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Predictive Value of Non-Invasive Blood Ammonia Level for the Presence of Oesophageal Varices in Egyptian Patients With Liver Cirrhosis

Iman Ramzy, Hanan Abdel Hafez, Hanan Madani, Nabil Sanad

Iman Ramzy, Hanan Abdel Hafez, Endemic Hepatogastroenterology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
Hanan Madani, Chemical Pathology Department, Faculty of Medicine, Cairo University, Egypt Nabil Sanad, Internal medicine Department, El Fayoum hospital. El Fayoum, Egypt

Correspondence to: Hanan Abdel Hafez, Endemic Hepatogastroenterology Department, Faculty of Medicine, Cairo University, Egypt
Email: hananahh@hotmail.com
Telephone: +201001542341
Fax: +223652504
Received: March 26, 2015
Revised: April 27, 2015
Accepted: April 30, 2015
Published online: May 21, 2015

ABSTRACT

Aims: Although recent guidelines recommend screening of cirrhotic patients by upper endoscopy for oesophageal varices prediction, Non-invasive parameters are needed due to high endoscopy cost and burden on endoscopic units particularly in poor countries. The aim of this study is to evaluate the accuracy of using ammonia blood level as potential non-invasive predictor of oesophageal varices in cirrhotic patients.

Materials and Methods: This prospective study was conducted on 150 Egyptian participants. Patients were categorized as group I which included 100 with oesophageal varices and group II included 30 patients without varices. There were 20 healthy control participants served as a control group (group III). All patients underwent for full clinical and laboratory workup, abdominal ultrasound and upper gastrointestinal endoscopy. Venous ammonia blood levels were calculated for all the contributors of this study.

Results: The mean ammonia level was higher in group I (88.29±42.82 µmol/L) than in group II (82.77±49.76 µmol/L) with no statistical significant difference between the two groups (p=0.34). Ammonia level in group III was 73.37±30.36 µmol/L with no statistical significant difference with the other groups (p>0.05). In group I; ammonia level is positively correlated with the splenic vein diameter with r = 0.22 (p=0.026) but did not correlate with the grade of oesophageal varices r =0.031 (p-value=0.762). In multivariate analysis; ammonia combined with platelets, Age, PT and PC shared in a significant prediction model (I) for esophageal varices grading (p=0.002). Prediction model (II) including portal and splenic veins diameters and the liver size was developed (p=0.016).

Conclusion: Non-invasive means could be used to monitor cirrhotic patients and consider treatment. Ammonia level can not be used alone but its use within a significant prediction model can help restricting the use of endoscopic screening in patients with a high probability of esophageal varices.

Key words:Non-invasive; Varices; Ammonia; Prediction model; Cirrhosis

© 2015 The Authors. Published by ACT Publishing Group Ltd.

Ramzy I, Hafez HA, Madani H, Sanad N. Predictive Value of Non-Invasive Blood Ammonia Level for the Presence of Oesophageal Varices in Egyptian Patients With Liver Cirrhosis. Journal of Gastroenterology and Hepatology Research 2015; 4(5): 1613-1617 Available from: URL: http://www.ghrnet.org/index.php/joghr/article/view/1207

Introduction

Oesophageal varices due to portal hypertension are a major concern in cirrhotic patients because of the risk of bleeding[1]. The prevalence of oesophageal varices in newly diagnosed cirrhotic patients is approximately 60-80% and the 1-year rate of first variceal bleeding is approximately 5% for small oesophageal varices and 15% for large oesophageal varices[2]. The determination of the presence of oesophageal varices by upper digestive endoscopy is therefore mandatory in patients with cirrhosis at diagnosis[3].

For long-term follow up, guidelines recommend monitoring of cirrhotic patients by routine endoscopy for the detection of the development of oesophageal varices and to initiate prophylactic measures to prevent the bleeding of oesophageal varices when they become larg[4]. Endoscopy is however a costly, invasive, and time-consuming procedure[5]. In Egypt; chronic liver diseases are common due to the higher prevalence of viral hepatitis C and Schistosomiasis[6].

In cirrhosis the main portion of blood ammonia carried by portal blood is shunted by portosystemic shunts to systemic circulation could be a good mirror of portosystemic collaterals and consequently portal hypertension[7]. The aim of this study is to evaluate the accuracy of using ammonia blood level as potential noninvasive predictor of esophageal varices in cirrhotic patients.

