Cirrhosis is the irreversible fibrosis of the liver. It is the end stage of a final shared pathway in chronic damage to a major vital organ. The pathophysiological features of cirrhosis involve progressive liver injury and fibrosis resulting in portal hypertension and decompensation, including ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, variceal hemorrhage, the hepatorenal syndrome, and hepatocellular carcinoma. The major causes of cirrhosis include chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, alcoholism, and nonalcoholic steatohepatitis. HCV infection and nonalcoholic steatohepatitis are the causes that are primarily responsible for the growing burden of cirrhosis in health care. Owing to the increasing prevalence of nonalcoholic fatty liver disease, cirrhosis related to nonalcoholic steatohepatitis is predicted to surpass HCV-related cirrhosis as the most common indication for orthotopic liver transplantation. Schistosomiasis and portal vein thrombosis can also cause cirrhosis and portal hypertension.
The risk in cirrhosis of the liver.
A diagnosis of compensated cirrhosis is associated with a risk of death that is 4.7 times as high as the risk in the general population, and decompensated cirrhosis is associated with a risk that is 9.7 times as high. The average life expectancy of a patient with compensated cirrhosis is 10 to 13 years, and the average life expectancy may be as low as 2 years if there is decompensation. Among patients with alcoholic cirrhosis, 65% of the patients who abstain from drinking alcohol are alive at 3 years, as compared with 0% who continue drinking alcohol.
Algorithm for management of cirrhosis of the liver. August 25, 2016
N Engl J Med 2016; 375:767-777.
Nutrition in Cirrhosis.
Will proteins cause encephalopathy?
Malnutrition occurs in 20 to 60% of patients with cirrhosis, and current guidelines recommend a daily protein intake of 1.0 to 1.5 g per kilogram of dry body weight. High-protein diets are well tolerated and are associated with sustained improvement in mental status, whereas restriction of protein intake does not have any beneficial effect in patients with acute hepatic encephalopathy. Therefore, avoid protein restriction in patients, regardless of whether they have a history of hepatic encephalopathy.
Because of a hypermetabolic state, overnight fasting contributes to muscle depletion in patients with cirrhosis. Late-evening meals may improve nitrogen balance without exacerbating hepatic encephalopathy. A randomized trial involving patients with cirrhosis who received two cans of high-protein nutritional supplement (474 ml per can) nightly showed that nocturnal supplementation resulted in sustained increases in total body protein.
(Plank LD, Gane EJ, Peng S, et al. Nocturnal nutritional supplementation improves total body protein status of patients with liver cirrhosis: a randomized 12-month trial. Hepatology 2008;48:557-566).
A 2000-mg limit in daily sodium intake is mandatory in the treatment of ascites. Dietary counseling is particularly useful for patients and the people who cook for them. We recommend fluid restriction only when the serum sodium concentration is less than 120 mmol per liter. Successful fluid restriction requires that the fluid intake be less than urinary volume.
Antihypertensive drugs in cirrhosis.
Patients with cirrhosis who have a history of hypertension gradually become normotensive and eventually hypotensive as cirrhosis progresses. Studies of blood pressure in patients with cirrhosis and ascites showed that a mean arterial pressure of 82 mm Hg or less was the single variable that was most strongly correlated with a reduced probability of survival.
In hypotension with a cardiac index below 1.5 liters per minute per square meter of body-surface area predicted the development of the hepatorenal syndrome and a decreased probability of survival among patients with cirrhosis and ascites. Because of these hemodynamic changes, antihypertensive agents should be discontinued in patients who have decompensated cirrhosis with ascites or hypotension.
Nonselective beta-blockers reduce portal pressures and are used in the primary and secondary prophylaxis of variceal hemorrhage. However, various studies caution the use of beta-blockers in situations such as decompensated cirrhosis with refractory ascites, spontaneous bacterial peritonitis, and severe alcoholic hepatitis.
These studies led to the “window hypothesis,” which postulates that beta-blockers are associated with higher rates of survival only within a clinical window. In patients who have early cirrhosis without moderate-to-large varices, beta-blockers do not prevent the development of varices and also result in adverse effects so do not start beta blockers early. The clinical window opens when moderate-to-large esophageal varices develop, with or without variceal bleeding, and beta-blockers are indicated for primary and secondary prophylaxis of variceal bleeding. Increasingly, evidence suggests that the clinical window for beta-blockers closes and that they are no longer effective when refractory ascites, hypotension, the hepatorenal syndrome, spontaneous bacterial peritonitis, sepsis, or severe alcoholic hepatitis develops, owing to unfavorable hemodynamic effects in advanced cirrhosis.
