pathology – Page 24 – Lablogatory

New Year. New Skills.

I do not recall if it was an email or if I saw it on the ASCP website, but the byline caught my attention: New Year. New Skills. My mind quickly started racing. January marks a fresh beginning, the time to make new resolutions, the time to feel the excitement of new possibilities.

The Issue

We are more than halfway through the month and I have yet to identify the skill I would next like to acquire. So many questions! So much to learn, so little time! How do you choose what to focus on? Where do you start? What can you manage? Is there anyone who can help or teach you? And if you are like me, you might also ask yourself, “Why do I always pile more on my plate?” Maybe this is the year you choose to learn to say no? Nah. So what’s it going to be?

The Solution

Since our lives are all different and there are millions of possible distinct scenarios, I will share what I decided to do. First, I evaluated my work-life balance and determined if I wanted to acquire a skill that would benefit my work (career and ambition) or lifestyle (health, pleasure, leisure, family) (1). I also took into consideration how much more I could fit onto my already overflowing plate.

I decided to work on something that would help me with both work and lifestyle (because who doesn’t like to maximize their return on investment?). I chose something I do not like to do, something that scares me, something I have difficulty with, something I avoid like the plague, but most importantly it’s something that I wish I could do better; a skill that I envy: having difficult conversations.

Communication is a vital component of our lives. We all communicate, but how many of us have mastered the skill of communicating? Also, there are many aspects of communication (2). Poor communication can make or break a situation or relationship. Being able to communicate well is a great skill to possess (3). Reference two provides a long list of skills that I highly recommend you also take a look at (https://www.thebalance.com/communication-skills-list-2063737). I went down the list and individually assessed which skills I feel that I do well with and which ones I do not (2). This little exercise served as a reality check as to where I stand in regard with my aptitude to communicate. I invite you to do the same. You may be surprised at what you find!

The Importance of Good Communication

As a laboratory director, many facets of my job depend on my ability to communicate well. I must communicate with clinicians, technologists, administrators, other coworkers, vendors, students, etc. Not only do I communicate with a variety of groups of people, in a multitude of different platforms (individually, small groups and meetings, or large groups; such as national conferences), but it is also important that my written, verbal, and non-verbal communication skills are clear and easily understood.

As laboratory professionals, one very important aspect of our job is to communicate critical results. It is essential that we not only relay the data, but it is equally important for us to communicate it well so that the clinician completely understands the information so that they can properly care for the patient. Moreover, we must not forget the golden rule: garbage in, garbage out. What I mean by this is that good communication should begin in the pre-analytical phase. We want the clinician to provide the laboratory with the best possible specimen so that in turn, we can provide them with the most accurate result. So how do we ensure that we obtain the best possible specimen? We communicate.

The laboratory communicates our needs to the provider in order to properly do our job. For example, we provide detailed information on how to properly collect specimens, which container type to use, how to handle the specimen, how much (volume) specimen to submit, which temperature to submit the specimen, etc. Properly communicating these details is essential.

The Difficult Conversation

As laboratory professionals, we are just one part of a larger healthcare team. If you stop to think about it, we all have to participate in difficult conversations as part of our jobs. Doctors have to tell patients that they are going to die, laboratory professionals have to tell clinicians we lost their specimen, executive administrators have to tell downstream leadership that the budget has been cut again, managers and supervisors have to tell employees they are being written up or worse. Being able to successfully have a difficult conversation would serve us all well. As such, most institutions provide classes or webinars to help employees develop this skill.

The definition of difficult is: not easily or readily done; requiring much labor, skill, or planning to be performed successfully; hard (4). Carrying out a difficult conversation with grace is an extraordinary skill that encompasses a variety of communication attributes. Regardless of the scenario, the communicator must be clear, articulate, and courteous. However, depending on the scenario, being concise, confident, strategic, diplomatic, convincing, empathetic, motivating, open-minded, and/or quick thinking may also be useful skills to possess during a difficult conversation. Other valuable skills are conflict management, being able to explain, and/or listening.

The Conclusion

For many, the New Year marks the time to set new goals, to accept new challenges, and welcome new beginnings. Why not use this opportunity to learn a new skill? The good news is that no matter what your new skill will be, it will also benefit your health. In order to acquire a new ability, you must work to actively learn to become proficient in that ability; therefore learning a new skill will also benefit your brain function. There are many studies that demonstrate that active learning keeps the mind sharp (5). Challenging your mind improves brain function and active learning slows cognitive decline (6). If you want to be brave, then don’t only choose a skill that will be fun or helpful, but choose to learn something that also challenges you to face one of your fears. For me, I hope to learn how to master the art of having difficult conversations….successfully. In the words of Marie Curie, “Nothing in life is to be feared, it is only to be understood. Now is the time to understand more, so that we may fear less.”

Happy learning! Happy New Year!

The References

Work-life Balance. https://en.wikipedia.org/wiki/Work–life_balance. Accessed January 16, 2018.
The balance. List of Communication Skills for Resumes. https://www.thebalance.com/communication-skills-list-2063737. Accessed January 16, 2018.
The balance. Communication Skills for Workplace Success. https://www.thebalance.com/communication-skills-list-2063779. Accessed January, 16, 2018.
com. Difficult. http://www.dictionary.com/browse/difficult. Accessed January 16, 2018.
Stenger, M. 2013. New Study Shows How Active Learning Improve Cognitive Function. https://www.opencolleges.edu.au/informed/other/new-study-highlights-activities-to-improve-cognitive-function-6008/. Accessed January 17, 2018.
Park, D.C., Bischof, G.N. 2013. The aging mind: neuroplasticity in response to cognitive training. Dialogues Clin Neurosci. 15(1): 109-119. PMC23576894. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3622463/. Accessed January 17, 2018.

Martinez Headshot-small 2017

-Raquel Martinez, PhD, D(ABMM), was named an ASCP 40 Under Forty TOP FIVE honoree for 2017. She is one of two System Directors of Clinical and Molecular Microbiology at Geisinger Health System in Danville, Pennsylvania. Her research interests focus on infectious disease diagnostics, specifically rapid molecular technologies for the detection of bloodstream and respiratory virus infections, and antimicrobial resistance, with the overall goal to improve patient outcomes.

Hematopathology Case Study: An 18-year-old Man with Acanthocytosis

Case History

We were asked to review the peripheral blood smear of an 18-year-old male who had presented to the emergency department with shortness of breath and abdominal distension. His past medical history was significant for numerous hospitalizations for recurrent fungal and bacterial pneumonia, pulmonary abscesses, osteomyelitis, necrotizing granulomas, and cervical lymphadenopathy requiring multiple lymphadenectomies. This history dates back to when he was 3 months old.

