Emergencies of the Liver, Gallbladder, and Pancreas

Troy W. Privette, Jr., MD ^a^,^b^,^*, Matthew C. Carlisle, MD ^a, James K. Palma, MD, MPH ^c

^a Emergency Medicine Residency, Department of Emergency Medicine, Palmetto Health Richland, 5 Richland Medical Park, Columbia, SC 29203, USA

^b Chest Pain Unit, Palmetto Health Richland ED, 5 Richland Medical Park, Columbia, SC 29203, USA

^c Department of Emergency Medicine, Palmetto Health Richland, 5 Richland Medical Park, Columbia, SC 29203, USA

^* Corresponding author.

E-mail address: priv@aol.com

Abstract

Abdominal pain is a common presenting complaint in today’s emergency department (ED). Disorders related to the liver, gallbladder, and pancreas are responsible for many of these presentations. With the increasing prevalence of gallstones, as well as alcohol use and abuse, the numbers of cases are likely to increase. This article examines hepatic emergencies including alcoholic hepatitis, spontaneous bacterial peritonitis, hepatorenal syndrome, and hepatic encephalopathy. In addition, the authors review the presentation, evaluation, and management of acute biliary tract disorders with some emphasis on bedside ultrasonography. Evaluation and treatment of pancreatitis and its complications in the ED are discussed.

Keywords

• Hepatic encephalopathy • Alcoholic hepatitis • Hepatorenal syndrome • Spontaneous bacterial peritonitis • Cholecystitis • Choledocholithiasis • Cholangitis • Pancreatitis

Disorders of the liver, gallbladder, and pancreas are common causes of abdominal pain. In this article, common emergencies related to the liver, gallbladder, and pancreas are reviewed. In each section, a brief discussion of underlying cellular and pathophysiological mechanisms is followed by a review of the emergency department (ED) diagnosis and management of these diseases.

Emergency diseases of the liver

The liver is the largest abdominal organ and performs many complex vital functions, including carbohydrate, protein, and fat metabolism; waste product metabolism and detoxification; destruction of old red blood cells; bile synthesis; and formation of plasma proteins and liver-dependent clotting factors.¹ Most food and drug products pass directly from the gastrointestinal (GI) tract to the liver via the portal venous system.¹ This process allows the liver to clear potentially toxic substances prior to circulation among the other organs of the body. In addition, the hepatocyte is responsible for the synthesis of albumin, as well as clotting factors I, II, V, VII, and X.¹ Thus, albumin levels and prothrombin times can be used as a guide to liver synthetic function.

Liver injury is often divided into acute and chronic depending on the duration of liver dysfunction. Acute insults may be reversible with the elimination of the offending agent. However, continuous acute liver injury may lead to hepatic fibrosis, the hallmark of chronic liver injury. Progressive fibrosis leads to cirrhosis and liver failure.² Mitochondrial dysfunction is the central molecular event in hepatocyte injury.²

In the ED, liver disease primarily presents as cholestasis from biliary tract disease, hepatitis, or as a complication of chronic liver disease. With regard to hepatitis, viral infections and alcohol are the most common offending agents. Other etiological factors to consider include acetaminophen, idiosyncratic drug reactions, hepatotoxins, and autoimmune disorders.

Cholestasis and hepatocellular injury/necrosis are the most common pathologic mechanisms for liver disease in the ED. Cholestasis is simply the obstruction of bile flow within the biliary tract. The obstruction may occur as secondary to intrahepatic or extrahepatic processes. Extrahepatic obstruction is covered in the section on gallbladder pathology. Disorders resulting in intrahepatic cholestasis include infection, alcoholic liver disease, pregnancy, infiltrative diseases, sclerosing cholangitis, and primary biliary cirrhosis.

