The accuracy of serum interleukin-6 and tumour necrosis factor as markers for ovarian torsion

Shlomo B. Cohen1,3, Arnaud Wattiez2, David Stockheim1, Daniel S. Seidman1, Arie L. Lidor1, Shlomo Mashiach1 and Mordechai Goldenberg1

1 J.Buchman Maternity Center, Department of Obstetrics and Gynecology, Sheba Medical Center, Tel-Hashomer, affiliated to the Sackler School of Medicine and Tel-Aviv University, Israel and 2 Department of Obstetrics, Gynaecology and Reproductive Medicine, Polyclinique de l'Hotel-Dieu, Clermont-Ferrand, France


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
BACKGROUND: The aim of this study was to investigate a possible role for interleukin-6 (IL-6) and tumour necrosis factor (TNF-{alpha}) as pre-operative markers for the diagnosis of ovarian torsion. METHODS: Twenty consecutive patients admitted to the gynaecological emergency room with suspected clinical diagnosis of ovarian torsion were prospectively assigned to the study. Blood samples were drawn pre-operatively and examined for serum concentrations of IL-6 and TNF-{alpha}. Surgeons were blinded to laboratory results prior to laparoscopy. RESULTS: The pre-operative diagnosis of ovarian torsion was confirmed during an urgent diagnostic laparoscopy in 8 (40%) patients. The surgical diagnosis among the remaining 12 patients was a large ovarian cyst not in torsion. In six out of eight (75.0%) patients with ovarian torsion serum IL-6 concentrations were elevated. None of the 12 patients without torsion had elevated serum IL-6 concentrations. This difference was statistically significant (P < 0.001). There was no significant difference in the proportion of women with elevated serum TNF-{alpha} concentrations, two of eight (25.0%) patients with torsion and four of 12 (33.3%) control cases. CONCLUSIONS: Elevated serum IL-6 concentrations, but not serum TNF-{alpha} concentrations, were significantly associated with the occurrence of ovarian torsion. In patients with vague clinical signs of ovarian torsion, serum IL-6 might help to distinguish which patients should undergo diagnostic laparoscopy.

Key words: interleukin-6/markers/ovarian torsion/tumour necrosis factor-{alpha}


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Torsion of the ovary is a surgical emergency (Haskins and Shull, 1986Go). Premenarchal girls and women of childbearing age are at increased risk of ovarian torsion (Haskins and Shull, 1986Go). Most of these women desire future fertility, and a loss of an ovary could later adversely affect their reproductive life. Rapid diagnosis and management are the keys to the salvage of the twisted ovary. However, the clinical diagnosis usually relies only on the presence of abdominal pain and an ultrasonographic finding of an ovarian mass.

According to our experience, most (56%) of the patients treated by an urgent diagnostic laparoscopy do not have a confirmed ovarian torsion (Cohen et al., 2001Go). Other diagnoses not necessitating an urgent laparoscopy are encountered. These unnecessary laparoscopies performed under urgent conditions might endanger the patient.

Specific laboratory markers that support the pre-operative diagnosis of ovarian torsion are not available today. Lately, a relationship between ischaemic insult to the heart and high concentrations of tumour necrosis factor (TNF-{alpha}) and interleukin-6 (IL-6) in peripheral blood was demonstrated (Nossuli et al., 2000Go). These two pro-inflammatory cytokines act as acute phase reactants and could be generated during ischaemia that occurs in the course of torsion of the ovary that involves ischaemia.

Therefore, the aim of this study was to investigate the relationship between pre-operative serum IL-6 and TNF-{alpha}, and the diagnosis of ovarian torsion.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Between January 1998 and December 1999, 35 women were admitted to the gynaecological emergency room at the Sheba Medical Center with signs and symptoms suggestive of ovarian torsion. The inclusion criteria were age: between 20 and 45 years, acute abdominal pain with or without peritoneal signs and ultrasonographic finding of an ovarian cyst or mass.

We excluded women with a positive pregnancy test, clinical or ultrasonographic signs of malignancy, and clear signs and symptoms of other pathologies, e.g. acute appendicitis or urinary tract infection (Figure 1Go). All patients enrolled in the study signed an informed consent approved by the institute's Institutional Review Board committee prior to the operation.



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Figure 1. Patients recruited to the study, and patients excluded.

