Cirrhosis of the Liver Part 3

Hepatopulmonary Syndrome

The hepatopulmonary syndrome (HPS), which is characterized by hypoxemia from intrapulmonary shunting, a ventilation-perfusion mismatch, or both, develops in some patients with cir-rhosis.41 Patients with HPS have no apparent parenchymal lung disease but have orthodeoxia, the unusual finding of increased hypoxemia with the change from a supine to a standing position. Other typical manifestations include exertional dyspnea, platyp-nea, and digital clubbing.42 The diagnostic workup includes arterial blood gas measurements, contrast-enhanced echocardiogra-phy, and scanning with technetium-99m-labeled macroaggregat-ed albumin. Pulmonary angiography may be necessary to detect discrete arteriovenous communications. Pharmacologic agents, such as almitrine bismesylate, prostaglandin F2a, indomethacin, somatostatin, and methylene blue, have been used to treat HPS, but results have been disappointing. Although TIPS may improve oxygenation, OLT is the only curative treatment; by 6 months after OLT, about 80% of patients with HPS have improved oxygenation.

Hepatic Encephalopathy

Hepatic encephalopathy is a syndrome observed in patients with advanced cirrhosis that is marked by personality changes, intellectual impairment, neuromuscular dysfunction, and a depressed level of consciousness.44 The pathogenesis involves altered brain-energy metabolism and increased permeability of the blood-brain barrier, facilitating the passage of neurotoxins.45 Putative neurotoxins include short-chain fatty acids, mercap-tans, false neurotransmitters (e.g., tyramine, octopamine, and phenylethanolamines), ammonia, and y-aminobutyric acid.46

The diagnosis of hepatic encephalopathy is made on the basis of altered mental status and neuromuscular signs in the absence of any specific mental or neurologic disease. Hepatic encephalop-athy is classified into five grades, according to clinical severity [see Table 4]. In addition, hepatic encephalopathy can be classified as episodic, persistent, or minimal. Minimal encephalopathy refers to patients with subtle manifestations of hepatic encephalop-athy that cannot be detected by standard clinical examination.47 Typical findings on physical examination include asterixis and fetor hepaticus. The serum ammonia level (arterial or free venous) is commonly elevated. Electroencephalography usually shows high-amplitude low-frequency waves and triphasic waves. CT scan and MRI studies of the brain may be important in ruling out neurologic diseases.

Common precipitating factors of hepatic encephalopathy include diuretic therapy, renal failure, GI bleeding, bacterial infections, and constipation. Dietary protein overload is an infrequent cause of worsening encephalopathy. Medications—no-tably opiates, benzodiazepines, antidepressants, and antipsycho-tic agents—also may worsen encephalopathy symptoms. Surgical portosystemic shunts and TIPS favor the development of en-cephalopathy. The differential diagnosis for hepatic enceph-alopathy includes intracranial lesions, central nervous system infections, metabolic encephalopathy, toxic encephalopathy from alcohol or drugs, organic brain syndrome, and postseizure encephalopathy. In the initial management of hepatic encepha-lopathy, precipitants should be identified and corrected.48 Lac-tulose, lactitol (not available in the United States), or both are helpful in patients with the acute onset of severe encephalopa-thy symptoms and in patients with milder, chronic symptoms.49 Lactulose stimulates the passage of ammonia from tissues into the gut lumen and inhibits intestinal ammonia production. The initial lactulose dosage is 30 ml orally once or twice a day. The dose is increased until the patient has two to four loose stools a day. The dose should be reduced if the patient complains of diarrhea, abdominal cramping, or bloating. In hospitalized patients with severe encephalopathy, higher doses of lactulose may be administered via either a nasogastric tube or a rectal tube.50 Neomycin (2 to 6 g/day), metronidazole (250 mg/day), rifaximin (1,200 mg/day), and other antibiotics (e.g., oral van-comycin, paromomycin, and oral quinolones) serve as second-line agents.51 Antibiotics work by decreasing the colonic concentration of ammoniagenic bacteria. Other chemicals capable of decreasing blood ammonia levels are L-ornithine-L-aspartate (available in Europe) and sodium benzoate. Low-protein diets are not recommended, because they worsen the catabolic status of these patients and may cause malnutrition. In patients with portosystemic shunts, including TIPS, shunt-diameter reduction can be considered when hepatic encephalopathy is severe and does not respond to medical therapy. Because hepatic en-cephalopathy carries a poor prognosis, patients with episodic or permanent encephalopathy should be evaluated for OLT. The specific prognosis of patients with minimal encephalopathy is still unknown.

