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

It is a Question of Fairness

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One of my professors in medical school frequently described ethical issues in terms of some things being unfair and some things being unfortunate.  A report in this month’s Liver Transplantation (2013: 19: 1330-42; editorial 1287-88) indicates that sometimes an individual does not receive a liver transplant due to an unfair allocation policy.  One potential problem with the current UNOS distribution is the use of exception points.  Because the Model for End-Stage Liver Disease (MELD) score does not work well for all patients, there are both recognized exceptional diagnoses (REDs) (eg. hepatocellular carcinoma) and non-REDs (eg. cholangitis).  The purpose of these exception points is to account for some conditions that may increase the risk of dying on the transplant list in which the MELD score is not an adequate predictor.

In this study of adult liver transplant candidates between 2002-2011, the authors examined non-REDs; among a cohort of 58,641, 7.4% applied for a non-RED.  The number of non-REDs increased over the course of the study.  In addition, approval rates which were <50% in 2002 increased to nearly 75% in 2010. Candidates with approved exceptions were more likely to undergo transplantation (68.3% vs. 53.4%, P <0.001).

There was significant variability among transplant centers with regard to requesting exception points. Centers with higher median MELD score at transplantation were more likely to have candidates with non-RED applications. The net result was that women, African-Americans, Hispanics, and patients with Medicaid insurance were statistically less likely to have an exception application.

In pediatrics, non-RED applications are more common. Thus, the problem of equitable distribution could be even greater among pediatric patients.

Bottomline: While physicians have a duty to their patients, it is vital to make sure that every effort is made to allocate organs in a fair manner.  Since the use of non-RED applications is inconsistent, it suggests that some transplant centers are utilizing this tool inappropriately (?too often, ?too few).  This report indicates that more work is needed to have a fair transplant allocation system.

Related blog posts:

Looking behind and looking forward in EoE (part 2)

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While yesterday’s article was good, today’s is really forward-thinking (Gastroenterol 213; 145: 1289-99).  Last year in this blog, I reviewed the use of microRNA for studying EoE (MicroRNA signature for eosinophilic esophagitis | gutsandgrowth), this study expands on this idea with the development of the EoE diagnostic panel (EDP) which is a 96-gene quantitative polymerase chain reaction assay.

The authors (one of whom [JG] has joined our group) used this assay initially in 15 pediatric with EoE, in 14 pediatric non-EoE, and then in a subsequent cohort of 194 pediatric and adult patient samples (fresh or formalin-fixed tissue from one esophageal biopsy).  Of the latter cohort, 91 had histologically-active EoE, 57 had either non-EoE or EoE in remission, 34 were histologically-ambiguous, and 12 had reflux.

Results -first of all you have to see the results to get the best sense of how impressive they are.  Numerous figures show the EDP depictions of patients’ EoE transcriptome patterns.

  • EDP had approximately 96% sensitivity and 98% specificity; EDP’s utility could be underestimated due to limitations in the current ‘gold standard’ for diagnosis
  • EDP can distinguish EoE in remission from healthy controls as well as identify patients exposed to swallowed glucocorticoids.  Thus, with current patients in remission, the tissue may appear healthy; nevertheless, EDP identifies molecular changes in this tissue.
  • EDP can distinguish EoE from reflux

What this study means:

  1. Currently both the diagnostic standards (eg. cutoff values for eosinophils) and remission standards remain questionable.  This molecular test has the potential to raise the standard for both diagnosis and response to treatment.
  2. EDP may elucidate differences in EoE pathogenesis which could vary from patient to patient.
  3. EDP may help in prospective trials and help in clinical practice by identifying patients who are most likely to benefit from the treatments that are available.
  4. EDP may help overcome the patchy nature of eosinophil distribution.
  5. EDP serves as a model for how molecular testing could influence many inflammatory conditions including asthma, inflammatory bowel disease and biliary atresia.

While I think this study is going to be highly influential, I have one unanswered question:  how much will it cost?  In the conclusion, the authors state “the EDP offers an accurate, rapid, informative, and low-cost diagnosis.”  Yet, the authors do not elaborate on the expense of this technology.

Related blog entries:

A Cautionary Tale –Is it Medical Child Abuse?

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From Jeff Schwimmer’s twitter feed:

A story in the Boston Globe highlighting the difficulty of differentiating Mitochondrial Disease from Medical Child Abuse; the latter term is now preferred over Munchausen Syndrome by Proxy. Her gastroenterologist was involved due to stooling problems (this child underwent a cecostomy tube) and feeding issues:

b.globe.com/1b6Vy4E -part 1.

PART 2: The family battles the state.

More bad press or Boston Children’s:

‘Campaign of Terror’: One of the Best Hospitals in the …

Looking behind and looking forward in EoE (part 1)

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Two important articles are provide additional insight into eosinophilic esophagitis (EoE).

In the first (Gastroenterol 2013; 145: 1230-36), the authors performed a retrospective review of the Swiss EoE Database (SEED). This SEED should not be confused with our SEED center (Home- The SEED Center of Atlanta– SouthEast Eosinophilic …).  While the database contains 783 EoE patients, only 200 who were followed by the senior author and had complete data were included.  The enrollment period dates back to 1989.

