Indications
Contraindications
Absolute
Relative
1. Young patient < 50 years
1. Age > 55 years
1. Age > 50 years
2. No viral infection
2. HBsAg–HBeAg-positive state
2. HBsAg-positive state
3. No alcohol and drug abuse
3. Active alcoholism
3. Intrahepatic or biliary sepsis
4. Ability to accept procedure/understand its nature
4. Inability to accept procedure or understand its nature or costs
4. Advanced alcoholic liver disease in abstinent alcoholic
5. Ability to accept costs
5. Sepsis outside hepatobiliary system
5. Prior abdominal surgerya
6. Normal vessel state
6. Portal vein thrombosis
6. Portal hypertension surgery
7. No CP or renal disease
7. Advanced CP or renal disease
8. No prior abdominal surgery
8. Severe hypoxemia (right to left shunts)
9. No infection
9. Metastatic hepato-biliary malignancy
10. No (advanced) malignancy
10. Primary malignant disease outside hepatobiliary system
Table 2
Indications for liver transplantation in 2014
Acute liver failure | Hepatitis A virus Hepatitis B virus Hepatitis D virus Hepatitis E virus Acetaminophen Other drugs Postoperative Posttraumatic Wilson disease Budd–Chiari syndrome Autoimmune hepatitis Cryptogenic Fatty infiltration – acute fatty liver of pregnancy Reye syndrome |
Cirrhosis from chronic liver disease | Chronic hepatitis B viral infection Chronic hepatitis C viral infection Chronic hepatitis B and D viral infection Chronic hepatitis E viral infection Cirrhosis viral related (other viruses) Cirrhosis drug related Alcoholic liver disease Autoimmune hepatitis Cryptogenic liver disease Nonalcoholic fatty liver disease |
Cholestatic liver diseases | Primary biliary cirrhosis Primary sclerosing cholangitis Caroli disease Secondary biliary cirrhosis Alagille syndrome Byler disease Severe graft-versus-host disease Congenital biliary fibrosis Extrahepatic biliary atresia |
Vascular liver disease | Budd–Chiari syndrome Hereditary hemorrhagic telangiectasia Veno-occlusive disease |
Metabolic liver diseases | Wilson disease Hereditary hemochromatosis Alpha-1 antitrypsin deficiency Glycogen storage disease I and IV Familial homozygous hypercholesterolemia Tyrosinemia Familial amyloid polyneuropathy Primary hyperoxaluria Protoporphyria Other types of porphyria Crigler–Najjar syndrome Cystic fibrosis Galactosemia Factor VIII (Hemophilia A and B) and V deficiency Thrombophilic disease (e.g., Protein C, S deficiency) |
Benign tumor | Hepatic adenoma Adenomatosis Giant hemangioma Focal nodular hyperplasia Nodular regenerative hyperplasia |
Malignant tumor | Hepatocellular carcinoma on cirrhosis Hepatocellular carcinoma on non-cirrhotic liver Intrahepatic cholangiocarcinoma Biliary tract carcinoma (Klatskin) Epithelioid hemangioendothelioma Hepatoblastoma NET metastasis Colorectal tumor metastasisa |
Miscellaneous | Polycystic liver disease Alveolar echinococcosis Cystic echinococcosis Hepatic trauma Schistosomiasis Choledochal cyst Sarcoidosis |
Today’s Indications for Liver Transplantation
Chronic Parenchymal Liver Diseases
Alcoholic Disease
Alcoholic liver disease , the first and second most common indication for LT throughout Europe and the USA, remains a controversial indication especially in terms of public attitude toward the responsibility of the patient and his/her environment for a self-inflicted disease. The main problem relates to the risk of relapse, a condition difficult to exclude even when optimal psychological evaluation and follow-up are provided. The 6-month abstinence rule, considered as a “safety belt” in many centers, reveals to be an unreliable selection criterion to justify LT. Alcohol use after LT remains therefore an issue of concern, the exact incidence of which remains poorly investigated (Mathurin and Ehrhard 2011). Probably, the best positive prognostic parameter is the preserved integration of the potential recipient within his/her familial, professional, and social environment. In this context the role of the general practitioner, knowing usually best these conditions, should be valued in the decision-making process.
Upcoming Features: The social debate about the justification of LT as a treatment of alcoholic liver disease has recently been fueled by the Lille group which proposed to perform LT even in case of severe alcoholic hepatitis not responding to medical therapy (Donckier et al. 2014). The medical treatment, based on glucocorticoid administration, indeed generates poor results as most patients die within 2–6 months. The survival rate only reaches 30 % in patients having a Lille score of ≥0.45 at day 7 of such treatment. A prospective study proposing early LT in 26 patients having a Lille score ≥0.45 allowed to raise significantly the 6-month survival rate to 77 %; only 11 % of patients presented alcohol abuse after LT (Mathurin et al. 2011).
Despite the fact that LT represents the best therapy for both alcoholic cirrhosis and severe hepatitis refractory to medical therapy, durable abstinence, the mandatory objective needed to link patient compliance and public awareness, can only be obtained by implementing a structured and tight follow-up. Close medical care might have another, neglected, but important “side effect.” Indeed as alcoholic liver disease is one of the few diseases that does not recur in the allograft, this patient group represents a unique and “fertile” domain in the research fields of minimization of immunosuppression (IS) and clinical operational tolerance (COT) protocols. Long-term follow-up biopsies in such patients will allow a more precise evaluation of liver biopsies as confounding factors such as viral and autoimmune allograft recurrences will be absent.
