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Type 2 diabetes:
biomarker models to predict risk
Pg.21
Compact hematology system
by Beckman Coulter
Pg.31
Meningitis/encephalitis panel
by BioFire Diagnostics
Pg.32
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EDITORS LETTER 3 April/May 2016
This years annual World Health Day wait in situ for a result that reects the available for around 9 a unit, surely up of subjects with positive test
on 7th April highlighted the dra- average blood glucose level over the cost-eective if a result of prediabetes results but surely such screen-
matic rise in the prevalence of Type past three months is clearly preferable precipitates patient lifestyle changes, ing programmes are more likely
2 diabetes (T2DM) and urged global to measuring fasting or random glu- and a diagnosis of diabetes leads to to have an eect on the T2DM
action to contain the epidemic. The cose levels, tests which require patient follow-up care. epidemic than frequently over-
number of people suering from forethought, laboratory facilities, weight healthcare workers pon-
T2DM has approximately quad- larger samples and frequently repeat Of course one must develop ticating about healthy diets
rupled in three and a half decades; tests. POC A1c tests are currently clear guidelines for the follow and exercise?
currently 8.5% of the global adult
population is aected. Because
uncontrolled, elevated levels of blood
glucose can eventually result in car-
diovascular disease, kidney failure,
lower limb amputation and loss of
sight, as well as premature death, the
disease has major socioeconomic
STart Max Max
Accuracy
impacts in addition to health issues.
Yet it is unlikely, at least in Western
populations, that interventions to Max
promote more balanced diets and Practicality
less sedentary lifestyles will reduce
the widespread overweight and obe-
sity that fuels the T2DM epidemic.
The general public in the West is con- Max
tinuously informed about the ben- Innovation
ecial eects of healthy eating and
sucient physical exercise, but mod-
phot s - 03/2016
ern working environments, family Max
commitments and social activities Reliability
tual photos
often preclude compliance with
photo
good health advice. And many of us,
Type 2 diabetes:
(T2DM). One of the most obvious, as suggested
biomarker models to predict risk
Frances Bushrod, Ph.D.
Pg.21
Compact hematology system
in a recent report on diabetes global burden, News Editor
by Beckman Coulter
Pg.31
by BioFire Diagnostics
Pg.32
Advertising Coordinator
of testicular cancer Pg. 6 in AML patient Pg. 14 diagnostic aspects Pg. 25
particularly worthwhile.
by Greiner Bio-One Pg.34
Jennifer Christophers
Circulation Manager
Arthur Lger
Publishing Executive / Advertising Manager
[6 - 13] TUMOUR MARKERS Astrid Wydouw
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[6 - 10] The clinical chemistry laboratory in the diagnosis and management of
Webmaster
testicular cancer Jennifer Christophers
[11- 13] Use of serum free light chain analysis in screening for multiple myeloma
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[21 - 22] Type 2 diabetes - biomarker models promise new means to predict risk COMING UP IN CLI JUNE 2016
[23 -24] The use of point-of-care ketone meters to diagnose and monitor
Molecular diagnostics focus
diabetic ketoacidosis in pediatric patients
Kidney disease diagnosis
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Table 1. World Health Organization (WHO) histological classication of testicular germ cell tumours Treatment and cure rates in TC
(GCTs) [sourced from 3, 8, 9, 11]. Advances in treatment strategies, such
7 April/May 2016
as the use of cisplatin therapies [13], intersex patients have also been associ- immunostaining profiling as appro-
careful staging at diagnosis, early inter- ated with an increased TC risk [3, 5, 7]. priate, and in the majority of cases,
vention using multidisciplinary teams, treatment options should be based on
rigorous surveillance follow-up, and Presentation of TC is often a painless the histology results [10]. Biochemi-
salvage therapy, means that GCTs are lump in the testis body, but due to a fre- cal analysis should include initial con-
highly curable. Currently, expected cure quent lack of pain, medical opinion is centrations of serum tumour markers
rates of 95% are observed in patients frequently delayed. A testicular mass or (STMs). Metabolic biochemistry, liver
who receive a TC diagnosis, and cure swelling, or episodic diffuse pain may be function tests and a full blood count
rates of 80% in patients with a diagnosis observed. More rarely, metastatic symp- should be undertaken to determine
of metastatic TC [3, 13]. toms such back pain arising from ret- general organ function, and may dem-
roperitoneal lymph node involvement, onstrate evidence of metastasis [9].
or coughing, pain or hemoptysis due to
Causes and presentation of TC lung metastasis may be reported [3, 7, 8]. This collective information can be used
The causes of TC cancer are still to reference the Tumour-node-metasta-
unknown, although cryptochordism is Diagnosis and staging of TC sis (TNM) Classification of Malignant
the best-characterized risk factor asso- Clinical suspicion of TC, such as Tumours staging system (Table 2). This
ciated with TC. Research has shown altered testicular shape or non-painful cancer staging system is based on pri-
that timing of orchiopexy impacts on swelling, should prompt a full physical mary tumour site, nearby lymph node
future risk of TC development, suggest- examination and patient history, imag- involvement, and presence of distal
ing hormonal changes during puberty ing to include testicular and abdomi- metastatic spread from initial primary
are strongly associated with TC etiology nal ultrasound, as well as chest X-ray tumour site [4, 15]. The use of STMs as
in males. However, prenatal risk factors, [14]. If metastasis is suspected, chest, a fourth staging system has added diag-
environmental exposures in adulthood, abdominal and brain computerized nostic and prognostic value, independ-
male infertility, certain genetic or con- tomography (CT), and bone scintig- ent of the TNM system (Table 3) [9].
genital disorders such as Downs syn- raphy should be undertaken [9]. Final The decision for chemotherapy or radi-
drome, Klinefelters syndrome, human diagnosis and prognosis requires otherapy treatment for non-surgical
immunodeficiency virus infection and biopsy sampling for histology and metastatic disease is based on CT and/
or magnetic resonance imaging (MRI)
results, and concentrations of STMs [4].
pT Primary tumour
pTx No primary tumour able to be identied The majority of patients (~75%) pre-
pT0 No evidence of a tumour (e.g. scar) senting with a testicular mass are diag-
pTis IGCNU nosed at stage 1 [7, 8]. At this stage,
PT1 Limited to testis and epididymis. Absence of vascular or lymphatic invasion, may invade tunica treatment options are typically surgery
albuginea but not tunica vaginalis with an excellent cure rate. For meta-
pT2 pT1 with vascular, lymphatic or tunica vaginalis invasion static disease, combinations of surgery,
pT3 Invasion of spermatic cord with or without vascular or lymphatic invasion
chemotherapy or radiotherapy are
required depending on cancer mass,
pT4 Invasion of scrotum cord with or without vascular or lymphatic invasion
location and distal lymph node involve-
pN Regional lymph nodes
ment [13]. Greater than 80% of patients
pNx Regional lymph node involvement unable to be identied with metastatic GCTs are successfully
pN0 No lymph node metastasis identied treated and cured.
pN1 Metastasis to 5 lymph nodes, no lymph nodes >2 cm OR no lymph node masses 2 cm
pN2 Metastasis to >5 lymph nodes, no lymph nodes >5 cm OR lymph node masses >2 cm but 5 cm OR Treatment of TC
extranodal spread TC cells are extremely sensitive to
pN3 Lymph node mass >5 cm chemotherapy [9, 10]. Specifically, the
standard chemotherapy regime consists
M Distant metastasis
of 3 or 4 cycles of bleomycin, etoposide
Mx Distant metastasis unable to be identied
and cisplatin (BEP) chemotherapy, or
M0 No distant metastasis etoposide and cisplatin (EP) chemo-
M1 Distant metastasis identied therapy every 21 days [8, 9]. Surgery
M1a Non-regional nodal or lung metastasis identied may be considered to remove residual
M1b Distant metastasis identied (excluding non-regional nodal or lungs) masses post-chemotherapy. Data sug-
S Serum tumour markers (STMs)
gests a higher relapse rate in patients
with NSGCTs than seminomas follow-
Sx STMs not available or not undertaken
ing an initial chemotherapy regime.
S0 STMs concentrations within normal limits This relapse rate can be used to further
LDH (U/L) hCG (U/L) AFP classify patients into good, intermedi-
S1 <1.5 N and <5000 and <1000 ate and poor prognostic groups, using
S2 1.510 N or 500050 000 or 100010 000 a combination of STM concentrations
S3 >10 N or >50 000 or >10 000
and location of primary tumour or
Table 2. Tumour-node-metastasis (TNM) classication system for testicular tumours [Sourced from
metastases. Around 5099% of patients
1416].
can still expect to survive [8].
