Cirrhosis and decompensated liver disease were the ninth leading cause of death for males in 2016 in the United States. Liver transplantation (LT) is a lifesaving gift and proven intervention in the management of patients with acute and chronic end-stage liver disease. It restores normal health, lifestyle, and extends lifespan by 15 years. The advent of LT came as a safety net to treat a variety of liver diseases when all other medical interventions have failed. Patient survival is overall excellent reaching 90% at 1 year following deceased donor LT and 77% at 5 years, according to the Scientific Registry of Transplant Recipients data. Since LT was first attempted in 1963, there have been continuous advances and major improvements in the surgical technique, type of organ donation with the expansion of the organ donation pool, and a major focus on the quality of life of both the recipients and donors. Still, there are important challenges, including the shortage of donor organs, selection of LT candidates, and organ allocation.
The liver is the largest organ of the human body that underlies the 8-12 ribs on the right. It is made of 4 anatomical lobes; the right and left lobes which are divided by the falciform ligament, the quadrate lobe as well as the caudate lobe. These four hepatic lobes are not true functional lobes. The true functional hepatic lobes are two; right and left lobes divided by the Cantlie line. The Cantlie line divides the liver into roughly two halves, as it passes through the bed of the gallbladder and the notch of the inferior vena cava. Each of these is divided into two segments that are further subdivided into two subsegments based on the blood supply from the hepatic artery and portal vein as well as biliary and hepatic venous drainage. The subsegments are assigned numbers from 1 to 8, with the caudate lobe being subsegment number 1 and the others numbered in a clockwise fashion, also known as the Couinaud system.
The liver is characterized by having dual blood supply from the systemic and portal circulations through the portal vein and hepatic artery. The functional unit of the liver is called a hepatocyte, and accordingly, these hepatocytes are organized into:
It is important to note that bile and blood move away from each other in opposite directions, so that bile produced in the liver flows out, and blood flows into it to supply the liver. Liver physiology is reviewed as a separate topic in StatPearls. The majority of people's liver volume consists of 60% from the right lobe and 40% from the left lobe, with 20% made of the left lateral segment alone.
Liver transplantation is indicated in acute and chronic end-stage liver disease where medical therapy has failed. Patients who develop hepatic decompensation such as hepatic encephalopathy, variceal hemorrhage, or ascites should receive medical therapy, and a comprehensive LT evaluation should be initiated in potential LT candidates. Up to 80% of liver transplantations are due to decompensated cirrhosis. Patients with cirrhosis are usually categorized according to the Child-Turcotte-Pugh score (CTP score). This score was developed based on the incorporation of biochemical tests and clinical information (serum albumin, serum bilirubin, international normalized ratio (INR), ascites, encephalopathy) to determine prognosis.
The Model of End-Stage Liver Disease (MELD score), initially developed to predict survival after transjugular intrahepatic portosystemic shunt (TIPS) procedure, was found to predict survival among patients with cirrhosis. It was well recognized as a tool to prioritize organ allocation for LT. The MELD score assesses the 3-month mortality rate of patients by incorporating mathematical calculations of serum level of creatinine, bilirubin, and INR. In the pediatric population, an edited formula of the MELD score is created that substituted creatinine and added instead age, albumin, and failure to thrive. In 2016, Organ Procurement and Transplantation Network updated their Policy for MELD Score to include serum sodium value as a factor in the calculation of the MELD score. Hyponatremia is a common problem in patients with cirrhosis, and the severity of the hyponatremia is a marker of the severity of the cirrhosis. A strong high indication for LT evaluation is in cirrhotic patients who have developed ascites, bleeding varices, hepatic encephalopathy, or hepatocellular dysfunction that lead to a MELD higher than 15.
Specific Indications for LT
While the indications for LT are becoming broader, the contraindications are getting less due to advancements in LT techniques. Still, liver transplantation has some absolute and relative contraindications.
Although AIDS is an absolute contraindication for LT, recent centers are selecting patients with HIV alone as candidates for liver transplantation.
To ensure the delivery of the greatest possible patient care, an interprofessional team approach should be followed.
