Liver Transplantation

Research into the possibility of liver transplantation (LT) started before the 1960s with the pivotal baseline work of Thomas Starzl in Chicago and Boston, where the initial LT techniques were researched in dogs. Starzl attempted the first human LT in 1963 in Denver, but a successful LT was not achieved until 1967.

In 1970, with an immunosuppressive regimen largely based on steroids and azathioprine, survival rates were dismal—approximately 15% at 1-year follow-up. LT did not become a clinical reality until the early 1980s, after the discovery of cyclosporine, which led to improvements in rejection rates.

In 1983, the US National Institutes of Health established, by consensus, that LT was to be considered out of the experimental realm and was to be clinically accepted as definitive therapy for end-stage liver disease (ESLD). Additional improvements in immunosuppression that were instrumental in advancing the science included the discovery of monoclonal antibodies (ie, muromonab-CD3 [OKT3]) in 1986.

The combination of improvements in rejection rates and in surgical technique led to an enormous growth of the field during the 1980s, with expansion from 3 centers in 1982 to more than 120 centers today. In 2017, over 8,000 procedures were performed, up from approximately 100 in 1982. 

Of great importance in this expansion was the development of the University of Wisconsin (UW) solution in 1988, which increased preservation time and allowed for a smoother surgical procedure, avoiding a rushed tour de force in the operating room. Finally, the development of newer immunosuppressants, such as tacrolimus and interleukin-2 (IL-2) receptor blockers, has paved the way for further growth in this field.

All those advances have produced excellent results, with current 1-year patient survival rates of 91-93% and 5-year survival rates of 75-84%. ^[1] Future advances may include the development of xenotransplantation, which was pioneered by Starzl in 1992, and the development of cloning techniques and their impact on organ availability.

Organ allocation has also evolved over time, with the current system based on the Model for End-Stage Liver Disease (MELD; see the MELD Score calculator), with a focus on maximizing transplant benefit. ^{[7, 8]} Further refinements of the model are always ongoing and aim to improve fairness in allocation and survival results. Hepatitis C virus, hepatocellular carcinoma (HCC), chronic kidney disease, and alcohol abuse relapse continue to be major challenges, and continued research in these areas will undoubtedly lead to better outcomes for transplant recipients.

According to the Centers for Disease Control and Prevention (CDC), from 2000 to 2015, death rates for chronic liver disease and cirrhosis in the United States increased 31% (from 20.1 to 26.4 per 100,000 population) among persons 45 to 64 years old and rates increased 3% (from 29.4 to 30.2 per 100,000) among those 65 or older.  Among 25 to 44 year olds, the death rate in men decreased 10% (from 6.1 to 5.5 per 100,000), but the rate in women increased 18% (from 2.8 to 3.3 per 100,000). ^[9]  

Globally, 80 million individuals are infected with hepititis C virus (HCV), and it is estimated that at least 3.5 million people are infected in the United States. Individuals born from 1945 to 1965 have a 3% prevalence of HCV antibodies, which is 5 times the prevalence in adults born in other years. The highest prevalences are reported in Egypt (15%), Pakistan (4.7%), and Taiwan (4.4%). Lower prevalences are seenin North America (range, 1.1%‐1.3%), Australia (1.7%), and eastern and western Europe (range, 0.5%‐4.5%). ^[10]  

Nonalcoholic fatty liver disease (NAFLD), which includes nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH), is an increasingly common cause of end-stage liver disease and is the second most common cause of hepatocellular carcinoma (HCC) requiring liver transplantation. A meta‐analysis of studies from 2006‐2014 estimated a NAFLD prevalence of 24% (20%‐29%) in the general population, fueled by the global epidemic of obesity. ^[11]

From a surgical point of view, the liver is divided into right and left lobes of almost equal size by drawing a line (called Cantlie's line) from the gallbladder fossa in front to the inferior vena cava fossa behind. This division is based on the right and left branches of the hepatic artery and the portal vein, with tributaries of bile (hepatic) ducts following. The middle hepatic vein (MHV) lies in Cantlie's line, or, depending on the anatomy, may be predominantly draining the right or the left sides of this liver so divided. The left pedicle (left hepatic artery [LHA], left branch of the portal vein, and left hepatic duct) has a longer extrahepatic course than the right.

Each lobe is divided into 2 sectors. The right hepatic vein (RHV) divides the right lobe into anterior and posterior sectors; the left hepatic vein (LHV) divides the left lobe into medial (quadrate) and lateral sectors. The posterior sector of the right lobe and the caudate lobe are not seen on a frontal view of the liver; the anterior sector of the right lobe forms the right lateral border in this view. For more information about the relevant anatomy, see Liver Anatomy.

