Hypoxic or Ischemic Hepatitis

The high metabolic activity of the liver and its complex vascular supply render it at risk of injury from hemodynamic insults, and “hypoxic” or “ischemic” hepatitis results from hepatocellular necrosis provoked by acute cellular hypoxia resulting from impaired hepatic oxygen delivery [2]. The prevalence of hypoxic hepatitis in hospital admissions is around 1/1000 but is probably at least an order of magnitude more common in ICU admissions. Diagnostic criteria vary but have included the triad of:

1. an appropriate clinical setting of cardiac, respiratory, or circulatory failure
   
2. an abrupt increase in serum transaminases reaching at least 20 times the upper limit of normal, and
   
3. exclusion other causes of acute liver cell necrosis, particularly severe viral or major drug‐induced liver injury (Figure 4.2a).

Major elevation of transaminases is usually of short duration and may be followed by coagulopathy, reflecting transient hepatic synthetic compromise. Significant jaundice follows in about 30% of patients and, if present, is associated with increased risk of complications and death [4]. Liver biopsy is seldom required or performed, but typically shows extensive centrilobular necrosis, reflecting the sensitivity of “zone 3” hepatocytes to ischemic insults.

Heart failure, respiratory failure, and septic shock are responsible for more than 90% of cases of hypoxic hepatitis, with these factors acting alone or in combination in individual patients (Figure 4.3). Compromise of cardiac output resulting from acute cardiac events, such as myocardial infarction, dysrhythmia, or pericardial tamponade, may reduce blood flow and oxygen delivery to the liver, with an important role now also recognized from passive congestion of the liver from right‐heart failure. The latter may occur in the setting of severe pulmonary disease, where concurrent hypoxemia may also contribute. Sepsis and the evoked inflammatory response play an important permissive role in the development of hypoxic hepatitis through the development of hepatic “dysoxia” and impairment of hepatic cellular respiratory function oxygen utilization and microcirculatory changes.

Effective management of hypoxic hepatitis depends on its early recognition and addressing the causative factors. In the ICU setting, this frequently involves assessment and monitoring of cardiac function through invasive or non‐invasive means. Electrocardiography and echocardiography are mandatory early diagnostic investigations. Prognosis is variable, depending on the trigger(s) for the development of hypoxic hepatitis, although death seldom results from liver failure alone, but rather from multiple organ failure from the underlying conditions responsible. Recognition of hypoxic hepatitis may be challenging, as its presence may be confounded by the absence of a classical “shock state.”

Drug‐Induced Acute Hepatocyte Necrosis

Sudden and extensive hepatocyte death that causes massive release of hepatocellular enzymes into the circulation may also result from drug‐induced liver injury. Although a number of drugs and toxins may be responsible (Figure 4.4), in the UK, United States, and Western Europe, paracetamol/acetaminophen‐induced hepatocyte necrosis, usually after overdose, is by far the most common cause. The pattern and magnitude of abnormalities of liver tests, particularly elevation of AST, closely mimics that seen hypoxic hepatitis and may be difficult to distinguish from it. Circumstantial evidence of overdose and/or detectable paracetamol in the blood may aid diagnosis, and its identification is clinically urgent, as there is a narrow time window for the maximal efficacy of the antidote N‐acetyl cysteine (NAC). However, the hepatic injury may not be apparent until paracetamol and its metabolites have become undetectable in blood and urine; thus, the absence of detectable levels of paracetamol or its metabolites do not preclude paracetamol toxicity. Some clinical risk factors may increase susceptibility to major paracetamol‐induced liver injury (Box 4.2). Given the very limited adverse effect profile of NAC, if there is clinical suspicion of paracetamol‐induced liver injury being responsible for or contributing to abnormal liver tests, there is little to be lost by its administration while confirmation is sought. If other drugs are suspected as being responsible for liver injury, their early withdrawal is key while alternative causes are excluded, and the severity of liver injury assessed (see Chapter 20).

Acute Viral Hepatitis

Globally, the most common case of gross hepatocellular blood test abnormalities in the critically ill is likely to be from severe acute viral hepatitis infections. Jaundice is often more prominent than in hypoxic hepatitis or acute drug‐induced hepatic necrosis. As detailed elsewhere in this volume, these infections include those from hepatitis A (HAV), hepatitis B (HBV), and hepatitis E (HEV) viruses. Other viruses that less commonly cause hepatitis include cytomegalovirus (CMV), herpes simplex virus (HSV), and Epstein–Barr virus (EBV), with a very large number of other infective causes described. The majority of acute hepatitis infections are likely to go unrecognized. If they are clinically apparent, infections usually resolve with supportive management alone, although in some instances targeted antiviral therapy is required. Virus‐specific serologic tests may be diagnostic and enable characterization of acute or more chronic infection, but assessment of liver injury severity uses more generic laboratory tests. as described below.

Hepatitis A and E are transmitted via the fecal–oral route and are common in developing countries or in travelers returned from endemic countries; symptomatic infection is uncommon and major liver injury is very rare. Acute hepatitis B infection is also usually asymptomatic and self‐resolves, but on rare occasions it may also present with liver failure. Reactivation of hepatitis B in the context of chemotherapy or B‐cell depleting immunosuppression is a potentially fatal event and may present many months after the precipitating treatment. Treatment is with immediate antiviral therapy.

CMV infection typically presents as reactivation in later life in an immunocompromised host, although acute hepatitis can also occur in immunocompetent individuals. Treatment with antiviral agents is indicated in many cases, with reduction in immunosuppression if relevant.

HSV infection rarely causes hepatitis, but when present is usually severe in nature and often fatal. Risk factors are the third trimester of pregnancy, immunosuppression, and advanced age. Symptoms maybe non‐specific and a characteristic rash is not frequently evident. A high index of suspicion should be maintained for early diagnosis and immediate antiviral treatment is essential.

Other Causes

Other causes of severe hepatocellular liver dysfunction and failure are much rarer but will often become apparent on investigation with cross‐sectional imaging. These include acute Budd–Chiari syndrome, hepatic veno‐occlusive disease, and diffuse malignant infiltration. A “fulminant” first presentation of autoimmune liver disease can also present in this way and may have characteristic immunoglobulin and autoantibody changes.