romanian journal of internal medicine

2 downloads 15 Views 4MB Size Report
potenÅ£ialul de reducere a incidenÅ£ei altor boli sistemice. Corresponding author: Alexandrina L. ...... J. of Oral. Biosciences 2005,47,115. 4. SZPADERSKA A.M. ...


No. 3, 2008

CONTENTS REVIEWS I. MATEI, Relapses in patients with idiopathic vasculitis: diagnostic difficulties ...................................................................... V. POMPILIAN, CAMELIA BADEA, ISABELA DRAGOMANU, ELENA BĂLĂŞESCU, C. TĂNĂSESCU, Traditional and nontraditional risk factors for atherosclerosis in patients with systemic lupus erythematosus ................................... R. TĂNĂSESCU, MARINA ŢICMEANU, INIMIOARA MIHAELA COJOCARU, DIMELA LUCA, ADRIANA NICOLAU, ADRIANA HRISTEA, C. BĂICUŞ, Central pontine and extrapontine myelinolysis ...................................................... ALEXANDRINA L. DUMITRESCU, L. ZETU, SILVIA TESLARU, Metabolic syndrome and periodontal diseases .............

187 195 199 207

ORIGINAL ARTICLES TEODORA MOCAN, LUCIA AGOŞTON-COLDEA, M. GATFOSSÉ, SOPHIE ROSENSTINGL, L.C. MOCAN, Risk factors for heart failure in patients with one prior myocardial infarction episode .................................................... SIMONA TÎRZIU, SIMONA BEL, COSMINA-IOANA BONDOR, MONICA ACALOVSCHI, Risk factors for gallstone disease in patients with gallstone having gallstone heredity. A case-control study ........................................................... C. IANCU, L.C. MOCAN, DANA TODEA-IANCU, TEODORA MOCAN, F.V. ZAHARIE, F. GRAUR, I.C. PUIA, D. MUNTEANU, O. BALA, LUCIA AGOŞTON-COLDEA, F. MIHĂILEANU, C. MITRE, DANA IONESCU, L.E. VLAD, Survival prognostic factors in patients with resection of liver metastasis from colorectal cancer ............... INIMIOARA MIHAELA COJOCARU, M. COJOCARU, R. TĂNĂSESCU, CECILIA BURCIN, ADINA NICOLETA ATANASIU, ISABELA SILOSI, Detection of autoantibodies to ribosome P in lupus patients with neurological involvement ...................................................................................................................................................................... COZIANA CIURTIN, VIORICA MĂDĂLINA COJOCARU, S. ARAMĂ, V. STOICA, Epidemiology of ocular involvement in autoimmune diseases ............................................................................................................................... SABINA ZURAC, MIHAELA GIRTAN, LUCIANA LAVRIC, G. PETSAKOS, FLORICA STĂNICEANU, ALEXANDRA BASTIAN, R. ANDREI, CRISTINA POPP, ELISABETA LABA, Local immune alterations in oral mucosa of the edentulous patients; possible cause of teeth loss? .............................................................................................................

213 223


239 243


CASE REPORTS RUXANDRA JURCUŢ, IOANA POP, D. CORIU, M. GRASU, DIANA ZILIŞTEANU, S. GIUŞCĂ, CARMEN GINGHINĂ, Compound heterozygosity for the C677T and A1298C mutations of the MTHFR gene in a case of hyperhomocysteinemia with recurrent deep thrombosis at young age ............................................................................. LUCIA AGOŞTON-COLDEA, L.D. RUSU, CAMELIA BOBAR, M.L. RUSU, TEODORA MOCAN, LUCIA MARIA PROCOPCIUC, Recurrent thrombembolic risk in patients with multiple thrombophilic disorders .................................

ROM. J. INTERN. MED., 2008, 46, 3, 185–266

255 261



Relapses in Patients with Idiopathic Vasculitis: Diagnostic Difficulties I. MATEI Internal Medicine Clinic, Colentina Hospital, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania

Idiopathic vasculitis are complex inflammatory diseases that affect small, medium and large sized vessels. The disease recurrence, or relapse, which frequently characterizes the vasculitis course, raises the morbidity and mortality in vasculitic patients. Relapse diagnosis is currently a difficult clinical problem, since the original vasculitis presentation may change during relapse, in some cases even to a more aggressive form. Furthermore, relapse may overlap “damage” syndromes and subclinical active lesions can occur in asymptomatic patients. We focus here on certain organ-specific and systemic manifestations associated to relapse, also presenting unusual and unexpected features of relapse in various vasculitic conditions. Assessment of disease activity to diagnose relapse, including serologic markers associated to or predicting relapse, and relapse diagnosis in subclinical vasculitis are also discussed. Key words: vasculitis, relapse, ANCA, diagnosis.

Immunosuppressive therapy achievements during the latest decades have converted many idiopathic vasculitis, inflammatory diseases which affect the small, medium and large vessels, from fatal into chronic relapsing disorders [1]. Due to the highly non-uniform course of vasculitis, the diagnosis of the relapse is known to be a puzzling matter. The clinical features of relapses could be similar to or more aggressive than those of the original presentation. The usual presentation of a particular vasculitis may also change during relapse. Thus, many patients in relapse present either incomplete or overlapping clinical syndromes, or new or atypical features, which should be considered either as overlaps of two distinct vasculitis or as subsets of the same disease. Moreover, drug toxicity, infections, as well as a diverse array of vasculitis sequelae may mimic the relapse [2]. In asymptomatic patients thought to be in remission, some subclinical active lesions occur, but biopsies often fail to evidence them. With all these aspects in sight, it becomes obvious that relapse diagnosis and therapy must benefit from an interdisciplinary approach and must imply a careful monitorization of the patient in remission, to detect as early as possibly clinical and serologic markers predicting a relapse. THE SIGNS OF ACTIVE VASCULITIS

The clinical components of an active disease are systemic inflammation and organ or tissue ROM. J. INTERN. MED., 2008, 46, 3, 187–194

ischemia. Systemic inflammation is evidenced by the nonspecific systemic syndrome of vasculitis, which involves constitutional features and inflammation-associated serum markers. The organ and tissue ischemia involvement is determined either by well defined clinical criteria or by biopsy [3]. The morphologic components of active vasculitis involve both vascular wall inflammatory events and inflammatory lesions of the extravascular tissue. They are often asymptomatic and the histological activity must be estimated by biopsy or by angiographic procedures. According to Langford, remission would be defined by the absence of active disease and relapse as the return of disease activity following remission [2]. “Persistent only disease” is due to active but not new or worse disease activity and includes low grade manifestations of vasculitis (grumbling activity), which are usually not felt to warrant an intensification of therapy [4][5]. The sequelae or complications of active lesions or of drug toxicity are referred to as “damage”. The concept of “damage” represents a non-healing and irreversible scar that is unlikely to respond to immunosuppressive therapy lasting longer than three months [4]. “Damage” includes chronic syndromes with specific clinical deteriorations (end-stage renal disease, aneurisms, systemic or pulmonary hypertension, chronic pulmonary dysfunctions, blindness, diminished hearing, chronic neuropathies), despite a good vasculitic activity


I. Matei

control [6]. Clinical practice revealed that these progressive clinical syndromes are true traps in making a correct therapeutic decision. A vasculitic patient can show simultaneously “damage” elements and some active components [7]. In this context, the clinical dilemma is to decide whether: i.

“damage” could account for all the findings in the patient; ii. there is a chronic progressive and underlying “damage” with a superimposed relapse; iii. a low grade grumbling disease is the cause of clinical symptoms. A correct differentiation between “activity” and “damage” helps to avoid unnecessary exposure to cytotoxic medication [8]. RATE OF RELAPSES

The interval between occurrence of remission and of first relapse may vary largely, from three months to sixteen years [9]. The risk to develop relapse depends upon the specific vasculitis diagnosed [10]. So, in primary, small and medium vasculitis, the number of patients suffering from one or more relapses varies from 25 to 81% [11][12]. Vasculitic patients with anti-proteinase-3 neutrophil cytoplasmic antibodies (PR3-ANCA), also known as cANCA (antibodies with cytoplasmic staining pattern), have a significantly higher relapsing rate than patients having antimyeloperoxidase neutrophil cytoplasmic antibodies (MPO-ANCA), known as pANCA (perinuclear staining pattern). In giant cell arteritis, about 30–40% of patients may relapse two years after diagnosis if the corticosteroids dose is reduced [13], withdrawn too quickly [14] or even independently of the corticosteroids regimens [15]. Patients may relapse as long as ten or more years after discontinuance of treatment or may have a more chronic relapsing course that requires low doses of corticosteroids for several years [16]. A 20 years study of NIH on Takayasu arteritis revealed that 45% of patients had at least one relapse, 23% never achieved a corticosteroid-free remission [17] and about 20% of patients had a monophasic and self-limiting vasculitis [15]. In polyarteritis nodosa the rate of relapse is significantly lower (7–10%) than in other vasculitis [15]. The occurrence of relapse is dependent on the treatment duration. Commonly, relapses develop through the first two years after interruption of all immunosuppressive drugs. The prolonged immunosuppression is not always


beneficial for relapse prevention, and it is not clear which is the actual benefit of extending the therapy duration. ASSESSMENT OF DISEASE ACTIVITY TO DIAGNOSE THE RELAPSE THE SCORING SYSTEMS

Scoring systems are applied to evaluate a given vasculitis at the time of diagnosis. They are the disease activity (the Birmingham vasculitis activity score, BVAS), the disease extent (disease extent index, DEI) and the damage post vasculitis (vasculitis damage index, VDI) [4]. These scoring systems have a prognostic value but have some limitations in defining the relapse [9]. THE SYSTEMIC SYNDROME OF VASCULITIS

The syndrome can predict the return of disease activity prior to other symptoms and signs that suggest ischemic organ injuries. In relapse, the systemic syndrome of vasculitis may appear very suddenly or gradually, over days or weeks. There are some serum biomarkers including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and inflammatory cytokines which are very useful in relapse diagnosis. The inflammation associated serum markers CRP and ESR have been found to be the convenient indicators of disease activity during relapse in idiopathic vasculitis [14]. The fever of unknown origin (FUO) can be due to a relapsing vasculitis and, in the elderly, the relapsing FUO can be the unique manifestation of aortic arch and cardiac valve vasculitis [18] or of chronic inflammatory periaortic syndrome [19]. Authors reported that a fluorodeoxyglucose-positronemission tomographic (FDG-PET) scan revealed a markedly enhanced glucose uptake in the aorta and cardiac valves, being the only investigation able to indicate vasculitis as the cause of FUO [18][19]. Scanning by FDG-PET has a great sensitivity (84%) and specificity (80%) for localizing the source of FUO [20]. Jayne and collab. [7] found for ANCAassociated relapse of vasculitis mean values of 26.1 mg/l and 49 mm/h for CRP and ESR levels, respectively. However, the three indicators, clinical systemic features, ESR and CRP, are not sufficiently sensitive and specific to undoubtedly


Diagnosis of vasculitis relapses

indicate relapse in all patients [15]. Other serum markers have also been described, to serve in the early diagnosis of relapses. Serum level of interleukin (IL)-6, soluble IL-2 receptor, soluble intercellular adhesion molecule I, as well as hyperferritinemia and hypoferremia are of help in giant-cell arteritis relapses [21]. Serum IL-6 level continues elevated for 69% of remissive patients after corticotherapy, despite the absence of clinical disease activity, and persistence of elevated levels is associated with a high relapse rate [13]. Von Willebrand factor antigen can predict relapse in Takayasu arteritis but is not sufficiently sensitive or specific [15]. Patients with ANCA-associated vasculitis have raised levels of circulating inflammatory cytokines compared to healthy controls, even during remission. Disease associated activity is kept under control in these patients by inhibitory cytokines, during clinical remission. Lower levels of IL-10 and higher levels of IL-6 predict a greater risk of relapse and raised IL-8 seems to be associated with a poor prognosis [22]. In Wegener’s granulomatosis patients, the serum levels of soluble Il-2 receptor, a marker of T-cell activation, correlate well with disease activity [23]. The so-called “proinflammatory phenotype” in PR3-ANCA vasculitis patients with end-stage renal disease is characterized by high secretion of IL-1β and low secretion of its antagonist IL-1 receptor (IL-1Ra) [24]. ORGAN SIGNS AND/OR SYMPTOMS IN RELAPSE

