Liver Cirrhosis Lecture Notes PDF

Al-Farabi University College/ Pharmacy Department Applied Therapeutics I 5th Stage/1st semester (2024/2025) Assist. Prof. Dr. Shaymaa Abdalwahed Liver Cirrhosis Lec 4...

Al-Farabi University College/ Pharmacy Department Applied Therapeutics I 5th Stage/1st semester (2024/2025) Assist. Prof. Dr. Shaymaa Abdalwahed Liver Cirrhosis Lec 4 ❑ Students will learn: 1. Define liver cirrhosis. 2. Identify the major etiology, signs and symptoms, complications of liver cirrhosis. 3. To know the pathophysiologic abnormalities. 4. Identify the treatment approach. Liver Cirrhosis (or End-Stage Liver Disease) is a diffuse injury to the liver characterized by conversion of the normal hepatic architecture (hepatocytes) into structurally abnormal nodules formation (fibrosis) with the consequent altered hepatic function, which results from a chronic or acute liver injury due to variable etiologies. The word cirrhosis is derived from the Greek kirrhos, meaning orange-yellow, and refers to the color of the cirrhotic liver. The resulting resistance to blood flow results in portal hypertension and the development of varices and ascites. Hepatocyte loss and intrahepatic shunting of blood result in diminished metabolic and synthetic function, which leads to hepatic encephalopathy and coagulopathy. Laboratory tests abnormalities in liver cirrhosis: 1. Hypoalbuminemia (< 3.8 mg/dl). 2. Elevated prothrombin time (PT). 3. Thrombocytopenia. 4. Elevated alkaline phosphatase (ALP), Elevated aspartate transaminase (AST), Elevated alanine transaminase (ALT), and Elevated γ-glutamyl transpeptidase (GGT). Liver biopsy plays a central role in the diagnosis and staging of liver disease. Causes/Etiology of liver cirrhosis: 1. Alcohol consumption. 2. Chronic viral hepatitis (types B and C). 3. Metabolic liver disease (Hemochromatosis (iron overload), Wilson disease (copper overload), α1- antitrypsin deficiency, nonalcoholic steatohepatitis (fatty liver), cystic fibrosis). 4. Immunologic disease (Autoimmune hepatitis, Primary biliary cirrhosis). 5. Vascular disease (Budd–Chiari syndrome, Heart failure (chronic right heart failure)). 6. Drugs and herbs (isoniazid, methyldopa, amiodarone, methotrexate, tamoxifen, retinol (vitamin A), estrogen, anabolic steroids, Jamaican bush tea and black cohosh). Note: World-wide, the most common etiologies of cirrhosis are chronic viral hepatitis (types B and C) and prolonged excessive alcohol consumption. 1  Signs and symptoms of liver cirrhosis: Cirrhosis is often asymptomatic until the late stages of disease. The presenting signs and symptoms of cirrhosis are: 1. Hepatomegaly and splenomegaly. 2. Pruritus and jaundice. 3. Encephalopathy. 4. Palmar erythema, spider angiomata and hyperpigmentation. 5. Gynecomastia and reduced libido. 6. Malaise, anorexia and weight loss. 7. Ascites, bilateral leg edema, pleural effusion, and respiratory difficulties. Palmar erythema spider angiomata Ascites Complications of Cirrhosis: Cirrhosis results in elevation of portal blood pressure because of fibrotic changes within the hepatic sinusoids, changes in the levels of vasodilatory and vasoconstrictor mediators, and an increase in blood flow to the splanchnic vasculature. The pathophysiologic abnormalities that cause it result in the following problems: 1. Ascites. 2. Portal hypertension and Esophageal varices. 3. Hepatic encephalopathy. 4. Pruritus. 5. Spontaneous Bacterial Peritonitis (SBP). 6. Coagulation disorders. 7. Hepatorenal syndrome (HRS). Treatment The desired therapeutic outcomes can be viewed in two categories: 1- Prevention of complications. 2- Resolution of acute complications. 2  General approach: Primarily, any cause of cirrhosis should be identified and eliminated (e.g., alcohol abuse). ❑ The pathophysiologic abnormalities Liver Cirrhosis: 1. Ascites: is the accumulation of an excessive amount of lymph fluids within the peritoneal cavity. Ascites is one of the earliest and most common occurring (major) complication of cirrhosis. The development of ascites is related to systemic arterial vasodilation that leads to the activation of the baroreceptors in the kidney and an activation of the renin-angiotensin-aldosterone system (RAAS), activation of the sympathetic nervous system, and release of antidiuretic hormone in response to the arterial hypotension. These changes cause sodium and water retention. Also the decrease in synthetic function leads to a decrease in production of albumin (hypoalbuminemia). Albumin is the major protein involved in maintaining the