6. Hepatic

Hyperbilirubinemia: total bilirubin (T Bil) >1.2 mg/dL (normal 0.2–1.2 mg/dL)

Jaundice: yellow discoloration of the sclera, skin, and mucus membranes (usually seen when total bilirubin>2.8 mg/dL)

Indirect bilirubin: unconjugated bilirubin (elevated in excess red cell destruction of various etiologies). Unconjugated hyperbilirubinemia exists when T Bil > normal and < 15% of T Bil is direct bilirubin

Direct bilirubin: conjugated bilirubin (composed of free bilirubin and bilirubin bound covalently to albumin [delta bilirubin])

Hepatic dysfunction: new onset of hyperbilirubinemia > 2 mg/dL in a patient without preexisting liver disease

Epidemiology

Hepatic dysfunction in ICU patients is common and can have important prognostic implications.

Early onset of new hepatic dysfunction (T Bil>2 mg/dL within 48 hours of ICU admission in the absence of preexisting liver disease) occurred in about 11% of adult ICU patients across specialties in a large prospective study of > 38,000 patients.

Smaller studies have suggested that liver dysfunction in mixed ICU patients is present at some point in > 30% of patients.

Risk factors for developing liver dysfunction in the ICU include shock, major surgery, sepsis (particularly gram-negative infections), and the use of total parenteral nutrition (TPN).

Hepatic dysfunction in the ICU is frequently multifactorial. An approach to the differential diagnosis of new onset hepatic dysfunction in the ICU is presented below, with emphasis on the more ICU-specific causes. A guiding principal is to look for treatable causes early.

Common Causes to Remember

Acute Hepatic Dysfunction

Extrahepatic Biliary Duct Obstruction

Choledocholithiasis/cholangitis

Common bile duct (CBD) stricture

Traumatic or iatrogenic injury to CBD

Acute pancreatitis

Malignancy

Increased Bilirubin Production

Massive transfusion

Resorption of blood collections

Acute hemolysis (e.g., dissemination intravascular coagulation [DIC] or immune-mediated hemolysis)

Impaired Bilirubin Excretion (Hepatocellular Dysfunction, Hepatitis, or Intrahepatic Cholestasis)

Drug-induced hepatitis, cholestasis, or hepatocellular necrosis

Viral hepatitis

Liver trauma/biloma

Sepsis/multiple organ failure (MOF)

Hypoxic hepatitis (shock liver)

TPN

Hyperbilirubinemia

History

Focus on recent trauma, surgery, drug/alcohol/toxin exposure

Physical Exam

Not very helpful in the ICU; classic features like Murphy sign and Courvoisier sign are unlikely to be appreciated in sedated, paralyzed patients or in patients who have undergone recent surgery.

Initial Laboratory Studies

Serum bilirubin (total and direct), AST/ALT, alkaline phosphatase (Alk PO₄), prothrombin time, albumin

Using a few common laboratory tests in the appropriate context can provide valuable clues to the etiology of jaundice.

If Unconjugated Hyperbilirubinemia

Tests of hemolysis (haptoglobulin, LDH, reticulocyte count) and ineffective erythropoiesis (hemoglobinopathies)

Consider imaging for concealed hematomas (such as retroperitoneal bleeds)

If Conjugated Hyperbilirubinemia

Alk PO₄ disproportionally elevated

Imaging: bedside ultrasound for evidence of cholecystitis, choledocholithiasis, or ductal dilatation)

CT/ERCP/MRCP as indicated

ALT/AST disproportionally elevated

Viral serologies (basic panel should include hepatitis A IgM antibody, hepatitis B surface antigen and core antibody, and hepatitis C RNA)

Toxicology screen (acetaminophen levels)

Hepatology consult for unusual causes including Wilson disease, autoimmune hepatitis, and rare causes of viral hepatitis. At this point, a liver biopsy may be considered.

