Appendicitis

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Sofii et al, Comparison of the diagnostic test of leukocyte count, percentage of neutrophyl, and CRPBerkala Ilmu KedokteranVol. 39, No. 1, Maret 2007: 37-45

Imam Sofii, Agus Barmawi, Ishandono Dachlan, Surgery Department,Faculty of Medicine, Gadjah Mada University/Dr. Sardjito Hospital, Yogyakarta

Comparison of the diagnostic test ofleukocyte count, percentage of neutrophyl,and C-reactive protein (CRP) in adultpatients with simple and complicatedacute appendicitis

Imam Sofii, Agus Barmawi, Ishandono DachlanSurgery Department,Faculty of Medicine, Gadjah Mada University/Dr. Sardjito Hospital, Yogyakarta

ABSTRACT

Background: acute appendicitis is one of the acute abdomen conditions that needs an emergency surgicalprocedure to prevent severe complication. If the perforation is present, the complications are generalperitonitis, abscess and postoperative complication such as fistula and operative wound infection. Latediagnosis can increase the mortality and morbidity. There are about 11.2%-30% cases with intestinalperforation caused by late diagnosis. The leukocyte count, percentage of neutrophyl and C-reactive protein(CRP) are valuable informations to diagnose the perforation and nonperforation acute appendicitis in adultpatients.Method: a prospective cross sectional study was held on diagnostic test from patient’s database for acuteappendicitis cases in Digestive Surgery Subdivision of Dr Sardjito Hospital from December 2005 untilOctober 2006. The data was classified as simple and complicated acute appendicitis based on thehistopathology result. Eighty two were found for both groups which fulfilled the inclusion and exclusioncriteria. The diagnostic test i.e. sensitivity, specificity, Positive Predictive Value (PPV), Negative PredictiveValue (NPV), Likelihood Ratio (LR+), Likelihood Ratio (LR-), accuracy and receiver operating characteristics(ROC) with area under the curve (AUC) were analyzed for the leukocyte count, neutrophyl, and C-reactiveprotein (CRP) in each group with histopathology result as a gold standard.Result: the leukocyte count, neutrophyl and C-reactive protein (CRP) had respectively sensitivity of: 70,07%;74,54%; 89,09%; specificity 70,37%; 70,37%; 81,48%; Positive Predictive Value (PPV): 82,97%;83,67%; 90,74%; Negative Predictive Value (NPV) 54,28%; 57,57%; 78,57%; Likelihood Ratio (LR+)2,36%; 2,51%; 4,56%, Likelihood Ratio (LR-) 0,42%; 0,22%; 0,13%, area under the curve (AUC)0,797; 0,744; 0,891, and accuracy 70,73%; 73,17%, 86,56%.Conclusion: C-reactive protein (CRP) was a better diagnostic test to differ simple from complicated acuteappendicitis in adult patient compared to leukocyte count and neutrophyl.

Key word: simple and complicated acute appendicitis, leukocyte count, neutrophyl, C - reactive protein(CRP).

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Berkala Ilmu Kedokteran, Volume 39, No. 1, Maret 2007: 37-45

ABSTRAKImam Sofii, Agus Barmawi, Ishandono Dahlan: Uji diagnostik jumlah leukosit, persentase neutrofil, danCRP pada apendisitis komplikata dan simpleks pasien dewasa.

