Markedly Elevated Liver Enzymes in a Young COVID-19 Positive Patient

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A 24-year-old man presented with malaise, severe abdominal pain, nausea, vomiting, and syncope. He had 2 years’ history of ulcerative colitis (UC), which was managed by infliximab. He stopped getting infliximab infusions for 7 months prior to presenting for UC flare a month earlier and was treated with steroid. In his prior admission for UC flare, he received Lovenox for DVT prophylaxis and tested negative for COVID-19. Abdominal computed tomography was consistent with UC flair, and liver was unremarkable. Laboratory results at current admission were significant for mixed metabolic and respiratory acidosis (pH 6.82, bicarbonate 10.2 mmol/L, and pCO2 67 mmHg), acute renal failure, and abnormal liver function tests including elevated alkaline phosphatase, gamma-glutamyl transferase (Table 1), and markedly elevated transaminase [alanine aminotransferase (ALT) 7699 IU/L, aspartate aminotransferase (AST) 11 911 IU/L], total bilirubin (4.9 mg/dL), and ammonia (>900 µmol/L). Coagulation tests showed prolonged partial thromboplastin time (57.8 s; reference range 25–38 s), elevated international normalized ratio (2.7; reference range 0.9–1.2), D-Dimer (>20), and decreased fibrinogen (68 mg/dL). COVID-19 and Epstein-Barr virus were positive by PCR. He did not receive vaccination for COVID-19. Electroencephalogram demonstrated a moderate to severe generalized encephalopathy. The patient had no known history of liver disease. Clinical differential diagnosis included ischemia, infection, and medication-induced injury. Toxicology tests were negative for acetaminophen, salicylate, ethanol, ethylene glycol, methanol, acetone, and isopropanol. Urine drug screen by immunoassay was negative for amphetamine/methamphetamine, barbiturate, benzodiazepine, cocaine metabolites, and opiates. En route to the emergency department, the patient was administered Narcan without improvement of the symptom. Viral hepatitis tests were negative for hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis E virus, and herpes simplex virus. Tests for antinuclear antibody, antismooth muscle antibody and antimitochondria antibody were all negative. Ultrasound showed portal vein thrombosis and patent hepatic arteries and veins. Computerized tomography showed nonocclusive thrombi within the portal vein, superior mesenteric vein, intrahepatic inferior vena cava, multiple peripheral hepatic veins and left iliac vein, and patent hepatic arteries. There was a moderate volume of ascites and no evidence of collaterals or splenomegaly. In addition to COVID-19 infection, his respiratory system was complicated with pulmonary aspergillosis with no evidence of invasive disease. He was treated with isavuconazole. For COVID-19, the patient received supportive care. Despite aggressive management and anticoagulant treatment with heparin sodium infusion, his liver function was not improving, and he underwent liver transplant 2 weeks after admission. Gross examination of the explanted liver identified vascular thrombi in multiple large vessels. Histologic sections showed variable degrees of ischemic-type changes in the liver parenchyma. In severely affected areas, hepatocyte necrosis and hemorrhage were present without significant portal or lobular inflammation (Fig. 1, A and B). Cholestasis was present with no apparent bile duct injury. Necrosis/infarction had a predominantly zone 3 distribution and extended to zone 2 focally. Macrovesicular steatosis and microvesicular steatosis were present in the viable hepatocytes with predominantly zone 3 distribution. Thrombus formation was identified in both portal veins and central veins, showing organizing thrombi, surface endothelization, and calcification (Fig. 1, C and D). Post-transplant his liver allograft started functioning immediately and liver function tests were normalized and remained stable during hospitalization. He was discharged 3 months after admission although his kidney function had not fully recovered and he required hemodialysis at an outpatient dialysis facility. (A)–(B), Hepatocytes necrosis and hemorrhage in zone 3 and zone 2, with a rim of viable periportal hepatocytes (arrow); (C), a portal tract with patent hepatic artery (middle arrow), bile duct (left arrow), and portal vein distended by a thrombus (right arrow). The thrombus shows focal calcification (inset); (D), a calcified thrombus in a terminal hepatic vein (arrow), with necrosis of surrounding hepatocytes and hemorrhage. Laboratory test results. Abbreviations: ALP, alkaline phosphatase; GGT, γ-glutamyl transpeptidase; pCo2, CO2 pressure; BUN, blood urea nitrogen; CBC, complete blood count; INR, international normalized ratio; EBV, Epstein-Barr virus; CRP, complement-reactive protein; BNP, B-type natriuretic peptide; CK, creatine kinase. Acute liver failure is a rare but life-threatening critical illness, and the incidence in the United States is fewer than 10 cases per million (1). Acute liver failure is defined as severe acute liver injury with clinical presentation including the presence of coagulopathy (international normalized ratio ≥ 1.5) and any grade of encephalopathy within 26 weeks of the first symptoms and no evidence of chronic liver disease, especially cirrhosis (2). This patient had an international normalized ratio of 2.7 with moderate to severe encephalopathy, consistent with the diagnosis of acute liver failure in the context of no prior history of chronic liver disease. Identifying the etiology of acute liver failure is not only critical for clinical therapy but is also an important factor of prognosis. Common etiology of acute liver failure includes drug-induced liver injury (e.g., acetaminophen-induced hepatotoxicity), autoimmune hepatitis, ischemic liver injury, viral infection, toxicity (e.g., mushroom poisoning), and infiltrating malignancy, with drug-induced liver injury as the leading cause in the United States (1). Infection by hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis E virus, and herpes simplex virus was excluded by negative viral screening tests in this case. Although serology for Epstein-Barr virus was positive, typical histologic features in Epstein-Barr virus hepatitis such as lymphocytic infiltrate in sinusoids and predominantly lymphocytic expansion of portal tracts are not present in the liver explant. Autoimmune hepatitis is unlikely given negative autoimmune antibodies. Liver injury can be broadly classified into 2 patterns: hepatocellular and cholestatic. The elevation of aminotransferases ALT and AST mainly reflects hepatocyte injury. ALT has a higher concentration in periportal hepatocyte (zone 1) and is a liver-specific marker. AST is also present in muscle, kidney, and brain. The magnitude of enzyme alteration can be classified into mild, moderate, and marked based on comparison to the upper reference limit (<5 times, 5–10times, and >10 times) (3). The elevation of alkaline phosphatase and γ-glutamyl transpeptidase are associated with cholestatic pattern of injury. In this patient, ALT and AST were over 100 times the upper limit of reference range, while alkaline phosphatase and γ-glutamyl transpeptidase were only mildly elevated, and this magnitude and pattern of enzyme elevation can be seen in both ischemic hepatitis and toxic injury such as acetaminophen-induced liver injury (4). A drug-screening test is critical in making a distinction between these 2 conditions. Common toxins and illicit drugs were ruled out by negative screening tests. Markedly elevated ALT/AST is consistently observed in ischemic hepatitis, and the presence of an acute elevation of aminotransferase levels to at least 20 times the upper limit is one of the criteria for the diagnosis of ischemic hepatitis (5). The liver is protected against hypoxia by multiple mechanisms, one of which is double-blood supply by the portal vein and hepatic artery. The liver receives 70% of its blood flow from the portal vein and 30% via the hepatic art

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