intravascular oncotic pressure. Hypoalbuminemia and reduced plasma oncotic pressure also contribute to the loss of fluids from the intravascular compartment into the peritoneal cavity. Treatment of Ascites: For patients with ascites, a serum-ascites albumin gradient (SAAG) (serum albumin minus (-) ascitic albumin) should be determined. If the SAAG is ≥ greater than or equal to 1.1 g/dL, the patient almost certainly has portal hypertension and ascites will usually respond to salt restriction and diuretics. The treatment of ascites includes abstinence from alcohol, sodium chloride (restriction to 2 g/day) and diuretics. If sodium restriction alone fails to result in diuresis and weight loss, diuretics should be prescribed with a goal of 0.5-kg maximum daily weight loss. Because of the role of hyperaldosteronism in ascites, spironolactone is the diuretic of 1st first choice. Loop diuretics (furosemide) may be added to the regimen. Diuretic therapy in cirrhosis is typically lifelong. Spironolactone is initially given at a dose of 50-100 mg/d with or without furosemide, 20-40 mg/d morning, and both agents may be increased (every 3–5 days) by maintaining the 100:40 mg ratio (to maintains serum potassium concentrations within the normal range) to a maximum daily dose of 400 mg/d spironolactone and 160 mg/d furosemide. Triamterene and Amiloride can be used as alternatives to spironolactone if intolerable side effects (e.g., gynecomastia) occur with spironolactone. The initial doses of Amiloride (20 mg) and potassium canrenoate (150 mg), and can increased up to 60 and 500 mg/day, respectively if no response occurred. Eplerenone can also be used usual dose is 25 to 50 mg/day. Potassium canrenoate is an active metabolite of spironolactone (aldosterone antagonist). 3  In patients with pronounced ascites or resistant to maximum doses of diuretics, paracentesis (removal of ascitic fluid from the abdominal cavity with a needle or a catheter) has proven to be an effective treatment. Concomitant albumin replacement by IV infusion is given to avoid depleting the intravascular space from this protein and precipitating hypotension because ascites fluid drained via paracentesis is rich in albumin. Use of albumin in combination with large volume paracentesis produces an expansion of circulating blood volume, increases cardiac output, and suppresses release of renin and norepinephrine. For large volume paracentesis greater than or equal to 6 L, 6 to 8 g of albumin is typically administered for each liter of ascites removed. Thus, Patients treated with large volume paracentesis (≥ 6 L/day) should take IV albumin (40 g after each tap). The major complications of overly aggressive, large-volume paracentesis include: hypotension, shock, oliguria, encephalopathy, and renal insufficiency, hemorrhage, perforation of the abdominal viscera, infection, and protein depletion. Transjugular intrahepatic portosystemic shunt (TIPS) or Liver transplantation should be considered in patients with refractory ascites. Clonidine may be of benefit in refractory ascites and those with an activated sympathetic nervous system. Clonidine decreased sympathetic activity and increased glomerular filtration rate (GFR). ✓ The addition of clonidine to diuretic therapy may be an effective therapeutic modality. ✓ Clonidine dose 0.075 mg BID for 8 days can be used. ❑ The pathophysiologic abnormalities Liver Cirrhosis: B. Portal hypertension and esophageal varices: Portal hypertension is results from a combination of increased portal venous inflow and increased resistance to portal blood flow through the portal vein because of fibrotic changes within the hepatic sinusoids. Portal hypertension can be further classified as prehepatic, intrahepatic, or posthepatic portal hypertension. The most important sequel of portal hypertension are the development of varices and alternative routes of blood flow. The varices develop in the esophagus, stomach, and rectum to compensate for the increased blood volume (congested blood). Varices are weak superficial vessels, and any additional increase in pressure can cause these vessels to rupture and bleed. Hemorrhage from varices occurs in 25% - 40% of patients with cirrhosis and is the cause of death for one third of patients. 