Liver transplant

Overview

After the kidney, the liver is the second most often transplanted major organ. In 2020, 8425 individuals had liver transplants, while 12,261 patients were added to the liver transplant waiting list.

In the United States, cirrhosis and decompensated liver disease were the tenth highest cause of death for males in 2016. Liver transplantation (LT) is a life-saving gift and a tried-and-true treatment option for individuals with acute and chronic end-stage liver disease. It restores normal health and lifestyle, as well as extending life by 15 years. When all other medical approaches had failed, the introduction of liver transplantation provided a safety net for the treatment of numerous liver ailments.

Liver transplant definition

For patients with chronic end-stage liver disease and abrupt liver failure, liver transplantation has become a life-saving treatment. A liver transplant might involve the entire liver, a portion of the liver, or a segment of the liver. The majority of transplants involve the entire organ, however segmental transplants are becoming more common.

Segmental transplantation permits two recipients to receive allografts from a single cadaveric donor or to donate a living donor's liver. When a person has a liver transplant to alleviate a medical condition (for example, familial amyloidosis), yet the liver is acceptable for transplant to another candidate, this is known as a Domino donation.

According to statistics from the Scientific Registry of Transplant Recipients, overall patient survival is high, reaching 90% one year after dead donor liver transplantation and 77% five years later. Since the first attempt at liver transplantation in 1963, there have been continual developments and significant improvements in surgical technique, type of organ donation with the growth of the organ donation pool, and a strong emphasis on the quality of life of both recipients and donors. There are still significant problems, such as the scarcity of donor organs, the identification of liver transplantation candidates, and organ distribution. 

Anatomy and Physiology

The liver is the biggest organ in the human body, and it sits beneath the 8-12 ribs on the right side. It is split into four anatomical lobes: the right and left lobes, which are separated by the falciform ligament, the quadrate lobe, and the caudate lobe. These four hepatic lobes do not operate properly. The Cantlie line separates the genuine functioning hepatic lobes, which are right and left lobes.

As it travels through the gallbladder bed and the notch of the inferior vena cava, the Cantlie line splits the liver nearly in half. Each of them is split into two segments, which are further separated into two subsegments depending on hepatic artery and portal vein blood supply, as well as biliary and hepatic venous outflow. The subsegments are numbered from 1 to 8, with the caudate lobe being number one and the others numbered clockwise, commonly known as the Couinaud system.

The liver has a dual blood supply from the systemic and portal circulations via the portal vein and hepatic artery. The functional unit of the liver is known as a hepatocyte, and these hepatocytes are classified as follows:

• Zone I is the periportal zone, which has the highest perfusion owing to its closeness to oxygenated blood from the portal vein. Functions mostly in metabolism that necessitates oxidation.
• The pericentral area is Zone II.
• Zone III is the furthest away from the blood supply and so receives the least amount of perfusion. Functions as a detoxifier for drugs and toxins.

Criteria for a liver transplant

When medical therapy has failed to treat acute or chronic end-stage liver disease, a liver transplant is recommended. Patients who develop hepatic decompensation, such as hepatic encephalopathy, variceal bleeding, or ascites, should receive medical care, and possible liver transplant candidates should undergo a full liver transplantation examination.

Decompensated cirrhosis accounts for up to 80% of liver transplants. Cirrhotic patients are often classified using the Child-Turcotte-Pugh score (CTP score). This score was established to evaluate prognosis by integrating biochemical testing and clinical information (serum albumin, serum bilirubin, international normalized ratio (INR), ascites, and encephalopathy).

The Model of End-Stage Liver Disease (MELD score), which was originally created to predict survival following a transjugular intrahepatic portosystemic shunt (TIPS) surgery, was discovered to predict survival in cirrhotic patients. It was widely acknowledged as a useful strategy for prioritizing organ allocation for liver transplantation. The MELD score evaluates a patient's 3-month mortality rate by using mathematical estimates of creatinine, bilirubin, and INR levels in the serum.