Latar belakang. Apendisitis akut merupakan salah satu keadaan abdomen akut yang memerlukan tindakanbedah darurat untuk mencegah komplikasi. Jika terdapat perforasi, maka komplikasi yang timbul adalahperitonitis general, abses, dan komplikasi pasca operasi seperti fistula dan infeksi luka operasi. Diagnosisterlambat meningkatkan mortalitas dan morbiditas. Sekitar 11,2–30% kasus apendisitis akut denganperforasi disebabkan oleh keterlambatan diagnosis. Persentase leukosit, neutrofil, dan CRP adalah informasiyang sangat berharga untuk mendiagnosis apendisitis akut perforasi atau nonperforaasi pada pasien dewasa.Tujuan. Penelitian ini dimaksudkan untuk mengetahui nilai diagnostik dari jumlah leukosit, persentaseneutrofil, dan CRP pada apendisitis akuta simpleks dengan apendisitis komplikata pasien dewasa.Bahan dan cara. Dilakukan studi secara potong lintang prospektif mengenai uji diagnostik dari databasepasien apendisitis akut di Subdivisi Bedah Digestif Rumah Sakit Dr. Sardjito dari Desember 2005 – Oktober2006. Data dikelompokkan sebagai appendicitis akut simpleks dan komplikata berdasarkan hasil pemeriksaanhistopatologi. Didapatkan 82 pasien dari kedua kelompok yang memenuhi kriteria inklusi dan eksklusi (27komplikata dan 55 simpleks). Dilakukan peprhitungan sensitivitas, spesifisitas, nilai ramal positif (NRP),nilai ramal negatif (NRN), likelihood ratio (LR) positif dan negatif, akurasi, dan receiver operating procedure(ROC) dengan area under curve (AUC) untuk jumlah leukosit, neutrofil, dan CRP pada tiap kelompokdengan hasil histopatologi sebagai baku emas.Hasil. Didapatkan jumlah leukosit, persentase neutrofil, dan CRP berturut-turut mempunyai sensitivitas70,0%, 74,54%, dan 89,09%; spesifisitas 70,37%, 70,37%, dan 81,48%; NRP 82,97%, 83,67%, dan90,74%; NRN 54,28%, 57,57%, dan 78,57%; LR+ 2,36%, 2,51%, dan 4,56%; LR- 0,42%, 0,22%,dan 0,13%; AUC 0,797, 0,744, dan 0,891; akurasi 70,73%, 73,17%, dan 86,56%.Simpulan. CRP merupakan uji diagnostik yang lebih baik untuk membedakan apendisitis akut simpleksdengan komplikata pada pasien dewasa di banding jumlah leukosit dan persentase neutrofil.

INTRODUCTION

Acute appendicitis is an acute abdomencondition which an immediate surgery is needed toprevent a worse complication. If a perforationoccurred, then complication could happen like ageneral peritonitis, an abscess, and postoperationcomplication such as fistula and surgical woundinfection1.2.

Appendicitis is one of the emergency diseasesin surgery. Acute appendicitis incidence walks inline with its lymphoid, with its peak on young adults.Davies (1997) in his studies in 22 American Statesfound appendicitis was 0.6% (252,682 cases) fromall the treated patients, with an average of 4 daytreatment, and 3 billion dollar total cost. The numberof treatment days will increase abscess appendicitiscase, peritonitis and postoperation infection1.3.

Factors that influence the delay of acuteappendicitis management which resulted incomplication could be originated from the patientsor medical hands. The patients’ factor is theknowledge and cost. As the medical hands factorare wrong diagnosis, postponing diagnosis, latenessin sending to the hospital, and postponing surgery3.

The accurate level of acute appendicitisdiagnosis in some studies is around 76% - 92%.The lateness of diagnosis could increase the numberof mortality and morbidity. There is a 11.2% - 30%of late diagnosis resulting in intestinal perforation,surgical wound infection increased to 17.5%, andabdominal abscess 15.5%. This condition increasespostoperation complication such as adhesion, social-economical burden consequence, lost of workingdays and productivity. A simple acute appendicitismortality rate is less than 1% (0.12%-0.27%) andbecoming 2.4% if perforation occurred. Themortality would also be increased in the elderly.The effort to increase the accurate diagnosis foracute appendicitis means to decrease morbidity,mortality and to increase the quality of life post-appendectomy4.5.6.

Basic laboratory examination could be used inacute appendicitis diagnosis. The values of leukocyte,the percentage of neutrophyl polymorphonuclearcell, and C-reactive protein (CRP) are signs whichcan be sensitive in inflammation process. Thisexamination is quite easy, quick, and cheap for aDistrict Hospital7.8.

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Sofii et al, Comparison of the diagnostic test of leukocyte count, percentage of neutrophyl, and CRP

Generally, leukocyte increases on acuteappendicitis. The value of leukocyte 11000-14000per mm3 occurred in simple appendicitis andleukocyte more than 18000 per mm3 showed thepresence of perforation/complication. The increas-ed leukocyte showed the presence of bacterialinfection rather than viral. The protein involved inthis acute phase response is called acute phaseprotein. CRP is one of the phase component ofacute protein which will be increased 4-6 hours (inother studies 6-12 hours) after the inflammationprocess, seen by serum protein electrophoresisexamination9.10.

