Operative procedure

Technical (procedure-related) complications

The abdominal wall incision used by most transplant surgeons is a bilateral subcostal incision that is extended in the upper midline. The xiphoid process is excised. Complications of these incisions include infections, hernias, and granulomas of the fascial sutures, which may occur as late as several years after transplantation. In addition to the abdominal incisions, adult patients also have cutdowns performed in the groin and axilla to accommodate the venovenous bypass system (placed in the axillary and saphenous veins). In addition to wound infections, lymphoceles are a frequent complication in these sites. Lymphoceles may require repeated aspirations or the placement of drains to allow complete resolution.

The four vascular anastomoses established in the transplantation procedur involve the suprahepatic inferior vena cava, infrahepatic inferior vena cava, portal vein, and hepatic artery. Complications related to these anastomoses usually present in the early postoperative period but may occur as late as several months to years after transplantation. These complications include bleeding, thrombosis, stenosis, infection, and pseudoaneurysm formation. Postoperative anastomotic bleeding requires reoperation in the immediately postoperative period and has been associated with a higher early mortality. Arterial thrombosis is the most frequent vascular complication in the early postoperative period and usually requires immediate retransplantation. Thrombosis of the portal vein or inferior vena cava is rare.

The biliary system of the recipient is reconstructed in one of two ways. If the patient has no intrinsic disease of the bile duct, a duct-to-duct anastomosis (choledochocholedochostomy) is performed over a T tube usually brought out through the recipient’s native bile duct. The T tube is left on dependent drainage until the patient’s total bilirubin level falls below 4 mg/dl. The tube is then clamped; it is usually removed as an outpatient procedure approximately 3 months later. Even after this prolonged period of clamping, T-tube removal may result in either bile peritonitis or a localized bile collection.

In patients in whom the native bile duct is diseased or judged too small to accommodate a T tube; the donor bile duct is anastomosed end-to-side to a Roux-en-Y limb of jejunum (choledochojejunostomy). The Roux-en-Y reconstruction drains all bile internally. A localized bile collection is usually amenable to percutaneous drainage, but bile peritonitis requires operative repair of the leaking common bile duct.

The biliary reconstruction is a frequent cause of early and late postoperative complications. Complications related to either type of biliary reconstruction are leak, stricture, infection, and formation of gallstones or sludge. Any patient who is noted to have laboratory evidence of liver dysfunction unrelated to a rejection episode or who has episodes of cholangitis during the first several months to years after liver transplantation should be evaluated radiologically or endoscopically (e.g., endoscopic retrograde cholangiopancreatography) to ascertain biliary patency and function. If the problem cannot be resolved percutaneously or endoscopically, operative reconstruction of the biliary tract may be required, often including the conversion of a choledochocholedochostomy to a Roux-en-Y choledochojejunostomy.

Perioperative graft failure

If a transplanted liver fails to function, the only recourse is retransplantation to prevent complications of fulminant hepatic failure before cerebral edema and brainstem herniation occur. Graft injury can allow short-term survival, but retransplantation or death remains the end point. Currently, the rate of retransplantation in the first 3 postoperative months is 10% to 20%. There are four general reasons for graft failure:

• A technically imperfect operation.
• Unrecognized liver disease in the donor liver.
• An ischemic injury to the graft.
• Accelerated rejection.

Obvious technical complications account for less than 10% of the primary graft failures in adults but 30% of those in infants and children. The risk in infants is inversely related to the patient’s size, and complications are mainly attributable to vascular thromboses.

Portal-vein thrombosis is rare and usually occurs only when the recipient’s splanchnic venous bed has been altered by a portal-systemic shunt, a splenectomy, or another operation. Early portal-vein thrombosis usually requires retransplantation, but a few patients have been saved by immediate or delayed secondary reconstruction of the portal vein.

Thrombosis of the hepatic artery may be asymptomatic in 20% to 30% of instances, and the diagnosis can be made only with the routine use of Doppler ultrasonography. The complications that can result are serious; they include failure of the primary graft to function, hepatic infarction, bacteremia, abscess, rupture of the dearterialized ducts resulting in bile peritonitis or bile leakage, and the formation of biloma within the graft parenchyma Later, these biliary duct lesions may form multiple intrahepatic biliary strictures that resemble sclerosing cholangitis. Although secondary rearterialization has been attempted, retransplantation is usually the only alternative.