April/May 2016 8 Tumour markers
Salvage therapy, often in combina- suffer a late relapse, i.e. >2 years post-
tion with chemotherapy, is reserved
Advances in treatment diagnosis but also potentially 10
for patients who have relapsed, or for strategies, such as the years post-diagnosis. These patients
patients where cancer progression are less responsive to chemotherapy,
continues after following a standard use of cisplatin therapies, so are treated primarily with sur-
chemotherapy regime. High-dose gery. Unfortunately, less than half
chemotherapy with autologous bone
careful staging at diagnosis, will remain disease-free following
marrow transplant is a controversial early intervention using surgical intervention [8, 9]. Chem-
approach for patients with a poor otherapy-induced side effects are
prognosis, and where a standard multidisciplinary teams, rigorous governed by the dose and combina-
chemotherapy regime and salvage tion of drugs used. This has triggered
therapy has been unsuccessful. Initial
surveillance follow-up, and more recent trials designed at main-
studies are encouraging but further salvage therapy, means that taining a cure rate but with reduced
trials are required. A small cohort associated chemotoxicity [8].
of patients have been identified who GCTs are highly curable
Upper
Tissue Conditions causing
Marker reference Serum t Use in testicular cancer
origin elevated serum markers
limit
-fetoprotein (AFP) ~10 kiU/L 57 days Fetal yolk sac, Benign liver disease Not secreted by pure cell
liver, GI tract Certain malignancies seminomas irrespective of
Mixed cell NSGCTs histology, or pure cell teratomas
Hepatocellular carcinoma Secreted by NSGCTs except
Gastric, colon, gall bladder, for choriocarcinomas or pure
pancreatic, lung cancer embryonal cell carcinomas
Hepatotoxicity (drug or viral) Exceptionally high levels seen in
Ataxia telangiectasia (>95% yolk sac NSGCTs
patients)
Hereditary persistence of AFP
Gestational trophoblastic disease
Poorly differentiated
adenocarcinoma
Tyrosinemia
& human 5 U/L 1624 hours Placental GCTs (pure seminomas, NSGCTs) Secreted by all NSGCTs except
chorionic (males) tiotrophoblasts Hydatidiform moles teratomas. Always secreted by
gonadotrophin Primary hypogonadism choriocarcinoma NSGCTs
(hCG) Gonadotroph adenoma High concentrations (>5000
Poorly differentiated U/L) suggestive of mixed GCTs
hCG adenocarcinoma Pure seminomas secrete hCG in
-subunit (hCG) Choriocarcinomas 1015 % of cases
typically the subunit Pancreas, islet cell, small/
detected by most large bowel, liver, stomach,
commercial assays lung, ovarian, breast and renal
malignancy
Gestational trophoblastic disease
Marijuana use
Lactate Laboratory 48113 Every tissue Muscle disease, MI, pernicious Not useful if the only tumour
dehydrogenase specic hours cell of body. anaemia, leukaemia, thalassemia, marker measured as not specic
subtype 1 Highest PE for TC resulting in high false-
(LDH-1) concentrations In vitro haemolysis positive rates. Most helpful in
found in all conjunction with AFP and hCG,
GCTs
muscle types, or for surveillance in patients with
liver and brain advanced seminoma
Placental alkaline <100 iU/L ~1567 Placental Normal testis, cervix, thymus, lung Elevated in seminomas
phosphatase (PLAP) hours blasts activity (Should not be measured in
GCTs, ovarian & lung malignancy smokers)
Table 3. Commonly used serum tumour markers in the diagnosis and management of germ cell tumours in testicular cancer patients [Sourced from 3, 4, 9,
10, 16]. NSGCTs, non-seminomatous germ cell tumours.
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The use of serum tumour of pure seminomas. Lactate dehydro- 2. Hameed A, White B, Chinegwundoh F, Thwaini A,
markers in TC genase is an enzyme found in all cell Pahuja A. A review in management of testicular
The discovery of serum and urine types, meaning it is less specific for TC, cancer: single centre review. World J Oncol. 2011;
tumour markers and the advent of although it does have prognostic value 2: 94101.
chemotherapy have significantly in advanced stage GCTs [3, 9]. A decline 3. Bosl GJ, Motzer RJ. Testicular germ-cell cancer. N
improved cancer staging, management in serial STM concentrations is useful to Engl J Med. 1997; 337: 242254.
and prognosis in patients with TC. The detect the presence of residual disease 4. Bahrami A, Ro JY, Ayala AG. An overview of tes-
benefit of initial STMs is predominantly following surgery, or to assess response ticular germ cell tumors. Arch Pathol Lab Med.
with regard to disease staging, whereas to chemotherapy. In both scenarios, the 2007; 131: 12671280.
serial STMs are particularly useful for decline in STM concentrations should 5. Sesterhenn IA,Davis, CJ. Pathology of germ cell
monitoring response to treatment after follow the half-lives of each marker [9]. tumors of the testis. Cancer Control 2004; 11:
surgery, chemotherapy or radiation 374387.
therapy. STMs are useful because they There are detailed STM surveillance 6. Wu X, Groves FD, McLaughlin CC, Jemal A, Mar-
are often detectable well before clini- guidelines in place following surgery, tin J, Chen, VW. Cancer incidence patterns among
cal radiological detection in patients. which recommend a meticulous time- adolescents and young adults in the United States.
Furthermore, concentrations can be table of STM measurements and radi- Cancer Causes Control. 2005; 3: 309320.
helpful to differentiate GCT type. The ology imaging to detect disease recur- 7. Hanna NH, Einhorn LH. Testicular cancer dis-
detection of at least one elevated STM rence depending on initial GCT type, coveries and updates. N Engl J Med. 2014; 371:
occurs in ~85% of NSGCTs, and the thereby avoiding relapse and presenta- 20052016.
presence of elevated STMs occurs in tion at a later date with advanced stage 8. Horwich A, Nicol D,Huddart R. Testicular germ
significant numbers of pure seminoma disease [8, 9]. cell tumours. BMJ 2013; 347: f5526.
cases [9, 10]. However, in rare cases 9. Barlow LJ, Badalato GM,McKiernan JM. Serum
where patients present with evidence of tumor markers in the evaluation of male germ
a testicular mass, radiographic evidence The discovery of serum and cell tumours. Nat Rev Urol. 2010; 7: 610617.
of metastatic disease, with significantly urine tumour markers and 10. Gilligan TD, Hayes DF, Seidenfeld J, Temin S.
elevated alpha-fetoprotein (AFP) or ASCO clinical practice guideline on uses of
human chorionic gonadotrophin (hCG) the advent of chemotherapy serum tumor markers in adult males with germ
serum concentrations, it is advised that cell tumors. J Clin Oncol. 2010; 6: 199202.
treatment is not delayed while awaiting have signicantly improved 11. Eble JN, Sauter G, Epstein JI, Sesterhenn IA.
histology results [10]. cancer staging, management World Health Organization classification of
tumours. Pathology and genetics of tumours
The American Society of Clinical Oncol- and prognosis in patients of the urinary system and male genital organs.
ogy recommend against using STMs as IARC 2004.
a screening test for GCTs in asympto- with testicular cancer 12. Ulbright TM. Germ cell tumours of the gonads:
matic males. Given the low incidence a selective review emphasizing problems in dif-
and mortality of TC combined with the ferential diagnosis, newly appreciated, and con-
high cure rate, it is suggested a screen- Future focus troversial issues. Mod Pathol. 2005; 18: S61S79.
ing programme would be neither cost- While the majority of patients diag- 13. Masters JR, Kberle B. Curing metastatic cancer:
effective nor decrease mortality [10]. nosed with TC will survive, challenges lessons from testicular germ-cell tumours. Nat
Furthermore, although STMs can be still persist. Serum tumours markers Rev Cancer. 2003; 3:517525.
helpful in combination with imaging have been pivotal to improved outcomes 14. Suspected cancer: recognition and referral
techniques in the diagnosis of TC, nor- for patients with and without metastatic guidelines [NG12]. National Institute for Health
mal STMs alone do not exclude TC and disease. Future research is focused on and Care Excellence (NICE) 2015. (https://www.
may also be raised in other conditions patients with an initial poorer prog- nice.org.uk/guidance/NG12/chapter/1-Recom-
[3, 810]. Routine testicular examina- nosis, patients who have relapsed fol- mendations-organised-by-site-of-cancer)
tion via palpation is recommended in lowing first-line chemotherapy and 15. Sobin LH, Gospodarowicz MK and Wittekind C.
all males from puberty up to ~45 years. patients who have a late relapse. Long- TNM classification of malignant tumours (7th
This is of particular importance for term health consequences for patients ed). International Union against Cancer (UICC).
males with a past medical history that surviving TC, in particular side effects Wiley-Blackwell 2009.
may suggest an increased GCT risk as associated with chemotherapy and radi- 16. Albers P. (Chair), Albrecht W, Algaba F, Boke-
detailed previously. otherapy such as cardiovascular disease, meyer C, Cohn-Cedermark G, Fizazi K, Horwich
impaired fertility and secondary can- A, Laguna MP, Nicolai N, Oldenburg J. Guide-
Commonly employed serum markers cers, continues to drive collaborative lines on testicular cancer. Eur Urol. 2015. (https://
include: AFP and hCG as mentioned studies nationally and internationally to uroweb.org/guideline/testicular-cancer/)
previously, hCG beta-subunit (hCGb), improve TC outcomes for the future.