 
All patients underwent an urgent diagnostic laparoscopy. Surgeons were blinded to laboratory results prior to laparoscopy. Blood samples were drawn pre-operatively and were centrifuged at 60 g for 10 min, the sera were then stored at –70°C. Serum concentrations of IL-6 and TNF-{alpha} were measured using a commercial solid phase immulite (Diagnostic Products Corporation (DPC), Los Angeles, CA, USA). In patients with ovarian torsion, detorsion was the only operative procedure done.

An elevated concentration of IL-6, >11.3 pg/ml, and of TNF-{alpha}, >8.1 pg/ml, were determined as positive results. (These threshold concentrations were set by DPC by using 40 and 58 healthy individuals with a range measurements between 0–11.3 pg/ml and 0–8.1 pg/ml for IL-6 and TNF-{alpha} respectively.) For TNF-{alpha} the interassay coefficients of variants (CV) were 4.4–6.5%, intra-assay CV were 2.6–3.6%, and the detection limit of the assay was defined as ~1.7 pg/ml. For IL-6 the interassay CV were 6.2–7.9%, intra-assay CV were 3.0–8.4% and detection limit was 1.0 pg/ml. The statistical analysis was performed using {chi}2 test and Fisher's exact test, and Student's t-test for categorical and continuous variables as appropriate. Statistical significance was defined as P < 0.05.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Of the 35 women a total of 20 patients was enrolled in this study. The pre-operative diagnosis of ovarian torsion was confirmed during an urgent diagnostic laparoscopy in only 8 (40%) patients. In those patients detorsion of the ovary was the only surgical procedure performed during the initial urgent laparoscopy. The surgical diagnosis among the remaining 12 patients was a large ovarian cyst not in torsion.

Among the patients without ovarian torsion, four patients had corpus luteum cysts, two had follicular cysts and the remaining six had dermoid cysts. There were no significant differences between the groups in regard to mean age, body weight, chronic diseases (hypertension, diabetes, ischaemic heart diseases, asthma, etc.) or smoking.

In six out of eight (75.0%) patients with ovarian torsion, serum IL-6 concentrations were elevated. None of the 12 patients without torsion had elevated serum IL-6 concentrations. This difference was statistically significant (P < 0.001). There was no significant difference between the two groups in serum TNF-{alpha} concentrations, two of eight (25.0%) patients with torsion and four of 12 (33.3%) respectively. Mean serum concentrations and thresholds of TNF-{alpha} and IL-6 are presented in Figure 2Go.



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Figure 2. TNF-{alpha} and IL-6 in patients with and without ovarian torsion.

 
Mean IL-6 concentrations were significantly increased in patients with ovarian torsion (P < 0.003) compared with patients without ovarian torsion. Table IGo presents the clinical and surgical features of the eight patients with ovarian torsion. Cystectomy was not performed in the patients in the group with ovarian torsion.


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Table I. Clinical and surgical features of patients with ovarian torsion
 

    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In this prospective study we demonstrated that pre-operative measurement of IL-6 in serum of patients with suspected ovarian torsion might improve the ability to predict which patients will benefit from urgent laparoscopy. The pre-operative diagnosis of ovarian torsion remains a clinical challenge. We therefore examined the possible role of IL-6 and TNF-{alpha} as pre-operative predictors. These cytokines were chosen as possible markers for ovarian torsion based on data from the mouse model of myocardial ischaemia reperfusion (Hirano et al., 1990Go).

IL-6 is a mediator of the immune system, which has a wide variety of biological actions. Many different cells are capable of IL-6 synthesis including macrophages, fibroblasts, endothelial cells, T cells and many tumour cell lines. IL-6 has an important effect on the differentiation of haematopoietic progenitor cells (Hirano et al., 1990Go). Elevated IL-6 serum concentrations may occur in different diseases including sepsis, auto-immune diseases and inflammation.

Lately Il-6 was shown, in a mouse model of myocardial ischaemia reperfusion, to be significantly elevated during the reperfusion phase (Hirano et al., 1990Go). TNF-{alpha} (cachectin) may also be produced by a variety of cells, among them smooth muscle cells. TNF-{alpha} like IL-6 is an acute phase reactant and is involved in inflammation and ischaemic processes (Jacob, 1992Go).

