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July2007 Vol.44 Issue:      2 Table of Contents
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Effect of Triple Therapy for Helicobacter Pylori Eradication on Hepatic Encephalopathy: A Randomized Controlled Trial

Amr A.H. Hassan1, Ahmed Osama2, Abdel-Hamid Serwah3, Alaa S. Abdel-Hamid4, Adel A Hassan1

Departments of Tropical Medicine1, Neurology2, Internal Medicine3,

Clinical Pathology4, Suez Canal University



ABSTRACT

Introduction: Helicobacter pylori (H. pylori) infection could potentially contribute to the development and severity of hepatic encephalopathy due to strong urease activity in the stomach of H. pylori infected cirrhotic patients. Objectives: To assess the effect of triple eradication therapy for H. pylori on hepatic encephalopathy. Design: Open randomized controlled clinical trial with 4 arms. Setting: liver diseases unit in Suez Canal University Hospital – tertiary care. Patients and Maneuver: Forty four Hp+ (Group 1) and 44 Hp- patients (Group 2) [based on rapid urease test of gastric biopsy] with hepatic encephalopathy grade 1 – 3. Interventions: Triple eradication therapy for H. pylori versus standard treatment for hepatic encephalopathy in group 1 and antimicrobial therapy (without Omeprazole) versus standard treatment in group 2 for 14 days. Main Outcome Measures: Blind assessment of the grade of encephalopathy before and within three days from end of treatment. One grade improvement was considered treatment success. Results: Success rate was 18.2% in standard treatment and 63.6% in triple therapy (p< 0.001) in H pylori  positive . While in H. pylori negative patients the success was 9.1% in standard treatment versus 59.1% (P< 0.001) in and antimicrobial therapy. Success rate was not significantly different between standard treatment or between triple therapy and antimicrobial therapy among both groups. Among other factors in logistic regression models both triple therapy (OR: 1.03<6.22<37.69, P= 0.047) and antimicrobial therapy (OR: 2.09<11.42<59.46, P= 0.02) were significant predictors of success in the respective groups. Conclusion: Both triple eradication therapy for H. pylori and antimicrobial therapy only, equally improve the outcome of management of hepatic encephalopathy. The improvement may be attributed to the effect of antimicrobial therapy on ammonia producing gut flora rather than H. pylori eradication. H pylori eradication therapy adds no benefit in hepatic encephalopathy.

(Egypt J. Neurol. Psychiat. Neurosurg., 2007, 44(2): 623-634)

 




INTRODUCTION

 

Hepatic encephalopathy (HE) is a dangerous complication affecting patients with liver cirrhosis. The reversible nature of this neuropsychiatric syndrome with its widespread cerebral changes suggests a metabolic mechanism. The brain is exposed to several neuroactive toxins, in particular ammonia, due to failed hepatic clearance or the abnormal peripheral mechanisms of the cirrhotic. Several neurotransmitter systems are involved and interrelated and changes are complex hence no one defect provides a unifying explanation1.

However ammonia plays a key role in HE and even the more recent theories that involve other agents also incorporate an increased ammonia level as an exacerbation factor2. Although kidney and muscle may liberate ammonia, most is of gut origin produced by action of bacterial flora on dietary protein and on epithelial and bacterial debris. Normally ammonia is extracted by the liver where it is used for synthesis of urea. In cirrhotics however, large quantities of ammonia reach the systemic circulation because of portal systemic shunting and impaired urea synthesis3-4.

Bacterial urease enzyme contributes significantly to absorbed ammonia as a result of daily hydrolysis of 15-30% of total body urea5. Although this activity is usually attributed to faecal bacteria, the stomach, which possesses strong activity when infected with Helicobacter pylori, is considered as an alternative site. H. pylori are known to produce copious amounts of ammonia due to its strong urease activity many times greater than that of urease positive enterobacteria. Urea readily diffuses from blood into the gastric lumen where, in the presence of H. pylori is hydrolyzed to ammonia leading to a rise in arterial levels in 50% of normal subjects and in virtually all cirrhotics6.

It has been shown that the ammonia concentrations in portal and venous blood significantly increased after the instillation of 1 ml 107 colony forming units (CFU)/ml of H. Pylori in the stomach of cirrhotic rats, suggesting that the ammonia produced by H. pylori has a role in the pathogenesis of hyperammonaemia when this organism is widely distributed and is present in large numbers in the stomach, particularly in the presence of liver cirrhosis7. Blood ammonia levels were found to be higher in cirrhotic patients with H. pylori infection than in uninfected patients in some studies8-11. This finding was supported by some therapeutic trials on the effect of H. pylori eradication therapy on hyperammonaemia in patients with liver cirrhosis12-14.

