Live longer -don’t take your vitamins?

A recent editorial by Paul Offit provides data that taking more vitamins than your daily requirement is more likely to increase your risk of cancer and death (this has been noted on this blog as well –see related links below).

Link: nyti.ms/1bhK2Eg 

Here is an excerpt:

last year, a Cochrane review found that “beta carotene and vitamin E seem to increase mortality, and so may higher doses of vitamin A.”

What explains this connection between supplemental vitamins and increased rates of cancer and mortality? The key word is antioxidants.

Antioxidation vs. oxidation has been billed as a contest between good and evil. It takes place in cellular organelles called mitochondria, where the body converts food to energy — a process that requires oxygen (oxidation). One consequence of oxidation is the generation of atomic scavengers called free radicals (evil). Free radicals can damage DNA, cell membranes and the lining of arteries; not surprisingly, they’ve been linked to aging, cancer and heart disease.

To neutralize free radicals, the body makes antioxidants (good). Antioxidants can also be found in fruits and vegetables, specifically in selenium, beta carotene and vitamins A, C and E. Some studies have shown that people who eat more fruits and vegetables have a lower incidence of cancer and heart disease and live longer. The logic is obvious. If fruits and vegetables contain antioxidants, and people who eat fruits and vegetables are healthier, then people who take supplemental antioxidants should also be healthier. It hasn’t worked out that way.

The likely explanation is that free radicals aren’t as evil as advertised. (In fact, people need them to kill bacteria and eliminate new cancer cells.) And when people take large doses of antioxidants in the form of supplemental vitamins, the balance between free radical production and destruction might tip too much in one direction, causing an unnatural state where the immune system is less able to kill harmful invaders. Researchers call this the antioxidant paradox.

In December 1972, concerned that people were consuming larger and larger quantities of vitamins, the F.D.A. announced a plan to regulate vitamin supplements containing more than 150 percent of the recommended daily allowance. Vitamin makers would now have to prove that these “megavitamins” were safe before selling them. Not surprisingly, the vitamin industry saw this as a threat, and set out to destroy the bill. In the end, it did far more than that.

Industry executives recruited William Proxmire, a Democratic senator from Wisconsin, to introduce a bill preventing the F.D.A. from regulating megavitamins. On Aug. 14, 1974, the hearing began.

Speaking in support of F.D.A. regulation was Marsha Cohen, a lawyer with the Consumers Union. Setting eight cantaloupes in front of her, she said, “You would need to eat eight cantaloupes — a good source of vitamin C — to take in barely 1,000 milligrams of vitamin C. But just these two little pills, easy to swallow, contain the same amount.” She warned that if the legislation passed, “one tablet would contain as much vitamin C as all of these cantaloupes, or even twice, thrice or 20 times that amount. And there would be no protective satiety level.” Ms. Cohen was pointing out the industry’s Achilles’ heel: ingesting large quantities of vitamins is unnatural, the opposite of what manufacturers were promoting.

A little more than a month later, Mr. Proxmire’s bill passed by a vote of 81 to 10. In 1976, it became law. Decades later, Peter Barton Hutt, chief counsel to the F.D.A., wrote that “it was the most humiliating defeat” in the agency’s history.

As a result, consumers don’t know that taking megavitamins could increase their risk of cancer and heart disease and shorten their lives; they don’t know that they have been suffering too much of a good thing for too long.

Paul A. Offit is the chief of the infectious diseases division of the Children’s Hospital of Philadelphia and the author of the forthcoming book “Do You Believe in Magic?: The Sense and Nonsense of Alternative Medicine.”

Related blog entries:

Expert review: Celiac disease

A recent article gives a concise expert update on Celiac disease (NEJM 2012; 367: 2419-26).

As this is an area that has been covered several times by this blog and is familiar to most of the followers, I will comment on a few issues that were particularly interesting to me.  Though, the review is thorough and a helpful reference on most aspects of celiac disease..

What is the gluten threshold?  In patients with celiac disease, a minimal degree of gluten contamination is difficult to avoid.  “The lowest amount of daily gluten that causes damage to the celiac intestinal mucosa over (the gluten threshold) is 10 to 50 mg per day (a 25-g slice of bread contains approximately 1.6 g of gluten).”  New regulations propose that foods which are labeled as gluten free have less than 20 ppm of gluten contamination.

When are intraepithelial lymphocytes increased in the duodenum?  The abnormal threshold is considered >25 per 100 enterocytes.

What proportion of celiac disease patients have been diagnosed?  According to a recent European study, only a small proportion (21%) of celiac patients are clinically recognized.