Method

This study was conducted on 130 adult Egyptian patients with HCV related liver cirrhosis from August 2011 to March 2012. Patients were assigned into: group I including 100 patients with esophageal varices documented by upper endoscopy. Group II including 30 patients without varices. Both groups were recruited from Endemic Medicine Department, Cairo University. Group III included 20 participants seronegative for HCV and HBV who were included in our study to serve as a control group. Written informed consents were obtained from all participants and the study protocol was approved by our institute ethical committee. Pregnant and lactating females, other causes of cirrhosis than HCV, Patients with hapotcellular carcinoma or portal vein thrombosis and previous variceal ligation or injection sclerotherapy were excluded from the start.

All patients were subjected to Full history taking and clinical examination. The following investigations had been done: Complete liver &kidney functions, coagulation profile, complete blood picture, ESR, HCV antibodies, HBsAg and HBc Ab. Abdominal ultrasound was performed to confirm liver cirrhosis, assess the spleen size and detect the presence of ascites. All patients underwent an upper gastrointestinal endoscopy. Grading classification of I - IV was used[8].

Ammonia determination

For the quantitative determination of Ammonia in plasma an Enzymatic UV-Method manual (RANDOX LABORATORIES LTD. Ardmore, Diamond Road, Crumlin, Co. Antrim, United Kingdom BT29 4 QY) was done[9].

Statistical analysis

Patients' data were analyzed using SAS 9.2 for windows. Quantitative variables were expressed by mean and SD (Standard deviation), compared using t-student test and Mann-Whitney test were used when appropriate. Qualitative variables were expressed by numbers (Frequency) and percent. Proportions were analyzed using Fisher’s exact test. Prediction model were performed for calculating predicted probabilities. P- Value was considered to be significant if less than 0.05.

Results

One hundred and thirty patients with HCV related liver cirrhosis were enrolled and divided into 2 groups according to the presence or absence of oesophageal varices of 100 and 30 patients respectively; in addition to group III of 20 healthy control participants. The epidemiological data revealed that, age was found statistically higher in patients of group II (51.50±11.02 years) as compared to those of group I (50.17±12.89 years) and group III (44.70±11.51years) and this is not significant.

There was no statistical significant difference among the studied groups regarding their sex distribution (group I included 62 males and 38 females, group II included 22 males and 8 females and group III included 12 males and 8 females) where the p- value was 0.2 & 0.8 on comparing withgroup I. The laboratory and ultrasonogaphic showed with no significant difference between group I and group II. The controls were normal in all their laboratory study. Data of the studied groups are shown in table 1.

Comparing the venous ammonia level among the 3 groups; The mean ammonia level was higher in group I (88.29±42.82 µmol/L) than in group II (82.77± 49.76 µmol/l) but with no statistical significant difference between the two groups (p-value = 0.34). Ammonia level in group III was 73.37±30.36 µmol/L with no statistical significant difference with the other groups (p-value <0.05).

When we categorized group I according to the degree of esophageal varices (I-IV) there was no statistical significant difference in venous ammonia level between patients with the different grades of esophageal varices (Table 2). With further division of group I into two subgroups IA and IB according to the varices grade into: Group IA (N =65) = esophageal varices grades I, II (small varices) and Group IB (N =35) = esophageal varices grades III, IV (medium and large varices). Patients of group IB have higher mean ammonia level (91.12±47.53) than those of group 1A (86.76±40.36) but this difference is not significant with p- value = 0.63.

Among patients of group I (n=100) we found that the ammonia level is positively correlated with the splenic and portal veins diameters with p=0.026 and 0.001 respectively, but did not correlate with the grade of oesophageal varices p=0.762 0.231 respectively. An inverse correlation was observed i.e., r = -0.341 (p=0.001) between the splenic size and the platelet count (Table 3).

By applying a prediction model (I) in patients of group I it was found that ammonia alone is not a significant predictor to the grade of the oesophageal varices, but in multivariate analysis it was found that ammonia shares in a significant prediction model for predicting the grade of oesophageal varices and this model is statistically significant with p- value= 0.002, where platelets, Age, PT and PC became a significant model for prediction of the grade of oesophageal varices (grade I, grade II, grade III or grade IV) with p-values 0.038, 0.040, 0.001, 0.001 respectively which were highly significant (Table 4).

Prediction model (2) replacing platelets and age in the previous model with portal vein diameter and liver size assessed using ultrasonography and adding group II cirrhotic patients without varices to group I (N= 130). Prediction of oesophageal varices grade using our second model is significant with p- value = 0.016 (Table 5).