Blood Smear findings

The CBC demonstrated severe anemia and mild leukopenia. The peripheral blood smear showed numerous acanthocytes and poikilocytosis shown below.

McLeodAcantyocytes3

McLeodAcantyocytes4

Additional Clinical Findings

Abdominal ultrasonography demonstrated hepatosplenomegaly with enlarged porta-hepatis lymph nodes. Additionally, chest CT scanning demonstrated bilateral mass-like consolidations, prominent hilar lymphadenopathy, and osteolytic lesions of the vertebral bodies. A comprehensive investigation for opportunistic infections was negative. Lung and vertebral body biopsies (not pictured here) revealed poorly formed granulomas. A blood transfusion was considered; however, the patient had previously been demonstrated to express anti-Kx antibodies, which would require transfusion with exceedingly rare blood products.

Diagnosis

The preceding case history describes a patient with a contiguous gene deletion syndrome that includes chronic granulomatous disease (CGD) and the McLeod phenotype, demonstrating a fascinating disorder with important implications in hematopathology and several other disciplines of pathology.

Discussion

McLeod syndrome is a rare, X-linked disorder characterized by the deletion of the XK gene which encodes for the Xk protein. Overall, the lack of synthesis of the Xk protein leads to the lack of expression of the Kx antigen which in turn leads to a marked decrease in the quantities of Kell antigens. In this case, due to the presence of an anti-Kx antibody, the patient would require transfusion with either Kell-null or McLeod phenotype blood products. Unfortunately, only one unit of compatible blood was identified when the rare blood donor database was queried. The clinical team therefore elected for treatment with erythropoietin and iron supplementation which eventually lead to a modest increase in the patient’s hemoglobin concentration.

Acanthocytes, or spur cells, are spiculated red cells with a few projections of varying size and surface distribution that can be seen in a variety of clinical conditions including CGD with McLeod red cell phenotype. Other conditions include (but are not limited to) neuroacanthocytosis, malnutrition states, infantile pyknocytosis, (Lu) null Lutheran phenotype, hypothyroidism, myxedema, and Zieve syndrome. Acanthocytes should be distinguished from echinocytes, or burr cells, that also demonstrate multiple small projections but these are uniformly distributed on the red cell surface.

The prominent acanthocytosis seen in McLeod syndrome is thought to be due to an imbalance of the number of lipids in the inner layer relative to the outer layer. Related to this phenomenon is McLeod neuroacanthocytosis syndrome, a disorder with neurologic manifestations including movement disorders, cognitive alterations, and psychiatric symptoms. Although our patient did not exhibit these symptoms, McLeod neuroacanthocytosis syndrome is known to start in early to middle adulthood and the patient will need to be monitored for the onset of neurologic sequelae.

The McLeod phenotype is frequently associated with CGD due to the proximity of the XK gene to the CYBB gene on the X chromosome. The CYBB gene encodes for a subunit of the NADPH oxidase enzyme complex. A deficiency in NADPH oxidase activity leads to the characteristic increased susceptibility to severe bacterial and fungal infections seen in CGD. The nitroblue-tetrazolium test can be used to evaluate NADPH oxidase activity in the white blood cells and can help make a diagnosis of CGD. Histologically, CGD can show prominent necrotizing and non-necrotizing granulomas in various locations throughout the body.

Overall, treatment of CGD with McLeod red cell phenotype is supportive. There is no known cure or definitive treatment. The patient will likely continue to have infections with opportunistic organisms which will be treated on a case by case basis.

References

Heyworth PG, Cross AR, Curnutte JT. Chronic granulomatous disease. Current opinion in immunology. 2003 Oct 31;15(5):578-84.

Jung HH, Danek A, Walker RH, Frey BM, Gassner C. McLeod neuroacanthocytosis syndrome.

Khodadad JK, Weinstein RS, Marsh LW, Steck TL. Shape determinants of McLeod acanthocytes. Journal of Membrane Biology. 1989 Mar 1;107(3):213-8.

Watkins CE, Litchfield J, Song E, Jaishankar GB, Misra N, Holla N, Duffourc M, Krishnaswamy G. Chronic granulomatous disease, the McLeod phenotype and the contiguous gene deletion syndrome-a review. Clinical and Molecular Allergy. 2011 Nov 23;9(1):13.

-Michael Moravek, MD is a 2nd year anatomic and clinical pathology resident at Loyola University Medical Center. Follow Dr. Moravek on twitter @MoravekMD

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-Kamran M. Mirza, MD PhD is an Assistant Professor of Pathology and Medical Director of Molecular Pathology at Loyola University Medical Center. He was a top 5 honoree in ASCP’s Forty Under 40 2017. Follow Dr. Mirza on twitter @kmirza.

Hematopathology Case Study: A 45 Year Old Man with Cytopenias and High Ferritin

Case history

A 45 year-old man presented with vomiting and diarrhea for 5 days. Laboratory studies demonstrated anemia and thrombocytopenia, an elevated ferritin level (23,772 ug/L) and methemoglobinemia. Chest roentgenography revealed cardiomegaly. A follow-up ECHO showed a desreased ejection fraction of 15%. Work-up confirmed viral myocarditis and G6PD deficiency as the cause of the cardiac findings and methemoglobinemia respectively. His clinical condition deteriorated despite therapy: he developed acute kidney and liver failure and had worsening cytopenias. A bone marrow biopsy was performed.

Histomorphological findings

BM17-228 HLH 100x-2 — Bone marrow aspirate smear (100x)

CPC Core biopsy 20x — Bone marrow core biopsy (H&E, 20x)

CPC Core biopsy 40x — Bone marrow core biopsy (H&E, 40x)

CPC Core biopsy 100x — Bone marrow core biopsy (H&E, 100x)

Evaluation of the peripheral blood (not pictured) confirmed a macrocytic anemia with marked anisopoikilocytosis including schistocytes, polychromasia, nucleated red blood cells, absolute neutrophilia, monocytosis and thrombocytopenia. The marrow aspirate smear demonstrated appropriate maturation in all cell lines. Scattered hemophagocytic histiocytes (pictured above) were noted. The bone core biopsy was high-normocellular for age with progressive trilineage hematopoeisis. Scattered histiocytes with internalized erythroid cells and debris were visualized. There was no increase in blasts. Flow cytometry analysis performed on the bone marrow aspirate did not show a significant increase in blast population. Gating on the lymphocytes did not show a B-cell monoclonal population or T-cell abnormality by markers assayed.