Nevertheless, other studies did not confirm the association of higher blood ammonia and H pylori infection15,16. Furthermore other studies attributed the beneficial effect of triple therapy to the non-specific effect of antibiotics on ammonia producing gastric flora rather than eradication of the H. pylori17,18.

The aim of this study was to address the hypothesis that H. pylori infection plays a role in pathogenesis of hyperammonemia and encephalopathy in cirrhotic patients. The approach was to assess the effectiveness of triple eradication therapy vs. standard treatment alone on HE in H. pylori positive (Hp+) cirrhotic patients and to compare it with the effectiveness of antimicrobial therapy in H. Pylori negative (HP-) patients. A randomized controlled trial design was selected as the most appropriate study design for evidence on effectiveness of interventions.

 

PATIENTS AND METHODS

 

Study design and sample size:

This study is a randomized controlled open frame clinical trial with 4 arms, to assess the impact of triple therapy for Hp+ cirrhotic patients on the outcome of HE and to compare the effect of triple therapy with antibiotics only in Hp- cirrhotics. Block randomization was done within each group using tables of random numbers with blocks of 4. The calculated sample size was 20/group. A total of 88 patients with HE were enrolled to accommodate for loss to follow-up (Fig. 1).

 

Patients and methods:

Patients attending the liver diseases clinic in Suez Canal University Hospital with clinical, laboratory and ultrsonographic evidence of liver cirrhosis were evaluated for clinical evidence and severity of HE. Those with evidence of HE grade 1- 3 were eligible for enrollment after exclusion of active gastrointestinal bleeding, antibiotic use within one month, hepatocellular carcinoma, renal failure (plasma creatinine > 2 mg/dl), and patients receiving benzodiazepines, narcotics, or alcohol within 2 weeks. Patients contraindicated to endoscopy, with other possible causes of encephalopathy (diabetic, hypertensive etc.), over 65 years age and those who refused to participate in the study were also excluded.

All eligible patients were enrolled consecutively to the study and underwent clinical and laboratory assessment [including liver enzymes, serum bilirubin, prothrombin time, serum albumin, and fasting blood ammonia]. The vast majority of the patients were known to have post-hepatitic cirrhosis. The severity of cirrhosis was graded according to Child-Pugh classification19 [Class A (n=3) Class B (n=31) Class C (n=54)].

The patients were immediately subjected to upper GI endoscopy. During endoscopy and just after entering the stomach, gastric juice was aspirated from the fundal pool through the suction channel of the endoscope and collected into a trap inserted in the suction line. Routine inspection of the gastrointestinal tract was then performed and four biopsies were taken from the antrum and gastric body for evaluation of H. pylori status by rapid urease test (RUT) and histopathological examination. Patients were considered positive for H. pylori if the rapid urease was positive and confirmation by histopathological examination was done later.

 

The intervention:

Positive cases for Helicobacter pylori (by RUT) were randomized to receive eradication therapy for Helicobacter pylori (triple regimen of Omeprazole 20 mg, Amoxicillin 1000 mg, Metronidazole 1000 mg), administered twice per day for 14 days in addition to standard treatment for HE (lactulose 30 ml orally and lactulose enema every 8 hours) or standard treatment alone. This triple eradication therapy regimen was selected because it was shown to produce eradication rate of 80% when given for 1 week20. This rate was suggested to be acceptable on an intention to treat basis by the European Helicobacter pylori Study Group (EHPSG)21.

Negative cases for Helicobacter pylori were randomized to receive the same antibiotics given for the triple therapy (Amoxicillin 1000 mg, Metronidazole 1000 mg) twice per day for 14 days but without Omeprazole in addition to standard treatment, or standard treatment alone.

Patient's compliance were evaluated by regular follow up twice weekly and each patient was advised to come to the follow up with the box of tablets and pill count was done. Patients from each group were not allowed to shift to other schedule or take any other drugs without permission from the investigator.

Assessment of Hepatic Encephalopathy:

HE was graded based on clinical parameters of disturbed mental function. This score represents a quantification of symptoms based on the Porto-Systemic Encephalopathy grading by Jones and Gammal22. Clinical assessment criteria consisted of the disordered sleep pattern with a score of (1), in combination with assessment of level of consciousness. Light disturbance of consciousness was scored if at least one of the following symptoms was present; drowsiness (tendency to fall asleep but wake up spontaneously or in response to normal voice or light), intermittent or permanent disorientation, inappropriate behavior, mood disorder and retardation of the ability to perform mental tasks (serial subtraction of sevens) with score of up to 10. 

