|Year : 2020 | Volume
| Issue : 3 | Page : 813-818
Study of glycated albumin to glycated hemoglobin ratio as a predictor of esophageal varices bleeding risk
Ehab A Elatty1, Elsayed I Elshayeb1, Mohammed H Badr1, Belal A. E Mohsen Montaser2, Mokhtar S Hewezy3
1 Department of Internal Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
3 Department of Internal Medicine, Al Mahalla El-Kobra General Hospital, Gharbia, Egypt
|Date of Submission||25-Sep-2019|
|Date of Decision||24-Oct-2019|
|Date of Acceptance||28-Oct-2019|
|Date of Web Publication||30-Sep-2020|
Mokhtar S Hewezy
Al Mahalla El-Kobra, Gharbia 31951
Source of Support: None, Conflict of Interest: None
To evaluate glycated albumin (GA) to glycated hemoglobin (HbA1c) ratio as a predictor of variceal bleeding in patients with liver cirrhosis.
Variceal hemorrhage is a severe complication of liver cirrhosis and can be a direct cause of bleeding-related death. Therefore, upper endoscopy is considered necessary for all cirrhotic patients to evaluate the risk of variceal bleeding.
Patients and methods
A prospective clinical study was conducted on 100 patients with chronic hepatitis C-related cirrhosis who attended the Gastrointestinal Endoscopy Unit of the Department of Internal Medicine, Menoufia University hospitals, during the period between January 2017 and March 2018. Liver cirrhosis was diagnosed depending upon clinical examination in addition to laboratory and imaging studies. Various indicators for hepatic functions, HbA1c, and GA were measured. GA/HbA1c ratio was measured, and its relationship with the presence and bleeding risk of esophageal varices was analyzed.
The GA/HbA1c ratio in hepatitis C virus (HCV)-positive cirrhotic patients increases with the severity of the esophageal varices. GA/HbA1c ratio may help in discrimination of low-risk from high-risk varices because GA/HbA1c ratio was the most significantly different among all of the other parameters tested; however, this is still doubtful.
Thrombocytopenia and prolonged prothrombin time parameters are associated with an increased risk of variceal bleeding. GA/HbA1c ratio in HCV-positive cirrhotic patients increases with the severity of the esophageal varices. GA/HbA1c ratio may help in discrimination of low-risk from high-risk varices. It is of interest and is not redundant to use the GA/HbA1c ratio to predict esophageal variceal bleeding risk in chronic HCV disease.
Keywords: bleeding, cirrhosis, endoscopy, glycated albumin/glycated hemoglobin ratio, high risk, varices
|How to cite this article:|
Elatty EA, Elshayeb EI, Badr MH, Mohsen Montaser BA, Hewezy MS. Study of glycated albumin to glycated hemoglobin ratio as a predictor of esophageal varices bleeding risk. Menoufia Med J 2020;33:813-8
|How to cite this URL:|
Elatty EA, Elshayeb EI, Badr MH, Mohsen Montaser BA, Hewezy MS. Study of glycated albumin to glycated hemoglobin ratio as a predictor of esophageal varices bleeding risk. Menoufia Med J [serial online] 2020 [cited 2020 Nov 26];33:813-8. Available from: http://www.mmj.eg.net/text.asp?2020/33/3/813/296659
| Introduction|| |
Cirrhosis is defined as the histological development of regenerative nodules surrounded by fibrous bands in response to chronic liver injury that leads to portal hypertension and end-stage liver disease. The major clinical consequences of cirrhosis are impaired hepatocyte (liver) function, an increased intrahepatic resistance (portal hypertension), and the development of hepatocellular carcinoma . Normal portal pressure is ~9 mmHg compared with an inferior vena cava pressure of 2–6 mmHg. This creates a normal pressure gradient of 3–7 mmHg. If the portal pressure increases above 12 mmHg, this gradient rises to 7–10 mmHg. A gradient greater than 5 mmHg is considered portal hypertension . Portal hypertension is typically progressive, with esophageal varices occurring in 5–10% of patients with cirrhosis each year, especially in patients with advanced or decompensated liver disease. Of those with compensated cirrhosis, 30% will have gastroesophageal varices compared with 60% of patients with decompensated cirrhosis . Esophageal varices are extremely dilated veins in the lower third of the esophagus . They are most often a consequence of portal hypertension, commonly owing to cirrhosis; patients with esophageal varices have a strong tendency to develop bleeding. Esophageal varices are diagnosed through upper endoscopy . Gastroesophageal variceal hemorrhage is a medical emergency that occurs in up to 10% of patients with cirrhosis each year . Bleeding is more likely in patients with Child's B or C cirrhosis. Red coloration (red wales) on varices is a marker of increased risk. Of all the causes of gastrointestinal bleeding in cirrhosis, varices account for more than 70% of bleeding episodes . Therefore, upper endoscopy should be routinely done to evaluate esophageal varices bleeding risk . The presence of variceal red color signs [e.g. cherry-red spots and red wale markings (longitudinal red streaks on varices)], blue varices, and the 'white nipple sign' (platelet fibrin plug overlying a varix, resembling a white nipple) indicates an increased risk of rebleeding . Several biochemical parameters have been reported as predictors of the presence of varices, such as a low platelet count, an advanced Child–Pugh class, hypoalbuminemia, and low prothrombin activity. However, it is still difficult to predict the presence of varices without esophagogastroduodenoscopy . The aim of the study was to evaluate glycated albumin (GA) to glycated hemoglobin (HbA1c) ratio as a predictor of variceal bleeding in patients with chronic liver disease.
