Key words : Challenges, COVID-19, End-stage liver disease, Liver transplantation, Techniques

Donor Sourcing and Evaluation

The shortage of available donor organs has become a substantial obstacle to the progression of organ transplant. In response to this shortage, approaches have been adopted that involve organ donation after circulatory death and split liver transplant.^1,2 Another approach is the use of organs from hepatitis C virus (HCV)-positive donors to HCV-positive recipients, which has been shown to further expand liver sources.³ Similarly, transplanting hepatitis B virus (HBV)-positive donors to HBV-positive recipients to avoid HBV infection is also recommended. To ensure the safety and efficacy of liver transplant procedures, an objective and effective functional evaluation of donor livers before transplant is essential. In China, the local organ procurement organization conducts pretransplant evaluations for liver transplant.⁴ When a donor is confirmed to be brain dead, the closest relatives of the donor provide consent and the donor’s ABO blood type, height, weight, and chest circumference are checked to find a match. To avoid postoperative primary nonfunction (PNF) and death in the short term, the ratio of graft volume to standard liver volume and graft weight-to-recipient weight ratio must be considered carefully.⁵ Currently, the safety range is between 30% and 40% for ratio of graft volume to standard liver volume and between 0.6% and 0.8% for graft weight-to-recipient weight ratio.^6,7

Donor Factors That Affect Recipient Outcomes

Recipients who undergo liver transplant with grafts from older donors may have laboratory values outside of reference ranges and lower survival rates compared with those who receive grafts from younger donors, with such presentations particularly shown within the first 24 months posttransplant.^7,8 Such presentations could be attributed to the decrease in liver blood flow, bile production, and metabolic enzymes in older donors. The risk of HCV infection recurrence is also elevated in recipients with HCV, resulting in graft loss and diminished recipient survival rates.^9,10 Older donors may also have increased risk of other complications, such as biliary stricture and hepatic artery thrombosis.^11,12 In our center, donor age greater than 65 years old is considered a relative contraindication.

Before liver transplant, factors related to graft steatosis should be considered. Studies have indicated that donor liver steatosis of ≥30% is associated with early dysfunction of the graft. Conversely, in recipients with graft steatosis <30%, 5-year survival rates similar to those with healthy grafts have been observed.^13,14 Risk of losing the graft is present when the donor’s liver has >30% macrovesicular steatosis.¹⁵ Transplant centers often attempt to avoid using marginally infiltrated livers and those with >50% fat content because of these risks.¹⁶ Chinese scholars posit that mild fatty liver does not have a great effect on postoperative transplant function or recipient prognosis; however, they suggest that moderate fatty degeneration in the donor’s liver may result in delayed recovery of early graft function and increased incidence of PNF in cases of severe degeneration.¹⁷

Recipients who receive grafts from donors with hypernatremia, defined as plasma sodium levels above 150 to 155 mmol/L, are reported to have poorer outcomes.18 Donor hypernatremia may serve as an indicator for various factors that could adversely affect graft function. These factors encompass an extended stay in the intensive care unit, excessive saline infusion, aggressive treatment of cerebral edema, and diminished secretion of antidiuretic hormone following brain death, leading to an unfavorable water balance.

Donor hypernatremia can also cause severe cell damage, possibly as a result of changes in liver cell osmotic pressure, which can lead to impaired liver function and increased risk of graft loss within 1 month posttransplant. In some cases, donor hypernatremia may even lead to the development of primary liver failure.^18,19 Thus, transplant teams should consider donor sodium levels and other factors that may affect graft function when selecting donors and assessing potential risks for recipients. Cold ischemia time is critical for organ transplant; a time of more than 12 hours is a known risk factor for transplant survival. Prolonged cold ischemia time increases the incidence of preservation injury and postoperative PNF of the liver, particularly if the time exceeds 14 hours.²⁰ The optimal cold ischemia time for grafts is ideally ≤8 hours. For marginal donor livers, the time should be limited to 12 hours or less.²¹ Guidelines on obtaining donor livers are similar (and available) in China.