Cholestatic disorders present with variable degrees of jaundice, dark-colored urine, clay-colored stools, and pruritus. Tender hepatomegaly will often be present. A palpable gallbladder indicates extrahepatic cholestasis. Characteristic laboratory findings include significant elevations of bilirubin (total and direct fraction >50%) and alkaline phosphatase.³ Total bilirubin levels greater than 30 mg/dL make intrahepatic causes of cholestasis more likely than extrahepatic ones. Mild elevations of aminotransferases may occur with progressive disease.³

Hepatocellular injury/necrosis results from infection, toxins, and autoimmune processes. The signs and symptoms include nausea, vomiting, anorexia, and fever. Tender hepatomegaly will often be present and splenomegaly may occur. Characteristic laboratory changes include a greater than fivefold increase in aminotransferase levels, mild increase in alkaline phosphatase, prolonged prothrombin time, and variable elevations in bilirubin levels.³ Continued insults will lead to chronic liver disease, cirrhosis, and liver failure.

The pathophysiology of liver disease relates to both alterations in hepatic anatomy and loss of functioning hepatocytes. Fibrosis is the final common pathway in sustained liver injury. Viral hepatitis results in early periportal fibrosis, whereas alcoholic liver disease causes centrolobular fibrosis. Continued insults by either will lead to panlobular fibrosis, nodule formation, and cirrhosis.⁴ Fibrotic changes lead to increased vascular resistance in the portal venous system, with resultant portal hypertension and splanchnic vasodilation and their sequelae.⁵ Loss of functional hepatocytes in association with alterations in hepatic circulation leads to decreased protein synthesis (albumin, coagulation factors), decreased detoxification, and changes in carbohydrate and fat metabolism.¹

Laboratory Abnormalities

Liver function tests and panels include a group of biochemical markers that reflect hepatic function, including markers for hepatocellular injury/necrosis, hepatic synthesis, catabolic activity, and cholestasis.¹ While these tests may be a guide to hepatobiliary activity, one must be aware that extrahepatic diseases can also cause abnormalities in hepatic function tests.

Laboratory tests for hepatocellular injury include aspartate aminotransferase (AST), alanine aminotransferase (ALT), and to a much lesser extent lactate dehydrogenase (LDH). In addition to the liver, AST is found in the heart, muscle, kidney, and brain. ALT is primarily present in the liver; thus it is a more specific test of hepatic necrosis. ALT is found mostly in the cytosol whereas AST is present in the cytosol and mitochondria. This fact in part explains the increased AST/ALT ratio in alcoholic liver disease where mitochondrial damage is a key factor. In cholestatic disorders, AST increases before ALT, and the levels usually do not exceed a fivefold increase. With viral hepatitis, AST and ALT levels increase over 1 to 2 weeks to levels in the thousands, and return to normal in 6 weeks in uncomplicated cases. Ischemic hepatitis results in a rapid increase to levels greater than 10,000 IU/L [B]. LDH is found in multiple tissues and is extremely nonspecific. However, significant elevation are indicative of ischemic hepatonecrosis.¹

Tests that evaluate the hepatic synthetic capability include albumin and prothrombin time (PT). Albumin is produced in hepatocytes, with levels decreasing in advancing disease. The half-life of serum albumin is approximately 20 days. Therefore, it is useful in subacute and chronic disease but not acute hepatocellular necrosis. One should bear in mind that albumin levels are also decreased in nephrotic syndrome, cachexia, malnutrition, malabsorption, and various other GI disorders. Coagulation factors I, II, V, VII, and X are synthesized by hepatocytes. In addition, cholestasis impairs vitamin K absorption decreasing the function of coagulation factors II, VII, IX, and X.³ The PT can prolong in as little as 24 hours of liver disease and therefore is much more sensitive than albumin for evaluating hepatic synthetic function.³

