TNF antagonists and UC

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In my fellowship (15 years ago), the use of thiopurines (eg. azathioprine, 6-mercaptopurine) for ulcerative colitis was debated.  Many physicians urged colectomy rather than using these drugs which could have long-term consequences.  At the time, the risk of thiopurines was less well-understood.  Over time, the use of these agents has become common when mesalamine products were ineffective.  The same issue comes up with TNF antagonists versus colectomy.

A recent study provides more information on the effectiveness of adalimumab for patients with moderate-to-severe UC but does not settle this debate (Gastroenterology 2012; 142: 257-65).  In this study, termed ‘ULTRA-2’ (Ulcerative colitis long-term remission and maintenance with adalimumab 2), the  efficacy of adalimumab for induction & maintenance of remission was studied in 494 patients.  This was a randomized, double-blind, placebo-controlled study; average age was 40 years.

Clinical remission in the adalimumab group were 16.5% at 8 weeks (9.3% placebo).  At 52 weeks, 17.3% in the adalimumab group were in remission (8.5% placebo).  Among patients naive to anti-TNF agents, the response rate was 21.3% at week 8 & 22% at week 52.  Safety overall was similar in both groups; however, in the adalimumab group one patient developed gastric cancer and one developed squamous cell carcinoma.

The authors conclude that adalimumab is safe and more effective than placebo in inducing and maintaining remission among patients with moderate-to-severe UC.

A second study, also published this past month, looks at the use of infliximab for maintenance therapy for UC (Inflamm Bowel Dis 2012; 18: 201-11).  Patients who had achieved benefit from ACT-1 and ACT-2 studies were followed for three years.  Dosage of infliximab could be adjusted.  A total of 229 patients entered the study.  During the study, 70 patients (30.6%) discontinued infliximab due to adverse effects (10.5%), lack of efficacy (4.8%) or other reasons (15.2%); the majority were able to continue infliximab.  The authors indicate that no new safety issues were identified. Yet, there were two deaths among the infliximab group including a 19 year-old nonsmoker who developed lung cancer and a lethal case of histoplasmosis.

Because the improvement compared to placebo is modest with both of these agents, the question about whether to use these medications or proceed to surgery in UC patients is unanswered.

Additional references:

  • -Aliment Pharmacol Ther. 2008 Oct 15;28(8):966-72. Epub 2008 Jul 24.  Long-term outcome of adalimumab therapy for ulcerative colitis with intolerance or lost response to infliximab: a single-centre experience.
  • -Am J Gastroenterol (Oussalah A et al) 2010; 105: 2617-25. Multicenter study of IFX for UC
  • -Gastroenterology 2010; 138: 2282. Severe pediatric UC. 25/33 responded to IFX. colectomy rate 19% at 1 year.
  • -Gastroenterology 2009; 137: 1204 (ed), 1250. lower colectomy rates at 54wks in IFX vs placebo (+concomitant meds): 10% vs. 17%.
  • -Clin Gastro & Hep 2008; 6: 1112. Do NOT use CYA post infliximab and vice versa. n=19. 1 death due to sepsis. Remission rates occur in ~1/3rd but are of short duration.
  • -NEJM 2005; 2462. 69% clinical response @ 8 weeks (vs. 37% placebo) & 45% at week 54 (vs. 20% placebo).
  • -JPGN 2004; 38: 298. 82% short-term response, 63% sustained response; n=16.

Common to be “D-ficient”

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Many of the children that a pediatric gastroenterologist sees are at risk for Vitamin D deficiency, including children with inflammatory bowel disease, cystic fibrosis, celiac disease, and liver diseases.  In addition, vitamin D deficiency is widespread: in U.S. 50% of children aged 1-5 years and 70% 6-11 years are vitamin D deficient or insufficient. A thorough review on this “D-lightful” vitamin was in a recent JPEN (JPEN J Parenter Enteral Nutr 2012; 9S-19S).

History: In 1822 Sniadecki recognized children in urban but not rural Poland developed rickets. He postulated the effects of the sun as the reason for rickets; his idea was dismissed.  In 1920s, the concept of irradiating milk to prevent rickets emerged. In 1950s, outbreak of hypercalcemia in infants in Great Britain was thought to be related to vitamin D fortification and curtailed this practice in Europe.  However, these cases were likely due to Williams syndrome.

Sources of vitamin D: oily fish (salmon), cod liver oil, some mushrooms, egg yolk, & sunlight. Exposure of an adult in a bathing suit to one minimal erythemal dose (MED) is equivalent to ingesting 20,000 IUs of Vitamin D. (The minimal dose that induces any visible reddening at that point is defined as one MED.)

