**2. Evolution of liver transplant indications**

Nowadays, liver transplantation is indicated for acute or chronic liver failure of any cause (**Table 3**).

Cirrhosis due to chronic hepatitis C infection is one of the most common indications for liver transplantation in the United States and Europe. Despite effective antiviral treatments including Pegylated Interferon, Ribavirin, and direct-acting antiviral agents (DAAs), this indication is likely to remain important for the coming decades given the large prevalence of chronic hepatitis C infection and the propensity of the disease to lead to cirrhosis and hepatocellular carcinoma (HCC) (Merion, 2010).

Chronic hepatitis B has become a less common indication, mostly due to the advent of universal vaccination. Additionally, dramatic improvements in the treatment of hepatitis B, such as the development of nucleoside/nucleotide analogues, has reduced the number of patients with chronic hepatitis B progressing to end-stage liver disease. However, in parts of the world where chronic hepatitis B is endemic, including much of Asia, this remains the most common indication (Perrillo, 2009).

Alcohol-related liver disease is an important indication for OLT in Western countries and is oftentimes associated with concomitant hepatitis C infection. In the past, patients with alcohol-related liver disease and alcohol dependence were often refused access to liver transplantation due to unjust societal allocation of scarce donor organs. However, a careful assessment with the support of a health care professional experienced in the management of patients with addictive behavior is associated with low rates of recidivism after OLT (Lucey,

Liver Transplantation in the Clinic – Progress Made During the Last Three Decades 181

patients and is associated with an increased risk of hepatocellular carcinoma (HCC), it is an increasingly frequent indication for liver transplantation (Burke, 2004). Considering the current obesity epidemic, NAFLD may become the most common indication for liver

Primary HCC is a unique and evolving indication for liver transplant. Initially, outcomes in liver transplantations for patients with unresectable HCC were not encouraging. Ninety percent of those transplanted for HCC developed recurrent disease within 2 years. As a result, HCC was considered a contraindication to transplantation for a number of years. Ongoing research on HCC post-transplant elucidated that important predictors of recurrence are tumor characteristics, such as tumor size, stage, and grade, number of nodules, micro- or macrovascular invasion, serum levels of alpha-fetoprotein, and demonstrated absence of extrahepatic spread. In 1996, Mazzaferro and colleagues defined the Milan criteria, which require a single tumor ≤ 5 cm in diameter or no more than three tumor nodules, each ≤ 3 cm in diameter. Liver transplant in patients meeting the Milan criteria have excellent outcomes and low recurrence rates (Mazzaferro, 1996). Augmentations to the Milan criteria are currently being debated in the liver transplant community. The San Francisco criteria, which require either a single lesion ≤ 6.5 cm or up to three lesions none of which is >4.5 cm and with total tumor diameter ≤ 8 cm, have been widely debated, but no consensus has yet emerged (Yao, 2001). Finally, more attention has been given to the role of downstaging by locoregional therapy for otherwise unsuitable candidates. Treatments to shrink nodules, including radiofrequency ablation, transcatheter arterial chemoembolization, and novel thermal and non-thermal techniques for tumor ablation offer

strategies for subsequent transplantation in patients with more advanced lesions.

Many inborn errors of metabolism have been successfully treated with liver transplantation

Acute liver failure has long been considered an appropriate indication for liver transplant. Patients with fulminant hepatic failure should be referred to a transplant center as quickly as possible for critical care management. If given appropriate critical care support, many patients spontaneously recover. Patients predicted to have little chance of spontaneous recovery should undergo transplantation as soon as possible. New technologies using bioartificial liver devices including both a biological component and an artificial scaffold may offer some promises for patients with acute liver failure. However, these technologies have not become widely available yet, and therefore OLT remains an important treatment

Splanchnic venous thrombosis and portal hypertension surgery are both part of the natural evolution of cirrhosis. Intra-operative mortality during OLT with these conditions was once nearly 50%. Those that survived OLT oftentimes had morbid conditions that diminished the utility of the transplant. In recent times, several technical advances have been made to overcome this problem. Eversion thrombectomy is a good treatment option for a majority of

transplantation in the coming years.

