Clinical Aspects of Liver Transplantation

Hepatitis C

The leading indication for liver transplantation in the United States is hepatitis C–related cirrhosis ( Box 37.2 ). HCV infects 1.5% of the US population and leads to chronic hepatitis in 65% to 85% of carriers, 15% to 25% of whom develop cirrhosis. Since the introduction of direct-acting antiviral therapy, more than 250,000 people have undergone treatment for this disease in the United States. The new therapy has transformed the disease. The virus is readily cleared in a large percentage of patients, taking an oral medication only, with few side effects. Aggressive screening measures are being implemented among the at-risk population to identify infected individuals, and to begin therapy before they develop chronic liver disease. These new medications have been proven effective in eradication of the virus, with individualized therapies used for different genotypes and based on resistance to previous treatment attempts.

HCV transmission is primarily through intravenous drug use and sexual contact. There are several HCV subtypes that have variable response to treatment. HCV genotype 1 accounts for approximately 70% of all infections and has the highest rate of progression to cirrhosis with the poorest response to treatment. HCV accounts for 40% of all liver transplants and is usually the result of a chronic and insidious disease progression over a 20- to 30-year period from the initial infection. There are a large percentage of transplant recipients who are infected with hepatitis C virus and carry additional diagnoses including alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD) and HCC. Data assessing the impact of hepatitis C combined with other disease processes injurious to the liver are incomplete and extrapolation regarding long-term disease progression has not been defined. Clinically, however, hepatitis C–infected patients with an extensive history of alcohol abuse appear to progress at a more rapid rate to ESLD.

HCV recurrence postliver transplant was previously universal and led to chronic damage to the liver allograft in the majority of patients. Now, a large percentage of patients with HCV cirrhosis arrive to transplant already cured of their HCV. Although long-term outcomes for this population are not yet available, it is expected that they will mirror those for non-HCV patients. Early clinical experience suggests that clearance of HCV in the cirrhotic patient tends to stabilize or improve the patient’s clinical status. Thus, treatment may result in delay, or complete avoidance, of liver transplantation. Use of HCV-infected organ donors in HCV-infected transplant recipients has been common practice for many years, with good long-term outcomes. Now, use of these HCV-infected donors is more problematic. There are fewer recipients able to accept these donors. Now, many centers are recommending that their high model for end-stage liver disease (MELD) score patients not be treated for HCV, undergo LT first, and then receive therapy to cure their HCV after the transplant.

Hepatitis B and Hepatitis A

Hepatitis B is the most common cause of liver cirrhosis worldwide and affects an estimated 400 million persons. Although hepatitis B (HBV) infection was previously a major cause of ESLD in the Western world, its prevalence has decreased dramatically with the development of an effective vaccine that is now administered to all children at infancy in many countries. There remains a high prevalence of HBV infection in Asia and Africa, where immunization is not yet widely available. In these areas, HBV remains the leading cause of ESLD, and the development of HCC with chronic HBV hepatitis is common. Posttransplant HBV recurrence was 80% with frequent progression to early graft failure, retransplantation, and death. However, the development of effective antiviral therapies, including hepatitis B immune globulin (HBIg) and lamivudine, has resulted in graft survival results similar to patients with nonviral liver disease and low rates of posttransplant recurrence. Acute hepatitis B infection can lead to acute liver failure in 1% to 4% of infected patients, but these patients can achieve reasonable survival results with transplantation and appropriate follow-up therapy.

Hepatitis A virus (HAV) infection is unusual in the United States and Europe but, in rare cases, can lead to acute liver failure. In general, HAV infection is self-limited and causes an acute illness that does not lead to chronic liver disease. In countries with poor sanitation and dense population, HAV accounts for 10% of cases of acute liver failure. Older patients (over age 40) and those with underlying liver disease (related to chronic HCV infection or alcoholic liver disease) are at increased risk of HAV-related acute liver failure.

Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) has grown at a rapid rate in Western countries in recent years as the general population has experienced an epidemic of obesity. Obesity is defined as a body mass index of 30 or higher. The prevalence of obesity has increased dramatically. More than 65% of the US population is considered to be overweight, with 35% being obese. More than 5% of the population is affected by NAFLD. Currently in the United States, HCV, NAFLD, and ALD comprise the top three indications for liver transplantation. However, although the prevalence of HCV- and ALD-related cirrhosis has stabilized or decreased, NAFLD-related cirrhosis continues to increase yearly and affect persons at younger and younger ages. It is now thought that NAFLD is the primary cause of cirrhosis in many patients previously diagnosed with cryptogenic cirrhosis. Extrapolation of current trends, including a cure for HCV, have led researchers to predict that NAFLD as a cause of cirrhosis will surpass HCV-cirrhosis as the primary indication for liver transplantation in the next 10 years. Posttransplant recurrence of NAFLD is common. The prevalence of moderate steatosis at 1-year posttransplant is 15% in patients with HCV or ALD but 60% in patients transplanted for NAFLD.

