Chapter 33: Hepatobiliary Disorders

GENERAL CONSIDERATIONS

Approximately 10–20% of the population has gallstones, making biliary pathology an increasing consideration in a patient with abdominal pain. Females are twice as likely to have gallstones. Gallstones are more frequently seen with increasing age and obesity, and are more common in Caucasians and Native Americans than African Americans. Most patients with cholelithiasis remain asymptomatic and never require surgery, but the sequelae of biliary disease remains significant: symptomatic cholelithiasis, gallstone pancreatitis, acute cholecystitis, chronic cholecystitis, choledocholithiasis, and ascending cholangitis. Understanding the basic pathophysiology of each of these conditions is essential to appropriately diagnose and treat patients with biliary disease.

A basic understanding of biliary disease requires a vocabulary of terms used in describing them. Many have similar sounding names and can be confusing. A summary of the definitions can be found in Table 33-1. Although the treatment of most biliary diseases ultimately requires cholecystectomy, each condition must be evaluated and treated in a unique fashion.

OPERATIVE PROCEDURES & COMPLICATIONS

Laparoscopic Cholecystectomy

Laparoscopic cholecystectomy has replaced the open operation as the gold standard for removing the gallbladder. Many studies have documented an improved recovery time, decreased postoperative ileus, and decreased pain along with improved aesthetics associated with laparoscopy.

Although associated with less morbidity, laparoscopic cholecystectomy does require pneumoperitoneum (insufflation of carbon dioxide gas into the abdomen) and may not be feasible in patients with other severe comorbid conditions (eg, the morbidly obese, severe congestive heart failure, advanced pulmonary disease, uncontrolled coagulopathy). If operation is required, open cholecystectomy remains the only viable option for these patients.

Advanced Laparoscopic & Robotic Cholecystectomy

In carefully selected patients, both single-incision laparoscopic cholecystectomy (SILC) and robotic cholecystectomy have been shown to be feasible and safe approaches in institutions with available technology. Although both techniques have been noted to have slightly longer operative times (mean difference of 18.5 minutes), a steep learning curve is observed and no increase in overall complication rates has been reported.

Postoperative Complications

The most feared complication of laparoscopic cholecystectomy is injury to the common bile duct. The reported incidence of bile duct injuries varies from 0% to 3% depending on the underlying pathology necessitating cholecystectomy. Minor biliary injuries include cystic duct leaks and biliary leaks from the hepatic parenchyma. These injuries may be managed with percutaneous drain placement or endoscopic retrograde cholangiopancreatography (ERCP) to facilitate drainage into the duodenum.

Major biliary injuries include clipping or transection of the common hepatic or common bile duct. When identified intraoperatively, these injuries are best managed with immediate repair, requiring open operation and a skilled surgeon. Those biliary injuries identified in the postoperative setting are best treated with externalization of the bile flow (percutaneous transhepatic biliary drainage) and a definitive repair at a later date, often 2–3 months following the initial injury. In most circumstances, a Roux-en-Y hepaticojejunostomy is required to reconstruct the biliary tree.

Patients who present with jaundice after elective cholecystectomy should be evaluated for retained common bile duct stones or a biliary injury. Presence of common bile duct dilatation on abdominal ultrasound should prompt immediate ERCP for both diagnosis and treatment. Patients undergoing elective cholecystectomy should be aware that ≤12% of those undergoing surgery may experience postcholecystectomy syndromes, including diarrhea (usually responsive to dietary measures), continued abdominal pain, or dyspepsia. Late sequelae of cholecystectomy can include bile duct strictures or recurrent bile duct stones. Patients suspected of these diagnoses should be promptly referred back to the operating surgeon.

CHOLELITHIASIS

Asymptomatic Cholelithiasis

A landmark study from the University of Michigan followed the course of 123 faculty members identified as having asymptomatic gallstones during a routine health examination. After >2 decades of follow-up, 14 (11%) patients went on to develop complications requiring surgery. Subsequent studies have not demonstrated a survival advantage with prophylactic cholecystectomy, and as a result, cholecystectomy for asymptomatic cholelithiasis is rarely indicated. Hemolytic conditions such as hereditary spherocytosis remain one indication to consider prophylactic cholecystectomy during other abdominal operations such as splenectomy.

Symptomatic Cholelithiasis

Unlike asymptomatic cholelithiasis, symptomatic cholelithiasis will generally necessitate operative intervention. The typical patient presentation will include RUQ abdominal pain, usually following a fatty meal and frequently associated with nausea (biliary colic). The pain can be severe and debilitating, and a trip to the emergency room is not an infrequent occurrence. Symptoms are related to transient obstruction of the gallbladder neck or infundibulum by stones or biliary sludge. As the gallbladder attempts to contract in response to cholecystokinin secretion, the obstructed cystic duct prevents the egress of bile from the gallbladder into the biliary system, resulting in acute RUQ pain. In addition to RUQ pain, the character of biliary colic is often described as a colicky or crampy pain that may radiate to the back or shoulder. The pain is generally postprandial in nature and typically resolves within 1–2 hours. Persistence of pain beyond this time should prompt the clinician to suspect acute cholecystitis or other disorders discussed later.

In most circumstances, there will be no abnormalities in the liver function tests or complete blood counts of patients with symptomatic cholelithiasis. An abdominal ultrasound will reveal the presence of cholelithiasis without gallbladder wall thickening or pericholecystic fluid. The treatment of symptomatic cholelithiasis remains elective cholecystectomy in patients suitable to undergo a general anesthetic. Following cholecystectomy, most patients (95%) with symptomatic cholelithiasis will have no further sequela of biliary diseases.

Chronic Cholecystitis

The term chronic cholecystitis is often used synonymously with symptomatic cholelithiasis. It may also be a result of multiple episodes of untreated acute cholecystitis. The gallbladder will become scarred from multiple episodes of inflammation. Pathological examination will demonstrate Rokitansky-Aschoff sinuses. The patient will usually describe multiple episodes of biliary colic. Ultrasound will demonstrate cholelithiasis and occasionally gallbladder wall thickening (from the scarring).

The treatment of chronic cholecystitis is cholecystectomy. Following cholecystectomy, most patients recover with no adverse effects.

ACUTE CHOLECYSTITIS

Acute cholecystitis is caused most commonly by obstruction of the cystic duct, resulting in localized edema and inflammation. Biliary cultures of most patients reveal bacteria. Women are 3 times more likely to develop acute cholecystitis than men. Over 90% of cases of acute cholecystitis are related to gallstones causing obstruction (calculous cholecystitis). The remaining cases are classified as acalculous cholecystitis, in which other comorbid conditions result in gallbladder wall ischemia or biliary stasis.

Acute cholecystitis is defined by the triad of RUQ pain, fever, and leukocytosis. Abdominal ultrasound will demonstrate gallbladder wall thickening (> 3 mm) with pericholecystic fluid. Symptoms typically begin after a meal. The pain is similar to, but far more severe than, that of symptomatic cholelithiasis. In cases where acalculous cholecystitis is suspected or when ultrasound is inconclusive, radionucleotide scanning [ie, hepatobiliary iminodiacetic acid (HIDA)] may be used. Presence of radionucleotide in the extrahepatic biliary tree without filling the gallbladder is diagnostic of acute cholecystitis.