placental alkaline phosphatase (PLAP) The authors
and lactate dehydrogenase (LDH). References Angela Cooper* PhD, Sen Costelloe,
Alpha-fetoprotein levels are elevated in 1. Cancer registration statistics, first release, Eng- PhD
teratocarcinoma or testicular embryo- land, 2014. Office for National Statistics 2014. Derriford Combined Laboratory, Plym-
nal carcinoma, while conversely, AFP (http://web.ons.gov.uk/ons/rel/vsob1/cancer- outh Hospital NHS Trust, Plymouth, UK
is never elevated in pure seminomas. statistics-registrations--england--series-mb1-
Human chorionic gonadotrophin ele- /2014--first-release-/rpt-cancer-stats-registra- *Corresponding author
vations are associated with 1015 % tions.html) E-mail: angelacooper5@nhs.net
Tumour markers 11 April/May 2016
Conclusion
The purpose of a medical screening pro-
gramme is to recognize a disease in its
preclinical phase to allow intervention at
an earlier stage. Such strategies have ben-
ets, risks and costs and the nal screen-
ing algorithm is often a compromise
between these three. However, a pro-
posed screening strategy should full the
criteria outlined by Wilson and Jungner
in 1968 [13]. Of note, criterion 4 suggests
there should be a detectable preclinical
Figure 1. Screening strategy 1: serum and urine protein electrophoresis with reexed serum stage, in this case MGUS, and criterion
immunotyping and urine immunoxation. 5 suggests there should be a suitable test
Number of patients in parentheses. EP, electrophoresis; IT, immunotyping; IF, immunoxation; M for screening strategies. This real-time
protein, monoclonal protein; MGUS, monoclonal gammopathy of undetermined signicance; LCMM, prospective study presents evidence of
light chain multiple myeloma; NAD, no clinical abnormality detected; MM, multiple myeloma; ?MM; the clinical utility of the sFLC assay and
likely but unconrmed multiple myeloma; WM, Waldenstrm macroglobulinaemia. its use in developing a more sensitive
screening strategy for PCD detection.
FLC (sFLC) assay (The Binding Site) MM [4]. This eliminates a traditional Standard screening practice combining
was rst developed in 2001 [10]. It is major challenge with MM diagnosis in sEP and uEP increased the sensitivity of
an immunoturbidimetric method using that disease denition was clinicopatho- the constituent index tests (78% and 30%
latex-enhanced polyclonal sheep anti- logical. The use of the sFLC ratio in this respectively) to 81%, meaning the addi-
bodies targeted to epitopes on the light way therefore marks a milestone in the tion of urinalysis to sEP increased the
chains of Ig that are exposed when the early detection of MM and highlights a sensitivity by only 3%. This reinforces
light chain is free, i.e. not bound to heavy disease transition to being a laboratory- the need for a more sensitive method
chain Ig. Results are expressed as a ratio dened rather than a symptom-dened for detecting sFLC than sEP alone. This
of kappa : lambda light chains. disease, allowing for earlier intervention. combination also displayed a good PPV
without compromising eciency (98%).
This sFLC assay can be used to replace There is, however, controversy as to Despite this, its use missed signicant
traditional urine methods for the labo- whether the sFLC assay is indeed a robust cases of PCDs including a light-chain
ratory detection of FLCs. This practice candidate for inclusion in PCD screening multiple myeloma, a possible but uncon-
has the obvious benet of using a single strategies. There is currently only limited rmed (in the time frame of the study)
serum sample and eliminating the need guidance on how it should be used in case of MM and 10 cases of MGUS,
for a paired urine sample, which may not clinical practice [4] and there is ongoing highlighting its limitation as a rst line
always be supplied. In addition to the debate regarding result interpretation, screening investigation.
reported increased diagnostic sensitivity especially for those mildly abnormal
of the sFLC assay, an unexpected nd- ratios. There are, therefore, many consid- Combining sEP with sFLC analysis
ing by Dispenzieri et al. was that baseline erations to be made before such screen- increased the sensitivity from sEP alone
sFLC results can be used in prognostica- ing could be implemented. by 20% (data not shown), again suggest-
tion and risk stratication of MGUS [11]. ing singular sEP testing is not sensitive
Although the rationale for this is poorly Study overview and results enough to detect minor abnormalities
understood, it is thought that a greater Our real-time prospective study aimed in FLC production. This proposed com-
degree of abnormality in the sFLC ratio to assess the clinical utility of three index bination of screening tests increased
reects an increasing tumour burden. laboratory investigations [serum and sensitivity by 17% when compared with
urine protein electrophoresis (sEP and current protocols, indicating that the
Studies such as these have informed uEP) and sFLC] to determine the most sFLC assay is more sensitive than uri-
changes to MM guidelines published eective rst-line testing strategy for nalysis for detecting PCDs. The sFLC
in 2016 [12] to acknowledge that sig- detecting PCDs in primary care patients. assay has been demonstrated to show a
nicantly abnormal FLC ratios, in the These laboratory investigations were per- high sensitivity for light chain MM and
absence of clinical features of end organ formed on 446 samples with no previous non-secretory MM [14]. These often pre-
damage, can be used in the diagnosis of history of, or investigations for, MM. The sent with normal sEP and uEP, especially
13 April/May 2016
Summary
On balance, there are several advantages Figure 2. Screening strategy 2: serum protein electrophoresis with reexed serum immunotyping and
to replacing urinalysis with the sFLC serum free light chain analysis.
assay. These include increased clinical Number of patients in parentheses. EP, electrophoresis; IT, immunotyping; M protein, monoclonal
sensitivity for detection of early-stage protein; MGUS, monoclonal gammopathy of undetermined signicance; LCMM, light chain
disease, patient convenience in submit- multiple myeloma; NAD, no clinical abnormality detected; MM, multiple myeloma; ?MM; likely
ting a single serum sample rather than but unconrmed multiple myeloma; WM, Waldenstrm macroglobulinaemia; Normal FLC ratio,
two separate specimens, increased use of (0.261.65).
automation and reduction in subjectiv-
ity in reporting of results. However, it is 4. Rajkumar SV, Dimopoulos MA, Palumbo A, 11. Dispenzieri A, Kyle R, Merlini G, Miguel JS,
also important to consider the potential Blade J, Merlini G, Mateos MV, Kumar S, Hillen- Ludwig H, Hajek R, Palumbo A, Jagannath S,
increased cost of performing sFLC on all gass J, Kastritis E, et al. International Myeloma Blade J, et al. International Myeloma Working
samples submitted for myeloma screen- Working Group updated criteria for the diag- Group guidelines for serum-free light chain
ing, the importance of using appropriate nosis of multiple myeloma. Lancet Oncol. 2014; analysis in multiple myeloma and related disor-
reference ranges and the need to develop 15(12): e538548. ders. Leukemia 2009; 23(2): 215224.
guidelines for interpretation of border- 5. Kariyawasan CC, Hughes DA, Jayatillake MM, 12. Myeloma: diagnosis and monitoring. National
line results. This latter point is particu- Mehta AB. Multiple myeloma: causes and con- Institute for Health and Care Excellence (NICE)
larly important in order that unneces- sequences of delay in diagnosis. QJM 2007; 2016. (https://www.nice.org.uk/guidance/ng35)
sary referrals are prevented, and should 100(10): 635640. 13. Wilson JM, Jungner YG. [Principles and prac-
involve close liaison with local hematol- 6. Howell DA, Smith AG, Jack A, Patmore R, tice of mass screening for disease]. Bol Ocina
ogy teams to ensure that primary care Macleod U, Mironska E, Roman E. Time-to- Sanit Panam. 1968; 65(4): 281393 (in Spanish).
clinicians are given clear guidance for diagnosis and symptoms of myeloma, lympho- 14. Jagannath S. Value of serum free light chain
further investigation and referral of their mas and leukaemias: a report from the Haema- testing for the diagnosis and monitoring of
patients. tological Malignancy Research Network. BMC monoclonal gammopathies in hematology. Clin
Hematol. 2013; 13(1): 9. Lymphoma Myeloma 2007; 7(8): 518523.