Bilirubin, alkaline phosphatase, and γ-glutamyl transpeptidase (GGT) are markers for hepatobiliary dysfunction and cholestasis. Bilirubin is a product of the breakdown of heme-containing proteins. Bilirubin is insoluble. In the liver, bilirubin is conjugated to glucuronic acid. Conjugated bilirubin is water soluble and excreted into bile.⁶ Direct bilirubin measures the level of conjugated bilirubin, whereas indirect bilirubin is the unconjugated fraction. Bilirubin levels are traditionally reported as total bilirubin and direct bilirubin. Direct hyperbilirubinemia indicates hepatocellular dysfunction or cholestasis.³ Indirect hyperbilirubinemia can also be caused by liver disease but also may be due to hemolysis or hereditary diseases, most commonly Gilbert syndrome (a benign genetic defect in bilirubin conjugation).³ Alkaline phosphatase is present in many tissues including bone, placenta, intestine, kidney, and liver. Hepatic alkaline phosphatase is produced in bile duct epithelial cells. Cholestasis stimulates increased production and release of alkaline phosphatase. The half-life of circulating alkaline phosphatase is approximately 1 week.¹ Alkaline phosphatase levels are nonspecific and need to be evaluated in context of the clinical scenario and other laboratory values. GGT is also present in biliary epithelial cells, and levels increase in cholestasis. When used in conjunction with alkaline phosphatase, GGT is useful to confirm cholestasis. GGT levels are elevated in chronic alcohol use, due to increased production and decreased clearance. Increased GGT levels are also found in chronic liver disease, on use of certain drugs (anticonvulsants, oral contraceptives), and in various nonhepatic disorders including chronic obstructive pulmonary disease, renal failure, and acute myocardial infarction.¹

Serum ammonia levels are used in the evaluation of hepatic encephalopathy. Ammonia is a by-product of protein metabolism in the intestines and liver. Ammonia produced by the intestinal flora enters the portal venous system. In the setting of portal hypertension, portal systemic shunting occurs, allowing the ammonia to bypass the liver. The result is increased levels of ammonia crossing the blood-brain barrier. In addition to shunting, hepatic dysfunction is associated with decreased metabolism of ammonia as well as increased levels.⁷

Viral Hepatitis

Viral infections are a common cause of hepatitis. The primary pathogens are hepatitis A (HAV), B (HBV), C (HCV), D (HDV), and E (HEV). Hepatitis D is a defective virus and requires coinfection with HBV.⁸ The strains differ in their route of infection and long-term course.

HAV and HEV are transmitted via the fecal-oral route, most commonly through contaminated food and water. Poor hygiene and sanitation are significant risk factors.⁹ HAV is most commonly nonfatal and self limited. However, HAV infection in the setting of preexisting HCV increases the risk of fulminant hepatic failure and death.⁹ HEV, similar to HAV, is usually self-limited and nonfatal. However, the clinical course is often more severe than that of HAV. HEV infection during the third trimester of pregnancy is a risk factor for acute fulminant hepatitis and death.¹⁰ In immunosuppressed patients, HEV may progress from acute to chronic hepatitis with persistent inflammation and viremia.⁹

HBV is transmitted through exposure to contaminated blood and body fluids via parenteral or mucosal exposure. During the acute phase, the presentation ranges from asymptomatic to fulminant hepatitis. Ninety-five percent of immunocompetent adults will recover from the acute infection. HBV can seroconvert to chronic hepatitis.¹¹ In chronic HBV, the clinical presentation ranges from asymptomatic carrier state to cirrhosis. The risk of conversion to chronic HBV is age related and much higher when the infection occurs at a very young age.¹¹ Chronic HBV is a risk factor for the development of hepatocellular carcinoma.¹¹

HDV is also transmitted via blood and body fluid exposure. HDV requires the presence of HBV to replicate, and is only infectious as a coinfection or superinfection on preexisting HBV. HDV portends a more severe course and an increased risk of fulminant hepatitis.⁸

HCV is contracted through blood or body fluid exposure. The acute phase is often asymptomatic or very mild. Whereas fulminant hepatitis is rare in HCV, chronic hepatitis is relatively common. Seventy percent of cases will seroconvert to chronic HCV.¹² Of those with chronic HCV, 15% to 20% will progress to cirrhosis.¹³ Chronic HCV, like HBV, increases the risk of hepatocellular carcinoma.