Viral Diseases
Hepatitis B-Related Cirrhosis (HBV): Worldwide, HBV infection is still the leading cause, mainly in Eastern countries, of cirrhosis and development of liver cancer despite aggressive vaccination campaigns aiming at disease prevention. The newer antiviral drugs dramatically improved results of both antiviral therapies and LT. Five-year recipient survival rates are now reaching more than 80 %, promoting nowadays HBV-related cirrhosis as one of the best indications for LT on the condition that a lifelong prophylactic therapy using specific anti-HB immunoglobulins (HBIg) is pursued. The introduction of nucleos(t)ide analogs, such as lamivudine, adefovir, and tenofovir, has even allowed to obtain excellent results in case of active viral replication at moment of LT (Samuel et al. 1993). These prophylactic therapies have eliminated the development of cholestatic fibrosis and allowed to reduce the incidence of allograft reinfection beneath 5 % on the condition that close monitoring of anti-HBs antibodies clearing and that immunoglobulins are administered, either intravenously or intramuscularly, lifelong. The drawback of this very efficacious prophylactic treatment is its high cost. A recent meta-analysis, including 1,484 liver recipients, showed that HBIg treatment reduces allograft reinfection in pre-LT HBV DNA-positive patients but did not confer a significant advantage in DNA-negative patients especially when receiving the newer nucleos(t)ide analogs. Combining HBIg and oral antivirals does not seem to improve results (Wang et al. 2014b).
Upcoming Features: Due to the very high costs (6,000–8,000 €/year) and low allograft recurrence after the third post-LT year, several alternative antiviral therapies have been proposed. Shifting to the less costly self-administered subcutaneous HBIg has shown to be safe and effective in an Italian cohort of 135 patients when maintaining anti-HBs levels >100 IU/L (Di Costanzo et al. 2013). Selected recipients can even be safely switched to the less expensive, oral nucleoside analog monotherapy. The Hong Kong group obtained in a cohort of 80 patients, receiving only entecavir, a 98.8 % clearance of post-LT HBV DNA levels and no evidence of mutations at sites able to confer resistance to entecavir (Fung et al. 2011). Recent European guidelines focused on these innovations (European Association for the study of the Liver 2012a).
Finally, besides this “pure viral” point of view, it is of note that HBV patients display low rejection rates which may be partly explained by the interaction of HBIg with dendritic allograft cells.
Hepatitis C-Related Cirrhosis (HCV): Especially in the Mediterranean Basin, HCV-related cirrhosis with or without hepatocellular cancer (HCC) has become the primary indication for LT. Unfortunately, HCV graft reinfection is the rule being responsible for the (more rapid) development of allograft cirrhosis in 30 % of patients and graft loss in 10 % of recipients after 5 years (Charlton 2007). Retransplantation (reLT) is the only option in case of allograft decompensation. The indication for reLT, especially if early, is controversial due to the poor results. A retrospective US multicenter study compared 43 retransplanted HCV patients with 73 non-HCV retransplanted and 156 HCV not retransplanted patients. In the retransplanted groups, 3-year patient survival rates were 49 % versus 55 % in HCV and non-HCV patients, respectively. The most common reasons for not listing for reLT were early recurrent HCV (<6 months) (22 %), fibrosing cholestatic hepatitis (19 %), and renal dysfunction (9 %) (McCashland et al. 2007).
Upcoming Features: Until recently, antiviral therapy combining pegylated interferon and ribavirin represented the unique strategy to avoid allograft reinfection. As this therapy can only be applied fully in about 20 % of the recipients due to its side effects, sustained viral response can only be obtained in 20 % of the recipients. The direct-acting antivirals (DAA) provided new therapeutic options (Gane and Agarwal 2014). The addition of the first-generation NS3/4A protease inhibitors (PI) boceprevir or telaprevir has increased the efficacy of pegylated interferon and ribavirin in patients with chronic HCV genotype 1 infection. In 37 recipients treated with boceprevir (n = 18) or telaprevir (n = 19), a sustained virologic response was observed after a 12-week treatment in 71 % and 20 % (Coilly et al. 2014). Unfortunately, the application of such triple therapy is hampered by the occurrence of anemia and DAA-IS interaction. Clinical trials including newer classes of DAA targeting different steps of HCV replication, including nucleotide polymerase (NUC-NS5B) inhibitors (sofosbuvir), non-nucleotide polymerase (non-NUC-NS5B) inhibitors (setrobuvir), and NS5A inhibitors (ledipasvir, daclatasvir), have been started. A phase III study combining once-daily oral sofosbuvir–ledipasvir with or without ribavirin reached a 99 % sustained virologic response in the absence of severe adverse events in 865 HCV patients (Afdhal et al. 2014). These extremely encouraging results obtained in naïve as well as in transplant patients will dramatically change the outlook of HCV-infected patients. The indirect consequence will be an enlargement of the scarce allograft pool due to the foreseen reduction of HCV patients in need for LT and the reduced incidence of graft loss and thus need for reLT.
Autoimmune Cirrhosis
In 1950, Waldenström first described a chronic form of hepatitis in young women termed “lupoid hepatitis” because of its association with other autoimmune disease manifestations. This disease was termed in 1965 “autoimmune hepatitis” (AIH); in the 1970s and 1980s, several specific autoantibodies could be identified. T–cell activity directed against hepatocytes leads to interface hepatitis, fibrosis, and finally cirrhosis. AIH is an archetype autoimmune condition, with female preponderance (F/M ratio 7:1), hypergammaglobulinemia, serum autoantibodies, response to corticosteroids, and association with other autoimmune features in 40 % of patients (Carbone and Neuberger 2014). Two distinct AIH subtypes have been identified based on the profile of serum antibodies: type 1 (AIH-1) is associated with antinuclear, anti-smooth muscle, anti-actin, anti-soluble liver antigen, or anti-liver–pancreas antigen antibodies; the less common type 2 (AIH-2) is associated with anti-liver–kidney microsomal antibodies type 1 and type 3 and anti-liver cytosol antibodies type 17. The heterogeneous immunoserology and genetics explain the great variability of the disease expression in relation to race, geographical distribution, and genetic predisposition (Manns and Vogel 2006). Despite the increased risk for infectious complications in the early post-LT period, especially in recipients aged over 50 years, 5-year patient survival rate post-LT nowadays reaches 80–90 %.