Effect of sunscreen: A sun protection factor (SPF) of 30 absorbs approximately 98% of solar ultaviolet radiation & thus lowers vitamin D production by 98%.

Ethnicity: Melanin is an effective SPF.  A person of african-american descent, on average, has an SPF of 15, which reduces vitamin D production by 90%.

Age: Aging decreases 7-dehydrocholesterol in human skin.  Due to this, the elderly produce much less vitamin D.  For example, a 70 year old has a 75% reduction compared to a 20 year old.

Forms of vitamin D:  25-hydroxyvitamin D (25OH-D) is the major circulating form of vitamin D & physicians measure 25OH-D. 25OH-D is metabolized in kidney to 1,25-dihydroxyvitamin D (1,25OH-D), also called calcitriol.  This is the most biologically-active and is responsible for increasing intestinal calcium absorption and mobilizing calcium from bone.  However, 1,25OH-D provides no information vitamin D deficiency; it can be elevated or normal in deficiency states.

  • Cholecalciferol (vitamin D-3) is formed in the skin from 5-dihydrotachysterol.
  • Ergocalciferol (Vitamin D-2) is the form in Drisdol (8000 IU/mL) & Ergocalciferol Capsules (1.25 mg =50,000 USP Units)

Vitamin D deficiency:  The exact numbers are debated.  The institute of medicine (IOM) has considered individuals deficient if 25OH-D is <20 ng/mL.  The Endocrine Society and the author suggest vitamin D deficiency as <20 ng/mL & insufficiency as <30 ng/mL.  The author recommends ideal levels between 40-60 ng/mL.

Consequences of deficiency:

Osteoporosis, Osteopenia, Rickets (see references below): Bone weakening occurs due to loss of phosphorus from the kidneys.  Vitamin D deficiency lowers accrual of calcium in skeleton and leads to osteoporosis, osteopenia, and rickets. Imaging for rickets: the best single radiographic view for infants and children younger than 3 years is an anterior view of the knee that reveals the metaphyseal end and epiphysis of the femur and tibia. This site is best because growth is most rapid in this location, thus the changes are accentuated.

Nonskeletal consequences: vitamin D deficiency is associated with increased risk for preeclampsia, URIs, asthma, diabetes (type 1), multiple sclerosis, hypertension, and schizophrenia.

Treatment:

  • Infants who are breastfed should be receiving supplemental vitamin D, 400 IU/day.
  • Adults/children (>1 year) RDA 600 IU/day –mostly from diet per IOM. Yet author states, “it is unrealistic to believe that diet alone can ….provide this requirement.”
  • In vitamin D deficient patients: (initial treatment) 2000 IU/day or 50,000 IU/week for 6 weeks.
Toxicity from vitamin D (from NEJM 2010; 364: 248-254.): “Toxicity from vitamin D supplementation is rare and consists principally of acute hypercalcemia, which usually results from doses that exceed 10,000 IU per day; associated serum levels of 25-hydroxyvitamin D are well above 150 ng per milliliter (375 nmol per liter). The tolerable upper level of daily vitamin D intake recently set by the Institute of Medicine (IOM) is 4000 IU.”

Additional references:

