Hepatic Transplantation

Hepatitis C

Estimates vary, but worldwide there are likely more than 200 million individuals infected with the hepatitis C virus (HCV). According to the Centers for Disease Control and Prevention (CDC), the prevalence of hepatitis C in the United States is estimated to be much more than 3 million. In fact, cirrhosis from HCV remains the most common indication for liver transplantation in the United States, accounting for approximately 29% of the activity at most centers. HCV is a parenterally transmitted RNA virus with no DNA intermediates. The HCV genome was elucidated in 1989 and screening of blood products began shortly thereafter. Acute HCV infections are usually subclinical with no icteric phase. The disease becomes chronic in the majority of those infected, with cirrhosis developing between 1 and 2 decades later. The interval to cirrhosis is greatly accelerated by heavy alcohol consumption. In the United States, 1% to 2% of the population is infected with HCV: from blood transfusions prior to 1990, intravenous drug use, or other parenteral routes, such as tattoos. Despite blood product screening and efforts at greater public awareness, and because of the prolonged course of the disease, HCV is predicted to be an increasing problem for at least another decade.

As the leading indication for liver transplantation in the United States, HCV recurrence postorthotopic liver transplant (OLT) is universal. Recurrence is associated with accelerated fibrosis progression and reduced graft and patient survival. With the introduction of the new direct-acting antiviral therapies for HCV in the past several years, studies treating decompensated cirrhotic patients were done with the goals of stabilizing disease, preventing decompensation, and preventing graft infection. Two large clinical trials done in Child B and C decompensated cirrhotic patients conducted in North America and Europe using sofosbuvir, ledipasvir, and ribavirin for 12 or 24 weeks yielded sustained virologic response (SVR) rates of 78% to 96%, with lower rates reported in the Child C cohort. Additionally, those treated post-OLT had excellent SVR rates if they were treated early fibrosis (F)0–F3 (96% to 98%). In the Model for End-Stage Liver Disease (MELD) era (see discussion on MELD that follows), determining the appropriate timing of therapy (pre- vs. post-OLT) is essential because in some cases treatment may improve MELD score but may leave the patient in “MELD limbo” as HCV cure may not prevent the need for liver transplant due to other complications (hepatocellular carcinoma [HCC] or portal hypertensive complications). The remarkable progress made in HCV therapies with cure rates of greater than 95%, even in advanced liver disease or post-OLT, will likely reduce the numbers of patients needing liver transplant in the future as other more challenging etiologies are increasing.

Hepatitis B

Hepatitis B is a DNA virus endemic in many countries, especially those of the Pacific Rim. Although effective vaccines have been available for more than 20 years, it continues to be a major worldwide health problem, due especially to vertical transmission. Hepatitis B virus (HBV)-related liver disease currently accounts for up to 15% of transplant activity at most centers. In the earlier days of liver transplantation, postoperative reinfection was a major issue leading to dismal results and the general acceptance of HBV as a relative contraindication to transplant. A dramatic success story followed the development of improved prophylactic strategies using HBV immune globulin, and the subsequent availability of effective antiviral agents. Hepatic allograft reinfection with HBV is no longer a significant clinical problem.

Cholestatic Diseases

Collectively, primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are referred to as the cholestatic liver diseases. Although both are idiopathic, each has a genetic/autoimmune element, and overlap syndromes with autoimmune hepatitis can occur. Together, on average, they account for roughly 8% of transplant activity at most centers.

Ninety percent of patients with PBC are female, presenting at an average age of 50 years and not uncommonly with familial clustering. Pruritus is the most common presenting symptom, whereas the diagnostic hallmark is the presence of antimitochondrial antibodies, which are present in virtually 100% of those with the disease.

