Cumulative proportion of patients transitioning from a compensated to a decompensated stage. Data from D’Amico et al. 
Cumulative risk of complications from cirrhosis over time. Data from Gentilini et al. 
Some clinical scenarios in patients with ESLD which should prompt the clinician to initiate the transplant evaluation process include:
Development of portal hypertension including bleeding secondary to gastroesophageal varices
Development of new ascites or complications related to ascites: refractory ascites (need for large volume paracentesis despite optimal diuretic therapy), spontaneous bacterial peritonitis (SBP), hepatorenal syndrome (HRS)
Onset of hepatic encephalopathy (HE).
Diagnosis of hepatocellular carcinoma (HCC)
Other pulmonary complications including portopulmonary hypertension (PPH) and hepatopulmonary syndrome (HPS)
Worsening hepatic synthetic function as manifested by low serum albumin and coagulopathy.
One of the objective ways to assess progression of liver disease is calculation of the Child-Turcotte-Pugh [CTP ] score [1, 2]. It was originally designed to predict mortality following surgery and later became a useful parameter to determine severity and prognosis of liver disease. The CTP score was also used to determine candidacy for liver transplantation (score greater than 7) until it was replaced by the Model for End-Stage Liver Disease [MELD] score .
The MELD score is calculated using the serum bilirubin, INR and creatinine level, and was originally developed to predict 30 day mortality in patients with cirrhosis who underwent a procedure such as the transjugular intrahepatic portosystemic shunt [TIPS] . As of 2002 the MELD score is used to prioritize organ allocation for LT.
Common etiologies of liver failure requiring LT may be categorized into acute versus chronic as presented in Table 26.1. Following is a brief description of individual etiologies of LT.
Common etiologies of liver failure which may require liver transplantation
Acute/fulminant liver failure
Hepatitis A, B, C, HSV, EBV, CMV
Drugs and toxins
Acetaminophen, Mushroom poisoning
Budd-Chiari syndrome, Sinusoidal Obstruction Syndrome
Pregnancy related, Rye’s syndrome
Chronic liver disease
Less common liver cancers include hepatoblastoma and fibrolamellar variant of HCC
Primary Biliary Cirrhosis, Primary Sclerosing Cholangitis, separate the pediatric etiologies; this may come in the last section of this table Biliary atresia, Alagille syndrome, Cystic Fibrosis
Autoimmune hepatitis-induced liver cirrhosis
Inherited disorders leading to liver cirrhosis
Hemochromatosis, Wilson Disease, Alpha-1-Antitrypsin Deficiency
Nonalcoholic steatohepatitis (NASH should be separate), cryptogenic cirrhosis, following this should be put in one bucket: amyloidosis, sarcoidosis, hyperoxaluria, urea cycle defects, polycystic liver disease, glycogen storage disease
Acute Liver Failure
Acute liver failure refers to the development of severe acute liver injury with encephalopathy and impaired synthetic function (INR of ≥1.5) in a patient without cirrhosis or preexisting liver disease . While the time course that differentiates acute liver failure from chronic liver failure varies between reports, a commonly used cut-off is an illness duration of <26 weeks .
Acute liver failure may also be diagnosed in patients with previously undiagnosed Wilson disease, vertically acquired hepatitis B virus, or autoimmune hepatitis, in whom underlying cirrhosis may be present, provided the disease has been recognized for <26 weeks .
Most patients requiring liver transplant following ALF have good prognosis as long as there is no significant neurologic deficit prior to liver transplant . The King’s College Criteria are used to identify patients who are unlikely to recover spontaneously without liver transplant (Table 26.2) . It is imperative to identify these patients to expedite transplant evaluation and listing. In a study conducted at 17 referral centers in US between 1998 and 2001, acetaminophen overdose (39 %) and idiosyncratic drug reactions (13 %) were the most common causes of liver failure . Further the survival of these patients was dependent on etiology (patients with acetaminophen overdose had better outcomes) and neurologic status at presentation .
