Malignancy Risk with Thiopurines

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Based on a large retrospective, nationwide cohort study, it has been estimated that patients with ulcerative colitis have a 4-fold increase in the risk of lymphoma compared with patients who have not been treated with thiopurines (Gastroenterol 2013; 145: 1007-15).  While this study enrolled data from 36,891 patients followed for a median of 6.7 years, this study should not be interpreted in isolation.  The editorial (pages 927-30) provides some important context.

Besides the risk of lymphoma in patients treated with the thiopurines, the editorial briefly states the potential for life-threatening infections, primarily varicella and hemophagocytic lymphohistiocytosis which may complicate primary EBV infection.  The latter is much more common in younger patients.

With regard to malignancy, besides lymphoma, thiopurines also increase the frequency of nonmelanoma skin cancer.  Since these are not life-threatening, in many patients the risk of lymphoma is “the major limiting factor for the prolonged use of thiopurines.”  Furthermore, the risk of lymphoma may increase relative to treatment duration according to the above-referenced study. The editorial notes that there are three types of lymphoma to be considered:

  1. Posttransplant-like lymphoma associated with EBV seropositivity. Absolute risk in all IBD patients ~ 1 per 1000 patient-years.  All EBV-seropositive patients are at risk.
  2. Early post-mononucleosis lymphomas. Absolute risk in all IBD patients ~0.1 per 1000 patient-years; however, the risk in young men who are seronegative for EBV (<35 years) is ~3 per 1000 patient-years.
  3. Hepatosplenic T-cell lymphomas.  Absolute risk in all IBD in all IBD patients ~0.05 per 1000 patient-years; again, in young patients (mostly men) the risk is ~0.1 per 1000 patient-years.

The second and third types of lymphomas can be reduced by limiting thiopurines in young men.

Despite the risks posed by thiopurines, the overall benefit-risk balance needs to consider the fact that the risk of colorectal cancer “is markedly reduced in patients with long-standing extensive colitis exposed to thiopurines.”  Thus, the lowered risk of colorectal cancer “may outweigh the excess risk of lymphoma.”

Also, in considering thiopurines:

Inflamm Bowel Dis 2013; 19: 2801-08.  “Thiopurines are Associated with a Reduction in Surgical Re-resections in Patient’s with Crohn’s Disease.”  This study was a retrospective review of 567 patients of whom 237 (41.8%) developed a surgical recurrence after a median of 70 months.  Taking thiopurine was associated with a hazard ratio of 0.51.  Due to small numbers, the results with anti-TNF therapy was not conclusive, but “seems promising as well.”

Related blog posts:

Liver fibrosis in determining treatment for Hepatitis B

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A recent editorial reviews current guidelines and makes the point that while patients with advanced fibrosis should receive antiviral treatment, treatment is also recommended for patients with high levels of HBV DNA and active liver disease (Clin Gastroenterol Hepatol 2013; 11: 1500-02).  The related study (Clin Gastroenterol Hepatol 2013; 11: 1493-99) indicated that guidelines do not predict accurately which patients have ≥F2 fibrosis.  The editorial argues that the study’s conclusions are “misguided” because ALT and HBV DNA are not used solely for identifying patients with fibrosis.

Key points:

  • 18-47% of HBV-related HCC occurs in the absence of cirrhosis.
  • Guidelines “agree that treatment should be initiated in non-cirrhotic patients with serum HBV DNA >20,000 IU/mL and alanine aminotransferase (ALT) levels higher than 2 times upper limit of normal (ULN) or histologic evidence of moderate-to-severe inflammation or fibrosis.”
  • For HBeAg-negative patients, AASLD guidelines suggest a lower threshold for HBV DNA (>2000 IU/mL) along with ALT >2 times ULN or ALT 1-2 times ULN with concerning liver biopsy (particularly in age >40 years).
  • “Since treatment does not eradicate the virus…and in many instances [is] lifelong treatment, we agree with Sanai et al that criteria for initiating hepatitis B treatment in guidelines must be carefully weight to avoid unnecessary treatment.”

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MIRTH Study -Laughter in Medicine

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From NY times review of a recent BMJ study:  http://t.co/RavJd8FgSJ

An excerpt:

Just in time to protect patients from the dangers of holiday cheer, a new scholarly review from a British medical journal describes many harmful effects wrought by laughter. 