Even more relevant is the division of the liver into 8 segments, 4 in the left side and 4 in the right.  Segments 1 (caudate lobe), 2, 3, and 4 (often subdivided into 4a, superiorly, and 4b, inferiorly) are located in the left lobe and segments 5 through 8 are in the right lobe. This allows for segmental resections of the organ without compromising other relevant flow to the remnant liver.

The United Network for Organ Sharing (UNOS) classifies patients using the Model for End-Stage Liver Disease (MELD) scoring system if they are aged 12 years or older, or the Pediatric End-Stage Liver Disease (PELD) scoring system if they are younger than 12 years. Medical urgency for liver allocation is determined either by the MELD or PELD score, or by the assignment of a status (1A or 1B). Currently, priority is given to status 1A, which includes patients with a life expectancy without a liver transplant of less than 7 days who are either in the intensive care unit (ICU) with fulminant liver failure without preexisting liver disease, or have primary non-function of a transplanted liver within 7 days of transplantation. ^[12]

The MELD and PELD scores are intended to reflect the candidate’s disease severity, or the risk of 3-month mortality without access to liver transplant. However, those scores do not always accurately predict risk of death without access to liver transplant or the complications of the liver disease. In these instances, an exception may be requested. Hepatocellular carcinoma (HCC) is the most common diagnosis requiring a MELD or PELD score exception. ^[13]  

Diagnoses indicating potential candidacy for liver transplantation can be broadly categorized as follows ^[1] :

• Noncholestatic cirrhosis, including post-necrotic cirrhosis from hepatitis B or C or non-alcoholic steatohepatitis (NASH)
• Cholestatic liver diseases (ie, primary biliary cirrhosis, secondary biliary cirrhosis,  primary sclerosing cholangitis)
• Biliary atresia
• Acute hepatic failure, including acutely decompensated Wilson disease
• Metabolic diseases (ie, alpha-1-antitrypsin deficiency, Wilson disease, tyrosinemia, glycogen storage disorder type I or type IV)
• Malignant neoplasms or benign tumors (ie, HCC, cholangiocarcinoma, hepatoblastoma, polycystic liver disease, hepatic adenoma)

Less common additional diagnoses include the following ^[1] :

• Cystic fibrosis
• Budd-Chiari syndome
• Total parenteral nutrition/hyperalimentation 
• Neonatal hepatitis
• Congenital hepatic fibrosis
• Byler disease
• Trauma
• Graft versus host disease

Clinical presentation

As a rule, the following complications of end-stage liver disease (ESLD) warrant LT:

• Recurrent variceal hemorrhage
• Intractable ascites
• Spontaneous bacterial peritonitis
• Refractory and disabling encephalopathy
• Severe jaundice
• Exacerbated synthetic dysfunction
• Sudden deterioration
• Fulminant hepatic failure

Ascites is associated with a poor prognosis in the mid to short term, especially when it becomes unmanageable with diuretic therapy and requires repeated paracentesis, transjugular intrahepatic portosystemic shunting (TIPS), or insertion of a peritoneovenous shunt. Encephalopathy may develop rather insidiously in most patients and may be difficult to elicit properly upon examination.

Clinically, encephalopathy is divided into 4 stages. Of these, the most obviously life-threatening are stages 3 and 4 (somnolence and coma).

Synthetic dysfunction is perhaps the earliest manifestation of ESLD, often manifested by decreased albumin levels alone or in combination with prolongation of the prothrombin time and jaundice. In its most severe form, it can lead to severe malnutrition. ^[14] Portal hypertension can manifest either silently (ie, decreased platelet count, white blood cell count, or both) or overtly, with variceal bleeding.

Other manifestations include the development of hepatocellular carcinoma (HCC), which is common in patients with hepatitis B and hepatitis C, or severe intractable pruritus. Finally, a controversial indication for transplantation in the face of the organ shortage is in those patients with severe disabling fatigue.

In general terms, diseases that cause ESLD do so by affecting either the function of the hepatocyte (eg, hepatocellular diseases) or the excretory function of the biliary system (eg, cholestatic diseases). Their prognoses are different, and their treatment must be individualized. As a general rule, hepatocellular diseases cause a more profound derangement of hepatic synthetic function early in the disease process. Conversely, cholestatic diseases preserve hepatocellular function until more advanced stages of the disease process.

Indications for liver transplantation can also be broadly categorized into severity of disease indications (ie, the patient's life is immediately threatened without transplantation) and quality of life indications (ie, the patient is permanently disabled, but his or her life is not in immediate danger). While the former obviously mandates urgent transplantation, great expertise is needed to address the latter.