Demographics: 153 men, mean age 39 years old, 94.5% had dysphagia at time of diagnosis and 35.5% had chest pain.  66% had concomitant allergies.

Terminology: The authors defined strictures as low-grade if a standard 9 mm endoscope could pass but met resistance, intermediate if a 6 mm endoscope could pass, and high-grade if it could not be passed with a 6 mm endoscope.

Results:

  • 37.5% (n=75) had strictures (other endoscopic findings noted in Table 2)
  • Peak eosinophil count (median): 35 proximally and 28 distally
  • Figure 2 showed the evolution of endoscopic features based on diagnostic delay.  With increasing diagnostic delay, there developed a preponderance of a mixed fibrotic/inflammatory picture whereas in those whose symptoms were of much shorter duration, the endoscopic features were often inflammatory without fibrosis.
  • For example, if diagnostic delay was between 0-2 years, then fibrotic findings were noted in 46.5%; in contrast, 87.5% had fibrotic features if symptoms had been present for > 20 years.
  • Strictures increased from 17.2% in those without significant diagnostic delay to 70.8% in those with symptoms present for > 20 years.
  • The authors note that diagnostic delay was greatest in those who developed symptoms in the first decade of life.

Study limitations: The categorization of strictures is straightforward; however, newer tools like the EndoFlip can detect esophageal narrowing more accurately.  Other limitations are related to retrospective nature of study and its reliance on patient’s reported outcomes (subject to recall bias).  Thus, the estimation of diagnostic delay may be inaccurate.

Take home message:

This article reinforces the concept that the presentation of EoE changes with time and that the long-term consequence of untreated EoE is increasing fibrosis and stricturing of the esophagus.

Related blog entries:

Electronic Order Sets Can Improve Care

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It is recognized that checklists can improve medical care as well as help you remember to pick up butter when you go shopping.  So, it is not surprising that a standardized electronic order set can improve patient care.  A recent prospective observational study has shown that implementation of an electronic order set improved the care of 123 patients with cirrhosis who presented with upper gastrointestinal hemorrhage (Clin Gastroenterol Hepatol 2013; 11: 1342-1348).

This study was conducted from 2011 to 2012.

Key findings:

  • Administration of antibiotics increased in patients in whom the order set was used: 100% compared with 89%. A previous Cochrane meta-analysis has noted a mortality risk reduction of nearly 20% in patients who received prophylactic antibiotics in this setting.
  • Order set usage was associated with quicker administration of antibiotics: 3h28min compared with 10h4min.
  • Time for octreotide administration was reduced in patients with the order set: 2h16min vs 6h21min.
  • Mortality was not reduced in this study by using an order set.  In fact, in those who used an order set there were 7 mortalities (out of 61) compared with only 2 mortalities (out of 62) who did not use order sets.

Order set use was at the discretion of the treating physician.  This could have led to selection bias.

Bottomline: Use of a standardized order set improved adherence and timeliness of recommended therapies.

Related blog posts:

What the “Post-Antibiotic Age” Really Means

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From the following site: When We Lose Antibiotics, Here’s Everything Else We’ll … – Wired

An excerpt:

If we really lost antibiotics to advancing drug resistance — and trust me, we’re not far off — here’s what we would lose. Not just the ability to treat infectious disease; that’s obvious.

But also: The ability to treat cancer, and to transplant organs, because doing those successfully relies on suppressing the immune system and willingly making ourselves vulnerable to infection. Any treatment that relies on a permanent port into the bloodstream — for instance, kidney dialysis. Any major open-cavity surgery, on the heart, the lungs, the abdomen. Any surgery on a part of the body that already harbors a population of bacteria: the guts, the bladder, the genitals. Implantable devices: new hips, new knees, new heart valves. Cosmetic plastic surgery. Liposuction. Tattoos.

We’d lose the ability to treat people after traumatic accidents, as major as crashing your car and as minor as your kid falling out of a tree. We’d lose the safety of modern childbirth: Before the antibiotic era, 5 women died out of every 1,000 who gave birth. One out of every nine skin infections killed. Three out of every 10 people who got pneumonia died from it.

And we’d lose, as well, a good portion of our cheap modern food supply. Most of the meat we eat in the industrialized world is raised with the routine use of antibiotics, to fatten livestock and protect them from the conditions in which the animals are raised.

Related posts:

GIKids Resource

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For those of you who have not visited GIKids.org website:

GIKids – A Resource for Pediatric Digestive Disorders

It has literally A-Z handouts on pediatric GI problems for families, including four new handouts:

Educated or Misinformed –Leading to Hemorrhagic Disease of the Newborn

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“Hemorrhagic Disease of the Newborn,” now termed “Vitamin K Deficient Bleeding,” has reemerged as a problem. Many well-intentioned parents are refusing vitamin K to keep things more ‘natural’ for their infants.  This phenomenon is likely encouraged by some alternative health websites and other parents; babies who are breastfed are at increased risk of vitamin K deficiency (without prophylaxis).  Unfortunately, they are playing Russian roulette with their infant’s safety. In addition, many practitioners will not readily recognize this disorder because of the effectiveness of Vitamin K prophylaxis that has been provided since 1961.

