Gastrointestinal varices medical therapy
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]
Overview
Medical therapy in cases of gastrointestinal varices includes goal-directed management of the cause of portal hypertension along with specific management of varices after their development. The treatment is aimed at optimizing portal venous inflow, portal pressure and portal resistance. The pharmacological therapy includes vasoconstrictors (beta blockers) and venodilators (nitrates). These therapies may be employed alone or in combination with endoscopic variceal ligation/sclerotherapy and transjugular intrahepatic shunt (TIPS) therapy depending upon the condition of the patient.
Medical Therapy
Medical therapy for gastrointestinal varices should include management of the underlying cause of portal hypertension and specific therapy for varices after they have developed.
Treatment of underlying causes
Alcoholic liver disease
- For a detailed description for treatment of alcoholic liver disease, click here.
- Mild to moderate alcoholic hepatitis:
- Abstinence from alcohol
- Preferred regimen (1): Aggressive enteral nutrition therapy
- Severe Alcoholic hepatitis:
- Preferred regimen (1): Four week course of prednisolone (40 mg/day for 28 days), typically followed by discontinuation or a 2-week taper (if no contraindications for steroid use).
- Preferred regimen (2):Pentoxifylline therapy (400 mg orally 3 times daily for 4 weeks) is an alternative in severe disease, especially if there are contraindications to steroid therapy
Hepatitis C
- Abstinence from alcohol as alcohol aggravates HCV associated fibrosis, cirrhosis and makes liver cancer more likely.
Genotypes HCV 1 and 4
- Preferred regimen (1): Peginterferon plus ribavirin for 48 weeks. The dose for peginterferon alfa-2a is 180 µg subcutaneously per week together with ribavirin using doses of 1,000 mg for those <75 kg in weight and 1,200 mg for those >75 kg; the dose for peginterferon alfa-2b is 1.5 µg/kg subcutaneously per week together with ribavirin using doses of 800 mg for those weighing <65 kg; 1,000 mg for those weighing >65 kg to 85 kg, 1,200 mg for >85 kg to 105 kg, and 1,400 mg for >105 kg.[7]
Genotypes HCV 2 and 3
- Preferred regimen (1): peginterferon plus ribavirin should be administered for 24 weeks, using a ribavirin dose of 800 mg.[8]
- Alternative regimen (1): Triple therapy- peginterferon plus ribavirin along with an additional dose of 100mg of amantadine q12h.
Hepatitis B
- For a detailed description for treatment of Hepatitis B, click here[9][10][11][12][13][14][15][16][17][18][13]
- Patients with HBeAg-positive chronic hepatitis B[19]
- a. ALT greater than 2 times normal or moderate/severe hepatitis on biopsy, and HBV DNA >20,000 IU/mL - treatment may be initiated with any of the 7 approved antiviral medications, but pegIFN-α, tenofovir or entecavir are preferred.
- b. ALT persistently normal or minimally elevated (<2 times normal) - should not be initiated on treatment.
- c. Children with elevated ALT greater than 2 times normal - treatment may be initiated with IFN-α or lamivudine if ALT levels remain elevated at this level for longer than 6 months.
- Patients with HBeAg-negative chronic hepatitis B (serum HBV DNA >20,000 IU/mL and elevated ALT >2 times normal) should be considered for treatment with pegIFN-α, tenofovir or entecavir.[20]
- Patients with compensated cirrhosis - best treated with tenofovir or entecavir.
- Patients with decompensated cirrhosis — Lamivudine or telbivudine may be used as initial treatment in combination with adefovir or tenofovir to reduce the risk of drug resistance.[21][22]
Autoimmune hepatitis
- For a detailed description for treatment of autoimmune hepatits, click here.
- Immunosuppressive treatment based on serum aspartate aminotransferase (AST), serum alanine aminotransferase (ALT), serum gamma-globulin levels, and histological features
- Prednisone or prednisolone with azathioprine (adults)
- Prednisone with azathioprine or 6-mercaptopurine (children)
- Prednisone or prednisolone alone.
- Alternative drug therapies for suboptimal response - (cyclosporine, tacrolimus, or mycophenolate mofetil)
Primary biliary cirrhosis
- For a detailed description for treatment of primary biliary cirrhosis, click here.