Upcoming Features: Recurrent (auto- or alloimmune) disease, de novo allograft hepatitis, and immunosuppressive therapy post-LT are all matters of debate in this difficult field of LT. Recurrent allograft disease, observed in 12–46 % of the recipients, is treatable in most patients by instauring or increasing steroid therapy. Progress to cirrhosis and graft failure is rather uncommon (Schreuder et al 2011). These patients need careful follow-up as they frequently present different manifestations of their primary disease such as polyarthritis, thyroiditis, and GI tract disease. Although many transplant groups advocate the necessary use of a steroid-based IS in order to avoid allograft recurrence and extrahepatic disease manifestations, LT can be done safely for this condition using a steroid-free IS (Strassburg and Manns 2011).
The “problem” of de novo hepatitis (DNH) after LT should also be addressed in this context as this condition is diagnosed more and more frequently. The real meaning of DNH is not yet fully understood, but it could be that DNH is a manifestation of a frust form of chronic rejection (Sebagh et al. 2013). A recent study focused on the role of atypical anti-liver–kidney microsome antibodies (LKMA) in the development of DNH, showing proteasome and carbonic anhydrase III as their respective autoantigens (Huguet et al. 2007). If diagnosed, careful, pathologic-based, follow-up and careful IS adaptation are required. Maybe the recent findings in relation to impact of donor-specific antibodies (DSA) on outcome in LT will allow to obtain further insights in this condition.
Cholestatic Diseases
Primary Biliary Cirrhosis (PBC): LT is the gold standard in the treatment of end-stage liver disease due to PBC. The number of LT for this condition declined during the last decades due to the introduction of an efficacious pharmacological treatment with ursodeoxycholic acid. PBC is an autoimmune liver disease whose two main features are the presence of highly specific antimitochondrial antibodies (AMAs) and lymphocytic cholangitis. The chronic destruction of small to medium caliber intrahepatic bile ducts leads to cholestasis, fibrosis, and biliary cirrhosis (Selmi et al. 2011). Indications for LT are anticipated death in <1 year, impaired quality of life, or intractable disease-specific symptoms such as pruritus. Despite the availability of prognostic models, serum bilirubin level of over 4 mg/dL provides a simple guide to time LT. Five-year patient survival rates reach 85 %. These patients seem to develop more frequently features of chronic rejection, although such changes are similar to recurrent allograft PBC. IS reduction should therefore be done cautiously. Following LT, AMAs usually persist, and histological features of recurrent allograft PBC are seen in about 50 % of the recipients 10 years post-LT (Rowe et al. 2008). Recurrence, which may occur in the presence of normal liver tests, is most often discovered on long-term protocol biopsies. In the medium term, disease recurrence rarely causes clinical problems. During follow-up, osseous complications (bone fractures) and flaring up of several other disease manifestations, such as polyarthritis, scleroderma, and thyroiditis, may compromise quality of life.
Upcoming Features: Still too much elderly women are transplanted presenting with very advanced osseous disease. Such condition may seriously compromise the LT outcome (Guichelaar et al. 2006). An active “osseous” follow-up should be addressed to these patients especially when already presenting severe pre-LT osteoporosis.
Primary Sclerosing Cholangitis (PSC): PSC is a chronic, cholestatic autoimmune liver disease leading to inflammation and fibrosis of the macroscopic, intrahepatic and extrahepatic, biliary system. The hallmark of PSC is the alternation of multiple biliary strictures and dilatations on imaging (Maggs and Chapman 2008). PSC is a progressive disease with no proven therapy, whose natural history may lead to the development of decompensated cirrhosis and biliary cancer. In LT series cholangiocellular carcinoma (CCC) has been diagnosed in up to 20 % of patients. Up to 70 % of patients present other major disease manifestations such as inflammatory bowel disease and vitiligo. Although patient selection and timing for LT are not always easy, serum bilirubin, splenomegaly, development of portal hypertension, and duration of disease are good practical guides for the LT indication. Pre-LT screening with MRI, PET scan, and brush cytology of the biliary tract is indicated in case of dominant strictures in order to exclude CCC. Although early patient and graft survival rates following LT are excellent, the one-year survival reaching 90 %, late outcome is frequently compromised due to allograft recurrence. Ten-year survival rates reach 50 % only, indeed the worst result of LT for benign liver diseases. Diagnosis of recurrent PSC is difficult as morphologic features of recurrent PSC and the frequently observed ischemic-type biliary lesions (ITBL) are similar (Graziadei 2002).
Recurrent PSC affects 20–40 % of the recipients, with higher reLT rates compared to PBC. Because of the enhanced risk of colonic cancer, annual colonoscopy is advised. Many patients however had and many will have complex GI tract surgery consisting of proctocolectomy with ileoanal reservoir because of their inflammatory bowel disease (Bjoro et al 2006). In a study performed in 303 PSC recipients, the only significant risk factor for colectomy was LT itself, while it did not affect the incidence of colorectal cancer (Dvorchik et al. 2002).
Upcoming Features: Some technical issues need to be addressed when transplanting PSC patients. Roux-en-Y hepaticojejunostomy is the preferred option for biliary reconstruction due to the involvement of the extrahepatic bile duct (Welsh and Wigmore 2004). However, the much easier duct-to-duct anastomosis and even choledochoduodenostomy have been reported more recently. A meta-analysis involving 692 patients showed that duct-to-duct anastomosis has very satisfactory results in terms of clinical outcome, graft survival, risk of biliary complications (leaks and strictures), infection, and PSC recurrence (Wells et al. 2013). A recent series of 98 PSC adults, 45 of whom with duct-to-duct and 53 with RY reconstruction, showed more episodes of cholangitis and late-onset non-anastomotic biliary strictures in case of biliodigestive anastomosis (Sutton et al. 2014). In this view choledochoduodenostomy or duct-to-duct reconstruction (in case of macroscopical “normal” recipient bile duct) can be accepted as an alternative technique in case of difficult intra-abdominal conditions.
