Intensive Care

Intensive Care

William Bernal and Sheital Chand

Institute of Liver Studies, Kings College Hospital, London, UK

Classification and Prevalence

Liver injury may be identified on initial admission of a patient to an intensive care unit (ICU) or may develop during the course of their admission. It may reflect the severity of systemic illness precipitating ICU admission or, alternatively, can be acquired as a complication of medical treatment or intervention delivered in ICU. It may also be a first manifestation of previously unrecognized underlying chronic liver disease.

The severity of blood test abnormalities may vary widely. Most commonly, abnormalities are at the more minor end of the severity spectrum, with transient and minor elevations in liver biochemical tests, with liver enzyme elevations to two to three times the upper limit of normal [1]. These elevations are typically self‐limiting without the need for intervention, and with little impact on the overall clinical course of the patient. At the other end of the spectrum, there may be rare major abnormalities in liver biochemical tests with enzyme elevations over 20 times the upper limit of normal, associated with loss of liver function and lactic acidosis, hyperammonemia, encephalopathy, and coagulopathy that require specific critical care support. Patients in ICU who develop abnormal liver biochemical tests can be assigned to three broad clinical groupings:

  • Acute liver injury: where abnormal liver enzyme biochemical tests are identified but without evidence of significant hepatic functional compromise. Abnormal results of blood tests reflecting liver injury are seen commonly in patients in the ICU and may be present in more than half of all critically ill patients over the course of an ICU admission.
  • Acute hepatic dysfunction: where abnormal liver enzyme biochemical tests are associated with laboratory evidence of synthetic and metabolic compromise, manifest either as the development of jaundice or coagulopathy. Liver dysfunction has prognostic implications: jaundice is seen approximately 10% of critically ill of patients early after ICU admission and is a specific and independent risk factor for death (Figure 4.1).
  • Acute liver failure: where there is evidence of major hepatic functional compromise with the development of encephalopathy, in the absence of pre‐existing chronic liver disease. This is often associated with other extrahepatic organ failure and is a rare medical emergency that often requires specialist management and, occasionally, liver transplantation.

Depending on the nature and severity of the insult responsible for liver injury and the presence or absence of pre‐existing liver disease, some patients may remain within the liver injury category alone or may only show evidence of minor dysfunction. Others may rapidly progress from liver injury to dysfunction and then failure over the course of hours. The latter course is rare, but its early recognition and prompt and effective management may be lifesaving.

Schematic illustration of adjusted risk of hospital mortality stratified by maximum bilirubin level within 48 hours of intensive care unit (ICU) admission; n = 38 036 first ICU admissions.

Figure 4.1 Adjusted risk of hospital mortality stratified by maximum bilirubin level within 48 hours of intensive care unit (ICU) admission; n = 38 036 first ICU admissions. Exclusion of patients with acute or acute on chronic liver disease and with adjustment for age, sex, primary diagnosis, and non‐hepatic organ dysfunction. DILI, drug‐induced liver injury; NAFLD, non‐alcoholic fatty liver disease.

Source: Kramer et al. 2007 [1] / Wolters Kluwer Health, Inc.

Some patients with pre‐existing liver disease may present to the ICU and, in some cases, the presence of pre‐existing liver damage may not be known. Common causes of hepatic decompensation requiring intensive care include sepsis, gastrointestinal bleeding (from varices, gastric erosions, or other causes), electrolyte disturbance, alcohol, or drug adverse effects. These causes require appropriate investigation and management, in conjunction with a hepatologist.

Patterns of Liver Test Abnormalities

Many factors may contribute to the development of liver injury and dysfunction in this setting, acting either in isolation or in concert. However, using clinical presentation and standard laboratory measures, patients with novel hepatic dysfunction in the setting of critical illness can be broadly classified into two categories of cholestatic or hepatocellular patterns of injury, with the former the more commonly observed. However, a “mixed” pattern may also be observed, and the pattern of abnormality may change over the course of illness.