- There is no known cure, but medication may slow the progression so that a normal lifespan and quality of life may be attainable.
- Ursodeoxycholic acid (Ursodiol) is the most frequently used treatment.
- Cholestyramine (a bile acid sequestrant) may be prescribed to absorb bile acids in the gut and be eliminated, and in turn give relief from itching. Alternative agents include naltrexone and rifampicin.
Primary sclerosing cholangitis
- For a detailed description for treatment of primary sclerosing cholangitis, click here.
- Standard treatment includes ursodiol which has been shown to lower elevated liver enzyme numbers in people with PSC.
- Symptomatic treatment includes:
- Anti-histaminics - for itching
- Cholestyramine - bile acid sequestrant
- Antibiotics - for infections
- Vitamin supplemantation - Vitamin A, D and K.
Wilson's disease
- For a detailed description for treatment of Wilson's disease, click here.
- Avoid intake of foods and water with high concentrations of copper.
- Initial treatment for symptomatic patients includes a chelating agent (D-penicillamine, trientine or zinc).
- Patients with acute liver failure due to Wilson's disease, or unresponsive to chelation treatment - should be referred to liver transplantation.
Treatment of Esophageal Varices
General considerations and disease stratification
The management of gastrointestinal varices in chronic liver disease should be tailored according to the clinical stage of liver disease and cirrhosis. The following table outlines the key stages of chronic liver disease and the treatment goals for the respective stage:
| Disease stage | HPVG | Varices | Complications of portal hypertension | Management goals |
|---|---|---|---|---|
| Compensated liver disease | Less than 10 mmHg | - | - | |
| Greater than equal to 10 mmHg | - | - | Prevent decompensation | |
| Greater than equal to 10 mmHg | + | - | Prevent decompensation | |
| Decompensated liver disease | Greater than equal to 12 mmHg | + | Acute variceal bleed | Control bleeding, prevent early rebleeding and death |
| Greater than equal to 12 mmHg | + | Previous variceal hemorrhage without ascites or encephalopathy | Prevent further decompensation (further bleeding, ascites and encephalopathy) | |
| Greater than equal to 12 mmHg | + | Prior variceal hemorrhage with ascites and/or encephalopathy | Prevent further decompensation and death |
Goal-directed management
The management of gastrointestinal varices is aimed at optimizing the following:[23][24]
- Portal venous inflow
- Portal resistance
- Portal pressure
This is achieved through the following pharmacological therapies:[25][23]
- Splanchnic vasoconstrictors:
- Vasopressin and analogues
- Somatostatin and analogues
- Nonselective β-blockers
- Venodilators:
The following table shows the major mechanism affected by the various pharmacological therapies used in the management of varices:[26][27][28][23][25]
| Major pharmacological therapy | Portal flow | Portal resistance | Portal pressure |
|---|---|---|---|
| Vasoconstrictors (e.g. β-blockers) | ↓↓ | ↑ | ↓ |
| Venodilators (e.g. nitrates) | ↓ | ↓ | ↓ |
| Endoscopic therapy | – | – | – |
| TIPS/Shunt therapy | ↑ | ↓↓↓ | ↓↓↓ |
1 Small non-bleeding varices
- 1.1 Adult
- 1.1.1 Child-Pugh B and C or increased risk of bleeding
- Preferred regimen (1): Propranolol immediate-release initial dose of 20 mg BID; adjust to maximal tolerated dose
- Alternative regimen (1): Nadolol initial dose of 40 mg once daily; adjust to maximal tolerated dose
- 1.1.2 No increased risk of bleeding
- Preferred regimen (1): Propranolol immediate-release initial dose of 20 mg BID; adjust to maximal tolerated dose
- Alternative regimen (1): Nadolol initial dose of 40 mg once daily; adjust to maximal tolerated dose
- 1.1.3 No previous use of beta blockers
- Preferred regimen (1): EGD should be repeated in 2 years
- 1.1.4 Hepatic decompensation
- Preferred regimen (1): EGD should be done at that time and repeated annually
