Liver transplant

Limited access to liver transplantation in the US is linked to black race, poverty, rural residence, poor health, literacy, or lack of medical insurance.

Only 54.4% of liver transplant recipients received their graft within one year after placement on the transplant waiting list, and the rate of death among patients awaiting transplant is 12.2 deaths per hundred waiting list years.

The procedure is extensive, complex, and technically difficult with multiple vascular transections and anastomoses.

Every year approximately 2400 people in the US die while awaiting a liver transplant.

Acute liver failure accounts for less than 5% of liver transplantation performed annually in the US, while the remaining transplantations are undertaken to treat patients with chronic fibrotic liver disease, portal, hypertension, liver cancer, or a combination of these processes.

There has been a decline in the number of patients placed on the liver transplant list because of hepatitis C infection, and alcohol associated liver disease and metabolic dysfunction associated with Steat tonic liver disease have  become the predominant indications for liver transplantation.

Indications for transplant include:

Fulminant hepatic failure

Complications of cirrhosis-ascites, synthetic dysfunction, encephalopathy

Liver malignancy,

Variceal hemorrhage refractory to standard therapy,

Chronic gastrointestinal bleeding secondary to portal hypertension

Systemic complications of chronic liver disease (hepatopulmonary syndrome and portopulmonary hypertension

Metabolic conditions that cause systemic disease (NASH, alpha1-antitrypsin deficiency, Wilson’s disease, amyloidosis, hemochromatosis, glycogen storage diseases, urea cycle enzyme deficiencies)

Cryptogenic cirrhosis , limiting therapeutic options and shortening survival time.

Extensive bleeding can occur in patients with portal hypertension due to end-stage liver disease.

Blood loss at the time of liver transplantation has been treated with large autologous transfusions of packed RBCs, fresh frozen plasma, platelets, cryoprecipitate, and other drugs.

MELD (model for end-stage liver disease) score used by the United Network for Organ Sharing to allocate organs for donation for liver transplantation.

Approximately 9000 liver transplantations per year in the U.S.

As of June 2007 1 year survival 82.1% for adults and 86.2% for children.

Management of the donated liver before implantation includes flushing the liver from a deceased donor with preservation solution at 4°C to reduce cellular metabolic processes, and then to transplant the organ to the transplantation site under cold storage.

Such a procedure, however, leads to cold, ischemic mitochondrial changes, including decreased cellular respiration, and accumulation of succinate, and NADH with concomitant ATP depletion.

Upon reperfusion reactive oxygen species are released from the mitochondria, leading to further cellular injury.

The ischemia/reperfusion injury may cause hemodynamic changes and lead to tissue injury in higher risk organs, older livers, and those recovery after circularity death.

Histologic evidence for recurrence of Hepatitis C after transplant is apparent in approximately 50% of patients, with ensuing graft failure in 10% of patients by the fifth postoperative year.

Despite the risk of Hepatitis C recurrence, patients undergoing liver transplant for Hepatitis C have comparable overall patient and graft survival rates compared with other indications for liver transplantation.

Currently one year, 5 year, in 10 year survival rates or orthoptic liver transplants, are 84%, 68%, and 54% respectively.

Overall patient survival in the absence of recurrent Hepatitis C were 82%, 76%, and 68% at 1, 5, and 8 years, respectively.

In recipients older than 70 years no reported difference in morbidity or mortality (Scheiner P), although some studies suggest longer hospital stays and higher mortality in individuals over the age of 60 years (Garcia CE).

Overall patient survival in patients with Hepatitis C recurrence are 94%, 71% and 63% at 1, 5, and 8 years, respectively.

Prolonged exposure of transplant recipients to immunosuppressive agents can lead to long-term medical complications, including chronic kidney disease: up to 18% of liver transplant recipients developed renal failure within five years after transplant, and those that require dialysis have good poor survival of 27% at six years (Gonwa TA et al, Diederich D et al).

Risk factors for renal disease in liver transplant patients include prolonged exposure to calcineurin based immunotherapy with cyclosporine and tacrolimus.

