Monitoring and Care

Routine Examination, Prophylaxis, and Immunization

Although the life-threatening complications of end-stage liver disease require a higher acuity of care and even lifesaving procedures, the general medical care of these patients should not be overlooked. Close follow-up of these patients is a must. The Model for End-Stage Liver Disease (MELD) is a useful tool that estimates the mortality of patients awaiting LT. It was implemented on February 26, 2002, by UNOS as the criterion for organ allocation in patients with chronic disease awaiting LT. Its implementation has been associated with an initial reduction in LT waiting list registrations and a drop in the number of deaths on the waiting list. As limitations to the use of the MELD score have been defined, several proposals to modify the MELD score have been communicated. Hyponatremia has been associated with a higher mortality risk independently of the MELD score ; this effect was more pronounced among patients with a lower MELD score. A modified model called MELD-Na has been proposed as a more valid measure of LT priority. A limitation in the use of a MELD-Na–based allocation policy has been the concern that serum sodium may be subject to laboratory variation and manipulation.

MELD predicts candidate mortality at different time points with adequate accuracy. For practical purposes the score is capped at 40, a point at which patients have virtual 100% mortality in 3 months. UNOS has made adjustments to the MELD score to compensate for the increased mortality from advancing disease in patients with small hepatocellular carcinoma (HCC) with long waiting time. The HCC patients who fulfill the so-called Milan criteria get a priority MELD score beyond their degree of hepatic compensation. Patients with stage T2 HCC (one lesion ≥ 2 cm but ≤ 5 cm or two or three lesions ≥ 1 cm and ≤ 3 cm) may be registered at a MELD score equivalent to a 15% probability of candidate death within 3 months. This level of compensation differs based on UNOS regional variations, and the impact of such an adjustment, despite several modifications over time, continues to stir strong discussion in the field.

Once patients are listed for LT, MELD maintenance requires regular visits to the transplant clinic ( Table 36-1 ). The frequency with which a patient should be monitored in clinic is based upon the MELD score. MELD scores of 10 or less warrant visits every 6 months to a year, whereas patients with MELD scores of 11 to 18 should be seen every 3 months, those with MELD scores of 19 to 24 should be seen monthly, and patients with MELD scores of 25 or higher should be evaluated weekly. These visits should be used not only to update the parameters used for MELD scoring but also to assess electrolyte levels, complete blood count, and coagulation profile. As with all cirrhotic patients, assessment of subclinical portosystemic encephalopathy, ascites, and peripheral edema are mandatory. If patients have been prescribed β-blockers, blood pressure and pulse measurements should be performed with the goal of adjusting medications optimally. Screening for HCC should be done with serum α-fetoprotein and abdominal triphasic computed tomography scan or magnetic resonance imaging. Select populations, including those with viral hepatitis B and C, hemochromatosis, and alcoholic liver disease, may warrant a more aggressive schedule because of elevated risk for HCC.

Vaccinations for hepatitis B virus (HBV) and hepatitis A virus (HAV) have significant value. Vento et al reported that fulminant hepatitis is associated with hepatitis A superinfection in chronic hepatitis C patients and recommended that these patients should be immunized for hepatitis A. Recent publications show that hepatitis A and B vaccination rates in adult patients with chronic liver diseases remain low. The vaccination rates in this patient population range between 20% and 30%.

Patients who do not have antibodies to the HBV surface antigen (HBsAg) should receive a complete vaccination schedule at the beginning of their evaluation. The response rate to these vaccines is also decreased among patients with decompensated cirrhosis. In view of a lower response rate, follow-up anti-HBsAg antibody levels should be obtained after the second injection. The final injection of the series, given 6 months after the first one, should be given even if the LT has already been performed. In addition to hepatitis A and B vaccination, these patients should also receive influenza vaccine yearly and pneumococcal vaccination (0.5 mL intramuscularly) every 5 years. Influenza vaccination has been shown to decrease influenza-related complications, including hepatic decompensation, in cirrhotic patients. Pneumococcal vaccination is recommended for cirrhotic patients because Streptococcus pneumoniae infections are more severe and accompanied with an increased fatality rate. Tuberculin skin testing should be done yearly. The introduction of interferon-γ release assays may improve the detection of latent tuberculosis in patients with more advanced liver disease.

Screening for breast, endocervical, colorectal, and prostate cancer should be performed as in other medical patients. A comprehensive ear, nose, and throat evaluation should be done in alcoholics with history of tobacco use because of their increased nasopharyngeal cancer incidence.