The treatment of acute cholecystitis is cholecystectomy. The timing of the operation is a controversial subject matter for general surgeons. Localized edema and subsequent scar formation after an episode of acute cholecystitis can make laparoscopic cholecystectomy difficult. Traditional teaching has been that cholecystectomy should be performed within 3 days of onset of symptoms—before myoepthelial changes can occur in the right upper quadrant. The localized edema associated with acute cholecystitis aides with dissection of tissue planes and facilitates cholecystectomy. Compared to delayed cholecystectomy (after 7 days of symptoms), this approach is associated with a decreased conversion rate to open operation (2% vs 30%) and decreased recovery time (12 vs 28 days). Many patients present, however, outside the initial 72-hour window. Most current recommendations extend the period for safely performing laparoscopic cholecystectomy during acute cholecystitis to within one week of symptom onset. If outside of this 7-day window, many surgeons advocate a course of intravenous and (later) oral antibiotics with a plan to perform cholecystectomy in a delayed fashion at least 6 weeks later. This delay will allow the scarring in the right upper quadrant to subside, allowing for safer and easier dissection during laparoscopy. If the patient has continued pain or recurrence of cholecystitis during this waiting period, laparoscopic cholecystectomy should be attempted immediately. The patient should be counseled on the high probability of conversion to an open operation. For patients who are not operative candidates, percutaneous tube cholecystotomy remains a viable option to drain the infected bile as a bridge to elective cholecystectomy when the patient has stabilized.

Untreated cholecystitis can lead to gallbladder ischemia, necrosis, or perforation, resulting in biliary leak or fistula formation to the surrounding structures. Those undergoing successful immediate cholecystectomy will generally have no further sequel of biliary disease. The potential for choledocholithiasis and common bile duct injury must be considered in patients presenting with jaundice after cholecystectomy.

Choledocholithiasis

Choledocholithiasis, or common bile duct stones, are present in ≤10% of patients undergoing cholecystectomy. The treatment is cholecystectomy with evaluation of the biliary tree and clearance of all stones within the ductal system. Choledocholithiasis should be suspected in any patient with biliary ductal dilatation seen on imaging, elevated bilirubin levels (conjugated), elevated alkaline phosphatase levels, or elevated amylase and lipase levels. Patients presenting with choledocholithiasis may develop symptoms related to obstruction of the bile duct, pancreatic duct, or both.

Gallstone Pancreatitis

Gallstones small enough to pass through the biliary tree may enter the pancreatic duct and potentially obstruct at the level of the ampulla of Vater. These stones will then cause obstruction of the pancreatic ductal system, resulting in pancreatitis. Gallstones are associated with approximately 45–50% of all cases of pancreatitis in the United States.

Patients presenting with pancreatitis typically have varying degrees of abdominal pain—usually located in the epigastrium or right upper quadrant. The pain may radiate to the back or shoulders. Nausea and vomiting are common. Laboratory studies will reveal elevation of lipase and (occasionally) amylase. If gallstones remain in the biliary tree, then liver transaminases and bilirubin may also be elevated. Although ultrasound is useful to confirm presence of gallstones, CT scanning is useful in delineating the severity of pancreatitis.

The treatment of gallstone pancreatitis is eventual cholecystectomy. As the gallbladder is the source of the stones, cholecystectomy will prevent subsequent episodes of pancreatitis. Cholecystectomy should not be attempted until the resolution of pancreatitis. Treatment for pancreatitis involves bowel rest with intravenous hydration. Severe cases of pancreatitis may require ICU admission with cardiovascular and respiratory support. Regardless of the patient’s condition, cholecystectomy should be postponed until after the pancreatitis has resolved. It has been suggested that morbidity and mortality is improved if these patients undergo ERCP within 2 days of onset of symptoms. ERCP may be able to remove an impacted stone and thus allow for pancreatic decompression. This approach is generally considered in patients with moderate or severe pancreatitis.

The presence or absence of a persistent bile duct stone should be determined prior to proceeding with cholecystectomy. In most circumstances, normalization of serum lipase, amylase, and liver function tests (if originally elevated) occurs rapidly. In these circumstances, no imaging of the biliary tree is required because of the low probability of a persistent bile duct stone. However, patients with persistent abnormalities of their liver functions, amylase, or lipase should be evaluated for the presence of common bile duct stones. Biliary imaging may be obtained by means of intraoperative cholangiography at the time of cholecystectomy, perioperative ERCP, or magnetic resonance cholangiopancreatography (MRCP). MRCP is the least invasive modality but is only diagnostic. ERCP allows for both visualization and extraction of stones of diameter ≤1.5 cm. ERCP may be utilized to extract common bile duct stones either antecedent or subsequent to cholecystectomy. Common bile duct stones not amenable to endoscopic removal are removed operatively by performing a common bile duct exploration.

The overall long-term outcome of patients is related to the severity of the pancreatitis. Localized morbidity includes pancreatic necrosis, splenic vein thrombosis with gastric varices, hemorrhagic pancreatitis, and pancreatic abscesss formation. Systemic morbidity can result in multisystem organ failure or even death.

Cholangitis

Cholangitis is defined as inflammation of the biliary system. It is most commonly caused by an impacted gallstone at the ampulla of Vater preventing bile drainage into the duodenum, although other etiologies such as extrinsic compression from an adjacent mass, inflammatory process, or a primary tumor of the ampulla, duodenum, or bile duct should also be considered. Cholangitis is considered a medical emergency.

Patients with cholangitis may present with Charcot’s triad (fever, RUQ pain, and jaundice) or with Reynold’s pentad (the addition of hypotension or mental status changes). Laboratory studies will show hyperbilirubinemia and leukocytosis. Ultrasound will likely show biliary ductal dilatation.

With clinical suspicion of cholangitis, patients should be immediately resuscitated and given broad-spectrum antibiotics. Biliary decompression should be urgently performed by ERCP. If ERCP fails to resolve the obstruction or is not available, percutaneous transhepatic cholangiography (PTC) with drainage may be performed. In the presence of stones, once biliary decompression has been performed, cholecystectomy should be performed electively following resolution of the cholangitis. In rare circumstances in which percutaneous or endoscopic biliary drainage is not possible, urgent cholecystectomy with common bile duct exploration should be performed.

The mortality associated with cholangitis varies widely and is related to the underlying etiology of the cholangitis. Cholangitis secondary to stones is associated with a low overall mortality provided the patient can be successfully supported through the infectious period. Cholangitis related to an underlying periampullary malignancy requires careful oncologic consideration prior to surgical intervention. This may require a more involved oncologic resection (such as a pancreaticoduodenectomy or extrahepatic biliary resection) or palliative care depending on the extent of the malignancy. In the event of an unresectable periampullary tumor, a biliary bypass (hepaticojejunostomy) may be considered. Most periampullary cancers are associated with very poor 5-year survival even with complete extirpation of the tumor.

Biliary Dyskinesia

A small group of patients will present with RUQ abdominal pain and symptoms that follow the pattern of biliary disease but will have essentially negative imaging for biliary pathology. One key factor in ascertaining whether the gallbladder is contributing to their pain would be to perform a HIDA scan with cholecystokinin (CCK) injection. Likewise, measurement of gallbladder ejection fraction (EF) during this scan can further identify patients with biliary pathology. Ejection fractions of <35% are considered pathophysiologic and warrant evaluation for cholecystectomy. Reproduction of pain with CCK injection is diagnostic for biliary dyskinesia, and these patients benefit from referral for cholecystectomy. Laparoscopic cholecystectomy has been reported to alleviate pain in ≤94% of patients with biliary dyskinesia. Patients with the highest success rate were those presenting with complaints of nausea, pain, or with EF <15% by HIDA scan. Patients with vague abdominal complaints should be cautioned that laparoscopic cholecystectomy is not guaranteed to alleviate their symptoms, and the decision to proceed with surgical intervention should be made carefully on a case-by-case basis.