This study’s aim is to know the sensitivity andspecificity of the leukocyte value as diagnosis test,neutrophyl, and CRP in simple acute appendicitisand complicated appendicitis in adult patientsuspected of acute appendicitis. The benefit of thisstudy is to be able to consider the appendix conditionbefore surgical, thus can give the right and clearinformation to the patient and family concerningthe disease, what should be do, and its prognosis. Itis expected decreasing the morbidity and mortality.

MATERIALS AND METHOD

A prospective cross sectional diagnostic teststudy was done on patients with acute appendicitisin Digestive Surgery, Dr. Sardjito General Hospital,

Yogyakarta from October 2005 until August 2006.Data were grouped according to simple acuteappendicitis classification and complication basedon histopathology results. 82 samples wereobtained in both groups which fulfill the inclusionand exclusion criteria. Sensitivity, specificity, positivepredictive value (PPV), negative predictive value(NPV), positive likelihood ratio (LR +), negativelikelihood ratio (LR -), accuracy and the receiveroperating characteristics (ROC) with an area underthe curve, were calculated based on the data:leukocyte value, neutrophyl, and C-reactive protein(CRP) of each groups with a histopathology resultas gold standard. To know the relation betweenoutside variable with sample, a statistical Mann-Whitney test was done.

RESULT

From the study done between December 2005until October 2006 on patients who came toEmergency Unit of Dr. Sardjito General Hospital,those suspected suffered from acute appendicitisand had laboratory examination leukocyte value andCRP were 82 patients. All patients had appendec-tomy and the appendixes were sent for histo-pathology examination.

Out of 82 study samples, there were male(54.87%) slightly greater compared to female

TABEL 1.The Relation between sex and age with acute appendicitis histopathology result

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(45.12%) with a ratio of 1.21: 1. This result showedthat there was no distribution difference in the totalsample according to sex (p > 0.05). The averageage for simple acute appendicitis was 30.45 +12.083 years and complicated acute appendicitiswas 35.22 + 14.136 years. There was a slightdifference in the average age of patients with simpleand complicated acute appendicitis. This result was

TABLE 2. The relation between the history of treatment and duration of illness with acute appendicitis histopathology result.

RR: relative risk; CI: Confidence Interval; SD: Standard Deviation, *antibiotic

statistically had no significant difference (p > 0.05).If the sample age was grouped into < 45 years and> 45 years, the result was relatively no differencebetween simple and complicated acute appendicitis.The risk of complicated acute appendicitis at theage of > 45 years is 1.24 times compared to theage < 45 years (RR: 1.24; CI: 0.70-2.20).

TABLE 2, showed that the average durationof illness of simple acute appendicitis patients was21.24+20,80 hours (1.33+0.67 days) and complicat-ed acute appendicitis 42.15+26.29 hours (2.11+0.80days). This result showed a significant differencebetween both group (p < 0.05). As many as 33patients (40.25%) had treatment history before: 21patients (25.60%) with simple acute appendicitisand 12 patients (14.63%) with complicated acuteappendicitis. This result showed no significant

difference statistically (p > 0.05). From 33 patients,those who had treatment history were patientstaking medicine (antibiotic) < 12 hours beforelaboratory examination were 14 patients (42.42%)and > 12 hours 19 patients (57.57%). This resultdid not show a significant difference statistically (p> 0.05).

TABLE 3 shows the result of leukocyte,neutrophyl and CRP cut off point compared tohistopathology result of simple and complicatedacute appendicitis. The cut off point of leukocytewas 15200 per mm3, neutrophyl 86.5% and CRP92 mg/L. The cut off point showed high sensitivityand specitivity.

TABLE 4 shows the result that leukocyte valueof 15200 per mm3, has a sensitivity value of 70.07%,specificity 70.37%m positive predictive value (PPV)82.97%, negative predictive value (NPV) 54.28%,the likelihood ratio (LR+) 2.36%, the likelihood ratio(LR-) 0.42%; and accuracy 70.73%.

TABLE 5 showed that neutrophyl value 86.5%had the best diagnostic values i.e. sensitivity74.54%, specificity 70.37%, positive predictivevalue (PPV) 83.67%, negative predictive value

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TABLE 3. The Relation of leukocyte, neutrophyl and CRO values with histopathology of simpleand complicated appendicitis.

(NPV) 57.57%, likelihood ratio (LR+) 2.51%,likelihood ratio (LR) 0.22%, and accuracy 73.17%.

