Gastrointestinal varices medical therapy: Difference between revisions

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__NOTOC__
__NOTOC__
{{Gastrointestinal varices}}
{{Gastrointestinal varices}}
{{CMG}}; {{AE}}  
{{CMG}}; {{AE}} {{HK}}


==Overview==
==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 system|portal venous]] inflow, portal pressure and portal resistance. The pharmacological therapy includes [[vasoconstrictors]] ([[beta blockers]]) and [[Venodilator|venodilators]] ([[nitrates]]). These therapies may be employed alone or in combination with endoscopic variceal ligation/[[sclerotherapy]] and [[Transjugular intrahepatic portosystemic shunt|transjugular intrahepatic shunt]] ([[Transjugular intrahepatic portosystemic shunt|TIPS]]) therapy depending upon the condition of the patient.


==Medical Therapy==
==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, [[Alcoholic liver disease medical therapy|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====
:'''For a detailed description for treatment of Hepatitis C, [[Hepatitis C medical therapy|click here]]'''<ref name="pmid8898645">{{cite journal |vauthors=Lai MY, Kao JH, Yang PM, Wang JT, Chen PJ, Chan KW, Chu JS, Chen DS |title=Long-term efficacy of ribavirin plus interferon alfa in the treatment of chronic hepatitis C |journal=Gastroenterology |volume=111 |issue=5 |pages=1307–12 |year=1996 |pmid=8898645 |doi= |url=}}</ref><ref name="pmid15777574">{{cite journal |vauthors=Everson GT |title=Management of cirrhosis due to chronic hepatitis C |journal=J. Hepatol. |volume=42 Suppl |issue=1 |pages=S65–74 |year=2005 |pmid=15777574 |doi=10.1016/j.jhep.2005.01.009 |url=}}</ref><ref name="pmid11984517">{{cite journal |vauthors=Poynard T, McHutchison J, Manns M, Trepo C, Lindsay K, Goodman Z, Ling MH, Albrecht J |title=Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C |journal=Gastroenterology |volume=122 |issue=5 |pages=1303–13 |year=2002 |pmid=11984517 |doi= |url=}}</ref><ref name="pmid12883493">{{cite journal |vauthors=Poynard T, McHutchison J, Manns M, Myers RP, Albrecht J |title=Biochemical surrogate markers of liver fibrosis and activity in a randomized trial of peginterferon alfa-2b and ribavirin |journal=Hepatology |volume=38 |issue=2 |pages=481–92 |year=2003 |pmid=12883493 |doi=10.1053/jhep.2003.50319 |url=}}</ref><ref name="pmid19403902">{{cite journal |vauthors=McHutchison JG, Everson GT, Gordon SC, Jacobson IM, Sulkowski M, Kauffman R, McNair L, Alam J, Muir AJ |title=Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection |journal=N. Engl. J. Med. |volume=360 |issue=18 |pages=1827–38 |year=2009 |pmid=19403902 |doi=10.1056/NEJMoa0806104 |url=}}</ref><ref name="pmid21449783">{{cite journal |vauthors=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 |title=Boceprevir for untreated chronic HCV genotype 1 infection |journal=N. Engl. J. Med. |volume=364 |issue=13 |pages=1195–206 |year=2011 |pmid=21449783 |pmc=3766849 |doi=10.1056/NEJMoa1010494 |url=}}</ref>
* Abstinence from [[alcohol]] as [[alcohol]] aggravates [[Hepatitis C|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 [[Pegylated interferon alfa-2a|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 [[Pegylated interferon alfa-2b|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.<ref name="pmid24747798">{{cite journal |vauthors=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 |title=Safety and efficacy of boceprevir/peginterferon/ribavirin for HCV G1 compensated cirrhotics: meta-analysis of 5 trials |journal=J. Hepatol. |volume=61 |issue=2 |pages=200–9 |year=2014 |pmid=24747798 |doi=10.1016/j.jhep.2014.03.022 |url=}}</ref>
====Genotypes HCV 2 and 3====
* Preferred regimen (1): [[Pegylated interferon alfa-2a|peginterferon]] plus [[ribavirin]] should be administered for 24 weeks, using a [[ribavirin]] dose of 800 mg.<ref name="urlMedscape Log In">{{cite web |url=https://www.medscape.com/viewarticle/833771 |title=Medscape Log In |format= |work= |accessdate=}}</ref>