BILIARY MALIGNANCIES

Gallbladder Polyps

Gallbladder polyps are present in ~5% of the population and are usually found incidentally during abdominal ultrasonagraphy. The different types of polyps include cholesterolosis, adenomyomatosis, hyperplastic cholecystosis, and adenocarcinomatosis. The goal of surgical management is to identify which polyps are cancerous (adenocarcinoma) or at risk of developing cancer (adenomyomatosis) and select these patients for cholecystectomy.

Unfortunately, short of cholecystectomy, there is currently no way to distinguish among the different types of gallbladder polyps. With the relative safety of laparoscopic cholecystectomy, some advocate surgery immediately after discovering polyps. Patients who have polyps with gallstones or are aged >50 years should be referred for cholecystectomy. Further imaging techniques, including endoscopic ultrasound (EUS), have been advocated for small polyps. Recent recommendations include removing polyps of diameter ≥6 mm because of an increased likelihood of malignancy. If cancer is present in the surgical specimen, the depth of invasion dictates the next course of therapy.

Gallbladder Cancer

Patients with gallbladder cancer have presentations similar to those with symptomatic cholelithiasis or chronic cholecystitis. Presentation is often late, and with advanced disease, systemic complaints such as gradual weight loss and loss of appetite also appear. Since presentation is often assumed to be related to gallstone disease, ultrasound is usually the initial diagnostic modality used. Ultrasound findings of a mass >1 cm, calcified gallbladder wall, discontinuity of gallbladder wall layers, and loss of interface between the gallbladder wall and the liver should raise suspicion of gallbladder cancer. Computed tomography is useful in these circumstances to delineate anatomic structures for resectability, as well as evidence of metastatic disease.

The presence of paraaortic or peripancreatic lymphadenopathy is deemed unresectable disease. This can be confirmed with endoscopic ultrasound with biopsies. Cancers that are limited to the mucosa or muscular layer of the gallbladder can be treated with cholecystectomy with negative margins alone. Tumors that invade the pericholecystic connective tissue require resection of the gallbladder fossa with en bloc cholecystectomy. Tumors that invade the liver require formal resection of the involved segments. Unfortunately, 15–50% of tumors that penetrate the muscular wall of the gallbladder have nodal disease that will render them unresectable. Gallbladder cancer may also be found incidentally in cholecystectomy specimens. If it is invasive, additional resection of involved hepatic margins will be necessary. The 5-year survival of early tumors (those confined to the muscular or mucosal layer) is excellent (90–100%). The survival for more advanced tumors is measured in terms of weeks or months.

Choledochal Cyst

Classically, a choledochal cyst is described as a palpable RUQ mass in a young female with jaundice. Most choledochal cysts are described in Asian populations but are increasingly seen in the United States, males, and older patients. Choledochal cysts are classified by their anatomic location; most involve solitary fusiform dilatation of the extrahepatic biliary tree. Their presentation in Western series is similar to that of symptomatic cholelithiasis. They can be easily seen on ultrasound—provided the ultrasonographer evaluates the biliary tree in addition to the gallbladder.

Choledochal cysts are associated with a 70-fold increased incidence of cholangiocarcinoma, so surgical resection is indicated when discovered. Operative treatment involves resection of the entire extrahepatic biliary tree, cholecystectomy, and reconstruction with a Roux-en-Y hepaticojejunostomy. Surgical resection is considered curative; Edil et al. (2008) reported no subsequent malignancy over 30 years in patients without cancer at the time of cyst excision.

Cholangiocarcinoma

For various reasons, cholangiocarcinomas along with other RUQ malignancies are associated with very poor survival: (1) these lesions often present late and are not amenable to resection; (2) their biological activity is not well understood, and systemic therapy offers little benefit; and (3) operative resection is technically difficult, and patients need to be seen in specialized centers.

The vast majority of cholangiocarcinomas present with jaundice, sometimes in the setting of cholangitis. Ultrasound will often show a dilated proximal biliary tree. ERCP and endoscopic ultrasound are useful to delineate the tumor. Preoperative endoscopic brushings are often nondiagnostic and should not be aggressively pursued in patients with resectable disease on cross-sectional imaging. While most proximal cholangiocarcinomas (70%) are not amenable to resection, approximately half of distal tumors may be resected. Resection involves pancreaticoduodenectomy for distal tumors and extrahepatic biliary resection with Roux-en-Y hepaticojejunostomy for proximal disease. The 5-year survival rate remains poor even after complete resection (20–25%). For patients with unresectable disease, survival is again measured in weeks or months.

VIRAL HEPATITIS

Acute viral hepatitis is a worldwide problem, and in the United States alone there are probably between 200,000 and 700,000 cases per year according to the Centers for Disease Control and Prevention (CDC). Over 32% of cases are caused by hepatitis A virus (HAV), 43% by hepatitis B virus (HBV), 21% by hepatitis C virus (HCV), and the remainder are not identified. Although few deaths (~250) due to acute hepatitis are reported annually, considerable morbidity can result from chronic hepatitis caused by HBV and HCV infections, and mortality from complications can be pronounced for years to come.

Hepatitis A

General Considerations

Hepatitis A virus (HAV), first identified in 1973, is the prototype for the former diagnosis of infectious hepatitis. Over the past several decades, the incidence of HAV infection has varied considerably, and a high number of cases have gone unreported. HAV is a very small viral particle that is its own unique genus (hepatovirus).

Most individuals infected worldwide are children. In general, there are four patterns of HAV distribution (high, moderate, low, and very low), which roughly correspond to differing socioeconomic and hygienic conditions. Countries with poor sanitation have the highest rates of infection. Most children aged <9 years in these countries manifest evidence of HAV infection. Countries with moderate rates of infection have the highest incidence in later childhood; food- and waterborne outbreaks are more common. In countries with low endemicity, the peak age of infection is likely to be at early adulthood, and, in very low endemic countries, outbreaks are uncommon.

Hepatitis A is usually transmitted by ingestion of contaminated fecal material of an infected person by a susceptible individual. Contaminated food or water can be the source of infection, but occasionally infection can occur by contamination of different types of raw shellfish from areas contaminated by sewage. The virus can survive for 3–10 months in water. Other cases of infection by blood exposures have been reported but are less common. The incubation period for HAV averages 30 days, with a range of 15–50 days.

In countries of low endemicity, persons at greatest risk for infection include travelers to intermediate and high-HAV-endemic countries, men who have sex with men (MSMs), intravenous drug users, and persons with chronic liver disease, including those who have received transplants. In areas of high endemicity, all young children are at increased risk.

Prevention

Currently in the United States, the CDC recommends that certain populations at increased risk be considered for preexposure vaccination; these include the groups listed earlier. In addition, the CDC now recommends universal immunization for all children aged >1 year. The immunization schedule consists of three doses for children and adolescents, and two for adults. In groups with the potential for high risk of exposure, including any adult aged >40 years, prevaccination testing for prior exposure may be cost-effective. The appropriate test is the total anti-HAV. Travelers aged <40 years who receive the vaccine may assume to be protected after receiving the first dose, although the second dose is desired for long-term protection. For certain travelers (older adults and those with underlying medical conditions), immunoglobulin (Ig) may be given in a different site for additional protection within 2 weeks of travel. A combination vaccine with HBV is available for persons aged >18 years who are immunocompetent and is used on the same three-dose schedule as HBV.

