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Clinical Nutrition (1999) 18(4): 227-231 1999 Harcourt Publishers Ltd

Improvement in lipid and haemostasis patterns after Helicobacter pylori infection eradication in type 1 diabetic patients
D. A. DE LUIS*, A. GARCIA AVELLO t, M. A. LASUNCION*, R. ALLER ~, C. MARTIN DE ARGILA , D. BOIXEDA DE MIQUEL , H. DE LA CALLE*

*Departments of Endocrinology, tHaematology, lnvestigation ~Gastroenterology, Hospital Ramon y Cajal, Universidad de Alcala de Henares, Madrid 28034, SPAIN (Correspondence to: DAD, C/Caama~o 51 Bis 3C, Valladolid 47013, Spain) Abstract--Helicobacter pylori has been implicated in the cardiovascular risk of diabetic patients. The aim of our study was to investigate whether the Helicobacter pylori infection plays a role in the lipid and haemostasis patterns of type 1 diabetic patients. Twenty nine patients with type 1 diabetes mellitus and H. pylori infection were enrolled (Chlamydia pneumoniae negative). The H. pylori infection status was assessed by serology and urease breath test. In all patients levels of total cholesterol, triglyceride, HDL cholesterol, LDL cholesterol, lipoprotein (a) (Lpa) C reactive protein (CRP), fibrinogen, thrombin/antithrombin III complex (TAT), plasminogen activator inhibitor type 1(PAl-I), tissue plasminogen activator (t-PA) and von Willebrand antigen were measured. All patients were evaluated before and after H. pylorieradicating treatment with amoxicillin, clarithromycin and omeprazole. Twenty two patients were eradicated and seven remained infected. In H. pylorieradicated patients, HDL cholesterol increased (59.7_+18.9 mg/dl vs 65.2+_15.9 mg/dl, P< 0.05) and lipoprotein (a) decreased (23.1_14.0 mg/dl vs 18.3_+12.3 mg/dl, P< 0.05), after treatment. After H. pylori eradication, the levels of CRP and TAT decreased (48_+0.7 ng/I vs 3.3_+0.4 ng/I; P< 0.05), (27.7_+44.7 pg/ml vs 2.1_1.4 pg/ml, P< 0.05), respectively. The decrease in TAT was higher in the group of H. pylori (+) patients with higher levels of TAT (TAT > 20 ng/ml, 92.8_+41.6 ng/ml vs 1.9_+2.0 ng/ml, P < 0.005; TAT 4-20 ng/ml; 10.1_+5.2 ng/ml vs 2.2+0.6 ng/ml, P < 0.05). These changes did not occur in patients without H. pylori eradication. Eradication of H. pylori infection in type 1 diabetic patients modifies some parameters of lipid and haemostasis patterns, (increase of HDL-cholesterol, reduction of Lpa and decrease of CRP and TAT) and so contributes to improvement of cardiovascular risk factors in these patients.

Key words: haemostasis; Helicobacterpylori; lipids

Introduction

Recent studies have suggested that chronic infections such as Helicobacterpylori may be associated with an increase of the risk of coronary heart disease in general population (1) and in diabetic patients (2). The possible mechanisms are unclear. It is postulated that chronic infection may contribute to an increase in the risk of coronary heart disease by unspecific ways as increasing the serum concentrations of acute phase reactants such as fibrinogen (3), C reactive protein (4), or by modifying the serum lipid pattern, decreasing HDL-cholesterol and increasing triglycerides (5-6). Another factor involving H. pylori in the atherogenesis is the promotion of the oxidation of LDL-cholesterol through the release of superoxide anion induced by bacterial lipopolysaccharides (7-8). Oxidation enhances the atherogenic capacity of those molecules (9). More recently, Miragliotta et al. have shown that H. pylori is able to induce blood coagulation through the stimulation of production of tissue-like factor by leukocytes, which in turn promotes the
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conversion of fibrinogen into fibrin (10); other abnormalities in haemostasis has also been described (11). Another possible mechanism in the cardiovascular risk caused by H. pylori infection is the direct action of H. pylori on the wall of the arteries, but this is a controversial point in the literature (12). The aim of our study was to determine changes in lipid and haemostasis patterns in type 1 diabetic patients when H. pylori infection was eradicated.

