h. pylori in arabs, final not published

25
Helicobacter pylori in Arabs; clinical aspects and related diseases in comparative study in three Arabian countries. Shendy Mohammed Shendy*, Naema I. El-Ashry** and Nihal M.El-Assly** Tropical medicine department* and Clinical Chemistry department, Theodor Bilharz Research Institute Abstract: Helicobacter pylori represents one of the most common infections worldwide. It has been established as an etiologic factor in the development of peptic ulcer disease and chronic gastritis; and associated firmly with development of gastric neoplasia, including gastric adenocarcinomas and gastric mucosa-associated lymphoid tissue lymphomas. Several extradigestive pathologies have been linked to H. pylori infection including cardiovascular, cutaneous, autoimmune, esophageal and other diseases such as sideropenic anaemia, growth retardation, and extragastric MALT- lymphoma. The aim of this work is to evaluate the contribution of H. pylori infection to the uncommon; digestive and extra-digestive; manifestations of patients in GIT clinics in some Arabian countries. Patients and methods : a total of 623 H pylori positive patients from three Arabian countries including 225 Egyptian patients, 188 Kuwait patients and 210 Saudiai patients were studied and evaluated for all the possible manifestations of this infection. Evaluation was done by history, medical examination, routine and specific laboratory investigations, endoscopic and histopathological diagnosis. Follow up after eradication was done to evaluate the response and improvement of such manifestations. Results : this study included 339 males and 274 females distributed in the three countries. Recurrent H pylori infection was found in 10.9 % of all patients and was significantly more common in Saudi patients and associated with significantly higher incidence of thyroid dysfunction and pancreatitis. Mouth ulcers, vertigo, diabetes, gastric polyps and low serum iron were significantly more common in Egyptian patients than other population. Constipation, history of atypical chest pain, pancreatitis, thyroid dysfunction and ALT elevation were significantly more common in Saudi patients than other populations. Presence of GERD and migraine were found significantly more common in both Saudi and Kuwaiti than Egyptian patients. Diabetes mellitus was one of the commonest associated manifestations in this study and was found in 16.5 % of all patients. Duodenal ulcer was found significantly more common in younger age group. Autoimmune haemolytic anaemia was found the only disease associated with significantly higher Cag A positivity. Constipation was also common in this population (11.9 % of all patients) and was directly correlated with the presence and severity of gastritis. Pancreatitis was directly correlated with history of past infection, gastric ulcer, GIT malignancy, gastric outlet obstruction, arthritis and skin rash. Low serum iron and hemoglobin were more significant in patients with peptic ulcer disease and GIT malignancy. After eradication of infection, marked improvement during follow up was noticed in patients with skin rash (28/37), mouth ulcer (37/59), and constipation (51/73) while mild to moderate improvement was noticed in those with migraine (11/260 and vertigo (19/49). Also, highly significant increase in serum iron and hemoglobin levels (P < 0.001) was found in all patients after eradication of infection when analyzed altogether and as separate groups without iron supplementation. The most sensitive and specific diagnostic tests for H pylori in this cohort was the microscopic examination, followed by rapid urease test; both depend on gastric biopsies. Conclusion : It is concluded from this study that H pylori infection is present in most Arabian countries nearly with similar, but of somewhat variable extent, manifestations wither digestive or extradigestive. The associated extradigestive manifestations described cannot be attributed to H pylori in all cases, but it is recommended to screen for this infection and eradicate it particularly if there are additional upper GIT complaints. The presence of GERD should not affect the decision of treatment of this infection. Finally, diagnosis and treatment of H pylori might be considered in the workup in the management of diseases with autoimmune pathogenesis such as ITP, autoimmune haemolytic anaemia, skin diseases, thyroid dysfunction, diabetes mellitus, and others.

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Page 1: H. pylori in arabs, final not published

Helicobacter pylori in Arabs; clinical aspects and related diseases in comparative study in three Arabian countries.

Shendy Mohammed Shendy*, Naema I. El-Ashry** and Nihal M.El-Assly**Tropical medicine department* and Clinical Chemistry department, Theodor Bilharz Research InstituteAbstract:Helicobacter pylori represents one of the most common infections worldwide. It has been established as an etiologic factor in the development of peptic ulcer disease and chronic gastritis; and associated firmly with development of gastric neoplasia, including gastric adenocarcinomas and gastric mucosa-associated lymphoid tissue lymphomas. Several extradigestive pathologies have been linked to H. pylori infection including cardiovascular, cutaneous, autoimmune, esophageal and other diseases such as sideropenic anaemia, growth retardation, and extragastric MALT-lymphoma. The aim of this work is to evaluate the contribution of H. pylori infection to the uncommon; digestive and extra-digestive; manifestations of patients in GIT clinics in some Arabian countries. Patients and methods: a total of 623 H pylori positive patients from three Arabian countries including 225 Egyptian patients, 188 Kuwait patients and 210 Saudiai patients were studied and evaluated for all the possible manifestations of this infection. Evaluation was done by history, medical examination, routine and specific laboratory investigations, endoscopic and histopathological diagnosis. Follow up after eradication was done to evaluate the response and improvement of such manifestations. Results: this study included 339 males and 274 females distributed in the three countries. Recurrent H pylori infection was found in 10.9 % of all patients and was significantly more common in Saudi patients and associated with significantly higher incidence of thyroid dysfunction and pancreatitis. Mouth ulcers, vertigo, diabetes, gastric polyps and low serum iron were significantly more common in Egyptian patients than other population. Constipation, history of atypical chest pain, pancreatitis, thyroid dysfunction and ALT elevation were significantly more common in Saudi patients than other populations. Presence of GERD and migraine were found significantly more common in both Saudi and Kuwaiti than Egyptian patients. Diabetes mellitus was one of the commonest associated manifestations in this study and was found in 16.5 % of all patients. Duodenal ulcer was found significantly more common in younger age group. Autoimmune haemolytic anaemia was found the only disease associated with significantly higher Cag A positivity. Constipation was also common in this population (11.9 % of all patients) and was directly correlated with the presence and severity of gastritis. Pancreatitis was directly correlated with history of past infection, gastric ulcer, GIT malignancy, gastric outlet obstruction, arthritis and skin rash. Low serum iron and hemoglobin were more significant in patients with peptic ulcer disease and GIT malignancy. After eradication of infection, marked improvement during follow up was noticed in patients with skin rash (28/37), mouth ulcer (37/59), and constipation (51/73) while mild to moderate improvement was noticed in those with migraine (11/260 and vertigo (19/49). Also, highly significant increase in serum iron and hemoglobin levels (P < 0.001) was found in all patients after eradication of infection when analyzed altogether and as separate groups without iron supplementation. The most sensitive and specific diagnostic tests for H pylori in this cohort was the microscopic examination, followed by rapid urease test; both depend on gastric biopsies. Conclusion: It is concluded from this study that H pylori infection is present in most Arabian countries nearly with similar, but of somewhat variable extent, manifestations wither digestive or extradigestive. The associated extradigestive manifestations described cannot be attributed to H pylori in all cases, but it is recommended to screen for this infection and eradicate it particularly if there are additional upper GIT complaints. The presence of GERD should not affect the decision of treatment of this infection. Finally, diagnosis and treatment of H pylori might be considered in the workup in the management of diseases with autoimmune pathogenesis such as ITP, autoimmune haemolytic anaemia, skin diseases, thyroid dysfunction, diabetes mellitus, and others.

Page 2: H. pylori in arabs, final not published

Introduction:

Helicobacter pylori represents one of the most common infections worldwide. Infection with this microaerobic, gram-negative bacterium has been established as an etiologic factor in the development of peptic ulcer disease and chronic gastritis. In addition, H pylori infection has been associated firmly with the development of gastric neoplasia, including gastric adenocarcinomas and gastric mucosa-associated lymphoid tissue lymphomas ( Dunn et al., 1997; Eslick et al. 1999; Weir et al., 1999 and James, 2003).

