Cirrhosis medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief:  Sudarshana Datta, MD [2]

## Overview

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The change that cirrhosis causes to the liver is irreversible, therefore treatment is mostly centered on ameliorating the complications of cirrhosis such as ascites, hepatic encephalopathy, spontaneous bacterial peritonitis, esophageal varices, and hepatorenal syndrome. Chronic constitutional symptoms such as pruritus, hypogonadism, osteoporosis, and anorexia must be treated in patients. Maintenance of adequate nutrition (especially protein intake) is extremely important in cirrhosis patients. The underlying cause of cirrhosis needs to be managed and the treatment varies depending upon the cause of cirrhosis.

## Medical Therapy

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* Treatment of cirrhosis is mostly directed towards the treatment of complications such as:[1][2]
* Ascites
* Hepatic encephalopathy
* Spontaneous bacterial peritonitis
* Esophageal varices
* Hepatorenal syndrome
* Chronic constitutional symptoms enlisted below are also treated:
* Pruritus
* Hypogonadism
* Osteoporosis
* Anorexia
* Alcohol abstinence:
* Alcohol should be avoided by all patients with cirrhosis. Improvement in liver function is noticed in patients with alcohol induced cirrhosis after abstinence from alcohol.[3][4]

### Pruritus

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* Pruritus is a common symptom in primary biliary cirrhosis and Hepatitis C.
* Endogenous opioids and increased serum bile acid levels are considered responsible for causing pruritus.
* Preferred regimen for pruritus in chronic liver disease:
* Cholestyramine
* Preferred regimen for mild itching:
* Antihistamines
* Ammonium lactate topical solution
* Preferred regimen for severe itching:
* Ultraviolet light therapy
* Plasmapheresis
* Alternative regimens for pruritus:
* Diphenhydramine
* Hydroxyzine
* Ursodeoxycholic acid
* Rifampin
* Naltrexone (opiate)

### Hypogonadism

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* Males with cirrhosis sometimes complain of loss of libido due to hypogonadism.
* Preferred regimen (1): Topical testosterone preparations
* Preferred regimen (2): Growth hormone therapy

### Osteoporosis

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* Cirrhosisis is one of the major causes of osteoporosis.[5]
* Calcium and vitamin D supplementation for all the following patients:
* At risk for osteoporosis
* On corticosteroid therapy for autoimmune liver disease
* Preferred regimen for osteoporosis: Alendronate sodium

### Pain management in cirrhosis

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* Cirrhotic patients can develop pain secondary to ascites (back and abdominal pain) and gynecomastia (mastalgia).
* Pain management in cirrhosis needs special consideration as many analgesic and anti-inflammatory drugs are metabolized by the liver and dosage regulations are required to prevent further liver damage and drug toxicity.
* Drug dosages should be titrated as per the level of hepatic functioning in the patient.
* Dosage changes are required in the following patients:
* Portal hypertension
* Renal failure
* Alcoholic patient on multiple medications
* Non-selective NSAIDs should be avoided in patients with cirrhosis because of the following complications:
* Increased bleeding from varices
* Impaired renal function
* Development of diuretic resistant ascites
* Alternative regimen for pain in cirrhosis: celecoxib
* Opioids should be used with caution in patients with cirrhosis because they are metabolized by the liver through oxidation and glucuronidation.
* Patients with cirrhosis have reduced liver blood flow, protein binding and hepatic enzyme capacity, leading to drug accumulation and increased vulnerability to developing opiate toxicity.

### Nutrition and exercise

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The following points need to be kept in mind regarding nutrition in cirrhosis patients:[6][7][8][9]

* Anorexia is common in cirrhosis patients with ascites due to the direct compression of the bowel by the ascitic fluid.
* Adequate calories and proteins should be added to the diet of the patient.
* Patients should consume a balanced diet and one multivitamin daily.
* Vitamin D and K supplementation is recommended in patients with cholestasis.
* Patients frequently benefit from the addition of commonly available liquid and powdered nutritional supplements to the diet.
* Patients are encouraged to exercise regularly to prevent muscle wasting.
* An exercise program under the direct supervision of a physical therapist may be proposed for patients.

#### Protein

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* The diet of cirrhosis patients should be adequately titrated for protein.
* Excessive protein in the diet places the patient at risk for hepatic encephalopathy.
* Low protein levels in the diet cause muscle wasting.
* As per the guidelines by the American Association for the Study of Liver Diseases and the American College of Gastroenterology, cirrhosis patients with protein malnutrition require multiple feedings per day with breakfast and a nightly snack.[10][11][8]
* Branched-chain amino acids (BCAA) can function as pharmacologic nutrients for patients with decompensated cirrhosis.