  • -Pediatrics 2008; 122: 398. Should give 400 IU/day to breastfed babies. Consequences of Vit D deficiency: increased risk for DM, multiple sclerosis, cancer (breast, prostate,colon), rickets, and schizophrenia. Article lists vit D content of foods (high in cod liver oil, shrimp, fortified milk, many fish). Severe deficiency when < 5ng/mL, deficient if < 15 ng/mL; probably should be >32 ng/mL. Causes of vit D deficiency: decreased synthesis (due to lack of sun -skin pigmentation, sunscreen/clothing, geography, clouds), decreased intake, decreased maternal stores & breastfeeding, malabsorption (eg celiac, CF, EHBA, cholestasis), increased degradation; treatment of rickets: double-dose of vitamin d (~1000 IU/day for babies & 5000 for older kids) x 3-4 months along with calcium (30-75/mg/kg/day). Follow Ca/phos/alk phos monthly. Alternatively, give ~100,000 units over 1-5 days.
  • -JPEN J Parenter Enteral Nutr. 2011;35:308-316-Results: The study included 504 IBD patients (403 Crohn’s disease [CD] and 101 ulcerative colitis [UC]) who had a mean disease duration of 15.5 years in CD patients and 10.9 years in UC patients; 49.8% were vitamin D deficient, with 10.9% having severe deficiency. Vitamin D deficiency was associated with lower HRQOL (regression coefficient –2.21, 95% confidence interval [CI], –4.10 to –0.33) in CD but not UC (regression coefficient 0.41, 95% CI, –2.91 to 3.73). Vitamin D deficiency was also associated with increased disease activity in CD (regression coefficient 1.07, 95% CI, 0.43 to 1.71). Conclusions: Vitamin D deficiency is common in IBD and is independently associated with lower HRQOL and greater disease activity in CD. There is a need for prospective studies to assess this correlation and examine the impact of vitamin D supplementation on disease course.
  • -JPGN 2011;53: 361. similar prevalence of low Vitamin D as general population –58% with less than 32.
  • -JPGN 2011; 53: 11. Guidelines for bone disease with inflammatory bowel disease.
  • -Pediatrics 2010; 125: 633. Increasing Vit D deficiency noted in minority children. n=290. 22% w levels <20, 74% <30.
  • -Hepatology 2011; 53: 1118. Good vitamin D levels are another favorable predictive factor in antiviral response to Hep C along with IL28B.
  • -NEJM 2010; 364: 248-254. Vitamin D insufficiency. Levels between 20-30 may be OK -not enough evidence to determine conclusively whether this level is detrimental
  • -J Pediatr 2010; 156: 948. High rate among african americans with asthma, 86%. n=63.
  • -Pediatrics 2009; 124:e362. n=6275. 9% of pediatric patients vit D deficient & 61% were insufficient.
  • -Pediatrics 2009; 124:e371. n=3577. low 25OH-D levels inversely assoc with SBP/metabolic syndrome.
  • -NEJM 2009; 360: 398. case report of rickets
  • -J Pediatr 2003; 143: 422 & 434
  • -Pediatrics 2003; 111: 908. 200 IU Vit D recommended for all breastfed infants.
  • -J Pediatr 2000;137: 153 & 143.. Nutritional rickets–primarily in blacks; rec vitamin D 400 IU per day.

HCV now more deadly than HIV

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Hepatitis C virus (HCV) now kills more people in the United States than HIV (Ann Intern Med 2012; 156: 271-78).  Data from the CDC followed the mortality burden of Hepatitis B (HBV), HCV, and HIV from 1999 to 2007.    The data were derived from death certificates & a limitation was that these are often completed by individuals other than the primary physician.  Sometimes the exact cause is difficult to discern.  However, this is more likely to result in underreports of deaths from viral hepatitis compared with those from HIV.

In total, 21.8 million death certificates were analyzed.

  • HBV death rate stayed relatively constant –in 2007: 1815 deaths*
  • HCV death rate increased steadily –in 2007: 15106 deaths*
  • HIV death rate improved –in 2007: 12734 deaths*

*When infection was cause or underlying contributor of death

One in 33 baby boomers are infected with HCV; most do not know they are infected.  Three-fourths of the deaths for HCV are in this age group as well.  In addition, it is expected that mortality from HCV will grow over the next 10-15 years without a major intervention. http://www.ajc.com/health/hepatitis-c-deaths-up-1356460.html

Given the increasing HCV disease burden, this strengthens the rationale for more aggressive case finding and the use of more effective & more expensive therapies (see previous blog: The cost of progress in treating Hepatitis C.  Among patients with HCV with advanced disease/cirrhosis, monitoring for HCC is important (Looking for trouble).

Additional references:

  • -Hepatology 2011; 54: 1547. Excess mortality (6x gen population) in those who achieve SVR
  • -Gastroenterology 2010; 138: 513. Predicts peak cirrhosis due to HCV in year 2020; peak HCV prevalence was year 2000.
  • -Clin Gastro Hep 2010; 8: 924. Epidemiology 2010.
  • -Hepatology 2010; 52: 1543. Visceral adiposity is associated with increased histological findings and higher viral loads.
  • -Gastroenterology 2010; 138: 136. Predicting clinical outcomes: plt<99, Alb <3.5, AST/ALT ratio >1.2, & TB>2 all assoc with 40-50% risk of developing ‘clinical outcome’ in next 3.5yrs. Outcomes: ascites, variceal hemorrhage, decompensation according to CTP (66%), peritonitis, death (2%), encephalopathy
  • -Hepatology 2009; 49: 729. 5-yr f/u after successful HCV RX, n=150. 2 developed HCC.
  • -Gastroenterology 2009; 136: 138, 39(ed). HCC occurring c HCV ~1%/yr in HALT-C study. prolonged Rx -not helpful. n=1005
  • -Hepatology 2008; 47: 1128. Increasing mortality of HCV between 1995-2004. Due to aging of infected individuals.
  • -Hepatology 2008; 47: 1371. Genotype 4 review.
  • -Hepatology 2008; 47: 836. 2/121 bx of children had cirrhosis.
  • -J Pediatr 2007; 150: 168. n=60. Looked at two populations: look back after transfusion and referrals. mean age at infection 7 months, mean time with infection 13yrs. 12% developed significant fibrosis.
  • -Hepatology 2007; 45: 1076. Large study: Lancet 2006; 368: 938. 39,109 c HBV, 75,834 c HCV, 2,604 c both. death rate: 3.2%, 5.3%, 7.1% respecively. Increased rate of dying c HCV due to drug use rather than liver dz.
  • -Clin Gastro & Hep 2006; 4: 1190-1191, 1271-78, 1278-1282. slow progression of HCV in 184 untreated women infected in 1977 (mean 27 years) — 2.1% developed cirrhosis. genotype 1B ALT values correlated with change in histology.
  • -JPGN 2006; 43: 209. Review of 91 cases; 7 c cirrhosis at presentation (mean 11.7yrs)
  • -Clin Gastro & Hep 2005; 3: 910. cirrhosis in 71% after 60 years in Asian patients; 25% in Caucasian pts 61-80 who presumably had disease for shorter interval.
  • -Gastroenterology 2003; 125: 1695. obesity/insulin resistance worsens fibrosis in HCV
  • -Gastroenterology 2002; 123: 483-491. IFN Rx improved survival; n=2889. retrospective study.
  • -JPGN 2001;33: 22A. spontaneous clearance in 30% during short f/u; n=145.
  • -Hepatology 2000; 32: 91-96. Low likelihood of progression in cohort followed for 20yrs.

More bad news for smokers

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Add two more cancer risks for tobacco smoke (Gastroenterology 2012: 142: 233-40, 242-47).  There is now evidence linking tobacco smoke to 18 different cancers and tobacco smoke is probably the most preventable cause of death in the world.

In the first study, the investigators examined 3167 patients with Barrett’s esophagus.  This retrospective study followed patients for 7.5 years.  Patients who were current smokers (any form of tobacco) had double the risk of developing high-grade dysplasia or cancer compared to those who had never smoked.  Former cigarette smokers had a hazard ratio of 1.53.

In the second study, 386 patients with Lynch syndrome were analyzed during a 10 month period.  The hazard ratio for developing colorectal adenomas was 6.13 for current smokers and 3.03 for former smokers compared with patients who never smoked.  In addition, the authors identified a trend for developing adenomas based on pack-years.

Two more reasons to quit smoking.  On a side note, my grandmother said quitting smoking was the easiest thing that she ever did.  So easy, she did it a thousand times.

Additional references:

  • -Gastroenterolgy 2005; 129: 1825-31.  1.6% incidence of BE in adult Swedish population. Alcohol & smoking increase risk.
  • -NEJM 2011; 365: 1222. Treating smokers -useful review.
  • -NEJM 2011; 365: 1193. Cytisine -inexpensive- helps with smoking cessation (8.4% success vs 2.4%in placebo)
  • -NEJM 2008 358; 2249. Smoking and role of social networks.
  • -Gastroenterology 2011; 141: 2000. Lower risk of Barrett’s in pts taking NSAIDs & statins. n=570.
  • -Gastroenterology 2011; 141: 1179. Lower risk of Barrett’s in pts with low-grade dysplasia than previously noted -similar to non-dysplastic Barrett’s.
  • -NEJM 2011; 365: 1375. Large Danish study, n=11028. Lower incidence of Barrett’s than previous estimates. Relative risk of 11.3 compared to general population for adenoca of Esophagus with absolute annual risk of 0.12%. Barrett’s patients have the same life expectancy as general population (ed. pg 1437). Detecting cancer only ~1 in 1460 scopes with screening whereas Barrett’s detected in 10% of pts.
  • -Gastroenterology 2011; 140: 1084. AGA statement on Barrett’s . Recs screening only in those with multiple risk factors (age 50, male, chronic GERD, white, incr BMI)
  • -NEJM 2005; 352: 1851. Cases of Lynch can be missed when following screening guidelines.
  • -Gastroenterology 2010; 138: 207-2177 (entire issue) Colon cancer, Lynch syndrome
  • -Gastroenterology 2008; 135: 380.  Review of colon cancer screening and prevention -2008 up-to-date- literature review
  • -Gastroenterology 1967; 53: 517-27.  Seminal article.  Lynch HT showed gene-related cancer in family cancer syndrome -different than polyposis syndromes.