| Patients and Methods|| |
A prospective clinical study was conducted on 100 patients with liver cirrhosis who attended the Gastrointestinal Endoscopy Unit of Department of Internal Medicine, Menoufia University hospitals, from January 2017 to March 2018. Patients were divided according to ultrasound and upper gastrointestinal endoscopy into three main groups: group I included 40 cirrhotic patients with esophageal varices with history of upper gastrointestinal bleeding, group II included 40 cirrhotic patients with esophageal varices without history of upper gastrointestinal bleeding, and group III included 20 cirrhotic patients without esophageal varices.
Ethical consideration: the study was approved by the ethical committee of Menoufia Faculty of Medicine and an informed consent was obtained from all patients before the study was commenced.
All the patients were subjected to thorough history taking (with special emphasis on symptoms suggesting chronic liver disease, symptoms suggesting hepatocellular carcinoma, and known duration of hepatitis C virus infection) and complete physical examination, including general and abdominal examination.
Laboratory investigations included complete blood count (Hematology Automated Analyzer, Vacutec Messtechnik Gmblt, Germany) . Liver function tests, alpha-fetoprotein (AFP), and international normalized ratio (INR) were measured by the spectrophotometric colorimetric method. Renal function tests were done using autoanalyzer Synchron CX5 (Beckman, Texas, USA). Fasting blood sugar (FBS) and 2-h postprandial sugar (2hPPBS) and viral markers were assessed using enzyme-linked immunosorbent assay (ELISA). Quantitative measurement of HbA1c was done using immunochemical technique by fully Automated AU-480 Chemical Autoanalyzer by Beckman Coulter Inc. (Fullerton, California, USA). Quantitative measurement of GA level and HbA1c was done by ELISA using DRG Glycated Albumin (Human) ELISA (EIA-5501), following the manufacturer instructions .
Abdominal ultrasound was done to assess the size of the liver, signs of portal hypertension (diameter of portal vein and portosystemic collaterals), signs of cirrhosis, size of spleen, presence of ascites, and presence of hepatic focal lesions. Upper gastrointestinal endoscopy was done for detection of presence of esophageal varices and detection of presence of risky signs such as presence of red wale marks [Figure 1]a, large size varices and cherry-red spots [Figure 1]b, and hepatocytic spots, and grading of esophageal varices was done by Modified Paquet classification : grade I: varices extending just above the mucosal level [Figure 2]a, grade II: varices projecting by one-third of the luminal diameter that cannot be compressed with air insufflation [Figure 2]b, and grade III: varices projecting up to 50% of the luminal diameter and in contact with each other [Figure 2]c.
|Figure 1: Grades of Oesophageal Varices (a) Grade I (b) Grade II (c) Grade III.|
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|Figure 2: Risk signs of Esophageal Varices (a) Red wale marks (b) Cherry red spots.|
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Results were tabulated and statistically analyzed by using a personal computer using Microsoft Excel 2016 and SPSS, v. 21 (SPSS Inc., Chicago, Illinois, USA). Statistical analysis was done using the following: descriptive, for example, percentage (%), mean, and SD, and analytical, which includes χ2, and analysis of variance or Kruskal–Wallis test. A value of P less than 0.05 was considered statistically significant.
| Results|| |
A total of 100 patients with CHC-related hepatic cirrhosis were included in the study; their ages ranged from 36 to 75 years, with a mean age was 54.32 ± 7.84 years. Overall, 70 (70%) patients were males and 30 (30%) were females. The mean age of group I was 59.93 ± 6.52 years; it comprised 27 males patients and 13 female patients. The mean age of group II was 52.90 ± 5.41 years; it comprised 31 male patients and nine female patients. The mean age of group III was 45.95 ± 5.41 years; it comprised 12 male patients and eight female patients. There was a nonsignificant difference among the studied groups regarding age, sex, and BMI.