- 1.1.1 Child-Pugh B and C or increased risk of bleeding
2 Large non-bleeding varices[29][30][31][32][33][34][35][36][37]
2.1 Adult
- 2.1.1 Child-Pugh B and C or increased risk of bleeding
- Preferred regimen (1): Propranolol immediate-release initial dose of 20 mg BID; adjust to maximal tolerated dose
- Preferred regimen (2): Endoscopic variceal ligation
- Alternative regimen (1): Nadolol initial dose of 40 mg once daily; adjust to maximal tolerated dose
- 2.1.2 No increased risk of bleeding
- Preferred regimen (1): Propranolol immediate-release initial dose of 20 mg BID; adjust to maximal tolerated dose
- Preferred regimen (2): Endoscopic variceal ligation
- Alternative regimen (1): Nadolol initial dose of 40 mg once daily; adjust to maximal tolerated dose
- 2.1.3 No previous use of beta blockers
- Preferred regimen (1): EGD should be repeated in 2 years
- Preferred regimen (2): Endoscopic variceal ligation
- 2.1.4 Hepatic decompensation
- Preferred regimen (1): EGD should be done at that time and repeated annually
- Preferred regimen (2): Endoscopic variceal ligation
3 Acute hemorrhage[38][39][40]
- 3.1 Adult
- Preferred regimen (1): Endoscopy (sclerotherapy or endoscopic variceal ligation) within 12 hours of bleed plus octreotide initial IV bolus of 50 µg followed by a continuous infusion of 50 µg/hour (should be continued for 3-5 days after confirmation of diagnosis) plus norfloxacin 400 mg PO BID for 7 days
- Preferred regimen (2): Vasopressin continuous IV infusion of 0.2–0.4 units/minute that can be increased to a maximal dose of 0.8 units/minute. It should always be accompanied by IV nitroglycerin at a starting dose of 40 µg/minute, which can be increased to a maximum of 400 µg/minute, adjusted to maintain a systolic blood pressure >90 mmHg
- Preferred regimen (3): Endoscopy within 12 hours of bleed plus telipressin initial dose of 2 mg IV every 4 hours and can be titrated down to 1 mg IV every 4 hours once hemorrhage is controlled (should be continued for 3-5 days after confirmation of diagnosis) plus norfloxacin 400 mg PO BID for 7 days
- Alternative regimen (1): Endoscopy (sclerotherapy or endoscopic variceal ligation) within 12 hours of bleed plus octreotide initial IV bolus of 50 µg followed by a continuous infusion of 50 µg/hour (should be continued for 3-5 days after confirmation of diagnosis) plus ciprofloxacin 400 mg PO BID for 7 days
- 3.1.1 Adult (Child-Pugh B and C)
- Preferred regimen (1): Endoscopy (sclerotherapy or endoscopic variceal ligation) within 12 hours of bleed plus octreotide initial IV bolus of 50 µg followed by a continuous infusion of 50 µg/hour (should be continued for 3-5 days after confirmation of diagnosis) plus IV ceftriaxone 1 g/day
- 3.1.2 Adult (Bleeding despite pharmacological plus endoscopic therapy)
- Preferred regimen (1): Transjugular intra-hepatic shunt operation (TIPS)
- 3.1.3 Adult (Temporary measure- in case of planned TIPS or endoscopy)
- Preferred regimen (1): Balloon tamponade (for a maximum of 24 hours)
Treatment of Gastric Varices
The following treatment options may be employed for the treatment of bleeding gastric varices:
1 Fundic varices
- 1.1 Adult
- Preferred regimen (1): Endoscopic variceal obturation using tissue adhesives such as cyanoacrylate
- 1.1.1 Adult (Uncontrolled bleeding)
- Preferred regimen (1): Transjugular intra-hepatic shunt operation (TIPS)
References
- ↑ Lai MY, Kao JH, Yang PM, Wang JT, Chen PJ, Chan KW, Chu JS, Chen DS (1996). "Long-term efficacy of ribavirin plus interferon alfa in the treatment of chronic hepatitis C". Gastroenterology. 111 (5): 1307–12. PMID 8898645.
- ↑ Everson GT (2005). "Management of cirrhosis due to chronic hepatitis C". J. Hepatol. 42 Suppl (1): S65–74. doi:10.1016/j.jhep.2005.01.009. PMID 15777574.
- ↑ Poynard T, McHutchison J, Manns M, Trepo C, Lindsay K, Goodman Z, Ling MH, Albrecht J (2002). "Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C". Gastroenterology. 122 (5): 1303–13. PMID 11984517.