In the pre-transplant phase, evaluation by a hepatologist, a transplant surgeon and a transplant nurse coordinator is crucial to assess the patient, discuss all required vaccinations, medications, lifestyle changes, types of surgeries, and have a detailed discussion about the post-transplant phase including immunosuppression and possible complications and outcomes.
Psychiatric evaluation by a specialized transplant psychiatrist is needed to address any alcohol or drug abuse issues, and to ensure the patient has insight about the surgery and the possible outcomes.
Social workers also have a role in ensuring the social support system to the patient, especially in the post-LT phase and home care and adjustments. A specialized team assesses for insurance coverage of the LT surgery and immunosuppressive drugs.
Nutritionists have a role in both the pre and post-transplant phases to ensure an adequate nutritional status and to address dietary changes related to chronic diseases like diabetes mellitus (DM), hypertension (HTN), and hyperlipidemia.
The pre-LT evaluation must address many important aspects and health concerns in LT candidates. This evaluation should include a detailed, comprehensive history and physical examination, laboratory tests, and imaging studies to conduct a full systematic review for patients and manage them accordingly. A comprehensive review is available at the American Association for the Study of Liver disease Practice Guidelines website. Below is a brief summary.
Obesity: Patients should be evaluated for increased BMI as it increases the perioperative risks and reduces survival in LT patients in the long run. Obese patients with a BMI of 30 kg/m2 and greater should be referred to a dietician, and a BMI above 40 kg/m2 is considered to be a relative contraindication for a liver transplant.
Coronary Artery Disease: Perioperative cardiac risk assessment is crucial. All patients should undergo cardiac stress testing, either physical or chemical stress testing. If patients were found to have stenosis, coronary revascularization should be done before LT.
Age: Although the prognosis of transplant in patients older than 70 years is not as good as in younger patients, older age is not a contraindication to LT in patients without or with controlled comorbidities. Recently, it has been shown that well-selected elderly LT candidates can benefit from LT restoring the expected lifespan. (PMID: 31233673)
Pulmonary HTN: When the mean pulmonary artery pressure (MPAP) is above or equal to 25 mmHg and is associated with portal HTN, the condition is referred to as portopulmonary HTN. Moderate to severe portopulmonary HTN is associated with a higher mortality rate after LT; the mortality rate can reach up to 100% if MPAP is above 50 mmHg. Pulmonary HTN is diagnosed by echocardiography, and if severe, right heart catheterization is a gold standard test to confirm the diagnosis. This condition is treated by vasodilators, and LT is indicated in patients who respond to vasodilator therapy with a reduction in MPAP to less than 35 mmHg and pulmonary vascular resistance less than 400 dynes.s.cm.
Hepatopulmonary Syndrome: It is a syndrome of shortness of breath and hypoxemia in patients with chronic liver disease, especially those with portal HTN. This is due to microvascular dilation of the pulmonary vessels that lead to intrapulmonary shunt. Patients should be screened with pulse oximetry prior to LT. Affected patients may require a longer recovery period and long-term supplemental oxygen post LT depending on the severity of hepatopulmonary syndrome.
Renal Dysfunction: Patients with renal disease must be diagnosed prior to LT, as renal dysfunction significantly increases the mortality. Simultaneous liver and kidney transplants are indicated if a patient has a glomerular filtration rate (GFR) less than 30 mL/min indicating chronic kidney disease or acute kidney failure that requires dialysis for more than eight weeks. This is also indicated in case severe glomerulosclerosis is present.
Cigarette Smoking: It increases mortality among LT recipients due to cardiac disease. It also increases the risk of hepatic artery thrombosis. Smoking should be prohibited, and many hospitals consider smoking cessation a requirement to be listed for LT.
Extrahepatic Malignancy: Patients should undergo all age-appropriate screening before undergoing LT, and if they have any increased risk factors for specific cancer, they should undergo further testing for the specific cancer type. Any patient with a diagnosed previous malignancy should be treated and cured prior to LT.
