Outpatient management of cirrhosis: a narrative review.

Abstract: Cirrhosis is the 12th leading cause of death in the United States. Individuals with cirrhosis are at risk for many potential complications. Complications can be managed or detected early with proper outpatient management. The most lethal of these complications is bleeding esophageal varices. All patients with cirrhosis should be screened for the presence of varices and treated when indicated. The most common complication seen in these patients is ascites. Ascites can be treated with dietary modifications and a diuretic regimen. Other potential complications include spontaneous bacterial peritonitis, hepatocellular carcinoma, hepatic encephalopathy, hepatorenal syndrome, and hepatopulmonary syndrome. The outpatient management of these complications will be discussed in this paper, along with the use of vaccinations, educating patients about the avoidance of hepatotoxic drugs, and when to refer a patient for liver transplant.

Key Words: cirrhosis, outpatient management, esophageal varices, ascites, hepatocellular carcinoma

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Cirrhosis is the 12th leading cause of death in the United States with more than 27,000 deaths (1) and over 421,000 hospitalizations annually. (2) Serious complications from cirrhosis, which may contribute to hospitalization and even death, include variceal bleeding, spontaneous bacterial peritonitis, hepatocellular carcinoma, hepatorenal syndrome, hepatic encephalopathy, and hepatopulmonary syndrome. Proper outpatient management may help prevent or delay complications, reduce hospitalizations, and improve survival.

Cirrhosis is a slowly progressive disease, causing irreversible scarring and nodularity of the liver in response to chronic injury from a variety of causes. This process distorts the normal liver architecture, interferes with blood flow through the liver, and disrupts the biochemical functions of the liver. In the US, the most common causes of cirrhosis are alcoholic liver disease and chronic viral hepatitis infection (Table 1). The liver biopsy is the gold standard for the diagnosis of cirrhosis; however, this procedure has its limitations and is not always necessary. In most cases, a presumptive diagnosis can be made with a high degree of certainty based on clinical and radiologic features. Clinical manifestations may include jaundice, telangiectasias, splenomegaly, ascites, palmar erythema, scarce pubic and axillary hair, gynecomastia, and encephalopathy. Laboratory data may show thrombocytopenia, hypoalbuminemia, and a prolonged international normalized ratio (INR). Radiologically, abdominal ultrasound or computed tomography may show alterations in the liver contour with nodularity, caudate and left lobe enlargement and right lobe atrophy.

Once the diagnosis of cirrhosis is made, proper outpatient management is indicated to improve symptoms. Important goals are to avoid complications and decompensation. Cirrhosis is considered decompensated once patients have a variceal bleed, jaundice, ascites, hepatic encephalopathy, or hepatocellular carcinoma. The five year survival rate is 50% for those with decompensated cirrhosis versus 91% for those with compensated cirrhosis. (3)

Major Complications of Cirrhosis

Esophageal Variceal Bleeding. Esophageal varices are present in 25 to 40% of all patients with cirrhosis. (4) Each episode of bleeding has a 10 to 30% mortality rate. (5,6) Left untreated, over 70% of patients experience a recurrent bleed within one year. (7) Therefore, prevention of variceal bleeding is vitally important.

In a review of 10 randomized control trials, in which over 1,100 patients were analyzed, the use of nonselective beta blockers showed a clear benefit. (8) Overall, upper gastrointestinal bleeding was reduced by 40%. In patients with medium to large varices, it was reduced by 53%. (8,9) This data supports the use of beta blockers in a subset of patients with cirrhosis. Patients with compensated cirrhosis should have a screening esophagogastroduodenoscopy (EGD) to evaluate for varices soon after diagnosis of cirrhosis. (10) If no or only small varices are present, beta blockers are not indicated; however, an EGD should be repeated in one to two years. If medium or large varices are found, these patients should be treated with nonselective beta blockers. Patients with decompensated cirrhosis should be treated with beta blockers, as they are already at high risk for variceal bleeding and have the highest mortality if bleeding occurs. (11) Experts recommend that the dose of nonselective beta blocker be titrated up to produce a 25% reduction in the patient's baseline heart rate or until the resting heart rate is maintained between 55 to 60 beats per minute. (12)

Prophylactic endoscopic band ligation is used for patients who are not able to tolerate, or have contraindications, to beta blocker therapy. Band ligation has a similar effect to beta blockers regarding upper gastrointestinal bleeding and survival. (13) Thus, the less invasive choice of beta blockers is the preferred treatment; however, those patients who are unable to tolerate beta blockers should be treated with band ligation.