Discussion

Portal hypertension contributes slowly and constantly to hepatic insufficiency[11]. Esophageal varices are the most critical portosystemic shunts that develop secondary to portal hypertension. Endoscopic prophylactic band ligation and non-selective beta blockers can reduce the risk of oesophageal bleeding by 50%[12]. Endoscopic screening of all cirrhotic patients would lead to a large number of unnecessary endoscopies and additional burden to endoscopic units[13]. Several studies have discussed how to identify patients with varices using non-invasive or minimally invasive methods[14]. The development of non-invasive methods for oesophageal varices prediction could reduce the use of upper gastrointestinal endoscopy in variceal screening and also provide an alternative way to confirm the results of conventional endoscopic diagnosis[15].

Concerning our study; As regards the epidemiological features of our patients; their age range from 18-75 years in agreement with the studies done by Cherian et al 2011[16] and Serag et al 2011[17] who reported that the age peak of cirrhotic patients was at the fifth decade. Males were more than females in agreement with Cherian et al, 2011[16] as they found that the incidence of infection was more predominant in male due to higher probability of viral exposure. All our cirrhotic patients were caused by HCV as Egypt has the highest prevalence of HCV worldwide (15%)[18] with genotype-4a accounting for almost 90% of infections. Egypt has an estimated annual incidence of HCV about 150,000 cases[19].

In our study; the mean ammonia level was higher in patients with oesophageal varices than in those without varices and controls. In addition, ammonia level was also higher in patients with higher grades of varices but with no statistical significant difference between the groups thus we can conclude that blood ammonia level can not differentiate between any of the studied groups although this disagree with Tarantino et al 2009[11] and Khondaker et al 2013[7]. To explain the relatively high ammonia level in our control group; as matter of fact, the blood ammonia determination suffers from some limits in its measurements. In fact, the collection, handling, storage, and analysis of blood samples are all potential sources of error. Anyway, recommendations ought to be made on the collection and processing of blood samples, for it is by standardization and rigid adherence to these techniques that the reliability of the test results will be improved[11].

Our continued analysis of blood ammonia concentrations highlighted a significant correlation between them and splenic vein diameter with no correlation existed with platelet count or splenic longitudinal length and this also disagree with Tarantino et al[11] who reported significant correlation of ammonia levels with platelet count but not with ALT or spleen diameter.

From all the above we concluded that ammonia alone can not predict the presence nor the grade of oesophageal varices. So, we put ammonia in a model with platelets, age, prothrombin time, prothrombin concentration, RBCs by applying this model in patients of group I we found that ammonia alone is not a significant predictor to the grade of esophageal varices, but in multivariate analysis it was found that ammonia shared in a significant prediction model for predicting the grade of oesophageal varices (prediction model I). By studying patients in both in groups (I&II) using another prediction model (prediction model II) that replace platelets, and age in the previous model with, RBCs; portal vein diameter and liver size by ultrasonography it was found that ammonia is not a significant predictor for the presence of esophageal varices ,but on multivariate analysis it was reported that ammonia shares in a significance with these prediction models. This is in agreement with Tarantino et al[11] who found that blood ammonia concentrations can predict the portosystemic veins by using the PLTs and SLD. Study that was done by Eslam et al 2013[20] who showed that presence of oesophageal varices was independently associated with lower platelet count low platelet count and advanced Child-Pugh score. Wang et al in 2014 showed that hemoglobin level, portal vein diameter and the ratio of platelet count/spleen diameter contributed significantly in univariate analysis for prediction of large varices.

In conclusion; despite the lower diagnostic accuracy of the models, but this models were good to be used as part of tools to monitor cirrhotic patients and consider treatment. However, upper digestive endoscopy remains the more reliable means to monitor cirrhotic patients.

CONCLUSION

Despite the lower diagnostic accuracy of the models, but this models were good to be used as part of tools to monitor cirrhotic patients and consider treatment. However, upper digestive endoscopy remains the more reliable means to monitor cirrhotic patients.

CONFLICT OF INTERESTS

There are no conflicts of interest with regard to the present study.