Liver retransplantation is the only therapy for irreversible graft failure and represents 10-22% of transplantations worldwide.

Long-term survival can be expected in nearly 50% of all retransplanted patients.

Preservation injury indicates hepatic dysfunction within 10 days of liver transplantation which usually resolves and is associated with a favorable survival.

Preservation injury that persists or occurs late is associated with poor survival and retransplantation should be considered.

Liver transplantation has advanced because of ability to use partial liver grafts obtained from a deceased donor or a living donor.

Most deceased donor livers, are from persons receiving life-support, who have irreversible cerebral and brainstem injury, and were declared brain dead.

Patients who have had a cessation of both circulatory and respiratory function, but who retain brainstem function, despite severe, irreversible, neurologic injury can contribute to the liver transplant population.

Living donor transplantation accounts for 6% of all liver transplantation in the US , whereas 90% of liver transplants in Asian countries are from living donors.

15-20% of patients awaiting orthotopic liver transplantation die before an organ is available.

Live-donor liver transplant can be achieved but the donor must retain at least 60% of his/her liver after donation.

Live-donor liver transplants are typically reserved for small recipients.

Live-donor transplants indicate the remarkable abilities of regeneration of the liver so that both the donor and recipient livers grow back to near full size within in a few weeks.

Outcomes after living donor liver transplantation is as good or better than outcomes from deceased donor liver transplantation

Donor CMV seropositivity and CMV infection following transplant increases the recipient’s risk for bacteria and fungal infections.

Donation of liver tissue is considered to be safe at an experienced center,  although serious injuries to the physical and mental health of the donor, including deaths, have occurred on rare occasions.

Survival rate of 48% at 18 years.

In a matched study of individuals 70 years or more compared to liver transplant patients less than 60 years: indicated that 5 year mortality and graft loss were comparable, suggesting age should not exclude older individuals from liver transplant (Aduen JF).

Risk of posttransplant cardiovascular complications 10% for patients under the age of 60 and 19% for those over the age of 70 years (Adjuen JF).

Older patients have higher incidence of infection and cancer and lower risk for graft rejection, indicating a weaker immune system with age (Steiber AC).

Malignancy is the most frequent cause of death in patients over the age of 65 years undergoing liver transplant (Cross TJ).

The use of calcineurin inhibitors causes chronic nephrotoxicity and is a factor in leading to morbidity and mortality after liver transplantation.

The incidence of recurrent hepatitis C after liver transplant is very significant but with the use of interferon and ribavirin retransplantation can frequently be prevented.

Recipients have greater than 40% risk of increased serum cholesterol and more than 60% have hypertension and increased risk of cardiovascular disease.

Hepatic allograft recipients have higher risk of cardiovascular deaths and ischemic events than control populations.

Complications after liver transplant at one year include non-hepatic related causes of death including malignancy of 22%, cardiovascular disease 11%, infection 9%, renal failure 6%, and liver low graft failure counts less than one third of deaths (Watt KD et al).

Metabolic syndrome which is uncommon in patients with end-stage liver disease before transplant increases with orthoptic liver transplant (OLT) to 44-58% of patients affected with an increase in cardiovascular morbidity.

Hypertension, which is uncommon in patients with chronic liver disease before transplant develops and 67% of patients following OLT.

Increased hypertension and cardiovascular disease following liver transplant probably related to immunosuppressant agents, particularly calcineurin inhibitors causing renal afferent arterial vasoconstriction and chronic sympathetic hyperactivity and corticosteroid use.

Following OLT the prevalence of type 2 diabetes increases to 30-40% from 50% before the procedure.

Approximately 80% of new onset diabetes cases developed within the first month after liver transplant and 12% at the first year followup, with 20-37% of patients remaining diabetic.

The risk of post OLT diabetes increases with obesity, pretransplant diabetes, hepatitis C, cortical steroid use, calcineurin inhibitor use and mTOR inhibitor use.

Diabetes before and after OLT associated with higher mortality and morbidity.