King’s College criteria for liver transplantation in patients with acute liver failure (ALF)
Arterial pH < 7.3
Grade 3 or 4 encephalopathy AND
Prothrombin Time >100 s AND
Serum creatinine >3.4 mg/dL
Other causes of ALF
Prothrombin time >100 s OR
Any three out of the following variables:
Age <10 years or >40 years
Non-A, Non-B hepatitis, idiosyncratic drug reactions
Duration of jaundice before development of encephalopathy greater than 7 days
Prothrombin time >50 s
Serum bilirubin >18 mg/dL
Presence of intracranial hypertension may be suspected based on assessment of physical signs such as impaired pupillary responses and posturing or may be based on direct measurement of intracranial pressure (ICP). If increased ICP is detected osmotically active agents such as mannitol may be used. In patients with renal insufficiency or those who have resistant intracranial hypertension barbiturates such as thiopental may be used. The potential for liver assist devices as definitive therapy or bridge to transplantation in ALF is an area of active investigation .
Alcoholic Liver Disease
Patients with decompensated liver disease secondary to alcohol abuse may benefit from LT since studies have shown similar graft and patient survival in patients with alcoholic liver disease when compared to other indications . This is possible after candidates for LT complete an alcohol rehab program (such as alcoholics anonymous) with documented period of sobriety for at least 6 months. This is to address concerns regarding recidivism and poor compliance to medical therapy following LT. It is important to recognize and treat comorbid psychiatric conditions such as anxiety and depression.
A proportion of patients resume drinking alcohol following liver transplant . A high index of clinical suspicion and periodic alcohol screens on the liver transplant wait list are required since patients may not volunteer this information. Even though there is no conclusive data whether this behavior translates into reduced patient or graft survival it is important to recognize and address alcohol abuse post LT. Another cause for mortality in patient with alcoholic liver disease posttransplantation is related to head, neck, and lung cancer which is a result of high risk behavior such as smoking. This is why all prospective transplant candidates undergo a pre transplant ENT evaluation.
Although controversial, early liver transplantation can improve survival in patients with the first episode of severe acute alcoholic hepatitis (AAH) which is not responding to medical therapy . In this study, severity of AAH was defined as Maddrey’s discriminant function of greater than 32. Nonresponse to medical therapy was defined as per the Lille model with a score of more than or equal to 0.45, 7 days after medical treatment, or a continuous increase in the MELD score. Medical therapy constituted of standard treatment of patients with acute liver failure in addition to prednisolone for at least 7 days.
Several important developments in prevention of graft reinfection with hepatitis B virus [HBV] has improved graft and patient survival following LT. Initial results of LT for HBV were disappointing because of the development of recurrent HBV infection resulting in death within 12–18 months after the transplant [12, 13]. Perioperative treatment with hepatitis B immune globulin and anti-viral agents has reduced the prevalence and severity of post-liver transplant reinfection with HBV [14, 15]. As a result excellent graft and patient outcomes are now routine and post-transplant survival of patients with HBV exceeds that for other indications.
Patients with chronic HBV infection with positive HBV DNA levels should receive optimal duration of anti-viral therapy prior to liver transplantation. Agents available for use include entecavir or tenofovir, the goal being to render the patient HBV DNA negative prior to liver transplantation, to lower the risk of graft reinfection with HBV.
Recent studies have shown that fewer patients with HBV registered for liver transplantation have ESLD and the increase in HCC is lowest in HBV patients when compared to patients with other indications for LT. This is most likely secondary to widespread use of highly effective antiviral therapy .
Recent data suggests that prevalence of HCV infection and related complications will continue to increase over the next decade mostly affecting patients over 60 years of age as shown in Fig. 26.3 . Current treatment strategies will likely have little impact on these outcomes. However widespread use of newer anti-HCV agents will significantly reduce the impact of HCV in future .
(a) Prevalence of HCV infection with respect to year and chronicity of HCV infection. (b) Stacked prevalence curves showing prevalence of HCV related cirrhosis according to age and gender at time of initial HCV virus infection. Data from Davis et al. 
Given the recent approval of an oral polymerase inhibitor, sofosbuvir for the management of chronic HCV, treatment of patients with HCV prior to LT can prevent HCV recurrence in the majority of patients who become HCV RNA negative at transplantation .