Immunoglobulin or hepatitis A vaccine (if previously unvaccinated) may also be used for postexposure prophylaxis in healthy patients between 12 months and 40 years of age, if given within 14 days, and would most often be used for household or intimate contacts of an infected person, in some institutional settings, or if a common source is identified. For persons with chronic illness, or those aged <12 months or >40 years, Ig is preferred.

Clinical Findings

A, Symptoms and Signs

The symptoms and signs of acute viral hepatitis are quite similar regardless of type and are difficult to distinguish on the basis of clinical findings. The prodrome for viral hepatitis is variable and may be manifested by anorexia, including changes in olfaction and taste, as well as nausea and vomiting, fatigue, malaise, myalgias, headache, photophobia, pharyngitis, cough, coryza, and fever. Dark urine and clay-colored stools may be noticed 1–5 days before jaundice.

Clinical jaundice varies considerably and may range from an anicteric state to rare hepatic coma. In acute HAV infection, jaundice is usually more pronounced in older age groups (ie, 70–80% in those aged 14 years) and rare in children aged <6 years (<10%). Weight loss may also be present, as well as an enlarged liver (70%) and splenomegaly (20%). Spider angiomata may be present without acute liver failure. Patients may also report a loss of desire for cigarette smoking or alcohol.

B. Laboratory Findings

Usually, the onset of symptoms coincides with the first evidence of abnormal laboratory values. Acute elevations of ALT and AST are seen, with levels as high as 4000 units or more in some patients. The ALT level is usually higher than the AST. When the bilirubin level is >2.5, jaundice may be obvious. Bilirubin levels may go from 5 to 20, usually with an equal elevation of conjugated and unconjugated forms. The prothrombin time is usually normal. If significantly elevated, it may signal a poor prognosis. The complete blood count may demonstrate a relative neutropenia, lymphopenia, or atypical lymphocytosis. Urobilinogen may be present in urine in the late preicteric stage.

Serum IgM antibody (anti-HAV) is present in the acute phase and usually disappears within 3 months, although occasionally it persists longer. IgG anti-HAV is used to detect previous exposure and persists for the lifetime of the patient. The more commonly available test for IgG anti-HAV is the total anti-HAV.

Treatment

Treatment for the most part is symptomatic, with many clinicians prohibiting only alcohol during the acute illness phase. Most patients can be treated at home.

Prognosis

In the vast majority of patients with HAV, the disease resolves uneventfully within 3–6 months. Rarely, fulminant hepatitis may develop, with acute liver failure and high mortality rates. Rare cases of cholestatic hepatitis, with persistent bilirubin elevations, have also been reported. Some patients develop relapsing hepatitis, in which HAV is reactivated and shed in the stool. Affected patients demonstrate liver function test abnormalities, but virtually all recover completely. HAV does not progress to chronic hepatitis.

Hepatitis B

General Considerations

Hepatitis B virus (HBV) is a double-shelled DNA virus. The outer shell contains the hepatitis B surface (HBsAg). The inner core contains several other particles, including hepatitis core antigen (HBcAg) and HBeAg. These antigens and their subsequent antibodies are described in more detail later.

Worldwide, over 400 million people are infected with HBV, but the distribution is quite varied. More than 45% of the global population live in areas of high incidence (infections in >8% of population). There, the lifetime risk of infection is over 60%, and early childhood infections are very common. Intermediate-risk areas (infections in 2–7% of the population) represent 43% of the global population. The lifetime risk of infection in these areas is between 20% and 60%, and infections occur in various age groups. In low-risk areas (infections in <2%), which represent ~12% of the global population, the lifetime risk of infection is <20% and is usually limited to specific adult risk groups.

In the United States, HBV is normally a disease of young adults. The largest numbers of cases are reported in adults aged 20–39 years, but many cases in younger age groups may be asymptomatic and go unreported. Of the specific risk groups in the United States, over 50% in recent studies are those with sexual risk factors (more than one sex partner in the past 6 months, sexual relations with an infected person, or MSM transmission). Over 15% had a history of injection drug use, and 4% had other risk factors such as a household contact with HBV or a healthcare exposure. The mode of transmission can thus be sexual, parenteral, or perinatal, through contact of the infant’s mucous membranes with maternal infected blood at delivery.

Body fluids with the highest degree of concentration of HBV are blood, serum, and wound exudates. Moderate concentrations are found in semen, vaginal fluid, and saliva, and low or nondetectable amounts are found in urine, feces, sweat, tears, or breast milk. Saliva can be implicated in transmission through bites, but not by kissing.

The average incubation period for HBV is between 60 and 90 days, with a range of 45–180 days. Although the incidence of jaundice increases with age (<10% of children <5 years demonstrate icterus compared with 30–50% of those aged >35 years), the likelihood of chronic infection with HBV is greater when infection is contracted at a younger age. Between 30% and 90% of all children who contract HBV before the age of 5 years develop chronic disease, compared with 2–10% of those aged >35 years.

Prevention

Current immunization recommendations in the United States call for routine immunization of all infants, children, adolescents, and adults in high-risk groups, including all diabetic patients aged 19–58 years, and all patients with chronic liver disease. Acknowledgment of a specific risk factor is not a requirement for immunizations. These recommendations include immunizing all children at birth, 1, and 6 months. Additionally, all high-risk groups should be screened, as well as all pregnant women. Prevaccination testing of patients in low-risk groups is probably not necessary, but in high-risk groups, this may be cost-effective. As illustrated in the first test scenario of Table 33-2, a negative HBsAg titer and a negative anti-HBs titer are evidence of susceptibility to HBV.

The vaccine contains components of HBsAg. Pretesting with anti-HB core antibody (anti-HBc) is probably the single best test, because it would identify those who are infected and those who have been exposed. Posttesting for vaccine is seldom recommended, except for individuals who may have difficulty mounting an immune response (eg, immunocompromised patients). In these patients, the HB surface antibody (anti-HBs) would be the appropriate test. Some authorities recommend revaccinating high-risk individuals if titer levels have fallen below 10 IU/L after 5–10 years, or if they have failed to mount an appropriate immune response with the standard dosing and schedule.

Children born to women of unknown hepatitis B status should receive a first dose of hepatitis B vaccine at birth and hepatitis B immune globulin (HBIG) within 7 days of birth if maternal blood is positive. Repeat testing of all infants born to HBV-infected mothers should be performed at 9–18 months with HBsAg and anti-HBs. Infants born to HBV-infected mothers should receive both the first dose of hepatitis B vaccine at birth as well as 0.5 mL of HBIG in separate sites within 12 hours after birth. Recommendations for postexposure prophylaxis of HBV can be reviewed in the current CDC recommendations.

