Liver Transplantation
Carolyn J. Driscoll, RN, PhD, FNP-C
Leslie Gallagher, RN, MS, ANP-BC
Margaret J. Schaeffer, RN, MS, MSHA, NE-BC
I. PRETRANSPLANT CARE: END-STAGE LIVER DISEASE AND FAILUREA. Overview
End-stage liver disease is a major health problem causing more than 30,000 deaths each year in the United States.1 Medical management may be effective for short or even extended periods of time. However, liver transplantation is recognized as a successful therapy for patients for whom standard medical and surgical therapies have failed.
Liver transplantation has shown excellent results worldwide. In 2013, 6,455 liver transplants were performed and approximately 60,000 people worldwide were living with a transplanted liver.
Five-year graft survival was 71.7% for recipients aged younger than 1 year, 74.9% for ages 1 to 5 years, 78.9% ages 6 to 10 years, 77.4% for ages 11 to 17 years, and 76.4% for adults.2
In the United States, the national Organ Procurement and Transplantation Network (OPTN) recognizes seven liver disease categories and lists 72 liver diagnoses as indications for transplantation.3 Discussion of the major indications for liver transplantation follows. Box 12-1 lists the indications for and contraindications to liver transplantation.
Chronic hepatitis C (viral disease) is the most common indication for liver transplantation in the United States.
Alcoholic liver disease is the second leading indication for liver transplantation.
Nonalcoholic fatty liver disease (NAFLD) is a prevalent form of disease caused by a variety of factors such as obesity, hyperglycemia, elevated serum lipids, and high blood pressure (BP).4
The progression of disease leading to nonalcoholic steatohepatitis (NASH) can result in cirrhosis and is the third most common indication for liver transplantation in the United States.
NASH is estimated to become the leading indication for liver transplant in the next 10 to 20 years.5
Hepatocellular carcinoma (HCC) has become the fifth most common cancer in the world and is an indication for liver transplantation.
BOX 12-1 Indications and Contraindications for Liver Transplantation
Indications for Liver Transplantation
Acute Liver Failure
Viral
Drug/medication toxicity
Ischemia
Wilson’s disease
Autoimmune
Idiopathic
Cirrhosis and Decompensation
Hepatitis B or C
Alcohol
Nonalcoholic steatohepatitis
Cholestatic disease
Autoimmune
Metabolic
Malignancy
Cryptogenic
Absolute Contraindications
Severe cardiopulmonary disease
Anatomic abnormalities precluding adequate surgical reconstruction
Uncontrolled human immunodeficiency virus
Poorly controlled psychiatric illness
Noncompliance with medical recommendations
Relative Contraindications
Extrahepatic malignancy
Hepatocellular carcinoma (exceeding Milan criteria)
Acute substance or alcohol abuse
Inadequate social or financial support
B. One of the largest barriers to transplantation is the shortage of available organs.
There are geographic disparities in the availability of organs for transplantation.
Consent rates for donation from deceased donors are not optimal.
Donation from a living donor is possible, although limited by the number of liver transplant programs that perform this procedure.
A living donor program is a component of an approved deceased donor transplant program within a transplant center.
In the United States, the Organ Procurement and Transplantation Network (OPTN), operated by the United Network for Organ Sharing (UNOS), must approve a program to perform living donor surgeries based on the OPTN criteria.
OPTN criteria require very specific training and experience for all the transplant surgeons and physicians involved in living donor liver transplantation.6
C. The overall goal of liver transplantation is to prolong life and improve the patient’s quality of life. Secondarily, there are economic benefits to the health care system as the cost of transplantation therapy is less of a burden on the system than care of a patient with liver failure.7
D. As of January 2015, approximately 16,000 patients were waiting for liver transplants in the United States.
6,455 liver transplants were performed in 2013, of which 252 were from living donors.
During the same period, 6,322 patients were removed from the waiting list because of death.8
II. DISEASES THAT MAY LEAD TO HEPATIC FAILURE9A. Hepatitis A viral infection is an acute, necroinflammatory disease of the liver.