- ↑ Poynard T, McHutchison J, Manns M, Myers RP, Albrecht J (2003). "Biochemical surrogate markers of liver fibrosis and activity in a randomized trial of peginterferon alfa-2b and ribavirin". Hepatology. 38 (2): 481–92. doi:10.1053/jhep.2003.50319. PMID 12883493.
- ↑ McHutchison JG, Everson GT, Gordon SC, Jacobson IM, Sulkowski M, Kauffman R, McNair L, Alam J, Muir AJ (2009). "Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection". N. Engl. J. Med. 360 (18): 1827–38. doi:10.1056/NEJMoa0806104. PMID 19403902.
- ↑ Poordad F, McCone J, Bacon BR, Bruno S, Manns MP, Sulkowski MS, Jacobson IM, Reddy KR, Goodman ZD, Boparai N, DiNubile MJ, Sniukiene V, Brass CA, Albrecht JK, Bronowicki JP (2011). "Boceprevir for untreated chronic HCV genotype 1 infection". N. Engl. J. Med. 364 (13): 1195–206. doi:10.1056/NEJMoa1010494. PMC 3766849. PMID 21449783.
- ↑ Vierling JM, Zeuzem S, Poordad F, Bronowicki JP, Manns MP, Bacon BR, Esteban R, Flamm SL, Kwo PY, Pedicone LD, Deng W, Dutko FJ, DiNubile MJ, Koury KJ, Helmond FA, Wahl J, Bruno S (2014). "Safety and efficacy of boceprevir/peginterferon/ribavirin for HCV G1 compensated cirrhotics: meta-analysis of 5 trials". J. Hepatol. 61 (2): 200–9. doi:10.1016/j.jhep.2014.03.022. PMID 24747798.
- ↑ "Medscape Log In".
- ↑ Perrillo RP (1990). "Factors influencing response to interferon in chronic hepatitis B: implications for Asian and western populations". Hepatology. 12 (6): 1433–5. PMID 1701755.
- ↑ Hoofnagle JH, di Bisceglie AM (1997). "The treatment of chronic viral hepatitis". N. Engl. J. Med. 336 (5): 347–56. doi:10.1056/NEJM199701303360507. PMID 9011789.
- ↑ Dienstag JL, Perrillo RP, Schiff ER, Bartholomew M, Vicary C, Rubin M (1995). "A preliminary trial of lamivudine for chronic hepatitis B infection". N. Engl. J. Med. 333 (25): 1657–61. doi:10.1056/NEJM199512213332501. PMID 7477217.
- ↑ Dienstag JL, Goldin RD, Heathcote EJ, Hann HW, Woessner M, Stephenson SL, Gardner S, Gray DF, Schiff ER (2003). "Histological outcome during long-term lamivudine therapy". Gastroenterology. 124 (1): 105–17. doi:10.1053/gast.2003.50013. PMID 12512035.
- ↑ 13.0 13.1 Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, Tanwandee T, Tao QM, Shue K, Keene ON, Dixon JS, Gray DF, Sabbat J (2004). "Lamivudine for patients with chronic hepatitis B and advanced liver disease". N. Engl. J. Med. 351 (15): 1521–31. doi:10.1056/NEJMoa033364. PMID 15470215.
- ↑ Lok AS, McMahon BJ (2004). "Chronic hepatitis B: update of recommendations". Hepatology. 39 (3): 857–61. doi:10.1002/hep.20110. PMID 14999707.
- ↑ Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, Marcellin P, Lim SG, Goodman Z, Ma J, Arterburn S, Xiong S, Currie G, Brosgart CL (2005). "Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B". N. Engl. J. Med. 352 (26): 2673–81. doi:10.1056/NEJMoa042957. PMID 15987916.
- ↑ Chang TT, Gish RG, Hadziyannis SJ, Cianciara J, Rizzetto M, Schiff ER, Pastore G, Bacon BR, Poynard T, Joshi S, Klesczewski KS, Thiry A, Rose RE, Colonno RJ, Hindes RG (2005). "A dose-ranging study of the efficacy and tolerability of entecavir in Lamivudine-refractory chronic hepatitis B patients". Gastroenterology. 129 (4): 1198–209. doi:10.1053/j.gastro.2005.06.055. PMID 16230074.
