Liver transplantation overview

# Overview
Liver transplantation is an important treatment option for patients with acute liver failure, end-stage liver disease, and primary hepatic malignancy, though it is not the initial or primary treatment modality for most liver diseases. Transplantation infrequently cures the underlying disease; recurrent liver disease after transplantation occurs in 0 to 100 percent of patients, depending on the disease for which transplantation was performed. Thus, the decision to list a patient for transplantation is a risk-benefit analysis in which the inherent risks of surgery, recurrent disease, and long-term immunosuppression must be weighed against the potential benefits of transplantation. These benefits differ for each patient but include improvements in survival, prevention of long-term complications, and better health-related quality of life. In most cases, the risks associated with recurrent disease do not outweigh the benefits of liver transplantation. In 1952, Vittorio Staudacher was the first to perform a liver transplantation (LT) in a canine species. In 1968, Roy Calne and Roger Williams reported 5 cases of liver transplant, discussing the technical problems by details. In 1984, Bismuth reported the first left-lobe LT in a child. Now, there are hundreds of liver transplant centres in over 80 countries. Indications for liver transplantation include acute liver failure, cirrhosis, Liver neoplasms, and metabolic disorders such as Familial amyloid polyneuropathy, Primary hyperoxaluria, Cystic fibrosis, alpha-1 antitrypsin deficiency, glycogen storage disease, tyrosinemia, hemochromatosis, Wilson disease, and Acute intermittent porphyria. Pre-surgical management for liver transplantation includes laboratory testings such as ABO-Rh blood typing, Liver biochemical and function tests (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, bilirubin, international normalized ratio, complete blood count, creatinine clearance,serum sodium, serum alpha-fetoprotein, and calcium and vitamin D levels. Cardiological testings include electrocardiogram, cardiac stress testing, echocardiography , pulse oximetry and ABG. Liver transplantation techniques includes left lobe transplantation, right lobe transplantation, split-liver transplantation, and marginal liver grafts. In left lobe technique, the left and middle hepatic veins, left hepatic artery, and left portal vein are dissected. Small portal vein branches are ligated. The left bile duct is divided. In right lobe technique, the right lobe fits correctly into the right subphrenic space, making the vascular anastomoses easier to perform. Right lobe grafts are prone to a variety of technical complications. After cholecystectomy, intraoperative ultrasound may be used to mark the position of the hepatic veins and portal branches. The right hepatic artery and right portal vein are dissected, followed by the retrohepatic vena cava, isolating the origin of the right hepatic vein. Marginal graft means grafts from a higher risk group of donors based on demographic, clinical, laboratory, and histological data. Acute rejection after liver transplantation depends on antigen recognition by antigen-presenting cell. This stimulates T-cell receptors CD28, CD154, CD2, CD11a, and CD54. This causes maturation of T-cells. Blockage of this pathway by drugs can stop rejection reaction. Glucocorticoids upregulate interleukin-10 expression (inhibitory), and downregulate IL-2, IL-6, and interferon-gamma (stimulatory) synthesis by T cells. Glucocorticoids are the first line of initial therapy and treatment of acute rejection. Cyclosporine inhibits T-cell activation by binding intracellular cyclophilin and reducing calcineurinactivation. That leads to diminish interleukin-2 production markedly and decreased T-cell response. Tacrolimus inhibits IL-2 and interferon-gamma production. Tacrolimus is 100 times more potent than cyclosporine. Sirolimus binds to FK-binding protein but does not inhibit calcineurin. Sirolimus blocks the transduction signal from the IL-2 receptor, thus inhibiting T-cell and B-cell proliferation. Sirolimusdoesn't cause nephrotoxicity and neurotoxicity. Everolimus is the hydroxyethyl derivative of sirolimus. The mechanism of action of everolimus is similar to sirolimus by inhibition of mammalian target of rapamycin (mTOR). Muromonab is a monoclonal antibody directed against the CD3-antigen complex on mature T cells. Basiliximab and daclizumab are monoclonal antibodies against the IL-2 receptor. Blockade of the IL-2 receptor prevents T-cell proliferation. Azathioprine is a prodrug of 6-mercaptopurine. Azathioprine inhibits the de novo synthesis of purines and interferes with RNA and DNA synthesis, azathioprine inhibits the replication of T cells and B cells. Infection is the most frequent cause of death following liver transplantation. According to the timing, infection can be divided into three sections; First month after transplantation, 1 to 6 months after transplantation, and more than 6 to 12 months after transplantation. Prevention of infection includes Screening potential liver donors and recipients for infection, certain vaccines such as pneumococcal and influenza vaccines should be repeated after transplantation in an attempt to lower the risk for these diseases. Empiric broad-spectrum antibiotics should be initiated if a bacterial infection is suspected in a liver transplant recipient until the specific bacterium and its sensitivities can be identified. Antibiotic regimens should include coverage for gram-positive cocci, gram-negative bacilli and anaerobes. In patients without sulfonamide allergy, trimethoprim-sulfamethoxazole is generally administered for 6 to 12 months after liver transplantation to reduce the risk of pneumocystis jirovecii pneumonia, listeria monocytogenes, nocardia, and toxoplasma gondii. Prophylaxis of CMV includes ganciclovir and valganciclovir are used to prevent CMV infection in patients at risk of CMV reactivation for three to six months. Prophylaxis of candida includes Fluconazole 400 mg orally daily is the drug of choice for one to four weeks or for as long as risk factors persist. Prophylaxis of aspergillosis includes fluconazole prophylaxis decreased invasive fungal infections by 75 percent.

