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

Cirrhosis

Continued liver injury results in irreparable damage with permanent loss of liver function and subsequent chronic disease states. Cirrhosis is the common end point of many chronic liver diseases characterized by the replacement of functioning hepatocytes with physiologically inactive fibrotic tissue. Patients with cirrhosis may have any number of symptoms or clinical conditions related to end-stage liver disease.

Portal Hypertension

Portal hypertension occurs when intraportal pressure is elevated 10 mm Hg above normal throughout the portal system. The cause is multifactorial, and the disorder can occur with conditions other than cirrhosis.

Parasitic infections are an extremely common cause of reversible portal hypertension in developing countries. Parasites, commonly those responsible for schistosomiasis, cause chronic inflammatory states in the portal sinusoids that lead to granuloma formation and fibrosis.

Portal hypertension develops in patients with cirrhosis because of increased intrahepatic resistance to greater portal flow. Numerous cellular disorders occur simultaneously in cirrhotic patients with increased portal pressure. Lack of intrahepatic vasodilation is caused by fibrocyte deposition and decreased nitric oxide production within the liver. Increased portal flow results from higher cardiac output and splanchnic flow associated with extrahepatic nitric oxide production. The greater pressure causes deposition of peritoneal fluid and redirection of blood flow. As these forces coincide, blood is rerouted around the liver to compensate. Collateral flow increases as portal pressure rises; pressures greater than 12 mm Hg promote the formation of varices—chronically dilated veins in the collateral bed that shunt blood flow away from the liver. Varices occur in the following locations:

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

Hepatorenal Syndrome

Hepatorenal syndrome exists as a chronic debilitating state or as a rapidly progressive and terminal condition. This syndrome occurs when kidney function declines in the setting of liver failure. All patients with cirrhosis have some degree of renal insufficiency; most continue to decline slowly, whereas others progress rapidly to renal failure.

Hepatorenal syndrome is diagnosed in a patient with cirrhosis who also has a rise in creatinine levels to more than 1.5 mg/dL in conjunction with a serum sodium level lower than 130 mEq/L. SBP, acute alcoholic hepatitis, and hypotension are common precipitants of this syndrome. Although hepatorenal syndrome frequently develops in patients being treated for SBP, some evidence has shown that administering albumin as a component of SBP management reduces the likelihood of development of this syndrome.

Liver transplantation is the only therapy that has been shown to reduce mortality in patients with fulminant hepatorenal syndrome.³⁴

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

Hepatitis B Virus

Hepatitis B virus (HBV) is a double-stranded DNA virus that has a cross-species reservoir. It infects human, ducks, and squirrels. HBV is transmitted person to person through sexual contact, blood exposure, transfusion, and perinatal vertical transmission. It is highly virulent—infection may be caused by a small number of virions. HBV is easily passed through contaminated needles, either from needle sharing among drug abusers or through occupational exposure in health care workers.

More than 1 million individuals have chronic HBV infection in the United States, and approximately 500 million are infected worldwide. From 1990 to 2004, the overall incidence of reported acute HBV infection declined 75% through vaccination efforts, from 8.5 to 2.1 per 100,000 persons.³⁷^–³⁹

Symptoms and Signs

Acute infection with HBV causes anorexia, nausea, emesis, diarrhea, fever, and eventually jaundice. Serum levels of alanine transaminase (ALT) and aspartate transaminase (AST) may both rise to greater than 10,000 U/L and cause constitutional symptoms that precede the appearance of jaundice.

Diagnostic Testing

HBV infection can be defined as acute, chronic, or carrier. If the patient has not been immunized against HBV and has not previously shown signs of the disease, the presence of hepatitis B surface antigen and expected symptoms confirms the diagnosis of acute infection.

Treatment and Prognosis

The prognosis of patients with HBV infection varies widely, although most individuals (90% to 95%) recover completely. Up to 10% of patients enter a chronic infectious state and are at risk for cirrhosis and hepatocellular carcinoma. Approximately 2% die of fulminant hepatic failure.