Among the alarms it sounds: The force of laughing can dislocate jaws, prompt asthma attacks, cause headaches, make hernias protrude. It can provoke cardiac arrhythmia, syncope or even emphysema (this last, according to a clinical lecturer in 1892).

Laughter can trigger the rare but possibly grievous Pilgaard-Dahl and Boerhaave’s syndromes…

And ponder, briefly, the mortifying impact of sustained laughter on the urinary tract (detailed in a 1982 The Lancet paper entitled “Giggle Incontinence”).

At the very least, the new review could be considered an affirmation for the perpetually dour….

The analysis, “Laughter and MIRTH (Methodical Investigation of Risibility, Therapeutic and Harmful),” was drawn from about 5,000 studies. It appears in BMJ, formerly known as The British Medical Journal, which for more than 30 years has traditionally featured rigorously researched but lighthearted articles in its Christmas issue. A deputy editor, Dr. Tony Delamothe, said that the MIRTH study was indeed peer-reviewed — presumably by a doctor with a carefully managed sense or humor (or humour).

This year, companion studies in the issue include “Were James Bond’s drinks shaken because of alcohol induced tremor?” , “The survival time of chocolates on hospital wards: covert observational study,”  and “Operating room safety: the 10 point plan to safe flinging”  (among the cautions: “Before flinging, identify your target and the area beyond it” and “Never fling an instrument straight up into the air”).

Dr. Ferner and Dr. Aronson considered holiday foods, for example, but their tastes were not in concert. “He likes sweet wines and I like dry wines,” Dr. Ferner explained. Then they found common cause: ”But we both like dry humor.”…

They winnowed down the papers that mentioned laughter to 785, putting them into three categories: benefits (85), harms (114) and conditions causing pathological laughter (586).

The question was timely, they argue, because BMJ had not addressed laughter in a serious fashion in over a century. In 1898, it had published a case study of heart failure in a 13-year-old girl following prolonged laughter. The next year, the laughter problem was raised again, when an editorial writer, in response to an Italian doctor’s suggestion that telling jokes could treat bronchitis, dismissively proposed the term “gelototherapy” (Gelos was the Greek god of laughter; in Italian, gelato is ice cream.)…

The harms, however, have been scrutinized. A 1997 discussion of Boerhaave’s syndrome, a spontaneous perforation of the esophagus, a rare though potentially lethal event, mentioned that one unusual precipitating cause is laughter.

Then there is the mysterious Pilgaard-Dahl syndrome, identified in a 2010 article  as a pneumothorax in middle-aged male smokers induced by laughter. It takes its name from Ulf Pilgaard and Lisbet Dahl, the Danish revue performers….

There were other respiratory threats occasioned by laughter, he said. The popping of alveoli (the air sacs in the lungs, which together typically contain about 600 million):  “If you’re going to make asthmatics laugh heartily,” Dr. Ferner said, “they might want to have an inhaler by their side.” (This, extrapolated from a 1936 experiment on the mechanism of laughter in asthmatics.)

There are choking hazards, such as ingesting food during belly laughs.

The MIRTH review did take an even-handed, cost-benefit approach to laughter, noting ample evidence of its salutary effects. It concluded that laughter’s benefits included reduced anger, anxiety and stress; reduced cardiovascular tension, blood glucose concentration and risk of myocardial infarction. “The benefit-harm balance,” the authors wrote, “is probably favourable.”

Studies in recent years concluded that laughter “reduces arterial wall stiffness” and “improves endothelial function.” And a 2008 study of patients with chronic obstructive pulmonary disease concluded that laughter inspired by Pello the clown improved lung function….

Despite such a comprehensive look at the medical literature on laughter, Dr. Ferner felt there was still territory to be charted. “We don’t know how much laughter is safe,” he said. “There’s probably a U-shaped curve: laughter is good for you, but enormous amounts are bad, perhaps. It’s not a problem in England.”

When to Screen Patients Taking Ondansetron (Zofran)

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A recent study indicates that a single oral dose of ondansetron (Zofran®) is safe.

