What happens to micronutrient levels in the hospital setting?

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When atypical labs need to be obtained, many times this is easier in the hospital setting for logistical reasons including insurance and accessibility to specialty labs.  One group of labs that may be less suited for checking in the hospital, despite convenience, would be micronutrients.  Many of the micronutrients can be affected by systemic inflammatory response (Am J Clin Nutr 2012; 95: 64-71).  Thanks to Kipp Ellsworth for this reference (from his @PedNutritionGuy twitter feed).

Previous studies on systemic inflammatory response (SIR), as assessed by elevated C-reactive protein (CRP) concentrations, has shown that with elective surgery there are transient decreases in plasma concentrations of zinc, selenium, iron, vitamin A, vitamin E, carotenoids, riboflavin, vitamin B-6, vitamin C, and vitamin D.

This current study adds to this body of information.  Between 2001-2011, 2217 whole-blood samples were taken from 1303 patients. Specific micronutrients that were studied: plasma zinc, copper, selenium, vitamins A, B-6, C, and E.  For vitamin D, the authors examined 4327 samples from 3677 patients. The authors did not include manganese, thiamine or riboflavin because these are measured in erythrocytes.

For each analyte, the concentrations were separated according to 6 categories of CRP values: <5, 6-10, 11-20, 21-40, 41-80, and >80 mg/L.

Key finding: Except for copper and vitamin E, all plasma micronutrient concentrations decreased with increasing severity of acute inflammatory response.  For selenium, vitamin B-6, and vitamin C, this occurred with only slight increases in CRP (5 to 10 mg/L).

The magnitude of the SIR effect on micronutrients was quite variable among patients and analytes.  When CRP was >80 mg/L, analyte deficiency rate was noted to be the following:

  • 60 % for selenium (vs. 33% with NL CRP)
  • 48% for vitamin A (vs. 7% with NL CRP)
  • 35% for vitamin B-6 (vs. 14% with NL CRP)
  • 80% for vitamin C (vs. 33% with NL CRP)
  • 88% for vitamin D (vs. 69% with NL CRP)
  • 81% for zinc (vs. 33% with NL CRP)
  • 9% for copper (vs. 4% with NL CRP)
  • 16% for vitamin E (vs. 9% with NL CRP)

**The specific normal value cutoffs and more data at all CRP values are noted in Table 9 of the manuscript.

The implications from this study are clear.  When micronutrient values are derived from plasma during a SIR, a false-positive diagnosis of a micronutrient deficiency is more likely. The study has several limitations and the findings may not be applicable to all types of medical conditions.

Authors conclusion: When CRP concentration is >20 mg/L (>2 mg/dL), “plasma concentrations of selenium, zinc, and vitamins A, B-6, C, and D are clinically uninterpretable.”

Related blog entries:

Predicting outcome in Pediatric Acute Liver Failure

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In a recent study, soluble interleukin 2 receptor alpha (sIL2Rα) was identified as a marker associated with patient outcome in pediatric acute liver failure (JPGN 2013; 56: 311-5).

Because systemic inflammatory response and immune function have potential effects on the outcomes of patients with acute liver failure (ALF), the authors decided to study markers of T-cell immune activation in patients enrolled in the pediatric ALF (PALF) cohort. The PALF cohort was derived from the PALF study group which consists of 20 sites.  All of the enrollees from this study were from the 17 U.S. sites.

Design: Blood was collected within 48 hours of enrollment into the PALF cohort.  Blood had to received by the testing laboratory within 24 hours of collection.  The final study group included 77 patients, though outcomes for two patients (who were discharged alive within 10 days of enrollment) were not known.  Blood was tested for numerous markers including “CD56 bright,” perforin, Natural Killer T-cell (NKT) perforin, NK lytic activity, granzyme B, CD8, CD16, CD56 and others.  Outcomes were assessed within 21 days of enrollment.