References 7. Elliss-Brookes L, McPhail S, Ives A, Greenslade 15. McTaggart MP, Lindsay J, Kearney EM. Replac-
1. Bird JM, Owen RG, DSa S, Snowden JA, Pratt M, Shelton J, Hiom S, Richards M. Routes to ing urine protein electrophoresis with serum
G, Ashcroft J, Yong K, Cook G, Feyler S, et al. diagnosis for cancer determining the patient free light chain analysis as a rst-line test for
Guidelines for the diagnosis and management journey using multiple routine data sets. Br J detecting plasma cell disorders oers increased
of multiple myeloma 2011. Br J Haematol. 2011; Cancer 2012; 107(8): 12201226. diagnostic accuracy and potential health ben-
154(1): 3275. 8. Bossuyt X. Separation of serum proteins by auto- et to patients. Am J Clin Pathol. 2013; 140(6):
2. Brenner H, Gondos A, Pulte D. Expected long- mated capillary zone electrophoresis. Clin Chem 890897.
term survival of patients diagnosed with multi- Lab Med. 2003; 41(6): 762772.
ple myeloma in 20062010. Haematologica 2009; 9. Kaplan IV, Levinson SS. Misleading urinary pro- The authors
94(2): 270275. tein pattern in a patient with hypogammaglobu- David Baulch* MSc, Beverley Harris MSc,
3. Rajkumar SV, Kyle RA, Therneau TM, Melton linemia: eects of mechanical concentration of FRCPath
LJ, III, Bradwell AR, Clark RJ, Larson DR, Ple- urine. Clin Chem. 1999; 45(3): 417419. Department of Clinical Biochemistry,
vak MF, Dispenzieri A, Katzmann JA. Serum free 10. Bradwell AR, Carr-Smith HD, Mead GP, Tang Royal United Hospitals Bath NHS Foun-
light chain ratio is an independent risk factor LX, Showell PJ, Drayson MT, Drew R. Highly dation Trust, Bath, UK
for progression in monoclonal gammopathy of sensitive, automated immunoassay for immu-
undetermined signicance. Blood 2005; 106(3): noglobulin free light chains in serum and urine. *Corresponding author
812817. Clin Chem. 2001; 47(4): 673680. E-mail: david.baulch@nhs.net
April/May 2016 14 Personalized medicine
Pharmacogenomics in an acute
myelogenous leukemia patient
This article examines the case of a patient who developed toxic changed so that the ALL-type therapy was
levels of voriconazole while taking the antifungal prophylactically as discontinued and standard AML therapy
that included cytarabine, daunorubicin,
part of her treatment regimen in addition to standard chemotherapy
and etoposide was begun. To address other
for a leukocyte neoplasm. The usefulness of molecular diagnostic specic issues, this patient was treated
testing as an aid in voriconazole dosing is discussed. with multiple medications along with her
chemotherapy drugs, including Ambien,
Bactrim, Benadryl, cefepime, cyprohepta-
by S. Resaei, L. Collier and Dr S. Taylor
dine, hydroxyzine, meropenem, vancomy-
cin, and voriconazole.
Case report CD45 (dim), Tdt, and myeloperoxidase On day 16, 8 days after the start of her new
The patient was a 14-year-old female who markers. These same markers were exhib- pharmacology regimen, the patient began
was referred to the emergency department ited by the circulating blasts in her periph- to experience uctuating confusion and
with a 10-day history of generalized bone eral blood. The co-expression of B-lym- auditory/visual hallucinations. Screening
pain and progressively worsening fatigue. phoid and myeloid antigens prompted an tests revealed no abnormalities that could
An initial complete blood count (CBC) initial diagnosis of biphenotypic acute leu- explain her altered mental status, so atten-
revealed a white blood cell (WBC) count kemia. After multiple expert consultations, tion turned to the medications that she
that was well within the normal range, and it was decided to model the patients treat- was receiving. All medications that seemed
only slight anemia and thrombocytopenia. ment on therapy for acute lymphocytic likely to contribute to her neurologic prob-
However, because marked neutropenia and leukemia (ALL). Thus, the patient received lems were suspended and then reintro-
elevated numbers of leukemic blasts were prednisone, vincristine, daunorubicin and duced gradually with no adverse eect.
noted in the dierential, a bone marrow PEG asparaginase as induction chemo- Voriconazole was not suspected of being
(BM) examination was performed. Mar- therapy, with vincristine and daunorubicin contributory to her altered mental status,
row aspiration was markedly hypercellular administered again 7 days later. and was not interrupted. This antifungal
with diuse clusters of blasts (Fig. 1). Flow was rst administered to the patient on day
cytometry on the aspirate disclosed a sig- Cytogenetic test results that were returned 8 of her ordeal, at 200 mg/twice daily. She
nicant (50% of total sample) blast popu- on day 8, revealed a chromosomal trans- continued to receive this dose from day 8
lation that exhibited CD33, CD13 (partial, location of (8;21)(q22;q22); RUNX1- onwards, until 4 days after her initial neu-
dim), CD34 (partial), CD15 (heterogene- RUNX1T1, which changed the patients rological trouble (day 20). At this time, her
ous), CD19 (dim), CD10 (dim), HLA-DR, diagnosis to an atypical form of acute mye- plasma voriconazole level was determined
CD64 (partial, dim), CD71 (dim), CD117, logenous leukemia (AML). Accordingly, to be >10.0 g/mL [normal range (NR):
CD123, CD58, CD38, cytoplasmic CD79a, the patients chemotherapy regimen was 1.06.0 g/mL]. The patients 200 mg twice
a day dosing regimen was reduced to 100
mg twice a day. Her plasma concentration
of voriconazole was monitored regularly
until its level plateaued at 2 g/mL (Fig. 2).
Pharmacogenomics
Voriconazole is an ecient triazole agent
used as an antifungal prophylactic in this
patient as she was receiving immuno-
suppressive chemotherapy. Patients with
hematologic malignancies are at high risk
of aspergillosis and candidiasis infec-
tions, because of the neutropenia that is
often caused by their chemotherapy regi-
mens [13].
M e d i z i n i s ch e
EUROIMMUN Labordiagnostika
AG
For further information contact Dr. Konstantin Ens (k.ens@euroimmun.de, +49 451 5855 25721)
EUROIMMUN AG D-23560 Luebeck (Germany) Seekamp 31 Tel +49 451 58550 Fax 5855591 E-mail euroimmun@euroimmun.de www.euroimmun.com
deviation from expected pharmacokinetic its clearance is aected by circumstances individualised medicine arrived for antifungals? A
behaviour is due to drugdrug interac- such as patient sex, age, disease state, liver review of antifungal pharmacogenomics. Bone Mar-
tions and/or the pathological circum- function, obesity and the presence of row Transplant. 2012;47(7): 881894.
stances of the patient [5, 6]. Generally, it inammation [11, 13, 14]. 5. Dolton MJ, McLachlan AJ. Voriconazole pharma-
is expected that disease circumstances or cokinetics and exposure-response relationships:
drug side eects that reduce liver enzyme Conclusion assessing the links between exposure, ecacy
activity (especially of CYP2C19, CYP2C9 The pharmacodynamic behaviour of vori- and toxicity. Int J Antimicrob Agents. 2014;44(3):
and CYP3A4) will decrease metabolism conazole remains dicult to predict as 183193.
and clearance of voriconazole, and thus it displays considerable interpatient and 6. Dolton MJ, Mikus G, Weiss J, Ray JE, McLachlan AJ.
increase patient exposure to the drug. intrapatient variablility. Although TDM Understanding variability with voriconazole using
for patients receiving voriconazole is rec- a population pharmacokinetic approach: implica-
Therapeutic drug monitoring ommended, establishing a patients phar- tions for optimal dosing. J Antimicrob Chemother.
The United States Food and Drug Adminis- macogenomic prole can provide clini- 2014;69(6): 16331641.
tration and the Infectious Diseases Society cians with valuable information to aid in 7. Owusu OA1, Egelund EF, Alsultan A, Peloquin CA,
of America recommend therapeutic drug appropriate voriconazole dosing, especially Johnson JA. CYP2C19 polymorphisms and thera-
monitoring (TDM) for patients receiv- in the initial stages of therapy. Pharmacog- peutic drug monitoring of voriconazole: are we
ing voriconazole [7]. Numerous studies enomic information is likely to contribute ready for clinical implementation of pharmacog-
indicate that voriconazole trough values to the goal of rapidly attaining a therapeutic enomics? Pharmacotherapy. 2014;34(7): 703718.
should be maintained above 1.0 g/mL for concentration while avoiding toxicity. It is 8. Moriyama B, Kadri S, Henning SA, Danner RL,
fungal prophylaxis. Moreover, some stud- possible that our patient has a PM pheno- Walsh TJ, Penzak SR. Therapeutic drug monitoring
ies indicate that voriconazole is more e- type for voriconazole and that pharmacog- and genotypic screening in the clinical use of vori-
cacious when trough levels are maintained enomic testing might have minimized her conazole. Curr Fungal Infect Rep. 2015;9(2): 7487.
at 2.0 g/mL or higher [11, 12]. exposure to toxic levels of voriconazole that 9. Swen JJ, Nijenhuis M, de Boer A, Grandia L, Mait-
arose from standard voriconazole dosing. land-van der Zee AH, Mulder H, Rongen GA, van
It is important to dose voriconazole accu- Schaik RH, Schalekamp T, Touw DJ, van der Weide J,
rately, as voriconazole ecacy is dependent References Wilert B, Deneer VH, Guchelaar HJ. Pharmacoge-
on adequate exposure to the drug; how- 1. Barreto JN, Beach CL, Wolf RC, Merten JA, Tosh netics: from bench to byte-an update of guidelines.
