Trends in the distribution of major indications for liver transplantation over the past decade in the United States. HCC hepatocellular carcinoma, HCV hepatitis C, ALD alcoholic liver disease, NASH nonalcoholic steatohepatitis, ALF acute liver failure
Alcoholic liver disease is another common cause of cirrhosis. Patients with alcoholic liver disease commonly have comorbidities such as Wernicke’s encephalopathy, malnutrition (including vitamin deficiency), and cardiomyopathy. It is important to maintain abstinence prior to transplantation, and some patients show stabilization and improvement of liver function such that transplantation is not required. Patients with substance abuse issues need an appropriate referral for a comprehensive evaluation and treatment. A multidisciplinary approach is required to address the multiple medical comorbidities related to cirrhosis and chronic illness as well as to ensure adequate psychosocial coping and a support structure to minimize the risk for recidivism. Any concern related to the patient’s compliance should be addressed before the patient is placed on the recipient list.
Acute Liver Failure
Hepatic failure occurs in patients without any previous history of chronic liver disease, and this rare disease entity is called fulminant hepatic failure or acute liver failure (ALF). Traditionally, fulminant liver failure was defined as severe liver injury in which hepatic encephalopathy occurred less than 8 weeks after the onset of symptoms in an individual without preexisting liver disease, whereas subfulminant liver failure was defined as an onset of encephalopathy after 8 weeks but before 26 weeks after the onset of symptoms. The previous subcategories of ALF based on timing and severity of clinical presentation—hyperacute as the onset of encephalopathy within 7 days, acute as the onset between 7 and 28 days, and subacute as the onset between 28 days and 24 weeks—are no longer advocated by the National Institutes of Health (NIH) working group .
In 2008, the NIH working group on acute liver failure recommended that the term “acute liver failure” is preferable and that the most reliable signs of severe acute liver injury are the presence of coagulopathy (international normalized ratio [INR] >1.5) and any degree of encephalopathy occurring within 24 weeks of the first onset of symptoms in patients without underlying liver disease . In 2014, acute liver failure accounted for 4 % of all liver transplantation indications in the United States. Acetaminophen (APAP) toxicity is the leading cause (40 %) of ALF. The other common etiologies are idiosyncratic drug-induced liver injury (13 %), hepatitis B infection (6 %), ischemic hepatitis (6 %), autoimmune hepatitis (4 %), Wilson’s disease (3 %), pregnancy (2 %), Budd-Chiari syndrome (2 %), malignancy (1 %), and indeterminate (17 %). Multiorgan failure is the most common cause of death from ALF, accounting for >50 %, followed by intracranial hypertension and infection. The progress of the disease is rapid once the patient develops encephalopathy and is associated with an extremely high mortality without OLT. With timely OLT, the long-term patient survival ranges from 60 to 80 %. As such, it is recommended to identify the etiology of ALF (i.e., APAP toxicity, mushroom poisoning, etc.), initiate an etiology-specific therapy for patients with ALF, and transfer the patients to a liver transplantation center as soon as ALF is suspected .
When Should Liver Transplantation Be Considered for Treatment of Liver and Bile Duct Cancers?
Curative treatment of hepatobiliary malignancy , complete extirpation of the tumor including all microscopically detectable disease, requires a multidisciplinary approach to provide the best chance for long-term tumor recurrence-free survival. It is prudent to have a comprehensive treatment plan in place prior to tumor manipulation. Incomplete resection (residual tumor) or invasive procedures (i.e. biopsy, locoregional therapy) increase the risk for tumor cell seeding that may negatively impact the overall patient survival. As such, all therapeutic modalities, including OLT, should be included in the initial treatment decision algorithm.
Hepatocellular carcinoma (HCC) is the most common type of liver cancer and a common indication for OLT. Hepatocellular carcinoma (HCC) accounts for 90 % of all primary liver cancers and it is projected to become the third leading cause of cancer-related death in the US by 2030. It is estimated that 80–90 % of all HCC cases result from cirrhosis. This explains the relatively high HCC morality rate, because management options are more limited in the setting of cirrhosis [11, 12]. Liver resection plays a limited role in HCC because of the higher rate of recurrence and post-hepatectomy liver failure in cirrhosis [12, 13].