Diagnosis

High-normocellular marrow with progressive trilineage hematopoeisis and prominent hemophagocytic histiocytes.

Overall the patient met the clinical criteria (see below) for Hemophagocytic Lymphohistiocytosis (HLH); with fever (≥38.5 C), splenomegaly, bicytopenia, presence of hemophagocytic histiocytes in bone marrow and high ferritin level (>500ng/mL).

A clinical diagnosis of HLH was rendered.

Discussion

HLH is an uncommon hematologic disorder that is often fatal. The underlying pathogenesis involves an exaggerated but ineffective inflammatory response of excessive macrophage and T-cell activation, and impairment of natural killer (NK) and cytotoxic T-cell function. HLH has familial and acquired forms. Secondary, or acquired HLH can be associated with infections (especially viral etiologies), underlying malignancy (particularly lymphomas and leukemias), and medications used for systemic lupus erythematosus. Clinically, autoimmune disease-associated HLH overlaps significantly with macrophage activation syndrome (MAS).

HLH is a clinical diagnosis that can be established with molecular testing or by meeting five of eight clinical and laboratory diagnostic criteria according to the HLH-2004 guidelines.

HLH-2004: Revised diagnostic guidelines for HLH10

The diagnosis HLH can be established if one of the two criteria below is met:

A molecular diagnosis consistent with HLH (i.e., reported mutations found in either PRF1 or MUNC13-4); or
Diagnostic criteria for HLH are fulfilled (i.e., at least five of the eight criteria listed below are present:
- Persistent fever
- Splenomegaly
- Cytopenias (affecting ≥2 of 3 lineages in the peripheral blood):
  - Hemoglobin <90g/L (in infants <4 weeks: <100g/L)
  - Platelets <100 x 109/L
  - Neutrophils <1.0 x 109/L
- Hypertriglyceremia and/or hypofibrinogenemia:
  - Fasting triglycerides ≥3.0 mmol/L (i.e., ≥ 265mg/dl)
  - Fibrinogen ≤1.5 g/L
- Hemophagocytosis in bone marrow* or spleen or lymph nodes, no evidence of malignancy
- Serum ferritin ≥ 500µg/L (i.e., 500 ng/ml)
- Low or absent NK cell activity (according to local laboratory reference)
- Increased serum sIL2Rα (according to local laboratory reference)

*In hematopathology, the finding of relevance is the presence of hemophagocytic histiocytes in the marrow or other biopsies organs. While debris-laden histiocytes are commonly noted in marrow aspirates, the findings of engulfed erythroid cells is warranted to call a ‘hemophagocytic’ histiocyte.

Often a bone marrow biopsy will be performed in cases where there is clinical suspicion for HLH. This serves to try and visualize the hemophagocytic activity, and to rule out other diseases with similar clinical presentations as HLH. The pathologic evaluation of HLH is tricky, since there is no established criteria for quantitation of hemophagocytic histiocytes in a bone marrow aspirate. Furthermore, hemophagocytosis is not specific to HLH and can be seen in other conditions such as: post-blood transfusion, chemotherapy, sepsis and major operations. Published data shows that the presence of hemophagocytosis has a sensitivity of 83% and a specificity of only 60% in diagnosing HLH.

What about immunohistochemical staining for the histiocytes? While IHC can help outline histicoytic cells, unfortunately, quantitation of hemophagocytic histiocytes in the core biopsy or clot sections with the aid of CD68 immunostains does not correlate well with disease probability either.

Overall, the nonspecificity of hemophagocytosis in the marrow, even when present in high amounts, should remind both pathologists and clinicians that an isolated finding of hemophagocytosis lacks specificity and does not necessarily suggest HLH when the clinical presentation and laboratory findings are not compatible with the diagnosis. However, there still remains value in bone marrow biopsy examination in cases where clinical suspicion for HLH is high; in order to exclude other marrow processes; and in the rare case where there may not have been clinical suspicion of HLH but the presence of hemophagocytic histiocytes can raise that differential.

For additional images of hemophagocytic histiocytes check out these amazing picture tweets by Dr. Kate Dannheim (@KDannheimMD) https://twitter.com/KDannheimMD/status/933128799818002432) and Dr. Bharat Ramlal (@BeRaad87): https://twitter.com/HHPathology/status/926087105381531648

References

Ho C, Yao X, Tian L, et al. Marrow Assessment for Hemophagocytic Lymphohistiocytosis Demonstrates Poor Correlation with Disease Probability. Am J Clin Pathol. 2014 Jan;141(1):62-71
Hunter JI et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007 Feb;48(2):124-31.

AIK

-Ayse Irem Kilic is a 1^st year anatomic and clinical pathology resident at Loyola University Medical Center. Follow Dr. Kilic on twitter @iremessa.

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Hematopathology Case Study: A 72 Year Old Female with History of Lung Adenocarcinoma

Case history

A 72 year-old female with a history of stage IA lung adenocarcinoma diagnosed in 2009 s/p resection underwent a surveillance CT scan of the chest which revealed an enlarged right upper lobe paramediastinal lung nodule. A subsequent MRI of the abdomen and PET scan revealed mediastinal lymphadenopathy with numerous boney lesions. Due to the prior history of lung cancer, a right iliac bone biopsy was performed.

Diagnosis

Sections of bone show an extensive intramedullary infiltration by large cells with moderate amounts of cytoplasm, irregular nuclear contours, moderately condensed chromatin and some cells with inconspicuous nucleoli.

By immunohistochemistry, the neoplastic cells are immunoreactive for CD45, MPO, CD68, CD56, and CD43. The cells are negative for cytokeratins, TTF-1, CD20, CD10, PAX5, BCL6, MUM1 and CD79a. CD3 and CD5 highlight rare scattered T-cells.

Overall, in the context of multiple osseous lesions, these findings are representative for a myeloid sarcoma.

Discussion

Myeloid sarcoma is a tumor mass consisting of myeloid blasts with or without maturation occurring at any site other than the bone marrow. Infiltration of blasts at any site are not classified as a myeloid sarcoma unless there is effacement of tissue architecture. Frequent sites for involvement by a myeloid sarcoma include skin, lymph node, gastrointestinal tract, bone, soft tissue, and testis.

Detection of a myeloid sarcoma is considered as an equivalent diagnosis of acute myeloid leukemia. It may precede or coincide with AML as well as be a presenting finding in those that relapse from AML.

