Postoperative period after liver transplantation

The postoperative period after liver transplantation is not easy, especially in adult patients. Further surgical treatment may be necessary, such as drainage of an abscess, biliary reconstruction, or stopping bleeding.

In 20-25% of patients, liver retransplantation is required. The main indications are a primary non-functioning graft, hepatic artery thrombosis, and chronic rejection, often associated with CMV infection. Hemodialysis may be required. The results are worse than with primary transplantation.

Unfavorable prognostic factors include exhaustion and poor general condition before surgery, Child's cirrhosis group C, elevated serum creatinine levels, and severe coagulation disorders. The results are also affected by the amount of blood and blood components transfused during surgery, the need for hemodialysis in the posttransplant period, and a severe rejection reaction. The operation is easier to perform in patients without cirrhosis and portal hypertension; perioperative mortality in these patients is significantly lower.

The causes of death are related to the operation itself: complications related to the surgical technique (early or late), bile leakage and liver rejection, which may be accompanied by infection, often associated with the use of high doses of immunosuppressants.

The patient usually spends about 10 days in the intensive care unit, 2 months in hospital or outpatient treatment; the full recovery period ends after 6 months. The quality of life and well-being of patients improve significantly, but a 9-month follow-up of surviving patients showed that only 43% were able to return to work. The ability to work of patients after liver transplantation is significantly affected by age, duration of disability before transplantation, and type of professional activity.

More than 87% of pediatric liver transplant survivors fully recover with normal growth, physical and psychosocial development.

Post-transplant complications

Complications after surgery can be divided into 3 main groups:

1. 1) primary transplant failure (1-2 days);
2. 2) infections (3-14 days and more);
3. 3) rejection (starting from 5-10 days).

All 3 groups of complications are characterized by similar features: a large, dense, painful liver, progressive jaundice, fever, and leukocytosis. Specialized investigations should be available. These include CT, ultrasound, and Doppler studies, lidophenine radionuclide scanning, angiography, percutaneous transhepatic cholangiography (PTC), and endoscopic retrograde cholangiopancreatography (ERCP).

A donor liver biopsy is performed before transplantation and subsequently - 5 days, 3 weeks and 1 year after the operation. There are no specific signs that allow predicting the functioning of the donor organ after transplantation. However, the presence of zonal or severe focal necrosis and neutrophil infiltration indicates a high risk of developing early complications.

Complications of liver transplantation

	Complications
Week 1	Primary non-functioning graft Bile leakage Kidney complications Pulmonary complications Complications of the central nervous system
1-4	Cellular rejection reaction Cholestasis Hepatic artery thrombosis
5-12	CMV-associated hepatitis Cellular rejection reaction Biliary complications Hepatic artery thrombosis Viral hepatitis C
12-26	Cellular rejection reaction Biliary complications Viral hepatitis B EBV-associated hepatitis Drug-induced hepatitis
More than 26	Chronic rejection (rare) CMV-associated hepatitis EBV-associated hepatitis Portal vein thrombosis Relapse of the original disease (HBV and HCV infection, tumors)

Primary non-functioning graft

This complication develops in less than 5% of patients 24-48 hours after surgery. It is associated with inadequate preservation of the donor liver, in particular a long (more than 30 hours) period of cold preservation and especially the time of warm ischemia, as well as a subacute rejection reaction or shock. The main manifestations are deterioration of the general condition, unstable hemodynamics, impaired renal function, lactic acidosis with increased PV, increased levels of bilirubin, potassium and serum transaminase activity. Blood glucose levels decrease.

The only treatment is retransplantation, which cannot be delayed in the hope of spontaneous improvement.

Surgical complications

Surgical complications develop in approximately half of patients, which significantly increases the risk of death within 6 months (32% versus 11%). They are most common in children with small diameter vessels and bile ducts.

To detect stenosis or thrombosis of the hepatic artery, hepatic, portal or inferior vena cava, Doppler ultrasound or, if necessary, angiography is used.

Standard ultrasound or CT are used to detect damage to the liver parenchyma, fluid accumulations around the liver, and dilation of the bile ducts.

Cholangiography through a T-shaped drainage is performed to detect changes in the bile ducts. Radioisotope scanning with lidofenine can be used to detect bile sacs.