 

The score items were weighted so that major disturbances of consciousness were scored as follows:

1-      Arousable to physical stimuli such as mild prodding or shaking only – score 11

2-      Localized motor response to pain – score 13

3-      Unavoidability, no or unlocalised motor reactions to painful stimuli – score 15

 

Patients were graded as stage 0 (score <3), stage 1 (score 3-4), stage 2 (score 5-10), stage 3 (score 11-14) and stage 4 (score 15 – 16). Success of intervention was considered if there was improvement by one stage at least. The assessment was done by an expert neurologist (A.O.), who was blinded to the treatment arm of the patient.

 

Rapid urease test of endoscopic biopsy:

The test was done utilizing the Christensen’s urea broth, to detect urease production. This medium was rehydrated by dissolving 29 gm in 100 ml distilled water and sterilized by filtration. The medium was poured into sterile small tubes, 1 ml in each, and kept in refrigerator at 2-4°C. The needed tubes were allowed to warm at room temperature before use. Each of the two-biopsy specimens was inoculated into a separate tube and left at room temperature. A positive result was indicated by a change in the color of the medium from yellow to pink within 24 hours.

Blood and gastric juice ammonia:

                The plasma and gastric juice samples were analyzed for NH3 concentrations using an enzymatic assay. The assessment was done using Sigma diagnostics ammonia reagents for the quantitative, enzymatic determination of ammonia in plasma at 340 mm. (sigma – Aldrich company, LTD. England). The upper limit of normal was 80 mg/dl.

 

Statistical analysis

Data collection was done using a standardized form. Data entry and verification was done by SPSS software version 6.1. Continuous data were expressed as mean and standard Deviation (SD). Student's t-test was used for various continuous variables. The level of significance set at a 5% probability level (P<0.05). The Chi-squared test was used to compare the categorical variable. The correlation between variables was tested by multivariable regression analysis. Kruskal Wallis test was used when appropriate. Analysis was based on the intention-to-treat and patients who failed to show up at end of trial were considered as failure of the intervention.

 

RESULTS

 

Eighty eight cirrhotic patients with encephalopathy according to PSE score were included in the study. H. pylori infection was diagnosed in this study by rapid urease test (RUT) of gastric biopsy. We also used histopathological examination to confirm H. pylori diagnosis. All Hp+ patients by RUT were confirmed by histopathology, while only 10 Hp- RUT patients were positive by histological examination. This gives a sensitivity of 81.4% and specificity of 100% in this study which justifies the use of RUT as a criterion for diagnosis23. Hp- patients and Hp+ patients (n=44 in each group) were randomized within the group to receive standard treatment for HE only or the intervention (antibiotics or triple therapy respectively) plus standard treatment.

There were no significant differences in clinical characteristics between patients in the four arms of the study (Table 1). Similarly the laboratory and endoscopic findings of patients in the four arms was not significantly different except for S. albumin which was slightly higher in the Hp+ than the Hp- patients (Table 2). These findings attest for the appropriateness of our randomization process which distributed all factors equally between groups.

Gastric juice and fasting blood ammonia levels were tested at entry in the time of endoscopy. The gastric ammonia level in Hp+ patients was nearly double that in Hp- patients and this difference was highly statistically significant (P < 0.001). Although blood ammonia level was elevated in the majority of patients, there was no statistically significant difference between Hp+ and Hp- patients (Table 3).

Table (4) shows the scores, grades and outcome of HE before and after intervention in the 4 arms of the study. The mean score of HE was reduced from 9.4±1.5 to 4.9±1.2 in the antibiotic treated Hp- patients with a difference of 4.4±1.4. This decrease was significantly different from the reductions in patients on standard treatment (8.6±1.7 before, 7.7±0.8 after, difference 0.8±1.3), (P<0.001). Also the grade of HE after intervention improved by 2 grades in 4.8% vs. none and by 1 grade in 57.1% vs. 10% in patients receiving the antimicrobial therapy compared to those receiving the standard therapy. Hence the success rate was 59.1% in patient receiving the antimicrobial therapy and only 9.1% in those receiving the standard therapy (P<0.001).

Similarly the mean score of HE was reduced from 9.2±1.7 to 4.7±0.7 in the Hp+ patients treated with triple therapy, with a difference of 4.4±1.6. This decrease was significantly different from the reductions in patients on standard treatment (8.6±1.9 before, 6.5±1.4 after, difference 2.2±1.9) (P<0.001). Also the grade of HE after intervention improved by 2 grades in 5.3% vs. none and by 1 grade in 68.4 % vs. 19.0 in patients receiving the triple therapy compared to those receiving standard therapy respectively. Hence the success rate was 63.6% in patient receiving the triple therapy and only 18.2% in those receiving the standard therapy (P<0.001).