Clinical Findings

Acute infection may range from an asymptomatic infection to cholestatic hepatitis to fulminant hepatic failure. HBsAg and other markers usually become positive about 6 weeks after infection and remain positive into the clinical signs of illness. Other biochemical abnormalities begin to show abnormalities in the prodromal phase and may persist several months, even with a resolving disease process. Anti-HB core IgM becomes positive early, with onset of symptoms, and both anti-HB core IGM and anti-HB core IgG may persist for many months or years. Anti-HBs is the last antibody to appear and may indicate resolving infection. The presence of HBeAg indicates active viral replication and increased infectivity (Figure 33-1). Liver function tests should be obtained early in the course of infection, and evidence of prolonged prothrombin time (>1.5 INR) should raise concern for hepatic failure. Patients who remain chronically infected may demonstrate HBsAg and HBeAg for at least 6 months, with a usual trend in liver function tests toward normal levels, although results may remain persistently elevated (Figure 33-2). Extrahepatic manifestations of HBV infection may occur and include serum sickness, polyarteritis nodosa, and membranoproliferative glomerulonephritis.

Complications

Complications of chronic infection may include progression to cirrhosis and hepatocellular carcinoma (HCC). Patients with active viral replication are at highest risk of chronic disease, with 15–20% developing progressive disease over a 5-year period. Continued positivity for HBeAg is associated with an increased risk of HCC. Most patients who are chronically infected remain HBsAg-positive for their lifetime. There is no general agreement concerning the appropriate screening for patients with chronic infection for HCC. Some experts would not screen carriers if all laboratory tests are normal but would screen with ultrasonography and α-fetoprotein for evidence of chronic active hepatitis every 2–3 years, and more frequently in patients with cirrhosis. It appears that the incidence of progression of disease is greater in countries with high endemicity, and clinicians in these countries screen as frequently as every 6 months.

Treatment

Treatment for chronic disease depends on evidence of viral activity, HBeAg status, HIV and HCV comorbidity, histologic evidence of liver injury, and elevated liver function tests. Currently approved treatment modalities include interferon alfa, pegylated interferon, lamivudine, telbivudine, adefovir, tenofovir, and entecavir. Other new antiviral agents are currently being tested. Sensitive tests for determination of response to therapy, such as covalently closed circular DNA (cccDNA), may be more readily available in the future.

Hepatitis C

General Considerations

Hepatitis C virus (HCV) has become the most common bloodborne infection as well as the leading cause of chronic liver disease and subsequently, liver transplantation in the United States. Worldwide, more than 180 million people are infected, but the infection rates vary considerably. In the United States, it is estimated that approximately 4 million people may be infected with HCV; it is the main cause of death from liver disease. The responsible virus is an RNA virus of the Flaviviridae family. Six major genotypes, numbered 1 through 6, are known, with additional subtypes. There are varying distributions of these genotypes, and they may affect the progression of disease and the response to treatment regimens.

Hepatitis C is spread primarily through percutaneous exposure to blood. Since 1992, all donated blood has been screened for HCV. Injection drug use is responsible for >50% of new cases. Within 1–3 months after a first incident of needle sharing, 50–60% of intravenous drug users are infected. Other risk factors include use of intranasal cocaine, hemodialysis, tattooing (debatable), and vertical transmission, which is rare. Breastfeeding carries a low risk of transmission. Sexual transmission is uncertain but is probably 1–3% over the lifetime of a monogamous couple, one of whom is infected. Healthcare workers are at particular risk following a percutaneous exposure (1.8% average incidence).

One-time screening of all individuals born between 1945 and 1965 has been recommended by the CDC, along with screening of patients with known risk factors.

Prevention

No immunizations are currently available for HCV infections. Prevention consists mainly of reduction of risk factors, including screening of blood and blood products, caution to prevent percutaneous injuries, and reduction in intravenous drug use.

Clinical Findings

A. Symptoms and Signs

1. Acute hepatitis

The incubation period for HCV varies between 2 and 26 weeks, but most commonly is 6–7 weeks. Most patients with HCV are asymptomatic at the time of infection. However, >20% of all recognized cases of acute hepatitis in the United States are caused by HCV, and as many as 30% of adults who are infected may present with jaundice. Acute, fulminant hepatic failure is rare.

2. Chronic hepatitis

In contrast to HAV and HBV, most people infected with HCV (85%) develop a chronic infection. The incidence of significant liver disease is 20–30% for cirrhosis and 4% for liver failure; over 1–4% of patients with chronic infection develop HCC annually, or 11–19% over 4–11 years in one study. It appears that certain risk factors increase the likelihood of progression to serious disease. These include increased alcohol intake, age >40 years, HIV coinfection, and possibly male gender and other liver coinfections.

Extrahepatic manifestations of chronic infection are fairly common and are similar to those of HBV, including autoimmune conditions and renal conditions such as membranous glomerulonephritis.

B. Laboratory Findings

Patients in a high-risk category for HCV should be tested with both an approved HCV antibody test such as the OraQuick HCV Rapid Antibody test or other approved tests and a confirmatory test by nucleic acid testing (NAT) to detect HCV RNA if positive. All patients with HCV infection should have quantitative NAT as well as HCV genotyping prior to therapy in order to predict a therapeutic response as well as duration of therapy. The appropriate role of liver biopsy in decisions concerning therapy is in a state of flux, particuarly regarding threatment for genotype 1 patients. Consultation with a liver specialist should be considered to ascertain the value of this additional information that a liver biopsy would provide.

Treatment

Treatment for both acute and chronic HCV has undergone significant strides in more recent years. A recent study documents the conversion of a significant number of patients to negative serology when treated in the acute phase of infection. Chronic HCV genotype 1 is treated with either a combination of direct acting antibody drugs (DAA) such as simeprevir and sofosbuvir with or without an interferon regimen and/or ribavirin. Treatment recommendations are rapidly changing. The other genotypes are less sensitive to therapy with the protease inhibitors and are usually managed with only interferon and rivavirin. Other new treatments are currently under investigation.

It is important to immunize patients with chronic HCV infection for HAV, because the incidence of fulminant hepatitis A has been shown to be significantly increased in this population. Patients infected with HCV should also abstain from alcohol. It has also been recommended that HCV-infected individuals be vaccinated for HBV, owing to the poor prognosis of coinfected individuals. Chronic hepatitis C can also progress to cirrhosis and HCC, and appropriate screening measures as discussed under Hepatitis B apply to hepatitis C-infected patients as well.

Other Types of Infectious Hepatitis

Over 97% of the viral hepatitis in the United States is either A, B, or C. Other types of viral hepatitis occur much less frequently, although worldwide, they may be more important.

Hepatitis D

Hepatitis D virus (HDV) can replicate only in the presence of HBV infection. HDV infection can occur either as a coinfection with HBV or as a superinfection in a chronically infected individual with HBV. Although coinfection can produce more severe acute disease, a superinfection poses the risk of more significant chronic disease, with 70–80% of patients developing cirrhosis. The mode of transfmission is most commonly percutaneous. The only tests commercially available in the United States are IgG–anti-HDV. Prevention of HDV depends on prevention HBV. There are no products currently available to prevent HDV infection in patients infected with HBV.

Hepatitis E

Hepatitis E virus (HEV) is the most common cause of enterically transmitted non-A, non-B hepatitis. Acute HEV infection is similar to other forms of viral hepatitis; no chronic form is known. Severity of illness increases with age, and for reasons that are unclear, case fatality rates are particularly high in pregnant women. Most cases of HEV reported in the United States have occurred in travelers returning from areas of high endemicity. In certain areas of the world (Mexico, North Africa, the Middle East, and Asia), epidemics of HEV may be common. Prevention includes avoidance of drinking water and other beverages of unknown purity, uncooked shellfish, and uncooked vegetables and fruits. No vaccines are currently available, although one recently developed has proven to be highly effective.