The risk of recurrent variceal bleeding is approximately 67%. (5) Given the risk of recurrent variceal bleeding and its associated morbidity and mortality, secondary prophylaxis should be instituted. Several randomized, placebo-controlled trials have demonstrated that nonselective beta blockers decrease the risk of recurrent bleeding and prolong survival. (14) The combination of nonselective beta blockers and endoscopic band ligation is more effective than either therapy alone. (15)

Ascites

Ascites is the most common complication of cirrhosis, developing in nearly 60% of all patients with compensated cirrhosis within 10 years. (16) Patients presenting with new onset ascites should undergo a diagnostic paracentesis to establish the cause of ascites and to rule out a bacterial infection. The treatment of ascites depends on the cause.

A serum-ascites albumin gradient (serum albumin concentration minus ascitic fluid albumin concentration) greater then 1.1 g/dL indicates that portal hypertension is the cause of the ascites. (17) If the gradient is less than 1.1 g/dL, other causes such as nephrotic syndrome, pancreatitis, or peritoneal carcinomatosis should be investigated.

Initial management consists of dietary sodium restriction to 1 to 2 g/d. If this fails, spironolactone is indicated at a starting dose of 50 to 100 mg once a day, titrated up to 400 mg/d. A weight loss of 0.5 to 1 kg (1-2 pounds) per day is a reasonable goal. Monitoring of serum electrolytes, urea nitrogen, and creatinine levels is indicated to avoid volume depletion and electrolyte abnormalities. If the patient continues to experience ascites despite salt restriction and spironolactone, then a second agent can be added. Furosemide is the usual second-line agent, with a starting dose of 20 to 40 mg once a day. It can be titrated up to 80 mg twice a day as electrolyte levels and renal function permit. (18)

Refractory ascites, defined as persistence despite compliance with a low-salt diet and maximum diuretic therapy, occurs in 5 to 10% of patients with cirrhosis. Greater than 50% of these patients die within two years after the onset of this condition. (19) Given the poor prognosis of refractory ascites, liver transplantation should be considered in potential candidates. Other potential options include repeated large-volume paracentesis, placement of a peritoneovenous shunt or transjugular intrahepatic portosystemic shunt. Repeated large-volume paracenteses are performed in an outpatient setting and are relatively safe, but early recurrence of the ascites is the main drawback. Placement of peritoneovenous shunts can control ascites shortly after placement, but are associated with low long-term patency rates, high rates of infection and disseminated intravascular coagulopathy. Transjugular intrahepatic portosystemic shunts provide better patency rates compared with peritoneovenous shunts, but are associated with significant hepatic encephalopathy and have significant mortality in patients with advanced liver disease. (20) Thus, treatment options are dependent on the local availability of surgical expertise and patient preference.

Spontaneous Bacterial Peritonitis

Spontaneous bacterial peritonitis (SBP) is seen in 8 to 25% of patients with cirrhosis and ascites at some time during their clinical course. (21) For patients with cirrhosis who have never had an episode of SBP and in whom the ascitic fluid protein concentration is low, the use of prophylactic antibiotics is not recommended by the International Ascites Club for prevention of an initial episode of SBP. (22) Although antibiotics will reduce the risk of a first episode of SBP, there is no beneficial effect on survival and there is an associated risk of infection with resistant organisms. However, following an episode of SBP, the one year recurrence rate without further intervention is 55% and the one year survival rate is less than 50%. (23) The International Ascites Club does recommend antibiotic prophylaxis in patients with cirrhosis who have had a prior episode of SBP. Norfloxacin at 400 mg per day reduces the rate of recurrence from 68 to 20% when compared with placebo. (24) If a quinolone cannot be used, amoxicillin-clavulanate or trimethoprim-sulfamethoxazole are acceptable alternatives. (22)

Hepatocellular Carcinoma

The incidence of hepatocellular carcinoma (HCC) in the US has doubled in the last 20 years. (25) The annual incidence of developing HCC is 1.4% in patients with compensated cirrhosis and 4% in patients with decompensated cirrhosis. (3,26) To decrease this incidence, new cases of cirrhosis must be prevented. However, once patients have cirrhosis, there is a shift from prevention of HCC to early detection. As with many cancers, early detection when the primary tumor is small and localized greatly increases survival (Table 2). (27,28) Survival is improved because patients with limited stage disease may be eligible for liver transplant or resection, which are potentially curative treatment options. Resection is the preferred treatment for patients without cirrhosis and for patients with cirrhosis and well-preserved liver function. Liver transplantation provides excellent outcomes in patients with T1 or T2 lesions (a single nodule [less than or equal to] 5 cm or 2 or 3 nodules, all [less than or equal to] 3 cm), no evidence of vascular involvement, and no extrahepatic metastasis. (29) For patients with more extensive disease, treatment options are limited.