Chronic gastritis due to H pylori infection may be separated into distinct, clinically relevant phenotypes (Rubin 1997 and Faller and Kirchner 2001). Nonatrophic pangastritis occurs in the majority of H pylori-infected individuals with no predisposition to peptic ulcer disease or gastric atrophy. Prominent mucosal inflammation in chronic active gastritis often is evident in the antrum (antral-predominant gastritis), predisposing to hyperacidity and duodenal ulcer disease. In contrast, multifocal atrophic pangastritis and atrophic corpus-predominant gastritis result from long-standing infection and are characterized by glandular atrophy, intestinal metaplasia, and sparse inflammatory cells. Both forms of atrophic gastritis and the presence of intestinal metaplasia are associated with an increased risk of gastric adenocarcinoma (Uemura et al. 2001). In addition, lymphocytic and granulomatous gastritis have been linked with H pylori infection. Although isolated cases of idiopathic granulomatous gastritis have been demonstrated in association with H pylori infection, it is unclear whether H pylori has an important role in the development of gastric granuloma (Shapiro et al., 1996).

Studies in developed countries showed that the overall prevalence of H pylori infection ranges from 25% to 30% (Dunn et al., 1997) and the seroprevalence increases with age, ranging from 5% to 27% in early childhood to levels exceeding 50% in adults older than 50 years. with an acquisition rate in adults of 3% to 4% per decade (Cullen et al., 1993, Kosunen et al., 1997 and Sipponen et al., 1996).

More than 90% of duodenal ulcers are associated with H pylori, which is present in highest concentrations in the gastric antrum. A proximal-distal gradient of increasing organism densities exists along the corpus and antrum in duodenal ulcer disease and extends toward the transitional zone and gastroduodenal junction. Consequently, virtually all patients with duodenal ulcer disease have chronic, active, antral-predominant gastritis. With respect to duodenal ulcer disease, endoscopic visualization of the ulcer may be sufficient for diagnosis (Greenberg et al., 1996). Diagnostic confirmation of the presence of H pylori necessitates biopsy sampling of the gastric corpus and antrum. In contrast, the diagnostic evaluation of gastric ulcers requires biopsy specimens of the ulcer base and areas adjacent to gross ulceration to assess the histological features for the presence of atrophic or neoplastic changes. Adjacent mucosa is evaluated directly for the presence of concomitant atrophy, dysplasia, intestinal metaplasia, or gastric adenocarcinoma (Kuipers, 1997).

Several extradigestive pathologies have been linked to H. pylori infection including cardiovascular, cutaneous, autoimmune, esophageal and other diseases such as sideropenic anaemia, growth retardation, and extragastric MALT-lymphoma. The potential role of H. pylori infection in the pathogenesis of these extradigestive disorders has been based on facts that 1) local gastric inflammation may exert systemic effects, 2) chronic infection of gastric mucosa induces immune responses that are able to cause the lesions remote to primary site of infection and 3) H. pylori eradication improves the extradigestive disorders (Konturek et al., 1999).

Page 3: H. pylori in arabs, final not published

The main aim of this work is to evaluate the contribution of H. pylori infection to the uncommon; digestive and extra-digestive; manifestations of patients in GIT clinics in some Arabian countries. The secondary aim is to give a good clinical expectation to such manifestations and if it is essential to eradicate this infection or not.

Materials and methods:

Patients from three countries were subjected to evaluation in this study. These countries included Egypt (patients attending some centers in Cairo; 225 patients), Kuwait (patients attending gastrointestinal tract clinic in El-Moasah hospital, Salemia, Kuwait; 188 patients) and Saudia Arabia (Elite medical center, El-Olia, Riyadh; 210). Patients presented with symptoms that may be attributed to H pylori infection such as dyspepsia, upper abdominal pain, heartburn, flatulence and distension or colonic disturbance. Some also complained of manifestations not directly related to upper GIT but were niether explained by other causes nor of typical nature of their origin such as biliary symptoms, chronic upper respiratory symptoms, bad odour of the mouth ,anorexia & general fatigue ,dyspeptic ulcers, persistant unexplained elevation of liver enzymes, constipation, migraine & cluster headache, vertigo, arthralgia, angina, arrhythmia, arthralgia, backache & urticaria. Patients with any systemic or another obvious cause for their symptoms were excluded.

The following was done for all patients:1- History and thorough clinical examination 2- CBC, Serum iron, stool and urine analysis3- C-Reactive Protein, ESR, and serum amylase and lipase in cases suspected of pancreatitis.4- Liver f. tests, kidney f. tests, fasting blood sugar, and serum lipid profile 5- Abdominal ultrasound, ECG, chest X-ray6- Hepatitis markers: HCV-Ab, HbsAg, HbcAb, CMV and EBV Abs.7- Urea-breath test, H. pylori IgG and Cag-A Ab by ELISA8- Endoscopy when indicated and approved, with gastric biopsies of any lesion found and rapid

urease test (clo test) for all patients.Inclusion criteria:

1. Patients aging from 8 to 60 years attending GIT clinics in these centers suffering from digestive or systemic manifestations that may be related to H. pylori infection but not explained by other diseases.

2. H pylori positivity by at least two tests specific for H pylori. 3. No evidences of hepatic (particularly viral), cardiac, pulmonary, renal, endocrinal (not

including Diabetes), hematological, neurological rheumatologic or biochemical abnormalities. 4. No history of medications with similar side effects.5. No history of treatment of H pylori or similar drugs in the 6 months before enrollment. 6. Written informed consent for the plan of the research

Treatment with standard therapy was given to all patients. Retreatment of relapsing cases after

at least one month was established using different regimens of quadruple therapy. Follow up of patients for a period of 3 months up to one year was conducted with repetition of breath test and serology for H pylori at end of follow up period.

Results:

Page 4: H. pylori in arabs, final not published

This study included 225 patients from Egypt, 188 patients from Kuwait and 200 patients from Saudia Arabia. The sex distribution and age of three categories are comparable as shown in table 1 and 2.

Table 1: Number and sex distribution among studied patients.

129 57.3% 103 54.8% 107 53.5%

96 42.7% 85 45.2% 93 46.5%

225 100.0% 188 100.0% 200 100.0%

males

females

Total

Count %

sex

Egyptian Ptients

Count %

sex

Kuwaiti patients

Count %

sex

Saudi patients

group

Table 2: Age distribution among studied patients.

225 31.91 12.122

188 33.43 12.939

200 33.55 11.908

age

age

age

groupEgyptian Ptients

Kuwaiti patients

Saudi patients

N Mean Std. Deviation

No significant differences in age or sex distribution between patients from the three nations as regards H pylori infection. No correlation between age and all manifestations or diagnostic tests of H pylori except for duodenal ulcers (indirect correlation; i.e. more in younger age patients) and constipation (direct correlation; more in older age patients).

Tables 3 and 4: History of previous infection in all patients.

211 93.8% 14 6.2%

170 90.4% 18 9.6%

165 82.5% 35 17.5%

groupEgyptian Ptients

Kuwaiti patients

Saudi patients

Count %

absent

Count %

present

546 89.1%

67 10.9%

613 100.0%

absent

present

Total

Count %

history of previousinfection

History of past H pylori infection was found in 10.9 % of all patients and was significantly more common in Saudi than Egyptian (P= 0.001) and Kuwaiti patients (P = 0.023).

Nearly all of these H. pylori positive patients complained of upper GIT symptoms including upper central abdominal pain, discomfort, dyspepsia, flatulence, heartburn, or colonic symptoms. These symptoms were very common in these patients and improved to a variable extent after eradication of Infection.

Table 5: some clinical manifestations in all patients studied

Page 5: H. pylori in arabs, final not published

576 94.0% 554 90.4% 540 88.1% 590 96.2%

37 6.0% 59 9.6% 73 11.9% 23 3.8%

613 100.0% 613 100.0% 613 100.0% 613 100.0%

absent

present

Total

Count %

Skin rash

Count %

Mouth Ulcer

Count %

Constipation

Count %

pancreatitis

Table 6: some clinical manifestations in different groups studied.