Acute Hepatitis: A Cost-Effective Approach

Because the vast majority of viral hepatitis cases are caused by HAV, HBV, or HCV, tests to determine the precise etiology are necessary for appropriate primary and secondary prevention for the patient, as well as potential for therapy. Figure 33-3 outlines one cost-effective approach. If these tests fail to indicate a diagnosis, the etiology may be due to less frequent causes of viral hepatitis such as Epstein-Barr virus, in which jaundice rarely accompanies infectious mononucleosis; cytomegalovirus or herpesvirus in immunocompromised patients; or other nonviral etiologies, such as alcoholic hepatitis, drug toxicity, Wilson disease, or an autoimmune hepatitis.

WEBSITES

ALCOHOLIC LIVER DISEASE

General Considerations

Alcoholic liver disease includes several different disease entities, spanning a large clinical spectrum. These diseases range from the syndrome of acute fatty liver to severe liver damage as manifested by cirrhosis. Fatty liver is usually asymptomatic except for occasional hepatomegaly and is the histologic result of excessive use of alcohol over a several-day period. In perivenular fibrosis, fibrous tissue is deposited in the central areas of the liver, particularly the central veins; this indicates that the individual may then rapidly progress to more severe forms of liver disease. Patients can progress from this stage directly to cirrhosis. Alcoholic hepatitis is a condition in which necrosis of hepatic cells occurs as part of an inflammatory response, which includes polymorphonuclear cells, along with evidence of fibrosis. Cirrhosis may result from continued progression of disease from alcoholic hepatitis or may occur without evidence of prior alcoholic hepatitis. Cirrhosis is characterized by distortion of the liver structure, with bands of connective tissue forming between portal and central zones. Changes in hepatic blood circulation may also occur, resulting in portal hypertension. Additionally, evidence of abnormal fat metabolism, inflammation, and cholestasis may be seen. Progression to hepatocellular carcinoma (HCC) may also occur, although the exact risk of cirrhosis itself in the progression to HCC is not clear.

It is known that women are more likely than men to develop alcoholic liver disease, although the reasons for this phenomenon are only now being clarified. There may be additional genetic factors, most notably in specific enzyme systems, such as the metabolism of tumor necrosis factor (TNF) and alcohol-metabolizing systems, which affect the development of disease. Concomitant disease, such as HCV infection, is also a risk factor. Other factors (eg, obesity) may also play a role in the progression of disease.

Clinical Findings

A. Symptoms and Signs

A history of drinking alcohol in excess of 80 g/day (six to eight drinks) is seen with the development of more advanced forms of the disease, although there is considerable individual variation. Numerous questionnaires have been designed for detection of excessive drinking, but the CAGE questionnaire (cut down, annoyed by criticism, guilty about drinking, eye-opener drinks) is probably the most useful.

Clinical findings may be limited at this stage to occasional hepatomegaly. Patients with alcoholic hepatitis may present with classic signs and symptoms of acute hepatitis, including weight loss, anorexia, fatigue, nausea, and vomiting. Hepatomegaly may be evident, as well as other signs of more advanced disease, such as cirrhosis, because the development of cirrhosis may occur concomitant with a new episode of alcoholic hepatitis. These signs include jaundice, splenomegaly, ascites, spider angiomas, and signs of other organ damage secondary to alcoholism (eg, dementia, cardiomyopathy, or peripheral neuropathy).

B. Laboratory Findings

Various commercially available laboratory tests have been used to detect excessive alcohol intake in the early stages. The sensitivity and specificity of these tests vary. Liver function tests for elevations of AST, ALT, and GGT are frequently used. Elevation of mean corpuscular volume (MCV) has also been noted in patients with early-stage disease.

Transaminase levels are usually only mildly elevated in pure alcoholic hepatitis unless other disease processes, such as concomitant viral hepatitis, or acetaminophen ingestion are present; AST is usually elevated to ≤200 IU/L; and AST, to ≤500 IU/L. AST elevation is usually greater than that of ALT. Elevated prothrombin time and bilirubin levels have a significant negative prognostic indication. The presence of jaundice may have special significance in any actively drinking person and should be carefully evaluated. Several instruments have been used for evaluation of severity, but the most common is the Maddrey discriminant function (MDF):

A score > 32 is indicative of high risk of death.

Treatment

Abstinence from alcohol is essential, and is probably the most important of all therapies. Recovery from the acute episode is associated with an 80% 7-year survival rate in patients who can abstain from alcohol versus 50% survival in those who continue drinking. The use of naltrexone or acamprosate in conjunction with counseling and support groups to prevent recidivism should be considered.

Initial treatment of the acutely ill patient centers on ensuring adequate volume replacement, with concern for the ability to handle normal saline. Diuretics should be avoided. Patients should be assessed for protein-calorie malnutrition and vitamin and mineral deficiencies. Adequate nutrition should be given to patients with severe disease, parenterally if necessary. There is no indication that avoidance of protein is helpful in patients with encephalopathy. Broad-spectrum antibiotics should be considered early in the treatment course. Many patients develop spontaneous peritonitis, pneumonia, or cellulitis, which should be treated aggressively. Corticosteroids have been suggested as beneficial, but considerable debate still ensues as to whether there is any benefit to survival, although current recommendations are that patients with severe disease (MDF ≥32) with or without encephalopathy and without contraindications for steroid use should be considered for a 4-week course of prednisone followed by a 2-week taper. Pentoxifylline, which modifies tumor necrosis factor alpha (TNFα), may also be considered, especially if steroids are contraindicated.

Liver transplantation may be an option. Alcoholic liver disease is currently the second most common reason for liver transplantation in the United States. To be considered for transplantation, patients should not have active alcoholic hepatitis, should have remained sober for more than 6 months, and should have had addictive treatment. The prognosis is excellent if relapse from drinking can be avoided. Relapse occurs in 15–30% of patients.

Other treatment methodologies in various stages of testing include other TNFα modifiers; antioxidant therapy with agents such as S-adenosyl-l-methionine (SAM-e), silymarin, or vitamin E; antifibrotics such as polyenylphosphatidylcholine (PPC); or other medications such as colchicine. Further studies are needed before these therapies can be recommended.

OTHER LIVER DISEASES

Nonalcoholic Fatty Liver Disease

A relatively new condition described around 1980, nonalcoholic fatty liver disease (NAFLD), encompasses a wide clinical spectrum of patients whose liver histology is similar to those of patients with alcohol-induced hepatitis, but without the requisite history. Women are affected more frequently than men. Many of these patients progress to cirrhosis. NAFLD is now the most common liver disease in the United States, occurring in ≤20% of the population in some studies. This condition is common in obese patients, as well as in patients with type 2 diabetes mellitus. It may be a part of the syndrome X, which includes obesity, diabetes mellitus, dyslipidemia, and hypertension. Clinical features include hepatomegaly (75%) and splenomegaly (25%), but no pathognomonic laboratory markers. Elevations of ALT and AST may be ≤5 times normal, with an AST:ALT ratio of <1. Evidence of steatosis can be seen on hepatic ultrasonography. Treatment includes weight reduction, treatment of diabetes, and treatment of lipid disorders. There is no current evidence of the efficacy of specific pharmacologic therapy.