Although the score of encephalopathy after treatment was significantly higher in the Hp+ patients receiving the standard therapy than those receiving the same therapy in the Hp- patients, the difference in grades of encephalopathy and success rate before and after treatment was not significantly different between them. Neither was the difference significant between Hp- patients receiving antimicrobial therapy and Hp+ patients receiving triple therapy. (Table 4- middle panel) 

Table (5) shows the best fitting logistic regression models for success of treatment (dependant factor), and various personal and disease characteristics as independent factors in Hp- and Hp+ patients. Among Hp- patients the best independent statistically significant predictors for the success of treatment were the score of HE pre-intervention, antibiotics use and lower gastric juice ammonia. The model was statistically significant (Chi-Square: 24.51, p<0.0001) and explains 70% of the success of treatment, as indicated by the value of R-square (0.7).

Similarly, among Hp+ patients the best independent statistically significant predictors for the success of treatment were the score of HE pre-intervention, jaundice, and the triple therapy for H. pylori. The model was statistically significant (Chi-Square: 29.12, p<0.0001) and explains 65% of the success of treatment, as indicated by the value of R-square (0.65).

Fig. (1): Study Design.


Table 1. Clinical Characteristics of Patients in the Four Study Groups.

 

 

H. pylori negative

H. pylori positive

X2

(P-value)

Standard treatment

Antibiotics

Standard treatment

Triple therapy

No.

%

No.

%

No.

%

No.

%

Sex:

Male

Female

 

18

4

 

81.8

18.2

 

18

4

 

81.8

18.2

 

14

8

 

63.6

36.4

 

17

5

 

77.3

22.7

 

2.69

0.44

Age(years):

Range

Mean ± SD

 

36.0-56.0

48.5±20.6

 

36.0-65.0

50.0±6.9

 

23.0-60.0

49.6±8.1

 

39.0-65.0

52.2±5.5

 

F=1.27

0.29

Previous encephalopathy

7

31.8

6

27.3

7

31.8

6

27.3

0.22

(0.97)

Previous hospital admission

12

54.5

12

54.5

11

50.0

13

59.1

0.37

(0.95)

Jaundice

11

50.0

17

77.3

16

72.7

11

50.0

5.96

(0.11)

LL Oedema

17

77.3

17

77.3

16

72.7

19

86.4

1.28

(0.73)

Shrunken Liver

13

59.1

14

63.6

9

42.9

14

63.6

2.54

(0.47)

Enlarged Spleen

21

95.5

22

100

21

95.5

21

95.5

……

Ascites

19

86.4

19

86.4

20

90.9

19

86.4

0.31

(0.96)

Child Pugh:

 

A & B

7

31.8

6

27.3

8

36.4

13

59.1

6.34

(0.39)

C

15

68.2

16

72.7

14

63.6

9

40.9

(F): ANOVA test                                  

 

Table 2. Laboratory and Endoscopic Characteristics of Patients in the Four Study Groups.

 

 

H. pylori negative

H. pylori positive

X2

(P-value)

Standard treatment

Antibiotics

Standard treatment

Triple therapy

No.

%

No

%

No.

%

No.

%

Total bilirubin

>1.1  mg/dl

22

100.0

21

95.5

22

100.0

21

95.5

2.05

(0.56)

Serum albumin 

<3.5 g/dl

22

100.0

22

100.0

22

100.0

20

90.9

6.14

(0.11)

Mean±SD

2.4 ± 0.4

2.5 ± 0.5

2.7 ± 0.5

2.8 ± 0.4

H =9.49

(0.02*)

Prolonged PT

21

95.5

22

100.0

22

100.0

22

100.0

3.03

(0.39)

Mean±SD (s)

3.1±1.7

3.9±1.9

2.9±1.3

3.3±1.5

0.28

ALT >2N

2

9.1

9.1

0.0

2

9.1

1

4.5

2.33

(0.51)

Mean±SD

61.3± 36.0

55.2 ± 16.8

64.9 ± 18.6

68.9 ± 17.7

0.06

AST >2N

5

22.7

2

9.1

5

22.7

5

22.7

1.97

(0.58)

Mean ± SD

87.2±55.5

74.3±23.8

72.5 ± 18.3

85.1 ± 34.4

0.50

Oesophageal varices

15

68.2

17

77.3

15

68.2

17

77.3

0.82

Portal hypertensive gastropathy

10

45.5

10

45.5

12

54.5

13

59.1

0.75

Peptic ulcer disease

11

50.5

6

27.3

11

50.5

5

22.7

0.11

(*) Statistically significant      (H): Kruskal Wallis test

Table 3. Blood and gastric juice ammonia among patients in the four study groups.