In patients with stable hypotension, midodrine may improve splanchnic and systemic hemodynamic variables, renal function, and sodium excretion. The combination of octreotide and midodrine is used for the treatment of type 1 hepatorenal syndrome. In patients without the hepatorenal syndrome, midodrine was shown to increase urinary volume, urinary sodium excretion, and mean arterial pressure and was associated with a reduction in overall mortality.
The most recent Baveno VI consensus guidelines regarding portal hypertension recommend the discontinuation of beta-blockers when the systolic blood pressure is less than 90 mm Hg, the serum sodium concentration is less than 120 mmol per liter, or acute kidney injury has developed.
Analgesic agents must be carefully selected in patients with cirrhosis. opiates are contraindicated. Because of the risk of acute renal failure and gastrointestinal bleeding, nonsteroidal anti-inflammatory drugs are contraindicated, except for low-dose aspirin in patients in whom the severity of cardiovascular disease exceeds the severity of cirrhosis. Acetaminophen is effective and safe in patients with liver disease, provided that the patient does not drink alcohol. The Food and Drug Administration has recommended limiting the total daily dose of acetaminophen to 4 g in all patients.
Proton-pump inhibitors are vastly overprescribed in hospitalized patients with cirrhosis, often without any documented indication. A large study involving patients with cirrhosis who were hospitalized with an initial infection showed that the risk of subsequent infection was increased among patients taking proton-pump inhibitors and those receiving long-term antibiotic agents as prophylaxis for spontaneous bacterial peritonitis.
Benzodiazepines should be avoided in patients with hepatic encephalopathy. For patients with alcoholic hepatitis or cirrhosis in whom severe symptoms of acute alcohol withdrawal develop, short-acting benzodiazepines such as lorazepam and oxazepam are preferred in order to minimize the risk of over sedation. For patients with insomnia, hydroxyzine at a dose of 25 mg at bedtime may be a reasonable alternative and has been studied in a small, randomized trial. Prescribed trazodone at a dose of 100 mg at bedtime.
3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) can be safely started and continued in patients with cirrhosis. Statins have established cardiovascular benefits in the treatment of nonalcoholic fatty liver disease.
Selective vasopressin V2–receptor antagonists (vaptans) have been evaluated for use in hyponatremia and ascites. A large, placebo-controlled study involving patients with cirrhosis and ascites showed that although satavaptan alleviated hyponatremia, mortality was higher among patients with recurrent ascites who were receiving satavaptan than among those who were receiving placebo. Because of these findings as well as hepatotoxicity reported with respect to tolvaptan, the use of vaptans in patients with cirrhosis and ascites is not recommended.
Protecting the liver from harm.
The fundamental principles in the management of cirrhosis focus on education, lifestyle modification, protecting the liver from harm, and care coordination. The liver has considerable regenerative potential, and “recompensation” and reversal of cirrhosis have been described in patients with alcoholic cirrhosis who abstained from alcohol, patients with HBV infection who underwent antiviral therapy, and patients with nonalcoholic steatohepatitis who underwent bariatric surgery. A study involving patients with decompensated HCV cirrhosis who received direct-acting antiviral therapy showed that a sustained virologic response at 12 weeks after the completion of treatment was associated with decreases in the Child–Pugh class and MELD score. Antiviral therapy in patients with HBV cirrhosis may reduce the risk of hepatocellular carcinoma.
Public education efforts are needed to discourage obesity, needle sharing, and excessive alcohol consumption.
It is recommended that patients undergo endoscopy for variceal screening and subsequently follow established guidelines for endoscopic surveillance. Endoscopic band ligation is preferred in patients with medium-to-large esophageal varices. A nonselective beta-blocker can be considered if the patient does not have refractory ascites, spontaneous bacterial peritonitis, severe alcoholic hepatitis, or hypotension.
It is recommended that all patients with cirrhosis undergo surveillance for hepatocellular carcinoma with the use of abdominal ultrasonography or computed tomography every 6 months. Serum measurement of the alpha-fetoprotein level in conjunction with abdominal ultrasonography may improve the effectiveness of surveillance for hepatocellular carcinoma.
Antibiotic prophylaxis may reduce the risk of bacterial infection (including spontaneous bacterial peritonitis) and increase survival rates in selected scenarios.
Patients with alcoholism are prone to relapse because of cravings and anxiety. We recommend baclofen for the suppression of alcohol cravings. A randomized trial involving patients with alcohol dependency and cirrhosis showed that 71% of patients receiving baclofen were able to maintain abstinence, as compared with 29% of patients receiving placebo.
Patients with decompensated cirrhosis may ultimately require orthotopic liver transplantation. Evaluation for transplantation is indicated when the MELD score is 17 or more.
The MELD Score (Model for End stage Liver Disease) has been validated as predictor of survival in patients with cirrhosis, alcoholic hepatitis, acute liver failure, and in patients with acute hepatitis.