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 [4]. 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 [4].

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 [4].

Most patients requiring liver transplant following ALF have good prognosis as long as there is no significant neurologic deficit prior to liver transplant [5]. The King’s College Criteria are used to identify patients who are unlikely to recover spontaneously without liver transplant (Table 26.2) [6]. 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 [7]. Further the survival of these patients was dependent on etiology (patients with acetaminophen overdose had better outcomes) and neurologic status at presentation [7].

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 [8].

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 [9]. 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 [10]. 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 [11]. 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 [16].

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 [17]. 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 [17].

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 [18].

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 [19]. 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 [19].

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 [20]. 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 [21]. 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 [23]. 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 [29]. 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 [30]. 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 [31]. 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 [31].

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 [32]. 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 [33]. 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 [34]. 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.

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 [40]. Liver Steatosis may represent a late complication of LT in some patients [41]. 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 [42].

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 [43] whereas the BCS-TIPS prognostic index score predicts transplant-free survival in patients who received TIPS [44]. A large prospective multicenter study validated the Rotterdam score to predict intervention-free survival and BCS-TIPS score for survival [45]. 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 [45].

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.

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.