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Serum S100B in pregnancy-related hypertensive disorders: a case-control study.

Eclampsia is defined as the occurrence of seizures and/or coma resulting from hypertensive encephalopathy on a background of preeclampsia (1). Eclampsia appears to be caused by a failure of the brains autoregulatory response to increases in blood pressure, leading to an increase in cerebral perfusion pressure with overperfusion injury similar to that observed in hypertensive encephalopathy (2, 3). Brain edema and hemorrhage ensue, as observed in imaging studies (4, 5), and there is evidence to suggest that these alterations can cause ischemia to brain cells.

These events lead to neurologic symptoms (6), including seizures as well as cortical blindness, aphasia, limb weakness, psychosis, coma, and cerebrovascular accidents. Studies have analyzed various diagnostic methods, such as transcranial Doppler measurements, as a way to evaluate neurologic involvement in preeclampsia (3, 7). To date, however, there is no reliable laboratory marker to identify patients at risk for eclampsia or its related complications.

S100B is a 21-kDa protein physiologically produced and released primarily by astrocytes in the central nervous system (CNS), where it exerts neurotrophic and gliotrophic actions (8). Because ~95% of S100B is located in the CNS, the results of several studies have suggested that an increase in S100B in blood and cerebrospinal fluid could be a potential marker of neural injury, indicating reactive gliosis, astrocytic death, and/or blood-brain barrier dysfunction. Accordingly, increased S100B concentrations in cerebrospinal fluid and/or blood have been reported in several pathologic conditions causing acute and chronic brain injury, such as head trauma (9), stroke (10), schizophrenia (11), and human T-lymphotropic virus type 1-associated myelopathy (12).

Some studies have also evaluated S100B as a marker of recent seizures. Although S100B has been shown to be increased in both cerebrospinal fluid and brain tissue of patients with temporal lobe epilepsy (13,14), studies in which serum S100B was measured have failed to show an increase after seizures (15-17). Nevertheless, taking into account that the pathophysiology of seizures in eclampsia involves ischemic damage to cells in the CNS, as well as the fact that increased S100B seems to be an indicator of increased intracranial blood pressure (18) and of hypertension-related injury during cardiopulmonary bypass (19), it is feasible that an increase in S100B could be observed in eclampsia, perhaps even before the occurrence of seizures.

In this study, serum S100B was measured in pregnant women with eclampsia, preeclampsia, chronic hypertension, or normal blood pressure to determine whether these concentrations could be an indicator of neurologic involvement in pregnancy-related hypertension. This case-control study was conducted between 2000 and 2002 in the obstetric emergency department of a tertiary hospital in southern Brazil. Approval from the institution's ethics review board was obtained before the study, and all patients provided written informed consent for participation. Patients eligible for the study were pregnant women with a gestational age [greater than or equal to] 20 weeks admitted for medical evaluation or labor assistance. Exclusion criteria were present diagnosis or past history of neurologic disease, renal dysfunction, seizures related to other causes, HIV infection, or microangiopathies. Obstetric examination was performed, and a questionnaire including information on current pregnancy features and past obstetric, medical, and family histories was obtained. Blood pressure measurements were performed, and patients were classified into four groups according to previously established criteria on high blood pressure in pregnancy (1) as follows: (a) normal blood pressure [patients with systolic blood pressure (SBP) <140 mmHg and diastolic blood pressure (DBP) <90 mmHg]; (b) preeclampsia (patients with SBP >140 mmHg or DBP >90 mm, evidence of proteinuria, and no history of hypertension outside of pregnancy); (c) chronic hypertension (patients with SBP >140 mmHg or DBP >90 mmHg with a history of hypertension outside of pregnancy and no evidence of proteinuria); (d) eclampsia (patients fulfilling criteria for preeclampsia with the additional manifestation of seizures). Patients with preeclampsia superposed on chronic hypertension and those with gestational hypertension but no proteinuria or other evidence of preeclampsia were not included in the study.

Blood samples (5 mL of venous blood) were collected at the time of admission in an evacuated anticoagulant-free system and sent to the laboratory for centrifugation. In patients presenting with eclampsia, blood was collected up to 6 h after a seizure. Serum was separated from the clot and stored at -70 [degrees]C until analysis. S100B was measured by a commercially available immunoluminometric assay (Sangtec 100[R]) as described previously (20). Briefly, this is a monoclonal two-site immunoassay that uses an antibody covalently bound to isoluminol as a tracer. All samples were measured in duplicate and were analyzed in the same experiment. The S100B calibration curve was linear up to 20 [micro]g/L, and the CV for duplicates across the entire concentration range for the calibrators and samples remained <_5%. The detection limit of the assay is 0.02 [micro]g/L.

Data are expressed as mean (SD). Statistical analysis was performed with SPSS, Ver. 10.0 (SPSS). Quantitative variables, including S100B serum concentrations, were compared by ANOVA followed by a Duncan post hoc test. Qualitative variables were compared by Fisher exact test. A P value <0.05 was considered to indicate statistical significance.