ever, increased trough levels are associ- PK, Wilson JW, Hogan WJ, Litzow MR. The inci- Clin Pharmacol Ther. 2011; 89(5): 662673.
ated with numerous severe adverse eects dence of invasive fungal infections in neutropenic 10. Kim SH, Yim DS, Choi SM, Kwon JC, Han S, Lee
(SAE). Voriconazole has been linked to patients with acute leukemia and myelodysplastic DG, Park C, Kwon EY, Park SH, Choi JH, Yoo JH.
several adverse events including abnor- syndromes receiving primary antifungal prophy- Voriconazole-related severe adverse events: clini-
mal liver function tests, gastrointestinal laxis with voriconazole. Am J Hematol. 2013; 88(4): cal application of therapeutic drug monitoring
disturbances, rash and vomiting. Neuro- 283288. in Korean patients. Int J Infect Dis. 2011;15(11):
toxicity (visual disturbances, hallucina- 2. Mattiuzzi GN, Cortes J, Alvarado G, Verstovsek S, 753758.
tions) is somewhat infrequently observed Koller C, Pierce S, Blamble D, Faderl S, Xiao L, Her- 11. Davies-Vorbrodt S, Ito JI, Tegtmeier BR, Dadwal
[1, 2]. Since CYP2C19 is a key metabo- nandez M, Kantarjian H. Ecacy and safety of intra- SS, Kriengkauykiat J. Voriconazole serum concen-
lizer of voriconazole, it seems reasonable venous voriconazole and intravenous itraconazole trations in obese and overweight immunocom-
to predict a patients drug metabolizing for antifungal prophylaxis in patients with acute promised patients: a retrospective review. Phar-
phenotype based on their CYP2C19 geno- myelogenous leukemia or high-risk myelodysplastic macotherapy. 2013 Jan;33(1): 2230.
type, and to use this information to guide syndrome. Support Care Cancer. 2011; 19(1): 1926. 12. Smith J, Safdar N, Knasinski V, Simmons W, Bhav-
dosing. In practice, the drug metabolizing 3. Rping MJ, Mller C, Vehreschild JJ, Bhme A, nani SM, Ambrose PG, Andes D. Voriconazole
genotype alone is not sucient to predict Mousset S, Harnischmacher U, Frommolt P, Was- therapeutic drug monitoring. Antimicrob Agents
the metabolizing phenotype. Confounding smer G, Drzisga I, Hallek M, Cornely OA. Vori- Chemother. 2006;50(4): 15701572.
variables include the fact that voricona- conazole serum concentrations in prophylactically 13. van Wanrooy MJ, Span LF, Rodgers MG, van den
zole has a high propensity for drugdrug treated acute myelogenous leukaemia patients. Heuvel ER, Uges DR, van der Werf TS, Kosterink
interactions, a narrow therapeutic index, it Mycoses. 2011; 54(3): 230233. JG, Alenaar JW. Inammation is associated with
exhibits non-linear pharmacokinetics, and 4. Ashbee HR, Gilleece MH. Has the era of voriconazole trough concentrations. Antimicrob
Agents Chemother. 2014;58(12): 70987101.
14. Brggemann RJ, Antonius T, Heijst Av, Hooger-
CYP2C19 allele Allelic functional status
brugge PM, Burger DM, Warris A. Therapeutic
*1 Normal function; normal activity; wild-type drug monitoring of voriconazole in a child with
*2, *3, *4, *5, *6, *7, *8 Loss-of-function; no or decreased activity invasive aspergillosis requiring extracorpor-
*17 Gain-of-function; increased activity eal membrane oxygenation. Ther Drug Monit.
2008;30(6): 643646.
Genotype Metabolizing phenotype
*17/*17 Ultrarapid (homozygous) The authors
*1/*17 Ultrarapid (heterozygous) Sahar Resaei BS; Laura Collier MLS(ASCP);
*1/*1 Extensive Sara Taylor* PhD, MLS(ASCP)MB
*1/*2-*8 Intermediate
Tarleton State University, Fort Worth, TX,
USA
*17/*2-*8 Ultrarapid, extensive, intermediate, unknown
*2-*8/*2-*8 Poor *Corresponding author
Table 1. CYP2C19 gene variants and drug metabolizing activity. E-mail: sataylor@tarleton.edu
Diabetes 17 April/May 2016
with WHO recommendations, are sum- FPG and 2-hour OGTT PG, there is For those individuals with pre-diabetes,
marized in Table 2. OGTTs, which are not full concordance between HbA1c structured lifestyle intervention, aimed
time-consuming, inconvenient and and glucose measurements: these three at increasing physical activity and
show poor reproducibility, are increas- different measures of glycemia repre- achieving a loss of body weight, may
ingly confined to the diagnosis of gesta- sent different physiological processes prevent, or at least delay, the develop-
tional diabetes. HbA1c confers definite and, therefore, inevitably, they iden- ment of diabetes. Within this category,
advantages over FPG (and OGTT): no tify somewhat different populations of for all three tests, the risk of future dia-
patient preparation; lower biological patients [17]. In fact, although HbA1c betes is curvilinear, extending below the
variation; less fluctuation in acute stress performs equally well as a predictor of lower limit of the range and becoming
and illness, and standardization of meas- retinopathy risk, in most populations, disproportionately greater at the higher
urement is now better than for glucose, its use results in a lower diabetes preva- end: accordingly, intervention and fol-
which has no internationally recognized lence (the OGTT 2-hour PG is the most low-up should be most aggressive for
reference method. However, there are a sensitive test). A study including 6890 those considered at particularly high
number of situations, in which the use adults from the US National Health and risk [3]. The associated increased risk
of HbA1c for diagnosis is not appropri- Nutrition Examination Survey (1999 of cardiovascular disease should also be
ate (Table 2): as a measure of chronic 2006) indicated that the prevalence of targeted, with appropriate management
hyperglycemia, HbA1c should not be undiagnosed diabetes was 2.3% using of other relevant risk factors (smoking,
used where rapidly developing hyper- HbA1c, compared to 3.6% using FPG lipids, blood pressure).
glycemia is suspected and results will be [18]. Other studies have confirmed this
unreliable in the presence of any factors discrepancy although, in fact, the mag- From glucose measurements
affecting erythrocyte lifespan [12]. nitude of the difference appears to vary to HbA1c in the diagnosis of
between populations, perhaps reflect- diabetes mellitus: one UK
Regardless of the test used, in an ing geographical or ethnic differences laboratorys experience of
asymptomatic patient, a diagnostic in hemoglobin glycation rates or the the change in clinical practice
result should be confirmed by repeat distribution of certain forms of anemia Guidance, outlining the WHOs posi-
testing on a separate day, preferably or hemoglobinopathy. It is anticipated tion on the use of HbA1c in the diag-
using the same test, in order to increase that, in practice, the lower sensitivity of nosis of diabetes, was issued to local
the likelihood of concordance. In the HbA1c will be mitigated by its ease of clinicians in 2012. Subsequently, in
same way that there is less than 100% use, which will facilitate its wider appli- September 2014, updated guidance was
concordance between the results of cation [3]. disseminated, advocating the use of
HbA1c as a diagnostic test for diabe- Summary 6. Expert Committee on the Diagnosis and Classica-
tes mellitus, except where inappropri- Local experience indicates an enthu- tion of Diabetes Mellitus. Report of the Expert Com-
ate, and providing advice on follow-up. siastic uptake in the use of HbA1c for mittee on the diagnosis and classication of diabetes
This was supported by modification of diagnosing diabetes and a concurrent mellitus. Diabetes Care 1997; 20: 11831197.
the requesting process, which allowed a fall in glucose measurements (FPG and 7. Inzucchi SE. Diagnosis of diabetes. N Engl J Med.
distinction to be made between HbA1c 2-hour OGTT PG) for this purpose. As 2012; 367(6): 542550.
requests made for monitoring estab- anticipated, the convenience of this test 8. Day A. HbA1c and diagnosis of diabetes. The test has
lished diabetes (designated HbA1cM) has led to increased screening for dia- nally come of age. Ann Clin Biochem. 2012; 49: 78.
and those being used for diagnosis (des- betes but there is concern that this ease 9. The Diabetes Control and Complications Trial
ignated HbA1cD). This facilitated the of use may mean that the limitations Research Group. The eect of intensive treatment
provision of additional targeted guid- of HbA1c as a diagnostic test are over- of diabetes on the development and progression of
ance in the form of interpretative com- looked, resulting in its application in long-term complications in insulin-dependent dia-
ments and, importantly, for HbA1cD circumstances when glucose measure- betes. N Engl J Med. 1993: 329: 977986.
requests, allowed flagging, as abnor- ments would, in fact, be indicated. There 10. United Kingdom Prospective Diabetes Study
mal, results that indicated pre-diabetes is a clear role for laboratory staff in the (UKPDS) Group. Intensive blood glucose control
(4247 mmol/mol). provision of ongoing education of clini- with sulphonylureas or insulin compared with con-
cians, in order to ensure the appropriate ventional treatment and risk of complications in
The pattern of fasting glucose, OGTT use and interpretation of these tests. patients with type 2 diabetes (UKPDS 33). Lancet
(excluding those from maternity ser- 1998; 352: 837853.