Patients with acute hepatitis will present with varying degrees of weakness, nausea, vomiting, right upper quadrant pain, and jaundice. Diagnosis is made by obtaining hepatitis viral serology. Interpretation of hepatitis viral panels is complex. These measurements can help assess the acuity or chronicity of the infection, as well as immunosuppression. However, this assessment, requiring consideration of the patients’ underlying illnesses and immune status, is beyond the scope of this article. Treatment of acute viral hepatitis in the ED is primarily symptomatic and supportive. Maintaining an adequate fluid and electrolyte balance is the goal of therapy. Admission versus outpatient care is dependent on the severity of the patient’s illness, the ability to maintain adequate hydration, and the absence of complications. If discharged, these patients should be referred for follow-up to monitor recovery and to determine the need for more specific treatments (antiviral, interferon).

Alcoholic Liver Disease

Alcoholic liver disease is a significant source of morbidity and mortality in the United States and worldwide. Alcoholism and its effects rank fifth on the global burden of disease by the World Health Organization.¹⁴ Alcoholic liver disease includes the entire spectrum from alcoholic hepatic steatosis (fatty liver), to alcoholic hepatitis, to fibrosis and cirrhosis. The morbidity and mortality is related to the degree of hepatic fibrosis and dysfunction, and its sequelae.

Alcoholic hepatitis

Alcoholic hepatitis is an acute inflammatory condition of the liver secondary to alcohol use and abuse. In most cases it occurs after many years of significant alcohol abuse. In its mild form the damage is reversible. However, severe cases are potentially lethal, with a mortality rate of up to 40% at 6 months.¹⁵ The most common age group for alcoholic hepatitis is 40 to 60 years.¹⁵ Clinically the presentation ranges from subclinical cases, with only laboratory abnormalities, to severe multisystem dysfunction.¹⁶ The rapid onset of jaundice is a key finding in alcoholic hepatitis.¹⁵ Other findings include right upper quadrant pain, fever, hepatomegaly, weight loss, fatigue, and anorexia. In severe cases, patients may exhibit signs of hepatic decompensation with ascites and encephalopathy.¹⁶ On examination, jaundice and hepatic tenderness are the key findings. In addition, clinical stigmata of chronic alcohol abuse such as spider angiomata, subcutaneous ecchymosis, feminization, and palmar erythema may be present.¹⁰

The pathogenesis of alcoholic hepatitis is multifactorial, involving gut permeability and endotoxemia, acetaldehyde formation, oxidant stress, and poor nutrition.¹⁶ Ingestion of ethanol alters gut permeability, allowing the absorption of endotoxin into the portal venous circulation. Once in the liver, endotoxin activates the inflammatory cascade leading to the release of inflammatory cytokines, which have local effects on the hepatocytes (injury and necrosis) as well as systemic effects such as fever, anorexia, and weight loss.¹⁵^–¹⁷ The metabolism of ethanol in the liver is an additional source of its toxicity, due to by-products of metabolism and oxidative stress.¹⁶ The breakdown of ethanol by alcohol dehydrogenase creates excess reducing equivalents, altering the NADH/NAD⁺ ratio, which subsequently leads to inhibition of fatty acid oxidation and promotes lipogenesis.¹⁵ In addition, ethanol-induced alterations in enzyme activity lead to increased hepatic lipid synthesis, fatty liver, and a decreased rate of fatty acid oxidation.¹⁸ Oxidative stress plays an important role as well. Ethanol ingestion stimulates the activity of cytochrome P450 2E1, which generates reactive oxygen radicals leading to hepatic necrosis.^15,¹⁶ Chronic alcohol abuse also impairs the regenerative capacity of the liver because inflammatory cytokines combined with poor nutrition (lack of metabolic substrates) impairs hepatic cellular replication.¹⁶