Morphologically, the blasts may or may not show features of maturation and efface the architecture of the involved site. Immunophenotypically, CD68 is considered the most commonly expressed marker followed by MPO, CD117, lysozyme, CD34, TdT, CD56, CD30, glycophorin and CD4. Interestingly enough, CD123 may be expressed in those cases that also have inv(16). It must be emphasized that those cases that meet criteria for a mixed phenotypic acute leukemia (MPAL) cannot be classified as a myeloid sarcoma.

By cytogenetics, 55% of myeloid sarcomas have aberrant cytogenetic findings including monosomy 7, MLL rearrangements, inv(16), and other chromosomal changes. In the pediatric population, t(8;21) may be observed and is less frequent in adults. NPM1 is mutated in 16% of cases.

Lastly, the differential diagnosis should be kept broad in cases that appear lymphoid in nature yet do not mark appropriately. It is often expressed that the primary morphologic differential is a lymphoma, including lymphoblastic lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma, blastic plasmacytoid dendritic cell neoplasm, and other small round blue cell tumors of childhood.

Reference

Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008

PhillipBlogPic-small

-Phillip Michaels, MD is a board certified anatomic and clinical pathologist who is a current hematopathology fellow at Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. His research interests include molecular profiling of diffuse large B-cell lymphoma as well as pathology resident education, especially in hematopathology and molecular genetic pathology.

Pathologist on Call: There Is No Perfect Lab Test for Smoking Assessment

Cigarette smoking can affect both innate and adaptive immunity, and introduces concerns when evaluating a patient’s eligibility for surgery. It has been shown to hinder time required for healing and long-term survival of patients. It can promote vascular complications, increase the rates of hepatocellular carcinoma and reduce lung function.¹ For lung transplantation, one of the common requirements of eligibility is smoking abstinence for at least 6 months. Smoking post-surgery is associated with worse outcomes for the patients including complications and higher rates of mortality.² Relapse to smoking post lung transplantation has been reported to range from 11% to 23% in various patient populations.³ As a result, clinical testing for cigarette smoking abstinence is an important part of initial workup and follow-up of transplant patients.

In some situations, the burden of lung allocation weighs heavily on a single clinical laboratory result that is perceived to definitively confirm or exclude active cigarette smoking. This subsequently factors into the decision by the physicians to deem the patient eligible to receive a lung transplant. The perception of nicotine testing as definitive proof of smoking is misleading and does not reflect the complexity of situations that can lead to a positive test result.

How can we assess smoking?

Ideally, many factors should weigh into the final smoking status determination including self-reporting (used historically), witnesses to behavior, odor, and past history including cessation attempts. Clinical laboratory testing is important and thought to be more reliable means for smoking assessment. It can involve testing for nicotine (originating from tobacco or nicotine replacement therapy, NRT) and its metabolites: cotinine, 3-hydroxycotinine (3-OH-cotinine), and nornicotine. Moreover, nicotine contains a number of alkaloids that are not usually present in nicotine-replacement therapies (NRTs) including anatabine and anabasine.⁴ Nicotine testing can involve a combination of metabolites such as cotinine as well as alkaloids like anabasine. Various sample types have been used including saliva, blood and urine.⁵ In addition, measurements of the exhaled carbon monoxide (CO) have been used to assess recent smoking status (within the last 8 hours).⁶

Clinical case: patient with detectable nicotine metabolites

A case involving a patient being considered for lung transplantation was received by our department. The patient had been tested for anabasine, nicotine, and its metabolites in urine. Testing of random urine specimens was performed by liquid chromatography tandem mass spectrometry (LC-MS/MS) at different time points from samples collected during hospital visits (days 0, 38, and 62). The urine contained variable concentrations of nicotine and its metabolites, with anabasine concentrations below the detection limit in 2 out of the 3 testing instances. Testing at day 0 showed an interfering substance that prevented the determination of accurate anabasine concentration. The nicotine and its metabolite concentrations in the random urine specimens were lower from day 0 to day 38, but a noticeable increase of 3-OH-cotinine and cotinine concentrations was observed in the specimen collected on day 62. The physician was seeking information about the current smoking status of the patient and was planning to use this information to determine the patient’s lung transplant eligibility.

smoking-1

Days	0	38	62
Analyte concentration (ng/mL)
3-OH-cotinine	4074	89	603
Anabasine	interf. subst.	< 3	< 3
Cotinine	1404	47	425
Nicotine	241	< 2	72
Nornicotine	58	< 2	6

Figure and table 1. Nicotine, metabolite and anabasine concentrations (ng/mL) at different time points for a patient evaluated for lung transplantation eligibility. Anabasine was not detected on days 38 and 62, with an interfering substance preventing quantitation on day 0.

How definitive are these results?

No information was available regarding self-reported smoking or NRT use history for this patient. The physician had high suspicion that the patient was an active smoker and was attempting to use higher concentrations of nicotine and metabolites observed on day 62 as evidence of recent tobacco use.

For cotinine, values can range from 20-550 ng/mL for daily tobacco use.⁵ Nicotine concentrations in urine can approach over 5000 ng/mL with daily use. Together, high nicotine and cotinine can support tobacco or high-dose nicotine patch use. Furthermore, presence of nornicotine above 30 ng/mL along with anabasine greater than 10 ng/mL would be consistent with current tobacco use rather than NRT.⁷

Given that these were random urine specimen and the urinary creatinine values are not routinely measured, it’s important to consider the possible contributions of the variable urine concentration to the analyte concentrations. It has previously been reported that individuals abstaining from smoking for at least two weeks should present with nicotine of <30 ng/mL, cotinine of < 23 ng/mL, 3-OH-cotinine of <120 ng/mL, nornicotine < 3 ng/mL, and anabasine of < 2 ng/mL in urine.⁷ Based on these cut-offs, all analytes except anabasine would suggest new nicotine intake within the last two weeks.