Alcoholic Liver Disease

Alcoholic liver disease (ALD) is the third leading indication for LT in the United States and is also a leading cause worldwide. The time interval from the onset of alcohol abuse to ESLD is variable and depends upon average daily consumption, alcohol-free intervals, comorbid diseases, and genetic predisposition. According to recent national surveys reported by the US Centers for Disease Control and Prevention (CDC), more than half of the adult US population drank alcohol in the past 30 days. Approximately 5% of the total population drank heavily, whereas 15% of the population binge drank. The US prevalence of ALD is reported at 0.75%, and excessive alcohol use is the third leading lifestyle-related cause of death for people in the United States each year.

Approximately 20% of liver transplant recipients have a history of ALD. There is a sizeable percentage of patients with HCV infection who also have ALD. Combining ALD with any other primary liver disease may result in a synergistic effect with more rapid progression to end-stage liver disease. Most US centers require a confirmed period of alcohol abstinence of 6 to 12 months before listing for liver transplantation. This abstinence period often includes a required period of intensive outpatient addiction-related therapy as well as random alcohol and drug screening. Posttransplant alcohol recidivism is a major concern as alcohol intake posttransplant can be particularly toxic to the transplant liver and can lead to rapid hepatic decompensation and death depending on total intake. Alcohol recidivism varies widely posttransplant, but most centers quote a 10% to 20% rate within 5 years. Many of these patients have additional addiction issues and require ongoing support and therapy related to the use of both legal and illegal addictive substances. In spite of these statistics, posttransplant survival for patients with ALD is excellent with results equivalent to those for patients with nonviral liver disease undergoing transplantation.

Autoimmune Hepatitis

Autoimmune hepatitis (AIH) is a chronic, inflammatory liver condition associated with autoantibodies that incite an interface hepatitis. This process can result in both acute liver failure and chronic liver disease. The prevalence is highest in young females (70%) and the disease typically responds to immunosuppressive therapy. Patients progress to LT when their condition becomes decompensated. Unfortunately, a clinical marker for onset of AIH has not been identified and its exact cause is unknown. As such, the diagnosis is one of exclusion in which other diseases have been ruled out and the patient fits with a set of clinical, histologic, and laboratory parameters. These patients typically do well with the transplant procedure because they tend to be young and otherwise well compensated. Disease recurrence and liver allograft failure is common, however, as the hyperactive immune system leads to high rates of acute and chronic allograft rejection and difficulty in modulating immunosuppression. Of note, de novo AIH can occur in patients who underwent liver transplantation for another primary disease process.

Primary Biliary Cholangitis

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease resulting from injury to septal and lobular bile ducts. The disease tends to affect middle-aged females, is thought to be immune-mediated, and affects 0.1% of the population in the United States. The primary treatment for PBC is ursodeoxycholic acid (UDCA), which prolongs transplant-free survival and prevents disease-associated complications such as esophageal varices and severe pruritus. No current studies provide evidence, however, that available medical therapy ultimately precludes the need for transplantation or prolongs transplant-free survival. A significant number of these patients, therefore, do progress to transplantation which prolongs their survival when compared with the natural history of the disease. PBC can recur posttransplant and the incidence may be as high as 10% to 20% at 5 years. Posttransplant survival for PBC patients is among the highest of all liver transplant recipients, exceeding 90% at 1 year and 80% at 3 years.

Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC) is characterized by chronic inflammation of the bile ducts of the liver, which leads to loss of ducts and duct strictures. PSC more commonly affects males, and 70% of patients with PSC also have inflammatory bowel disease (primarily ulcerative colitis). Current medical therapy has little impact on the progression of this disease, and the inability of the liver to excrete bile leads to cirrhosis and chronic cholangitis and the need for LT. Importantly, patients with PSC carry an increased risk of cholangiocarcinoma, which occurs in 10% to 20% of cases. Predictive factors for cholangiocarcinoma are inadequate, which results in PSC patients undergoing frequent screening with endoscopic retrograde cholangiopancreatography (ERCP) to obtain bile duct brushings for pathologic review. Patients with PSC carry a higher risk of liver rejection and are often placed on a more aggressive immunosuppression regimen posttransplant.

The transplant procedure for PSC has historically required the use of Roux-en-Y choledochojejunostomy to avoid use of the remaining posthepatectomy bile duct for a duct-to-duct anastomosis. This duct was felt to be at risk for stricture that could compromise the transplant liver. However, with the increasing safety and utility of ERCP, some centers are now connecting the transplant common bile duct to the native bile duct, if it is normal in appearance. The duct-to-duct anastomosis permits ongoing posttransplant ERCP surveillance of the native duct, which remains at risk for cholangiocarcinoma. This surveillance is not possible with the alternative duct reconstruction. Although overall posttransplant survival is excellent, PSC can recur posttransplant. The diagnosis of posttransplant PSC is complicated. There is a high rate of biliary complications that exist for any liver transplant and these must be ruled out before entertaining a diagnosis of posttransplant PSC. Common transplant issues that affect the biliary system include technical issues (stenosis), poor arterial flow, donation after cardiac death donor, an episode of profound hypotension, or severe preservation injury or ABO incompatibility.