vices) and HbA1c requesting between References 11. The American Diabetes Association, European
April 2012 and March 2016 is summa- 1. McCulloch DK. Clinical presentation and diagno- Association for the Study of Diabetes, International
rized in the Figure 1. Between late 2012 sis of diabetes mellitus in adults. UpToDate. (http:// Federation of Clinical Chemistry and Laboratory
and September 2014, there was a steady uptodate.com/contents/clinical-presentation-and- Medicine and the International Diabetes Fed-
increase in HbA1c requests, which was diagnosis-of-diabetes-mellitus) eration Consensus Committee. Consensus state-
mirrored by a decrease in the number of 2. Global Report on Diabetes. World Health Organi- ment on the worldwide standardisation of the
fasting glucoses requested and OGTTs zation 2016. (http://apps.who.int/iris/bitstr HbA1c measurement. Diabetologia 2007; 50(10):
performed. Since the introduction of eam/10665/204871/1/9789241565257_eng.pdf) 20422043.
the two separate requests, HbA1cD and 3. American Diabetes Association Position Statement. 12. Use of glycated haemoglobin (HbA1c) in the diag-
HbA1cM, in September 2014, it can be Diagnosis and classication of diabetes mellitus. nosis of diabetes mellitus. Abbreviated report of a
seen that, with regard to monitoring, Diabetes Care 2011; 34(Suppl 1): S62S69. WHO consultation. World Health Organization
the number of requests has remained 4. Report of a WHO Consultation. Denition, diag- 2011. (http://www.who.int/diabetes/publications/
at around 2200 per month, about 10% nosis and classication of diabetes mellitus and its report-hba1c_2011.pdf)
higher than the number being done complications. World Health Organization 1999. 13. Colagiuri S, Lee CMY, Wong TW, Balkau B, Shaw
early in 2012 (when all such requests (https://www.sta.ncl.ac.uk/philip.home/who_dmg. JE, Borch-Johnsen K. Glycemic thresholds for dia-
were for this purpose). In contrast, pdf) betes-specic retinopathy: implications for diag-
those requested for diagnostic pur- 5. Denition and diagnosis of diabetes mellitus and nostic criteria for diabetes. Diabetes Care 2011; 34:
poses increased rapidly and, since late intermediate hyperglycemia. World Health Organi- 145150.
2015, the number of HbA1cD requests zation 2006. (http://www.who.int/diabetes/publica- 14. Zhang X, Gregg EW, Wiliamson DF, Barker LE,
has been similar to the total number of tions/Definition%20and%20diagnosis%20of%20 Thomas W, Imperatore G, Williams DE, Albright
HbA1c requests/month in 2014. diabetes_new.pdf) AL. A1c level and future risk of diabetes: a system-
atic review. Diabetes Care 2010; 33(7): 16651673.
15. International Expert Position Report on the role of
the A1C assay in the diagnosis of diabetes. Diabetes
Care 2009; 32: 13271334.
16. Expert Position Statement: Use of HbA1c in the
diagnosis of diabetes mellitus in the UK. The imple-
mentation of World Health Organization guidance
2011. Diabetic Medicine 2012; 29: 13501357.
17. American Diabetes Association. Classication and
diagnosis of diabetes. Diabetes Care 2015; 38(Suppl
1): S8S16.
18. Carson AP, Reynolds K, Fonseca VA, Muntner P.
Comparison of A1C and fasting glucose criteria to
diagnose diabetes among U.S. adults. Diabetes Care
2010; 33: 9597.
The author
Shirley A. Bowles MB ChB, MSc, FRCPath
Department of Blood Sciences, Countess
of Chester Hospital NHS Foundation
Figure 1. Pattern of diabetes test requesting: Fasting glucoses, oral glucose tolerance tests (OGTT) and Trust, Chester, UK
HbA1c, 20122016. (For a laboratory in a UK District General Hospital, serving a population of
~ 260 000). E-mail: shirleybowles@nhs.net
Diabetes 21 April/May 2016
to predict new cases in a large, prospec- The Danish model Answers to these are still emerging. In
tively examined, community-based cohort. One predictive model that has emerged in 2013, a study on 2,198 community-living
However, the outcome, in terms of risk Denmark selected a panel of six biomark- Chinese by the Shanghai Institutes for
prediction, was less than encouraging. In ers out of a total of 64, to assess T2DM risk. Biological Sciences endorsed the use of
reality, it proved to be only slightly better The selected biomarkers include adiponec- ferritin as a biomarker. Though the focus
at making a prediction than did traditional tin and ferritin, as well as four of their of the research was on iron storage, two of
risk factors on their own. The authors con- more common counterparts: glucose and three other biomarkers used in the eort
cluded: Our ndings underscore the view insulin, as well as the inammation mark- were the same as those in the Danish study,
that identication of adverse phenotypic ers C-reactive protein (CRP) and interleu- namely adiponectin and CRP (the fourth
characteristics remains the cornerstone of kin-2 receptor A (IL2RA). was -glutamyltransferase).
approaches to predicting the risk of type 2 The model was developed by a research
diabetes. team from Copenhagens Glostrup Hospi- Biomarker search continues
tal and Steno Diabetes Centre, along with Meanwhile, the search for TD2M biomark-
Adiponectin and ferritin the Copenhagen and Aarhus universities, ers continues.
Meanwhile, the eort to identify and vali- and Tethys Bioscience of the US. Two endothelial dysfunction biomarkers
date alternate biomarkers for prediction The researchers used the so-called Inter99 being investigated for T2DM risks consist
and screening continue. Two especially cohort, a study of about 6,600 Danes with of E-selectin and ICAM-1. The US Nurses
promising ones appear to be adiponectin, the primary outcome of 5-year conversion Health Study mentioned above also found
an adipocyte-derived, insulin-sensitizing to T2DM, to select 160 individuals who that signicantly elevated levels of the lat-
peptide, and ferritin, a protein that binds developed T2DM and 472 who did not. ter predicted incident diabetes in women
to iron and accounts for most of the iron They carefully measured several clinical independent of traditional risk factors
stored in the body. variables and candidate biomarkers from a such as BMI, family history, diet and activ-
multitude of diabetes-associated pathways, ity. In addition, adjustment for baseline
Studies in the early 2000s in the US and using an ultrasensitive immunoassay micro- levels of C-reactive protein, fasting insulin,
Germany conrmed that adiponectin was sample molecular counting technology. and hemoglobin A (1c) did not alter these
independently associated with a reduced Their eort ultimately led to six biomarkers associations.
risk of type 2 diabetes. that gave a Diabetes Risk Score. This, they
Interest in this area goes back a long time, concluded in a July 2009 issue of Diabetes
to a cross-sectional and longitudinal study Care, provided an objective and quantita- Incretins and melatonin
of Arizonas Pima Indians, who have the tive estimate of the 5-year risk of develop- Incretins, metabolic hormones which
worlds highest reported prevalence and ing type 2 diabetes, performs better than lower blood glucose by causing an increase
incidence of non-insulin-dependent dia- single risk indicators and a noninvasive in insulin after eating, are another poten-
betes mellitus (NIDDM). The study dates clinical model, and provides better strati- tially signicant biomarker. An incretin
to the early 1980s when it sought to docu- cation than fasting plasma glucose alone. eect is associated with the fact that oral
ment the sequence of metabolic events glucose elicits a higher insulin response
occurring with the transition from normal Expert acclaim than does intravenous glucose. There are
to impaired glucose tolerance and then to The researchers who developed the Dan- two hormones responsible for the incretin
diabetes. ish Diabetes Risk Score are modest in their eect: glucose-dependent insulinotropic
claims. In an appendix to their report in hormone (GIP) and glucagon-like pep-
In 2004, a prospective study within the US Diabetes Care, they point out that their tide-1 (GLP-1).
Nurses Health Study investigated iron stor- selection process for biomarkers may not In patients with type 2 diabetes, the incre-
age, given a belief that T2DM was a mani- have identied the best possible model, but tin eect is reduced. In addition, about
festation of hemochromatosis, due to iron do state that they identied a good model. half rst-degree relatives of patients with
overload. Researchers have established that Some outside observers are however less T2DM show reduced responses toward
higher iron store (reected by an elevated circumspect, given what many acknowl- GIP, without any signicant change in GIP
ferritin concentration and a lower ratio of edge to be one of the most exhaustive and or GLP-1 secretion after oral glucose. To
transferrin receptors to ferritin) is associ- profound selection eorts to date. James some researchers, this opens the possibil-
ated with increased T2DM risk in healthy Meigs of Harvard Medical School calls ity that a reduced responsiveness to GIP is
women, independent of known diabetes the Danish Diabetes Risk Score the most an early step in the pathogenesis of type 2
risk factors. robust multimarker prediction model diabetes.