This excerpt from Eric Benchimol’s twitter feed: ow.ly/rBaV0:

New research from The Hospital for Sick Children (SickKids) and the University of Calgary’s Alberta Children’s Hospital Research Institute helps to clarify the actual risk of ondansetron administration and cardiac arrhythmias in both children and adults. The study is published in the December issue of Annals of Emergency Medicine. 

In 2011, the Food and Drug Administration notified health-care professionals and patients of an ongoing safety review and labelling changes for the anti-nausea drug linking its use to the possibility of inducing abnormal and potentially fatal arrhythmias.  The warning also implied that doctors needed to rule out conditions that might place patients at risk for developing an abnormal heart rhythm prior to giving patients the drug.  Screening all patients for such conditions requires ECG monitoring and blood testing, which are associated with discomfort, delayed care and may lead to additional unnecessary investigations and anxiety.  In 2012, the FDA issued an update linking the risk only to the administration of the drug in high doses intravenously. However, there was no change in the universal screening recommendations to all patients before receiving ondansetron, in any dose or route…

Through an in-depth post-marketing analysis which included a systematic review of published literature, the FDA Adverse Events Reporting System and the World Health Organization Individual Safety Case Reports Database, Drs. Yaron Finkelstein and Stephen Freedman explored this association. They did not find any reports of arrhythmia related to the administration of a single oral dose of ondansetron, the most common administration route, employed in over 85 per cent of doses given to children in emergency departments…

The study’s principal investigator, Dr. Yaron Finkelstein, staff physician in Paediatric Emergency Medicine and Clinical Pharmacology and Toxicology and Associate Scientist at SickKids. “Despite more than 22 years of use and hundreds of millions of ondansetron doses administered worldwide, we did not find evidence to support screening of patients without known risk factors before administering a single oral ondansetron dose.” 

Bottomline:  “The authors concluded that ECG screening and electrolyte testing should be targeted to patients with known risk factors such as patients with cardiac diseases or those concomitantly receiving other arrhythmia-inducing medications and those receiving ondansetron intravenously or repeated doses, while it is not warranted in low-risk individuals who are receiving a single oral dose.”

Related blog post: A drug that makes a difference: ondansetron | gutsandgrowth

Hemophagocytic Lymphohistioctosis: Advances

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A recent medical progress report provides a concise update on hemophagocytic lymphohistiocytosis (HLH) (J Pediatr 2013; 163: 1253-59).

  • Table 1 summarizes the subtypes of HLH.
  • Atypical presentations include colitis and hypogammaglobulinemia.
  • Table 2 provides the diagnostic criteria.
  • The treatment approach is outlined as well.  In the short-term, with primary HLH, the goal is controlling the hyperinflammatory state (often with dexamethasone and etoposide).  The long-term goal aims to definitively correct the underlying genetic defect by allogeneic hematopoietic stem cell transplantation (HCT)

Other points:

  • A genetic diagnosis of familial HLH can be made in 40-80% of HLH cases with the identification of PRF1, UNC13D, STX11, and STXBP2 genes.
  • UNC13D are the predominant defects identified in Caucasians in U.S.
  • PRF1 is most common in African-American patients.
  • Ferritin remains an excellent screening tool.  A level >500 mcg/L is suggestive (but not specific) for HLH; a level >10,000 has much greater specificity (96%) along with fairly high sensitivity (90%).
  • HLH is commonly referred to as macrophage activation syndrome (MAS) in the setting of a rheumatologic illness.
  • There is no broad consensus on management of secondary HLH.  In MAS, therapy often includes pulsed steroids and/or cyclosporine.

Related blog post:

Healthy Obesity?

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From NY Times,  nyti.ms/1diH2d4 –an excerpt:

The idea that there are obese people who are nonetheless healthy may be a myth.

Although some overweight or obese people have normal cholesterol, glucose levels and blood pressure — elements of so-called metabolic health — a new study suggests that obesity by itself increases the risk for heart disease, stroke, diabetes and death.

Researchers analyzed 12 studies that had together followed more than 61,000 adults, most for at least 10 years. About 9 percent of the subjects were obese and metabolically healthy — that is, they had normal LDL, HDL and total cholesterol, along with healthy blood pressure and blood sugar levels. The report was published online last week in Annals of Internal Medicine.