REFERENCES

1 Bosch J, Abraldes JG, Berzigotti A, Garcia-Pagan JC. Portal hypertension and gastrointestinal bleeding. Seminars in Liver Disease 2008; 28 (1): 3-25

2 Garcia-Tsao G, Bosch J. Management of varices and variceal hemorrhage in cirrhosis. New England Journal of Medicine 2010; 362(9): 823-832

3 Berzigotti A, Seijo S, Reverter E, Bosch J. Assessing portal hypertension in liver diseases. Expert review of gastroenterology and hepatology 2013; 7 (2); 141-155

4 R De Franchis. Evolving Consensus in Portal Hypertension Report of the Baveno IV Consensus Workshop on methodology of diagnosis and therapy in portal hypertension. Journal of Hepatology 2005; 43 (1): 167-176

5 Abu El Makarem MA, Shatat ME, Shaker Y, Abdel Aleem AA, El Sherif AM, Moaty MA, Abdel Ghany HS, Elakad A, Kamal Eldeen AM. Platelet count/bipolar spleen diameter ratio for the prediction of esophageal varices: The special Egyptian situation: Noninvasive prediction of esophageal varices. Hepat Mon 2011 Apr; 11 (4): 278-284

6 El-Zayadi AR. Curse of schistosomiasis on Egyptian liver. World J Gastroenterol 2004; 10 (8): 1079-1081

7 Khondaker MFA, Ahmad N, Al-Mahtab M, Sumi SA. Correlation between Blood Ammonia Level and Esophageal Varices in Patients with Cirrhosis of Liver. Euroasian Journal of Hepato-Gastroenterology 2013; 3 (1): 10-14

8 Alempijevic T. Bulat V, Djuranovic S, Kovacevic N, Jesic R, Tomic D, Krstic S, Krstic M. Right liver lobe/albumin ratio: Contribution to non-invasive assessment of portal hypertension. World J. Gastroenterol 2007; 13 (40): 5331-5335

9 Neeley WE, Phillipson J. Automated enzymatic method for determining ammonia in plasma, with 14- day reagent stability. Clin Chem 1988; 34: 1868-1869

10 Garcia-Tsao G, Sanyal AJ, Grace ND, Carey W. Practice Guidelines Committee of the American Association for the Study of Liver Diseases; Practice Parameters Committee of the American College of Gastroenterology. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology 2007; 46 (3): 922-938

11 Tarantino G, Citro V, Esposito P, Giaquinto S, de Leone A, Milan G, Tripodi FS, Cirillo M, Lobello R. Blood ammonia levels in liver cirrhosis: a clue for the presence of portosystemic collateral veins. BMC Gastroenterol 2009 Mar 17; 9:21. doi: 10.1186/1471-230X-9-21

12 Giannelli V, Lattanzi B, Thalheimer U, Merli, M. Beta-blockers in liver cirrhosis. Ann. Gastroenterol 2014; 27 (1): 20-26

13 De Franchis R. Noninvasive diagnosis of esophageal varices: is it feasible? Am. J. Gastroenterol 2006; 101: 25202

14 De Franchis R. Non-invasive (and minimally invasive) diagnosis of esophageal varices. J Hepatol 2008; 49: 520-527

15 Wang L, Hu J, Dong S, Jian YC, Hu L, Yang G, Wang J, Xiong W. Noninvasive prediction of large esophageal varices in liver cirrhosis patients. Clin Invest Med 2014 Feb 1; 37 (1): E38-46

16 Cherian J, Deepak N, Prabhn Ponnusamy R, Somasundaram A, Jayanthan V. Noninvasive predictors of esophageal varices. The Saudi Journal of Gastroenterology 2011; 17: 64-68

17 Serag E, Omran D, Rashid L. Can we consider the right hepatic lobe size/albumin ratio a noninvasive predictor of esophageal varices in hepatitis cC virus related liver cirrhotic Egyptian patients. European Journal of internal medicine 20011; 23: 267-272

18 Guerra J, Garenne M, Mohamed MK, Fontanet A. HCV burden of infection in Egypt: results from a nationwide survey. J Viral Hepat 2012; 19: 560-567

19 Galal IF, Zakaria Z, Allam WR, Mahmoud MA, Ezzat AR, Ahmed Osman A, Waked I, Strickland GT, Abdelwahab SF. Cross Reactive Cellular Immune Response to HCV Genotype 1 and 4 Antigens among Genotype 4 Exposed Subjects. PLoS One 2014; 9 (6): e101264

20 Eslam M, Ampuero J, Jover M, Abd-Elhalim H, Rincon D, Shatat M, Camacho I, Kamal A, Lo Iacono O, Nasr Z, Grande L, Banares R, Khattab MA, Romero-Gomez M. Predicting portal hypertension and variceal bleeding using non-invasive measurements of metabolic variables. Ann Hepatol 2013 Jul-Aug; 12 (4): 588-598

Peer reviewer: Ivan Gentile, Department of Public Medicine and Social Security- Section of Infectious Diseases (Ed. 18), University of Naples “Federico II”, via S. Pansini, 5- I-80131 Naples, Italy.

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