OLT offers the best oncologic resection of HCC, treats cirrhosis, and restores normal hepatic function. The proportion of OLT for HCC has remarkably increased. In 2014, 25 % of OLTs in the US were for HCC (Fig. 36.1). HCC may recur even when OLT is performed without evidence of extrahepatic spread (e.g., major vascular invasion or distant metastasis). The Milan criteria were introduced to select patients with early HCC who would benefit from OLT. These criteria are based on the size and number of tumors: one lesion ≤5 cm or two or three lesions ≤3 cm. A systemic review reported a 5-year survival rate ranging from 65 to 78 % for patients who underwent OLT for HCC within the Milan criteria, which is comparable to the survival rate of patients with noncancer indications .
The current MELD system allows exception points to a patient with HCC meeting one of the following criteria: one lesion ≥2 cm and ≤5 cm or two or three lesions ≥1 cm and ≤3 cm. All eligible patients with HCC meeting specific criteria are immediately granted MELD exception points (independent of the patient’s calculated laboratory MELD score). In patients with localized HCC, OLT provides an excellent curative treatment for eligible patients, 5-year tumor recurrence-free survival between 60 and 70 %.
Cholangiocarcinoma (CCA) is a malignant neoplasm arising from epithelial cells of the extrahepatic and intrahepatic bile ducts, excluding the papilla of Vater and the gallbladder . CCA is the second most common primary hepatobiliary malignancy in the US. The incidence of CCA is increasing, and its prognosis remains grim without surgical treatment [16, 17]. Early diagnosis has been a constant challenge, because there is no effective screening test, and most patients with unresectable disease die within 6–12 months of diagnosis. Anatomically, CCA is classified into the proximal type, also known as hilar (HCCA), perihilar, or Klatskin tumors, that accounts for 60–70 % of cases; distal type for 20–30 %; and intrahepatic (ICCA) or peripheral for the remaining 5–10 %. The three different types of CCA have distinct pathophysiology, differ in their epidemiological features and clinical presentations, and vary in surgical treatments . The primary modality of treatment for HCCA is radical bile duct resection with partial hepatectomy; for ICCA, partial hepatectomy; and for the distal type of CCA, pancreaticoduodenectomy . For patients with unresectable HCCA or ICCA, OLT presents a viable option and has been reported to provide survival benefits . A predictive index for tumor recurrence after liver transplantation for locally advanced intrahepatic and hilar cholangiocarcinoma has been reported to facilitate patient selection. Based on this patient-tumor stratification system, a survival benefit of 5-year tumor recurrence-free of up to 78 % can be achieved with neoadjuvant therapy followed by OLT in the low risk category. There was no long-term survivor for patients in the high-risk group . However, current MELD allocation only grants exception points for patients with HCCA meeting stringent Mayo Criteria (Table 36.1).
Criteria for MELD exception for liver transplant candidates with cholangiocarcinoma
• Centers must submit a written protocol for patient care to the UNOS Liver and Intestinal Committee before requesting a MELD score exception for a candidate with CCA. This protocol should include selection criteria, administration of neoadjuvant therapy before transplantation, and operative staging to exclude patients with regional hepatic lymph node metastases, intrahepatic metastases, and/or extrahepatic disease. The protocol should include data collection as deemed necessary by UNOS.
• Candidates must satisfy diagnostic criteria for hilar CCA: malignant-appearing stricture on cholangiography and biopsy or cytology results demonstrating malignancy, carbohydrate antigen 19-9 >100 U/mL, or aneuploidy. The tumor should be considered unresectable on the basis of technical considerations or underlying liver disease (e.g., PSC).
• If cross-sectional imaging studies (CT scan, ultrasound, MRI) demonstrate a mass, the mass should be ≤3 cm.
• Intra- and extrahepatic metastases should be excluded by cross-sectional imaging studies of the chest and abdomen at the time of initial exception and every 3 months before score increases.
• Regional hepatic lymph node involvement and peritoneal metastases should be assessed by operative staging after completion of neoadjuvant therapy and before LT. Endoscopic ultrasound-guided aspiration of regional hepatic lymph nodes may be advisable to exclude patients with obvious metastases before neoadjuvant therapy is initiated.
• Transperitoneal aspiration or biopsy of the primary tumor (either by endoscopic ultrasound, operative, or percutaneous approaches) should be avoided because of the high risk of tumor seeding associated with these procedures.
When Should Evaluation for Liver Transplantation Be Considered?
Regardless of the etiology of cirrhosis, patients may suffer from complications of portal hypertension and hepatic dysfunction, including hepatic encephalopathy, variceal bleeding, ascites, spontaneous bacterial peritoniti s and/or hepatorenal syndrome . While the initial episodes of hepatic decompensation typically respond well to medical treatments, the underlying liver disease progresses, which leads to more frequent and severe occurrences of these complications. For patients with decompensated cirrhosis, the annual mortality and 5-year patient survival rates are approximately 20 % and 50 %, respectively.
