Plasma biomarkers to study mechanisms of liver injury in patients with hypoxic hepatitis.

BACKGROUND & AIMS: Hypoxic hepatitis is a clinical condition precipitated by prolonged periods of oxygen deprivation to the liver. It can have several underlying causes. Despite its prevalence in critically ill patients, which can reach upwards of 10%, very little is known about the mechanisms of injury. Thus, we set out to measure previously identified circulating biomarkers in an attempt to describe mechanisms of injury following hypoxic hepatitis. METHODS: Plasma from patients diagnosed with hypoxic hepatitis was collected for this study. Biomarkers of hepatocellular injury, mitochondrial damage and cell death were measured. These results were compared against results obtained from well-characterized acetaminophen overdose patients. RESULTS: At peak injury, ALT measured 4082±606 U/L and gradually decreased over 5 days, corresponding to the clinically observed pattern of hypoxic hepatitis. Levels of GDH showed a similar pattern, but neither ALT nor GDH were significantly higher in these patients than in acetaminophen patients. Plasma levels of DNA fragments mimicked hepatocellular injury as measured by ALT and miRNA-122. Interestingly, we found a significant increase in caspase-cleaved cytokeratin-18; however, the full-length form greatly exceeded the cleaved form at the time of maximum injury (45837±12085 vs 2528±1074 U/L). We also found an increase in acHMGB1 at later time points indicating a possible role of inflammation, but cytokine levels at these times were actually decreased relative to early time points. CONCLUSIONS: The mechanism of injury following hypoxic hepatitis involves mitochondrial damage and DNA fragmentation. Importantly, necrosis, rather than apoptosis, is the main mode of cell death.

Green neutrophil and monocyte inclusions - time to acknowledge and report.

Bright green inclusions in neutrophils have been reported as a sign of impending patient death. Here we report a series of 20 patients in whom green inclusions were identified in neutrophils or monocytes. Thirteen (65%) of the patients died within days of the detection of the inclusions. A common feature to almost all patients was ischaemic or hypoxic hepatitis which, in fatal cases, was associated with lactic acidosis. Light and electron microscopy indicated that the inclusions were lipid-rich, probably derived from lipofuscin-like material released from necrotic liver parenchymal cells. The majority of patients were known to be seriously ill at the time of detection of neutrophil inclusions. We recommend that the detection of green inclusions, which we refer to as 'critical green inclusions', is acknowledged and reported by laboratories and correlated with clinical findings.

Incidence of hypoxic hepatitis in patients with cardiogenic shock and association with mortality.

AIMS: Shock of any cause leads to end-organ damage due to ischaemia, especially in perfusion-sensitive organs such as the liver. In septic shock, hypoxic hepatitis (S-HH) is defined as the 20-fold increase of the upper normal limit of aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) and is associated with a mortality of up to 60%. However, as pathophysiology, dynamics, and treatment differ between septic and cardiogenic shock (CS), the S-HH definition may not be suitable for CS. Therefore, we aim to evaluate if the S-HH definition is applicable in CS patients. METHODS AND RESULTS: This analysis was based on a registry of all-comer CS patients treated between 2009 and 2019 at a tertiary care centre with exclusion of minors and patients without all necessary ASAT and ALAT values. N = 698. During in-hospital follow-up, 386 (55.3%) patients died. The S-HH was not significantly associated with in-hospital mortality in CS patients. To define HH among patients with CS (C-HH), optimal cut-off values were found to be ≥1.34-fold increase for ASAT and ≥1.51-fold increase for ALAT in serial measurements. The incidence of C-HH was 254/698 patients (36%) and C-HH showed a strong association with in-hospital mortality (odds ratio 2.36, 95% confidence interval: 1.61, 3.49). CONCLUSION: The C-HH is a frequent and relevant comorbidity in patients with CS, although its definition varies from the established definition of HH in patients with septic shock. As C-HH contributed to excess mortality risk, these findings emphasize the need for further investigation of therapies reducing the occurrence of C-HH and also improving the associated outcome.

Ischaemic hepatitis precipitated by recurrent episodes of atrial fibrillation.

We report a case of ischaemic hepatitis associated with recurrent fast atrial fibrillation (AF) episodes in a 59-year-old male who presented with shortness of breath, nausea and vomiting. The patient had a history of ischaemic cardiomyopathy. An emergency electrocardiogram showed fast AF with a ventricular rate of 190 min(-1). The aspartate aminotransferase (AST) level was 2222Ul(-1), alanine aminotransferase (ALT) was 1255Ul(-1), lactate dehydrogenase (LDH) was 1842Ul(-1) and serum creatinine was 150 µmoll(-1). An ultrasound of the abdomen showed an enlarged liver with hypoechoic lesions. The patient received digoxin. In the next few days, while liver enzymes and serum creatinine started to return to normal levels, the patient had two attacks of fast AF, each associated with elevated liver enzymes and a concomitant rise in serum creatinine. The patient was transferred to the intensive care unit to improve control of his AF, after which his liver enzymes and renal function gradually returned to normal.

Acute Liver Impairment in a Young, Healthy Athlete: Hypoxic Hepatitis and Rhabdomyolysis following Heat Stroke.

Any process that substantially diminishes arterial blood flow or arterial oxygen content to the liver can result in hypoxic (ischaemic) hepatitis. 90% of hypoxic hepatitis occurs in unstable patients in intensive care units with haemodynamic failure secondary to heart failure, respiratory failure and toxic shock. The rate of in-hospital mortality in hypoxic hepatitis is very high with studies recording mortalities of 61.5%. It tends to be very uncommon in healthy, young patients with no underlying medical problems. We report here the case of a young healthy athlete who developed heat stroke associated with rhabdomyolysis and hypoxic hepatitis while he was running the final stages of a marathon. The patient required intensive care admission and inotropic support for a few hours after he was admitted with heat stroke. He underwent a rapid recovery after he was resuscitated with fluids. N-acetyl cysteine was also given during the acute stage of the hepatitis. This case highlights an uncommon case of hypoxic hepatitis in a young, healthy patient secondary to hypotension and heat stroke. Inotropic support might have precipitated the hypoxic hepatitis in this young patient.