However, there still are reasons for cau- possible.
tion. In July 2014, or more than a decade Variation in the Circadian system has also
after the US Nurses Health Study, a meta- Beyond Europeans to Chinese drawn a great deal of attention.
analysis of T2DM risk and ferritin in the One of the only major caveats in the Dan- Reverse transcription polymerase chain
journal Diabetes/Metabolism Research ish eort consisted of demographics. The reaction (RT-PCR) analyses, led by a team
and Reviews warned that though evidence report on the Danish model in Diabetes at the University of Lille in France, inves-
suggested a causal link, publication bias Care noted that it may only apply to white tigated melatonin receptor 2 (MT2 tran-
and unmeasured confounding cannot be Northern Europeans enrolled in a lifestyle scripts) in neural tissues and MT2 expres-
excluded. intervention trial and that it was an open sion in human pancreatic islets and beta
Nevertheless, ferritin and adiponectin question whether the model would pro- cells. Their ndings suggest a link between
do appear to play a key role in predicting duce the same biomarkers or discriminate circadian rhythm regulation and glucose
T2DM when combined with other selected well in race/ethnicity populations that are homoeostasis through the melatonin sig-
biomarkers. dierentially aected by diabetes. nalling pathway.
Diabetes 23 April/May 2016
values under 1 mmol/L, leading them to recommend waiting for Most of the studies mentioned are close to 10 years old, but measuring
the two successive low values before ending treatment. In addi- serum BHB to diagnose DKA or monitor its resolution has not become
tion to allowing an earlier treatment endpoint, this approach ena- standard practice. A recent review of the standard treatment guidelines
bles less time to be spent in the ICU, with decreased cost associ- for DKA in children and adolescents raises the question of whether
ated with treatment. Using a POC ketone meter can also result blood ketones should be evaluated during management of DKA [9].
in fewer tests being ordered overall. Rewers and colleagues asked The authors recommend using serum BHB measurement, either from
whether monitoring serum BHB values at the bedside could result the laboratory or at the point of care, to both diagnose DKA and moni-
in a decrease in laboratory testing in pediatric patients [7]. Their tor treatment. Despite the inaccuracies of POC meters seen at high
results indicated that the real-time changes observed in POC BHB values [57], use of a diagnostic cut-o of >3 mmol/L is well
serum BHB values correlated strongly with changes in pH, bicar- within the accurate range of the meters and can be used to condently
bonate, and pCO2 and also had good correlation with the labora- diagnose DKA and monitor the patients response to treatment.
tory BHB method. While initial measurement of pH, bicarbonate
and pCO2 is encouraged, following up the patient with POC BHB Conclusions
can replace serial laboratory measurements of those analytes and Despite the increasing body of knowledge indicating that meas-
decrease the amount of laboratory testing [7]. Similarly, a separate urement of serum BHB can aid in both diagnosis and manage-
study showed that use of a POC BHB meter at home decreased ment of DKA, a study conducted in 2014 indicated that although
diabetes-related hospital visits and hospitalizations of pediatric 89% of pediatric emergency medicine and critical care providers
diabetics when compared to urine ketone testing by allowing ear- responding to a survey stated that they had a DKA protocol at
lier identication of ketosis and initiation of treatment [8]. their institution, 67% perceived no clinical advantage in the use
of serum ketone measurements [10]. This suggests that evalua-
tion of serum ketone monitoring during DKA management from
a quality improvement and research perspective may be necessary
before clinical adoption is widespread. The next iteration of DKA
management guidelines should address the potential utility of
serum ketone monitoring.
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25 29 September 2016
Congress-Centrum Ost Koelnmesse, Cologne, Germany The authors
Angela M. Ferguson*1 PhD, DABCC, FACB; Jeery Michael1 D.O.,
www.iap2016.com
FAAP; Stephen DeLurgio2 PhD; Mark Clements1 MD, PhD, CPI
1
www.esp-congress.org Childrens Mercy Hospital, Kansas City, MO, USA
2
Bloch School, University of Missouri, Kansas City, MO, USA
jointly organised by
e German Division of the IAP
e European Society of Pathology *Corresponding author
E-mail: amferguson@cmh.edu
Hematology 25 April/May 2016
ing, gastroenterology, acute medicine, that if specic treatment with either heme misdiagnosis or indeed delayed diagnosis
dermatology, neurology, endocrinology preparations or carbohydrate loading of acute porphyria attacks [10].
and hematology amongst others [2]. In has been instigated prior to the test these
general, cutaneous porphyrias should interventions could reduce the urine PBG In conjunction with PBG, urine ALA
not pose a diagnostic diculty for an level signicantly, including normaliza- is often measured simultaneously and
experienced dermatologist used to inves- tion [3]. Furthermore, if the measurement although also elevated it does not tend
tigating photosensitive skin disorders, of urine PBG is delayed or undertaken at a to reach the levels of PBG in acute
but biochemical testing is still required time removed from the actual acute clini- porphyrias. The one exception is the
to dene the type of porphyria present. cal presentation e.g. by weeks or months, extremely rare instance of autosomal
However, denitive diagnosis of an initial then the nding of a normal urine PBG at recessive ADP due to defective ALA syn-
acute hepatic porphyria attack is criti- that later stage cannot eectively rule out thase 2 (ALAS2) activity, where markedly
cally dependent on biochemical testing, as acute porphyria [3]. In this authors expe- elevated urine ALA levels are reported
symptoms are often non-specic in nature rience another important caveat concerns while PBG may be normal or only slightly
(Tables 1 & 2). patients with a previous conrmed diag- elevated [2, 3]. In addition, a similar pat-
nosis acute porphyria who present with tern of urine ALA predominance relative
The diagnosis of an acute hepatic por- symptoms suggestive of recurrent acute to PBG (although not as elevated) may be
phyria attack is founded on demonstrat- attack. In many instances these patients observed in the context of lead poisoning,
ing an increase in urine PBG levels in have a perpetually elevated urine PBG, wherein patients may also present with
direct temporal association with the char- even in between attacks, and therefore abdominal pain and neuropathy [1, 3].
acteristic acute symptom complex, the an elevated urine PBG cannot eectively
minimum level of increase being between guide diagnosis. In these situations a deci- Once the diagnosis of acute porphyria
2- and 5-fold [9, 10]. The urine PBG may sion to treat as an acute attack has to be has been made based on the urine PBG
be measured either as a random sample, made on the basis of clinical ndings. the next phase involves determining the
where it should be reported as urine PBG type of porphyria present. This is very
to creatinine ratio or as a 24-hour urine Therefore, a clinically eective service much dependent on the specic pattern
collection, where total PBG is reported. for acute porphyria diagnosis requires of porphyrin overproduction observed in
The former has proven to be clinically that a timely, quality assured laboratory samples of urine, feces, plasma and eryth-
ecacious and has the advantage of time- method for urine PBG should be available rocytes. It is critically important that the
liness, reduced within-subject variation for analysis [11]. Although a qualitative laboratory analytical methods available
and convenience over the requirement for method for urine PBG may suce for the extend beyond the sole measurement of
a 24 hour urine collection [9]. If the urine purposes of establishing a diagnosis this total porphyrin levels [1012]. In particu-
PBG is not elevated this eectively rules should be supported by the availability lar, it is essential that individual porphy-
out an acute porphyria attack at the time of a conrmatory quantitative method rin analysis and isomer fractionation in
of sampling, however, there are certain for urine PBG. The lack of availability of both urine and feces is available to facili-
caveats to this. Thus it is important to note urine PBG assay is very often the basis for tate the identication of the porphyria-
Table 1. Overview of porphyrias including genes involved, inheritance pattern and basic clinical features.
27 April/May 2016
specic patterns of porphyrin overproduction [1012]. In many stress, prolonged fasting, menstruation [13], have long been
instances non-porphyria disorders aecting the gastrointestinal recognized in triggering acute porphyria attacks, it is the pres-
and hepatobiliary systems or certain dietary factors may cause ence of a pathogenic mutation which is still the single most
non-specic secondary elevations in porphyrins, e.g. copropor- important factor determining the overall susceptibility for an
phyrinuria, which can be diagnostically misleading [3]. In such acute porphyria episode. Therefore, all patients carrying a path-
cases urine PBG levels will not be elevated and the pattern of ogenic mutation should be regarded as pre-symptomatic carri-
porphyrins observed will not be indicative of any one of the spe- ers, i.e. capable of developing an acute attack, and one of the key
cic porphyrias per se. Therefore, it is important to realize that applications of genetic analysis in the area is in identifying pre-
a nding of elevated porphyrin levels does not automatically symptomatic carriers to allow for appropriate counselling and
equate to a diagnosis of underlying porphyria. This further high- management advice to prevent attacks [3, 14].
lights the importance of developing specialist porphyria centres
to ensure that the appropriate repertoire of quality assured test- In this authors experience another useful role for molecular
ing and expert interpretation and support are available for diag- diagnostics in porphyrias is in relation to those patients with
nosis and management of porphyria patients [11, 13]. an historic diagnosis of acute hepatic porphyria in whom the
biochemical abnormalities have subsequently normalized over
The diagnosis of cutaneous (non-acute) porphyrias is also very years. In such instances genetic analysis can provide a deni-
much based on the specic patterns of porphyrins observed in tive diagnosis for the type of porphyria and will accommodate
urine and feces. In addition, the pattern of free and zinc proto- a more extensive family screening programme for potential pre-
porphyrin in erythrocytes can be useful in the diagnosis of CEP, symptomatic carriers.