Men are twice as likely as women to be afflicted with PSC, usually presenting between 25 and 45 years of age. Many cases are discovered incidentally on routine blood tests with the finding of an elevated serum alkaline phosphatase. Patients with symptoms are equally likely to present with either pruritus or jaundice. In the proper clinical context, diagnosis is confirmed with endoscopic retrograde cholangiography showing irregular stricturing and beading of the intrahepatic biliary tree. As discussed in some detail later, there is a strong association between PSC and inflammatory bowel disease. A major concern among patients with PSC is the 15% to 30% overall associated risk for the development of cholangiocarcinoma (CCA). Unfortunately there is as yet no reliable method for predicting or detecting this malignancy in its early stages. Ironically, demonstrable disease was, until relatively recently, considered a contraindication for transplantation because of generally dismal outcomes. However, those transplanted and found to have incidental CCA actually fare quite well. As of November 2009, organ allocation policies now facilitate transplantation in highly selected patients with early-stage CCA in the context of aggressive adjuvant therapy.

Alcoholic Liver Disease

Alcoholic liver disease ranks as one of the most common causes of death in the United States and the second most common indication for liver transplantation in adults. Interestingly, only between 10% and 15% of alcoholics develop cirrhosis. Nevertheless, it has been determined that upward of 80 g of alcohol per day for more than 5 years will put most individuals at risk. As already noted, alcohol acts synergistically with HCV or HBV infection. Alcohol-related liver injury can manifest across a spectrum, from acute alcoholic hepatitis to chronic fatty changes and on to cirrhosis and HCC. Most transplant centers maintain strict abstinence guidelines for determining candidacy when alcohol is the cause of liver failure. Most often, a 6-month period of sobriety is required to allow demonstration of insight and compliance. Another very practical reason for a period of abstinence is to avoid transplanting those who will recover from the acute effects of alcohol and no longer meet transplant criteria.

Unresectable Hepatocellular Carcinoma

HCC is one of the most common malignancies worldwide, ranking eighth among all cancers while accounting for approximately 90% of those that are primary to the liver. The incidence of HCC in endemic regions of Asia and sub-Saharan Africa can be as high as 20 to 40 cases per 100,000. Although rates found in the United States and Western Europe are much lower (1 to 5 cases per 100,000) the incidence is rising. In the United States, the incidence of HCC is currently estimated to be from 8500 to 11,500 new cases per year.

Even though environmental toxins pose a major risk in some parts of the world, the incidence of HCC is primarily related to the prevalence of cirrhosis from chronic viral hepatitis B and C, with a relative risk several-hundred-fold greater than those who are unaffected. Cirrhosis per se is a premalignant condition, regardless of etiology. Although cirrhosis remains the common denominator, the DNA intermediates in the replicative cycle of HBV may be directly carcinogenic, even in the absence of cirrhosis. The irony of HCC is that such tumors are typically multifocal and almost exclusive to those with underlying cirrhosis that precludes resection. The intuitive appeal of OLT is the elimination of the tumor as well as the underlying liver disease, which creates a fertile environment for developing neoplasms.

Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is generally considered to be a benign disease and is typically diagnosed incidentally on abdominal imaging confirming steatohepatitis with or without minor elevations in liver function tests. In the United States, the prevalence of NAFLD approaches 30% to 40% in parallel with the obesity epidemic and is associated with type 2 diabetes mellitus, dyslipidemia, and metabolic syndrome, all of which are presumed to occur secondary to a common pathophysiology of insulin resistance. Nonalcoholic steatohepatitis (NASH) is differentiated from NAFLD by evidence of fatty accumulation causing histologic hepatocyte injury with inflammation. NASH has the potential to progress to hepatic fibrosis and cirrhosis and lead to significant morbidity and mortality. Nearly 15% to 20% of patients with NAFLD develop NASH, which is predicted to be the most common reason for OLT in the near future. Unfortunately, there is currently no cure for NASH and most treatment options are targeted toward controlling its underlying associated disease states.

Unusual Tumors

The early transplant experience in patients with secondary hepatic malignancy was dismal, and consequently metastatic tumors are generally still considered an absolute contraindication. However, a few exceptions do exist. Although largely anecdotal, acceptable outcomes have been described in patients with metastatic midgut carcinoid tumors, whereas patients transplanted for other unresectable neuroendocrine tumors have generally not fared as well. Outcomes for primary hepatic angiosarcoma and biliary cystadenocarcinoma have been disappointing. Hepatic epithelioid hemangioendothelioma has also been successfully treated using OLT but outcomes are unpredictable. When considering OLT in this setting of secondary tumors, the tradeoff is between the survival advantages offered by traditional therapies for otherwise slowly progressive tumors versus the potential for rapid progression of occult residual disease under the influence of posttransplant immunosuppression. A small number of symptomatic and otherwise unresectable benign tumors, or those with the potential for malignant degeneration, such as adenomas, have also been treated with transplantation.