Results:

  • Acetaminophen was the most common identifiable reason for PALF (n=13) and all acetaminophen patients survived without liver transplantation.
  • Other etiologies included autoimmune marker positive-ALF (n=8), Drug-induced ALF (n=2), viral ALF (n=6), metabolic (n=7), hemophagocytic lymphohistiocytosis (HLH) (n=3), and shock/ischemia (n=3).  Besides indeterminant ALF (n=27), all other diagnosis had n=1.
  • Age was distributed across all pediatric groups: < 5 years (n=24), 5-9 years (n=19), >9 years (n=34).
  • Of all the markers of T-cell immune activation, only sIL2Rα was identified as being able to discriminate between survival with native liver, liver transplantation, and death.
  • Of the 15 subjects with markedly elevated sIL2Rα (>5000 IU/mL), 5 (33%) survived with native liver, 2 died, and 8 underwent liver transplantation. In contrast, all 37 patients with normal sIL2Rα lived, 30 (81%) with their native livers.

Study limitations included the cross-sectional design which entailed measuring sIL2Rα at a single point in time.  In addition, it is not clear whether sIL2Rα levels reflect a causal role in liver injury or a response to liver injury.

Take home message:

sIL2Rα along with traditional measures could improve the ability to predict hepatic recovery in PALF.

Related blog posts:

Anti-TNFs and Pregnancy

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While pregnancy does not occur commonly while patients are in a pediatric gastroenterology practice, the possibility of becoming pregnant certainly influences our choice of medications.  With inflammatory bowel disease (IBD), I rarely recommend methotrexate in young women due to its teratogenicity.  With regard to the anti-TNF agents, there is less data available.   Two recent studies add some insight into this issue.

The first study ((Clin Gastroenterol Hepatol 2013; 11: 318-21) followed 31 pregnancies in 28 women with IBD (2006-2011).  18 patients received infliximab (IFX) and 13 adalimumab (ADA).  Most were receiving lower doses; only one IFX patient was receiving 10 mg/kg/dose and only two ADA patients were receiving weekly dosing.  Levels of anti-TNF agents were measured from cord blood from 18 newborns (12  IFX, 6 ADA).

Results:

  • 28 live births.  3 miscarriages (1 IFX, 2 ADA).  No congenital malformations were noted.
  • Mean cord IFX level was 6.4 mcg/mL.  A level of 2.8 mcg/mL was noted in the early discontinuation group –stopping 10 weeks prior to delivery .
  • Mean ADA level was 1.7 mcg/mL in five infants.  One infant had an undetectable level. All mothers had stopped ADA at gestational week 22.

In the second study (Clin Gastroenterol Hepat 2013; 11: 286-92) there were 31 pregnant patients. Anti-TNF treatment: Certolizumab (CZP) (n=10), IFX (n=11), ADA (n=10).  Serum levels were measured at birth in the mother, infant, and in cord blood. Then, levels were followed monthly until undetectable.  Among women receiving IFX, two were receiving 10 mg/kg/dose.  Women were identified through the Crohn’s Colitis Foundation of America Pregnancy IBD and Neonatal Outcomes (PIANO) Registry.

Results:

  • IFX was detectable for 2-7 months postpartum (median interval prior to delivery and last dose was 35 days).  Median IFX level in the cord was 160% that of the mother.
  • ADA was detectable for at least 11 weeks in infant’s circulation (median interval prior to delivery and last dose was 5.5 weeks). Median ADA in the cord was 153% of the mother.
  • Median CZP in the cord was 3.9% that of the mother.
  • No congenital anomalies or complications were reported in any of the infants.

Bottomline from these studies:

Stopping these drugs after the second trimester lowers the level of these medications in the infant.  This likely results in a lower likelihood of the infant developing an opportunistic infection but also results in a low risk for the mother of an IBD flareup.  Certolizumab pegol has very low levels of placenta transfer.