Multiple drug regimens exist for the treatment of HBV, most notably peginterferon alfa-2b with or without lamivudine. Such regimens have never been shown to be effective in the acute setting, and recommendations are to withhold treatment until evidence of ongoing viral replication is present.

HBV immune globulin (HBV-IG) effectively prevents transmission if given within 72 hours of exposure and should be administered to patients after high-risk exposure. Centers for Disease Control and Prevention guidelines recommend administration of HBV-IG and HBV vaccine to unvaccinated health care workers exposed to patients known to have HBV and administration of HBV-IG to persons with unknown HBV status after high-risk exposure. Nonoccupational postexposure prophylaxis should follow similar recommendations (e.g., sexual assault or coincident with human immunodeficiency virus postexposure prophylaxis).

Disposition

Patients with HBV infection may require admission for parenteral control of vomiting and administration of fluids. Evidence of possible hepatic failure is reflected in prolongation of the prothrombin time (PT), which should be measured if HBV infection is suspected. Liver function values are often markedly elevated, but this finding is not an indication for admission.

Hepatitis C Virus

An RNA virus that is extremely complex and diverse, hepatitis C virus (HCV) has at least six distinct genotypes and 50 subtypes. This genetic diversity complicates development of a vaccine against it. HCV infection is the leading reason for liver transplantation; chronic infection commonly causes cirrhosis and hepatocellular carcinoma.³⁸ Transmission occurs through sexual contact and sharing needles with infected individuals.

HCV transmission peaked in the United States in the 1980s before its discovery, with an estimated 250,000 new cases per year in that decade. Infection rates have dropped to approximately 40,000 annually. Carriers with chronic HCV infection number almost 3 million.⁴⁰ The prevalence of HCV in trauma patients is 15% to 20%.^41,⁴²

Diagnosis

Unlike acute infection with HAV or HBV, acute HCV infection is much more likely to pass without symptoms—up to 80% of infected persons are asymptomatic. HCV can produce a flulike illness that is easily ignored. It is ultimately diagnosed with anti-HCV antibody screening, which is confirmed by polymerase chain reaction for HCV RNA.

Treatment and Prognosis

HCV is much more destructive than either HAV or HBV. Approximately 15% of infected persons fully recover, but cirrhosis develops in 15% and hepatocellular carcinoma eventually develops in 5%. HCV accounts for 50% of cases of cirrhosis diagnosed in the United States.

Treatment with various drug regimens is available, although none are recommended for use in the ED in patients with suspected infection. Viral replication must be verified and serotyped to guide treatment. Neither vaccine prophylaxis nor postexposure prophylaxis is currently available.

Disposition

Patients infected with HCV may have to be admitted to the hospital for parenteral control of vomiting and administration of fluids. Evidence of possible hepatic failure is reflected in prolongation of the PT, which should be measured if HCV infection is suspected. Liver function values are often markedly elevated, but this finding is not an indication for admission.

Amebiasis

Amebic liver infections are of growing concern in the United States, although the infection is much more prevalent in the developing world. Amebiasis affects 50 million persons worldwide and is estimated to cause 50,000 to 100,000 deaths per year.⁴³

Amebiasis is frequently manifested as colitis. It is unknown what percentage of cases progress to abscess formation, although approximately one third of patients with abscesses have prodromal nausea, emesis, diarrhea, and bloating.^44,⁴⁵ Solitary abscess formation is common in patients with amebic abscesses, as opposed to the multiple foci often seen in those with pyogenic abscesses. Amebic abscesses have a predilection for males, with a 10 : 1 ratio of infection; such gender bias is not seen with pyogenic abscesses.