There are differences in the clinical profile of relapse for different vasculitis. The knowledge of these differences helps in the selection of the most appropriate strategy, i.e. type and frequency of clinical serologic and imaging procedures for monitoring the patients in remission. Relapse can occur in any part of the body, in the same or in a different situs compared to the initial presentation. Any tissue or organ may be at risk [25]. There are some “surrogate” signs of relapse vasculitis. The acute onset, during remission, of nephritic syndrome, mononeuritis multiplex, palpable purpura, microangiopathic hemolytic anemia or retinal signs, associated or not with constitutional features (fever) can support a clinical diagnosis of relapse [26–28]. Relapse may be pointed out by a new pain with variable localization: i) peripheral, being suggestive for neuropathy, or ischemia of the skin


or ii) abdominal, due to ischemia of gastrointestinal tract, angor pectoris or claudication of arms. Waxing and waning pulmonary infiltrates made relapsing vasculitis to be considered. Recurrent ischemic optic neuropathy (ION) was reported to occur in 10% of patients with giant-cell arteritis [29]. Six of seven patients with recurrent ION had a new headache at the time of recurrence, but only in one of these patients this feature was recognized as preceding the ION. In Takayasu arteritis or periarteritis nodosa, periodical clinical examination is useful to detect newly vascular bruits, pulse reduction, blood pressure differences between arms or recent elevated diastolic blood pressure. Organ-Specific Differences in Rate of Relapse There are organ specific differences in the rate of relapse. Half of the patients with microscopic polyangiitis who entered end-stage renal failure beyond one year after diagnosis had relapse of renal vasculitis. So, it is necessary to maintain the immunosuppressive therapy in addition to hemodialysis. Hogan et al. found in these patients an association between relapse and subsequent progression to endstage renal failure. Undetected, persistent active nephritis may be a risk factor for patients with microscopic polyangiitis without overt signs of systemic vasculitis [3]. Gastrointestinal involvement in patients with Churg-Strauss syndrome is associated with a high rate of relapse [5][30]. An increased frequency of relapsing heart disease was detected in the ANCAnegative Churg-Strauss syndrome, while a higher rate of relapsing glomerulonephritis was registered in the ANCA-positive patients [31][32]. Differently, asthma and eosinophilia are not strictly included in the diagnosis of relapse in Churg-Strauss syndrome [2]. Patients with limited Wegener’s granulomatosis were found to more frequently develop systemic disease relapses following remission. In these patients trimetoprim-sulfametoxazole reduced relapse of nasal or upper airway lesions but not the relapse involving other organs [2]. Unusual and/or Unexpected Manifestations of Relapse Sometimes the manifestations of relapse are unusual or unexpected. Thus, signs mimicking relapsing polychondritis were shown by a patient with microscopic polyangiitis [33] and Wegener’s


I. Matei

granulomatosis patients revealed either relapsing esophageal and gastric ulcers [34] or large-vessel (pulmonary artery) vasculitis [35]. Liver dysfunctions (elevated levels of alkaline phosphatase, gamma glutamyl transpeptidase or of alanine transaminase and aspartate transaminase) had been registered prior to renal relapse of microscopic polyangiitis [36][37]. Unusual presenting symptoms such as respiratory symptoms, peripheral neuropathy or skin rash, Reinaud symptoms [38], and also interstitial nephritis [personal data] were reported in relapses of giant cell arteritis. DIAGNOSIS OF RELAPSE IN SUBCLINICAL VASCULITIS

In a number of asymptomatic patients thought to be in remission, unexpected disease activity was found by laboratory testing, diagnostic imaging or histopathological exploration. Active disease in asymptomatic patients with Takayashu arteritis was recognized by periodic arteriographic monitorization which revealed new stenosed sites or aneurism formation [39]. Thoracicaortic aneurism occurs as a late event usually several years after the diagnosis of giant-cell arteritis and after other symptoms have subsided [14]. Finding of histopathologically active giant-cell artheritis of the tissue of surgery for aortic aneurisms or at the time of post mortem examination has also been described [15]. Recently, tridimensional contrast enhanced magnetic resonance angiography (3D-CE-MRA) in whole body MRA imaging has emerged as a modality for monitoring disease progression or stability in two idiopathic vasculitis, Takayashu arteritis and polyarteritis nodosa [40]. This is a noninvasive method and without involvement of radiation, requiring only a peripheral venous injection of a non-nephrotoxic contrast agent (gadolinium). All studies pointed out the importance of intraoperative biopsy in all patients with Takayasu arteritis, giant-cell arteritis and other idiopathic vasculitis of large and medium vessels undergoing vascular surgery and recommended suppression before surgery of any suspicious sign of disease activity, by corticosteroid therapy [15]. Subclinical vasculitis may be present in temporal arteritis of patients with polymyalgia rheumatica. Rarely, the only histological abnormality may be a small-vessel vasculitis surrounding a normal temporal artery [14]. Studies involving positron-emission


tomography emphasized vascular involvement in patients with polymialgia rheumatica who do not have clinical signs of giant-cell arteritis [41]. Since in idiopathic systemic small-vessel vasculitis repeated biopsies are not routinely performed for diagnosis of relapse, the clinician takes advantage on other diagnostic tools: i.

Persistent or relapsing active glomerulonephritis may be asymptomatic [2][3]. Newonset hematuria with red blood cell casts, from non-urologic or gynecologic sources, isolated non-nephrotic proteinuria and/or decline in glomerular filtration rate (8 ml/min or more over 4 months) were considered the clinical expressions of renal relapsing vaculitis [42]. It has been also found that a higher serum creatinine level at the end of therapy of renal vasculitis is associated with a higher risk of relapse [3]. ii. Up to 34% of Wegener’s granulomatosis patients having thoraco-pulmonary radiography abnormalities may lack pulmonary symptoms. Post mortem studies in patients with Wegener’s granulomatosis indicated that persistent airway inflammation is more common than it has been appreciated clinically [2]. That is why the asymptomatic patients with Wegener’s granulomatosis, microscopic polyangiitis or ChurgStrauss syndrome should be monitored by chest radiographs at 6–12 month intervals [2][43]. It is assumed that every patient with Wegener’s granulomatosis has a low grade chronic infection of the nasal mucosa, predominantly caused by Staphylococus aureus. The chronic carriage of S. aureus was associated with increased ANCA positivity [44], constituting an independent risk factor for relapse. Popa et al. found that the relapse risk was modulated by the type of S. aureus antigens, the toxicshock syndrome toxin 1 being associated with a higher risk for relapse [45]. In the presence of staphylococcal protein A antigen, ANCAproducing B cells could be induced to proliferate, resulting in augmentation of the pool of autoantibodies [46]. iii. In cerebral vasculitis, in the absence of other reliable markers, the use of serial cranial magnetic resonance imaging scans is of help to monitor the course of central nervous system disease [47]. However, the finding of normal vessels on either conventional or magnetic resonance angiography does not exclude a



Diagnosis of vasculitis relapses

diagnosis of cerebral vasculitis. So, in one series of 14 patients with biopsy-proven primary cerebral vasculitis, 64% had normal angiograms. Therefore, brain biopsy is considered the “good” standard in diagnosis of central nervous system vasculitis [48]. MOLECULAR MARKERS ASSOCIATED OR PREDICTING RELAPSE

Antineutrophil Cytoplasmic Antibodies (ANCA) It is a commonly accepted point of view in clinical practice for assessment of PR3-ANCA and MPO-ANCA as diagnosis and disease activity monitoring tools in patients with systemic small vasculitis [2, 9]. Prevalence of ANCA depends on vasculitis activity and extent [49] and, moreover, patients who remain persistently ANCA-positive have a higher risk of relapse [50]. In patients with MPO-ANCA-associated necrotizing crescentic glomerulonephritis, persistent ANCA positivity may even be a risk factor for development of endstage renal failure in the absence of signs of a relapse [3]. The time interval between detection of a rise in PR3-ANCA level and a relapse ranged from 0 to 616 days, and the interval between a MPO-ANCA rise and the relapse ranged from 121 to 217 days. The patients with slightly higher CRP and ESR levels during the first three months after ANCA level elevation may have an “ensuing” relapse [9]. The quality of ANCA antibodies might influence their pathogenicity. Thus, an elevated level of IgG3 subclass of PR3-ANCA increases the positive predictive value of these antibodies for the relapse occurrence. In patients with Wegener’s granulomatosis, disease activity correlated better with the capacity of PR3-ANCA antibodies to inhibit complexation of PR3 enzyme with alpha1antitrypsin than with the titre of PR3-ANCA [9]. Antiendothelial Cell Antibodies (AECA) More recent studies showed that the presence of AECA, detected by cyto-ELISA on fixed or nonfixed endothelial cells, reflects the activity of vasculitis and may serve as an independent risk factor of relapse [51][52]. In active Takayasu arteritis, AECA antibodies have a great prevalence (95%) and are macrovascular endothelial cells specific, with distinct predilection to human umbilical vein

endothelial cells, saphenous vein or aorta endothelial cells, but not to microendothelial cells (omental microvasculature) [53]. Large vessels strongly express von Willebrand factor antigen [52] and its elevated serum level can predict relapse in Takayasu arteritis patients [15]. In Kawasaki disease, IgM-type AECA were detected in up to 72% of patients and titres of antibodies cytotoxic to macrovascular human umbilical vein endothelial cells correlated with disease activity and disappeared in convalescent patients [53]. Rise in AECA titres unclassified as macrovascular or microvascular specific [52] can precede the development of relapse in ANCAnegative Wegener’s granulomatosis patients and the persistence of ANCA after remission associates with a highly increased risk of relapse [54]. Other Relevant Biomarkers Receptor for the Fc fragment of IgG (FcγR) In the first five years after diagnosis, the probability of relapse in patients with Wegener’s granulomatosis is elevated if they are homozygous for both the R131 form of FcγRIIa and F158 form of FcγRIIIa (relative risk of 3.3). These polymorphisms are associated with decreased FcγRmediated clearance and persistence of nasal carriage of S. aureus [9]. B-cell activating factor of the TNF family (BAFF) Serum levels of BAFF were significantly increased in chronically relapsing Wegener’s granulomatosis patients compared to the healthy controls [55]. T-cell activation markers Increased levels of T-cell activation markers such as soluble interleukin-2 receptor and soluble CD30 receptor were described in Wegener’s granulomatosis and Churg-Strauss syndrome and they correlated with clinical disease activity. In patients with Wegener’s granulomatosis, relapse was often associated with or preceded by raised levels of these markers [56]. Soluble vascular cell adhesion molecule-1 (sVCAM-1) Elevated levels of serum sVCAM-1 have been reported in active ANCA-positive systemic vasculitis [57].


I. Matei


Vasculitele idiopatice sunt boli inflamatorii complexe care afectează vasele mici, medii şi mari. Evoluţia lor este frecvent de tip recurent, cu recăderi care cresc morbiditatea şi mortalitatea. Diagnosticul recăderilor constituie o dificilă problemă clinică, datorită faptului că tabloul clinic al vasculitei se poate schimba în cursul recăderii, uneori cu un pattern mai agresiv. În plus, semnele de recidivă se pot suprapune peste sindromul de tip „damage”, iar la pacienţii asimptomatici se pot întâlni leziuni active subclinice. Sunt discutate manifestările organ-specifice şi sistemice care pot apărea în cursul recăderilor, prezentând şi unele aspecte neobişnuite sau neaşteptate care se pot întâlni în recidivele din diferite vasculite. Se descriu de asemenea modalităţile de determinare a activităţii bolii în vederea diagnosticării recidivei, inclusiv markerii serologici care se asociază sau prezic recăderea, precum şi diagnosticul recăderilor în vasculitele subclinice. Corresponding author:

Prof. Dr. I. Matei Clinic of Internal Medicine, Colentina Hospital 19–21, Şos. Ştefan cel Mare, 020125 Bucharest, Romania Email: [email protected]


2. 3. 4. 5. 6. 7. 8. 9.

10. 11. 12. 13. 14. 15. 16. 17. 18.