Laboratory findings in alcoholic hepatitis include liver function test abnormalities as well as nonhepatic laboratory changes. Liver function abnormalities include elevations of AST and ALT—up to 7 times the normal.¹⁹ Characteristically the ratio of AST/ALT will be greater than 2:1.²⁰ The total serum bilirubin is usually greater than 5 mg/dL and the PT is also elevated.¹⁵ Nonhepatic abnormalities include an elevated white blood cell (WBC) count and neutrophil count.¹⁵ The primary management of alcoholic hepatitis is supportive, including the maintenance of fluid and electrolyte balance, glucose supplementation as needed, thiamine, and control of withdrawal symptoms. Abstinence from alcohol is the mainstay of long-term therapy. Abstinence will prevent ongoing liver injury and allow resolution of alcoholic steatosis.²¹ Nutritional support is another cornerstone of therapy for alcoholic hepatitis. A large Veteran’s Affairs study found a 100% prevalence of protein calorie malnutrition in these patients; and the degree of malnutrition correlated with the severity of the liver dysfunction.¹⁹ Numerous other agents have been studied for therapy in alcoholic hepatitis. Corticosteroids have shown some benefit in control of the inflammatory cascade, and are currently indicated for severe cases.^15,²¹ Pentoxifylline appears to show some promise through reduction of inflammatory cytokines and decreased incidence of subsequent hepatorenal syndrome (HRS).²¹ After promising early reports, randomized controlled trials of infliximab and etanercept (direct anti–tumor necrosis factor-α agents) in patients with alcoholic hepatitis found them to be associated with increased rates of serious infection and death.^15,²¹

Complications of Chronic Liver Disease

In chronic liver disease, complications occur increasingly with rising portal venous pressures and diminishing hepatic metabolic activity. This section focuses on those complications that may present to the ED including HRS, ascites, spontaneous bacterial peritonitis (SBP), and hepatic encephalopathy (HE). Esophageal variceal bleeds are covered in the article elsewhere in this issue on GI hemorrhage.

Hepatorenal syndrome

Renal failure is a common complication in patients with liver disease. HRS is the cause in a specific subset of these patients. The combination of liver disease and renal failure portends a poor prognosis and is associated with increased mortality.²² HRS is the most common fatal complication of cirrhosis.²³

HRS is defined as acute or subacute renal failure in the presence of advanced liver disease and structurally normal kidneys. It is a functional renal failure secondary to severe renal vasoconstriction.²³ The systemic vascular resistance is markedly reduced, leading to low arterial pressures and subsequent renal vascular constriction.²⁴ While this most commonly occurs in patients with cirrhosis and ascites, it can occur in alcoholic hepatitis and in the setting of acute fulminant hepatic failure.²⁴ Renal vasoconstriction is the hallmark event in the pathophysiology of HRS. Several theories exist to explain this phenomenon. However, the resulting final common pathway is vasoconstrictor activation, which leads to sodium retention and ascites, water retention and hyponatremia, and renal vasoconstriction and HRS.²⁵

The diagnosis of HRS is complex and is beyond the scope of ED evaluation and management of liver failure patients, because it requires proof that the renal impairment is not due to volume status, shock, infection, nephrotoxic drugs, or acute tubular necrosis.²⁶ However, the diagnosis should be suspected in any patient with chronic liver disease and an elevated creatinine.

HRS is classified as type 1 and type 2. Type 1 HRS is characterized by a severe and rapidly progressive renal failure with a doubling of the serum creatinine to greater than 2.5 mg/dL in less than 2 weeks. Type 1 HRS usually develops in the face of an acute precipitant, with SBP the most common insult.²⁷ Type 1 HRS is rapidly progressive, and has an extremely high mortality with a median survival of 1 to 2 weeks.²³ Type 2 HRS is characterized by a slow and gradual increase in serum creatinine with no precipitating events. Refractory ascites is the dominant clinical feature.²⁷ It is important clinically to distinguish between types 1 and 2 HRS, because type 1 is an indication for evaluation for liver transplantation.²³