Virus is detectable in blood or feces for 2 weeks before the onset of jaundice and for up to 8 days afterward.
Acquired through the oral-fecal route such as by ingestion of contaminated food or water.
Symptoms may include malaise, fatigue, anorexia, low-grade fever, nausea, and vomiting.
Most patients will have full recovery within 3 months.
Acute liver failure occurs in approximately 1% of cases. Chronic infection is never seen.
B. Hepatitis B is an acute or a chronic liver disease.
Most infections develop as a result of exposure to contaminated blood or body fluids including
Vertical transmission from an infected mother to her newborn child
Unprotected sexual contact with an infected person
Blood and blood product infusions (rare since blood screening in 1971)
Sharing of needles during intravenous (IV) drug use
Exposure may lead to an acute infection, which usually resolves, although liver failure can occur. A number of adult patients fail to clear the virus and develop a chronic infection, which leads to cirrhosis and/or liver cancer. Conservatively, 54% of liver cancer cases are due to hepatitis B infection. An effective vaccination is available; however, hepatitis B remains a major health problem.10
C. Hepatitis C is the leading indication for liver transplantation in the United States.
Viral disease can be transmitted by the following:
Infected blood products or organs (uncommon since July 1992)
Injection drug use
Needlestick injuries in health care settings
Less commonly from vertical transmission from an infected mother or sex with an infected person
Chronic disease is related to chronic inflammatory process, reflective of an unresolved wound healing response, which causes fibrotic changes within the liver.11
75% to 80% of people who become infected will develop chronic disease. Most cases progress asymptomatically and may be detected many years after infection. Approximately 20% develop cirrhosis and 4% of those will develop hepatocellular cancer (HCC).
D. Hepatitis D infection occurs only in the presence of concurrent or underlying chronic hepatitis B.
Transmitted through percutaneous or mucosal contact with infected blood.
Can be acute or chronic. Chronic hepatitis D may be completely asymptomatic or present with nonspecific symptoms like fatigue.
Uncommon in the United States.
E. Hepatitis E may occur in epidemics or sporadic cases.
Acquired similarly to hepatitis A and thought to be waterborne
More serious for pregnant mothers and fetuses
F. Alcoholic liver disease12
Alcoholic liver disease has a spectrum of presentation including fatty liver, alcoholic hepatitis, or cirrhosis.
Fatty liver, which occurs after acute or chronic alcohol ingestion, is reversible with abstinence.
Alcoholic hepatitis occurs with consumption of large amounts of alcohol over a prolonged period of time. It has a spectrum of severity that can lead to fulminant liver failure and death. Ability to reverse the process varies.
Clinical manifestations of cirrhosis are similar to other etiologies. Complications of portal hypertension and liver failure can develop. It is not reversible.
G. Hepatocellular carcinoma (HCC)13
HCC is a malignant cancer of liver cells, one of the most common cancers worldwide, and is responsible for >1 million deaths annually.
Risk factors include male gender, cirrhosis, and chronic hepatitis B or C infection.
Liver transplantation is an option in select patients. Patients are screened by the Milan criteria, which assess the suitability of patients and outcome based on tumor size and number that include the following:
One lesion smaller than 5 cm
Three lesions total each being <3 cm
No extrahepatic manifestations
No vascular invasion
H. Primary biliary cirrhosis (PBC) is a rare, chronic, progressive cholestasis (retention of bile) disorder.14
Gradual destruction of the interlobular bile ducts leads to the development of cirrhosis.
PBC is an autoimmune hepatitis.
Pruritus and fatigue are common symptoms.
The disease primarily affects middle-age women.
I. Primary sclerosing cholangitis (PSC) is a chronic progressive disease of unknown etiology.15
Multiple fibrosing inflammatory strictures of the extra- and intrahepatic bile ducts
Progresses to cirrhosis, liver failure, and sometimes cholangiocarcinoma
Closely associated with inflammatory bowel disease, predominantly ulcerative colitis
J. Autoimmune hepatitis is a chronic inflammatory disease of the liver thought to be caused by a combination of autoimmunity, environmental triggers, and a genetic predisposition.16
More common in females. Can occur at any age and affects all ethnic groups.