Diagnosis

Most patients in the United States in whom amebic liver abscess is diagnosed are seen in the southwestern states and are males of Mexican origin.⁴⁶ The symptoms may mimic those of cholecystitis, with right upper quadrant abdominal pain, fever, chills, and nausea. In one series, 20% of patients with amebiasis had isolated pulmonary complaints.⁴⁶

Abscesses are easily seen on ultrasonography. The ultrasonographic appearance in combination with acute symptoms makes the diagnosis in at least two thirds of patients.^45,^47,⁴⁸ Computed tomography (CT) is sensitive as well and should be used when the diagnosis is in question.

Tests for Entamoeba histolytica–specific antibodies should be performed if an amebic abscess is suspected.

Treatment and Prognosis

Metronidazole remains the first-line treatment (a high-dose schedule consisting of 750 mg three times daily for 10 days provides a 90% cure rate).⁴⁹ Aspiration has traditionally been recommended for abscesses larger than 5 cm, although the results of studies examining this practice are equivocal.^50,⁵¹

Disposition

Patients with amebic abscesses smaller than 5 cm are at low risk for rupture. If they are able to tolerate oral fluids and medications, such patients should be discharged after high-dose metronidazole therapy is started and appropriate follow-up is arranged.

When the diagnosis of amebic abscess cannot be confirmed in the ED by serologic testing, the patient should be admitted to exclude potential pyogenic abscesses.

Pyogenic Liver Abscesses

Liver abscesses in the United States and worldwide are most often due to amebiasis, although pyogenic abscesses represent a more serious condition. Pyogenic abscesses were diagnosed in 3000 patients per year in one European study.⁵²

Patients with pyogenic abscesses are more ill, have multiple abscesses, and suffer a worse prognosis than do those with amebic abscesses. Unlike those with amebic abscesses, approximately 50% of patients have multiple pyogenic abscesses, either from hematogenous spread (as a result of infections such as diverticulitis) or through direct extension from suppurative cholangitis (now thought to be the most common cause).

Bacterial causes of pyogenic abscess are diverse and include E. coli, Klebsiella, Staphylococcus aureus, and various anaerobes.

Patients with pyogenic abscesses are much less likely to have the classic symptoms of liver abscesses seen with amebic infections, such as right upper quadrant pain, fever, nausea, and vomiting.

Diagnosis

Because the causes of pyogenic abscesses are so varied, the abscesses are not manifested in a uniform fashion. Right upper quadrant tenderness and hepatomegaly are noted in approximately 50% of cases.⁵³ Patients commonly show signs of systemic disease, such as fever, malaise, weight loss, and anorexia.

Liver function values may or may not be elevated and should not be used to exclude the diagnosis. Ultrasonography and CT are both excellent imaging modalities, with sensitivities of 85% and 95%, respectively.^53,⁵⁴

Treatment and Prognosis

Pyogenic liver abscesses are treated with a combination of antibiotics and drainage. Catheter drainage and needle aspiration produce similar success rates of 60% to 90%, although these two options have not been compared directly. The largest published trials have demonstrated success rates exceeding 95% with ultrasound-guided aspiration without catheter placement followed by broad-spectrum intravenous antibiotics (to cover gram-positive, gram-negative, and anaerobic organisms).^55,⁵⁶ Antibiotic therapy without abscess drainage is generally unsuccessful.

Disposition

Even with appropriate therapy, the mortality rate in patients with pyogenic abscesses is 5% to 10%. Any patient with a suspected pyogenic abscess must be admitted to the hospital.

Parasitic Infections

The most common parasitic infections of the liver are schistosomiasis (which commonly affects the portal and mesenteric circulation) and clonorchiasis (found in the biliary tree). Both parasitic infections are very common outside the United States—an estimated 1 in 30 persons worldwide are infected with Schistosoma, and 25% of all Asian immigrants to the United States are infected with Clonorchis sinensis. These parasites cause portal hypertension in a large percentage of patients in developing countries and often go undetected for years because of lack of symptoms.

