A 48-year-old man comes to the emergency department due to fever and malaise for the past 2 days. He also complains of fatigue and lethargy but not nausea, vomiting, diarrhea, or dysuria. Medical history is significant for alcoholic cirrhosis, which was treated with an orthotopic liver transplant 10 weeks ago. Current medications include tacrolimus, mycophenolate mofetil, and low-dose prednisone. Temperature is 38.1 C (100.6 F), blood pressure is 125/82, pulse is 80/min, and respirations are 12/min. The patient is awake and oriented to person, place, and time. Scleral icterus is present. Cardiopulmonary examination is unremarkable. There is a well-healed surgical scar on the abdomen but no tenderness or distension. Laboratory results are as follows:
| Complete blood count | ||
| Hemoglobin | 12.9 g/dL | |
| Leukocytes | 6,000/mm3 | |
| Platelets | 345,000/mm3 | |
| Liver function studies | ||
| Total bilirubin | 3.2 mg/dL | |
| Alkaline phosphatase | 378 U/L | |
| Aspartate aminotransferase (SGOT) | 345 U/L | |
| Alanine aminotransferase (SGPT) | 473 U/L | |
A liver biopsy shows inflammatory infiltration of the portal tracts consisting of lymphocytes, eosinophils, and neutrophils. Interlobular bile duct destruction and prominent endotheliitis are both present. Which of the following is the best next step in management?
This patient with a recent liver transplant who now has fevers, malaise, and liver function test (LFT) elevations exhibits histologic findings concerning for acute cellular rejection (ACR).
ACR usually occurs within the first 3 months after transplant and results from the patient's own immune system targeting the liver allograft. Although some patients have fevers, malaise, and lethargy, many are completely asymptomatic. Therefore, in patients with a recent liver transplant, ACR is often suspected based upon the development of LFT abnormalities (eg, elevations in aminotransferases, bilirubin, and alkaline phosphatase). Definitive diagnosis is made by liver biopsy, which classically reveals:
The mainstay of therapy for ACR is increased immunosuppression, which typically reverses the rejection. Most patients are treated successfully with high-dose corticosteroids. In steroid-refractory cases, thymoglobulin, sirolimus, and other immunosuppressants can be used. Very rarely, if a patient fails to respond to any immunosuppressant, a repeat transplant is required.
(Choice B) The immunosuppressant mycophenolate is most commonly associated with cytopenias and gastrointestinal (eg, pain, vomiting, diarrhea) side effects. It is generally discontinued in patients with active infection due to the risk of neutropenia. This patient's findings do not suggest side effects of mycophenolate (eg, no cytopenia, no gastrointestinal symptoms), and his biopsy results are consistent with ACR.
(Choice C) Ursodeoxycholic acid is used in the treatment of primary biliary cholangitis (PBC). The classic histologic finding in PBC is a florid duct lesion, defined as inflammation limited to the bile duct. Endotheliitis and mixed-inflammatory infiltration of the portal tract are not expected in PBC.
(Choice D) Calcineurin inhibitors (eg, tacrolimus) are associated with acute renal injury, but significant hepatic injury is rare. Dose reduction is not indicated and would likely worsen the ACR in this patient.
(Choice E) Metronidazole is commonly used to treat intraabdominal abscesses or other infections that can occur in the posttransplant period. Such an infection would present with fever and, potentially, transaminase elevations; however, leukocytosis is expected and the infection would not explain this patient's histologic findings.
Educational objective:
Acute cellular rejection typically occurs within the first 3 months after liver transplant and can present with fevers, malaise, and a rise in aminotransferases, bilirubin, and alkaline phosphatase. Liver biopsy is diagnostic, demonstrating mixed inflammatory infiltration of the portal tracts, interlobular bile duct destruction, and endotheliitis. Most patients can be treated successfully with high-dose corticosteroids.