Targeted puncture allows aspiration of fluid accumulations.

Subcapsular necrosis of the liver is caused by a body weight mismatch between the donor and recipient. This necrosis can be visualized by CT. It usually resolves spontaneously.

Bleeding is more common if a non-peritonealized portion of the diaphragm remains after removal of the affected liver or if there are adhesions from previous surgeries or infectious complications. Treatment consists of transfusions and, if necessary, relaparotomy.

Vascular complications

Hepatic artery thrombosis is most common in children. It may be due to hypercoagulability, which develops in the first few days after surgery. Thrombosis may be acute and manifest as clinical deterioration, fever, and bacteremia. It may also be asymptomatic with bile reflux developing after a few days or weeks. Cessation of blood flow through the hepatic artery may cause necrosis of the common bile duct of the donor liver. Subsequently, liver infarction, abscess, and intrahepatic bile accumulation may occur. The diagnosis can be established using Doppler ultrasound. Angiography can confirm the diagnosis. Usually, the only treatment for this complication is liver retransplantation, although the elimination of vascular anastomotic stenosis by balloon angioplasty has been described.

Portal vein thrombosis is often asymptomatic and presents with bleeding from varices weeks to months after transplantation. In some cases, splenorenal shunt placement and balloon angioplasty are effective treatments. Retransplantation is often necessary.

Hepatic vein occlusion is common in patients who have undergone liver transplantation for Budd-Chiari syndrome.

Sometimes a stricture of the suprahepatic anastomosis of the vena cava occurs. In this case, balloon dilation can be performed.

Complications of the biliary tract

Bile secretion is restored spontaneously 10-12 days or more after surgery and largely depends on the secretion of bile acids. Complications include bile leakage, incorrect placement of the T-shaped drainage, and obstruction, usually caused by stricture of the common bile duct.

Bile leakage may occur in the early postoperative period (in the first 30 days after liver transplantation) and is associated with failure of the bile duct anastomosis or in the late stages (approximately 4 months after surgery) after removal of the T-shaped drainage. Abdominal pain and peritoneal symptoms may be mild against the background of immunosuppressive therapy.

Early bile leakage is diagnosed by routine cholangiography through a T-shaped drain on the 3rd day or after drainage removal by ERCP. Lidophenin scanning may be helpful.

Biliary complications after liver transplantation

Expirationbile

• Early (3-4 weeks)
• Related to anastomosis
• Associated with T-drainage
• Later (4 months later), after removal of the T-shaped drainage

Strictures

• Anastomoses (6-12 months)
• Intrahepatic ducts (3 months)

Bile leakage is usually treated with nasobiliary catheter placement with or without stent placement. Bile leakage from an anastomosis, especially from a Roux-en-Y choledochojejunostomy, usually requires surgical intervention.

Extrahepatic anastomotic strictures develop approximately 5 months after surgery and are accompanied by intermittent fever and fluctuations in serum biochemical parameters. PTC or ERCP is performed with subsequent dilation and stent placement.

Nonanastomotic ("ischemic") strictures develop in 2-19% of patients. They are caused by damage to the arterial plexus around the bile ducts. Contributing factors include prolonged cold ischemia, hepatic artery thrombosis, ABO incompatibility, rejection, foam cell arteriopathy, and a positive lymphocytotoxic compatibility test. Endothelial damage to the periductal arterioles leads to segmental microvascular thromboses and the development of multiple segmental ischemic strictures of the bile ducts.

Ischemic strictures usually develop several months after surgery. They are treated with balloon dilation and stent placement. Liver retransplantation may be necessary if conservative measures are ineffective. Early strictures usually require retransplantation.

Renal failure

Oliguria is almost always observed after liver transplantation, but in some cases more severe renal failure develops. It may be due to previous kidney disease, arterial hypotension and shock, sepsis, use of nephrotoxic antibiotics and cyclosporine or tacrolimus. All these factors occur in severe graft rejection or infectious complications. Hemodialysis does not affect survival.

Pulmonary complications

Mechanical factors play a role in the genesis of pulmonary complications. Air passing through an abnormal pulmonary vascular bed can lead to cerebral air embolism.