Patients often have other autoimmune disorders, such as Crohn’s disease, PSC, lupus, type 1 diabetes, or ulcerative colitis.
Treatment includes medications to suppress or slow the overactive immune system. May require liver transplantation.
K. Hemochromatosis is an inherited disease in which an excessive amount of iron is absorbed, cannot be excreted from the body, and is deposited in the liver and other organs. Eventually, cirrhosis may develop.17
Equally affects males and females
Signs of the disease manifest in men in their 40s and 50s.
Women typically demonstrate signs in their 60s and 70s.
More common in those of Northern European descent
L. Wilson’s disease is a genetic disorder of copper metabolism.18
Copper is a component of many enzymes and plasma proteins.
Biliary excretion of copper and ceruloplasmin synthesis is impaired in Wilson’s disease leading to the accumulation of copper in the liver and other organs, including the brain and eyes.
Wilson’s disease can present as chronic liver disease or acute liver failure.
M. Alpha-1 antitrypsin deficiency (A1AT): A1AT is an enzyme made by the liver, which helps to break down trypsin and other tissue proteases.19
A1AT deficiency is an inherited disorder; structural abnormalities of the protein may disrupt normal cellular transport of A1AT in hepatocytes and accumulation of the defective protein results in potentially severe liver disease.
Lungs can also be affected, leading to emphysema and even lung transplantation.
N. Non-alcoholic Steatohepatitis (NASH) is an increasingly common liver disease.
Fatty changes (steatosis) and lobular infiltration in the liver develop in people who drink little or no alcohol. Liver damage can range from steatosis to cirrhosis.20
Associated with metabolic syndrome, obesity, diabetes, and dyslipidemia.
O. Cryptogenic cirrhosis is a term given to patients with cirrhosis where no diagnosis of the underlying liver disease can be established.
P. Drug-induced liver disease is a syndrome in which hepatotoxicity is caused by drugs, toxins, or other foreign chemicals. More than 900 drugs, toxins, and herbs have been reported to cause liver injury. Drugs account for 20% to 40% of fulminant liver failure.21
Presentation may be acute liver failure or fibrosis and cirrhosis that may develop over many years.
In the United States, United Kingdom, and Australia, acetaminophen (paracetamol) is one of the most common causes of acute liver failure, often resulting from deliberate or inadvertent overdoses.22
Other selected common drugs that cause hepatotoxicity include the following:
Antimicrobials (i.e., amoxicillin/clavulanate)
Dietary and herbal supplements
Isoniazid
Nonsteroidal anti-inflammatory drugs
Antiseizure medication
Q. Budd-Chiari syndrome occurs as a result of thrombosis of the hepatic veins. Patients present with abdominal pain, ascites, and hepatomegaly. It is a rare disease and affects mainly young adults.23
May develop in patients with underlying thrombotic conditions.
When occlusion of the hepatic veins is more gradual, collateral vessels form and fibrosis develops leading to cirrhosis.
When thrombosis occurs rapidly, acute liver failure may develop.
R. Liver diseases during pregnancy24
Patients usually present in their third trimester of pregnancy. Symptoms vary from none to acute liver failure.
Hyperemesis gravidarum presents with severe and persistent vomiting. Half of women who are hospitalized with this syndrome have liver disease.
Intrahepatic cholestasis is reversible but possibly predictive of liver disease later in life.
Acute fatty liver of pregnancy (AFLP) is rare but serious. The pathogenesis is largely unknown, and prompt recognition and delivery of the fetus is necessary to save the mother and child.
HELLP syndrome is a cluster of symptoms that occur in pregnant women (1 to 2 in 1,000 pregnancies). The grouping includes hemolysis, elevated liver enzymes, and a low platelet count.