In the pediatric population, an altered MELD score formula is established that replaces creatinine with age, albumin, and failure to thrive. The Organ Procurement and Transplantation Network's Policy for MELD Score was amended in 2016 to add serum sodium value as a consideration in calculating the MELD score. Hyponatremia is a prevalent condition in cirrhotic individuals, and the severity of hyponatremia is a measure of cirrhosis severity.

Cirrhotic individuals with ascites, bleeding varices, hepatic encephalopathy, or hepatocellular dysfunction who have a MELD more than 15 have a strong high indication for liver transplantation investigation.

Specific Indications for Liver Transplantation

• Until 2015, the most prevalent indication for liver transplantation was chronic hepatitis C with cirrhosis. Since 2016, decompensated cirrhosis caused by chronic hepatitis C infection has surpassed alcohol-related liver disease and nonalcoholic steatohepatitis as the third most prevalent reason for liver transplantation. It was critical to remove chronic hepatitis C infection prior to liver transplantation to avoid re-infection and graft failure. Over the last decade, however, innovative direct antiviral medicines have developed, enabling for chronic hepatitis C treatment following liver transplantation.

• Hepatitis B infection formerly led in an increase in the number of chronic liver diseases; however, with the use of Hepatitis B Immunoglobulins (HBIG) and the development of antivirals, hepatitis B has resulted in a drop in the number of liver transplants. Furthermore, treating and controlling the infection is critical to preventing re-infection following transplant. Hepatocellular carcinoma can aggravate hepatitis B, which is an essential reason for liver transplantation.

• Even with long-term corticosteroid and immunosuppressive medication, autoimmune hepatitis (AIH) can progress to liver cirrhosis and failure. Liver transplantation is recommended in situations of acute liver failure caused by autoimmune hepatitis or persistent decompensated cirrhosis caused by autoimmune hepatitis. Poor outcomes and the need for a liver transplant can be anticipated by the following factors: young age, MELD score more than 12, frequent relapses, and a delayed downward slope of aminotransferase after therapy.

• Patients with primary biliary cirrhosis (PBC) who have decompensated cirrhosis or severe pruritis that is resistant to various medical therapies require liver transplantation. The use of Ursodeoxycholic acid to treat PBC, which delays disease development, has reduced the need for liver transplantation throughout the years.

• Primary sclerosing cholangitis (PSC); Because there is no effective medical treatment for PSC, liver transplantation is regarded an effective therapeutic method in individuals with decompensated illness or those who develop perihilar cholangiocarcinoma (within specified criteria) or repeated episodes of bacterial cholangitis. Because PSC is linked to inflammatory bowel disease (IBD), regular colonoscopies are required to check for CRC before and after liver donation.

• The most prevalent reason for liver transplantation is alcohol-related liver damage. Patients with alcohol use disorder should be referred for psychosocial and mental treatment prior to liver transplantation to assure at least six months of abstinence and to avoid relapses, especially because relapses result in the patient being removed from the waiting list. In situations of acute alcoholic hepatitis that do not respond to medical treatment, liver transplantation may be necessary if fewer than six months of abstinence is accomplished.

• Patients suffering from acute liver failure (ALF) rapidly worsen, developing significant liver dysfunction, increased bilirubin, aminotransferases, encephalopathy, and coagulopathy (INR above 1.5). Acetaminophen is responsible for about half of all ALF cases in the United States. ALF is regarded as a strong high (1a) indication for liver transplantation since it trumps all other causes of chronic liver disease and takes precedence on the UNOS (The United Network for Organ Sharing) waiting list. The following requirements must be completed in order to obtain precedence on the waiting list as in (1a) ALF case:

1. ICU admission
2. On ventilatory support
3. Requiring hemodialysis
4. Elevated INR above 2
5. Development of hepatic encephalopathy within a period of 8 weeks from the onset of symptoms
6. It is important to note that compared to liver transplantation due to chronic disease, the one-year survival in liver transplantation due to ALF is worse, but with higher survival rates following the first year. 
7. Patients with hepatocellular carcinoma (HCC) 

• Nonalcoholic steatohepatitis (NASH) is one of the most common reasons for a liver transplant. NASH is part of the nonalcoholic fatty liver disease continuum, which includes everything from steatosis alone to NASH with cirrhosis. These liver illnesses are associated with metabolic syndrome, a high body mass index (BMI), and obesity. Because there is presently no viable therapy for NASH or fibrosis, the number of liver transplants has increased as a result of NASH. Furthermore, people with NASH, both with and without cirrhosis, have an increased risk of developing HCC.