Fifty patients were enrolled for the study and classified as described above. The clinical and epidemiologic data for the patients are shown in Table 1. Chronically hypertensive patients were older and had more previous pregnancies than the other groups. Both the SBP and DBP were statistically lower in normotensive patients compared with the other groups. None of the patients allocated to the normotensive, chronic hypertension, or preeclampsia groups developed seizures during their stay at the hospital.

As shown in Fig. 1, there were no significant differences among the serum S100B concentrations of women with chronic hypertension [0.186 (0.12) [micro]/L], preeclampsia [0.185 (0.14) [micro]/L]. and normal blood pressure [0.147 (0.07) [micro]/L]. However, serum S100B was significantly higher in eclampsia patients [0.424 (0.194) [micro]/L] compared with all other groups (P <0.05).

To our knowledge, this is the first study designed to assess serum S100B in pregnancy-related hypertensive disorders. Our results demonstrate increased concentrations of the protein in pregnant women with eclampsia, but not in those with preeclampsia or chronic hypertension, compared with controls. Several cellular events associated with CNS involvement in eclampsia could account for the present findings. The increased S100B may be secondary to cerebral vascular changes leading to overperfusion, edema, and ischemia, as well as to seizures themselves (2, 4, 6). However, it is unlikely that seizures per se are responsible for the increase in serum S100B because studies on epileptic patients have not found any increases (15-17). Therefore, it is possible that the increases in serum S100B observed in this study could actually precede the occurrence of seizures or other neurologic manifestations in eclampsia.

[FIGURE 1 OMITTED]

Other causes of S100B production that do not involve vascular brain injury cannot be completely excluded by our study. Recent evidence suggests that extracerebral sources may also influence serum S100B (21), although usually in a minor way. Moreover, S100B production by the fetus could also be feasibly playing a role in our findings because concentrations of the protein are known to be quite high in cord blood compared with those found in adult serum (22,23).

Current diagnosis of imminent eclampsia is based mostly on the clinical assessment of patients with preeclampsia, focusing on neurologic symptoms such as headache and visual alterations. The peripheral measurement of brain proteins such as S100B, however, has been shown to offer a sensitive alternative indicator of cell damage in the CNS when clinical and radiologic assessments are negative. S100B appears to satisfy various criteria for a peripheral marker of brain injuries, such as (a) simplicity of measurement with good reproducibility, (b) detection in various biological fluids, (c) possibility of use in longitudinal monitoring because of its short half-life, and (d) well-established use as an early and quantitative marker of CNS injury. S100B can also offer the additional advantage of providing a quantitative indicator of the extent of brain lesions in various diseases (10,11,13,14), and several previous studies have demonstrated the prognostic value of serum S100B in predicting neurologic prognosis in various conditions, including head trauma, stroke, and cardiac arrest (9,10,18, 24).

In spite of the small size of our sample, our findings provide preliminary evidence that increased S100B is associated with eclampsia. Further studies with larger samples are required to determine whether these values can be used to predict the development of eclampsia before it leads to overt clinical manifestations. If this turns out to be the case, the use of S100B measurements to predict CNS involvement in pregnancy-related hypertension might conceivably play a useful role in the clinical management of this condition.

This research was supported by the following Brazilian funding agencies: Conselho Nacional de Pesquisa/Programa Nacional de Excelencia (No. 41960904), Fundacao de Ampara a Pesquisa do Estado do Rio Grande do Sul; Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior; Pro-reitonia de Pesquisa/Universidade Federal do Rio Grande do Sul; and Fundacao de Incentivo a Pesquisa e Eventos/Hospital de Clinicas de Porto Alegre.

DOI : 10.1373/clinchem.2003.027391

References

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(4.) Naidu K, Moodley J, Corr P, Hoffmann M. Single photon emission and cerebral computerised tomographic scan and transcranial Doppler sonographic findings in eclampsia. Br J Obstet Gynaecol 1997;104:1165-72.

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(6.) Rutherford JM, Moody A, Crawshaw S, Rubin PC. Magnetic resonance spectroscopy in pre-eclampsia: evidence of cerebral ischaemia. BJOG 2003;110:416-23.

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(9.) Ingebrigtsen T, Waterloo K, Jacobsen EA, Langbakk B, Romner B. Traumatic brain damage in minor head injury: relation of serum S-100 protein measurements to magnetic resonance imaging and neurobehavioral outcome. Neurosurgery 1999;45:468-75.

(10.) Wunderlich MT, Ebert AD, Kratz T, Goertler M, Jost S, Herrmann M. Early neurobehavioral outcome after stroke is related to release of neurobiochemical markers of brain damage. Stroke 1999;30:1190-5.

(11.) Lara DR, Gama CS, Belmonte-de-Abreu P, Portela LV, Goncalves CA, Fonseca M, et al. Increased serum S100B protein in schizophrenia: a study in medication-free patients. J Psychiatr Res 2001;35:11-4.

(12.) Walz R, Portela LV, Tort AB, Neto EC, Fernandes LN, Goncalves CA, et al. Serum S100B levels in patients with HTLV-I-associated myelopathy/tropical spastic paraparesis. Neurology 2000;54:2021-2.