SANDERS J.S., STASSEN P.M., VAN ROSSUM A.P., CALLENBERG C.G., STEGEMAN C.A., Risk factors for relapse in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis: tools for treatment decision? Clin. Exp. Rheumatol., 2004, 22:S94–101. LANGFORD C.A., How can relapses be detected and prevented in primary systemic small-vessel vasculitides? Best Pract. Res. Clin. Rheumatol., 2005, 19:307–320. HOGAN S.L., FALK R.J., CHIN H., CAI J., JENNETTE C.E. et al., Predictors of relapse and treatment resistance in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis. Ann. Inter. Med., 2005, 143:621–631. FLOSSMANN O., BACON P.A., DE GROOT K., JAYNE D.R., RASMUSSEN N. et al., Development of comprehensive disease assessments in systemic vasculitis. Ann. Rheum. Dis., 2007, 66:283–292. LUQMANI R.A., FLOSSMANN O., Outcome of small-vessel systemic vasculitis. J. Rheumatol., 2006, 33:1224–1227. MUKHTYAR C., HELLMICH B., JAYNE D., FLOSSMANN O., LUQMANI R., Remission in antineutrophil cytoplasmic antibody-associated systemic vasculitis. Clin. Exp. Rheumatol., 2006, 24:S093–098. JAYNE D., RASMUSSEN N., ANDRASSY K., BACON P., COHEN TERVAERT J.W. et al., A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic antibodies. N. Engl. J. Med., 2003, 349:36–44. SEO P., LUQMANI R.A., FLOSSMANN O., HELLMICH B., HERLYN K. et al., The future of damage assessment in vasculitis. J. Rheum., 2007, 34:1357–1371. BOOMSMA M.M., STEGEMAN C.A., KALLENBERG C.G.M., COHEN TERVAERT J.W., Prevention of relapsing disease in anti-neutrophil cytoplasmic antibody related necrotising small-vessel vasculitis: the role for autoantibody guided and antibacterial treatment. In: Disease-modifying Therapy in Vasculitides (C.G.M. Kallenberg, J.W. Cohen Tervaert, Eds.), 2001, p. 181–199. GORDON M., LUQMANI R.A., ADU D., GREAVES I., RICHARDS N. et al., Relapses in patients with a systemic vasculitis. Q. J. Med., 1993, 86:779–789. SAMARKOS M., LOIZOU S., VAILOPOULOS G., DAVIES K.A., The clinical spectrum of primary renal vasculitis. Semin. Arthritis Rheum., 2005, 35:95–111. BACON P.A., The spectrum of Wegener’s granulomatosis and disease relapse. N. Engl. J. Med., 2005, 325:330–332. COHEN TERVAERT J.W., STEGEMAN C.A., KALLENBERG C.G.M., Standard therapeutic regimens for vasculitis. In: Disease-modifying Therapy in Vasculitides (C.G.M. Kallenberg, J.W. Cohen Tervaert, Eds.), 2001, 21–40. SALVARANI C., CANTINI F., BOIARDI L., HUNDER G.G., Polymyalgia rheumatica and giant-cell arteritis. N. Engl. J. Med., 2002, 347:261–278. LANGFORD C.A., HOFFMAN G.S., Methotrexate as an alternative to classic immunosuppressive therapies. In: Diseasemodifying Therapy in Vasculitides (C.G.M. Kallenberg, J.W. Cohen Tervaert, Eds.), 2001, 21–40. GAYRAUD M., GUILLEVIN L., LE TOUMELIN P., COHEN P., LHOTE F. et al., Long-term followup of polyarteritis nodosa, microscopic polyangiitis, and Churg-Strauss syndrome. Arthritis Rheum., 2001, 44:666–675. HOFFMAN G.S., LEAVITT R.Y., KERR G.S., ROTTEM M., SNELLER M.C., FAUCI A.S., Treatment of glucocorticoidresistant or relapsing Takayasu arteritis with methotrexate. Arthritis Rheum., 1994, 37:578–582. OBERMEIER F., HEROLD T., SCHONBERGER J., TARNER I., EILLES C. et al., Vasculitis of the aortic arch and cardiac valves as the cause of relapsing fever of unknown origin in an elderly white man. Clin. Rheumatol., 2006, 25: 923–925.


Diagnosis of vasculitis relapses


19. VAGLIO A., BUZIO C., Chronic periaortitis: a spectrum of diseases. Curr. Opin. Rheumatol., 2005, 17:34–40. 20. MEYER G.S., HALES C.A., AMREIN P.C., SHARMA A., KRADIN R.L., Case 26-2007: A 61-year-old man with recurrent fevers. N. Engl. J. Med., 2007, 347:807–816. 21. DOCKEN W.P., MARK E.J., Case 23-2002: A 73-year-old man with leg pains, occipital headaches, and night sweats. N. Engl. J. Med., 2002, 347:272––278. 22. OHLSSON S., WIESLANDER J., SEGELMARK M., Circulating cytokine profile in anti-neutrophilic cytoplasmatic autoantibody-associated vasculitis: prediction of outcome. Mediators Inflamm., 2004, 13:275–283. 23. CRAYTON A.R., SAVAGE C.O.S., What you should know about PR3-ANCA. Evidence for the role of T cells in the pathogenesis of systemic vasculitis. Arthritis Res., 2000, 2: 260–262. 24. BORGMANN S., ENDISCH G., HACKER U.T., SONG B.S., FRICKE H., Proinflammatory genotype of interleukin-1 and interleukin-1 receptor antagonist is associated with ESRD in proteinase 3-ANCA vasculitis patients. Am. J. Kidney Dis., 2003, 41:933–942. 25. SMYTH L., GASKIN G., PUSEY C.D., Microscopic polyangiitis. Semin. Respir. Crit. Care. Med., 2004, 25:523–533. 26. McLAREN J.S., McRORIE E.R., LUQMANI R.A., Diagnosis and assessment of systemic vasculitis. Clin. Exp. Rheumatol., 2002, 20:854–862. 27. HELLMICH B., GROSS W.L., Difficult to diagnose manifestations of vasculitis: does an interdisciplinary approach help? Best Pract. Res. Clin. Rheumatol., 2005, 19:243–261. 28. ARISTODEMOU P., STANFORD M., Therapy insight: the recognition and treatment of retinal manifestations of systemic vasculitis. Nat. Clin. Pract. Rheumatol., 2006, 2:443–450. 29. CHAN C.C.. PAINE M., O’DAY J., Predictors of recurrent ischemic optic neuropathy in giant cell arteritis. J. Neuroophthalmol., 2005, 25:14–17. 30. PAVONE L., GRASSELLI C., CHIERICI E., MAGGIORE U., GARINI G., RONDA N. et al., Outcome and prognostic factors during the course of primary small-vessel vasculitides. J. Rheumatol., 2006, 33:1299–1306. 31. HOFFMAN G.S., LANGFORD C.A., Are there different forms of life in the antineutrophil cytoplasmic antibody universe? Ann. Intern. Med., 2005, 143:683–685. 32. SABLE-FOURTASSOU R., COHEN P., MAHR A., PAGNOUX C., MOUTHON L., JAYNE D. et al., Antineutrophil cytoplasmic antibodies and the Churg-Strauss syndrome. Ann. Intern. Med., 2005, 143:632–638. 33. OGAWA H., NISHI E., KAMEDA H., AMANO K., TAKEUCHI T., Manifestations mimicking relapsing polychondritis in a patient with microscopic polyangiitis. Japan. J. Clin. Immunol., 2005, 28:104–108. 34. ARISTA S., SAILLER L., ASTUDILLO L., Relapsing esophageal and gastric ulcers revealing Wegener’s granulomatosis. Am. J. Med., 2005, 118:923–924. 35. CLARK T., HOFFMAN G.S., Pulmonary artery involvement in Wegener’s granulomatosis. Clin. Exp. Rheumatol., 2003, 21:S124–126. 36. NAKAMOTO T., YOSHIKAWA M., NAKATANI T., YAMANE Y., IWASAWA S., MATSUMOTO M. et al., Microscopic polyangiitis that presented liver dysfunction prior to noted renal manifestations. Intern. Med., 2000, 39: 517–521. 37. HASHIMOTO H., Antineutrophil cytoplasmic antibody-related vasculitis and liver diseases. Intern. Med., 2000, 39: 449–450. 38. NESHER G., GUR H., EHRENFELD M., RUBINOW A., SONNENBLICK M., The change in clinical presentation of temporal arteritis in Israel. A multicenter study. Isr. Med. Assoc. J., 1999, 1:17–19. 39. SCHMIDT W.A., GROMNICA-IHLE E., What is the best approach to diagnosing large-vessel vasculitis? Best Pract. Res. Clin. Rheumatol., 2005, 19:223–242. 40. LIN J., CHEN B., WANG J., Diagnosis of systemic arterial diseases with whole-body contrast-enhanced magnetic resonance angiography. Chin. Med. J., 2006, 119:1772–1778. 41. VALLAT J.N., CROS D.P., HEDLEY-WHYTE E.T., Case 9-2007: A 27-year-old woman with pain and swelling of the legs. N. Engl. J. Med., 2007, 356:1252–1259. 42. AKIOKA Y., HATTORI M., KAWAGUCHI H., ITO K., A case of chronic relapsing ANCA-associated microscopic polyangiitis successfully treated with plasma exchange. Ther. Apher. Dial., 2004, 8:223–226. 43. TANIGUCHI H., HONDA R., ADACHI Y., ABO H., NOTO H., IZUMI S., A case of Wegener’s granulomatosis without PR3ANCA at relapse. J. Jpn. Respir. Soc., 2005, 43:547–551. 44. STEGEMAN C.A., COHEN TERVAERT J.W., SLUITER W.J., MANSON W.L., DE JONG P.E., KALLENBERG C.G.M., Association of chronic nasal carriage of S. aureus and higher relapse in Wegener’s granulomatosis. Ann. Intern. Med., 1994, 120:12–17. 45. POPA E.R., STEGEMAN C.A., KALLENBERG C.G.M., COHEN TERVAERT J.W., Staphylococcus aureus and Wegener’s granulomatosis. Arthritis Res., 2002, 4:77–79. 46. POPA E.R., STEGEMAN C.A., BOS N.A., KALLENBERG C.G.M., COHEN TERVAERT J.W., Staphylococcal superantigens and T cell expansions in Wegener’s granulomatosis. Clin. Exp. Immunol., 2003, 132:496–504. 47. GITTINS N., BASSU A., EYRE J., GHOLKAR A., MOGHAL N., Cerebral vasculitis in a teenager with Goodpasture’s syndrome. Nephrol. Dial. Transplant, 2004, 19:3168–3171. 48. NESHER G., GUR H., EHRENFELD M., RUBINOW A., SONNENBLICK M., The changing clinical presentation of temporal arteritis in Israel: a multicenter study. Isr. Med. Assoc. J., 1999, 1:17–19. 49. WIIK A., What you should know about PR3-ANCA: An introduction. Arthritis Res., 2000, 2:252–254. 50. HOFFMAN G.S., STONE J.H., LANGFORD C., Implications of antineutrophil cytoplasmic antibody status when switching to maintenance therapy. Arthritis Care Res., 2005, 53:1–2.


I. Matei


51. SHOENFELD Y., Classification of anti-endothelial cell antibodies into antibodies against microvascular and macrovascular endothelial cells: the pathogenic and diagnostic implications. Clev. Clin. J. Med., 2002, 69:SII-65–67. 52. PRAPROTNIK S., BLANK M., MERONI P.L., ROZMAN B., ELDOR A., SHOENFELD Y., Classification of anti-endothelial cell antibodies into antibodies against microvascular and macrovascular endothelial cells: the pathogenic and diagnostic implications. Arth. Rheum., 2001, 44:1484–1494. 53. EICHHORN J., SIMA D., THIELE B., LINDSCHAU C., TUROWSKI A., SCHMIDT H. et al., Anti-endothelial cell antibodies in Takayasu arteritis. Circulation, 1996, 94:2396–2401. 54. GOBEL U., EICHHORN J., KETTRITZ R., BRIEDIGKEIT L., SIMA D., LINDSCHAU C. et al., Disease activity and autoantibodies to endothelial cells in patients with Wegener’s granulomatosis. Am. J. Kidney Dis., 1996, 28:186–194. 55. KRUMBHOLZ M., SPECKS U., WICK M., KALLED S.L., JENNE D., MEINL E., BAFF is elevated in serum of patients with Wegener’s granulomatosis. J. Autoimmun., 2005, 25:298–302. 56. SCHMITT W.H., HAGEN E.C., VAN DER WOUDE F.J., T-cell directed treatment: anti-thymocyte globulin. In: Diseasemodifying Therapy in Vasculitides (C.G.M. Kallenberg, J.W. Cohen Tervaert, Eds.), 2001, p. 113–123. 57. WIKMAN A., LUNDAHL J., JACOBSON S.H., Neutrophil activation in anti-proteinase 3-positive vasculitis – a prospective study. Scand. J. Immunol., 2005, 62:539–545. Received July 28, 2008

Traditional and Nontraditional Risk Factors for Atherosclerosis in Patients with Systemic Lupus Erythematosus V. POMPILIAN, CAMELIA BADEA, ISABELA DRAGOMANU, ELENA BĂLĂŞESCU, C. TĂNĂSESCU 2nd Medical Clinic, Colentina Clinical Hospital, Bucharest, Romania

Premature atherosclerosis (ATS) in SLE patients is an important clinical problem. It is explained not only by excess of traditional risk factors, but also by specific factors linked to disease activity and therapy. Such specific factors include the following: antioxLDL and anti CRP antibodies, immune complexes, mannose-binding lectin, disturbances of metabolism of annexin A5, antiphospholipid syndrome, immunologically determined dyslipidemia, influence of medication. As a conclusion,atherosclerosis in SLE patients results from an interplay between traditional and nontraditional risk factors. Therapeutic influences suggest antiatherogenic effects for hydroxychloroquine and immunosuppressants and a doubtful proatherogenic influence of cortisone. Key words: atherosclerosis, lupus, risk factors, nontraditional, antioxLDL, antiCRP, mannose binding, lectin, annexin, antiphospholipid, antilipoproteinlipase, hydroxychloroquine, cortisone, immunosuppression.

