Cirrhosis is defined as a diffuse process characterized by fibrosis and a conversion of the normal hepatic architecture into structurally abnormal nodules. The end result is destruction of hepatocytes and their replacement by fibrous tissue.
The resulting resistance to blood flow results in portal hypertension and the development of varices and ascites. Hepatocyte loss and intrahepatic shunting of blood results in diminished metabolic and synthetic function, which leads to hepatic encephalopathy and coagulopathy.
Cirrhosis has many causes (Table Etiology of Cirrhosis). In the United States, excessive alcohol intake and chronic viral hepatitis (types B and C) are the most common causes.
Cirrhosis and the pathophysiologic abnormalities that cause it result in the commonly encountered problems of ascites, portal hypertension and esophageal varices, hepatic encephalopathy, and coagulation disorders.
Ascites is the pathologic accumulation of lymph fluid within the peritoneal cavity. It is one of the earliest and most common presentations 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 rennin-angiotensis system, with sodium and water retention.
Portal hypertension and varices
Portal hypertension exists when the portal venous pressure is 5 to 10 mm Hg.
The most important sequelae of portal hypertension are the development of varices and alternative routes of blood flow. Patients with cirrhosis are at risk for varices when portal pressures exceed the vena cava pressure by greater than or equal to 2 mm Hg.
|TABLE. Etiology of Cirrhosis|
Hemorrhage from varices occurs in 25% to 40% of patients with cirrhosis, and each episode of bleeding carries a 5% to 50% risk of death.
Hepatic Encephalopathy/Portal Systemic Encephalopathy
Hepatic Encephalopathy is a complex neuropsychiatric syndrome with a broad spectrum of clinical signs and symptoms of neurologic impairment that occurs in cirrhotic patients.
The symptoms are thought to result from an accumulation of gut-derived nitrogenous substances in the systemic circulation as a consequence of shunting through portosystemic collaterals. These substances then enter the central nervous system and result in alterations of neurotransmitters that affect conciousness and behavior.
Serum ammonia levels are poorly correlated with the grade of Hepatic Encephalopathy .
Hepatic Encephalopathy presents in one of three forms: acute, chronic, and subclinical.
Acute Hepatic Encephalopathy is defined as a distinct event of altered sensorium lasting less than 4 weeks, followed by complete recovery to baseline mental status.
Chronic encephalopathy is defined as a cognitive or neuropsychiatric abnormality that persists for at least 4 weeks.
Subclinical encephalopathy refers to subtle alterations in neuropsychiatric function that are not clinically apparent.
Complex coagulation derangements can occur in cirrhosis. These derangements include the reduction in the synthesis of coagulation factors and the clearance of activated clotting factors.
Portal hypertension is accompanied by a qualitative and quantitative reduction in platelets.
The net effect of these events is the development of bleeding diathesis.
The range of presentation of patients with cirrhosis may be from asymptomatic with abnormal laboratory tests to acute life-threatening hemorrhage.
Table Clinical Presentation of Cirrhosis describes the presenting signs and symptoms of cirrhosis.
|TABLE. Clinical Presentation of Cirrhosis|
Jaundice is often a late manifestation of cirrhosis, and its absence does not exclude the diagnosis.
On questioning, a patient who abuses alcohol will often underestimate the amount of alcohol consumed.
An elevation of prothrombin time is the single most reliable manifestation of cirrhosis. The combination of thrombocytopenia, encephalopathy, and ascites had the highest predictive value for sepsis.
The clinical manifestations of Hepatic Encephalopathy can range from subtle mental status abnormalities to deep coma.
Hepatic Encephalopathy associated with acute fulminant liver failure has a rapid onset and a short prodrome. Patients can progress from drowsiness to delirium, convulsions, and coma in 24 hours.
Routine liver assessment tests include alkaline phosphatase, bilirubin, aspartate transaminase, alanine transaminase, and Оі -glutamyl transpeptidase. Additional markers of hepatic synthetic activity include albumin and prothrombin time.
The aminotransferases, aspartate transaminase and alanine transaminase, are enzymes that have increased concentrations in plasma following hepatocellular injury.
Alkaline phosphatase levels and Оі -glutamyl transpeptidase are elevated in plasma with obstructive disorders that disrupt the flow of bile from hepatocytes to the bile ducts or from the biliary tree to the intestines.
The levels of Оі -glutamyl transpeptidase in plasma correlate well with elevations of alkaline phosphatase and thus are a sensitive marker for biliary tract disease.
Elevations of serum bilirubin are common in end-stage liver disease, but other causes of hyperbilirubinemia are numerous.
|TABLE. Criteria and Scoring for the Child-Pugh Grading of Chronic Liver Disease|
Albumin and coagulation factors are markers of hepatic synthetic activity and are used to estimate hepatocyte functioning in cirrhosis.