# Historical perspectives
In 1952, Vittorio Staudacher was the first to perform a liver transplantation (LT) in a canine species. In 1968, Roy Calne and Roger Williams reported 5 cases of liver transplant, discussing the technical problems by details. In 1984, Bismuth reported the first left-lobe LT in a child. Now, there are hundreds of liver transplant centres in over 80 countries.

# Liver transplantation indications
Indications for liver transplantation include acute liver failure, cirrhosis, Liver neoplasms, and metabolic disorders such as Familial amyloid polyneuropathy, Primary hyperoxaluria, Cystic fibrosis, alpha-1 antitrypsin deficiency, glycogen storage disease, tyrosinemia, hemochromatosis, Wilson disease, and Acute intermittent porphyria.

# Pre-surgical management
Pre-surgical management for liver transplantation includes laboratory testings such as ABO-Rh blood typing, Liver biochemical and function tests (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, bilirubin, international normalized ratio, complete blood count, creatinine clearance,serum sodium, serum alpha-fetoprotein, and calcium and vitamin D levels. Cardiological testings include electrocardiogram, cardiac stress testing, echocardiography , pulse oximetry and ABG.

# Choice of donor
Liver transplantation choice of donorLiver transplantation choice of donor includes laboratory testing for donors includes ABO blood type, complete blood count, prothrombin time, activated partial thromboplastin time, hepatitis B surface antigen, anti-hepatitis B core antigen, anti-hepatitis C virus, anti-HIV antibody, venereal disease research laboratory, rapid plasma reagin, anti-cytomegalovirus antibody, and nucleic acid testing for HIV and HCV. Donor risk index is a predictive model comprised of donor factors known at the time an organ is offered to quantify the risk of graft failure.

# Liver transplantation techniques
Liver transplantation techniques includes left lobe transplantation, right lobe transplantation, split-liver transplantation, and marginal liver grafts. In left lobe technique, the left and middle hepatic veins, left hepatic artery, and left portal vein are dissected. Small portal vein branches are ligated. The left bile duct is divided. In right lobe technique, the right lobe fits correctly into the right subphrenic space, making the vascular anastomoses easier to perform. Right lobe grafts are prone to a variety of technical complications. After cholecystectomy, intraoperative ultrasound may be used to mark the position of the hepatic veins and portal branches. The right hepatic artery and right portal vein are dissected, followed by the retrohepatic vena cava, isolating the origin of the right hepatic vein. Marginal graft means grafts from a higher risk group of donors based on demographic, clinical, laboratory, and histological data. Marginal liver grafts donors include those with any of the following characteristics: Liver donor age >70 years, livers from hepatitis C positive donors, livers with cold ischemia time >12 hours, livers from donation after cardiac death donors, livers with >30 percent steatosis, and livers split between two recipients.

# Complications
Complications of liver transplantation include vascular, biliary, and immunosuppression drugs complications. Hepatic artery complications include thrombosis, stenosis, and pseudoaneurysm. IVC complications include thrombosis and stenosis, usually at the site of surgical anastomosis. Biliary complications include stenosis, fistula, obstruction, stone formation, dysfunction of the Oddi sphincter, and recurrent biliary disease. Complications of immunosupression include infections, metabolic syndrome, hypertension, diabetes mellitus, obesity, dyslipidemia, coronary heart disease, acute and chronic renal disease, metabolic bone disease, and malignancy.