H, hemolysis; EL, elevated enzymes; LP, low platelets
Primary treatment is delivery of the baby.25
S. Acute liver failure26
Rare and life-threatening critical illness, occurring most often in patients with no previous history of liver disease
Types of acute liver failure:
Hyperacute liver failure, defined by the development of encephalopathy within 7 days of becoming jaundiced.
Fulminant, defined by 2 weeks from jaundice to encephalopathy.
Subacute liver failure is often used to describe development of jaundice and encephalopathy over 5 to 12 weeks.
Etiology of acute liver failure
The etiologies for acute liver failure include viral hepatitis, druginduced liver injury, autoimmune hepatitis, toxins, metabolic diseases, and others as listed above.
III. WORSENING LIVER FUNCTIONA. Conditions that warrant concern and action
Patients should be referred for transplant assessment when they develop or experience complications that are no longer managed successfully with treatment. For example:
B. Objective and subjective indications of deterioration in liver failure include the following:
Increasing jaundice: occurs as the liver fails to metabolize bilirubin normally.
Increased risk of bruising and bleeding from decreased platelets (secondary to splenomegaly).
There is decreased synthesis of coagulation proteins in the liver, which results in elevated prothrombin time (PT) and international normalized ratio (INR).
In addition, there is decreased production of other components of the coagulation cascade, which help ameliorate the risk of bleeding.
Pruritus: caused by increased concentration of bile salts or other chemicals in the blood due to impaired excretion of bilirubin.
Peripheral edema: caused by low albumin (usually below 30 g/L SI units or 3 g/dL conventional units) and/or massive ascites blocking venous return.
Prominent abdominal wall veins (caput medusa): collateral vessels bypass the scarred liver to carry portal blood to the superior vena cava.
Hemorrhoids: internal veins dilate with increased portal hypertension.
Anemia due to
Gastrointestinal blood loss
Erythrocyte destruction by pooling in enlarged spleen
Decreased folic acid due to dietary deficiency
Infection: leukopenia (low white cells) due to splenic sequestration.
Emaciation: caused by malnutrition and hypoalbuminemia.
Fatigue: mechanism is not well understood.
Most patients are generally hemodynamically compensated while exhibiting some symptoms of volume overload. However, in more advanced cirrhosis, peripheral vasodilation can occur, manifested as decreasing BP.26
C. Complications of worsening liver failure include
Portal hypertension
Defined as the elevation of hepatic venous pressure gradient (HVPG) to >5 mm Hg
Caused by increased resistance to the passage of blood flow through the liver and increased splenic blood flow secondary to vasodilation within the splenic vascular bed
Ascites27
Accumulation of fluid in the peritoneal cavity caused by portal hypertension and low albumin, leading to excess formation of fluid within congested hepatic sinusoids
Treated with reduction in sodium intake, diuretics, and abdominal paracentesis
Spontaneous bacterial peritonitis (SBP)
Infection from bacterial translocation and diagnosed by analysis of ascites fluid.
Symptomatic patients should be admitted to the hospital and treated with a 10- to 14-day course of antibiotics, followed by a repeat peritoneal fluid analysis to assure declining polymorphonuclear (PMN) counts and sterilization of the ascetic fluid.28
Esophageal and gastric varices29
Abnormal and enlarged veins in the esophagus and stomach develop secondary to portal hypertension. Develop when normal blood flow to the liver is obstructed.
Treatments include non-selective beta blocker medications to reduce portal hypertension and “banding”: the use of elastic bands to tie off veins that are bleeding or in danger of bleeding or rupture.
Encephalopathy and coma
Decreased excretion of ammonia and other toxins can lead to elevated levels that result in confusion and other mental status changes, including coma.
Treatment includes the following:
Lactulose and rifaximin are used to reduce ammonia levels.
Lactulose should be titrated to obtain three to four bowel movements a day.
Measurement of serum ammonia levels can be deceiving as results can be adversely affected by testing methods. Clinical examination of mental status and asterixis (hand tremor) is often sufficient to identify encephalopathy.
Normal ammonia levels are <40 µmol/L.