 

 

H. pylori negative

H. pylori positive

Kruskal Wallis test

Standard treatment

Antibiotics

Standard treatment

Triple therapy

Blood ammonia: (#)

 

   Range

20 -820

150±160

20 0320

130±90

20 -940

210±200

20 - 430

160±110

H=2.84

0.42

   Mean±SD

Gastric juice ammonia: (#)

 

   Range

330-2940

1270±600

690-2780

1210±480

610-3790

2540±870

690-3870

2610±870

H=39.79

<0.001*

   Mean±SD

 (#) mg/dl; (*) Statistically significant;    (H): Kruskal Wallis test

                 

Table 4. Scores, grades and outcome of encephalopathy before and after standard treatment or intervention in H. pylori negative and H. pylori positive patients.

 

 

 (*) Statistically significant;    (H): Kruskal Wallis test;  (#) Statistically significant after exclusion of histopathological +ve cases; ($) missing numbers are lost to follow-up at end of trial

Table 5. Best fitting stepwise logistic regression model for success of treatment and patients' characteristics among H. pylori negative.

 

Variable

Beta coefficient

SE

p-value

OR

( 95% CI)

H. pylori negative patients

Score of encephalopathy $

0.86

0.44

0.04*

1.00

(2.36- 5.57)

Gastric juice ammonia level

-0.37

0.17

0.033*

0.69

(0.49 - 0.97)

Antibiotic treatment #

4.71

2.03

0.020*

11.14

(2.09- 59.46)

Constant

-7.63

4.26

0.07

 

R-square:          0.70                                            Model Chi-Square: 24.51, p<0.0001*

H. Pylori positive patients

Score of encephalopathy $

1.34

0.52

0.010*

3.83

(1.37- 10.72)

Jaundice

-4.04

1.65

0.015*

 0.02

(0.001- 0.45)

Triple treatment #

 

1.82

0.92

0.047*

 6.22

( 1.03- 37.69)

Constant

-11.12

4.12

0.007*

 

R-square:          0.65                                            Model Chi-Square: 29.12, p<0.0001*

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

(*) statistically significant

($) pre-intervention                (#) reference: standard treatment                             

Dependent variable: success of treatment - one stage improvement at least. (Yes =1 - No =0)

 

DISCUSSION

 

The Hypothesis that H. pylori are a significant risk factor for HE is still being debated, and the effectiveness of eradication therapy as treatment in Hp+ patients remains controversial. Although studies continue to be published on the subject, the results are still inconclusive24-27. This is probably due to the differences in case selection, diagnostic criteria, methods for assessment of the outcomes and small sample size in many cases. Further more most of the studies focused on the association between H. pylori infection on one hand and levels of gastric or blood ammonia and/or HE on the other28-32. Even the few studies that examined the question of effectiveness of eradication therapy were not conclusive because of flaws in the methodologies involved33-36.

The present study aimed to answer the most clinically relevant question of whether eradication therapy would improve the outcome of HE in cirrhotic patients who most commonly present to our clinical practice. Namely ambulatory patients, who present with mild to moderate grades of encephalopathy (Grade 1–3). We used a randomized controlled design which provides best evidence on effectiveness of interventions. We used 4 arms to compare triple eradication in Hp+ patients with antimicrobial therapy alone in Hp- patients. We compared the interventions with conventional standard treatment for HE alone. To the best of our knowledge this is the first study to implement such a design to answer this question.

In this study the mean level of gastric juice ammonia was significantly higher in Hp+ patients in comparison to Hp- patients. This is in accordance with the known strong urease activity of H. pylori on splitting urea present in the gastric juice into ammonia and carbon dioxide 7. Although the level of blood ammonia was also high in our study patients in general, there was no significant difference between Hp+ and Hp- patients. Hence, the higher level of gastric juice ammonia was not significantly associated with higher levels of fasting blood ammonia. These findings indicate that ammonia production in the stomach by H. Pylori urease appears to be too small and inadequate to clinically affect ammonia disposal and to contribute to HE in the majority of cirrhotic patients 25.

Miquel et al. in 200434 found that initial fasting blood levels of ammonia were comparable in H. pylori infected and non-infected patients with advanced cirrhosis of the liver and sub clinical HE, and no reduction was observed after H. pylori eradication among infected patients. Similarly, Chakrabarti et al., in 2002 and Nam et al. in 2004 also found that patients with H. pylori infection had significantly higher gastric juice ammonia concentrations than those without infection. However, no difference in arterial ammonia levels emerged between the two groups and no significant correlation was found between gastric juice ammonia concentrations and arterial ammonia levels30,32. Conversely, a recent large study from China showed that blood ammonia concentration in H pylori (-) was significantly lower than in Hp+ cirrhotics (P<0.01), and that it was significantly reduced due to H pylori eradication (P<0.01)36. 