The most common cause of postoperative graft dysfunction is ischemic injury to the donor liver, which may occur during the death of the donor, the procurement operation, or the period of refrigeration. The preservation solution, which is infused through the portal vein or hepatic artery, allows the safe cold storage of donor livers for at least 24 hours. The restoration of clotting function and the absence of lactic acidosis are also important predictors of success of the transplanted liver. Measurements of blood amino acid clearance and other products of intermediary metabolism have been used to distinguish between patients in whom the new liver is expected to recover and those in whom it is not.

Host immune factors and hyperacute rejection may result in primary failure of the liver graft. Compared to other transplanted organs such as kidney and heart, the human liver seems to be more resistant to antibody-mediated injury. Because of this resistance, liver transplantation is often performed in spite of major blood-group incompatibilities. However, a progressive and severe coagulopathy that develops shortly after hepatic revascularization should arouse suspicion of an accelerated rejection.

Nontechnical complications

Hypertension is almost universally present in a transplant recipient, especially in the early postoperative period, and requires aggressive treatment. The cause of the hypertension is probably multifactorial and includes the use of cyclosporine. Blood pressure control often requires at least two antihypertensive medications, usually a vasodilator and a beta- blocker. In addition, patients need diuretics both for blood pressure control and to relieve the ascites that usually develops after transplantation. Hypertension is usually less severe after the first 6 months after transplantation, and many patients require no antihypertensive medications by 1 year after the procedure.

Infection

Serious bacterial, viral, and fungal infections may occur in «routine» liver transplantation patients up to several years after the transplant operation. However, infectious complications are much more common in patients who require multiple re operations or who have poor initial function of the transplanted liver. Therefore, fever in any posttransplant patient requires a thorough investigation to rule out infection. The initial workup of fever should begin with a detailed history and physical examination and appropriate cultures of blood, urine, and sputum. Suspected bacterial infections should be treated aggressively with broad-spectrum antibiotics, which are modified when culture results become available.

Fever may be one of the earliest signs of rejection of the transplanted liver, and patients experiencing an acute rejection episode may complain of flulike symptoms. Therefore, the workup of any fever must include a close examination of the patient’s most recent liver function tests.

Liver transplantation patients do not appear to be more susceptible to common viral illnesses than other people. However, if the physical examination reveals oral or cutaneous lesions compatible with either herpes simplex or herpes zoster, the lesions should be cultured and acyclovir therapy instituted for at least 2 weeks. When the cause of the fever cannot be identified or the patient fails to respond to initial treatment, repeat cultures and serum titers for cytomegalovirus and Epstein-Barr virus should be obtained and compared to those obtained before transplantation to identify patients with acute viral infections. Biopsy specimens, especially of liver, skin, and lung, should be cultured and histologically examined for evidence of virus. Any patient with evidence of a severe viral infection should return to the transplantation center for treatment. Appropriate management includes careful reduction in the patient’s immunosuppression and treatment with antiviral agents.

Opportunistic infections may occur in the posttransplant patient and require prompt diagnosis and treatment. Pneumocystis carinii pneumonitis, rare in the early posttransplantation period, most commonly presents between 3 and 6 months after surgery. In most patients the presenting symptom is tachypnea. Physical examination and chest x-ray are usually normal initially, but arterial blood gases reveal moderate-to-severe hypoxemia. All patients with suspected pneumocystic pneumonia should be started on intravenous trimethoprim/ sulfamethoxazole and undergo immediate bronchoscopy with bronchoalveolar lavage to confirm the diagnosis. A dramatic worsening of the pulmonary status commonly occurs after treatment is initiated, and the patient may require intubation and mechanical ventilation. Early diagnosis and treatment usually result in a relatively brief, limited illness, whereas failure to make the diagnosis expediently may prove fatal.

Because a reduction in the dosage of immunosuppressive medications is essential, a transplant patient with a serious infection should return to the transplantation center for treatment of the infection. Too rapid or aggressive a reduction in the immunosuppressive regimen may put the patient at risk for acute rejection. Full immunosuppressive therapy should be reinstituted as soon as possible. If full immunosuppression is reinstituted before complete recovery, however, the infection may recur; on the other hand, failure to resume full immunosuppressive therapy at the appropriate time may lead to an acute rejection episode, which could result in loss of the transplanted liver.