Recipient Selection and Preoperative Evaluation

Patients with end-stage liver disease should undergo preoperative examinations and preparations to enhance transplant safety. Indications for transplant include acute liver failure, cirrhosis, and liver tumors. Acute liver failure is defined as severe acute liver injury in patients without preexisting liver disease or in patients with preexisting liver disease and impaired synthetic function (international normalized ratio ≥1.5), accompanied by hepatic encephalopathy.²² Different reports use different lengths of illness to distinguish acute liver failure from chronic liver failure, with a commonly used threshold of fewer than 26 weeks for acute liver failure.²³ The causes of acute liver failure are numerous, but viral hepatitis and drug-induced hepatitis are the most common causes in adults. Patients with acute liver failure have the highest priority for liver transplant. The presence of liver cirrhosis alone is not sufficient to constitute an indication for liver transplant. Transplant should be considered when patients have developed complications of portal hypertension or signs of impaired liver function.²⁴ Variceal bleeding, ascites, and hepatic encephalopathy are the primary manifestations of end-stage liver disease and are considered signs of decompensation. Decompensated liver cirrhosis can adversely affect survival rate.

Cirrhosis can also be complicated by hepatorenal syndrome, signifying an urgent requirement for transplant evaluation. Patients with cirrhosis who have a Model for End-Stage Liver Disease (MELD) score ≥15 are usually suitable for liver transplant. Nonetheless, liver transplant may also be suitable for some patients with cirrhosis and Child-Pugh class B, portal hypertension, and lower MELD scores.²⁵ Once a patient’s MELD score exceeds 10 points, routine pretransplant evaluation should commence. If a patient obtains a “bonus” to their standard MELD score due to a certain complication or situation, the patient may also be suitable for liver transplant.²⁶ Liver transplant may be considered a treatment option for primary liver tumors if the patient meets Milan criteria (a single lesion ≤5 cm or ≤ 3 independent lesions, all < 3 cm, with no obvious signs of vascular invasion, and no regional lymph node or distant metastasis).²⁷

Liver transplant of neuroendocrine tumors metastasized to the liver is so far limited, although some centers have attempted transplant of livers with multiple nodules that exceed the Milan criteria.²⁸ Such treatment may reduce the tumor burden to some extent and benefit patient survival; however, further verification in large sample studies is needed. Partial liver segment (segments II-III) transplant followed by delayed total hepatectomy has also been explored as a potential treatment for unresectable colon liver metastases, with some patients surviving and generally staying in good condition after 2 years.²⁹ However, the efficacy of this procedures requires further clinical verification before it is included as a routine practice.

Certain congenital metabolic liver diseases, such as Wilson disease or copper storage disease, alpha-1 antitrypsin deficiency, homocystinuria, porphyria, type I and IV glycogen storage disease, among others, have intricate pathological processes. As the disease advances, patients may present with other complications, resulting in multiorgan dysfunction, with some patients dying during infancy or childhood. Liver transplant is effective in curing numerous congenital diseases. Given that most patients needing liver transplant are children, viable options include living donor liver transplant or split liver transplant.³⁰

During the recipient evaluation process before transplant, the collection of detailed medical history is necessary. In addition to routine medical history, information should be collected on the type, cause, course, and treatment of the primary liver disease, as well as the presence of severe complications of systemic diseases affecting other vital organs. Other important information includes whether the patient has received immunosuppressive agents, surgical history of the abdomen, and a history of drug addiction or drug abuse.³¹

Common laboratory tests include ABO-Rh blood typing, liver biochemistry and liver function tests, complete blood count, kidney function, serum sodium, serum alpha-fetoprotein, calcium and vitamin D levels, urine analysis, and serology tests for cytomegalovirus, Epstein-Barr virus, varicella, HIV, hepatitis A virus, HBV, and HCV.31 Patients may also need to be evaluated on the extent of liver atrophy or splenomegaly, the presence of ascites and edema, varices in the esophagus, stomach, and abdominal wall, overall nutritional and physical condition, cardiac, pulmonary, and renal function, as well as indications of liver tumor metastasis.³² Evaluations should also assess the patient’s ability to tolerate surgical stress and immunosuppression, as well as the need for posttransplant treatment.