Increased atherosclerosis (ATS) prevalence in patients with systemic lupus erythematosus (SLE) is an epidemiologic certainty. Urowitz [1] describes a bimodal mortality pattern in SLE, with an early spike caused by severe visceral complications and a late spike, which is almost entirely due to atherosclerosis-related vascular phenomena. Another striking aspect is that in the population segment represented by women between 35–45 years old (in which there is a high prevalence of SLE) ischemic heart disease is 50 times more frequent than in control population [2]. In the search to find an explanation for the high association between SLE and ATS it was first noticed that traditional ATS risk factors (such as: hypertension, diabetes mellitus, hyperlipoprotemias, obesity) are overrepresented in SLE patients. However, a bulk of epidemiological studies [3–6] drew attention to the item that solely excess of traditional risk factors is unable to explain increased prevalence of ATS. Additional atherogenic factors in SLE patients are linked to: endothelial immune conflict, antiphospholipid antibodies (APLAs), corticotherapy. Many of these factors belong to the inflammatory pathogenesis, which is common to both SLE and ATS. There is an overlap between traditional and nontraditional ATS risk factors in SLE patients. A ROM. J. INTERN. MED., 2008, 46, 3, 195–198

typical example is represented by dyslipidemias. Dyslipidemias may be caused by immune disturbances, such as anti lipoproteinlipase antibodies; on the other hand, they are able to generate autoimmune phenomena. Some of the supplementary ATS risk factors linked to SLE activity and therapy deserve a deeper analysis. 1. ENDOTHELIAL IMMUNE CONFLICT

Vascular endothelial lesions, caused by: antibodies (antiendothelial, APLAs, antioxLDL, antiCRP, etc.), immune complexes, complement activation products, cytokines, etc. lead to precocious ATS. This process amplifies the immune reaction toward oxLDL and HSP, which are initial steps in ATS in the general population. Supplementary factors are: interference between oxLDL and APLAs; displacement of annexin V from endothelium; immune complexes influencing endothelial lipid metabolism; mannose-binding lectin and its role in the regulation of the oxidation level of LDL.A further discussion is necessary for some of the items above: a) Immunogenicity of oxLDL: oxLDL not only have a toxic effect on the endothelium, but also


V. Pompilian et al.

are immunogenic. At least two mechanisms account for the latter: antioxLDL antibodies and dendritic cell maturation. • antioxLDL: A possible proatherogenic role for antioxLDL in SLE patients is controversial. Some studies conclude that they are proatherogenic [7], whereas others find them neutral [8] or even antiatherogenic [9]. These contradictory results most likely yield from the heterogeneity of antioxLDL: different subsets could have different effects on atherogenesis. AntioxLDL are also correlated wih SLE activity and with APLS; • dendritic cell maturation induced by oxLDL, with a subsequent overexpression of MHC II and costimulatory molecules is an accelerating factor for atherogenesis in autoimmune diseases [10]. b) AntiCRP antibodies (ACRP): they are present in 23–78% of SLE patients and are rarely encountered in healthy persons [11]. They are correlated with disease activity, especially with renal manifestations. There is also an association with APLAs. ACRP may provide a link between a marker of inflammation and ATS in SLE patients (although it is well known that high levels of CRP are quite uncommon in SLE).ACRP are targeted to monomeric CRP (native CRP is pentameric); they emerge as a consequence of apoptosis. 2. IMMUNE COMPLEXES (IC)

They link to C1q receptors on the endothelium, resulting in upregulation of adhesion molecules (ICAM1, VCAM1, E-selectin) on its surface. IC also have effects on lipid metabolism: they inhibit sterol27dehydrogenase, which contributes to accumulation of cholesterol inside the endothelial cell. 3. MANNOSE-BINDING LECTIN (MBL)

MBL has a classical role in complement activation. Besides, it is also implicated in regulation of the oxidation level of oxLDL [12] [13]. MBL binds to oxLDL, favoring clearance of the latter. It also exerts other antiatherogenic effects, such as: clearance of apoptotic cells; clearance of IC; diminishing of macrophage-


dependent inflammatory processes. Antibodies toward MBL have been described in SLE patients, but their significance is uncertain. Homozygous state for certain alleles of MBL in SLE patients is correlated with a risk for thrombosis. 4. ANNEXIN V(ANXA5)

Annexins [14][15] make up a superfamily of more than 1000 molecules, expressed by most eukaryotic cells, ubiquitous, with a large tissue distribution, mostly intracellular (annexins represent 2% of intracellular proteins).They are involved in intracellular signal transmission and endocytosis. There are 12 subtypes with structural and functional differences encoded by variability of N terminal region. Annexin V (ANXA5) is encoded by a gene located on chromosome 4:q26-g28. Although ANXA5 is mainly intracellular, there is a normal plasmatic level ranging between 1–28ng/ml. In placental microcirculation ANXA5 forms a protective barrier between the fetal and maternal blood. A very important physiological aspect of ANXA5 is represented by the antithrombotic properties. The process of coagulation needs cofactors like phosphatidylserine(PS) and calcium. ANXA5 has a high (calcium-dependent) affinity for PS, which allows for shielding of PS-expressing surfaces. Other antithrombotic mechanisms include downregulation of surface-expressed tissue factor, upregulation of urokinase-type plasminogen activator, as well as interference with hemostasis ligands, such as sulfatides and heparin. Thrombogenicity of the atheroma plaque is determined by the presence of phospholipids and tissue factor (TF) linked by cell membranes. TF and proinflammatory cytokines have been demonstrated in rupture-prone areas, such as the “shoulder” of the plaque and also in highly thrombogenic areas, such as the lipid-laden necrotic core. ANXA5 is abundant in advanced stage plaques, mainly in areas with high risk for thrombosis. Here it exerts a yet unknown role, but it probably acts as an antithrombotic “band aid”. This effect is the result of shielding of procoagulant sites and also of inhibition of uptake of apoptotic material by phagocytic cells. In SLE patients diminished endothelium binding of ANXA5 induced by APLAs has been experimentally demonstrated. It is also suggested that APLAs might neutralize the antithrombotic



Risk factors for atherosclerosis in SLE

properties of ANXA5. Polymorphism of the ANXA5 gene has been described in SLE, consisting of a 1C→T mutation; it is involved in both atherosclerosis and spontaneous abortions. Antibodies against ANXA5 have also been found, but they seem irrelevant to the risk of thrombosis. In the setting of atherosclerosis, ANXA5 has at least two important effects: it links oxLDL and it acts as a negative regulator of interferon gamma signaling pathway. As a conclusion, ANXA5 is an important antithrombotic molecule which might exert antiatherosclerotic effects in general population as well as in SLE patients.It also might become therapeutically useful. 5. ANTIPHOSPHOLIPID SYNDROME (APLS)

One of the manifestations of APLS (besides vascular thromboses and obstetrical pathology) is premature atherosclerosis. The atherogenic mechanism in APLS is related to β2GPI, a natural anticoagulant with a molecular weight of 50kD, present in mammalian plasma. Antibodies toward β2GPI (Aβ2GPI) generate activation of endothelium, of platelets and production of tissue factor.β2GPI becomes immunogenic by binding to negatively charged surfaces or to oxLDL. A vicious circle has been described between the concentration of APLAs and the oxidation level of oxLDL:on the one hand, APLAs have a higher affinity for oxidated phospholipids; one the other hand, APLAs are prooxidant, by inhibiting paraoxonase, an antioxidant enzyme [16]. Experiments with animals [17] have shown that both APLAs and cellular immune response toward phosphorlipids are atherogenic. 6. DYSLIPIDEMIAS IN SLE

The chronic immunoinflammatory processes in SLE can generate dyslipidemia [18]. One of the responsible mechanisms is insulinoresistance. There are also immunological reasons for dyslipidemia, such as antibodies directed to lypoproteinlipase (LPL) and to lipoprotein (a). Some dyslipidemias are secondary to corticotherapy. Anti LPL antibodies were demonstrated in 47% of SLE patients. They generate a lipid profile characterized by: increased VLDL and triglycerides

and decreased HDL and apo A1, resembling the metabolic syndrome. The amplitude of dyslipidemia is correlated to the level of antiLPL antibodies.


a) Corticotherapy: is classically thought to be proatherogenic. However, two prestigious studies [19] [20] cast doubt on this item. The authors studied prevalence of ATS in a population of treated SLE patients. It was noticed that the patients with higher doses of corticoids had fewer plaques. A lower number of plaques was also correlated with: active disease, hydroxylchloroquine treatment, immunosuppressive therapy. Similar results were obtained in rheumatoid arthritis: the DMARD treated patients had fewer plaques than the other ones. b) Immunosuppressants (IS): the above-mentioned studies find them antiatherogenic. It was postulated that IS could induce a “resetting” of endothelium, rendering it more resistant to ATS. c) Hydroxychloroquine: has a positively antiatherogenic effect, explained by several mechanisms: hypolipemiant, hypoglycemiant, antiplatelet, decreased production of APLAs, corticoid sparing effect. d) Hypolipemiant drugs: statins are antiatherogenic by means of their “pleiotropic”, antiinflammatory effect; they counteract endothelial dysfunction in ATS, both in general population and in SLE patients. Fibrates exert a similar action on atherogenesis. As a conclusion, association between ATS, SLE and APLS is fascinating, highlighting the correlations between three fundamental pathological processes: ATS, inflammation and thrombosis. Excess of traditional atherogenic factors as well as disease and therapy-related factors account for the high prevalence of ATS in SLE patients. There are important therapeutic influences: hydroxychloroquine is certainly antiatherogenic, immunosuppressants are possibly antiatherogenic and glucocorticoids have a possible proatherogenic effect, doubted however by recent important studies. Hopefully, in the near future progress in vascular biology will lead to novel therapeutic weapons against atherosclerosis.


V. Pompilian et al.


Ateroscleroza prematură este o problemă clinică importantă la pacienţii cu LES. Ea se explică nu doar printr-un exces de factori de risc tradiţionali, ci şi prin factori specifici, legaţi de activitatea bolii, ca şi de tratamentul acesteia. Asemenea factori specifici includ următoarele: anticorpi antioxLDL şi antiCRP, complexe imune, lectina care leagă manoza, tulburări ale metabolismului anexinei A5, sindromul antifosfolipidic, dislipidemia de cauză imunologică, influenţe medicamentoase. Ca o concluzie, ateroscleroza la pacienţii cu LES rezultă dintr-o interrelaţie între factori de risc tradiţionali şi nontradiţionali. Hidroxiclorochinul şi imunosupresoarele au efect antiaterogen, în vreme ce cortizonului i se atribuie un îndoielnic efect proaterogen. Corresponding author:

V. Pompilian, MD Clinic of Internal Medicine, Colentina Clinical Hospital 19–21, Şos.Ştefan cel Mare, 020125 Bucharest, Romania Email: [email protected]

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.

UROWITZ M.B., The bimodal mortality pattern of systemic lupus erythematosus. Am. J. Med., 1976, 60: 221–5. KARRAR A., Coronary artery disease in systemic lupus erythematosus: a review of literature. Semin. Arthr. Rheum., 2001, 6, 30. ROMAN M.J., Prevalence and relation to risk factors of carotid atherosclerosis. Am. J. Cardiol., 2001, 5, 87. VLACHOYANNOPOULOS P.G., Atherosclerosis in premenopausal women with APLS and SLE. Rheumatol. (Oxford), 2003, 5, 42. FROSTEGARD J., Autoimmunity,oxLDL and cardiovascular disease. Autoimm Rev., 2002, 4, 1. ESDALE J.M., Traditional Framingham risk factors fail to fully account for accelerated atherosclerosis in SLE. Arthr. Rheum., 2001, 10, 44. SVENNUNGSSON E., Risk factors for cardiovascular disease in systemic lupus erythematosus. Circulation, 2001, 104, 1887. ROCH B., Oxidatively modified lipoproteins and their antibodies in patients with antiphospholipid syndrome and systemic lupus erythematosus. Z. Rheumatol., 2004, 63(4): 331–7. FORBACH, Atherogenic antiphospholipid antibodies in antiphospholipid syndrome. Ann. NY Sci., 2007, 1108: 489–96. ZAGUI R., Danger effect of LDL and oxLDL in human immature dendritic cells. Clin. Exp. Immunol., 2007, 149(3): 543–52. O’ NEILL, Could antibodies to CRP link inflammation and cardiovascular disease in SLE? ARD, 2007, 66 (8): 989–92. TSUTSUMI A., Mannose binding lectin:genetics and autoimmune diseases. Autoimm. Rev., 2005, 4 (6): 364–72. FONT J., Association of mannose-binding lectin polymorphism with antiphospholipid syndrome,cardiovascular disease and chronic damage in patients with systemic lupus erythematosus. Rheum. (Oxford), 2007, 46(1): 76–80. CEDERHOLM A., Annexins as a novel player in prevention of atherosclerosis in SLE and in general population. Ann. NY Acad. Sci., 2007; 1108: 96–103. DE LAAT B., Annexin V polymorphism and antiannexin in antiphospholipid syndrome. ARD, 2006, 65(11): 1468–72. KISS E., Reduced paraoxonase1 activity is a risk factor for atherosclerosis in patients with systemic lupus erythematosus. Ann. NY Sci., 2007, 1108: 83, 91. GEORGE J., Antiphospholipid syndrome. Rheum. Clin. N. Am., 2001, 3, 27. BORBA E.F., Mechanisms of dyslipidemias in SLE. Clin. Dev. Immunol., 2006, 13 (2–4): 203–8. ROMAN M.J., Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus. NEJM, 2003, 349 (25): 2399–2406. ASANUMA Y., Premature coronary atherosclerosis in systemic lupus erythemetosus. NEJM, 2003, 349 (25): 2407–2415.