Sarcopenia, fatigue, and nutrition in chronic liver disease

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Several articles from a recent Clinical Gastroenterology and Hepatology have addressed nutritional aspects of chronic liver disease.

1. Sarcopenia?  This term refers to generalized loss of skeletal muscle.  It does not equate to malnutrition though there is significant overlap.  (Clinical Gastroenterology and Hepatology 2012; 10: 166-73 & editorial 100).  In this study, 112 adults with cirrhosis had CT scans which examined skeletal muscle at the L3 level; 40% had sarcopenia. Sarcopenia was independently associated with mortality and was not reflected in MELD score.  Patients had increased risk of death from sepsis and liver failure (HR 2.18).  Thus, sarcopenia joins hyponatremia, refractory ascites, hepatic encephalopathy as additional factors which add prognostic information to MELD score.

2. Fatigue in cirrhosis. (Clinical Gastroenterology and Hepatology 2012; 10: 174-81 & editorial 103).  Fatigue is common in cirrhosis and is multifactorial.  In this prospective study, 108 patients were evaluated with a fatigue impact scale. Fatigue improved after liver transplantation. Fatigue can be peripheral due to muscle weakness and dysfunction. And, fatigue can be central due to difficulty performing physical and mental activities.  Central fatigue is associated with an increased perceived effort for tasks and often related to depression; this type of fatigue is much more common with cirrhosis.  Although improved, fatigue often does not completely resolve with liver transplantation.

3. Nutrition recommendations. (Clinical Gastroenterology and Hepatology 2012; 10: 117-25).  A summary of nutrition recommendations in adults  with chronic liver disease is given in this article.  One common misconception is protein restriction.  This is not beneficial.  Protein recommendations are for adult patients with cirrhosis to receive 1-1.5 g/kg/day.  This amount is higher than for healthy individuals.  Protein restriction leads to protein catabolism, muscle breakdown and increases the likelihood of hepatic encephalopathy.

Additional references:

  • -Age Ageing 2010; 39: 412-23.  Sarcopenia consensus definitions in older people.
  • -Gastroenterology 2008; 134: 1741. Evaluation and management of end-stage liver disease in children. Recs vaccines due to functional asplenia/portal hypertension at age 2 for Neisseria (MCV4) or polysaccharide (MPSV4); at 6 weeks of age for pneumococcal conjugate vaccines. Reviews nutrition, varices, ascites, encephalopathy….
  • -Liver Transplant 2008; 14: 585-591. Poor growth often due to growth hormone resistance. Chronic malnutrition is a factor, but children with advanced liver dz may not grow despite adequate calories. Recs: for chronic liver dz: 130-150% of RDA based on ideal body wt; in infants 120-150 cal/kg/day. Increase MCT either thru formula or supplemental MCT.
  • -Liver Transplant 2006; 12: 1310. Review article on nutrition for OLTx patient.
  • -JPGN 2000; 30: 361. nutrition review and chronic liver disease.

Methotrexate and liver toxicity

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There are drawbacks with all of the therapies for inflammatory bowel disease; however, usually the inflammatory bowel disease is worse than any of the medications. One of the therapies that  has started to see increased usage in Crohn’s disease is methotrexate (MTX), both as an alternative to thiopurines and as an adjunct to Remicade.  There are a number of side effects; a patient handout is available at the following: http://www.ccdhc.org/diseases/MethotrexateLetter.pdf

One of the concerns with MTX has been liver toxicity, in part because of descriptions in the rheumatology literature with long-term usage.  In Crohn’s disease patients, it appears that the risk is much lower (Inflamm Bowel Dis 2012; 18: 359-67).  This study found 13 trials for their meta-analysis.  A total of 632 participants were included: 373 MTX, 131 thiopurines, 128 placebo.  In the MTX group, elevated hepatic aminotransferases occurred in 1.4 per 100 person-months.  The rate of elevation more than 2-fold the upper limit of normal was 0.9 per 100 person-months.  Thus, of the initial 373 patients, 39 had an abnormal aminotransferase.  26 of these 39 had spontaneous resolution, 3 improved with dose reduction & 10 withdrew from MTX treatment (0.8 per 100 person-months).  Seven of these withdrawals were from one of the earlier studies (Feagan et al. NEJM 1995; 332: 292-97). Besides the low likelihood of needing to stop MTX due to liver toxicity, the other observation was that the liver toxicity was mostly dependent on the dose; therefore, dosage reduction would likely be effective if needed.