Wilson Disease

Wilson disease, which is characterized by hepatolenticular degeneration, is caused by abnormal metabolism of copper. It is inherited in an autosomal-recessive pattern and has a prevalence in the general population of approximately 1 in 30,000. Although patients in asymptomatic stages may manifest only transaminasemia or Kayser-Fleischer rings (golden-greenish granular deposits in the limbus), hepatomegaly or splenomegaly may already be present. In most symptomatic patients (96%), the serum ceruloplasmin level is <20 mg/dL. In patients with more advanced disease, symptoms of acute hepatitis or cirrhosis may be present. Neurologic signs include dysarthria, tremors, abnormal movements, and psychological disturbances. HCC may occur in patients with advanced disease. Treatment includes penicillamine, trientine, or zinc salts.

Hemochromatosis

An inborn error of iron metabolism leading to increased iron absorption from the diet, hemochromatosis is associated with diabetes, bronze skin pigmentation, hepatomegaly, loss of libido, and arthropathy. Patients may also show signs of cardiac or endocrine disorders. Symptoms usually first manifest between 40 and 60 years of age, and men are 10 times more likely than women to be affected. Hemochromatosis is the most common inherited liver disease in people of European descent. Physical signs include hepatomegaly (95% of symptomatic patients), which precedes abnormal liver function tests. Cardiac involvement includes congestive heart failure and arrhythmias. Many patients have cirrhosis by the time they are symptomatic (50–70%), 20% have fibrosis, and 10–20% have neither. HCC is common in patients with cirrhosis (30%) and is now the most common cause of death. Laboratory findings include elevated serum iron concentration, serum ferritin, and transferrin saturation. Therapy involves treatment of the complications of hemochromatosis, removal of excess iron by phlebotomy, and, in patients with cirrhosis, surveillance for HCC and treatment of hepatic and cardiac failure.

Autoimmune Hepatitis

Autoimmune hepatitis is a hepatocellular inflammatory disease of unknown etiology. Diagnosis is based on histologic examination, hypergammaglobulinemia, and presence of serum autoantibodies. The condition may be difficult to discern from other causes of chronic liver disease, which need to be excluded before diagnosis. Immunoserologic tests that are essential for diagnosis are assays for antinuclear antibodies (ANAs), smooth-muscle antibodies (SMAs), antibodies to liver and kidney microsome type 1 (anti-LKM1), and anti-liver cytosol type 1 (anti-LCI), as well as perinuclear antineutrophil cytoplasmic antibodies (aANCAs). Treatment, when indicated, is usually immunosuppressive with either prednisone, azathioprine, or both.

Drug-Induced Liver Disease

More than 600 drugs or other medicinals have been implicated in liver disease. Worldwide, drug-induced liver disease represents approximately 3% of all adverse drug reactions; in the United States, more than 20% of cases of jaundice in the elderly are caused by drugs. Acetaminophen and other drugs account for 25–40% of fulminant hepatic failure. Diagnosis is based on the discovery of abnormalities in hepatic enzymes or the development of a hepatitis like syndrome or jaundice. Most cases occur within 1 week to 3 months of exposure, and symptoms rapidly subside after cessation of the drug, returning to normal within 4 weeks of acute hepatocellular injury. Hepatic damage may manifest as acute hepatocellular injury (isoniazid, acetaminophen), cholestatic injury (contraceptive steroids, chlorpromazine), granulomatous hepatitis (allopurinol, phenylbutazone), chronic hepatitis (methotrexate), vascular injury (herbal tea preparations with toxic plant alkaloids), or neoplastic lesions (oral contraceptive steroids).

Statins, on the other hand, are widely used and can commonly cause mild liver enzyme elevations, but mild elevations of ALT or AST (<3 times the upper limit of normal) do not appear to contribute to liver toxicity.

Primary Biliary Cirrhosis

This autoimmune disease of uncertain etiology is manifested by inflammation and destruction of interlobular and septal bile ducts, which can cause chronic cholestasis and biliary cirrhosis. It is predominantly a disease of middle-aged women (female-to-male ratio of 9:1) and is particularly prevalent in northern Europe. The condition may be diagnosed on routine testing or be suspected in women with symptoms of fatigue or pruritus, or in susceptible individuals with elevated serum alkaline phosphatase, cholesterol, and IgM levels. Antimitochondrial antibodies are frequently found. Ursodeoxycholic acid is the only therapy currently available, although some patients may benefit from liver transplantation.

Hepatic Tumors & Cysts

Hepatocellular carcinoma is the most common malignant tumor of the liver; it is the fifth most common cancer in men and the eighth most common in women. Incidence increases with age, but the mean age in ethnic Chinese and African populations is lower. Signs of worsening cirrhosis may alert the clinician to consider HCC, but, in many cases, the onset is subtle. There are no specific hepatic function tests to detect HCC, but elevated serum tumor markers, most notably α-fetoprotein, are useful. Ultrasonography can detect the majority of HCC but may not distinguish it from other solid lesions. CT and MRI are also helpful in making the diagnosis. Risk factors for HCC include HBV, HCV, all etiologic forms of cirrhosis, ingestion of foods with aflatoxin B₁, and smoking. In these patients, ultrasonography and α-fetoprotein measurements every 4–6 months are recommended. In moderate-risk patients (ie, with later-onset HBV), measurement of α-fetoprotein every 6 months and annual ultrasound study are suggested.

Benign Tumors

Benign tumors include hepatocellular adenomas, which have become more common with the use of oral contraceptive steroids, and cavernous hemangiomas, which may occur with pregnancy or oral contraceptive steroid use and are the most common benign tumor of the liver.

Liver Abscesses

Liver abscesses can be the result of infections of the biliary tract or can have an extrahepatic source such as diverticulitis or inflammatory bowel disease. In ~40% of cases, no source of infection is found. The most common organisms are Escherichia coli, Klebsiella, Proteus, Pseudomonas, and Streptococcus species. Amebic liver abscesses are the most common extraintestinal manifestation of amebiasis, which occurs in >10% of the world’s population and is most prevalent in the United States in young Hispanic adults. Amebic abscesses may have an acute presentation, with symptoms present for several weeks; few patients report typical intestinal symptoms such as diarrhea. Ultrasonography or CT scans with serologic tests such as enzyme-linked immunosorbent assay (ELISA) or indirect fluorescent antibody tests help confirm the diagnosis.

ACUTE PANCREATITIS

General Considerations

Hospital admissions for acute pancreatitis are fairly frequent, and the most common causes vary with the age and sex of the patient. In the United States, gallstones and alcohol abuse are the most frequent etiologies (20–30%), but infectious causes such as mumps virus or parasitic disease should be considered, as well as medications, tumors, trauma, and metabolic conditions. Approximately 20% of cases are idiopathic. It is important to determine the etiology of pancreatitis, as early recognition of acute biliary pancreatitis in particular may be important in selecting the appropriate therapeutic approach.

A more detailed discussion of gallstone pancreatitis appears earlier in this chapter.

Clinical Findings

A. Symptoms and Signs

Abdominal pain—usually epigastric, which may radiate to the back—is an common presenting sign. However, the pain may not be significant, and some cases of acute pancreatitis are missed or diagnosed after more significant complications have occurred. Abdominal tenderness ranging from rigidity to mild tenderness may be present. Lack of a specific diagnostic test may affect the accuracy of an early diagnosis.

