ASCP Call for Abstracts

Do you want to present your research at a national meeting? The American Society for Clinical Pathology is currently accepting abstract submissions for their Annual Meeting. This year it’s in October in Tampa, Florida. Soak up the sun while presenting your work and networking with your peers.

The Poisoner’s Handbook by Deborah Blum–Book Review

I recently read The Poisoner’s Handbook by Deborah Blum, a book about poison and forensic investigation in Jazz-age New York City. Dr. Norris and Dr. Gettler transformed death investigation from a good-old-boy coroner system to one based on science and data analysis. Blum weaves several cases into a narrative that covers several poisons used during the 1920s and ‘30s. Over time, poisoning deaths decreased due to public awareness as well as the realization that murderers were increasingly likely to get caught. Blum discusses Prohibition at length and its contribution to poisoning deaths in New York City. I found this particularly fascinating; not only were people willing to risk their lives to drink alcohol, the government tried to dissuade people from drinking by actively poisoning the supply.

Several of the reviews of this book note Blum’s lack of chemistry knowledge, and I can’t disagree. While my own knowledge base isn’t wide, even I notice a few inaccuracies (HCN isn’t a “potent” acid, for example). One must remember that Blum is a journalist, not a chemist; I tend place blame on the publisher’s fact-checker as well as the author. Because this book is about the evolution of the public perception of forensic toxicology and not just the science behind it, I could overlook the scientific stumbles.

As a laboratory professional, I loved reading about the early days of forensic science and forensic toxicology. While these professions existed in Europe well before 1920, Norris and Gettler forever changed how we treat death, murder, and justice in this country.

 

Swails

Kelly Swails, MT(ASCP), is a laboratory professional, recovering microbiologist, and web editor for Lab Medicine.

 

 

Glucose Meters

There’s been a serious buzz in the laboratory community recently (especially among the Point of Care [POC] community) about glucose meters. Most laboratory professionals know that glucose measurements on the average glucometer are not as reproducible as those performed on the average main lab analyzer. Some of the reason for that is simply related to issues around proper sampling and use of the glucometers. However, glucometers are only required by the FDA to have precisions of ±20%. For that reason, glucometers are not recommended to be used for diagnosing disorders, for monitoring critically ill patients, or for maintaining tight glycemic control. And yet, glucometers are routinely used nearly everywhere for all three of these purposes.

Recently, the FDA began to try to get a handle on the utilization of glucometers by coming out with two draft guidance documents (links below). By releasing these documents they have essentially reclassified glucometers into two categories: those suitable for over-the-counter (ie home) use, and those suitable for by prescription or health-care-setting(ie professional) use. The differences include:

  1. OTC meters – 95% of values within ±15% of reference measurement, 99% within ±20%; Professional – 99% within ±10% or ±7 mg/dL below 70 mg/dL
  2. OTC meters – AMR 50 – 400 mg/dL; Professional – AMR 10 – 500 mg/dL
  3. Professional – should also include neonatal studies
  4. OTC meters – labeling – for use by persons with diabetes for at home monitoring; Professional – labeling – with intended use, but not for use in critically ill or tight glycemic control

Thus the FDA has reiterated that glucometers should not be used for critically ill patients.If they are used for any purpose not specified in the package insert, their use must be classified as a moderate complexity off-label use of the glucometer, requiring the extensive validations specified by CLIA for non-FDA approved tests. These draft guidance documents have already caused the New York State Department of Health to react and send a letter to all laboratory directors stating that “…the use of glucose meters in health fairs, other community screening events, and/or critical care settings must be discontinued” until such time as CLIA validations have been performed. Thus a huge burden has been placed on the POC community in NY to either pull their POC glucometers from their facilities or validate their uses. And the rest of the country is waiting to see how it will all fall out.  Glucometers are ubiquitous in the majority of health care settings and it will not be easy to meet the new FDA draft guidelines.

http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM380325.pdf

http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM380327.pdf.

 

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-Patti Jones PhD, DABCC, FACB, is the Clinical Director of the Chemistry and Metabolic Disease Laboratories at Children’s Medical Center in Dallas, TX and a Professor of Pathology at University of Texas Southwestern Medical Center in Dallas.

Estimated Average Glucose

Most people in the clinical lab and among the Diabetes population are aware that there is not a good correlation between a blood glucose level and a hemoglobin A1C (HbA1c) level. This only makes sense. A blood glucose is essentially a snapshot of what the glucose concentration is in your body at that particular point in time when the blood sample is collected. HbA1c is a measure of the percent of your hemoglobin that has glucose attached to it. The longer your glucose is high and the higher it is, the more glucose will be attached to hemoglobin and the higher your percent HbA1c.  The hemoglobin with glucose attached stays around for the life of the red blood cell that holds it, 120 days.  Therefore, a HbA1c level is an indication of what your blood glucose has been averaging for the last 4 months.