In general, a positive anabasine result, in combination with the presence of nicotine metabolites, is consistent with active use of a tobacco product, whereas anabasine values of < 2ng/mL may suggest that NRT is the likely source.⁸ This can imply that the patient is abstinent from smoked or chewed tobacco if anabasine is not detected. However, anabasine is not a sensitive marker of smoked tobacco. It has been reported that the compound may not be detectable in 60% of self-reported smokers (N=51; 3 ng/mL cut-off in urine)⁹ and its urinary concentrations do not correlate well with self-reported tobacco use.⁸

As a result, anabasine has low sensitivity for determining eligibility for UNOS (United network for organ sharing) listing. There are some recommendations that this marker should not be used alone. Given that other alkaloids can originate from tobacco plant, it has been proposed that anatabine should be added to analysis due to higher expected concentration.⁹ However, this alkaloid is not completely specific to tobacco as it has been proposed to also arise from other plant sources ¹⁰^,¹¹ leading to possible implications for the patient that may be misclassified. In addition, anatabine sensitivity in detecting smoked tobacco use varies depending on the tobacco source and the clinical cut-off used. Clinical tests that include anatabine are not routinely available.

Can we improve this process?

Unfortunately, there is no definitive marker distinguishing smoking from NRT.

The determination of smoking status has advanced from reliance on self-reporting to quantitative and specific measurements of metabolites of nicotine and minor components of tobacco. Additional analyte incorporation into a test panel leads to additional complexities and considerations in interpretation of the results. Therefore, it is important to educate the physicians about various nicotine sources causing a positive nicotine and/or metabolite test result including NRT or e-cigarettes. It is also important to convey the limitations of tobacco alkaloid testing in such scenarios. Both the lab and the physician need to be cautious about implying active smoking in the absence of indirect supporting evidence and/or positive clinical test results.

At the same time, there is a need to improve the utility and availability of other tobacco alkaloid testing in distinguishing cigarette smoking from NRT in specific transplant populations and consider the value of testing alternative specimens. This may lead to a more effective implementation of secondary markers of tobacco use.

References

Qiu, F.; Fan, P.; Nie, G. D.; Liu, H.; Liang, C.-L.; Yu, W.; Dai, Z., Effects of Cigarette Smoking on Transplant Survival: Extending or Shortening It? Frontiers in Immunology 2017, 8, 127.
Zmeskal, M.; Kralikova, E.; Kurcova, I.; Pafko, P.; Lischke, R.; Fila, L.; Valentova Bartakova, L.; Fraser, K., Continued Smoking in Lung Transplant Patients: A Cross Sectional Survey. Zdravstveno varstvo 2016, 55 (1), 29-35.
Vos, R.; De Vusser, K.; Schaevers, V.; Schoonis, A.; Lemaigre, V.; Dobbels, F.; Desmet, K.; Vanaudenaerde, B. M.; Van Raemdonck, D. E.; Dupont, L. J.; Verleden, G. M., Smoking resumption after lung transplantation: a sobering truth. The European respiratory journal 2010, 35 (6), 1411-3.
Hukkanen, J.; Jacob, P., 3rd; Benowitz, N. L., Metabolism and disposition kinetics of nicotine. Pharmacological reviews 2005, 57 (1), 79-115.
Raja, M.; Garg, A.; Yadav, P.; Jha, K.; Handa, S., Diagnostic Methods for Detection of Cotinine Level in Tobacco Users: A Review. Journal of clinical and diagnostic research : JCDR 2016, 10 (3), Ze04-6.
Sandberg, A.; Skold, C. M.; Grunewald, J.; Eklund, A.; Wheelock, A. M., Assessing recent smoking status by measuring exhaled carbon monoxide levels. PloS one 2011, 6 (12), e28864.
Moyer, T. P.; Charlson, J. R.; Enger, R. J.; Dale, L. C.; Ebbert, J. O.; Schroeder, D. R.; Hurt, R. D., Simultaneous analysis of nicotine, nicotine metabolites, and tobacco alkaloids in serum or urine by tandem mass spectrometry, with clinically relevant metabolic profiles. Clinical chemistry 2002, 48 (9), 1460-71.
Jacob, P., 3rd; Hatsukami, D.; Severson, H.; Hall, S.; Yu, L.; Benowitz, N. L., Anabasine and anatabine as biomarkers for tobacco use during nicotine replacement therapy. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 2002, 11 (12), 1668-73.
Feldhammer, M.; Ritchie, J. C., Anabasine Is a Poor Marker for Determining Smoking Status of Transplant Patients. Clinical chemistry 2017, 63 (2), 604-606.
Lanier, R. K.; Gibson, K. D.; Cohen, A. E.; Varga, M., Effects of dietary supplementation with the solanaceae plant alkaloid anatabine on joint pain and stiffness: results from an internet-based survey study. Clinical medicine insights. Arthritis and musculoskeletal disorders 2013, 6, 73-84.
von Weymarn, L. B.; Thomson, N. M.; Donny, E. C.; Hatsukami, D. K.; Murphy, S. E., Quantitation of the minor tobacco alkaloids nornicotine, anatabine, and anabasine in smokers’ urine by high throughput liquid chromatography mass spectrometry. Chemical research in toxicology 2016, 29 (3), 390-397.

-Dr. Valentinas Gruzdys developed interest in clinical chemistry early in his academic training which led him to pursue and obtain a PhD in Clinical and Bioanalytical Chemistry at Cleveland State University. Valentinas is enthusiastic about teaching and helping improve the understanding of limitations and utility of clinical laboratory testing. He is currently enrolled in a clinical chemistry fellowship program at the University of Utah. He enjoys learning more about various aspects of clinical chemistry and cannot wait to make his own contributions to the field after his training.

Hematopathology Case Study: A 56 Year Old Male with an Enlarged Lymph Node

Case History

A 56-year-old male with a past medical history significant for HIV currently on HAART presented to his primary care physician with an isolated enlarged left inguinal lymph node. In the context of his immunocompromised state, the patient was sent for a core needle biopsy of the lymph node to further elucidate the etiology of the isolated lymphadenopathy.

Diagnosis

The core needle biopsy demonstrated multiple suppurative granulomata with a mixed inflammatory background including abundant plasma cells. The plasma cells are also found to surround small blood vessels. A Treponema immunostain was performed which highlighted the spirochetes. Overall, the diagnosis is that of luetic lymphadenitis.

Discussion

Syphilitic infections can cause isolated lymphadenopathy, especially in the inguinal lymph nodes. The morphologic features of luetic lymphadenitis include interfollicular plasmacytosis, capsular fibrosis, endarteritis, and occasionally sarcoid-like granulomata with rare cases demonstrating suppurative features. The differential diagnosis includes rheumatoid arthritis associated lymphadenopathy but a key histologic difference is that the capsular fibrosis of luetic lymphadenitis will have an infiltrate of lymphocytes and plasma cells while RA associated lymphadenopathy traditionally does not. Immunohistochemistry for Treponema organisms also serves to confirm the diagnosis. It is important to keep in mind the patient’s clinical history when interpreting the biopsy was as well as the differential for interfollicular plasmacytosis with capsular fibrosis.

