Pancreatic and biliary cancer associated with jaundice may be manifested as pain.² Patients with cirrhosis from chronic hepatitis are likely to describe painless jaundice but also complain of fatigue, pruritus, and constitutional symptoms. Patients who are acutely ill with jaundice, nausea, emesis, and fever should be tested for causes of acute hepatitis; similar manifestations without fever occur in toxic ingestions.

Nausea

Nausea is a common extrahepatic symptom that may complicate hepatitis, toxic liver injury, cholestasis, and many other causes of acute or chronic liver disease. Management of nausea is sometimes the sole reason that a patient with acute hepatitis requires hospital admission.

Particular attention should be given to patients with known liver disease who have nausea, emesis, and changes in mental status; the emergency physician should consider the possibility of cerebral edema, especially in patients with advanced liver disease.

Neuropsychiatric Signs and Symptoms

Changes in mental status in the setting of liver disease should be treated aggressively. The degree of encephalopathy is directly correlated to the degree of liver dysfunction. Patients with a sudden change in mental status and acute hepatic insufficiency usually have an advanced stage of disease that will frequently progress to acute, fulminant liver failure.

Cerebral edema often occurs in tandem with encephalopathy because of elevated ammonia levels; immediate treatment with ammonia-clearing agents (e.g., lactulose) is required. Note that lactulose is less effective in treating mental status changes associated with acute liver failure than in treating those associated with chronic disease. Caregivers of patients with chronic hepatic insufficiency often titrate lactulose dosing in accordance with cognitive function.

Hepatomegaly

In patients with hepatomegaly, the liver becomes significantly enlarged and easily palpable as a result of sudden edema from hepatitis or the appearance of fatty infiltrates with alcohol binging. If the enlargement is significant enough to cause portal hypertension, the spleen is often enlarged and palpable as well. As the liver scars and hepatocytes are replaced by fibrous tissue in cirrhosis, the organ shrinks and eventually becomes small and nodular. The presence or absence of hepatomegaly on examination is an unreliable estimate of liver function and should not be used to exclude a particular diagnosis.^3,⁴

Rash

Many patients with liver disease complain of skin irritation. Hepatitis has been associated with livedo reticularis, a lacy, erythematous rash caused by capillary spasm. Dermatitis caused by autoimmune hepatitis that promotes jaundice has an intense pruritic component. Patients with liver disease may be unable to control scratching, and infections develop in the self-induced excoriations. Finally, patients may complain of a “rash” that represents ecchymosis secondary to coagulopathy; such bruising without reported trauma should raise concern for advanced liver disease.

Signs and Symptoms of Advanced Liver Disease

Encephalopathy

Changes in mental status may occur with either acute or chronic liver disease. The pathophysiology of hepatic encephalopathy is not completely understood, but it is clear that pronounced encephalopathy is associated with poor outcomes. Although many chemical markers have been implicated as the cause of hepatic encephalopathy, most studies identify two important factors, γ-aminobutyric acid (GABA) and ammonia (NH₃).

Serum GABA levels are elevated in patients with cirrhosis. Administration of a GABA receptor antagonist (flumazenil) results in transient but significant improvements in cirrhotic patients’ mental status.

The second and more easily measurable toxicity results from an increased ammonia concentration. The serum ammonia concentration rises as liver function declines, with intermittent fluctuations occurring in chronically ill patients. Many factors affect ammonia production, including changes in diet, constipation, hepatorenal syndrome, and gastrointestinal bleeding. Ammonia readily crosses the blood-brain barrier, and in patients with hepatic encephalopathy, ammonia causes cerebral toxicity, which promotes mental status decline and eventually coma.⁵^–⁷

Ammonia is clearly toxic, and in animal models, ammonia infusions alone have been directly linked to the development of cerebral edema. In the setting of acute liver failure, ammonia levels higher than 200 mcg/dL are strongly associated with the development of cerebral edema and herniation.⁸^–¹⁰ In patients with advanced liver disease and cirrhosis, however, mental status may not correlate directly with measured ammonia levels. Ammonia tends to accumulate in the brain, and although blood levels may be normal, the patient may still have enough ammonia in cerebrospinal fluid to induce encephalopathy.