The main results of the present study (table 4) showed that the score, grades and success rate of HE significantly improved in Hp+ cases who received triple eradication therapy than those who received the standard treatment only. Similarly, the same outcomes improved significantly in the Hp- patients who received antimicrobial therapy without omeprazole than those who received the standard treatment only. This is confirmed by the logistic regression models (Table 5), that showed that antimicrobial therapy and triple therapy were among the significant predicting factors explaining the success outcome in the Hp- (OR: 11.14, CI: 2.09- 59.46) and Hp+ (OR: 6.22, CI: 1.03- 37.69) groups respectively. In addition the score of encephalopathy at entry of the study, and other factors of liver impairment were also significant predictors of response.

These findings are in contradiction to the results of Miquel et al in 2001 who observed no improvement of psychometric and/or electrophysiological tests after H. pylori eradication among 19 patients in their study 34. Also Demirtürk et al in 2001 found that H. pylori eradication in cirrhotics does not provide an improvement in visual evoked potentials (VEP) recordings in 24 patients35. These and other studies who reported negative outcome of triple eradication therapy had small sample size and did not have a control group. Only Wang LJ, et al. in 2006, who used a large number of patients (457 cirrhotics) showed that HE significantly dropped from 47.0% to 34.1% (p<0.01) after eradication therapy among Hp+ patients36. 

However, comparison of the eradication therapy among the Hp+ vs. antimicrobial therapy among Hp- Patients did not show any significant difference in the outcomes. Similarly the grade and success rate of treatment was not significantly different between Hp+ than Hp- patients who received standard therapy in spite of the significant improvement of the mean score of encephalopathy in the former (table 4-middle panel). These findings indicate that the improvement of outcome in the intervention arms vs. standard treatment in both groups could be attributed to the non-specific effect of antimicrobial therapy on ammonia producing gut flora rather than H. pylori eradication. Liver impairment and ammonia production in the gut remain crucial in ammonia disposal in cirrhotic patients. No benefit on HE could be expected from testing and treating liver cirrhosis patients for H. pylori unless otherwise indicated

In conclusion: Although gastric juice ammonia was higher in Hp+ patients it did not affect the blood ammonia level. Both triple eradication therapy and antimicrobial therapy were equally effective in improving the outcome of HE. The improvement may be attributed to the effect of antimicrobial therapy on ammonia producing gut flora rather than H. pylori eradication. H. pylori infection does not seem to play a major role in the pathogenesis of hyperammonemia and HE in those patients.

 

REEFRENCES

 

1.      Sherlock S and Dooley J. (1996): Hepatic Encephalopathy. In: Sherlock S. and Dooley J. eds. Disease of the liver and biliary system. 10th ed. Blackwell Scientific Publications, U. K. p. 103.

2.      Butterworth RF. (1996): The neurobiology of hepatic encephalopathy. Semi Liv Dis

3.      Cordopa J. and Blei AT. (1997): Treatment of hepatic encephalopathy. Am. J. Gastroentrol. ; 92: 1429-39.

4.      Summerskill W. and Wolpert E. (1997): Ammonia metabolism in the gut. Am J Clin Nutr. 23: 633-9.

5.      Jackson A., Picou D. and Landman J. (1984): The non invasive measurement of urea kinetics in normal man by a constant infusion of NN-Urea. Hum Clin Nutrit; 38: 393-94.

6.      Conn H. (1994): Trailmaking and number connection test in the assessment of mental state in portal systemic encephalopathy. Am. J. Dig. Dis.; 22:c 541-550

7.      Ito S, Kohli Y, Kato T, Abe M, Ueda T. (1994): Significance of ammonia produced by Helicobacter pylori. Eur J Gastroenterol Hepatol; 6: 167–7

8.      Attili A., Rinaldi V., Caschera M., et al. (1994): Helicobacter Pylori: A major determination of serum ammonia levels in cirrhotic patients? Hepatology; 20-56. 

9.      Al-Kareemy E and, Zakhary M. (1996): Helicobacter Pylori: Is it a risk factor for hepatic encephalopathy in cirrhotic patients? Gut; 39-121.

10.    Cho Y., Bong H., Lee Y., et al. (1997): The role of gastric H. pylori infection on the blood level of ammonia in patients with liver cirrhosis. Gastroenterology; 112: 89.

11.    Si J, Cao Q, Gao M, Fang L, Qian G, Wang Y. Changes in serum ammonia concentration in cirrhotic patients with Helicobacter pylori infection. Chin Med J (Engl.) 2000; 113:1080-1.