In my practice, when considering MTX treatment, I usually recommend the following:

  • Monitoring: Baseline: CXR, CBC, Amylase, Renal, LFTs, urine HCG & then Q2-4 weeks initially, then Q3months
  • Give Folate during therapy.
  • Use zofran if needed for nausea
  • Avoid NSAIDs during treatment due to renal toxicity
  • Contraindicated with pregnancy (MTX=teratogen) -females should see gynecology
  • Families warned in writing that this medication is given once a week; more often can be deadly

Additional references:

  • -IBD 2011; 17: 2521. ~25% remission at 1yr, 16% at 2yrs.. n=93.
  • -JPGN 2011;53: 389. n=64. Supports use of zofran for 1st few months to prevent nausea.
  • -JPGN 2010; 51: 714. Use of MTX after thiopurines. n=27. 48% in remission at 6 months.
  • -JPGN 2009; 48: 526. Use in pediatric CD, n=25. 64% response
  • -JPGN 2009; 48 suppl 2: S111. MTX may be effective for UC.
  • -NEJM 2008; 359: 2790. Similar safety of AZA and MTX in vasculitis patients. AZA may be safer.
  • -IBD 2008; 14: 756. MTX in Crohn’s. n=39. 71% remission (20% steroid-free).
  • -J Clin Pharm & Therapeutics 2007; 32: 327-31.
  • -Am J Health Syst Pharm 2004; 61: 1380-84. review of MTX errors -FDA reported
  • http://www.npsa.nhs.uk/patientsafety/alerrts-and-directives/alerts/oral-methotrexate/
  • -Am J Gastro 2007; 102: 2804-2812. n=60 pediatric patients. ~42% in remission with MTX & ~50% improved. 13% (8) had to stop due to increased LFTs or sepsis.
  • -IBD 2006; 12: 1053. n=61. MTX for AZA nonresponders/breakthroughs: 80% with improvement/ 45% with long-term response; 10% discontinued due to side effects. Steroids stopped in 36.
  • -JPGN 2005; 40: 445. Oral MTX works as well as IM/SC.
  • -JPGN 2003; 37: 392 (194A) 0.4 mg/kg/weekly. 91% response at 2 mo, most still needed remicade
  • -Gastroenterology 2003; 124: suppl 1, A-41 (305) 11/12 responded – able to stop remicade
  • -Feagan et al. NEJM 1995; 332: 292-97.
  • -J Pediatr 1999: 134: 47. Hepatotoxic risk factors. (enzymes & obesity). Consider bx if serial enzymes increased >40% of the time over 1 year
  • -Arthritis Rheum 1997; 40: 2226.

More imaging needed?

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With new tools at our disposal in diagnosing inflammatory bowel disease, we need to decide how and when to use them.  Potential new modalities include stool inflammatory markers, video capsule endoscopy, CT enterography (CTE), and MR enterography (MRE).  Several studies have shown that the information that these studies yield may change management. The latest of these studies (Inflamm Bowel Dis 2012; 18: 219-25) looked at how the knowledge of CTE effected management and physician confidence with Crohn’s disease.

The authors prospectively assessed 273 patients with established or suspected Crohn’s disease.  In their analysis, 70 patients (48%) of established cases had altered management because of CTE and 69 (54%) of suspected cases.  These changes were considered to be  independent of clinical, serological or histologic findings.  Changes included medication modification in 45 (16.2%), excluding Crohn’s disease in 46 (16.8%), surgery referral in 10 (3.7%), alternate diagnosis established in 9 (3.2%), & canceling surgery in 7 (2.6%).  The authors considered excluding active small disease as an important management plan change; this occurred in 18 patients (6.6%).

The authors state that their current practice is to use MRE for serial imaging rather than CTE, to minimize risks from radiation; though CTE is often the initial imaging.

My take on this article is that information from imaging often increases the certainty about the diagnosis and gives a more complete picture of the severity.  It is likely that more information leads to more aggressive therapy.  At the same time, in pediatric gastroenterology, the trend towards using more effective therapy earlier in the course of the disease has developed even in the absence of extensive imaging (see previous: Only one chance to make first impression).  Whether more imaging in pediatric patients would be worthwhile is not known.