Material and methods

Population
Twenty nine outpatients of our Diabetes unit (13 males and 16 females) with type 1 diabetes mellitus and H. pylori infection were enrolled. The clinical characteristics of these patients included an age of 44.7_+17.1 years, body mass index (BMI) 24.8_+3.9 kg/m 2 and a duration of diabetes of 10.3_+6.2 years (Table 1). Patients were not taking drugs which would affect their serum lipid levels of haemostasis and maintained stable insulin doses, BMI and dietetic habits

228 HELICOBACTER PYLORI AND CARDIOVASCULARRISK Table 1 Clinical characteristics of type 1 diabetic patients TOTAL GROUP (n=29) Age (years) Sex (male/female) Diabetes course (years) BMI (Kg/m2) HbAlc (%) Insulin (U/day) Microangiopathy (%) 44.7+17.1 13/16 10.1_+6.2 24.8_+3.9 7.4_+1.6 42.1_+20 38.5% ERADICATED NON P ERADICATED (n=22) (n=7) 45.2_+16.1 11/11 9.3_+5.1 25.0_+4.3 7.5_+1.5 43.1_+21 40.9% 45.7_+21.2 2/5 13.1_+6.2 24.2_+3.2 7.3_+1.3 38.9_+18 37.9% NS NS NS NS NS NS NS

terol was determined enzymatically in the supematant after precipitation of other lipoproteins with dextran sulfate-magnesium. LDL cholesterol was calculated using Friedewald formula. Lpa was determined by immunonephelometry with the aid of a Beckman array analyzer (Beckman Instruments, Calif, USA).

Haemostasis assessment
Fibrinogen was determined by a functional quantitative assay according to the method of Clauss (15). PAI-1 and tissue t-PA were determined by enzyme immunoassay, (TintElize PAI Umea, Sweden) and (TintELize tPA, UrnEa, Sweden), respectively (16, 17). Thrombin/antithrombin III TAT was determined by enzyme immunoassay with a commercial kit (Enzygnost TAT micro, Marburg, Germany). vW was determined by Laurell method (18). CRP was determined by nephelometry with Beckman array analyzer (Beckman Instruments, CA, USA).

Microangiopathy (retinopathy or/and nephropathy).

during the follow-up. The study was approved by the local ethical committee and each patient gave their informed consent to participate in the study.

Design
All patients underwent the following examinations: serology for H. pylori infection, with blood sampling for lgG Hp antibodies, urease breath test (BT), assessment of serum lipid pattern including total cholesterol (t-C), high density cholesterol (HDL-cholesterol), low density cholesterol (LDL-cholesterol), triglycerides (TG), and lipoprotein (a) (Lpa), and assessment of haemostasis pattern including fibrinogen, plasminogen activator inhibitor type I(PAI-1), thrombin/antithrombin III complex (TAT), tissue plasminogen activator (t-PA), von Willebrand antigen (vW) and C reactive protein (CRP). These examinations were performed at baseline and 3 months after the eradicating H. pylori treatment. No patient dropped-out of the study. The eradicating H. pylori treatment consisted of amoxicillin 1 g/b.i.d., clarithromycin 500 mgPo.i.d., and omeprazole 20 mg/b.i.d., for 10 days. Eradication was defined as a negative urease breath test 3 months after treatment.

Statistical analysis
Results were expressed as mean _+ standard deviation. The distribution of variables was analyzed with KolmogorovSmirnov test. Quantitative variables with normal distribution were analyzed with a two-tailed, paired Student's-t test. Non-parametric variables were analyzed with the U-MannWhitney test. ANOVA with Bonferroni correction was used as needed. Qualitative variables were analyzed with the chisquare test, with Yates correction as necessary, and Fisher's test. A P-value under 0.05 was considered statistically significant. The statistical package employed was SPSS, Inc.,II, USA.

