Postoperative period after liver transplantation

The postoperative period after liver transplantation is not easy, especially in adult patients. You may need further surgical treatment, for example, drainage of the abscess, biliary reconstruction or stopping bleeding.

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

Adverse prognostic factors include depletion and severe general condition prior to surgery, the association of a patient with cirrhosis to the C group on Child, an increase in serum creatinine and severe coagulo- logical disorders. The results are also affected by the amount of blood transfused and its components during the operation, the need for hemodialysis in the post-transplant 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 much lower.

The causes of death are associated with the operation itself: complications associated with the technique of surgery (early or late), the expiration of bile and liver rejection, which may be accompanied by an infection often associated with the use of large doses of immunosuppressants.

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

More than 87% of children surviving liver transplantation recover completely, while maintaining normal growth, physical and psychosocial development.

Post-transplant complications

Complications after surgery can be divided into 3 main groups:

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

All 3 groups of complications are characterized by similar signs: large dense painful liver, progressive jaundice, fever and leukocytosis. Special research should be provided. These include CT, ultrasound and Doppler studies, radio isotope scanning with lidophenin, angiography, transcutaneous transhepatic cholangiography (CHCHKH), and endoscopic retrograde cholangiopancreatography (ERCP).

Biopsy of the donor liver is performed before transplantation, and afterwards - 5 days, 3 weeks and 1 year after the operation. There are no definite signs that allow us to predict the functioning of the donor organ after its transplantation. However, the presence of zonal or severe focal necrosis and infiltration by neutrophils indicates a high risk of developing early complications.

Complications of liver transplantation

	Complications
Weeks 1	Primarily non-functional graft Expiration of bile Kidney complications Pulmonary complications Complications from the central nervous system
1-4	Cell Rejection Reaction Cholestasis Thrombosis of the hepatic artery
5-12	Hepatitis due to CMV Cell Rejection Reaction Biliary complications Thrombosis of the hepatic artery Viral hepatitis C
12-26	Cell Rejection Reaction Biliary complications Viral hepatitis B Hepatitis due to EBV Medical Hepatitis
More than 26	Chronic rejection (rarely) Hepatitis due to CMV Hepatitis due to EBV Thrombosis of the portal vein Relapse of the initial disease (HBV- and HCV-infection, tumors)

Primarily non-functional graft

This complication develops in less than 5% of patients 24-48 h after the operation. It is associated with inadequate preservation of the donor liver, in particular a prolonged (more than 30 hours) period of cold preservation and especially the time of thermal ischemia, as well as a subacute reaction of rejection or shock. The main manifestations are worsening of the general condition, unstable hemodynamics, renal dysfunction, lactic acidosis with increased blood pressure, increased levels of bilirubin, potassium, and activity of serum transaminases. The level of glucose in the blood decreases.

The only method of treatment is re-transplantation, which can not be postponed 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% vs. 11%). Most often they occur in children with a small diameter of blood 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.

To identify lesions of the hepatic parenchyma, fluid accumulations near the liver and dilatation of the bile ducts, use standard ultrasound or CT.

Cholangiography through T-shaped drainage is performed in order to detect changes in the biliary tract. To detect bile ducts, radioisotope scanning with lidophenin can be used.

Aimed puncture allows you to aspirate fluid accumulations.

Subcapsular necrosis of the liver is caused by a mismatch between the body weight of the donor and the recipient. This necrosis can be visualized by CT. Usually it is solved spontaneously.

Bleeding is observed more often if, after removal of the affected liver, an unperitonized portion of the diaphragm remains or if there are adhesions as a result of previous surgical interventions or infectious complications. Treatment consists in transfusions and, if necessary, relaparotomy.

Vascular Complications

Thrombosis of the hepatic artery is most common in children. It can be caused by hypercoagulability, which develops in the first few days after the operation. Thrombosis can be acute and manifest as clinical deterioration, fever and bacteremia. There may also be an asymptomatic course with the appearance of bile in a few days or weeks. Termination of blood flow through the hepatic artery can 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 by means of Doppler ultrasound. Angiography allows you to confirm the diagnosis. Usually the only method for treating this complication is liver transplantation, although the elimination of stenosis of vascular anastomoses by balloon angioplasty has been described.

Thrombosis of the portal vein often proceeds asymptomatically and is manifested by bleeding from varicose veins after weeks and months after transplantation. In some cases, effective methods of treatment are the application of a splenorenal shunt and balloon angioplasty. Often there is a need for re-transplantation.

Occlusion of the hepatic vein often occurs in patients to whom liver transplantation has been performed about the Budd Chiari syndrome.