That’s where an estimated average glucose (eAG) comes in. eAG is a value that’s calculated from the HbA1c, so it is also an indicator of what your blood glucose has averaged over the last 120 days rather than being a snapshot of your current blood glucose. Like HbA1c, its utility lies in that a person may not have been in control of their glucose for the last 4 months, but they are careful the day they come in to have their glucose checked. Their snapshot blood glucose may be 130 mg/dL or close to the normal range, but their eAG would still be 200 mg/dL or more, indicating what they’ve been averaging the last 4 months.

The formula for calculating eAG was developed by Nathan et al (1). Their study in which they derived it is impressive.  They collected roughly 2700 separate glucose measurements on each of 507 study subjects. The study cohort contained 268 persons with type 1 diabetes, 159 persons with type 2 diabetes and 80 normal controls. All participants in their study had their glucose under control for the 3 month run of the study. With so many individual measurements on each study subject, the authors were able to determine an average glucose for each subject and correlate it with the subject’s HbA1c. The formula they derived is:

      eAG = 28.7 X HgbA1C – 46.7 (for US units of mg/dL)

Interestingly, HbA1c gives you essentially the same information as eAG: an indication of what a person’s average glucose has run over the last 120 days. The difference is this: most people monitoring blood glucose know what a glucose value means and when their glucose value is too high. Thus an eAG of 250 mg/dL may make more sense to them than an HbA1c of 10.3 %.  They now know that they have been averaging a glucose of 250 mg/dL, even if today’s glucose was 126 mg/dL.  Whether it’s true or not that eAG is easier to understand than HbA1c, HbA1c has become widely used and eAG has not. Despite that, it does have the potential to be a useful calculation.

1. Nathan DM, Kuenen J, Borg R, Zheng H, Schoenfeld D, Heine JR. Translating the A1C assay into estimated average glucose values. Diabetes Care, 31(8):1473-1478. 2008.

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-Patti Jones PhD, DABCC, FACB, is the Clinical Director of the Chemistry and Metabolic Disease Laboratories at Children’s Medical Center in Dallas, TX and a Professor of Pathology at University of Texas Southwestern Medical Center in Dallas.

Procalcitonin: Sepsis Marker Extraordinaire?

Sepsis is one of the most common causes of significant morbidity and mortality in hospitalized patients as well as the most common cause of death in ICU patients.  In addition, the earlier sepsis is identified and treated, the better the prognosis for the patient. We actually do not have a biochemical marker which can be used to effectively diagnose sepsis. Sepsis diagnosis depends on finding microbial infection by culture, and while PCR methods do exist to quickly identify bacteremia, in most institutions cultures take at least 24 hours to grow.  To aid in the diagnosis, clinicians can check three biomarkers commonly considered “sepsis” markers: C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and procalcitonin (PCT).

Despite being very different tests, these three assays are ultimately indicators of inflammation or the inflammatory response. ESR is a simple manual test that measures how far red cells sediment out of a blood sample in one hour. It is used as a marker of inflammation but is quite unspecific; several conditions can cause inflammation. The ESR can tell a clinician that inflammation exists but not the cause of that inflammation CRP is an acute phase reactant protein. Its production by the liver increases in acute inflammation. However, its levels will be affected by liver dysfunction. PCT is a pro-hormone produced by extra-thyroidal immune cells within 2-4 hours of a bacterial insult or an inflammatory response.

Deciding whether a biomarker is a good indicator of sepsis is made difficult by its complex pathology. Studies that show one marker performs better are contradicted by other studies that show it does not. The utility of PCT for predicting sepsis remains controversial for this reason. However PCT has shown to be useful for predicting prognosis in sepsis. Increasing PCT concentrations correlate with increasing severity and a poor prognosis. Decreasing or low concentrations indicate a good prognosis. PCT is also being used to guide antibiotic therapy, although this use should be limited to non-surgical/trauma ICU patients, which is where the studies have been done. Thus although PCT proponents consider it to be the best available biomarker indicator of sepsis, none of the three tests have been shown to be good at diagnosing sepsis. Unfortunately, all three of these biomarkers are indicative of an inflammatory response and not specific for sepsis itself. However, once sepsis is known, all three biomarkers can be used to monitor its progression and response to therapy.

