Primary Biliary Cirrhosis PBC

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PBC has a relatively predictable natural history and accurate prognostic models. The most important variable, common to all prognostic models, is the serum total bilirubin level. Shapiro et al. (Gut, 1979;20:137-145) reported that patients with PBC typically have a long and stable course, followed by an accelerated preterminal phase of hyperbilirubinemia, with a mean survival time of 1.4 years in patients with bilirubin of more than 10 mg/dL. The Mayo Clinic PBC

survival model is based on patients' age, total serum bilirubin and serum albumin concentrations, prothrombin time, and severity of edema. These prognostic models have aided clinicians' decision-making process regarding optimal timing of LT, but they do not take into account fatigue, pruritus, or severity of bone disease in PBC. These complications must be taken into account separately when considering LT timing for patients with PBC. Nevertheless, these patients tend to have the highest levels of postoperative survival, with little risk of recurrent PBC after LT.

1.2.3. Primary Sclerosing Cholangitis (PSC)

PSC is a chronic cholestatic disease characterized by obliterative fibrosis of the bile ducts, leading to biliary cirrhosis and liver failure. Survival models have been developed based on such variables as age, serum bilirubin, histologic stage, and presence or absence of splenomegaly. The natural history of this disease includes recurrent cholangitis, progressive jaundice, or cholangiocarcinoma. The latter complication is an absolute contraindication for LT.

Besides offering potential therapeutic benefits, endoscopic retrograde cholangiopancreatography (ERCP) with biopsy and brushing of the biliary tract radicles is a common screening tool for cholangiocarcinoma. Early enthusiasm about CA 19-9 antigen and other serum tumor markers for cholangiocarcinoma has diminished following reports of poor sensitivity and specificity. Because of the risk of cholangiocarcinoma, patients with PSC should be referred early for LT.

1.2.4. Chronic Viral Hepatitis

Chronic viral hepatitis is one of the most common causes of end-stage liver disease, and this is reflected in the number of patients referred for LT. A better understanding of the mechanism of viral replication and of viral transmission has led to improved results with LT for patients with end-stage liver disease caused by viral hepatitis. Patients with hepatitis fi-related liver disease (HBV) that are HBV-DNA negative can expect excellent survival after LT. Patients with hepatitis D virus (HDV) infection who are HBV-DNA negative can also expect an excellent survival rate. HBV-DNA-positive patients may patients may benefit from the addition of lamivudine to the prophylactic regimen both before and after LT. Lamivudine has proven to be effective in the treatment of both de novo and recurrent HBV infection after LT. However, viral resistance can develop.

Cirrhosis due to hepatitis C virus (HCV) infection is now the most common indication of LT in Western Europe and the United States. Although recurrent HCV infection was suspected to be the cause of posttransplant hepatitis in many of these patients, the actual incidence of reinfection was indeterminate until the development of polymerase chain reaction (PCR) tests for HCV in the early 1990s. It has become clear that graft reinfection is universal after LT for HCV. Recent data show that, despite universal reinfection of recipients, 5-year actual survival rate does not seem to be affected by the presence of HCV infection. However, liver biopsies may reveal an increased incidence of chronic hepatitis and cirrhosis in patients transplanted for HCV infection. An aggressive, acute cholestatic hepatitis can occur in 4-6% of patients transplanted for HCV within 6 months after LT. These patients inevitably will need retransplantation, but their overall post-LT prognosis is poor. Prognostic indicators have not been clearly delineated to determine which patients will do poorly after LT due to severe recurrence of HCV infection. One factor that is now widely accepted is an infected graft with HCV genotype 1. HCV+ donor to HCV + recipient does not seem to be a predictive factor at this time. Post-LT therapy for HCV infection is investigational at this time, and trials with combination alpha-interferon and ribavirin are presently under way. However, a second LT for HCV-related allograft failure can be performed safely in patients, if performed before the onset of liver failure or other organ system failure.