Surgery Process

Liver transplant surgery includes 3 main steps: donor liver preparation, diseased liver removal, and donor liver implantation.

Donor liver preparation
Donor liver preparation involves immersing the donor liver in University of Wisconsin solution at 4 °C to prevent ischemia-reperfusion injury. The bile duct is separated upward to the level of the duodenal artery, and careful dissection of the hepatic artery is performed. The portal vein is separated from the pancreatic head, and its small branches are ligated while maintaining adequate length. Preparation of the inferior vena cava (IVC) includes double ligation of the right adrenal vein, ligation of the phrenic vein, removal of excess diaphragmatic tissue, and ligation of the bottom of the gallbladder. Avoiding damage to the portal vein branches of the caudate lobe or the blood supply to the bile duct during dissection is crucial.

Diseased liver removal
During liver surgery, an inverted “Y-shaped” incision is made below the ribs, and a multifunctional or suspended hook is used for exposure. During abdominal cavity exploration, extrahepatic metas-tasis is checked in liver cancer patients and ascites is drained in patients with hepatic cirrhosis and ascites. For classic liver resection, the liver ligament is separated, followed by dissection of the first and second porta hepatis and the IVC. The bile duct is transected above the level of the cystic duct, the hepatic artery is dissected upward, and the left and right hepatic arteries are isolated and transected. The portal vein is separated, and enough length is dissected for anastomosis. To reduce anhepatic time, the portal vein can be temporarily left unclamped. Only the hepatic supra- and infra-caval veins need to be dissected. The phrenic veins entering the caval vein should be freed and cut, and the diaphragmatic tissue wrapped around the caval vein should be separated. After hemostasis, the portal vein and supra- and infra-caval veins should be occluded and divided close to the liver parenchyma, followed by removal of the diseased liver and attached caval vein. The patient is checked for bleeding, and blood vessels are prepared for anastomosis.

For piggyback liver transplant, separation of the first hepatic portal vein is the same as in classical liver transplant, except that the third hepatic portal vein is dissected instead of dividing the posterior IVC. The third hepatic portal vein is made up of small hepatic veins that flow into the IVC from the liver parenchyma, which are ligated and cut one by one. The right posterior inferior hepatic vein should also be carefully separated and sutured. The IVC ligament is cut upward, and the right, middle, and left hepatic veins are separated in sequence. The right hepatic vein is usually cut first, followed by the portal vein; finally the left hepatic vein is ligated and cut to complete the liver resection.

Donor liver implantation
During classic liver transplant procedures, the donor’s suprahepatic and infrahepatic vena cava are end-to-end anastomosed with the recipient’s vena cava with the use of 3-0 Prolene sutures. Continuous suturing is needed to prevent external eversion and ensure a smooth inner surface. After anastomoses of the suprahepatic and infrahepatic vena cava are completed, the donor’s infrahepatic vena cava is end-to-end anastomosed with the recipient’s infrahepatic vena cava with the use of 4-0 Prolene sutures. Before the anterior wall is closed, the donor liver is perfused with 800 mL of 4 ℃ isotonic NaCl solution containing 5% albumin to flush out the residual preservation solution and remove air from the recipient’s infrahepatic vena cava. The donor’s and recipient’s portal veins are end-to-end anastomosed with the use of 6-0 Prolene sutures. The portal vein should be trimmed appropriately to avoid twisting caused by excessive length or tensional stenosis caused by insufficient length. When suturing is completed, immediate knotting should be avoided. A clamp can be used to obstruct the portal vein above the anastomosis site. Opening of the recipient’s portal vein will release 200 to 300 mL of blood. Before initiation of blood flow, blood potassium levels should be assessed and promptly addressed for elevated levels to prevent sudden cardiac arrest.