Sometimes there is a stricture of the superhepatic anastomosis of the hollow vein. In this case, balloon dilatation can be performed.

Complications from the biliary tract

Biliary secretion is restored independently 10-12 days or more after the operation and is largely dependent on the secretion of bile acids. Complications include bile flow, an improper arrangement of T-shaped drainage and obstruction, usually caused by stricture of the common bile duct.

Biliary outflow can occur in the early postoperative period (in the first 30 days after liver transplantation) and is associated with the inadequacy of bile duct anastomosis or in later periods (approximately 4 months after the operation) after removal of the T-shaped drainage. Pain in the abdomen and peritoneal symptoms may not be pronounced in the background of immunosuppressive therapy.

Early bleeding is diagnosed on the basis of routine cholangiography via T-shaped drainage on day 3 or after drainage removal by ERCPH. It may be useful to scan with lidophenin.

Biliary complications after liver transplantation

Bile flow

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

Structures

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

Biliary outflow is usually treated by inserting a nasolabial catheter in combination with or without a stent. At the expiration of the bile from the anastomosis, especially from the choledochojunoanastomosis with the liver of the jejunum turned off by Roux, surgical intervention is usually necessary.

Strictures of extrahepatic anastomoses develop approximately 5 months after the operation and are accompanied by intermittent fever and fluctuations in serum biochemical parameters. Conduct CCHHG or ERPHG with the subsequent dilatation and installation of the stent.

Non-anastomotic ("ischemic") strictures develop in 2-19% of patients. They are caused by damage to the arterial plexus around the bile ducts. The contributing factors include a long time of cold ischemia, thrombosis of the hepatic artery, incompatibility of blood in the AVO system, rejection, arteriopathy with foam cells and a positive lymphocytotoxic compatibility test. The defeat of the endothelium of the circulatory arterioles results in segmental microvascular thrombosis and the occurrence of multiple segmental ischemic strictures of the bile ducts.

Ischemic strictures usually develop a few months after surgery. They are eliminated by balloon dilatation and stent placement. Retransplantation of the liver may be necessary if the conservative measures are ineffective. Early strictures usually require re-transplantation.

Renal insufficiency

After liver transplantation, oliguria is almost always observed, but in some cases, more pronounced renal failure develops. It can be caused by a previous kidney disease, arterial hypotension and shock, sepsis, the use of nephrotoxic antibiotics and cyclosporine or tacrolimus. All these factors take place with severe graft rejection or infectious complications. Conducting hemodialysis does not affect survival.

Pulmonary complications

In the genesis of pulmonary complications, mechanical factors play a role. Air, passing through the abnormal pulmonary vascular channel, can lead to air embolism of the brain.

In infants, death during liver transplantation may be due to the formation of platelet aggregates in small pulmonary vessels. Intravascular catheters, platelet infusion and the entry of fragments of liver tissue into the vascular bed can also lead to the patient's death during surgery.

The right dome of the diaphragm is in a state of relaxation, in connection with which often occurs atelectasis of the lower lobe of the right lung. In one study, 20% of patients had bronchoscopy. Respiratory distress syndrome in adults with thrombocytopenia can be caused by endotoxemia and requires intubation.

In almost all cases, pleural effusion is noted; while approximately 18% of patients require the evacuation of free fluid from the pleural cavity. Approximately 20% of patients develop infectious pulmonary complications, including pneumonia, empyema and lung abscesses. They are often caused by opportunistic microorganisms.

Post-transplant hyperdynamic syndrome is resolved with time.

The hepatic-pulmonary syndrome is usually corrected by liver transplantation, but the course of the posttransplant period is severe, with prolonged hypoxemia, the need for mechanical ventilation and intensive therapy.

During the operation and in the postoperative period, the overload of the vascular bed can lead to pulmonary edema, especially in patients with previous pulmonary hypertension.

Nonspecific cholestasis

Nonspecific cholestasis is common in the first few days after surgery, the serum bilirubin level reaches its maximum values after 14-21 days. Liver biopsy suggests an extrahepatic obstruction of the biliary tract, but with cholangiography, pathological changes are not detected. Possible causes of this complication include mild liver damage due to preservation, sepsis, bleeding and kidney failure. If it is possible to cope with infectious complications, the function of the liver and kidneys is usually restored, but it often requires a long stay in the intensive care unit.

Rejection reaction

From the immunological point of view, the liver in transplantology occupies a privileged position. It is more resistant than other organs to attacking the immune system. There may be fewer surface antigens on the surface of the hepatocytes. Nevertheless, almost all patients have episodes of rejection reaction of varying severity.