EPP and the related disorder, XLP. Moreover, the identication
of the porphyria subtype, either acute or cutaneous, may also be The current methods of genetic analysis vary but usually involve
enhanced by identifying characteristic plasma porphyrin uo- a conrmatory step using direct nucleotide sequencing of the
rescence emission peaks, e.g. VP emission peak between 625 and putative pathogenic variants as the gold standard. However, the
628 nm [13]. Finally, it is essential that all samples for porphy- emergence of next generation sequencing platforms has further
rin and precursor measurement are protected from light prior galvanized the diagnostic possibilities in this area. Overall, in
to analysis. autosomal dominant acute hepatic porphyrias, approximately
95% of mutations are identiable [3, 14]. This sensitivity includes
Role of genetic diagnosis the application of additional methods such as multiplex ligation-
Given the heritable nature of porphyrias it is not surprising dependent probe amplication (MLPA) and gene dosage analy-
that molecular genetic analysis has also become an important sis for identifying complex mutations, such large gene deletions,
diagnostic adjunct. There is an extensive allelic heterogeneity of
pathogenic mutations among the implicated genes for each por-
phyria disorder, which means that most mutations are uniquely
Hemostat
conned to one or at most a few kindreds. There are, however, a
few exceptions to this trend, most notably in relation to founder
mutations among the Swedish population and the Afrikaner
population in South Africa. The general approach in the appli-
Worlds Fastest Hemoglobin Meter
cation of genetic diagnostic strategies is rstly to characterize
the causative mutation in a known aected individual (proband)
using a mutation scanning approach [14]. Once a putative muta-
tion has been identied its pathogenicity for a particular por-
phyria should be armed and then more extensive family cas-
cade genetic screening can be organized based on the analysis of
this kindred-specic mutation [14].
Table 2. Biochemical diagnosis of porphyrias using porphyrin and porphyrin precursor analysis in urine, feces, plasma and red blood cells.
which may not be detected using standard Biochemistry Metabolic and Clinical Aspects. for autosomal dominant acute porphyrias: Ret-
sequencing-based approaches [14]. Churchill Livingstone Elsevier 2014; pp. 533549. rospective analysis of 467 unrelated patients
4. Elder G, Harper P, Badminton M, Sandberg S, Dey- referred for mutational analysis of HMBS, CPOX
In autosomal recessive porphyrias includ- bach JC. The incidence of inherited porphyrias in or PPOX gene. Clin Chem. 2009; 55: 14061414.
ing ADP, CEP and EPP, the clinical pen- Europe. J Inherit Metab Dis. 2013; 36: 849857. 13. Tollnes MC, Aarsand AK, Villanger JH, Stle E,
etrance approaches 100%. These disorders 5. Simon NG, Herkes GK. The neurologic manifes- Deybach JC, Marsden J, To-Figueras J, Sandberg
also display a level of genetic heterogene- tations of the acute porphyrias. J Clin NeuroSci. S; European Porphyria Network (EPNET). Estab-
ity. In the case of EPP the presence of a 2011; 18: 11471153. lishing a network of specialist porphyria centres
relatively common low expression single 6. Sonderup MW, Hift RJ. The neurological manifes- eects on diagnostic activities and services.
nucleotide polymorphism (SNP) located tations of the acute porphyrias. S Afr Med J. 2014; Orphanet J Rare Dis. 2012; 7: 93.
in the ferrochetalase gene, FECH (IVS3- 104: 285286. 14. Whatley SD, Badminton MN. The role of genetic
48C), appears to be essential for the clini- 7. Crimlisk HL. The little imitator-porphyria: a neu- testing in the management of patients with
cal expression of the cutaneous phenotype ropsychiatric disorder. J Neurol Neurosurg Psy- inherited porphyria and their families. Ann Clin
in the vast majority of cases [15]. chiatry. 1997; 62: 319328. Biochem. 2013; 50: 204216.
8. Siegesmund M, van Tuyll van Serooskerker AM, 15. Gouya L, Puy H, Robreau AM, Bourgeois M,
The application of molecular genetics has Poblete-Gutierrez P, Frank J. The acute hepatic Lamoril J, Da Silva V, Grandchamp B, Deybach
provided a means of establishing denitive porphyrias: Current status and future challenges. JC. The penetrance of dominant erythropoietic
porphyria susceptibility, however, similar Best Pract Res Gastroenterol. 2010; 24: 593605. protoporphyria is modulated by expression of
to the situation for biochemical testing 9. Aarsand AK, Petersen PH, Sandberg S. Estimation wildtype FECH. Nat Genet. 2002; 30: 2728.
services any genetic diagnostic services in and application of biological variation of urinary
this area must be quality assured to a high delta-aminolevulinic acid and porphobilinogen in The authors
standard and need to adopt appropriate healthy individuals and in patients with acute inter- Vivion E. F. Crowley*1 MB MSc FRCPath
mutation scanning assay validation pro- mittent porphyria. Clin Chem. 2006; 52: 650656. FFPath(RCPI) FRCPI, Nadia Brazil2 BA
tocols in accordance with international 10. Kauppinen R, von und zu Fraunberg M. Molecu- (Mod) FAMLS, Sarah Savage3 BSc MSc
1
standards and best practice recommenda- lar and biochemical studies of acute intermittent Consultant Chemical Pathologist, Head of
tions [1114]. porphyria in 196 patients and their families. Clin Department, Biochemistry Department, St
Chem. 2002; 48: 18911900. Jamess Hospital, Dublin 8, Ireland
References 11. Aarsand AK, Villanger JH, Stle E, Deybach JC, 2
Porphyrin Laboratory, Biochemistry
1. Puy H, Gouya L, Deybach JC. Porphyrias. Lancet Marsden J, To-Figueras J, Badminton M, Elder Department, St Jamess Hospital, Dublin 8,
2010; 375(9718): 924937. GH, Sandberg S. European specialist porphyria Ireland
3
2. Balwani M, Desnick RJ. The Porphyrias: advances laboratories: diagnostic strategies, analytical Molecular Diagnostic Laboratory, Bio-
in diagnosis and treatment. Blood 2012; 120: quality, clinical interpretation and reporting as chemistry Department, St Jamess Hospital,
44964504. assessed by an external quality assurance pro- Dublin 8, Ireland
3. Badminton MN, Elder GH. The porphyrias: inher- gramme. Clin Chem. 2011; 57: 15141523.
ited disorders of haem synthesis. In: Marshall 12. Whatley S, Mason N, Woolf J, Newcombe R, *Corresponding author
W, Lapsley M, Day A, Ayling R, editors. Clinical Elder G, Badminton M. Diagnostic strategies E-mail: vcrowley@stjames.ie
April/May 2016 29 INDUSTRY NEWS
Prep automation in culture-inde- Zika Virus real time PCR of Zika virus in clinical samples from patients
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EDTA blood, CSF, BAL, aspirates from complete the identication of the virus in the been developed with an extended open
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Smaller than a standard microwave, the new
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April/May 2016 32 PRODUCT NEWS
New assay range including ensures laboratories can provide a fast, easy EUROIMMUN
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ADVIA Cen- as becoming more productive and ecient. POC hemoglobin
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The Siemens IMMULITE 2000 XPi thyroid (ANCA) and now also Crithidia luciliae 5 - 26 g/dL. Battery life allows 3,000 tests to
stimulating immunoglobulin (TSI) assay (CLIFT), EUROPLUS antigens and cell- be performed. By using Hemostat, a check of
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PRODUCT NEWS 33 April/May 2016
CALENDAR OF EVENTS
Vacuum sample tube with glycolysis inhibition
The rapid break- centrifugation. Unlike in tubes where liq-
down of glucose uid is added, the nely granulated additive May 21-24, 2016 September 25-
(glycolysis) in does not cause a dilution eect. There is no European Human 30, 2016
venous blood need to convert the measurement result. Genetics Conference European Con-
samples is very The citrate/citric acid buer reduces the pH 2016 (ESHG 2016) gress of Pathology
signicant for the value in the sample. As a result, the enzymes Barcelona, Spain Cologne, Ger-
diagnosis of both diabetes mellitus and ges- needed for the glycolysis process are inhib- www.eshg.org/ many
tational diabetes which should be detected at ited and the actual in vivo level is stabilized home2016.0.html www.esp-con-
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have drafted guidelines, which recommend The VACUETTE FC Mix tube is available www.esgar.org Allergy & Clinical
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July 31-August 4, cn/g1250.aspx
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Walk-away 25-OH vitamin D3 samples fully automatically without AACC
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