Journal of Diabetes, Endocrinology and Metabolic Diseases no. p.p. vol. 42 4 92-115 UDC 616.379-008.67.43 ISSN 0351-0042 VUK VRHOVAC UNIVERSITY CLINIC, ZAGREB, DAMA - DIABETOLOGY ALUMNI MEDICAL ASSOCIATION 2013. CONTENTS ORIGINAL RESEARCH ARTICLES ACCREDITATION OF MEDICAL BIOCHEMISTRY LABORATORIES IN CROATIA AND ITS ROLE IN IMPROVING PATIENT SAFETY Z. Flegar-Meštrić, S. Perkov, M. Vučić Lovrenčić, D. Škegro . . . . . . . . . . . . . . . . . . 94 REVIEWS THE ASSOCIATION BETWEEN TUBERCULOSIS AND DIABETES MELLITUS – A REVIEW D. Majić Milotić, K. Peroš, S. Popović-Grle, K. Kljajić Babić . . . . . . . . . . . . . . . . . 104 SUBACUTE GRANULOMATOUS THYROIDITIS K. Peroš, D. Majić Milotić, M. Šunjić Stakor, V. Đermanović Dobrota. . . . . . . . . . 110 Vol. 42 No. 4 (pp. 92 - 115) 2013 / Zagreb, September 2015
Transcript
Journal of Diabetes, Endocrinology and Metabolic Diseases
no.
p.p.
vol.
42
4
92-115
UD
C 6
16.3
79-0
08.6
7.43
ISSN
035
1-00
42
VUK VRHOVAC UNIVERSITY CLINIC, ZAGREB, DAMA - DIABETOLOGY ALUMNI MEDICAL ASSOCIATION
2013.
CONTENTS
ORIGINAL RESEARCH ARTICLES
ACCREDITATION OF MEDICAL BIOCHEMISTRY LABORATORIES INCROATIA AND ITS ROLE IN IMPROVING PATIENT SAFETYZ. Flegar-Meštrić, S. Perkov, M. Vučić Lovrenčić, D. Škegro . . . . . . . . . . . . . . . . . . 94
REVIEWS
THE ASSOCIATION BETWEEN TUBERCULOSIS AND DIABETESMELLITUS – A REVIEWD. Majić Milotić, K. Peroš, S. Popović-Grle, K. Kljajić Babić . . . . . . . . . . . . . . . . . 104
SUBACUTE GRANULOMATOUS THYROIDITISK. Peroš, D. Majić Milotić, M. Šunjić Stakor, V. Đermanović Dobrota. . . . . . . . . . 110
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. 4 (
pp
. 92
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b, S
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DIABETOLOGIA CROATICA
MEDICAL SCIENTIFIC JOURNAL OF THE VUK VRHOVAC INSTITUTE
UNIVERSITY CLINIC FOR DIABETES, ENDOCRINOLOGY AND METABOLIC DISEASES
SCHOOL OF MEDICINE, UNIVERSITY OF ZAGREB
SOCIETY FOR DIABETES AND METABOLIC DISEASES OF THE
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DIABETOLOGY ALUMNI MEDICAL ASSOCIATION
VUK VRHOVAC UNIVERSITY CLINIC, ZAGREB
VOLUME 42, NUMBER 4, 2013
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Department of Medical Biochemistry and Laboratory Medicine,Merkur University Hospital, Zagreb, Croatia
Original Research Article
ACCREDITATION OF MEDICAL BIOCHEMISTRY
LABORATORIES IN CROATIA AND ITS ROLE IN IMPROVING
PATIENT SAFETY
Z. Flegar-Meštrić, S. Perkov, M. Vučić Lovrenčić, D. Škegro
Key words: accreditation according to theISO 15189, patient safety, harmonization of laboratorytest results, diabetes care
Summary
Providing patient safety and maintaining a high levelof quality is the most important priority for anymedical biochemistry laboratory. Accreditationaccording to the ISO 15189, Medical laboratories –Requirements for quality and competence, providesobjective proof that the medical biochemistrylaboratory operates competently and safely, is patientfocused and delivers testing results that can be reliedon. It enables national/international recognition oftechnical competence of medical biochemistrylaboratories and is a prerequisite for globalharmonization of laboratory test results. Accreditation
according to HRN EN ISO 15189, Medicallaboratories - Requirements for quality andcompetence can assure continuous improvement ofquality and reliable diagnostic service of medicalbiochemistry laboratories in Croatia at the nationaland international level. Laboratory medicinededicated to diabetes care is among most prominentexamples of the importance of accreditation due to thepivotal role of laboratory in the diagnosis andmonitoring of diabetes mellitus.
INTRODUCTION
Laboratory medicine has a broad impact on clinicalmanagement and patient outcomes. For this reason, themain goal of medical laboratories is to be able tosupport clinicians with the best achievable quality inall laboratory results and reports. Ongoing evaluationand improvement processes are essential to provelaboratory competence to provide performance incompliance with the highest professional standards inorder to reduce diagnostic errors and improve patientsafety. One of the most practical tools for managingquality is accreditation, which is defined as a process
Diabetologia Croatica 42-4, 2013 94
Corresponding author: Zlata Flegar-Meštrić, PhD, Department of MedicalBiochemistry and Laboratory Medicine, Merkur University Hospital,Zajčeva 19, HR-10000 Zagreb, Croatia
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95
by which an independent and authorized official bodyaccredits the quality system and competence of alaboratory to perform certain activities on the basis ofsome predefined standards (1). Accreditationaccording to the International Standard ISO 15189,Medical laboratories – Requirements for quality andcompetence has become a practical, generallyaccepted method of quality management andconfirmation of technical competence of medicallaboratories in the whole world. It focuses on patientcare, quality of examination results and their correctinterpretation, maintenance of the whole laboratoryprocess quality and ethics in laboratory medicine, andhas been recommended by the International Federationof Clinical Chemistry and Laboratory Medicine(IFCC).
ACCREDITATION OF MEDICAL
BIOCHEMISTRY LABORATORIES IN
CROATIA
The International Standard ISO 15189, Medicallaboratories – Special requirements for quality andcompetence has been translated into Croatian andaccepted by the Croatian Institute for Norms asCroatian norm in 2003. Accreditation of medicallaboratories according to this norm is carried out inCroatia on voluntary basis by the CroatianAccreditation Agency (HAA) (2). HAA wasestablished as a national accreditation body in 2005and has full membership in the European co-operationfor Accreditation (EA). It has been evaluated by peersas competent and signed arrangements that enhancethe acceptance of accreditation of these services (EAMLA, Multilateral Agreement) in 2009. Accreditationaccording to this norm supports the development andmaintenance of high quality practice standards forlaboratory testing to assure patient safety and reducediagnostic errors associated with laboratory medicine(3,4). Up to now, HAA has accredited 8 medicalbiochemistry laboratories in the Republic of Croatia.The Department of Medical Biochemistry andLaboratory Medicine of the Merkur UniversityHospital has been accredited according to HRN ENISO 15189 since 2007 (5). It grew up in 2010 out of
the merger of the Merkur University HospitalDepartment of Clinical Chemistry and the VukVrhovac University Clinic Department of LaboratoryMedicine (Statute of the Merkur University Hospitalof October 24, 2010) and nowadays provides specialistand consulting medical biochemistry services pursuantto the Health Care Act (NN 150/2008, articles 28 and29). Employees of the Department of MedicalBiochemistry and Laboratory Medicine areinternationally recognized experts and scientistsinvolved in a range of activities, including researchprojects, publishing and international cooperation. Thescope of accreditation comprises 164 laboratory testexaminations using different laboratory technology, asillustrated in Table 1. In this way, the laboratory istrying to continuously support clinicians who want tobe able to carry out the right investigation on the rightpatient at the right time to ensure optimum patientoutcome (4).