The cell rejection reaction is initiated when specific cells transmit information about the antigens of the donor HLA system to the host T helper in the transplant. 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 response.

Oververting rejection is rare and is caused by preliminary sensitization to donor antigens. Acute (cellular) rejection is completely reversible, but chronic (duuktopenic) 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 conducted for the purpose of preventing rejection promotes the development of infectious complications.

The reaction of acute cellular rejection

The reaction of acute cellular rejection occurs 5-30 days after transplantation. The patient complains of poor state of health, low fever and tachycardia are noted. The liver is enlarged in size and painful. The serum bilirubin level and the activity of serum transaminases are increased, PV is increased. Changes in the activity of liver enzymes are nonspecific, and liver biopsy is necessary.

The primary targets for infiltrating immunocytes are the epithelial cells of the bile ducts and the endothelium of the hepatic arteries and veins. Rejection is manifested by a classical triad, including inflammatory infiltration of portal tracts, lesions of bile ducts and subendothelial inflammation of the portal vein and terminal section of the hepatic veins. Possible detection of eosinophils and necrosis of hepatocytes.

Rejection reaction can be mild, moderate and severe. When biopsy in the dynamics can identify eosinophils, which resembles an allergic reaction to the drug, as well as infarct-like zones of necrosis, probably due to obstruction of the lymphocytes of the portal vein. Hepatic arteriography reveals the dissociation and narrowing of the hepatic arteries. In very rare cases, acute rejection can go to the BTWR. Low concentrations of cyclosporine or tacrolimus in the liver tissue are accompanied by cellular rejection. Strengthening immunosuppressive therapy is effective in 85% of patients. Pulse therapy with methylprednisolone (3000 mg) is performed every other day. In cases of steroid-resistant rejection, monoclonal antibodies OKT3 are prescribed for 10-14 days. You can try to tacrolimus. With ineffectiveness of immunosuppressive therapy, the process progresses with the development of duktopenic rejection. With non-repelling rejection, transplantation may be necessary.

Chronic duoptopenic rejection

With this form of rejection, signs of progressive damage and disappearance of the bile ducts are noted. This process is based on an immune mechanism with anomalous expression of antigens of the class II HLA system on the epithelium of the bile ducts. The incompatibility of the donor and recipient with HLA class I antigens with the expression of Class I antigens on the epithelium of the bile ducts is also significant.

Ductopenic rejection is defined as the loss of interlobular and septal bile ducts in 50% of portal tracts. The magnitude of the loss of ducts is calculated as the ratio between the number of branches of the hepatic arteries and bile ducts in the portal tract (normally this ratio exceeds 0.7). It is preferable to explore 20 portal tracts. Obliterating arteriopathy with foam cells strengthens the damage of the bile ducts. Ductopenic rejection by degree of histological changes can be mild, moderate and severe.

Mononuclear cells infiltrate the epithelium of bile ducts, causing its focal necrosis and rupture. Subsequently, the bile ducts disappear, and portal inflammation is resolved. In larger arteries, foam cells under intima and sclerotic and hyperplastic changes in the intima are revealed. Centrilobular necrosis and cholestasis develop, and subsequently biliary cirrhosis.

Following early cell rejection, usually there is a duoptopenic rejection (approximately on the 8th day) with degeneration of the bile ducts (approximately on the 10th day) and duktopenia (approximately on the 60th day). Ductopenic rejection usually develops during the first 3 months, but may occur earlier. Progression of cholestasis.

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

Ductopenic rejection usually can not be stopped by increasing the dose of immunosuppressive drugs, although some patients in the early stages of the development of the process have a positive effect on tacrolimus and corticosteroids. Usually the only effective method of treatment is re-transplantation. Irreversible duktopenicheskoe rejection slows down with the use of better methods of immunodepression.

Infectious complications

More than 50% of patients in the posttransplant period develop infectious complications. Infection can be primary, due to the reactivation of an infection that has already been transferred, or associated with infection with opportunistic microorganisms. It is important to establish the degree of immunodepression and to obtain information about previous infections.

Bacterial infections

Bacterial infections develop within 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 can be caused by invasive interventions (for example, catheterization of blood vessels). Bacterial infections are usually caused by endogenous microorganisms, which is why selective decontamination of bile is used for preventive purposes in some centers.

CMV infection

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

Cases of infection become more frequent when treating with antilymphocytic globulin, with re-transplantation or thrombosis of the hepatic artery.

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

The clinical picture of the disease resembles the syndrome of mononucleosis 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 a syndrome of disappearance of bile ducts.