210 198 211 217

93.3% 88.0% 93.8% 96.4%

15 27 14 8

6.7% 12.0% 6.2% 3.6%

177 182 170 188

94.1% 96.8% 90.4% 100.0%

11 6 18

5.9% 3.2% 9.6%

189 174 159 185

94.5% 87.0% 79.5% 92.5%

11 26 41 15

5.5% 13.0% 20.5% 7.5%

Count

%

absent

Count

%

present

Count

%

absent

Count

%

present

Count

%

absent

Count

%

present

groupEgyptian Ptients

Kuwaiti patients

Saudi patients

Skin rash Mouth Ulcer Constipation pancreatitis

History or presence of skin rash was found in 18.1 % (37 patients) of all patients, mostly of urticaria- like nature (28 patients) and rosacea (9 patients). These patients were referred to Dermatologist to complete their management. Diagnosis of pancreatitis, by history, clinical data and pancreatic enzymes, was found significantly more common in Saudi than Egyptian (P = 0.009) and Kuwaiti patients (P = 0.001). Constipation was significantly more common in Saudi than Egyptian and Kuwaiti patients (P = 0.001) and (P = 0.003) respectively. Mouth ulcers were significantly more common in Egyptian and Saudi patients than in Kuwaiti patients (P = 0.001). No statistically significant differences between patient’s categories in other parameters. Except for autoimmune hemolytic anemia (P = 0.02), no correlation was detected between all these manifestations and Cag positivity (P > 0.05). There was correlation between presence of constipation and presence of GIT malignancy and presence and severity of gross and microscopic gastritis. During follow up after eradication therapy, skin rashes, mouth ulcers and constipation were markedly improved in 28/37; 37/59 and 51/73 respectively.

Table 7: some autoimmune manifestations in all patients studied.

512 589 605 605 605

83.5% 96.1% 98.7% 98.7% 98.7%

101 24 8 8 8

16.5% 3.9% 1.3% 1.3% 1.3%

613 613 613 613 613

100.0% 100.0% 100.0% 100.0% 100.0%

Count

%

absent

Count

%

present

Count

%

Total

DM Arthritis AI anemia ITPSjogren'sSyndrome

Table 8: some autoimmune manifestations in the different groups.

Page 6: H. pylori in arabs, final not published

198 216 221 223 222

88.0% 96.0% 98.2% 99.1% 98.7%

27 9 4 2 3

12.0% 4.0% 1.8% .9% 1.3%

160 183 187 185 187

85.1% 97.3% 99.5% 98.4% 99.5%

28 5 1 3 1

14.9% 2.7% .5% 1.6% .5%

154 190 197 197 196

77.0% 95.0% 98.5% 98.5% 98.0%

46 10 3 3 4

23.0% 5.0% 1.5% 1.5% 2.0%

Count

%

absent

Count

%

present

Count

%

absent

Count

%

present

Count

%

absent

Count

%

present

groupEgyptian Ptients

Kuwaiti patients

Saudi patients

DM Arthritis AI anemia ITPSjogren'sSyndrome

Table 9: Thyroid dysfunction in all patients.

567 92.5% 23 3.8% 23 3.8% 613 100.0%Thyroid disCount %

absent

Count %

hyperthyroidism

Count %

hypothyroidism

Count %

Total

Table 10: Thyroid dysfunction in different groups.

213 94.7% 7 3.1% 5 2.2%

176 93.6% 7 3.7% 5 2.7%

178 89.0% 9 4.5% 13 6.5%

Thyroid dis

Thyroid dis

Thyroid dis

groupEgyptian Ptients

Kuwaiti patients

Saudi patients

Count %

absent

Count %

hyperthyroidism

Count %

hypothyroidism

Diabetes was the most commonly associated disease detected in these patients. It was found in 16.5% in all patients with the highest association found in Saudi patients. It was found that diabetes mellitus was significantly more common in Saudi patients than Egyptians (P = 0.003) and Kuwaitis (P = 0.04) and thyroid diseases were also significantly more common in Saudi patients than Egyptians (P = 0.02) and more than Kuwaitis but didn’t reach statistical significance (P = 0.07). No statistically significant differences between patient’s categories in other parameters. Thyroid dysfunction and pancreatitis were found more significant in patients with recurrent H pylori infection (P = 0.04) and (P = 0.002) respectively. Presence of DM correlated directly and significantly with the presence of mouth ulcers (P = 0.002) and atypical chest pain (P = 0.001). Presence of arthritis correlated directly and significantly with the presence of pancreatitis (P = 0.001) and AI hemolytic anemia (P = 0.002). The course of these manifestations is fluctuant and prolonged; and long follow up was not applicable.

Table 11: some other clinical manifestations in all patients studied.

579 584 577 564 547

94.5% 95.3% 94.1% 92.0% 89.2%

34 29 36 49 66

5.5% 4.7% 5.9% 8.0% 10.8%

613 613 613 613 613

100.0% 100.0% 100.0% 100.0% 100.0%

Count

%

absent

Count

%

present

Count

%

Total

Atypicalchest pain Arrhythmia Migraine Vertigo Headache

Table 12: some other clinical manifestations in different groups studied.

Page 7: H. pylori in arabs, final not published

219 217 221 204 197

97.3% 96.4% 98.2% 90.7% 87.6%

6 8 4 21 28

2.7% 3.6% 1.8% 9.3% 12.4%

180 182 173 180 171

95.7% 96.8% 92.0% 95.7% 91.0%

8 6 15 8 17

4.3% 3.2% 8.0% 4.3% 9.0%

180 185 183 180 179

90.0% 92.5% 91.5% 90.0% 89.5%

20 15 17 20 21

10.0% 7.5% 8.5% 10.0% 10.5%

Count

%

absent

Count

%

present

Count

%

absent

Count

%

present

Count

%

absent

Count

%

present

groupEgyptian Ptients

Kuwaiti patients

Saudi patients

Atypicalchest pain Arrhythmia Migraine Vertigo Headache

It was found that history of atypical, non-cardiac chest pain was significantly more common in Saudi patients than Egyptian (P = 0.003) and Kuwaiti (P = 0.001) patients. The prevalence of such symptom is low in patients studied (5.5% of all patients).History of migraine was found significantly more common in Kuwaiti and Saudi patients than Egyptian patients (P = 0.003) and (P = 0.001) respectively. History of vertigo was significantly more common in Egyptian and Saudi patients than Kuwaiti patients (P = 0.04) and (P = 0.03) respectively. No statistically significant differences between patient’s categories in other parameters. After eradication, migraine and vertigo showed marked improvement in 11/26 and 19/49 respectively.

Two cases in Saudi patients had moderate form of ulcerative colitis in association with severe gastritis due to H pylori. Eradication and specific treatment of UC resulted in complete cure of patients and withdrawal of treatment in few weeks (average 9.4 weeks).

Table 13: Gastroduodenal manifestations and complications in all patients.

569 557 554 600 605

92.8% 90.9% 90.4% 97.9% 98.7%

44 56 59 13 8

7.2% 9.1% 9.6% 2.1% 1.3%

613 613 613 613 613

100.0% 100.0% 100.0% 100.0% 100.0%

Count

%

Absent

Count

%

Present

Count

%

Total

Gastric ulcerDuodenal

ulcerGastricPolyps

Bleedingfrom ulcers

Gastric outletobstruction

Table 14: Gastroduodenal manifestations and complications in different groups.

204 90.7% 202 89.8% 190 84.4% 218 96.9% 222 98.7%

21 9.3% 23 10.2% 35 15.6% 7 3.1% 3 1.3%

172 91.5% 172 91.5% 180 95.7% 185 98.4% 186 98.9%

16 8.5% 16 8.5% 8 4.3% 3 1.6% 2 1.1%

193 96.5% 183 91.5% 184 92.0% 197 98.5% 197 98.5%

7 3.5% 17 8.5% 16 8.0% 3 1.5% 3 1.5%

Absent

Present

Absent

Present

Absent

Present

groupEgyptian Ptients

Kuwaiti patients

Saudi patients

Count %

Gastric ulcer

Count %

Duodenal ulcer

Count %

Gastric Polyps

Count %

Bleeding from ulcers

Count %

Gastric outletobstruction

The prevalence of peptic ulcer disease among the three nations was not statistically significant. Gastric ulcer was detected in 7.2 % and duodenal ulcer in 9.1 of all patients (both in 16.3%). Gastric polyps are found statistically more significant in Egyptian patients than Kuwaiti and Saudi

Page 8: H. pylori in arabs, final not published

patients (P = 0.017) and more in Saudi than Kuwait patients but not statistically significant (P = 0.127). There is direct correlation between presence of pancreatitis and all of gastric outlet obstruction, gastric ulcer, gastrointestinal malignancy, history of recurrent H pylori infection, arthritis and skin rash.

Table 15: presence and severity of Gastro-oesophageal reflux in all patients.