Secondary Biliary Cirrhosis (SBC): SBC, the end-stage evolution of a prolonged chronic damage such as caused by iatrogenic bile duct injury (mostly following laparoscopic cholecystectomy), graft-versus-host disease following bone marrow transplantation, cystic fibrosis, and status after Kasai operation during infancy because of biliary atresia, is an uncommon (less than 1 %) indication in adult LT. Few series have been published. An Argentinian study reported about 20 patients with end-stage liver disease secondary to biliary injury; four patients died on the waiting list, and 16 were transplanted. All patients had surgical treatment(s) before being considered for a LT. The median time between biliary lesion and liver transplant was 60 months. The 5-year survival reached 75 % (de Santibañes et al. 2008).
Upcoming Features: The message of this experience is that such patients should be referred early to specialist hepatobiliary centers in order to avoid SBC and thus LT.
Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH)
The term “nonalcoholic fatty liver disease” was first used in the 1980s to describe a slowly progressive disease linked to fat accumulation within liver cells without evident reasons (Ludwig et al. 1980). NAFLD can range from simple steatosis to NASH, a condition leading to fibrosis and cirrhosis due to ongoing inflammation. NAFLD and NASH are associated with obesity and metabolic syndrome. Due to the current obesity epidemic, NASH-related cirrhosis has become the third leading indication for LT in the USA, accounting for up to 11 % of the liver recipients (Younossi et al. 2011). NASH represents the second leading etiology for HCC requiring LT in the USA and is the most rapidly growing indication in LT for liver cancer (Wong et al. 2014). Overall 5-year survival rates of these patients are similar to other indications. Although the risk for graft failure is lower, these recipients have a higher post-LT mortality due to cardiovascular events or sepsis. Risk factors for NASH such as increased BMI, insulin resistance, and diabetes are moreover worsened because of steroid- and CNI-based IS. Weight control after LT is mandatory in order to avoid allograft steatosis which has been reported in up to 100 % of patients. Adapted diet and physical activity are advised besides various pharmacological interventions using metformin, vitamin E, pioglitazone, statins, ursodeoxycholic acid, pentoxifylline, and orlistat. However, none of them has proved to be effective in reverting liver fibrosis (Khullar et al. 2014).
Upcoming Features: Bariatric surgery has been introduced with a good safety and efficacy profile either before, during, or after LT. A US experience reported about 44 prospectively enrolled patients having a BMI >35 at the moment of wait-list insertion. Thirty-four patients had an “isolated LT”; 21 raised their weight above BMI >35, twelve had post-LT diabetes, seven had steatosis, and three patients died. Seven patients had combined LT–sleeve gastrectomy procedure. There was no death, graft loss, diabetes, nor steatosis. One patient developed a leak from the gastric staple line. All patients had substantial weight reduction (mean BMI 29) (Heimbach et al. 2013). Further investigations are underway to explore specific polymorphisms involved (PNPLA3, IL28) in the development of post-LT NASH in order to define mechanisms and therapies against this pathology.
Hepatobiliary Oncology
Primary Tumors
Hepatocellular Cancer (HCC) in Cirrhotic or Fibrotic Liver: HCC represents the fifth most common malignant tumor worldwide and the third leading cause of cancer-related death. Ninety percent of HCC develop in a diseased liver, 5–10 % in a normal, non-cirrhotic or non-fibrotic liver (NC-HCC). LT is the therapeutic gold standard as it simultaneously removes tumor and underlying (precancerous) disease. The introduction in 1996 of the Milan criteria (MC) (one lesion smaller than 5 cm or up to three lesions smaller than 3 cm, without extrahepatic manifestations or vascular invasion) and the steady improvement of neoadjuvant locoregional therapies (LRT) allow to obtain 5-year disease-free survival rates reaching 85 % (Ciccarelli et al. 2012). These too restrictive MC and the unexpected good results in some recipients outlying the MC on pathologic examination of the total hepatectomy specimen led to the development of many (mostly center based) wider inclusion criteria in the West as well as in the East (i.e., San Francisco, Kyoto, Kyushu, Hangzhou, Toronto, Seoul, and Milan up to seven) (Yao et al. 2001, Mazzaferro et al. 2009). Up to now, only the extended San Francisco criteria have been accepted by the international transplant community. Despite the fact that the Zurich Consensus Conference about HCC and LT reviewed the current practice of LT in HCC patients aiming at streamlining the approach of the transplant community toward HCC, many questions remain unanswered (Clavien et al. 2012).
Upcoming Features: Sound oncologic principles such as “dynamic” morphologic (number and diameter) and biologic tumor criteria (evolution of tumor markers or response to LRT) will be necessary to justifiably extend the inclusion criteria. Combining alpha-fetoprotein (AFP) and/or des-gamma carboxyprothrombin (DCP) (or protein induced by vitamin K absence [PIVKA II]) values and dynamics, inflammatory markers such as neutrophil-to-lymphocyte or platelet-to-lymphocyte ratios and radiological response to LRT based on RECIST criteria (also called downstaging) will be necessary to refine the HCC therapeutic algorithm in order to discriminate between utile and futile LT (Lai and Lerut 2014). Clear identification and definition of cutoff values as well as of downstaging will allow to progress in this field. Living donor liver transplantation (LDLT) represents a unique soil to safely explore the expansion of inclusion criteria for LT. It is also of notice to underline that adaptation of IS (steroid-free IS regimens, introduction of mTor inhibitors) will help to further support this development.