Other manifestations include retinitis resembling pizza and gastroenteritis.

With liver biopsy, clusters of polymorphonuclear leukocytes and lymphocytes with intranuclear inclusions of CMV are detected. Atypia of bile ducts and endothelium are absent. Staining with monoclonal antibodies to the early antigen of SMU contributes to the timely diagnosis of this infectious complication. The culture methods of the study in closed vials give positive results within 16 hours.

Long-term (up to 100 days) ganciclovir, starting from 1 day after surgery, almost completely eliminates CMV infection. Unfortunately, this is an expensive method of treatment and, in addition, the drug is administered intravenously.

If possible, doses of immunosuppressants should be reduced. Chronic CMV infection is an indication for liver transplantation.

Herpes simplex

This infection is usually caused by the reactivation of the virus against the background of immunosuppressive therapy. In the biopsy of the liver, fused areas of necrosis, surrounded by viral inclusions, are visible. Herpetic infection is almost not observed after the preventive use of acyclovir.

EBV infection

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

Possible development of monoclonal B-cell lymphoma with an unfavorable prognosis.

Adenovirus infection

This infection occurs in children. It usually has a mild course, but fatal hepatitis can develop. Specific treatment is not.

Chickenpox

Varicella can complicate the post-transplant period in children. Treatment consists of intravenous administration of ganciclovir.

Nocardial Infection

This infection is usually located in the lungs, but there may also be lesions of the skin and brain.

Fungal infections

Candidiasis is the most frequent fungal complication observed in the first 2 months after transplantation, which usually develops 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 made on the basis of bronchoscopy and bronchoalveolar lavage. Prevention consists in the appointment of Bactrim (septrim) 1 tablet daily for the first 6 months after transplantation.

Malignant tumors

In 6% of recipients develop malignant tumors, usually within 5 years after transplantation. The emergence of many of them associated with immunosuppressive therapy. These include lymphoproliferative diseases, skin tumors and Kaposi's sarcoma. All patients who have undergone liver transplantation should undergo an annual oncological examination.

Drug toxicity

Any signs of hepatitis and cholestasis can 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 a period of 2 to 12 months and within 1 to 3 years can lead to cirrhosis and hepatic insufficiency. Viral hepatitis C can occur at any time after the first 4 weeks. Malignant hepatocellular tumors recur in the transplant or metastasize usually in the first 2 years after surgery.

Badda-Chiari syndrome may occur again shortly after transplantation when anticoagulant therapy is discontinued.

Toxic complications from the central nervous system

After liver transplantation, severe changes in the central nervous system may develop. In half of the patients, convulsions are noted, and in children they develop more often than in adults. The cramps caused by cyclosporine are amenable to phenytoin therapy, but this drug accelerates the metabolism of cyclosporine.

Central pontinous myelinolysis is caused by sudden electrolyte disorders, possibly in combination with the toxic effect of cyclosporine. CT scan reveals foci of enlightenment in the white matter of the brain.

Cyclosporine binds to lipoprotein fractions in the blood. In patients with low serum cholesterol, the risk of developing toxic reactions from the central nervous system after liver transplantation is particularly high.

Infarction of the brain is due to arterial hypotension during surgery or embolism caused by air bubbles or microthrombi.

The use of high doses of corticosteroids for the treatment of rejection can cause psychosis.

An abscess of the brain is a local manifestation of a generalized infection.

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

A common side effect of immunosuppressive therapy is tremor. It can cause, in particular, corticosteroids, tacrolimus, cyclosporine and OKT3. Tremor is usually poorly expressed, but in some cases, a reduction in the dose of drugs or their complete elimination is required.

Retransplantation is accompanied by more pronounced mental disorders, seizures and focal disturbances of motor function.

Defeat of bones

In recipients of the donor liver, usually initially marked by varying degrees of hepatic osteodystrophy. In the posttransplant period, changes in bone tissue are aggravated. In 38% of patients in the period from the 4th to the 6th month after the operation compression fractures of the vertebrae are observed. The cause of complications from the osseous system is many. These include cholestasis, corticosteroid therapy and bed rest. Over time, there is a restoration of bone tissue.

Ectopic calcification of soft tissues

This complication can have a diffuse character and is accompanied by respiratory insufficiency and fractures of bones. It is caused by hypocalcemia caused by citrate in the transfused fresh frozen plasma, as well as by kidney failure and secondary hyperparathyroidism. Damage to tissues and the appointment of exogenous calcium lead to its deposition in soft tissues.

[1], [2], [3], [4], [5], [6]