B. Laboratory Findings

Useful laboratory tests include serum amylase (elevated 3–5 times above normal), serum lipase (more than twice normal), and, for determining the etiology, liver function tests, especially ALT. Serum amylases that are significantly elevated in the presence of epigastric pain are strong indicators of pancreatitis. However, amylase clears rapidly from the blood, and levels may be normal even in patients with severe pancreatitis. A urine dipstick test for trypsinogen-2 may also be useful. The triglyceride levels should be checked, as well as calcium in an attempt to identify pancreatitis associated with hyperlipemia and hyperparathyroidism.

C. Prognostic Tests

Over 20% of patients have a severe case of pancreatitis, and of these a significant number die. It is therefore important to accurately stage the severity of the illness and treat accordingly. Attempts to quantify severity of disease have lead to certain scoring criteria, such as the Acute Physiology and Chronic Health Evaluation (APACHE) II score (>7 on admission is indicative of severe illness), or the Ranson or Glasgow scores. All are complicated and have varying degrees of sensitivity and specificity. A simplified scoring test, the Bedside Index of Severity in Acute Pancreatitis (BISAP), has recently been introduced, and utilitzes two additional components of risk assessment—a rise in blood urea nitrogen (BUN) and the systemic inflammatory response syndrome (SIRS) as well as age, presence of pleural effusion, and mental status. Peritoneal lavage has also been used, but it is difficult to justify in patients with mild symptoms. C-reactive protein scores of >150 mg/L in the first 48 hours, interleukin-6 values of >400 pg/mL, and interleukin-8 values of >100 pg/mL on admission have also been suggested as indicators of severe pancreatitis. Other prognostic tests that may indicate severe illness are described in the following paragraphs, but their usefulness in clinical practice is still under review.

D. Imaging Studies

Ultrasonography of the right upper quadrant is helpful in identifying the etiology of pancreatitis, and is usually the initial imaging study of choice However, it has limited value in staging the severity of disease. (See the discussion earlier in the chapter on gallstone pancreatitis). Contrast-enhanced CT is the most common currently available imaging technique for staging the severity of pancreatitis and can determine the presence of glandular enlargement, intra- and extrapancreatic fluid collections, inflammation, necrosis, and abscesses. This study may not be necessary for patients with mild disease. MRCP may be just as accurate and has some advantages over contrast-enhanced CT in certain patients. Magnetic resonance imaging (MRI) is an alternative when CT is not helpful or feasible.

Complications

Complications include organ failure, cardiovascular collapse, and fluid collections around the pancreas. The latter may be asymptomatic or they may enlarge, causing pain, fever, and infection. Extrapancreatic infections, either bacteremia or pneumonia, have recently been shown to complicate the management of acute pancreatitis in a significant number of patients, usually within the first 2 weeks. Pancreatic pseudocysts may occur in patients with very high amylase levels and obstruction of the pancreatic duct. Pancreatic necrosis may also occur and can be fatal. Infection of necrotic tissue should be suspected in patients with unexpected deterioration, fever, and leukocytosis, and confirmed by CT scan and fine-needle aspiration. Sterile necrosis should probably be managed nonoperatively unless progressive deterioration occurs. Septic necrosis usually requires surgical débridement.

Treatment

Patients who have the potential to develop severe pancreatitis, or who already have severe pain, dehydration, or vomiting, should be hospitalized and their hydration needs monitored closely. These patients should receive nothing by mouth and should be given intravenous pain medication. Patients should be monitored carefully to assess adequate renal function, because renal failure is a major cause of morbidity and mortality. Signs of worsening condition include rising hematocrit, tachycardia, and lack of symptom improvement in 48 hours.

Nutritional treatment has evolved in recent years, but areas of controversy remain. Increasing evidence indicates that in cases of mild pancreatitis, there is no benefit to nasogastric suction, and patients who are not vomiting may continue on oral fluids or resume oral fluids after the first week. There is also growing evidence that in severe pancreatitis, early enteral feeding within the first week may lower endotoxin absorption and reduce other complications. If patients cannot absorb adequate quantities via the enteric route, then parenteral feeding may be necessary.

The use of antibiotics is also controversial. Prophylactic antibiotics have been used in severe pancreatitis, but there is some concern that they may predispose patients to fungal infections. The general consensus is to use antibiotics, preferably broad-spectrum agents, for severe pancreatitis and for as brief a period as possible (ie, <7 days).

PANCREATIC CANCER

General Considerations

Although pancreatic cancer is diagnosed in only 30,000 patients each year in the United States, it is the fourth most ­common cause of death from cancer and the second most common gastrointestinal malignancy. Pancreatic cancer has a very poor prognosis: >80% of patients die within the first year, and the 5-year survival rate is <4%. In the vast majority of patients, the cancer is discovered at too late a stage to benefit from resection, and the response to chemotherapy is very poor. Over 90% of pancreatic cancers are ductal adenocarcinoma.

Cigarette smoking is the major risk factor established to date. Diet may also be a factor, with high intake of fat or meat and obesity associated with an increased risk; fruits, vegetables, and exercise help protect against pancreatic cancer. Likewise, a history of chronic pancreatitis is considered a risk factor, along with surgery for peptic ulcer disease, hereditary pancreatitis, and some genetic mutations (eg, BRAC2, associated with hereditary breast cancer). No guidelines currently exist regarding screening of the general population for pancreatic cancer, although some experts feel that patients with a family history of hereditary pancreatitis should be screened.

Clinical Findings

A. Symptoms and Signs

The clinical presentation of pancreatic cancer can vary widely; tumors that occur in the head of the pancreas (two-thirds of all pancreatic cancer) may produce early signs of obstructive jaundice. Tumors in the body and tail of the pancreas may grow quite large and cause fewer signs of obstruction. Symptoms more likely to be associated with pancreatic cancer include abdominal pain, jaundice, dark urine, light-colored stools, and weight loss. Pain may be worse when the patient is lying flat or eating. Other physical signs associated with pancreatic cancer include Courvoisier sign (palpable, nontender gallbladder in a patient with jaundice).

B. Laboratory Findings

Laboratory evaluation should include liver function tests. The serum tumor antigen CA 19-9 may be useful in confirming a diagnosis but is not an appropriate screening tool. Other markers are under consideration.

C. Imaging Studies

There is some debate as to the best imaging study. Dual-phase spiral CT with a pancreatic protocol has a high rate of sensitivity and can also assist in staging of the tumor, which is important for clinical management. Endoscopic ultrasonography may become the most accurate test for diagnosis. If patients have jaundice, then transabdominal ultrasound may be the first imaging test performed.

Treatment

Because the only hope for a cure is surgical resection, staging of pancreatic tumors is important for management. The difficulty lies in identifying the small fraction of patients who will benefit from surgery from those who will not—patients with metastatic disease who would otherwise be subjected to unnecessary invasive procedures and the resultant increased morbidity and mortality.

For patients with metastatic disease, chemotherapy and palliative care should be offered; surgery is avoided. Patients with advanced local disease but no metastases may benefit from radiotherapy and chemotherapy, and those without invasion or metastases may be candidates for resection. Even with resection, the outlook is poor (5-year survival rates of <25%). Radiation therapy may be useful in some patients with localized but nonresectable tumors, and chemotherapy (5-fluorouracil and gemcitabine) has some limited success.

Pain management can be a significant problem, and various modalities may need to be utilized. Biliary decompression may be required for jaundice.