Constipation, dehydration, infection, and hyponatremia may result in elevated ammonia levels and encephalopathy.30
Grades of encephalopathy
Minimal hepatic encephalopathy. No specific symptoms, but abnormal specialized testing results.
Grade 1—Nonspecific changes without asterixis, with abnormal specialized testing results.
Minimal hepatic encephalopathy and Grade 1 encephalopathy may be grouped together and called “covert hepatic encephalopathy.”
Grade 2—Drowsiness.
Grade 3—Confusion, reactive only to vocal stimuli.
Grade 4—Presence of deep coma with absence of reaction to vocal stimuli.
Grades 2, 3, and 4 can be grouped together and called “overt hepatic encephalopathy.” No specialized testing is required for diagnosis.31
Hepatorenal failure involves a rapid decrease in renal function.
Occasionally precipitated by volume depletion
Often seen in patients with advanced liver disease
May need to be treated with dialysis
IV. CHRONIC LIVER DISEASEA. Definition: a gradual destruction of liver tissue over time
B. Clinical manifestations: Early symptoms may include the following:
V. LIVER TRANSPLANT ASSESSMENT23A. Patients with liver disease undergo a thorough assessment before they are accepted for placement on the liver transplant waiting list.
Each transplant program has an individualized transplant evaluation process for patients. The evaluation may be done in an outpatient setting or, if the patient’s condition dictates, while the patient is in the hospital.
Patient and family education is a major focus in the assessment process.
At the first meeting, patients sign consents to participate in the evaluation process; the entire evaluation process is outlined for them at this time.
National and center-specific liver transplant outcome data are given to patients to aid them in their decision making.
See chapter on Patient Education for additional information
B. Assessment includes the following:
Laboratory tests.
Radiologic and other clinical tests.
Evaluation for suitability by an interdisciplinary transplant team.
The Centers for Medicare and Medicaid (CMS) regulate specific roles of an interdisciplinary team in the assessment.
The members of the team are defined by CMS and must include, at a minimum:
Surgeon
Physician
Anesthesiologist
Pharmacist
Registered dietician
Social worker
Transplant coordinator
Psychiatrist/psychologist
Evaluation of the patient’s family/social situation is of major importance.
This evaluation is the role of the social worker, psychologist, and transplant coordinator.
Identifying the key caregiver for the patient both pre- and posttransplant is necessary in order to facilitate
Adherence to the medical regimen, including keeping hospital appointments and medication management
A timely, effective, and safe hospital discharge
Chronic illness, loss of employment, as well as travel to the transplant center, especially for patients living a long distance away, can have financial implications for individuals and the ability to comply with posttransplant requirements.
Assessment by and involvement with social workers are needed to deal with these issues.
In some programs, patients with alcoholic cirrhosis will undergo a thorough assessment by a team of experts in addiction medicine.
Data suggest that long-term posttransplant survival rates for patients with alcoholic cirrhosis are no different than survival rates for patients with other types of cirrhosis.
In the United States, many transplant programs require 6 months of abstinence before a patient can be placed on the liver transplant waiting list. However, this time period is arbitrary and no studies to date have shown it to impact posttransplant survival.32
Programs also have different criteria regarding whether or not patients must sign a contract or agreement that states they will participate in formal alcohol treatment programs and abstain from alcohol following transplantation.
C. Patients with acute liver failure can deteriorate rapidly. Therefore, the assessment process may be expedited so that these patients can be listed very quickly. In cases of acute and fulminant liver failure, family members may be interviewed to gather the patient’s history and pertinent information.
D. The medical assessment of the patient for transplantation includes the following:
Basic laboratory tests
Hepatic panel (liver function tests [LFTs])
Basic metabolic panel (creatinine, electrolytes, blood urea nitrogen [BUN])
Complete blood count (CBC)
PT, INR, and partial thromboplastin time (PTT)
Antinuclear antibody (ANA) and antimitochondrial antibody (AMA)
Alpha fetoprotein (AFP cancer marker)
Blood type: per OPTN Policy 3 (Candidate Registrations, Modifications, and Removals)
Transplant programs must determine each candidate’s blood type by testing at least two candidate blood samples prior to registration on the waiting list. Transplant programs must test at least two blood samples from two separate blood draws taken at two different times.