Hepatocellular Pattern of Liver Injury

Hepatocellular abnormality is defined by predominant elevation of the serum aminotransferases alanine transaminase (ALT) and aspartate transaminase (AST). AST is released into the circulation as a result of hepatocyte damage and has a plasma half‐life of 12–24 hours. AST is also released by cellar injury of skeletal and cardiac muscle and from erythrocytes, all of which may be injured in critical illness, so elevated AST levels do not always imply liver cell damage. ALT has a plasma half‐life of 36–50 hours and its release is more specific for hepatic injury. Major hepatocellular biochemical abnormalities may develop very rapidly, over hours, particularly in hypoxic hepatitis or severe drug‐induced hepatic necrosis, and may be detected well before the onset of clinically apparent jaundice. The decrease in serum aminotransferase levels is usually more gradual and the rate of resolution may reflect the effectiveness of the correction of the cause of liver injury. The major causes of severe hepatocellular liver injury are shown in Box 4.1.

Principal Causes of Hepatocellular Liver Injury

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).

Schematic illustration of illustrative changes in liver biochemistry in hypoxic hepatitis and critical illness cholestatic liver injury.

Figure 4.2 Illustrative changes in liver biochemistry in hypoxic hepatitis and critical illness cholestatic liver injury. (a) Hypoxic hepatitis. In hypoxic hepatitis, oxygen supply to the liver is impaired, resulting in hepatocyte cellular necrosis. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and to a lesser degree ALP and gGT, are released into the circulation. Excretory function as measured by means of bilirubin (Bili) and bile acids (BA) levels may be mildly impaired. In the recovery phase, oxygen supply to the liver is restored, and hepatocytes regenerate. In 30% of patients, clinical jaundice develops after hypoxic hepatitis. (b) Intensive care unit (ICU) cholestatic liver injury. During ICU cholestasis, intrahepatic alterations in the liver transport machinery result in higher circulating Bili and BA levels. Biliary stasis promotes release of ALP and gGT from cholangiocytes. Mild elevation of ALT and AST levels may also be present.

Source: After Jenniskens et al. 2018 [3]. With permission of Elsevier.

Schematic illustration of factors contributing to the development of hypoxic hepatitis.

Figure 4.3 Factors contributing to the development of hypoxic hepatitis.

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.

Schematic illustration of medication most commonly responsible for drug-induced liver injury in intensive care and pattern of liver dysfunction.

Figure 4.4 Medication most commonly responsible for drug‐induced liver injury in intensive care and pattern of liver dysfunction. NSAIDs, non‐steroidal anti‐inflammatory drugs.

Source: Based on Horvatits et al. (2019) [4].

For reference citations in this figure, please refer to Horvatits et al. (2019).

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.

Cholestatic Pattern of Liver Injury

Cholestatic liver injury is characterized by elevation in alkaline phosphatase (ALP) and gamma‐glutamyl transferase (GGT), with or without the presence of elevated bilirubin. ALP has a plasma half‐life of 72 hours and is released by the liver, but also by the kidney, bone, placenta, and ileum. GGT has a plasma half‐life of 7–10 days, and is primarily secreted by cholangiocytes in the liver.

Cholestatic liver dysfunction typically has a more insidious onset than hypoxic hepatitis, usually manifest in a critically ill patient days after ICU admission, with progressive elevation of bilirubin, ALP, and GGT (Figure 4.2b). Investigation is hampered by a lack of universally accepted diagnostic criteria, but in clinical practice a bilirubin of over 2–3 mg/dl and ALP and GGT of two to three times normal may be accepted [4]. Overt mechanical obstruction of bile ducts is seldom the cause, although biliary “sludge” may be observed on hepatic imaging, cholestatic liver dysfunction is thought to result from critical illness‐induced alteration of hepatobiliary transport mechanisms. Clinical risk factors for its development include sepsis, both through endotoxemia and the evoked inflammatory cytokine response, parenteral nutrition and hyperglycemia, and super‐added drug‐induced cholestasis (Box 4.3). A wide variety of drugs may be responsible (Figure 4.4).

Feb 20, 2024 | Posted by in GASTROENTEROLOGY | Comments Off on Intensive Care

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