After the suprahepatic and infrahepatic vena cava and the portal vein are sequentially opened, the liver should be rapidly flushed with warm isotonic NaCl solution for rewarming. In cases of liver blood stasis, the liver should be gently massaged to enhance blood circulation. For livers with good function, bile flow should be observable within minutes during perfusion posttransplant.

Once negligible bleeding is confirmed, arterial reconstruction can commence. Typically, the donor hepatic artery, recipient hepatic artery, and gastroduodenal artery are trimmed to form a trumpet-like opening, followed by end-to-end anastomosis. Continuous suturing can be used if the artery diameter exceeds 3 mm; otherwise, intermittent suturing under a microscope can be used for diameters of <3 mm. Finally, 6-0 absorbable sutures are used to conclude the reconstruction of the biliary system.

In piggyback liver transplant, the anastomosis process for the portal vein, hepatic artery, and bile duct mirrors that of classic liver transplant. The key divergence lies in the anastomosis of the hepatic vein (outflow tract). Presently, a commonly adopted approach is the modified piggyback technique. With the use of a large occlusion clamp, the anterior wall of the recipient’s IVC is partially occluded, and an incision is made on the anterior wall with a diameter similar to that of the hepatic vein in the donor liver. The donor and recipient hepatic veins are then meticulously anastomosed end-to-end with 4-0 Prolene sutures in a continuous manner, starting with the right side followed by the left side, with a preference for an outside-in suturing technique. Once the reconstruction of the outflow tract is finalized, an 800-mL solution of 4 ℃ isotonic NaCl containing 5% albumin is used to flush the donor liver, ensuring the removal of any residual preservative solution within the liver. Subsequently, the donor hepatic IVC is ligated, and the portal vein anastomosis resumes.

After anastomosis is completed, the donor hepatic vein is opened, followed by the portal vein. The advantage of piggyback liver transplant lies in the partial occlusion of the IVC during the surgical procedure. This minimizes its effect on the recipient hemodynamics, thereby aiding in the preservation of kidney and cardiopulmonary function. Currently, no clear advantage between classic liver transplant and piggyback liver transplant has been shown, and the optimal surgical technique should be chosen based on the individual recipient’s circumstances.

Complications and Management Principles After Liver Transplant

The incidence of complications after liver transplant currently ranges from approximately 14% to 35%, constituting substantial risks to recipient survival.^33,34 Common complications posttransplant include early allograft dysfunction (EAD), PNF, postoperative bleeding, vascular issues, biliary complications, and metabolic complications.

Early allograft dysfunction and primary nonfunction
Both EAD and PNF are diagnosed when there is abnormal liver function after liver transplant; diagnosis requires the exclusion of other causes, such as vascular complications, rejection reactions, or infection. In deceased donor liver transplant, the incidence of EAD is approximately 45%. The current widely accepted mechanism for the onset of EAD involves inflammatory responses and oxidative stress as a result of ischemia-reperfusion injury following the implantation of the graft. Early allograft dysfunction is primarily clinically manifested as partial and reversible liver dysfunction occurring within the first week posttransplant. Despite its reversible nature, EAD has been associated with lower graft and patient survival rates.

Within graft dysfunction, PNF is a less common but more severe type, with an incidence that ranges from about 2% to 9%,³⁵ Primary nonfunction is caused by high-risk donor factors such as age >50 years, steatosis of >60%, hypernatremia, and prolonged cold or warm ischemia time and recipient-related factors such as obesity, excessive endotoxin production, portal vein thrombosis, hepatotoxic drugs, and certain primary diseases.¹³ Clinical manifestations include liver failure, increased transaminase levels, hepatic encephalopathy, ascites, coagulation dysfunction, hemodynamic instability, and renal or pulmonary complications.¹³

To diagnose and prevent EAD and PNF, liver biopsy is essential and avoiding high-risk marginal donor livers is key. For PNF, retransplant is the only effective treatment. Currently, the definitions for EAD and PNF mostly rely on static fixed numerical criteria related to postoperative aspartate aminotransferase, alanine aminotransferase, and international norma-lized ratio levels.³⁵ Reliance on static numerical criteria can result in recipients who have not yet met the diagnostic criteria in real clinical scenarios who are diagnosed with EAD and PNF, even though they may still experience graft dysfunction. Therefore, it is advisable to appropriately develop diagnostic criteria that better meet clinical demands. Some recent work has established risk prediction models for EAD and PNF, such as nomograms,³⁶ to assist in clinical scenarios, but larger multicenter studies are still needed for validation.

