Alicia Martin,Matthew Smale,Arthur Grillas
Deranged Liver Function in a Critically Ill Patient With COVID-19: A Cautionary Case
COVID-19,Cholangitis,Cholangiopathy
Deranged Liver Function in a Critically Ill Patient With COVID-19: A Cautionary Case

Question: A 29-year-old critically ill white man with COVID-19 was referred to our consulting service for investigation of deranged liver function tests (LFTs). He had no past medical history or medications and was a nonsmoker and abstinent from alcohol and recreational drugs. He was double vaccinated with Astra Zeneca mRNA 9 and 10 months before presentation. On days 1 to 4 of his illness, he experienced myalgias, fatigue, and chills without respiratory symptoms. On day 5, he developed abdominal pain, vomiting, and diarrhea. Confusion prompted presentation via ambulance to our emergency department, where he had a tonic-clonic seizure that self-terminated. A computed tomographic (CT) image from brain to pelvis revealed only ground-glass changes in the lung apices, consistent with COVID-19 pneumonitis. A provisional diagnosis of COVID-19 encephalitis was treated with intravenous (IV) ceftriaxone, aciclovir, and dexamethasone. His LFTs on day 5 of his illness (day 1 of admission) were unremarkable. Remdesivir was commenced and given for a total of 4 days. A cerebrospinal fluid sample via lumbar puncture showed 4 × 106/L mononuclear cells, 0 × 106/L polymorphs, high protein of 0.52 g/L (reference 0.15–0.45 g/L), and normal glucose of 4.2 mmol/L (reference 2.5–5.5 mmol/L). Bacterial and yeast cultures, as well as an extended viral panel from the cerebrospinal fluid, were unremarkable. He was intubated owing to agitation on day 2 of his admission, with vasopressor and inotropic support required. Magnetic resonance imaging of the brain demonstrated cortical hyper-intensity in the bilateral temporal lobes consistent with viral encephalitis. On day 5, he had a cardiac arrest requiring cardio-pulmonary resuscitation—this was attributed to a potassium of 6.7 mmol/L (reference 3.5–5.2 mmol). Also on day 5, he developed a transaminitis, with alkaline phosphatase (ALP) of 63 U/L (reference 30–110 U/L), gamma glutamyl transpeptidase (GGT) 31 U/L (reference 5–50 U/L), alanine transaminase (ALT) 187 U/L (reference <51 U/L), and aspartate transaminase (AST) 1051 U/L (reference <36 U/L), the latter of which peaked at 3813 U/L on day 6. His bilirubin, prothrombin time (PT) and activated partial thromboplastin time (APTT) were normal. This isolated AST rise was the first biochemical manifestation of a COVID-19–associated myositis, complicated by compartment syndrome, rhabdomyolysis with a creatinine kinase peak of 230,000 U/L (45–250 U/L) and an acute kidney injury necessitating continuous renal replacement therapy (CRRT). Extensive right forearm and bilateral lower limb fasciotomies with muscle debridement were required on day 8. Given the cytokine storm effect and its related sequelae, and with toculizumab contraindicated because of concern for brain hemorrhage, a trial of plasmapheresis was commenced on day 9. By day 10, his transaminitis had greatly improved, with ALP of 24 U/L, GGT 5 U/L, ALT 58 U/L, and AST 264 U/L, still with normal bilirubin, PT, and APTT. He received plasmapheresis for several days, during which 4 further washouts and debridements of his limb wounds were required. He was successfully extubated on day 22 of his admission, having been intubated for a total of 19 days. Gastroenterology was consulted on day 37 of his admission for investigation of newly cholestatic LFTs. His CRRT had ceased 3 days earlier and he had no inotropic support. On review, he described right upper quadrant pain without nausea, vomiting, jaundice, or subjective fevers. On examination, he