4  Portal hypertension is characterized by hyperdynamic circulatory state which include hypervolemia, increased cardiac index (CI), hypotension and decreased systemic vascular resistance (SVR). Management of Portal hypertension and Variceal Bleeding: The management of varices involves three (3) strategies: A. Primary prophylaxis to prevent a first variceal bleeding. B. Treatment of active variceal bleeding. C. Secondary prophylaxis to prevent rebleeding in patients who have already bled. A. Primary Prophylaxis (prevention of a first variceal bleeding) ▪ Pharmacotherapy is not recommended to prevent the development of varices in patients with cirrhosis who have not yet developed varices. ▪ All cirrhotic patients who develop portal hypertension with varices should receive primary prophylaxis with β-Adrenergic blockers (BB) to reduce portal pressure, thereby reducing the likelihood of variceal rapturing. ▪ BB therapy should be continued for life, because bleeding can occur when therapy is abruptly discontinued. ▪ Therapy should be initiated with Propranolol, 10 mg thrice daily (or 20 mg twice daily) or Nadolol, 20 mg once daily (or 40 mg once daily), and titrated to a reduction in resting heart rate of 20-25% of the baseline, or an absolute heart rate of 55 - 60 beats/min. B- Treatment of active variceal bleeding (Acute Variceal Hemorrhage): 1. Fluid resuscitation: Variceal hemorrhage is life-threatening; rapid resuscitation with fluids and/or blood products are essential. (Shock reduces liver blood flow and causes further deterioration of liver function). 2. Vasoactive drug therapy (somatostatin, octreotide (a synthetic analogue of somatostatin but with longer half-life), or terlipessin). These agents are potent vasoconstrictor that decrease splanchnic blood flow (by splanchnic vasoconstriction) and reduce portal and variceal pressures, without significant adverse effects reducing or stopping variceal bleeding. Therapy should be initiated as soon as variceal hemorrhage is suspected and continued for 2 to 5 days since (time which the risk of rebleeding is highest). Octreotide is administered as a 50 to 100 mcg bolus followed by an infusion of 25 to 50 mcg/hour for 18 hours to 5 days. 3. Combination pharmacologic therapy/(vasoactive drugs) plus endoscopic variceal ligation (EVL) or sclerotherapy (when EVL is not technically feasible) is the most rational approach to treatment of acute variceal bleeding. 4. Prophylactic acid suppression with proton pump inhibitors (PPI) reduces the risk of secondary bleeding which may result from EVL-induced ulcers. 5 5. All patients with cirrhosis and gastrointestinal bleeding should receive prophylactic antibiotics (because of risk severe bacterial infections and sepsis) to improve outcome. Oral Norfloxacin 400 mg BID for 7 days or ciprofloxacine 200 mg intravenously (IV) twice a day if the oral route is not possible or IV ceftriaxone 1 g/day for 7 days. 6. If standard therapy fails to control bleeding, an invasive procedure such (TIPS) is done. C-Prevention of rebleeding (secondary prophylaxis): All patients with a history of variceal bleeding should receive secondary prophylaxis to prevent recurrent bleeding. 1. A combination of EVL and nonselective β-blockers (Propranolol or Nadolol) is considered the most effective regimen. 2. The combination therapy of a nonselective β-blocker with isosorbide mononitrate can be used in patients unable to undergo EVL. 3. Patients who cannot tolerate or who fail pharmacologic and endoscopic interventions can be considered for Transjugular intrahepatic portosystemic shunt (TIPS) to prevent rebleeding. ✓ Transjugular intrahepatic portosystemic shunt (TIPS) is a non-surgical procedure to decrease the pressure in the portal vein and involves the placement of one or more stents between the hepatic vein and the portal vein. The stent then is placed so that one end is in the high pressure portal vein and the other end is in the low pressure hepatic vein. This tube shunts blood around the liver and by so doing lowers the pressure in the portal vein and varices and prevents bleeding from the varices. Major complications of TIPS include severe encephalopathy and shunt occlusion. ❑ The pathophysiologic abnormalities Liver Cirrhosis: C-Hepatic encephalopathy (HE): A. Serious complication of chronic liver disease and is broadly defined as an alteration in mental status and cognitive function occurring in the presence of liver failure. B. The symptoms of HE range from forgetfulness, mental confusion, lethargy, personality changes, somnolence, confusion, and coma. 6 C.The symptoms are thought to result from an accumulation of gut-derived nitrogenous substances (neurotoxins) in the systemic circulation. These substances have the ability to enter the CNS and result in alterations of neurotransmitters that affect consciousness and behavior. Precipitating causes of HE can include: 1. GI bleeding, 2. Diuretic-induced hypovolemia and/or electrolyte abnormalities, 3. Metabolic alkalosis, 4. Drugs [opioids (morphine, methadone, meperidine, codeine), sedatives (benzodiazepines, barbiturates, chloral hydrate), and tranquilizers (phenothiazines)]. Hepatic encephalopathy may be classified as episodic, persistent or minimal. Types of hepatic encephalopathy: 1. Type A is induced by acute liver failure. 