Postoperative bleeding
Postoperative bleeding is the most common complication after liver transplant and typically occurs within 48 hours posttransplant.³⁴ Postoperative bleeding is primarily attributed to incomplete hemostasis during the operation, followed by inadequate synthesis of coagulation factors and impaired coagulation function due to liver dysfunction. Reoperation for hemostasis proves to be the most effective treatment. If significant oozing is observed during the operation, accompanied by poor coagulation indicators, worsening liver function, and metabolic acidosis, and treatment with exogenous coagulation factors fails to improve the situation, PNF could occur.

Hepatic artery thrombosis and stenosis
Hepatic artery thrombosis and stenosis often result from improper anastomosis, intimal invagination, angulation, and endothelial damage. Diagnosis typically involves ultrasonography and hepatic artery angiography. Prevention hinges on precise techniques, including matching of donor and recipient diameters, alignment, tension-free anastomosis, and preserving an intact vascular endothelium.³⁷ Adult transplant procedures commonly use a trumpet-shaped end-to-end anastomosis. If thrombosis is confirmed, prompt intervention such as embolectomy, thrombolysis, or reconstruction is necessary. Stenosis, which occurs in 4% to 13% of cases, usually manifests at the anasto-mosis site and can be addressed through techniques like percutaneous transluminal angioplasty or other interventional approaches.³⁷

Portal vein thrombosis and stenosis
The postoperative incidence of complications related to the portal vein can range from 1% to 12.5%, similar to the occurrence rate of complications associated with the hepatic artery.^34,37 Improper vascular anastomosis can lead to anastomotic stenosis as a result of severe intimal injury, and long vascular anastomosis can cause torsion or angulation after anastomosis. The main symptoms include a rapid deterioration of liver function and portal hypertension. In advanced stages, collateral circulation is established, often accompanied by varicose veins, ascites, or heightened activity in the splenic artery. For cases of thrombosis, interventional thrombectomy or thrombolysis may be attempted when liver function is only mildly affected. However, if liver function deteriorates, immediate thrombectomy should be performed along with portal vein reconstruction. After surgery, stenosis can be primarily addressed through percutaneous transluminal angioplasty balloon dilation or stent placement.

Hepatic artery thrombosis
Hepatic artery thrombosis is typically caused by improper anastomosis, excessively tight or tugged sutures, angulation issues, elongated hepatic veins, and hematomas.³⁴ Clinical symptoms vary from mild to severe, including liver congestion, edema, low blood pressure, oliguria, and hepatic or pleural effusions. Diagnosis is usually conducted by use of ultrasonography and vascular imaging. To prevent hepatic artery thrombosis, precise anastomotic techniques and proper fixation of the graft are crucial.

Bile leakage and bile duct obstruction
Bile leakage is caused by poor biliary reconstruction, insufficient blood supply, transection, and T-tube removal.³⁴ Symptoms include abdominal pain, drainage of bile-like fluid, fever, and elevated white blood cell counts. Diagnosis is done by ultraso-nography and aspiration. Treatment includes percutaneous drainage, endoscopic retrograde cholangiopancreatography (ERCP) with stent/nasal biliary drainage, open drainage, biliary repair or reconstruction, and biliary-enteric anastomosis.

Biliary obstruction is caused by anastomosis issues, thrombosis, ischemia-reperfusion injury, and hypoperfusion.³⁴ Symptoms include cholangitis, jaundice, and elevated levels of aminotransferases and alkaline phosphatase. Diagnosis is conducted through magnetic resonance cholangiopancreatography, ERCP, and ultrasonography. Treatment involves urso-deoxycholic acid, hepatoprotective drugs, ERCP, balloon dilation, stent placement, removal of the anastomotic site and biliary-enteric anastomosis, and magnetic compression anastomosis.