Recurrent HCV infection results in reduced patient and graft survival post LT. It is important to identify and treat patients at risk for rapid progression of liver fibrosis. This is because patients with an initial (within 3 years post liver transplant) mild recurrence could progress to cirrhosis within 5 years . Several studies have identified predictors of severe recurrent HCV infection. These include high viral load pre- and post liver transplantation, older deceased donor age, and multiple episodes of acute cellular rejection .
Cholestatic Liver Disease
Patients with ESLD secondary to Primary Biliary Cirrhosis [PBC ] and Primary Sclerosing Cholangitis [PSC] are candidates for liver transplant with 1 and 3 year survival close to 90 % and 85 % respectively . Patients should be referred for liver transplant evaluation when their survival as predicted by Mayo risk score is less than 95 %.
PBC is a chronic cholestatic disorder most commonly seen in middle aged women and may progress to cirrhosis. Numerous studies have shown survival benefit for patients who undergo liver transplantation which is evident as early as 3 months after surgery . Most patients have excellent prognosis after liver transplant with 10 year survival close to 70 % [21, 22]. Some patients with PBC who have disabling pruritis and sleep disturbance despite maximal medical therapy may need to be evaluated for liver transplantation due to disabling symptoms.
PSC is a stricturing disease involving the intra and extra-hepatic bile ducts and typically occurs in young men. There is no specific treatment and patients develop liver cirrhosis within 10–15 years. About 75 % of these patients have concomitant inflammatory bowel disease . Liver transplantation has been shown to have survival benefit for patients with PSC [24, 25]. Success after liver transplantation is shown by 3 year survival rates that exceed 90 % [26–28]. Recurrent disease is common after liver transplantation but does not tend to have significant impact on posttransplant survival unless patient is discovered to have cholangiocarcinoma before or during surgery . While awaiting liver transplantation, patients with PSC require surveillance for cholangiocarcinoma, the usual approach being six monthly serum tumor markers—Ca 19-9; CEA and cross-sectional abdominal imaging—MRI abdomen/MRCP.
Most cases of primary hepatocellular carcinoma [HCC] occur in the setting of underlying cirrhosis one exception being chronic HBV infection where HCC may develop in the absence of cirrhosis. Certain patient populations such as those with hemochromatosis are also at high risk for HCC.
HCC is one of the primary indications for liver transplantation in the US and currently 20 % of liver transplants are performed for HCC. About half of these are secondary to allocation of exception MELD points for patients who are within MILAN criteria [see definition below]. The survival rate post LT for HCC is similar to those for patients with decompensated cirrhosis without HCC.
Based on the Milan criteria successful LT may be carried out with a single lesion of diameter >2 cm and <5 cm or no more than three lesions provided that the largest is no greater than 3 cm without any vascular invasion, locoregional lymphadenopathy, or distant metastasis . There is recent criticism for Milan criteria to be excessively restrictive and various expanded criteria have been suggested to extend the tumor size and number without compromising patient survival . The UCSF criteria allows LT in patients with a single lesion smaller than 6.5 cm; in patients with three or fewer nodules with the largest being smaller than 4.5 cm, or total diameter less than 8.5 cm without any evidence of vascular invasion .
Pre liver transplant evaluation of patients with HCC includes assessment of locally advanced and distant disease. A bone scan and computed tomography (CT) of chest is obtained to investigate for extra-hepatic spread of the tumor. The current wait times for LT for patients with HCC despite a MELD upgrade vary from 3 to 12 months. Hence strategies need to be devised to provide bridge therapies to LT in this patient population. In addition living donor liver transplantation may be an alternate option for liver transplantation in selected patients.
Recurrent tumor tends to occur in the graft due to micrometastasis in the vascular system. As a result several adjuvant treatments have been devised while awaiting liver transplantation . An important strategy to expand criteria for liver transplantation is to downstage the tumor with the use of loco-regional therapy so that it meets Milan criteria. One such approach is using trans-arterial chemoembolization (TACE) in selected patients with stage III/IV HCC; the tumor can be downstaged with TACE resulting in outcomes similar to stage II HCC . Another strategy is radio-frequency ablation (RFA) which is being increasingly adopted in the management of these patients and has been shown to result in good tumor-free survival rates . Oral therapy with sorafenib is being studied as a possible agent for adjuvant therapy post resection or liver transplantation in patients with HCC [35, 36].