# Acute rejection
Early acute cellular rejection mostly occurs within 90 days. Risk factors for acute rejection include elevated transplant recipient prothrombin time or bilirubin, donors older than 50 years, donor pre-surgical acidosis, cytomegalovirus infection especially genotype gB1, fewer human leukocyte antigen (HLA)-DR matches, and cold ischemia time greater than 15 hours. Clinical picture include fever, malaise, abdominal pain, and hepatosplenomegaly. elevated serum aminotransferases, alkaline phosphatase, gamma-glutamyl transpeptidase, and bilirubin level.

# Immune therapy
Acute rejection after liver transplantation depends on antigen recognition by antigen-presenting cell. This stimulates T-cell receptors CD28, CD154, CD2, CD11a, and CD54. This causes maturation of T-cells. Blockage of this pathway by drugs can stop rejection reaction. Glucocorticoids upregulate interleukin-10 expression (inhibitory), and downregulate IL-2, IL-6, and interferon-gamma (stimulatory) synthesis by T cells. Glucocorticoids are the first line of initial therapy and treatment of acute rejection. Cyclosporine inhibits T-cell activation by binding intracellular cyclophilin and reducing calcineurinactivation. That leads to diminish interleukin-2 production markedly and decreased T-cell response. Tacrolimus inhibits IL-2 and interferon-gamma production. Tacrolimus is 100 times more potent than cyclosporine. Sirolimus binds to FK-binding protein but does not inhibit calcineurin. Sirolimus blocks the transduction signal from the IL-2 receptor, thus inhibiting T-cell and B-cell proliferation. Sirolimusdoesn't cause nephrotoxicity and neurotoxicity. Everolimus is the hydroxyethyl derivative of sirolimus. The mechanism of action of everolimus is similar to sirolimus by inhibition of mammalian target of rapamycin (mTOR). Muromonab is a monoclonal antibody directed against the CD3-antigen complex on mature T cells. Basiliximab and daclizumab are monoclonal antibodies against the IL-2 receptor. Blockade of the IL-2 receptor prevents T-cell proliferation. Azathioprine is a prodrug of 6-mercaptopurine. Azathioprine inhibits the de novo synthesis of purines and interferes with RNA and DNA synthesis, azathioprine inhibits the replication of T cells and B cells.

# Post-surgical infection
Infection is the most frequent cause of death following liver transplantation. According to the timing, infection can be divided into three sections; First month after transplantation, 1 to 6 months after transplantation, and more than 6 to 12 months after transplantation. Prevention of infection includes Screening potential liver donors and recipients for infection, certain vaccines such as pneumococcal and influenza vaccines should be repeated after transplantation in an attempt to lower the risk for these diseases. Empiric broad-spectrum antibiotics should be initiated if a bacterial infection is suspected in a liver transplant recipient until the specific bacterium and its sensitivities can be identified. Antibiotic regimens should include coverage for gram-positive cocci, gram-negative bacilli and anaerobes. In patients without sulfonamide allergy, trimethoprim-sulfamethoxazole is generally administered for 6 to 12 months after liver transplantation to reduce the risk of pneumocystis jirovecii pneumonia, listeria monocytogenes, nocardia, and toxoplasma gondii. Prophylaxis of CMV includes ganciclovir and valganciclovir are used to prevent CMV infection in patients at risk of CMV reactivation for three to six months. Prophylaxis of candida includes Fluconazole 400 mg orally daily is the drug of choice for one to four weeks or for as long as risk factors persist. Prophylaxis of aspergillosis includes fluconazole prophylaxis decreased invasive fungal infections by 75 percent.

# Prognosis
Prognosis is good. One-year survival rates are 83%, 5-year survival is 76% and 10-year survival is 66%. Mortality rates in donors are 0.2% in the USA and vary from 0.1 to 1.0% worldwide. The risk associated with left-lobe donation may be lower than that with right-lobe donation. Recurrence varies according to the cause; hepatitis B virus is the commonest cause of recurrence followed by hepatitis C  virus. Recurrence of HBV after liver transplantation can be prevented by administering hepatitis B immune globulin at the time of transplantation. There is no established role for prophylactic or therapy following transplantation in HCV. Combination therapy for HCV may be peginterferon or standard interferon and ribavirin, monotherapy may be peginterferon, standard interferon, or ribavirin, and anti-HCV immune globulin.