Additional references:

  • -JPGN 2008; 47: 31.  Capsule endoscopy may reclassify pediatric IBD
  • -NEJM 2010; 363: 1, 4. Safety of CT. Can have overdose of radiation and even standard doses could cause complications. Also, a big issue is downstream unnecessary testing due to incidental findings.
  • -Clin Gastro 2008; 6:283. Use of CT enterography.
  • -JPGN 2010; 51: 603.  MRE for suspected IBD.  Useful in Crohn’s disease.
  • -IBD 2004;10: 278-285.  WCE for Crohn’s (review)  Capsule can help differentiate UC from Crohn’s.

What to make of FODMAPs

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Consumption of FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) may trigger irritable bowel syndrome (IBS) symptoms.  Some research indicates that a diet low on FODMAPs may be beneficial (J Hum Nutr Diet 2011; 24: 487-95).  This study tried to assess whether a low FODMAPs diet which had been reported from a single center in Australia would be effective for IBS.

In this study, consecutive patients with IBS were divided into two groups.  39 received standard dietary advice based on UK National Institute for Health and Clinical Excellence (NICE) guidelines.  43 patients were placed on a low FODMAP dietary advice.  Patients were selected into each group consecutively (not randomized). This study reported a 76% satisfactory symptom response in the FODMAP group vs a 54% response in the control group (p=0.038).  Overall, 86% of FODMAP group had improved composite score compared with 49% of standard treatment group. Specific improvements were noted in bloating, abdominal pain, and flatulence.  The average age of the study population was 38 and 71% were females.  60% had diarrhea-predominant IBS.

NICE guidelines for IBS:

  • Healthy eating principles: regular eating, taking time to eat
  • Limit high fat foods and fizzy drinks
  • Limit insoluble fiber for diarrhea and gradually increase for constipation
  • Limit sugar-free sweets and foods with sorbitol
  • Limit fruit to 3 portions/day
  • Avoiding ‘resistant’ starch may be useful (eg. sweetcorn, green bananas, part-baked and reheated bread)
  • Addition of oats and linseeds may be helpful

Low FODMAP diet

  • Reduce high fructan foods (eg wheat and onion)
  • Reduction in high galactooligosaccharide foods (eg chickpeas, lentils)
  • Reduce high polyol foods and polyol-sweetened sources.  Replace with suitable fruits and vegetables
  • In patients with lactose malabsorption, reduce high lactose foods (eg milk, yoghurt) to smaller volumes or substitute lactose-free products
  • In those with fructose malabsorption, decrease excess fructose

Of course, reading the author’s description of a low FODMAP diet is confusing.  Translation:

Include more bananas, blueberries, lettuce, potatoes, gluten-free breads or cereals, rice, oats, hard cheeses, lactose-free milk, sugar, molasses, and artificial sweeteners that do not end in “ol.”

Avoid/eliminate apples, pears, canned fruits in natural juices, high-fructose corn syrup, cows’ milk (due to lactose), soft cheese, broccoli, cabbage, pasta, bread, baked goods from wheat/rye, mushrooms, and sweeteners like sorbitol or others that end in “ol.”

Since this diet has attracted more widespread attention, basic familiarity is important for all physicians who treat IBS.  A useful resource to explain this diet is the Wall Street Journal:

http://online.wsj.com/article/SB10001424052970204554204577023880581820726.html

This link has a good table illustrating the recommended dietary choices.

Whether FODMAPs will be superior to other dietary advice for IBS is still uncertain.  Though, given the limited number of effective treatments for IBS, this small study is a promising development.

Additional references:

  • -Clin Gastro & Hep 2009; 7: 706. n=17. 13 responded to very low carb diet (<20g/day)
  • -Clin Gastro & Hep 2008; 6: 765. Dietary triggers for IBS include fructose/fructans: honey, high fructose corn syrup, wheat, fruits.
  • -IBD 2006; 13: 91. Dietary guidelines for IBS.
  • -Clin Gastro Hepatol 2005; 10: 992-996. Obesity increases IBS symptoms; diet with low fat, high fruit/fiber have fewer symptoms
  • -Gut 2004; 53: 1459-1464. Food elimination based on IgG antibodies. Patients did better on diet with implicated foods than with control diet (diet was blinded/randomized).
  • -Am J Gastro 2011; 106: 508-514. randomized, double-blind trial showing efficacy of GFD for non-celiacs.  60% vs 32& placebo response.
  • -Nutr Clin Pract. 2011;26:294-299.  GFD for non-celiacs.
  • -Gastroenterology 2011; 141: 1941./Am J Gastro 2011; 106: 915.  Exercise improves IBS symptoms.