THE IMPACT OF ACCREDITATION
PROCESS ON CLINICAL MANAGEMENT
AND PATIENT SAFETY
Patient safety is influenced by the frequency andseriousness of errors that occur in the health caresystem. The process of laboratory testing traditionallyhas been divided into preanalytical process, analyticalprocess and post-analytical process, commonlyreferred to as total testing process (TTP) (6). While allthree components are important for ensuring patientsafety, the greatest impact for overall improvementwould be to focus on the pre- and post-analyticalprocesses (extra-analytical phases of laboratorytesting), where most errors occur. The evaluationcarried out by Plebani and Plebani et al. has clearlyshown that, where diagnostic error arises fromlaboratory testing, the pre- and post-analytical phasesare much more vulnerable to error than the trueanalytical phase (7-9). A high frequency of errors andrisk of errors that could harm patients has beendescribed in both the pre-pre- and post-post-analyticalsteps that usually are not under the laboratory control(4). The release of a Technical Specification ISO/TS22367:2008 by the International Organization for
Standardization played a key role in collecting theevidence and changing the per spective on laboratoryerrors, especially in the pre- and post-examinationprocesses, emphasizing the need for a patient-centeredapproach to errors in laboratory testing (10). ThisTechnical Specification characterizes the applicationof ISO 15189 as an effective system for reducinglaboratory errors and improving patient safety byapplying the principles of risk management includingidentifying and controlling non-conformities,establishing preventive and corrective actions,carrying out internal audits and management reviews,and implementing continual improvement. Theapplication of risk management process enables thelaboratory to identify weaknesses in the measuring
system and environment that are weighed against theprobability of error, the effectiveness of controlprocesses built into the measuring system, and thelaboratory tolerance of risk considering the clinical useof laboratory result (11,12).
In the scope of the preanalytical processes, aretrospective analysis of preanalytical qualityindicators has been carried out at the Department ofMedical Biochemistry and Laboratory Medicine for a1-year period to evaluate data regarding the frequencyof the main factors affecting the preanalytical qualityof serum samples (Fig. 1). In addition, clinical auditand evaluation of the preanalytical phase in all MerkurUniversity Hospital departments was provided by
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Table 1. Description of the scope of accreditation according to HRN EN ISO 15189 of the Department of Medical
Biochemistry and Laboratory Medicine, Merkur University Hospital, Zagreb
Medical field Technology Materials Number of tests
Becton Dickinson Laboratory Consulting Services™Preanalytical Q.C. (Fig. 2). The results obtainedshowed the preanalytical phase to be a complex anddynamic error-prone process with clear distinctionbetween the errors exclusively inside the laboratoryand errors outside the laboratory (13). Inappropriatesamples due to misidentification, quantity (insufficientvolume to perform the analysis, inadequateblood/anticoagulant ratio) or quality issues (hemolytic,clotted, contaminated specimens, or samples collectedinto a wrong container) still represent the leadingpreanalytical problem that has to be solved throughinter-department cooperation and design to improvethe quality of specimen collection as an essentialprerequisite for improving patient safety.
In the scope of analytical processes, besides internalquality control of testing procedures that is performedas daily routine, medical biochemistry laboratories useproficiency testing (EQA, External QualityAssessment) to improve analytical performance oflaboratory tests required for patient care and todocument quality (14). In Croatia, EQA programshave been continuously performed since 1973, by theCommittee for External Quality Assessment, which in2012 outgrew into the Croatian Center for Quality
Assessment in Laboratory Medicine (CROQALM),conducted by the Croatian Society of MedicalBiochemistry and Laboratory Medicine as a non-profit, non-governmental organization dedicated toperform nationwide quality assessment in laboratorymedicine (15). The major benefits of the national EQAare to enhance patient care through improvedanalytical quality and working conditions in medicalbiochemistry laboratories in Croatia (16,17).Participation in the international EQA schemes is ofutmost importance, since one of the main purposes ofEQA in medical-biochemical laboratories is to provideindependent and objective evaluation of laboratory testresults at the international level in order to promoteglobal standardization/harmonization of the wholelaboratory process and achieve a high degree of inter-laboratory comparability (14). The Department ofMedical Biochemistry and Laboratory Medicine meetsthe analytical quality goals for all laboratory testexaminations within the scope of accreditation throughparticipation in different EQA schemes organized bythe international EQA providers: RfB, ReferenceInstitute for Bioanalytics, Germany; UKNEQAS,Edinburgh Department of Laboratory Medicine,United Kingdom; INSTAND, Gesellschaft zurFörderung der Qualitätssicherung in medizinischenLaboratorien, Germany; ERL, European ReferenceLaboratory for the Glycohemoglobin,
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Figure 1. Retrospective analysis of preanalytical
quality indicators in the Department of Medical
Biochemistry and Laboratory Medicine, Merkur
University Hospital, for a one-year period (0.54%
samples from 97975 patients found inappropriate for
The Netherlands; EMQN, European MolecularGenetic Quality Control Network, United Kingdom;and ECAT, External Quality Control of DiagnosticAssays and Tests, The Netherlands. In order tominimize the risk for and ensure safety of the patients,it is of utmost importance to assure full traceability ofall laboratory procedures. Based on the data of internaland external quality control, measurement uncertaintyis calculated for quantitative measuring proceduresand published on the Merkur University Hospitalwebsite (http://www.kb-merkur.hr/) (18).
In the scope of the post-analytical processes,information technology enhances the performance andsafety of the test result management processes. In theDepartment of Medical Biochemistry and LaboratoryMedicine, results are reported in electronic formseparately for each medical request or in the tableform, which enables long-term evaluation oflaboratory results, thus contributing considerably tofaster and more efficient patient care (Fig. 3).Availability of the right interpretation is essential toensure optimum patient outcome (19).
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Figure 3. Long-term evaluation of laboratory test results at Merkur University Hospital, Zagreb, Croatia.
The Department of Medical Biochemistry andLaboratory Medicine is involved scientifically andprofessionally in producing reference values ofclinically relevant biochemical and hematologicalblood and serum constituents since 1981. Thereference intervals for the Croatian population havebeen produced for 34 clinically relevant blood andserum constituents under strictly controlled conditionsaccording to the IFCC recommendations on therepresentative reference sample group of 2246 adultsand 998 children, age 8-70 years (20). Based on theachievements in the field, the Department of MedicalBiochemistry and Laboratory Medicine wasdesignated by the Ministry of Health of the Republicof Croatia as the national Reference Center forDetermination of Reference Values in GeneralMedical Biochemistry in 2000. Today’s activities ofthe Reference Center are directed to harmonization oflaboratory test results based on metrological criteriaand traceability concept in laboratory medicine (21-25).
The seven-year experience of the Department ofMedical Biochemistry and Laboratory Medicineapproves that accreditation according to HRN EN ISO15189 supports the development and maintenance ofhigh quality standards for laboratory testing and offersopportunities for the laboratory to proactively respondto the developing performance trend with timelyaction to prevent failure in order to assure reliablediagnostic service and improve patient safety (5,26).
RELEVANCE OF ACCREDITATION FOR
THE LABORATORY MEDICINE
DEDICATED TO DIABETES CARE
Considering the rising prevalence of diabetes inCroatia, with estimated one-third of asymptomaticindividuals, accurate and reliable laboratory glucosemeasurement is the ultimate tool for early detection ofdiabetes (Table 2) (27). Our recent survey revealed ahigh degree of variability and poor compliance toguidelines in preanalytical procedures associated withglucose measurement in Croatian laboratories, whichcould seriously compromise reliability of diabetesdiagnosis (28).
If HbA1c is used for the diagnosis of diabetes, it isrecommended to be measured in an accreditedlaboratory, with a method traceable to the globallyaccepted standards and total within-laboratoryimprecision <2% (29).