Early detection of HCC lies in an aggressive screening plan for all patients with cirrhosis. Screening options consist of following [alpha]-fetoprotein (AFP) levels and imaging the abdomen with ultrasound, helical CT scan, or spin-echo MR. The sensitivity, specificity, and cost vary depending on the test, with helical CT scan being the most cost-effective strategy for imaging (Table 3). (30-34) Based on the current limited evidence that is available, we recommend screening all patients with cirrhosis with AFP levels and helical CT scans, MRI, or ultrasound at 6- to 12-month intervals.

Hepatic Encephalopathy

Hepatic encephalopathy is a complication of cirrhosis seen in 27 to 75% of all patients with cirrhosis depending on the mechanism of testing and the diagnostic criteria. (35,36) We recommend initiating treatment when patients develop any of the early symptoms of encephalopathy. The most common complaint is sleep disturbance, but patients may also complain of mood disturbance, speech difficulties, or disorientation. Treatment is initiated with lactulose at a dose of 30 g twice a day with titration of dose for two to three soft stools per day. (37) For patients with refractory hepatic encephalopathy despite adequate titration of lactulose, the next recommendation is to add an antibiotic such as metronidazole, neomycin, or rifaximin. Previously, aggressive protein restriction was recommended as first-line treatment, but this only worsened the nutritional status of these patients. (38,39)

Acute worsening of hepatic encephalopathy should prompt an evaluation for a precipitating cause. Reversible causes include gastrointestinal bleeding, hypovolemia, increases in protein consumption, hypokalemic metabolic alkalosis, hypoglycemia, infection (often SBP), constipation, hypoxia, or the use of sedatives. In the outpatient setting, education regarding precipitating factors and evaluation for them can help minimize the effects of hepatic encephalopathy.

Immunization 

Hepatitis A and B infections are more clinically significant when they occur in individuals with existing liver disease. In a review of over 115,000 hepatitis A cases, the fatality rate increased from 0.2% to 11.7% when the infection occurred in patients with liver disease. (40) In patients infected with both hepatitis B and C, more than 90% will develop cirrhosis (50% if only one virus) and more than 60% will develop hepatocellular carcinoma (20% if only one virus). (41)

Prevention can be accomplished with available vaccines against hepatitis A and B. Patients with compensated cirrhosis have better immunogenicity to the vaccines as compared with patients with decompensated cirrhosis. Thus, the timing of the vaccine administration is important. (42) Patients susceptible to hepatitis A and/or hepatitis B, as determined by serologic testing, should be immunized early in the disease process.

In addition, patients with cirrhosis should receive the pneumococcal polysaccharide vaccine and a yearly influenza vaccine. The pneumococcal vaccine may help prevent some episodes of SBP, as Streptococcus pneumonia is the third most common cause of SBP.

Medications and Herbal Remedies

Liver function is affected by exposure to medications and ingested substances, as it is involved in clearance, detoxification, and excretion. In general, most medications can still be given to patients with cirrhosis; however, each individual medication should be carefully evaluated. All medications should be researched for potential liver toxicity and alternatives should be considered when possible.

A commonly used group of drugs, nonsteroidal anti-inflammatory drugs (NSAIDs), should be avoided in almost all clinical situations as they present multiple problems to patients with cirrhosis. Case reports have documented hepatic injury with 10-fold increases in the transaminase levels when patients with chronic liver disease received NSAIDs. (43,44) In addition, NSAIDs inhibit platelet function which can cause bleeding in patients who may already have thrombocytopenia. Lastly, NSAIDs decrease renal prostaglandins which could result in renal failure. Patients with cirrhosis are more dependent on prostaglandin-mediated blood flow as a result of the relative decreased volume of blood flow to the kidneys. As an alternative for first line pain control, acetaminophen can be used; however, the daily dose should not exceed two grams per day. (45)

Alternative health therapies are commonly used by patients with chronic illnesses. Hepatotoxicity has been reported with some of these agents (Table 4); therefore it is important that the physician frequently inquire about any additional therapies the patient is taking. In general, we recommend avoidance of any potentially hepatotoxic alternative therapies.