* Alternative regimen (1): Triple therapy- [[Pegylated interferon alfa-2a|peginterferon]] plus [[ribavirin]] along with an additional dose of 100mg of [[amantadine]] q12h.
====Hepatitis B====
:'''For a detailed description for treatment of Hepatitis B, [[Hepatitis B medical therapy|click here]]'''<ref name="pmid1701755">{{cite journal |vauthors=Perrillo RP |title=Factors influencing response to interferon in chronic hepatitis B: implications for Asian and western populations |journal=Hepatology |volume=12 |issue=6 |pages=1433–5 |year=1990 |pmid=1701755 |doi= |url=}}</ref><ref name="pmid9011789">{{cite journal |vauthors=Hoofnagle JH, di Bisceglie AM |title=The treatment of chronic viral hepatitis |journal=N. Engl. J. Med. |volume=336 |issue=5 |pages=347–56 |year=1997 |pmid=9011789 |doi=10.1056/NEJM199701303360507 |url=}}</ref><ref name="pmid7477217">{{cite journal |vauthors=Dienstag JL, Perrillo RP, Schiff ER, Bartholomew M, Vicary C, Rubin M |title=A preliminary trial of lamivudine for chronic hepatitis B infection |journal=N. Engl. J. Med. |volume=333 |issue=25 |pages=1657–61 |year=1995 |pmid=7477217 |doi=10.1056/NEJM199512213332501 |url=}}</ref><ref name="pmid12512035">{{cite journal |vauthors=Dienstag JL, Goldin RD, Heathcote EJ, Hann HW, Woessner M, Stephenson SL, Gardner S, Gray DF, Schiff ER |title=Histological outcome during long-term lamivudine therapy |journal=Gastroenterology |volume=124 |issue=1 |pages=105–17 |year=2003 |pmid=12512035 |doi=10.1053/gast.2003.50013 |url=}}</ref><ref name="pmid15470215">{{cite journal |vauthors=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 |title=Lamivudine for patients with chronic hepatitis B and advanced liver disease |journal=N. Engl. J. Med. |volume=351 |issue=15 |pages=1521–31 |year=2004 |pmid=15470215 |doi=10.1056/NEJMoa033364 |url=}}</ref><ref name="pmid14999707">{{cite journal |vauthors=Lok AS, McMahon BJ |title=Chronic hepatitis B: update of recommendations |journal=Hepatology |volume=39 |issue=3 |pages=857–61 |year=2004 |pmid=14999707 |doi=10.1002/hep.20110 |url=}}</ref><ref name="pmid15987916">{{cite journal |vauthors=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 |title=Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B |journal=N. Engl. J. Med. |volume=352 |issue=26 |pages=2673–81 |year=2005 |pmid=15987916 |doi=10.1056/NEJMoa042957 |url=}}</ref><ref name="pmid16230074">{{cite journal |vauthors=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 |title=A dose-ranging study of the efficacy and tolerability of entecavir in Lamivudine-refractory chronic hepatitis B patients |journal=Gastroenterology |volume=129 |issue=4 |pages=1198–209 |year=2005 |pmid=16230074 |doi=10.1053/j.gastro.2005.06.055 |url=}}</ref><ref name="pmid14647053">{{cite journal |vauthors=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 |title=Adefovir dipivoxil therapy for lamivudine-resistant hepatitis B in pre- and post-liver transplantation patients |journal=Hepatology |volume=38 |issue=6 |pages=1419–27 |year=2003 |pmid=14647053 |doi=10.1016/j.hep.2003.09.040 |url=}}</ref><ref name="urlEASL Clinical Practice Guidelines: Management of chronic hepatitis B virus infection - Journal of Hepatology">{{cite web |url=http://www.journal-of-hepatology.eu/article/S0168-8278(12)00167-5/abstract |title=EASL Clinical Practice Guidelines: Management of chronic hepatitis B virus infection - Journal of Hepatology |format= |work= |accessdate=}}</ref><ref name="pmid15470215">{{cite journal |vauthors=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 |title=Lamivudine for patients with chronic hepatitis B and advanced liver disease |journal=N. Engl. J. Med. |volume=351 |issue=15 |pages=1521–31 |year=2004 |pmid=15470215 |doi=10.1056/NEJMoa033364 |url=}}</ref>