Related references:

  • -J Am Acad Dermatol 2011; 65: 870.  Death noted in infant whose mother took IFX after BCG vaccination.
  • -J Crohns Colitis 2011; 5: 555-8.  Low levels of IFX detected in infants from nursing mothers with IBD  (1/200th of the maternal level in serum 2 to 3 days after infusion).
  • -Clin Gastroenterol & Hep 2010; 8: 509. n=2377. Crohn dz assoc w prematurity but not birth defects.
  • -Gastroenterol 2003;124: 9-17. Safety of 6-MP in pregnancy. n=155, at least 1 pregnancy. No adverse effect noted.
  • -Clin Gastroenterol & Hepatology; 2006: 4: 1255.  Infliximab crosses placenta but was not detected breastmilk.

Trends in Adolescent Bariatric Surgery

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Despite increased numbers of obese adolescents, the number of inpatient bariatric surgery cases has plateaued (JAMA Pediatr 2013; 167: 126-32).  Thanks to Ben Gold for sharing this reference.

In this retrospective cross-sectional study using an administrative dataset (Healthcare Cost and Utilization Project Kids’ Inpatient Database), the authors documented the following bariatric surgery rates:

  • In 2000: 0.8 per 100,000 (328 procedures)
  • In 2003: 2.3 per 100,000 (987 procedures)
  • In 2006: 2.2 per 100,000 (925 procedures)
  • In 2009: 2.4 per 100,000 (1009 procedures)

The other observations in this study were that procedures were predominantly performed on females (75%), the prevalence of comorbidites increased (49% in 2003 vs. 59% in 2009), and complications rates were low.  68.3% had private insurance.

Take-home points:

The number of adolescents who would qualify for bariatric surgery has increased but the rates have not changed.  Why?

  1. Societal barriers.  Obesity is more common in lower socioeconomic groups with lower educational levels.  Yet, the rates of bariatric procedures is the same in low-income and high-income populations.
  2. Insurance coverage.  In many states, medicaid does not cover bariatric surgery.
  3. Physicians limiting access.  After initial enthusiasm (2000-2003), published guidelines to identify appropriate patients and to highlight recommendations prior to surgery may have led to more cautious referral patterns.

Over the past decade, there are increased numbers of qualified surgeons and there has been more use of laparascopic techniques.  The Roux-en-Y gastric bypass (RYGB) was the most common bariatric procedure in this population, accounting for 67.6% of cases in 2009 (60.6% were laparascopic, 7% were open).  Laparascopic adjustable gastric banding (LAGB) accounted for the remaining 32.1% of cases.

Since this study relied on administrative data, there are several limitations.  Billing codes may not reflect the procedures accurately.  For example, ICD-9 codes for laparascopic sleeve gastrectomy were not available until 2011.  Nevertheless, this study provides some insight into the trends with bariatric procedures in adolescents.

Related blog link:

Six year outcomes with bariatric surgery | gutsandgrowth

Closer to Star Trek Medicine

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In Star Trek, Dr. Leonard McCoy used a medical tricorder to effortlessly diagnose a lot of conditions (Tricorder – Wikipedia, the free encyclopedia, Medical tricorder – Wikipedia, the free encyclopedia).  While many of the newest diagnostic tests are not as portable, they share a feature of being able to diagnose a wide range of conditions quickly.  These tests include imaging studies like MRI and CT, genetic microarrays, and now PCR panels to diagnose a broad array of respiratory and gastrointestinal ailments.

One of the newest is the “xTAG GPP.”  With one stool sample, this Gastrointestinal Pathogen Panel (GPP) can detect at least 11 common bacteria, viral, and parasitic pathogens in about five hours.  Thus, all patients with identifiable gastroenteritis illnesses can be diagnosed more quickly.  The test relies on a “multiplex nucleic acid test.”