Compared with metabolically healthy people of normal weight, the obese group had a 24 percent increased risk for fatal and nonfatal cardiovascular events like heart attack and stroke, and for death by any cause.

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Expert Commentary on GERD Surgery in Infants

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In this month’s “GI & Hepatology News,” Dr. Ben Gold and Dr. Jose Garza comment on antireflux surgery in infants (page 12) (related article on page 1 of same issue). Initial reference: JAMA Surg 2013 [doi: 10.1001/jamasurg.2013.2685]. See the following link.  They comment on the lack of workup for many of these infants who undergo this major surgery and the frequent lack of involvement by pediatric gastroenterologists.

PDF: December issue – American Gastroenterological Association

Vitamins: often ‘throwing money down the drain’

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From USA Today: Medical journal: ‘Case closed’ against vitamin pills

“it’s time for most consumers to stop wasting money on multivitamins and other supplements, because they have no proven benefits and some possible harms.”

That declaration comes in a strongly worded editorial that accompanies two new studies and an expert panel’s report published Monday in the Annals of Internal Medicine.

“The message is simple: Most supplements do not prevent chronic disease or death, their use is not justified, and they should be avoided,” says the editorial, signed by two researchers from Johns Hopkins University in Baltimore, one British researcher and one of the journal’s senior editors…

The new results from that study will disappoint anyone who hoped a multivitamin might keep them sharp in old age. The study followed male physicians over age 65 for an average of 11 years and found multivitamins had no effect on cognitive decline…

A second, unrelated, new study in Annals found high-dose multivitamins had no effect on the progression of heart disease in heart attack survivors…

there are exceptions. For example, health officials strongly urge women of childbearing age to take folic acid, to prevent birth defects. Some ongoing studies of vitamin D, he says, are justified because some benefits…

most of the 53% of U.S. consumers who use supplements are wasting money, to the tune of $28 billion a year.

Same story from NY Times: http://t.co/kEwrk1mGyQ

Related blog entry:  Live longer -don’t take your vitamins? | gutsandgrowth

Risk of Vitamin B12 Deficiency with Persistent PPI Usage

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From NY Times, nyti.ms/1kwQHPF :

People who use certain acid-suppressing drugs for two years or longer are at increased risk of vitamin B12 deficiency, which can lead to anemia, neurological problems or dementia, researchers reported on Tuesday.

The drugs in question are called proton-pump inhibitors, or P.P.I.’s, and histamine 2 receptor antagonists, and they are available by prescription and over the counter under brand names like Prevacid, Prilosec and Nexium. Nearly 157 million prescriptions were written for P.P.I.’s alone last year.

“People who are taking these medications are more likely than the average person to be vitamin B12 deficient, and it’s a potentially serious problem,” said Dr. Douglas A. Corley, senior author of the new study, published in The Journal of the American Medical Association. “This raises the question of whether people taking these medications for long periods should be screened for vitamin B12 deficiency.”

Dr. Corley has received funding from Pfizer, which makes a P.P.I. called Protonix.

He and his colleagues at Kaiser Permanente in Oakland, Calif., examined the medical records of 25,956 adults who received vitamin B12 deficiency diagnoses between 1997 and 2011, comparing them with 184,199 patients without B12 deficiency during that period.

Patients who took P.P.I’s for more than two years were 65 percent more likely to have a vitamin B12 deficiency, the researchers found. Higher doses of P.P.I’s were more strongly associated with the vitamin deficiency, as well.

Twelve percent of patients deficient in vitamin B12 had used P.P.I.’s for two years or more, compared with 7.2 percent of control patients. The risk of deficiency was less pronounced among patients using H2RA’s long term: 4.2 percent, compared with 3.2 percent of nonusers.

The new study is the largest to date to demonstrate a link between taking acid suppressants and vitamin B12 deficiency across age groups. Earlier small studies focused primarily on the elderly.

Robert J. Valuck, a professor of pharmacy at the University of Colorado in Aurora, was surprised that the association in the new report was strongest in adults younger than age 30. “It’s not safe to assume vitamin B12 deficiency is only an issue in the elderly,” he said.

Bottomline: patients (not just elderly) on chronic PPIs may need to be tested for vitamin B12 deficiency.

Related blog entries:

Are we missing Vitamin B12? | gutsandgrowth