* Patients with HBeAg-positive chronic [[hepatitis B]]<ref name="pmid16083710">{{cite journal |vauthors=Lai CL, Leung N, Teo EK, Tong M, Wong F, Hann HW, Han S, Poynard T, Myers M, Chao G, Lloyd D, Brown NA |title=A 1-year trial of telbivudine, lamivudine, and the combination in patients with hepatitis B e antigen-positive chronic hepatitis B |journal=Gastroenterology |volume=129 |issue=2 |pages=528–36 |year=2005 |pmid=16083710 |doi=10.1016/j.gastro.2005.05.053 |url=}}</ref>
:'''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 [[Interferon alfa-2b|pegIFN-α]], [[tenofovir]] or [[entecavir]] are preferred.
:'''b.''' [[Alanine transaminase|ALT]] persistently normal or minimally elevated (<2 times normal) - should not be initiated on treatment.
:'''c.''' Children with elevated [[Alanine transaminase|ALT]] greater than 2 times normal - treatment may be initiated with [[IFN-α]] or [[lamivudine]] if [[Alanine transaminase|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 [[Interferon alfa-2b|pegIFN-α]], [[tenofovir]] or [[entecavir]].<ref name="pmid19616339">{{cite journal |vauthors=Manolakopoulos S, Triantos C, Theodoropoulos J, Vlachogiannakos J, Kougioumtzan A, Papatheodoridis G, Tzourmakliotis D, Karamanolis D, Burroughs AK, Archimandritis A, Raptis S, Avgerinos A |title=Antiviral therapy reduces portal pressure in patients with cirrhosis due to HBeAg-negative chronic hepatitis B and significant portal hypertension |journal=J. Hepatol. |volume=51 |issue=3 |pages=468–74 |year=2009 |pmid=19616339 |doi=10.1016/j.jhep.2009.05.031 |url=}}</ref>
* 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.<ref name="pmid10613747">{{cite journal |vauthors=Villeneuve JP, Condreay LD, Willems B, Pomier-Layrargues G, Fenyves D, Bilodeau M, Leduc R, Peltekian K, Wong F, Margulies M, Heathcote EJ |title=Lamivudine treatment for decompensated cirrhosis resulting from chronic hepatitis B |journal=Hepatology |volume=31 |issue=1 |pages=207–10 |year=2000 |pmid=10613747 |doi=10.1002/hep.510310130 |url=}}</ref><ref name="pmid12198698">{{cite journal |vauthors=Fontana RJ, Hann HW, Perrillo RP, Vierling JM, Wright T, Rakela J, Anschuetz G, Davis R, Gardner SD, Brown NA |title=Determinants of early mortality in patients with decompensated chronic hepatitis B treated with antiviral therapy |journal=Gastroenterology |volume=123 |issue=3 |pages=719–27 |year=2002 |pmid=12198698 |doi= |url=}}</ref>
====Autoimmune hepatitis====
:'''For a detailed description for treatment of autoimmune hepatits, [[Autoimmune hepatitis medical therapy|click here]].'''
* Immunosuppressive treatment based on serum aspartate aminotransferase ([[Aspartate transaminase|AST]]), serum alanine aminotransferase ([[Alanine transaminase|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, [[Primary biliary cirrhosis medical therapy|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.
** [[Ursodiol|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, [[Primary sclerosing cholangitis medical therapy|click here]].'''
* Standard treatment includes [[ursodiol]] which has been shown to lower elevated liver enzyme numbers in people with [[Primary sclerosing cholangitis|PSC]].
* Symptomatic treatment includes:
** Anti-histaminics - for [[Itch|itching]]
** [[Cholestyramine]] - [[bile acid sequestrant]]
** [[Antibiotic|Antibiotics]] - for [[Infection|infections]]
** [[Vitamin]] supplemantation - [[Vitamin A]], [[Vitamin D|D]] and [[Vitamin K|K]].
====Wilson's disease====
:'''For a detailed description for treatment of Wilson's disease, [[Wilson's disease medical therapy|click here]].'''
* Avoid intake of foods and water with high concentrations of [[copper]].
* Initial treatment for symptomatic [[Patient|patients]] includes a [[Chelation|chelating]] agent ([[D-penicillamine]], [[trientine]] or zinc).
* Patients with acute [[Hepatic failure|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 ===
=== 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 treatement goals for the respective stage:
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:


{| class="wikitable"
{| class="wikitable"
!Disease stage
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Disease stage
!HPVG
! align="center" style="background:#4479BA; color: #FFFFFF;" + |HPVG
!Varices
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Varices
!Complications of portal hypertension
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Complications of portal hypertension
!Management goals
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Management goals
|-
|-
| rowspan="3" |Compensated liver disease
| rowspan="3" |Compensated liver disease
Line 34: Line 104:
|-
|-
| rowspan="3" |Decompensated liver disease
| rowspan="3" |Decompensated liver disease
|Greater than equal to 12 mmHG
|Greater than equal to 12 mmHg
| +
| +
|Acute variceal bleed
|Acute variceal bleed
|Control bleeding, prevent early rebleeding and death
|Control [[bleeding]], prevent early rebleeding and death
|-
|-
|Greater than equal to 12 mmHG
|Greater than equal to 12 mmHg
| +
| +
|Previous variceal hemorrhage without ascites or encephelopathy
|Previous variceal hemorrhage without [[ascites]] or [[encephalopathy]]
|Prevent further decompensation (further bleeding, ascites and encephelopathy)
|Prevent further decompensation (further bleeding, [[ascites]] and [[encephalopathy]])
|-
|-
|Greater than equal to 12 mmHG
|Greater than equal to 12 mmHg
| +
| +
|Prior variceal hemorrhage with ascites and/or encehelopathy
|Prior variceal hemorrhage with [[ascites]] and/or [[encephalopathy]]
|Prevent further decompensation and death
|Prevent further decompensation and death
|}
|}
=== Goal-directed management ===
The management of gastrointestinal varices is aimed at optimizing the following:<ref name="pmid3301517">{{cite journal |vauthors=Blei AT, Garcia-Tsao G, Groszmann RJ, Kahrilas P, Ganger D, Morse S, Fung HL |title=Hemodynamic evaluation of isosorbide dinitrate in alcoholic cirrhosis. Pharmacokinetic-hemodynamic interactions |journal=Gastroenterology |volume=93 |issue=3 |pages=576–83 |year=1987 |pmid=3301517 |doi= |url=}}</ref><ref name="pmid3734100">{{cite journal |vauthors=Reichen J, Le M |title=Verapamil favorably influences hepatic microvascular exchange and function in rats with cirrhosis of the liver |journal=J. Clin. Invest. |volume=78 |issue=2 |pages=448–55 |year=1986 |pmid=3734100 |pmc=423578 |doi=10.1172/JCI112596 |url=}}</ref>
* [[Portal venous system|Portal venous]] inflow
* Portal resistance
* Portal pressure
This is achieved through the following pharmacological therapies:<ref name="pmid23864788">{{cite journal |vauthors=Kong DR, Ma C, Wang M, Wang JG, Chen C, Zhang L, Hao JH, Li P, Xu JM |title=Effects of propranolol or propranolol plus isosorbide-5-mononitrate on variceal pressure in schistosomiasis |journal=World J. Gastroenterol. |volume=19 |issue=26 |pages=4228–33 |year=2013 |pmid=23864788 |pmc=3710427 |doi=10.3748/wjg.v19.i26.4228 |url=}}</ref><ref name="pmid3301517">{{cite journal |vauthors=Blei AT, Garcia-Tsao G, Groszmann RJ, Kahrilas P, Ganger D, Morse S, Fung HL |title=Hemodynamic evaluation of isosorbide dinitrate in alcoholic cirrhosis. Pharmacokinetic-hemodynamic interactions |journal=Gastroenterology |volume=93 |issue=3 |pages=576–83 |year=1987 |pmid=3301517 |doi= |url=}}</ref>
* [[Splanchnic]] [[vasoconstrictors]]:
** [[Vasopressin]] and analogues
** [[Somatostatin]] and analogues
** [[Beta blockers|Nonselective β-blockers]]
* [[Venodilator|Venodilators]]:
** [[Nitrates]]
The following table shows the major mechanism affected by the various pharmacological therapies used in the management of varices:<ref name="pmid10643630">{{cite journal |vauthors=D'Amico G, Pagliaro L, Bosch J |title=Pharmacological treatment of portal hypertension: an evidence-based approach |journal=Semin. Liver Dis. |volume=19 |issue=4 |pages=475–505 |year=1999 |pmid=10643630 |doi=10.1055/s-2007-1007133 |url=}}</ref><ref name="pmid10445794">{{cite journal |vauthors=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 |title=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 |journal=Eur J Gastroenterol Hepatol |volume=11 |issue=7 |pages=741–5 |year=1999 |pmid=10445794 |doi= |url=}}</ref><ref name="pmid15300580">{{cite journal |vauthors=Merkel C, Marin R, Angeli P, Zanella P, Felder M, Bernardinello E, Cavallarin G, Bolognesi M, Donada C, Bellini B, Torboli P, Gatta A |title=A placebo-controlled clinical trial of nadolol in the prophylaxis of growth of small esophageal varices in cirrhosis |journal=Gastroenterology |volume=127 |issue=2 |pages=476–84 |year=2004 |pmid=15300580 |doi= |url=}}</ref><ref name="pmid3301517">{{cite journal |vauthors=Blei AT, Garcia-Tsao G, Groszmann RJ, Kahrilas P, Ganger D, Morse S, Fung HL |title=Hemodynamic evaluation of isosorbide dinitrate in alcoholic cirrhosis. Pharmacokinetic-hemodynamic interactions |journal=Gastroenterology |volume=93 |issue=3 |pages=576–83 |year=1987 |pmid=3301517 |doi= |url=}}</ref><ref name="pmid23864788">{{cite journal |vauthors=Kong DR, Ma C, Wang M, Wang JG, Chen C, Zhang L, Hao JH, Li P, Xu JM |title=Effects of propranolol or propranolol plus isosorbide-5-mononitrate on variceal pressure in schistosomiasis |journal=World J. Gastroenterol. |volume=19 |issue=26 |pages=4228–33 |year=2013 |pmid=23864788 |pmc=3710427 |doi=10.3748/wjg.v19.i26.4228 |url=}}</ref>
{| class="wikitable"
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Major pharmacological therapy
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Portal flow
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Portal resistance
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Portal pressure
|-
|[[Vasoconstrictors]] (e.g. [[β-blockers]])
|↓↓
|↑
|↓
|-
|[[Venodilator|Venodilators]] (e.g. [[nitrates]])
|↓
|↓
|↓
|-
|[[Endoscopy|Endoscopic therapy]]
|–
|–
|–
|-
|[[Transjugular intrahepatic portosystemic shunt|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 (tablet)|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): [[Esophagogastroduodenoscopy|EGD]] should be repeated in 2 years
** '''1.1.4 Hepatic decompensation'''
*** Preferred regimen (1): [[Esophagogastroduodenoscopy|EGD]] should be done at that time and repeated annually
'''2 Large non-bleeding varices'''<ref name="pmid11731997">{{cite journal |vauthors=Abraczinskas DR, Ookubo R, Grace ND, Groszmann RJ, Bosch J, Garcia-Tsao G, Richardson CR, Matloff DS, Rodés J, Conn HO |title=Propranolol for the prevention of first esophageal variceal hemorrhage: a lifetime commitment? |journal=Hepatology |volume=34 |issue=6 |pages=1096–102 |year=2001 |pmid=11731997 |doi=10.1053/jhep.2001.29305 |url=}}</ref><ref name="Garcia-TsaoSanyal2007">{{cite journal|last1=Garcia-Tsao|first1=Guadalupe|last2=Sanyal|first2=Arun J.|last3=Grace|first3=Norman D.