Thrombocytopenia is a relatively common feature in both acute and chronic liver disease and is proportional to the extent of liver disease.
Liver biopsy plays a central role in the diagnosis and staging of liver disease.
The Child-Pugh classification system uses a combination of physical and laboratory findings to assess and define the severity of cirrhosis and is a predictor of patient survival, surgical outcome, and risk of variceal bleeding (Table Criteria and Scoring for the Child-Pugh Grading of Chronic Liver Disease).
Clinical improvement or resolution of acute complications, such as variceal bleeding, and resolution of hemodynamic instability for an episode of acute variceal hemorrhage.
Prevention of complications, achieving adequate lowering of portal pressure with medical therapy using β- adrenergic blocker therapy, or supporting abstinence from alcohol.
Identify and eliminate the causes of cirrhosis (e.g., alcohol abuse).
Assess the risk for variceal bleeding and begin pharmacologic prophylaxis where indicated, reserving endoscopic therapy for high-risk patients or acute bleeding episodes.
The patient should be evaluated for clinical signs of ascites and managed with pharmacologic treatment (e.g., diuretics) and paracentesis. Careful monitoring for spontaneous bacterial peritonitis should be employed in patients with ascites who undergo acute deterioration.
Hepatic encephalopathy is a common complication of cirrhosis and requires clinical vigilance and treatment with dietary restriction, elimination of central nervous system depressants, and therapy to lower ammonia levels.
Frequent monitoring for signs of hepatorenal syndrome, pulmonary insufficiency, and endocrine dysfunction is necessary.
Management of portal hypertension and variceal bleeding
The management of varices involves three strategies: (1) primary prophylaxis to prevent rebleeding, (2) treatment of variceal hemorrhage, and (3) secondary prophylaxis to prevent rebleeding in patients who have already bled.
The mainstay of primary prophylaxis is the use of nonselective β- adrenergic blocking agents such as propranolol or nadolol. These agents decrease blood low to the mesenteric vascular system and deceased portal vein pressure. They prevent bleeding, and there is a trend toward reduced mortality.
β- Adrenergic blocker therapy should be continued for life, unless it is not tolerated, because bleeding can occur when therapy is abruptly discontinued.
All patients with cirrhosis and portal hypertension should be considered for endoscopic screening, and patients with large varices should receive primary prophylaxis with β- adrenergic blockers.
Therapy should be initiated with propranolol, 10 mg thrice daily, or nadolol, 20 mg once daily, and titrated to a reduction in resting heart rate of 20% to 25%, an absolute heart rate of 55 to 60 beats/min, or the development of adverse effects.
Nitrates may be considered for patients with contraindications or intolerance to β- adrenergic blockers.
Combination therapy with β- blockers is recommended for patients with inadequate lowering of portal pressure from β- blockers alone.
Acute Variceal Hemorrhage
Initial treatment goals include: (1) adequate fluid resuscitation, (2) correction of coagulopathy and thrombocytopenia, (3) control of bleeding, (4) prevention of rebleeding, and (5) preservation of liver function.
Prompt stabilization and aggressive fluid resuscitation of patients with active bleeding is followed by endoscopic examination.
The American College of Gastroenterology recommends esophagogastroduodenoscopy employing endoscopic injection sclerotherap or endoscopic band ligation of varices as the primary diagnostic and treatment strategy for upper gastrointestinal tract hemorrhage secondary to portal hypertension and varices.
Fluid resuscitation involves colloids initially and subsequent blood products.
Vasoactive drug therapy (somatostatin, octreotide, or terlipessin) to stop or slow bleeding is routinely employed early in patient management to allow stabilization of the patient and to permit endoscopy to proceed under more favorable conditions. These agents decrease splanchnic blood flow and reduce portal and variceal pressures, without significant adverse effects.
Patients experiencing variceal hemorrhage require prompt resuscitation with colloids and blood products to correct intravascular losses and to reverse coagulopathies.
Treatment with octreotide of somatostatin should be initiated early to control bleeding and facilitate endoscopy. Octreotide is preferred and is administered as an intravenous bolus of 50 to 100 mcg and is followed by a continuous infusion of 25 mcg/h, up to a maximum rate of 50 mcg/h. Patients should be monitored for hypo- or hyperglycemia.
Vasopressin, alone or in combination with nitroglycerin, can no longer be recommended as first-line therapy for the management of variceal hemorrhage. Vasopressin causes nonselective vasoconstriction and can result in hypertension, severe headaches, coronary ischemia, myocardial infarction, and arrhythmias.