Received June 2, 2008


University of Medicine and Pharmacy Carol Davila, Bucharest, Romania 2 Department of Neurology, Colentina Hospital, Bucharest, Romania 3 Department of Internal Medicine, Colentina Hospital, Bucharest, Romania 4 National Institute of Infectious Diseases “Matei Bals”, Bucharest, Romania * Réseau d’Epidémiologie Clinique International Francophone (RECIF)

At the crossover of specialties, the osmotic demyelination syndromes are under-diagnosed clinical entities. Even if the knowledge and the management of these entities have evolved in the latest years, many issues are still unsolved. Initially described as diseases affecting alcoholics and malnourished and considered affecting solely the pons, it is now known that osmotic demyelination can produce extrapontine lesions (extrapontine myelinolysis). Rapid correction of sodium in hyponatremic patients is pathogenically involved in the genesis of central pontine and extrapontine myelinolysis. The aim of this review is to focus on the main characteristics of the disease, which can represent a challenge for the clinicians in respect to its recognition and treatment. Key words: central pontine myelinolysis, extrapontine myelinolysis, hyponatremia, osmotic demyelination.

At the crossover of specialties, the osmotic demyelination syndromes include central pontine myelinolysis (CM) and extrapontine myelinolysis (EM). Adams et al. described CM as a unique clinical entity in 1958 [1]. Alcoholic or malnurished patients developed spastic quadri-plegia, pseudobulbar palsy, and varying degrees of encephalopathy resulting from acute, noninflam-matory demyelination in the basis pontis [2]. Today is accepted that in more than 10% of CM patients, the demyelination lesions occur also outside the pons (EM, see below). CM seem to occur more frequently in females than in males, but the exact incidence is unknown. In Afro-Americans, CM was present in 29% of postmortem examinations of liver transplant patients [3]. Concerning the denomination of these pathological entities, some authors argued that the term “osmotic myelinolysis” is more appropriate than “central pontine myelinolysis” or “extra-pontine myelinolysis” for demyelination occurring in extrapontine regions after the correction of hyponatremia, trying so to eliminate the inflammatory hypothesis when considering the diagnosis in these patients. However, the two (CM and EM) are considered part of the same pathogenical process of “osmotic myelinolysis”, and the striking particular disposition of the lesions in the pons as reflected by MRI is highly suggestive for the mechanism that ROM. J. INTERN. MED., 2008, 46, 3, 199–205

characterizes the appearance of the lesional process (see below). In this respect, “osmotic myelinolysis” can be in practice more vague than CM, for example, but both CM and EM are “osmotic demyelination syndromes” [4]. CLINICAL FEATURES AND TOPOGRAPHICAL CONSIDERATIONS

Concerning the localization, CM is predominantly a lesion of the basis pontis, sparing the tegmentum, as a pathological process started in the central pons, near the median raphe, and it may extend up to the midbrain, and only very rarely down to the medulla, reaching at its maximum the two pyramids side by side with their bases at the origin of the trigeminal nerve [5]. A particularity of the topographical localization is that the lesion’s centre is situated at a point equidistant from the CSF spaces around the brainstem, maybe explained by the fact that this is a region of maximal admixture of grey and white matter elements, and EM similarly seem to affect regions of grey-white apposition. The description of morphological characters of the lesions suffered some changes in the last fifty years, since their genesis was influenced by the widespread introduction of intravenous fluid therapy. Microscopically, the


R. Tănăsescu et al.

lesion shows degeneration and loss of oligodendrocytes with preservation of axons unless the lesion is very advanced. The term demyelination was deliberately avoided in the initial description, in order to distinguish this condition in which the myelin loss occurs without any obvious inflammatory infiltrate from inflammatory processes [5]. The clinical characters of CM include usually a biphasic clinical course. The first phase is due to hyponatraemia that can manifest with encephalopathy or seizures, and is often recovering rapidly as normonatraemia is restored. The second phase can present with dysarthria and dysphagia (secondary to corticobulbar fibre involvement), a flaccid quadriparesis (from corticospinal tract involvement, which later can become spastic), due to involvement of the basis pontis. If the lesion extends into the tegmentum of the pons, then pupillary, oculomotor abnormalities may occur. Moreover, there may be an apparent change in the capacity of the patient to communicate reflecting the “lockedin syndrome” that a large lesion in this site is particularly liable to produce. If lesions of EM are also associated, the clinical picture may represent a challenge for the clinician since it can be very confusing, adding a variety of apparently psychiatric and behavioral changes and movement disorders [5]. More occulted than CM, EM have pathological changes identical to those of CM, as said before. Studies show that lesions can occur with or without CM. Necropsy series showed that isolated CM is present in about half, accompanied with EM in about 60%, and isolated EM in about 40% of cases [6]. A variety of sites may be involved: in descending order of frequency we must retain pons, cerebellum, lateral geniculate body, external capsule, extreme capsule, hippocampus, putamen, cerebral cortex/subcortex, thalamus, caudate nucleus. Only in 10% or less of the cases, lesions can occur in the claustrum, internal capsule, midbrain, internal medullary lamella, mamillary body, medulla oblongata [7]. The lesions are often strikingly symmetrical. Cerebral cortical sclerosis and lesions of the posterior columns have been described. The age of lesions in various sites in EM is contemporaneous, and it must be emphasized that CM and EM are the same disease, sharing the same pathology, associations, and time course but only differing in clinical manifestations. Movement disorders are encountered in EM [5]. There have been reported mutism, parkinsonism, dystonia, and catatonia, as a result of widespread of lesions. Cases with catatonia have been reported on


a couple of occasions, either as a brief episode lasting days before resolving and being replaced with parkinsonian features, or following the resolution of spastic tetraparesis the last settled over two weeks. It must be emphasized that these manifestations may be under-recognized. The evolving character of clinical features in EM is an important point to be known by the clinician. There have been reported cases with progression from spastic paraparesis with postural limb tremor and myoclonic jerks to a parkinsonian syndrome with choreoathetosis, or a parkinsonian state with signs of pyramidal dysfunction that resolved in a few months, being followed by transient retrocollis and oromandibular and brachial dystonia and dysphonia. The movement disorders of EM represent a treatable manifestation, responding well to dop-aminergic treatment in those with parkinsonian features [5]. PATHOGENICAL ASSOCIATIONS

Several entities have been described in relation with CM and EM, even if they were initially described as occurring in alcoholics mal-nourished, as had been said before [1]. CM or EM can occur frequently after prolonged diuretic use, post-liver transplantation, and more rarely in the context of burns, post-pituitary or post-urological / gynecological surgery, or psychogenic polydipsia. It must be emphasized that CM or EM rarely occurs in the absence of another significant illness. Hyponatraemia is frequently associated with the context of CM/EM occurrence, but only a small number of hyponatremic patients develops these pathologic entities, especially when large osmolality shifts occur [8]. A noteworthy association is with alcoholism, in up to 40% of cases, and similarities with demyelination of the corpus callosum and other commissural fiber systems known as Marchiafava-Bignami disease were discussed. In this spirit, Wernicke’s encephalopathy is a not infrequent accompaniment (30% in pathological series). Alcohol can interfere with sodium/water regulation by suppression of antidiuretic hormone (ADH) also in the context of insufficient nutrition of alcoholics [5]. It what concerns liver transplantation, CM is a classical complication, occurring in 2% of cases, maybe underestimated since postmortem studies showed a higher incidence. It also appears that EM can be an explanation for a proportion of the “acute encephalopathy” which is the most frequent neurological complication following liver transplantation [9].


Central pontine and extrapontine myelinolysis

Renal dialysis is, on the other hand, less frequently associated with CM/EM, maybe explained by the fact that urea contributes to measured osmolality, but as it easily crosses cell membranes, does not contribute to tonicity, thus protecting from the rapid shifts in sodium which can occur in haemodialysis [10]. Also, CM/EM occurs very rarely in diabetes, despite the pronounced shifts in osmolality that occur [5]. Etiology of CM/EM is linked to physiological changes in hyponatraemia and its correction [8][10][11]. Severe hyponatraemia is defined as Na+ levels fall under 120 mmol/l. The acute character is defined by a hyponatraemia known to date of less than 48 hours duration or developing at a rate of 0.5 mmol/hour, chronic character meaning the reverse. Tonicity (or effective osmolality) is the proportion of total osmolality that has the potential to induce transmembrane water movement. As water flows freely across the blood-brain barrier and cell membranes a fall in serum sodium (in the absence of a compensatory rise in other osmoles) will cause entry of water into brain cells and consequent brain swelling. In the brain, the first protective mechanism to act during the development of serum hypotonicity precedes mechanisms occurring in all cell types and it is the forcing of interstitial sodium-rich fluid into cerebrospinal fluid (CSF) as a result of hydrostatic pressure, occurring in minutes in the murine model [10][11]. Over the next few hours potassium is lost, and this is maximal after 24 hours. The maximum cation loss that occurs is 18% but this would put a theoretical limit on survivable hyponatraemia at 103 mmol/l if the loss of inorganic ions were the only available mechanism, and rats, like man can survive Na+ concentrations below this. Other solutes contribute: organic osmoles (such as myoinisotol, taurine, and glutamate) which are lost over a day to a very few days (in 48 hours in the murine model), rendering the cell isotonic to the extracellular fluid and maintaining cell volume [10]. The ion channels involved in the electrolyte shifts in the first phase of volume change involved in steady state volume regulation are different from those involved in “regulatory volume decrease” in response to hypotonic challenge as well as from the “regulatory volume increase” involved in hypertonic challenge. The relative proportions of the contribution of main organic and inorganic osmolytes involved in regulatory volume decrease


in the murine model are potassium – 29%, chloride – 19%; aminoacids (taurine, glutamine, glutamate, aspartate, glycine) – 15%, sodium being only the fourth most significant (13%) [5]. Correction of hyponatraemia is accompanied by specific changes. The reaccumulation of electrolytes lost in response to a hypertonic environment is not the same process “in reverse” as their loss in adaptation to chronic hyponatraemia [8]. Shrinkage of the cell can occur once inorganic ion shifts have been exhausted and when the rate of rise of tonicity is faster than the rate at which organic osmoles can be synthesized and/or transported into the cell. Oligodendrocytes are especially vulnerable to death, presumably from volume loss. The nutritional status of the patient has a contribution, since it impairs the ability to regenerate organic osmoles. Since this ability cannot be assessed, it is not possible to determine a threshold rate of change considered safe, and recommendations for safe rates of Na+ rise are based on animal models [10]. The persistent physical shrinkage of cells induced by hypertonic stress leads to cell death in a variety of cell types [12]. Oligodendrocytes are particularly vulnerable to apoptosis, a good example being hypoxic brain damage in infants. There is indeed some evidence for apoptosis in CM, since the ratio of pro- to anti-apoptotic markers (death receptor 3, Bax, and Bak) has a shift in favor of apoptosis [13]. Interestingly, apoptosis recruits a particular potassium channel (the two pore domain potassium channel) that is used for homeostatic volume regulation, and it was speculated that osmotic stress via activation of these ion channels can trigger apoptosis [13]. Concerning the appropriate treatment of hyponatraemia, the issue is complex because it is difficult to deal with the risk-benefit ratio between correcting promptly the ionic disequilibrium and assuming a risk of osmotic disorder, or to temporize the correction of hyponatremia, exposing the patient to the danger of its consequences [14]. The picture is complicated in every-day practice also by the rapidity of rise in the concentration of Na+ within the first day of treatment, even when avoiding hypertonic saline. On the other hand, mortality from severe hyponatraemia is between 40–50%, and the slow correction of sodium levels can be seen with considerable controversy in this light [5][8][11][14][15].