1.2.5. Alcoholic Liver Disease

Alcohol abuse is the most common cause of liver disease, and the extent of application of LT to alcoholic liver disease remains controversial. Available evidence suggests that, among selected alcoholics, survival after LT up to 3 years is comparable to that of nonalcoholic patients. Cost analyses in North American transplant centers also suggest that resource utilization by alcoholic recipients is essentially the same as that by nonalcoholic recipients. A recent study from France (Gut 1999;45:421-426) concluded that LT can be successful in alcoholic cirrhosis, and that recidivism did not affect survival or compliance with immunosuppressive regimen. However, this area is still controversial. At present, most centers require 6 months of documented sobriety, psychosocial evaluation, completion of a rehabilitation program, and appropriate social support systems in place, before a candidate is accepted for LT.

1.2.6. Hepatic Malignancy

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. Surgical resection is an effective treatment for highly selected patients with HCC. Unfortunately, fewer than 30% of tumors are resectable. In selected patients with unresectable HCCs (single lesion =£ 5 cm; or =s three lesions, each =s 3 cm), survival rates of 75% four years after LT have been reported (Annals of Surgery

1994;279:236-247). A recent study (New England Journal of Medicine 1996; 334:693-699) comparing hepatic resection with LT in cirrhotic patients with HCC concluded that, in the face of severe organ shortage, HCC carcinoma developing in a well-compensated cirrhotic liver initially may be treated with hepatic resection, and LT should be applied selectively to patients with tumor recurrence and/or progressive liver failure. Long-term evaluation of adjuvant chemotherapy, including preoperative hepatic artery chemoembolization and postoperative chemotherapy, will further define the optimal approach.

1.3. UNCOMMON INDICATIONS FOR LIVER TRANSPLANTATION

LT has been successfully utilized as a therapeutic modality for numerous uncommon indications (Table 1.1). Because the products of hepatic synthesis permanently retain the metabolic specificity of the donor, patients with congenital enzyme deficiencies and other inborn errors of metabolism can be cured by LT. The cure afforded by LT is functional and phenotypic, not genetic.

Metabolic disorders considered for hepatic LT fall into two broad categories. Diseases not associated with any evidence of clinical or histologic hepatic injury include defects of the urea cycle, familial homozygous hypercholesterolemia, and primary hyperoxaluria. The other category consists of metabolic diseases dominated by hepatocyte injury, such as Wilson's disease, tyrosinemia, alpha-1-

TABLE 1.1. Uncommon Indications for Liver Transplantation

MeIabolie and genetic deficiencies

Other

Alpha-1-antitrypsin deficiency

Familial hypercholesterolemia

Wilson's disease

Hemochromatosis

Primary hyperoxaluria

Protoporphyria

Crigler-Najjar syndrome

Urea cycle deficiencies

Glycogen storage disease

Lysosomal storage diseases

Tyrosinemia

Galactosemia

Hemophilia A and B

Cystic fibrosis

Protein C. S deficiencies

Amyloidosis Sarcoidosis

Budd-Chiari syndrome Veno-oeclusive disease Severe graft-vcrsus-host disease Hepatic adenoma Polycystic liver disease Alagilie syndrome Hepatic trauma sourck: Rosen HR, Shackleton CR, Martin P. Indications for and timing of LT. Medical Clinics of North America 1996;80(5):1069-1102.

antitrypsin deficiency, and several types of glycogen storage disease. In contrast to other nonmetabolic liver diseases for which LT is performed, there is no risk of disease recurrence, and 5-year survival rates of 75% have been reported. Other systemic diseases for which LT has been performed include Alagille syndrome (arteriohepatic dysplasia), amyloidosis, sarcoidosis, cystic fibrosis, and severe polycystic disease.

1.4. CONTRAINDICATIONS TO LIVER TRANSPLANTATION 1.4.1. Absolute Contraindications

As LT has evolved, the list of absolute contraindications to LT has been refined, whereas the list of indications has expanded. Absolute contraindications (Table 1.2) make the outcome of LT unsatisfactory to the point that it should not be offered. Patients with human immunodeficiency virus (HIV) infection are generally excluded from consideration for LT. LT shortens the interval to development of acquired immunodeficiency syndrome (AIDS), and the majority of deaths post-LT in HIV-positive patients are related to complications of AIDS. Extrahepatic malignancy is also a contraindication for LT. Results of LT are so poor for patients with cholangiocarcinoma that most centers consider this malignancy an absolute contraindication.