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Hematopathology Case Study: A 68 Year Old Man with Dyspnea on Exertion

Case History

A 68 year old male with no significant past medical history who enjoys long distance cycling presented to an outside emergency department with dyspnea on exertion. Laboratory values at the outside facility showed profound anemia (Hb 10 g/dL) and physical exam revealed lymph adenopathy. The patient was discharged but presented again to his primary care physician with profound dyspnea on exertion, especially after climbing one flight of stairs. Of note, his anemia had worsened with a new Hb of 7 g/dL. For evaluation of the anemia, the patient had a Coomb’s test and it was positive, overall consistent with cold agglutinin disease. For evaluation of the lymphadenopathy, a CT abdomen and chest revealed celiac, portocaval, mesenteric and retroperitoneal lymphadenopathy as well as mild splenomegaly. Due to these findings, the patient presented to Beth Israel Deaconess Medical Center for further evaluation and biopsy of a retroperitoneal lymph node.

A core needle biopsy of a retroperitoneal lymph node was obtained per the recommendation of hematology/oncology.

Diagnosis

The core needle biopsy material demonstrated a lymphoid population that was polymorphic in appearance with medium to large sized lymphocytes with moderate amounts of pale cytoplasm, irregular nuclei, vesicular chromatin, and some cells with prominent nucleoli. The background cellular population is composed of a mixed inflammatory component including small lymphocytes, scattered neutrophils, eosinophils, and histiocytes.

By immunohistochemistry, the medium to large sized cells with pale cytoplasm are positive for CD3, CD2, CD4, and CD5 with complete loss of CD7. CD20 highlights scattered background B-cells. CD21 is positive in disrupted follicular dendritic meshworks. CD10 and BCL6 are negative in neoplastic cells. PD1 is positive in neoplastic cells with a subset co-expressing CXCL13. By Ki-67 immunostaining, the proliferation index is 50-70%. By in situ hybridization for Epstein-Barr virus encoded RNA, a subset of cells are positive.

Overall, with the morphologic and immunophenotypic features present, the diagnosis is that of angioimmunoblastic T-cell lymphoma.

Discussion

Angioimmunoblastic T-cell lymphoma (AITL) is one of the most common types of peripheral T-cell lymphoma and accounts for 15-20% of T-cell lymphoproliferative disorders and 1-2% of all non-Hodgkin lymphomas. Clinical features include presentation with late stage disease with associated generalized lymphadenopathy, hepatosplenomegaly, systemic symptoms, and polyclonal hypergammaglobulinemia. Of note, this patient did have an SPEP that was within normal limits. Other findings, although less common, include effusions and arthritis. Laboratory findings often include cold agglutinins with hemolytic anemias, a positive rheumatoid factor (RF), and anti-smooth muscle antibodies. A hallmark of AITL is the expansion B-cells positive for EBV is seen, which may be an indicator of underlying immune dysfunction. The clinical course is often aggressive with a median survival of less than three years and often succumb to infectious etiologies because of an immune dysregulation.¹

The pathogenesis and relation to other TFH neoplasms of PTCL, NOS is poorly understood. Recent literature indicates dysregulation in key pathways, including the CD28 and TCR-proximal signaling genes, NF-kappaB/NFAT pathway, PI3K pathway, MAPK pathway, and GTPases pathway.²The complexity of these pathways has long been an issue for TFH lymphoproliferative disorders and has provided insight to potential molecular signatures (see figure 1 adapted from Vallois 2016).

Another recent publication provided additional information regarding molecular insights. Confirmed mutational analyses reveals a high proportion of cases carry a TET2 mutation with less frequent changes in DNMT3A, IDH2, RHOA, and PLCG1. Specifically, RHOA, PLCG1, and TNFRSF21 encode proteins critical for T-cell biology and most likely promote differentiation and transformation into an aggressive clinical course (see figure 2 adapted from Wang 2017).³

AITL-15 — Figure 2 adapted from Wang 2017

Overall, AITL is an uncommon TFH cell derived lymphoproliferative disorder characterized by a TFH immunophenotype, expanded and arborizing high endothelial venules, expansion of the follicular dendritic cell meshworks, and EBV positive B-cells in a background of a polymorphic infiltrate. Although it is hypothesized that the underlying mechanism of neoplasia is related to immune dysfunction, new molecular insights have demonstrated that multiple events occur ranging from early molecular changes to later acquired mutations that allow for malignant transformation.

References

Swerdlow, S., et al., WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th. ed., IARC press: 2008
Vallois, D., et al. “Activating mutations in genes related to TCR signaling in angioimmunoblastic and other follicular helper T-cell-derived lymphomas,” 2016; 128(11): 1490-1502.
Wang, M., et al., “Angioimmunoblastic T cell lymphoma: novel molecular insights by mutation profiling,” 2017; 8(11): 17763-17770.

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Will Anyone See This Test Result?

We are all aware that there is substantial waste in testing. The mantra of utilization management is “the right test for the right patient at the right time.” This month, I want to focus on the right time. It turns out that many test results are never seen because they arrive after the patient has been discharged. This occurs for both routine and send-out testing. I will examine both.

Turnaround times for send-out testing are generally longer than those for tests performed in house. This means that results for tests ordered toward the end of a hospital stay are likely to be received after the patient has been discharged. Sendout tests are often expensive and, unlike tests performed in house, reducing sendout testing saves the hospital the full charge of the test. The savings can be substantial.

How do you prevent this? A recent article by Fang et al. shows one approach.[1] In this study, conducted at Stanford University, researcher displayed the cost and turnaround time of sendout tests in the computerized provider order entry (CPOE) system and achieved a 26% reduction in orders. I am aware of another hospital that restricts orders of sendout tests when the expected turnaround time is close to the expected remaining length of stay. Consider the graph in Figure 1. The upper panel shows the expected length of stay for a particular patient. The lower panel shows the expected turnaround time for a sendout test. In this case, there is a 62% chance that the test result will arrive after the patient has left the hospital. Expected discharge dates are routinely kept and it is relatively easy to maintain a database of turnaround times. A hospital could combine these data and set a threshold for orders based on the probability that the result will arrive in time.

