Harfinddall

Cirrhosis
J. Richard Brown
Definition 1346 Treatment Goals 1346 Epidemiology 1346 Pathophysiology 1347 Clinical Presentation and Diagnosis 1348 Signs and Symptoms 1348 Diagnosis 1348 Psychosocial Aspects 1351
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Therapeutic Plan 1351 Treatment 1351 Pharmacotherapy 1351 Nonpharmacologic Therapy 1360 Alternative Therapy 1360 Improving Outcomes 1361 Prognosis 1361 Pharmacoeconomics 1361 Key Points 1361
DEFINITION
Cirrhosis is defined as irreversible chronic injury of the liver characterized by diffuse fibrosis and the formation of regenerative nodules. Areas of necrosis and regeneration of he-
patic parenchyma impart the classic glandular or nodular appearance of the liver. Necrosis of hepatocytes leads to deposition of connective tissue, which distorts the vasculature and alters the flow of blood through the liver, resulting in portal hypertension. These pathologic changes are the end result for many types of chronic liver injury.
TREATMENT GOALS

Currently, there is no specific pharmacotherapy that will cure cirrhosis. Management is limited to the prevention or treatment of complications. The primary goal of therapy is to prevent symptoms and maintain a reasonable quality of life. Specific complications of the disease are treated to reduce morbidity and the need for frequent hospitalizations. Once the diagnosis of cirrhosis is established, it is of utmost importance therapeutically that patients discontinue consumption of all alcohol.
EPIDEMIOLOGY
Although cirrhosis is frequently encountered in medicine, it is difficult to cite an accurate incidence because patients often have no symptoms until the later stages of disease. Postmortem data from various hospitals show an incidence of 3% to 15%. In 1989, cirrhosis was the ninth leading cause of death in the United States.1 Worldwide, the annual death rate from cirrhosis of all causes is as high as 15 to 40 per 100,000 people.2 However, death and hospitalization rates of patients with chronic liver disease and cirrhosis are on the decline in the United States. In 1989, chronic liver disease was the underlying cause of death for 26,720 people and a contributing cause of death for an additional 14,101 people. From 1980 through 1989 the age-adjusted death rate for chronic liver disease decreased 23%, from 13.5 to 10.4 per 100,000 people. Chronic liver disease appeared as the
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first diagnosis in an estimated 72,232 hospitalizations in 1989 and as a secondary diagnosis in an additional 218,156 hospitalizations. From 1980 through 1989 the hospitalization rate attributed to chronic liver disease and cirrhosis declined 44%, from 50.6 to 28.2 per 100,000 people.3 Centers for Disease Control and Prevention data from 2001 reported 27,035 deaths, or 9.5 per 100,000. In 2000, 360,000 discharges from chronic liver disease and cirrhosis were recorded. In 2002, chronic liver disease and cirrhosis was the 12th leading cause of death in the United States, accounting for 1.2% of all deaths recorded.4 Table 50.1 lists the relative frequencies of the various types of cirrhosis encountered in the clinical setting. The largest percentage is alcohol-related cirrhosis, which occurs principally in patients between 40 and 60 years of age and is more common in men. (The management of alcoholism is discussed in greater detail in Chapter 58.) In the United
CHAPTER 50 Cirrhosis
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TABLE 50.1 Cirrhosis: Incidence and Causes

Type
Alcohol-associated Biliary (primary and secondary) Postnecrotic
Frequency (%)
6070 1015 1015
Causes
Alcohol abuse and protein deficiency inducing fatty changes, inflammation, and scarring of liver Obstruction of bile flow (e.g., immune complexes, stones, and carcinoma); often secondary to long-standing bacterial infection Scarring following massive hepatic necrosis, such as that seen in chronic viral hepatitis, after exposure to hepatotoxic drugs, or in immune-mediated hepatitis Unknown Excessive iron (hemochromatosis) or excessive copper (Wilsons disease) deposition, 1-antitrypsin deficiency, other inborn errors of metabolism
Cryptogenic Metabolic
1015 510
States, 50% to 90% of these patients have a history of chronic alcoholism. The quantity of ethanol needed to cause cirrhosis is 80 g per day for 5 years. With approximately 11 to 12 g in the average drink, six or seven drinks per day over this period could be considered a factor in the development of cirrhosis. In developing countries, children often acquire hepatitis B by maternal transmission.1,2,5
PATHOPHYSIOLOGY
Several major types of cirrhosis have been described (Table 50.1), but cirrhosis associated with chronic hepatitis C infection is currently the most commonly encountered form in the United States, followed by alcohol-related cirrhosis.5,6 (Viral hepatitis is discussed further in Chapter 49.) Alcoholic liver disease usually begins with severe fatty changes in the liver (steatosis). In the early stages this fatty infiltration is not associated with fibrosis and scarring. Later stages are marked by a prominent inflammation, an increase in fibrous tissue, and a progressive shrinkage, nodularity, and hardening of the liver. In experimental animal models, dietary derangements can induce significant fatty changes in the liver, with subsequent development of cirrhosis. Therefore, it is often claimed that dietary indiscretion in alcoholics may be an important underlying associated cause of cirrhosis. This concept is supported by the observation that when a chronic alcoholic is hospitalized and placed on an appropriate diet, excess fat can be mobilized and the liver structure and function may return to normal. This reversibility is less clear if fibrosis is present. Other evidence implicates alcohol as a direct hepatotoxin. One group of investigators showed development of cirrhosis in baboons that were maintained on a balanced diet but given large daily doses of alcohol.7 Biliary cirrhosis is caused by chronic obstruction of bile flow (cholestasis). Primary biliary cirrhosis (PBC) follows long-standing cholestasis that is generally of unknown ori-
gin, but it may have an underlying immunologic basis with elevated immunoglobulin M (IgM), autoantibodies, and circulating complement-fixing immune complexes. The presence of antimitochondrial antibodies is the serologic hallmark for PBC. Secondary biliary cirrhosis may be caused by bile stones or a tumor obstructing bile flow, leading to an inflammatory reaction and scarring. Other causes of cirrhosis are related to chronic viral hepatitis (e.g., chronic hepatitis B), autoimmune hepatitis, and various metabolic disorders (Table 50.1). In 10% to 15% of cirrhotic patients, the cause is never determined. This is referred to as cryptogenic cirrhosis. The liver has a unique blood supply. The hepatic artery, which supplies oxygen-rich blood, provides approximately 20% of the blood supply to the liver. The remaining 80% of the blood supply comes from the portal vein. The portal vein, formed from the confluence of the splenic and mesenteric veins, provides nutrient-rich blood that comes from the gastrointestinal (GI) tract. A second set of microvasculature (or sinusoids) runs throughout the liver and then rejoins to empty into the hepatic veins and eventually the inferior vena cava. The main function of the portal venous system is to act as a pathway for detoxification and metabolism by the liver of substances absorbed from the GI tract. The anatomy of the portal system allows for first-pass (presystemic) metabolism of orally administered drugs such as propranolol, verapamil, and morphine. With the development of cirrhosis, fibrosis, and the formation of regenerative nodules, the normal flow of blood through the liver parenchyma is impeded, resulting in a dramatic rise in the portal venous pressure and that of its tributaries. This is referred to as portal hypertension. Blood may also be shunted around the liver via collateral veins in the distal esophagus and gastric fundus. The increase in blood flow through these normally low-pressure tributaries results in engorgement of the submucosal veins, commonly referred to as esophageal and gastric varices.
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SECTION XIV Hepatic and Pancreatic Disorders
CLINICAL PRESENTATION AND DIAGNOSIS

DIAGNOSIS
The diagnosis of cirrhosis is usually made based upon clinical, laboratory, and radiologic data. Cirrhosis can be confirmed and staged based on histologic evidence from liver biopsy.
SIGNS AND SYMPTOMS

Cirrhosis is insidious in its development and is often asymptomatic until the late stages of disease. Up to 50% of all cases are discovered only at postmortem examination. Many patients seek medical help, complaining of vague, nonspecific symptoms such as weight loss, loss of appetite, nausea, vomiting, and ill-defined digestive disturbances. Others enter the hospital acutely ill with the full syndrome of acute hepatitis (a precursor to cirrhosis). These patients have jaundice (bilirubin levels range from 2 mg per deciliter to more than 40 mg per deciliter), mildly elevated serum alanine and aspartate aminotransferase (ALT and AST) and alkaline phosphatase levels, a low serum albumin level, evidence of impaired coagulation (prolonged prothrombin time and elevated INR), and right upper quadrant pain. In the later stages of cirrhosis, patients may have the complications of cirrhosis: ascites, variceal bleeding, and hepatic encephalopathy. The clinical manifestations include visible collateral venous engorgement on the abdominal wall (caput medusa), testicular atrophy, parotid gland enlargement, nail clubbing, skin hyperpigmentation, amenorrhea, jaundice, edema, palmar erythema, fetor hepaticus, loss of body hair, spider angiomas, gynecomastia, ascites, splenomegaly, and muscle wasting. Patients can also experience intense pruritus due to hyperbilirubinemia. Hepatocellular carcinoma develops in as many as 10% of subjects with long-standing cirrhosis. Ascites. Ascites, characterized by the accumulation of protein-rich fluid in the peritoneal cavity, is one of the most
striking features of cirrhosis. Complaints associated with ascites include a rapidly developing inability to fit into ones clothes, weight gain, abdominal and low-back pain, gastroesophageal reflux, and shortness of breath secondary to impaired diaphragm movement or the development of pleural effusions. The amount of fluid in the abdomen can vary from a few liters to 20 liters or more, leading to a large protuberant abdomen and an umbilical hernia. Ascitic fluid is a good medium for bacterial growth. Infection of the peritoneal cavity can occur spontaneously (spontaneous bacterial peritonitis). An unexplained high fever or elevated white blood cell count is an indication for obtaining a sample of the ascitic fluid for bacterial culture or initiating empiric antibiotic therapy. Several mechanisms have been postulated to explain the formation of ascites (Fig. 50.1), none of which is fully accepted as the definitive answer.8,9 Most agree that disruption of hepatic architecture and blood flow caused by inflammation, cell necrosis, fibrosis, or obstruction leads to hemodynamic alterations, causing an elevated lymphatic pressure within the hepatic sinusoids, which eventually causes excessive transudation (weeping) of protein-rich fluid from the surface of the liver into the peritoneal cavity. According to the underfill theory, both the lymphatic leakage and high prehepatic venous pressure (portal hypertension) cause a net flow of volume from the vascular space to the peritoneal cavity via hydrostatic forces. The high protein content of the ascitic fluid may also help to draw fluid out of the vasculature. As a result, effective vascular volume throughout the body decreases, causing secondary sodium and water retention by the kidney. The renin angiotensin system is a major mediator of the sodium and water retention, ultimately causing release of aldosterone from the adrenal gland. Antidiuretic hormone (ADH) release may also increase. Serum levels of aldosterone and ADH remain elevated because of impaired metabolism secondary to liver failure. These processes are accentuated by a reduced oncotic pressure within the intravascular space due to hypoalbuminemia. A major
Underfill theory
Cirrhosis
Portal hypertension
Ascites
Intravascular blood volume Overfill theory
2 renal Na/H2O retention Renal Na/H2O retention Blood volume
Cirrhosis
Ascites
Integrative theory
Cirrhosis
Peripheral arterial vasodilation Blood volume
Intravascular blood volume
FIGURE 50.1 Mechanisms of ascites development.
Renal Na/H2O retention
Ascites
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inconsistency with the underfill theory is that some patients have an increased, not decreased, total intravascular volume, and not all patients have demonstrable hyperaldosteronism. According to the overfill theory, the primary defect in ascites formation is excessive renal reabsorption of sodium and water. As plasma volume expands, ascites results from overflow of fluid out of the splanchnic circulation and increased pressure in the portal system. This implies that an unknown primary renal stimulus initiates the volume expansion. Increased sympathetic activity and a variety of hormonal substances have been proposed as factors affecting renal function in cirrhotic patients.10 Schrier et al8 proposed an integration of these two theories, citing a possible systemic intravascular vasodilation that causes a relative decrease in effective plasma volume or pressure, followed by excessive renal retention of sodium and water. Central blood volume has a primary influence on renal circulation. In cirrhotic patients, there is reduced circulating volume even in patients who have not yet developed ascites. This volume reduction results from vasodilation of the peripheral vascular system. Sensing a shift from the central circulation, the kidneys and arterial baroreceptors activate vasoconstrictive systems to enhance sodium reabsorption. The renin-angiotensin-aldosterone system and the release of vasopressin act to increase central vascular filling.9 It is believed that both intrahepatic hypertension and a primary renal defect are responsible for the early stages of ascites.7 Hypoalbuminemia, secondary to decreased hepatic synthesis and lymphatic leakage into the peritoneum, may further contribute to accumulation of ascites. A low serum albumin concentration reduces serum oncotic pressure, which favors the flow of fluid from the vasculature into the extravascular space. Not all patients with cirrhosis have hypoalbuminemia, but those who do may have both ascites and extensive peripheral edema with a relative systemic hypovolemia. Ascites from portal hypertension can be distinguished from other causes (hepatoma, pancreatic ascites, biliary ascites) by evaluation of a serum albumin ascites gradient. This gradient is calculated by subtracting the ascitic fluid albumin value from the serum albumin value. If the value of the gradient exceeds 1.1 g per dL, the patient has portal hypertension with 97% certainty.10 Patients often have hyponatremia from retention of free water, induced by elevated ADH levels. Hypokalemia may develop secondary to hyperaldosteronism or excessive vomiting. Gastrointestinal Bleeding. GI hemorrhage occurs in about one fourth to one third of patients. About one third of these patients die of the initial hemorrhage. Even nonfatal GI hemorrhages can be massive. The major cause of GI bleeding associated with cirrhosis is shunting of blood away from the high-pressure portal system to low-pressure collaterals in the esophagus or gastric fundus (esophageal or gastric varices respectively), rectum (hemorrhoids), and other parts of the GI tract. The increased blood flow causes these
veins to become enlarged and tortuous, which means they can easily rupture. The risk of bleeding can be compounded by a coagulopathy from a deficiency of vitamin Kdependent clotting factors (II, VII, IX, X). Esophageal varices account for about 50% to 60% of the cases of GI bleeding in patients with cirrhosis, while peptic ulcer disease accounts for another 25%. The presence of varices in the cirrhotic patient accounts for a 20% higher 2-year mortality rate and a 30% higher 5-year mortality rate. Hepatic Encephalopathy. Hepatic encephalopathy is a spectrum of neuropsychiatric abnormalities seen in patients with liver failure. Other neurologic or metabolic causes of encephalopathy must be excluded first. Reversal of the daynight sleep cycle (insomnia or hypersomnia) usually precedes other symptoms. Other manifestations range from forgetfulness, mental confusion, personality changes, hyperreflexia, asterixis (characteristic flapping of the fingers when the hands are dorsiflexed) to somnolence, confusion, and coma. Hepatic encephalopathy can be divided into five stagesstage 0, no abnormality; stage 1, mild impairment (insomnia or hypersomnia, reversal of sleep pattern); stage 2, moderate impairment (slow responsiveness, lethargy); stage 3, severe impairment (somnolence, confusion, semistupor); and stage 4, coma (stupor, unconsciousness). As the disease progresses, a characteristic sweet, pungent odor (fetor hepaticus) may be present on the patients breath. The cause of the odor is unclear but may be related to exhalation of mercaptans. The diagnosis of hepatic encephalopathy may be complicated by other neurologic disorders, including alcohol withdrawal-induced tremors, Wernickes disease (mental disturbances, ataxia, and nystagmus from acute thiamine deficiency), Korsakoffs syndrome (psychosis and confabulation from chronic thiamine deficiency), and cerebellar damage from chronic alcohol ingestion. The presence of asterixis is a major differentiating factor. The pathogenesis of hepatic encephalopathy is not well understood, but it may be related in part to increased arterial and central nervous system (CNS) ammonia levels. No direct cause-and-effect relationship has been shown between encephalopathy and blood ammonia concentration. Elevation of blood ammonia is seen in 60% to 80% of encephalopathic patients. When factors that influence ammonia production are decreased, the patients sensorium often clears. Ingestion of a protein-rich (more than 70 g per day) diet or bleeding into the GI tract (e.g., esophageal bleeding) introduces a source of protein into the intestinal tract. Ammonia is produced in the lower GI tract when these proteins and urea are metabolized by bacterial enzymatic action. The ammonia is then absorbed into the bloodstream. Normally, the liver converts the ammonia into glutamine and urea for excretion by the kidney, but when the liver is failing or the blood is being shunted away from it, as in advanced cirrhosis, serum
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ammonia levels increase and encephalopathy ensues. Hypokalemia can also contribute to renal ammonia production. Hypokalemia should be promptly corrected. It is theorized that the cerebrotoxicity of ammonia results from inhibition of oxidative metabolism by the citric acid cycle in the brain. Alpha-ketoglutarate combines with ammonia to produce high CNS levels of glutamine (a byproduct of ammonia metabolism) while robbing the citric acid cycle of the ketoglutarate needed for production of high-energy adenosine triphosphate (ATP), impairing brain energy metabolism. Cerebrospinal fluid (CSF) glutamine levels are occasionally measured to confirm hepatic encephalopathy. An alternative explanation for the pathogenesis of hepatic encephalopathy concerns derangements in plasma and brain amino acid patterns.1115 Characteristically, there is a relative elevation in methionine and aromatic amino acid (AAA) levels (e.g., phenylalanine, tyrosine, and tryptophan) and a corresponding relative deficiency in branched-chain amino acids (BCAA; e.g., valine, leucine, and isoleucine). These derangements lead to an imbalance of brain neurotransmitters, causing elevated levels of serotonin, octopamine, and phenylethanolamine and a decrease in dopamine and possibly norepinephrine. Serotonin is an end product of tryptophan metabolism, whereas phenylethanolamine and octopamine are byproducts of phenylalanine and tyrosine metabolism. Although the exact reason for these derangements in plasma and brain amino acids is unknown, a number of observations have been made.911 The normal ratio of BCAAs to AAAs is 4:1 to 6:1. In both sepsis and liver failure, catabolic states lead to a negative nitrogen balance and preferential use of BCAAs as a source of energy. As ammonia levels rise, glucagon secretion is stimulated, which in turn stimulates hepatic gluconeogenesis to convert amino acids into glucose for energy. In response to gluconeogenesis, insulin is secreted, which leads to increased uptake and metabolism of BCAAs by skeletal muscle. As liver failure progresses, the liver can no longer store or release glucose in adequate amounts, so greater quantities of BCAAs must be metabolized by skeletal muscle for energy. Simultaneously, the plasma clearance of AAAs and methionine, which depends on hepatic metabolism, is diminished. The net result is an alteration of the BCAA:AAA ratio. In acute liver failure the AAAs rise dramatically while BCAAs remain normal. In chronic hepatic disease the AAAs remain abnormally high while BCAA concentrations drop to low levels, further lowering the BCAA:AAA ratio. Although controversial, BCAA supplementation is used in an effort to restore the BCAA:AAA ratio. If patients are protein intolerant, this approach may offer some merit.16 In addition to alterations in amino acid metabolism, there appears to be a derangement of the bloodbrain barrier during chronic liver disease. In people with hepatic encephalopathy, there is a selective increase in transport of AAAs across the bloodbrain barrier, possibly via an exchange of CSF glutamine (from ammonia metabolism) for AAAs in the
plasma. The arterial concentration of ammonia and other amines may be accentuated by excessive dietary protein consumption, GI hemorrhage (source of protein), overdiuresis leading to dehydration, or other conditions that lead to severe electrolyte imbalance and metabolic alkalosis. An entirely different avenue of research suggests that the -aminobutyric acid (GABA) benzodiazepine receptor complex is involved in the pathogenesis of hepatic encephalopathy.17 GABA is the primary inhibitory neurotransmitter in the CNS. According to this theory, an increase in CNS GABAergic neurotransmission may partially account for the behavioral and electrophysiologic manifestations of encephalopathy. This hypothesis is based on the observation that an accentuation of CNS inhibitory neurotransmitter tone can cause ataxia, sedation, and coma. Although GABA levels do not seem to be elevated in patients with encephalopathy, it is speculated that other endogenous or exogenous GABAlike ligands may be involved. Not surprisingly, these patients also demonstrate unusual sensitivity to benzodiazepine-like drugs that elicit GABAergic-like activity. Other Associated Disorders. Anemia and other hematologic disorders commonly accompany cirrhosis. Chronic alcohol abusers tend to malabsorb folic acid and iron. In addition, their diets may be deficient in both iron and folate. Iron deficiency may be aggravated by a blocking of iron uptake into the bone marrow induced by chronic alcoholism and by slow GI bleeding caused by gastritis. Thrombocytopenia and leukopenia may occur because of folic acid deficiency and alcohol-related bone marrow suppression. Hypersplenism, secondary to portal hypertension, may also contribute. Endocrine disorders are seen in advanced cirrhosis because of the livers inability to metabolize the steroid hormones of the adrenals and gonads. In men, increased circulating estrogen levels cause gynecomastia, testicular atrophy, loss of male-pattern body hair, impotence, spider angiomas, and palmar erythema. The concurrent impairment of renal function with hepatic failure is called hepatorenal syndrome (HRS). HRS develops in about 4% of patients with decompensated cirrhosis and is associated with a poor prognosis; more than 95% of these patients die within a few weeks after the onset of azotemia. HRS is characterized by increased renal vascular resistance and decreased systemic vascular resistance. The complex hemodynamic changes occur in response to vasoactive agents that produce different effects on the systemic and renal circulation. The vasoactive agents and systems involved in HRS are the renin-angiotensin-aldosterone system, the sympathetic nervous system, ADH, and the renal prostaglandin and kinin systems. HRS may occur acutely or progressively. The acute onset generally occurs in patients with end-stage cirrhosis or with other complications such as encephalopathy, bacterial infections, and bleeding. Clinical symptoms include oliguria that develops within a few days, along with a rapid increase in plasma urea and creatinine levels, tense ascites, dilutional
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hyponatremia, hypotension, and jaundice. A slower progressive type involving other chronic types of renal conditions associated with liver disease exhibits a gradual decrease in glomerular filtration rate that may last for several weeks or months. These patients may also demonstrate ascites that is poorly responsive to diuretics.18
PSYCHOSOCIAL ASPECTS
It is generally accepted that more than 90% of Americans drink alcohol at some time. The social drug clearly is the most widely abused substance in our society. Problems associated with the chronic use of alcohol are impressive in their pathologic magnitude and the costs incurred by society. For the alcoholic patient with cirrhosis, psychological therapy with consideration for structured rehabilitation should be a component of the overall care plan.
THERAPEUTIC PLAN
Management of cirrhosis is largely symptomatic (Table 50.2). Patients with complications of cirrhosis such as ascites, hepatic encephalopathy, and esophageal varices should receive appropriate treatment. Treatment of chronic hepatitis B or C may slow the progression of disease. Liver transplantation should be considered for patients with end-stage liver disease. Patients and their caregivers should be referred to a transplant center to determine whether liver transplantation will be a viable option (see Chapter 27). All patients with liver disease should refrain from further alcohol consumption. Other potentially hepatotoxic drugs should also be discontinued. Acetaminophen-induced hepatotoxicity may be more common in alcoholic patients due to compromised nutritional intake and diminished hepatic reserves. Acetaminophen can be safely used, if the dose is limited to less than 2 g per day. The use of aspirin or nonsteroidal anti-inflammatory drugs may worsen gastritis or precipitate GI bleeding or renal dysfunction. Other analgesics, such as narcotics, may lead to profound CNS and respiratory depression if liver function is severely compromised or the patient is obtunded. If the patient experiences nausea, antiemetics may be used with caution. Phenothiazine-type antiemetics (e.g., prochlorperazine, promethazine) have been associated with cholestasis and can also cause altered sensorium. Benzodiazepines, sedatives, hypnotics, and other drugs that can alter sensorium should be avoided, as they may worsen or precipitate hepatic encephalopathy.
those with a recent history of alcohol abuse. Replacement of thiamine at 50 to 100 mg per day along with a balanced diet may improve mentation, decrease symptoms of nutritional polyneuropathy, and improve gait disorders. Continuation of thiamine therapy beyond 1 or 2 weeks is of questionable value because it is a water-soluble vitamin whose stores are rapidly replaced. Up to 1 g per day is occasionally needed if the patient displays severe nystagmus, Wernickes encephalopathy, or oculogyric crisis. Iron replacement and folic acid supplements may be needed if the patient is anemic or folate-deficient. Iron deficiency can be determined by a blood smear and measurement of serum iron, total iron-binding capacity, and ferritin concentrations (see Chapter 31). Vitamin K 10 mg subcutaneously daily for 3 days is given if the prothrombin time/INR is elevated. Lack of response to vitamin K implies an impaired synthetic capacity that accompanies vitamin K deficiency from advanced liver disease. If the prothrombin time/INR is not reversed after three to five doses of vitamin K, further doses should be avoided because there may be a paradoxical lengthening of the prothrombin time from excessive vitamin K. This paradoxical effect is thought to be a result of consumptive processes induced by overstimulation of the production of clotting factors, leading to an eventual depletion of the body stores. Vitamin K1 , or phytonadione (AquaMephyton), gives a more rapid response when given parenterally than either vitamin K3 (menadione) or vitamin K4 (menadiol). Neither menadione nor menadiol is available in the United States. If giving phytonadione parenterally, the subcutaneous route is preferred, but it may also be given by very slow intravenous infusion in 50 mL of 5% dextrose in water over 15 to 20 minutes. Intramuscular injections are contraindicated if the patient has a prolonged prothrombin time/INR or is thrombocytopenic because of the possibility of hematoma and other bleeding complications. Because phytonadione is a colloidal suspension, there is a small risk of development of fever, chills, and even anaphylactic reactions with rapid intravenous injection. If the patient is malabsorbing fats or is cholestatic, the absorption of fat-soluble vitamins (A, D, E, and K) from the GI tract may be compromised. Subcutaneous phytonadione would be the preferred route in this setting. Patients should be assessed for signs and symptoms of vitamin deficiency and should receive vitamin supplementation if found deficient (see Chapter 29). Ascites. Ascites reversal, especially with drug therapy, is a time-consuming process that entails weeks or months of conservative management including bed rest to decrease plasma renin release, sodium restriction (500 mg to 2 g perday), and, in some cases, fluid restriction. Approximately 5% of patients have a spontaneous diuresis with bed rest alone, while another 10% to 25% respond to salt restriction.9 Fluid restriction is warranted only in cases of hyponatremia (serum sodium below 120 mmol/L) because excessive fluid restriction may lead to decreased renal blood flow and prere-
TREATMENT
Pharmacotherapy
Vitamin Supplementation. Specific vitamin supplementation is essential in most cirrhotic patients, especially
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TABLE 50.2 Drugs Used in Cirrhotic Patients