Active alcohol or illicit drug use is an absolute contraindication to LT. At present, most centers require abstinence for 6 months before considering such patients for LT. Patients undergo psychosocial evaluation as part of their transplant

TABLE 1.2. Absolute Contraindications to Liver Transplantation (LT)

HIV seropositivity Extrahepatic malignancy Cholangiocarcinoma Hemangiosarcoma Active sepsis

Active alcoholism or subs lance abuse

Fulminant hepatic failure Willi sustained 1CP > 50mm Hg or CPP < 40mm H g

Advanced cardiac or pulmonary disease

Inability to comply with immunosuppression protocol

Anatomic abnormalities precluding I.T

CPP = cerebral perfusion pressure (mean arterial pressure minus ICP); HIV = human immunodeficiency virus; ICP = intracranial pressure source: Rosen HR, Shackleton CR, Martin P. Indications for and timing of LT. Medical Clinics of North America 1996;S0(5):1069-1102.

evaluation, primarily to identify adequate support systems to ensure that rehabilitation will be durable after discharge, and that compliance with medical care is maintained. Whether a patient should be excluded from LT because of advanced cardiac or pulmonary disease usually rests on the consensus of consulting specialists as well as members of the transplant team. Coronary artery disease, if mild or corrected by bypass surgery or angioplasty, is not a contraindication provided that left ventricular function is adequate. Advanced chronic obstructive lung disease or pulmonary fibrosis precludes LT. Following reports of improvement in arterial after LT, hepatopulmonary syndrome has become an indication rather than a contraindication.

It is important that the LT candidate be free of active infection before LT and onset of immunosuppression. This is particularly so because of the extensive upper abdominal surgery, multiple vascular and biliary anastomoses, prolonged period of anesthesia, and frequent need for extended ventilatory support in these patients. Serious chronic infectious diseases, such as osteomyelitis, chronic fungal disease, and abscesses, are significant contraindications to LT. The number of anatomic abnormalities that preclude LT has decreased with refinement of surgical techniques. Isolated portal vein thrombosis, previously an absolute contraindication, is now considered a relative contraindication.

1.4.2. Relative Contraindications

Conditions that may reduce the likelihood of survival after LT without being absolute contraindications are included in this group. It is often a combination of factors, rather than a single factor, that lead to the exclusion of a patient from LT. Furthermore, there is considerable variation from one transplant center to another regarding relative contraindications. The high recurrence rate and inferior survival rate associated with patients transplanted for HBV-related liver disease had led to the exclusion of HBV-related liver disease as an indication for LT at some centers. However, good results have been reported in patients who are HBV-DNA negative, have fulminant hepatic failure, or have HDV coinfection. These results have been achieved with the use of hepatitis B immune globulin (HBIg) therapy and with the recent introduction of lamivudine. Patients who are HBV-DNA positive remain at high risk for severe HBV recurrence after LT.

Patients older than 65 years are receiving LT with increasing frequency and are experiencing 1- and 3-year survival rates generally identical to those of their younger counterparts. They require vigorous evaluation pre-LT because of the increased risk of comorbid conditions, including cardiac and pulmonary disease, malignancy, and osteoporosis. Many centers believe that a well-motivated patient approaching age 70, who is physically active and mentally alert, may be a better candidate than an emaciated 50-year-old. The impact of previous treated extra-

hepatic malignancies on posttransplant outcome has been extrapolated from renal transplant literature. Low recurrence rates (0-10%) have been associated with renal tumors, lymphomas, testicular tumors, cervical tumors, and thyroid carcinomas. Intermediate recurrence rates (11-25%) occurred for carcinomas of the uterus, colon, prostate, and breast. High recurrence rates (>25%) occurred for carcinomas of the bladder, sarcomas, malignant melanomas, nonmelanomatous skin cancers, and myelomas.

An important issue in LT candidates is renal function. In a multivariate analysis from Barcelona (Hepatology 1991;18:46A), renal function was shown to be the only independent prognostic variable for survival after LT for nonbiliary cirrhosis. Some centers consider severe hyponatremia a relative contraindication because of its association with central pontine myelinolysis. Severe malnutrition has been associated with longer hospital stay and poorer survival following LT.

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