In infants, death during liver transplantation may be due to platelet aggregates in small pulmonary vessels. Intravascular catheters, platelet infusions, and liver tissue fragments entering the vascular bed may also cause death during surgery.

The right dome of the diaphragm is in a state of relaxation, which often causes atelectasis of the lower lobe of the right lung. In one study, 20% of patients underwent bronchoscopy. Adult respiratory distress syndrome with thrombocytopenia may be due to endotoxemia and requires intubation.

Almost all cases involve pleural effusion, with approximately 18% of patients requiring evacuation of free fluid from the pleural cavity. Approximately 20% of patients develop infectious pulmonary complications, including pneumonia, empyema, and lung abscesses. These are often caused by opportunistic organisms.

Post-transplant hyperdynamic syndrome resolves over time.

Hepatopulmonary syndrome is usually corrected by liver transplantation, but the post-transplant period is severe, with prolonged hypoxemia, the need for mechanical ventilation and intensive care.

During surgery and in the postoperative period, vascular overload can lead to pulmonary edema, especially in patients with pre-existing pulmonary hypertension.

Non-specific cholestasis

Non-specific cholestasis is common in the first few days after surgery, with serum bilirubin levels peaking at 14–21 days. Liver biopsy may suggest extrahepatic biliary obstruction, but cholangiography does not reveal pathological changes. Possible causes of this complication include mild liver injury due to conservation, sepsis, bleeding, and renal failure. If infectious complications are managed, liver and kidney function usually recovers, but prolonged intensive care unit stays are often required.

Rejection reaction

From an immunological point of view, the liver occupies a privileged position in transplantology. It is more resistant to attack by the immune system than other organs. It is possible that there are fewer surface antigens on the surface of hepatocytes. Nevertheless, almost all patients experience episodes of rejection reactions of varying severity.

The cellular rejection reaction is initiated when special cells transmit information about the donor's HLA antigens to the host's T helper cells in the graft. These T helper cells secrete IL-2, which in turn activates other T lymphocytes. The accumulation of activated T cells in the graft leads to a T cell-mediated cytotoxic effect and a generalized inflammatory reaction.

Hyperacute rejection is rare and is caused by prior sensitization to donor antigens. Acute (cellular) rejection is completely reversible, but chronic (ductopenic) rejection is irreversible. Both types of rejection can occur simultaneously. Diagnosis of rejection caused by opportunistic infections is difficult and requires multiple liver biopsies. Immunosuppressive therapy used to prevent rejection contributes to the development of infectious complications.

Acute cellular rejection reaction

Acute cellular rejection occurs 5-30 days after transplantation. The patient complains of feeling unwell, with low-grade fever and tachycardia. The liver is enlarged and painful. Serum bilirubin levels and serum transaminase activity increase, and PT increases. Changes in liver enzyme activity are nonspecific, and a liver biopsy is necessary.

The primary targets for infiltrating immune cells are bile duct epithelial cells and the endothelium of the hepatic arteries and veins. Rejection is characterized by the classic triad of inflammatory infiltration of the portal tracts, bile duct damage, and subendothelial inflammation of the portal vein and terminal hepatic veins. Eosinophils and hepatocyte necrosis may be seen.

Rejection may be mild, moderate, or severe. Dynamic biopsy may reveal eosinophils, reminiscent of an allergic reaction to a drug, and infarct-like areas of necrosis, probably due to portal vein lymphocyte obstruction. Hepatic arteriography reveals dissociation and narrowing of the hepatic arteries. Very rarely, acute rejection may progress to GVHD. Low concentrations of cyclosporine or tacrolimus in liver tissue are accompanied by cellular rejection. Increased immunosuppressive therapy is effective in 85% of patients. Pulse therapy with methylprednisolone (3000 mg) is administered every other day. In cases of steroid-resistant rejection, monoclonal antibodies OKT3 are prescribed for 10-14 days. Tacrolimus therapy may be attempted. If immunosuppressive therapy is ineffective, the process progresses with the development of ductopenic rejection. If rejection is not stopped, retransplantation may be necessary.

Chronic ductopenic rejection

In this form of rejection, signs of progressive damage and disappearance of the bile ducts are observed. This process is based on an immune mechanism with abnormal expression of HLA class II antigens on the epithelium of the bile ducts. Incompatibility of the donor and recipient for HLA class I antigens with expression of class I antigens on the epithelium of the bile ducts is also important.