Metabolic disorders requiring liver transplantation can be divided into disorders that manifest as liver injury (Wilson’s disease and Hereditary hemochromatosis) and disorders that do not manifest as obvious liver disease (familial hyperoxaluria and hypercholesterolemia). The two most common indications for liver transplantation in adults are Wilson’s disease and hemochromatosis.
Wilson’s disease : Most patients with CLD secondary to Wilson disease have good response to chelating therapy . Some patients who develop ESLD and suffer from complications may become candidates for LT. A small proportion of patients with Wilson disease develops ALF and requires urgent LT. Good long-term survival has been reported for patients with Wilson disease after LT . There is conflicting reports regarding neurologic improvement following LT [38, 39].
Hereditary Hemochromatosis : Phlebotomy is the primary treatment for patients with hemochromatosis and may result in normal life expectancy. In patients who progress to ESLD with associated complications including HCC the only effective treatment is LT.
Nonalcoholic Fatty Liver Disease (NAFLD)
NAFLD has been projected to become one of the common indications for LT. The post-transplant course of these patients may be complicated by many of the same risk factors which are present prior to LT. These include diabetes, obesity, hypertension, and hyperlipidemia. These may be worsened post LT under the influence of the immunosuppressive regimen. Recurrence of NAFLD post LT can lead to graft injury however graft loss does not typically occur and 1, 3, and 5 year survival rates are similar when compared to patients who get LT for indications other than NAFLD . Liver Steatosis may represent a late complication of LT in some patients . Management of post transplant NAFLD is similar to pre transplantation and involves dietary and lifestyle intervention and use of lipid lowering therapy. In a recently published case series a select group of patients underwent Roux-en-Y gastric bypass after LT with good outcomes including therapeutic weight loss, better glycemic control, and lower LDL levels .
Budd Chiari syndrome (BSC) is characterized by hepatic venous outflow obstruction which in most instances is secondary to thrombosis. This condition is frequently associated with an underlying prothrombotic state. Treatment approaches for this condition range from medical (i.e. anticoagulants and diuretics) to invasive including angioplasty, transjugular intrahepatic portosystemic shunt (TIPS), surgical portosystemic shunts, and LT.
Various scoring systems have been described to support medical decision making in these patients as shown in Table 26.3. The Rotterdam score has been reported to predict survival in patients with BCS at the time of admission  whereas the BCS-TIPS prognostic index score predicts transplant-free survival in patients who received TIPS . A large prospective multicenter study validated the Rotterdam score to predict intervention-free survival and BCS-TIPS score for survival . Moreover the authors suggested a step wise approach in the management of patients with BCS from medical to more invasive therapies based on clinical situation .
Scoring systems that may be used in clinical decision making for patients with BCS
Rotterdam score 
BCS-TIPS prognostic index score 
• 1.27 × encephalopathy + 1.04 × ascites + 0.72 × prothrombin time + 0.004 × bilirubin (where ascites was scored as present “1” or absent “0”)
• Age (years) × 0.08 + bilirubin (mg/dL) × 0.16 + international normalized ratio (INR) × 0.63
• The 5-year survival rate was 89 % (95 % confidence interval [CI]: 79–99) for class I (good prognosis), 74 % (95 % CI: 65–83) for class II (intermediate prognosis), and 42 % (95 % CI: 28–56) for class III (poor prognosis)
• The cutoff of 7 points had a sensitivity of 58 %, a specificity of 99 %, a positive predictive value of 88 %, and a negative predictive value of 96 % for death or OLT 1 year after TIPS
Autoimmune Hepatitis (AIH)
LT is indicated for patients with AIH who present with ALF or those with ESLD and associated complications who fail to respond to immunosuppression. In patients with ALF predictors of need for LT despite corticosteroid therapy include MELD score >28, massive necrosis on liver histology, no significant decline in bilirubin and INR values 4 days into treatment, and unchanged MELD-Na score after 1 week of corticosteroids [46, 47]. Once LT is performed patients need combination of prednisolone and calcineurin inhibitor with excellent outcomes. There should be low index of suspicion for recurrence of AIH once steroids are tapered. In such instances treatment with steroids and azathioprine is usually successful [48, 49]. Acute severe AIH or fulminant AIH may also represent an indication for LT.