Hepatitis B Virus

In HBV-related cirrhosis, antiviral therapy should be considered if HBV replication is present. Successful antiviral therapy with viral clearance may stop disease progression, reverse clinical manifestations of hepatic decompensation, and decrease significantly HBV recurrence after LT. Fontana et al reported the outcome of lamivudine therapy in 309 patients awaiting LT for chronic hepatitis B; lamivudine did not improve the overall pre-LT survival or LT-free survival. Moreover, their data suggest that a subset of patients with less advanced liver failure may derive clinical benefit from lamivudine treatment, thus delaying the need for LT. Adefovir therapy has also been associated with beneficial effect among pre-LT patients as well as post-LT recurrence. A vexing problem has been the need to keep treatment with nucleos(t)ides long term or indefinite to accomplish viral suppression. This long-term therapy has been accompanied by the emergence of resistant strains of HBV.

Recently the combination of entecavir plus tenofovir has been used as a rescue therapy in pretreated patients with chronic HBV. Fifty-seven patients who had previously received a median of three antiviral therapies were treated with entecavir plus tenofovir; 51 of 57 patients became HBV-DNA undetectable. The viral suppression was also associated with a 23% drop in alanine aminotransferase levels. There were no serious side effects associated with this combination therapy. This is a promising study that will have to be expanded to be able to reach more definitive conclusions. Seven drugs are now approved for treatment of chronic hepatitis B by the Food and Drug Administration (FDA): interferon alfa-2b, pegylated interferon alfa-2a, lamivudine, adefovir, entecavir, telbivudine, and tenofovir. Patients with compensated cirrhosis and evidence of HBV replication should be treated preferentially with nucleos(t)ides because of the possibility of serious hepatic decompensation associated with flares related to interferon-α. Entecavir and tenofovir are the preferred drugs in this setting because of high intrinsic barriers to resistance. Combination therapy should be considered in patients with decompensated disease and with a high probability of resistant HBV strains.

Hepatitis C Virus

The treatment of chronic HCV has been revolutionized by the approval of two direct antiviral agents (DAAs), telaprevir and boceprevir. These two DAAs are inhibitors of the HCV nonstructural protein 3/4A (NS3/4A) serine protease. Both agents have been approved by the FDA for chronic HCV infection with genotype1. Patients with compensated cirrhosis should complete therapy for 48 weeks when treated with telaprevir or boceprevir, following FDA-approved directions. Therapy consisting of pegylated interferon, ribavirin, and one DAA has not been evaluated in decompensated cirrhotic patients; use in this specific patient population has to be done carefully and only in the context of a clinical trial and with the patient approved for LT.

Treatment of HCV in the setting of decompensated cirrhosis using interferon alpha-interferon has been fraught with serious and sometimes lethal complications and should not be done outside a clinical trial by experienced clinicians.

Everson et al have proposed a low accelerating dosage regimen (LADR) of interferon and ribavirin in patients with decompensated cirrhosis. Forty seven of 124 patients who were placed in LADR underwent LT; 22 of these patients had an end-of-treatment response. Fifteen patients were HCV RNA negative before LT; 12 of them remained negative for at least 6 months after LT.

Genetic polymorphism in the region of the IL28B gene on chromosome 19 has been found to be associated with sustained viral response among patients infected with HCV genotype 1. This polymorphism has also been associated with spontaneous HCV clearance and severity of histological recurrence and treatment response following LT. Recipient and donor TT genotype was associated with more severe histological recurrence of HCV after LT. The authors suggested that CC donor livers could be preferentially allocated to recipients infected with HCV.

Hemochromatosis

The practice guidelines from the American Association for the Study Liver Diseases (AASLD) state that all patients with hereditary hemochromatosis and evidence of iron overload should be strongly encouraged to undergo regular phlebotomies until iron stores are depleted. Phlebotomies should be continued for life with the frequency of maintenance therapy determined by the serum ferritin level. Patients with hereditary hemochromatosis have a 20-fold relative risk for developing HCC; therefore regular screening for HCC is recommended. Screening of first-degree relatives with iron studies and hemochromatosis mutation analysis is recommended for early diagnosis and prevention of complications.

Primary Biliary Cirrhosis

All patients with primary biliary cirrhosis (PBC) with abnormal liver enzyme levels should be considered for specific therapy. Ursodeoxycholic acid (UDCA) treatment is associated with a marked improvement in serum biochemical markers of cholestasis (bilirubin, alkaline phosphatase, and γ-glutamine transferase). Although not a cure for PBC, treatment with UDCA slows the progression of disease, improves survival, and decreases need for LT. The recommended dosage for UDCA is 13 to 15 mg/kg, usually in divided doses.