Ductopenic rejection is defined as loss of interlobular and septal bile ducts in 50% of portal tracts. The amount of duct loss is calculated as the ratio between the number of hepatic artery branches and bile ducts in the portal tract (normally, this ratio is greater than 0.7). Preferably, 20 portal tracts are examined. Foam cell obliterating arteriopathy increases bile duct injury. Ductopenic rejection can be mild, moderate, or severe based on the degree of histologic changes.

Mononuclear cells infiltrate the bile duct epithelium, causing focal necrosis and rupture. The bile ducts subsequently disappear and portal inflammation resolves. In larger arteries, foamy cells are seen under the intima and sclerotic and hyperplastic changes in the intima. Centrilobular necrosis and cholestasis develop, followed by biliary cirrhosis.

Early cellular rejection is usually followed by ductopenic rejection (approximately day 8) with bile duct degeneration (approximately day 10) and ductopenia (approximately day 60). Ductopenic rejection usually develops within the first 3 months, but may occur earlier. Cholestasis progresses.

Hepatic arteriography reveals significantly narrowed hepatic arteries, not filled with contrast material at the periphery and often with occlusion of branches. Occlusion of large branches of the hepatic artery leads to strictures of the bile duct, which are revealed on cholangiograms. In cholangitis caused by CMV infection, a picture of sclerosing cholangitis may also be observed.

Ductopenic rejection usually cannot be controlled by increasing the dose of immunosuppressive drugs, although some patients have shown early benefit from tacrolimus and corticosteroid therapy. Retransplantation is usually the only effective treatment. Irreversible ductopenic rejection is slowed by more advanced immunosuppressive methods.

Infectious complications

More than 50% of patients develop infectious complications in the post-transplant period. The infection may be primary, caused by reactivation of a previous infection, or associated with infection by opportunistic microorganisms. It is important to establish the degree of immunosuppression and obtain information about previous infections.

Bacterial infections

Bacterial infections develop during the first 2 weeks after transplantation and are usually associated with surgical complications. These include pneumonia, wound infection, liver abscess, and biliary tract infections. These complications may be due to invasive procedures (eg, vascular catheterization). Bacterial infections are usually caused by endogenous microorganisms, and some centers use selective bile decontamination prophylactically.

CMV infection

This infection almost always complicates liver transplantation and manifests itself with severe symptoms in 30% of patients. It can be primary (the source is transfused blood components or donor liver) or secondary, caused by reactivation of the virus. The single most important risk factor is the presence of anti-CMV antibodies in the donor [48]. The main preventive measure is the use of liver from seronegative donors.

Cases of infection increase with antilymphocyte globulin therapy, retransplantation, or hepatic artery thrombosis.

The infection manifests itself within 90 days after transplantation, the peak is on the 28-38th day. In patients with impaired transplant function, who require intensive immunosuppressive therapy, the duration of CMV infection is calculated in months and even years. The most common cause of hepatitis in the transplanted liver is cytomegalovirus infection.

The clinical picture of the disease resembles mononucleosis syndrome with fever and increased activity of serum transaminases. In severe forms of the disease, the lungs are affected. Chronic infection is accompanied by cholestatic hepatitis and bile duct disappearance syndrome.

Other manifestations include pizza retinitis and gastroenteritis.

Liver biopsy reveals clusters of polymorphonuclear leukocytes and lymphocytes with intranuclear CMV inclusions. Bile duct atypia and endothelitis are absent. Staining with monoclonal antibodies to the early CMV antigen facilitates timely diagnosis of this infectious complication. Culture methods in closed vials yield positive results within 16 hours.

Long-term (up to 100 days) administration of ganciclovir, starting from the first day after surgery, almost completely eliminates CMV infection. Unfortunately, this is an expensive treatment method and, in addition, the drug is administered intravenously.

If possible, immunosuppressant doses should be reduced. Chronic CMV infection is an indication for liver retransplantation.

Herpes simplex

This infection is usually caused by viral reactivation during immunosuppressive therapy. Liver biopsy shows confluent areas of necrosis surrounded by viral inclusions. Herpes infection is virtually absent after prophylactic use of acyclovir.