R. Tănăsescu et al.

Ideally, we should conform to the axiom that metabolic disorders should be treated at a rate commensurate with the rate at which they have developed, but as it was above said, this is only a desideratum, difficult to apply in every-day practice. It the setting of a better management of hyponatremia, evaluation of its cause is important, but sometimes difficult. One has to differentiate between the false hyponatraemia, occurring if a significant non-aqueous phase is included in the volume of serum sampled, diluting sodium titers. It can be the case of hyperlipidaemic states like hypertriglyceri-daemia, or multiple myeloma and administration of intravenous immunoglobulin [5]. In the same spirit of false diagnostic appreciation, the Syndrome of inappropriate ADH (SIADH) may be over-diagnosed since in Romanian hospitals urine osmolality or urinary sodium is sometimes difficult to assess. For a correct SIADH diagnosis, the presence of features like euvolaemia, normal renal function, and absence of hypothyroidism / Addison’s hypoadrenalism are mandatory. Another condition generating hyponatremia is the syndrome of cerebral salt wasting. This entity will not be discussed here in detail, but it occurs most characteristically with subarachnoid haemorrhage and its existence has been controversial, even if now is accepted [16]. However, to diagnose it in practice is not easy, and it deserves special attention. It has to be emphasized that treatment of acute hyponatraemia, even rapid, does not preclude frequently CM/EM, as it has been shown in studies of correction of severe symptomatic acute hyponatraemia in patients with psychogenic polydipsia [10]. On the other hand, it is also true that in practice it is often difficult to assess the chronicity of hyponatraemia in the new admitted patient with severe hyponatraemia. There seems a consensus among most authors that the correction of acute hyponatraemia can be rapid; but for chronic hyponatraemia this is more restrictive [5]. The correction of not more than 10 mmol/l/day was the consensus, although a more recent recommendation is not in excess of 8 mmol/l/day. It must be emphasized that conceptions have changed over years: although recommendations for slow correction have been standard for years, the reference has changed [5]. Here are listed some of these recommendations: “If Na+ is 105 mmol/l correct at 2 mmol/l/hour for first 20 mmol/l, and then allow drifting to normal. If Na+ >105 mmol/l correct at 2 mmol/l/hour to 125–130 mmol/l” (Ayus 1985);


“correct less than 12 mmol/l/day for first day, and subsequent days slower” (Sterns 1987–1992); “2.5 mmol/l/hour and no more than 20 mmol/day” (Berl 1990); “correct less than 8 mmol/l/day” (Oh 1995); “correct less than 15 mmol/l in 24 hours” (Kumar and Berl 1998); “correct less than 10 mmol/l/day” (Laureno and Karp 1997); “correct 10 mmol/l/day in first 24 hours and less on subsequent days” (Karp and Laureno 2000); “correction should not exceed 1–2 mmol/l/hour and never more than 8 mmol/l/day” (Brown 2000); “correction should not exceed 8 mmol/l on any day of correction” (Adrogue, 2000) [5]. Some authors suggest that it may be appropriate to stabilize the patient in a mild hyponatraemic state after initial correction [17]. However, it is important to emphasize those cases having their special particularities, it may be impossible to define a level of correction that is always completely free of risk’. Moreover, the difficulty is raised also by the fact that the clinician has only indirect control over the rate of Na+ rise which may correct faster despite the measures taken in order to prevent this. Obviously, correction into hypernatraemic concentrations should be avoided, but one should probably include potassium correction in the total daily correction [18]. Other metabolic etiologies can lead to CM or EM. Hypernatraemia had been reported in association with CM, especially in burn patients [19]. Also, hypokalaemia has been reported as a possible trigger, and it must be taken into consideration even the lowest serum K+ compatible with survival cannot produce a very significant shift in effective osmolality. In more than 80%, sodium disorders with hyponatremia are accompanied by hypokalaemia [18]. The significance of other electrolytes is less certain, but associations with hypophosphataemia, magnesium, and lithium therapy have all been proposed [5]. However, to affirm a clear relationship is difficult between CM/EM and these ionic disorders, since either hyponatraemia was present or the Na+ was not measured at the beginning of the disease. Paraclinical assessment of CM/EM must include, associated with laboratory tests, imaging investigations. Before imagistic techniques were emerged, brainstem auditory evoked potentials were used, but modern imaging has superseded its use. Electroencephalography in CM may demonstrate diffuse bihemi-spheric slowing [5].


Central pontine and extrapontine myelinolysis

CM can be seen on CT, but magnetic resonance imaging (MRI) is the imaging technique of choice, having a greater sensitivity for CM/EM than CT. Hyperintense lesions are seen on T2, and hypointense lesions on T1 weighted images, and these lesions are non-contrast enhancing. It must be emphasized that the timing of the appearance of lesions on MRI may be significantly delayed, and often a control imaging exam at 10–14 days may reveal lesions not apparent on early scans [20]. The reverse situation has been reported in which the MRI changes characteristic of CM were seen without any pathological changes on postmortem examination one month after imaging, evoking that the pathological process beside MRI lesions was reversible edema [21]. There is no impact on the duration nor prognosis offered by MRI [22]. Diffusion weighted imaging (DWI) might have the capability of detecting lesions undetectable on T2, mainly during the first 24 hours from clinical onset. MRI appearance of CM is characteristic and this has the potential for misdiagnosis and may account for cases without characteristic shifts in Na+. In this respect, it has been argued that large asymptomatic pontine lesions are unlikely to be CM lesions [5] (Fig. 1).

Fig. 1. – Brain MRI showing altered signal intensity in the central pons due to CM.

The clinical context, laboratory and MRI should help to exclude some differentials that may explain the clinical signs: multiple sclerosis, brainstem


gliomas, cerebellar, brainstem or intracranial hemorrhage, subarachnoid hemorrhage, complex partial seizures, lacunar syndromes, leptomeningeal carcinomatosis, alcohol related neuropathy, uremic encephalopathy, cyclosporine neurotoxicity (liver transplant patients). There have been no trials on treatment of CM/EM. Very small series reported suggested the known perception that this condition has an excessively high mortality. At present, only supportive treatment is all that can be recommended with certainty [5]. There are some data on the use of small case series or single case reports of treatments including steroids, intravenous immunoglobulin, and thyrotrophin releasing hormone, have all shown good outcomes but they are difficult to interpret. Intriguing is the possible benefit of reinducing hyponatraemia, as has been reported in animal studies and two human cases [17]. Animal work on the administration of organic osmolytes during the correction phase showed this to be a potential treatment [14][17]. The prognosis of the osmotic demyelination syndrome has long been regarded as poor, primarily because before CT/MRI this was a postmortem diagnosis. The imaging era showed that the outcome may be death, disability, or recovery to a virtually normal level of function: mortality is about less than 10%, 30% of patients are surviving but left dependent, 30% with some deficits but independent, and 30% recover completely [22]. It must be emphasized that an individual prognosis is difficult, neither clinical nor radiological findings being predictive [22]. Patients who survive CM likely require extensive and prolonged neurorehabilitation. Incorporate occupational, physical, speech, and language therapists early in the care of such patients. Swallowing studies are necessary to evaluate for dysphagia and determine the risk for aspiration pneumonia. Once medically stable, the patient should be evaluated by a neurorehabilitation specialist and, if appropriate, transferred for further inpatient recovery-oriented therapy. Possible complications include those associated with severe central nervous system injury and reduced activity: ventilator dependency, aspiration pneumonia, venous thrombosis pulmonary embolism, contractures and muscle wasting, decubitus ulcers, urinary tract infections, depression. It is important to inform, in practice, the family of the patient on the possibility of late deterioration as soon as severe hyponatraemia


R. Tănăsescu et al.

is detected and correction is begun. This becomes very important in the setting of Romanian families mentality, who barely accept the possibility of a deterioration in the patient’s condition which has followed a period of initially gratifying improvement. In conclusion, CM/EM are a complication of treatment of patients with profound, life threatening hyponatraemia, occurring usually as a consequence of a rapid rise in serum tonicity in these patients who have made intracellular adaptations to the prevailing hypotonicity [5]. Elevation in serum sodium is the overwhelming contributor to the rise in tonicity, but potassium elevation may contribute and malnutrition and alcoholism seem to be conditions to predispose. Evidence for other electrolyte shifts (with the exception of prolonged hypernatraemia) as causative is not very consistent


[5]. It has to be considered in a patient who has failed to recover as expected after a severe illness requiring intravenous fluids, and in patients manifesting “psychiatric” symptoms after such an illness, even if imaging is negative. Na+ rise need not be in excess of 10 mmol/l/day for condition to develop. There may be no “safe” limit for the rate of Na+ rise. Prognosis is not uniformly bad; MRI changes may be delayed and are not prognostic. EM may manifest in a number of different ways, the clinical picture can evolve over days, and some of the manifestations may be symptomatically treatable. CM and EM are conditions important to be known and included in the differential diagnosis algorithm of a patient exposed to ionic variations. When CM or EM are suspected, a mixed team composed of a neurologist and an internist must be involved in the management of these patients.

Sindroamele de mielinoliză osmotică includ mielinoliza centrală pontină şi extrapontină. Considerate iniţial a fi apanajul alcoolismului sau malnutriţiei, astăzi este acceptat că pot apărea asociate unui număr larg de condiţii patologice, fiind datorate unei afectări celulare secundare dezechilibrului osmotic postcorecţie rapidă a nivelelor sodiului seric după ce acestea au fost scăzute. Există şi alte dezechilibre ionice care pot fi associate sindroamelor de mielinoliză osmotică, cum ar hipernatremia sau hipopotasemia. Articolul de faţă îşi propune să schiţeze principalele aspecte legate de patogenia, dificultăţile de diagnostic şi tratament al mielinolizei centrale pontine şi extrapontine, entităţi deseori necunoscute suficient în practică. Corresponding author: R. Tănăsescu MD, PhD Department of Neurology, Colentina Hospital, 19–21, Ştefan cel Mare, sector 2, Bucharest, Romania E mail: [email protected]

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9.

ADAMS R.A., VICTOR M., MANCALL E.L., Central pontine myelinolysis: a hitherto undescribed disease occurring in alcoholics and malnourished patients. Arch. Neurol. Psychiatry, 1959; 81:154–72. WRIGHT D.G., LAURENO R., VICTOR M., Pontine and extrapontine myelinolysis. Brain, 1979; 102:361–85. SINGH N., YU V.L., GAYOWSKI T., Central nervous system lesions in adult liver transplant recipients: clinical review with implications for management. Medicine (Baltimore), 1994; 73(2):110–8. KARP B.I., LAURENO R., Pontine and extrapontine myelinolysis: a neurologic disorder following rapid correction of hyponatremia. Medicine (Baltimore), 1993; 72(6):359–73. MARTIN R., Central Pontine and Extrapontine Myelinolysis: The Osmotic Demyelination Syndromes. J. Neurol. Neurosurg. Psychiatry, 2004; 75:22–28. GOCHT A., COLMANT H.J., Central pontine and extrapontine myelinolysis: a report of 58 cases. Clin. Neuropath., 1987; 6:262–70. TICMEANU M., NICULESCU C.T.H., NITA C., Extrapontine demyelination following a severe drop in the Na blood level. The Official Journal of the Romanian Society of Anatomist, 2000, 1; 4:233(348). KARP B.I., LAURENO R., Central pontine and extrapontine myelinolysis after correction of hyponatraemia. The Neurologist, 2000; 6:255–66. LAURENO R., KARP B.I., Myelinolysis after correction of hyponatremia. Ann. Intern. Med., 1997; 126(1):57–62.


Central pontine and extrapontine myelinolysis


10. BERL T., Treating hyponatremia: damned if we do and damned if we don’t. Kidney Int., 1990; 37:1006–18. 11. STERNS R.H., The management of symptomatic hyponatraemia. Semin. Nephrol., 1990; 10:503–14. 12. OKADA Y., MAENO E., SHIMIZU T. et al., Receptor-mediated control of regulatory volume decrease (RVD) and apoptotic volume decrease (AVD). J. Physiol., 2001; 532:3–16. 13. DELUCA G.C., NAGY Z.S., ESIRI M.M. et al., Evidence for a role for apoptosis in central pontine myelinolysis. Acta Neuropathol., 2002; 103:590–8. 14. OH M.S., KIM H.-J., CARROLL H.J., Recommendations for treatment of symptomatic hyponatremia. Nephron, 1995; 70:143–50. 15. CHENG J.C., ZIKOS D., SKOPICKI H.A. et al., Long-term neurologic outcome in psychogenic water drinkers with severe symptomatic hyponatremia: the effect of rapid correction. Am. J. Med., 1990; 88:561–6. 16. CERDÀ-ESTEVE M., CUADRADO-GODIA E., CHILLARON J.J. et al., Cerebral salt wasting syndrome: review. Eur. J. Intern. Med., 2008 Jun., 19(4):249–54. 17. OYA S., TSUTSUMI K., UEKI K. et al., Reinduction of hyponatraemia to treat central pontine myelinolysis. Neurology, 2001; 57:1931–2. 18. LOHR JW. Osmotic demyelination syndrome following correction of hyponatremia: association with hypokalemia. Am. J. Med., 1994; 96:408–13. 19. CHANG C.H., LIAO J.J., CHUANG C.H., LEE C.T., Am. J. Med. Sci., 2008 May, 335(5):390–3. 20. DEWITT L.D., BUONANNO F.S., KISTLER J.P. et al., Central pontine myelinolysis: demonstration by nuclear magnetic resonance. Neurology, 1984; 34(5):570–6. 21. HASPOLAT S., DUMAN O., SENOL U. et al., Extrapontine myelinolysis in infancy: report of a case. J. Child Neurol., 2004; 19(11):913–5. 22. MENGER H., JORG J., Outcome of central pontine and extrapontine myelinolysis. J. Neurol., 1999; 246:700–5. Received July 21, 2008


R. Tănăsescu et al.


Metabolic Syndrome and Periodontal Diseases ALEXANDRINA L. DUMITRESCU1, L. ZETU2, SILVIA TESLARU2 1

“Carol Davila” University of Medicine and Pharmacy, Faculty of Dental Medicine, Bucharest, Romania 2 “Gr.T. Popa” University of Medicine and Pharmacy, Faculty of Dental Medicine, Iassy, Romania

The metabolic syndrome (also known as syndrome X, insulin resistance syndrome, dysmetabolic syndrome, deadly quartet and plurimetabolic syndrome) is a cluster of factors associated with increased risk of developing coronary heart disease and/or type 2 diabetes. Several recent studies reviewed in the present paper have indicated an association between the metabolic syndrome and periodontitis, and suggest that people exhibiting several components of metabolic syndrome should be encouraged to undergo a periodontal examination. Further investigations are required to clarify the mechanisms of the relationship between metabolic syndrome and periodontal disease in men, and to determine whether oral health care in individuals exhibiting metabolic syndrome has the potential to reduce the incidence of various systemic diseases. Key words: metabolic syndrome, obesity, periodontitis.