376 73 65 38 21 36 4

61.3% 11.9% 10.6% 6.2% 3.4% 5.9% .7%

Count

%

GERD,grade

Absent Grade 1 Grade 2 Grade 3 Grade 4

Any gradewith Barrett'esophagus Stricture

Table 18: presence and severity of Gastro-oesophageal reflux in different patients.

158 70.2% 30 13.3% 18 8.0% 4 1.8% 3 1.3% 10 4.4% 2 .9%

112 59.6% 18 9.6% 30 16.0% 14 7.4% 3 1.6% 10 5.3% 1 .5%

106 53.0% 25 12.5% 17 8.5% 20 10.0% 15 7.5% 16 8.0% 1 .5%

GERD, grade

GERD, grade

GERD, grade

groupEgyptian Ptients

Patients from Kuwait

Saudi patients

Count %

Absent

Count %

Grade 1

Count %

Grade 2

Count %

Grade 3

Count %

Grade 4

Count %

Any grade with Barrett'esophagus

Count %

Stricture

The presence and severity of GERD are more significant in Saudi and Kuwaiti than Egyptian patients and in Saudi than Kuwaiti patients. The overall prevalence of GERD of all grades in such population is 38.83% (233 patients). Most of cases (183) showed no changes in their symptoms after treatment of H pylori. Few cases (23 patients) showed worsening and few cases showed little improvement after eradication (27 patients).

Table 19: Gastritis in all patients as diagnosed endoscopically.

177 274 162

28.9% 44.7% 26.4%

Count

%

Macroscopicgastritis

None Antral diffuse

Table 20: Gastritis in different groups as diagnosed endoscopically.

59 107 59

26.2% 47.6% 26.2%

58 81 49

30.9% 43.1% 26.1%

60 86 54

30.0% 43.0% 27.0%

Count

%

Macroscopicgastritis

EgyptianPtients

Count

%

Macroscopicgastritis

Patients fromKuwait

Count

%

Macroscopicgastritis

Saudi patients

groupNone Antral diffuse

Table 21: Gastritis in all patients as diagnosed by histopathology of antral biopsies.

54 159 213 125 62

8.8% 25.9% 34.7% 20.4% 10.1%

Count

%

Microscopicgastritis

Absent Mild Moderate Severe

With atrophy,intestinal

metaplasia+/-dysplasia

Table 22: Gastritis in different groups as diagnosed by histopathology of antral biopsies.

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16 55 85 46 23

7.1% 24.4% 37.8% 20.4% 10.2%

11 57 66 36 18

5.9% 30.3% 35.1% 19.1% 9.6%

27 47 62 43 21

13.5% 23.5% 31.0% 21.5% 10.5%

Count

%

Microscopicgastritis

EgyptianPtients

Count

%

Microscopicgastritis

Patients fromKuwait

Count

%

Microscopicgastritis

Saudi patients

groupAbsent Mild Moderate Severe

With atrophy,intestinal

metaplasia+/-dysplasia

The presence and grades of severity of gastritis whether gross as seen during endoscopy or microscopic as examined by gastric biopsies, showed no significant differences between all patients studied.

Table 23: Presence and types of cholecystitis in different patients.

202 9 14

174 7 7

182 14 4

CountCholecystitis

CountCholecystitis

CountCholecystitis

groupEgyptian Ptients

Patients from Kuwait

Saudi patients

Absent Calcular Non-Calcular

No significant differences in the presence of cholecystitis (as diagnosed clinically and by ultrasound) whether calcular or non-calcular, between patient’s categories. Calcular cholecystitis in these patients was present in 4.9% in all patients.

Table 24: Types of malignancies detected in patients of different groups.

213 94.7% 5 2.2% 3 1.3% 1 .4% 3 1.3%

180 95.7% 1 .5% 2 1.1% 2 1.1% 3 1.6%

192 96.0% 2 1.0% 3 1.5% 1 .5% 2 1.0%

Egyptian Ptients

Kuwaiti patients

Saudi patients

groupCount %

Absent

Count %

Esophageal

Count %

Gastric

Count %

duodenal

Count %

Lymphoma

Malignancies diagnosed in these patients included 7 oesophageal, 8 gastric adenocarcinoma, 8 gastric lymphoma, and 4 duodenal adenocarcinoma. All were advanced and managed in the usual way of such tumors. Table 25: Results of different tests used to diagnose H pylori in all patients.

191 84.9% 183 81.3% 213 94.7% 218

34 15.1% 42 18.7% 12 5.3% 7

156 83.0% 144 76.6% 178 94.7% 182

32 17.0% 44 23.4% 10 5.3% 6

161 80.5% 151 75.5% 184 92.0% 188

39 19.5% 49 24.5% 16 8.0% 12

positive

negative

positive

negative

positive

negative

groupEgyptian Ptients

Patients from Kuwait

Saudi patients

Count %

Anti-H Pylori Ab

Count %

Breath test

Count %

Rapid Urease T.

Count

H pylori byMicroscopic E.

No differences between patient’s categories in the positivity of different diagnostic tests used to diagnose H pylori infection. The most sensitive test for diagnosis in all patients and different

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patient’s categories is the microscopic examination of gastric biopsies which is statistically more positive than all other tests. It is significantly more positive than serology and breath tests but not rapid urease test when comparison is done according patient’s categories. Rapid urease test on gastric biopsies is found more significantly positive than breath test and serology in all patients and different categories. Antibody positivity is more significant than breath test only if compared between all patients. Breath test showed significant direct correlation with all other tests and Cag positivity. Also, rapid urease test, breath test and microscopic detection of the bacteria correlated directly with each others but not with antibody positivity.

Table 26: Cag A positivity in all groups

Cag positivity * group Crosstabulation

57 22 29 108

25.3% 11.7% 14.5% 17.6%

168 166 171 505

74.7% 88.3% 85.5% 82.4%

225 188 200 613

100.0% 100.0% 100.0% 100.0%

Count

% within group

Count

% within group

Count

% within group

ngative

positive

Cag positivity

Total

EgyptianPtients

Patientsfrom Kuwait

Saudipatients

group

Total

Cag positivity was significantly higher in Saudi and Kuwaiti patients than Egyptian patients (P = 0.001) and (P = 0.005). Cag positivity showed significant correlation with breath test positivity and presence of autoimmune hemolytic anemia but no correlation with all other tests or manifestation of H pylori infection.

Table 21: Serum iron (µg /dl); in total patients; (Normal value: 37-170 in females, 49-181 in males) before and after eradication of H pylori.

401 65.4% 559 91.3%

212 34.6% 53 8.7%

Above 50

Below 50

Count %

S. iron before eradication

Count %

S. iron after Eradication

Table 22: Serum iron (µg /dl); in all groups (Normal value: 37-170 in females, 49-181 in males).

161 71.6% 113 60.1% 127 63.5%

64 28.4% 75 39.9% 73 36.5%

Above 50

Below 50

Count %

S iron

Egyptian Ptients

Count %

S iron

Patients from Kuwait

Count %

S iron

Saudi patients

group

Table 23: Blood Hb (g /dl) before and after treatment; in all patients.

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398 64.9% 531 86.6%

215 35.1% 82 13.4%

Above 10 gm

Below 10 gm

Count %

Hb level beforeeradication

Count %

Hb level aftereradication

Table 23: Blood Hb (g /dl) before and after treatment; in all groups.

142 192 125 164 131 175

63.1% 85.3% 66.5% 87.2% 65.5% 87.5%

83 33 63 24 69 25

36.9% 14.7% 33.5% 12.8% 34.5% 12.5%

Count

%

Above 10gm

Count

%

Below 10 gm

Hb levelbefore

eradicationHb level aftereradication

Egyptian Ptients

Hb levelbefore

eradicationHb level aftereradication

Patients from Kuwait

Hb levelbefore

eradicationHb level aftereradication

Saudi patients

group

No significant differences between different patient’s categories in serum iron or hemoglobin levels except for significantly less serum iron in Egyptian patients than patients from Kuwait (P=0.014). Low serum iron showed significant correlation with hemoglobin low level. Serum iron and hemoglobin levels were significantly lower in females than males. Serum iron level was significantly lower in patients with peptic ulcers (P = 0.014) and GIT malignancy (P = 0.011). Hemoglobin level was significantly lower in patients with thyroid disease (P = 0.04). Statistically, highly significant increase in serum iron and hemoglobin levels (P < 0.001) was found in all patients after eradication of infection when analyzed altogether and as separate groups without iron supplementation.