2. Type B results from portal-systemic bypass without intrinsic liver disease. 3. Type C occurs with cirrhosis. Management of Hepatic Encephalopathy (HE): 1. During episode of acute HE, temporary protein restriction (1 to 1.5 g) to decrease ammonia production can be useful adjunctive measure to pharmacological therapy. ✓ Long term protein restriction is Not recommended because cirrhotic patients are already in a nutritional deficient state, and any further protein restriction on long term will exacerbate the problem. 2.Treatment approaches include: Reduction of blood ammonia concentrations by: A. Inhibiting ammonia production or enhancing its removal (Lactulose/or lactitol and Antibiotics). B. Inhibition of γ -aminobutyric acid–benzodiazepine receptors by Flumazenil (selective Gamma- aminobutyric acid antagonist (GABAA)). The levels of GABA-like activity in peripheral blood plasma increase before the onset of hepatic encephalopathy, due at least in part to impaired hepatic extraction of gut-derived GABA from portal venous blood. 3- The use of lactulose is standard therapy for HE. Lactulose is broken down by GI bacteria to form lactic, acetic, and formic acids. It is believed that acidification of colonic contents converts ammonia (NH3) into the less readily absorbed ammonium ion (NH4+). Lactulose Dose: 45 mL orally every 1–2 hours until the patient has a loose bowel movement; then titrate to 2 or 3 loose bowel movements a day (dose typically, a 15- to 45-mL dose 2–3 times/day). Lactulose enemas (300 ml in 1L of water) in patients who are unable to take it by mouth (p.o). Lactulose-induced osmotic diarrhea may also decrease the intestinal transit time available for ammonia production and absorption, and may help clear the GI tract of blood. 7  Lactitol is 67-100 g lactitol powder diluted in 100 mL of water. Lactulose and lactitol may be given as enemas, if patients are unable to take them orally, as 1-3 L of a 20 percent solution. 4-Antibiotic therapy with Metronidazole, Neomycin, Vancomycin, Paromomycin, Quinolone is reserved for patients who have not responded to lactulose. More recently, Rifaximin has been very effective in treating encephalopathy (dosages ranged from 550 mg twice daily to 400 mg every 8 hours). ✓ Rifaximin plus lactulose is more effective than lactulose as monotherapy in recurrent hepatic encephalopathy following second recurrence. ✓ Rifaximin can decrease colonic levels of ammoniagenic bacteria, with resulting improvement in the symptoms of HE. ✓ The alternating administration of neomycin and metronidazole (250 mg bid) has commonly been employed to reduce the individual side effects of each neomycin (cause nephrotoxicity and ototoxicity) and metronidazole (cause peripheral neuropathy, GIT disturbance and neurotoxicity). ✓ Neomycin use at dosages of 500 mg to 1 g orally four (4) times daily for 6 day, or as a 1% solution (125 mL) given as a retention enema (retained for 30–60 minutes) 4 times daily, is effective in reducing plasma ammonia concentrations. 5-Zinc acetate supplementation is recommended for long term management in patients with cirrhosis who are zinc deficient, especially with alcohol-induced liver injury. It decrease serum ammonia levels and altering neurotransmitters like gamma-aminobutyric acid and norepinephrine in the brain. Give elemental zinc is 11 mg in adult males and 8 mg in adult females. Zinc is an essential cofactor of ornithine transcarbamylase enzymes which enhance the conversion of ammonia to urea and promote glutamine synthetase for the metabolism (detoxification) of ammonia to glutamine in the skeletal muscle. 6. Bromocriptine (dopamine receptor agonist) is indicated for chronic hepatic encephalopathy in patients who are unresponsive to other treatments. It is given 30 mg orally twice daily. It lead to improvement in cerebral blood flow and cerebral glucose consumption. Note: Probiotics are formulations of microorganisms that modify gut flora to acid resistant, non-urease producing flora, resulting in diminished ammonia production and absorption. Probiotics include compounds such as lactulose and fermentable fiber which promote the growth of beneficial gut flora. The most beneficial species of gut flora in the treatment of HE appears to be Lactobacilli and bifidobacterial. ❑ The pathophysiologic abnormalities Liver Cirrhosis: D-Spontaneous Bacterial Peritonitis (SBP) 1-SBP is a common and severe complication of ascites and is defined as the spontaneous infection of the ascitic fluid. This condition has a mortality rate of about 30% to 50%. 