In the current study, it was found that there are no significant differences between the studied groups regarding liver function, AFP, FBS, and 2hPPBS, but there were significant differences between studied groups regarding prothrombin time (PT), serum albumin and total bilirubin, complete blood count, alkaline phosphatase test, blood urea, serum creatinine, INR, GA, HbA1c, and their ratio [Table 1]. Moreover, the child score was significantly lower in group III than groups I and II. Moreover, in the Model for End-Stage Liver Disease score, there was a significant difference among all groups [Table 2]. Regarding esophageal varices grade [Figure 2]a, it was significantly lower in group II than group I [Figure 2]b and [Figure 2]c; however, there was no significant difference between the studied groups regarding risk signs [Figure 2] and [Table 3]. Aspartate aminotransferase (AST) to platelet ratio index score was significantly lower in group III than groups I and II. As for the fibrosis-4 score, there was a nonsignificant difference among all studied groups.
|Table 1: Comparison between the three studied groups regarding laboratory investigations|
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|Table 2: Comparison between the three studied groups regarding liver cirrhosis|
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|Table 3: Comparison between the three studied groups regarding grades and risk signs of varices by upper gastrointestinal endoscopy|
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| Discussion|| |
In patients with cirrhosis, esophageal varices are commonly observed with an estimated prevalence of 50% . In cirrhotic patients, variceal rupture is the cause of 60–65% of the bleeding episodes in these patients . Owing to the increased risk of fatality in cirrhotic patients with esophageal variceal bleeding (EVB), the risk status in patients must be routinely evaluated such that the appropriate prophylactic therapy is administered to prevent variceal bleeding events. The EVB risk is assessed through endoscopic screening to assign a grade to the variances and determine if red signs are present which is currently recommended for all patients with diagnosed cirrhosis . However, it is invasive, painful, and costly, especially to those in developing countries, which ultimately limit the frequency of examinations. One way to overcome the obstacle of frequent endoscopies is to develop a safe, noninvasive, and affordable system to better predict the risk of variceal hemorrhage in cirrhotic patients. An ultrasound approach that includes duplex ultrasonography and color Doppler is a simple, precise, noninvasive, and affordable imaging method that is predominantly used to diagnose and stage cirrhotic portal hypertension. Transient elastography with Fibro Scan has been recognized as a rapid, noninvasive technique for evaluating the severity of liver disease and found to be useful in the diagnosis of the underlying stage of fibrosis in recent studies ,. Therefore, Fibro Scan has the potential to be used for the noninvasive evaluation of esophageal variceal . Despite the fact that small varices with severe red signs have same chance of bleeding as large varices without red signs, none of the known/minimally invasive methods, except capsule endoscopy, can evaluate patients for red signs; thus, they fail to detect small varices that are associated with a high risk of bleeding . This study was performed to clarify a relationship between GA/HbA1c ratio and risk of bleeding from esophageal varices regardless of cirrhosis in patients with chronic hepatitis C disease. The GA/HbA1c ratio is a simple and unique tool that is calculated based on the levels of the two glycated proteins and is associated with the endoscopic findings of esophageal varices. In our study, the presence of jaundice, spider nevi, hepatic encephalopathy, and palmar erythema was found to be significantly higher in cirrhotic patients with varices than those without varices. Moreover, demographic data showed that the distribution of the studied population was homogenous and representative of the population of cirrhotic patients seen in the clinical practice and there was a nonsignificant difference among the studied groups regarding age, sex, and BMI. The same findings were reported by El Hassafi et al.. Regarding complete blood count, there was a significant difference among groups I, II, and III regarding Hb level, white blood cells (WBCs) count, and platelets count. Hb level was significantly lower in group I (9.21 ± 0.92) than group II (10.71 ± 0.75) and group III (11.24 ± 0.97). Hb level of group II was significantly lower than group III. As for WBCs count, there was no significant difference between group I (7.11 ± 2.0) and group II (7.28 ± 1.92), whereas it was significantly higher in both of them than group III (5.43 ± 0.85). Platelets count was significantly lower