Postoperative psychiatric complications are also common after liver transplant and include delirium, delusions, hallucinations, mania, and cognitive impairment. Causes may be poor preoperative liver function, drug reactions, infections, electrolyte disturbances, and neurological complications. Treatment involves treatment of underlying causes, psychological therapy, and possibly changes to immunosuppressive drugs and reduction of neuroexcitatory drugs.

Long-Term Management of Recipients

Immunosuppressive drugs are an essential part of successful transplant and involve a combination of prednisone, one or more calcineurin inhibitors (CNIs), and sometimes mycophenolate mofetil. In the early posttransplant period, 2 or 3 drugs are used. After 6 months, a single CNI may be sufficient as maintenance therapy, but mycophenolate mofetil may still be needed for those who are at increased risk of rejection. All immunosuppressive drugs can potentially lead to side effects such as hypertension, diabetes, renal dysfunction, and interactions with other drugs and supplements. Because of the prolonged suppression of various T cells by long-term use of immunosuppressants, patients are at an increased risk of infections and the development of tumors.³⁸ Other common issues after transplant include infections, hypertension, diabetes, obesity, dyslipidemia, renal disease, metabolic bone disease, and malignancies. Infections are the most serious concern and should be promptly evaluated if symptoms arise.^39,40

COVID-19 and Liver Transplantation

In recent years, the COVID-19 pandemic caused by SARS-CoV-2 has significantly affected health care departments, including solid-organ transplantation. Patients undergoing prolonged immunosuppression represent a distinct group of solid-organ transplant recipients, potentially at a higher risk of contracting COVID-19 because of diminished immune response to vaccines. Physicians should carefully consider the risks associated with infections in liver transplant recipients and donors.

It remains unclear whether liver transplant recipients face a higher risk of SARS-CoV-2 infection compared with the general population. However, prolonged immunosuppression may compromise immune control, potentially increasing the risk of rejection after infection. Compared with other recipients, those who have had SARS-CoV-2 may have a larger and longer duration of viral clearance and may be more likely to transmit the infection to others. Nevertheless, further data are needed to confirm and quantify the virological and transmission risks among liver transplant recipients.

The safety of organ donation remains uncertain for donors who have recently recovered from or have an unclear history of COVID-19. However, transplant of nonlung organs from donors infected with SARS-CoV-2 has not been shown to result in viral transmission and can have favorable short-term outcomes.⁴¹ Long-term outcomes, however, still lack clarity. Therefore, routine screening for COVID-19 in both the potential donor and recipient before transplant is necessary to ensure the safety of the transplant recipient and the organ procurement team. To minimize infection and save medical resources, some transplant centers have postponed elective and nonurgent deceased donor organ transplant in areas with high-risk of infection.

All recipients, unless contraindicated because of allergic reactions, are recommended to receive the COVID-19 vaccine. Although efficacy may be lower in transplant recipients, recipients have shown a lower immune response to the vaccine. Therefore, it is advisable to maintain active preventive measures even after vaccination. Following transplant, the immunosuppressive regimen should be tailored to the severity of the disease and personalized for each patient. In patients with moderate to severe COVID-19 disease, it is advisable to minimize or avoid the use of metabolic agents such as mycophenolate or sodium mycophenolate, especially among patients with lymphocyte depletion.⁴² Calcineurin inhibitors can be continued for suppression of the interleukin 1 and interleukin 6 pathways.^43-45

Conclusions

Liver transplant surgery is intricate and demands experienced surgeons. To ensure a successful recovery, it is crucial to meticulously screen both donors and recipients, standardize operations to mitigate complications, and tailor immunosup-pressive treatment. In the context of COVID-19, transplant procedures should adhere to local policies to minimize complications for patients on wait lists.

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