Rejection

Despite advances in immunosuppression, rejection of the grafted liver is one of the most common indications for retransplantation. Acute rejection episodes may occur at any time after transplantation but become less frequent with time. Severe rejection episodes should be treated at the liver transplant center, but mild rejection episodes usually can be handled by the patient’s physician in consultation with the transplant surgeons.

After transplantation, the follow-up of the patient may continue at the transplantation center or may be done by the patient’s physician. Initially, routine blood work is performed 3 times/week, including a complete blood count with platelet count, electrolytes, blood urea nitrogen, creatinine, aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transpeptidase, alkaline phosphatase, total and direct bilirubin, and a cyclosporine trough level. If the patient remains stable, the frequency of routine blood work may be decreased to once or twice a month by 6 months after transplantation.

Most acute rejection episodes that occur in the late postoperative period are due to either too rapid a reduction in immunosuppressive drugs or a decreased cyclosporine level. The cyclosporine level depends on absorption from the small intestine and is affected by vomiting, diarrhea, and interaction with other drugs taken by the patient, e.g., phenytoin (Dilantin), ketoconazole, and rifampin. Gastroenteritis and diarrheal illnesses may be associated with a rapid fall in the patient’s cyclosporine level and may result in a severe rejection episode. Therefore, these patients may require hospitalization for the administration of intravenous cyclosporine and corticosteroids until the gastrointestinal function returns to normal.

Drug interactions that may affect cyclosporine levels also should be closely monitored. Patients with mild rejection episodes may be entirely asymptomatic or may have flulike symptoms. Such episodes are generally diagnosed by a slight elevation in any of the liver chemistry tests; after consultation with the transplant surgeons, they are usually treated with a single 500- to 1,000-mg bolus of methylprednisolone or with a short course (usually 5 days) of an increased dosage of oral prednisone. If the liver chemistry tests improve, nothing else may be required except a temporary increase in the frequency of laboratory tests.

Patients who fail to respond to steroid therapy or respond only temporarily should be returned to the transplant center for additional investigation and treatment of the suspected rejection episode. The workup includes a liver biopsy and an ultrasound study of the biliary tract to rule out obstruction, and Doppler ultrasound to ascertain the patency of the hepatic artery and portal vein. The liver biopsy may differentiate rejection from cholangitis, hepatitis, and ischemic injury, all of which may clinically mimic rejection. Because therapy for most of these disorders is vastly different from treatment of acute rejection, making an accurate and prompt diagnosis is essential.

Treatment of biopsy-confirmed rejection is initiated with a short course of high-dose steroids. Patients who fail to respond to this therapy are usually given a 10- to 14-day course of either antilymphocyte globulin or the monoclonal antibody OKT3. Repeat liver biopsy to confirm continued rejection and to rule out the other diagnoses should be performed if liver chemistry tests do not improve after a course of either of these drugs. Patients in whom rejection is confirmed should be treated with whichever therapy they have not yet received. Cytomegalovirus hepatitis may develop during the antirejection therapy. A liver biopsy is necessary to make this diagnosis so that appropriate antiviral therapy may be initiated.

If repeat biopsy reveals a severely damaged liver secondary to rejection, additional antirejection therapy is not administered and the patient is considered at high priority for retransplantation. Retransplantation should be considered for any patient who continues to demonstrate severe liver dysfunction despite adequate therapy for rejection.

Chronic rejection, in contrast to acute rejection, often fails to respond to any form of antirejection therapy. It is a more indolent process, characterized by a gradual, progressive, and unrelenting rise in the patient’s liver chemistry tests. This form of rejection may occur at any time after transplantation, and most of these patients eventually require retransplantation. Approximately 20% of all liver transplantation patients require retransplantation. The 1-year survival rate after retransplantation is approximately 50%.

Immunosuppression

Most transplant centers use similar immunosuppression protocols. The primary immunosuppressive agents currently used are cyclosporine and corticosteroids.

Corticosteroids

Adults receive 1,000 mg of methylprednisolone intravenously after revascularization of the donor liver. The dosage of methylprednisolone is tapered rapidly over the first 6 days by 40 mg/day until a baseline of 20 mg/day is reached. By day 6, most patients are able to tolerate oral medications, and prednisone 20 mg/day is begun. Most adult patients are discharged with this dosage of prednisone; depending on the frequency and severity of rejection episodes, the dosage is reduced in 2.5 mg increments in the first year until a baseline of 5 to 10 mg is reached in adult patients.