(Kayler, 2003).

(Demetriou, 2004; Ellis, 1996).

**3.1 Absolute contraindications** 

**3.1.1 Splanchnic venous thrombosis** 

**3. Historical contraindications to OLT** 


1992). Nowadays, this indication has become more commonly accepted, as long as patients demonstrate sobriety of at least 6 months duration.

a 2008 Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry for Transplant Recipients: Transplant Data 1998–2007. Rockville, MD: U.S. Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation; 2009

Table 3. Primary Diagnosis of Deceased Donor Liver Transplant Recipients, 1998 to 2007a

Cholestatic liver disease is becoming an increasingly uncommon indication for OLT. Data from UNOS show that among cadaveric liver transplants in 1991, 18% were for cholestatic liver disease, compared with 10% in 2000 and only 7.8% in 2008 (UNOS, 2010). The incidence and prevalence of primary biliary cirrhosis (PBC) are steadily increasing whereas the absolute number of OLT performed for PBC is falling (UNOS, 2010; ELTR, 2010). Reasons for this decline in the number of transplants for PBC are not clear but may relate to a changing pattern of disease, increased rates of diagnosis, and more effective treatment. The number of transplants for primary sclerosing cholangitis (PSC) in western countries during the period 1995-2006 has remained stable and represents 8% of all liver transplants. In some areas that have a relatively low prevalence of hepatitis C and alcoholic liver disease (ALD), such as the Scandinavian countries, PSC is the leading indication for OLT, accounting for 16% of the indications (Nordic Liver Transplant Registry, 2010).

Nonalcoholic fatty liver disease (NAFLD) is becoming one of the most common liver disorders in developed countries. Because this disorder can lead to cirrhosis in a number of

1992). Nowadays, this indication has become more commonly accepted, as long as patients

**Year of Transplant** 

**Diagnosis 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007** 

Total 4,424 4,498 4,595 4,673 4,969 5,351 5,847 6,120 6,362 6,223

cirrhosis 2,790 2,899 2,956 2,973 3,091 3,151 3,514 3,709 3,732 3,547

liver disease 563 499 475 471 492 513 510 467 552 555

necrosis 349 405 436 366 369 355 425 448 371 368

disease 163 152 165 170 152 183 180 200 215 175

neoplasm 98 87 84 142 3311 371 481 610 774 783

Other 247 258 318 378 370 603 550 507 575 608

a 2008 Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry for Transplant Recipients: Transplant Data 1998–2007. Rockville, MD: U.S. Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems

Table 3. Primary Diagnosis of Deceased Donor Liver Transplant Recipients, 1998 to 2007a

accounting for 16% of the indications (Nordic Liver Transplant Registry, 2010).

Cholestatic liver disease is becoming an increasingly uncommon indication for OLT. Data from UNOS show that among cadaveric liver transplants in 1991, 18% were for cholestatic liver disease, compared with 10% in 2000 and only 7.8% in 2008 (UNOS, 2010). The incidence and prevalence of primary biliary cirrhosis (PBC) are steadily increasing whereas the absolute number of OLT performed for PBC is falling (UNOS, 2010; ELTR, 2010). Reasons for this decline in the number of transplants for PBC are not clear but may relate to a changing pattern of disease, increased rates of diagnosis, and more effective treatment. The number of transplants for primary sclerosing cholangitis (PSC) in western countries during the period 1995-2006 has remained stable and represents 8% of all liver transplants. In some areas that have a relatively low prevalence of hepatitis C and alcoholic liver disease (ALD), such as the Scandinavian countries, PSC is the leading indication for OLT,

Nonalcoholic fatty liver disease (NAFLD) is becoming one of the most common liver disorders in developed countries. Because this disorder can lead to cirrhosis in a number of

Biliary atresia 214 188 161 172 164 175 187 179 143 174

demonstrate sobriety of at least 6 months duration.

**Primary** 

Noncholestatic

Cholestatic

Acute hepatic

Metabolic liver

Malignant

Bureau, Division of Transplantation; 2009

patients and is associated with an increased risk of hepatocellular carcinoma (HCC), it is an increasingly frequent indication for liver transplantation (Burke, 2004). Considering the current obesity epidemic, NAFLD may become the most common indication for liver transplantation in the coming years.