Other Etiologies

A number of other chronic disorders that can also lead to liver failure and the need for transplantation do exist, but they are beyond the scope of this discussion. Metabolic abnormalities of iron and copper underlie the disorders of hemochromatosis and Wilson disease, respectively. Other entities include autoimmune hepatitis, α ₁ -antitrypsin deficiency, nonalcoholic fatty liver disease, and the Budd-Chiari syndrome. In addition, there are a host of other disorders that occur in the pediatric population, the most common of which is biliary atresia.

Acute Liver Failure

Although the vast majority of patients undergoing liver transplantation suffer from chronic diseases, an estimated 2000 individuals in the United States each year present with conditions leading to acute (or fulminant ) liver failure (ALF) ( Table 127.2 ). The most common etiologies include toxic drug exposures such as acetaminophen or idiosyncratic reactions to other drugs. Mushroom poisoning (e.g., Amanita phalloides ) and industrial or environmental toxins have also led to ALF. Other causes include acute hepatitis A, acute or reactivated hepatitis B, and Wilson disease (a hereditary disease of copper metabolism). Other conditions, such as an acute Budd-Chiari syndrome, fatty liver of pregnancy, autoimmune conditions, and even shock can give rise to ALF. In up to 20% of cases, no apparent etiology can be identified. As discussed later, patients presenting with ALF must undergo urgent evaluation and listing for transplantation, as death can occur within hours.

Hemodynamics

Perhaps the most pervasive physiologic changes associated with cirrhosis are those affecting hemodynamics which, in turn, can affect each of the organ systems. Cirrhosis leads to a generalized vasodilation and hyperdynamic state. In addition to a reduced systemic vascular resistance, a host of attendant changes can occur, including increased peripheral blood flow, reduced arteriovenous oxygen difference, reduced effective blood volume with reduced cortical renal blood flow, and activation of the renin-angiotensin axis with sodium and water retention contributing to ascites formation. Patients with cirrhosis are generally observed to have an elevated cardiac output, tachycardia, and low blood pressure. As cirrhosis progresses, patients with a history of hypertension no longer require antihypertensive medications. Many of the common physical findings seen in cirrhotic patients, such as palmar erythema and cutaneous spider angiomata, are also explained by these vascular changes.

Heart

Iron overload states, such as that seen with genetic hemochromatosis, can lead to cardiac iron deposition. Although overt abnormalities may be discovered with echocardiography, those afflicted are at risk for conduction abnormalities, severe dysrhythmias, and right heart failure, especially during the significant stress of surgery. Magnetic resonance imaging can detect cardiac iron overload, and cardiac catheterization is usually required to determine transplant candidacy. In some circumstances, patients have been considered for simultaneous dual-organ (heart-liver) transplantation. As a group, those with either primary or secondary iron overload fare worse with transplantation than those without iron overload.

Lung

Up to one-third of patients with cirrhosis may be found to have reduced arterial oxygen saturation. A number of conditions common to cirrhosis may affect pulmonary function ( Box 127.1 ). Two of the most serious conditions are portopulmonary hypertension and the hepatopulmonary syndrome. Both are likely related to the hyperdynamics of cirrhosis.

Although the etiology of portopulmonary hypertension is unclear and the incidence is low, 2% of patients with severe liver disease are at risk for developing pulmonary arterial changes indistinguishable from those seen in primary idiopathic pulmonary hypertension. If suspected based on echocardiography, right heart catheterization must be performed. A mean pulmonary arterial pressure (MPAP) greater than 25 mm Hg defines the disease, whereas an MPAP greater than 35 mm Hg (peripheral vascular resistance [PVR] ≥240 dynes/s per⋅cm ⁵ ) is considered the threshold for an increased risk of death. Treatment with prostacyclins, nitric oxide, or similarly active agents can be used in an attempt to lower pressures and facilitate a safe OLT.