- ↑ Schiff ER, Lai CL, Hadziyannis S, Neuhaus P, Terrault N, Colombo M, Tillmann HL, Samuel D, Zeuzem S, Lilly L, Rendina M, Villeneuve JP, Lama N, James C, Wulfsohn MS, Namini H, Westland C, Xiong S, Choy GS, Van Doren S, Fry J, Brosgart CL (2003). "Adefovir dipivoxil therapy for lamivudine-resistant hepatitis B in pre- and post-liver transplantation patients". Hepatology. 38 (6): 1419–27. doi:10.1016/j.hep.2003.09.040. PMID 14647053.
- ↑ "EASL Clinical Practice Guidelines: Management of chronic hepatitis B virus infection - Journal of Hepatology".
- ↑ Lai CL, Leung N, Teo EK, Tong M, Wong F, Hann HW, Han S, Poynard T, Myers M, Chao G, Lloyd D, Brown NA (2005). "A 1-year trial of telbivudine, lamivudine, and the combination in patients with hepatitis B e antigen-positive chronic hepatitis B". Gastroenterology. 129 (2): 528–36. doi:10.1016/j.gastro.2005.05.053. PMID 16083710.
- ↑ Manolakopoulos S, Triantos C, Theodoropoulos J, Vlachogiannakos J, Kougioumtzan A, Papatheodoridis G, Tzourmakliotis D, Karamanolis D, Burroughs AK, Archimandritis A, Raptis S, Avgerinos A (2009). "Antiviral therapy reduces portal pressure in patients with cirrhosis due to HBeAg-negative chronic hepatitis B and significant portal hypertension". J. Hepatol. 51 (3): 468–74. doi:10.1016/j.jhep.2009.05.031. PMID 19616339.
- ↑ Villeneuve JP, Condreay LD, Willems B, Pomier-Layrargues G, Fenyves D, Bilodeau M, Leduc R, Peltekian K, Wong F, Margulies M, Heathcote EJ (2000). "Lamivudine treatment for decompensated cirrhosis resulting from chronic hepatitis B". Hepatology. 31 (1): 207–10. doi:10.1002/hep.510310130. PMID 10613747.
- ↑ Fontana RJ, Hann HW, Perrillo RP, Vierling JM, Wright T, Rakela J, Anschuetz G, Davis R, Gardner SD, Brown NA (2002). "Determinants of early mortality in patients with decompensated chronic hepatitis B treated with antiviral therapy". Gastroenterology. 123 (3): 719–27. PMID 12198698.
- ↑ 23.0 23.1 23.2 Blei AT, Garcia-Tsao G, Groszmann RJ, Kahrilas P, Ganger D, Morse S, Fung HL (1987). "Hemodynamic evaluation of isosorbide dinitrate in alcoholic cirrhosis. Pharmacokinetic-hemodynamic interactions". Gastroenterology. 93 (3): 576–83. PMID 3301517.
- ↑ Reichen J, Le M (1986). "Verapamil favorably influences hepatic microvascular exchange and function in rats with cirrhosis of the liver". J. Clin. Invest. 78 (2): 448–55. doi:10.1172/JCI112596. PMC 423578. PMID 3734100.
- ↑ 25.0 25.1 Kong DR, Ma C, Wang M, Wang JG, Chen C, Zhang L, Hao JH, Li P, Xu JM (2013). "Effects of propranolol or propranolol plus isosorbide-5-mononitrate on variceal pressure in schistosomiasis". World J. Gastroenterol. 19 (26): 4228–33. doi:10.3748/wjg.v19.i26.4228. PMC 3710427. PMID 23864788.
- ↑ D'Amico G, Pagliaro L, Bosch J (1999). "Pharmacological treatment of portal hypertension: an evidence-based approach". Semin. Liver Dis. 19 (4): 475–505. doi:10.1055/s-2007-1007133. PMID 10643630.
- ↑ Calés P, Oberti F, Payen JL, Naveau S, Guyader D, Blanc P, Abergel A, Bichard P, Raymond JM, Canva-Delcambre V, Vetter D, Valla D, Beauchant M, Hadengue A, Champigneulle B, Pascal JP, Poynard T, Lebrec D (1999). "Lack of effect of propranolol in the prevention of large oesophageal varices in patients with cirrhosis: a randomized trial. French-Speaking Club for the Study of Portal Hypertension". Eur J Gastroenterol Hepatol. 11 (7): 741–5. PMID 10445794.