The mainstay of ED management of HRS is supportive, although the only definitive therapy is transplantation.²⁸ Early therapy should be aimed at correcting any precipitating events such as SBP, infection, and GI bleeding. In type 1 HRS, the underlying precipitating event should be treated aggressively. Early antibiotic support is indicated, because infectious processes are the most common precipitating events.²³ Diuretics should be discontinued and the intravascular volume should be assessed. Early volume expansion with albumin may improve the renal blood flow.²³

Spontaneous bacterial peritonitis

Cirrhosis leads to portal hypertension through the obstruction of portal blood flow. This process stimulates a cascade of events, leading to activation of the renin-angiotensin-aldosterone axis, sodium and water retention, and the development of ascites due to overflow of hepatic lymphocytic fluid into the peritoneal cavity. In addition, increased hepatic sinusoidal hydrostatic pressure and decreased plasma oncotic pressure lead to the excess production of hepatic lymphatic fluid, which ultimately leaks into the peritoneal cavity forming ascites.²⁹ SBP is an infection of ascitic fluid.³⁰

SBP should be suspected in a patient with abdominal pain and preexisting liver disease and ascites. Fever is not always present and the abdominal pain may not be severe. Worsening ascites may be the only early symptom.³⁰ The patient may also have an altered mental status, GI bleeding, and azotemia.²⁹ The prevalence of SBP ranges from 10% to 30% in patients with preexisting ascites.⁵ While SBP is readily treatable, its development increases the risk of other complications, such as type 1 HRS.

The pathogenesis of SBP involves the translocation of bacteria, most commonly from the GI tract, into the blood stream. The resulting bacteremia leads to infection of the ascitic fluid through exchange of fluids between the intravascular space and the peritoneal fluid. Escherichia coli is the most common pathogen isolated, with Klebsiella pneumoniae the second most common.³¹

The diagnosis of SBP is relatively straightforward. An abdominal paracentesis should be performed in anyone suspected of having SBP and without contraindications to the procedure. The finding of an ascitic WBC count of greater than 1000 cells/μL and a polymorphonuclear count of greater than 250 cells/μL is diagnostic. A pH of less than 7.35 in the ascitic fluid is supportive of the diagnosis. The ascitic fluid should be cultured, but a positive culture is not necessary to make the diagnosis. Approximately 30% will return a positive culture.³⁰

Treatment should be started with the finding of inflammatory ascitic fluid. Third-generation cephalosporins are the treatment of choice. Regarding prevention, treatment with norfloxacin has been shown to be effective at decreasing the incidence of primary SBP as well as recurrence of SBP.³² The most feared complication of SBP is type 1 HRS, which occurs in up to 30% of patients and carries an exceptionally high mortality. Recurrence of SBP occurs in approximately 70% of patients in 1 year. Long-term prophylaxis with fluoroquinolones has decreased this percentage, but SBP due to quinolone-resistant bacteria is on the increase.⁵

Hepatic encephalopathy

HE is a condition in which a patient with liver dysfunction and/or portal-systemic shunting displays neurologic and/or psychological abnormalities without another pathologic condition to explain the findings. HE may present in acute or chronic liver failure. HE is a key feature of fulminant hepatic failure and a is common complication of chronic liver disease. HE includes presentations ranging from mild altered mental status to coma, and neuromuscular abnormalities ranging from tremor and asterixis to decerebrate posturing.³³ The symptoms result from the inability of the liver to detoxify intestinal toxins.³³

HE is classified into 3 types based on the underlying liver disease. Type A HE occurs in acute liver failure. Type B is caused by portosystemic shunting without intrinsic hepatocellular disease. Type C, the most common form, arises from cirrhosis-induced portal-systemic shunting, and may be persistent or episodic.³⁴ HE is staged using the West Haven Criteria from stage 0 to 4. Stage 0 shows no change in consciousness and behavior and no neuromuscular changes. Stage 1 involves a trivial lack of awareness with a shortened attention span, and impairment in addition and subtraction abilities. Asterixis and tremor may also begin to appear. Stage 2 involves lethargy, disorientation, and inappropriate behavior. Slurred speech and asterixis will be present as well. Stage 3 involves gross disorientation and bizarre behavior with a somnolent (but arousable) state. The patient may have muscular rigidity, and asterixis is usually absent. Stage 4 involves a comatose state that may progress to decerebrate posturing.³⁴