Results

Assessment of H. pylori infection


The diagnosis of H. pylori infection was established by positive serology and urease breath test. Levels of lgG Hp antibodies were determined in a serum sample using a commercial ELISA technique (Varelisa, Elias USA, Inc. Osceola, WI, USA) (13), with a cut off point set at 10 U/ml. Radiolabelled urea breath test for 13C levels (as delta-13CO2) and the 13C/12C ratio in expired air were determined, first in basal conditions and then 30 min after the administration of 75 mg of I3C labelled urea per os. A mass spectrophotometer (automated breath carbon analysis, Tracermass, USA) was used for these determinations. Values higher than five per 1000 were considered positive (14). All the patients were negative to C. pneumoniae serology.

Lipid assessment
Serum total cholesterol and triglyceride concentrations were determined by enzymatic colorimetric assay (Technicon Instruments, Ltd, New York, NY, USA), while HDL choles-

All patients had a positive serology and urease breath test to H. pylori. Erradication of H. pylori was achieved in 22 patients, whereas seven patients remained infected. Their clinical characteristics are shown in Table 1. There were no statistical differences between groups. The BMI and the HbAlc were similar at the baseline and at follow-up. In the group of H. pylori eradicated patients, lipid levels showed changes in HDL-cholesterol (59.7_+18.9 mg/dl vs 65.2_+15.9 mg/dl; P < 0.05) and Lpa (23.0_+14.0 mg/dl vs 18.3_+12.3 mg/dl, P < 0.05) after treatment. The other parameters such as total cholesterol, LDL-cholesterol, and triglycerides remained unchanged (Table 2). In patients with Lpa > 30 mg/dl (high cardiovascular risk), the levels decreased (51.4_+23.6 mg/dl vs 46.1_+20.2 mg/dl; P < 0.05) as in the group with Lpa < 30 mg/dl (low cardiovascular risk) (10.9_+9.1 mg/dl vs 8.4.+7.6 mg/dl, P < 0.05) after H. pylori eradication. In this group of H. pylori eradicated patients, the haemostasis pattern and acute phase reactants showed changes in thrombin/antithrombin complex (27.7_+44.7 ng/mi vs 2.1_+1.4 ng/ml, P < 0.05) and C reactive protein

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Table 2

Changes in lipid parameters after H. pylori eradication BASE LINE 3 MONTHS P

Table 5

Epidemiological characteristics of patients, according to TAT TAT 4-20 NG/ML > 20NG/ML P < 4 NG/ML (n=17) (n=6) (n=6)

levels Total cholesterol (mg/dl) Triglycerides (mg/dl) LDL-cholesterol(mg/dl) HDL-cholesterol (mg/dl) Lipoprotein (a) (mg/dl) 191.2_+35.7 186.8_+34.4 ns 103.2_+67.1 102.8_+56.3 ns 111.9-+28.2 101.7_+26.9 ns 59.7_+18.9 65.2_+15.9 P<0.05 23.1_+14.1 18.3_+12.3 P<0.05

Table 3

Haemostasis parameters in patients with H. pylori eradication after treatment BASE LINE 3 MONTHS 14.8_+11.2 7.3_+5.7 150.9_+77.8 2.1-+1.4 3.3_+0.4 269.1_+108.4 P n.s n.s n.s P < 0.05 P < 0.05 n.s

Age (years) Sex (male/female) Diabetes course (years) BMI (Kg/mz) HbAlc (%) Insulin (U/day) Microangiopathy (%)

42.5+16.2 8/9 8.6_+3.1 24.3_+3.4 7.3+1.5 45.2_+15.5 36%

44.1+19.3 3/3 7.2_+6.2 24.7_+2.5 7.2_+1.2 43.2_+18.4 50%

45.6+22.2 2/4 8.7_+6.1 27-+7 7.6_+2 45.6+22.3 33%

NS NS NS NS NS NS NS

No statistical differences among groups.