|last4=Carey|first4=William|title=Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis|journal=Hepatology|volume=46|issue=3|year=2007|pages=922–938|issn=02709139|doi=10.1002/hep.21907}}</ref><ref name="pmid15709985">{{cite journal |vauthors=Khuroo MS, Khuroo NS, Farahat KL, Khuroo YS, Sofi AA, Dahab ST |title=Meta-analysis: endoscopic variceal ligation for primary prophylaxis of oesophageal variceal bleeding |journal=Aliment. Pharmacol. Ther. |volume=21 |issue=4 |pages=347–61 |year=2005 |pmid=15709985 |doi=10.1111/j.1365-2036.2005.02346.x |url=}}</ref><ref name="pmid21499579">{{cite journal |vauthors=Li L, Yu C, Li Y |title=Endoscopic band ligation versus pharmacological therapy for variceal bleeding in cirrhosis: a meta-analysis |journal=Can. J. Gastroenterol. |volume=25 |issue=3 |pages=147–55 |year=2011 |pmid=21499579 |pmc=3076033 |doi= |url=}}</ref><ref name="pmid15825071">{{cite journal |vauthors=Jutabha R, Jensen DM, Martin P, Savides T, Han SH, Gornbein J |title=Randomized study comparing banding and propranolol to prevent initial variceal hemorrhage in cirrhotics with high-risk esophageal varices |journal=Gastroenterology |volume=128 |issue=4 |pages=870–81 |year=2005 |pmid=15825071 |doi= |url=}}</ref><ref name="pmid15825093">{{cite journal |vauthors=Boyer TD |title=Primary prophylaxis for variceal bleeding: are we there yet? |journal=Gastroenterology |volume=128 |issue=4 |pages=1120–2 |year=2005 |pmid=15825093 |doi= |url=}}</ref><ref name="pmid16374843">{{cite journal |vauthors=de Franchis R |title=Endoscopy critics vs. endoscopy enthusiasts for primary prophylaxis of variceal bleeding |journal=Hepatology |volume=43 |issue=1 |pages=24–6 |year=2006 |pmid=16374843 |doi=10.1002/hep.21026 |url=}}</ref><ref name="pmid14997127">{{cite journal |vauthors=Lo GH, Chen WC, Chen MH, Lin CP, Lo CC, Hsu PI, Cheng JS, Lai KH |title=Endoscopic ligation vs. nadolol in the prevention of first variceal bleeding in patients with cirrhosis |journal=Gastrointest. Endosc. |volume=59 |issue=3 |pages=333–8 |year=2004 |pmid=14997127 |doi= |url=}}</ref><ref name="pmid15239087">{{cite journal |vauthors=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 |title=Ligation versus propranolol for the primary prophylaxis of variceal bleeding in cirrhosis |journal=Hepatology |volume=40 |issue=1 |pages=65–72 |year=2004 |pmid=15239087 |doi=10.1002/hep.20284 |url=}}</ref>
'''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 (tablet)|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): [[Esophagogastroduodenoscopy|EGD]] should be done at that time and repeated annually
** Preferred regimen (2): Endoscopic variceal ligation
'''3 Acute hemorrhage'''<ref name="pmid12939586">{{cite journal |vauthors=D'Amico G, De Franchis R |title=Upper digestive bleeding in cirrhosis. Post-therapeutic outcome and prognostic indicators |journal=Hepatology |volume=38 |issue=3 |pages=599–612 |year=2003 |pmid=12939586 |doi=10.1053/jhep.2003.50385 |url=}}</ref><ref name="pmid15349904">{{cite journal |vauthors=Carbonell N, Pauwels A, Serfaty L, Fourdan O, Lévy VG, Poupon R |title=Improved survival after variceal bleeding in patients with cirrhosis over the past two decades |journal=Hepatology |volume=40 |issue=3 |pages=652–9 |year=2004 |pmid=15349904 |doi=10.1002/hep.20339 |url=}}</ref><ref name="pmid12650802">{{cite journal |vauthors=Chalasani N, Kahi C, Francois F, Pinto A, Marathe A, Bini EJ, Pandya P, Sitaraman S, Shen J |title=Improved patient survival after acute variceal bleeding: a multicenter, cohort study |journal=Am. J. Gastroenterol. |volume=98 |issue=3 |pages=653–9 |year=2003 |pmid=12650802 |doi= |url=}}</ref>
* '''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 intrahepatic portosystemic shunt|Transjugular intra-hepatic shunt operation]] ([[Transjugular intrahepatic portosystemic shunt|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 intrahepatic portosystemic shunt|Transjugular intra-hepatic shunt operation]] ([[Transjugular intrahepatic portosystemic shunt|TIPS]])