HCC developed in a non–cirrhotic, non–fibrotic liver: Inclusion criteria for LT differ importantly. Despite the dogma that partial liver resection is “the” therapeutic gold standard in these patients, 5-year recurrence rates are very high ranging from 40 % to 70 %. LT might therefore be of value both in the treatment of initially non-resectable HCC or in case of recurrence after resection (Lerut et al. 2011). The ELTR–ELITA analysis, dealing with 62 patients with initially “non-resectable” NC-HCC, confirmed that excellent 5-year disease-free survival rates of 60 % and 48 % can be obtained after primary and salvage LT for intrahepatic recurrence (Mergental et al. 2012). Macrovascular and lymph node invasion, interval of less than 12 months between partial resection and recurrence, are unfavorable factors, in contrast to HCC developed in a cirrhotic liver tumor diameter and MC do not significantly influence outcome. The best results of LT for NC-HCC are achieved in the presence of AFP level <100 ng/mL, number of tumors less than four, and absence of vascular and lymph node involvement (Decaens et al. 2012).
Cholangiocellular Carcinoma (CCC) : CCC, a very aggressive primary neoplasm arising from malignant transformation of the biliary epithelium, has been for a long time considered an absolute contraindication to LT (DeOliveira 2014).
Upcoming Features: CCC has evolved from an absolute to a relative contraindication for LT. The Nebraska, Mayo and Dublin transplant teams pioneered a strategy of neoadjuvant radiochemotherapy followed by LT for patients with unresectable hilar CCC; recently the French health authorities even authorized to extend this indication to resectable CCC. The Mayo Clinic protocol is based on a strict, multidisciplinary therapeutic project combining external beam radiation, endo-biliary brachytherapy, and 5-FU chemotherapy. After negative surgical laparoscopic exploration, capecitabine is started until moment of LT. This protocol needs to adapt surgical timing and technique. This protocol is restricted to highly selected patients presenting a tumor <3 cm and absent extrahepatic metastases including negative lymph nodes. Despite the complex algorithm, the high dropout, and the very strict patient selection, 5-year recurrence-free survival rates reached 68 % (Rosen et al. 2010). In the most recent update concerning 199 patients, elevated CA 19–9 (>120 UI/mL), portal vein encasement, and residual tumor on explant pathology were the most significant predictors of CCC recurrence (Darwish Murad et al. 2012).
LT is not yet considered an option to treat intrahepatic CCC. LT is till now only proposed for small tumors developed in a cirrhotic liver. One 1- and 5-year recurrence for mixed HCC–intrahepatic CCC reach 42 % and 65 % (Razumilava and Gores 2014). A recent multicenter study from Spain analyzed 27 and 15 patients with mixed tumors and intrahepatic CCC comparing them with 84 HCC matched controls. Intrahepatic CCC showed worse results with respect to their controls (5-year actuarial survival rates of 51 vs. 93 %), but no differences were observed between mixed tumor patients and HCC controls (78 vs. 86 %) (Sapisochin et al. 2014). These results reflect the aggressiveness of intrahepatic CCC and also raise the question about the “necessity” of pre-LT as well as pre-LRT tumor biopsies. More data on HCC–CCC patients should be obtained, but their absolute exclusion from transplant option is controversial.
Secondary Liver Tumors
Neuroendocrine Liver Metastases (NETLM): LT for unresectable NETLM is another controversial area in the field of LT. A recent review reports about 706 such patients. Five-year survival rate from the time of diagnosis was approximately 70 %. Metastases confined to the liver and not poorly differentiated are favorable candidates for LT; evolution of tumors over 6 months is an unfavorable feature (Fan et al. 2015). The initial French multicenter transplant experience comprising 85 patients reported a 5-year survival rate of 47 %. Factors of poor prognosis were concomitant upper abdominal exenteration and primary tumor in the duodenum or pancreas with accompanying hepatomegaly. Recipients presenting with these unfavorable prognostic factors had significantly worse results (5-year survival rates of 12 vs. 68 %) (Le Treut et al. 2008). Similar results were obtained in the UNOS cohort including 150 patients (Gedaly et al. 2011).
Upcoming Features: Two recent publications indicate that LT will have to be considered in the therapeutic algorithm of NET patients. The Milan group indeed showed that LT can cure 85 % of patients with non-resectable NET metastases when adhering to strict inclusion criteria consisting of low proliferation index (Ki < 5 %), delay between R0 resection of the primary tumor and LT of more than 6 months, tumor location in the portal venous drainage system, adapted IS and neoadjuvant and adjuvant therapies (Mazzaferro et al. 2007). Without any doubt, LT will take a more important place in the treatment of these patients in the near future as LT (Bonaccorsi-Riani et al. 2010).
The large ELTR–ELITA, retrospective, multicentric study including 213 patients transplanted during the period 1982–2009 supports the Milan experience. The 5-year overall and disease-free survival rates for the whole patient cohort reached 52 % and 30 %. Since 2000, 5-year OS increased to 59 % as a result of better selection process (Le Treut et al. 2013). More importantly is the fact that this detailed multivariate analysis identified major resection in addition to LT (or multivisceral resection), poor tumor differentiation, hepatomegaly and age >45 years as poor prognostic factors.
Colorectal Liver Metastases (CRLM): CRLM were considered an absolute contraindication for LT due to the very poor obtained survivals. A review of the earlier ELTR–ELITA experience including 48 patients revealed that near half of these patients died due to non-tumoral causes and that two thirds of patients had heavy IS (Foss et al. 2010).