Absolute and Relative Contraindications of LT
There are several conditions which may present absolute or relative contraindications for LT. Generally patients should be “medically fit” to tolerate the physiological stress on the human body due to LT. One of the aims of pre LT evaluation is to identify patients who do not meet the required medical criteria for LT as described below.
Hepatic and Extra-hepatic Malignancy
HCC is one of the common indications for LT. Some tumor characteristics such as large size (beyond Milan Criteria) present contraindication to LT. Other hepatic tumors such as angiosarcoma have an extremely poor outcome following transplantation and their presence is an absolute contraindication to liver transplantation.
In regard to extra-hepatic malignancies there should be a substantial disease-free duration after curative therapy for a patient to be considered a candidate for LT. This may depend in part on the particular malignancy. Most transplant centers would consider 5 year disease-free survival as appropriate for LT, however, for some cancers such as malignant melanoma a longer duration may be required .
Alcohol and Substance Abuse
Current alcohol and illicit drug use is an absolute contraindication to liver transplantation because of concern for compliance to medical treatment following LT. History of narcotic drug use such as methadone is a cause of concern for pain management post LT, however it is not a contraindication for LT [51, 52]. Use of NSAIDs prior to LT should be avoided due to concern for kidney dysfunction and gastrointestinal distress.
Smoking is also prohibited due to risk for potential adverse effects such as hepatic artery thrombosis and malignancy post liver transplantation. In one study on patients with ESLD active smoking was found to be associated with higher mortality post LT and this was primarily related to increased incidence of cardiovascular and sepsis related events . Herbal supplements may be associated with drug interactions so their use should be avoided in the post LT setting.
With advances in surgical techniques vascular abnormalities such as portal vein or superior mesenteric vein thrombosis are no longer a contraindication to performing liver transplantation though it may require more extensive vascular reconstruction. Some patients who cannot undergo vascular reconstruction may need to be considered for multi-visceral transplantation
Patients with ESLD have a similar prevalence of coronary artery disease (CAD) when compared with age matched controls . Risk factors for CAD in this patient population include diabetes, hypertension, hyperlipidemia, and obesity. In patients post LT immunosuppression may be a risk factor for hypertension. Patients with NAFLD who undergo LT may be at higher risk for CAD post liver transplantation . All patients undergo cardiac work-up including stress testing prior to LT.
Most patients with ESLD cannot undergo routine exercise stress testing because of poor stamina. These patients usually undergo dobutamine stress echo and in patients selected for LT it has a high negative predictive value for perioperative and long-term cardiac events . Cardiac catheterization with angioplasty and stenting may be performed as clinically indicated however coronary artery bypass surgery may be associated with prohibitive risk in terms of bleeding and postoperative complications. Patients who undergo LT for hemochromatosis may have a higher risk of cardiac arrhythmias in the postoperative setting. Current guidelines mandate updating the stress test on a yearly basis while awaiting transplantation
Pulmonary evaluation is an important component in the pre liver transplant assessment of patients with ESLD. This is because pulmonary circulation may be affected as a result of cirrhosis and portal hypertension. It is also important to have a low index of suspicion for certain preexisting conditions such as chronic obstructive pulmonary disease and pulmonary fibrosis since these are generally a contraindication for LT.
Hepatopulmonary syndrome (HPS) is a result of dilation of the pulmonary vasculature leading to formation of arteriovenous fistulae. Portopulmonary hypertension (PPH) is a consequence of pulmonary vascular constriction. Both disorders can result in abnormal oxygenation and should be evaluated to determine candidacy for LT.
The hepatopulmonary syndrome (HPS ) is characterized by triad of ESLD, intrapulmonary vascular dilations (IPVDs) (with right to left shunting) and hypoxemia (PaO2 < 70 mmHg on an ABG in the supine position). The diagnosis of HPS can be confirmed by demonstration of intrapulmonary vascular dilations by contrast enhanced echocardiogram (usually performed with agitated saline). The demonstration of air bubbles in the left atrium within three cardiac beats after visualization of the right atrium is diagnostic of IPVDs. Perfusion lung imaging with 99mTc-labeled macroaggregated albumin is an alternative technique to investigate for IPVDs but is considered less sensitive than echocardiography .