in group I (76.23 ± 13.7) than group II (85.45 ± 15.13) and group III (134.5 ± 29.6) and it was significantly lower in group II than group I, which was reported also by Sakai et al.. Regarding liver functions, there was a significant difference among groups I, II, and III regarding alkaline phosphatase, albumin, and total bilirubin level (P = 0.001 for all); however, there was no significant difference among groups I, II, and III regarding ALT, AST, PT, INR, and AFP (P > 0.05). This is explained by that patients in groups I and II have advanced liver cirrhosis, whereas patients in group III have compensated liver cirrhosis, which was also reported by El Nakeeb et al.  and Osama et al.. On the contrary, there was a nonsignificant difference among the studied groups regarding FBS and PPBS. This is consistent with the aim of the study, as it excluded all diabetic patients, known to cause alterations in HbA1c and GA levels. This allows deciding the relationship between GA/HbA1c ratio and the risk of variceal bleeding. Regarding upper endoscopy, findings showed that group I patients who have more advanced liver cirrhosis have larger esophageal varices with a high incidence of risk signs (high-risk group), whereas group II patients with less advanced liver cirrhosis has lower grades of esophageal varices with lower incidence of risk signs (low-risk group). The same finding was reported by El Nakeeb et al.  and Sakai et al., who found ultrasound imaging showed the nonsignificant difference among the three studied groups regarding splenic diameter and right lobe diameter. However, regarding the portal vein diameter, groups I and II have a larger portal vein diameter than group III, with no significant difference between groups I and II. This indicates that the larger the portal vein diameter, the larger the size of esophageal varices. The same findings were reported by El Hassafi et al., El Nakeeb et al., and Mandal et al.. In our study, GA/HbA1c ratio was significantly higher in group I (high-risk group) than in group II (low-risk group) and group III (no risk group), whereas HbA1c was significantly lower in group I than in groups II and III. Furthermore, according to our results, the receiver operator characteristic curve [Figure 3] granted that a cutoff ratio of 4.4 can differentiate cirrhotic patients with and without esophageal varices and could predict esophageal varices bleeding with area under the curve of 0.99 with 95% confidence interval, sensitivity 100% and specificity of 95%, with positive predicted value of 95.2%, negative predicted value of 100% and accuracy 97.5%. In concordance with our study, El Hassafi et al.  revealed GA/HbA1c ratio cutoff of 6.35 to discriminate cirrhotic patients with and without esophageal varices. Moreover, Sakai et al.  found that GA/HbA1c ratio was significantly higher in the high-risk varices group than in patients without varices. The same findings were reported by El Nakeeb et al.  who found a significant increase in the GA/HbA1c ratio in high-risk varices group (5.03 ± 0.22) than low-risk varies group (3.77 ± 0.24). In our results also age, Hb, WBCs, platelets, PT, INR, alkaline phosphatase, blood urea, serum creatinine, AST to platelet ratio index, fibrosis-4, grading of esophageal varices, portal vein diameter, splenic vein diameter, and right lobe diameter showed significant correlation with GA/HbA1c ratio. Morever, linear regression analysis showed that predictors of Esophageal Varices bleeding are platelet count, grade of esophageal Varices, risk signs and GA/HbA1C ratio. So, GA/HbA1c ratio seemed to be a promising marker for the severity of liver cirrhosis, which in turn reveals the severity of portal hypertension, size of esophageal varices, and risk of EVB.
| Conclusion|| |
Development of safe, noninvasive, and affordable system to better predict the risk of variceal hemorrhage in cirrhotic patients is mandatory to overcome frequent endoscopies. Larger portal vein diameter was a strong predictive of the progression of the degree of esophageal varices. GA/HbA1c ratio in hepatitis C virus-positive cirrhotic patients increases with the severity of the esophageal varices. GA/HbA1c ratio may help in discrimination of low risk from high-risk varices.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Pinzani M, Rosselli M, Zuckermann M. Liver cirrhosis. Best Pract Res Clin Gastroenterol 2011; 25
Arguedas M. The critically ill liver patient: the variceal bleeder. Semin Gastrointestinal Dis 2003; 14
Merli M, Nicolini G, Angeloni S, Rinaldi V, De Santis A, Merkel C, et al
. Incidence and natural history of small esophageal varices in cirrhotic patients. J Hepatol 2003; 38
Rubin R, Raphael S, David S, Emanuel R. Rubin's pathology. In: M. D. Rubin, Raphael (Editor), Ph.D. Strayer, David S. (Editor). (eds). Clinicopathologic foundations of medicine
ed; Philadelphia, USA: Lippincot Williams & Wilkins; 2012. 612.