The ovary has been found to be an organ relatively resistant to long periods of ischaemia caused by torsion (Cohen et al., 1999Go). We further believe that when an ovarian enlargement is present, the ovary may undergo several spontaneous cycles of torsion–detorsion until finally it is fully twisted (>=360°). The ovary may receive collateral blood supply, so when the vascular pedicle is twisted some blood may find its way to the organ and supply some of the basal metabolic demand.

This is the reason we now routinely perform only detorsion of every twisted ovary encountered during laparoscopy for suspected torsion even when ischaemic features are found (Cohen et al., 1999Go). We have demonstrated a high index (93%) of rescue to the ovary using this strategy (Cohen et al., 1999Go).

The diagnosis of ovarian torsion is usually done under the urgent conditions of the gynaecological emergency room. Moreover, several other gynaecological and non-gynaecological pathologies must be excluded. Urgent laparoscopy is considered the gold standard for accurate diagnosis (Cohen et al., 2001Go). Thus, many gynaecologists elect to perform an urgent diagnostic laparoscopy rather than delay the definite diagnostic procedure. The risk associated with urgent laparoscopy, often undertaken during the night, especially when performed by inexperienced personnel, may be increased.

It is well known that under such urgent conditions the rate of complications is increased. A simple and more precise test, such as determining the IL-6 concentrations in the sera, may assist in making the diagnosis. If this test is found to be accurate then the patient might benefit from a justified urgent laparoscopy due to ovarian torsion, rather than risk damage to the ovary following conservative observation. Additional imaging modalities may further delay the decision to operate and are not always helpful (Pena et al., 2000Go).

Lately, it has been found that when normal blood flow is detected by Doppler sonography, in 60% of the patients ovarian torsion was missed, and time interval to diagnosis was further prolonged (Pena et al., 2000Go).

In our study, IL-6, and not TNF-{alpha}, was found to be increased in cases of ovarian torsion. We believe that the reason for these findings might be explained by the fact that TNF-{alpha} is a non-specific cytokine that is involved in many pathological processes whereas IL-6 is might be more specific for ovarian ischaemia reperfusion.

IL-6 concentrations in the sera of patients with vague clinical signs of ovarian torsion might assist in decision-making prior to urgent laparoscopy. Further studies are required with larger series of patients in order to examine the role for bedside IL-6 commercial kits in cases that are in the grey zone of clinical signs of ovarian torsion.


    Notes
 
3 To whom correspondence should be addressed at: Obstetrics and Gynecology, Sheba Medical Center, Tel-Hashomer, 52621 Israel. E-mail: s_cohen_eylon{at}hotmail.com Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Cohen, S.B., Oelsner, G., Seidman, D.S. et al. (1999) Laparoscopic detorsion allows sparing of the twisted ischaemic adnexa. J. Am. Assoc. Gynecol. Laparosc., 6, 139–143.[ISI][Medline]

Cohen, S.B., Weisz, B., Seidman, D.S. et al. (2001) Accuracy of the pre-operative diagnosis in 100 emergency laparoscopies performed due to acute abdomen in non-pregnant women. J. Am. Assoc. Gynecol. Laparosc., 8, 92–94.[ISI][Medline]

Haskins, T. and Shull, B. (1986) Adnexal torsion: a mind-twisting diagnosis. South. Med. J., 79, 576–577.[ISI][Medline]

Hirano, T., Akira, S., Tega, T. and Kishimoto, T. (1990) Biological and clinical aspects of interleukine-6. Immunol. Today, 11, 443–449.[ISI][Medline]

Jacob, C.O. (1992) Tumor necrosis factor {alpha} in autoimmunity: pretty girl or old witch? Immunol. Today, 13, 122–125.[ISI][Medline]

Nossuli, T.O., Lakshminarayanan, V., Baumgarten, G. et al. (2000) A chronic mouse model of myocardical ischaemia reperfusion: essential in cytokine studies. Am. J. Phisiol. Heart. Circ. Physiol., 278, 1049–1055.

Pena, J.E., Ufberg, D., Cooney, N. and Denis, A.L. (2000) Usefulness of Doppler sonography in the diagnosis of ovarian torsion. Fertil. Steril., 73, 1047–1050.[ISI][Medline]

Submitted on January 23, 2001; accepted on May 8, 2001.





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