(13.) Griffin WS, Yeralan 0, Sheng JG, Boop FA, Mrak RE, Rovnaghi CR, et al. Overexpression of neurotrophic cytokine S100B in human temporal lobe epilepsy. J Neurochem 1995;65:228-33.

(14.) Steinhoff BF, Tumani H, Otto M, Mursch K, Wiltfang J, Herrendorf G, et al. Cisternal S100 protein and neuron-specific enolase are elevated and site-specific markers in intractable temporal lobe epilepsy. Epilepsy Res 1999;36:75-82.

(15.) Buttner T, Lack B, Jager M, Wunsche W, Kuhn W, Muller T, et al. Serum levels of neuron-specific enolase and S-100 protein after single tonic-clonic seizures. J Neurol 1999;246:459-61.

(16.) Palmio J, Peltola J, Vuorinen P, Laine S, Suhonen J, Keranen T. Normal CSF neuron-specific enolase and S-100 protein levels in patients with recent non-complicated tonic-clonic seizures. J Neurol Sci 2001;183:27-31.

(17.) Leutmezer F, Wagner 0, Baumgartner C. Serum S-100 protein is not a suitable seizure marker in temporal lobe epilepsy. Epilepsia 2002;43: 1172-4.

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(22.) Gazzolo D, Vinesi P, Marinoni E, Di lorio R, Marras M, Lituania M, et al. S100B protein concentrations in cord blood: correlations with gestational age in term and preterm deliveries. Clin Chem 2000;46:998-1000.

(23.) Gazzolo D, Marinoni E, di lorio R, Lituania M, Bruschettini PL, Michetti F. Circulating 5100/3 protein is increased in intrauterine growth-retarded fetuses. Pediatr Res 2002;51:215-9.

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Adriana P. Schmidt, [1] Adriano B.L. Tort, [2] Olavo B. Amaral, [2] Andre P. Schmidt, [2] Roger Walz, [3] Janete Vettorazzi-Stuckzynski, [1] Sergio H. Martins-Costa, [1] Jose Geraldo L. Ramos, [1] Diogo O. Souza, and Luis V.C. Portela [2] *

([1]Departamento de Ginecologia e Obstetricia, Hospital de Clinicas de Porto Alegre, Porto Alegre, RS, Brazil; [2] Departamento de Bioquimica, Instituto de Ciencias Basicas da Saude, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; [3] Centro de Cirurgia de Epilepsia, Hospital de Clinicas, Departamento de Neurologia, Psiquiatria e Psicologia Medica, Universidade de Sao Paulo, SP, Brazil; * address correspondence to this author at: Departamento de Bioquimica, ICBS, Universidade Federal do Rio Grande do Sul, Avenida Ramiro Barcelos, 2600-Anexo, CEP 90035-003, Porto Alegre, RS, Brazil; fax 55-51-33165540 or 55-51-33165535, e-mail roska@ufrgs.br)
Table 1. Clinical features of patients and controls.

 Chronic
 Normotensive hypertension

n 16 11
Age, years
 Mean 21.8 32.4 (a)
 SD 4.8 7.2
Race, %
 White 69 82
 Black 25 18
 Others 6 0
Smoking history, %
 Yes 25 27
 No 75 73
Family history of
preeclampsia, %
 Yes 31 36
 No 69 64
Previous preeclampsia, %
 Yes 0 0
 No 100 100
No. of previous
pregnancies
 Mean 2.3 4.9 (a)
 SD 1.4 3.5
Gestational age, weeks
 Mean 34.6 36.8
 SD 6.4 1.9
SBP/DBP, (c) mmHg
 Mean 109.3/67.9 (d) 157.8/98.9
 SD 14.4/9.8 26.4/12.7

 Preeclampsia Eclampsia

n 18 10
Age, years
 Mean 24.8 19.6
 SD 6.2 6.9
Race, %
 White 83 80
 Black 17 20
 Others 0 0
Smoking history, %
 Yes 22 20
 No 78 80
Family history of
preeclampsia, %
 Yes 33 40
 No 67 60
Previous preeclampsia, %
 Yes 28 (b) 10
 No 72 90
No. of previous
pregnancies
 Mean 2.0 1.2
 SD 1.6 0.4
Gestational age, weeks
 Mean 34.7 33.5
 SD 4.1 3.9
SBP/DBP, (c) mmHg
 Mean 146.2/93.8 160.0/102.2
 SD 14.5/12.6 18.0/18.6

(a) Significantly different from preeclamptic, eclamptic,
and normotensive patients (P <0.05).

(b) Significantly different from eclamptic, chronically
hypertensive, and normotensive patients (P <0.05).

(c) Mean blood pressures during admission.

(d) Significantly different from chronically hypertensive,
preeclamptic, and eclamptic patients (P <0.05).
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Title Annotation:Technical Briefs
Author:Schmidt, Adriana P.; Tort, Adriano B.L.; Amaral, Olavo B.; Schmidt, Andre P.; Walz, Roger; Vettorazz
Publication:Clinical Chemistry
Date:Feb 1, 2004
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