Differential Diagnosis

Hypoxic Hepatitis

Epidemiology and diagnosis

Also known as “shock liver” and “ischemic hepatitis”

Diagnostic criteria

Appropriate clinical setting with cardiac, respiratory, or circulatory failure

An acute increase in AST/ALT levels (to > 20 times normal)

Exclusion of other causes of hepatocellular damage

Histologic pattern of centrilobar necrosis on liver biopsy (rarely required)

Prevalence of between 12% to 22% in ICU patients

Key pathophysiology

The common feature is reduced oxygen delivery to the liver (hence hypoxic hepatitis). It is important to remember that shock is NOT essential (hence the term “shock liver” is something of a misnomer). Hypoxic hepatitis has been described in cases of congestive heart failure (CHF) with passive congestion, acute circulatory failure (shock), acute respiratory failure, or some combination of the three.

Heart failure is the main condition underlying hypoxic hepatitis, and accounts for up to 70% in some series.

AST/ALT levels rapidly increase after the initial insult, peaking at approximately 24 hours, and normalizing in 10 to 15 days.

PT is also prolonged, recovering in about 1 week.

No specific diagnostic test exists.The combination of the appropriate clinical scenario with the typical enzyme profile is often sufficient. A liver biopsy is almost never required.

Management and treatment

Management of hypoxic hepatitis is completely supportive, and aimed at correction of the underlying medical issues, and attention to hepatic blood flow. In other words, provide adequate hemodynamic support while seeking to reverse the initial insult that precipitated liver injury.

The MARS (molecular adsorbents recirculating system, or artificial liver) system has been used very rarely in patients with hypoxic hepatitis; however, this must be considered experimental therapy at this point.

Outcomes

The prognosis of hypoxic hepatitis is poor, and largely reflects the underlying medical comorbidities. Among the five largest series (all published after 2003) the overall in-hospital mortality was 56%, with 1-year survival of only 25%.

Sepsis/Multiple Organ Failure

Epidemiology

Sepsis is responsible for up to 20% of hyperbilirubinemia in all age groups and across the spectrum of severity of illness. In ICU patients, sepsis is the most common cause of hyperbilirubinemia.

The most common source is intraabdominal infections, but hyperbilirubinemia has been documented with meningitis, endocarditis, pneumonia, and urinary tract infections.

Key pathophysiology

Hepatic dysfunction from sepsis is multifactorial, and can be divided into two phases: an initial stage resulting from hepatic hypoperfusion and a later stage resulting from hepatocellular dysfunction and cholestasis. Overproduction of bilirubin may also play a role. The various components are summarized in the table below.

Etiology of Liver Dysfunction in Sepsis

Primary hepatic dysfunction secondary to liver hypoperfusion

Secondary hepatic dysfunction due to the liver’s response to infection

These responses include:

Hemolysis (immunologic and nonimmunologic mechanisms)

Hepatocellular dysfunction, resulting in decreased bilirubin uptake, decreased canalicular transport, and decreased clearance of conjugated bilirubin

Cholestasis due to decreased basolateral transport of bile acids in the hepatocytes, and decreased canalicular transport of bile acids

Management and treatment

There is no specific diagnostic test given the multifactorial nature of sepsis induced liver dysfunction. Typical laboratory values include a conjugated hyperbilirubinemia, modestly elevated alk PO₄ (2–3 times normal), and mildly elevated transaminases.

Treatment is primarily aimed at the underlying cause of sepsis, with aggressive resuscitation, early and appropriate antibiotics, and adequate source control.

Total Parenteral Nutrition (TPN)

Epidemiology

A recent prospective cohort study of 40 ICUs in Spain showed that hepatic dysfunction occurred in almost 30% of patients who were on TPN.

The above study also noted that patients with sepsis and those getting nutrition targeted at >25 kcal/kg/d were at a higher risk of developing liver dysfunction.

Key Pathophysiology

Mild hepatomegaly with abdominal pain, along with elevated aminotransferase levels

The most common form of TPN-induced injury is hepatic steatosis and occasionally cholestasis

Liver histology shows periportal fat that may progress to panlobular steatosis in more severe cases

The mechanisms leading to TPN-induced liver dysfunction are incompletely understood, however possible contributing factors may include a high insulin to glucagon ratio induced by dextrose that increases lipogenesis and bowel rest leading to intestinal bacterial overgrowth, hepatic steatosis, and cholestasis