Liver Transplantation

Updated: Oct 02, 2015
  • Author: Cosme Manzarbeitia, MD, FACS; Chief Editor: Julian Katz, MD  more...
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Overview

History of the Procedure

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 expansion of the field during the 1980s, with expansion from 3 centers in 1982 to more than 120 centers today. In 1999, 4,500 procedures were performed, up from approximately 100 in 1982. Currently, approximately 16,000 patients are on the liver waiting list, and slightly more than 6,300 liver transplants were performed in 2008 (United Network for Organ Sharing [UNOS] data as of September 15, 2009). [1]

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 (IL)–2 receptor blockers, has paved the way for further growth in this field. All these advances have produced excellent results, with current 1-year patient survival rates of 80-90% and 5-year survival rates of 62-80%. [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 upon the Model for End-Stage Liver Disease (MELD; see the MELD Score calculator), with a focus on maximizing transplant benefit. [2, 3] 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 renal dysfunction, and alcohol relapse continue to be major challenges, and continued research in these areas will undoubtedly lead to better outcomes for transplant recipients.

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Problem

ESLD magnitude and organ shortage

The following list shows potential International Classification of Diseases, Ninth Revision, Clinical Modification diagnoses that could indicate candidacy for LT. The number of patients hospitalized with these primary and secondary diagnoses is enormous. However, only a small percentage of these patients ultimately are candidates for transplantation because other criteria are also used to determine candidacy. Diagnoses indicating potential candidacy for LT include the following:

  • 1550-1552 Malignant neoplasm of liver and intrahepatic bile ducts
  • 2115 Benign neoplasm of liver and biliary passages
  • 2308 Carcinoma of liver and biliary system
  • 2353 Neoplasm of uncertain behavior in liver and biliary passages
  • 2390 Neoplasm of unspecified nature in digestive system
  • 2710 Glycogenesis
  • 2720 Pure hypercholesterolemia
  • 2727 Lipidoses
  • 2751 Disorders of copper metabolism
  • 2770-2776 Cystic fibrosis, disorders of porphyrin metabolism, other disorders of purine and pyrimidine metabolism, amyloidosis, disorders of bilirubin excretion, mucopolysaccharidosis, other deficiencies of circulating enzymes
  • 2860 Congenital factor VIII disorder
  • 2861 Congenital factor IX disorder
  • 570 Acute and subacute necrosis of liver
  • 5712 Alcoholic cirrhosis of liver
  • 5714 Chronic hepatitis
  • 5715 Cirrhosis of liver without mention of alcohol
  • 5718 Other chronic nonalcoholic liver disease
  • 5719 Unspecified liver disease without mention of alcohol
  • 5728 Other sequelae of chronic liver disease
  • 5758 Other specified disorders of gallbladder
  • 5761,5762 Cholangitis, obstruction of bile duct
  • 75161,75169 Biliary atresia, other anomalies of gallbladder, bile ducts, and liver
  • 7744 Perinatal jaundice due to hepatocellular damage
  • 7778 Other specified perinatal disorders of digestive system
  • 864 Injury to liver
  • 3483 Encephalopathy, unspecified
  • 452 Portal vein thrombosis

The major constraint to meeting the demand for transplants is the availability of donated (cadaver) organs. [4] Several steps have been taken, nationally and locally, to alleviate the organ shortage. National required request laws mandate that families of every medically suitable potential donor be offered the option to donate organs and tissues. In addition, the National Organ Donation Collaborative efforts, currently ongoing, and laws that require all deaths to be reported to organ procurement organizations have resulted in increased organ donations. Rising public awareness about organ transplantation should continue to reduce the organ shortage. Finally, aggressive usage of extended donors and reduced-size, split, and living-related LT continue to expand the organ donor pool, though these efforts still fail to meet the need for organs.

In terms of procurement and distribution, major improvements are being made nationally to optimize distribution and to ensure good matches. Criteria for inclusion on the waiting list are being standardized with the recent development of listing criteria for all degrees of sickness. UNOS maintains a computerized registry of all patients waiting for organ transplants. All organs procured within a region are shared first within the region; if an appropriate recipient cannot be found within the region, UNOS personnel direct the organ to the recipient with the greatest need in another region. Organ recovery coordinators are on call 24 hours a day and arrange for serologic testing, removal, preservation, and distribution; additionally, they educate the public regarding organ donation.