5 year likelihood of advanced fibrosis increases in diabetics compared to patients with normal insulin sensitivity, and there is an increased late onset hepatic artery thrombosis risk, acute and chronic rejection risk and fatty liver disease post transplant, as well.

After orthoptic liver transplant 45-69 7 patients develop dyslipidemia.

Risk factors for post transplant dyslipidemia include pretransplant obesity, diabetes, cholestatic liver disease and immunosuppressant medications.

Cyclosporine increases low-density lipoproteins and total cholesterol more than tacrolimus.

Sirolimus is strongly associated with dyslipidemia as an affects insulin signaling pathway by increasing adipose tissue lipase activity and decrease his lipoprotein lipase.

Transfusion related complications with liver transplantation include infection, transfusion reaction, drug overdose, graft rejection or graft death, and patient death.

Increased blood requirements during transplant surgery are associated with a more frequent episodes of sepsis, a prolongation of hospital stay, a higher rate of cytomegalovirus infection, and higher rates of graft failure and patient death.

Presently the procedure can now be performed in as little as 4 hours.

Blood loss during liver transplantation can be associated with liver failure, cirrhosis, cholestasis, and splenomegaly.

Patients with liver failure may not synthesize normal amounts of clotting factors II, VII, IX, and X.

Decreased production of these liver factors may lead to a coagulopathy, which is identified by a prolonged prothrombin time, and in patients with severe deficiencies a prolonged activated partial thromboplastin time may be present.

Cholestasis leads to decreased synthesis of vitamin K–dependent clotting factors (II, VII, IX, and X), and contributes to abnormal clotting.

Thrombocytopenia is common problem in cirrhotic patients.

Thrombocytopenia in end-stage liver disease is multifactorial as the liver is the primary site of thrombopoietin synthesis, and thrombopoietin deficiency leads to low platelet production.

Splenomegaly caused by portal hypertension with cirrhosis leads to platelet sequestration and destruction.

Some patients with end-stage liver disease demonstrate increased fibrinolytic activity, with DIC-like activity.

Liver transplantation may be divided into 3 stages: Stage I-begins with dissection of the inflow and outflow vascular structures of the liver, and ends with removal of the liver.

Stage II refers to the implantation of the donor liver and ends with its reperfusion.

Stage III begins with reperfusion of the grafted liver and ends with completion of the surgery.

Blood loss in stage I is mainly from transection of the fragile vascular collaterals from the portal hypertension.

In Stage I extensive bleeding may occur from raw areas remaining after removing the liver.

Replacement of the new liver usually restores the patient’s clotting function during the procedure.

A dysfunctional graft may not immediately produce clotting factors.

The thromboelastogram is used to monitor coagulation, fibrinolysis, and bleeding time during transplantation.

Fibrinolysis may be a problem during the procedure due to the uptake of tissue plasminogen activator (t-PA), accumulation of fibrinolytic activators, and enhanced release of t-PA from the donor liver, and alpha-2 antiplasmin, the principal inhibitor of plasmin and plasminogen activity, is decreased.

Platelet trapping in the transplanted liver occurs leading to thrombocytopenia, and remaining platelets are degranulated or nonfunctional.

Bleeding after reperfusion may be related to release of heparinlike factors from the graft, release of preservative solution into the systemic circulation, and dysfunction of the graft.

Postoperative bleeding can occur from vascular suture leaks or from the cut surfaces at bowel anastomoses.

Failure of the graft to function may cause a coagulopathy.

Thrombocytopenia following liver transplantation can cause bleeding.

Transfusion requirements include the severity of liver disease or Child classification, preoperative PT, history of prior abdominal operations, and factor V levels, and oprative time.

Portal vein hypoplasia and decreased donor liver size are predictive of blood loss.

Partial liver graft may create a graft with a raw surface that can bleed after reperfusion.

Surgical techniques to minimize blood loss include the use of venovenous bypass, autologous blood transfusion, volume expansion, and a cell saver.

Transjugular intrahepatic portosystemic shunt (TIPS) can decompress the portal system in order to decrease the risk of variceal rebleeding and minimize ascites decreases blood requirements, shorter operative times, and shorter hospital stays.