Infectious Disease: All infectious diseases should be treated effectively before LT. Screening serologies in the blood should include viral infections such as hepatitis A and B (to ensure immunity by vaccinations and no active infection), cytomegalovirus (CMV), Epstein-Barr virus (EBV), bacterial infections including tuberculosis, syphilis, and fungal infections such as Strongyloides and coccidiomycosis. All live attenuated viral vaccines should be administered prior to LT as they are contraindicated once immunosuppression is initiated after LT.
Nutrition: Patients should be evaluated by a nutritionist prior to LT, as it is important to address all nutritional deficiencies related to chronic liver disease and fat malabsorption. Adequate dietary control related to other comorbidities such as DM, HTN, and hyperlipidemia should be stressed.
Bone Disease: Densitometry, vitamin D, and calcium levels should be obtained before LT in all candidates. Osteoporosis is fairly common in all patients with chronic liver disease due to malabsorption of vitamin D and in cases of autoimmune hepatitis due to corticosteroid use.
Human Immunodeficiency Viral I infection (HIV): Affected patients can be candidates for LT only if CD4 counts are above 100 µL, and the viral load is undetectable prior to LT. HIV is not considered a contraindication to LT nowadays due to the advent of effective antiretroviral therapy.
Psychological Evaluation: It is important to evaluate LT candidates for any psychiatric disorders that might affect their prognosis, compliance with medication, and medical directives. It is also essential to evaluate the social support systems and the availability of a caregiver, especially in patients with encephalopathy. For example, patients who have depressive symptoms, mainly in the immediate postoperative period, usually have a poor outcome after LT. Substance abuse should be carefully evaluated.
Any liver transplant procedure has two components, the donor and the recipient.
Recipient operations are done through total removal of the patient's native liver, after dissection of the hepatic ligamentous attachments and hilar structures. The inferior vena cava (IVC) should be encircled to ensure adequate blood control. Donors are either deceased or living donors, which are discussed below.
Deceased Donor Liver Transplantation (DDLT): Whole liver transplantation is more common. The donor's liver is usually prepared on a separate table, and once the recipient's body is prepared, the donor's liver is brought to the table, and anastomoses are initiated accordingly. First, the suprahepatic IVC is connected, then the infra hepatic IVC, followed by the portal vein. Once these steps are done, the clamps are removed, and the portal vein initiates the inflow of blood to perfuse the liver. The hepatic artery of both the recipient and donor are connected near the anastomoses of the gastroduodenal artery; after that, the bile duct is reconstructed. In 2003 the first attempt of a split graft was done, in which the deceased donor liver is divided into for transplantation into two recipients, the right lobe is used as an allograft without the middle hepatic vein similar to the modified technique used in LDLT right lobe graft, and the left part of the liver with the inferior vena cava and the common hepatic artery.
Living Donor Liver Transplantation (LDLT): In the past, living donors were only used in pediatric cases that require LT. Nowadays, due to the increasing numbers of patients requiring LT and the shortage of deceased donors, living donors are used in adults too. LT from living donors is more complex and requires much careful dissection. Living donor graft is partial, unlike the whole graft provided from a deceased donor. A living donor graft has a noticeably smaller hepatic artery, hepatic vein, and portal vein, which needs to be implanted, so the most important part is to make adequate room by incising the hepatic vein along the sides to ensure adequate sources for arterial hepatic, portal, and biliary reconstruction. The anastomosis is performed for the hepatic vein, which needs to have an adequate length for anastomosis, then the portal vein, and finally, the hepatic artery, which is difficult due to many short tributaries. Lastly, duct to duct anastomosis is performed for the bile duct. Grafts used from a living donor include the left lateral sector, which comprises 20% of the total liver volume, the left lobe, which makes 40% of the volume, and the right lobe, which makes the other 60% of the liver volume. Sometimes dual graft is used in which two left lobes from two donors are implanted in one recipient. All donors undergoing hepatectomy have a characteristic incision in the right subcostal region that extends into the midline, and so dissection of the rectus muscle on both sides is spared. In cases of right hepatic lobe donation, the left lobe should be attached to the anterior abdominal wall before wound closure.
Complications are either early or late after liver transplantation:
In the first week, the abnormal liver enzymes usually trend down back to normal, and the liver graft starts to regenerate.