Table 4 Grading of Hepatic Encephalopathy

Hepatocellular Carcinoma

HCC is currently the main cause of mortality in cirrhotic pa-tients.52 The annual incidence of HCC in cirrhosis from HCV is 3% to 5%. Surveillance to detect early HCC involves the use of ultrasound examination and serum a-fetoprotein measurement every 6 months. In patients with nodules smaller than 1 cm, which are malignant in less than 50% of cases, close follow-up is recommended. HCC diagnosis is based on elevated serum a-fe-toprotein levels, ultrasonography, helical CT and MRI findings, and positive cytohistology. The prognosis in patients with early-stage HCC depends on tumor status, liver function, and the treatment applied. Different staging systems (e.g., Barcelona Clinic Liver Cancer [BCLC] or Okuda) use tumor characteristics and liver function to classify patients with HCC.53 Unfortunately, many HCC patients are diagnosed at advanced stages of disease that preclude the use of curative treatments. The 3-year survival rates of patients at intermediate and advanced stages of HCC are 65% and 16%, respectively. Curative treatments for HCC include surgical resection, OLT, and percutaneous ablation. In well-se-lected patients, resection and OLT achieve the best outcomes, with 5-year survival rates of 60% to 70%, whereas 5-year survival rates with percutaneous treatments are only 40% to 50%. Transplantation is the ideal treatment for patients with one tumor and decompensated cirrhosis or multicentric small tumors.54 Arterial embolization may improve quality of life and, in some cases, even increase survival. Tamoxifen does not seem to have a significant beneficial effect.

Table 5 Indications for Liver Transplantation

Indications for Liver Transplantation

OLT is a central tool for the management of advanced cirrho-sis.55 In the United States, more than 3,000 liver transplants are performed each year. However, because there are many more candidates for transplantation than there are available donor livers, the selection and timing of patient referral are critical. The general indications for OLT are broadly categorized as clinical and biochemical [see Table 5]. Biochemical indexes vary, depending on whether liver disease is caused by hepatocellular conditions or chronic cholestatic disorders. Patients should be referred for transplant workup if the serum bilirubin level is greater than 3 mg/dl in noncholestatic disease or greater than 5 mg/dl in cholestatic disorders; if the prothrombin time is prolonged by more than 5 seconds; or if the serum albumin level is below 2.5 g/dl. Clinical criteria include HCC, hepatic encephalopathy, refractory ascites, recurrent variceal bleeding, SBP, and intractable pruritus. The clinical complications of cholestatic liver disease, such as intractable pruritus, recurrent bacterial cholangitis, and progressive bone disease, often warrant liver transplantation before hepatic encephalopathy or variceal hemorrhage develops. HCV-infected patients with decompensated cirrhosis awaiting OLT can be treated with pegylated interferon plus ribavirin; in these patients, treatment can be initiated several months before OLT to prevent graft reinfection.

Contraindications for OLT include severe cardiovascular or pulmonary disease, active drug or alcohol abuse, malignancy outside the liver, sepsis, or psychosocial problems that may jeopardize a patient’s ability to follow medical regimens after transplantation. The presence of HIV infection was considered a contraindication to transplantation, but successful liver transplantations are now being performed in patients in whom antiretroviral therapy has eliminated any detectable HIV viral load. Additional clinical study is required before OLT can be offered routinely to such patients.

In the United States, the Model for End-Stage Liver Disease (MELD) is the scoring system used by most liver transplant centers for determining priority for OLT.57 MELD relies primarily on the bilirubin level, INR, and creatinine level to determine a patient’s risk of dying within 3 months if OLT is not performed.58 Patients’ scores are calculated continuously while they are on the waiting list for OLT. Scores typically range from 6 (less ill) to 40 (gravely ill). A MELD calculator is available on the Internet (http://www.unos.org/resources/MeldPeldCalculator.asp? index=98).

Advances in surgical technique, organ preservation, and im-munosuppression have resulted in dramatic improvements in postoperative survival over the past 2 decades.59 In the early 1980s, 1-year and 5-year survival after liver transplantation were only 70% and 15%, respectively; the current rates are 85% and more than 70%. In most cases, patients can anticipate a good quality of life after liver transplantation.

Approximately 15% of patients listed as candidates for liver transplantation die before a donor organ becomes available. Strategies to improve the current donor organ shortage include programs to increase public awareness of the importance of organ donation, increased utilization of living-donor liver transplantation for pediatric recipients, and exploration of the efficacy and safety of living-donor liver transplantation in adults.60

Prognosis

The prognosis of patients with cirrhosis depends on the underlying disease, the occurrence of major complications (i.e., ascites, GI bleeding, encephalopathy, HRS, or bacterial infections), the degree of liver insufficiency, and the existence of HCC. In patients with compensated cirrhosis, the 10-year probability of major clinical complications is 58% and that of survival is 47%. For patients with decompensated cirrhosis, prognosis can be estimated by the older Child-Pugh classification and by the MELD score.61 The variables included in the Child-Pugh score reflect the synthetic (albumin and prothrombin time) and elimination (bili-rubin) functions of the liver, as well as major complications (as-cites and encephalopathy). In contrast, the MELD score includes only numeric variables that reflect liver function (INR and biliru-bin level) and renal function (creatinine level). The principal advantages of the MELD score are that it is based on objective variables selected for their influence on prognosis and that continuous recalculation helps in scoring individuals more precisely among large populations.58 However, the MELD score has not been validated in some clinical situations. For example, in patients with type 1 HRS, the MELD score may underestimate survival.