Hepatopulmonary syndrome is another uncommon entity defined by the triad of (1) chronic hypoxemia (Pa o ₂ <60 mm Hg), (2) pulmonary vascular dilation as seen on examinations such as angiography or bubble echo, both in the context of (3) severe underlying chronic liver disease. This is a progressive condition that can be reversed following transplantation.

Gastrointestinal

Portal hypertensive bleeding is a well-known complication of cirrhosis and about 90% of such episodes can be successfully treated with endoscopic and/or pharmacologic interventions. When indicated, an experienced interventional radiologist can place transjugular intrahepatic portal systemic shunts (TIPSS). Surgical shunts remain appropriate in the nonacute setting when the most prominent feature of disease is bleeding in an otherwise well-compensated patient. TIPSS may be contraindicated by significant hepatic encephalopathy or bilirubin levels elevated much higher than 3.0 mg/dL, in which case progressive liver failure may ensue without shunt reversal.

Inflammatory bowel disease is strongly associated with PSC. Among patients with PSC, there is a 75% prevalence of ulcerative colitis (UC), whereas the converse is true in only 5%. PSC may also be associated with colonic Crohn disease. In those with PSC and UC, the risk for colonic malignancy may be greater than for those with UC alone and is an indication for vigilant screening colonoscopy, both before and after transplantation.

Bone

Hepatic osteodystrophy can be a complication of end-stage liver disease, especially among those with cholestatic diagnoses. Steroid treatments before or after transplantation can also exacerbate this problem. Consequences include bone pain, fractures, and vertebral collapse. Aggressive calcium replacement and hormonal therapy are usually indicated.

Kidney

In the absence of other identifiable pathology, the development of severe renal dysfunction in the presence of end-stage liver failure defines the hepatorenal syndrome. Although the etiology remains uncertain, it is likely related to the hemodynamic changes noted earlier. Because this is largely a functional problem, renal failure can be expected to resolve after liver transplantation. However, in patients with long-standing hepatorenal dysfunction, normalization may be unpredictable. The hepatorenal syndrome has been subdivided into type I and type II based on the pace of functional loss. Patients with type I hepatorenal syndrome experience a rapidly progressive deterioration, with a doubling of the initial serum creatinine in a period of less than 14 days. Such patients have 90% mortality within 90 days. Those with type II syndrome have a less rapid progression and fare better as a group. In either case, patients often require hemodialysis. When renal dysfunction is severe and of a long-standing nature, consideration must be given to combined liver and kidney transplantation. Because one of the parameters for the MELD calculation is serum creatinine, such patients are favored and nationwide there are an increasing number of patients undergoing dialysis at the time of transplantation as well as a growing population of liver transplant recipients receiving simultaneous renal transplants.

Brain

Hepatic encephalopathy is a neuropsychiatric condition associated with severe liver disease. It can have manifestations that affect the spectrum of neurologic function from changes in personality and intellect to altered levels of consciousness ( Table 127.3 ). Although it can complicate either chronic liver disease or acute liver failure, there are distinct clinical differences between the two conditions. In chronic disease, symptoms of encephalopathy may wax and wane with dietary indiscretion, poor compliance to medications, gastrointestinal bleeding, or infection. In the worst scenario, stage IV coma may require endotracheal intubation for airway protection. However, with proper management, even in the most severe circumstance, the mental status changes are temporary and reversible. On the other hand, encephalopathy associated with acute liver failure may also lead to coma, but unlike its counterpart, it is also associated with cerebral edema and acute brainstem herniation. The optimal management of acute hepatic encephalopathy may require intracranial pressure monitoring, which is not indicated in the chronic setting.

Infectious Diseases

Cholangitis can be a significant pretransplant issue, especially in those patients with biliary strictures, such as those seen with PSC or other rarer congenital or acquired conditions. Such patients may require repeated endoscopic balloon dilations or stenting of prominent strictures. Occasionally, the chronic administration of rotating antibiotics may be necessary. Although extrahepatic infection is a contraindication to liver transplantation, it may be impossible to clear cholangitis in a patient with biliary strictures and chronic liver disease until the liver is removed. In the absence of florid sepsis, such patients may still remain candidates for liver transplantation.