FDA News Release Jan 15, 2013  (Press Announcements > FDA permits marketing of first test that can …):

“Infectious gastroenteritis is an inflammation of the stomach and intestines caused by certain viruses, bacteria, or parasites. Common symptoms include vomiting and diarrhea, which can be more severe in infants, the elderly, and people with suppressed immune systems. Gastroenteritis can be spread easily through person-to-person contact and contaminated food, water, and surfaces. 
 
The Centers for Disease Control and Prevention reports that between 1999 and 2007 gastroenteritis-associated deaths in the United States increased from nearly 7,000 to more than 17,000 per year. Norovirus and Clostridium difficile accounted for two-thirds of the deaths. 
 
The xTAG Gastrointestinal Pathogen Panel (GPP), a multiplexed nucleic acid test, detects the following causes of gastroenteritis:
 
Bacteria
  • Campylobacter
  • Clostridium difficile (C. difficile) toxin A/B
  • Escherichia coli (E. coli) O157
  • Enterotoxigenic Escherichia coli (ETEC) LT/ST
  • Salmonella
  • Shigella
  • Shiga‐like Toxin producing E. coli (STEC) stx 1/stx 2
 
Virus
  • Norovirus
  • Rotavirus A
 
Parasite
  • Cryptosporidium
  • Giardia
 
“Tests such as the XTag GPP that can detect viruses, bacteria, and parasites from one sample at the same time can help clinicians more quickly identify and treat what’s causing gastroenteritis,” said Alberto Gutierrez, Ph.D., director of the Office of In Vitro Diagnostics and Radiology at the FDA’s Center for Devices and Radiological Health. “The test could also allow clinicians and public health professionals to more quickly identify and investigate the source of potential gastroenteritis outbreaks.”
The manufacturer demonstrated the performance of the xTAG GPP by collecting samples from 1,407 patients with suspected infectious gastroenteritis and comparing the xTAG GPP results to individual tests that are known to separately and reliably detect the 11 viruses, bacteria, or parasites associated with the xTAG GPP. The manufacturer also ran the test on 203 samples from patients with previously confirmed infectious gastroenteritis, and 313 additional specimens from pediatric patients with suspected infectious gastroenteritis. Results were comparable to the individual tests. Due to the risk of false positives, all positive results from the xTAG GPP need to be confirmed by additional testing (blog entry underlined for emphasis, not in original FDA release).
 
Luminex, Inc., of Austin, Texas, manufactures the xTAG.”
According to manufacter’s website, the test also detects Yersinia, Entamoeba histolytica, and adenovirus.  It reports sensitivity of of >94% for almost all pathogens (except Salmonella which was 84%) and specificity of >94% for all of the pathogens.

Copper in Cholestasis

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More data indicate that copper levels in infants receiving parenteral nutrition are usually not affected by cholestasis (JPEN 2013; 37: 92-96).

A retrospective study reviewed all patients younger than 1 year who had copper levels measured between 1999-2009 at Riley Hospital for Children.  Inclusion criteria: parenteral nutrition for at least 50% of caloric needs and cholestasis (direct bilirubin >2 mg/dL).

Key findings:

  • 26 of 28 patients had gastrointestinal disorders.  82% were receiving standard parenteral nutrition (PN) dose of copper (20 mcg/kg/day).
  • Only one elevated copper level was found in a child with congenital heart disease.
  • 46% (n=13) of cholestatic infants had low copper levels.  Three of theses infants had no copper in their PN.
  • There was no correlation between bilirubin level and measured copper values.

Bottomline:

Measure copper values periodically in patients requiring parenteral nutrition.  Most patients, even cholestatic patients, will require standard dosing but some will need less and some more.