The pathogenesis of HE is complex and multifactorial. The key feature is hepatic dysfunction (most commonly cirrhosis-induced portal-systemic shunting) or noncirrhotic portal-systemic shunting leading to the inability of the liver to clear ammonia, γ-aminobutyric acid agonists, and manganese. These substances subsequently cross the blood-brain barrier, leading to altered neurotransmission and neuronal impairment. Neurologic impairment occurs through both direct toxic effects and indirect effects through neuroinhibition. Oxidative stress and inflammatory cytokines play a role as well.^7,^33,³⁵

The diagnosis of HE requires a thorough history as well as physical and laboratory/radiological evaluation. The diagnosis should be suspected in any patient with known liver disease who presents with altered mental status and neuromuscular abnormalities. However, a thorough evaluation is indicated to rule out other causes of the altered mental status. The differential diagnosis of HE includes, but is not limited to, metabolic encephalopathy (uremia, sepsis, hypoxia, and hypoglycemia), intracranial bleeding, cerebrovascular accident/transient ischemic attack, central nervous system infections or neoplasms, and alcohol withdrawal/intoxication states.³⁶ An elevated serum ammonia is typical of HE. There has been extensive controversy over the years as to whether serum ammonia levels correlated with the severity of HE; however, it appears that if drawn and analyzed appropriately, serum ammonia levels do correlate with the severity of HE.³⁷ Computed tomography (CT) of the head should be performed to rule out structural causes for the altered mental status, and finally the workup should include an evaluation for precipitating causes.³⁶

The management of HE involves simultaneous attention to multiple goals that include general supportive care, treatment of precipitating events, inhibition of ammonia production and absorption, and avoidance of sedatives unless absolutely necessary. General supportive care entails management of the patient’s fluid and electrolyte balance, protection of the airway, and cardiovascular stabilization. Treatment and correction of the precipitating events is extremely important, given that HE will not improve until the precipitant is removed. Common precipitants include gastrointestinal bleeding, infection, renal failure, and dehydration.³⁸ Nonabsorbable disaccharides such as lactulose and lactitol are administered to help decrease the ammonia load from the gut. These medications work by decreasing both the absorption and production of intestinal ammonia, and are considered first-line therapy for HE.³⁹ Antibiotics are administered in HE to decreased ammonia production by decreasing the number of urease-producing bacteria in the gut.³⁹ Oral neomycin has been used for many years although it is potentially ototoxic and nephrotoxic.³⁹ Other antibiotics studied for this purpose include metronidazole, oral vancomycin, and rifaximin.³⁶ Rifaximin has a favorable side effect profile compared with neomycin.³⁹ Finally, recurrent or intractable HE is an indication for evaluation for liver transplantation.³⁸

Emergency diseases of the gallbladder

Biliary tract disease is one of the most common gastrointestinal disorders in the United States, ranging from asymptomatic cholelithiasis to biliary colic, cholecystitis, choledocholithiasis, cholangitis, and malignancy. With direct costs of $5.8 billion annually, biliary disease is the second most expensive digestive disease in the United States,⁴⁰ and accounts for 3% to 9% of hospital admissions for acute abdominal pain.⁴¹ Cholecystitis is the most prevalent surgical disease in industrialized countries. An estimated 700,000 cholecystectomies are performed annually in the United States.⁴² The vast majority of biliary tract disease is caused by gallstones.^42,⁴³ Approximately 20 to 25 million Americans have gallstones,^42,⁴⁴ of which 1% to 2% per year become symptomatic.⁴⁵ Thus, whereas the annual percentage of patients who develop complications is low, the incidence of acute disease is high because of the high prevalence of gallstones in the population.

