syndrome) and low risk of GI bleeding.  Rates of bleeding due to aspirin are about 4% per year and for serious bleeding about 2% per year. In addition, other adverse effects, including macular degeneration, have been reported with aspirin use (Ophthalmology 2012; 119: 112-8).

Additional references:

  • Link to pdf copy of cited article:http://extremelongevity.net/wp-content/uploads/asa-ca.pdf
  • -Lancet 2011; 377: 31-41. Aspirin effect on cancer mortality -decreased by 30-40% (esophageal, gastric, pancreatic, colorectal)
  • -Lancet 2010; 376: 1741 – 1750. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lowers risk of colon Ca.
  • -JAMA 2009; 302: 649. Aspirin use likely increases survival after dx of colon cancer.
  • -Gastro 2010;138: 2012. Commentary on aspirin for decreasing risk after diagnosis of colon cancer.
  • -NEJM 2007; 356: 2131, 2195. Aspirin can decrease high-expressing COX-2 colon adenoca; not recommended as routine prophylaxis at this time

Who needs aspirin?

Posted on by

Despite a lot of good press for aspirin with regards to prevention of cardiovascular events and cancer prevention, determining who should take aspirin is quite tricky.  This blog entry will discuss the vascular rationale and a subsequent post will tackle the potential of aspirin for colorectal cancer prevention.

At this time, the cardiovascular disease (CVD) rationale includes preventing myocardial infarction [MI] and stroke.  These are the main determinants of risk/benefit for taking aspirin.  In 2009, guidelines from US Preventive Services Task Force (USPSTF) for taking aspirin were published (Ann Intern Med 2009; 150: 396-404).  The following link can be used to access this article:

http://www.uspreventiveservicestaskforce.org/uspstf09/aspirincvd/aspcvdrs.pdf

The recommendations include the following:

Men <45:  Not encourage aspirin for MI prevention

Women <55: Not encourage aspirin for stroke prevention

Men 45-79:  Encourage aspirin when CVD benefit.  Benefit likely if:

  • 45-59 years, 10 -year CVD risk ≥4%
  • 60-69 years, 10-year CVD risk ≥9%
  • 70-79 years, 10-year CVD risk ≥12%
To calculate 10-year CVD risk: http://www.mcw.edu/calculators.htm
Risk factors: age, high blood pressure, diabetes, smoking, history of CVD, total cholesterol level, and HDL cholesterol level

Women 55-79:  Encourage aspirin when stroke benefit.  Benefit likely if:

  • 55-59 years, 10 -year stroke risk ≥3%
  • 60-69 years, 10 -year stroke risk ≥8%
  • 70-59 years, 10 -year stroke risk ≥11%

To calculate 10 -year stroke risk: http://my.clevelandclinic.org/p2/stroke-risk-calculator.aspx

Risk factors: age, high blood pressure, diabetes, smoking, history of CVD, atrial fibrillation, and left ventricular hypertrophy

In addition, it is noted that aspirin is NOT recommended when other NSAIDs are being administered or if history of GI ulcers/risk of serious GI bleeding.

While these recommendations are a useful starting point and the risk calculators are fascinating, the absolute benefit of aspirin remains unclear.  A recent article on this subject indicates that aspirin may not improve mortality (Arch Intern Med. 2012;172(3):209-216. doi:10.1001/archinternmed.2011.628).  This article reviewed nine large randomized placebo-controlled studies, each with at least 1000 participants.  In total, more than 100,000 patients were described in these studies.  While CVD events were reduced by 10%, there was no reduction in mortality for cardiovascular disease (OR 0.99) or for cancer (OR 0.93) among aspirin takers over a mean of 6 years.  Most of the reduction in CVD events were due to a lower rate of non-fatal MI (OR 0.80).  In addition, there was an increase in significant GI bleeding among patients taking aspirin (OR 1.31)

Due to these results, the authors conclude that routine use as primary prevention is not warranted; “treatment decisions need to be considered on a case-by-case basis.”

Additional reference:

  • –Arch Intern Med 2012;172:217-218.  Aspirin Therapy in Primary Prevention: Comment on “Effect of Aspirin on Vascular and Nonvascular Outcomes”