Although most patients with the disease are treated by specialists, diagnosis and regular management of symptoms often fall to the primary-care clinician.
Cirrhosis is the 12th-highest cause of death in the United States and the fifth leading cause of mortality in patients 45-54 years old.1 Annually, the disease is responsible for 421,000 hospitalizations and 27,000 deaths.1,2
Cirrhosis has many causes, ranging from systemic diseases to ingestion of alcohol or certain medications (Table 1). The common pathway is chronic liver inflammation, which, after several years, results in irreversible fibrosis.3 The liver, normally soft and rubbery, becomes firm and nodular, and the loss of functioning hepatocytes results in a multitude of symptoms.
While most patients with cirrhosis are under the care of a liver specialist, they also continue to follow closely with their primary-care clinician. A better understanding of cirrhosis and its complications will allow the clinician to effectively co-manage these patients. This is increasingly important in geographical regions where it can take several weeks to get a patient evaluated by a specialist.
Compensated and decompensated disease
The liver is a remarkable organ. It will continue to operate effectively until <10% of it is functioning. When the liver is cirrhotic but still functioning well, the patient is said to have compensated cirrhosis. At this level, laboratory studies are often nearly normal and the patient generally feels well. In fact, most patients are surprised to learn that they have the condition.
When the disease has progressed to <10% of liver function, such clinical signs as jaundice, ascites, variceal bleeding, and encephalopathy occur. This stage is referred to as decompensated cirrhosis. The five-year survival rate for decompensated cirrhosis is 50%, as opposed to 91% for compensated disease.4 Unfortunately, because compensated cirrhosis is often asymptomatic, it is quite common for patients to present only after they have developed decompensated disease.
Liver biopsy is the preferred diagnostic test.2 In patients with decompensated disease, however, biopsy may not be necessary and can actually be quite dangerous because the risk of bleeding is high secondary to thrombocytopenia and prolonged clotting times. Clinically, patients with decompensated disease will often present with ascites, jaundice, GI bleeding from ruptured varices, confusion (encephalopathy), splenomegaly, and a firm, nodular liver on exam. Ultrasound or CT will often indicate a small, shrunken liver, an enlarged spleen, and abdominal ascites.
Once cirrhosis is diagnosed, the cause of the disease should be identified.3 At this point, patients are usually referred to a hepatologist, who initiates the workup and begins appropriate treatment, if necessary. Table 2 lists some common diagnostic studies for causes of cirrhosis.
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Alcoholic liver disease
Alcoholism is a leading cause of cirrhosis in the United States.2,3,5Because no amount of alcohol is safe for a cirrhotic liver, total abstinence is mandatory. This is an important point to stress because liver transplantation may eventually be required, and most centers will not consider a patient for transplant until he or she has abstained from alcohol and recreational drugs for several months.
Patients with cirrhosis should be immunized against hepatitis A and B, if not already immune to the respective viruses.2,3 The addition of a potentially hepatotoxic virus to a cirrhotic liver can lead to fulminant hepatic failure and death.2,3 Some patients have already been exposed to hepatitis A or B and have developed a natural immunity, as evidenced by a positive hepatitis A immunoglobulin G antibody or positive hepatitis B surface antibody. If these studies are negative and the underlying cause of cirrhosis is unrelated to hepatitis B, vaccinations should be given. In the absence of pre-existing liver disease, hepatitis A is usually a self-limited illness and is not generally associated with the development of cirrhosis.
Cirrhosis often results in a less-than-optimal immune system. As such, most experts also recommend the pneumococcal vaccine and annual influenza vaccination.2,3
As the liver slowly transitions from healthy, spongelike tissue to the diseased scar tissue of cirrhosis, pressure increases in the vessels emptying into the organ. In addition, as liver production of albumin decreases, serum osmotic pressure decreases and fluid passively moves out of the blood vessels and into the interstitial space.
