Outpatient management of cirrhosis.

Cirrhosis is an advanced stage of liver disease caused by a variety of insults to hepatic parenchyma including infections, autoimmune processes, genetic disorders and toxins. It is characterized by extensive fibrosis with nodule formation and interruption of normal hepatic blood flow. The major complications of cirrhosis are ascites, gastroesophageal varices-related bleeding, hepatic encephalopathy, hepatorenal syndrome and hepatocellular carcinoma (HCC). Therefore, ultimate treatment of decompensated cirrhosis is liver transplantation. Hence, cirrhotics with the above complications should be referred to a hepatologist at a liver transplant center for transplant evaluation and possible listing for liver transplant. Some of the complications such as variceal bleeding and refractory ascites require hospitalization and inpatient treatment, but many of the complications can be managed on an outpatient basis. Proper outpatient care decreases the number of hospitalizations leading to decreased morbidity and mortality until the patient receives liver transplant. Cirrhotics without any complications are usually managed by screening for HCC and periodic measurement of liver tests, including coagulation profiles, until the development of complications. Abstinence from alcohol is imperative even if the cirrhosis is not a result of alcohol. Other hepatotoxins and nonsteroidal anti-inflammatory drugs should also be avoided. Acetaminophen up to 2 g/d may safely be used in most cirrhotics for pain control.

Ascites is the most common complication of cirrhosis, which is the result of portal hypertension. There is no evidence that fluid removal improves survival, but patients feel better and it may also protect against bacterial infection of ascitic fluid. (1) It also decreases the amount of energy wasted in heating the fluid and reduces the risk of cellulites and chances of hernia formation or diaphragmatic rupture associated with tense ascites. (2) The dietary sodium restriction and diuretics with a goal weight loss of 0.5kg/d-1 kg/d (if peripheral edema is present) is the usual treatment. Higher weight loss may lead to an increased intravascular volume loss since the absorptive capacity of the peritoneal membrane is about 300 to 500cc/d. Small bowel dysmotility and bacterial overgrowth have been documented to be related to spontaneous bacterial peritonitis (SBP). A recent study has shown that the addition of a prokinetic agent, cisapride, to the prophylactic regimen of norfloxacin reduces the incidence of SBP in high-risk cirrhosis patients. (3) However, safety, efficacy and long-term data on cisapride among cirrhotic patients are lacking. Therefore, due to potential cardiotoxicity, the prophylactic use of cisapride for SBP is not recommended at present time. Cirrhotics who develop SBP should be admitted to the hospital and treated with IV antibiotics and albumin since addition of albumin decreases the short-term mortality-related renal insufficiency. (4) Hypokalemia should be avoided since it can increase renal ammonia production and precipitate hepatic encephalopathy.

Variceal bleeding is the major cause of morbidity and mortality in patients with liver cirrhosis. Each episode of bleeding carries a 30% risk of mortality. (5-6) In cirrhosis, elevated portal pressure results from a combination of increased portal inflow due to splanchnic arteriolar vasodilatation and elevated resistance to outflow through distorted hepatic sinusoids. Varices develop in response to portal hypertension to decompress the portal vein and return blood to systemic circulation. All patients with cirrhosis should undergo diagnostic endoscopy to document the presence of varices and to determine their risk of variceal hemorrhage. (7) Propranolol or nadolol can be recommended for primary prophylaxis of variceal bleeding. Multiple studies have shown that endoscopic variceal ligation (EVL) is as good as nonselective [beta]-blockers for primary prophylaxis of esophageal variceal bleeding without having an increased risk for complications. (8-9) However, EVL has been recommended for high-risk patients who are intolerant to [beta]-blocker therapy due to side effects such as dizziness, hypotension, fatigue, sexual dysfunction, bronchoconstriction and heart failure, considering the invasive nature of EVL. Furthermore, whether there is a benefit of adding [beta]-blockers to patients who have undergone EVL for primary prophylaxis has not been well studied, but EVL may be considered in high risk patients who can tolerate [beta]-blocker therapy.

