INTRODUCTION

HBV and HCV are the most important causes of CLD leading to cirrhosis.1 Patients with cirrhosis develop EV due to portal hypertension2 and although 90% of patients with cirrhosis develop varices, only 30% of them bleed and 30 – 50% die of the first episode.3 Two thirds of the survivors will rebleed within six months if not treated with prophylactic -blockers or endoscopic therapy.4 Those receiving such therapy are less likely to bleed5 and that is why screening such patients for EV is recommended.6 Periodic endoscopy can be a expensive.7 Non-endoscopic surrogate markers directly or indirectly linked to portal hypertension have, therefore, been sought to identify patients at high risk of having varices. Hepatic venous pressure gradient is useful, but invasive and not widely available.8 Portal hypertension (portal pressure >12 mm Hg or >5 mm Hg gradient between the wedged hepatic venous pressure and the free hepatic venous pressure9) has been shown in animal studies to induce hypoalbuminemia.10 Conversely, serum albumin is increased by 20% when portal pressure is reduced after Transjugular Intrahepatic Portosystemic Shunt Procedure11 suggesting a link between portal hypertension and hypoalbuminemia. Aim of this study was to evaluate relationship of serum albumin and EV in CLD.

METHOD

This prospective, cross-sectional study was carried out at Al-Ibrahimi Hospital and Khyber Teaching Hospital, Peshawar, from October 2006 to December 2007. Patients with CLD due to HBV/HCV (HBs Ag positive, Anti-HCV antibodies positive by ELISA) were assessed as per Child-Pugh class (Ascites, Encephalopathy, Serum Albumin, Serum Bilirubin, Prothrombin time). Exclusion criteria is given in Table 1.

All patients had abdominal ultrasound and EGD the same day. Hypoalbuminemia was defined as serum albumin level <3.5 gm%. Patients with hypoalbuminemia were placed in group A and those with serum albumin level >3.5 gm% were placed in group B. Classification of EV was based on Japanese Research Society for Portal Hypertension. Sensitivity, specificity, positive predictive value (PPV), negative predictive values (NPV), odds ratio and correlations of serum albumin with presence or absence of EV (using Spearman's rank correlation) were calculated to predict EV. SPSS 14 was used for data analysis.

RESULTS

One hundred and ninety-seven patients [97 male (49.2%) and 100 female (50.8%)] were evaluated. Mean age was 41.57 years (range, 15-80). One hundred and fifty five patients (78.7%) were Anti-HCV positive, 38 (19.3%) were HBsAg positive and four (2%) were coinfected with HCV and HBV. Child-Pugh score is shown in Table. 2.

ROC showed 70.7% area under the curve (Fig. 1) for albuminemia of <3.5 gm%. The area under curve increased to 94.1% for albuminemia of <=2.5 gm%.

DISCUSSION

Albumin (50%-60% of total plasma protein), globulin, and fibrinogen make up the major share of plasma proteins15 with 24%-56% increased risk of death per 2.5 g% fall in serum albumin.16 Child-Pugh score (serum albumin being integral part of the score) predicts advanced liver disease.17 Liver produces albumin at a rate of 130–200 mg/kg/day.15 Hypoalbuminemia in cirrhosis is multifactorial and may be due to reduced production (liver parenchyma replaced by fibrous tissue), increased removal by reticuloendothelial system (spleen) or increased loss through gut20 (portal gastropathy/enteropathy): all related to portal hypertension. Hypoalbuminemia with associated ultrasonographic features e.g. gall-bladder wall thickness17 and right liver lobe diameter18 have been cited as non-endoscopic predictors of esophageal varices. Similarly, Serum Ascitic Albumin Gradient (the difference between the serum and ascitic albumin concentration) i.e. SAAG, is thought to be an indirect marker of portal hypertension,19 with a high gradient (>1.1 g/dL) indicating portal hypertension and presence of EV.19 Torres E et al reported a SAAG value of >or=1.435±0.015 g/dl as an accurate indicator of the presence of EV with PPV of 87.5% and NPV of 66.7%.
We used albuminemia of <3.5 gm% while Schepis et al21 and Sarwar et al22 used level of <2.95 gm% to predict the presence of EV. Higher frequency of hypoalbuminemia above age 30 (27.4%) suggests worsening of albumin levels as the disease advances with growing age. Bressler et al23 found albuminemia of <4gm% as an independent risk factor for EV with odd ratio of 6.02. It was a retrospective analysis including 235 patients with CLD of diverse etiologies. Our odds ratio was 11.57 and the difference could be explained by <3.5 gm% albumin level we used and our study population with uniform etiology of the infective hepatitis. Zein et al24 in a study of 183 patients with primary sclerosing cholangitis, found 66% sensitivity, 80% specificity, 53.4% PPV, 87.2% NPV and odd ratio of 7.8 for albuminemia of <3.5 gm%; almost similar to our results. The minor differences in figures could be explained on the basis of difference in etiology of the study population.

Specificity of 91% and PPV of 73.3% suggests that hypoalbuminemia is a good indicator of EV. Negative correlation of '-0.494' indicates that falling serum albumin level in CLD is associated with rising frequency of EV. The same is reconfirmed by the ROC curve: area under curve increased from 76.8% for albuminemia of <3.5 gm% to 94.1% for albuminemia of <2.5 gm%. However, low sensitivity of hypoalbuminemia (53.2%) and NPV of 80.8% indicates that absence of hypoalbuminema does not rule out EV.