After the candidate’s blood type data are reported to UNOS, the candidate is added to the waiting list but is not registered as an active candidate until secondary reporting and verification of the candidate’s blood type have been completed.
The secondary reporting and verification of the candidate’s blood type must be completed by someone:
Other than the individual who reported the candidate’s blood type at registration on the waiting list
Using source documents from the two blood samples used for the blood type testing
Alcohol and drug toxicology levels
Virology screen, may include the following:
Hepatitis A virus
Hepatitis B virus
Hepatitis C virus
Human immunodeficiency virus (HIV)
Cytomegalovirus (CMV), IgG/IgM
Epstein-Barr virus (EBV)
Varicella-zoster virus (VZV)
Other tests
Liver biopsy.
Chest radiograph.
Electrocardiogram (ECG).
Echocardiogram (ECHO) and/or cardiac stress testing: dynamic or nuclear.
Pulmonary artery pressure and ejection fraction should be assessed. This may be done by echocardiogram or cardiac catheterization.
Ultrasound (US) scan of liver to assess patency of portal and hepatic veins and lookfor the presence of mass lesions.
If patency of portal vein cannot be documented on Doppler US, computed tomography (CT) imaging or magnetic resonance imaging (MRI) should be done.
Significant variation in normal anatomy of both the vascular and biliary trees in the liver may exist. This dictates the specific surgical approaches in transplantation; it is therefore important to map out these variations.
Spirometry tests are usually an adequate screen of lung function.
If readings are abnormal or lung function abnormality is suspected (e.g., alpha-1 antitrypsin or pulmonary fibrosis), formal lung function tests are required.
Upper endoscopy: to observe for esophageal varices.
Colonoscopy:
Primary sclerosing cholangitis, as these patients are at increased risk of colon cancer
Inflammatory bowel disease (Crohn’s disease or ulcerative colitis) to assess severity of disease or the presence of polyps or cancer
Age 50 or older who meet criteria for screening or diagnostic colonoscopy.
Interdisciplinary team consultations as indicated (e.g., infectious disease, oncology, etc.)
E. Candidate selection process
Patients are presented at an interdisciplinary transplant team selection meeting. During this meeting, candidates for transplant are discussed and evaluated based on the program’s inclusion and exclusion criteria.
Reasons for not accepting a patient for liver transplantation vary by individual program and may include the following:
HCC that is outside Milan criteria
Active substance abuse
Extrahepatic malignancy
Advanced cardiac or pulmonary disease
A demonstrated inability to be adherent with medication regimens and an overall lifestyle that is a barrier to successful transplant outcome.
VI. LISTING FOR TRANSPLANTATION AND ORGAN ALLOCATIONA. Split or reduced-size livers may be used for transplantation because of the regenerative capacity of the liver.
An adult patient can be listed to receive either a split or whole liver.
Pediatric patients can receive a whole, split, or reduced-size graft. (See chapter on Pediatric Transplantation for additional information.)
B. When a patient has been placed on the transplant waiting list in the United States, priority is based on the UNOS organ allocation policy.33,34
The current allocation is based either on the Model for End-Stage Liver Disease (MELD) scoring system for adults or the Pediatric End-Stage Liver Disease (PELD) scoring system, which are predictive models of death within a 3-month period.
The MELD score is calculated using serum creatinine, serum bilirubin, INR, and serum sodium.
As of January 2016, the MELD score has been modified to incorporate serum sodium.
The score ranges from 6 to 40.
MELD score is calculated using the following formula: 0.957 × loge (creatinine mg/dL) + 0. 378 × loge (bilirubin mg/dL) + 1.120 × loge (INR) + 0.643.
Laboratory values <1.0 will be set to 1.0 when calculating a candidate’s MELD score.
The following candidates will receive a creatinine value of 4.0 mg/dL:
Candidates with a creatinine value >4.0 mg/dL
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