Upcoming Features: Impressive improvements in chemotherapy, surgical technique (such as repeated surgery and ALPPS procedure), and imaging paved the way for the prospective Norwegian SECA (secondary cancer) study looking at the value of LT in the treatment of unresectable CRLM (Foss and Lerut 2014). The outcomes of 21 SECA-LT patients and 47 non-transplanted unresectable liver-only CRLMs were compared in the NORDIC VII study. Although disease-free survivals were similar, substantial different 5-year actuarial overall survival rates were observed (56 % vs. 9 % in patients starting first-line chemotherapy) (Dueland et al. 2014). The recurrence rate was 100 %, but one third of patients could be rendered disease-free after resection of pulmonary metastases. The historic Vienna and recent Oslo experiences paved the way for larger multicenter studies that will be soon launched (Kappel et al. 2006).
Metabolic (Liver Based) Diseases
Hereditary Hemochromatosis (HH): HH, a disorder of iron metabolism leading to iron overload due to reduced hepatic hepcidin secretion, is a rather uncommon indication for LT. These patients have a higher risk to develop cardiac complications and HCC. After LT, hepcidin secretion is normalized, preventing the recurrence of hepatic iron overload (Bardou-Jacquet et al. 2014). These recipients have a higher morbidity and mortality due to a higher incidence of cardiac, diabetic, and infectious complications, cancer recurrence, and post-LT iron reaccumulation.
Wilson Disease (WD): This rare inherited autosomal recessive disease of copper metabolism is responsible for systemic copper accumulation that damages especially the liver, brain, cornea, and kidney (European Association for the Study of the Liver 2012b). Such accumulation can be prevented with copper-chelating agents or zinc salts. The progression of systemic complications and hepatic involvement under an adequate long-term therapy is rare. LT may be required in the setting of acute liver failure (ALF) , subacute liver disease, and end-stage liver disease, with or without neuropsychiatric manifestation. Adult patients always present in a stage of cirrhosis. WD-related ALF can be stratified according to Nazer index, revised King’s College Criteria, and PELD/MELD scores (Devarbhavi et al. 2014). Outcomes after LT for WD are excellent with 5-year survival rates of 86–89 %. Although copper metabolism normalizes in the long run (Arnon et al. 2011a), neuropsychiatric disorders do not recover in half to one third of patients, and in some patients they may even progress (Medici et al. 2005). Living donation is a safe option for heterozygote carrier relatives.
Hemophilia: Hemophilia is a family of X-liked coagulation disorders most commonly caused by the deficit of factor VIII (F VIII, hemophilia A) or factor IX (F IX, hemophilia B). The most severe forms result in persistent risk of prolonged bleeding. During the last decades, life expectancy of hemophilic patients has been dramatically improved, initially by plasma derivatives, later by recombinant factors. Unfortunately insufficient inactivation processes of human derivatives were responsible for the development of end-stage liver disease due to transmission of HCV and HIV infections (Soucie et al. 2014). Most patients are therefore transplanted because of liver decompensation and/or HCC development. Perioperative evolution can be more complicated due to HIV/HCV coinfection. Coagulopathy usually is not an important matter as the allograft very rapidly corrects the hematologic condition (Horton et al. 2012). Adapted perioperative care allows nowadays to obtain results comparable to those of non-hemophilic patients (Lerut et al. 1995).
Familial Amyloid Polyneuropathy (FAP): FAP is a slow but fatal disease, belonging to a group of systemic disorders caused by an amyloidogenic transthyretin variant. More than 100 genetic variants have been identified explaining the widely variable clinical expression. Patients with a same mutation can even present, an until now unexplained, variation in the clinical presentation. The most frequent mutation is the Val30Met variant. Non-Val30Met variants have a significantly different clinical presentation and outcome. The V30M mutation has an early-onset (between 25–35 years), a more benign course and cardiac involvement in the form of rhythmic disturbances. The NV30M-FAP has a late-onset (> 50 years) presentation, a more rapid evolution with more functional impairment, development of restrictive/mechanical cardiomyopathy and lower survival. Isolated cardiac involvement in African-Americans is invariably associated with the V122I mutation (Zeldenrust 2012). LT eliminates the source of the variant molecule, therefore representing till now the only known curative treatment for this disease. LT was first performed for this pathology in 1990 in Sweden. The FAP World Transplant Registry (Herlenius et al. 2004) collected up to 2,000 LT recipients during the period 1995–2012 done in 77 centers distributed in 19 countries. Today, approximately 120 LT are performed annually worldwide. Patient survival is comparable to the survival with LT performed for other chronic liver disorders. The main causes of death have been cardiac related and septicemia (21 % each) (http://www.fapwtr.org/ 2014). Recent experiences identified time interval between diagnosis and LT and preoperative modified body mass index (mBMI) <700 kg g/L m2 as poor prognostic factors (Franz et al. 2013).
A major plus of LT for FAP is to transfer their normally functioning liver to another recipient, a procedure better known as sequential or domino LT. This procedure was introduced by Furtado in Coimbra in 1993. According to the Domino Liver Transplantation Registry, from 1999 to December 2012, 1085 domino LT have been performed in 62 hospitals located in 21 countries. Transfer of polyneuropathy by the domino graft has been documented in very rare cases (Tincani et al. 2011). Survival after LT is similar to this obtained in other benign liver disorders. The main causes of recipient death after domino LT were tumor recurrence (24 %) and septicemia (16 %) (http://www.fapwtr.org/ 2014).