- ↑ Merkel C, Marin R, Angeli P, Zanella P, Felder M, Bernardinello E, Cavallarin G, Bolognesi M, Donada C, Bellini B, Torboli P, Gatta A (2004). "A placebo-controlled clinical trial of nadolol in the prophylaxis of growth of small esophageal varices in cirrhosis". Gastroenterology. 127 (2): 476–84. PMID 15300580.
- ↑ Abraczinskas DR, Ookubo R, Grace ND, Groszmann RJ, Bosch J, Garcia-Tsao G, Richardson CR, Matloff DS, Rodés J, Conn HO (2001). "Propranolol for the prevention of first esophageal variceal hemorrhage: a lifetime commitment?". Hepatology. 34 (6): 1096–102. doi:10.1053/jhep.2001.29305. PMID 11731997.
- ↑ Garcia-Tsao, Guadalupe; Sanyal, Arun J.; Grace, Norman D.; Carey, William (2007). "Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis". Hepatology. 46 (3): 922–938. doi:10.1002/hep.21907. ISSN 0270-9139.
- ↑ Khuroo MS, Khuroo NS, Farahat KL, Khuroo YS, Sofi AA, Dahab ST (2005). "Meta-analysis: endoscopic variceal ligation for primary prophylaxis of oesophageal variceal bleeding". Aliment. Pharmacol. Ther. 21 (4): 347–61. doi:10.1111/j.1365-2036.2005.02346.x. PMID 15709985.
- ↑ Li L, Yu C, Li Y (2011). "Endoscopic band ligation versus pharmacological therapy for variceal bleeding in cirrhosis: a meta-analysis". Can. J. Gastroenterol. 25 (3): 147–55. PMC 3076033. PMID 21499579.
- ↑ Jutabha R, Jensen DM, Martin P, Savides T, Han SH, Gornbein J (2005). "Randomized study comparing banding and propranolol to prevent initial variceal hemorrhage in cirrhotics with high-risk esophageal varices". Gastroenterology. 128 (4): 870–81. PMID 15825071.
- ↑ Boyer TD (2005). "Primary prophylaxis for variceal bleeding: are we there yet?". Gastroenterology. 128 (4): 1120–2. PMID 15825093.
- ↑ de Franchis R (2006). "Endoscopy critics vs. endoscopy enthusiasts for primary prophylaxis of variceal bleeding". Hepatology. 43 (1): 24–6. doi:10.1002/hep.21026. PMID 16374843.
- ↑ Lo GH, Chen WC, Chen MH, Lin CP, Lo CC, Hsu PI, Cheng JS, Lai KH (2004). "Endoscopic ligation vs. nadolol in the prevention of first variceal bleeding in patients with cirrhosis". Gastrointest. Endosc. 59 (3): 333–8. PMID 14997127.
- ↑ Schepke M, Kleber G, Nürnberg D, Willert J, Koch L, Veltzke-Schlieker W, Hellerbrand C, Kuth J, Schanz S, Kahl S, Fleig WE, Sauerbruch T (2004). "Ligation versus propranolol for the primary prophylaxis of variceal bleeding in cirrhosis". Hepatology. 40 (1): 65–72. doi:10.1002/hep.20284. PMID 15239087.
- ↑ D'Amico G, De Franchis R (2003). "Upper digestive bleeding in cirrhosis. Post-therapeutic outcome and prognostic indicators". Hepatology. 38 (3): 599–612. doi:10.1053/jhep.2003.50385. PMID 12939586.
- ↑ Carbonell N, Pauwels A, Serfaty L, Fourdan O, Lévy VG, Poupon R (2004). "Improved survival after variceal bleeding in patients with cirrhosis over the past two decades". Hepatology. 40 (3): 652–9. doi:10.1002/hep.20339. PMID 15349904.
- ↑ Chalasani N, Kahi C, Francois F, Pinto A, Marathe A, Bini EJ, Pandya P, Sitaraman S, Shen J (2003). "Improved patient survival after acute variceal bleeding: a multicenter, cohort study". Am. J. Gastroenterol. 98 (3): 653–9. PMID 12650802.