Best screening test currently? Anti-tissue transglutaminase (TTG) IgA antibody –both sensitivity and specificity are >95%.  Consider TTG IgG in patients with IgA deficieny or possibly deamidated gliadin IgG.

Potential complications of untreated celiac disease? Osteoporosis, impaired splenic function, neurologic disorders, infertility or recurrent abortion, ulcerative jejunoileitis, and cancer.

Biopsy needed? Usually, “although recent guidelines suggest that biopsy may not be necessary in selected children with strong clinical and serologic evidence of celiac disease.”

Population-based screening or case-finding?  At this time, population-based screening is not recommended.  Case-finding based on symptoms and screening of at-risk groups is recommended though this is likely to miss >50% of cases.

Related blog posts:

Critical drug shortages in U.S.

While the U.S. spends a lot of money on health care, there is little incentive to produce older drugs with small profit margins.  In addition to the financial aspects, there are many other factors involved including the following:  limited number of manufacturers, increased worldwide demand, aging production plants, shortages of materials, stockpiling, and regulatory demands. This is resulting in detrimental outcomes (NEJM 2012; 367: 2461-63).

A specific example is the shortage of mechlorethamine (nitrogen mustard).  Since the 1960s it has been part of a MOPP regimen for Hodgkin’s lymphoma.  For pediatric patients, a modification of this regimen, the Stanford V regimen, has had good success rates for Hodgkin’s lymphoma.

Due to the shortage of mechlorethamine, cyclophosphamide has been substituted into the regimen.  While this substitution was thought to be equally efficacious, a group of investigators from St. Jude/Univ Tennessee, Dana-Farber/Boston Children’s, and Lucile Packard Children’s/Stanford have found that this substitution has resulted in a much lower 2-year event-free survival: 75% with new regimen compared with 88% with previous regimen.  This is despite the fact that patients receiving the newer regimen did not have a more unfavorable treatment profile.

Patients who relapsed had salvage therapy with stem-cell transplantation.  The long-term outcome of the newer regimen group, nevertheless, appears substantially worsened.

This example is not isolated.  Other cancer-drug shortages have included cytarabine, daunorubicin, and methotrexate.  While some of these shortages have been resolved quickly, the frequency of these shortages as well as drugs used for multiple other diseases is alarming.  When physicians and pateints are faced with the prospect of receiving inferior care due to drug shortage, this is extremely “hard to swallow.”

Dietary supplements — safe and effective?

Most people consider dietary supplements as likely to be beneficial but at the very least ‘there not going to make you worse.’  That sentiment is wrong.  A review recently published has shown that some dietary supplements may increase the risk of cancer (Journal of the National Cancer Institute 2012; 104: 732-39).

Nearly half of the US adult population uses one or more dietary supplements but there is very little evidence that these supplements reduce cancer risk; in fact, the contrary is true.  Based on numerous studies, the authors make extensive comments regarding the studies of antioxidants, folic acid, and vitamin D/calcium which are summarized below.

Antioxidants

While observational data has suggested benefits from fruit and vegetable consumption, data on antioxidant supplement consumption has not shown a beneficial effect.  The review highlights a number of studies with regard to β-carotene, vitamin A, vitamin C, and vitamin E/α-tocopherol.  Specifically, vitamin C and E do not protect against total cancer incidence. α-tocopherol and β-carotene do not protect against cancer or cancer mortality.

  • The Selenium and Vitamin E Cancer Prevention Trial (SELECT) followed 35,533 men at average risk for prostate cancer for approximately 5.5 years.  This study was halted due to lack of benefit.  In addition, the extended followup reported that α-tocopherol significantly increased the risk of prostate cancer by 17%.
  • The β-carotene and Retinol Efficacy Trial (CARET) had a 39% increase in lung cancer incidence compared to the placebo arm.
  • In two of three large studies of β-carotene, the intervention increased the risk of all-cause mortality.
  • The Nutritional Prevention of Cancer (NPC) extended followup found that selenium supplementation statistically increased the risk of squamous cell skin cancer by 25% and non-melanoma skin cancer by 17%.

Folic Acid

Folic acid which is a synthetic oxidized form of folate is commonly used in fortification and supplements.  Recent meta-analysis of randomized controlled trials (RCTs) has found no effect of folic acid supplementation on the risk of colorectal adenomas over a 3-year treatment period.  In addition, one study demonstrated an increased risk of advanced colorectal adenomas (relative risk = 1.67).  Also, in observational studies, higher intake of folic acid has been linked with increased prostate cancer risk.

