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Table 9.22. Common causes of bacterial infection following liver transplantation

1. Line sepsis

2. Infected peritoneal fluid

3. Pneumonia

4. Intra-abdominal abscess

5. Biliary anastomotic leak

6. Cholangitis secondary to biliary tract obstruction

7. Urinary tract infection

Table 9.23. Frequency of outpatient visits and laboratory investigations

Outpatient Visits

0 - 4 weeks Twice weekly

5 - 8 weeks Weekly

9 - 12 weeks Every other week

3 - 6 months Monthly

6 - 9 months Every 2 months 9 months - 1 year Every 3 months After 6 months, patients are returned to their referring physician.

Laboratory Investigations

1 - 2 months Twice weekly

2 - 3 months Weekly

3 - 6 months Every 2-3 weeks 6 - 12 months Monthly

12 - 18 months Every 2 months

18 - 24 months Every 3 months

Over 2 years Every 6 months and, therefore, require readmission. These reactions can be mild consisting of fever, diarrhea, and general feeling of malaise with myalgias. Alternatively, OKT3 treatment can be associated with violent reactions consisting of shaking chills, dyspnea, pulmonary edema requiring intubation especially in patients who are volume overloaded, and other manifestations of cytokine release.

ATG administration requires a central venous catheter and does not tend to be associated with overt cytokine release syndrome. When anti-lymphocyte therapy is used, ganciclovir prophylaxis intravenously administered concomitantly has been associated with an decreased incidence of CMV infection. More recently, treatment with high-dose Prograf has been used to reverse acute cellular rejection.

If the biopsy does not reveal the cause for elevation in liver function tests, visualization of the biliary tree is imperative, in order to rule out obstruction. If a T-tube was used, a T-tube cholangiogram can be obtained in order to visualize the biliary tree even in the absence of a dilated biliary duct by ultrasound evaluation. Some centers use cystic duct stents and these also can be injected with radiopaque material in an attempt to visualize the biliary tree. If a T-tube or cystic duct stent is not used, visualization of the bilary tree requires ERCP for both diagnosis and intervention if necessary.

On occasion, despite these diagnostic maneuvers, the reason for elevation of liver function tests remains elusive. In the case of recurrent hepatitis C, the biopsy can be misleadingly normal or show the occasional 'Councilman Body' or apoptosis of hepatocytes despite significant elevations in liver function tests. In these cases, conservative management and close observation will eventually reveal the cause for liver function tests abnormality. Not infrequently, repeat biopsies are required before a diagnosis can be established.

The use of routine protocol biopsies is controversial. Although some centers use protocol biopsies in every patient, the occasional findings of histologic rejection in a patient with normal liver function tests and no clinical evidence for rejection can pose a management dilemma. Consequently, most transplant centers have abandoned the use of routine protocol biopsies and rely on either laboratory or clinical abnormalities as a stimulus for liver biopsy and other investigations.

In addition to abnormalities in liver function tests, patients are encouraged to report any potential signs of infection such as fever or chills. If a patient experiences a fever, this is quickly investigated with pancultures for bacterial, fungal, g and viral infections including CMV. A chest x-ray is also part of the routine fever workup and, if there is an indwelling central venous catheter, retrograde cultures are also used. Antibiotic therapy is instituted empirically in the immunosuppressed patient while awaiting the results of the cultures especially if the patient appears septic or toxic. Low-grade fevers can be investigated and managed in an outpatient setting, whereas high fevers, especially in a toxic patient, require urgent readmission to the hospital and may require more thorough investigation such as a CT scan of the abdomen to rule out intra-abdominal sepsis.

Side effects of the immunosuppressive agents need to be considered. The most common drugs which result in significant side effects are the calcineurin inhibitors. These side effects include nephrotoxicity, neurotoxicity, hyperkalemia, hy-pomagnesemia, hypertension, and tremor. Prograf has the additional side effect of inducing new onset diabetes and is more prone to result in GI symptoms of abdominal pain and diarrhea. Both drugs are metabolized through the cytochrome P450 system and, therefore, drugs which increase the effective level include erythromycin and antifungal agents ketoconazole, fluconazole, and itraconazole, as well as calcium channel blockers such as diltiazem, verapamil, and nicardipine. Drugs which decrease levels are primarily the anti-seizure medications in general (pheny-toin, phenobarbital, and carbamazepine) and most of the anti-tuberculosis medications such as isoniazid, rifampin, and rifabutin. Twelve-hour serum trough levels are measured and monitored closely and the dosage of these agents is guided by these levels.

Imuran and Cellcept primarily cause leukopenia and, when used, these agents must be adjusted according to the white blood cell count. If the white blood cell count is below 3,000, as a rule, these agents should be held. The use of GCSF and GM-CSF have made leukopenia in these patients much easier to manage. The use of these agents has not resulted in increased rejection.

In patients undergoing transplantation for hepatitis B-related chronic liver disease, human hepatitis immunoglobulin (HBIg) preparations are administered in high doses during the perioperative period. Typically, 10,000 U are administered intravenously during the anhepatic phase and then daily for six to seven days. Titers of antibody are measured and are maintained above 300. At one week following transplantation, the HBIg are administered intravenously weekly at first and then monthly. Eventually HBIg can be administered intramuscularly at monthly intervals always maintaining titers above 300 IU (Table 9.24). In addition, antiviral agents have been used, particularly in patients with HBV DNA posi-tivity prior to transplant. DNA positivity is considered a contraindication to transplant unless patients can be rendered DNA negative with the use of antivirals such as lamivudine. In patients who are rendered HBV DNA negative with lamivudine, over time, lamivudine-resistant mutants arise and, therefore, the combination of HBIg and lamivudine is thought to provide better recurrence prophylaxis than either agent alone. Lamivudine is continued in the posttransplant period and the optimal combination regimen for HBIg and lamivudine in the long term remains to be worked out.

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