was oriented with a blood pressure of 115/75 mm Hg, heart rate 75 beats/min, oxygen saturation 96% on room air, and respiratory rate 15 breaths/min. He was febrile to 100.4°F and had right upper quadrant tenderness without features of cholecystitis clinically. His hemoglobin was 84 g/L (reference 130–180 g/L), white cell count 12.4 × 109/L (reference 3.5–11 × 109/L) with predominant neutrophilia, creatinine 335 μmol/L (reference 60–100 μmol/L), and urea 25.1 mmol/L (reference 3.5–8.0 mmol/L). His bilirubin was 16 μmol/L (reference 0–20 umol/L), ALP 946 U/L, GGT 1,169 U/L, ALT 119 U/L, and AST 148 U/L. His PT was 10.9 seconds (reference 9–13 s) and APTT 30.9 seconds (reference 25–37 s). Abdominal ultrasound revealed a thickened common bile duct (CBD) measuring 7 mm at the porta hepatis but no dilation of the intrahepatic ducts (Figure A). The gallbladder was contracted with a thickened wall of 5 mm and contained multiple tiny calculi (Figure B). Antibiotic therapy with IV amoxicillin and clavulanic acid was broadened to IV piperacillin-tazobactam. Endoscopic retrograde cholangiopancreatography (ERCP), performed with the patient off vasopressors but still febrile, revealed choledocholithiasis (sludge), treated with biliary sphincterotomy, balloon sweep, and placement of a 9-cm 10-F straight plastic biliary stent. A balloon occlusion cholangiogram was limited to the extra-hepatic system to prevent further sepsis and demonstrated a CBD free of filling defects (Figure C). Despite this, his LFTs progressively worsened to an ALP of 1806 U/L, GGT 1305 U/L, ALT 292 U/L, and AST 217 U/L, with bilirubin of 260 μmol/L. Although intermittent fevers persisted, he did not require further vasopressor or inotropic support. Abdominal ultrasound revealed intrahepatic duct dilation of 3.3 mm, with a patchy and heterogeneous appearance of the parenchyma (Figure D). Abdominal CT with IV contrast demonstrated dilated intrahepatic ducts with multiple low-density foci throughout the liver (Figure E). After removal of the biliary stent during repeated ERCP, balloon occlusion cholangiography revealed diffuse abnormalities of the second-order intrahepatic ducts with beading and loculation (Figure F). A full liver screen was unremarkable: specifically, alpha 1 antitrypsin of 3.5 g/L (reference 0.9–2.0 g/L), ceruloplasmin 0.6 g/L (reference 0.2–0.6 g/L); microsomal, smooth muscle, and liver-kidney antibodies negative, anti-nuclear antibodies (ANA) negative, extractable nuclear antigen antibody negative, hepatitis A immunoglobin M (IgM) negative and immunoglobulin G (IgG) positive, hepatitis B core antibody negative, hepatitis C antibody negative, cytomegalovirus IgM and IgG negative, Epstein-Barr virus IgM negative and IgG positive, human immunodeficiency virus antigen negative, IgG 18.6 g/L (reference 7.0–16.0 g/L), and specifically IgG subclass 4 0.53 g/L (reference 0.03–2.01 g/L), and iron studies with transferrin saturations 34.2% (reference 20%–52%) and ferritin 1397 μg/L (reference 30–400 μg/L) . Magnetic resonance cholangiopancreatography (MRCP) was completed on day 76 of his admission to reaffirm the diagnosis (Figure G). Liver biopsy (Figure H, I, J, and K) revealed bile duct epithelial damage, peripheral bile duct proliferation, edema, and inflammation, ultimately with concentric fibrosis of the larger ducts. The lobules were remarkable for both canalicular and hepatocellular cholestasis, surrounded by damaged hepatocytes. The latter were characterized by vacuolization, ballooning, and feathery degeneration suggesting bile infarcts. Hepatic architecture was preserved, without fibrosis. What is the diagnosis? See the Gastroenterology website (www.gastrojournal.org) for more information on submitting to Gastro Curbside Consult.