Primary Hyperoxaluria (PH): PHs are a group of autosomal recessive disorders of endogenous oxalate overproduction typically developing in childhood. PH type 1 is caused by hepatocellular alanine–glyoxylate aminotransferase deficiency, the more aggressive form. Type 2 is related to glyoxylate reductase/hydroxypyruvate reductase deficiency. The latter type is associated with lower morbidity and mortality. Deposition of calcium oxalate crystals in the kidney, nephrocalcinosis, progressive renal failure, and systemic deposition of oxalate (oxalosis) are the main clinical manifestations of PH1. Different approaches have been proposed for the treatment of this pathology such as isolated renal transplantation, isolated preemptive LT to correct the metabolic defect before the occurrence of significant renal damage, and finally combined kidney–liver transplantation (CKLT) to correct both problems simultaneously. Isolated renal transplantation offers only a temporary solution as oxalate deposition results in recurrent disease and renal graft failure, with a 3-year renal graft survival of only 17–45 %. Isolated liver transplant is an attractive treatment option, but its timing remains controversial. CKLT, firstly introduced in 1984, has been accepted as the treatment of choice, considerably improving patient and graft survival (Nair et al. 2013). According to the European PH1 transplant registry, 117 patients received CKLT during the period 1984–2004, showing 5-year patient survival rates of 80 % (Jamieson 2005). A recent multicenter study from France analyzed 54 patients with PH1. Ten-year patient survival was similar between the 33 CKLT and 21 KT patient groups (78 % vs. 70 %). Kidney graft survival at 10 years was however much better after CKLT (87 % vs. 13 %, respectively). Recurrence of oxalosis occurred in 11 renal grafts (52 %) of the KT group versus none in CKLT group (Compagnon et al. 2014). Five cases of domino LT in the setting of PH1 have been reported; all rapidly developed dialysis-dependent kidney failure within the first 4 weeks after LT (Saner et al. 2010).
Tyrosinemia Type I (TT1): TT1 is an autosomal recessive metabolic disorder, caused by the deficiency of fumarylacetoacetate hydrolase (FAH), an enzyme involved in the final step of the catabolism of tyrosine and phenylalanine. Its deficiency induces accumulation of toxic metabolites stimulating apoptosis of both hepatocytes and kidney tubular epithelial cells and increasing the risk for HCC development. TT1 has an incidence of about 1:100.000; in specific areas such as Scandinavia and Quebec, its incidence is higher. TT1 can present either in an acute or a chronic form. The acute form occurs within the first months of life and leads to ALF during the first year. Chronic form features are characterized by failure to thrive, hepatomegaly and chronic liver disease , renal tubular dysfunction, rickets, cardiomyopathy, and porphyria-like neurological syndrome (Fagiuoli et al. 2013). The mainstays of TT1 treatment are tyrosine-/phenylalanine-free diet and the use of 2-(2-nitro-4-trifluoromethylbenzoyl)-1-3-cycloexenedione (NTBC), which blocks the second step of tyrosine catabolism. This combination prevents toxic metabolites’ accrual and hepatic and renal deterioration, improves nutritional and neurological status, and reduces HCC development cutting the need for LT from 35 % to 12 % (Paradis 1996).
Indications for LT include end-stage liver disease despite medical treatment, unresponsive ALF, poor quality of life, and HCC. The risk of HCC is high in cirrhotic patients with histologically proven dysplastic nodules, so early LT is indicated. Five-year survival rates are currently above 90 % (Arnon et al. 2011b). As heterozygosity does not induce the disease, healthy relatives can be considered as living liver donors. Renal FAH deficiency is not corrected by LT, but renal-sparing properties of NTBC have reduced the rate of CKLT.
Glycogen Storage Disease Type I (GSD I): This autosomal recessive inborn error of carbohydrate metabolism is caused by defects in the glucose-6-phosphate transporter (G6PT)/glucose-6-phosphatase (G6Pase) complex. Deficient activity of G6Pase causes GSD Ia, and deficient activity of G6PT causes GSD Ib. GSD I is a rare disorder with an incidence of 1:100.000, represented in 80 % of the patients by GSD Ia and in 20 % by GSD Ib. Clinical complications include hepato- and nephromegaly, hypoglycemia, hyperlipidemia, hyperuricemia, lactic acidemia, and growth retardation (Rake et al. 2002). Because of the prominent hepatic manifestations in GSD I, LT represents a solution for this pathology. A recent literature review included 58 cases of GSD Ia and 22 cases of GSD Ib transplanted during the period 1982–2012. In the GSD I group, LDLT was performed 16 times, and six patients had CKLT. Main indications for LT were hepatic adenomas/liver abnormalities/focal nodular hyperplasia, poor metabolic control, growth retardation, and renal failure. In the 54 surviving cases, a metabolic control was obtained, and in 13 cases catch-up growth was mentioned. In the GSD Ib group, LT was indicated for poor metabolic control, recurrent infection, and growth retardation. In all 19 survivors metabolic abnormalities were corrected also, and catch-up growth was reported twice (Boers et al. 2014).
Upcoming Features: More confidence with LT should instigate the LT community to opt for prophylactic transplant procedures. Indeed nowadays the recovery after successful LT of these patients is many times hampered by the already, irreversible, damages caused by the metabolic deficit. The role of LDLT should also be explored as a less expensive and prophylactic treatment of many metabolic diseases (Tsukada et al. 2011). The frequently absent portal hypertension in such conditions makes it possible to implant a smaller (left) liver graft, reducing thereby the donor risk.
FAP patients represent a valuable source of allografts (Inomata et al. 2001). Because of the very low rate of disease transmission, domino livers should be more frequently directed also to younger, non-HCC recipients (Azoulay et al. 2012). Results of LT for FAP will probably improve in the near future due to the introduction in clinical practice of stabilizers of TTR tetramers (tafamidis and diflunisal), and gene therapies to suppress TTR expression (antisense methods and the use of small interfering RNAs) are in progress. These therapies might be useful for the treatment of patients transplanted in an advanced disease stage. Apart from FAP, fibrinogen a-chain amyloidosis, maple syrup urine disease, and hypercholesterolemia represent the only other metabolic diseases in which domino LT should be considered. Primary hyperoxaluria is indeed a contraindication to such LT as all recipients rapidly develop renal failure due to oxalic acid overload (Franchello et al. 2005).
Last but not least, a small number of auxiliary LT have been reported in order to cure metabolic diseases; firm conclusions cannot yet be drawn from these experiences (Trotter and Milliner 2014).