An excerpt from the St. Louis Dispatch provides more information: Four babies hemorrhage after parents refuse vitamin K shot, a practice on the rise

Maternity care providers here and nationwide are on high alert for life-threatening vitamin K deficiencies in newborns, at the same time they are seeing more parents refusing a routine preventive injection.

The Centers for Disease Control and Prevention released a report last month about four babies in Nashville, Tenn., who hemorrhaged after their parents refused vitamin K injections at birth. The babies were diagnosed with life-threatening vitamin K deficiency bleeding between February and September. Three had bleeding in the brain, and one had gastrointestinal bleeding. They survived, but the infants with brain hemorrhages could have long-term neurological problems.

“Not giving vitamin K at birth is an emerging trend that can have devastating outcomes for infants and their families,” CDC director Dr. Tom Frieden stated in the report. “Ensuring that every newborn receives a vitamin K injection at birth is critical to protect infants.”

The vitamin is necessary for normal blood clotting, but because vitamin K does not transfer well across the placenta, most babies are born with low levels. The deficiency can lead to a rare, sudden bleeding disorder up to 6 months of age.

The CDC investigation found that parents refused the injection for several reasons, including a concern about an increased risk for cancer from the injection, an impression that it was unnecessary and a desire to minimize exposure to “toxins.” A 1992 study associated vitamin K and childhood leukemia, but the findings have been debunked by subsequent studies…

The number of parents refusing is more alarming at birth centers, which provide care led by midwives who support natural birth. Among the most recent 75 births at the Birth and Wellness Center in O’Fallon, Mo., 23 percent refused the injection, and 14 percent opted for the oral dose, said Jessica Henman, the center’s certified nurse midwife.

The CDC studied a random sample of births this year in the Nashville, Tenn., area and found that parents of 3.4 percent of 3,080 newborns discharged from hospitals had refused the vitamin K injection, while parents of 28 percent of 218 born at birth centers had refused…

A newborn not getting the injection is 81 times more likely to get the late form of the disorder than a baby who gets the shot, according to the CDC. [my emphasis in bold]

Related link from Stanford:  Guidelines for Vitamin K Prophylaxis – Newborn Nursery at LPCH

Bottomline: When seeing an infant with bleeding, ask about vitamin K prophylaxis after birth.

If a parent caused intracranial hemorrhage in an infant by shaking the infant, they would probably be jailed.  What should be done in these cases?

Related blog post:

Bleeding due to vitamin K deficiency | gutsandgrowth

More Cents in Value-Added Care

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While health policy experts of all political backgrounds agree that moving to a value-based (rather than volume-based) payment is worthwhile, there are many problems with this that were alluded to in the previous post. As an aside, I would like to see sports teams move to a value-based system so that I don’t have to hear that my team is paying its worst-performing players gobs of money.

Due to the potential pitfalls in transitioning to a value-based care system, an alternative strategy of working on the relative-value units (RVUs) has been advocated (NEJM 2013; 369: 2176-79).  RVUs has provided a “uniform, formulaic metric for myriad clinical services” and serve as the method for setting fee-for-service payments for both Medicare and private insurance.

“Ideally, physicians’ work would be reimbursed on the basis of metrics that signal whether their clinical services efficiently improve patient outcomes and that use effective clinical risk adjustment. In reality, using patient outcomes as a basis for payment can work well at the health-system level, but small samples and inadequate risk adjustment limit their use for individual physicians and many group practices.”

Advantages of using an RVU-based system over other pay-for-performance benchmarks:

  • Long experience with RVUs (developed in 1988)
  • RVUs influence care delivery.  “RVU distortions drove the development of …(ambulatory) procedural centers and the movement of cardiac imaging from physicians’ offices to hospital outpatient units.” This was “associated with a tripling of the proportion of cardiologists employed by hospitals.”
  • RVUs can be weighted towards activities that improve patient outcomes and high-value clinical services.  Proposed examples: increased RVUs for smoking cessation counseling, and increased RVUs for stenting within 60 minutes for ST-segment elevation myocardial infarction
  • To start, “RVU levels for cognitive clinical work could be increased and those for procedural work could be decrease to create incentives for primary care services.”

Disadvantages of RVUs:

  • RVU levels are set  by the American Medical Association’s Relative Value Update Committee; the process for setting RVUs is secretive and proprietary (though these can be modified by Medicare or other insurance companies)
  • RVU levels are not designed for team-based care

Bottomline: “Ultimately, refining this durable, well-entrenched system may be preferable to replacing it with unproven alternatives.”

Update -Last week I overestimated cost of sofusbuvir for hepatitis C (only $84,000 rather than $90,000), each pill is $1000, nyti.ms/1d6YxNk :

Gilead said the wholesale cost of Sovaldi, which is known generically as sofosbuvir, would be $28,000 for four weeks — or $1,000 per daily pill. That translates to $84,000 for the 12 weeks of treatment recommended for most patients, and $168,000 for the 24 weeks needed for a hard-to-treat strain of the virus.