Apart from glucose and HbA1c, other laboratory testsused for diagnosis and monitoring of diabetes alsoneed to be performed and/or confirmed in anaccredited laboratory. Thus, it is recommended thatislet cell autoantibodies, used for classification ofdiabetes in adults and prospective studies in variouspopulations, be measured only in an accreditedlaboratory with an established quality-control programand participation in an external quality controlprogram (29). Also, positive albuminuria resultsobtained by semi-quantitative and point-of-caredevices on annual check-up are recommended to beconfirmed by a quantitative assay in an accreditedlaboratory (29).
Diabetes diagnosis and management involves bothroutine and highly specialized laboratory assessment.However, even ordinary glucose testing, available atthe level of primary healthcare laboratory services,might be very challenging due to the complexity ofpreanalytical and analytical factors influencing plasmaglucose results. Accreditation according to the ISO15189 enabling continuous and systematic supervisionand quality management of total laboratory processesmight be the ultimate tool in attaining high-qualitylaboratory services dedicated to diabetes care inCroatia.
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Venous plasma glucose (mmol/L)
Fasting ≥7.0
Random ≥11.1
HbA1c (%/mmol/mol)
≥6.5 (48)
Table 2. Venous plasma glucose- and HbA1c
-based
diagnostic criteria for diabetes (27)
CONCLUSIONS
Systematic control of the total testing process withcontinuous monitoring and management of theevidence-based quality indicators and performancecharacteristics is the obligation of all medicalbiochemistry laboratories accredited according to ISO15189 as an effective tool for improving quality,decreasing the risk of errors and increasing patientsafety. It is the most practical tool for managingquality and standardization of laboratory workflow
resulting in cost reduction (26). Accreditationsignificantly increases confidence in laboratory resultsand facilitates achieving global harmonization inlaboratory medicine. Accreditation according to theHRN EN ISO 15189, Medical laboratories –Requirements for quality and competence can assurecontinuous quality improvement and reliablediagnostic service of medical biochemistrylaboratories in Croatia at the national and internationallevel.
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REFERENCES
1. International Organization for Standardization.ISO 15189:2012 Medical laboratories –requirements for quality and competence. Geneva,2012.
2. Križanec D. HRN EN ISO 15189; Pravila ipostupak akreditacije. In: Galjanić S, Vukasović I,Flegar-Meštrić Z, editors. Akreditacijamedicinsko-biokemijskog laboratorija. Priručniktečaja trajnog usavršavanja za medicinskebiokemičare. Zagreb: Medicinska naklada,2010;15-30. (in Croatian)
3. Howanitz PJ. Errors in laboratory medicine,practical lessons to improve patient safety. ArchPathol Lab Med 2005;129:1252-1261.
4. Epner PL, Gans JE, Graber ML. When diagnostictesting leads to harm: a new outcomes-basedapproach for laboratory medicine. BMJ Qual Saf2013 Aug 16. doi: 10.1136/bmjqs-2012-001621.
5. Flegar-Meštrić Z, Nazor A, Perkov S, Šurina B,Kardum Paro MM, Šiftar Z, Sikirica M, Sokolić I,Ožvald I, Vidas Ž. Accreditation of medicallaboratories in Croatia – Experiences of theInstitute of Clinical Chemistry, Merkur UniversityHospital, Zagreb. Coll Antropol 2010;34:181-186.
6. Plebani M, Laposata M, Lundberg GD. The brain-
to-brain loop concept for laboratory testing 40
years after its introduction. Am J Clin Pathol
2011;136:829-833.
7. Plebani, M. Laboratory-associated and diagnostic
errors: a neglected link. Clin Chem Lab Med
2014;1(1):89-94.
8. Plebani M. Exploring the iceberg of errors in
laboratory medicine. Clin Chim Acta 2009;404:16-
23.
9. Bonini PA, Plebani M, Ceriotti F, Rubboli T. Errors
in laboratory medicine. Clin Chem 2002;48:691-
698.
10. International Organization for Standardization
ISO/TS 22367:2008 Medical laboratories –
Reduction of error through risk management and
continual improvement. Geneva, 2008.
11. CLSI, Laboratory Quality Control Based on Risk
Management; Proposed Guideline, CLSI
document , EP23-P; Vol. 30, No. 4. Clinical and
Laboratory Standards Institute, Wayne,
Pennsylvania, USA, 2010.
12. CLSI, Development and Use of Quality Indicators
for Process Improvement and Monitoring of
Laboratory Quality; Approved Guideline; CLSI
document , GP35-A; Vol. 30, No. 24. Clinical and
Laboratory Standards Institute, Wayne,
Pennsylvania, USA, 2010.
13. Perkov S, Flegar-Meštrić Z, Šiftar Z. Auditing the
preanalytical phase: evaluation of hemolysis in
samples drawn by hospital versus laboratory staff.
In: Plebani M, editor. IFCC WorldLab Istanbul
2014. Berlin, Boston: Walter de Gruyter,
2014;S1025-S1025.
14. CLSI, Using Proficiency Testing to Improve the
Clinical Laboratory; Approved Guideline, 2nd edn.
CLSI document, GP27-A2; Vol. 27, No. 8, Clinical
and Laboratory Standards Institute, Wayne,
Pennsylvania, USA, 2007.
15. Juretić D, Flegar-Meštrić Z. Vanjska procjena
kvalitete medicinsko-biokemijskih laboratorija u
Hrvatskoj. In: Šimundić A-M, editor. 60 godina
Hrvatskog društva za medicinsku biokemiju i
laboratorijsku medicinu, 1953.-2013. Zagreb:
Hrvatsko društvo za medicinsku biokemiju i
laboratorijsku medicinu, 2013;51-64. (in Croatian)
16. Flegar-Meštrić Z, Nazor A, Parag G, Sikirica M,
Perkov S, Juretić D. Ciljevi analitičke kvalitete u
vanjskoj procjeni kvalitete rada medicinsko-
biokemijskih laboratorija u Republici Hrvatskoj.
Biochem Med 2005;15(1-2):15-25. (in Croatian)
17. Flegar-Meštrić Z. The role of external quality
assessment in accreditation of medical laboratories
in Croatia. In: Herbert A, Cochand-Priollet B,
editors. Cytopathology, Vol. 23, Supplement 1.
Oxford, UK: Blackwell Publishing Ltd., 2012;39.
18. Flegar-Meštrić Z, Šurina B, Perkov S, Ožvald I,
21. Flegar-Meštrić Z, Perkov S, Šimonović B, JuretićD. Applicability of common reference intervals forserum creatinine concentrations to the Croatianpopulation. Clin Chem Lab Med 2010;48(2):231-235.
23. Flegar-Meštrić Z. Novi pristupi izradi i primjenibioloških referentnih intervala premaakreditacijskim zahtjevima. In: Stavljenić-Rukavina A, editor. Organizacija i poslovanjemedicinsko-biokemijskih laboratorija u kontekstureforme zdravstvenog sustava. Priručnik tečajatrajnog usavršavanja za medicinske biokemičare.Zagreb: Medicinska naklada, 2009;55-71. (inCroatian)
24. Flegar-Meštrić Z. Standardizacija/harmonizacija upodručju izrade i primjene bioloških referentnihintervala za odraslu i pedijatrijsku populaciju. In:Flegar-Meštrić Z, editor. Harmonizacija izvje -štavanja o rezultatima medicinskobiokemijskihpretraga: upravljanje poslijeanalitičkom fazomlaboratorijskog procesa. Priručnik tečaja trajnogusavršavanja za medicinske biokemičare. Zagreb:Medicinska naklada, 2014;15-27. (in Croatian)
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25. Radeljak A, Flegar-Meštrić Z, Baković L.Prihvatljivost referentnih intervala za odraslu ipedijatrijsku populaciju. In: Flegar-Meštrić Z,editor. Harmonizacija izvještavanja o rezultatimamedicinskobiokemijskih pretraga: upravljanjeposlijeanalitičkom fazom laboratorijskog procesa.Priručnik tečaja trajnog usavršavanja zamedicinske biokemičare. Zagreb: Medicinskanaklada, 2014;27-38. (in Croatian)
26. CLSI Understanding the Cost of Quality in theLaboratory; a Report, CLSI document, QMS20-R;Vol. 34, No.7. Clinical and Laboratory StandardsInstitute, Wayne, Pennsylvania, USA, 2014.