Primary HCC is a unique and evolving indication for liver transplant. Initially, outcomes in liver transplantations for patients with unresectable HCC were not encouraging. Ninety percent of those transplanted for HCC developed recurrent disease within 2 years. As a result, HCC was considered a contraindication to transplantation for a number of years. Ongoing research on HCC post-transplant elucidated that important predictors of recurrence are tumor characteristics, such as tumor size, stage, and grade, number of nodules, micro- or macrovascular invasion, serum levels of alpha-fetoprotein, and demonstrated absence of extrahepatic spread. In 1996, Mazzaferro and colleagues defined the Milan criteria, which require a single tumor ≤ 5 cm in diameter or no more than three tumor nodules, each ≤ 3 cm in diameter. Liver transplant in patients meeting the Milan criteria have excellent outcomes and low recurrence rates (Mazzaferro, 1996). Augmentations to the Milan criteria are currently being debated in the liver transplant community. The San Francisco criteria, which require either a single lesion ≤ 6.5 cm or up to three lesions none of which is >4.5 cm and with total tumor diameter ≤ 8 cm, have been widely debated, but no consensus has yet emerged (Yao, 2001). Finally, more attention has been given to the role of downstaging by locoregional therapy for otherwise unsuitable candidates. Treatments to shrink nodules, including radiofrequency ablation, transcatheter arterial chemoembolization, and novel thermal and non-thermal techniques for tumor ablation offer strategies for subsequent transplantation in patients with more advanced lesions.

Many inborn errors of metabolism have been successfully treated with liver transplantation (Kayler, 2003).

Acute liver failure has long been considered an appropriate indication for liver transplant. Patients with fulminant hepatic failure should be referred to a transplant center as quickly as possible for critical care management. If given appropriate critical care support, many patients spontaneously recover. Patients predicted to have little chance of spontaneous recovery should undergo transplantation as soon as possible. New technologies using bioartificial liver devices including both a biological component and an artificial scaffold may offer some promises for patients with acute liver failure. However, these technologies have not become widely available yet, and therefore OLT remains an important treatment (Demetriou, 2004; Ellis, 1996).

## **3. Historical contraindications to OLT**

#### **3.1 Absolute contraindications**

#### **3.1.1 Splanchnic venous thrombosis**

Splanchnic venous thrombosis and portal hypertension surgery are both part of the natural evolution of cirrhosis. Intra-operative mortality during OLT with these conditions was once nearly 50%. Those that survived OLT oftentimes had morbid conditions that diminished the utility of the transplant. In recent times, several technical advances have been made to overcome this problem. Eversion thrombectomy is a good treatment option for a majority of

Liver Transplantation in the Clinic – Progress Made During the Last Three Decades 183

The most recent development in the field of OLT is the treatment of metastatic colorectal malignancy. The Oslo-SECA (SEcondary CAncer) study indicates that OLT will have a role in the treatment of colorectal metastases on the condition that adapted chemotherapy and immunosuppression are employed after the transplant procedure. Preliminary results obtained in the Oslo-SECA cases show nearly 50% 5-year survival after OLT (Foss, 2011).

OLT in active alcoholic patients has always been discussed heavily within the medical community (Starzl, 1990). The 'six month abstinence rule' is not generally enforced, and some French groups even advocate OLT in cases of severe acute alcoholic hepatitis

Although also heavily debated, some groups in New York showed that OLT can be

Both alcohol and drug abusers need exceptionally tight follow-up during the pre- and posttransplant period. It is of utmost importance to take familial, professional, and social

Two-staged cardiac and hepatic transplantion is becoming more frequent (Starzl, 1990). Several case reports have been published about simultaneous liver and heart transplantation in the context of familial amyloid polyneuropathy (FAP) and hemochromatosis. Simultaneous OLT with coronary, valvular, or arrythmia surgery has also been reported. These surgeries are complex and have stimulated major interest in both cardiovascular and