The etiology of the patient’s liver disease generally dictates the timing for referral to a transplant center or specialist. In patients with cirrhosis, the progression of the disease is initially slow and may take many years. However, once the patient shows the first signs of complications of cirrhosis, it is difficult to predict the clinical course of the patient, and the patient’s health condition may rapidly deteriorate. Furthermore, chronic illness frequently leads to multiple patient comorbidities, i.e., malnutrition, debilitation, psychosocial issues, cardiopulmonary risk factors, that need to be addressed prior to orthotopic liver transplantation (OLT) . As such, it is recommended to start the evaluation of the patient’s candidacy for OLT after the first episode of hepatic decompensation, defined a major complication of cirrhosis, i.e., variceal hemorrhage, and hepatorenal syndrome.
In those with acute (fulminant) liver failure, the course of the disease is rapid and the risk of death without transplantation is extremely high. Whenever this diagnosis is suspected, early transfer to a transplant center is imperative in order to ensure timely evaluation and if deemed suitable for liver transplantation, medical optimization, and subsequent OLT. It is important to take into consideration the inherent waiting time for organ availability for transplantation due to an ongoing organ crisis.
How Long Is the Waiting Time for a Deceased-Donor Liver After Placement on the Waiting List?
For patients with end-stage liver disease, OLT is the only life-saving treatment modality. With the scarcity of organs for transplantation, the current Model for End-Stage Liver Disease/Pediatric End-Stage Liver Disease (MELD/PELD) liver allocation system prioritizes the organ based on medical urgency based on the patient’s risk of death while awaiting liver transplantation. In short, the deceased donor liver graft is allocated for the sickest patient on the waiting list, based on the patient’s MELD score, to reduce the number of patients dying while on the waiting list.
For patients 12 years of age and older, the MELD scoring system uses the patient’s values for serum bilirubin , serum creatinine, and the international normalized ratio to predict the 90-day mortality risk while on the waiting list. It is calculated according to the following formula :
UNOS has made the following modifications to the score:
For candidates with an initial MELD score greater than 11, the MELD score is then re-calculated as follows:MELD Score = MELD(i)+1.32*(137-Na)−[0.033*MELD(i)*(137-Na)]MELD(i) is initial MELD score without consideration of serum sodium values. Sodium values less than 125 mmol/L will be set to 125, and values greater than 137 mmol/L will be set to 137.
If the patient has been dialyzed twice within the last 7 days, then the value for serum creatinine used should be 4.0
Any value less than 1 is given a value of 1 (i.e., if bilirubin is 0.8, a value of 1.0 is used) to prevent the occurrence of scores below 0 (the natural logarithm of 1 is 0, and any positive value below 1 would yield a negative result)
MELD score ranges from 6 to ≥40. Patients having a MELD score < 9 are associated with 1.9 % mortality whereas patients having a MELD score ≥40 are associated with a mortality rate of >70 %.
For patients less than 12 years of age, the PELD scoring system uses the values for serum bilirubin, serum albumin, INR, whether or not the patient is less than 1 year old, and whether or not the patient has growth failure (<−2 standard deviation) to predict survival.
While the MELD score correlates well with a 3-month risk of mortality for the majority of the patients on the waiting list, there are some conditions associated with chronic liver disease that may diminish patient survival but that are not directly accounted for in the MELD scoring system. In short, the severity of illness in patients with certain liver disease types and comorbidities may not be reflected on the patient’s calculated laboratory MELD score. For patients who meet these specific disease-related criteria, MELD exception s points maybe granted. These standard MELD exceptions were developed to more accurately reflect the patient’s mortality risk while awaiting OLT. Standard MELD exceptions include: HCC, hepatopulmonary syndrome, portopulmonary hypertension, familial amyloid polyneuropathy, primary hyperoxaluria, hilar cholangiocarcinoma, and hepatic artery thrombosis occurring within 14 days after OLT.
The implementation of the MELD/PELD system has decreased the mortality rate while on the waiting list. It is important to note that while the MELD scoring system is a powerful predictor of pre-transplant survival, it does not predict survival rate after OLT.