Diagnosis

Patients with parasitic infections exhibit symptoms based on the number of parasites causing infection. Those with a smaller number of organisms are asymptomatic or may have only malaise and diarrhea. With higher numbers of parasites, more constitutional symptoms are present, such as fever, chills, and weight loss.

ED patients with hepatobiliary symptoms after travel to Asia should be considered at high risk for parasitic infection. Ultrasonography and CT may show indirect signs of infection, such as biliary stones and dilation; these imaging methods are not helpful for identifying the organisms themselves.⁵⁷

Treatment and Prognosis

Praziquantel is effective for both clonorchiasis and schistosomiasis, with cure rates of 60% to 95%.⁵⁸ Reversal of portal hypertension is observed in 95% of children and 85% of adults with these parasitic diseases.⁵⁹

Disposition

Patients with suspected acute parasitic disease should be admitted to the hospital because of a significant risk for mortality from Schistosoma japonicum. Chronic infection may be managed with supportive care and outpatient follow-up.

Noninfectious Liver Disorders

Alcoholic Liver Disease

Alcohol consumption is responsible for half of all chronic liver disease in the United States.¹ Alcohol may poison the liver acutely or may damage hepatocytes through repeated insult, with permanent destruction of hepatic architecture and the eventual development of cirrhosis. Alcohol consumption causes accumulation of fat in the liver that displaces hepatocytes; the accumulation is normally reversible, but if the liver is subject to repeated insult, the accumulation of fat slowly becomes permanent. Chronic fatty liver is subject to inflammatory changes that induce scarring and permanent replacement of functional hepatocytes with lipocytes and fibrous tissue. The smaller numbers of hepatocytes cannot handle the physiologic requirements of the body. This pathologic progression is significantly accelerated by coexisting HCV or HBV infection.⁶⁰ Women are much more prone to alcohol-induced hepatic injury.⁶¹

Acute hepatitis secondary to alcohol consumption is termed alcoholic hepatitis or alcoholic steatohepatitis. Steatohepatitis, so named from the overwhelming fatty infiltration seen with alcohol metabolism, is associated with impairment of liver function. Acute alcoholic hepatitis is common in heavy, chronic, binge-type alcohol users.

Diagnosis

Patients with alcoholic hepatitis often admit to heavy alcohol use and may appear jaundiced or complain of dark urine. Constitutional symptoms are common—weakness, nausea, emesis, and malaise. Patients often display signs of chronic liver insufficiency, including asterixis and spider angiomas.

Treatment and Prognosis

Treatment is mostly supportive, although as with other forms of liver disease, both coagulopathy and changes in mental status should be treated aggressively. The mortality rate in hospitalized patients with alcoholic hepatitis is approximately 10%.⁶² Higher mortality is observed when patients have concomitant encephalopathy and coagulopathy; immediate liver transplantation may be required for their survival.

Corticosteroid use in hospitalized patients with alcoholic hepatitis is controversial. During the 1980s and early 1990s, a number of published studies proclaimed significant reductions in mortality with the use of corticosteroids (particularly convincing was one study of the use of prednisolone in 1992 ⁶³). However, a carefully performed metaanalysis published in 1995 that examined 12 controlled trials did not find any benefit.⁶⁴ The use of corticosteroids should be reserved for inpatient units and not be initiated in the ED.

Disposition

Admission to the hospital is necessary for patients with acute alcoholic hepatitis because of high mortality rates and a significant need for transfusion, vasopressors, and aggressive resuscitation.

Autoimmune Liver Disorders

The two major immunologic causes of liver disease are autoimmune hepatitis and primary biliary sclerosis. Patients with immune-related liver disease are mostly female and show signs of autoimmune disease, as well as liver disease. The clinical signs regularly include myalgia, polyarthritis, rash, and findings consistent with other autoimmune disorders, such as Sjögren syndrome and systemic lupus erythematosus.