Table 24: Serum ALT (µg /dl); before and after treatment; in all patients.

437 71.3% 494 81.0%

98 16.0% 85 13.9%

78 12.7% 31 5.1%

normal

Less than 2folds increase

More than 2folds increase

Count %

ALT before eradication

Count %

ALT after eradication

Table 25: Serum ALT (µg /dl); before and after treatment; in all groups.

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176 188 128 155 133 151

78.2% 84.7% 68.1% 82.4% 66.5% 75.5%

35 24 39 24 24 37

15.6% 10.8% 20.7% 12.8% 12.0% 18.5%

14 10 21 9 43 12

6.2% 4.5% 11.2% 4.8% 21.5% 6.0%

Count

%

normal

Count

%

Less than 2 foldsincrease

Count

%

More than 2 foldsincrease

ALT beforeeradication

ALT aftereradication

Egyptian Ptients

ALT beforeeradication

ALT aftereradication

Patients from Kuwait

ALT beforeeradication

ALT aftereradication

Saudi patients

group

ALT was found elevated in 28.7 % with more affection in Saudi, then Kuwaiti than Egyptian patients but not statistically significant. Follow up of this parameter was not done. Statistically, highly significant decrease in ALT level (P < 0.001) was found in all patients after eradication of infection when analyzed altogether and as separate groups

Discussion

The prevalence of H pylori infection varies widely by geographic area, age, race, and ethnicity. Rates appear to be higher in developing than in developed countries, with most of the infections occurring during childhood, and they seem to be decreasing with improvements in hygiene practices. Infection probably occurs via feco-oral route which is a common way in areas with low socioeconomic standard. However, this infection remains common also in well civilized areas and developed countries. Adequate nutritional status, especially frequent consumption of fruits and vegetables and of vitamin C, appears to protect against infection with H pylori. In contrast, food prepared under less than ideal conditions or exposed to contaminated water or soil may increase the risk. Overall, inadequate sanitation practices, low social class, and crowded or high-density living conditions seem to be related to a higher prevalence of H pylori infection (Brown, 2000). It can cause a wide spectrum of manifestations including those related to local infection in the upper gastrointestinal tract and those related to the presence of chronic infection in the body with systemic manifestations.

In the patients of this study, the mean age seemed to be low with the mean age around 33 years (32.91). It probably depends on the rate of exposure to infection in the active age group. It can be due to coincidence of H. pylori epidemic with this age, while older age has escaped such exposure in the community.

The sex distribution is somewhat towards the male side probably due to more exposure through taking meals outside in the work. However, the difference is not significant and females are equally susceptible and seem to be more manifest. In this study, sex was only related to low serum iron and low hemoglobin level which were more in females. This finding is probably related to iron loss in menstrual blood in addition to iron malabsorption and iron loss due to gastric pathology. Low serum iron was detected in 34.6% of all patients with no differences between the three groups. In previous studies, it was found that H pylori infection can contribute to iron deficiency anaemia, and that infection should be suspected when the iron deficiency anaemia is refractory to iron administration. It was also proposed that treatment for iron deficiency anaemia coexistent with H pylori infection should include H pylori eradication (Sanstead et al., 1971; Chwang et al., 1988; Hallberg et al., 1993 and Yon Ho Choe 2000). In one of these studies, eradication of H pylori was followed by significant increase in serum iron; ferritin and hemoglobin levels in all patients (Choe et al., 2001). Thus, this study supports such

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findings of association of iron deficiency anemia and H pylori infection that necessitates eradication to correct these abnormalities. Peptic ulcers and GIT malignancy cause more decrease in serum iron level. Also and as expected, it was found that hemoglobin level was significantly lower in patients with thyroid disease. In another study, it was found that hemoglobin and MCV values rose significantly compared with baseline values after H. pylori eradication without iron supplementation in children with iron deficiency anaemia (IDA). Ferritin values increased significantly after H. pylori eradication in children with iron deficiency (ID). It was concluded that complete recovery of ID and IDA can be achieved with H. pylori eradication without iron supplementation in children with H. pylori infection (Kurekci et al., 2005). Therefore, iron status should be evaluated in such patients and corrected in addition to H pylori eradication.

History of past H pylori infection was found in 10.9 % of all patients. Recurrent infection is significantly more seen in Saudia Arabia than the other two countries. This can be due to more exposure, higher prevalence of infection in the community, more eating outside door, drug resistance due to frequent use of effective antibiotics for other infections or incomplete treatment. Thyroid dysfunction and pancreatitis were significantly more common with history of previous infection. This may be due to immune pressure exerted by repeated or prolonged infection or prolonged exposure of pancreas to the bacteria or its toxins or inflammatory mediators if there is role for such exposure. Similar association was found between arthritis, autoimmune hemolytic anemia and pancreatitis, and between diabetes mellitus and mouth ulcers.

The percentage of peptic ulcer was as expected without differences in all patients. It was diagnosed in 7.2% in stomach and in 9.1% in duodenum and gastric polyp was found in 9.6 %. Bleeding occurred in 2.1% of cases; 8 fro duodenal ulcers and 5 from gastric ulcers. Studies demonstrated that H. pylori infection was found in more than 90% of patients with duodenal ulcers, and some 70% of patients with gastric ulcers (Marshal et al., 1985 and Gaham et al., 1988). The declining incidence and prevalence of peptic ulcer in developed countries has paralleled the falling prevalence of H. pylori infection, especially in populations with high infection rates. Only H. pylori eradication is an effective treatment for both duodenal and gastric ulcers (Xia et al., 2001 and Perez-Aisa et al., 2005).

In this survey, it was found that atypical, non-cardiac chest pain was significantly more common in Saudi patients than Egyptian and Kuwaiti patients. The prevalence of such symptom is low in all patients (5.5% of all patients) despite the higher prevalence of GERD in such population (38.83%). Migraine was found significantly more common in Kuwaiti and Saudi patients than Egyptian patients. Vertigo was significantly more common in Egyptian and Saudi patients than Kuwaiti patients. However, the prevalence of such symptoms was low in all patients studied. Also, there are no convincing evidences that these symptoms are strongly related to H pylori infection apart from improvement of such symptoms after treatment. Ischemic chest pain was not investigated in these patients. However, there were many studies and reports about the relation of H pylori infection and atherosclerosis which is the main cause of coronary heart disease. Emerging evidence seems to give a potential role for H. pylori in ischemic heart disease via a cross mimicry between antibodies against heat shock protein 65 which are produced in the consequence of infection, but which are also expressed in atherosclerotic lesions (Gasbarrini and Franceschi, 1999). In General, it has been hypothesized that H pylori infection-associated chronic inflammation leads to elevated plasma levels of fibrinogen, C-reactive protein, and leukocytes -- all known risk factors for CHD. Other hypotheses include a gastritis that causes vitamin B deficiency, leading to hyperhomocysteinemia or a stimulated leukocyte procoagulant activity. None of the four prospective studies examining the relationship between

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H pylori seropositivity and CHD prevalence has been statistically significant (Folsom, 1998). In one epidemiological study, it was found that in diabetic men but not in all men, seropositivity was significantly associated with CHD prevalence but no consistent associations of H pylori infection with diabetes prevalence or variables of the insulin resistance syndrome were found in American men aged 40-74 years (Gillum, 2004). The most recent study concluded that: 1) There is a significant link between CAD and infection with H. pylori, especially expressing CagA proteins; 2) Patients infected with CagA-positive H. pylori show significantly greater coronary artery lumen loss and arterial re-stenosis after PTCA with stent implantation; 3) H. pylori eradication significantly attenuates the reduction in coronary artery lumen in CAD patients after PTCA possibly due to the elimination of chronic inflammation and the decline in proinflammatory cytokine release and 4) The identification of DNA in atherosclerotic plaques of patients with severe CAD supports the hypothesis that infection with H. pylori (especially CagA positive) may influence the development of atherosclerosis (Kowalski M, 2005). If this study is supported with more controlled double blind studies; it may revolutionize the prevention and management of coronary artery disease in such patients particularly of young age.