Drug
Thiamine
Reason
Reverse or prevent mental confusion secondary to thiamine deficiency (Wernickes syndrome) and decrease peripheral neuropathies Prevent bleeding secondary to decreased production of factors II, VII, IX, and X (vitamin Kdependent factors) Diuresis in ascites; specific for antagonism of preexisting hyperaldosteronism
Dose
100200 mg/day, occasionally higher
Monitoring Parameters
Mental status Decrease in nystagmus, peripheral neuropathies; 10 days of therapy is unwarranted
Vitamin K (phytonadione)
10 mg/day, not to exceed 3 doses
Hypersensitivity (fever, chills, anaphylaxis, flushing, sweating) Prothrombin time/INR
Spironolactone
100400 mg/day, occasionally higher; may be given as a single daily dose
Weight (avoid more than 1-kg weight loss per day) Mental status Serum K Urine Na and K (Na should not exceed K at therapeutic doses) Abdominal girth Blood urea nitrogen (increased in dehydration) Gynecomastia (prolonged use) Blood pressure Same as spironolactone except urine electrolytes are of no value Possible hearing loss with rapid IV bolus Rate of GI bleeding Signs of ischemia (chest pain, elevated blood pressure, bradycardia) GI cramping Serum Na Signs of GI bleeding Chest pain, fever, local ulceration
Loop diuretics furosemide
Diuresis in ascites used in combination with spironolactone
Start at 40 mg, titrate to 1-kg weight loss per day; occasionally very high doses (200600 mg/day) needed 0.20.4 units/min IV infusion
Vasopressin
Vasoconstrictor for esophageal bleeding
Sodium tetradecyl sulfate, ethanolamine oleate, or sodium morrhuate
Sclerosing agents for esophageal variceal bleeding
0.52 mL of 11.5% tetradecyl, 5% ethanolamine, or 5% sodium morrhuate solution in each varix about 2 cm apart 20320 mg/day titrated to 5560 bpm resting pulse rate if tolerated
Propranolol
Prevent GI bleeding
Signs of GI bleeding Mental changes Vital signs: pulse, blood pressure Signs of congestive heart failure, bradycardia Signs of bronchospasm Renal function Mental status, liver flap (asterixis), diarrhea
Lactulose
Hepatic encephalopathy; converted to acids to lower bowel pH and prevent absorption of NH3 Hepatic encephalopathy; sterilizes gut to prevent bacterial breakdown of protein and thus decreases serum NH3 levels
2030 g QID or 300 mL lactulose QS to 7001,000 mL as rectal enema titrated to 34 soft stools per day 26 g/day, orally or rectally
Neomycin
Mental status, liver flap (asterixis) Diarrhea, bacterial overgrowth Renal function Signs of ototoxicity
(continued )
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TABLE 50.2 continued