CONCLUSION

Hypoalbuminemia is a good non-endoscopic marker for the presence of esophageal varices; however the absence of hypoalbuminemia does not rule out the presence of esophageal varices as the NPV is <100% i.e 80.8%, hence it can not be used as a single factor for the purpose.

1. Pontisso P, Ruvoletto MG, Fattovich G, Chemello L, Gallorini A, Ruol A, et al. Clinical and virological profiles in patients with multiple hepatitis virus infections. Gastroenterology 1993;105:1529-33.
2. Gupta TK, Chen L, Groszmann RJ. Pathophysiology of portal hypertension. Clin Liver Dis1997;1:1-12.
3. Jalan R, Hayes PC. UK guidelines on the management of variceal haemorrhage in cirrhotic patients. British Society of Gastroenterology. Gut 2000;46 Suppl 3-4:III1-III15.
4. Boyer T. Natural history of portal hypertension. Clin Liver Dis 1997;1:31-44.
5. Poynard T, Cales P, Pasta L, Ideo G, Pascal JP, Pagliaro L, et al. Beta-adrenergic antagonists in the prevention of first gastrointestinal bleeding in patients with cirrhosis and oesophageal varices: an analysis of data and prognostic factors in 589 patients from four randomized clinical trials. N Engl J Med. 1991;324:1532-38.
6. Grace ND. Diagnosis and treatment of gastrointestinal bleeding secondary to portal hypertension. American College of Gastroenterology Practice Parameter Committee. Am J Gastroenterol1997;92:1081-91.
7. D'Amico G, Pagliaro L, Bosch J. The treatment of portal hypertension: a meta-analytic review. Hepatology 1995;22:332-54.
8. Vorobioff JD. Hepatic venous pressure in practice: how, when, and why. J Clin Gastroenterol 2007;41(10 Suppl 3):S336-43.
9. Dib N, Oberti F, Cales P. Current management of the complications of portal hypertension: variceal bleeding and ascites. CMAJ. 2006;174:1433-43.
10. Nava MP, Aller MA, Vega M, Prieto I, Valdes F, Arias J. Altered proteinogram in short term portal vein stenosed rats. Chinese Physiol. 2002;45(2):89-93.
11. Ochs A, Rössle M, Haag K, Hauenstein KH, Deibert P, Siegerstetter V. The Transjugular intrahepatic portosystemic stent–shunt procedure for refractory ascites. N Engl J Med 1995;332:1192-97.
12. Krige JE, Beckingham IJ. ABC of diseases of liver, pancreas, and biliary system. Portal hypertension-1: varices. BMJ 2001;322:348-51.
13. Goldwaser P, Feldman J. Association of serum albumin and mortality risk. J Clin Epidemiol 1997;50:693-03.
14. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973;60:646-9.
15. Rainey TG, Read CA. Pharmacology of colloids and crystalloids. In: Chernow B, editor. The Pharmacologic approach to the critically ill patient. Baltimore MD: Williams and Wilkins, 1994:p.272-90.
16. El Saadani MA, Habib ESM, El Gengehy MT, Fayez MA. Albumin TurnEVer in Schistosomal Liver Cirrhosis. Am J Trop Med Hyg 1968;17:844-50.
17. Galip E, Ömer O, Salih AU, Mustafa Y, Zeki K, Yücel B. Gallbladder wall thickening as a sign of esophageal varices in chronic liver disease. Turkish Gastroenterol 1999;10:11-14.
18. Alempijevic T, KEVacevic N. Right liver lobe diameter:albumin ratio: a new non-invasive parameter for prediction of oesophageal varices in patients with liver cirrhosis (preliminary report). Gut 2007;56:1166-67.
19. Runyon BA, Montano AA, Akriviadis EA, Antillon MR, Irving MA, McHutchison JG. The serum-ascites albumin gradient is superior to the exudate-transudate concept in the differential diagnosis of ascites. Ann Intern Med1992;117:215-20.
20. Torres E, Barros P, Calmet F. Correlation between serum-ascites albumin concentration gradient and endoscopic parameters of portal hypertension. Am J Gastroenterol 1998;93:2172-8.
21. Schepis F, Camma C, Niceforo D, Magnano A, Pallio S, Cinquegrani M, et al. Which Patients With Cirrhosis Should Undergo Endoscopic Screening for Esophageal Varices Detection? Hepatology 2001;33:333-38.
22. Sarwar S, Khan AA, Butt AK, Shafqat F, Malik K, Ahmad I, et al. Non-endoscopic prediction of esophageal varices in cirrhosis. J Coll Physicians Surg Pak 2005;15:528-31.
23. Bressler B, Pinto R, El-Ashry D, Heathcote EJ. Which patients with primary biliary cirrhosis or primary sclerosing cholangitis should undergo endoscopic screening for esophageal varices detection. Gut 2005;54: 407-10.
24. Zein CO, Lindor KD, Angulo P. Prevalence and predictors of esophageal varices in patients with primary sclerosing cholangitis. Hepatology 2004; 39:204-10.