27. World Health Organization. Use of glycatedhaemoglobin (HbA1c) in the diagnosis of diabetesmellitus. Abbreviated report of a WHOconsultation. Geneva: WHO, 2011.
28. Vučić Lovrenčić M, Božičević S, Radišić Biljak V,Mesić R, Poljičanin T, Metelko Ž. Implications ofvariable preanalytical procedures for the diagnosisof diabetes mellitus in Croatia. Biochem Med2012;22(Suppl 1):A92-A93
29. Sacks DB, Arnold M, Bakris GL, Bruns DE,Horvath AR, Kirkman MS, et al. Guidelines andrecommendations for laboratory analysis in thediagnosis and management of diabetes mellitus.Clin Chem 2011;57:e1-e47.
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The incidence of diabetes mellitus is increasing,especially in developing countries where tuberculosisis more prevalent. Diabetes mellitus impairs theimmunity of patients and triples the risk of activetuberculosis, and therefore, diabetes will make animportant contribution to the tuberculosis epidemic.Diabetes is associated with an increased risk oftuberculosis treatment failure, recurrence of formerinfection or re-infection with a new strain ofMycobacterium tuberculosis, and also with anincreased risk of death. Symptoms of manifesttuberculosis in diabetics are often scarce and thediagnosis is frequently delayed. Clinical managementof patients suffering from both diseases may bedifficult. In general, there is no difference intuberculosis treatment of patients with tuberculosisand diabetes and patients with tuberculosis without
diabetes. Diabetics with manifest tuberculosis shouldbe treated with insulin therapy and optimal glycemiccontrol probably may improve health outcomes. Thisarticle reviews the association between tuberculosisand diabetes.
INTRODUCTION
The global burden of tuberculosis (TB) and diabetes
One-third of the world population are believed to beinfected by TB in its latent form, a disease caused byMycobacterium (M.) tuberculosis. These individualshold a 5%-10% average lifetime risk of progressinginto the active stage of the disease (2). Tuberculosis isa major and still neglected cause of death anddisability in low-income and middle-income countries.Although the disease is treatable and even preventable,it has a limited political background and little interestfrom private sector. This neglect is partly related to thefact that the greatest burden of the disease is amongthose who are poor. Also, until the early 1990s, therewas a firm belief that TB had been defeated (at least inindustrialized countries) and that the disease no longerjustified a priority status. The reality is quite different.In 2012, 8.6 million people developed TB and 1.3million died from the disease (3). Diabetes prevalenceis increasing, from estimated 151 million adults in2000 to 382 million in 2013; this number is expectedto rise to 592 million by 2035 (4). In Croatia, therewere 241 990 registered diabetics older than 18 yearsin 2013 (5). The risk of developing TB is at leasttripled in individuals with diabetes and is highest inyoung people. Therefore, diabetes will make animportant contribution to the TB epidemic.
DIABETES AND THE RISK OF POOR
TUBERCULOSIS OUTCOMES
Diabetes is not only a risk factor for active TB, but isalso a risk factor for poor TB treatment outcomes.Many studies showed that patients with TB and DMwere more likely to remain sputum smear positive at2-3 months after starting treatment for TB (4).Diabetes increases the risk of TB treatment failure anddeath. Patients with DM were four times more likelyto develop TB relapse than patients without DM, theymay have been cured but experienced recurrence offormer infection, or they may have been re-infectedwith a new strain of TB (6). The frequency ofmultidrug-resistant TB among DM patients with TB ishigher than that among TB patients (17.7% vs. 8.4%,P<0.01) (7).
BI-DIRECTIONAL SCREENING OF THE
TWO DISEASES
Screening for DM in patients with TB is now widelyrecommended for all adults older than 18 years.Various studies have shown that up to 30% of patientswith TB have DM as well (8). Measurement of bloodglucose at a single time point might lead to a falsediagnosis of DM in patients with TB because theycould have intermittent hyperglycemia throughinduction of insulin resistance, mediated byinflammation due to TB infection (4). Assessment bythe 75 g oral glucose test (OGTT) and particularlyglycosylated hemoglobin (HbA1c) proved to be moresensitive when used as screening tests for newlydiagnosed DM in TB patients (9). If screening for DMis done just prior to initiation of anti-tuberculosistherapy, a second test during TB treatment or aftertreatment completion should be performed. Retestingshould also be done in patients who develop symptomsof hyperglycemia during anti-tuberculosis treatment.Screening for latent tuberculosis infection (LTBI) inindividuals with DM, especially those with poorglycemic control, can help identify a high-riskpopulation that could be offered preventive therapy,which is not yet recommended. It is still unknownwhether chemoprophylaxis is equally effective inLTBI individuals with and without diabetes. Arandomized controlled trial of preventive use of TBtherapy in LTBI individuals with and without DMshould be done (10). The number of diabetics neededto be screened to find one extra case of TB is directlyrelated to the local TB prevalence. For example, insettings with a TB prevalence less than 25 per 100 000persons, at least 1000 diabetics need to be screened tofind one extra case of TB, so TB screening in diabeticsis recommended in countries with a high prevalence ofTB (>100 per 100 000 population) (11). In 2013, theincidence of TB in Croatia was 12.2 per 100 000persons (5). It is reasonable that diabetic patient withsuggestive symptoms such as cough for more than 2 to3 weeks, weight loss, fever, or an abnormal imagingstudy should be investigated for the presence of activeTB, especially in diabetics with poor glycemic controland in diabetic children with recent TB exposure(9,12).
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CLINICAL PRESENTATION
Lungs in diabetic patients have weak defensemechanisms because of 1) dystrophy of alveolarmacrophages, pneumocyte type II and fibroblasts, andimpaired cell-mediated immunity; 2) generalizedaffection of the vascular system of the lung(microangiopathy); and 3) enhanced connective tissueformation (13,14). Symptoms of manifest TB indiabetics are scarce due to autonomic neuropathy;atypical forms of tuberculosis are frequent, such asinfiltrate or abscess of the middle and lower lunglobes, frequently multilobular (15-17), so thediagnosis of TB in diabetics is frequently delayed.Patients with TB and DM are usually older and heavierthan the general TB population and are more likely tobe male (8,18,19). Foot ulcers are common indiabetics, and in countries with a high prevalence ofTB it should be included in the differential diagnosisof non-healing diabetic foot ulcer becauseosteoarticular TB is the fourth leading cause ofextrapulmonary TB (20).
DIAGNOSIS
Tuberculin skin test (TST) is in vivo test for detectionof M. tuberculosis infection and is available for morethan one century, but now a novel whole blood test (invitro) QuantiFERON (QFT) is available. TST is basedon the fact that infection with M. tuberculosisproduces a delayed-type hypersensitivity skin reaction(type IV) to certain components of the bacterium (21).QFT detects the release of interferon-gamma (IFN-γ)in fresh heparinized whole blood from sensitizedpersons when incubated with a mixture of syntheticpeptides simulating proteins present in M.tuberculosis. QFT results are available in less than 24hours and there is no need for second visit, whereasTST requires second encounter to read the results 48-72 hours after test administration (22,23). QFT hasbeen shown to be more sensitive than TST (78% vs.50%) in patients with DM, chronic renal failure,malignancies, and other immunosuppressiveconditions (24), and can also predict progression ofLTBI to manifest TB 6 times more accurately (25). Toverify the diagnosis of manifest TB in diabetics with
proven LTBI, other tests should be done irrespective ofthe patient being asymptomatic or not (loss of weight,loss of energy, poor appetite, fever, productive cough,night sweats): chest x-ray, computed tomography,sputum analysis, and analysis of other samples (urine,stool, pleural fluid). The only reliable evidence of TBis isolation of M. tuberculosis in sputum or othersamples (urine, stool, pleural fluid) (26).