Drug
Rifaximinb
Reason
Hepatic encephalopathy; decreases urease producing, bacteria Hepatic encephalopathy; replace branched-chain amino acids
Dose
400 mg orally three times daily Titrate to caloric and nitrogen needs
Monitoring Parameters
Mental status, liver flap (asterixis) Mental status Serum ammonia, cerebrospinal fluid glutamine Serum amino acid levels (branchedchain: aromatic amino acid ratio) Electrolyte balance Mental status, liver flap (asterixis) Urine output Blood pressure Nausea, abdominal pain, diarrhea Reduction in incidence of SBP
Hepatamine, Hepatic-Aid, and Nutihepa
Dopaminea
Hepatorenal syndrome
14 g/kg/min
Colchicinea,b Cefotaxime, norfloxacina, ciprofloxacin, trimethoprim/ sulfamethoxazole Flumazenila,b Octreotide Midodrine
Anti-inflammatory and antifibrotic effects Treatment or prevention of spontaneous bacterial peritonitis
0.6 mg PO BID or 1 mg PO QD 5 days/wk Norfloxacin 400 mg daily or 400 mg BID (ciprofloxacin 750 mg weekly, TMP/SMX 1 DS QD, M through F) 0.20.4 mg titrated to response 50-g bolus, 50200-g/hr infusion for 5 days Dosed orally to maintain increase of 15 mm Hg in mean arterial pressure
Acute reversal of hepatic encephalopathy Treat GI bleeding Hepatorenal syndrome (investigational use)
Reversal of mental obtundation Diarrhea Improvement in GI bleeding Blood pressure Glomerular filtration rate Renal sodium excretion
Not recommended for all patients. bInvestigational use only; efficacy unclear.
nal azotemia. Hospitalization usually is recommended for refractory patients for the following reasons: intensive education on medications and diet; close monitoring of serum and urine electrolytes, urea nitrogen, and creatinine; and investigation of the cause of the liver disease. Diuretics are the cornerstone of drug therapy for the treatment of ascites. Diuresis must be slow and controlled to minimize complications. If urinary losses exceed the volume of fluid reabsorbed from ascites or peripheral edema, volume depletion with hypotension and renal insufficiency can develop. In patients treated with sodium restriction alone, no more than 300 mL of ascites can be reabsorbed per day. Even with the use of a diuretic, the maximum rate of reabsorption is 1,440 mL per 24 hours.19,20 Diuresis should be limited to 0.2 to 0.3 kg weight loss per day in those without edema and 0.5 to 1 kg per day in patients with edema. Others allow a slightly more liberal diuresis of 0.75- to 2-kg weight loss per day.20 These recommendations assume that each liter of volume lost is equivalent to a 1-kg weight loss. In patients with concurrent peripheral edema, a greater diuresis may be acceptable for the first 1 to 2 days because peripheral edema equilibrates more readily with the vasculature than does ascitic fluid. Other monitoring parameters include urine output, changes in abdominal girth, postural blood pressures, blood urea nitrogen, serum creatinine, increase in the urine-
potassium:sodium ratio from pretreatment baseline, and mental status changes. Although slow diuresis with any diuretic may be acceptable for treating ascites, typically the first diuretic given is spironolactone with or without furosemide. Spironolactone is a gentle, slow-acting diuretic that antagonizes the effects of the hyperaldosteronism that exists in many of these patients. In contrast to the small doses of spironolactone that are used as an adjunct in hypertension and congestive heart failure, the initial dose for the treatment of ascites is usually 50 to 100 mg per day. A 3- to 5-day lag period exists for the onset and maximum response from spironolactone, so frequent dose adjustments prior to this time period should be avoided. Doses are titrated upward in 50- to 100-mg increments every 3 to 5 days, with 400 mg per day being required in approximately 75% of patients. The delayed onset and long duration of spironolactone result from the long halflife (approximately 17 to 20 hours) of its active metabolite, canrenone. For patient convenience and to improve compliance, once-daily dosing is recommended. Multiple daily doses are not necessary unless the patient cannot swallow the necessary number of tablets at one time without gastric distress. Other concomitant diuretics such as furosemide offer an additional mechanism of diuresis. Runyon et al advocated
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the use of furosemide initially or early in treatment in a ratio of 40 mg to every 100 mg of spironolactone, given once daily in the morning to avoid nocturnal diuresis.21 An added advantage of this combined approach is to maintain potassium balance in the face of diuresis. Triamterene (Dyrenium) and amiloride (Midamor) are potassium-sparing diuretics that have a slightly more rapid onset of action, but they are not specific inhibitors of aldosterone. The relative efficacy of these potassium-sparing diuretics compared to spironolactone has not been evaluated extensively. They may be useful in patients who develop gynecomastia with spironolactone. The new and more selective aldosterone antagonist eplerenone (Inspra) is associated with less gynecomastia, but it has not been adequately studied in this patient population. Besides the general monitoring parameters cited for diuretic therapy, serum and urine electrolyte levels, especially potassium, must be monitored. If hyperaldosteronism is present, it is not uncommon to see very little or no urinary sodium excretion and large urinary potassium losses. One measure of having achieved the desired spironolactone dose is a reversal of the urine electrolyte pattern to normal (i.e., sodium loss greater than potassium loss). Patients with urine sodium:potassium ratios greater than 1 tend to respond to lower doses of spironolactone (100 to 150 mg per day); those with ratios less than 1 often need larger doses, averaging 400 mg per day.9 Hyperaldosteronism, if present, may also cause a reduction in the serum potassium concentration. Although the use of spironolactone with potassium supplements is usually contraindicated in treatment of other diseases because of a high risk of inducing hyperkalemia, this combination may be necessary early in the treatment of ascites, especially if the patient has additional GI losses of potassium secondary to vomiting or diarrhea. Serum potassium must be monitored daily to avoid hypokalemia or hyperkalemia. Because these patients often are placed on a low-sodium diet, the use of salt substitutes that contain potassium use should be discouraged to further limit the complexity of potassium supplementation in this setting. Long-term use of spironolactone increases the risk of gynecomastia, a problem that is common in cirrhosis independent of diuretic use. Patients should be informed of this side effect of spironolactone. High doses of spironolactone alone may not produce the desired diuresis in some patients or may cause hyperkalemia. In this situation, the addition of more potent diuretics such as thiazides or loop diuretics may be warranted. Some patients are especially refractory, often requiring several hundred milligrams per day of furosemide to obtain the desired weight loss of 0.5 to 1 kg per day. One drawback to the use of thiazides and loop diuretics is that they cause a significant natriuresis, which interferes with the ability to interpret urine electrolytes. Intravenous furosemide should be avoided if possible because it can decrease glomerular filtration rates and adds additional unnecessary cost.22 Use of nonsteroidal anti-inflammatory drugs and COX-2 inhibitors
should be avoided because they may blunt the effects of diuretics and decrease renal blood flow. Paracentesis (aspiration of peritoneal fluid with a needle), except for the removal of small volumes (250 to 1,500 mL) to decrease pain and respiratory distress from abdominal distention, has traditionally been discouraged because of the risk of abdominal perforation and infection. If a large volume is removed, 15% to 100% (mean 58%) of the fluid may reaccumulate over the next 24 to 48 hours, leading to transient hypovolemia and the possibility of shock, encephalopathy, or acute renal failure.19 More recently, the combination of a therapeutic paracentesis with or without intravenous albumin infusion (to maintain volume in the vascular space) has become an accepted mode of therapy.2326 A typical regimen is the removal of 4 to 6 L per day via paracentesis, with replacement of 40 to 50 g albumin after each paracentesis (approximately 10 to 12.5 g of albumin per liter of ascites fluid removed). Paracentesis with albumin replacement is superior to diuretic therapy; it decreases ascites faster and shortens the hospital stay without significant worsening of hepatic, renal, or cardiovascular function. Single large-volume (about 5 L) paracentesis without albumin replacement also appears to be safe in patients with painful, tense ascites,27 but repeated large-volume paracentesis without albumin replacement may result in hyponatremia or renal impairment in some patients.24 Another possible concern is an increased risk of spontaneous bacterial peritonitis secondary to reduced ascitic fluid opsonic activity.21 Arguments about the high cost of albumin are counterbalanced by the decreased length of hospital stay. The use of dextran as a volume expander after paracentesis has been evaluated as an alternative to albumin.23 It has been shown to help prevent the asymptomatic abnormalities in laboratory values at a lower cost,22 although its use remains controversial.28,29 Albumin has also been used without paracentesis in an attempt to increase intravascular volume and induce diuresis. The drawbacks to this treatment are a short duration of response, the risk of inducing variceal hemorrhage, and high cost. Generally, treatment with albumin without paracentesis is to be avoided unless all other therapies have failed. In Europe, ascites recirculation (removal, concentration, and reinfusion of peritoneal fluid) has been found to be safe and effective.30 The possibility of reaccumulation of ascites after paracentesis necessitates continuation of a lowsodium diet and diuretics. The peritoneovenous (LeVeen or Denver) shunt, in use extensively for the past 20 to 25 years, was devised for use in diuretic-refractory ascites.31,32 This type of shunt consists of a surgically implanted one-way valve in the abdominal wall, an intra-abdominal cannula, and an outflow tube tunneled subcutaneously from the valve to a vein that empties directly into the inferior vena cava. As the diaphragm descends, the pressure in the intrathoracic veins drops and intraperitoneal pressure rises. This pressure differential pushes ascitic fluid via the shunt into the venous system. The results may be dramatic, with urine output as high as 15 L occurring during the first 24 hours. Supplemental diuresis with furose-
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mide may be needed to prevent vascular overload. However, use of this procedure is limited by such complications as fever, shunt occlusion, hypokalemia, infection, shunt leak, disseminated intravascular coagulopathy, and less often variceal hemorrhage, bowel obstruction, pulmonary edema, and pneumothorax.31 A Veterans Administration Cooperative study involving 3,860 patients showed a lack of improvement in survival and significant morbidity rates in patients treated with a peritoneovenous shunt compared with those treated with diuretic therapy.32 However, shunting alleviated disabling ascites more rapidly than medical management did. A more widely accepted shunting approach is the transjugular intrahepatic portosystemic shunt (TIPS). A transjugular approach is used to place a stent within the liver that creates a low-resistance conduit between a branch of the portal vein and the hepatic vein. Blood will flow directly through the TIPS and decompress the portal venous system. Adverse effects of the TIPS include worsened hepatic encephalopathy, hepatic ischemia, and bleeding. The value of the TIPS in refractory ascites has been evaluated. In this study, the TIPS in combination with medical treatment was proven superior to medical management alone; however, the TIPS did not improve either survival or the quality of life.33 These relatively aggressive shunting options are generally reserved for patients with ascites refractory to medical intervention. Spontaneous Bacterial Peritonitis. Spontaneous bacterial peritonitis (SBP) is infection of the ascitic fluid in the absence of an intra-abdominal source (e.g., bowel perforation or abscess). SBP occurs in approximately 30% to 40% of cirrhotic patients.34 Although some patients are asymptomatic, commonly observed signs and symptoms include fever, chills, vomiting, abdominal pain or tenderness, decreased bowel sounds, worsened renal function, and encephalopathy. The diagnosis of SBP is made by evaluating a small sample of the ascitic fluid. A polymorphonuclear cell count greater than 250 cells per cubic millimeter of ascitic fluid or a positive bacterial culture is diagnostic for SBP.35,36 SBP is thought to be the consequence of alterations in the immune defense of patients with advanced liver disease. It is believed that the gut is the main source of infecting bacteria in SBP; however, hematogenous spread from the urinary or respiratory tract or skin can occur. Bacterial translocation (passage of bacteria from the lumen of the GI tract to extraintestinal sites such as the peritoneum) is an important step in the pathogenesis of SBP. Bacterial overgrowth and bowel wall edema from portal hypertension contribute to the translocation of bacteria. Mesenteric lymph nodes and the hepatic reticuloendothelial filtering system would normally kill translocated bacteria, but in cirrhotic patients, some bacteria can escape this and reach the ascitic fluid. Defects in the local immune response such as decreased opsonization and phagocytosis by macrophages further contribute to infection of the ascitic fluid.35
Predisposing factors for SBP include a previous episode of SBP, the severity of underlying liver disease, GI hemorrhage, and an ascitic fluid total protein concentration of 1 g per dL or less. Enteric gram-negative bacilli such as Escherichia coli and Klebsiella pneumoniae, and Streptococcus pneumoniae are the most common organisms seen with SBP. Anaerobic bacteria, Pseudomonas sp, Staphylococcus sp, and fungi are not common pathogens in SBP. Infection in SBP is usually monobacterial. If multiple species of bacteria or anaerobic bacteria are cultured, secondary bacterial peritonitis (e.g., bowel perforation) should be considered. Empiric therapy has traditionally been ampicillin or a first-generation cephalosporin in combination with an aminoglycoside. More recently, the use of less toxic alternative agents such as ampicillin/sulbactam, ticarcillin/clavulanate, piperacillin/tazobactam, second- and third-generation cephalosporins, and quinolones have also resulted in favorable outcomes. Caution is advised with the use of cefotetan and other cephalosporins with a methylthiotetrazole (MTT) side chain, which can interfere with vitamin K and cause a hypoprothrombinemic state. Cefotaxime 2 g every 8 hours is generally accepted as the current drug of choice for SBP.37,38 The antibiotic regimen should be tailored based upon culture and sensitivity results. Duration of therapy is approximately 5 days because of the relatively low inoculum of organisms in the ascitic fluid.39 Administration of intravenous albumin in patients with SBP has been shown to reduce the mortality rate and decrease the incidence of renal dysfunction. SBP is associated with significant morbidity and mortality. Recurrence of SBP is common following treatment. Long-term prophylaxis with antibiotics to prevent recurrent SBP has been evaluated in several clinical trials. Norfloxacin 400 mg once daily has been used successfully in high-risk patients. This fluoroquinolone results in a selective intestinal decontamination that decreases gram-negative bacilli but preserves the remaining normal flora. Norfloxacin has been shown to markedly reduce the incidence of SBP in patients with previous episodes of SBP.40 Twice-daily dosing for the first 7 days of a prophylaxis regimen may be needed in patients experiencing a GI hemorrhage.41 Other regimens such as trimethoprim/sulfamethoxazole 1 double-strength tablet daily given 5 days per week or ciprofloxacin 750 mg once a week have been shown to be effective in preventing SBP.42,43 When a fluoroquinolone is chosen, it is important that concomitant administration with medications containing divalent and trivalent cations be avoided to minimize the drugdrug interaction. Gastrointestinal Bleeding. Bleeding from esophageal or gastric varices is one of the most feared complications of portal hypertension. Variceal hemorrhage is a grave sign and may be difficult to stop. Mortality from a single bleeding episode is approximately 17% to 57%.44 Varices are portosystemic collateral veins that are dilated due to portal hypertension. Varices are present in up to 60% of patients with cirrhosis, but bleeding occurs in only about
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one third of patients. Factors associated with increased riskof a variceal hemorrhage include continued alcohol consumption, poor liver function, and large varices seen on endoscopy. In the setting of an acute bleed, multiple blood transfusions and intravenous fluids may be necessary to maintain circulatory volume. Balloon tamponade, pharmacologic therapy, and endoscopic intervention are methods to stop bleeding. Application of direct pressure with a balloon tube (Linton, Minnesota, or Sengstaken Blakemore tube) that can be inflated in the esophagus and/or stomach can slow bleeding. As the balloon is inflated, the varix is compressed between the balloon and the esophageal wall, slowing or even stopping bleeding. While bleeding is stopped in 40% to 80% of patients, it is only a temporary measure. This procedure is complicated by vomiting, a high risk of aspiration, ischemia of the esophageal mucosa, perforation, and recurrence of bleeding as soon as the balloon is deflated. Endoscopic therapies include sclerotherapy and variceal ligation. Injection of sclerosing agents into esophageal varices has revolutionized the care of patients with bleeding varices.4550 This approach is considered by many to be the therapy of choice. The most commonly used sclerosing agents in the United States are sodium tetradecyl sulfate (Sotradecol), ethanolamine oleate (Ethamolin), and sodium morrhuate (Scleromate). Injection of these agents into a bleeding varix leads to an intense inflammatory response, thrombus formation, and cessation of bleeding within 2 to 5 minutes. A more permanent fibrotic obliteration of the vessel develops over several days. Sclerotherapy controls acute variceal bleeding in 90% to 95% of patients.45 A single treatment controls bleeding in 90% of patients; the remainder may require multiple treatments over several weeks. Success rates are lower in actively bleeding patients than in those in whom bleeding was controlled initially by more conservative methods. Failure of therapy is defined as continuation of bleeding after two injections of a sclerosing agent during a single admission.51 Compared with portacaval and splenorenal shunt procedures, sclerotherapy is almost equally effective in stopping bleeding, there is no difference in survival, and there is much lower morbidity.47,48 Prophylactic sclerotherapy in patients with endoscopic evidence of varices but no history of past or current bleeding is of no clinical benefit.49,50 A 0.5% to 3% solution of tetradecyl sulfate or a premixed solution of ethanolamine 5% or morrhuate 5% for injection is used. After the endoscope is passed, approximately 0.5 to 2 mL of the sclerosing solution is injected into each varix at points about 2 to 4 cm apart. If bleeding recurs, therapy can be repeated. Although it appears that sclerotherapy is effective in stopping acute bleeding and preventing rebleeding, more than 50% of patients will rebleed, and the longterm mortality is not lower than with conventional therapy. Side effects associated with sclerotherapy include pericardi-
tis, chest pain, dysphagia, pyrexia, cardiac tamponade, formation of esophagobronchial or tracheoesophageal fistulas, and local ulcerations. Following sclerotherapy, prophylaxis with antacids, histamine-2 (H2) antagonists, proton pump inhibitors, or sucralfate may be initiated. Dosing of these drugs is the same as that recommended for treating peptic ulcer disease or reflux esophagitis (see Chapter 45). Careful monitoring of mental status in those who are treated with cimetidine is warranted because cirrhosis may predispose patients to the mental confusion associated with this agent.52 With the available acidsuppressing alternatives, one could make an argument for avoiding cimetidine altogether in this setting. The pharmacokinetics of ranitidine may also be altered in cirrhosis, resulting in its accumulation.53 Sucralfate suspension has been used to prevent ulcers at the sclerosis site. Investigators using endoscopy have shown that the drug complex seems to coat the varices, decreasing ulcer formation.54 The aluminum component of sucralfate may complex with coadministered norfloxacin or ciprofloxacin, resulting in poor absorption. The importance of divalent and trivalent cations complexing with quinolones could be questioned in SBP prophylaxis because of local intestinal rather than systemic action. However, because the complex does not enter bacteria as well,55 it is prudent to space the administration of these agents even with SBP prophylaxis. A newer endoscopic technique for control of variceal bleeds is endoscopic variceal banding therapy or ligation. The success rate of this procedure may be as high as 90%.56 The procedure involves the endoscopic placement of a small rubber band over a distal varix. A large varix is drawn by suction aspiration into the end portion of the sleeve, and the rubber band is released over the base of the varix. A specially modified endoscope that carries a triggering device and rubber band on a small sleeve over the objective end of the scope is required. Endoscopic variceal banding therapy has a control rate of 86% for acute bleeding. It has also been associated with a lower complication rate, although the risk of rebleeding may be slightly higher than with sclerotherapy.57,58 Historically, the hormone vasopressin (ADH) was used to treat bleeding varices before the advent of sclerotherapy and octreotide. Vasopressin decreases portal blood flow and pressure by constricting portal and other splanchnic arterioles. This slows or stops bleeding long enough to allow thrombus formation at the site of bleeding in 60% to 80% of patients. The use of this drug is declining and it remains controversial because the benefits in terms of morbidity and mortality have never been proven.59 Sclerotherapy has been shown consistently to be more effective than vasopressin, but vasopressin may be given first to slow bleeding and facilitate endoscopic visualization of the bleeding varix. The major limitation to vasopressin therapy is its side effects. The intense vasoconstriction decreases cardiac output and may cause coronary ischemia. This is especially problematic in patients with coronary artery disease or hy-
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pertension; however, ischemic changes have also been reported in patients with no prior evidence of ischemic disease. Bradycardia caused by stimulation of the vagus nerve is the most widely observed side effect of vasopressin. It may also produce skin blanching, GI cramping, and even bowel necrosis. Women may experience uterine pain similar to menstrual cramps. Finally, vasopressin may lead to excess water retention and a dilutional hyponatremia.59 A continuous intravenous infusion starting at 0.2 to 0.4 units per minute and direct intra-arterial infusion via a catheter into the superior mesenteric artery at 0.05 to 0.4 units per minute have been tried. The maximum recommended intravenous infusion rate is 0.9 units per minute. Infusions may be continued for up to 72 hours, with a slow tapering of the dose over time. The results have been varied, with some authors claiming up to 50% to 70% effectiveness.59 Others claim poor response and a high incidence of complications, including bleeding from the site of catheter insertion and septicemia.60 A combination of vasopressin infusion and intravenous nitroglycerin (10 to 50 g per minute titrated according to blood pressure to a maximum of 400 g per minute)61 or sublingual nitroglycerin (0.6 mg every 30 minutes for 6 hours)62 may cause an additional decrease in portal pressure. In the study using intravenous nitroglycerin, there was less bleeding with combination therapy; in the trial with sublingual nitroglycerin, the rate of bleeding cessation was equal to that with vasopressin alone. In both studies, combination therapy led to a marked reduction in cardiac complications. Somatostatin and its analogue, octreotide, have also been evaluated in controlling variceal bleeding. Somatostatin reduces portal pressure and blood flow after a bolus dose followed by continuous intravenous administration. It offers efficacy equal to that of vasopressin, with considerably fewer side effects.63 Its use is limited only by its higher acquisition cost.47,64 Somatostatin dosing consists of a 250-g bolus followed by an infusion of 250 g per hour. The equally effective somatostatin analogue, octreotide, is dosed with a 50-g bolus and continued as an infusion at a rate of 50 g per hour for 5 days. Octreotide is considered the agent of choice in the management of acute variceal bleeding used alone and with endoscopic sclerotherapy or banding.65,66 Bleeding from other GI sites, especially bleeding caused by gastritis and peptic ulcer, usually is treated with nasogastric suction, H2 receptor antagonists, or proton pump inhibitors or hourly antacids.67 Occasionally, 20 units of vasopressin, 1 to 2 (4 to 8 mg) ampules of norepinephrine, or ice is used in a gastric lavage to cause localized vasoconstriction in an attempt to slow bleeding. No evidence documents these latter maneuvers to be any more effective than tap water lavage or acid suppression alone; therefore, their use is generally discouraged. It has been suggested that because propranolol, nadolol, and possibly other nonselective -adrenergic blockers decrease portal venous pressure, they may prevent GI bleeding associated with portal hypertension.6873 Primary prophy-
laxis is defined as treatment of patients with known varices but without a history of active bleeding. Secondary prophylaxis involves administering the drug after resolution of an acute bleeding episode to prevent subsequent bleeding. Although data are limited, overall analysis of the benefit of primary therapy is positive.6870 For example, in the European Cooperative study group, after a median dose of 160 mg per day (range 40 to 320 mg), 74% of patients in the propranolol group were free of bleeding after 2 years, compared with 39% in the placebo group. Two-year survival was 72% in the treated patients and 37% in the untreated subjects.70 Propranolol also appears to be a cost-effective approach, with savings between $450 and $14,600 over 5 years in 1997 dollars.71 The results for secondary prophylaxis are also encouraging but somewhat more complex. Lebrec et al72 showed that oral propranolol in doses that reduced the heart rate by 25% to a resting rate of 50 to 60 beats per minute led to a significantly lower frequency of rebleeding than did placebo, during a 2-year study in chronic alcoholic patients with a history of esophageal bleeding. Only 21% of patients in the propranolol group had recurrence of bleeding, compared to 68% in the placebo group. Cumulative survival was 90% in the propranolol group and 57% in the placebo group. None of the patients showed deterioration of hepatic or renal function while taking propranolol. Because propranolol may decrease cardiac output and liver blood flow, patients should be monitored closely. A similar study by Burroughs et al73 failed to confirm the findings of Lebrec. However, the patients in Burroughs et als study had more severe liver disease and some had cirrhosis from causes other than chronic alcoholism. Selective -blockade with atenolol or metoprolol appears to be less effective than sclerotherapy in arresting acute variceal bleeding.68,69 A follow-up study by Poynard et al74 confirmed the benefits of propranolol, with 71% of subjects free of bleeding at 1 year and 57% at 2 years. In this study, five factors were identified that increased the risk of rebleeding: hepatocellular carcinoma, continued alcohol abuse, lack of suppression of pulse rate by propranolol, a history of rebleeding, and noncompliance with drug therapy. Of particular concern, 12 of 14 (86%) patients who discontinued -blocker therapy abruptly had an episode of rebleeding. The time of greatest risk for rebleeding is within the first 3 to 4 days after stopping therapy, but it may occur up to 150 days later.68,69,7476 It is not possible to be certain that drug discontinuation is responsible for rebleeding in the delayed rebleeding cases. A randomized controlled study by Teres et al77 in Barcelona compared sclerotherapy with propranolol in the prevention of rebleeding for varices. Although the incidence of rebleeding was less with sclerotherapy (26 of 58 subjects) than with propranolol (37 of 58 subjects) titrated to reduce the resting heart rate by 25%, complications were significantly more common and of greater severity with sclerotherapy. The authors could not recommend either approach on the basis of the study findings.
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Another published trial compared isosorbide-5-mononitrate with propranolol in long-term follow-up (128 patients followed up over 7 years). Isosorbide-5-mononitrate was as effective as propranolol in reducing mortality.78 Additional perspective on this approach was offered in an accompanying editorial.79 However, at least one trial comparing isosorbide mononitrate to nadolol showed a greater risk of bleeding with the nitrate.80 Currently, -blockade alone seems more established and safer than nitrates when used alone or when combined with -blockade. Because patients with cirrhosis often have a low blood pressure, -blockers should always be used with extreme caution. Surgical treatment may be needed for patients who have repeated GI bleeding (especially esophageal varices) or those who have bleeding that cannot be stopped by the more conservative measures already described.45 A portacaval shunt involves anastomosis of the portal vein directly to the inferior vena cava, thus bypassing the cirrhotic liver. This surgical procedure decreases portal hypertension. Unfortunately, these patients often have a poor prognosis because the blood that normally flows to the liver for detoxification and metabolism is now shunted away from the liver. If they survive the initial surgery, patients may die of sepsis or develop hepatic failure and encephalopathy. The Warren (distal splenorenal) shunt decompresses the varices by shunting splenic blood flow to the renal vein and does not alter hepatic perfusion as much. The TIPS procedure also effectively decompresses the portal system and is an option in the treatment of and prevention of variceal bleeding. Hepatic Encephalopathy. Clinical manifestations of hepatic encephalopathy should be recognized and addressed promptly, because most are reversible with appropriate therapy.81 If the patient exhibits signs of hepatic encephalopathy (e.g., confusion, drowsiness, asterixis), lactulose is indicated, as well as dietary protein restriction to approximately 0.8 to 1 g per kilogram per day. Use of CNS depressants (e.g., benzodiazepines, narcotics) should be minimized or avoided; this is especially true of benzodiazepines. Except for cautious use of spironolactone or furosemide, diuretics usually should be withheld at this stage because hypovolemia, hypokalemia, and metabolic alkalosis may aggravate encephalopathy. Lactulose is a synthetic disaccharide of galactose and fructose that is neither absorbed nor hydrolyzed in the small bowel. It is degraded by colonic bacteria to lactic, acetic, and formic acid, thus lowering the pH of the colonic contents. The effect of lactulose was originally attributed to replacement of proteolytic bacteria such as E. coli, Proteus, and Bacteroides with organisms such as Lactobacillus that thrive in a more acidic medium and lack urease and other enzymes that are used in the production of ammonia. However, most investigators have not found a marked change in the colonic flora and have attributed the effects of lactulose solely to the change in pH of the colonic contents. As the colon becomes more acidic, this favors the conversion from
ammonia to ammonium. Ammonium is a charged particle and is not absorbed. There may also be back-diffusion of ammonia from the blood to the intestinal lumen under acidic pH conditions. Regardless of which mechanisms are in effect, lactulose therapy results in a decrease in arterial ammonia levels.82 Each 15 mL of lactulose oral liquid contains 10 g lactulose; it is usually given in a dose of 30 to 40 mL three or four times daily (approximately 45 to 90 g per day). Retention enemas of 300 mL of lactulose syrup diluted with 700 mL of tap water can also be used.83 The onset of effect by either route is 12 to 48 hours, with an endpoint of two or three loose stools daily and an improvement in mental capacity. The success rate with lactulose has been reported to be around 85%. Patient tolerance can be improved by diluting the drug in water, fruit juice, or carbonated beverages. Patients may require prolonged therapy to prevent recurrence of symptoms. The most common complaints of patients treated with lactulose are nausea (because of the sweet taste of the drug), gaseous distention, bloating, belching, or diarrhea caused by osmotic effects in the bowel. Diarrhea may account for part of the therapeutic effects of lactulose by flushing out toxins,84 but compared with sorbitol, lactulose is more effective in treating the encephalopathy, indicating that other mechanisms are working such as decreasing ammonia levels. Excessive diarrhea may lead to dehydration and electrolyte abnormalities such as hypernatremia. Patients should be closely monitored during lactulose therapy to avoid these fluid and electrolyte abnormalities. Neomycin, an alternative to lactulose, is an aminoglycoside antibiotic that kills the urease-producing bacteria in the colon, thus reducing the production of intestinal ammonia. Neomycin is given at a dose of 1 to 2 g four times a day. When the patient improves, the dose may be lowered to 2 to 4 g per day. For patients who cannot take medications orally, a retention enema of 2 to 4 g in 200 mL of saline thickened with methylcellulose may be used twice a day. One well-controlled study failed to show a clear superiority of neomycin (83% effective) or lactulose (90% effective) in treating acute encephalopathy. For long-term use, lactulose has the potential advantage of less toxicity, but it is considerably more expensive.85 The possibility that sterilization of the gut by neomycin might decrease the effectiveness of lactulose appears to be of minimal consequence;86 in fact, the two drugs are more effective when used together.87 Even though neomycin is not well absorbed from the GI tract, approximately 1% to 3% of a dose is absorbed.79 Neomycin can cause nephrotoxicity and ototoxicity in patients on chronic therapy.88,89 Most of these patients had been taking neomycin for at least 8 months and had coexisting renal dysfunction. An auditory test should be performed at baseline and annually to assess for hearing impairment. Other oral antibiotics that have been evaluated with some success include metronidazole, vancomycin, and rifaximin, a derivative of rifamycin.81
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There are multiple approaches to the management of hepatic encephalopathy. Avoiding the use of drugs that can alter sensorium is of paramount importance. Lactulose is typically the drug of choice. Neomycin or rifaximin are alternatives for patients who are intolerant to lactulose or in whom the effects of lactulose are waning. Dietary interventions such as protein restriction and avoiding large protein loads are also useful. Therapeutic Value of -Aminobutyric Acid Antagonists. Some investigators believe that endogenous or exogenous GABAergic-like compounds that stimulate the GABAbenzodiazepine receptor complex in the brain may be responsible for symptoms of encephalopathy.17,90 Preliminary data suggest that the benzodiazepine antagonist flumazenil may be valuable in both short-term and long-term management of hepatic encephalopathy. In 14 subjects, 71% showed short-term improvement in symptoms after intravenous administration of flumazenil.91 Arousal was greatest in patients with deeper coma (stage III or IV encephalopathy). Although response was rapid, the duration of effect was only 1 to 2 hours. The usual dose was 0.2 to 0.4 mg, with some subjects receiving up to 10 doses. A single case report describes the long-term use of oral therapy.92 A patient given 25 mg twice daily experienced complete reversal of symptoms for 14 months. Previously, this patient had experienced 12 episodes of coma over a 2-year period. Discontinuation of the drug led to a recurrence of symptoms within 48 hours. A randomized double-blind placebo-controlled crossover trial from Canada showed a significant clinical improvement in 5 of 11 (45%) patients with hepatic coma receiving flumazenil in the initial treatment phase and 1 of 2 (50%) in the crossover phase of the study. The authors concluded that the agent is efficacious and safe for reversing neurologic symptoms in cirrhotic patients with hepatic coma.93 This trial has been criticized.94 A recent analysis of this approach has also shown efficacy, but it is short-lived and not associated with mortality reduction. Thus, the use of a benzodiazepine receptor antagonist in these patients remains investigational and controversial95 and is not the standard of care. Therapeutic Value of Corticosteroids. Cirrhotic patients with biopsy-proven alcoholic hepatitis may benefit from the anti-inflammatory effects of corticosteroid therapy. The beneficial effect may be related to the corticosteroids inhibition of cytokine production. The efficacy of steroids in treating liver disease remains controversial. Clinical trials have shown conflicting results with regard to mortality. A meta-analysis of the randomized trials was completed to determine the efficacy of steroids on short-term mortality in patients with alcoholic hepatitis. The combined data indicated that steroids provide a protective efficacy of 27% in patients with hepatic encephalopathy. This figure increased in patients without active GI bleeding. Among subjects without hepatic encephalopathy, steroids had no protective efficacy. These data suggest that only pa-
tients with severe disease would benefit from steroid therapy. Patients with severe disease are defined as those with hepatic encephalopathy or a discriminant function higher than 32 [discriminant function 4.6 (Patients prothrombin time control prothrombin time) bilirubin]. Patients with severe disease who have active GI bleeding or need treatment for active infection should be excluded from steroid therapy.96 Prednisolone is the most studied and appears to be the preferred corticosteroid. The typical dosing regimen is 40 mg per day for 4 weeks and is then tapered over 2 to 4 weeks.97 Overall, the available data on this subject are less than consistent in their conclusions and outcomes. The American College of Gastroenterology consensus position on steroid use in hepatitis related to alcohol was recently published.98 Hepatorenal Syndrome Therapeutic Value of Vasoactive Agents. HRS is the development of renal failure in patients with cirrhosis. Dopamine and norepinephrine are important neurotransmitters in the CNS, the periphery, and the kidneys. Some of the neurologic manifestations of hepatic failure, and HRS, may be caused by accumulation of other -hydroxylated phenylethylamines such as octopamine and serotonin. These compounds may replace normal transmitters and act as false neurotransmitters in sympathetic nerve terminals. Precursors of false neurotransmitters, such as phenylalanine and tyrosine (Fig. 50.2), are produced from protein in the gut by bacterial amino acid decarboxylases. Normally, these precursors are metabolized rapidly in the liver by monoamine oxidase, allowing norepinephrine that is formed elsewhere in the body to predominate. When hepatic function is impaired or when blood is shunted away from the liver, these false neurotransmitters may replace normal transmitters. Systemically, this may lead to lowered peripheral vascular resistance and shunting of blood away from the kidney. Similarly, asterixis and other signs of hepatic encephalopathy might result from displacement of transmitters such as dopamine and norepinephrine in the basal ganglia and other areas in the brain.
FIGURE 50.2 Synthetic pathway of neurotransmitters. Monoamine oxidase (MAO) action occurs mainly in the liver and is depressed in hepatic disease and shunting.
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If the displacement of normal central and peripheral transmitters by less active amines can account for hepatic coma and its cardiovascular complications, then the restoration of normal transmitter stores might restore normal function. For hospitalized patients, this is accomplished with low-dose infusions of dopamine at 1.3 to 5 g per kilogram per minute.99 This may increase renal blood flow and help to reverse HRS. Failure to improve urine output or increase blood pressure within the first 24 hours of dopamine treatment is a poor prognostic sign. Because dopamine does not cross the bloodbrain barrier, encephalopathy will not improve. However, as shown in Figure 50.2, dopamine is also a precursor to norepinephrine, which may help to restore natural neurotransmitter balance. Use of the alpha agonist midodrine in combination with octreotide has also shown efficacy in reducing mortality in HRS.100 Although not universally effective, this combination is becoming established as a trial modality to offer patients with this often fatal complication. There is no structural abnormality of the kidneys in HRS; rather, it is most likely due to humoral imbalances from liver failure. HRS is associated with a mortality rate that approaches 100%. While many therapeutic methods have been tried to improve renal function, most have either a minor or a temporary effect, with the exception of liver transplantation. Pharmacotherapy of Primary Biliary Cirrhosis. Colchicine, a drug with both anti-inflammatory and antifibrotic properties, has been evaluated as a potential disease-modifying agent. In one study, 57 patients with biopsy-proven PBC were treated with 0.6 mg colchicine twice daily or placebo.101 The colchicine-treated patients had a significant improvement in biochemical parameters (serum bilirubin and aminotransferase levels) but no difference in histologic progression when compared to placebo. A second group of investigators conducted a randomized, double-blind, placebocontrolled trial of colchicine, 1 mg per day, 5 days per week, in 100 patients with cirrhosis caused by alcohol abuse or a history of hepatitis.102 Median survival was 3.5 years in the placebo group and 11 years in the colchicine-treated patients, while deaths from liver failure were 24% in the placebo group and 15% in the treatment group. Side effects in both trials were mild, consisting primarily of nausea, abdominal pain, and diarrhea. Although these results are encouraging, flaws in the study design and the small number of subjects treated prevent widespread endorsement of colchicine therapy at this time. Numerous other drugs have been tried in treating PBC, including penicillamine, chlorambucil, azathioprine, cyclosporine, corticosteroids, and methotrexate.103 Each of these therapies is based on the hope that anti-inflammatory or immunomodulating effects may alter the disease process. Cyclosporine showed modest improvement in symptoms, enzyme levels, and histologic findings in a controlled trial of PBC. However, toxicity with this drug is a limiting factor in therapy. Sequestration of copper by penicillamine may have a therapeutic effect, but most of the trials with these
drugs have been limited by a small sample size without adequate controls, and the improvement obtained has been only marginal. At this time, none of these drugs can be recommended. A controlled, multicenter trial with ursodeoxycholic acid also showed improvement in symptoms, enzyme levels, and histologic findings in some patients, but there was little effect in patients with advanced disease.104 Ursodiol may be effective in slowing the progression of PBC and may decrease the need for transplantation.105 Ursodiol (ursodeoxycholic acid) is a naturally occurring bile acid with choleretic properties. The dose of ursodiol in the treatment of PBC is 13 to 15 mg per kilogram per day given in four divided doses.
NONPHARMACOLOGIC THERAPY
It is imperative to provide adequate nutritional support in patients with liver disease. Positive nitrogen balance must be established without exacerbating hepatic encephalopathy. Diets high in BCAAs and low in AAAs and methionine may help to restore normal amino acid balance and reduce encephalopathy.1315,106 HepatAmine is an 8% amino acid solution that contains more BCAAs than standard parenteral amino acid solutions. The ratio of BCAAs to AAAs in HepatAmine is 37:1, compared to 5:1 with crystalline amino acid solutions. The indications for use and the efficacy of this special amino acid formulation are debated. The expense and questionable efficacy have limited its use to select patients with life-threatening encephalopathy refractory to conventional therapy. An amino acid screen can be used to assess the BCAA:AAA ratio in patients. The cost of an amino acid screen is approximately equal to 1 days therapy with HepatAmine. For the awake patient without central venous access, therapy with enteral nutrition is preferred. One such dietary supplement is Nutrihep, a calorically dense product with a high calorie to nitrogen ratio that helps maintain protein utilization for lean muscle mass in liver disease. This product provides a 50:50 ratio of aromatic and branch amino acids. Use of oral BCAAs has been limited because of its questionable efficacy, its expense, and its disagreeable taste. The American Society of Parenteral and Enteral Nutrition (ASPEN) has published guidelines for nutritional supplementation in patients with liver disease.107 Growth hormone resistance has also been associated with the protein catabolic state seen in cirrhosis. From the limited data available, it appears that treatment with growth hormone can improve nitrogen utilization.108 In addition, because Helicobacter pylori has strong urease activity, there is evidence that supports treatment. If present, H. pylori eradication can reduce hyperammonemia.109
ALTERNATIVE THERAPY
The use of herbal supplements and other alternative remedies have become popular in patients with liver disease. The natu-
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rally occurring whole extract of the milk thistle ( Silybum marianum ) is known as silymarin. This flavonoid complex has been shown to have a liver-protective effect in experimental models of hepatotoxicity from acetaminophen, ethanol, carbon tetrachloride, and phenylhydrazine. Use of silymarin has been popularized by the lay press and internet sources, with some scientific validation of efficacy. Silymarin has been found to prevent lipid peroxidation, changes in the phospholipid composition of membranes, and hepatic glutathione depletion. It also appears to normalize hepatic function markers in patients with alcoholic liver disease. This positive effect may be attributed to an isomer of the silymarin complex, silibinin, on inhibiting leukotriene formation by Kupffer cells.110 There is the potential for silymarin to inhibit the activity of cytochrome P-450 3A4 (CYP3A4) and P-glycoprotein. Studies have confirmed this inhibitory effect, but the clinical significance has yet to be conclusively shown.111,112 Caution is thus advised when it is used with any drugs that are substrates for CYP3A4 or P-glycoprotein. Zinc deficiency is observed in patients with chronic liver disease, and zinc sulfate is often given to reverse this deficiency. Zinc may also improve dysgeusia and thus improve appetite. Zinc supplementation has also been suggested to improve cirrhosis-related hepatic encephalopathy, but outcomes data are inconclusive.113
with symptoms already present (ascites, history of bleeding, or encephalopathy) had a survival of only 21% at 6 years and a much higher incidence of hepatocellular carcinoma. The severity of disease can be classified according to various systems. The Child-Pugh score and the Model for Endstage Liver Disease (MELD) score can be used to assess surgical risk and short- and long-term mortality in patients with cirrhosis.115118 Given the irreversible nature of cirrhosis and the high morbidity and mortality, liver transplantation may be an option for select patients with end-stage liver disease.
PHARMACOECONOMICS
The management of cirrhosis can have a major economic impact, primarily because of the chronicity and progressive nature of the disease. Patients who do not abstain from alcohol and do not adhere to their diet and drug therapy can be expected to have multiple hospital admissions as the disease progresses. Management of patients with end-stage liver disease is expensive. The preventive approaches discussed in this chapter, such as SBP prophylaxis, diuretics, treatment of hepatic encephalopathy, vitamin supplementation, and dietary modification, are cost-effective and must be implemented early in the care plan.
IMPROVING OUTCOMES
KEY POINTS In the United States, cirrhosis is the 12th most common cause of death in people over age 40 Despite extensive investigation, no effective drug therapy has been found to reverse cirrhosis Discontinuation of alcohol intake in patients with proven cirrhosis is of the utmost importance. Use of naltrexone in an effort to decrease craving may prove valuable in this setting119 Although therapy for cirrhosis focuses mainly on symptom management, other forms of chronic liver disease, such as viral hepatitis and autoimmune hepatitis, can be successfully treated Portal hypertension, a complication of cirrhosis, can manifest as ascites, hepatic encephalopathy, esophageal varices, and hepatorenal syndrome Although the fibrosis from advanced cirrhosis is irreversible, it is estimated that 70% or more of liver tissue must be destroyed before the body is unable to eliminate drugs and toxins via the liver.120 Unfortunately, it is difficult to tell which patients have reached this stage of involvement. Practitioners should always be aware of the potential inability of patients with advanced liver disease to metabolize various drugs normally cleared by the liver, and should adjust doses accordingly Limited pharmacokinetic dosing research and guidance are available for the aging liver and the diseased
The outcome for patients with cirrhosis depends on the stage of disease and the presence of complications. Once the diagnosis of liver disease has been established, consumption of alcohol should stop. If the patient continues to drink alcohol, the prognosis is poor. Adherence to a low-sodium, proteinrestricted diet is important in minimizing the formation of ascites and maintaining adequate nitrogen balance. Compliance with the prescribed medical regimen is critical in the management of the complications arising from cirrhosis. A multidisciplinary approach can improve the outcome of this complex disease. It is also important to develop a rapport with family members and other caregivers to ensure their support of the treatment plan and lessen the risk of noncompliance and recidivism.
PROGNOSIS
In a series of 1,155 patients with cirrhosis from a variety of causes, the over-5-year survival was about 40%.114 The causes of death were liver failure in 49%, hepatocellular carcinoma in 22%, bleeding in 14%, HRS in 8%, and other causes. Patients who entered the study with compensated cirrhosis (absent or mild symptoms) became symptomatic at a rate of 10% per year. Survival was higher in this group of patients (54% at 6 years). Patients who entered the study
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liver.121,122 Dose reductions continue to be made empirically because data quantifying the degree of adjustment necessary in liver disease generally are unavailable
SUGGESTED READINGS
Carithers RL Jr. Liver transplantation. Liver Transplant 6:122135, 2000. Gerber T, Schomerus H. Hepatic encephalopathy in liver cirrhosis: pathogenesis, diagnosis and management. Drugs 60:13531370, 2000. Gines P, Arroyo V. Hepatorenal syndrome. J Am Soc Nephrol 10: 18331839, 1999. Mowat C, Stanley AJ. Spontaneous bacterial peritonitis: diagnosis, treatment and prevention. Aliment Pharmacol Ther 15:18511859, 2001. Runyon BA. AASLD Practice guideline: management of adult patients with ascites due to cirrhosis. Hepatology 39:116, 2004. Sharara AI, Rockey DC. Gastroesophageal variceal hemorrhage. N Engl J Med 345:669681, 2001.
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Pancreatitis
Jennifer W. Beall and Paula A. Thompson
Anatomy 1365 Physiology 1366 Overview of Exocrine Function 1366 Secretion of Water and Electrolytes 1366 Enzymes 1367 Regulation of Exocrine Function 1368
51
ACUTE PANCREATITIS 1368 Definition 1368 Etiology 1369 Epidemiology 1369 Pathophysiology 1370
Analgesia 1375 Antibiotics 1375 Correcting Biliary Tract Disease 1375 Alternative Therapies 1376 Future Therapies 1376 Improving Outcomes 1376 Pharmacoeconomics 1376
Clinical Presentation and Diagnosis 1371 Signs and Symptoms 1371 Diagnosis and Clinical Findings 1371 Laboratory Tests 1371 Pancreatic Enzymes 1371 Imaging 1371 Assessing Severity 1371 Complications 1371 Psychosocial Aspects 1373 Therapeutic Plan 1374 Treatment Goals: Acute Pancreatitis 1374 Treatment 1374 General Supportive Measures 1374 Nutrition 1375
CHRONIC PANCREATITIS 1376 Definition 1376 Epidemiology 1377 Pathophysiology 1377