 

The following conditions are currently considered absolute contraindications to liver transplantation (LT) by most programs:

• Untreated spontaneous bacterial peritonitis (SBP) or other active infection
• Severely advanced cardiopulmonary disease, unless already addressed successfully (eg, with coronary artery bypass grafting [CABG])
• Extrahepatic malignancy that does not meet cure criteria
• Active alcohol or substance abuse, with exceptions on a case-by-case basis
• Inability to comply with immunosuppression protocols because of psychosocial situations

SBP, which is sometimes protean in its manifestations (eg, malaise, abdominal discomfort), can be devastating and can cause decompensation in an otherwise stable patient with cirrhosis. The development of SBP in a patient with cirrhosis is an indicator of a very poor prognosis. SBP may present as encephalopathy, hypotension, fever, leukocytosis, and an elevated white blood cell count in the peritoneal fluid. The absolute criteria for a diagnosis of SBP are one or more of the following:

• Peritoneal fluid polymorphonuclear leukocyte count > 250 cells/μL
• Identification of bacteria in peritoneal fluid by light microscopy
• Subsequent positive bacterial culture results in the appropriate clinical setting

If pneumonia or other active infections are present, mortality rates after transplantation are greatly increased. This emphasizes the need to have a high index of suspicion for infection. If any doubt exists about the presence of infection, abdominal paracentesis, chest radiograph, urinalysis, and/or pan cultures may be indicated. In patients with a prior history of drug use, examine arms and legs for evidence of new track marks. Patients with a history of alcohol abuse should have an alcohol level test performed as part of the preoperative workup through contract arrangements and upon admission for transplantation.

Secondary liver malignancies are contraindications to LT because of the universal recurrence of the tumors under immunosuppression. Exceptions to this rule include metastatic neuroendocrine malignancies such as carcinoid tumors. An elicited history of previous malignancy in a transplant candidate should prompt an extensive workup for metastatic disease, staging before and after surgery or therapy, and consultation with an oncologist.

Relative contraindications to LT are multiple, and each should be weighed when considering the prospective recipient's severity of illness. While no single relative contraindication alone may prevent a given patient from receiving a liver transplant, these are red flags, which, if multiple or if manifesting in an otherwise high-risk recipient, may proscribe LT. Most commonly, these red flags include the following:

• Chronic renal failure (in which combined liver-kidney transplantation may be required)
• Advanced cachexia and frailty
• Large HCCs (more advanced than stage II (ie, Milan criteria, as described by the UNOS–modified American Joint Committee on Cancer [AJCC] classification)
• Medication-resistant hepatitis B virus (HBV) cirrhosis
• Portal and mesenteric vein thrombosis 
• History of prior cancer not meeting full AJCC cure criteria
• Active infection
• Multisystem organ failure

Note that many of those contraindications are program-specific and depend greatly on the volume and experience of each individual program.

Age is no longer considered an absolute contraindication. Physiological age, rather than chronological age, dictates the individual's suitability for candidacy. However, careful judgment should be used in allocating donors to these patients, given the organ shortage.

With the development of refinements in surgical techniques, selected patients with portal and/or mesenteric venous thrombosis have undergone successful transplantation. The availability of venous jump grafts to restore portal flow permits transplantation in these generally advanced cases. One study found that living donor liver transplantation may be safely performed in patients with portal vein thrombosis without increased mortality. When thrombectomy fails in type II and II portal vein thrombosis, jump grafting using a cryopreserved vessel may be a viable option to restore portal flow. ^[15]

In cases of mesenteric thrombosis, cavoportal hemitransposition may offer a chance of successful liver engraftment.  Alternatively, multivisceral transplantation may be considered.

If studied carefully, all patients with cirrhosis are found to have a certain degree of intrapulmonary shunting. In certain patients, this can be disabling and can lead to hypoxia at rest (hepatopulmonary syndrome). The successful reversal of these shunts after LT makes this an indication rather than a contraindication. However, selection of these candidates must be adequate and precise, with sophisticated and directed pulmonary function testing.

The presence of established anatomical portopulmonary hypertension is probably an absolute contraindication for LT, but the situation varies for nonfixed pulmonary hypertension. LT is contraindicated in patients with severe pulmonary hypertension (mean pulmonary artery pressure of ≥35 cm H₂O, as directly measured by an indwelling Swan-Ganz catheter, in a euvolemic patient), especially if coupled with increased pulmonary vascular resistance. However, for patients with mild-to-moderate pulmonary hypertension and reasonable right-sided heart function, treatment with vasodilators, prostaglandin, or both allows safe LT.

A history of prior abdominal surgery and portosystemic shunts does not preclude successful transplantation, although these factors make it a technical tour de force and dramatically increase blood loss because of existing portal hypertension. Some groups have reported good results with selective shunting or transjugular intrahepatic portosystemic shunting (TIPS).