The global obesity epidemic has been described by the World Health Organisation [1] as one of the most blatantly visible, yet most neglected, public health problems that threaten to overwhelm both more- and less-developed countries [2]. Obesity is a growing problem in Europe, currently affecting between 10 and 20% of the population [3]. Understanding the various factors that have contributed to this trend and understanding why obesity is so difficult to treat has become an increasingly important health issue. The metabolic syndrome (also known as syndrome X,

insulin resistance syndrome, dysmetabolic syndrome, deadly quartet and plurimetabolic syndrome) is a cluster of factors associated with increased risk of developing coronary heart disease and/or type 2 diabetes. Metabolic syndrome comprises insulin resistance (fasting blood sugar >10 mg/l), dyslipidaemia (triacylglycerol >15 mg/l, HDL15 mg/l), essential hypertension (blood pressure of >130 mmHg for systolic and >85mmHg for diastolic) and visceral obesity (waist circumference of >1020mm for men and >890mm for women) [4] (Table I).

Table I WHO definition of metabolic syndrome [1] Insulin resistance: Type 2 diabetes Impaired fasting glucose Impaired glucose tolerance (> 110 mg/dl or > 6.1 mmol/l) Plus at least 2 of the following: High blood pressure (> 140 mmHg systolic or > 90 mmHg diastolic) Plasma triglycerides > 150 mg/dl (> 1.7 mmol/l) HDL cholesterol < 35 mg/dl (< 0.9 mmol/l) in men or < 39 mg/dl (< 1.0 mmol/l) in women BMI 430 kg/m2 and/or waist: hip ratio 40.9 in men or 40.85 in women Urinary albumin excretion rate > 20 mg/min or albumin: creatinine ratio > 30 mg/g HDL, high-density lipoprotein; BMI, body mass index. ROM. J. INTERN. MED., 2008, 46, 3, 207–212


Alexandrina L. Dumitrescu et al.




A recent number of studies focused on the relationship between periodontal disease and metabolic syndrome. Shimazaki et al. [5] examined the relationship between periodontitis and 5 components of the metabolic syndrome – abdominal obesity, triglyceride level, high-density lipoprotein cholesterol level, blood pressure, and fasting blood sugar level – in 584 Japanese women. Of the 5 components of metabolic syndrome, large waist circumference, low HDL cholesterol level, and high fasting plasma glucose level were associated with significantly higher odds ratios for greater pocket depth values; the adjusted odds ratios for these components were 1.8 (95% confidence interval, 1.2–2.8), 2.2 (95% confidence interval, 1.4–3.6), and 2.2 (95% confidence interval, 1.3–3.9), respectively. The participants with low HDL cholesterol had a higher odds ratio (odds ratio, 2.8; 95% confidence interval, 1.4–5.6) for a greater clinical attachment loss value after adjustment for age and smoking status. In multivariate analyses, persons exhibiting more components of metabolic syndrome had significantly higher odds ratios for a greater pocket depth and clinical attachment loss than did those with no components; the odds ratios for a greater pocket depth and clinical attachment loss of the persons exhibiting 4 or 5 components were 6.6 (95% confidence interval = 2.6–16.4) and 4.2 (95% confidence interval = 1.2–14.8), respectively. In a cross-sectional study Borges et al. [6] analyzed data from 1,315 Japanese-Brazilians ranging from 30 to 92 years of age, submitted to physical, laboratory, and dental exams. 484 (36.8%) of the 1,315 were edentulous, 215 (16.4%) enjoyed periodontal health, 513 (39%) had gingivitis, 85 (6.5%), showed initial or moderate periodontitis, and 18 (1.4%) suffered from chronic periodontitis. Prevalence of metabolic syndrome was 54.3%, higher among individuals with periodontitis than in the healthy (51.5% vs. 48.8%), but this association was not statistically significant. Individuals with metabolic syndrome showed a worse metabolic and anthropometric profile. These results indicate that metabolic syndrome increases the risk of periodontitis, and suggest that people exhibiting several components of metabolic syndrome should be encouraged to undergo a periodontal examination [5].

During the past 15 years, mounting evidence for the association between periodontal and cardiovascular disease has been presented in epidemiological studies. Left ventricular mass is an established independent predictor of cardiovascular disease. In the present cross-sectional study, we tested the association between periodontitis and left ventricular mass in subjects with essential hypertension. One hundred four untreated subjects with essential hypertension underwent clinical examinations, including echocardiographic study, laboratory tests, and assessment of periodontal status according to the community periodontal index of treatment needs (CPITN) [7]. It was observed that with increasing severity of periodontitis, there was a progressive increase in left ventricle mass. Mean values (g/height) were 39.0 (±2.7) in CPITN 0 (periodontal health), 40.2 (±6.4) in CPITN 1 (gingival bleeding), 42.7 (±6.8) in CPITN 2 (calculus), 51.4 (±11.7) in CPITN 3 (pockets 4 to 5 mm), and 76.7 (±11.3) in CPITN 4 (pockets 6 mm) (overall F 51.2; P12h) employing enzymatic colorimetric methods (Konelab 30 equipment, Finland).



A questionnaire including family history, past and current diseases, diet, alcohol use, smoking, pregnancies and medications were completed for each patient. The presence of obesity (evaluated by body mass index, BMI) and diabetes mellitus were assessed in all subjects. Plasma cholesterol, HDL-cholesterol and triglycerides levels, as well as glycaemia were evaluated after


The characteristics of the subjects and controls were compared using Student’s t test (cholesterol, HDL-cholesterol, age at onset of diabetes mellitus, age at onset of obesity), Mann-Whitney test (age, BMI, triglycerides, glycaemia) and chi square test (gender, presence of diabetes mellitus). A p value less than 0.05 was considered statistically significant. Multiple regression logistic analysis was assessed to identify the risk factors for gallstone disease.


Most of the subjects included in our study were females (87.16% in patients and 91.51% in controls, p=0.19) (Table I).

Table I Characteristics of the patients with gallstone disease and of the controls Mean ± SD


95/14 (87.16%) 248/23 (91.51%) 54.36 ± 11.12 52.82 ± 10.94 49.58 ± 11.17

0.19 0.22

Age at diagnosis of gallstone disease

patients=109 controls=271 patients=109 controls=270 patients=48

Symptoms (N, %)


100 (91.74%)

BMI (kg/m2)

patients=109 controls=271 patients=24 controls=4 patients=109 controls=271 patients=108 controls=270 patients=108 controls=270

29.06 ± 5.36 26.00 ± 4.63 34.25 ± 11.01 32.75 ± 12.63 3


172.94 ± 95.89 133.37 ± 78.41 213.43 ± 49.90 226.53 ± 48.38


patients=90 controls=263 patients=105 controls=262 patients=109 controls=271 patients=11 controls=5

48.84 ± 14.90 55.39 ± 13.88 105.20 ± 34.75 94.44 ± 25.01 20 12 48.91 ± 11.16 55 ± 9.59


patients=109 controls=271

2.84± 3.21 2.89 ± 2.25

Gender (female/male, %) Age (years)

Age at obesity onset (mean, years) Rapid reduction in weight Triglycerides (mg/dl) Cholesterol (mg/dl ) HDL-cholesterol (mg/dl) Glycemia (mg/dl) Diabetes mellitus (N) Age at diagnosis of diabetes mellitus (mean, years) Pregnancies (mean in females)

0.95 –


0.00006 0.00001 0.39 0.15



Risk factors for gallstone disease

The mean age of the patients was 54.36± 11.12 years (range 26 to 80 years) and in controls 52.82±10.94 years (range 21 to 80 years), without a significant difference between them (p=0.22). The mean age at diagnosis of gallstones in patients was 49.58±11.17 years. Most of the patients had symptomatic gallstones (91.74%) and had had cholecystectomy (82.56%) (Table I). The mean value of the number of pregnancies was similar for patients and controls (p=0.15) (Table I). The familial aggregation of gallstone disease was the major inclusion criteria of the cases. All patients had at least one affected sibling (97 pedigrees with two affected siblings, 11 pedigrees with 3 affected siblings and one pedigree with 4 affected siblings). The parents were also affected in 19 pedigrees.

20% of their weight within 4 to 6 weeks due to strict diet. Fasting plasma triglyceride levels were significantly higher in cases than in controls (p=0.00001). Significantly more patients had hypertriglyceridaemia (≥150 mg/dl) as compared with controls (50.46% patients vs. 29.63% controls). The mean value of serum cholesterol was over the normal range in controls (≥220 mg/dl) and it was higher than in patients with gallstones (p=0.02). There were significantly more controls with hypercholesterolemia than patients (50.37% controls vs. 40.37% patients). The HDL-cholesterol levels were lower in patients than in controls (Table I). The mean value of glycemia à jeun was higher in patients with gallstone disease than in controls (Table I). The prevalence of diabetes mellitus (in all cases type 2 diabetes) was higher in patients than in controls (p=0.00001), but the mean age at diabetes diagnosis was similar in patients and controls (Table I). In all subjects, BMI positively correlated with serum triglycerides (r=0.26, p=0.0000004) and negatively with HDL-cholesterol (r= –0.24, p=0.000006). In the multiple logistic regression analysis, we obtained a significant effect for BMI and no effect for HDL-cholesterol, serum triglycerides or glycaemia (Table II). The Likelihood ratio was 359.94 and Hosmer Lemeshow goodness of fit was p=0.000002 for the entire model.


Both in patients and in controls, the mean value of BMI indicated overweight (>25 kg/m2). The mean value of BMI was significantly higher in patients than in controls (Table 1). The prevalence of obesity (BMI>30 kg/m2) was also higher in patients than in controls (40.37% in patients vs. 16.75% in controls). The age at obesity onset was similar in patients and in controls. Three patients have declared episodes of rapid loss of weight (mean=2.33 kg/week). The patients have lost 5.71%, 12.19% and respectively,

Table II Multivariate logistic regression analysis (OR) for quantitative values of the factors associated with gallstone disease

BMI Triglycerides HDL-cholesterol Glycemia Constant

Coefficient B

Standard error



0.09 0.00 –0.02 0.00 –3.15

0.03 0.00 0.01 0.00 1.05

0.001 0.08 0.05 0.41 0.003

1.09 1.00 0.98 1.00 0.04


Age is a major risk factor for the gallstone disease. Patients and controls were sex and agematched in our study. Gallstone disease was diagnosed at the age of 50 years. Puppala et al. (16) have shown that heredity was significantly higher in patients with symptomatic

95% CI for OR Lower 1.03 1.00 0.96 0.99

Upper 1.15 1.01 1.00 1.01

gallstone disease (h2=64 in symptomatic vs. h2=26 all patients with gallstone disease). They suggested that symptomatic phenotype is more appropriate for genetic analysis. In our study, most of the patients were symptomatic and had a strong familial aggregation (at least one sibling with gallbladder stones). But we have to admit that we selected for the study hospitalized patients, some of them having gallstone symptoms as reason for hospitalization.


Simona Tîrziu et al.