Allocation of Liver Grafts
It is estimated that approximately 3000 patients on the liver transplantation waiting list become too sick and die every year in the US. Therefore, it is imperative to have an effective and fair organ allocation system. The first national computer-based matching system was introduced in 1977 by the United Network for Organ Sharing (UNOS) , an independent nonprofit organization. The organ allocation policy has been revised multiple times, and allocations are based on three major factors: geographic location, ABO blood type, and the severity of illness of the patients. UNOS divided the US into 11 regions and 59 service areas, and organs are primarily allocated by this geographic system. Blood type is another important consideration. In general, ABO-incompatible deceased liver transplantation is not performed due to the high incidence of posttransplant liver failure and severe ischemic cholangiopathy. The third and the most important factor is the severity of illness of a patient, and to improve the allocation efficiency, UNOS has been using the model for end-stage liver disease (MELD) score to prioritize candidates for liver transplantation since 2002. The MELD score was originally introduced to predict mortality in cirrhotic patients undergoing a transjugular intrahepatic postosystemic shunt procedure. Multiple follow-up studies have validated that the MELD score correlates to the 3-month mortality rate of cirrhotic patients in a variety of settings. For example, a prospective observational study of 3437 adult liver transplant candidates reported that the 3-month mortality rate in patients with a MELD score of less than 9 was 2 %; in contrast, the mortality rate of patients with a MELD score of 40 or higher was 71 % . The MELD score is based on the results of three blood tests: the prothrombin time international normalized ratio (PT-INR) and the serum levels of total bilirubin and creatinine. Because this score is based on objective laboratory findings, the process has become more transparent and efficient. An Internet-based calculation tool is also available at the Organ Procurement and Transplantation Network (OPTN) website, and it notes that a candidate for liver transplantation has a MELD score ranging from 6 to 40 . The MELD score has also been utilized to stratify the risk of patients. Waitlist and posttransplant mortality analyses have demonstrated that patients with a MELD score that is less than 15 do not gain survival benefit from liver transplantation . On the other hand, if a patient’s MELD score is 35 or higher, UNOS prioritizes the patient to a liver graft from donors in the expanded geographic area in order to increase the probability of an organ offer for that sick patient. It is important to note that the MELD score, which is a powerful predictor of pre-transplant survival, does not predict survival rate after liver transplantation.
In some specific patient groups, the MELD score does not reflect the severity of the liver disease or the patient’s actual waiting list mortality risk. Liver function may be normal in patients with HCC, and an allocation system based on “raw” MELD score may not allow a timely transplant prior to cancer progression beyond transplant eligibility. For HCC patients whose outcome after liver transplantation is reasonably good enough to justify the use of deceased-donor organs (a 5-year tumor recurrence-free survival between 60 and 70 %), the current MELD system allows exception points to the patients with HCC meeting one of the following criteria: one lesion ≥2 cm and ≤5 cm or two or three lesions ≥1 cm and ≤3 cm. Prior to October 8, 2015, all eligible patients with HCC meeting specific criteria were immediately granted MELD exception points of 22 (independent of the patient’s calculated laboratory MELD score), which is equivalent to 15 % risk of 3-month mortality. However, 5 % of all HCC patients still dropped out within 3 months of the listing . Additional MELD points were granted every 3 months as long as the patient remained within Milan criteria. While HCC patients are waiting on the list, various types of locoregional therapies (i.e., transarterial embolization (TACE) , microwave ablation, Yttrium 90 radioembolization, radiofrequency ablation) are available to control tumor burden progression . These neoadjuvant therapies have been effective bridge treatments to OLT.
Most recently, a revision to the OPTN/UNOS policy on the timing of exception scores assigned and maximum value of exception scores for candidates with HCC was implemented on October 8, 2015. The revised policy is intended to create a better balance in transplant opportunities between candidates with HCC and those with allocation priority based on their calculated MELD and PELD scores. Under this modification, a new timetable delays assignment of new or extended exception scores. The transplant candidate will be registered with their calculated MELD and PELD scores for at least 6 months and should remain within the HCC criteria prior to receiving a MELD exception score of 28 and PELD score of 34. The revised policy also capped a maximum MELD exception score of 34 for transplant candidates meeting the HCC criteria.
Patients with unresectable, localized hilar cholangiocarcinoma can be considered for liver transplantation after neoadjuvant radio-chemotherapy, and they receive MELD exception points at a UNOS-qualified transplant center. On the other hand, the survival benefit from liver transplantation in patients with intrahepatic cholangiocarcinoma is being debated, and under the current UNOS policy, they do not receive MELD exception points . Other examples of the MELD exception include hepatopulmonary syndrome, portopulmonary hypertension, and neuroendocrine tumor liver metastasis.