Clinical Presentation and Diagnosis 1378 Signs and Symptoms 1378 Diagnosis and Clinical Findings 1378 Psychosocial Aspects 1379 Therapeutic Plan 1379 Treatment Goals: Chronic Pancreatitis 1379 Treatment 1379 Pharmacotherapy 1379 Future Therapies 1383 Improving Outcomes 1383 Pharmacoeconomics 1383
Pancreatic inflammatory disease may be classified as either acute or chronic based on the reversibility of the functional and structural changes that arise within the gland. Although these are usually treated as discrete clinical entities, they may actually be part of a continuum of pancreatic disease.1,2 Following an acute attack of pancreatitis, the pancreas will usually recover normal exocrine and endocrine function and morphology once the underlying cause of acute inflammation is eliminated. While most attacks have a mild, selflimited course, severe disease complicated by multiple organ system failure and life-threatening infection may develop. Although pancreatic necrosis can result in transient or, occasionally, permanent impairment of gland function and structure, acute pancreatitis rarely progresses to chronic disease.3,4 In contrast, the persistent inflammation from chronic pancreatitis is associated with a permanent and often progressive loss of pancreatic exocrine and endocrine function, and irreversible structural damage. Recurrent exacerbations of pancreatitis, which frequently complicate chronic disease, are virtually impossible to distinguish clinically from discrete attacks of acute pancreatitis.4,5
Reliable incidence and prevalence data are difficult to obtain. The incidence of both acute and chronic forms varies considerably among geographic areas as a consequence of differences in regional environmental and genetic factors.5,6 Both acute and chronic pancreatitis will be discussed after a brief review of pancreatic anatomy and physiology. An understanding of normal structure and function is necessary background for this discussion.
ANATOMY
The adult pancreas is a flattened and elongated gland, usually ranging from 12 to 20 cm in length and weighing 70 to 110 g. It is lobular, like the salivary glands, and its lack of a fibrous capsule makes it soft in texture. The pancreas lies retroperitoneally, the head nestled within the curve of the duodenum as it exits the stomach and the tail extending obliquely to the left (Fig. 51.1).7,8 Blood is supplied to the pancreas by the celiac and superior mesenteric arteries, and the blood ultimately drains into the hepatic portal vein. The lymphatic vessels draining the
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FIGURE 51.1 Structure of the pancreas. A. Dissected to show ductal system. B. Enlargement of a representative acinus.
pancreas terminate primarily in the pancreatosplenic and pancreatoduodenal lymph nodes. Sympathetic innervation is predominately through splanchnic neurons synapsing in the celiac plexus, and parasympathetic innervation is derived from the vagus nerve.7,8 The pancreas contains exocrine (about 80%) and endocrine (about 2%) tissue. The remaining 18% of the gland is ductular. The secretory unit of the exocrine pancreas is the acinus (Latin for berries in a cluster). Each acinus consists of 20 to 50 pyramid-shaped cells surrounding a central lumen. The acini are connected to the main pancreatic duct through a network of interconnecting ductules. The islets of Langerhans (pancreatic islets) make up the endocrine pancreas and are composed of four major cell types, each apparently secreting a single hormone. Approximately 50% to 80% of the islet cell mass is comprised of cells, which secrete insulin. Glucagon, somatostatin, and pancreatic polypeptide are secreted by cells, cells, and PP cells, respectively. Insulin and glucagon are critical in the regulation of carbohydrate metabolism (see Chapter 40). In addition to the systemic effects exerted by each of these hormones, they also play a role in the regulation of pancreatic exocrine secretion. Insulin may potentiate the actions of stimulatory factors, while glucagon, somatostatin, and pancreatic polypeptide exert inhibitory effects.7
PHYSIOLOGY
Overview of Exocrine Function
Pancreatic exocrine function is complex and incompletely understood. During the course of a day, the pancreas can secrete 1 to 2.5 liters of isosmotic alkaline fluid containing over 20 enzymes and proenzymes (zymogens). This fluid, commonly termed pancreatic juice, is produced by acinar and ductular cells. The acinar cells synthesize and secrete the digestive enzymes. Proximal ductular cells, termed centroacinar cells, extend into the lumen of the acinus and are primarily responsible for secretion of water and electrolytes. The intralobular ductules draining the acini coalesce with interlobular ductules, ultimately emptying into the main pancreatic duct. The main pancreatic duct and the common bile duct enter the duodenum at the ampulla of Vater (hepatopancreatic ampulla). The sphincter of Oddi (sphincter of the hepatopancreatic ampulla) regulates flow from both ducts.911
SECRETION OF WATER AND ELECTROLYTES