Patients with autoimmune liver disorders have progressive disease and a survival rate of 10% to 50% at 5 years if untreated. As the disease advances, the patient exhibits signs of liver insufficiency similar to those in other patients with chronic liver disease.^65,⁶⁶

These diseases are difficult to detect and differentiate from other forms of chronic liver disease—such differentiation is not a goal of ED care.

Management of patients with autoimmune liver disorders is complicated by the immunosuppressive drugs used for treatment (prednisone and azathioprine are most commonly prescribed). When caring for patients in the ED, the clinician must consider complications of immunosuppressive therapy and administer stress-dose corticosteroids when required.

The prognosis has improved with liver transplantation, which provides a 10-year survival rate of 75%; recurrence is seen in 42% of patients.⁶⁷

Drug-Induced Liver Disease

Many pharmaceutical and naturally occurring substances can cause catastrophic liver injury (Box 42.1). The manifestation of drug-induced liver disease varies from benign jaundice to fulminant hepatic failure. Almost 40% of cases of acute hepatic failure in the United States are caused by drug-induced injury; almost half of these cases are due to acetaminophen alone.^68,⁶⁹

Box 42.1

Drugs That Cause Liver Disease

Anesthetics

Halothane

Enflurane

Isoflurane

Antimicrobials

Anticonvulsants

Analgesics

Miscellaneous

From Lewis J. Drug-induced liver disease. Med Clin North Am 2000;84:1275-311.

Care of Patients with Liver Transplants

More than 36,000 patients living in the United States have undergone liver transplantation.⁷⁰ Transplantation patients come to the ED with common complaints, such as fever and abdominal pain, which are associated with high morbidity in this population. Almost 70% of liver transplant recipients who seek care in an ED require hospitalization.⁷¹

Transplant recipients are immunosuppressed, and any fever must be taken seriously. Serious febrile illnesses associated with liver transplantation are bacteremia and pneumonia; otitis media is common. Immunosuppressive medications also raise the risk for viral and fungal infections.

Infectious Complications

The most common serious infection seen in the first few months after transplantation is cytomegalovirus, which is manifested as fever, arthralgias, and malaise. Other viral infections, such as herpes simplex virus, varicella-zoster virus, and herpes zoster virus, are also common but are not as serious as cytomegalovirus.⁷⁰ Infections with fungi such as Candida should also be suspected.

Serious infections may be present in the absence of fever or leukocytosis. Half of liver transplant recipients with the eventual diagnosis of a serious infection had neither a fever nor an elevated white blood cell count.

Mechanical Complications

Liver transplant recipients are subject to vascular or structural problems surrounding and within the transplant. Hepatic artery stenosis and hepatic artery thrombosis are each present in approximately 10% of liver transplant recipients, frequently because of rejection. Either stenosis or thrombosis of the hepatic artery can be manifested as abdominal pain, and both are accurately detected with ultrasonography.⁷¹ Timely discussion with a transplant team and early use of angiography are recommended because of the need for a rapid decision on corrective treatment.

The portal system may also be affected; ultrasonography should be used to evaluate the portal system at the time that the arterial system is examined because another 10% of liver transplant recipients have portal vein or hepatic vein thrombosis. Magnetic resonance venography is needed to confirm suspected portal or hepatic vein thrombosis.

Finally, the biliary tree is also affected by stenosis or ischemia in approximately 10% of patients and is diagnosed by ultrasonography or anigiography.⁷²

Liver Function Tests

Liver function may be measured indirectly through a variety of laboratory tests. Laboratory abnormalities are neither specific nor sensitive and can therefore be misleading; however, certain abnormalities can help guide the astute physician toward further diagnostic testing in search of a specific diagnosis.