The portal vein is the vessel that transports nutrient-rich blood from the GI tract into the liver. When enough pressure builds in the portal vein, a number of mechanisms occur. Backward pressure, along with capillary dynamics, forces plasma into the abdominal cavity, resulting in ascites.5 Ascitic fluid may become infected, a condition referred to as “spontaneous bacterial peritonitis” (SBP).6
Portal hypertension results in the formation of varices, weakened vessels that are prone to rupture.3 Ruptured esophageal varices are a common cause of death in patients with cirrhosis. Because the spleen eventually empties into the impaired portal vein, splenic vein pressure increases, resulting in stasis of splenic blood and splenomegaly. Since the spleen naturally destroys blood cells, pancytopenia often develops. Resulting thrombocytopenia and leukocytopenia places the patient at risk for hemorrhage and infection.
Another consequence of portal hypertension is the failure of the liver to metabolize toxins, such as ammonia. This occurs because the blood is unable to effectively enter the liver for processing. Portal hypertension also prevents the liver from metabolizing aldosterone, resulting in fluid retention with worsening of ascites.
Ascites is often increasingly difficult to treat as the liver progressively decompensates. Sodium restriction (no more than 2 g/day), along with diuretics, is the mainstay of management.6 Dietary counseling is mandatory.
Current thinking dictates that fluid restriction is not generally necessary.6 However, serum sodium should be closely monitored and fluid restriction should be implemented when serum sodium levels reach 120-125 mEq/L.6
Furosemide plus spironolactone is often effective in managing ascites. Start with a ratio of furosemide 40 mg/day to spironolactone 100 mg/day, increasing to a maximum daily dose of furosemide 160 mg and spironolactone 400 mg.6 Although this combination generally results in normal potassium levels, close monitoring of electrolytes is essential. Because azotemia is possible with diuretic therapy, blood urea nitrogen and creatinine should be monitored.
Spironolactone, an aldosterone antagonist, is particularly effective since it inhibits the action of aldosterone, which is increased during cirrhosis because the diseased liver is unable to metabolize it. Nonsteroidal anti-inflammatory drugs (NSAIDs) often reduce urinary sodium excretion and alter the effectiveness of diuretics.6 Therefore, NSAIDs should be avoided; if necessary, they should be used with extreme caution.
If these measures are ineffective, therapeutic paracentesis can be performed.6 Fluid removed during paracentesis should be analyzed for infection and malignancy.
Should the ascites remain refractory, a transjugular intrahepatic portosystemic shunt (TIPS) should be considered.6,7 A TIPS diverts portal blood away from the liver, carrying it directly to the vena cava.6,7 The advantage of shunt placement is prevention of ascites and esophageal varices. Disadvantages include a decrease in filtering of toxins. Patients who undergo TIPS placement are at risk for developing encephalopathy.
Bleeding, infection, and sepsis are possible following TIPS placement. A thrombus can develop, resulting in rapid reaccumulation of ascites. If this occurs, a Doppler ultrasound should be performed to assess patency of the shunt.7SBP occurs in up to 25% of patients with ascites at some point in their life.2 Rapid accumulation of ascites, abdominal pain, fever, leukocytosis, and confusion can occur with SBP. Patients with these symptoms should undergo diagnostic paracentesis.6 In the presence of SBP, analysis of fluid obtained during paracentesis demonstrates increased polymorphonuclear cells (at least 250/µL).5,6 Culture and sensitivity testing of the fluid should also be performed. Treatment of ascites involves antibiotic therapy. IV cefotaxime 2 g every eight hours for 5-10 days is effective in the hospitalized patient.6 In the nontoxic hospitalized patient who can tolerate oral intake, ofloxacin has been shown to be as effective as IV cefotaxime.6
Esophageal varices occur in 25%-40% of patients with cirrhosis.8Approximately 33% of patients will eventually hemorrhage significantly, and 70% will rebleed within one year.9-11 Variceal bleeding results in a 10%-30% mortality per episode.2 Patients diagnosed with cirrhosis should undergo upper endoscopy to screen for varices.2 If varices are present, it is possible for the endoscopist to place bands on them or perform sclerotherapy, thereby decreasing the risk of rupture and hemorrhage.3
Beta blockers, such as propranolol and nadolol, have been shown to prevent variceal bleeding by decreasing pressure in the portal vein.12 Patients with a history of variceal bleeding and those at high risk of mortality from variceal bleeding, e.g., in decompensated disease, should be treated with a nonselective beta blocker, such as nadolol or propranolol.2,9 Although it is controversial whether patients with compensated cirrhosis who have minimal or no varices identified during endoscopy should receive beta-blocker prophylaxis, at least one study has shown a reduction in risk of bleeding and decreased variceal progression with the use of these medications.13
Dosage should be patient-specific, with the goal being a 25% decrease in baseline heart rate or a resting heart rate between 55 and 60 beats per minute.14 Nadolol or propranolol should be used with extreme caution in patients with spastic lung disease, diabetes mellitus, and peripheral vascular disease.