The principal cations of pancreatic juice are sodium and potassium, which are secreted at fixed concentrations similar to their plasma concentrations. The principal anions are bi-
CHAPTER 51 Pancreatitis
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FIGURE 51.2 Relationship between ion concentration in pancreatic juice and secretory flow rate. (Reprinted with permission from Pandol S, Pancreatic physiology. In: Sleisenger MH, Fordtran JS. Gastrointestinal Disease: Pathophysiology, Diagnosis, Management. 5th ed. Philadelphia: WB Saunders, 1993:1586.)
carbonate and chloride, which vary reciprocally in concentration, maintaining the sum of the two fairly constant at approximately 150 mEq per liter (Fig. 51.2). Bicarbonate is secreted by the centroacinar cells, whereas secretions from the acinar cells are rich in chloride. The relative concentration of each reaching the duodenum depends on the amount secreted and the exchange of bicarbonate for chloride in the ductules. The concentration of bicarbonate, physiologically the most important of the electrolytes, increases with increasing flow rates. Flow rates range from a basal level of 0.2 to 0.3 mL per minute to 4 mL per minute during stimulation. At maximal rates of secretion, bicarbonate concentration approaches 120 mEq per liter, and the pH of the resulting pancreatic juice is approximately 8.3. This alkalinity buffers the acidic chyme delivered to the duodenum from the stomach and maintains a pH that is optimal for the functioning of pancreatic enzymes. Other ions present in pancreatic juice include calcium and trace amounts of magnesium, zinc, phosphate, and sulfate. Water enters the ductules passively down the concentration gradient established by the active transport of solute, maintaining iso-osmolality.911
ment of trypsinogen to form active trypsin, which can then activate other zymogens, including additional trypsinogen molecules. The pancreas is protected from autolysis not only by secretion of proteolytic enzymes in zymogen form, but also by the presence of trypsin inhibitor, which binds to trypsin in a 1:1 ratio, rendering it inactive. This protein is present
TABLE 51.1 Major Digestive Enzymes Secreted by the

Pancreas
Proteolytic TrypsinogenEnterokinase, Trypsin trypsin ChymotrypsinogenTrypsin chymotrypsin ProelastaseTrypsin elastase Procarboxypeptidase ATrypsin carboxypeptidase A Procarboxypeptidase B Amylolytic -Amylase Lipolytic Lipase ProcolipaseTrypsin colipase [cofactor essential for optimal lipase activity] Prophospholipase A2Trypsin phospholipase A2 Carboxylesterase lipase Nucleolytic Deoxyribonuclease (DNAse) Ribonuclease (RNAse)
(Adapted from Pandol SJ. Pancreatic physiology and secretory testing. In: Feldman M, Sleisenger MH, Scharschmidt BF. Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management. 6th ed. Philadelphia: WB Saunders, 1998:871.)
Trypsin
carboxypeptidase B
ENZYMES
Protein represents up to 10% of pancreatic juice, and over 90% of this protein consists of digestive enzymes and proenzymes.911 These enzymes are synthesized in the rough endoplasmic reticulum of the acinar cells and are stored in secretory vesicles (zymogen granules) prior to their release by exocytosis. There are four major categories of enzymes, corresponding to the four classes of organic compounds found in food: proteins, carbohydrates, lipids, and nucleic acids (Table 51.1). The proteases and phospholipases are secreted as inactive zymogens that become active in the intestinal lumen through the action of enterokinase produced by the duodenal mucosa. Enterokinase cleaves a small frag-
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in sufficient quantity to protect against small amounts of trypsin, which may become active in the ductules, but its activity is insignificant in the duodenal lumen.9,10,12
REGULATION OF EXOCRINE FUNCTION

A discussion of all the putative regulatory factors of pancreatic exocrine function, both neural and hormonal, is beyond the scope of this text. The roles of secretin, cholecystokinin (CCK), and cholinergic neurons in pancreatic secretions have been well established and will be reviewed briefly. Secretin, a peptide hormone released from the mucosa of the duodenum and jejunum, stimulates bicarbonate and water secretion, primarily in response to the presence of acid in the small intestine. The pH threshold for secretin release is 4.5. The presence of bile salts and some fatty acids within the intestinal lumen can also trigger secretin release. In addition to its effect on bicarbonate, secretin may cause a weak stimulation of pancreatic enzyme release.911 CCK, also a peptide hormone secreted by the mucosa of the small bowel, causes the release of an enzyme-rich juice from the pancreas. Production of CCK occurs when amino acids or fatty acids enter the duodenum. Intravenous administration of CCK also stimulates enzyme release, while pancreatic response is substantially reduced by the administration of CCK antagonists. The combined release of secretin and CCK potentiates the pancreatic response, increasing bicarbonate and volume secretion.911 Inhibitory mechanisms are less well understood than stimulatory ones. Intravenous infusions of amino acids or glucose inhibit pancreatic function, probably due at least in part to the release of glucagon and somatostatin from islet cells. Pancreatic polypeptide may also decrease exocrine function by modulating cholinergic pathways, although the physiologic significance of this has not been delineated. The presence of lipids in the colon inhibits CCK-stimulated pancreatic output, possibly acting through a mediator called pep-
tide YY.911,13 A negative feedback loop has also been hypothesized whereby trypsin in the intestinal lumen inactivates a CCK-releasing peptide, decreasing CCK release and pancreatic enzyme secretion.9,10,12,14 Increasing our understanding of these inhibitory mechanisms may help to guide the development of effective therapeutic modalities for pancreatitis. Phases of Pancreatic Secretion. Pancreatic function can best be described in terms of interdigestive (fasting) and digestive (postprandial) periods. Digestive secretion can be further subdivided into cephalic, gastric, and intestinal phases. The pancreas is not quiescent between meals, but rather displays a basal secretion that is cyclical. Although overall secretion is low, there are fluctuations that parallel changes in gastrointestinal motility.911 Vagal nerves mediate the cephalic phase, in which pancreatic secretion can be stimulated by the sight, smell, or taste of food. In sham feeding experiments (patients chew food without swallowing it), pancreatic enzyme secretion increased to approximately 50% of the maximal secretion elicited by intravenous CCK. Gastric acid production is also stimulated during this phase, triggering secretin release, which increases bicarbonate and enzyme secretion. The gastric phase begins when food enters the stomach. Gastric distention causes increased pancreatic secretion, mediated through a gastropancreatic vagovagal reflex. The most important phase is triggered when chyme enters the small intestine. This intestinal phase is regulated by the hormones secretin and CCK and by enteropancreatic vagovagal reflexes triggered by volume or hyperosmolality in the gut. During all phases of pancreatic secretion, it is the interplay of neural and hormonal factors that result in the coordinated response of the pancreas to feeding.912 This brief overview of normal anatomy and physiology should serve to clarify the subsequent discussions of acute and chronic pancreatitis.
A C U T E DEFINITION
P A N C R E A T I T I S
pancreatic parenchyma and large areas of peripancreatic fat necrosis.16,18 Thrombus is also common in acute necrotizing pancreatitis. Acute pancreatitis can also be classified clinically as mild or severe.16 Although interstitial pancreatitis may be associated with serious systemic toxicity, its clinical course is usually mild, with minimal organ dysfunction and a resultant mortality of less than 2%. In contrast, the mortality of severe acute pancreatitis, involving organ failure or local complications such as abscess or pseudocyst, is 10% to 30%.17,18 Severe pancreatitis is most often the clinical expression of pancreatic necrosis.
Acute pancreatitis is an acute inflammatory process of the pancreas with variable involvement of other regional tissues or remote organ systems.15 The inflammation may remain localized in the pancreas or may involve tissues elsewhere.16 Approximately 80% of patients have interstitial pancreatitis, which is characterized by interstitial edema resulting from inflammatory cells, yet there is no destruction to the architecture of the gland.1720 The remaining patients develop necrotizing pancreatitis, with diffuse or focal areas of nonviable
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ETIOLOGY
Acute pancreatitis is associated with many other disease processes and events (Table 51.2). Biliary tract stone disease and ethanol abuse account for 60% to 80% of acute bouts of pancreatitis, with the incidence of each depending on the patient population being evaluated.6,17 Women tend to have pancreatitis as a result of biliary tract stone disease, whereas ethanol abuse is more often associated with pancreatitis in men.6,17 A number of miscellaneous causes account for 10% to 15% of pancreatitis attacks, with another 10% to 15% of cases classified as idiopathic.17,21 However, recent studies suggest that up to two thirds of idiopathic cases may be caused by biliary microlithiasis.6
TABLE 51.2 Causes of Acute Pancreatitis