Viral cirrhosis was once an absolute contraindication to OLT because of the universal recurrence of the disease in the liver allograft (Lerut, 1998). The landmark paper of Samuel in 1993 showed that adequate antiviral prophylaxis using specific anti-HBs antibodies protects the allograft from reinfection (Samuel, 1993). Further improvement has been achieved by combining nucleoside and nucleotide analogues with immunoglobulins. This prophylactic combination was able to reduce the incidence of allograft reinfection from 100% to 5%. Moreover, those with HBV gain an immunologic advantage from immunoglobulin treatment due to immunoglobulins producing a tolerogenic effect on

Increasing numbers of transplants are done in patients aged over 65 and 70 years of age (Starzl, 1990). The initial Pittsburgh results have now been confirmed by most transplant

**3.1.5 Alcohol abuse** 

(Mathuri, 2005).

**3.1.6 Drug abuse** 

successful in recipients on methadone maintenance.

**3.1.7 Advanced cardiopulmonary disease** 

hepatic experts of transplant centers.

**3.1.8 Viral infections** 

dendritic cells.

**3.1.9 Age** 

centers.

conditions into consideration in these potential patients (Starzl, 1990).

patients with splanchnic venous thrombosis. If eversion thrombectomy is not possible, a free iliac interposition graft between the allograft portal vein and the superior mesenteric vein is indicated. Sometimes it is possible to connect the allograft portal vein to a collateral vein. In cases of extended splanchnic thrombosis, cavo-portal hemi-transposition or combined liverintestinal transplantation are the last resorts for treatment (Lerut, 1997).

### **3.1.2 Hepatopulmonary Syndrome (HPS)**

HPS is defined as a pO2 < 70 mmHg in an upright position. It is present in up to 20% of cirrhotic patients. Even in cases where oxygen saturation is below 50 mmHg, this situation can be reversed by a successful OLT. The post-transplant recovery is usually more complicated necessitating adapted respiratory care. The pre-transplant baseline macroaggregated albumin shunt fraction may indicate the limits of correction following OLT (Starzl, 1990).

#### **3.1.3 Sepsis outside the hepatobiliary system**

Active extra-hepatic infection compromises outcomes of OLT. Nonetheless, transplantation can be performed successfully if the infection is confined to the lungs or the ascites and does not cause hemodynamic instability (Starzl, 1990). Post-transplant care is usually much more prolonged and expensive if the patient has sepsis outside the hepatobiliary system.

### **3.1.4 Primary malignant disease outside the hepatobiliary system**

Based on the embryological development theory, Starzl advocated the 'en block' or 'cluster transplant' in order to treat extended hepatobiliary malignancies and liver metastases from neuroendocrine tumors. Although initial success was promising, longterm results were disappointing. (Lerut, 2007, 2011; Starzl, 1990).

Pre-OLT malignancies or malignancies discovered incidentally during the OLT-procedure are no longer contraindications to OLT as shown by the Kings' College study. Metastatic hepatobiliary malignancy is an emerging indication for OLT. After successful chemotherapeutic treatment of hepatic and thoracic tumor involvement in children with hepatoblastoma, excellent results have been obtained with OLT. Similarly, excellent longterm results have been obtained for epithelioid hemangio-endothelioma. In the latter group some centers propose sequential or simultaneous hepatopulmonary transplantation (Lerut, 2007).

The role of OLT in the treatment of neuroendocrine tumors with hepatic involvement is continuously evolving. Excellent OLT results can be obtained in select, young (<50 years) patients after R0 resection of the primary tumor for more than six months prior to transplant. Furthermore, if the primary lesion has favorable tumor biology (as expressed by a Ki67 index of < 5-10%) and has a portal vein drainage, results are significantly improved (Bonaccorsi-Riani, 2010).

It is evident that all oncologic patients that undergo OLT will benefit from adapted immunosuppression. Minimization of immunosuppression and use of the m-TOR inhibitor, rapamycin, are of paramount importance. Rapamycin has antitumor activity based on antiangiogenic properties.

