The liver in systemic disease: Sepsis and critical illness

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Abbreviations

APR

acute phase reaction

AST

aspartate aminotransferase

BILI

bilirubin

BSEP

bile salt export pump

CI

confidence interval

CLD

cholestatic liver dysfunction

HH

hypoxic or ischemic hepatitis

ICU

intensive care unit

INR

international normalized ratio

j

30 patients who developed bilirubin greater than 3 mg/dL

LD

liver dysfunction

MDR

multidrug resistance protein

MRP

multidrug resistance–associated protein

nj

67 patients who did not develop bilirubin greater than 3 mg/dL

NTCP

high‐affinity Na⁺‐dependent bile acid transporter

OATP

organic anion transporting polypeptide

Normal Physiological Response

Critical illness, and particularly severe sepsis, induces profound changes in the function of the normal liver. The balance of hepatic metabolic activity may be shifted rapidly in response to systemic inflammation with an “acute phase reaction (APR).” This results in a series of phenomena that includes complex changes in circulating and functional levels of immunological, transport, and coagulation proteins. Further, complex changes in specific hepatocellular processes occur, particularly in relation to hepatobiliary transport pathways, with practical consequence both to prognostic assessment and to therapeutic interventions.

The liver plays a central role in the systemic response to critical illness both through the clearance of pathogenic microorganisms and toxins from the circulation and through the APR and release of liver‐derived cytokines, inflammatory mediators, and coagulation cascade components.1, 2 These mediators and bacterial or endotoxin “spillover” from impaired hepatic clearance may have important systemic effects and contribute to the pathogenesis of multiple organ failure.2

The evolution of new hepatic dysfunction in the setting of critical illness is of great prognostic importance. By example, jaundice is seen in approximately 10% of critically ill patients early after intensive therapy unit admission, and it is a specific and independent risk factor for death (Figure 1).3 Many factors may contribute to the development of liver dysfunction (LD) in this setting, acting either in isolation or in concert, but 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, Hypoxic (or ischemic) Hepatitis and Cholestatic Liver Dysfunction.

Figure 1.

Adjusted risk for hospital mortality stratified by maximum bilirubin level within 48 hours of ICU admission. n = 38,036 first ICU admissions. Exclusion of patients with acute or acute‐on‐chronic liver disease and adjustment for age, sex, primary diagnosis, and nonhepatic organ dysfunction. Abbreviation: CI, confidence interval. Adapted with permission from Critical Care Medicine.3 Copyright 2007, Society of Critical Care Medicine.

Hypoxic or Ischemic Hepatitis

The high metabolic activity of the liver and its complex vascular supply render it at risk for injury from hemodynamic insults, and “hypoxic” or “ischemic hepatitis” (HH) results from hepatocellular necrosis provoked by acute cellular hypoxia resulting from impaired hepatic oxygen delivery. The prevalence of HH in hospital admissions is approximately 1 in 1000, but is probably at least an order of magnitude more common in intensive care unit (ICU) admissions. Diagnostic criteria vary but have included the triad of an appropriate clinical setting of cardiac, respiratory, or circulatory failure, an abrupt increase in serum transaminases reaching at least 20× the upper limit of normal and with exclusion of other causes of acute liver cell necrosis, particularly viral or drug‐induced liver injury.4 Major elevation of transaminases is usually of very short duration and is followed by coagulopathy, reflecting transient hepatic synthetic compromise; significant jaundice follows in a minority of patients and is associated with increased risk for complications and death (Figure 2).5 Liver biopsy is seldom required or performed but typically shows extensive centrilobular necrosis, reflecting the sensitivity of “zone 3” hepatocytes to ischemic insults.

Figure 2.

Laboratory parameters during the course of hypoxic hepatitis. Abbreviations: AST, aspartate aminotransferase; BILI, bilirubin; INR, international normalized ratio; j, 30 patients who developed bilirubin greater than 3 mg/dL; nj, 67 patients who did not develop bilirubin greater than 3 mg/dL. Adapted with permission from Hepatology.5 Copyright 2012, American Association for the Study of Liver Diseases.

Heart failure, respiratory failure, and septic shock are responsible for more than 90% of cases of HH, with these factors acting alone or in combination in individual patients (Figure 3). Compromise of cardiac output resulting from acute cardiac events such as myocardial infarction, dysrhythmia, or 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 HH through the development of hepatic “dysoxia” and impairment of hepatic cellular respiratory function oxygen utilization and microcirculatory changes.4

Figure 3.