Hepatic encephalopathy (HE) results from portosystemic venous shunting. In addition to accumulation of ammonia, various other mechanisms such as the production of false neurotransmitters, activation of central [gamma]-aminobutyric acid--benzodiazepine receptors by ligands of endogenous origin, altered cerebral metabolism, zinc deficiency, deposition of manganese in the basal ganglia and disturbed activity of Na+/[K.sup.+][+ or -]ATPase, have been implicated in the pathogenesis of HE. (10-16) Management of HE includes treatment of the precipitating cause and oral lactulose titrated to produce 2 to 3 bowel movements per day. Currently, rifaximin is often used for HE in cirrhotics who are intolerant to lactulose due to an increased frequency of diarrhea, dehydration, abdominal distention and bloating. (17) However, further studies are needed to document a long-term safety and efficacy of rifaximin. In difficult to control cases, neomycin and/or metronidazole can be used to decrease colonic bacteria in an attempt to decrease ammonia production leading to improvement of HE. However, long-term neomycin use is not recommended due to an increased risk for ototoxicity and nephrotoxicity.

Hepatorenal syndrome (HRS) results from extreme underfilling of the arterial circulation that is secondary to severe vasoconstriction of renal circulation. The HRS may be diagnosed after the nonfunctional causes of renal failure are ruled out. (18) The prognosis of HRS is poor, but vasopressin analogues and [alpha]-adrenergic agents in combination with albumin may be effective in approximately two-thirds of patients for a short-term period. (18-24) This treatment may act as a bridge to liver transplantation.

Hepatopulmonary Syndrome (HPS) is considered when patients have a triad of liver disease, increased arterial-alveolar gradient while breathing on room air, and evidence of intrapulmonary vascular abnormalities. The pathophysiology of HPS includes V/Q mismatch, intrapulmonary shunting and limitation of oxygen diffusion. These effects are caused by failure of damaged liver to clear circulating vasodilators and inhibition of circulating vasoconstrictors. Proposed factors in the pathogenesis of HPS include nitric oxide, prostaglandins, vasoactive intestinal polypeptide (VIP), calcitonin, tyrosine, serotonin, and endothelin. A variety of different agents and techniques such as methylene blue (nitric oxide inhibitor), sympathicomimetic agents, somatostatin analogues, exchange plasma pheresis and physical occlusion of intrapulmonary vascular dilatations have been employed in attempts to treat HPS, although none should be recommended for use at present. (25-26) Liver transplantation appears to be most promising for patients with severe and refractory hypoxemia, but time course for resolution of HPS after transplantation is variable.

Cirrhosis is a major risk factor for the development of HCC. Generally, serum [alpha]-fetoprotein (AFP) and ultrasound of liver (US) are recommended at six-month intervals to screen for HCC. However, serial triphasic CT scan of abdomen showing an enhancing lesion during arterial phase is considered sufficient evidence for hepatocellular carcinoma, especially if the serum [alpha]-fetoprotein level exceeds 500 ng/mL. (27) MRI of the abdomen can also be used as a screening tool in selected patients where CT scan is not possible or contraindicated. Treatment options for HCC include curative treatment with liver transplantation, hepatic resection and radiofrequency ablation depending upon the stage of HCC. Liver transplantation is considered if there is one lesion <5 cm or up to 3 lesions <3 cm. Therefore, patients with HCC should be promptly referred to a liver transplant center. However, advanced lesions are palliatively treated with chemoembolization, percutaneous ethanol injection, radiofrequency ablation, chemotherapy and radiotherapy as recommended by hepatologists and oncologists depending upon the stage of HCC.

In conclusion, management of ascites, HCC and HE, prophylaxis for SBP and gastroesophageal varices along with timely referral to a transplant center are the most important factors of outpatient care. These patients should be followed by primary care physicians and/or hepatologists at 3 to 6 month intervals, or more frequently depending upon the complications associated with cirrhosis. Imaging and lab work should be done on follow-up visits. Patient education is also a vital part of outpatient care to improve clinical course in cirrhotics.

References

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When fascism comes to America, it will be wrapped in the flag and
carrying the cross.
--Sinclair Lewis

Adeel B. Shibli, MD, Allan Tachauer, MD, and Smruti R. Mohanty MD, MS

From the Department of Internal Medicine, Weiss Memorial Hospital, and the Section of Gastroenterology, Department of Medicine, Center for Liver Diseases, The University of Chicago, Chicago, IL.

Reprint requests to Smruti R. Mohanty, MD, MS, Assistant Professor of Medicine, The University of Chicago, Department of Medicine, Section of Gastroenterology, Center for Liver Diseases, 5841 S. Maryland Avenue, MC 7120, Chicago, IL 60637. E-mail: [e-mail]

Accepted January 25, 2006.