Allograft dysfunction

Liver allograft dysfunction is relatively common during the initial hospitalization (80percent) following transplantation, but it is relatively uncommon as an outpatient (20 percent). The same causes and investigations are required for both clinical situations. Causes of dysfunction which must be investigated promptly include acute rejection, chronic rejection, hepatitis (either A, B, or C), bile duct stricture or leak, systemic infection, cyclosporine hepatotoxicity, late portal vein or hepatic artery thrombosis, and drug toxicity. It is usually necessary to investigate allograft dysfunction occurring within the first three months following transplantation in the inpatient setting.

The possibility of systemic source of sepsis is usually the first area investigated. Liver transplant patients do not tolerate untreated or inadequately treated sepsis very well, or for very long. These patients will show the cardinal signs of bacterial infection such as fever, tachycardia, malaise, and localized pain. Furthermore, they usually have elevated white blood cell counts, and elevated numbers of immature granulocytes (bands) in their peripheral blood smear.  Exceptions include viral infection (herpes, and cytomegalovirus), unusual opportunistic infections such as Legionella or Pneumocystis carinii, and patients with preexisting hypersplenism.(see "Fever and Sepsis" for exact step-wise investigation).

Biliary complications within the first three months can usually be defined by a t-tube cholangiogram. If the t-tube is not present, the patient may undergo an abdominal ultrasound. This test is noninvasive and helpful if positive for biliary dilation or a fluid collection (i.e., if a bile leak is suspected). In contrast, this test is not sensitive (5 percent positivity in our hands) in defining biliary strictures or obstruction. Therefore, in patients without a t-tube, endoscopic retrograde cholangiopancreatography or percutaneous transhepatic cholangiogram is required to exclude this cause of liver allograft dysfunction, if the ultrasound is normal.

Cyclosporine hepatotoxicity has been well described in renal transplantation patient series. These patients usually have a high cyclosporine blood level (i.e. > 250 ng/ml, whole blood, 12 hour trough, HPLC), and usually have other evidence of cyclosporine toxicity (i.e. headaches, tremors , hypertension, acidosis, and hyperkalemia). We have uncommonly seen this as a cause of allograft dysfunction.  This low incidence in our patients may be due to our insistence on a "low dose" regime. Establishing this as a cause of hepatic allograft dysfunction requires exclusion of more common causes of dysfunction followed by resolution of the dysfunction with lower cyclosporine dosages. We have not been able to find any reliable histologic allograft biopsy findings which diagnoses this clinical phenomenon.

Acute rejection is very uncommon during the late postoperative period (after three months posttransplantation). It usually occurs with either medication noncompliance, or with episodes of malabsorption of immunosuppressive drugs. A careful history to document episodes of noncompliance and/or episodes of diarrhea or vomiting should be obtained. We recommend that the recipient immediately contact our service or their appropriate referring physician if either of these events occur. With persistent (i.e, more than one day of diarrhea or vomiting,) they should usually be admitted to the hospital to receive cyclosporine and Solumedrol intravenously to assure therapeutic immunosuppression. For appropriate intravenous dosages see, "Immunosuppression". The usual histologic findings include increasing numbers of eosinophils and lymphocytes within the portal tracts, and uniform "spill-out" of these inflammatory cells from the portal tracts into the lobule of the biopsy. A comparison with previous protocol biopsies improves the accuracy of this diagnosis. The treatment is high dose corticosteroids (i.e., 17.5 mg/kg Solumedrol intravenously as a single dose on two consecutive days).

Chronic rejection is also very uncommon during the late postoperative period. The predisposing causes of this condition are unknown and perplexing. This problem usually arises within the first six months following transplantation, and presents as a slow but progressive increase in bilirubin and alkaline phosphatase. The liver allograft biopsy confirms the diagnosis with findings of reduced or absent bile ductules, fibrosis of the portal tract and "thickening" of the arterioles. The only treatment for this condition is retransplantation.

Although all prescription drugs may cause cholestasis by idiosyncratic reaction in normal and transplanted livers, certain drugs have higher propensity to cause cholestasis. These drugs include: Methyl testosterone, Methimazole, Erythromycin, Norethynodrel with mestranol, Chlorpropamide, Chlorpromazine, Tetracycline, Diphenylhydantoin, Alpha-Methyldopa, Isoniazid, Chlorothiazide, and Oxyphenisatin. When all other causes of dysfunction are excluded, the suspected drug should be discontinued and liver function tests monitored for improvement.

Vascular anastomotic thrombosis more than 12 weeks after liver transplantation is extremely uncommon. These abnormalities can be diagnosed by the use of Doppler ultrasound, and confirmed by selective aortic angiography and vena cavography. In contrast to biliary complications sonography is highly sensitive and specific for these vascular complications.

Infections with hepatitis virus are relatively uncommon and usually self-limited. The occurrence of Hepatitis A,B, or C can usually be rapidly determined by the appropriate serology. Usually no specific intervention is required.

In summary, a routine evaluation for allograft dysfunction should include:

1. Thorough history and physical

2. Sepsis investigation (see Fever and Sepsis)

3. Ultrasound of liver allograft for vascular patency of all vessels (i.e., hepatic artery, portal vein, hepatic veins, and abdominal vena cava)

4. Cholangiogram (percutaneous transhepatic cholangiogram if no t-tube is in place)

5. Liver allograft biopsy with comparison to past protocol biopsies

6. Whole blood 12 hour trough Cyclosporine level (HPLC)

7. Serology for Hepatitis A,B, and C, and for Herpes and CMV

8. Review possible drug interactions which might induce hepatic allograft dysfunction.