PAI- l(ng/ml) t-PA (ng/mi) vW (%) TAT (ng/ml) CRP (rag/l) Fibrinogen (mg/dl)

14.9-+12.4 7.1_+4.9 126.6_+53.0 27.7_+44.7 4.8_+0.7 283.1_+127.5

Lipid and haemostasis parameters in patients without H. pylori eradication after treatment
Table 6

BASE LINE LIPID PARAMETERS TOTAL CHOLESTEROL (mg/dl) TRIGLYCERIDES (mg/dl) LDL-cholesterol (nagfldl) HDL-cholesterol (mg/dl) Lipoprotein (a) (mg/dl) HAEMOSTASIS PARAMETERS PAI-1 (ng/ml) t-PA (ng/ml) vW (%) TAT (ng/ml) CRP (mg/1) Fibfinogen (mg/dl) 213.7+55.9 118.8_+68.6 131.6_+51.1 55.0_+16.6 10.3_+13.3 14.5_+2.1 6.7_+2.6 186.0_+108.7 3.4+2.5 3.8_+1.5 364.4_+124.4

3 MONTHS 207.0+63.2 124.3_+61.4 129.1_+50.1 52.0_+18.1 13.7_+9.5 12.0_+2.0 6.2_+2.3 203.0_+147.2 2.0_+0.4 3.4_+1.1 361.9_+70.7

P ns ns ns ns ns ns n.s n.s ns ns ns

Table 4

Haemostasis parameters in patients with H. pylori eradication after treatment, according to TAT levels BASE LINE 3 MONTHS P n.s n.s n.s n.s n.s n.s n.s n.s n.s P < 0.05 P < 0.05 n.s n.s n.s n.s P < 0.05 n.s n.s

GROUP WITH TAT <4 Ng/ml (n = 10) PAI-1 (ng/ml) 9.9+3.8 11.4-+8.3 t-PA (ng/ml) 5.6+4.6 6.3-+5.1 vW (%) 125.3+58.5 210.8_+127.1 TAT (ng/ml) 1.4+0.8* 2.2-+1.5 CRP (mg/1) 3.8+1.1 3.2-+0.4 Fibrinogen (mg/dl) 266.3+164.0 279.6_+45.7 GROUP WITH TAT 4-20 Ng/ml (n = 6) PAI-1 (ng/ml) 14-+7 11.2-+4.8 t-PA (ng/ml) 4.3_+0.6 4.1_+0.9 vW (%) 145.0_+62.1 152.4_+44.9 TAT (ng/ml) 10.1_+5.1" 2.2_+0.6 CRP (nag/I) 6.4_+0.9 3.6_+0.7 Fibrinogen (mg/dl) 287.6_+101.6 360.0_+267.9 Group with TAT >20 Ng/ml (n = 6) PAI-1 (ng/ml) 24.8_+15.9' t-PA (ng/ml) 9.2_+5.9 vW (%) 109.4-+43.8 TAT (ng/mi) 92.8_+41" CRP (rag/l) 4.9_+2.1 Fibrinogen (mg/dl) 254.2_+126.2 22.0_+15.9 10.5_+7.4 129.6-+42.2 1.9_+2.1 3.3_+0.1 289.8_+117.5

see T a b l e 6. T h e lipid and haemostasis basal parameters w e r e similar in both groups.

Discussion

In other clinical settings, a possible relationship b e t w e e n

H. pylori infection and cardiovascular risk has b e e n detected


by e p i d e m i o l o g i c a l data in general population (1, 19) as e x e m p l i f i e d by the high i n c i d e n c e ( 8 4 . 1 - 8 5.7 % ) o f H. pylori seropositivity in patients with c o r o n a r y heart disease and in diabetic patients (2). C h r o n i c infection m a y increase c a r d i o v a s c u l a r risk for different m e c h a n i s m s such as changes in acute phase reactants (3-4), lipid ( 5 - 9 ) and haemostasis ( 1 0 - 1 1 ) patterns. T h e effect o f H. pylori on lipid levels m a y be m e d i a t e d via certain cytokines, including interleukin-6 (IL-6) that can increase hepatic triglycerides synthesis and t u m o r necrosis factor alpha ( T N F ) that inhibits lipoprotein-lipase activity and stimulates hepatic lipogenesis, altering the lipid levels. T h e concentrations o f these cytokines are increased in the gastric m u c o s a (20) and s e r u m (21) o f H. pylori infected patients. T h e systemic effects o f g r a m n e g a t i v e bacilli on lipoprotein levels h a v e b e e n described both in animals and humans; the m o s t frequent alterations b e i n g an increase in the triglyceride and v e r y - l o w density lipoproteins ( V L D L ) levels, and a decrease in the levels o f high density lipoproteins ( H D L ) (22-25). This decrease in H D L - c h o l e s t e r o l levels can be related to an increase in s e r u m a m y l o i d A