It was found that constipation correlated directly with the presence and severity of gastritis as detected by endoscopic examination and gastric biopsies and most of patients improved to a considerable extent after eradication treatment. The two cases in Saudi patients who had ulcerative colitis and showed complete cure in few weeks after treatment specific for this disease in addition to eradication therapy could add this gastrointestinal disease as another probable association. In another study, H pylori DNA was detected in biopsies of six patients from total of 60 with ulcerative colitis while no one tested positive in 29 controls (Streutker et al., 2004). Further studies, enrolling a higher number of patients, are needed in order to confirm these results, to characterize the Helicobacter sp. detected and to assess their role in IBD pathogenesis.

Skin rash of different forms, mostly urticaria and rosacea, were detected in 6% of all patients with no statistically significant differences between patients studied. Evidence for a potential link of H. pylori infection exists for chronic urticaria although the data are still conflicting. Thus, the search for H. pylori should be included in the diagnostic management of chronic urticaria (Wedi and Kapp, 1999). The bacterium has been implicated also other skin diseases such as rosacea, but a causal role for the bacterium is missing (Valsecchi et al., 1998; Wustlich et al., 1999; Pakodi et al., 2000 and Greaves 2000). Only single of few cases have been reported so far for other skin diseases such as hereditary or acquired angioedema due to C1-esterase inhibitor deficiency, systemic sclerosis, Schonlein-Henoch purpura, Sjogren's syndrome, Behcet’s disease, sweet's syndrome, and atopic dermatitis. Caution must be taken not to accuse H. pylori as the infectious agent responsible for every disease, particularly since H. pylori infection is very common. Although from an epidemiological and morphological view the skin diseases to which H. pylori has been linked seem to be completely different. It is striking that in most of them an autoimmune pathogenesis is suspected or considerable vascular impairment can be found (Wedi and Kapp, 1999).

One of the more common associations in this study is recurrent dyspeptic oral ulcer. It was detected in 9.6% of all patients. It was higher in Egyptian and Saudi than Kuwaiti patients but not statistically significant. Recurrence rarely happened after eradication of H pylori in most cases. A prospective, controlled clinical trial done in Otolaryngology Department of Tanta University Hospitals, Tanta, Egypt; a total of 146 patients with recurrent multiple aphthous ulcers of the oral cavity and pharynx and 20 normal control subjects were assigned to group 1 (n = 58), in which the ulcers were strictly limited to the lymphoid tissues, or group 2 (n = 88), in which the ulcers were randomly distributed in the oral cavity and pharynx. Helicobacter pylori

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DNA was extracted from 3-mm-diameter tissue samples, and polymerase chain reaction amplifications were performed for the 16S ribosomal RNA gene. In group 1, 39 patients (67%) were positive for H pylori DNA, while in group 2, 9 patients (10%) were positive (P<.001). It was not detected in any of the 20 control samples. It was concluded that these results support a possible causative role for H pylori in recurrent aphthous ulcerations with a characteristic distribution and affinity to mucosa-associated lymphoid tissues of the pharynx (Elsheikh and Mahfouz, 2005). In 13 patients with Behcet’s disease, the number and size of oral and genital ulcers diminished significantly and various clinical manifestations regressed after the eradication of HP. It was concluded that HP may be involved in the pathogenesis of BD (Avci et al., 1999).

The presence and severity of GERD are more significant in Saudi and Kuwaiti than Egyptian patients and in Saudi than Kuwaiti patients. The overall prevalence of GERD of all grades in such population is (38.83%). The role of H pylori and its eradication in the aetiology or severity of this disease remains unclear. Some cases improved after eradication; while others worsened. However, most cases were not affected by eradication. Thus, it could be stated that neither the presence of H pylori nor its eradication has any significant role in such disease. Therefore, the presence of GERD by itself shouldn’t influence the decision of treatment of H pylori. The appearance of new cases of GERD after eradication was not followed in this study. One study showed that at 3 years, patients who had successful eradication of H. pylori had an incidence of endoscopically proven esophagitis of 25% compared to patients who had ongoing infection who had roughly half the rate of developing erosive esophagitis, 13% . In the same study, it was found that only 3% of these patients actually had newly developed symptoms of GERD. In another study, 250 patients with endoscopically documented duodenal ulcer disease underwent rapid urease test and histology both before and 6 months after therapy. After 6 months, they found only one patient with erosive esophagitis out of 242 (Nimish Vakil, 2001). However, meta-analysis of 14 case-controlled studies and 10 clinical trials (after exclusion of the remaining of 811 papers reviewed) showed significant association between absence of H. pylori infection and GERD symptoms, and a positive association between anti-H. pylori therapy and occurrence of both de novo and rebound/exacerbated GERD. The magnitude of this association was higher for de novo GERD than for rebound/exacerbated GERD. The analyses performed cannot exclude, however, that odds ratios from some larger studies may have in part inflated the estimate of the pooled odds ratios, or that geographical or racial differences significantly interact to influence the estimates (Cremonini et al., 2003). However, it was stated that patients with peptic ulcer disease are more likely to benefit from anti-H. pylori therapy rather than risk the development of GERD. Also, recent data showing prospectively the 8-year incidence of gastric cancer in ulcer and non-ulcer patients creates a major argument in favour of H. pylori eradication, given its carcinogenic potential (Uemura et al., 2001). At the other end of the spectrum, H. pylori positive patients with minimal symptoms or dyspepsia rather than peptic ulcer disease may receive more harm than benefit from eradication therapy. But still a population-based dyspepsia trial has shown similar incidence of heartburn symptoms after treatment in patients receiving eradication therapy and in those receiving placebo (Moayedi et al., 2000).A prospective, double-blind study demonstrated, using excellent GERD quantifying measures including validated symptom severity scores, endoscopy, and 24-h pH-metry, that there exist no clinically significant differences in clinical or laboratory-related GERD manifestations between H. pylori-infected and non-infected GERD patients (Fallone et al., 2004).

As regards cholecystitis in these patients, it was found that it was not higher than general population with calcular cholecystitis present in 4.9% homogeneously in all groups. However, it is recommended to study the presence of H pylori antigens or DNA in surgically removed calcular gall bladder to certainly prove any association. No significant differences in the presence

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of cholecystitis, whether calcular or non-calcular, between patient’s categories. Recent epidemiologic results suggest a possible association between enterohepatic Helicobacter spp and cholesterol cholelithiasis, chronic cholecystitis, and gallbladder cancer. More than 25 Helicobacter spp have been isolated from the stomach, intestinal tract, and liver of humans, other mammals, and birds. Many of these organisms cause extragastric disease and several are able to grow in bile, including Helicobacter hepaticus, Helicobacter bilis, and Helicobacter pullorum. These nongastric (enterohepatic) Helicobacter spp generally colonize the distal small intestine, cecum, and large intestine and subsequently the liver, where they have been implicated in, or suggested to cause, hepatitis, hepatocellular carcinoma, cholecystitis, typhlocolitis, and colonic adenocarcinoma (Maurer et al., 2005).

Diabetes mellitus was one of the most commonly associated disease detected in these patients. It was found in 16.5% in all patients with the highest association (23%) found in Saudi patients which is nearly equal to the prevalence in Saudi patients ~ 24% (Al-Nozha et al., 2004). Diabetes mellitus is a common disease in the three nations studied. This percentage in such young age group might be taken as an evidence of the close relation between the two diseases. It was correlated directly and significantly with the presence of mouth ulcers (P = 0.002) and atypical chest pain but not with any other autoimmune related manifestations such as ITP, AI haemolytic anaemia, arthritis or skin rash. Many studies raised the issue of the association between DM; particularly type 1 IDDM; and H pylori infection. In one study, Thirty-four IDDM patients and 40 dyspeptic patients previously treated for H. pylori infection and successfully eradicated (confirmed both by UBT and histology) were re-evaluated after 12 months. H. pylori re-infection was significantly higher in IDDM patients compared to controls: (38% vs 5% respectively, p<0.001). It was found also that, daily insulin requirement and glicated haemoglobin were significantly higher in re-infected compared to uninfected patients (Ojetti et al., 2001). Another study showed that H pylori infection, when present in participants with halitosis, seems to predict a worse metabolic control than in H pylori-negative patients with halitosis (Candelli et al., 2003). In another study, 429 patients with type 1 (n = 49) or type 2 (n = 380) diabetes mellitus and 170 nondiabetic controls were evaluated. Seroprevalence of H. pylori was 33% and 32%, respectively, in patients with diabetes and controls (NS). It was concluded that H. pylori infection appeared not to be associated with diabetes mellitus or upper GI symptoms in diabetes mellitus (Xia et al., 2001). Other study (of 195 diabetic type I and II patients and 216 blood donors) has shown a lower seroprevalence of H. pylori in diabetic patients in comparison with the healthy population (27% vs. 51%, p < 0.001). Such finding differs from the generally accepted experience of the higher sensitivity of these patients to infection (Zenlenkova et al., 2002). The practical significance of these observations remains unsolved. In our study, pancreatitis was found significantly more common in Saudi (7.5%) than Egyptian (3.6%) and Kuwaiti (0%). Experimental study in rats showed that H pylori infection increased the severity of ischemia-induced pancreatitis and aggravated disturbances in pancreatic microcirculation in acute pancreatitis. It was found also to increase production of pro-inflammatory IL-1beta (Warzecha et al. 2002).