Acute liver failure is a rare, lethal, and rapidly progressing type of liver disease. Therefore, UNOS classifies the disease as a special category called “Status 1A.” To be listed as Status 1A, an acute liver failure patient must meet at least one the following criteria: ventilator dependence, requirement of dialysis (or continuous hemofiltration), or an international normalized ratio (INR) greater than 2.0. Status 1A patients get top priority for liver organs over all other candidates, regardless of their MELD score. In general, with the exception of Wilson’s, acute decompensation of the underlying liver disease is not considered to be a criterion for Status 1A. The immediate failure of liver transplantation (primary nonfunction or hepatic artery thrombosis) is also categorized as Status 1A. All other potential liver transplantation patients receive points based on their MELD score or the MELD exception criteria.
The Key Considerations and Contraindications for Liver Transplantation
Liver transplantation is a spectrum of care including the donor/recipient selection, the surgical procedure, the postoperative management with immunosuppression , education, and rehabilitation. The candidacy should be evaluated from many different angles with the best prediction of short-term and long-term outcomes. The candidate’s overall medical history, including the status of the primary liver disease, should be reviewed, and a posttransplant management plan should be established. When the candidate is on the list and eventually receives the organ offer, the quality of the donor and the physical condition of the candidate should be evaluated before the final decision for transplantation is made (Table 36.2).
Contraindications to liver transplantation
Other systemic factors
• Severe coronary artery disease or valvular heart disease not amenable to treatment
• Persistent severe pulmonary hypertension with medical treatment
• Severe respiratory failure with maximum ventilator support
• Shock with maximum use of vasopressor agents
• Uncontrolled active infection
• A recent history of cancer from nonhepatic origin with high risk of recurrence
• Any cancer with distant metastasis
• Irreversible severe brain injury
• Significant psychosocial issues precluding recovery from transplantation
Careful review of the candidate’s medical history is an important initial step. Severe hemodynamic instability is not infrequent during a liver transplantation procedure and the candidate’s baseline cardiopulmonary function should be healthy enough to tolerate it. In addition to the risk factor assessment, electrocardiograms and echocardiograms are used to screen candidates for ischemic heart disease, congestive heart failure, valvular heart disease, and arrhythmias. Patients at risk of coronary artery disease, especially those who are elderly or who have diabetes, need a coronary angiogram. Severe coronary artery disease or valvular heart disease, which are not amenable to treatment, preclude liver transplantation. If the echocardiogram result suggests high right ventricular systolic pressure, right heart catheterization is indicated. If the right heart catheterization confirms significant pulmonary hypertension, appropriate medical treatment should be offered to correct it, because the outcome of liver transplantation with persistent severe pulmonary hypertension is dismal. Patients whose pulmonary hypertension responds to medical therapy are considered candidates for transplantation. Patients with fluid overload from acute kidney injury may underestimate the cardiac function and they may require dialysis for an accurate estimation of that function. Some patients have hypoxemia from hepatopulmonary syndrome, and the 5-year mortality rate of those patients reaches 76 % without liver transplantation; however, liver transplantation can decrease the mortality rate to 23 % . UNOS assigns MELD exception points to a patient with significant hepatopulmonary syndrome. After liver transplantation, the hypoxia gradually recovers within a period of 3 months or more. When a suitable donor is available, the cardiopulmonary function of the patient should be re-evaluated. A patient with severe respiratory failure or with shock who requires maximum supportive care cannot tolerate surgical stress from liver transplantation. Uncontrolled active infection, such as pneumonia, is also a known contraindication.
Renal dysfunction is relatively common in patients with liver cirrhosis and ascites. Accurate assessment of renal function is difficult as the Cockcroft-Gault equation overestimates the glomerular filtration rate (GFR) in cirrhotic patients. The Modification of Diet in Renal Disease (MDRD-6) equation with six variables has been suggested as an alternative calculation method for cirrhotic patients . Assessment of renal function in liver transplant candidates is important, because patients with renal impairment frequently develop metabolic acidosis, hyperkalemia , and volume overload during liver transplantation. Planned intraoperative renal replacement therapy can improve the outcome in patients with renal impairment . Hepatorenal syndrome (HRS) is an important cause of acute kidney injury in cirrhotic patients, and the patient’s kidney function may return after liver transplantation in 58–94 %. However, 1-year patient survival after liver only transplantation in hepatorenal syndrome was reported low at 66–74 %. Therefore, patients with irreversible acute kidney injury and advanced chronic kidney disease require a combined liver and kidney transplantation. In light of the fact that GFR of liver transplantation recipients drops up to 40 %, consideration for combined liver and kidney transplantation should be individually evaluated. Criteria for combined liver-kidney transplantation based on GFR from MDRD-6 were proposed, but there is a wide disparity in the selection criteria for a simultaneous combined liver and kidney transplantation among transplantation centers [29, 30].