2-The primary mechanism for SBP is bacterial translocation from the gut due delay in intestinal transit time, intestinal bacterial overgrowth and increased intestinal wall permeability observed in cirrhotic patients allowing gut bacteria to pass into ascitic fluid. 3- Enteric Gram-negative bacilli (most commonly Escherichia coli, Klebsiella pneumoniae) account for the majority of SBP episodes. The most common gram-positive pathogen is Streptococcus pneumoniae. 8 4- Patients may be asymptomatic, or may present with unexplained fever, or nonspecific abdominal pain. Note: The diagnosis of SBP is defined by a polymorphonuclear cell count (PMN) of greater than or equal to 250 cells/μL of the ascitic fluid or a positive bacterial culture of the ascitic fluid. Note: Patients with cirrhosis have a state of intravascular hypovolemia and organ hypoperfusion; SBP is thought to enhance this effect, resulting in progressive renal hypoperfusion and precipitation of renal failure or hepatorenal syndrome (HRS). Management of Spontaneous Bacterial Peritonitis (SBP): 1) Theraputic antibiotics: Patients with diagnosed or suspected SBP should receive broad spectrum antibiotic. Examples of antibiotic: A-Third-generation cephalosporin: Cefotaxime, 2 g every 8 hours I.V, or ceftriaxone 2 g/day I.V for 5 days is considered the drug of choice. Also can use Ampicillin /sulbactam (2g /1g I.V. every 6 h) B-Fluoroquinolones (ciprofloxacin or ofloxacin) may be used. Oral ofloxacin, 400 mg BD every 12 hours for 8 days, is equivalent to IV cefotaxime. Ampicillin and Gentamicin may be used. 2) Albumin: Plasma volume expansion with albumin in addition to antibiotics decreases the incidence of hepatorenal syndrome (HRS) and improves survival. 3) Prophylactic antibiotics: A. Primary prevention (prevention of SBP in patients who never develop SBP previously) should be considered in all patients who are at high risk for this complication (e.g. those who experience a variceal hemorrhage). Oral norfloxacin (400 mg BD day), Oral ciprofloxacin 250 – 500 mg once daily or Oral levofloxacin 250 mg once daily (q.d.) or IV ceftriaxone (1 g/day), which may be preferable, for 7 days reduces the risk of bacterial peritonitis in patients hospitalized for acute variceal bleeding. B. Secondary prevention: (prevention of SBP in patients who do develop a previous infection): After SBP, there is a high probability of a further episode; therefore, all patients recovering from an initial episode of SBP should be treated with oral prophylactic antibiotics indefinitely. Examples of antibiotic used for secondary prevention are: ✓ Norfloxacin (400 mg PO daily). ✓ Ttrimethoprim-sulfamethoxazole single dose of 2 tablet (160/800 mg/day) given for 5 days/week. ✓ Ciprofloxacin 750 mg once weekly. 4) The patients should be considered for liver transplantation because 2-year survival is 25%– 30% after recovery. Note: Probiotic therapy in conjunction with antimicrobial treatment does not improve efficacy in the treatment of spontaneous bacterial peritonitis (SBP). 9  ❑ The pathophysiologic abnormalities Liver Cirrhosis: E-Abnormalities in Coagulation: Most clotting factors are synthesized in the liver, and the levels of these factors can be significantly reduced in chronic liver disease. Abnormalities in coagulation include the reduction in the synthesis of coagulation factors, excessive fibrinolysis, disseminated intravascular coagulation, thrombocytopenia and platelet dysfunction. Vitamin K–dependent clotting factor levels are decreased, with factor VII affected first because it has a short half-life. The net effect of these events is the development of bleeding tendency. Management of Coagulation disorders: ✓ Treatment is vitamin K (phytomenadione), 10 mg given IV for 3 days. ✓ The patient's INR and prothrombin time are monitored. ✓ Patients with cirrhosis who are actively bleeding receive resuscitation with packed red blood cells targeting a hemoglobin of 7 to 9 g/dL. ✓ Platelet transfusion is used to maintain platelets over 50,000/mm3 during the period of active bleeding. Cryoprecipitate to maintain