==References==
==References==
{{reflist|2}}
{{reflist|2}}

Latest revision as of 18:11, 4 January 2018

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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.

Hepatitis C

For a detailed description for treatment of Hepatitis C, click here[1][2][3][4][5][6]

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

Hepatitis B

For a detailed description for treatment of Hepatitis B, click here[9][10][11][12][13][14][15][16][17][18][13]
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.

Autoimmune hepatitis

For a detailed description for treatment of autoimmune hepatits, click here.

Primary biliary cirrhosis

For a detailed description for treatment of primary biliary cirrhosis, click here.

Primary sclerosing cholangitis

For a detailed description for treatment of primary sclerosing cholangitis, click here.

Wilson's disease

For a detailed description for treatment of Wilson's disease, click here.

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]

This is achieved through the following pharmacological therapies:[25][23]

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

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)
  • 3.1.3 Adult (Temporary measure- in case of planned TIPS or endoscopy)

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

References

  1. ↑ 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.
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ "Medscape Log In".
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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. ↑ 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.
  14. ↑ Lok AS, McMahon BJ (2004). "Chronic hepatitis B: update of recommendations". Hepatology. 39 (3): 857–61. doi:10.1002/hep.20110. PMID 14999707.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ "EASL Clinical Practice Guidelines: Management of chronic hepatitis B virus infection - Journal of Hepatology".
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ 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. ↑ 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.
  24. ↑ 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. ↑ 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.
  26. ↑ 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.
  27. ↑ 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.
  28. ↑ 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.
  29. ↑ 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.
  30. ↑ 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.
  31. ↑ 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.
  32. ↑ 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.
  33. ↑ 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.
  34. ↑ Boyer TD (2005). "Primary prophylaxis for variceal bleeding: are we there yet?". Gastroenterology. 128 (4): 1120–2. PMID 15825093.
  35. ↑ 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.
  36. ↑ 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.
  37. ↑ 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.
  38. ↑ 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.
  39. ↑ 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.
  40. ↑ 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.
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