(*) Statistical differences among basal levels of TAT in the three groups (p < 0.05) ($) Statistical differences arnaongPAI-1 in group (TAT < 4) and group (TAT > 20).

4.8_+0.7 mg/1 vs 3.3_+0.4 mg/1, P < 0.05) after treatment. Other parameters such as P A l - l , t-PA, and fibrinogen r e m a i n e d u n c h a n g e d (Table 3). T h e s e H. pylori eradicated patients w e r e d i v i d e d in three groups a c c o r d i n g to the pre-treatment levels o f T A T (Table 4); 1) T A R < 4 n g / m l (normal), 2) T A T 4-20 n g / m l (moderately high), and 3) T A T > 20 n g / m l (very high). In groups two and three, T A T d e c r e a s e d significantly, w h i l e group 1 the levels o f T A T r e m a i n e d similar. T h e clinical characteristics o f these groups w e r e similar (Table 5). In the group o f patients without H. pylori eradicated, the lipid levels and haemostasis parameters r e m a i n e d unchanged,

230 HELICOBACTERPYLORIAND CARDIOVASCULAR RISK

(SAA) during chronic infection or inflammation; this protein became the major HDL apoprotein. The SAA-enriched particles become denses (density of HDL3) and larger (size of HDL 2), while the apoAI disappear from the circulation (7-8). These changes in HDL-cholesterol increase the clearance of this lipoprotein from serum and it has been reported that SAA inhibits lecithin-cholesterol acyltransferase activity. Both mechanisms reduce the concentrations of HDL-cholesterol (25). Our results show increase in HDLcholesterol levels but not in triglycerides or LDL-cholesterol after H. pylori eradication. A decrease in lipoprotein (a) levels after H. pylori eradication was also observed. This effect was more marked on higher Lpa levels in patients with a high cardiovascular risk. The cause of this change is not clear but it could be related with IL-6. Crook et al. (26) found that patients with endometriosis had high levels of Lpa and IL6 and a possible mechanism behind these increases in Lpa levels is suggested by the demonstration of multiple functional IL-6 responsive elements in the apo(a) gene promoter (27), the main apoprotein of Lpa. Our data also show an improvement in the haemostasis pattern with decrease of TAT and acute phase reactants (C reactive protein). This improvement was also found by other~ authors (4, 7). These changes could be explained by the effect of the eradicating treatment on IL-6 and tumor necrosis factor alpha: IL-6 is relevant for activation of coagulation and TNF plays a pivotal role in the induction of a shortened fibrinolytic response (28). The differences in TAT levels before treatment do not seem to be due to the clinical characteristics of patients and could be related with different subtypes of H. pylori; it is known that CagA positive strains are related with higher serum and mucosal levels of TNF and IL-6 (29). Improvement in coagulation with decrease TAT was more accentuated in patients with higher levels of TAT, the reason of this different response is unknown. This paper provides a new point of view in all this controversy, with articles that show association between cardiovascular risk and H. pylori infection (1) and others with negative results (30). In conclusion, the epidemiological linking between cardiovascular diseases and H. pylori infection could be explained, in part, by the ability of H. pylori to alter lipid profiles and haemostasis patterns increasing the cardiovascular risk factors. The fact that H. pylori infection can be effectively treated permits to improve some of these factors and opens new intriguing possibilities of lowering the macrovascular disease in diabetic patients, already burdened by this important complication.

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Submission date: 4 December 1998 Accepted: 22 March 1999

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