Osteopenia, with progression to osteoporosis, is a well-known complication of PBC, with a relative risk of 4.4. Both decreased osteoblastic activity and increased osteoclastic activity contribute to the development of osteoporosis in PBC patients. Patients with PBC should have bone mineral density testing at the time of diagnosis, with screening every 2 to 3 years thereafter. Calcium (1000 to 1500 mg/day) and vitamin D (1000 International Units/day) supplementation should be considered for postmenopausal women and anyone with osteopenia, and vitamin D levels should be checked annually. Bisphosphonate therapy is recommended for patients with osteoporosis; patients with advanced fibrosis and cirrhosis should first have upper endoscopy to exclude esophageal varices.

Primary Sclerosing Cholangitis

Unlike PBC, there is currently no specific medical therapy for primary sclerosing cholangitis (PSC). At the dose of 13 to 15 mg/kg/day, UDCA failed to slow the progression of disease. A trial using high-dose UDCA (28 to 30 mg/kg/day) was stopped early when the treatment arm showed higher rates of death and need for LT. The AASLD practice guidelines currently recommend against the use of UDCA in PSC. Other agents, including steroids, immunosuppressants, antimetabolites, and tumor necrosis factor-α antagonists, have failed to demonstrate improvements in disease activity or outcomes and are not recommended for treatment of PSC.

Cholangiocarcinoma (CCA) is the most feared complication of PSC. The incidence of CCA is 7% to 9% over 10 years in patients with PSC, and the development of this malignancy portends a dismal prognosis. Surgical resection should be considered in patients with limited disease, although survival after resection remains low. LT for early-stage hilar CCA is now performed at selected institutions, with overall 5-year survival of 70%. Transplantation for CCA occurs only in a highly selected group of patients meeting a strict diagnostic and therapeutic protocol; therefore potential candidates should be seen at a transplant center as soon as possible to maximize their candidacy (biopsy of the primary lesion, for example, excludes the patient from transplantation).

The differentiation between benign and malignant biliary strictures remains a challenge, complicating the diagnosis of CCA. Any patient with clinical or biochemical deterioration should be evaluated for CCA. The tumor marker CA 19-9 level is elevated in up to 85% of patients with CCA. A cutoff of 130 units/mL yields a sensitivity of 79% and specificity of 98%. However, the CA 19-9 level can also be elevated in the presence of cholangitis, which occurs frequently in patients with PSC and extensive biliary strictures. Positive results of cytologic studies on biliary brushings have a specificity of 100%; however, the sensitivity is limited to 18% to 40%. The addition of fluorescent in situ hybridization (FISH) may increase the sensitivity of conventional cytologic examination. The role of [ ¹⁸ F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) in the diagnosis of CCA has not yet been determined, and clinicians need to be aware that inflammation can cause false-positive results. Despite the clinical concern for the development of CCA, formal surveillance protocols have not been endorsed by the major hepatology societies. Annual surveillance with imaging and CA 19-9 is reasonable for most patients. Because of an elevated risk for gallbladder cancer, an annual ultrasound examination is recommended in all patients with PSC.

The majority of patients with PSC also suffer from inflammatory bowel disease, predominantly ulcerative colitis (UC). Compared to patients with UC alone, patients with PSC and UC have an increased risk for colorectal cancer and dysplasia, with an odds ratio of 4.79. Some retrospective studies have suggested a chemoprotective effect of UDCA in patients with PSC and UC; however, this finding is not universal. Furthermore, high-dose UDCA is associated with adverse outcomes in PSC. Routine use of UDCA for chemoprophylaxis in patients with PSC and UC is not recommended. Surveillance colonoscopy with biopsies every 1 to 2 years is advised.

Autoimmune Hepatitis

Autoimmune hepatitis (AIH) can present with severe hepatic decompensation, prompting urgent evaluation for LT. With appropriate therapy, many patients will have stabilization of liver disease and may not require transplantation. Approximately 25% of patients with AIH will have cirrhosis at the time of diagnosis, and LT may be warranted. Patients with inactive, or “burned-out” AIH with normal liver enzyme levels do not need therapy. For patients with active disease the standard treatment includes corticosteroids with or without azathioprine; 80% of patients will respond to treatment. Although patients with cirrhosis and active disease are likely to respond to treatment, they are more likely to experience treatment-related side effects, especially cytopenia, compared to patients without cirrhosis. Although none have been tested in randomized trials, multiple options exist for patients who cannot tolerate azathioprine, including mycophenolate mofetil, cyclosporine, tacrolimus, and rituximab.

Portal Hypertension

Portal hypertension is the main complication of liver cirrhosis. This syndrome develops in the majority of patients with cirrhosis and is responsible for most life-threatening complications of cirrhosis, including gastrointestinal bleeding from ruptured gastroesophageal varices, hepatorenal syndrome, and hepatic encephalopathy (HE). The management of these complications in the LT candidate will be discussed in detail.