Factors that contribute to the development of hypoxic hepatitis.

Effective management of HH depends on its early recognition, which may be confounded by the absence of a classical “shock state,” and addressing the causative factors. In the ICU setting, this frequently involves assessment and monitoring of cardiac function through invasive or noninvasive means. Prognosis is variable dependent on the trigger(s) of HH development, although death seldom results from liver failure alone but rather from multiple organ failure.

Cholestatic Liver Dysfunction

Cholestatic liver dysfunction (CLD) typically has a more insidious onset than HH, manifest in a critically ill patient usually days after ICU admission with progressive elevation of bilirubin, alkaline phosphatase, and gamma‐glutamyltransferase.6 Investigation is hampered by a lack of universally accepted diagnostic criteria, but in clinical practice a bilirubin level of more than 2 to 3 mg/dL and alkaline phosphatase and gamma‐glutamyltransferase of two to three times normal may be accepted. Overt mechanical obstruction of bile ducts is seldom the cause, although biliary “sludge” may be observed on hepatic imaging. CLD is thought to result from critical illness–induced alteration of hepatobiliary transport mechanisms. Clinical risk factors for its development include sepsis (Figure 4), both through endotoxemia and the evoked inflammatory cytokine response, parenteral nutrition and hyperglycemia, and super‐added drug‐induced cholestasis.6, 7

Figure 4.

Source and causative agent of infection in 141 consequtive patients without preexsiting liver diseases admitted to intensive care according to presence or absence of development of LD. LD defined as serum bilirubin ≥2 mg/L lasting at least 48 hours. *P < 0.05. Adapted with permission from Intensive Care Medicine.7 Copyright 2006, European Society of Intensive Care Medicine and the European Society of Paediatric and Neonatal Intensive Care.

A complex series of hepatobiliary transporter proteins exists to take up biliary components from the blood, traffic them through the hepatocyte, and secrete them into the bile canaliculi. This tightly regulated process is markedly altered in critical illness where uptake transporters on the basolateral surface of the hepatocyte are downregulated and alternate export transport proteins upregulated, while transport proteins located on the apical canalicular surface are downregulated.8 The net effect of these changes is reflected by increasing circulating levels of conjugated bile acids and bilirubin (Figure 5). It is not clear whether this represents an adaptive or maladaptive response as moderate elevations of conjugated bilirubin may have beneficial antioxidative or cytoprotective effects, and bile acids may modulate fundamental aspects of energy and metabolic activity and contribute to the stress response by inhibiting cortisol breakdown. Conversely, detrimental effects may include modulation of intestinal flora and increase release of endotoxin to the systemic circulation and impairment of xenobiotic excretion with clinically important effects upon drug metabolism and handling.8

Figure 5.

Schematic representation of hepatobiliary transport system in health and in critical illness. In normal conditions, uptake of bile acids from the blood into the hepatocyte via the high‐affinity Na⁺‐dependent bile acid transporter (NTCP) and the less specific organic anion transporting polypeptide (OATP). Excretion into the bile canaliculus at the apical surface of the hepatocyte is mainly through the bile salt export pump (BSEP) with less specific transporters that include those from the multidrug resistance–associated protein (MRP) and the multidrug resistance protein (MDR) families. Export transporters MRP3 and MRP4 are also expressed at low levels on the basolateral membrane and transport bile acids to the systemic circulation. In animal models and critically ill humans, NTCP and to a lesser degree OATP are downregulated and uptake of bile acids into the hepatocyte declines. Bilirubin may still enter the cell via OATP for conjugation. BSEP is markedly downregulated, and MRP2, MDR1, and MDR2 are expressed at increased levels, favoring excretion of xenobiotic toxic compounds into the bile. On the basolateral membrane, MRP3 and MRP4 upregulation occurs in response to cholestasis and inflammation, shifting transport of bile acids into the blood. Adapted with permission from Intensive Care Medicine.8 Copyright 2016, European Society of Intensive Care Medicine and the European Society of Paediatric and Neonatal Intensive Care.

Although N‐acetylcysteine and ursodeoxycholic acid are often administered, no specific intervention of proven benefit exists for the treatment of CLD. Management rather seeks to exclude mechanical obstruction and to remove or ameliorate the insults that may be responsible. Sepsis is treated effectively, secondary drug‐induced insults minimized, and where possible the enteral rather than parenteral route is chosen for nutritional support.