Standing orders are another source of waste. I recently performed an analysis of the test rate as a function of the time until discharge (Figure 2). The test rate was 249 tests per hour for patients who were within 12 hours of discharge and 349 tests per hour for all other patients. It seems odd to me the testing rate in the final 12 hours is 70% of the “normal” testing rate. Further, the distribution of tests in both groups (those about to be discharged vs. all other patients) is very similar (Table 1). The main tests are basic metabolic panels and complete blood counts. I suspect the majority of the testing within 12 hours of discharge is due to standing orders and the results were not needed for patient care. The best intervention is less clear in this case because some peri-discharge testing is appropriate and it is difficult to distinguish the appropriate testing from the inappropriate testing. Education is one option. Perhaps the CPOE could raise a flag on orders for patients who are about to be discharged; however, this could be cumbersome and clinicians object to flags and popups that interfere with their workflow. I would be interested in readers’ thoughts on methods to reduce inappropriate peri-discharge testing.

In summary, some results do not reach clinicians in time to affect patient care. This is a source of waste. It is relatively easy to create an intervention to reduce inappropriate sendout testing but more difficult to reduce unnecessary peri-discharge testing.

Reference

Fang DZ, Sran G, Gessner D, Loftus PD, Folkins A, Christopher JY, III, Shieh L: Cost and turn-around time display decreases inpatient ordering of reference laboratory tests: A time series. BMJ Quality and Safety 2014, 23(12):994-1000.

8-2017-fig-1 — Figure 1: Comparison of expected length of stay (upper) and turnaround time (lower) for a sendout test.

8-2017-fig-2 — Figure 2: Peri-discharge testing

8-2017-tab-1 — Table 1: Test patterns stratified by time to discharge. The table shows the percentage of total testing accounted for each group. For example, BMP represents 15% of the total test volume among patients who are within 12 hours of discharge.

-Robert Schmidt, MD, PhD, MBA, MS is a clinical pathologist who specializes in the economic evaluation of medical tests. He is currently an Associate Professor at the University of Utah where he is Medical Director of the clinical laboratory at the Huntsman Cancer Institute and Director of the Center for Effective Medical Testing at ARUP Laboratories.

Owning Safety in the Autopsy Suite

The hospital security guard placed the deceased patient into the morgue refrigerator while chatting with his co-worker. They walked away without realizing the door did not close completely. Within the hour the automated temperature recording system sent an alert to the lab on the third floor.

The body had been unclaimed, and it stayed on the bottom shelf in the morgue. No one in the hospital wanted to take ownership of it. After a couple of months, fluids began to fill the shelf where the body was. The environmental services staff refused to clean up the mess since some staff were afraid.

The pathologist wanted to finish the autopsy quickly, so he started before the complete patient chart arrived. When the phone rang in the morgue, the physician on the other end of the phone said he believed the patient may have Creutzfeldt-Jakob Disease (CJD).

Managing safety in the autopsy suite can be difficult, but as these case studies show, it is important. One reason for the struggle is that clear ownership of the area is often not defined. Multiple internal departments and even external agencies may work in the morgue and autopsy suite. Pathologists, medical examiners, research physicians, security personnel, nurses, and organ procurement staff are just some of the various people that may perform tasks in the autopsy suite. This can create some unique and unwanted problems. The laboratory should take the lead in making sure all safety regulations are followed and that other users of the suite comply to avoid any unfortunate mishaps.

The morgue should be treated as a laboratory space, and it should be designed similarly to a BSL-3 laboratory space which includes an anteroom. Warning signs indicating the presence of biological and chemical materials should be placed on entry doors. Whenever work is performed in the area, proper personal protective equipment should be utilized. This PPE may include lab coats, gowns, gloves, respirators, and face protection. Make sure PPE is available in the area at all times. The autopsy space should be adequate, such that procedures may be performed effectively and that items such as knives and saws can be stored and used safely. Ventilation should be adequate (with a recommended minimum 12 air exchanges per hour), and the ambient temperature should be monitored as well.

While other personnel may access the morgue body storage refrigerator, it is often the lab or security departments who monitor the temperature. Since CAP inspectors set specific morgue refrigerator temperature ranges (1.1 to 4.4° Celsius), it can be important to communicate with the people who utilize the unit often. If placing or removing a body takes longer than expected, make sure there is adequate communication so that proper documentation of the temperature outages can be made. If a department other than the lab is responsible for temperature monitoring, make sure it is done correctly so there are no citations during an inspection.

Proper decontamination in the morgue is crucial. Instruments, tables, and counters must be disinfected to remove contamination of bloodborne pathogens. Use a chemical germicide for instrument and surface decontamination such as a 10-percent solution of sodium hypochlorite (or bleach). This intermediate-level disinfection will eliminate most bacteria (including Mycobacterium tuberculosis), and all fungi, and it inactivates viruses such as the hepatitis B virus. Rinsing with water or ethanol after disinfecting will help prevent the pitting of any stainless-steel surfaces.

Dealing with Creutzfeldt-Jakob Disease (CJD) in the autopsy suite requires special safety measures. Procedures should be posted in the area directing staff how to handle tissue and clean up in cases where patients are infected with CJD. The intact brain should be fixed in formaldehyde for one to two weeks before handling or cutting in order to reduce the prion activity. Non-disposable implements used with such patients should be immersed in 1N sodium hypochlorite (NaOH) for one hour before reuse. Surfaces on which autopsies occurred should also be immersed in NaOH for one hour for disinfection purposes.

Chemicals are stored and used in the autopsy suite, and standard safe lab practices should be used. Make sure staff is trained in proper the handling, labeling, and storage of chemicals as well as prepared to handle spills. Spill kits should be available and suitable to the chemicals used in the area. If formaldehyde is used, be sure an appropriate neutralizer is available for spill incidents.

As the most involved and best educated about its dangers, laboratory personnel should take the lead in making sure safety is a priority in the morgue, and educate all who may enter the area. Make sure communication is clear about who will use the suite and when- it’s never good to have someone walk in during an autopsy or organ removal. Use signage when necessary, and be willing to help in any unusual situations, because with a morgue, they definitely will arise. Work together as a team with all who utilize the area, and that ownership of safety will translate into safety for all.

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–Dan Scungio, MT(ASCP), SLS, CQA (ASQ) has over 25 years experience as a certified medical technologist. Today he is the Laboratory Safety Officer for Sentara Healthcare, a system of seven hospitals and over 20 laboratories and draw sites in the Tidewater area of Virginia. He is also known as Dan the Lab Safety Man, a lab safety consultant, educator, and trainer.