TABLE 6 shows that CRP value 92 mg/L hadsensitivity value of 89.09%, specificity 81.48%,

positive predictive value (PPV) 90.74%, negativepredictive value (NPV) 78.57%, likelihood ratio(LR+) 4.56%, likelihood ratio (LR) 0.13%, andaccuracy 86.56%, the best compared to the others.

TABLE 4. The Relation of Leukocyte value with simple and complicated acute appendicitis

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TABLE 5. The diagnostic of neutrophyl value with simple and complicated acute appendicitis

TABLE 7 shows the result of area under thecurve (AUC) which was obtained from the graphic.

TABLE 6. The Relation of CRP value with simple and complicated acute appendicitis

TABLE 7. The Result of Area Under the Curve (AUC) leukocyte, neutrophyl and CRP

The AUC of leukocyte, neutrophyl, and CRP were0.797, 0.744 and 0.891.

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FIGURE 1. Receive Operating Characteristik (ROC)leukocyte, neutrophyl and CRP value to the result of

acute appendicitis histopathology.

Figure 1 shows a Receiver Operating Characte-ristics (ROC) that illustrates the relation betweensensitivity and specificity values of leukocyte,neutrophyl and CRP.

DISCUSSION

The history and physical examination are still basicdiagnosis of acute appendicitis. Although there are nosymptoms or clinical signs that can predict accuratelythis acute appendicitis, but the combination betweensymptoms and signs can support a more accuratediagnosis. The presence of pain and tenderness onthe right bottom part, migration pain accompanied byinflammation signs, the increase of temperature,leukocytes and CRP serum should suspect the pre-sence of acute appendicitis. No signs of inflammationis still a doubtful diagnosis of appendicitis (positivelyfake). The diagnosis of acute appendicitis is sometimesdifficult for infant or elderly patients, thus the numberof complication increases more 8.11.

Chung & Lai (2000) studied on the latenessdiagnosis of acute appendicitis caused by patients,treated in the emergency unit and the surgeon. It wasfound that this lateness was caused by patient factorin 65 complicated appendicitis cases from 140 cases(46.4%). The rate of the simple acute appendicitispatients who were admitted in the hospital was 24.9hours and for complicated acute appendicitis 42.0hours. The rate of lateness caused by the treatmentin the emergency unit on acute appendicitis 5.8 hours

and complicated appendicitis 17.9 hours. The rateof lateness caused by treatment by a surgeon onacute appendicitis was 10.9 hours and complicatedappendicitis 16.3 hours 6.12.

Antibiotic administration can decrease the numberof complication caused by acute appendicitis. Everson(1977) in his control study found that 16 out of 19cases (84.2%) experienced complication withoutsystemic antibiotic administration, compared to 9 from30 cases (30%) experienced complication by systemicantibiotic administration (Ellis, 1989)1.

Styrud (2006) in his randomized controlledtrial (RCT) study compared the usage of antibioticand appendectomy on acute appendicitis. As manyas 252 subjects with a suspect on acute appendicitiswas male with the age of 18-50 years. There were124 subjects in which appendectomy was done, 92%were simple acute appendicitis, 5% perforatedappendicitis, the rest were with normal appendix, and14% postsurgery complications. As many as 128subjects were administered intravenous antibiotic for2 days and oral as long as 10 days. There were 111samples (86%) recovered without appendectomy, 18samples (14%) were appendectomy for 24 hoursobservation, and 15 samples (16%) appendectomywas done with 1 year follow up. There were 6 cases(5.4%) experienced perforated acute appendicitis13.

The number of complicated acute appendicitisdepends on a lot of factors. Complicated acuteappendicitis in children is 19.0% and adult 13.8%. Thecondition of complicated acute appendicitis in childrenat the ages of < 6 years and adults >60 years, this isnearly the same as 10% and 9%. Lee (2006) withsimple acute appendicitis 6.6% and the complicatedone 14.6%. Kozar & Roslyn (1999) found thenumber of simple acute 70%, complicated 16% andthe rest is normal appendix2.

Inflammation factor has long been used toincrease the accuracy of the diagnosis of acuteappendicitis. A lot of studies can be found on sensitivity,specificity, inflammation factor such as leukocyte,neutrophyl and CRP completed by cut off point andROC. Laboratory examination is much used ROCgraphicas well because its cheapness of its easy waywith an exact result, and it is widely available inhospitals mainly in small cities14.