Vitamin D and Calcium

The Institute of Medicine published recommendations with regard to Vitamin D and calcium intake in 2011 and found that “there is not enough evidence to state that there is a causal association between low vitamin D intake and increased cancer risk.”  The authors summarize several conflicting results with regard to breast, colorectal, and prostate cancers. In addition, a recent meta-analysis of RCTs indicated that calcium supplementation was associated with a statistically-increased myocardial infarction risk.

Why are supplements so widespread if they are not beneficial and potentially dangerous?

  • The authors also summarize regulatory efforts.  In 1990, due to unsubstantiated health claims by food manufacturers, Congress passed the Nutrition Labeling Education Act (NLEA).
  • To limit FDA authority over supplements, at the behest of nutritional supplement manufacturers, in 1994 Congress passed the Dietary Supplement Health and Education Act.  This classified supplements as food and limited the role for the FDA.
  • In 2006, in reaction to deaths from ephedra, Congress passed the Dietary Supplement and Non-prescription Drug Consumer Protection Act.  This allows the FDA to collect adverse reports on supplements but did not give additional regulatory powers.

Conclusions from this review

  1. In populations with a high background of normal nutrient status, risk is accentuated if there can be harm at higher doses.  For selenium (in the NPC study), apparent benefits have been confined to individuals with the lowest baseline blood selenium levels.
  2. It is not reasonable to assume that consumption of a single nutrient would exert a chemopreventive effect equally in all tissues.  In addition, there are substantial variations in formulations and doses of supplements available.
  3. Efficacy and harm are typically tested over several years.  Given the natural history of cancer, it may take decades to assess supplement impact.
  4. Multiple consensus recommendations have indicated that supplements do not prevent cancer and do not prevent chronic disease (Table 1 in reference).  The most recent was from the American Cancer Society in 2012. “Present knowledge indicates that dietary supplements do not lower cancer risk.”
  5. Despite the evidence, the authors note that believers in supplements are unlikely to accept ‘mainstream’ science.  Some may think that unconventional treatments are ignored by science for monetary reasons. Some may think that these products are regulated and would not be offered if they were not beneficial.

Related post:

common to be “d-ficient” | gutsandgrowth

Staggering cost of obesity

For a single individual, the burden of obesity can be enormous; for a society, the projected costs for health and economics are hard to fathom (Lancet 2011; 378: 815-25).

By 2030, this report projects that there will be 65 million more obese adults in the US and 11 million more in the UK.  This is expected to cause an additional  6-8.5 million cases of diabetes, 5.7-7.3 million cases of heart disease/stroke, about 500,000 cases of cancer, and loss of 26-55 milion life years.  The medical costs are estimated to increase $48-66 billion/year in the US.

These projections are based on expected increases in the percentage of individuals who are obese.  In 2008, approximately 32% of US adult men were obese based on BMI; in 2030, the projected number is 50-51% for men.  Among US women: 35% in 2008 –> 45-52% in 2030.

To flatten the curve on spending, we will need to look at flattening other curves.

Additional references:

  • A liver disease tsunami
  • -NEJM 2011; 365: 1597. Persistence of hormonal adaptations with weight loss. Due to persistent changes in hormones like leptin & peptide YY, hard to keep wt off -result is increased appetite.
  • -NEJM 2009; 360: 859. Composition of diet does not seem to be important. Total calories important.
  • -Pediatrics 2007; 120: suppl 4: S164-S287.
  • -NEJM 2007; 357: 370. obestiy spreads in social network.  Your friends may be more influential than your genetics.
  • -Gastroenterology 2007; 132: 2085-2276. Special issue on obesity issues.
  • -NEJM 2006; 355: 1593. Case review on obesity c DDx and mgt.
  • -Pediatrics 2003; 112: 424. Position paper on prevention in childhood.
  • -Gastroenterology 2001; 120: 669-681. (review)
  • -J Pediatr 2005; 147: 429. TV viewing predicts adult BMI.
  • -Lancet 2001; 357: 505-8. One extra soda/day incr risk of obesity by 60%
  • -NEJM 1999; 341: 1097. BMI & mortality.

More bad news for smokers

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.

A cure for satiety

A safe cure for excessive appetite is a holy grail in pharmacology.  Although gluttony is a much more pervasive problem that poor appetite, an effective cure for satiety is also needed.  In the clinical setting, poor appetite remains a common problem with and without underlying problems.  Treatments to this point, such as cyproheptadine or megestrol, may be useful in some patients.  Better treatments are needed.  One drug of interest is ghrelin (Cancer 2012; DOI: 10.1002/cncr.27430).

The introduction summarizes ghrelin’s biologic activity: “Ghrelin is an endogenous ligand for the growth hormone (GH) secretagogue receptor and is secreted predominantly by gastric endocrine cells.  It induces dose-dependent, GH-releasing activity; stimulates appetite and food intake; and triggers a positive energy balance through a central mechanism involving hypothalamic neuropeptides.”