Hepatorenal Syndrome

Hepatorenal syndrome (HRS) is a late complication of cirrhosis resulting in progressive kidney failure. It is classified as either type 1 or type 2 depending on the rate of progression. Type 1 HRS is defined by rapid and progressive impairment of renal function. The initial serum creatinine doubles to a level greater than 2.5 mg/dL in less than 2 weeks. Type 2 HRS is less severe renal insufficiency seen in patients with cirrhosis with a creatinine usually > 1.5 mg/dL. It is a more chronic form of HRS that is considered to be a risk factor for progression to type 1. (46)

Patients with refractory ascites have a greater risk for developing HRS with a one year incidence of 18%. If type 1 HRS develops, the median survival is less than two weeks if untreated. (47) Treatments are still evolving for type 1 HRS with the only definitive treatment being liver transplantation. Some patients have temporarily been treated with dialysis or a combination of midodrine (selective [alpha]-1 adrenergic agonist) and octreotide (somatostatin analog) as a bridge to transplant. (48) Even if transplanted, the prior history of HRS decreases overall survival after transplant by approximately 10%. (49)

In the outpatient setting, the patient's kidney function should be closely monitored. With any evidence of HRS, the patient should be referred for transplant evaluation as the presence of this syndrome is potentially an acute indication for transplant. Prevention of HRS begins with preventing infections. The incidence of one of the main precipitators of the syndrome, SBP, can be reduced with antibiotic prophylaxis, as previously discussed. In addition, avoidance of NSAIDs and hypovolemia may also help to prevent development of HRS.

Hepatopulmonary Syndrome

Hepatopulmonary syndrome (HPS) is present in 8 to 17% of patients with cirrhosis. (50) Median survival in these patients is reduced from 41 months to 11 months. (51) The pathogenesis of this syndrome is complex and there is no prevention. The only available treatment is liver transplant, which is only an option if HPS is detected early. Patients with more severe hypoxemia before transplant have increased mortality after transplant compared with those without hypoxemia. (52) Early detection allows these patients to be given higher priority for transplant and may decrease mortality.

A recent study at our institution has shown that screening patients for HPS is cost-effective. (53) All patients with cirrhosis should be screened by pulse oximetry to determine their room air oxygen saturation. If their saturation is [less than or equal to] 97%, further evaluation for HPS should be conducted with a contrast-enhanced echocardiograph (unpublished observation).

Referral for Liver Transplantation

Unfortunately, many patients will still develop medically refractory conditions that require referral for liver transplantation. The prognosis in general for patients with cirrhosis is highly variable and dependent on many factors. However, once a patient becomes clinically decompensated, prognosis is poor. The model for end-stage liver disease (MELD) score, which is used nationally to help determine priority for liver transplant, gives a predicted 3-month mortality based on a formula using laboratory values. (54) The MELD score ranges from 6 to 40; the higher the score the higher the short-term mortality rate. Calculation of a patient's MELD score can be determined at http://www.unos.org. For patients with a MELD score of less than 18, their one-year survival rate is better with their current liver than with a transplanted liver. (53) However, for scores greater than 18, one-year survival is better with a liver transplant. Thus, patients should be considered for liver transplantation once their MELD score starts approaching 15. (55)

Conclusion

Patients with cirrhosis face many potential complications. However, many of them may be prevented or treated early with a proper outpatient plan (Table 5). These patients can be managed by their primary care physicians for most of their clinical course, but a referral to a hepatologist at diagnosis is recommended. This allows the patient to establish a relationship with a physician who will play an important role in their care in the future. In addition, a complete evaluation for potentially reversible causes of cirrhosis can be completed. After an initial visit, most patients with cirrhosis should be seen by a hepatologist every one to two years.

Once there is evidence of decompensation, patients should be evaluated as soon as possible by a hepatologist. These patients usually require regular follow-up with a hepatologist. The option of transplant is becoming more available, but the demand continues to exceed the supply. This reinforces the importance of delaying or preventing the need for transplant when possible and the need to identify patients in need of transplant as soon as possible.

Using the outpatient treatment plan presented in this paper can improve the care of all patients with cirrhosis. Primary care physicians should work with a hepatologist to coordinate their patients' care to ensure that they receive the necessary screening, treatment, and evaluation for transplant. If cared for properly, these patients can have improved quality of life with or without liver transplantation.

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Ronnie E. Mathews, Jr, MD, Brendan M. McGuire, MD, and Carlos A. Estrada, MD, MS

From the Division of General Internal Medicine, Division of Gastroenterology and Hepatology, and Department of Medicine, University of Alabama at Birmingham and Birmingham Veterans Affairs Medical Center, Birmingham, AL.