#### Zinc

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* Zinc deficiency is commonly observed in patients with cirrhosis.
* Zinc supplementation can also help resolve muscle cramps.
* Low dose zinc supplementation could prevent deterioration of the clinical status of cirrhosis and prevent excess copper accumulation in non-alcoholic cirrhotic patients.
* Zinc supplementation produces metabolic effects and trends towards improvements in liver function, hepatic encephalopathy, and nutritional status.[12]
* Preferred regimen: 220 mg Zinc po q12h may improve dysgeusia and also helps in stimulating the patient's appetite.

### Vaccination

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* Patients with cirrhosis must be vaccinated against the following:
* Hepatitis A
* Pneumococci
* Influenza

## Treatment of Underlying Causes

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### Alcoholic Liver Disease

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Alcoholic Liver Disease Medical Therapy

* 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

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Hepatitis C Medical Therapy[13][14][15][16][17][18]

* Abstinence from alcohol as alcohol aggravates HCV associated fibrosis, cirrhosis and makes liver cancer more likely.

#### Genotypes HCV 1 and 4

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* 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.[19]

#### Genotypes HCV 2 and 3

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* Preferred regimen (1): peginterferon plus ribavirin should be administered for 24 weeks, using a ribavirin dose of 800 mg.[20]
* Alternative regimen (1): Triple therapy- peginterferon plus ribavirin along with an additional dose of 100mg of amantadine q12h.

### Hepatitis B

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Hepatitis B Medical Therapy[21][22][23][24][25][26][27][28][29][30][25]

* Patients with HBeAg-positive chronic hepatitis B[31]

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.[32]
* 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.[33][34]

### Autoimmune Hepatitis

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Autoimmune Hepatitis Medical Therapy

* 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

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Primary Biliary Cirrhosis Medical Therapy

* 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

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Primary Sclerosing Cholangitis Medical Therapy

* 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

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Wilson's Disease Medical Therapy

* 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 Complications

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### Ascites

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Ascites Treatment[35][36][37][38][39][40][41][42][43]

* Abstinence from alcohol.
* Salt restriction to less than 2000 mg per day.
* Fluid restriction unless the serum sodium is less than 120 - 125 mmol/L.
* Diuretics are the first line drugs for the treatment of ascites.
* Therapeutic paracentesis in tense ascites. Serial therapeutic paracentesis is a treatment option for refractory ascites.
* Intravenous albumin infusion may also be considered in refractory cases. [44]
* TIPS may be used in refractory cases of ascites.[45]

### Esophageal Variceal Bleeding

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Esophageal Varices Treatment[46][47]

* Patients with no varices and bleeding:[48]
* EGD should be performed at regular intervals.[49]
* Patients with small varices that have not bled:[50][51][52][53][54][55][56][57]
* Non-selective beta blockers should be used to prevent the first variceal bleeding[58][59][60][61][62][63]
* Those not receiving beta blockers, should be followed up with EGD every 2 years
* If the liver decompensates, EGD should be performed at that time and then annually
* Those who recieve beta blockers may not require a regular follow up with EGD
* Patients with medium/large varices that have not bled: [64][65]
* Endoscopic variceal ligation or non-selective beta blockers may be used to prevent first variceal bleeding, as these patients are at a higher risk for bleeding with beta blockers being the first choice of treatment and endoscopic variceal ligation reserved for those who are unable to tolerate the drugs
* Nitrates, sclerotherapy and shunts alone are not used as primary prophylaxis to prevent bleeding
* Patients with cirrhosis and an acute episode of variceal hemorrhage:[66][67]
* Fluid replacement
* Blood transfusions to keep hemoglobin above 8gms/dl
* Antibiotics prophylaxis
* Oral norfloxacin\- 400mg BD
* Intravenous ciprofloxacin
* Intravenous ceftriaxone (1 gm/day) in centers with high prevalence of quinolone resistance
* Somatostatin or its analogues octreotide and vapreotide; terlipressin should be initiated as soon as variceal bleeding is suspected and continued for 3 to 5 days after diagnosis is performed [68]
* Endoscopic variceal ligation [69][70]
* Sclerotherapy [71][72][73]
* Transjugular intrahepatic portosystemic shunt (TIPS)[74][75][76][77][78]
* Balloon tamponade: temporary measure to stop bleeding for 24 hours until one of the above procedures is initiated
* Patients who have cirrhosis and have recovered from a variceal bleed:[79][80][81]
* Combination of endoscopic variceal ligation (EVL) and non-selective beta blockers
* EVL should be repeated every 1-2 weeks until obliteration with first surveillance EVL performed 1-3 months and then every 6-12 months to check for recurrence
* Refractory cases should be referred for transplantation.