Obstruction Gallstones Sphincter of Oddi spasm or stenosis Periampullary or pancreatic tumors Periampullary duodenal diverticula Pancreas divisum with accessory duct obstruction Infection Parasitic: ascariasis, clonorchiasis Viral: Coxsackie B virus, mumps, rubella, Epstein-Barr virus, cytomegalovirus, varicella, hepatitis A, hepatitis B Bacterial: Mycoplasma sp, Legionella sp, Salmonella sp, Shigella sp, Mycobacterium tuberculosis, Campylobacter sp Toxins Alcohol Drugs (see Table 51.3) Scorpion venom Organophosphate insecticides Trauma Postoperative Endoscopic retrograde cholangiopancreatography Endoscopic sphincterotomy Coronary artery bypass Blunt abdominal trauma Metabolic Hypertriglyceridemia Hypercalcemia Vascular Vasculitis Atherosclerotic emboli Hypoperfusion Miscellaneous Idiopathic Hereditary pancreatitis Cystic fibrosis Penetrating duodenal ulcer Inflammatory bowel disease Hypothermia
(Data from Mitchell RMS, Byrne MF, Baille J. Pancreatitis. Lancet 361:14471455, 2003; Steer ML, Waxman I, Freedman S. Chronic pancreatitis. N Engl J Med 332:14821490, 1995; and Owyang C, Levitt MD. Chronic pancreatitis. In: Yamada T. Textbook of Gastroenterology. 2nd ed. Philadelphia: JB Lippincott, 1995:2061.)
EPIDEMIOLOGY
The incidence of acute pancreatitis varies widely and depends on the incidence of precipitating factors in a population.6 The incidence of acute pancreatitis in the United States is thought to range from 54 to 238 episodes per 1 million people per year.22 Disease incidence has been extensively studied in the United Kingdom and appears to have increased 10-fold from the 1960s to the 1980s.21 This may reflect an increase in alcohol abuse and diagnostic advances. Cholelithiasis increases a patients relative risk of developing acute pancreatitis; however, the condition develops in only a few patients with this condition.23 Biliary pancreatitis may be associated with recurrent episodes of acute disease, but chronic pancreatitis is rare. In contrast, many patients with alcoholic pancreatitis have consumed large amounts of alcohol for many years before the initial onset of symptoms. Pancreatitis in an alcoholic patient was previously thought to be an acute exacerbation of chronic pancreatitis. However, despite continued abuse of alcohol, not all will progress from acute to chronic disease.6,15,21 Because clinical pancreatitis develops in only 5% of alcoholics, unidentified factors must affect susceptibility to pancreatic injury.21 Gallstones are the most common obstructive cause of acute pancreatitis, but inflammation may also result from other lesions that interfere with the flow of pancreatic juice through the ductal system. Thus, pancreatitis may result from ductal strictures, sphincter of Oddi dysfunction, or tumors of the pancreas, ampulla, or duodenum.3,21 Blunt trauma to the abdomen may also cause pancreatitis by disrupting the pancreatic ductal system. Similarly, pancreatitis can occur as a postoperative complication of procedures that involve manipulation of the pancreas or during endoscopic retrograde cholangiopancreatography (ERCP), in which a sideviewing endoscope is passed into the duodenum and a catheter introduces a radiopaque contrast medium into the pancreatic duct. Certain viral, parasitic, and bacterial infections may also precipitate acute attacks. Other causes of acute pancreatitis include penetrating duodenal ulcer, vascular compromise, hypertriglyceridemia, and various toxins.3,6,21
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Debate continues about the association of acute pancreatitis with pancreas divisum, a congenital abnormality in which the dorsal and ventral pancreatic ducts fail to fuse. Because pancreas divisum is a common anatomic abnormality with an overall incidence of about 7%, it may be an incidental finding in many patients with idiopathic pancreatitis.6,21 More than 85 drugs have been associated with acute pancreatitis, although the frequency of drug-induced disease generally is low.2436 Because scattered case reports make up the bulk of the literature on drug-induced pancreatic disease, it usually is difficult to link drugs with pancreatic inflammation conclusively. Mallory and Kern25 classified drugs into three categories based on the clinical evidence implicating them in the development of acute pancreatitis: definite, probable, and questionable. The association is considered definite when drug therapy results in abdominal pain combined with hyperamylasemia that resolves when therapy is discontinued or recurs when the drug is reintroduced (Table 51.3). Because drug-induced acute pancreatitis cannot be distinguished clinically from that induced by other causes, it should be considered when other causes of disease have been ruled out.
TABLE 51.3 Agents Associated with Acute Pancreatitis

Definite Association Amiodarone Angiotensin-converting enzyme inhibitors Asparaginase Azathioprine Codeine Cytarabine Didanosine Estrogens Furosemide Isoniazid Losartan Mercaptopurine Mesalamine Metronidazole Pentamidine Sulfonamides Sulindac Tetracycline Thiazides Valproic acid Probable Association Bumetanide Chlorthalidone Cimetidine Clarithromycin Clozapine Corticosteroids Ethacrynic acid Ifosfamide Ketorolac Methyldopa Phenformin Procainamide
Data from references 2535.
Salicylates Sulfasalazine Zalcitabine Questionable Association Acetaminophen Ampicillin Carbamazepine Cholestyramine Cisplatin Clonidine Colchicine Cyclosporine Cyproheptadine Diazoxide Diphenoxylate Ergotamine Erythromycin Gold compounds Indomethacin Interleukin-2 Isotretinoin Ketoprofen Mefenamic acid Metolazone Naproxen Nitrofurantoin Opiates Oxyphenbutazone Phenolphthalein Piroxicam Propoxyphene Ranitidine Tryptophan
PATHOPHYSIOLOGY
The inflammation and necrosis of acute pancreatitis begin as an autodigestive process initiated by the inappropriate activation and release of proteolytic and lipolytic enzymes into the interstitium of the organ. The activation of trypsinogen to trypsin within the acinar cells is the initial step in the pathogenesis of acute pancreatitis.3 Trypsin can then activate other pancreatic proteases, including elastase, chymotrypsin, and carboxypeptidase, and phospholipase A2 , which then contribute to acinar cell inflammation. Elastase causes vascular damage by dissolving the elastic fibers of blood vessels. Chymotrypsin augments this vascular damage and the resulting edema, and phospholipase A2 destroys acinar cell membranes. These pancreatic enzymes, after damaging acinar cells, leak into the interstitium, causing local inflammation. Lipase is also liberated from peripheral acinar cells, resulting in peripancreatic fat necrosis. The kinin and complement systems are activated by trypsin, leading to the release of vasoactive peptides, which cause vasodilation, increased vascular permeability, and accumulation of leukocytes.17 In severe disease, pancreatic enzymes, vasoactive peptides, and other toxic factors extravasate from the pancreas into peripancreatic spaces and the peritoneal cavity, causing a widespread chemical irritation.18 These materials may also reach the systemic circulation through retroperitoneal lymphatic and venous circulation to contribute to systemic complications, including shock, respiratory failure, and renal failure.18 Factors in acute pancreatitis that contribute to the transformation from a local inflammatory process into a multiorgan illness are not entirely understood. The contribution of
leukocytes and their products in amplifying pancreatic inflammation into a generalized systemic inflammatory response has been recognized.3,37 Neutrophils, macrophages, and monocytes invade the inflamed pancreas and release destructive mediators such as elastase, phospholipase A2 , platelet activating factor, nitric oxide, oxygen free radicals, and cytokines.3 The inflammatory cytokines, particularly interleukin-1, interleukin-6, and tumor necrosis factor, appear
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to be important systemic mediators of acute pancreatitis.37 Cytokines are produced not only locally, but also systemically in sites such as the spleen, liver, and lung, where they have been linked to organ dysfunction. Circulating levels of cytokines are higher in patients with severe acute pancreatitis, and these levels can be predictive of disease severity, end-organ failure, and mortality.38,39 Consequently, cytokine antagonism may prove beneficial in treating patients with acute pancreatitis. Furthermore, impairment of the pancreatic microcirculation by the deleterious effects of leukocyte products on the vascular endothelium appears to be an important mechanism in pancreatic necrosis.40 The mechanism by which pancreatic enzymes become prematurely activated within the gland to initiate the cascade of events that causes acute pancreatitis is unknown. Proposed mechanisms focus on biliary tract stone disease, postulating that reflux of hepatic bile or duodenal contents into the pancreatic ductal system may activate enzymes within the pancreatic parenchyma.3,6 More recently, investigators have proposed that activation of trypsin may occur within the pancreatic acinar cell rather than in the ductal or intercellular space.3,21 Obstruction in the pancreatic duct could disturb the normal events that maintain segregation of lysosomal enzymes, including cathepsin B, from digestive enzymes, thus allowing them to mix intracellularly. Cathepsin B can convert trypsinogen to trypsin, which could then activate the remaining digestive zymogens. The mechanism of ethanolinduced pancreatitis is not understood but may include relaxation or spasm of the sphincter of Oddi, obstruction of small pancreatic ductules with proteinaceous plugs, or direct toxic effects of ethanol or one of its metabolites.3,6,20 The pathogenesis of drug-induced pancreatic injury has not been elucidated, but it does not appear to differ substantially from that of acute pancreatitis induced by other causes. Possible mechanisms include pancreatic ductal constriction, immune suppression, arteriolar thromboses, direct cellular toxicity, hepatic production of free radicals, and osmotic or metabolic effects.26
reported infrequently. Nausea and vomiting are almost invariably present and are usually preceded by the onset of pain. Epigastric tenderness is a consistent finding on abdominal examination, as is abdominal distention. Bowel sounds often are diminished but not absent. Fever in the range of 100 to 102F is seen in most patients as the pyrogenic products of pancreatic injury enter the circulation. Tachycardia and hypotension progressing to circulatory shock can occur in severe cases as a result of hypovolemia caused by vomiting, hemorrhage, and fluid sequestration within the retroperitoneal space. Circulating kinins and cytokines contribute to this circulatory instability through vasodilatory effects and increased vascular permeability.17 Disorientation, delirium, or hallucinations are sometimes observed, although most patients present without changes in mental status.3
DIAGNOSIS AND CLINICAL FINDINGS

The diagnosis of acute pancreatitis is based on careful clinical evaluation of the patient, laboratory tests, and radiographic imaging. Mild cases of acute pancreatitis often represent a diagnostic dilemma because symptoms may be nonspecific and pancreatic enzyme levels and imaging studies are often virtually normal.17 Occasionally, acute pancreatitis must be distinguished from other processes that present with abdominal pain and hyperamylasemia, such as acute cholecystitis or appendicitis, intestinal ischemia or infarction, perforated gastric or duodenal ulcer, intestinal obstruction, ectopic pregnancy, and common bile duct obstruction.41
LABORATORY TESTS
Leukocytosis, ranging from 10,000 to 25,000 cells per cubic millimeter, is a common finding during routine laboratory evaluation of patients with acute pancreatitis.3,17 Hyperglycemia, transient hypertriglyceridemia, and hypoalbuminemia also are common. Liver function tests often reveal mild hyperbilirubinemia and elevated serum alkaline phosphatase and transaminase levels, which tend to be more pronounced with biliary pancreatitis. Hypovolemia may result in hemoconcentration, as evidenced by elevated hematocrit, blood urea nitrogen, and serum creatinine levels.

Signs and Symptoms
The classic presentation of acute pancreatitis consists of abdominal pain, nausea, and vomiting; however, a patients symptoms and physical findings may vary with the severity of disease.15 The abdominal pain is usually located in the epigastrium or diffusely throughout the upper abdomen.3 Pain is usually sudden in onset and peaks within 10 to 30 minutes.41 Pain may be severe, and it is most commonly described as a steady, dull, or boring pain that often radiates to the back. Patients may move about continually in search of a comfortable position, with little relief.6,15 Pain resolves over 1 to 3 days in mild cases but may last many days to weeks during severe attacks. Painless pancreatitis has been
PANCREATIC ENZYMES
Elevation of the serum amylase level has remained central to the diagnosis of acute pancreatitis since its first association with the disease in 1929.17,21 The pancreas and salivary glands account for most of the serum amylase activity in healthy people. The serum amylase level typically rises rapidly (from the normal range of 35 to 118 IU per liter) during the initial hours of an attack and then declines over the following 3 to 10 days.3,6 The sensitivity of the test may be compromised if patients do not present early in the course of the disease. Furthermore, the test lacks specificity because hyperamylasemia is associated with a variety of nonpancreatic conditions, including diseases of the biliary tract, intestines, female genitourinary tract, lungs, prostate, and sali-
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vary glands.42 Generally, patients with biliary pancreatitis present with a more marked hyperamylasemia than do patients with alcohol-related disease.17,42 The measurement of serum amylase isoenzymes has been largely abandoned because most nonpancreatic abdominal diseases that simulate pancreatitis are associated with increased pancreatic rather than nonpancreatic amylase levels.42 In contrast, serum lipase is derived almost exclusively from the pancreas (normal range 2.3 to 20 IU per deciliter). Thus, it is more specific for acute pancreatitis and remains normal in a variety of conditions associated with elevations of serum amylase, including salivary gland disease, gynecologic disorders, and macroamylasemia associated with renal insufficiency.3 However, hyperlipasemia may also occur in nonpancreatic acute abdominal conditions.6,42 Although serum lipase typically parallels amylase in onset of elevation, lipase elevation persists longer, thus enhancing its diagnostic utility in patients who present several days after the onset of symptoms. In summary, elevations in serum amylase and lipase activity support the diagnosis of acute pancreatitis. The assays are widely available and can be performed rapidly and reliably at low cost.42 Values of serum amylase and lipase greater than three times the upper limit of normal are characteristic of acute pancreatitis and rarely occur in nonpancreatic conditions.3 The magnitude of increase in serum amylase and lipase activity has no prognostic value and does not correlate with the severity of the acute attack.41 Furthermore, daily measurement of pancreatic enzymes has little value in assessing a patients progress or prognosis.3 The use of other pancreatic enzymes, such as immunoreactive trypsinogen, chymotrypsin, elastase, and phospholipase A2 , as markers for acute pancreatitis does not appear to provide any diagnostic advantage over the determination of serum amylase and lipase activity. In addition, measuring the urinary amylase level and the amylase:creatinine clearance ratio offers little benefit in improving diagnostic accuracy. However, a rapid assay of urinary trypsinogen 2 may prove to be a reliable test in the future.17,20,42
fying pancreatic necrosis, should be performed after the first 3 days in patients with severe acute pancreatitis to distinguish interstitial from necrotizing disease.41
ASSESSING SEVERITY
Multiple clinical criteria systems have been developed to assess the severity and prognosis of acute pancreatitis. Predictors of severity allow early identification of patients with the greatest likelihood of developing severe pancreatitis.16,17,41 Ranson et al developed 11 prognostic criteria that can be measured 48 hours after hospital admission to assess the severity of an acute attack (Table 51.4).41,43 The Acute Physiology and Chronic Health Evaluation II (APACHE II) is another list of clinical and laboratory values used to assess patients with acute pancreatitis that can be calculated within hours of admission and at daily intervals thereafter6,21,44 (Table 51.5). Severe acute pancreatitis is characterized by three or more Ranson criteria or at least eight APACHE II points.16 According to recent guidelines, the APACHE II score should be generated on the day of admission.41 After 48 hours, the APACHE II or Ranson score may be used to follow the course of the patient with pancreatitis.41
COMPLICATIONS
The clinical course of acute pancreatitis is uncomplicated in approximately 80% of attacks. Thus, most patients with acute pancreatitis have mild disease that resolves promptly with conservative therapy.1719 The remaining patients de-
TABLE 51.4 Ransons Prognostic Criteria

Nonbiliary Pancreatitis
On Admission Age (years) White cells/mL Glucose (mg/dL) Lactate dehydrogenase (LDH) (IU/L) Aspartate aminotransferase (AST) (IU/L) Within 48 Hours of Admission Decrease in hematocrit (points) Increase in blood urea nitrogen (mg/dL) Calcium (mg/dL) PaO2 (mm Hg) Base deficit (mEq/L) Fluid deficit (L)a
a
Biliary Pancreatitis
70 18,000 220 400 250
55 16,000 200 350 250
IMAGING
Radiographic studies play an important role in confirming the diagnosis of pancreatitis and provide important etiologic and prognostic information. Although abdominal radiography is not considered diagnostic, it has several uses in this setting.42 Most importantly, it may help to exclude nonpancreatic diseases that may mimic pancreatitis, including bowel obstruction and perforated viscus. The primary role of ultrasonography is in evaluating the biliary tract for stones, dilation, or obstruction.42 Guidelines from the American College of Gastroenterology recommend performing an abdominal ultrasound within 24 to 48 hours of hospitalization for the initial episode of acute pancreatitis.41 Computed tomography (CT) is useful for excluding other serious intra-abdominal conditions, but its utility early in an acute attack is controversial.41 Dynamic contrast-enhanced CT scan, the best test for identi-
10 5 8 60 4 6
10 2 8 5 4
Input minus output. (From Ranson JHC. Etiological and prognostic factors in human acute pancreatitis: a review. Am J Gastroenterol 77:633638, 1982.)
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TABLE 51.5 APACHE II Variables