Additional References:

  • -JPGN 2010; 50: 650-54.  n=28.  (only 2 had elevated Cu). Typical Cu supplementation in HAL did not lead to significant increase in Cu toxicity or worsening of liver disease in cholestatic infants.  Study prompted by single infant who developed Cu deficiency/anemia.
  • -Clin Gastro & Hepatol 2004; 2: 1074. Two patients with Cu deficiency after bariatric surgery
  • -JPGN 2000; 31: 102-111. (review)

More options for Hepatitis C

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As noted in numerous blog entries (see below), there has been increasing availability of new and more effective treatments for Hepatitis C virus (HCV).  Two more drugs have promising results:

  • NEJM 2013; 368: 34-44
  • NEJM 2013; 368; 45-53

The first study provides encouragement with regard to sofosbuvir (previously known as GS-7977) which is a direct-acting nucleotide polymerase inhibitor targeting the NS5B polymerase.

In this open-label study, there were eight groups of patients.  Of 40 previously untreated patients (genotype 2 or 3), all patients received sofosbuvir (400 mg daily) for 12 weeks.  All 10 who received the study drug with ribavirin (& without interferon) and all 30 who received the study drug with ribavirin and peginterferon had a sustained virologic response (SVR) at 24 weeks.  Among patients with sofosbuvir monotherapy, 6 of 10 had a SVR.  Among HCV genotype 1 patients, 21 of 25 (84%) previously untreated patients had a SVR. The most common adverse effects were headache, fatigue, insomnia, rash and anemia.

The second study also was a phase 2a, open-label study for HCV genotype 1 non-cirrhotic patients using ABT-333 and ribavirin.  ABT-333 is a nonnucleoside NS5B polymerase inhibitor.  Results: 17 of 19 (89%) patients in group 1 (Rx with ABT-333, ribavrin, ABT-450, and ritonavir), 11 of 14 (79%) patients in group 2 (Rx with same drugs at lower doses of latter two drugs) had extended rapid virologic response.  SVR was achieved in 95% and 93% respectively.  Groups 1 and 2 were previously untreated.  Group 3 were patients who had either a null or partial response to previous treatment achieved a 47% SVR.  The most common adverse effects were abnormalities in liver function tests, headache, fatigue, insomnia, pruritus, nausea and rash.

Bottom-line:

These preliminary results suggest that Sofosbuvir is effective in all genotypes and may allow a short duration all-oral regimen.  ABT-333 similarly is effective in an all oral regimen in genotype 1 patients.

Related blog posts:

Is functional pain more common in children with Celiac disease?

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A recent study adds information to the title question but does not resolve it (J Pediatr 2013; 162: 505-09).

The authors note that they expected to find a higher prevalence of abdominal pain and abdominal pain/functional gastrointestinal disorders among children with diagnosis of celiac disease.  They note that functional disorders have been more common after acute gastroenteritis and cow’s milk hypersensitivity of infancy presumably due to preceding inflammation.  Persistent low-grade intestinal inflammation and immune activation have been proposed as precipitating susceptibility to functional abdominal pain.

In this small retrospective study, a statistically significant difference in functional GI disorders was not observed.  Enrolled families were contacted by telephone at least 6 months after the diagnosis of Celiac disease.  They completed a telephone questionnaire and a separate Rome III questionnaire.

Celiac cases (n=49):  abdominal pain (24.5%), functional abdominal pain (4.8%), IBS (6.1%), dyspepsia (4.8%), abdominal migraine (4.8%), nonspecific abdominal pain (6.1%)

Control cases (n=48): abdominal pain (14.6%), functional abdominal pain (6.3%), IBS (2.1%), nonspecific abdominal pain (6.1%)

Given the question that the authors were trying to answer, this study was unlikely to be helpful.  Problems with the study:

  • The biggest problem is the small number of patients.
  • Cross-sectional design
  • Reliance of recall symptoms
  • Lack of information on dietary adherence
  • Collection of information from only parents contributed

Bottomline: While screening for celiac disease is common in patients with possible functional abdominal pain, treatment with a gluten-free diet may not resolve these symptoms. Functional abdominal pain is at least as common in children with celiac disease as in the general population.