The diseases with possible autoimmune pathogenesis were detected in low percentages in these patients. These include, in addition to diabetes, isolated arthritis, autoimmune haemolytic anaemia, ITP, Sjogren’s disease; arthritis and thyroid dysfunction; with arthritis being the most common association (3.9%) with no differences between the three national groups. Thyroid dysfunction was detected in 7.5% of all patients and equally divided between hpo- and hyperthyroidism with no differences between the three groups of patients. The role for H. pylori has also been postulated in other autoimmune diseases such as membranous nephropathy and some acute immune polyneuropathies. The mechanisms behind these clinical observations still

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remain unclear. Some studies showed that eradication of H. pylori infection may be effective in the disappearance of autoimmune thrombocytopenia, Sjogren syndrome and Schonlein-Henoch purpura. However, if confirmed, these findings could revise the diagnostic and therapeutic approach to diseases previously considered as idiopathic (Gasbarrini and Franceschi, 1999). In one study from Japan, H pylori infection was found to be involved in most ITP patients older than 40 years, and it was recommended that eradication therapy should be the first line of treatment in H pylori-positive ITP patients. In this study, complete remission and partial remission rates were 23% and 42%, respectively, 12 months after eradication. In the majority of responders, the platelet count response occurred 1 month after eradication therapy, and the increased platelet count continued without ITP treatment for more than 12 months. H pylori eradication therapy was effective even in refractory cases, which were unresponsive to splenectomy (Fujimura et al., 2005). Similar findings were reported by other group also in Japan (Hashino et al., 2003). The prevalence of H. pylori infection in patients with chronic autoimmune hepatitis and controls was similar in one study of patients (Durazzo et al., 2002).

History of recurrent migraine, headache and vertigo was obtained in low percentage of cases, but some of cases improved markedly after eradication therapy (migraine and vertigo showed improvement in 11/26 and 19/49 respectively). This might be taken as evidence of the role of chronic H pylori infection in the pathogenesis of these disorders. However, the percentages seen in such disorders were not probably higher than general population.

Malignancies diagnosed in these patients included 7 oesophageal, 8 gastric adenocarcinoma, 8 gastric lymphoma, and 4 duodenal adenocarcinoma. All were advanced and managed in the usual way of such tumors. It is now well recognized that chronic Helicobacter pylori infection is a significant contributory factor in the development of gastric cancer, primarily in noncardiac gastric cancer. An important meta-analysis published in 2001 reviewed 12 case-control studies in which infection was determined by serology, demonstrating a relative risk of 5.9 for gastric cancer outside the gastric cardia (Crowe 2005). More than 1500 Japanese subjects were followed for a mean of 7.8 years. In those with H. pylori infection, the average rate of gastric cancer was 2.9% compared with 0% in those without infection. This observational study provides some of the strongest evidence to date for the association of H. pylori infection with gastric cancer and, interestingly, the highest risk was seen in infected subjects with nonulcer dyspepsia, in whom the rate was 4.7%. As might be expected, no gastric cancers developed in infected subjects presenting with duodenal ulcers, whereas the rate of gastric cancer for those presenting with gastric ulcers was 3.4% (Uemura et al., 2001).Multivariate analyses in one study of gastric adenocarcinoma, it was found that H pylori was an independent prognostic factor for relapse-free survival and overall survival. Depth of tumour invasion, lymph-node metastasis, and patient age 67.5 years or older were also independent prognostic factors for overall survival (Meimarakis et al., 2006). H. pylori infection is also associated with the development of lymphoma arising from the mucosa-associated lymphoid tissue (MALT) of the stomach. Primary high-grade B-cell gastric lymphoma in stages I(E) through II(E1) associated with H pylori may regress completely after successful cure of the infection (Morgner et al., 2001). One case of gastric lymphoma of the MALT type with a high-grade component was cured with disappearance of B-cell monoclonality by Helicobacter pylori eradication alone (Miki et al., 2001). In another study, only half of the patients showed disappearance of B-cell monoclonality while the remaining half showed persistence of this monoclonality for several years (Thiede et al., 2001). Treatment of low-grade gastric mucosa-associated lymphoid tissue lymphoma by eradication of Helicobacter pylori is reported to result in complete lymphoma remission in approximately 75% of cases (Morgner et al., 2001). In another study, H pylori and HCV were detected and localized in stomach in association with chronic lymphocytic inflammatory response. Oligoclonal IgH gene

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rearrangements were detected in three (from 60) patients who harboured both H. pylori and HCV in their stomach and it was concluded that when both present, may favour the selection of clonal B cells (Cammarota et al., 2002). Gastric carriage of Helicobacter pylori may play a role in the development of exocrine pancreatic cancer (Stolzenberg-Solomon, 2001). In his study, he found that subjects with H. pylori or CagA+ strains had a significantly higher risk of pancreatic cancer than seronegative subjects, with odds ratios of 1.87 and 2.01, respectively. However, no cases of pancreatic cancers were detected probably because of young age. Helicobacter pylori also can be detected in liver tissue resected from patients with hepatocellular carcinoma. Conflicting reports regarding the relationship between H. pylori and hepatocellular carcinoma were reported. This means that it is uncertain whether H. pylori acts as a troublemaker, co-risk factor or innocent bystander to the development of hepatocellular carcinoma. One study showed that H. pylori seropositivity was more prevalent among patients with HCC (36/46, 78.2%) than in controls (25/46, 54%) (P<0.05) ( Leone et al., 2003). In patients with HCV chronic liver disease, the vacA sequence was amplified from 10 of 41(24%) samples (including 27% of those with HCC). These data confirm the presence of H. pylori DNA sequences in human liver and suggest an association of Helicobacter spp. with HCV-related chronic liver diseases. Further studies are needed to ascertain which Helicobacter spp. infection plays a role in the development of HCC (Dore et al., 2002). Also no cases of HCC were detected in this study.

No colon cancers detected in these patients. Also, colonoscopic examination was not done to search for premalignant neoplasm. Patients who are seropositive for Helicobacter pylori are more likely than seronegative patients to display colorectal neoplasia, according to a new report by researchers in Japan. In one study of 332 Japanese patients who underwent routine high-resolution colonoscopy and serologic testing for anti-H. pylori antibodies, it was found that 42% of H. pylori-positive subjects had tubular adenomas of the colon compared with 19% of seronegative patients (p < 0.0001). Similarly, the percentage of subjects with a totally normal colonoscopic examination was lower in the H. pylori-positive group: 32% vs. 55% (p < 0.0005) (Inui et al., 2005). Among patients infected with H. pylori, CagA+ seropositivity was found to be associated with increased risk for both gastric and colonic cancer. Serum IgG antibodies against H. pylori (ELISA) and CagA protein (Western blot assay) were tested in 67 patients with colorectal adenocarcinoma, 36 with gastric adenocarcinoma, 47 with other malignancies (cancer controls), and 45 hospitalized for transesophageal echocardiography (TEE controls). H. pylori infection was noted in 50 colon cancer patients, 31 gastric cancer patients, 31 cancer controls, and 32 TEE controls. In all, 41 (82%), 29 (94%), 11 (35%), and 13 (41%), respectively, of these H. pylori-positive sera expressed CagA reactivity (p < 0.001 for all pairwise comparisons between cases and controls) (Shmuely et al.,2001). However, more studies including prospective, long-term examination of large groups of patients are needed to evaluate exactly the clinical outcomes in the colon of H. pylori and its eradication, as well as to examine the biological basis of H. pylori-associated neoplasia in the gastrointestinal tract.