Our initial impression of the cholestatic LFTs after the first ERCP was a drug-induced liver injury, given that adequate drainage was achieved endoscopically and with the aforementioned antibiotics. The dilated biliary ducts on ultrasound and CT, however, suggested obstruction. Worse, the low-density foci raised concern for biloma. The results of the second and more extensive ERCP occlusion cholangiogram—beading and loculation—were then highly suggestive of sclerosing cholangitis. MRCP results strengthened this provisional diagnosis, showing extensive irregular intra-hepatic duct dilation and beading, as well as extra-hepatic dilation (Figure G). Potential etiologies of secondary sclerosing cholangitis (SSC) were considered within a multi-disciplinary forum that entailed gastroenterology, radiology, histopathology and infectious disease clinicians. Of the infectious etiologies, recurrent pyogenic or bacterial cholangitis was not a feature of the patient’s history, and AIDS cholangiopathy was excluded by means of serologic testing, leaving COVID-19 cholangiopathy the most likely infective etiology. Of the ischemic etiologies, critical illness–associated cholangiopathy (or ischemic cholangiopathy) were considered as a reasonable differential given his cardiac arrest and period of inotrope requirement. Systemic vasculitis was the only other feasible differential, although a negative vasculitic screening made this less likely. ERCP exposure was the only potential toxic etiology considered, but the chronology of the patient’s LFT derangement did not support this. Finally, a normal serum IgG4 of 0.53 g/L (reference 0.03–2.01 g/L) and lack of plasmacytic infiltrate on histo-pathologic examination excluded IgG4, and other immunologic etiologies also were considered to be unlikely. Ultimately, the etiology was favored to be COVID-19 cholangiopathy, with critical illness–associated cholangiopathy a reasonable second differential.

Reported cases of secondary sclerosing cholangitis in the context of COVID-19 are increasing in the literature. However, distinguishing between direct COVID-19 cholangiopathy and critical illness–associated cholangiopathy as an etiology can be difficult. The former manifests on average 118 days after COVID-19 diagnosis, and MRCP shows beading of the intrahepatic bile ducts in 92% of cases, as seen here. Unique histologic features include severe cholangiocyte injury and intrahepatic micro-angiopathy suggestive of direct hepatocyte injury from COVID-19. One explanation for this cholangiocyte injury may be the expression of angiotensin-converting enzyme 2 receptors in 59.7% of cholangiocyte clusters. Common risk factors of reported cases include multi-organ failure, admission to intensive care, and ventilation. In one case series, 5 of 12 patients were referred for liver transplantation for persistent jaundice, hepatic insufficiency, or recurrent bacterial cholangitis. Another case series followed 4 male patients: 2 required liver transplantation owing to refractory cholangitis (1 of whom died after transplantation), 1 died from hepatic hemorrhage, and 1 had not required transplantation at the time of writing.

Although the literature is currently limited to case reports, there is a clear trend toward either transplantation or death in patients with COVID-19 cholangiopathy. The present patient received a deceased-donor split liver transplant 249 days after his initial admission. His transplant operation was uncomplicated, and he was successfully extubated and weaned from vasopressors the following day with good graft function. He was discharged from hospital 13 days after transplantation. LFT 5 weeks after transplantation showed bilirubin of 12 umol/L, ALP 116 U/L, GGT 185 U/L, ALT 46 U/L, and AST 29 U/L. Renal function also remained normal with creatinine 82 μmol/L and urea 8.2 mmol/L. His immunosuppression regimen at the time of writing includes 3 mg tacrolimus twice daily and 20 mg prednisolone daily, with antimicrobial prophylaxis using 400 mg/80 mg sulfamethoxazole-trimethoprim thrice weekly and 500 mg valaciclovir twice daily. Diagnosis of this rare sequela may be delayed owing to its insidious onset and delayed consideration. Although an estimated 14% to 58% of patients hospitalized with COVID-19 demonstrate elevated transaminase levels, cholestatic derangement with hyper-bilirubinemia should prompt early consideration of secondary sclerosing cholangitis in these critically ill patients. This early consideration may be imperative to patient survival.