Plasma ghrelin levels decrease after gastric resection, helping to maintain weight loss. Therefore, the stomach may act as endocrine organ to maintain appropriate weight. Exogenous administration may increase appetite.

This cited article reports a prospective randomized placebo-controlled phase 2 study in which ghrelin was administered to 21 patients with esophageal cancer, receiving cisplatin-based chemotherapy; the dosage was 3 μcg/kg twice daily for 1 week.  A placebo group  (n=20) received saline.  The ghrelin group consumed 18.2 kcal/kg/day compared with 12.7 kcal/kg/day.  A measure of appetite, an appetite visual analog score, was also higher in the ghrelin-treated patients, 6.2 vs 4.1.  Patients in the ghrelin group had fewer adverse effects of chemotherapy related to anorexia and nausea than patients in the control group.  One patient receiving ghrelin stopped therapy because of excessive diaphoresis.

Although this medication is being studied in adult chemotherapy patients, down the road ghrelin and potential analogs may have a role in pediatric patients with a variety of disorders which inhibit their appetite.

Additional references:

  • -Adachi S, Takiguchi S, Okada K, et al. Effects of ghrelin administration after total gastrectomy: a prospective, randomized, placebo- controlled phase II study. Gastroenterology. 2010;138:1312-1320.
  • -NEJM 2002; 346: 1623-30, 1662. Plasma ghrelin levels decrease after gastric resection.   Therefore, stomach may act as endocrine organ to maintain appropriate weight. However, ghrelin levels are reduced in obesity; so it is not clear that further reduction of these levels is clinically important.
  • -Gastroenterology 2003; 125: 1492. Review of ghrelin.
  • -Yamamoto K, Takiguchi S, Miyata H, et al. Randomized phase II study of clinical effects of ghrelin after esophagectomy with gastric tube reconstruction. Surgery. 2010;141:31-38.
  • -Nakazato M, Murakami N, Date Y, et al. A role for ghrelin in the central regulation of feeding. Nature. 2001;409:194-198.
  • -Kojima M, Hosoda H, Date Y, et al. Ghrelin is a growth-hormone- releasing acylated peptide from stomach. Nature. 1999; 402:656- 660.
  • http://www.surgjournal.com/article/S0039-6060(09)00784-3/abstract
  • http://pennmedicine.adam.com/content.aspx?productId=16&pid=16&gid=50495 Review of cited article.

Good News for Celiac Disease

With the discovery of precise serologies to identify celiac disease, the likelihood of complications of celiac disease has been changing.  In addition, the presentation of celiac disease is different now.  Instead of seeing children with malabsorption and abdominal distention, many children and adults are identified with mild or no symptoms.  Also, the risk of severe complications including malignancy and autoimmune disease has been reevaluated based on larger cohorts.  Twenty years ago, the risk of these complications did serve as a motivator for continuation of a gluten free diet (GFD).   While a GFD remains important, these risks are much lower than previously reported.  The most recent article to support this contention is the following:

Clinical Gastroenterology and Hepatology 2012; 10: 30-36.  This study examined ~45,000 patients with either celiac disease (villous atrophy, Marsh score of 3), duodenal inflammation (Marsh 1 or 2), or latent celiac disease (normal mucosa & positive serology).  After the first year, there was no significant increase risk for GI cancers.  During the first year, cancers that were identified may not have been causally-related to celiac disease but due to coincident detection.

This article due to its large cohort is very useful, but other articles have come to different conclusions.  Irregardless, there are still compelling reasons to continue a GFD.  Many individuals feel better on a GFD & did not recognize prior symptoms.  Maintaining this diet probably lowers the risk of developing certain autoimmune conditions and definitely improves bone health.

Other recent &/or related articles:

Gastroenterology 2010; 139: 763. Mortality NOT worsened in undiagnosed celiac disease (identified by review of serology) in Olmstead County, though bone density decreased. n=129 of 16,847. (?milder cases undiagnosed)
J Pediatrics 2010; 157: 373, 353. Even patients without villous atrophy & positive serology, benefited from GFD with regard to GI symptoms and serological markers.
JAMA 2009; 302: 1171-78. n=29,096. Mortalitiy increased in celiac disease: 35% for latent, 72% for inflammation, 39% for celiac dz.

Clin Gastro & Hep 2008; 6: 753.  Incidence of autoimmune diseases less in those celiac patients who were compliant with GFD. n=178.

Gastroenterology 2002; 123; 1428-1435. n=12,000.  Risk for cancer 1.3 odds ratio (lower than in previous studies).