Jaffe vs. Enzymatic Method for Serum Creatinine Measurement

The Jaffe and enzymatic methods are the two most common methods for measuring serum creatinine. The Jaffe method is less expensive than the enzymatic assay ($0.30 vs $2.00 per test based on 2014 list prices) but is more susceptible to interferences. Although these tests are not expensive, they are high-volume tests and the savings could be substantial. We were using the enzymatic assay at the University of Utah and estimated that we could save about $50,000 per year by switching to the Jaffe assay; however, we were uncertain whether the Jaffe assay was safe to use due to the potential for interferences. For that reason, we decided to conduct a risk assessment to evaluate the suitability of the Jaffe assay.

Risk is defined as the expected cost of an action. The expected cost has two components: 1) the probability that an event will occur and 2) the consequences or cost of an event:

Risk = prob(event) x cost(event)

The event of interest was misclassification of a patient due to an error in serum creatinine measurement. Nephrologists classify kidney disease based on the estimated glomerular filtration rate which is based on the creatinine value. The distribution of eGFR for patients at our hospital is shown in Figure 1. The dashed lines show decision limits that nephrologists use to classify kidney disease. An eGFR is considered normal or healthy.

We spoke with the nephrologists and learned that they were relatively unconcerned about errors in eGFR in healthy patients (eGFR above 60 ml/min) because there was no potential for harm. Similarly, they felt there was relatively little risk of harm to patients with low eGFRs because these patients are routinely monitored and no major decision would be based solely on a single eGFR measurement. An error in creatinine measurement in a low eGFR patient would be detected by repeat measurements or be inconsistent with other measurements. From the nephrologists’ point of view, the only area of concern was in the region around 60 ml/min. Patients about 60 ml/min are considered healthy whereas those below 60 ml/min are diagnosed with stage 3a chronic kidney disease. In this zone, an error in serum creatinine could result in a false negative (i.e. observed eGFR greater than 60 ml/min when the true eGFR was less than 60 ml/min). In such cases, a patient may go without care and their disease could progress. The nephrologists believed that the potential for harm was relatively minor, but potential for harm did exist.

We compared the eGFRs provided by the enzymatic and Jaffee methods to estimate how often patients might be misclassified (Figure 2).¹ Focusing on the 60 ml/min decision limit, we found that 17 of 500 (3.4%) of measurements were discordant. Some of these discordant results would be due to imprecision. Discordance due to imprecision would have small differences (bottom of Figure 2) and are unavoidable – they would occur using any method. Discordance due to interference would be expected to have larger differences (top of Figure 2) and could be avoided by using the enzymatic method. We used statistical techniques to estimate the proportion of discordances that were due to interference vs imprecision and found that about 60% of the discordance at the 60 ml/min limit was due to interference. In summary, our risk analysis showed that using the Jaffe method would pose about a 2% rate of avoidable misclassification which presented some potential risk to patients. The nephrologists felt the risk was low but, in theory, disease could unnecessarily progress in a patient with a false negative diagnosis.

Our risk analysis was based on analytical error. We compared magnitude of analytical error to the biological variation in eGFR and found that the analytical error was relatively small in comparison to biological variation (data not shown). Biological variation was likely to be a more significant cause of misclassification than analytical error.

So, what to do? Was the potential savings of the Jaffe method worth the risk? Some experts recommend against using the Jaffe method. ^2-4 On the other hand, most US laboratories use the Jaffe assay. A recent College of American Pathologists proficiency challenge found that 70% of the submitted results were based on the creatinine assay.⁵

We decided to get the best of both worlds by using BOTH methods. We defined a zone of risk surrounding the 60 ml/min eGFR decision limit (Figure 3). Results in this zone would have some risk of misclassification whereas results outside of the zone would be unlikely to be misclassified using the Jaffee method. All creatinine measurements are initially performed using the Jaffe method. If the result is outside the risk zone, the result is reported. If results fell within the risk zone, they were repeated with the enzymatic method and the results of the enzymatic method are reported. This reflex procedure saves money while avoiding risk. The reflex rate is approximately 15%.

There are circumstances in which one would want to order the best possible test. To that end, we created a special orderable test, based on the enzymatic method, that the nephrologists could use to insure the most accurate results when required. For example, the enzymatic test may be indicated when making decisions regarding biopsies for renal transplant patients. The order volume for the special test has been less than 100 orders per year.

creat1 — Figure 1. Distribution of Estimated Glomerular Filtration rates (eGFR). The distribution is for outpatients at University of Utah for calendar year 2014. The dashed lines indicate decision limits used for classification of chronic kidney disease (15, 30, 45 and 60 ml/min). eGFRs greater than 60 ml/min are considered disease free.

creat2 — Figure 2. Discordances in estimated glomerular filtration rate (eGFR) at the 60 ml/min decision limit. The length of each arrow, represents the difference between estimates based on the Jaffe (head) and enzymatic (tail) methods. The dashed line represents two standard deviations of expected imprecision of the difference. Differences greater than 2 standard deviations would most likely be due to analytical interference (loss of specificity).

creat3 — Figure 3. Reflex test strategy. The figure shows the distribution of eGFR values for outpatients at the University of Utah. The dashed lines represent clinical decision limits. The yellow zone represents the range of eGFR values where misclassification could pose a risk to patients. Creatinine is first measured by the Jaffe method. The Jaffe result is reported if the estimated eGFR is outside the yellow zone. If the eGFR is within the yellow zone, the measurement is repeated using the enzymatic method and the result based on the enzymatic method is reported.

References

Schmidt RL, Straseski JA, Raphael KL, Adams AH, Lehman CM. A Risk Assessment of the Jaffe vs Enzymatic Method for Creatinine Measurement in an Outpatient Population. PloS one. 2015;10(11):e0143205.
Cobbaert CM, Baadenhuijsen H, Weykamp CW. Prime time for enzymatic creatinine methods in pediatrics. Clinical Chemistry. 2009;55(3):549-558.
Drion I, Cobbaert C, Groenier KH, et al. Clinical evaluation of analytical variations in serum creatinine measurements: Why laboratories should abandon Jaffe techniques. BMC Nephrology. 2012;13(1).
Panteghini M. Enzymatic assays for creatinine: time for action. Scand J Clin Lab Invest Suppl. 2008;241:84-88.
College of American Pathologists. Chemistry/Therapeutic Monitoring, Participant Survey. 2014.

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-Robert Schmidt, MD, PhD, MBA, MS is currently an Associate Professor at the University of Utah where he is Medical Director of the clinical laboratory at the Huntsman Cancer Institute and Director of the Center for Effective Medical Testing at ARUP Laboratories.