ALT was found elevated in 28.7 % with more affection in Saudi, then Kuwaiti than Egyptian patients but not statistically significant. Elevation of ALT in these patients had no explanation from the history, examination and viral study. However, many patients have fatty liver by ultrasound and non-alcoholic fatty liver disease was suspected but not thoroughly evaluated. However, statistically, highly significant decrease in ALT level (P < 0.001) was found in all patients after eradication of infection when analyzed altogether and as separate groups. Thus, H pylori may at least partially participate in elevation of this liver enzyme. In patients with HCV chronic liver disease, the vacA sequence was amplified from 10 of 41(24%) samples (including 27% of those with HCC). These data confirm the presence of H. pylori DNA sequences in human liver and suggest an association of Helicobacter spp. with HCV-related chronic liver diseases

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(Dore et al., 2002). In another study, it was found that 70.2% (33/47) of cirrhotic patients and 47.5% (28/59) of noncirrhotic patients were H. pylori-positive (Queiroz et al., 2006). H. pylori infection is associated to an impairment of cytochrome P-450 liver metabolic activity (Giannini et al., 2003). Patients with chronic liver diseases, except autoimmune hepatitis patients, showed increased antibody levels to other Helicobacter spp. Such as H. bilis/H. hepaticus compared with the population and blood donors indicating a possible role of enteric Helicobacter in the natural course of chronic liver diseases (Vorobjova et al., 2006).

Regarding the diagnostic tests of H pylori, no differences between the three patient categories in the positivity of different tests. The most sensitive test was the microscopic examination of gastric biopsies which is statistically more positive than all other tests except rapid urease test. Rapid urease test on gastric biopsies is found more significantly positive than breath test and serology in all patients and different categories. Cag A positivity correlated only with breath test and presence of autoimmune haemolysis, but not with any other digestive or systemic manifestations in these patients. It was stated that infection with a more virulent H pylori strain was associated with a higher degree of antral and body colonisation grade, inflammation, and activity (Cover, 1996 and Kim et al., 2001). Although certain H. pylori strains are associated with pathological outcomes, the specific mechanisms that lead to these relationships have not been fully delineated. Cag A positive bacteria is associated with an augmented risk for ulcer disease and distal gastric cancer (Censini, S. et al.1996). However, the gastric inflammatory reaction induced by H pylori does not depend on a single factor, but probably results from the synergistic effect of multiple virulence factors, which work together in a complex way, causing damage to the host (Zambon et al., 2003).

Conclusion:

It is concluded from this study that H pylori infection is present in most Arabian countries nearly with similar, but of somewhat variable extent, manifestations wither digestive or extradigestive. The associated extradigestive manifestations described cannot be attributed to H pylori in all cases, but it is recommended to screen for this infection and eradicate it particularly if there are additional upper GIT complaints. The presence of GERD should not affect the decision of treatment of this infection, even if it is suspected that some cases may have exaggeration of their symptoms. Also, chronic gastric inflammation due to virulent H pylori infection may have some sort of hepatotoxic effect for which eradication of this organism must be considered. Finally, diagnosis and treatment of H pylori might be considered in the workup in the management of diseases with autoimmune pathogenesis such as ITP, autoimmune haemolytic anaemia, skin diseases, thyroid dysfunction, diabetes mellitus, and others.

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العربى الملخص

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رمقارنة دراسة فى الصلة ذات والرمراض الكلينيكى البوابية: المجال الحلزونية الباكترياعربية أقطار ثل ث فى

شندى محمد شندى شريف* و نعيمة العشرى**. معهد تيودور حبلهارس للحبحاث الكيمياء اللكلينيكية* قسمى المراض المتوطنة والكبد والجهاز الهضمى و**

المعششدة لرمششراض الرئيسششى المسششبب أنهششا ثبششت العششالم. وقششد فششى انتشششارا الرمراض أكثر رمن البوابية الحلزونية البكتريا تعتبر الوعيششة و والقلششب الجلد أرمراض رمثل أخرى بأرمراض علقة لها يكون قد المعدة, وأنه أورام و المزرمن المعدى واللتهاب كالقرح دور تقييم و دراسة هو البحث هذا رمن الهدف الفطفال. وكان فى النمو وبطئ الدم وفقر اللمفاوية الغدد وأورام المناعة و الدرموية

الششدول بعششض فششي الهضششمى الجهاز عيادات على المترددين للمرضي هضمية والغير الهضمية العراض ظهور فى الميكروب هذا المملكششة رمششن ٢١٠ و الكششويت رمن ١٨٨و رمصر رمن٢٢٥ هم و الميكروب بهذا رمريض٦٢٣ على البحث هذا أجرى قد العربية. و

المعششدة ورمنظار بالميكروب الخاصة و التقليدية الفحوص وعمل المرضى وفحص المرضى التاريخ أخذ تم السعودية. وقد العربيةالعراض. هذه على تأثيره لبيان العل ج بعد الحالت رمتابعة المرضى. وتم لجميع النسيجي الفحص و

في أكثر بمعدل رمصحوبة وكانت السعوديين المرضى في انتشارا أكثر كانت المتكررة الصابة حالت أن النتائج أوضحت وقد الحديششد نقششص و المعدة زوائد و والسكري والدوار الفم قرح أرمراض لن وجد البنكرياس. :رما والتهاب الدرقية الغدة وظائف خلل الدرقيشة الغشدة وظشائف وخلشل الصشدر ألم و المزرمشن الرمسشاك غيرهشم. وأن عشن المصشريين المرضشى فى حدوثا أكثر كانت بالدم

و المشرئ المعشدي ارتششداد أن غيرهم. و عن السعوديين المرضى فى حدوثا أكثر كانت الكبد إنزيمات ارتفاع و البنكرياس والتهاب( شششيوعا الرمششراض أكششثر رمششن السششكري كششان المصششريين. و عششن الكويششتيين و السششعوديين المرضششى فششى حششدوثا أكششثر كانششا الدوار

لء فى تزارمنا %) و١٦٠٥ التهششاب بشششدة رمباشششرا ارتبافطا رمرتبطا كان الذى %) و١١٠٩( المزرمن الرمساك ويتبعه المرضى ٶه Cagأ" "الكا ج بايجابية المرتبط الوحيد المرض السن. وكان صغار المرضى فى حدوثا أكثر عشر الثنى قرحة المعدة. وكانت

Aإصشابة بوجشود رمباششرا ارتبافطشا رمرتبطشا البنكرياس التهاب . وكان الذاتية المناعة اضطراب عن الناتج التكسرى الدم فقر هو الششدم فقششر كان الجلدي. وقد الطفح و المفاصل والتهاب المعدة رمخر ج انسداد و الهضمى الجهاز أورام و المعدية القرح و رمتكررةالهضمى. الجهاز أورام رمع و عشر والثنى المعدة تقرحات رمع شيوعا أكثر الحديد ونقص

) و٣٨/ ٢٨الجلششدى( الطفششح حششالت فششى المتابعششة أثنششاء كششبيرا تحسششنا هناك كان فقد الميكروب على والقضاء العل ج بعد أرما١٩⁄٩( ) والششدوار١١⁄٢٨( النصششفى الصششداع فششى رمتوسطا و بسيطا تحسنا ) و٥١⁄٧٣( المزرمن ) والرمساك٣٧⁄٥٩( الفم قرحة

الحالت. جميع فى والهيموجلوبين الحديد رمعدل فى الدللة عالية زيادة هناك كان ). و٤

المعدة. نسيج لعينة السريع اليورياز اختبار ثم الميكروسكوبى الكشف هو الميكروب هذا عن للكشف التحاليل أدق وكان فششي كششبير تشششابة رمششع العربيششة البلششدان هششذه فششى عام بشكل شائعة عدوى هى البوابية الهيلكوباكتر أن البحث هذا رمن يستنتج

تكششن لششم الحششالت بعششض فششى الهضششمية الغيششر العراض أن كما بسيطة اختلفات يوجد لكن و هضمية الغير و الهضمي العراض وجشود فشي وخاصشة رمنهشا اليجابيششة للحالت والعل ج الحالت هذه في التحليل بعمل ينصح فانه ذلك البكتريا. ورمع بوجود رمرتبطةالذاتية المناعة بات اضطرا أرمراض أو العلوى الهضمى الجهاز التهابات أعراض

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