TREATMENT FOR CONCURRENT
TUBERCULOSIS AND DIABETES
MELLITUS
The optimal treatment strategy for concurrent TB andDM is not known. Diabetes is associated with anincreased risk of TB treatment failure, death andrelapse, but whether optimal glucose control can partlyor fully alleviate these negative effects, and whetherTB treatment should be adjusted in patients with DM,is uncertain (4). Treatment of TB is standardized andconsists of two drugs (rifampicin and isoniazid) thatare taken for 6 months, combined with two other drugs(pyrazinamide and ethambutol) during the first twomonths of treatment. In general, there is no differencein the treatment of TB patients with and without DM(4). There are significant interactions and side effectsof anti-tuberculosis therapy. Long-term anti-tuberculosis therapy interferes with bowelcarbohydrate absorption. Rifampicin is a potenthepatic enzyme-inducing agent; it increases hepaticmetabolism of several oral antidiabetic drugs,especially biguanides and sulfonylureas, andconsequently leads to great inter-individual variationsof their concentration in plasma, which makes doseadjustments difficult and increases patient risk ofhyperglycemia and hypoglycemia. Based on this fact,the use of sulfonylurea and biguanides iscontraindicated in patients with manifest TB. Also, theuse of rifampicin can increase the dose of insulinneeded to maintain normal blood glucose value (27).Patients with diabetes have by 53% lower exposurearea under curve (AUC; 0-6 h) to rifampicin thanpatients with TB without DM, especially ifoverweight, and may need a higher dose of rifampicin(28). Isoniazid antagonizes the action of sulfonylureas,
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impairs insulin release and action, and shortens plasmahalf-life of sulfonylureas (29). The dosage ofethambutol and pyrazinamide should be reduced withregard to renal function. Less is known about newerantidiabetic drug classes and no data have beenpublished on patients with TB treated with these drugs.Rifampicin probably has no effect on glucagon-likepeptide-1 receptor antagonist and has only a slighteffect on dipeptidyl peptidase-4 inhibitors (30);however, poor availability and high costs of thesedrugs restrict their use in TB endemic area. Thegeneral recommendation is that diabetics withmanifest TB should be treated with insulin injections(31,32). If a diabetic patient with TB is already takingoral antidiabetic drug, it is necessary to stop oraltherapy and start insulin therapy: basal bolus regimenor premixed insulin. Nevertheless, repeatedcounseling about lifestyle interventions (e.g.,nutrition, weight loss, smoking cessation and physicalactivity) should be performed. Monitoring of liver andkidney functions may need to be more intense than inpatients with TB only. After completion of TBtreatment, diabetics need continued diabetesmanagement and increased alertness for TB symptoms
because relapse is common in these patients(recurrence of former infection or re-infection with anew strain of TB) (6).
CONCLUSION
The relationship between TB and diabetes is bi-directional. Each disease worsens the outcome of theother. Tuberculosis screening in diabetic patients isrecommended in countries with a high prevalence ofTB. Screening for diabetes in patients with TB isrecommended for all adults older than 18 years,preferably by using OGTT and HbA1c. In patients withdiabetes, QFT is a significantly more sensitive test fordetection of M. tuberculosis than TST and can alsomore accurately predict progression of LTBI tomanifest tuberculosis. Anti-tuberculosis treatment(especially rifampicin and isoniazid) may interact withsome oral antidiabetic drugs, so diabetics withmanifest TB should be treated with insulin therapy.The association between diabetes and TB is the nextchallenge for global TB control.
REFERENCES
1. Restrepo BI. Convergence of the tuberculosis anddiabetes epidemics: renewal of old acquaintances.Clin Infect Dis 2007;45:436-438.
3. Das P, Horton R. Tuberculosis – time to accelerateprogress. Lancet 2010;375:1755-1757.
4. Riza AL, Pearson F, Ugarte-Gil C, Alisjahbana B,van de Vijver S, Panduru NM, et al. Clinicalmanagement of concurrent diabetes andtuberculosis and the implications for patientservices. Lancet Diabetes Endocrinol 2014;2:740-753.
5. Hrvatski zdravstveno-statistički ljetopis za
2013.godinu. Available at: http://hzjz.hr/wp-
content/uploads/2014/04/ljetopis_2013_.pdf. (in
Croatian)
6. Baker MA, Harries AD, Jeon CY, Hart JE, Kapur
A, Lonnroth K, et al. The impact of diabetes on
tuberculosis treatment outcomes: a systematic
review. BMC Med 2011;9:81.
7. Zhang Q, Xiao H, Sugawara I. Tuberculosis
complicated by diabetes mellitus at Shanghai
Pulmonary Hospital, China. Jpn J Infect Dis
2009;62:390-391.
8. Ruslami R, Aarnoutse RE, Alisjahbana B, van der
Ven AJ, van Crevel R. Implications of the global
increase of diabetes for tuberculosis control and
patient care. Trop Med Int Health 2010;15:1289-
1299.
9. Kumpatla S, Aravindalochanan V, Rajan R,
Viswanathan V, Kapur A. Evaluation of
performance of A1c and FPG tests for screening
newly diagnosed diabetes defined by an OGTT
among tuberculosis patients – a study from India.
Diabetes Res Clin Pract 2013;102:60-64.
10. WHO and International Union against TB and
Lung Disease. Collaborative framework for care
and control of tuberculosis and diabetes. Geneva:
World Health Organization, 2011.
11. Baghei P, Marjani M, Javanmard P, Tabarsi P,
Masjedi MR. Diabetes mellitus and tuberculosis
facts and controversies. J Diabetes Metab Disord
2013;12:58.
12. Ottmani SE, Murray MB, Jeon CY, Baker MA,
Kapur A, Lonnroth K, et al. Consultation meeting
on tuberculosis and diabetes mellitus: meeting
summary and recommendations. Int J Tuberc Lung
Dis 2010;14:1513-1517.
13. Pezo Nikolić B. Tuberkuloza i šećerna bolest. In:Popović-Grle S, editor. Tuberkuloza – ponovniizazov medicini na početku trećeg tisućljeća.Zagreb: Klinika za plućne bolesti “Jordanovac”,Ministarstvo zdravstva Republike Hrvatske,Institut Otvoreno društvo Hrvatska, 2004;75-77.(in Croatian)
14. Harries AD, Billo N, Kapur A. Links betweendiabetes mellitus and tuberculosis: should weintegrate screening and care? Trans R Soc TropMed Hyg 2009;103:1-2.
15. Nakamoto A, Saito A. Diagnosis and managementof tuberculosis in diabetics. NihonRinsho1998;56:3205-3208.
16. Shaikh MA, Singla R, Khan NB, Sharif NS, SaighMO. Does diabetes alter the radiologicalpresentation of pulmonary tuberculosis. SaudiMed J 2003;24:278-281.
18. Dooley KE, Tang T, Golub JE, Dorman SE, CroninW. Impact of diabetes mellitus on treatmentoutcomes of patients with active tuberculosis. AmJ Trop Med Hyg 2009;80:634-639.