Kovalak M, Lake J, Mattek N, Eisen G, Lieberman D, Zaman A. Endoscopic screening for varices in cirrhotic patients: data from a national endoscopic database. Gastrointest Endosc 2007; 65
Friedman S, Schiano T. Cirrhosis and its sequelae. In: Goldman L, Ausiello D, (eds). Cecil textbook of medicine
ed. Philadelphia, PA: Saunders; 2004. 936–944.
Sanyal AJ, Fontana RJ, Di Bisceglie AM, Everhart JE, Doherty MC, Everson GT, et al
. The prevalence and risk factors associated with esophageal varices in subjects with hepatitis C and advanced fibrosis. Gastrointest Endosc 2006; 64
Riggio O, Angeloni S, Nicolini G, Merli M, Merkel C. Endoscopic screening for esophageal varices in cirrhotic patients. Hepatology 2002; 35
Khan NM, Shapiro AB. The white nipple sign: please do not disturb. Case Rep Gastroenterol 2011; 5
De Franchis R. Non-invasive (and minimally invasive. diagnosis of esophageal varices. J Hepatol 2008; 49
Jones JR, Owens DR, Williams S. Glycosylated serum albumin: an intermediate index of diabetic control. Diabet Care 1993, 6
Chhabra N, Gaurav R. Automated hematology analyzers: recent trends and applications. J Lab Phy 2018; 10
Tajiri T, Yoshida H, Obara K, Onji M, Kage M, Kitano S, et al
. General rules for recording endoscopic findings of esophagogastric varices. Dig Endosc 2010; 22
Garcia-Tsao G. Current management of the complications of cirrhosis and portal hypertension: variceal hemorrhage, ascites, and spontaneous bacterial peritonitis. Gastroenterology 2001; 120
D'Amico G, García-Tsao G, Calés P, Escorsell A, Nevens F, Cestari R. Diagnosis of portal hypertension. How and when?. In: De Franchis R, ed. Portal hypertension III. Proceedings of the Third Baveno International Consensus Works-hop on Definitions, Methodology and Therapeutic Strategies
. London: Oxford; 2001; 36–64.
De Franchis R. Evolving consensus in portal hypertension. Report of the Baveno IV consensus workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol 2005; 43
Kwok R, Tse YK, Wong GL, Ha Y, Lee AU, Ngu MC, et al
. Systematic review with meta-analysis: non-invasive assessment of non-alcoholic fatty liver disease – the role of transient elastography and plasma cytokeratin-18 fragments. Aliment Pharmacol Ther 2014; 39
Castera L, Pinzani M, Bosch J. Noninvasive evaluation of portal hypertension using transient elastography. J Hepatol 2012; 56
Bosch J. Prediction from a hard liver. J Hepatol 2006; 45
El hassafi M, Amin G, Zaki M. Glycated albumin to glycated hemoglobin ratio in patients with liver cirrhosis and its relation to severity of cirrhosis and risk of bleeding of esophageal varices. J Egypt Soc Endocrinol Metab 2012; 46
Sakai Y, Enomoto H, Aizawa N. Relationship between elevation of glycated albumin to glycated hemoglobin ratio in patients with a high bleeding risk of esophageal varices. Hepatogastroenterology 2012; 59
El Nakeeb N, El Sayed E, El Baz H Prediction of esophageal varices and its grades using the glycated albumin to glycated haemoglobin ratio in Egyptian pateints with liver cirrhosis. Eur Acad Res 2017; 5
Osama A, Mohie S, Basyoni M. Evaluation of glycated albumin to glycated hemoglobin ratio as a predictor for esophageal varices and its risk of bleeding. Egypt J Hospit Med 2018; 73
Mandal L, Mandal SK, Bandyopadhyay D. Correlation of portal vein diameter and splenic size with gastro-oesophageal varices in cirrhosis of liver. JIACM 2011; 12
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]