• Liver transplantation is recommended for people who have acute liver failure due to Wilson disease or who have decompensated cirrhosis and have failed all medicinal treatments. Even in situations of metabolic problems such as renal failure, which recovers after liver transplantation, liver transplantation has excellent results in Wilson disease. 

• Adults with no history of liver illness are frequently diagnosed with alpha-1 antitrypsin deficiency. Liver transplantation is the primary and only therapeutic option for decompensated liver disease caused by alpha-1 antitrypsin deficiency. There is no danger of recurrence following liver transplantation due to the expression of the donor's alpha-1 antitrypsin gene. Chest imaging and pulmonary function tests should be used to screen patients for lung disease.

• Liver transplantation is recommended in individuals with decompensated cirrhosis or HCC who have hereditary hemochromatosis (HH). Cirrhosis caused by HH has the highest chance of developing HCC when compared to all other types of cirrhosis. The use of iron reduction treatment before to transplantation by phlebotomy has resulted in improved results post-liver transplantation.

Contraindications

While the criteria for liver transplantation are increasing larger, the contraindications are becoming fewer as liver transplant methods improve. Nonetheless, there are several absolute and relative contraindications to liver transplantation.

Absolute Contraindications  

• MELD score of less than 15
• Advanced cardiac or pulmonary disease
• Acquired immunodeficiency syndrome (AIDS)
• Active alcohol or illicit substance use
• HCC or perihilar cholangiocarcinoma with metastatic spread
• Untreated septic shock or sepsis
• An anatomic abnormality that precludes liver transplantation
• Intrahepatic cholangiocarcinoma
• Extra-hepatic malignancy (outside the liver), unless the patient is tumor-free for more than two years with a low probability for recurrence.
• Hemangiosarcoma
• Fulminant hepatic failure leading to sustained intracranial pressure (ICP) above 50 mmHg or cerebral perfusion pressure (CPP) less than 40 mmHg.
• Lack of psychosocial support and severe psychologic disease
• Severe pulmonary hypertension

Despite the fact that AIDS is an unequivocal contraindication to liver transplantation, several hospitals are now considering HIV-positive patients as candidates for liver transplantation.

Relative Contraindications

• General debility
• Persistent non-compliance
• Advanced age
• Extensive previous abdominal surgery
• Extensive portal or mesenteric thrombosis

Preparation

Many essential features and health problems in liver transplant candidates must be addressed during the pre-transplantation examination. This assessment should involve a complete, comprehensive history and physical examination, laboratory testing, and imaging scans in order to perform a full systematic review and manage patients appropriately. 

• Obesity: Patients should be assessed for increased BMI since it increases perioperative risks and lowers long-term survival in liver transplant patients. Obese individuals with a BMI of 30 kg/m2 or above should see a dietician, and a BMI of 40 kg/m2 or more is regarded a relative contraindication for a liver transplant.

• Coronary Artery Disease: The evaluation of perioperative cardiac risk is critical. All patients should have cardiac stress tests, either physical or chemical. If stenosis is discovered, coronary revascularization should be performed prior to liver donation.

• Age: Although the prognosis for transplant in people over the age of 70 is not as excellent as in younger patients, greater age is not a contraindication to liver transplantation in patients who do not have or have manageable comorbidities. It has recently been demonstrated that well-selected elderly liver transplant candidates can benefit from liver transplantation, hence recovering their predicted longevity.

• Hepatopulmonary Syndrome: It is a condition characterized by shortness of breath and hypoxemia in individuals suffering from chronic liver disease, particularly those with portal HTN. This is related to pulmonary vessel microvascular dilatation, which results in intrapulmonary shunt. Pulse oximetry should be used to screen patients prior to liver transplantation. Depending on the severity of the hepatopulmonary syndrome, patients may require a prolonged recovery period and long-term supplementary oxygen after a liver transplant.