Most our cases were females, according to the higher prevalence of gallstones in women showed in epidemiological studies. We found no significant difference between patients with gallstones and controls concerning the mean number of pregnancies, in spite of the data from literature suggesting the importance of the pregnancy number as a lithogenic risk [17][18]. A number of epidemiologic studies have linked obesity, diabetes mellitus type 2 and high serum triglycerides and low HDL-cholesterol to cholesterol gallstone disease (19–21). These conditions are included in the metabolic syndrome which is based on the insulin resistance. Obesity is a major risk factor for gallstone disease with a linear association between BMI and gallstones incidence [12]. Both supersaturated bile in cholesterol due to an increased activity in HMGCoA reductase, [1][12] and impaired gallbladder motility [22] account for the gallstone risk in obese subjects. Indeed, BMI was significantly higher in patients with gallstone disease than in controls. The young age at the onset of obesity in patients and controls, along with the high prevalence of obesity in cases (40.37%) argue for the fact that obesity is a major health problem in Romania. Only three patients in our study had lost up to 20% of their initial weight in 4 to 6 weeks. The loss of 14.8% to 24% of the initial weight is known to be associated with an 5–10% increase in the risk of gallstone disease [23]. Epidemiologic studies have also shown that high serum triglyceride and low serum HDLcholesterol levels are risk factors for the formation of gallstones [24][25]. In our patients, the serum triglyceride levels were significantly higher and HDL-cholesterol serum levels significantly lower in patients with gallstones as compared to controls. The serum cholesterol levels were higher in controls as compared to patients with gallstone disease. This finding could be due to the fact that most of our cases had symptomatic gallstone disease (prior cholecystectomy), a strong reason for changing alimentary habits by reducing the fat content of their diet. Our results are consistent with a study that showed an inverse association between cholesterol concentration in symptomatic and asymptomatic patients with gallstone disease, after


adjusting by age, gender and BMI [26]. An inverse relationship was also observed in the MICOL study between total serum cholesterol and the risk of gallstones, both in men and women [27]. The prevalence of hypertriglyceridaemia in cases was higher than in controls and than in general population of our country too (40.37% in cases vs. 23% in general population) [28]. The high prevalence of hypercholesterolemia in controls (50.37%) is above the ranges of the general population in Romania (24%) [28]. Although many epidemiological studies sustained the role of diabetes mellitus in gallstone disease, it was long time controversial. It is especially true for type 2 diabetes, which was 2.4 times more prevalent in patients with gallbladder disease than in controls [15]. Ruhl and Everhart showed that diabetes mellitus is an independent risk factor for gallstone disease [29]. We also found a higher basal glycaemia and a higher prevalence of diabetes mellitus in patients with gallstone disease than in controls. In multivariate logistic regression analysis, only BMI had a significant effect on gallstone disease. The absence of a significant effect for triglycerides and HDL-cholesterol in multivariate logistic regression analysis might be due to their strong correlation with BMI. The limits of our study are the selection bias, given the recruitment of patients with gallstones mainly from hospital patients and the recruitment of controls maybe not representative for the general population because of the high prevalence of dyslipidemia (hypertriglyceridemia, hypercholesterolemia). Anyway, we must take into consideration that this is a prospective study, including a large number of subjects of identical ethnicity, and that all our cases had a definite genetic component for gallstone disease. CONCLUSION

Our study confirms that the main risk factors for gallstone disease in a population with a strong heredity are BMI, triglycerides, HDL-cholesterol, increased glycaemia and diabetes mellitus. When analysing for the independent risk factors, only BMI was the major risk factor for gallstones in this population.

Scop. Litiaza biliară colesterolică este o afecţiune comună, ce rezultă din interacţiunea dintre factorii genetici şi factorii de mediu. În studiul nostru am


Risk factors for gallstone disease


evaluat factorii de risc pentru litiaza biliară la pacienţii cu ereditate certă pentru această boală. Metoda. Nivelele plasmatice ale HDL-colesterolului, trigliceridelor, colesterolului şi ale glicemiei à jeun au fost evaluate la 109 de pacienţi cu litiază biliară, care aveau cel puţin un frate sau o soră cu litiază biliară (femei/bărbaţi=95/14, vârsta 54,36±11,22 ani, IMC 29,06±5,36 kg/m2) şi la 271 martori fără litiază biliară (femei/bărbaţi=248/23, vârsta 52,82±10,94 ani, IMC 26,00±4,63 kg/m2). Testul t-Student, testul Mann-Whitney şi testul chi-pătrat au fost folosite pentru a compara IMC, nivelele plasmatice de lipide, prevalenţa diabetului zaharat şi sarcinile. Rezultate. Pacienţii cu litiază biliară au prezentat valoarea medie a IMC-ului semnificativ mai mare decât martorii fără litiază biliară (p=0,0000005). Nivelele plasmatice de trigliceride au fost semnificativ mai mari şi ale HDL-colesterolului semnificativ mai mici la pacienţii cu litiază biliară faţă de martori (p=0,00001, respectiv, p=0,0002). Glicemia à jeun a fost semnificativ mai mare la pacienţi faţă de martori (p=0,00006). Prevalenţa diabetului zaharat a fost semnificativ mai mare în rândul pacienţilor decât la martori (p=0.00001). În analiza univariată, IMC, trigliceridele, HDL-colesterolul, glicemia crescută şi diabetul zaharat s-au asociat semnificativ cu riscul de litiază biliară, dar în analiza multivariată, numai IMC a avut un efect semnificativ. Concluzii. Principalul factor de risc asociat cu litiaza biliară la pacienţii cu ereditate certă este IMC. Corresponding author: Simona Tîrziu, MD 3rd Medical Clinic, 19–21, Croitorilor Str., University of Medicine and Pharmacy, Cluj-Napoca [email protected]


PAIGEN B., CAREY M.C., Gallstones. In: The Genetic Basis of Common Disease (King R.A., Rotter J.F., Motulsky A.G., Eds.), 2nd ed. New York-Oxford University Press, 2002, p. 298–335. 2. KOSTERS A., JIRSA M., GROEN A.K., Genetic background of cholesterol gallstone disease. Bioch. Biophys. Acta., 2003, 1637, 1–19. 3. NAKEEB G., COMUZZIE A.G., MARTIN L. et al., Gallstones: genetic versus environment. Ann. Surg., 2002, 235, 842–849. 4. LAMMERT F., SAUERBRUCH T., Mechanisms of disease: the genetic epidemiology of gallbladder stones. Nat. Clin. Pract. Gastroenterol. Hepatol., 2005, 9, 423–433. 5. BARTOLI E., CAPRON J.P., Epidemiologie et histoire naturelle de la lithiase biliare. Rev. Prat., 2000, 50, 2112–16. 6. GILAT T., FELDMAN C., HALPERN Z., DAN M., BAR-MEIR S., An increase familial frequency of gallstones. Gastroenterology., 1983, 84, 242–246. 7. SARIN S.K., NEGI V.S., DEWAN R., SASAN S., SARAYA A., High familial prevalence of gallstones in the first-degree relatives of gallstone patients. Hepatology., 1995, 22, 138–141. 8. KATSIKA D., GRJIBOVSKI A., EINARSSON C., LAMMERT F., LICHTENSTEIN P., MARSCALL HU., Genetic and environmental influences on symptomatic gallstone disease: a Swedish study of 43141 twin pairs. Hepatology, 2005, 41, 1138– 1143. 9. LYONS M.A., WITTENBURG H., Cholesterol gallstone susceptibility loci: A mouse Map, candidate gene evaluation, and guide to human LITH genes. Gastroenterology, 2006, 131, 1943–1970. 10. WITTENBURG H., LYONS M.A., LI R., CHURCHILL G.A., CAREY M.C., PAIGEN B., FXR and ABCG5/ABCG8 as determinants of cholesterol gallstone formation from quantitative trait locus mapping in mice. Gastroenterology, 2003, 125, 868–881. 11. GRUNHAGE F., ACALOVSCHI M., TIRZIU S. et al., Increased gallstone risk in humans conferred by common variant of hepatic ATP-binding cassette transporter for cholesterol. Hepatology, 2007, 46, 793–801. 12. STAMPFER M.J., MACLURE K.M., COLDITZ G.A., MANSON J.E., WILLETT W.C., Risk of symptomatic gallstones in women with severe obesity. Am. J. Clin. Nutr., 1992, 55, 652–658.


Simona Tîrziu et al.


13. JORGENSEN T., Gallstones in a Danish population. Relation to weight, physical activity, smoking, coffee consumption and diabetes mellitus. Gut., 1989, 30, 528–534. 14. THIJS C., KNIPSCHILD P., Serum lipids and gallstones: A case-control study. Gastroenterology, 1990, 99, 843. 15. DE SANTIS A., ATTILI A.F., CORRADINI S.G. et al., Gallstones and diabetes: A case-control study in a free-living population sample. Hepatology, 1997, 25, 787. 16. PUPPALA S., DODD G.D., FOWLER S. et al., A genomewide search finds major susceptibility loci for gallbladder disease on chromosome 1 in Mexican Americans. Am. J. Hum. Genet., 2006, 78, 377–392. 17. KO C.W., BERESFORD S.A.A., SCHULTE S.J., MATSUMOTO A.M., LEE S.P., Incidence, natural history, and risk factors for biliary sludge and stones during pregnancy. Hepatology, 2005, 41, 359–365. 18. MARINGHINI A., CIAMBRA M., BACCELLIERE P. et al., Biliary sludge and gallstones in pregnancy: incidence, risk factors and natural history. Ann. Intern. Med., 1993, 119, 116–120. 19. DOWLING R.H., Review: pathogenesis of gallstones. Aliment. Pharmacol. Ther., 2000, 14 (suppl.2), 39–47. 20. AMIGO L., ZANLUNGO S., MENDOZA H., MIQUEL J.F., NERVI F., Risk factors and pathogenesis of cholesterol gallstones: state of art. Eur. Rev. Med. Pharmacol. Sci., 1999, 3, 241–246. 21. PAUMGARTNER G., SAUERBRUCH T., Gallstones: pathogenesis. Lancet, 1991, 338, 1117–1121. 22. PETRONI M.L., Review article: gall-bladder motor function in obesity. Aliment. Pharmacol. Ther., 2000, 14 ( suppl 2), 48–50. 23. EVERHART J.E., Contribution of obesity and weight lost to gallstone disease. Ann. Intern. Med., 1993, 119, 1029–1035. 24. THE ROME GROUP FOR EPIDEMIOLOGY AND PREVENTION OF CHOLELITHIASIS (GREPCO). The epidemiology of gallstone disease in Rome, Italy. Part I. Prevalence data in men. Hepatology, 1988, 8, 904. 25. BARBARA L., SAMA C., MORSELLI-LABATE A.M. et al., A ten year incidence of gallstone disease: The Sirmione Study. J. Hepatol., 1993, 18, S43. 26. DUQUE-L M.X., SEGUNDO MORÁN S., SALMERÓN-CASTRO J. et al., Inverse association between Plasma cholesterol and gallstone disease. Arch. Med. Res., 1999, 30, 190–197. 27. ATTILI A.F., COPACACCIA R., CARULLI N. et al., Factors associated with gallstone disease in the MICOL experience. Multicenter Italian Study on Epidemiology of Cholelithiasis. Hepatology, 1997, 26, 809–818. 28. DOROBANŢU M., BĂDILĂ E., DARABONT E. et al., Studiul Sephar – studiu de prevalenţă a HTA şi evaluarea riscului cardiovascular în România. Rev. Rom. Cardiologie, 2006, 3, 179–189. 29. RUHL C.E, EVERHART J.E., Association of diabetes, serum insulin and C-peptide with gallbladder disease. Hepatology, 2000, 31, 299–303. Received June 15, 2008

Survival Prognostic Factors in Patients with Resection of Liver Metastasis from Colorectal Cancer C. IANCU1, L.C. MOCAN1, DANA TODEA-IANCU1, TEODORA MOCAN2, F.V. ZAHARIE1, F. GRAUR1, I.C. PUIA1, D. MUNTEANU1, O. BALA1, LUCIA AGOŞTON-COLDEA3, F. MIHĂILEANU1, C. MITRE1, DANA IONESCU,1 L.E. VLAD1 1

Department of Surgical Disciplines, Department of Normal Morphology and Functions, 3 Department of Medical Disciplines, “Iuliu Haţieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania 2

Background and aim. Case selection criteria for resection of liver metastasis after colorectal cancer are still incompletely elucidated and represent a subject of great interest recently. Our aim was to evaluate 2-year survival after resection and to identify the survival risk and prediction factors in those cases. Methods. 63 patients diagnosed and undergoing liver resection for colorectal metastatic disease to the liver at the Surgical University Hospital No.3 (Cluj-Napoca, Romania) between 01.01.2002 and 31.12.2005 were included in the study. Exclusion criteria were: palliative treatment as well as surgical treatment performed in a different surgical centre. After the surgical treatment, patients were followed regularly using clinical assessment on a 3 monthly basis with abdominopelvic ultrasound or computerised tomography annually. The following variables were recorded: age, gender, coexisting medical diseases, blood tests results, tumour site, maximal tumour diameter after resection, duration of surgery, surgical procedure and the clinical outcome until last follow-up, including date of death where appropriate. Results. 2-year post-operative survival was 65.1%. In univariate analysis: age (=65 years, p=0.041), metastasis number (=3 tumors, p=0.049), maximal tumor dimension (=3 cm, p=0.047), glutamine-oxaloacetic transaminase (GOT) preoperative level (=42 mg/dl, p=0.018) were significant factors correlated to median survival time. However, non of the above mentioned factors presented independent prediction power in multivariate analysis (Cox regression, p