19. Faurholt-Jepsen D, Range N, Praygod G, JeremiahK, Faurholt-Jepsen M, Aabye MG, et al. Diabetesis a risk factor for pulmonary tuberculosis: a case-control study from Mwanza, Tanzania. PloS One2011;6:e24215.
20. Baveja C, Nidhi V, Jain M, Jha H. Foot ulcercaused by multidrug-resistant Mycobacteriumtuberculosis in a diabetic patient. J Med Microbiol2010;59:1247-1249.
21. Menzies D. Interpretation of repeated tuberculintests: boosting, conversion, and reversion. Am JRespir Crit Care Med 1999;159:15-21.
22. CDC. Guidelines for Using the QuantiFERON-TBGold Test for Detecting Mycobacteriumtuberculosis Infection, United States. MMWR2005;54(RR15):49-55.
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23. Menzies D, Pai M, Comstock G. Meta-analysis:new tests for the diagnosis of latent tuberculosisinfection: areas of uncertainty andrecommendations for research. Ann Intern Med2007;146:340-354.
24. Kobashi Y, Mouri K, Obase Y, Fukuda M,Miyashita N, Oka M. Clinical evaluation ofQuantiFERON TB-2G test inimmunocompromised patients. Eur Respir J2007;30:935-950.
25. Diel R, Loddenkemper R, Meywald-Walter K,Niemman S, Nienhaus A. Predictive value of awhole-blood IFN-γ assay for the development ofactive TB disease. Am J Respir Crit Care Med2008;177:1164-1170.
26. Katalinić-Janković V. Mjesto mikrobiološkihmetoda u otkrivanju i praćenju tuberkuloze. In:Popović-Grle S, editor. Tuberkuloza – ponovniizazov medicini na početku trećeg tisućljeća.Zagreb: Klinika za plućne bolesti “Jordanovac”,Ministarstvo zdravstva Republike Hrvatske,Institut Otvoreno društvo Hrvatska, 2004;51-53.(in Croatian)
27. Atkin SL, Masson EA, Bodmer CW, Walker BA,White MC. Increased insulin requirement in apatient with type 1 diabetes on rifampicin [letter].Diabet Med 1993;10:392.
28. Nijland HM, Ruslami R, Stalenhoef JE, NelwanEJ, Alisjahbana B, Nelwan RH, et al. Exposure torifampicin is strongly reduced in patients withtuberculosis and type 2 diabetes. Clin Infect Dis2006;43:848-854.
29. Lebovitz HE. Oral hypoglycemic agents. In:Rifkin H, Porte Jr D, editors. Ellenberg andRifkins’s Diabetes mellitus: theory and practice,4th ed. New York: Elsevier; 1990;554-574.
30. Tornio A, Niemi M, Neuvonen PJ, Backman JT.Drug interactions with oral antidiabetic agents:pharmacokinetic mechanisms and clinicalimplications. Trends Pharmacol Sci 2012;33:312-322.
31. Rao PV. Persons with type 2 diabetes and co-morbid active tuberculosis should be treated withinsulin. Int J Diab Dev Ctries 1999;19:79-86.
32. Niazi AK, Kalra S. Diabetes and tuberculosis: areview of the role of optimal glycemic control. JDiabetes Metab Disord 2012;11:28.
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Subacute granulomatous thyroiditis is a transient,inflammatory thyroid condition presumed to be causedby viral infection or postviral inflammatory process.The anterior neck pain is the leading clinical feature inthe majority of patients. Patients have a higherythrocyte sedimentation rate and low thyroidradioactive iodine uptake values. The diagnosis ispredominantly based on clinical and laboratory data.Most patients need anti-inflammatory therapy with anonsteroidal anti-inflammatory drug or prednisone,and during the symptomatic thyrotoxic phase shouldreceive a beta blocker until the thyrotoxicosis phase isspontaneously resolved. During the hypothyroidphase, if the thyroid-stimulating hormone level isabove 10 mU per L, or if the patient has morepronounced symptoms of hypothyroidism,levothyroxine therapy should be given and usuallymay be discontinued after a few months. The long-term prognosis is excellent regarding thyroid function
and approximately 5% of patients have permanenthypothyroidism requiring long-term levothyroxinetherapy.
INTRODUCTION
Subacute granulomatous thyroiditis (SAGT) is atransient, self-limited, inflammatory thyroid conditionthat is presumed to be caused by viral infection orpostviral inflammatory process, predominantlyoccurring in genetically predisposed individuals.SAGT is also called de Quervain’s thyroiditis afterFritz de Quervain, a Swiss surgeon, who was the firstto describe the pathology of SAGT in 1904. Thedisease is often preceded by upper respiratory tractviral infection and many viruses have been implicatedincluding Coxsackie, mumps, adenovirus, influenza,and others (1). The overall age- and sex-adjustedincidence rate from 1960 through 1997 was 4.9 casesper 100,000/year, but in the most recent years of thesurvey the incidence rate was 3 cases per 100,000 peryear (2). Most often, SAGT occurs at 40-50 years ofage (2), and it affects women three to five times moreoften than men (2,3). The significant seasonal clustersof cases were noticed during the summer and earlyautumn (4), but not all studies are consistentconsidering seasonal development of the disease.
110Diabetologia Croatica 42-4, 2013
Division of Endocrinology, Vuk Vrhovac University Clinic,Merkur University Hospital, Zagreb, Croatia
Review
SUBACUTE GRANULOMATOUS THYROIDITIS
K. Peroš, D. Majić Milotić, M. Šunjić Stakor, V. Đermanović Dobrota
Corresponding author: Kristijan Peroš, MD, Division of Endocrinology, VukVrhovac University Clinic, Merkur University Hospital, Dugi dol 4a, HR-10000 Zagreb, Croatia
In all ethnic groups tested, there is an associationbetween SAGT and human leukocyte antigen (HLA)B35, and approximately two-thirds of patientsmanifest HLA-B35 (5). Also, familial occurrence ofSAGT is associated with HLA-B35 (6). In patientswho are carriers of HLA-B35 antigen, thyroid injuryin SAGT is considered to be the result of binding ofviral antigen and HLA-B35 molecules onmacrophages creating a complex that activatescytotoxic T-lymphocytes. Consequently, becausethyroid cells share partial structural similarity with theinfection related antigen, thyroid follicular celldestruction occurs, so thyroxine (T4) andtriiodothyronine (T3) are released into the circulationas long as the stores of thyroglobulin are exhausted.The resulting increase in serum thyroid hormoneconcentration leads to decreased serum concentrationof thyroid-stimulating hormone (TSH) and newhormone synthesis is postponed not only because ofthyroid follicle destruction but also because of lowlevel of TSH. After the inflammation subsides, newhormone synthesis resumes and this period may lastfor several months.
CLINICAL COURSE
The clinical course of SAGT is highly variable.Typically, SAGT begins with a prodrome of fatigue,myalgia, fever and pharyngitis, and then the patientpresents with severe pain in the neck (7). The anteriorneck pain is the leading clinical feature in the majorityof patients (2), and results from stretching of thethyroid capsule due to the underlying inflammatoryprocess (8). It can be unilateral or bilateral and mayirradiate to adjacent structures. Thyroid gland istypically enlarged and tender, so some patients cannottolerate even slight palpation of the neck. Manypatients, before they reach the endocrinologist, havealready received antibiotic therapy because it waswrongly assumed that they had bacterial pharyngitis.Also, some patients are referred to the dentist becauseof suspected toothache; some of these referrals resultin extractions of healthy teeth. In the majority ofpatients, thyroid function tests characteristically
evolve through the phase of thyrotoxicosis, followedby hypothyroid phase and finally euthyroid phase. Inthe initial, destructive phase, the patient hasbiochemical findings of thyrotoxicosis and up to 50%of patients have symptoms and signs of thyrotoxicosis;this phase lasts for up to three months (7).Hypothyroid phase may or may not be accompaniedwith symptoms and signs of hypothyroidism and mayalso last for several months. There are many casereports of SAGT in patients that had atypical clinicalpresentation including thyroid mass, vocal cordparalysis and hypercalcemia (9), morning stiffness insmall joints of the hand, intermittent abdominal pain,malaise, fever, and myalgia without neck pain (10), oracute psychosis (11).