The most serious complication post-LT is the primary non-function of the allograft. This immediate complication presents with either the lack of production of bile or the production of clear bile, associated with worsening liver enzymes and bilirubin. This immediate complication requires a new graft for the patient to survive.
The first 48-72 hours post LT usually shows abnormal liver enzymes and indicates injury to the graft secondary to cold and warm ischemia during removal and implantation into the recipient. However, it is crucial to exclude hepatic artery thrombosis post-LT, and a Doppler US should be done. Hepatic artery thrombosis usually occurs in the early phase post-LT but can develop later. The clinical presentation varies, and the patients can be asymptomatic or can develop a fever and increased liver enzymes. This can lead to hepatic ischemia, necrosis, and ischemic cholangiopathy. Depending on the severity of graft dysfunction, patients may require a re-transplant, especially when it occurs in the first-week post-LT.
Acute cell rejection is common, and it occurs in up to 50% of patients post-LT. The majority of cases occur in the first 2 months post-LT, and the majority respond to corticosteroids. In the case of corticosteroid-resistant rejection, anti-thymocyte globulin is needed. Liver biopsy should be performed for definitive diagnosis. Long term outcomes are favorable.
The biliary anastomosis is the most common site of biliary strictures. This can be managed with endoscopic dilation, stenting, or less commonly, surgical revision. Non-anastomotic or ischemic strictures can also develop secondary to hepatic artery thrombosis, ABO incompatibility, long graft ischemia time (warm or cold), or in grafts donated after cardiac death.
Immunosuppression post-LT increases the risk of opportunistic infections such as CMV (most common viral infection), candida infections (most common fungal infection), Pneumocystis carinii, Aspergillus, Nocardia, Cryptococcus. Neurologic and renal impairment and the development of hyperglycemia can occur due to the use of tacrolimus and cyclosporine.
Late complications are mainly attributed to the toxic effects of immunosuppressive drugs. The most common being chronic kidney disease (CKD), HTN, DM, and dyslipidemia. Calcineurin inhibitors, in combination with CKD and HTN that are present prior to transplant, contribute to the development of renal failure post-LT. This is managed by strict control of BP and dose reduction or discontinuation of calcineurin inhibitors.
Immunosuppressive drugs increase the risk of cardiovascular disease due to an increase in its risk factors such as DM, HTN, obesity, and dyslipidemia. This is in combination with a high-risk lifestyle in patients that leads to a marked increase in atherosclerosis.
Osteoporosis risk is increased due to the use of corticosteroids in the long term, in addition to malnutrition and vitamin D deficiency related to liver disease. Recently this complication was reduced due to the successful treatment with bisphosphonates and reducing corticosteroid doses.
Neurologic impairments most commonly tremor in addition to insomnia and parasthesia are due to calcineurin inhibitors.
Recurrent disease post-LT include recurrent hepatitis C or B infections. Both can be well-managed post-LT. Other chronic liver diseases can recur, including NASH, PBC, PSC, AIH, and HCC.
Malignancies arise de novo and are a major cause of death in recipients of LT in the long term. This is due to multiple risk factors that increase the risk of malignancy, including immunosuppression, viral infections, alcohol consumption, cigarette smoking, and older age. More frequent malignancies among LT recipients include skin cancer, lymphoproliferative disease (PTLD) and cervical, vulvar and anal cancer.
When living donor liver transplant was first introduced, outcomes were inferior to DDLT However, LDLT has proved to decrease the mortality by shortening the time on the waiting list in pediatrics and adults. East Asian countries have contributed to the evolution of techniques, surgeries, graft characteristics and portal and blood flow for LDLT due to the scarcity of deceased donors in their countries, which has revolutionized LT worldwide and led nowadays to comparable survival rates between DDLT and LDLT, and improved the quality of life of patients with chronic liver disease, or acute liver failure with high MELD score above 30.
Healthcare workers, including surgeons, hepatologists, nurses, nutritionists, therapists, and social workers, all contribute majorly to the outcomes of LT. Attention should be given to prevent and minimize the long term effects that are related to immunosuppression, manage early and late complications as well as disease recurrence that lead to patients' deterioration and may require re-transplantation.
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