EBV infection

This is the most common primary infection in children. It causes a picture of mononucleosis and hepatitis. The disease is often asymptomatic. The diagnosis is established serologically. Lymphoproliferative syndrome is a complication manifested by diffuse lymphadenopathy or widespread polyclonal lymphoproliferation in internal organs. Treatment consists of reducing the doses of immunosuppressive drugs and prescribing high doses of acyclovir.

Development of monoclonal B-cell lymphoma with an unfavorable prognosis is possible.

Adenovirus infection

This infection occurs in children. It is usually mild, but fatal hepatitis can develop. There is no specific treatment.

Chicken pox

Chickenpox may complicate the post-transplant period in children. Treatment consists of intravenous ganciclovir.

Nocardial infection

This infection is usually localized in the lungs, but skin and brain lesions may also occur.

Fungal infections

Candidal infection is the most common fungal complication observed in the first 2 months after transplantation, usually developing on the 16th day. Fungal infections reduce survival. The drug of choice is amphotericin B.

Pneumocystis pneumonia

Pneumocystis pneumonia develops in the first 6 months after transplantation. The diagnosis is established based on bronchoscopy and bronchoalveolar lavage. Prevention consists of prescribing Bactrim (Septrim) 1 tablet daily for the first 6 months after transplantation.

Malignant tumors

Malignancies develop in 6% of recipients, usually within 5 years of transplantation. Many of these are related to immunosuppressive therapy. These include lymphoproliferative disorders, skin tumors, and Kaposi's sarcoma. All patients who have had a liver transplant should undergo annual cancer screening.

Drug toxicity

Any signs of hepatitis and cholestasis may be due to the toxic effects of drugs, in particular azathioprine, cyclosporine, tacrolimus, antibiotics, antihypertensive drugs and antidepressants.

Relapse of the disease

Viral hepatitis B recurs within 2 to 12 months and can lead to cirrhosis and liver failure within 1 to 3 years. Viral hepatitis C can occur at any time after the first 4 weeks. Malignant hepatocellular tumors recur in the transplant or metastasize, usually within the first 2 years after surgery.

Budd-Chiari syndrome may recur shortly after transplantation when anticoagulant therapy is discontinued.

Toxic complications of the central nervous system

Severe CNS changes may develop after liver transplantation. Convulsions occur in half of patients, and they occur more frequently in children than in adults. Cyclosporine-induced convulsions respond to phenytoin, but this drug accelerates the metabolism of cyclosporine.

Central pontine myelinolysis is caused by sudden electrolyte disturbances, possibly in combination with cyclosporine toxicity. CT shows white matter lucencies.

Cyclosporine binds to lipoprotein fractions in the blood. Patients with low serum cholesterol levels are particularly at risk for developing CNS toxicity after liver transplantation.

Cerebral infarction is caused by arterial hypotension during surgery or by embolism caused by air bubbles or microthrombi.

The use of high doses of corticosteroids to treat rejection may cause psychosis.

Brain abscess is a local manifestation of a generalized infection.

Headaches may occur during the first few weeks after surgery. In some patients, the cause is cyclosporine therapy, but in most cases, the cause is unknown.

Tremor is a common side effect of immunosuppressive therapy. It can be caused by, among others, corticosteroids, tacrolimus, cyclosporine and OKT3. Tremor is usually mild, but in some cases it is necessary to reduce the dose of drugs or to stop them completely.

Retransplantation is accompanied by more pronounced mental disorders, seizures and focal motor dysfunction.

Bone damage

Liver transplant recipients usually initially have varying degrees of hepatic osteodystrophy. In the post-transplant period, bone tissue changes worsen. In 38% of patients, vertebral compression fractures are observed in the period from the 4th to the 6th month after surgery. There are many causes of complications from the skeletal system. These include cholestasis, corticosteroid therapy, and bed rest. Over time, bone tissue is restored.

Ectopic soft tissue calcification

This complication may be diffuse and is accompanied by respiratory failure and bone fractures. It is caused by hypocalcemia caused by citrate in transfused fresh frozen plasma, as well as renal failure and secondary hyperparathyroidism. Tissue damage and administration of exogenous calcium lead to its deposition in soft tissues.

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