The most recent development in the field of OLT is the treatment of metastatic colorectal malignancy. The Oslo-SECA (SEcondary CAncer) study indicates that OLT will have a role in the treatment of colorectal metastases on the condition that adapted chemotherapy and immunosuppression are employed after the transplant procedure. Preliminary results obtained in the Oslo-SECA cases show nearly 50% 5-year survival after OLT (Foss, 2011).

#### **3.1.5 Alcohol abuse**

182 Liver Regenaration

patients with splanchnic venous thrombosis. If eversion thrombectomy is not possible, a free iliac interposition graft between the allograft portal vein and the superior mesenteric vein is indicated. Sometimes it is possible to connect the allograft portal vein to a collateral vein. In cases of extended splanchnic thrombosis, cavo-portal hemi-transposition or combined liver-

HPS is defined as a pO2 < 70 mmHg in an upright position. It is present in up to 20% of cirrhotic patients. Even in cases where oxygen saturation is below 50 mmHg, this situation can be reversed by a successful OLT. The post-transplant recovery is usually more complicated necessitating adapted respiratory care. The pre-transplant baseline macroaggregated albumin shunt fraction may indicate the limits of correction following OLT

Active extra-hepatic infection compromises outcomes of OLT. Nonetheless, transplantation can be performed successfully if the infection is confined to the lungs or the ascites and does not cause hemodynamic instability (Starzl, 1990). Post-transplant care is usually much more

Based on the embryological development theory, Starzl advocated the 'en block' or 'cluster transplant' in order to treat extended hepatobiliary malignancies and liver metastases from neuroendocrine tumors. Although initial success was promising, longterm results were

Pre-OLT malignancies or malignancies discovered incidentally during the OLT-procedure are no longer contraindications to OLT as shown by the Kings' College study. Metastatic hepatobiliary malignancy is an emerging indication for OLT. After successful chemotherapeutic treatment of hepatic and thoracic tumor involvement in children with hepatoblastoma, excellent results have been obtained with OLT. Similarly, excellent longterm results have been obtained for epithelioid hemangio-endothelioma. In the latter group some centers propose sequential or simultaneous hepatopulmonary transplantation

The role of OLT in the treatment of neuroendocrine tumors with hepatic involvement is continuously evolving. Excellent OLT results can be obtained in select, young (<50 years) patients after R0 resection of the primary tumor for more than six months prior to transplant. Furthermore, if the primary lesion has favorable tumor biology (as expressed by a Ki67 index of < 5-10%) and has a portal vein drainage, results are significantly improved

It is evident that all oncologic patients that undergo OLT will benefit from adapted immunosuppression. Minimization of immunosuppression and use of the m-TOR inhibitor, rapamycin, are of paramount importance. Rapamycin has antitumor activity based on

prolonged and expensive if the patient has sepsis outside the hepatobiliary system.

**3.1.4 Primary malignant disease outside the hepatobiliary system** 

intestinal transplantation are the last resorts for treatment (Lerut, 1997).

**3.1.2 Hepatopulmonary Syndrome (HPS)** 

**3.1.3 Sepsis outside the hepatobiliary system** 

disappointing. (Lerut, 2007, 2011; Starzl, 1990).

(Starzl, 1990).

(Lerut, 2007).

(Bonaccorsi-Riani, 2010).

antiangiogenic properties.

OLT in active alcoholic patients has always been discussed heavily within the medical community (Starzl, 1990). The 'six month abstinence rule' is not generally enforced, and some French groups even advocate OLT in cases of severe acute alcoholic hepatitis (Mathuri, 2005).

#### **3.1.6 Drug abuse**

Although also heavily debated, some groups in New York showed that OLT can be successful in recipients on methadone maintenance.

Both alcohol and drug abusers need exceptionally tight follow-up during the pre- and posttransplant period. It is of utmost importance to take familial, professional, and social conditions into consideration in these potential patients (Starzl, 1990).

#### **3.1.7 Advanced cardiopulmonary disease**

Two-staged cardiac and hepatic transplantion is becoming more frequent (Starzl, 1990). Several case reports have been published about simultaneous liver and heart transplantation in the context of familial amyloid polyneuropathy (FAP) and hemochromatosis. Simultaneous OLT with coronary, valvular, or arrythmia surgery has also been reported. These surgeries are complex and have stimulated major interest in both cardiovascular and hepatic experts of transplant centers.