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### Hepatic Encephalopathy

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The treatment of hepatic encephalopathy in cirrhosis is as follows: [82]

Hepatic Encephalopathy Treatment

* Lactulose: orally or rectally to effect a bowel purge
* Those who progress to Grade III or IV encephalopathy should undergo endotracheal intubation
* Seizures can be controlled with phenytoin and benzodiazepines with short half lives
* Intracranial pressure is monitored and frequent neurological examination is done in those with high grade encephalopathy
* Mannitol bolus (0.5-1.0 gm/kg body weight) is recommended as first-line therapy
* In patients at highest risk for cerebral edema (serum ammonia >150 µM, grade 3/4 hepatic encephalopathy, acute renal failure, requiring vasopressors to maintain mean arterial pressure [MAP]), the prophylactic induction of hypernatremia with hypertonic saline to a sodium level of 145-155 mEq/L is recommended
* Short acting barbiturates and induction of hypothermia in refractory cases as a bridge to liver transplantation.

Prevention of hepatic encephalopathy:

* Reduced protein intake
* May lead to protein malnutrition and negative nitrogen balance
* Correction of hypokalemia
* Lactulose
* Decreases absorption of ammonia from the gastrointestinal tract
* Works as a laxative, increasing the transit time and reducing absorption of ammonia
* Lactulose can be given rectally for patients who cannot take oral medications.[83][84][85] One regimen is 300 mL (200 gm) of lactulose syrup (10 gm/15 ml) in 1 L of water which is retained for 1 hour, with the patient in the Trendelenburg position.[86]
* Antibiotics
* Killing bacteria in the gut reduces the bacterial conversion of protein to ammonia
* Neomycin
* Metronidazole
* Rifaximin[87][88]
* Dose of 400 mg taken orally 3 times a day was as effective as lactulose or lactilol at improving hepatic encephalopathy symptoms.[89] Similarly, rifaximin was as effective as neomycin and paromomycin.[90][91]
* Benzodiazepines receptor agonists
* Flumazenil\- 2 milligrams over 10 minutes

### Hepatorenal Syndrome

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Hepatorenal Syndrome Treatment[92][72][93][94]

* Albumin infusion
* 1 gm albumin per kg of body weight intravenously on day one followed by followed by 20-40 grams daily
* Octreotide
* Midodrine
* Vasopressin analogs
* Ornipressin- limited use by ischemic complications
* Terlipressin
* Transjugular intrahepatic portosystemic shunt
* Liver dialysis
* Molecular adsorbents recirculation system (MARS)
* Hemodialysis[95]

Other treatment modalities:

* Pentoxifylline
* Acetylcysteine
* Misoprostol

### Spontaneous Bacterial Peritonitis

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Spontaneous Bacterial Peritonitis Medical Therapy[96][97][98][99][100][101]

* Abdominal paracentesis
* Intravenous antibiotics\-
* Cefotaxime 2 g every 8 hours
* Oral ofloxacin (400 mg twice per day) as a substitute for cefotaxime
* Patients with ascitic fluid PMN counts greater than or equal to 250 cells/mm3 (0.25 X 109/L) and clinical suspicion of SBP who also have a serum creatinine greater than 1 mg/dL, blood urea nitrogen greater than 30 mg/dL, or total bilirubin greater than 4 mg/dL should receive 1.5 g albumin per kg body weight within 6 hours of detection and 1.0 g/kg on day 3.

### Contraindicated medications

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Cirrhosis is considered an absolute contraindication to the use of the following medications:

* Acetazolamide
* Methazolamide
* Ranolazine
* Ticagrelor
* Triamterene[102]

