42 Liver Disorders
Key Points• Causes of jaundice are best categorized by the fraction of measured bilirubin implicated in disease—unconjugated or conjugated hyperbilirubinemia.
• The possibility of cerebral edema should be considered in patients with advanced liver disease and nausea, vomiting, and changes in mental status.
• As a result of the uncertain relationship of measured serum ammonia and cerebral ammonia concentration, patients with known or suspected hepatic encephalopathy should be treated for hyperammonemia regardless of the measured level.
• The prevalence of spontaneous bacterial peritonitis is high in cirrhotic patients, with rates of 3.5% in those with no symptoms to 30% in patients who seek treatment in a hospital for any reason and undergo paracentesis.
• Hepatitis B virus immune globulin effectively prevents transmission of hepatitis B virus if administered within 72 hours of exposure; it should be given for any high-risk exposure.
• Pyogenic liver abscesses are best treated with a combination of antibiotics and percutaneous drainage. Antibiotics alone are insufficient treatment.
Epidemiology
Chronic liver disease accounts for 70,000 hospitalizations annually in the United States and is one of the top 10 leading causes of death. Almost half of the 40,000 deaths per year in the United States are related to alcohol abuse. Although the majority of deaths are due to chronic liver disease and cirrhosis, 2000 deaths per year are associated with fulminant hepatic failure.1 Many of these patients die while awaiting liver transplantation. Hepatitis B and hepatitis C infections account for 40% of chronic liver disease, although many of these cases are exacerbated by concomitant alcohol abuse.
Common Signs and Symptoms of Liver Disease
Jaundice
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.
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
Signs and Symptoms of Advanced Liver Disease
Encephalopathy
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 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
Spontaneous Bacterial Peritonitis
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
Portal Hypertension
Abdominal wall: Varices involving the abdominal wall are called caput medusae, so named for their serpentine appearance. They arise from dilation of the abdominal wall and umbilical veins.
Rectum: Hemorrhoids represent a form of rectal varices. They are often friable and subject to significant bleeding.
Esophagus: Esophageal varices are a common source of gastrointestinal bleeding in patients with portal hypertension. Bleeding may be massive and difficult to control because of concomitant coagulopathy.
Hyponatremia
Cirrhotic patients have impaired excretion of free water. Low sodium levels, found in a third of all patients with cirrhosis, contribute to ascites, frequent falls, and cognitive decline. Hyponatremia is associated with a decreased response to diuretic therapy and a poor prognosis.32 In 2009 the U.S. Food and Drug Administration approved the novel drug tolvaptan for the treatment of hyponatremia; tolvaptan acts as a vasopressin antagonist. As with any new pharmaceutical class, data are limited, but the early results are promising.33
Infectious Causes of Liver Disease
Hepatitis A Virus
Hepatitis A virus (HAV) is a single-stranded RNA enterovirus in the disease-producing family Picornaviridae, which also includes poliovirus. Also known as epidemic hepatitis because of its ability to spread swiftly and suddenly, HAV infects an average of 60,000 individuals annually worldwide. Transmission is fecal-oral, as in settings such as day care, or through sexual contact. It may also be transmitted by contaminated water or food sources; shellfish is a common vector, although seemingly innocuous food sources, such as imported lettuce, have been implicated in outbreaks as well.35,36