#### **3.1.8 Viral infections**

Viral cirrhosis was once an absolute contraindication to OLT because of the universal recurrence of the disease in the liver allograft (Lerut, 1998). The landmark paper of Samuel in 1993 showed that adequate antiviral prophylaxis using specific anti-HBs antibodies protects the allograft from reinfection (Samuel, 1993). Further improvement has been achieved by combining nucleoside and nucleotide analogues with immunoglobulins. This prophylactic combination was able to reduce the incidence of allograft reinfection from 100% to 5%. Moreover, those with HBV gain an immunologic advantage from immunoglobulin treatment due to immunoglobulins producing a tolerogenic effect on dendritic cells.

#### **3.1.9 Age**

Increasing numbers of transplants are done in patients aged over 65 and 70 years of age (Starzl, 1990). The initial Pittsburgh results have now been confirmed by most transplant centers.

Liver Transplantation in the Clinic – Progress Made During the Last Three Decades 185

Criteria for placement on the waiting list have become more quantitative. Continuous refinement of the allocation system will improve the management of the waiting list

Alternative techniques such as split liver transplantation (SLT) and living donor liver transplantation (LDLT) will allow for expansion of the allograft pools. The bipartition of the liver is especially important in pediatric patients for whom size-matched whole liver allografts are scarce. Split grafts have been associated with reduction in the risk of death on the pediatric waiting list. However, SLT is much less successful in the adult-adult SLT. Donor selection for splitting and technical and logistical expertise to decrease total ischemia time are important factors in successful transplantation. A better understanding of the liver anatomy and improving surgical skills have allowed living liver donation to become a routine procedure in some centers. Given the major risks of the operation required for the

As there will always be more potential recipients than donors, many researchers are working in the field of artificial tissue engineering and regenerative medicine (RM) (Orlando, 2011a, 2011b, 2011c, 2011d, 2012a, 2012b, 2012c). RM holds the promise of regenerating tissues and organs by either stimulating previously irreparable tissues to heal themselves, by treating liver disease with cell therapies, or by manufacturing tissues *ex vivo*

This last approach, uses ECM scaffolds that have an intact but decellularized vascular network that is repopulated with autologous or allogeneic stem cells and/or adult cells. Liver ECM scaffolds may be produced from humans or animals. In the latter case, human cells are used to repopulate a scaffold of animal origin, coining a new concept called semi-xenotransplantation (Orlando, 2011a, 2011b). Importantly, preemptive transplantation with regenerated tissues will

Future progress in the medical treatment of oncology will enhance outcomes in OLT (Lerut, 2007, 2011; Bonaccorsi-Riani, 2010, Foss, 2011). As treatments of vascular tumors, advanced hepatocellular cancer, cholangiocellular cancer, neuroendocrine tumors, and colorectal liver metastases improve, indications for OLT in the 21st century will become more inclusive of

Combined organ transplantation is becoming more frequent as many liver diseases are accompanied by renal function impairment. Nowadays, 15% of all liver recipients have

Transplant teams should focus more on late morbidity and mortality. Currently, the majority of long-term survivors die from infectious disease, cardiovascular disease, or cancer while having a functional graft. This mortality is directly related to the strength of the maintenance immunosuppression. Minimization or even withdrawal of immunosuppressive protocols must become a priority in organ transplantation (Lerut, 2003, 2008). Unfortunately, tolerance protocols are frequently based on a trial and error approach, as good markers to predict tolerance are not yet available (Lerut, 2006). As the liver is an immunoprivileged organ with relatively high resistance against immune responses, liver recipients should be at the forefront

donor, whether this procedure will ever find wide application is unclear.

improve outcomes, especially in cases of metabolic and cystic liver disease.

using extracellular matrix (ECM) scaffolds.

advanced oncologic disease states.

of this research.

combined liver-kidney transplantation.

**4. Future perspectives** 

(Metsellaar, 2011).