Anatomy and Pathophysiology

Hepatocytes secrete bile into the bile canaliculi, which are formed by the cell walls of the hepatocytes. Bile then flows into ductules, which coalesce into successively larger ducts. The hepatic ducts course along with branches of the portal vein and hepatic artery, which together form the portal triad. The right and left hepatic ducts join to form the common hepatic duct. The cystic duct drains the gallbladder and joins the common hepatic duct to form the common bile duct. The common bile duct is usually situated anterior and to the right of the portal vein; it courses caudally behind the first portion of the duodenum, then anterior to the pancreas where it is joined by the pancreatic duct. It drains into the second part of the duodenum at the ampulla of Vater, the orifice of which is controlled by the sphincter of Oddi. Variations in hepatobiliary anatomy are common.⁴⁶

Bile is necessary for proper digestion and absorption of dietary fats and fat-soluble vitamins, as well as the fecal excretion of excess cholesterol and the by-products of red blood cell catabolism. The gallbladder stores bile between meals and also actively concentrates it by removing water and inorganic anions (chloride, bicarbonate).⁴⁴ Gallstones are formed when cholesterol and calcium salts precipitate out of supersaturated bile. Bile stasis and a nidus for nucleation/crystallization are also factors.⁴⁴ Although most gallstones are composed primarily of cholesterol (cholesterol stones), pigmented stones can also occur. Brown pigmented stones are more common in Asians and with bacterial contamination of the biliary tree, whereas black stones are associated with hemolytic disorders, cirrhosis, cystic fibrosis, and ileal disease.⁴⁴ Historically in the United States, up to 10% to 25% of stones were pigmented⁴⁷; however, the percentage of cholesterol stones seems to be increasing as obesity becomes more common.^44,⁴⁸ Biliary sludge is a viscous mixture of small cholesterol or calcium bilirubinate crystals that have begun to precipitate; it can lead to the same symptoms and complications as gallstones.

Gallstones become symptomatic when they cause obstruction of the biliary system. When the gallbladder contracts against an obstructing gallstone (typically lodged in the gallbladder neck), biliary colic ensues. If the obstruction is relieved, the pain resolves. Prolonged obstruction leads to increased intraluminal pressure, wall edema, and an acute inflammatory response.⁴⁹ If the obstruction continues, the gallbladder wall becomes ischemic and further inflammatory mediators are released. Secondary bacterial infection may result in formation of an abscess or empyema within the gallbladder. Perforation may lead to diffuse peritonitis. Gas-forming organisms may lead to emphysematous cholecystitis.

Bacteria are cultured from the bile of patients undergoing cholecystectomy for uncomplicated gallstone disease in 13% to 32% of patients, and in 41% to 54% of those with acute cholecystitis; healthy individuals do not have bacterial isolates.⁵⁰ It is more common to find bacteria in pigment-stone–containing bile than in cholesterol-stone–containing bile (82% vs 26% in one study).⁵¹ Bacteria are more commonly found in the bile of those with biliary obstruction, acute cholecystitis, common duct stones, cholangitis, and nonfunctioning gallbladders; in males, the elderly, and those with biliary stents.⁵² Typical bacterial isolates include enterobacteriaceae (68%), enterococci (14%), bacteroides (10%), and Clostridium species (7%).⁵³

Risk factors for cholesterol gallstones are listed in Box 1.^44,^54,⁵⁵ Age and gender are the most important risk factors for development of gallstone disease. Gallstones are rare in children, but may be associated with congenital anomalies, Down syndrome, and hemolytic diseases (such as sickle cell disease). By the fifth decade of life, approximately 15% of women have gallstones, increasing to approximately 40% by the ninth decade⁴⁷; the incidence of gallstones increases by 1% to 3% per year in adulthood,^44,⁵⁴ depending on risk factors. The female to male ratio of gallstones is approximately 4:1 in those younger than 40 years, and 2:1 in older age groups.⁵⁴ More females develop gallstones, so the overall incidence of cholecystitis is higher in females (the overall female to male ratio is 3:1), but a higher percentage of men with gallstones develop cholecystitis.⁴²