A 48-year-old man, eight months after orthotopic liver transplantation, presents with insidious onset of pruritus, worsening jaundice, and dark urine. Over the last two weeks, despite escalation of immunosuppression with high-dose corticosteroids for suspected rejection, his liver function tests have continued to deteriorate. Laboratory results reveal total bilirubin 18.5 mg/dL (baseline 1.2), alkaline phosphatase 450 U/L (baseline 90), AST 80 U/L, and ALT 75 U/L. A liver biopsy demonstrates loss of intrahepatic bile ducts in more than 50% of portal tracts. Based on these findings, which pathophysiological process best explains his condition?

A 62-year-old man, three years after orthotopic liver transplantation for autoimmune hepatitis, is admitted to the ICU for progressive graft dysfunction. He is mechanically ventilated on assist-control ventilation for acute respiratory failure and requires norepinephrine 0.1 µg/kg/min via a central line to maintain MAP ≥65 mm Hg. His maintenance immunosuppression consists of tacrolimus (target trough 5–8 ng/mL), mycophenolate mofetil 500 mg twice daily, and prednisone 5 mg daily. Liver biopsy shows acute cellular rejection with significant portal and lobular inflammation. Laboratory values: total bilirubin 12.5 mg/dL, direct bilirubin 9.8 mg/dL, AST 850 U/L, ALT 920 U/L. What is the MOST appropriate initial management strategy?

A 48-year-old patient, 3 months after bilateral lung transplantation, presents with progressive dyspnea and dry cough. Surveillance transbronchial biopsy demonstrates grade A2 acute cellular rejection. Baseline FEV1 was 2.5 L (95% predicted); after a 3-day pulse of methylprednisolone 10 mg/kg/day, repeat spirometry one week later shows FEV1 2.45 L (93% predicted) with persistent symptoms. What is the most appropriate next step in management?

A 48-year-old man, 8 months after liver transplantation, is admitted to the ICU with progressive jaundice and fatigue. He is intubated for hepatic encephalopathy and requires vasopressor support via a central venous catheter. Over the past week, his total bilirubin has risen from 3.2 to 12.8 mg/dL, alkaline phosphatase from 180 to 450 U/L, and gamma-glutamyl transpeptidase from 250 to 780 U/L. AST is 85 U/L and ALT is 92 U/L. He is afebrile and denies chills. His immunosuppression includes tacrolimus and mycophenolate, with tacrolimus levels consistently within target range. A liver biopsy is pending. Which of the following is the MOST likely diagnosis?

A 55-year-old man, 6 months after orthotopic liver transplantation, presents with two weeks of progressive jaundice and pruritus. His immunosuppression consists of tacrolimus and mycophenolate mofetil. Laboratory studies show total bilirubin 12.5 mg/dL (baseline 0.8), alkaline phosphatase 450 U/L (baseline 90), gamma-glutamyl transpeptidase 380 U/L (baseline 50), AST 65 U/L, and ALT 70 U/L. A liver biopsy demonstrates significant loss of intrahepatic bile ducts in the portal tracts. Which of the following is the most likely diagnosis?

A 45-year-old man, 6 months after bilateral lung transplantation for pulmonary fibrosis, is admitted to the ICU with 48 hours of worsening dyspnea and hypoxemia. He is on volume-control mechanical ventilation (FiO₂ 0.6, PEEP 8 cm H₂O). Vital signs: T 37.2 °C, HR 102 bpm, BP 118/72 mm Hg, RR 22 breaths/min. Laboratory studies: WBC 7.5 ×10³/µL, CRP 2 mg/L (normal <5), Tacrolimus trough 8 ng/mL. Chest X-ray shows diffuse interstitial infiltrates without focal consolidation; blood and endotracheal cultures are pending. Pulmonary function testing the prior week showed a 30% drop in FEV₁ from baseline. A bronchoscopy with transbronchial biopsy is planned today. Which of the following is the most appropriate initial pharmacologic intervention?

A 48-year-old man, 3 months after bilateral lung transplantation, presents with a significant decline in FEV₁ on routine pulmonary function testing. Transbronchial biopsy reveals moderate acute cellular rejection (Grade A2). His maintenance immunosuppression includes tacrolimus (target trough 8–12 ng/mL), mycophenolate mofetil, and prednisone 5 mg daily. Which of the following is the most appropriate initial management for his acute cellular rejection?

A 55-year-old man presents to the pulmonary telemetry unit 6 months after bilateral lung transplantation with 5 days of progressive dyspnea and a persistent dry cough. His maintenance immunosuppression consists of tacrolimus (goal trough 8–12 ng/mL), mycophenolate mofetil 1 g twice daily, and prednisone 5 mg daily. On examination, temperature is 37.8 °C, heart rate 100 bpm, blood pressure 128/78 mm Hg, respiratory rate 22/min, and SpO₂ is 91% on 3 L nasal cannula. His forced expiratory volume in 1 second (FEV₁) has declined from a baseline of 2.5 L (80% predicted) to 2.0 L (64% predicted), representing a 20% drop. Chest radiograph shows no new infiltrates. Transbronchial biopsy performed yesterday confirmed grade A2 acute cellular rejection. He completed a 3-day course of pulse methylprednisolone (500 mg IV daily) with minimal symptomatic or spirometric improvement. Which of the following is the most appropriate next step in management?

A 48-year-old man, 6 months after orthotopic liver transplantation, is intubated on assist-control ventilation and receiving norepinephrine for hemodynamic support. Over 24 hours, his total bilirubin has risen to 12.5 mg/dL, AST to 450 U/L, ALT to 520 U/L, and alkaline phosphatase to 300 U/L. A liver biopsy confirms moderate acute cellular rejection. His tacrolimus trough level from yesterday is 6.2 ng/mL (target 8–10 ng/mL), and he has gained 10 kg in 48 hours from third-spacing. What is the most appropriate initial management?

A 48-year-old man, 6 months after orthotopic liver transplant for primary sclerosing cholangitis, is admitted to the ICU with acute liver dysfunction (AST 350 U/L, ALT 420 U/L, total bilirubin 12.5 mg/dL, INR 2.5) and new-onset acute kidney injury requiring continuous venovenous hemodiafiltration (CVVHDF) at 20 mL/kg/h. He is intubated on assist-control ventilation and on norepinephrine 0.1 µg/kg/min via central line. His maintenance immunosuppression is tacrolimus 5 mg PO every 12 hours (last dose given at 10:00 PM last night). He was started on ciprofloxacin 400 mg IV q12h 48 hours ago for suspected cholangitis. This morning’s tacrolimus trough is 28 ng/mL (target 5–10 ng/mL). Which of the following is the most appropriate initial action regarding his tacrolimus regimen?