Cyclosporine and Tacrilumus

Dose. Cyclosporine is given as a single dose (2 mg/kg intravenous) before the start of the transplantation procedure, and the next dose is given immediately postoperatively when the patient is in the intensive care unit. If urinary output is adequate; a dose of 2 mg/kg is administered q8h. The frequency of the cyclosporine dose of 2 mg/kg may be reduced to twice daily in patients with marginal urinary output or with prior evidence of renal dysfunction.

Oral cyclosporine is initiated at a dosage of 10 mg/kg twice daily as soon as adequate gastrointestinal function has returned. When oral cyclosporine therapy is begun, the intravenous dose of cyclosporine is gradually reduced and eventually eliminated. All additional adjustments in dosage are based on daily cyclosporine trough levels. A cyclosporine level of 1,000 ng/dl by radioimmunoassay is accepted as ideal. The intestinal absorption of cyclosporine tends to be erratic, and the maintenance of stable blood levels is sometimes difficult. The cyclosporine level is maintained at a level that is proportionately lower than 1000 ng/dl if toxicity develops.

In patients in whom cyclosporine is not well tolerated, it may be necessary to add azathioprine 1.5 to 2.5 mg/kg daily to ensure adequate immunosuppression. After a stable course of several months, the dosage of cyclosporine may be reduced gradually to obtain a blood level of 500 to 800 ng/dl by 1 year after transplantation. During the late postoperative period, it is difficult to predict how much the dosages of immunosuppressive medications can be lowered without causing an acute rejection episode. However, doses should be maintained at as low a level as possible, because most side effects of immunosuppressive drugs are dose related. Except for the immunosuppressive regimen, which is usually managed indefinitely by the transplant surgeon, care is resumed by the referring physician when the patient returns home.

Side effects

The most common side effects directly related to cyclosporine are hypertension, nephrotoxicity, hepatotoxicity, hirsutism, gum hyperplasia, and a fine motor tremor.

Hypertension

The hypertension may be quite severe initially but becomes less severe during the first year after transplantation. Often the referring physician is left with the task of gradually reducing the patient’s antihypertensive medications during the first year after transplantation.

Nephrotoxicity

Some degree of nephrotoxicity is experienced by most patients taking cyclosporine, but in most cases it is not clinically significant. During the early postoperative period, some degree of nephrotoxicity is tolerated because the patient is most vulnerable to severe rejection episodes during this time. This nephrotoxicity is usually reversible when the dosage of cyclosporine is reduced. However, patients who require continued high dosages of cyclosporine because of repeated rejection episodes might have a significant deterioration in renal function after an otherwise successful liver transplantation. Azathioprine may be added as a third immunosuppressive drug in patients in whom severe nephrotoxicity develops so that the dosage of cyclosporine may be reduced. In most liver transplant patients, however, close monitoring of the patient’s renal function and cyclosporine trough levels allows the cyclosporine dosage to be adjusted appropriately both to prevent rejection and to avoid significant toxicity without the addition of a third drug.

Hepatotoxicity is common when the patient’s cyclosporine level is greater than 1200 ng/dl; therefore, it is rarely seen in patients who take a lower dosage of cyclosporine.

Hirsutism, tremor, and gum hyperplasia

These side effects are less serious but may be indicative of overimmunosuppression. If clinically possible, the transplant surgeon may reduce the dose of the immunosuppressants. To prevent serious gum disease, all liver transplant patients should receive frequent dental examinations. Excessive hair growth may require the use of a depilatory, especially in young female patients with body and facial hair.

Carcinogenesis

The incidence of cancer is significantly increased in immunosuppressed patients. The most common cancers are carcinoma of the cervix, vulva, perineum, shin, and lip; Kaposi’s sarcoma; and non-Hodgkin lymphoma. Most lymphomas appear to be related to infection with or reactivation of the Epstein-Barr virus. In most patients the presenting problem is fever, lymphadenopathy, gastrointestinal perforation, obstruction, or hemorrhage.

The treatment of these lymphomas is controversial. Some authorities believe that reduction of immunosuppression is sufficient, and others recommend chemotherapy or radiation therapy or both. All physicians involved in the long-term care of transplantation patients must be aware that these patients are at increased risk of the development of some cancers (especially lymphomas). Any patient suspected of having a lymphoma should be evaluated promptly and referred back to the transplant center.