Maintenance of a low CVP decreases blood transfusion needs.

Recombinant factor VIIa (rFVIIa) during liver transplant may significant decrease transfused PRBCs, FFP, and platelets.

Antifibrinolytic agents may counter accelerated fibrinolysis in liver transplantation and include aprotinin, epsilon amino caproic acid, and tranexamic acid.

Platelet transfusions is an independent risk factor for survival after orthotopic liver transplantation.

Massive blood transfusion with infusion of citrated blood products may cause hypocalcemia and hypomagnesemia.

To prevent thrombosis following liver transplantation unfractionated heparin or low molecular weight heparin is used.

Liver transplantation obtained  from donors if the circulatory death is associated with an increased risk of non-anastomotic biliary structures.

Nonanastomotic biliary structures are a major complication after liver transplantation causing cholestasis, cholangitis, and frequently the use of biliary interventions or even re-transplantation.

The incidence of nonanastomatic biliary strictures is approximately three times as high  after the transplantation of livers obtained from donors after  circulatory death as after the transplantation of liver is obtained from brain dead donors.

Ischemia-re-perfusion injury is a key mechanism in the pathogenesis of bile duct injury and the development of biliary structures after liver transplantation.

Hypothermic oxygenated machine perfusion is associated with a lower risk of non-anastomotic biliary structures following liver transportation obtained from donors after circulatory death than conventional static cold storage.

All patients undergoing liver transplantation are at risk for perioperative death, ischemia-perfusion injury syndrome, and primary allograft non-function or early poor function of the allograft, as well as acute kidney injury.

The one year patient and graft survival rates after primary liver transplantation in adults are 94 and 92%, respectively.

The mean estimated survival time of patients following a liver transplant in the 1990s is 20 years.

The one and 10 year patient survival rates for liver transplants in childhood are 94.4 and 90.7%, respectively and pediatric graft survival rates for the same intervals are 90.9 and 79.1%

Adult recipients of a split liver allograft have excellent long-term patient and graft survival rates.

Surgical complications include biliary, vascular and hemorrhage in the first 90 days after transplantation.

Biliary ischemia causes biliary structures, bile lakes, bile duct casts (cholangiopathy).

Cholangiopathy occur is more frequently in recipients of livers donated after circulatory death than recipients of liver donated after declared brain death.

The incidence of T cell mediated rejection occurs in 10 to 30% of cases within the first 90 days.

After the first year, the incident rate is just 3%.

T cell mediated rejection has an increased risk of graft loss and death, particularly if it occurs more than one year after transplantation: progression to vasculopathy bile duct obliteration is the major concern.

Treatment for moderate to severe T cell mediated rejection is high dose glucocorticoids, and anti-lymphocyte antibody if the rejection does not respond to glucocorticoids.

Immunosuppression usually comprises a calcineurin inhibitor  such as tacrolimus,  often with mycophenolate, prednisone or both.

These drugs are reduced gradually during the first 3 to 6 months following transportation is the risk of T cell mediated rejection declines.

Complete wothdrawal of immunosuppressive therapy occurs in less than 5% of long-term survivors of liver transplants.

Post transplant infections occur due to reactivation of latent infection in the recipient, transmission of infectious agents by the allograft, or acquisition of the new infection in the recipient.

Increased risk of infections following transplant include surgical complications of vascular, biliary anastomoses, poor wound healing, or organ failure, prolonged assistant ventilation, or kidney replacement therapy.

Increased risk for cytomegalovirus, pneumocystis, and aspergillus infections occur, and these risks are mitigated by prophylactic antimicrobial therapy.

Increased risk of infection occurs as a result of neutropenia from immunosuppressive drugs.

Patients who undergo liver transplant as for liver cancer are at risk for recurrence of the cancer in the transplanted liver.

Due to immunosuppressive factors, oncogenesis may occur in liver transplant patients leading to skin cancers, lung cancers in cigarette smokers, colon cancer, sclerosing cholangitis, and virus associated cancers, such as cervical cancer or post transplant lymphoproliferative disorders.