Big gift, how much risk

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When an individual is considering donating a part of their liver, it is no exaggeration to say this may be lifesaving.  In pediatric hepatology, live donor liver transplantation (LDLT) is frequently considered by desperate parents. The risk of this gift has been poorly understood due to a lack of a LDLT registry.

This month (Gastroenterology 2012; 142: 273-80) better data has emerged.  By combining information from UNOS and the Social Security Death Master File, the authors were able to follow 4111 LDLTs (donors) in the U.S. between 1994 and 2011. Key findings:

  • Seven early deaths (1.7 per 1000)
  • Death rate was not affected by portion of liver donated
  • 11 early catastrophic events: early deaths or acute liver failure (2.9 per 1000)
  • Long term mortality was similar to that for live kidney donors and NHANES III healthy participants over 11 year followup (1.2%, 1.2%, and 1.4% respectively)

Although these data are somewhat reassuring, there is a definite increase in mortality and morbidity among LDLT donors.  An editorial in the same issue (pg 207-09) states that LDLT donors are probably healthier than the general population; up to 65% of donor candidates are rejected during the evaluation process.  As such, when survival at 11 years is similar to NHANES III participants, this indicates the likelihood of a detrimental effect on long-term health. Besides early perioperative deaths, suicide and drug overdoses among donors was significant (n=4) and 4% of donors may develop psychiatric problems.  Specific complications include biliary leaks (9%), bacterial infections (12%), and incisional hernias (6%).

At the same time, the direct benefit of this gift including the potential of saving a loved one cannot be measured.  In addition to avoid a protracted uncertain period on the waiting list for a recipient, a donated liver may help another unidentified individual obtain a deceased donated liver.

Additional references:

-Gastroenterology 2008; 135: 468. Donor morbidity/mortality. n=393. 62% without complications. 3 deaths and significant morbidity.
-Liver Transplantation 2006; 12: 499. Review.
-DDW 2003, T Tran, n=56. only 27% of prospective donors c nl histology.
-NEJM 2003; 348: 818-25. (L & R-Lobe) complications from donating in 449. 6% biliary complications, reop in 4.5%, death 0.2%
-NEJM 2002; 346: 1074-1082. & 1038. R lobe Tx.
-J Pediatr 1999; 134: 280.  Results of LDLT: 92% 1 yr survival; higher biliary complications 19-34%.

Holes in the fiber theory

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Since the 1970s, it has been accepted that diverticular disease is related to low fiber intake and the Western diet.  Problem is that this might not be right (Gastroenterology 2012; 142: 205-10).  In this observational cross-sectional study (n=2104), low dietary fiber was not associated with diverticulosis; just the opposite.  High fiber intake, after adjusting for other factors, had an adjusted prevalence ratio of 1.3.  Due to the nature of the study, there may be potential bias that would not be present with a prospective study, especially with regard to dietary recall.  An editorial in the same issue (pg 205-07) lists three other studies; two of these also could not demonstrate a protective effect of fiber.  In addition to these findings, this study did not find an association between fat, red meat, physical activity and diverticulosis.

Although these data throw a big question mark regarding the pathogenesis of diverticular disease, this does not mean you should throw away your fiber bars quite yet.  Although low fiber may not cause diverticular disease, several large prospective studies have been completed which convincing show an association with lower complications/hospitalizations among individuals with higher fiber intake.  In addition, increased fiber in the diet has been shown to lower cardiovascular complications.

Additional references:

  • -Br Med J 1971; 2: 450-54.  Seminal article on diverticular disease and association with Western countries with low fiber intake.
  • -Am J Clin Nutr 1994; 60: 757-64.  Prospective study showing benefits of fiber in preventing diverticular complications (n=47,888); RR=0.58 for developing symptomatic diverticulitis.
  • -BMJ 2011; 343: d4131.  EPIC study, n=47,033, showing benefit of fiber in reducing hospitalizations due to diverticular dz over 12yrs (0.59 RR)
  • -NEJM 1999; 340: 169. fiber does not decrease Colon Ca risk.
  • -NEJM 2000; 342: 1149 & 1159. fiber does not decrease risk of recurrent adenomas.
  • -Am J Clin Nutr 2000; 70: 1433-1438. Fiber lowers cholesterol & can decrease risk of heart attack by 15%.