## References

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1. ↑ Garcia-Tsao G (2001). "Current management of the complications of cirrhosis and portal hypertension: variceal hemorrhage, ascites, and spontaneous bacterial peritonitis". Gastroenterology. 120 (3): 726–48. PMID 11179247.
2. ↑ Tsochatzis EA, Bosch J, Burroughs AK (2012). "New therapeutic paradigm for patients with cirrhosis". Hepatology. 56 (5): 1983–92. doi:10.1002/hep.25915. PMID 22729954.
3. ↑ "Effects of ethanol consumption on hepatic hemodynamics in patients with alcoholic cirrhosis - Gastroenterology".
4. ↑ "EASL clinical practical guidelines: management of alcoholic liver disease". J. Hepatol. 57 (2): 399–420. 2012. doi:10.1016/j.jhep.2012.04.004. PMID 22633836.
5. ↑ Giouleme OI, Vyzantiadis TA, Nikolaidis NL; et al. (2006). "Pathogenesis of osteoporosis in liver cirrhosis". Hepatogastroenterology. 53 (72): 938–43. PMID 17153457.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
6. ↑ Kondrup J, Nielsen K, Hamberg O (1993). "[Nutritional therapy in patients with liver cirrhosis]". Ugeskr. Laeg. (in Danish). 155 (29): 2248–51. PMID 8328092.CS1 maint: Unrecognized language (link)
7. ↑ Silk DB, O'Keefe SJ, Wicks C (1991). "Nutritional support in liver disease". Gut. Suppl: S29–33. PMC 1405219. PMID 1916467.
8. ↑ 8.0 8.1 Plank LD, Gane EJ, Peng S, Muthu C, Mathur S, Gillanders L, McIlroy K, Donaghy AJ, McCall JL (2008). "Nocturnal nutritional supplementation improves total body protein status of patients with liver cirrhosis: a randomized 12-month trial". Hepatology. 48 (2): 557–66. doi:10.1002/hep.22367. PMID 18627001.
9. ↑ Plauth M, Cabré E, Riggio O, Assis-Camilo M, Pirlich M, Kondrup J, Ferenci P, Holm E, Vom Dahl S, Müller MJ, Nolte W (2006). "ESPEN Guidelines on Enteral Nutrition: Liver disease". Clin Nutr. 25 (2): 285–94. doi:10.1016/j.clnu.2006.01.018. PMID 16707194.
10. ↑ O'Shea RS, Dasarathy S, McCullough AJ (2010). "Alcoholic liver disease". Am. J. Gastroenterol. 105 (1): 14–32, quiz 33. doi:10.1038/ajg.2009.593. PMID 19904248.
11. ↑ Córdoba J, López-Hellín J, Planas M, Sabín P, Sanpedro F, Castro F, Esteban R, Guardia J (2004). "Normal protein diet for episodic hepatic encephalopathy: results of a randomized study". J. Hepatol. 41 (1): 38–43. doi:10.1016/j.jhep.2004.03.023. PMID 15246205.
12. ↑ Somi MH, Rezaeifar P, Ostad Rahimi A, Moshrefi B (2012). "Effects of Low Dose Zinc Supplementation on Biochemical Markers in Non-alcoholic Cirrhosis: A Randomized Clinical Trial". Arch Iran Med. 15 (8): 472–6. PMID 22827782.CS1 maint: Multiple names: authors list (link)
13. ↑ 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.
14. ↑ 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.
15. ↑ 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.
16. ↑ 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.
17. ↑ 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.
18. ↑ 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.
19. ↑ 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.
20. ↑ "Medscape Log In".
21. ↑ 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.
22. ↑ 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.
23. ↑ 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.
24. ↑ 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.
25. ↑ 25.0 25.1 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.
26. ↑ Lok AS, McMahon BJ (2004). "Chronic hepatitis B: update of recommendations". Hepatology. 39 (3): 857–61. doi:10.1002/hep.20110. PMID 14999707.
27. ↑ 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.
28. ↑ 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.
29. ↑ 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.
30. ↑ "EASL Clinical Practice Guidelines: Management of chronic hepatitis B virus infection - Journal of Hepatology".
31. ↑ 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.
32. ↑ 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.
33. ↑ 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.
34. ↑ 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.
35. ↑ Pedersen JS, Bendtsen F, Møller S (2015). "Management of cirrhotic ascites". Ther Adv Chronic Dis. 6 (3): 124–37. doi:10.1177/2040622315580069. PMC 4416972. PMID 25954497.
36. ↑ Ginès P, Cárdenas A, Arroyo V, Rodés J (2004). "Management of cirrhosis and ascites". N. Engl. J. Med. 350 (16): 1646–54. doi:10.1056/NEJMra035021. PMID 15084697.
37. ↑ Runyon BA (2009). "Management of adult patients with ascites due to cirrhosis: an update". Hepatology. 49 (6): 2087–107. doi:10.1002/hep.22853. PMID 19475696.
38. ↑ Hernández-Gea V, Aracil C, Colomo A, Garupera I, Poca M, Torras X, Miñana J, Guarner C, Villanueva C (2012). "Development of ascites in compensated cirrhosis with severe portal hypertension treated with β-blockers". Am. J. Gastroenterol. 107 (3): 418–27. doi:10.1038/ajg.2011.456. PMID 22334252.
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