DIAGNOSIS
Diagnosis of SAGT is predominantly based onclinical and laboratory data. The patient has a higherythrocyte sedimentation rate (ESR), usually between50 and 100 mm/hour, and low thyroid radioactiveiodine uptake values. Low radioactive iodine uptake isindicating damage to the gland, as well as suppressedvalues of TSH in serum (12). The characteristicultrasound findings in this disease are ill-definedhypoechoic areas with a nonhomogeneous pattern(13), and, rarely, SAGT may present as a solitarynodule. In patients with SAGT, color-flow dopplerultrasonography shows low-to-normal vascularity(14). Tissue diagnosis is rarely needed (15), but ifdone, thyroid cytology reveals multinucleate giantcells and epithelioid granulomas in all patients (16). Inthe initial phase of the disease, thyroid function testsshow suppressed TSH and increased T4 and T3 levelsdue to the release of preformed hormones into thecirculation; afterwards, there is a thyroid hormonedecline, usually below the lower limit of normal, whileTSH level becomes increased; finally, normalizationof thyroid function is seen in approximately 95% ofpatients. Thyroid function tests should be checkedevery two to four weeks in order to monitor thedynamics of hormonal findings and subsequentnormalization of thyroid function. Most patients alsohave an elevated serum C-reactive protein level (17),as this disease represents an inflammatory condition.
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Rare patients have transiently detectable antithyroidperoxidase or antithyroglobulin antibodies in serumdue to the release of thyroid antigens during the periodof inflammation. Approximately 50% of patients haveelevated aminotransferase and alkaline phosphatase(ALP). Quantification of ALP isoenzymes inthyrotoxicosis has shown this increase to be of onlyliver origin in some patients, of only bone origin inother patients, and sometimes of both liver and boneorigin (18). There are suggestions by some authors thatthe elevation of liver biochemical tests inthyrotoxicosis is caused by hepatic ischemia due toincreased metabolism (19), but others consider it aspart of the diffuse inflammatory process.
DIFFERENTIAL DIAGNOSIS
Subacute granulomatous thyroiditis is the mostcommon cause of thyroid pain (2) but one shouldalways consider other possible causes of thyroid pain.Acute thyroiditis is a very rare condition that can becaused by all kinds of pathogens other than viruses. Itshould be suspected if the patient also has leukocytosisand predominantly unilateral pain with a cystic orcystic/solid mass on ultrasound that may represent anabscess. To confirm this disease, fine needle aspirationbiopsy is required. Hemorrhage into a thyroid nodulemay also present as unilateral pain or discomfort; inthese patients, ESR is normal, and thyroid ultrasoundexamination is helpful in distinguishing theseconditions. Fast-growing primary thyroid cancer orprimary thyroid lymphoma may also present with painin the thyroid area and thyroid ultrasound examinationmay be helpful again. Few patients with Hashimoto’sthyroiditis and Graves’ disease may have neck painand tenderness, although they have pain of muchlower intensity than is the pain in SAGT; radioactiveiodine uptake in patients with Graves’ disease is highin contrast to patients with SAGT.
TREATMENT
The goal of treatment of SAGT is to provide thyroidpain relief and ameliorate symptoms of thyrotoxicosis,if present. Most patients need anti-inflammatory
therapy with a nonsteroidal anti-inflammatory drug orprednisone (20). In patients with mild and moderateforms of the disease, acetylsalicylic acid in a dose of2.6 grams per day in divided doses (21) is efficacious.However, according to clinical experience of theauthors, the efficacious dose in most patients may bemuch lower (for example, 3x300 mg daily). Ibuprofenin a dosage of 1200 to 3200 mg per day in divideddoses also proved its efficacy in reducing pain in thethyroid. If nonsteroidal anti-inflammatory drug fails toprovide pain relief over several days, it should bediscontinued and corticosteroid therapy should beinitiated. Corticosteroids are very efficacious inrelieving thyroid pain promptly, within 24-48 hours(21). If pain still exists after 48 hours of initiatingprednisone therapy, the patient probably does not haveSAGT. Initial dose of prednisone is 40 mg daily (21)and after the pain has been relieved, the dose ofprednisone should be reduced by 5-10 mg every 7days; it usually may be completely discontinued after4-6 weeks. If thyroid pain reappears during theprednisone dose reduction, the dose should beincreased to the prior dose and maintained for twoweeks and then more gradually reduced. In patientswith severe thyroid pain, prednisone may also be first-line therapy. During the biochemical phase ofthyrotoxicosis, approximately 50% of patients havesymptoms and signs of thyrotoxicosis and shouldreceive a beta blocker until the thyrotoxicosis phase isspontaneously resolved (e.g., propranolol 40 to 120mg daily in divided doses or atenolol 25 to 50 mgdaily). In the hypothyroid phase, if the TSH level isabove 10 mU per L, or if the patient has morepronounced symptoms of hypothyroidism, levo -thyroxine therapy should be given (e.g., 25-100 mcgdaily) and usually may be discontinued after severalmonths.
LONG-TERM OUTCOME
Subacute granulomatous thyroiditis recurs in about2% of patients (22), and recurrence during the courseof time is associated with HLA-B35 (23). Thyroidfunction spontaneously normalizes in 95% of patients
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within one year, but approximately 5% of patientshave permanent hypothyroidism (24) requiring long-term levothyroxine therapy.
CONCLUSION
In conclusion, SAGT is a relatively rare thyroiddisease that should be suspected if the patient hassevere anterior neck pain, especially if havingprodromal symptoms (malaise, myalgia and fever).
High ESR, characteristic ultrasound findings and lowthyroid radioactive iodine uptake values are veryhelpful in establishing the correct diagnosis; tissuediagnosis is rarely needed. Most patients requiresymptomatic therapy. In the great majority of patients,thyroid function spontaneously normalizes and nolong term-therapy is required.
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REFERENCES
1. Desailloud R, Hober D. Viruses and thyroiditis: anupdate. Virol J 2009;6:5.
2. Fatourechi V, Aniszewski JP, Fatourechi GZ,Atkinson EJ, Jacobsen SJ. Clinical features andoutcome of subacute thyroiditis in an incidencecohort: Olmsted County, Minnesota study. J ClinEndocrinol Metab 2003;88:2100-2105.
3. Erdem N, Erdogan M, Ozbek M, Karadeniz M,Cetinkalp S, Ozgen AG, et al. Demographic andclinical features of patients with subacutethyroiditis: results of 169 patients from a singleuniversity center in Turkey. J Endocrinol Invest2007;30:546-550.
4. Nishihara E, Ohye H, Amino N, Takata K,Arishima T, Kudo T, et al. Clinical characteristicsof 852 patients with subacute thyroiditis beforetreatment. Intern Med 2008;47:725-729.
5. Nyulassy S, Hnilica P, Buc M, Guman M,Hirschová V, Stefanovic J. Subacute (deQuervain’s) thyroiditis: association with HLA-Bw35 antigen and abnormalities of thecomplement system, immunoglobulins and otherserum proteins. J Clin Endocrinol Metab1977;45:270-274.
6. Kramer AB, Roozendaal C, Dullaart RP. Familial
occurrence of subacute thyroiditis associated with
human leukocyte antigen-B35. Thyroid
2004;14:544-547.
7. Pearce NE, Farwell AP, Braverman LE.
Thyroiditis. N Engl J Med 2003;348:2646-2655.