Antibiotic therapy should be used early to prevent sepsis in patients with signs of infection or ascites.
endoscopic injection sclerotherapy or endoscopic band ligation is often used for upper gastrointestinal tract hemorrhage secondary to portal hypertension and varices. Sclerosing agents used in endoscopic injection sclerotherapy include ethanolamine, sodium tetradecyl sulfate, polidocanol, and sodium morrhuate.
If standard therapy fails to control bleeding, a salvage procedure such as balloon tamponade (with a Sengstaken-Blakemore tube), transjugular intrahepatic portosystemic shunt (TIPS), or surgical shunting is necessary.
Prevention of Rebleeding
β- Adrenergic blockers have traditionally been used for prevention of rebleeding; however, endoscopic injection sclerotherapy or endoscopic band ligation is emerging as the preferred treatment option.
In patients without contraindications, β- adrenergic blocking agents should be the initial step in prevention of rebleeding, along with endoscopic injection sclerotherapy or endoscopic band ligation. Use of a long-acting β- adrenergic blocker (such as nadolol) is usually recommended to improve compliance, and gradual, individualized dose escalation may help to minimize side effects. Propranolol may be given at 20 mg three times daily (or nadolol, 20 to 40 mg once daily) and titrated weekly to achieve a goal of heart rate 55 to 60 beats/min or a heart rate that is 25% lower than the baseline heart rate. Patients should be monitored for evidence of heart failure, bronchospasm, or glucose intolerance.
For patients who fail to achieve sufficient reductions in portal pressure with β- blocker therapy alone, combination therapy with nitrates or spironolactone may more effectively lower portal pressures.
For patients with ascites, a serum-ascites albumin gradient (SAG) should be determined. If SAG is greater than 1.1, portal hypertension is present with 97% accuracy.
The treatment of ascites secondary to portal hypertension includes abstinence from alcohol, sodium restriction, and diurectics. Sodium chloride should be restricted to 2 g/day.
|TABLE. Treatment Goals; Acute and Chronic Hepatic Encephalopathy|
Diuretic therapy should be initiated with single morning doses of spironolactone, 100 mg, and furosemide, 40 mg, with a goal of 0.5-kg maximum daily weight loss. The dose of each can be increased together, maintaining the 100:40 mg ratio, to a maximum daily dose of 400 mg spironolactone and 160 mg furosemide.
If tense ascites is present, a 4- to 6-L paracentesis should be performed prior to institution of diuretic therapy and salt restriction.
Patients who experience encephalopathy, severe hyponatremia despite fluid restriction, or renal insufficiency should have diuretic therapy discontinued.
Liver transplantation should be considered in patients with refractory ascites.
Spontaneous bacterial peritonitis
Patients with documented or suspected Spontaneous bacterial peritonitis should receive broad-spectrum antibiotic therapy to cover Escherichia coli, Klebsiella pneumoniae, and Streptococcus pneumoniae.
Cefotaxime, 2 g every 8 hours, or a similar third-generation cephalosporin is considered the drug of choice.
Oral ofloxacin, 400 mg every 12 hours, is equivalent to intravenous cefotaxime in terms of resolution of infection as well as survival.
|TABLE. Portosystemic Encephalopathy: Precipitating Factors and Therapy|
|TABLE. Management Approach and Outcome Assessments|
Short term fluoroquinolone therapy for the prevention of sbp should be considered in all patients at high risk of this complication, including those who have experienced a prior episode of sbp or variceal hemorrhage, and those with low-protein ascites (less than 1 g/dl).
Table Management Approach and Outcome Assessments describes the treatment goals for Hepatic Encephalopathy .
The first approach to treatment of Hepatic Encephalopathy is to identify any precipitating causes.
Treatment approaches include: (1) reduction of blood ammonia concentrations by dietary restrictions and drug therapy aimed at inhibiting ammonia production or enhancing its removal (lactulose), (2) inhibition of Оі -aminobutyric acid-benzodiazepine receptors by flumazenil, and (3) inhibition of false neurotransmitters by optimizing amino acid balance.
Approaches to reducing blood ammonia concentrations include: In patients with acute Hepatic Encephalopathy , limit protein intake to 10 to 20 g/day while maintaining the total caloric intake. Protein intake can be titrated by increasing 10 to 20 g/day every 3 to 5 days to a total of 0.8 to 1 g/kg/day. With chronic Hepatic Encephalopathy , restrict protein intake to 40 g/day.
In acute Hepatic Encephalopathy , lactulose is initiated at 45 mL every hour (or 300 mL lactulose syrup with 700 mL water given as a retention enema) until catharsis begins. The dose is then decreased to 15 to 30 mL orally 4 times daily and titrated to produce two to four soft, acidic stools per day.
With chronic Hepatic Encephalopathy , initiate lactulose at 30 to 60 mL/day with titration to the same end point.
Antibiotic therapy with metronidazole or neomycin is reserved for patients who have not responded to diet and lactulose.