Reprint requests to Brendan M. McGuire, MD, 1530 Third Avenue South, MCLM 262A, Birmingham. AL 35294. Email: [e-mail]

Brendan McGuire. Speaker's Bureau-Roche Pharmaceuticals; Research funding from Roche Pharmaceuticals, Protective Life Insurance, NIH; Consultant for Medicis Pharmaceuticals, HepaHope Inc.

Accepted February 23, 2006.

RELATED ARTICLE: Key Points

* Cirrhosis has many potential complications; however, they can be managed or detected earlier if an aggressive outpatient treatment plan is utilized.

* Esophageal variceal bleeding is the most lethal complication of cirrhosis and the risk of bleeding can be decreased with endoscopic screening and use of beta blockers and variceal ligation or banding for prophylaxis.

* Ascites is the most common complication of cirrhosis and can be treated with a combination of medications and dietary modifications.

* Patients with cirrhosis are at an increased risk of developing hepatocellular carcinoma and should be screened regularly.

Table 1. Etiologies of cirrhosis

Alcoholic liver disease
Chronic hepatitis B or C infection
Drug induced (amiodarone, methotrexate)
Autoimmune hepatitis
Nonalcoholic steatohepatitis
Cardiac/Vascular
  Right-sided heart failure
  Budd-Chiari syndrome
  Portal vein thrombosis
Metabolic
  Hemochromatosis
  Wilson disease
  Alpha-1-antitrypsin deficiency
Biliary
  Primary biliary cirrhosis
  Primary sclerosing cholangitis
  Cystic fibrosis
  Sarcoidosis

Table 2. Survival rates in hepatocellular carcinoma (27,28)

Stage                                                  Median survival

T1 -- 1 lesion <2 cm                                   48 months
T2 -- 1 lesion <5 cm or 2 or 3 lesions, largest <3 cm  37 months
T3 -- >T2 with no metastasis                           23 months
T4 -- metastatic disease                               15 months

Table 3. Comparisons of sensitivity, specificity, and cost amongst
screening options for hepatocellular carcinoma (HCC) (30-32,34)

                                                        Cost/year of
Test                Sensitivity  Specificity  Cost (a)  life saved

Alpha-fetoprotein                              $25
  >20 ng/mL         39%          76%
  >100 ng/mL        13%          97%
Ultrasound          15-65%       95-100%      $200       $22,500
Helical computed    70-90%       95-100%      $590       $14,700
  tomography
Magnetic resonance  75-95%       95-100%      $950      $101,000
  imaging

(a) Average Medicare reimbursements for the year 2000

Table 4. Hepatotoxicity in herbal remedies, vitamins, and minerals (45)

Vitamins/Minerals
  Megadose vitamin A
  Excess iron replacement
  Niacin
Teas
  Sassafras
  Bush teas (crotalaria, senecio, Heliotropium)
  Chinese herbal tea
Health tonics
  Chaparral
  Valerian
  Skullcap
Jin bu huan
Germander
Senna fruit extracts
Comfrey
Mistletoe
Pennyroyal oil
Kalms tablets
Gentian
Asafetida

Table 5. Outpatient management of cirrhosis

Complication                  Prevention/Screening            References

Esophageal variceal bleeding  Screening EGD                   (9,11,12)
                                - on presentation, then
                                  repeat based on results
                              Beta blockers
                                - use in patient with
                                  medium to large varices
Ascites                       Dietary modifications
                                - <2 grams of Na/day          (18)
                              Spironolactone
                              Furosemide
Spontaneous bacterial         Quinolone                       (23,24)
  peritonitis                   - initiate prophylaxis
                                  therapy after one episode
Hepatocellular carcinoma      Alpha-fetoprotein levels        (30-34)
                              Helical CT scan
                                - repeat yearly
Hepatic encephalopathy        Lactulose
                                - initiate when patient       (37)
                                  presents with any early
                                  symptoms
                              Evaluate for precipitating
                                causes
Infection                     Vaccines                        (40-42)
                              Hepatitis A and B
                              Influenza and pneumococcal
Hepatotoxicity                Avoid NSAIDS                    (43-45)
                              Limit acetaminophen
                              Caution with alternative
                                therapies
Hepatorenal syndrome          Monitor renal function          (46,47)
                              Prophylaxis against infections
                              Avoid NSAIDS and hypovolemia
Hepatopulmonary syndrome      Screening pulse oximetry        (50-52)
                              Contrasted echo when indicated