Alanine Transaminase And Aspartate Transaminase

Both ALT and AST, which are called transaminases, are concentrated intrahepatocyte enzymes (although AST exists in measurable quantities elsewhere in the body as well). Any hepatocyte necrosis elevates these enzymes. The often quoted 2 : 1 ratio of AST to ALT in patients with alcoholic liver disease is not supported by the literature.^73,⁷⁴

Chronic disease states such as HCV, alcoholic cirrhosis, and autoimmune hepatitis are often associated with persistent elevations in ALT and AST, although normal values should not be used to exclude the possibility of disease. More than 15% of patients with biopsy-proven chronic HCV disease have transaminase elevations.⁷⁵

Alkaline Phosphatase And γ-Glutamyltransferase

Both alkaline phosphatase (AP) and γ-glutamyltransferase (GGT) are markers of cholestasis. However, AP is present at significant levels in many other organ systems—bone, intestine, and placenta. AP values are elevated in normal pregnancy and with metastatic disease involving bone (e.g., prostate cancer). Children also have physiologically normal elevations in AP during growth. GGT is much more highly concentrated in the liver and can be used in conjunction with AP to determine whether an abnormality is intrahepatic or extrahepatic.

Prothrombin Time

The PT measures the activity of certain clotting factors in both the intrinsic and extrinsic pathways. The liver is the primary site for manufacture of these clotting factors, and decreases in synthesis by an impaired liver can be inferred from a prolonged PT. Vitamin K is a cofactor in clotting factor synthesis, and medications that block its absorption, such as warfarin, prolong PT values.

Bilirubin

Bilirubin exists in two distinct forms, conjugated (direct) and unconjugated (indirect). Bilirubin is a by-product of hemoglobin metabolism. Unconjugated bilirubin is present in serum bound to albumin in a water-insoluble state. It is transported to the liver, where it is conjugated with glucuronide in preparation for excretion into bile.

Understanding this process of bilirubin metabolism helps focus the differential diagnosis of patients with hyperbilirubinemia or jaundice, or with both (Tables 42.1 and 42.2). Unconjugated hyperbilirubinemia results from increased production of bilirubin (hemolysis) or from decreased uptake in the liver (as seen in various inherited conditions). Conjugated hyperbilirubinemia results from loss of excretory capacity, which can occur as a result of intrahepatic diseases (e.g., drug reactions, hepatitis, cirrhosis) or biliary obstruction. Obstructive jaundice is due to a lesion that blocks the excretion of bile through the biliary ducts, either proximally at the hepatic duct or more distally at the common bile duct.^73,⁷⁶

Table 42.1 Causes of Hyperbilirubinemia

TYPE	CAUSE	CLINICAL FEATURES AND BIOCHEMICAL ABNORMALITIES
Unconjugated hyperbilirubinemia	Hemolysis	Decreased hemoglobin and haptoglobin levels Increased reticulocyte count
	Gilbert syndrome	None
	Hematoma reabsorption	Increased creatine kinase and lactic dehydrogenase levels
	Ineffective erythropoiesis	—
Conjugated hyperbilirubinemia	Bile duct obstruction	Preceded by a marked increase in transaminase levels Presence of suggestive symptoms (right upper quadrant pain, nausea, fever)
	Hepatitis (various causes)	Concomitant moderate to marked increase in transaminase levels
	Cirrhosis	Transaminase levels may be normal or only slightly increased Presence of other physical and instrumental signs of chronic liver disease
	Autoimmune cholestatic diseases (primary biliary cirrhosis, primary sclerosing cholangitis)	Marked increase in ALP levels with normal or mildly increased transaminase levels Presence of other autoimmune diseases or associated diseases (e.g., inflammatory bowel disease)
	Total parenteral nutrition	Increased ALP and γ-glutamyltransferase levels
	Drug toxins	Concomitant increase in ALP levels
	Vanishing bile duct syndrome	Can be associated with drug reactions or occur with orthotopic liver transplantation

ALP, Alkaline phosphatase.

From Giannini E, Testa R, Savarino V. Liver enzyme alteration: a guide for clinicians. CMAJ 2005;172:367-79.

Table 42.2 Guide to Interpretation of Hepatic Function Panel Results

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