Korner et al (1999), found an accurate resultbased on clinical symptoms in emergency unitbetween 70%-80%. To increase accuracy of acute

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appendicitis diagnosis, an examination of leukocyte,neutrophyl and CRP values is beneficial. Kornergot the result that the perforation appendicitis casewas 49 from 434 cases (11%). The cut off pointfor perforation acute appendicitis case was 17200per mm3, with sensitivity and specificity values were71% and 61%, AUC was 0.66. The cut off pointfor neutrophyl perforation acute appendicitis was89%, with a value of sensitivity and specificity 88%and 46%, AUC was 0.68. The cut off point forCRP perforated acute appendicitis was 101 mg/L,with sensitivity and specificity 79% and 47%, AUCwas 0.604.

Gronroos & Gronroos (1999) compared leuko-cyte and CRP value in simple, complicated acuteappendicitis case and normal appendix on 300patients. In the study the cut off point result ofleukocyte and CRP values of complicated acuteappendicitis were 14300 per mm3 and 99 mg/L. Inthis study the sensitivity and specificity were notmentioned15.

Andersson (2004) in a 24 meta-analysis studyfound a result that clinical variables, i.e. peritonealirritation symptoms (suppressed pain, loss-pressedpain, local tenderness and muscular defense) andmoving pain were the main discriminate variable in

acute appendicitis with an UAC 0.78 and 0.68.Leukocyte, neutrophyl and CRP values had a highaccuracy mainly in perforated acute appendicitisUAC between 0.85-0.87. Andersson also found resultthat perforated appendicitis showed leukocyte cut offpoint value 15000 per mm3, with LR+ 7.20%, withLR- 0.66%, and UAC 0.85. The neutrophyl cut offpoint value in perforated acute appendicitis was90% with a positive likelihood ratio (LR-) 0.39%,and UAC 0.86. The value of CRP cut off point inperforated acute appendicitis was 101 mg/L, withLR+ 4.24%, LR- 0.39%, and AUC 0.878.

Yang et al (2006) found a result that perforatedappendicitis case was 196 from 740 cases (36%).The cut off point leukocyte value of perforatedacute appendicitis was 14900 permm3. The cut offpoint neutrophyl value of perforated acute appendicitiswas 86.4%. The cut off point CRP value of perforatedacute appendicitis was 96.8 mg/L9.

The researcher found the result of perforatedappendicitis case was 27 from 82 cases (32,9%).The cut off point leukocyte value of perforatedacute appendicitis was 15200 permm3. Theleukocyte value of 15200 permm3, the sensitivityvalue 70.07% was obtained, specificity 70.37%,PPV was 82.97%, NPV 54.28%, LR+ 2.36%, the

TABLE 8. A Result Comparison among some Simple and Complicated Acute Appendicitis studies

LR- 0.42%, the AUC was 0.797, accuracy 70.73%.The cut off point neutrophyl value in perforatedacute appendicitis was 86.5%. On neutrophyl value86.5% the sensitivity value was 74.54%, specificity70.37%, the PPV was 83.67%, the NPV was57.57%, the LR+ was 2.51%, the LR was 0.22%,and AUC was 0.744, accuracy 73.17%. The CRPcut off point value in perforated acute appendicitiswas 92 mg/L with a sensitivity value of 89.09%,

specificity 81.48%, PPV 90.74%, NPV 78.57%,LR+ 4.56%, LR- 0.13%, AUC 0.891, accuracy86.56%. The AUC was nearly close to 1, showingthat diagnosis test had an increasing sensitivity andspecificity value.

CRP will increase dramatically starting 4-6hours after the onset of the inflammation and the peaklevel occurred on the third day. CRP desensitized byhepatocyte and a minimum number is desensitized

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by other mRNA cells, such as lymphocyte.Hepatocytes are stimulated by IL-1, IL-6, TNF andINF to start sensitizing CRP, just as inflammationappears. In patients with a suspect of acuteappendicitis, CRP could be used as an indicator ofa continuing inflammation16.17.

Laboratory examination to determine thediagnosis of a disease is often done with somelaboratory examination at a time. Examining sometests is useful to diagnose more closely, to increasethe sensitivity and specificity. The method used isby parallel or serial multiple diagnosis tests. Byparallel multiple diagnosis tests the sensitivity canbe greater, but the specificity value smaller. By aserial multiple diagnosis tests a reversed result isobtained, that is the specificity value is greaterwhereas the sensitivity value was small18, meaningthat the diagnosis is more accurate.