Variceal bleeding that is refractory to variceal banding and pharmacologic treatment should be managed with a TIPS.7 As with ascites management using TIPS, the trade-off is a higher risk of encephalopathy.
Because bleeding varices are among the most common causes of death in those with cirrhosis, patients should be instructed to immediately seek assistance at their nearest emergency department if they develop such symptoms as hematemesis or melena.
Managing hepatic encephalopathy
When liver function decreases in patients with cirrhosis, the liver becomes ineffective at carrying out its duties. A major function of the hepatocyte is the detoxification of blood. As the liver decompensates, toxins increase, with ammonia being measurable in the serum. Elevated ammonia levels signify hepatic decompensation and indicate a rise in other toxins.
As ammonia levels rise, patients develop mental status changes, or “hepatic encephalopathy.” Early signs include difficulty sleeping, followed by fatigue, forgetfulness, confusion, and, eventually, coma. On exam, such patients are often lethargic and exhibit asterixis, a flapping tremor of the hands.
Dehydration, medications affecting the central nervous system, GI bleeding, hypoglycemia, and infection, particularly SBP and UTIs, commonly mimic or worsen hepatic encephalopathy.2 These conditions should all be considered in the encephalopathic patient.
Initial treatment for hepatic encephalopathy is lactulose, starting with two tablespoons per day and titrating upward as needed to achieve three to four soft bowel movements daily. If ineffective, antibiotics, such as metronidazole (Flagyl) or rifamixin, are used to decrease intestinal bacteria with resultant reduction in ammonia synthesis.2
This late complication of cirrhosis is the result of vasoconstriction of renal arteries.5 Symptoms include oliguria and elevated creatinine, which often occur in the setting of SBP.5 Close monitoring should be performed with creatinine levels. NSAIDs can exacerbate the syndrome, so they should be avoided. Because hepatorenal syndrome is often fatal, patients should be referred for transplant evaluation.5
Patients with cirrhosis are at greater risk for developing hepatocellular carcinoma (HCC) than the general population.15 While the rate of HCC varies with the cause of cirrhosis, all cirrhosis patients should be monitored for HCC, as should chronic carriers of hepatitis B, whether or not they have developed cirrhosis.15
Recommended screening involves serum a-fetoprotein (AFP) levels and liver imaging, usually ultrasound, every 6-12 months.15 HCC is often accompanied by an increase in AFP levels; however, this is a relatively nonspecific test.15 Combining AFP levels with routine imaging has been shown to be an effective screening combination.15 If a tumor is suspected, biopsy can confirm the diagnosis.
Screening for HCC in cirrhosis patients is controversial because it is expensive. However, new therapies, such as laser ablation of small liver cancers, can provide a bridge to liver transplant. In addition, a cirrhosis patient who is awaiting a transplant often moves to the top of the list if a tumor is identified, as transplantation is often curative.
When medical intervention fails, a liver transplant is often a lifesaving intervention. However, not all patients with cirrhosis are candidates for transplantation. Those who have decompensated disease should be referred for possible transplantation.16 Patients with elevated bilirubin, prolonged clotting times, and elevated creatinine should also be referred. 16
The Model End-Stage Liver Disease (MELD) score can be used to determine the urgency for transplantation. The higher the score, which takes into consideration the total bilirubin, serum creatinine, and international normalized ratio, the sicker the patient. Patients with a MELD score ≥10 should be referred for transplant evaluation, as should those with hepatorenal syndrome and HCC.16 A MELD calculator is available online at www.unos.org, accessed November 7, 2006.
Mr. Askey is a certified registered nurse practitioner in the Department ofHepatology/ Gastroenterology at the Guthrie Clinic in Sayre, Pa., and a contributing editor to The Clinical Advisor.
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