12.    Ito S., Miyaji H. and Azuma T. (1995): Hyperammonaemia and Helicobacter  pylori. Lancet, 346: 124.

13.    Dasani BM, Sigal SH and Lieber CS (1998): Analysis of risk factors for chronic hepatric encephalopathy: The role of Helicobacter pylori infection. Am J Gastroenterol, 93 (5): 726.

14.    Miyaji H., Ito S., Azuma T., et al. (1997): Effect of Helicobacter pylori eradication therapy on hyperammonaemia in patients with liver cirrhosis. Gut; 40: 726-30.

15.    Rossle M., Haag K., Ochs A., et al. (1994): Helicobacter Pylori is not associated with an increased risk of hepatic encephalopathy. Hepatology; 20-57.

16.    Plevris J., Morgenstern R., Hayes P., et al., (1995): Hyperammonaemia in cirrhosis and Helicobacter Pylori infection. Lancet; ii:1104

17.    Quero J., Hartmann I. and de Rooij F. (1995): hyperammonaemia and Helicobacter Pylori. Lancet; ii: 713-4.

18.    Taylor S., Jackson N. and Buckley C. (1997): Helicobacter Pylori, ammonia and the brain. Gut; ;40:805-6

19.    Pugh RHN, Murray-Lyon IM, Dawson J I, et al., (1973): Transaction of the oesophagus for bleeding oesopageal varices. Br J Surg; 60:646-9

20.    Lind T, Veldhuyzen van Zanten S, Unge P, et al. (1996): Eradication of Helicobacter pylori using one-week triple therapies combining omeprazole with two antimicrobials: the MACH 1 study. Helicobacter; 1:138–44.

21.    The European Helicobacter pylori Study Group (EHPSG). (1997): Current European concepts in the management of Helicobacter pylori infection. The Maastricht Consensus Report. Gut; 41:8–13.

22.    Jones E.A., Gammal S.A. (1988): Hepatic Encephalopathy. In: Arias IM, Jakoby WB, Popper H, et al, Eds. The liver: Biology and pathobiology, 2nd Ed. New York: Raven press.

23.    Sanchez-Mete L, Zullo A, Hassan C, Rinaldi V, Magno MS, Festuccia F, Morini S, Attili AF. (2003): Helicobacter pylori diagnosis in patients with liver cirrhosis. Dig Liver Dis. Aug; 35(8):566-70.

24.    Zullo A, Hassan C, Morini S. (2001): Hepatic encephalopathy and Helicobacter pylori: a critical reappraisal. J Clin Gastroenterol; 37:164-8.

25.    Calvet X, Nogueras C, Roqué M, Sanfeliu I. (2001): Helicobacter pylori is not a risk factor for HE. Dig Liver Dis ; 33:414-9

26.    Duseja A, Sachdev A, Dhiman RK, Chawla YK. (2003): Helicobacter pylori and hepatic encephalopathy. Indian J Gastroenterol; 22 Suppl. 2:S31-2.

27.    Zullo A., Hassan C. and Morini S. (2003): Helicobacter pylori infection in patients with liver cirrhosis: facts and fictions. Digestive and liver disease; 35(3):197-205.

28.    Kini D, Aggarwal R, Saraswat VA, Naik SR. (2001): Role of Helicobacter pylori infection in hyperammonemia and subclinical HE in cirrhosis of liver. Indian J Gastroenterol; 20:237-40.

29.    Scotiniotis IA, Lucey MR, Metz D C. (2001): Helicobacter pylori infection is not associated with subclinical hepatic encephalopathy in stable cirrhotic patients. Dig Dis Sci; 46:2744-51

30.    Chakrabarti P, Zullo A, Hassan C, Pandit A, Chowdhury A, Santra A, Hazra B, Morini S, Roy T.( 2002): Helicobacter pylori, gastric juice, and arterial ammonia levels in patients with cirrhosis. Clin Gastroenterol. May-Jun;34(5):578-81

31.    Sethar GH, Ahmed R, Zuberi BF, Afsar S. (2004): Frequency of Helicobacter pylori antibodies in porto-systemic encephalopathy. J Coll Physicians Surg Pak; 4:530-3.

32.    Nam YJ, Kim SJ, Shin WC, Lee JH, Choi WC, Kim KY, Han TH. (2004): Gastric pH and Helicobacter pylori infection in patients with liver cirrhosis. Korean J Hepatol 2004; 10:216-22

33.    Nandakumar R, Naik AS, Pandit B, Kamat R, Bhatia SJ. (2003): Effect of Helicobacter pylori eradication on serum ammonia levels in patients with chronic liver disease. Indian J Gastroenterol ; 22:221-3.