• Renal Dysfunction: Patients with renal illness must be detected prior to receiving a liver transplant, since renal impairment dramatically increases mortality. If a patient's glomerular filtration rate (GFR) is less than 30 mL/min, it indicates chronic kidney disease or acute renal failure that necessitates dialysis for longer than eight weeks. This is also recommended if there is significant glomerulosclerosis.

• Cigarette Smoking: It raises the risk of death among liver transplant patients owing to heart illness. It also raises the likelihood of hepatic artery thrombosis. Smoking should be forbidden, and many hospitals consider smoking cessation to be a prerequisite for being considered for a liver transplant.

• Extrahepatic Malignancy: Before having liver transplantation, patients should have all age-appropriate screenings. If they have any heightened risk factors for a specific cancer, they should be tested for that cancer type. Any patient who has been diagnosed with a past cancer should be treated and cured before undergoing a liver transplant.

• Nutrition: Prior to liver transplantation, patients should be assessed by a nutritionist, since it is critical to treat any nutritional deficits associated with chronic liver disease and fat malabsorption. Adequate dietary management in relation to other comorbidities such as diabetes, hypertension, and hyperlipidemia should be emphasized.

• Psychological Evaluation: It is critical to screen liver transplant candidates for any psychological illnesses that may impact their prognosis, medication compliance, and medical directions. It is also critical to assess social support networks and caregiver availability, especially in encephalopathy patients.

Liver transplant surgery

There are two parts to each liver transplant procedure: the donor and the recipient.

Following dissection of the hepatic ligamentous attachments and hilar structures, the patient's native liver is completely removed. The inferior vena cava (IVC) should be encircled to ensure adequate blood control. Donors can be either deceased or alive.

Transplantation of Livers from Deceased Donors (DDLT): Whole-liver transplants are becoming more prevalent. The donor's liver is often prepped on a separate table, and once the recipient's body has been prepared, the donor's liver is transported to the table, and anastomoses are established as needed.

The suprahepatic IVC is linked first, then the infrahepatic IVC, and finally the portal vein. After these stages are completed, the clamps are released, and the portal vein begins to draw blood into the liver to perfuse it. The recipient's and donor's hepatic arteries are joined at the anastomoses of the gastroduodenal artery, and the bile duct is then repaired.

In contrast to the full graft delivered by a deceased donor, a living donor graft is partial. Because a living donor graft has a notably smaller hepatic artery, hepatic vein, and portal vein to implant, the most important component is to make appropriate room by incising the hepatic vein along the sidewalls to guarantee adequate sources for arterial hepatic, portal, and biliary reconstruction.

The hepatic vein is anastomosed first, which requires a suitable length for anastomosis, followed by the portal vein, and lastly, the hepatic artery, which is problematic owing to many short tributaries. Finally, duct to duct anastomosis for the bile duct is done.

Grafts from a living donor include the left lateral sector, which accounts for 20% of the total liver volume, the left lobe, which accounts for 40% of the volume, and the right lobe, which accounts for the remaining 60% of the liver capacity. A dual transplant is occasionally utilized, in which two left lobes from two donors are implanted in one recipient.

Donors having hepatectomy all have a distinctive incision in the right subcostal area that extends into the midline, preventing dissection of the rectus muscle on both sides. Before wound closure in situations of right hepatic lobe donation, the left lobe should be connected to the anterior abdominal wall.

Complications

Complications are either early or late after liver transplantation:

Early Complications

• Primary non-function of the liver allograft
• Hepatic artery thrombosis
• Acute cell rejection
• Biliary complications
• Infection

The abnormal liver enzymes normally return to normal in the first week, and the liver graft begins to regenerate. The major non-function of the allograft is the most significant post-liver transplant consequence. This immediate consequence manifests as either a lack of bile production or the formation of clear bile, both of which are linked with deteriorating liver enzymes and bilirubin levels. This immediate consequence necessitates the use of a fresh transplant in order for the patient to survive.

The first 48 to 72 hours after a liver transplant typically show abnormal liver enzymes, indicating graft harm due to cold and warm ischemia during removal and implantation into the recipient. However, it is critical to rule out hepatic artery thrombosis after a liver transplant, and a Doppler ultrasonography should be performed.