If you’d like to read more about PCT and sepsis, you can do so here:

http://www.nlm.nih.gov/medlineplus/ency/article/000666.htm

http://www.webmd.com/a-to-z-guides/sepsis-septicemia-blood-infection

http://www.medscape.com/viewarticle/720621_1

https://www.aacc.org/members/nacb/NACBBlog/lists/posts/post.aspx?ID=16#

 

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-Patti Jones PhD, DABCC, FACB, is the Clinical Director of the Chemistry and Metabolic Disease Laboratories at Children’s Medical Center in Dallas, TX and a Professor of Pathology at University of Texas Southwestern Medical Center in Dallas.

Inborn Errors of Metabolism in Adults

In general when people think of a genetic defect or an inborn error of metabolism (IEM), they think in terms of disorders that are diagnosed and treated in infancy or early childhood. Interestingly, the more we learn about IEM, the more we see that IEM can be diagnosed at nearly any age. Milder forms of the disorders may present in later years, anywhere from adolescence through adulthood.

Classical presentations of IEM are generally due to total or near total enzyme deficiencies that result in life-threatening medical crises, or major developmental delay and mental retardation. Adults or near adults who present with a range of milder symptoms may be misdiagnosed or nor diagnosed at all.

A few examples of IEM that may have later and milder presentations include:

1)  Ornithine transcarbamylase (OTC ) deficiency, the most common urea cycle defect which is often fatal in newborn male infants, can and does present in the teenage years as altered mental status, when a protein load cannot be handled and ammonia levels rise and impact brain function.

2)  Carnitine palmitoyltransferase 2 (CPT2) deficiency, a disorder of fatty acid metabolism, presents with cardiomyopathy and liver failure in the newborn period. It can also present with muscle weakness, myopathy and rhabdomyolysis in the teenage or young adult years when the teenager tries out for a sports team and the muscle cannot metabolize adequate fats.

3)  3-methylcrotonyl-CoA carboxylase (3MCC) deficiency, a disorder of leucine metabolism, may present in infants or toddlers as feeding difficulties, neurological symptoms including seizures, and can cause death. 3MCC can also present in a completely asymptomatic mother whose infant is picked up on newborn screening because of the Mom’s abnormal metabolites in the infant’s blood.

In most of these cases the deficiency is mild enough that the individual is self-regulating, avoiding foods or activities that make them feel bad. In addition, the IEM may not manifest unless some other confounding factor precipitates it, such as stress, illness, or fasting. The important thing to remember though, is that altered mental status in a teenager does not always represent alcohol, drug or other mood altering substances. IEM can be diagnosed at any age and should always be considered as part of the differential diagnosis.

 

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-Patti Jones PhD, DABCC, FACB, is the Clinical Director of the Chemistry and Metabolic Disease Laboratories at Children’s Medical Center in Dallas, TX and a Professor of Pathology at University of Texas Southwestern Medical Center in Dallas.

Is Sample Quality in the Eye of the Beholder?

Here’s a simple experiment to try in your lab: Find a hemolysed sample and separately ask five different medical laboratory scientists to judge the amount of hemolysis present. What you’ll probably find is that “grossly hemolyzed” is most definitely in the eye of the beholder.

Along with hemolysis, lipemia and icterus are determined by judgment calls made by laboratory scientists. Considering that these three interferences make up the bulk of interferences found in patient samples, “eye of the beholder” may not be good enough. Luckily, with most modern chemistry analyzers, it does not have to be.

Most major chemistry analyzers now perform what we like to call “indices”. The HIL (hemolysis, icterus, lipemia) indices are directly measured by the instrument for a given sample. If any of these three interfering substances are present, the instrument will determine both its presence and its concentration. This last point is important also, because some analytes are only affected by a significantly large amount of the interfering substance. Being able to directly measure these interfering substances, allows the instrument to be set to deal with the affected sample in the most appropriate way. It can be set to not analyze those tests affected, or to not report the results on affected tests, or to simply flag the result for footnoting. Computer systems across the interface can likewise be automatically programmed to accept the HIL numbers and respond appropriately.

Analyzers measure the HIL indices in different ways and until recent years, pediatric labs have often been unable to take advantage of analyzer-measured indices. In pediatrics, especially in infant patients, sample volume is often an issue, and so this feature has traditionally been turned off in pediatric labs. However, there are instruments on the market that measure the indices through the pipet tip without using up any sample volume including most of the Ortho Diagnostics analyzers, like the Fusion 5,1 and the 5600. This feature is one of the reasons these instruments are so often found in pediatric labs. In addition, those instruments that use sample volume are now capable of using microliter quantities, like the Siemens Vista or the Roche Cobas 6000.  Utilizing minimal sample volume for this measurement allows the HIL features to be used on these instruments in almost all situations.

Thus the good news is that the sample quality and appropriateness for any given test no longer needs to be in the eye of the beholder.

-Patti Jones