Because of the uncertain relationship of the measured serum ammonia and cerebral ammonia concentration, patients with known or suspected hepatic encephalopathy should be treated for hyperammonemia regardless of measured serum levels. No convincing evidence suggests that arterial sampling for measurement of ammonia is superior to venous measurements.⁷

Treatment

Emergency department (ED) management of hepatic encephalopathy consists of appropriate airway control and resuscitation, followed by the administration of ammonia-lowering agents. Lactulose (15 to 45 mL once or twice daily) is the most common treatment of choice in the United States, although sodium benzoate has been shown to be equally effective and less expensive.¹¹ Lactulose is a nonabsorbable disaccharide that decreases intestinal transit time through a direct cathartic effect, thus lowering intestinal bacterial loads. Lactulose also lowers intestinal pH, which favors competitive non–ammonia-producing bacteria. Lactulose may be given orally, by nasogastric tube, or in severely obtunded patients, as a retention enema.¹²

Neomycin is a poorly absorbed aminoglycoside used as secondary treatment to further reduce intestinal bacterial counts. Even though it is poorly absorbed, neomycin does cause systemic toxicity and should be used only when lactulose is ineffective. Mannitol (0.5 to 1 g/kg) effectively reduces cerebral edema and improves survival in patients with hepatic encephalopathy secondary to acute liver failure.^8,¹³

The following therapies have been shown to be ineffective and should be avoided: hyperventilation,^8,¹⁴ corticosteroids,^8,¹³ and terlipressin.¹⁵

Ascites

Ascites is the abnormal accumulation of peritoneal fluid, a common feature in patients with advanced liver disease. The exact pathogenesis of ascites has not been established, but multiple theories focus on the interaction of the liver with various other organ systems. The combination of portal hypertension and decreased albumin production contributes significantly to the accumulation of ascitic fluid.

Ascites associated with cirrhosis has a poor prognosis. One episode of ascites has a 3-year mortality rate of 50%, and recurrent ascites has the same 50% mortality at 1 year.^16,¹⁷ Comorbid conditions contribute to mortality, including the development of hepatocellular carcinoma, gastrointestinal hemorrhage, coma, and infection.

One important infectious cause of death in patients with ascites is spontaneous bacterial peritonitis (SBP). The prevalence of SBP in cirrhotic patients is high, with rates of 3.5% in asymptomatic patients to 30% in patients who seek treatment in a hospital for any reason and undergo paracentesis.^18,¹⁹

Paracentesis for the relief of tense ascites has been shown to improve cardiac function.²⁰ Reduction of intraabdominal hypertension and resolution of an effective abdominal compartment syndrome improve venous return to the heart.²¹

Patients with symptomatic ascites require paracentesis. Given the high rate of occult SBP in these patients, peritoneal fluid should always be sent for analysis. Previously, it was thought that large-volume paracentesis was associated with complications and should be avoided, but this common misperception has been disproved. Large-volume (>5 L) paracentesis is safe and is associated with shorter hospitalization than is the case with diuretic therapy in patients with refractory ascites.^22,²³

Complications of paracentesis are rare, even in thrombocytopenic patients. Most complications involve bleeding or persistent leakage from the puncture site and occur within 24 hours. Patients with such complications should be admitted to the hospital for observation.^24,²⁵

Controversy exists regarding volume expansion with colloids in conjunction with paracentesis. Studies have not demonstrated any short-term improvements in mortality or morbidity with the use of plasma expanders, although some alterations in renal function, such as elevations in blood urea nitrogen and decreased sodium levels (both of which are associated with a worse prognosis), have been observed. Albumin is the least expensive, safest, and usually most effective colloid for intravascular volume expansion and should be used in patients with paracentesis volumes of 5 L or larger.²⁶^–²⁸

Paracentesis is improved when ultrasonography is used to identify ascites and guide the paracentesis. In one study, paracentesis performed under ultrasonographic guidance was successful in 95% of patients as opposed to 65% of procedures without such guidance.²⁹

Outpatient treatment of ascites should center on dietary sodium restriction in combination with diuretics. Management by a primary care physician includes frequent checks of potassium and sodium levels, both of which have been implicated in morbidity in these patients. Patients with recurrent ascites should be referred for surgical evaluation for a possible transjugular intrahepatic portosystemic shunt procedure.

Spontaneous Bacterial Peritonitis

Symptoms of SBP are often vague. Although abdominal pain and fever are common, both may be absent. Patients may complain only of increased fatigue, myalgia, worsening ascites, or decline in mental status.

SBP is thought to be caused by translocation of intestinal flora, although this long-held premise is now under question. Previously, SBP was almost entirely associated with gram-negative bacteria, mostly Escherichia coli; a growing number of patients with SBP now have gram-positive organisms.³⁰

The diagnosis is confirmed by culture of peritoneal fluid aspirated during paracentesis. SBP is likely if peritoneal fluid neutrophil counts are greater than 250 cells/µL. Peritoneal fluid lactate levels may be even more accurate.^26,²⁷

Patients with suspected SPB should have as much fluid drained as possible. Empiric antibiotic treatment should begin as soon as the diagnosis is considered. SBP in cirrhotic patients carries a mortality rate of 20% to 40%, with a 1-year survival rate of just 40%.²⁶ Treatment should begin with a third-generation cephalosporin, such as ceftriaxone or cefotaxime. Quinolones should not be used because bacterial resistance to these agents is high and will worsen if the incidence of gram-positive infections continues to rise. Failure rates have been increasing regardless of which antibiotic regimen is used—it is often necessary to tailor individual therapy to the organisms found on culture.³¹