Examination on acute appendicitis in EmergencyUnit often use more than one laboratory examination.The result of leukocyte value, neutrophyl and CRPseparately or together often become a considerationin diagnosing acute appendicitis 9.

CONCLUSION

Laboratory examination on leukocyte,neutrophyl and CRP values is still a good diagnostictool that can be used to compare between simpleand complicated acute appendicitis. CRPexamination has a better result compared toleukocyte and neutrophyl on simple and complicatedacute appendicitis diagnostic test with sensitivity89.09%, specificity values 81.48%, with positivepredictive value (PPV) 90.74%, negative predictivevalue (NPV) 78.57%, positive likelihood ratio (LR+)4.56, negative likelihood Ratio (LR-) 0.13.

REFERENCES

1. Ellis H. Appendix. In: Schwartz SI, Elli H, Husser, WC.eds. Maingot’s Abdominal Operations. Toronto.Appleton & Lange. p:953-67.

2. Kozar RA, Roslyn JJ. Appendix. In: Schwartz SI, ShiresGT, Daly JM, Fischer JE, Golloway AC. eds. PrinciplesOf Surgery. 7th ed. New York. McGraw-Hill. 1999:1383-93.

3. Davies GM, Dasbach EJ, Teutsch S. The Burden ofAppendicitis-Related Hospitalization in The UnitedStates in 1997. Surg Infect (Larchmt). 2004;5.:160-5.

4. Korner H, Soreide, JA, Sondenaa K. Diagnostic Accuracyof Inflammatory Markers in Patients Operated on forSuspected Acute Appendicitis: a Receiver OperatingCharacteristic Curve Analysis. Eur J Surg. 1999;164:679-85.

5. Virginia A. Appendicitis: Why so complicated? Analysisof 5755 consecutive appendectomies. The Am Surg.2000;66:548-63

6. Chung CP, Lai KK. Delays by patients, EmergencyPhysicians, and, Surgeons in the Management of AcuteAppendicitis: Retrospective Study. Hongkong Med J.2000;3:245-9.

7. Choy K.Ng, Lay SW. Clinical Analysis of The RelatedFactors in Acute Appedicitis. Yale J Biol Med.2000;70:41-5.

8. Andersson REB. Meta-analysis of The Clinical andLaboratory Diagnosis of Appendicitis. Br J Surg. 2004;91:28-37.

9. Yang HR, Wang YC, Chung PK, Chen WK, Jeng LB,Chen RJ. Laboratory Test in Patients with AcuteAppendicitis. ANZ J Surg. 2006;76:71-4.

10. Sheehan C. ed. Clinical Immunology: Principles andLaboratory Diagnosis. 2nd ed. New York. Lippincott.1997. p:47-51.

11. Lawrence WW. Appendix. In: Lawrence, W.W., Doherty,G.M. eds. Current Surgical and Treatment. 11th ed.Boston: McGraw Hill. 2003. p:668-73.

12. Lee .L, Ho HS. Acute appendicitis: Is there a differencebetween children and adults? Am J Surg. 2006;5:409-13.

13. Styrud, J., Eriksson, S., Nisson, I., et al. 2006.Appendectomy versus Antibiotic Treatment in AcuteAppendicitis. A Prospective Multicenter RandomizedControlled Trial. Eur J Surg. 164:1033-37.

14. Cardall T, Glasser J, Guss,.A. Clinical Value of the TotalWhite Blood Cell Count and Temperature in theEvaluation of Patients with Suspected Appendicitis.Acad Emerg Med. 2004;11:1021-7.

15. Gronroos J M, Gronroos P. Leucocyte Count and C -reactive protein in the Diagnosis of Acute Appendicitis.Br J Surg. 1999;86:501-4.

16. Richard A, McPherson JY. Specific Proteins. In: HenryJ.B. ed. Clinical Diagnosis and Management byLaboratory Methods. New York: WB sandersCompany.2001. p:249-77.

17. Myron, J., Elizabeth, M.R., Lawrence, M.S. 2001.Proteins. In: Carl, A.B., Edward, R.A eds. TietzFundamentals of Clinical Chemistry. 5th ed. NewYork:WB Saunders Company. 325-50.

18. Fletcher, R.H., Fletcher, S.W., Wagner, E.H. 1988.Clinical Epidemiology The essentials. 2nd. Ed. Baltimore:Williams & Walkins.

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