34.    Miquel J, Barcena R, Boixeda D.(2001): Role of helicobacter pylori infection and its eradication in patients with subclinical hepatic encephalopathy. Eur. J. Gastro. Hepatol. 13(9):1067-72

35.    Demirturk L, Yazgan Y, ZCI O, Ozel M, Togrol E, Gultepe M, Gurbuz AK, Yildirim S. (2001): The effect of Helicobacter pylori eradication on gastric juice and blood ammonia concentrations and on visual evoked potentials in cirrhotics. Helicobacter  ;6(4):325-30

36.    Wang LJ, Cai JT, Chen T, Lu B, Si JM. (2006):.The effects of Helicobacter pylori infection on hyperammonaemia and hepatic encephalopathy in cirrhotic patients Zhonghua Nei Ke Za Zhi. Aug;45(8):654-7[Article in Chinese] abstract from PubMed


  

الملخـص العربى

 

أثر العلاج الثلاثي لاستئصال ميكروب هيليكوباكتر بيلورى على الاعتلال الدماغي الكبدي

 

تعتبر أمراض الكبد ومضاعفاتها من أكثر الأمراض انتشارا في مصر وقد تمت دراسات مختلفة لمعرفة عوامل المخاطرة لمرض اعتلال الدماغ الكبدي في مرضى تليف الكبد وقد ظهرت في السنوات الأخيرة بعض الدراسات التي تشير إلى احتمال وجود دور هام للبكتيريا (الهيلكوباكتر بايلورى) في حدوث هذا الاعتلال  على أساس أن هذه البكتيريا تعد مصدرا هاما لإنتاج الامونيا. وقد تم إجراء هذا البحث بهدف دراسة العلاقة بين ميكروب الهيلكوباكتر بايلورى ومرض اعتلال الدماغ الكبدي.

تم اختيار 88 مريضا باعتلال الدماغ الكبدي بعد تقييم درجة الاعتلال من خلال استمارة خاصة بذلك وتم إجراء منظار علوي على الجهاز الهضمي واخذ عينة من السائل المعدي لقياس نسبة الامونيا ومقارنتها بنسبة الامونيا في الدم. وتم تقسيم المرضى إلى مجموعتين الأولى ايجابية لميكروب الهيلكوباكتر بايلورى والتي تم تقسيمها عشوائيا إلى مجموعتين احدهما يتم علاجها ضد ميكروب الهيلكوباكتر بايلورى والأخرى تأخذ العلاج التقليدي وكل مجموعة 22 مريضا. المجموعة الثانية سلبية لميكروب الهيلكوباكتر بايلورى تم تقسيمها عشوائيا إلى مجموعتين احدهما يتم علاجها بالمضادات الحيوية والأخرى تأخذ العلاج التقليدي وكل مجموعة 22 مريضا. بعد انتهاء العلاج تم تقييم حالة المريض من حيث درجة اعتلال الدماغ الكبدي.

وقد أثبتت النتائج التالي:

- نسبة الامونيا في السائل المعدي للمرضى المصابين بميكروب الهيلكوباكتر بايلورى أكثر من نسبتها في المرضى الغير مصابين بالميكروب وهذه الزيادة لها دلالة إحصائية ولكن هذه الزيادة لم تؤثر على زيادة نسبة الامونيا بالدم بين المجموعتين.

- حدث تحسن في درجة اعتلال الدماغ الكبدي في 59.1% من المرضى الذين تم علاجهم بالمضادات الحيوية من المجموعة السلبية لميكروب الهيلكوباكتر بايلورى بينما حدث هذا التقدم في حوالي 9.1% فقط من المرضى الذين تم علاجهم بالعلاج التقليدي وهذا الاختلاف له دلالة إحصائية.

-  63.6% من المجموعة الايجابية لميكروب الهيلكوباكتر بايلورى والذين تم علاجهم من هذا الميكروب حدث تحسن في درجة اعتلال الدماغ الكبدي بينما حدث هذا التقدم في حوالى18.2% فقط من المرضى الذين تم علاجهم بالعلاج التقليدي. وهذا الاختلاف له دلالة إحصائية.

-  بمقاربة درجة التحسن في المرضى المصابين بميكروب الهيلكوباكتر بايلورى والذين تم علاجهم ضد الميكروب وبين المرضى الغير مصابين بهذا الميكروب و الذين تم علاجهم بالمضادات الحيوية وجد انه لا يوجد اى اختلاف له دلالة إحصائية بين المجموعتين.

-  من خلال هذه الدراسة وجد أن استئصال ميكروب هيليكوباكتر بيلورى ليس له دور مؤثر علي الاعتلال الدماغ الكبدي يفوق استخدام المضادات الحيوية.



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