fibrinogen levels over 100 mg/dL is also usually recommended. Aspirin, non-steroidal anti-inflammatory drugs (NSAIDs) and anticoagulants should be avoided in all patients with liver disease because of the risk of altering platelet function, causing gastric ulceration and bleeding. Most hepatologists permit the use of paracetamol in patients with cirrhosis at doses of up to 2000 mg daily. ❑ The pathophysiologic abnormalities Liver Cirrhosis: F- Hepatorenal syndrome (HRS) It is characterized by an intense renal vasoconstriction, which leads to a very low renal perfusion and glomerular filtration rate, as well as a severe reduction in the ability to excrete sodium and free water. The hepatorenal syndrome (HRS) is a form of renal failure, but without renal pathology. This renal failure occurs in about 10% of patients with advanced cirrhosis or acute liver failure. ✓ Hepatorenal syndrome can be classified into two categories: 1. Type 1 HRS is acute and progressive kidney failure and characterized by progressive oliguria, a rapid rise of the serum creatinine (>2.5 mg/dL in less than 2 weeks) and a very poor prognosis. ✓ Type 1 HRS precipitated by factors: SBP, large volume paracentesis, hypotension, activation of endogenous vasoconstrictor, impaired cardiac and liver functions and encephalopathy. 2. Type 2 HRS is more slowly progressive deterioration of kidney function with a serum creatinine from 1.5 to 2.5 mg/dL. It is often associated with refractory ascites (diuretic-resistant ascites) and has a better survival rate/outcome than that of patients with type 1 HRS. Management of Hepatorenal syndrome (HRS): 1- Precipitating factors such as infection (SBP), fluid loss, and blood loss should be investigated and treated appropriately. 2-The definitive treatment for HRS is liver transplantation, which is the only treatment that assures long-term survival. 10  ✓ The main goal of pharmacologic therapy is to reverse HRS sufficiently so that patient can survive until suitable donor organs available. 3-Diuretic therapy must be stopped because this can worsen the kidney disease. 4-Management of HRS includes expanding the intravascular volume with IV albumin (50-100 g IV/d) plus vasoconstrictors either terlipressin or (α-agonist midodrine combine with octreotide) or Norepinephrine for at least 7 day. ✓ Terlipressin (give IV 2–12 mg/day) use in combination with albumin (20–40 g/day after 1 g/kg on the first day), and mention that about 60% of renal failure cases recover with this therapy. ✓ All patients should receive albumin 100 g on day 1 and 25 g daily until the end of treatment. The primary end point (treatment success) at day 14 was defined as a SCr level less than or equal to 1.5 mg/dL on two occasions at least 48 hours apart. Octreotide administration started at 100 mcg S.C TID, with the goal to increase the dose to 200 mcg subcutaneous TID to increase mean arterial pressure by 15 mm Hg. Midodrine administration started at 5, 7.5, or 10 mg TID orally (p.o), with the goal to increase the dose to 12.5 or 15 mg if necessary. ✓ All patients received IV expansion of plasma volume with 1.5 L of saline combined with an average of 120 g of human albumin after diuretic withdrawal. ✓ The goal of treatment is to increase renal perfusion. ❑ The pathophysiologic abnormalities Liver Cirrhosis: G-Pruritus: 1-Antihistamines are not very effective for pruritus in liver disease. If given, non-sedating antihistamines would be preferable (e.g. loratidine), as sedating antihistamines could mask the symptoms of hepatic encephalopathy. 2-Anion exchange resins (colestyramine) bind to the bile acids that cause itching and is first line therapy. Liver Transplantation in cirrhosis is considered in patients with severe, irreversible liver disease. Liver transplantation is the only treatment that can offer a cure for complications of end-stage cirrhosis. The outcome of Liver transplantation in cirrhosis is good, with an overall survival rate of 70-85%. The calcineurin inhibitors (tacrolimus and ciclosporin) remain the mainstay of immunosuppressive therapy. Corticosteroids are still commonly used, at least during the first 3 months after transplantation. The other drugs used regularly for long-term immunosuppression include azathioprine, mycophenolate sodium, sirolimus and everolimus (derivative of sirolimus). References/ Further reading: 1.Roger Walker, Clive Edwards (eds), Clinical Pharmacy& Therapeutics. 2. Barbara G.Wells & Joseph T. Diriro, Pharmacotherapy hand book 7th Edittion. 3. British National Formulary (BNF) Thank You 11