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Epidemiology

Frequency

According to the latest US Centers for Disease Control and Prevention sources, cirrhosis remains the 12th leading cause of death for adults in the United States, with 27,013 deaths reported in 2004 and a death rate of nearly 9.2 cases per 100,000 persons. [5] This accounts for 1.1% of total deaths. Unfortunately, this number may grossly underestimate the real impact of ESLD because it does not include acute liver failure or other etiologies that may lead to the need for LT (see Problem).

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Etiology

See Problem.

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Presentation

Patients present with signs and symptoms of ESLD, which is discussed in more detail in the next section.

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Indications

Currently, any patient who has chronic or acute liver disease that leads to the inability to sustain a normal quality of life or that results in life-threatening complications should be considered a candidate for LT.

The common etiologies and indications for LT in adults can be seen in the red portion of the pie chart shown below.

Frequency of liver transplantation based on diagno Frequency of liver transplantation based on diagnosis.

The red portion represents the hepatocellular group of diseases, ie, those that primarily affect hepatocyte function and, thus, lead to faster clinical deterioration and life-threatening complications. The green portion represents the group of cholestatic diseases, in which the excretory function of the liver is primarily compromised. In these latter cases, synthetic function is preserved for prolonged periods. Additional indications, such as transplantation for metabolic or inherited diseases (eg, familial hypercholesterolemia, amyloidosis), are considered on a case-by-case basis.

Clinical presentation

As a general rule, the following complications of ESLD warrant LT:

  • Recurrent variceal hemorrhage
  • Intractable ascites
  • Spontaneous bacterial peritonitis
  • Refractory encephalopathy
  • Severe jaundice
  • Exacerbated synthetic dysfunction
  • Sudden deterioration

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 shunt (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. [6] Portal hypertension can manifest either silently (ie, decreased platelet count, WBC 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 LT 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.

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Relevant Anatomy

From a surgical point of view, the liver is divided into right and left lobes of almost equal size by a major fissure (Cantlie’s line) running from the gallbladder fossa in front to the IVC 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. 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.

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Contraindications

Currently accepted absolute contraindications to LT by most programs include spontaneous bacterial peritonitis (SBP) or other active infection, severely advanced cardiopulmonary disease, extrahepatic malignancy that does not meet cure criteria, active alcohol or substance abuse, and inability to comply with immunosuppression protocols because of psychosocial situations.

SBP, sometimes protean in its manifestations (eg, malaise, abdominal discomfort), can be devastating and can cause decompensation in an otherwise stable patient with cirrhosis. The patient may present with encephalopathy, hypotension, fever, leukocytosis, and an elevated WBC count in the peritoneal fluid. The absolute criteria for a diagnosis of SBP are the presence of more than 200-250 polymorphonuclear leukocytes, the identification of bacteria in the fluid by light microscopy, subsequent positive bacterial culture results in the appropriate clinical setting, or a combination thereof. The development of SBP in a patient with cirrhosis is an indicator of a very poor prognosis.

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, urine analysis, 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 not indications for hepatic replacement 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 patients with chronic renal failure (in which combined liver-kidney transplantation may be required), advanced cachexia, large HCCs (more advanced than stage II, 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 infections, and multisystem organ failure states. Note that many of these 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 demonstrates 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. [7]

In cases of mesenteric thrombosis, cavoportal hemitransposition may offer a chance of successful liver engraftment in these patients.

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 degrees of pulmonary hypertension (mean peak airway pressure of ≥35), especially if coupled with increased pulmonary vascular resistance. However, for those 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. Recently, some groups have reported good results with selective shunting or TIPS.

The great likelihood of recurrent and aggressive disease precludes transplantation in patients with actively replicating HBV infection. Recently, some groups have tried xenotransplantation in this population, but better results must be obtained prior to using this resource more widely. A subgroup of these patients with a small viral load and/or no active replication but with ESLD may be considered for candidacy. In these patients, the institution of lamivudine or adefovir therapy may render the viral replicative activity undetectable, hence allowing safe transplantation. The emergence of lamivudine-resistant strains may limit the long-term use of these therapies.

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

Frequently, cirrhosis is associated with development of HCCs. 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 (the largest < 3 cm), ie, AJCC stages I and II, 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.

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