Hepatic artery thrombosis is most common in the first few months after a liver transplant, but it can develop later. The clinical manifestation varies, and individuals may be asymptomatic or develop a fever and elevated liver enzymes. Hepatic ischemia, necrosis, and ischemic cholangiopathy can result from this. Patients may require a re-transplant depending on the severity of graft malfunction, especially if it happens during the first week after liver transplantation.

Acute cell rejection is prevalent, affecting up to 50% of patients after a liver transplant. The majority of occurrences occur within the first two months after a liver transplant, and the majority of patients react to corticosteroids. Anti-thymocyte globulin is required in the case of corticosteroid-resistant rejection. For a definite diagnosis, a liver biopsy should be conducted. Long-term prospects are promising.

Biliary strictures are most commonly found at the biliary anastomosis. Endoscopic dilation, stenting, or, less usually, surgical revision can be used to treat this. Non-anastomotic or ischemic strictures can also occur as a result of hepatic artery thrombosis, ABO incompatibility, prolonged graft ischemia (warm or cold), or grafts donated after cardiac death.

Immunosuppression after liver transplantation raises the risk of opportunistic infections such CMV (the most frequent viral infection), Candida infections (the most common fungal infection), Pneumocystis carinii, Aspergillus, Nocardia, and Cryptococcus. Tacrolimus with cyclosporine can cause neurologic and renal impairment, as well as the development of hyperglycemia.

Late Complications

• Complications related to immunosuppression
• Recurrent disease post-liver transplantation
• De novo malignancy

The harmful effects of immunosuppressive medications are mostly blamed for late problems. The most prevalent are chronic kidney disease (CKD), hypertension, diabetes, and dyslipidemia. Calcineurin inhibitors, in conjunction with pre-transplant CKD and HTN, contribute to the development of renal failure after liver transplantation. This is handled with tight blood pressure management and dosage decrease or cessation of calcineurin inhibitors.

Immunosuppressive medicines raise the risk of cardiovascular disease by increasing risk factors such as diabetes, hypertension, obesity, and dyslipidemia. This, along with a high-risk lifestyle in patients, results in a significant rise in atherosclerosis.

Long-term corticosteroid usage, malnutrition, and vitamin D insufficiency caused by liver illness all raise the risk of osteoporosis. This problem has recently been minimized as a result of effective therapy with bisphosphonates and lower corticosteroid dosages.

Calcineurin inhibitors cause neurologic deficits, most notably tremors, as well as sleeplessness and paresthesias. Recurrent hepatitis C or B infections are examples of recurrent illness after liver transplantation. Both can be well-managed after a liver transplant. Other chronic liver disorders, such as NASH, PBC, PSC, AIH, and HCC, might reoccur.

Malignancies develop spontaneously and are a leading cause of mortality in liver transplant patients over time. This is related to a combination of risk factors, including immunosuppression, viral infections, alcohol intake, cigarette smoking, and advanced age. Skin cancer, lymphoproliferative disease (PTLD), and cervical, vulvar, and anal cancers are the most common malignancies among liver transplant recipients.

Cost of a liver transplant

Out-of-pocket costs for a liver transplant for individuals with health insurance often include doctor visit, lab, and prescription medicine copays, as well as coinsurance of 10% to 50% for surgery and other procedures, which can quickly exceed the yearly out-of-pocket maximum. A liver transplant is frequently covered by health insurance.

A liver transplant can cost up to $575,000 or more for people who do not have health insurance, including follow-up treatment and drugs for the first six months following the operation.

Conclusion 

Liver transplantation is a tremendously difficult process that necessitates an extraordinarily high level of interprofessional coordination among all members of the medical team. Surgeons, hepatologists, OR and floor nurses, nutritionists, therapists, and social workers are all important components of the healthcare team who contribute significantly to the results of liver transplantation.

Attention should be paid to preventing and minimizing the long-term consequences of immunosuppression, as well as managing early and late problems and disease recurrence, which lead to patient deterioration and may necessitate re-transplantation. With open communication and cross-disciplinary collaboration, liver transplantation can have a far better probability of success with less morbidity and death.