Related blog post:

New FDA warning for azithromycin (Zithromax)

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“The FDA is warning that a widely used antibiotic from Pfizer can cause rare but deadly heart rhythms in some patients. The agency is adding new warnings to the label of Zithromax, which is used to treat bronchitis, pneumonia and other infections.

Doctors should consider prescribing other antibiotics to patients at risk of heart problems, including those with irregular heartbeats or low levels of potassium or magnesium in their blood. Zithromax is popular because it often can be taken for fewer days than other antibiotics. The warning may prompt doctors to choose other options, though the new label notes that other antibiotics have similar effects on the heart.”

Read more here: http://www.thenewstribune.com/2013/03/13/2511288/fda-issues-warning-about-zithromax.html#storylink=cpy

Also from previous FDA statement:
[05-17-2012] “The U.S. Food and Drug Administration (FDA) is
aware of the study published in the New England Journal of Medicine,
on May 17, 20121, that compared the risks of cardiovascular death in patients treated with azithromycin (Zithromax), amoxicillin, ciprofloxacin (Cipro), levofloxacin (Levaquin), and no antibacterial drug.  The study reported a small increase in cardiovascular
deaths, and in the risk of death from any cause, in persons treated with a 5-day
course of azithromycin (Zithromax) compared to persons treated with amoxicillin,
ciprofloxacin, or no drug. The risks of cardiovascular death associated with
levofloxacin treatment were similar to those associated with azithromycin
treatment.”  Thus, levofloxacin also was associated with an increased risk.
Related link:

Build the information medical highway and expect more traffic

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A recent article indicates that increased patient access to online records was associated with increased in-person and telephone contacts (JAMA 2012; 308: 2012-19).

Background (from study introduction): The Institute of Medicine’s report on “Crossing the Quality Chasm” indicated that electronic patient-physician messaging was a promising technology to improve quality and efficiency.  Furthermore, previous studies have suggested that 25-70% of all visits to physicians do not require face-to-face appointments.

Design: To explore this topic further, the authors performed a retrospective cohort study on the use of health care services between 2005-2010 at Kaiser Permanente in Colorado.  This study examined patients ≥18 years old and looked at health care utilization before and after initiation of MyHealthManager (MHM). Users of MHM were compared with nonusers.  And, both groups (users and nonusers) were examined with regard to their health care utilization before and after MHM rollout. The first 30 days before and after activation of MHM were excluded from analysis to minimize the effect of increased utilization at the initiation of MHM.

Results:

  • By June 2009, patient use of MHM had increased to 53.8%.  In total, 87,206 MHM patients were identified and 71,663 nonusers were identified for study participation. 
  • MHM users were slightly older and more likely to be female.
  • After initiation of MHM, the rate of office visits increased by 0.7 per member per year (p<0.001) and the number of telephone encounters increased by 0.3 per member per year (p<0.001).  
  • The authors breakdown this data based on age, absence of chronic disease, presence of specific diseases (diabetes, coronary artery disease, congestive heart failure).  In all of these scenarios, MHM users had increased visits after initiation of MHM.  Nonusers generally had the same or less visits at the same time.
  • Figure 2 shows that MHM and nonusers had identical health care utilization beforehand.  Afterwards, the MHM users maintained a parallel line of increased usage that was fairly consistent for a year after rollout.

Why did this happen?  The authors note that the result was contrary to their expectations.  They speculate that individuals may have increased their in-person use after developing additional concerns following their review of information online and that individuals may sign up who are already more likely to use services.  Online access, in these individuals, may facilitate access to more frequent visits.

I think this article points to a more pervasive miscalculation of the effect of information technology and health care utilization.  While electronic health records (EHRs) can help organize and communicate vast amounts of information, the proposition that they will ultimately reduce health care costs/utilization or improve efficiency is looking dubious.  In my opinion, the best we can hope for is that EHRs, when used optimally, will improve the quality of the care.  It is equally possible, however, that EHRs could result in more legible but less accurate information due to well-recognized issues like copy-forwarding with inadequate editing.

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