Acute Liver Failure (ALF)
Various, heterogeneous conditions may lead to ALF. ALF has been defined by Trey as a massive necrosis of previously normally functioning liver. The definition of acute and subacute failure relates to the time span between jaundice and encephalopathy of less than two weeks or from two to eight weeks. The main cause of ALF is drug-induced toxicity, mainly in the setting of deliberate ingestion with suicidal intent of acetaminophen. ALF caused by an identified hepatotropic virus accounts for 15–50 % of cases in Europe, with an additional 20 % of cases related to hepatitis of unknown etiology; in these cases viral etiology is frequently presumed. HCV infection is rarely responsible for ALF in Western countries but accounts for a higher proportion of cases in Japan. Hepatitis E infection, commonly observed in the Indian subcontinent, may also lead to ALF particularly in pregnant women. Uncommon nonviral-related causes of ALF are represented by Wilson disease or poisoning after ingestion of the mushroom Amanita phalloides.
ALF is a rapidly progressive critical illness with still a high mortality. Complex intensive care protocols and emergency LT represent the strategies to adopt. The most widely used criteria to justify indication for LT are the 1989 and updated 1993 King’s College Criteria (O’Grady 2007). A review related to the clinical course of 2095 “ALF adults” admitted at this institution during the period 1973–2008 revealed an improvement of hospital survival from 17 % in 1973–1978 to 62 % in 2004–2008. In non-transplanted patients, survival rose from 17 % to 48 % and in liver recipients (n = 387) from 56 % in 1984–88 to 86 % in 2004–2008 (Bernal et al. 2013).
Similarly the ELTR reported 5-year patient and graft survival rates of 68 % and 57 % in 4903 ALF patients transplanted during the period 1988–2009. Despite increased donors age over 60 years from 1.8 % to 21 %, survival further improved during the period 2004–2009. The combination of recipient age >50 and donor age >60 years resulted in the highest mortality/graft loss rates within the first post-LT year (57 %) (Germani et al. 2012).
As the King’s College Criteria have a low negative predictive value for non-acetaminophen-induced ALF; a score was needed to better identify indication for LT in patients presenting viral induced ALF. The Clichy group developed criteria combining age, severe encephalopathy and factor V disorder group developed. Mortality without LT was predicted with a positive predictive value of 82 % and a negative predictive value of 98 %. As several studies reported contradictory data, there is still no agreement about the best selection criteria for LT in these critically ill patients.
The US-based Drug-Induced Liver Injury Network (DILIN) aimed at prospectively collecting all cases of drug-induced liver injuries in order to get a usable overview of all hepatotoxic drugs causing ALF. A recent study prospectively enrolled 839 patients diagnosed with hepatotoxicity due to conventional medications, herbals, and dietary supplements: 45 had injury due to bodybuilding dietary supplements, 85 to other dietary products, and 709 due to different medications. Liver injury from non-body building dietary supplements was most severe with significant differences in unfavorable outcome, death, and transplantation (Navarro et al. 2014). Another study on 660 adults with drug-induced ALF showed that nearly one out of ten patients died or underwent LT within 6 months, and nearly one out of five remaining patients evidenced persistent liver injury at 6 months (Fontana et al. 2014).
Upcoming Features: Artificial liver support devices may represent a possible way to avoid LT in ALF patients. Most of these (costly) devices still have to be considered as “bridge to” rather than a way to avoid LT. A prospective randomized US study analyzed the role of an extracorporeal porcine hepatocyte-based bioartificial liver (BAL) in 171 patients (86 control and 85 BAL). Patients with fulminant/subfulminant hepatic failure and primary nonfunction following LT were included. Thirty-day survival was 71 % versus 62 % for BAL and control groups; excluding primary nonfunction patients resulted in similar survival rates (73 % vs. 59 %). When survival was analyzed accounting for confounding factors, no difference between the 2 groups was observed (Demetriou et al. 2004). Another randomized controlled trial involving 16 French LT centers evaluated the role of albumin dialysis (molecular adsorbent recirculating system, MARS) (Gambro, Lund, Sweden), a “non-cell” artificial liver support device, in 102 patients: 49 patients were randomized to conventional and 53 to MARS and conventional treatment. Sixty-six patients had LT (41 % among paracetamol-induced ALF; 79.4 % among non-paracetamol-induced ALF). The short delay from randomization to LT (medium 16.2 h) precluded however to evaluate efficacy and safety profiles; only 39 MARS patients had at least one session of 5 h or more. Six-month survival was 75.5 % with conventional treatment and 84.9 % with MARS. In patients with paracetamol-related ALF, 6-month survival was 68.4 % with conventional treatment and 85 % with MARS. Adverse events between groups were similar (Saliba et al. 2013). A monocentric Italian study including 45 ALF patients treated with MARS during the period 1999–2008 is worthwhile to mention. Thirty-six patients survived: 21 were bridged to LT, 15 continued their extracorporeal treatment until liver and clinical recovery, and nine patients died before LT due to multiorgan failure. Six prognostic relevant parameters were identified: reduction of lactate, IL-6 and intracranial pressure, systemic vascular resistance index values, Glasgow Coma Scale <9, and number of MARS treatments. Patients with 0–2 risk factors all survived without LT; patients with 5–6 risk factors all died before LT. Patients with improved neurological status, cytokines, lactate, and hemodynamic parameters could “escape” LT (Novelli et al. 2009). The fractionated plasma separation and adsorption system (FPSA) (Prometheus, Fresenius Medical Care) represents another support device. A Turkish study utilized 85 sessions to treat 27 patients (median three treatments/patient) with ALF or acute-on-chronic liver failure. The overall survival was 48.1 % (Sentürk et al. 2010). Four patients (14.8 %) were transplanted, and in nine (33 %) LT could be avoided; the remaining 14 patients were not transplanted because they were judged as inappropriate candidates or because of organ unavailability.
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