Temperature Heart rate Mean arterial pressure Respiratory rate Oxygenation Arterial pH Age points Serum sodium Serum potassium Serum creatinine Hematocrit White blood count Glasgow Coma Scale score Chronic health assessment points
(Adapted from Agarwal N, Pitchumoni CS. Assessment of severity in acute pancreatitis. Am J Gastroenterol 86:13851391, 1991.)
velop severe disease that is usually the clinical expression of pancreatic necrosis.16 Although the mortality of interstitial pancreatitis remains low (less than 2%), necrotizing pancreatitis has a mortality ranging from 10% (sterile necrosis) to 30% (infected necrosis).18 Acute pancreatitis may be complicated by either local or systemic events (Table 51.6). Local events include the development of acute fluid collections in or near the pancreas, occurring early in the course of 30% to 50% of attacks.45 Acute fluid collections lack a well-defined wall and
TABLE 51.6 Complications of Acute Pancreatitis

Local Necrosis (sterile or infected) Pancreatic fluid collection (sterile or infected) Pseudocyst Abscess Pancreatic ascites Blood vessel rupture or thrombosis Bowel necrosis, obstruction, perforation Ileus Fistula Systemic Shock Renal failure Pulmonary insufficiency (including adult respiratory distress syndrome) Coagulopathy Gastrointestinal hemorrhage Encephalopathy Retinopathy Hypocalcemia Hyperglycemia
(Compiled from Steer ML, Waxman I, Freedman S. Chronic pancreatitis. N Engl J Med 332:14821490, 1995; and Owyang C, Levitt MD. Chronic pancreatitis. In: Yamada T. Textbook of Gastroenterology. 2nd ed. Philadelphia: JB Lippincott, 1995:2061.)
regress spontaneously in 50% of cases.45 Fluid collections may also progress to become pseudocysts or abscesses. A pseudocyst is a collection of pancreatic juice enclosed by a well-defined wall of fibrous tissue forming 4 or more weeks after the onset of an acute attack.45 Approximately 40% of these acute pseudocysts resolve within 6 weeks.45 Pseudocysts may be clinically silent or they may cause severe abdominal pain and elevation of pancreatic enzymes. Pancreatic abscess, another late-developing complication, is a circumscribed intra-abdominal collection of pus containing little or no pancreatic necrosis.45 The term pancreatic abscess is also used to describe infection within a pseudocyst. In contrast, the development of pancreatic necrosis is an early event appearing within the first 4 days of an acute attack. Necrosis can be found in approximately 20% of acute pancreatitis cases and is necessary for the subsequent development of infection. Pancreatic infection, which occurs in 30% to 50% of patients, usually develops in the second to third week of illness.41 Infectious complications account for 80% of deaths from acute pancreatitis.6,16,17 Severe acute pancreatitis may be complicated by multiple organ system failure, which most commonly involves the cardiovascular, renal, and pulmonary systems.6,21 Organ failure is the most important indicator of the severity of acute pancreatitis.16,18 Cardiovascular decompensation, the result of hypovolemia and vasodilation caused by circulating vasoactive peptides and cytokines, is associated with morbidity and mortality. Acute renal failure is a consequence of hypovolemia and decreased renal perfusion. Pulmonary complications vary from mild arterial hypoxemia, usually detected during the first 2 days of an attack, to adult respiratory distress syndrome, the result of pulmonary parenchymal injury caused by circulating inflammatory mediators.3 Systemic complications related to organ failure are responsible for death early in the course of acute pancreatitis.
There have been few studies evaluating the psychosocial aspects of acute pancreatitis. These studies have primarily assessed patients with severe disease, whose quality of life is most likely to be affected. Even patients who recover from an acute attack can have long-term complications, such as diabetes, recurrent disease, and continued abdominal pain.46 Another important factor in quality of life after severe pancreatitis is the role of alcohol, which can affect quality of life and mortality beyond the disease state. Up to 72% of those patients who had alcohol-induced pancreatitis will decrease their alcohol intake after their disease episode. This type of positive change could improve a patients quality of life overall. When compared with population control groups, most patients who have recovered from an attack of severe acute pancreatitis rate their physical and mental health equivalent to that of the controls.47
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THERAPEUTIC PLAN
In the absence of effective specific therapy for the underlying disease process, the treatment of acute pancreatitis remains largely supportive. In patients with mild disease, principles of management include eliminating oral intake, maintaining adequate hydration with intravenous fluid, and providing parenteral analgesia.21,41 With standard conservative therapy, the majority of cases of acute pancreatitis subside within 3 to 10 days.17 In contrast, severe acute pancreatitis almost invariably warrants treatment in an intensive care unit. Quantification of the attack severity with the APACHE II system or Ransons criteria is an important early step.22,41 A dynamic contrast-enhanced CT scan should be performed in patients with severe acute pancreatitis, as evidenced by the development of organ failure, to detect necrotizing pancreatitis (Fig. 51.3).41 In the absence of clinical improvement, a CT-guided percutaneous aspiration should be performed to detect infected necrosis, which necessitates surgical de bridement.41 Patients must be reassessed and monitored throughout the attack for the development of complications, particularly organ failure and infection. In addition, eliminating factors that precipitated the acute attack may improve the patients course and prevent recurrence of disease.17,21
Acute pancreatitis
Assess severity (first few days) Severe CT scan
Mild
Supportive care
Interstitial pancreatitis
Necrotizing pancreatitis
Improvement
Deterioration
Percutaneous aspiration
Sterile
Infection
Surgical debridement
FIGURE 51.3 Algorithm for the management of acute pancreatitis. (Adapted with permission from Banks PA. Practice guidelines in acute pancreatitis. Am J Gastroenterol 92:384, 1997.)
TREATMENT GOALS: ACUTE PANCREATITIS

Correct any underlying predisposing factors Correct biliary tract disease Discontinue any possible causative drugs Provide supportive care Maintain adequate hydration with intravenous fluids Provide parenteral analgesia to relieve pain Provide adequate nutritional intake Evaluate the need for antibiotics in the setting of necrotizing pancreatitis
TREATMENT
General Supportive Measures
Acute pancreatitis may be associated with severe intravascular volume contraction and hypovolemia that result from exudation of protein-rich fluid into the inflamed peripancreatic retroperitoneum and peritoneal cavity. In addition, volume losses are incurred through vomiting, hemorrhage, and nasogastric suction. The primary goal of therapy early in the course of acute pancreatitis is to replace intravascular volume and electrolytes to avoid cardiovascular compromise and renal failure. Aggressive fluid resuscitation may also support the pancreatic microcirculation, limiting the development of necrosis. Volume replacement with crystalloid solutions is adequate for most patients, but intravenous colloids may be needed if protein-rich fluid losses are massive.
Potassium, calcium, and magnesium losses may also necessitate intravenous replacement. Hyperglycemia should be managed with insulin as needed. Clinical status, vital signs, and appropriate laboratory and radiographic studies should be reassessed frequently. Severe acute pancreatitis for which aggressive fluid resuscitation and maximal supportive care are needed should be managed in the intensive care setting. The complicated course of severe disease often necessitates continuous hemodynamic and arterial blood gas monitoring, as well as intensive management of cardiovascular, pulmonary, renal, and septic complications. Traditionally, it has been standard practice to eliminate oral intake of food and liquids early in an acute attack to minimize pancreatic exocrine secretion and halt the autodigestive process. Nasojejunal feedings have been shown to be equally effective compared to total parenteral nutrition
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(TPN) without some of the more serious complications seen with TPN and are preferred over TPN. Although it may be reasonable to restrict fat and protein intake to limit pancreatic stimulation, there is little evidence to support the benefit of a low-fat, low-protein diet.3 Nasogastric suction has not been shown to improve the clinical course of mild to moderate pancreatitis,47,48 but it is appropriate therapy for patients with severe nausea and vomiting or significant abdominal distention and ileus.6,17,19,21
a clinically significant difference in the degree of sphincter spasm produced by any particular opiate, efficacy should be the primary guide for analgesic treatment of these patients.3
ANTIBIOTICS
Infection is a serious complication in severe acute necrotizing pancreatitis: mortality rates are reported to be approximately 20% to 30% in this patient population.51 Even though infection has emerged as an important cause of death in acute pancreatitis, the role of prophylactic antibiotics remains to be firmly established. Early studies evaluating the use of antibiotics in patients with mild disease failed to show any clinical benefit; therefore, they are not recommended.52 One study suggested that imipenem reduced the incidence of pancreatic infections, but the incidence of organ failure and the mortality rate were not affected.53 Prophylactic cefuroxime has been shown to reduce mortality but not to decrease the incidence of infection.54 It is appropriate to initiate empiric antibiotic therapy in patients with pancreatic necrosis confirmed by dynamic contrast-enhanced CT scan and clinical evidence of infection or a deteriorating clinical condition. The presence of infected necrosis should be confirmed with a CT-guided percutaneous needle aspiration of fluid from necrotic areas for Gram stain and culture (Fig. 51.3).18,41 Pathogens most often isolated from infected necrosis include Escherichia coli, Klebsiella pneumoniae, Enterococcus sp, Staphylococcus aureus, Pseudomonas aeruginosa, Proteus mirabilis, Enterobacter aerogenes, and Bacteroides fragilis, presumably originating in the colon.55 The possibility that infection results from a fungal source cannot be ruled out, as fungi are found in the intestine as normal flora and the opportunity for superinfection exists with prophylactic antibiotics.56 An estimated 10% of cases of acute necrotic pancreatitis are thought to involve fungal organisms. There are no clear recommendations for prophylactic antifungal therapy in severe acute pancreatitis. Antibiotics that can achieve bactericidal concentrations in pancreatic tissue, such as the fluoroquinolones, metronidazole, and imipenem, should be used.18,52,55 Once infection develops in the necrotic pan bridement is mandatory.41 creas, surgical de
NUTRITION
In 2002 the European Society for Clinical Nutrition and Metabolism (ESPEN) published a consensus article on the use of nutritional strategies in acute pancreatitis.49 There are several risks from parenteral nutrition in a patient with acute pancreatitis, such as catheter-related sepsis, hyperglycemia, suppression of the immune system, and bacterial translocation resulting from a breakdown of the barrier the intestinal mucosa provides. There was no difference in outcomes in patients with acute pancreatitis who received either nasojejunal feedings or TPN. Disadvantages of TPN include sepsis and hyperglycemia, which can be a result of overfeeding. In addition, TPN costs four times more than nasojejunal feedings.49 An important part of therapy for acute pancreatitis is enteral nutrition early in the disease. Not only does this help to preserve body mass, but it also maintains the integrity of the structure and prevents the loss of function of the gastrointestinal tract. Even hypocaloric feedings can be beneficial, as noted by McClave et al.49 Eighty-two percent of patients in this study who received nasojejunal feedings met their caloric goal, in contrast with 96% of TPN patients. Despite the number of patients not receiving adequate caloric intake, the patients receiving nasojejunal feedings showed no difference in terms of infections or length of stay compared to TPN patients. Similar results have been seen in patients with severe pancreatitis. Improvements in systemic inflammatory responses were seen in patients who received nasojejunal feedings, compared to patients receiving TPN, who showed little improvement.50 Oral feedings may be restarted once pain is under control and the pancreatic enzymes have returned to normal levels. The initial diet should consist mainly of carbohydrates and protein, with fats being instituted gradually over 3 to 6 days.49
CORRECTING BILIARY TRACT DISEASE

Virtually all clinicians agree that removing residual biliary tract stones is necessary to prevent recurrent attacks of biliary pancreatitis. However, the optimal timing of stone removal and the choice between endoscopic and surgical treatment are subjects of continuing debate. Early ERCP (within 72 hours of admission) is recommended for patients with gallstone pancreatitis who have evidence of biliary sepsis or organ failure.3,41 Stones in the common bile duct should be removed and a sphincterotomy performed.41 Otherwise, it appears that either surgical or endoscopic procedures for biliary duct clearance should be performed before discharge from the hospital once pancreatic inflammation has resolved.6,17
ANALGESIA
Narcotic analgesics are usually needed to control the severe abdominal pain that often accompanies acute pancreatitis. Transient elevations in serum amylase and lipase that often follow the administration of opiates should not preclude their use, because these effects do not appear to be detrimental to the disease course. Therapy is commonly initiated with meperidine administered parenterally at regular intervals in doses of 50 to 100 mg because it reportedly causes less spasm of the sphincter of Oddi than morphine and its derivatives.17 However, because there is little evidence to suggest
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ALTERNATIVE THERAPIES
There are few studies of alternative therapies in acute pancreatitis. Based on the observation that serum antioxidants are depleted in acute pancreatitis and the correlation between the amount of depletion and severity of pancreatitis, antioxidant therapy (N-acetylcysteine, ascorbic acid, and sodium selenite given intravenously along with alpha-tocopherol and -carotene given via a nasogastric tube) in patients with severe acute pancreatitis has been investigated. Although antioxidant levels returned to normal, there did not appear to be any additional benefit from this therapy.57 Some benefit has been shown from including glutamine in TPN formulations for acute pancreatitis; however, TPN is no longer a preferred therapy.58
IMPROVING OUTCOMES
Early identification of severe acute pancreatitis should enhance patient outcomes.41 Formalized scoring systems and clinical evidence of organ failure can assist the clinician in this regard. Severe disease almost invariably warrants management in an intensive care unit for aggressive cardiovascular and pulmonary support. Patients must be reassessed and monitored throughout the attack for complications, particularly organ failure and infection. When infection is suspected, pharmacists should assist in selecting and monitoring appropriate antibiotic therapy. Invasive procedures such as bridement of infected necrosis and endoscopic or surgical de surgical removal of gallstones also are important for optimizing patient outcome.41 Cytokine antagonism may eventually have a role in reducing the morbidity and mortality of severe acute pancreatitis.37 In addition, eliminating factors that precipitated the acute attack may improve the patients course and prevent recurrence of disease.17,21 Pharmacists can assist in identifying drug-induced pancreatitis and recommend therapeutic alternatives for the offending agent. Because alcoholic pancreatitis is associated with chronic pancreatic damage, substance abuse counseling should be offered to support the patients efforts to abstain.6,21
FUTURE THERAPIES
Although medical treatment of acute pancreatitis is currently supportive, major goals in the future should include limiting systemic complications and preventing pancreatic necrosis.41 Attempts at inflammatory mediator antagonism have focused on activated pancreatic enzymes; however, the destructive products of leukocytes, including elastase, phospholipase A2 , platelet activating factor, nitric oxide, and cytokines, have not been addressed in prospective, randomized trials. Preliminary studies with the platelet activating factor antagonist lexipafant have demonstrated that a therapeutic window exists for cytokine antagonism.59,60 Animal studies have also shown that colloidal hemodilution may improve the pancreatic microcirculation and minimize necrosis.3 Well-designed, controlled, prospective studies are warranted to establish the value of these medical therapies. Additional studies are also needed to determine the optimal use of prophylactic antibiotics for improving mortality in patients with pancreatic necrosis.
PHARMACOECONOMICS
Although data about the economic impact of acute pancreatitis are sparse, experts have recognized the resource demands of intensive care management in severe disease.61 Because survivors of severe acute pancreatitis report excellent quality of life, these substantial costs may be justified.61 As diseasespecific therapies, such as cytokine antagonists, become available, their contribution to cost containment must be analyzed.
C H R O N I C DEFINITION
P A N C R E A T I T I S
monis review of chronic pancreatitis from the first description of the pancreas in 300 BC to the present.62
Chronic pancreatitis is generally defined as an inflammatory disease process leading to irreversible damage to pancreatic structure and function. All patients experience fibrosis and loss of exocrine tissue, and many lose endocrine function as well. The clinical course may consist of recurrent acute attacks, which are difficult to distinguish from acute pancreatitis, or chronic symptoms that usually, but not inevitably, progress. Students of medical history are referred to Pitchu-
ETIOLOGY
Subclassification of chronic pancreatitis based on etiologic, pathologic, radiologic, or other criteria has proved difficult. One classification system that has been used is the Marseilles-Rome system, which distinguishes three types.63 The
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first type, chronic calcifying pancreatitis, is the most common, accounting for more than 95% of cases.64 It usually results from alcohol abuse and is characterized by intraductal protein plugs and, often, calcified stones. The second type, chronic obstructive pancreatitis, is relatively uncommon and occurs as a result of obstruction of the main pancreatic duct by tumor, stricture, or congenital abnormalities. This type is notable in that protein plugs and stones are absent, and damage may be reversible in part when the obstruction is alleviated. The third type, chronic inflammatory pancreatitis, is characterized by fibrosis, infiltration by monocytes, and atrophy of exocrine tissue. This form has been associated with autoimmune disease. A more recent classification is the TIGAR-O system.2,65 This system proposes that there are several risk factors that may interact with each other to predispose patients to pancreatic disease. As a result, this system better addresses the complexity and heterogeneity of chronic pancreatitis. Toxic-metabolic. This classification includes alcohol, the most common etiology of chronic pancreatitis in the United States and other developed countries. However, only 10% to 20% of alcoholics develop chronic pancreatitis.66 Idiopathic. Up to 30% of patients have no identifiable risk factors for the development of chronic pancreatitis. Genetic. Several genes have been identified that seem to predispose patients to developing pancreatic disease. Autoimmune. Although this has been thought to be rare, it may account for some of the cases of idiopathic chronic pancreatitis. Recurrent and severe acute pancreatitis. Although historically acute pancreatitis and chronic pancreatitis have been regarded as discrete clinical entities, it is now thought that severe acute pancreatitis may cause permanent damage to the gland. Obstructive. Obstruction of the main pancreatic duct by neoplasms, stenosis, or other mechanisms can cause chronic pancreatic damage. In summary, the precise etiology of chronic pancreatitis is poorly understood and the subject of ongoing debate.2 Multiple factors may be involved. The role of genetic predisposition has not yet been elucidated, although several genetic mutations have been associated with some forms of chronic pancreatitis. Ethanol abuse is involved in most cases of chronic pancreatitis, particularly in Western countries, accounting for approximately 70% of reported cases. Although a relatively small percentage of alcoholics actually develop clinical symptoms of chronic pancreatitis, as many as 45% show evidence of the disease at autopsy (approximately 50 times the incidence in nondrinkers).5 A tropical form also exists in some Afro-Asian countries; malnutrition and perhaps dietary toxins are presumed to play a role.67,68 Other potential etiologic factors include trauma, hyperparathyroidism/hypercalcemia, hyperlipidemia, autoimmune disease, and tobacco use.2,3,5,69 Up to 30% of cases are classified as
idiopathic, and this form appears to have two subsets: early and late onset. Although gallstone disease may coexist with chronic pancreatitis, cholelithiasis does not appear to predispose a patient to this disease.35,62,7072
EPIDEMIOLOGY
As mentioned previously, the incidence and prevalence data are meager and specific to geographic area. Prevalence estimates range from 0.03% to 5%, and the incidence may approximate 3 to 9 per 100,000 inhabitants per year. Men are substantially more likely to be affected than women.35,62
PATHOPHYSIOLOGY
Over the past several decades, numerous theories have been advanced in an attempt to explain the complex pathogenesis of chronic pancreatitis. Although each may describe a piece of the puzzle, none adequately accounts for all findings. This may be due in part to the heterogeneity of the disease, as evidenced by the classification systems discussed previously.2,3 Alcohol-related injury to the pancreas is perhaps the best understood process. Ethanol is metabolized in pancreatic acinar cells by both oxidative and nonoxidative pathways. Ethanol, its metabolites, and the resulting increase in oxidative stress may all contribute to increased local levels of digestive enzymes and an increased risk of autodigestion. This results in inflammation and the release of proinflammatory cytokines. Although transforming growth factor- has received much attention in recent years, other mediators may include platelet-derived growth factor, interleukin-1 and interleukin-6, and tumor necrosis factor-. These mediators in turn activate pancreatic stellate cells that synthesize collagen and fibronectin, leading to fibrosis.2,73,74 A related theory that has been widely accepted in the past proposes that alcohol changes the nature of pancreatic secretions, predisposing to the formation of protein plugs and stones, leading to ductal obstruction. In the presence of alcohol, the absolute amount of protein in pancreatic secretions increases, facilitating the formation of protein plugs, particularly in the smaller ductules. GP2, a 97kilodalton protein that is analogous to the renal cast protein uromodulin, has been isolated from ductal plugs and may play a role in their formation.75 The resulting obstruction can lead to inflammation and fibrosis, and protein plugs act as a nidus for the formation of calcium carbonate stones.35 In addition, there is decreased secretion of lithostatine, also known as pancreatic stone protein, which normally inhibits the formation of insoluble calcium salts in the ductules. Hence, a deficiency of this protein may allow increased precipitation of calcium salts, exacerbating
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obstruction, inflammation, and fibrosis.35,76 Stones, however, are not found in all cases of alcoholic pancreatitis, and this process may not play a central role in the pathogenesis.2 However, alcohol-related injury is only one piece of the puzzle. A better understanding of the pathogenesis of chronic pancreatitis may lead to strategies for disease mitigation or prevention.
worse the prognosis), smoking, and drinking.90 Chronic pancreatitis is also associated with an increased risk of pancreatic cancer.9193
DIAGNOSIS AND CLINICAL FINDINGS