8. Meier DA, Nagle CE. Differential diagnosis of a
tender goiter. J Nucl Med 1996;37:1745-1747.
9. Huang C, Wang X. Subacute thyroiditis
manifesting as a thyroid mass, vocal cord
paralysis, and hypercalcemia. Endocr Pract
2012;18:e17-20.
10. Peroš K, Božek T, Prkačin I, Stakor SM, Žmire J.
An unusual clinical presentation of subacute
granulomatous thyroiditis. Acta Clin Croat
2013;52:380-382.
11. Lee KA, Park KT, Yu HM, Jin HY, Baek HS, Park
TS. Subacute thyroiditis presenting as acute
psychosis: a case report and literature review.
Korean J Intern Med 2013;28:242-246.
12. Cooper SD. Hyperthyroidism. Lancet
2003;362:459-468.
13. Park SY, Kim EK, Kim MJ, Kim BM, Oh KK,Hong SW, et al. Ultrasonographic characteristicsof subacute granulomatous thyroiditis. Korean JRadiol 2006;7:229-234.
14. Hiromatsu Y, Ishibashi M, Miyake I, Soyejima E,Yamashita K, Koike N, et al. Color Dopplerultrasonography in patients with subacutethyroiditis. Thyroid 1999;9:1189-1193.
15. Ross D. Syndrome of thyrotoxicosis with lowradioactive iodine uptake. Endocrinol Metab ClinNorth Am 1998;27:169-185.
16. Joy J, Upadhyaya K. Clinical andcytomorphological study of de Quervain’sthyroiditis. Int J Biomed Res 2014;9:559-562.
17. Pearce EN, Bogazzi F, Martino E, Brogioni S,Pardini E, Pellegrini G, et al. The prevalence ofelevated serum C-reactive protein levels ininflammatory and noninflammatory thyroiddisease. Thyroid 2003;13:643-648.
18. Tibi L, Patrick AW, Leslie P, Toft AD, Smith AF.Alkaline phosphatase isoenzymes in plasma inhyperthyroidism. Clin Chem 1989;35:1427-1430.
19. Aydemir S, Bayraktaroglu T, Demircan N, Sert M,Acikgoz S, Tekin IO, et al. Effect of hyperthyroidand propylthiouracil treatment on liverbiochemical tests. Int J Clin Pract 2005;59:1304-1308.
20. Yamamoto M, Saito S, Sakurada T, Fukazawa H,Yoshida K, Kaise K, et al. Effect of prednisoloneand salicylate on serum thyroglobulin level inpatients with subacute thyroiditis. Clin Endocrinol(Oxf) 1987;27:339-344.
21. Volpe R. The management of subacute (deQuervain’s) thyroiditis. Thyroid 1993;3:253-255.
22. Iitaka M, Momotani N, Ishii J, Ito K. Incidence ofsubacute thyroiditis recurrences after a prolongedlatency: 24-year survey. J Clin Endocrinol Metab1996;81:466-469.
23. Yamamoto M, Saito S, Sakurada T, Tamura M,Kudo Y, Yoshida K, et al. Recurrence of subacutethyroiditis over 10 years after the first attack inthree cases. Endocrinol Jpn 1988;35:833-839.
24. Kitchener MI, Chapman IM. Subacute thyroiditis:a review of 105 cases. Clin Nucl Med1989;14:439-442.
114Diabetologia Croatica 42-4, 2013
K. Peroš, D. Majić Milotić, M. Šunjić Stakor, V. Đermanović Dobrota / SUBACUTE GRANULOMATOUS THYROIDITIS
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DIABETOLOGIA CROATICA publishes origi nal articlesfrom the fields of diabetology, endocrinology and metabolicdisturbances, as well as papers intended for the education ofmedical personnel in the areas. It is printed in English.
ARTICLES submitted for publication should con tain originalinformation not previously published or submitted forpublication elsewhere.
MANUSCRIPTS. Original manuscripts in English should betypewritten, double-spaced and pages numbered consecutivelyin the following order: Title page containing the title of the article, the name(s) of theauthor(s) including the first name and highest academicdegree(s), the name of department and institution in which thework was done, and the address for correspondence, includingtelephone and/or fax number and e-mail address. Summary and Key Words should be written on a separate page.
Text should be divided into following sections:
• Summary: should not contain more than 150 words,stating the purpose of the study, basic procedures, mainfindings with specific data and their statistical significance,and the principal conclusions. Summary should befollowed by 3 to 10 key words or short phrases based onMedical Subject Headings list from Index Medicuswhenever possible.
• Introduction: concisely indicate the importance of thework, its relation to previous work and (if it is a method)reasons why it is preferable to other methods.
• Materials and methods: describe the selection ofsubjects. Identify the methods, apparatus (includingmanufacturer’s name and address) and procedures.
• Results: present your results in concise language andlogical sequence, using tables and illustrations if necessary.
• Discussion: discuss significance of the results andemphasize conclusions that follow from them. Results andconclusions should be compared and contrasted with thoseof comparison methods or previous studies.
• References:
REFERENCES should be numbered consecutively as they arecited in the text. They must be indicated by Arabic numerals.References cited only in tables or figure legends should benumbered in accordance with the sequence established in thetext. Journal abbreviations should be those of the List of
Journals Indexed for MEDLINE. List the first six authorsfollowed by "et al." when there are seven or more. Examples ofreferences:
Examples of references:
• Journals Pepeonik-Rogulja Z, Pinter S, Metelko Z. Canthe age at diagnosis of type 1 diabetes mellitus affect thecourse of diabetic retinopathy. Diabetologia Croatica2004;33:97-101.
• Books International Diabetes Federation. Diabetes Atlas,3rd ed. Brussels: International Diabetes Federation; 2006.
• Chapter in Book Reaven GM. Insulin resistance and itsconsequences: type 2 diabetes mellitus and the insulinresistance syndrome. In: LeRoith D, Taylor SI, OlefskyJM, editors. Diabetes mellitus: a fundamental and clinicaltext. 3rd ed. Philadelphia: Lippincott Williams & Wilkins;2004. pp. 899-915.
• Electronic Material Gazzaruso C, Garzaniti A,Giordanetti S, Falcone C, Fratino P. Silent coronary arterydisease in type 2 diabetes mellitus: the role oflipoprotein(a), homocysteine and apo(a) polymorphism.Cardiovasc Diabetol [Internet] 2002 Nov [accessed 2002Dec 9];1(5). Available from: URL:http://www.cardiab.com/content/1/1/5
TABLES should be typed double spaced on separate sheets.Each should be provided with a brief title. Each column shouldhave a heading with clearly defined units. All non-standardabbreviations should be explained in footnotes.
ILLUSTRATIONS. Figures should be professionally drawnand photographed. Glossy black-and-white prints are requested.Each figure should have a label on its back indicating thenumber of the figure, the names of authors and the top of thefigure. Figures should be cited in the text in consecutive order.Illustration legends should be typewritten on a separate sheet ofpaper.
REVIEW AND PUBLICATION. The manuscripts arereviewed anonymously. If the article is not accepted forpublication or certain alternations or additions are suggested, acopy of the review, without the name of the reviewer, will besent to the author for final decision. The editorial board is notobliged to publish articles in the order they are received.Manuscripts are not returned and all printed supplementsbecome the property of the medical-scientific journalDiabetologia Croatica.
INSTRUCTIONS TO AUTHORS
Submission of Manuscripts in Electronic FormatDiabetologia Croatica welcomes the submission of manuscripts in electronic format. The text stored as electronic file will be useddirectly for typesetting. Manuscripts should be submitted as e-mail attachments or CD-ROMs. Figures and legends should be sentas separate files. Any major word processing program that works on IBM or IBM-compatible computers is acceptable.
All manuscripts are to be forwarded to the Editorial Board’s address:Tel:(385-1) 2 35 38 00