Actively replicating HBV infection precludes transplantation, because of the great likelihood of recurrent and aggressive disease. A subgroup of these patients—those with a small viral load, good response to antivirals (with at least a 2-log decrease in their HBV DNA counts), and/or no active replication but with ESLD—may be considered for candidacy. In these patients, the institution of lamivudine, adefovir ,or entecavir therapy may render the viral replicative activity undetectable, hence allowing safe transplantation. The emergence of drug-resistant strains may limit the long-term use of these therapies.

Very weak and malnourished patients are poor candidates for LT because of their extremely poor reserve. If their nutritional status can be improved by means of total enteral or parenteral nutrition, their odds improve. This is difficult to accomplish in the face of a failing liver.

Frequently, cirrhosis is associated with development of HCC. In these patients, transplantation must be performed under strict guidelines and protocols to minimize or prevent recurrence. As a rule, single-lesion HCCs smaller than 5 cm or 3 or fewer lesions with the largest < 3 cm (ie, AJCC stages I and II, Milan criteria), are associated with less chance of recurrence and survival rates equal to those of patients undergoing transplantation because of nonmalignant conditions. Protocols using chemoembolization have shown promising early results for larger tumors. Finally, the widespread use of chemoembolization protocols while on the waiting list and aggressive radiofrequency ablation may change the indications and therapeutic approaches in the immediate future.

LT is a standard proven therapy for ESLD and should be offered to any patient who needs it. Careful selection of both donors and recipients maximizes usage by optimizing outcomes. This requires a dedicated multidisciplinary team of health care providers, usually concentrated in a transplantation center. Living-related LT may be one of the solutions to the donor shortage.

A study of 1427 liver recipients who received transplant between January 1, 1998, and January 31, 2014, at 12 North American centers found survival probability at 10 years was 70% for living-donor recipients and 64% for deceased-donor recipients. ^[16]  In 2019, the incidence of graft failure at 1 year was 8.9% for recipients of deceased-donor livers. The 5‐year survival rate for recipients of living-donor livers was more than 80%. ^[2]

In addition, patients are surviving longer with improved quality of life compared with pretransplantation status. However, this prolonged longevity has brought about new concerns, such as the long-term effects of immunosuppression, as they relate to effects on the cardiovascular system, infections, and propensity for malignancy. Thus, the search for newer immunosuppressive strategies to minimize these adverse effects continues today.

Excessive alcohol consumption negatively impacts long-term survival after liver transplant, regardless of the primary indication. Mortality is due largely to the recurrence of liver disease and non-hepatic cancer, along with cardiovascular disease. ^[17]

Renal function is an integral component of MELD; since the institution of MELD, patients with cirrhosis and renal failure have been given increased priority. An investigation of the UNOS system revealed that combined kidney-liver transplants have increased since the introduction of MELD, as have the number of transplant recipients requiring preoperative renal replacement therapy. ^[18]  Despite this, patient posttransplant survival did not change in the MELD era; however, kidney-liver recipients requiring pretransplant renal replacement therapy had better survival than liver-alone recipients requiring pretransplant renal replacement therapy.

It is unknown whether post-transplantation renal replacement therapy has an effect on the rate and types of bacterial infections. In a 2011 study, 16% of patients required post-transplant renal replacement therapy. Bacterial infections were more prevalent in renal replacement therapy recipients  than in those who did not require renal replacement therapy. A total of 49% of the renal replacement therapy group required long-term therapy, while 51% required short-term therapy, with the long-term therapy being a significant predictor of infections. The most common infections were bacteremia and intra-abdominal infections, and Enterobacteriaceae and enterococci were the most common pathogens in both groups. The mortality rate did not differ for the long- and short-term groups, but it was higher in patients requiring renal replacement therapy compared with those not requiring the therapy. ^[19]

To maximize the utility of organ allocation, a system that balances both pretransplant medical urgency and posttransplant survival is needed. Although the MELD score is a good predictor of pretransplant survival, it is only a weak predictor of posttransplant survival. ^{[8, 20, 21]}  Donor factors, surgical factors, and posttransplant complications play a significant role in posttransplant outcomes. Further changes to liver allocation schemes should include the investigation and incorporation of other objective parameters that add to the prediction of posttransplant mortality. Newer systems should incorporate donor characteristics to the MELD score to ensure the best possible recipient-donor pairing that is associated with improved posttransplant survival. ^[22]

In one assessment of health-related quality of life (HRQoL) and employment of postransplant patients, questionnaire results showed HRQoL rates to be generally high and comparable among all groups of patients regardless of the reason for transplant. ^[23]

Occasionally, improvement in quality of life does not bring a parallel increase in the employment capabilities of the patient. Much social mistrust and misconceptions about liver disease still exist because it is frequently perceived as self-inflicted. Further education of the population in this respect should alleviate this problem.