A diagnosis of chronic pancreatitis is generally straightforward in an alcoholic patient with recurrent bouts of epigastric pain and evidence of calcification of the pancreas by radiography. The diagnosis is made more difficult, however, if the patient is without pain, or if a distinction is sought between chronic pancreatitis and either recurring acute pancreatitis or pancreatic cancer. Physical examination and routine laboratory tests are of limited utility, since the results are usually within normal limits. Even serum amylase and lipase levels are generally normal, although they may be elevated during acute exacerbations or decreased late in the disease. Imaging techniques and pancreatic function tests provide the most useful diagnostic tools.35 They are presented below in approximately the order in which they should be considered based on effectiveness, invasiveness, and expense. A review of diagnostic criteria and methodologies has been recently published.91 Imaging Studies. Radiography can reveal calcifications (usually diagnostic for chronic pancreatitis) and displacement of the stomach or duodenum, indicating the presence of a pseudocyst. Ultrasonography usually shows calcifications, pancreatic enlargement, and pseudocysts, although CT is superior at detecting pseudocysts and can reveal dilated pancreatic ducts as well as pancreatic enlargement and calcifications. ERCP is the most sensitive procedure for viewing changes in the ductal system and is currently considered the gold standard of imaging; however, there is the risk of causing pancreatitis.1,3,5,94,95 Newer techniques such as magnetic resonance cholangiopancreatography (MR-CP) and endoscopic ultrasonography (EUS) are gaining popularity.3,94 Pancreatic Function Tests. Pancreatic function tests may be used if imaging studies are inconclusive. These tests, which can be classified as direct or indirect, have been reviewed extensively.3,5,9699 Direct tests, including the secretin-pancreozymin and Lundh tests, are invasive, requiring intubation of the duodenum. In the secretin-pancreozymin test, usually considered the gold standard for measuring pancreatic secretory function, a patient is given intravenous secretin and CCK, and the subsequent increase in secretion is measured. The Lundh test is similar, with pancreatic secretion measured after the ingestion of a test meal. Indirect tests measure markers of pancreatic function in the blood, urine, breath, or stool. Indirect tests are of limited usefulness due to their relative lack of sensitivity early in the course of chronic pancreatitis. Examples of indirect tests include measurement of fat or chymotrypsin in stool samples and measuring urinary excretion of para-aminobenzoic acid (PABA) after hydrolytic cleaving of PABA from NBTPABA by chymotrypsin in the intestine (bentiromide test).

Signs and Symptoms
Pain and maldigestion are the hallmarks of chronic pancreatitis, although a significant number of patients also develop diabetes mellitus, pseudocysts, or jaundice.3,5,70,77 The causes of pain have not been delineated, but increased intraductal and parenchymal pressure, ischemia, pseudocyst, obstruction of the bile duct, or inflammation, especially in and around the pancreatic nerves, may be involved.3,5,7884 Pain may also be caused by extrapancreatic complications such as biliary stricture or duodenal stenosis.3,5,84 This pain, sometimes accompanied by nausea and vomiting, is similar to that of acute pancreatitis. It is epigastric and often described as deep and penetrating, with a characteristic radiation to the back. Relief may be obtained by leaning forward from a sitting position, and pain is usually aggravated by eating. This pain with eating, in addition to maldigestion and malabsorption, contributes to the weight loss often observed in these patients.3,5,82 Up to 20% of patients may be pain-free, but this is more commonly the case with idiopathic rather than alcoholic pancreatitis.4,5,62,73,85 Loss of exocrine function occurs in all cases of chronic pancreatitis, but it may remain subclinical until fairly late in the disease. Malabsorption does not manifest itself until less than 10% of pancreatic secretory function remains.1,84 Lipase activity decreases relatively more than protease activity; therefore, steatorrhea presents earlier and is usually more severe than azotorrhea.3,5,84,86,87 Although some decrease in absorption of carbohydrates and fat-soluble vitamins does occur, symptoms rarely develop.5,84,87 Bicarbonate secretion also declines with disease progression.64,84,88 The following scenario summarizes the clinical course of a representative patient. He is an alcoholic who began to drink heavily at age 20 and who started to experience attacks of pain by age 30. Abdominal radiographs showed calcification of the pancreas. At 40 years of age, pancreatic insufficiency had progressed to the point that steatorrhea was troublesome, and he developed glucose intolerance. He was dead at 50, probably from complications of alcoholism rather than pancreatitis per se.3,4,84,89 Major predictors of mortality appear to be the age at diagnosis (the older the patient, the
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A combination of imaging studies and pancreatic function tests may be necessary for a definitive diagnosis of chronic pancreatitis, particularly early in the disease (Table 51.7).
TABLE 51.7 Selected Diagnostic Tests for Chronic

Pancreatitis
Imaging Techniques Plain abdominal radiography Ultrasonography Computed tomography Magnetic resonance cholangiopancreatography Endoscopic retrograde cholangiopancreatographya Pancreatic Function Tests Direct tests: measurement of pancreatic exocrine secretions Secretin-pancreozymin testa Lundh test Indirect tests: measurement of enzyme action Bentiromide (NBT-PABA) test Fecal chymotrypsin concentration Fecal fat analysis
a
Many patients develop chronic pancreatitis as a result of alcoholism. This patient population can be very difficult to manage. If the patient is still actively drinking, every effort should be made to convince him or her to abstain. Unfortunately, however, this may not slow the course of the disease.4 Alcoholics may also be at increased risk for addiction to opioid analgesic agents, complicating pain management. Treatment regimens and follow-up need to be tailored to individual patient profiles.
THERAPEUTIC PLAN
Chronic pancreatitis is usually progressive and, with the possible exception of the obstructive form, irreversible. Treatment, therefore, is directed at managing the pain, maldigestion, and other complications that arise from this disease. When a patient presents for medical treatment, assessment of
Currently considered gold standards. (1,3,69)
symptoms and prior medication use is an important starting point. In particular, narcotic use and potential for addiction should be evaluated.
TREATMENT GOALS: CHRONIC PANCREATITIS Pain is the symptom that commonly brings patients to the attention of the medical community. Alleviation of this pain is an important goal of therapy. In addition, both exocrine and endocrine insufficiency must be appropriately managed. Treating exocrine insufficiency will be discussed in this chapter, while insulin insufficiency is covered in Chapter 40. Diabetes develops in 40% to 80% of chronic pancreatitis patients, usually late in the course of the disease.3,5 One key difference between type 1 diabetes mellitus and pancreatic diabetes should be mentioned, however: in chronic pancreatitis, there is loss of glucagon as well as insulin secretion, leading to diabetes that is very hard to control, or brittle.3
Control pain using analgesics, enzyme replacement, and endoscopic and surgical treatment Manage maldigestion and malabsorption through enzyme replacement Manage diabetes
TREATMENT
Pharmacotherapy
Pain. The pain of chronic pancreatitis, which may be episodic or persistent, is a poorly understood phenomenon, complicating decisions about therapy. The lack of controlled clinical trials makes it difficult to define treatment strategies. As a result, there has not been a universally accepted standard of care for these patients. Warshaw et al sought to address this in their review of pain management,98 and they
proposed an algorithm for the treatment of pain in chronic pancreatitis (Fig. 51.4).99 Abstinence from alcohol may reduce pain in up to 50% of patients, but the majority will require some form of analgesia.79,82,85,87 Having patients keep a log of their pain may aid in assessment.98 Salicylates, nonsteroidal anti-inflammatory drugs, or acetaminophen should be tried initially, perhaps in conjunction with a low-fat diet.98 Adjunctive therapy with tricyclic antidepressants or selective serotonin reuptake inhibitors may prove beneficial in some patients, although evidence of efficacy is merely anecdotal.81,83,85,98
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Patient with chronic pancreatitis and pain
CT ERCP EUS upper endoscopy or upper GI Pseudocyst, biliary stricture, duodenal stenosis, peptic ulcer disease, pancreatic cancer
Medical (PUD), surgical (PS, BS, DS), or endoscopic (PS) therapy
Low-fat diet, nonnarcotic analgesics, no alcohol; have patient keep log of pain and fill out quality-of-life questionnaire
No response
8 week trial of high-dose pancreatic enzymes (in tablet form) acid suppression
No response
Consider trial of endoscopic therapy
Endoscopic therapy not performed or no response
Discuss with patient watchful waiting vs. narcotic analgesics and risk of addiction vs. benefits and risks of surgery
Surgery chosen
Small ducts
Large ducts
Consider nerve ablation in controlled setting
Surgical drainage
Pancreatic resection
FIGURE 51.4 Guideline for treatment of pain in chronic pancreatitis. BS, biliary stricture; CT, computed tomography; DS, duodenal stenosis; ERCP, endoscopic retrograde cholangiopancreatography; EUS, endoscopic ultrasonography; PS, pseudocyst; PUD, peptic ulcer disease. (Reprinted with permission from Warshaw AL, Banks PA, Fernandez-del Castillo C. AGA technical review on treatment of pain in chronic pancreatitis. Gastroenterology 115:763764, 1998.)
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Enzyme replacement therapy, which will also be discussed for the treatment of maldigestion, may help to alleviate pain, especially in patients with nonalcoholic chronic pancreatitis.3,7,72,8284,98 Clinical trial data have not always shown effectiveness, however.3,73,84,98,100 It is presumed that the presence of exogenous proteases in the duodenum suppresses pancreatic function through a negative feedback mechanism. This mechanism involves degradation of a CCK-releasing peptide by trypsin in the duodenum, inhibiting the release of CCK.3,14,98,101 Enzymes contained in nonenteric-coated preparations may be more reliably delivered to the duodenum than enzymes from enteric-coated dosage forms, since the latter are sometimes released in more distal portions of the small intestine. This is due to the relatively low duodenal pH caused by decreased bicarbonate secretion in chronic pancreatitis.63,88 As a result, nonenteric preparations may be more effective at suppressing CCK release and reducing pain.1,3,72,98 In theory, the addition of an H2-receptor antagonist or a proton pump inhibitor could decrease acid-stimulated pancreatic secretion and diminish pain, but this has not been demonstrated. These agents are frequently tried due to their ease of use and relative safety.84,98 Other agents may also have utility in the control of pain. Octreotide, a somatostatin analogue, has not consistently demonstrated efficacy in chronic disease,1,84,98 but it may have a role in the management of pancreatic pseudocysts102,103 and in decreasing complications after pancreatic surgery.104 Antioxidant therapy may also prove beneficial, since patients with chronic pancreatitis seem to be deficient in endogenous antioxidants.3,84,98 Further study is required before specific recommendations can be made, however. For patients still experiencing pain, the choices remaining are opioid analgesics and interventional therapy. Unfortunately, there are no well-defined criteria for making this decision. Opioid analgesics may prove very effective, although there is a very real risk of addiction, particularly in this patient population.73,84,98,105 Refer to Chapter 64 for a discussion of these agents. Despite maximum medical management, up to 30% of patients still experience pain.89 This pain may diminish, or burn out, over time as the pancreas becomes progressively more fibrotic, but this phenomenon may not occur in as many patients as was once thought.3,73,98 Approximately half of chronic pancreatitis patients will require endoscopic or surgical intervention to control pain, although this may not reliably improve qualify of life.1 Endoscopic treatment may be effective for stenosis, strictures, or stones. Stent placement relieves intraductal pressure and pain in many patients, although there is a risk of ductal injury. Patients may also experience pain relief with the elimination of intraductal pancreatic stones by lithotripsy or pancreatic duct sphincterotomy. Improvement is reported in 50% to 85% of patients undergoing endoscopic therapy, but many questions remain.3,95,98,106
Surgery is usually reserved for the patients with intractable pain. The procedure of choice for patients with dilated ducts (larger than 6 or 7 mm) is surgical drainage with a procedure called lateral pancreaticojejunostomy. For patients with small duct disease, surgical denervation and pancreatic resection are options. These procedures have been reviewed extensively.3,72,98,107109 Maldigestion/Malabsorption. Patients with documented weight loss and steatorrhea should receive treatment for maldigestion. Two types of pancreatic enzyme replacement preparations are currently available. Pancreatin is derived from freeze-dried porcine or bovine pancreases and contains at least 2 USP units of lipase and 25 USP units each of protease and amylase per milligram. Pancrelipase, extracted from porcine pancreases, is more potent, containing at least 24, 100, and 100 USP units of lipase, protease, and amylase per milligram, respectively (Table 51.8).108 Rapid-release and enteric-coated dosage forms are available. While rapid-release forms more reliably deliver proteases to the upper duodenum, where they may exert a negative feedback inhibitory effect, they expose lipase to the acid environment of the stomach. Lipase is pH labile, maximally active at pH 8 and irreversibly inactivated at pH less than 4. Enteric-coated microspheres, which dissolve at approximately pH 5.6 to 6.0, better protect lipase from gastric acidity, but enzyme release may be delayed. While rapid-release forms are preferable for pain control, enteric-coated products are more effective in the treatment of steatorrhea.1,72,84 Since lipid malabsorption and steatorrhea are the primary clinical problems associated with pancreatic insufficiency, the dose of lipase to be delivered to the duodenum is a paramount concern. Maximal postprandial delivery of lipase from a normal pancreas is 140,000 units per hour for 4 hours. Supplying 5% to 10% of this will significantly decrease steatorrhea; therefore, the enzyme supplement should usually provide approximately 30,000 (25,000 to 40,000) units over a 4-hour period, although regimens should be individualized for each patient.3,70,84,109111 Efficacy of therapy can be assessed by monitoring the fat content of stools. If steatorrhea persists, another agent can be added to increase gastric pH in an attempt to increase the delivery of active lipase to the duodenum. Agents that may be useful include H2-receptor antagonists and proton pump inhibitors.12,73,84,108,112 Even with careful management of supplements, however, the elimination of steatorrhea is very difficult.12,109 Research into other forms of enzyme replacement therapies, including bacterial lipase and bioengineered human gastric lipase, are ongoing.109,110 Figure 51.5 presents one possible approach to enzyme replacement therapy for steatorrhea. Patients should be counseled to take supplements just before or with meals. The microspheres/microtablets contained in capsules should not be crushed, but they may be mixed with soft food such as applesauce, if necessary. The pH of the food should be below 5 to avoid premature dissolu-
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TABLE 51.8 Some Commercial Pancreatic Enzyme Preparations

Enzyme Content (USP Units) Product
a
Formulation
PL PC PL PL PC PC PL PL PL PL PL PL PL PL PL PL PL PL PL PL PL PL PL PL PL PL PL PL PL PL PL PL PL PL PL 8x USP
Dosage Form
C T C T T T P T T MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MT MT MT MT MS MS MS MT MT MT MS
Lipase
8,000 1,000 8,000 8,000 12,000 22,500 16,800 8,000 16,000 5,000 5,000 10,000 20,000 10,000 4,500 10,000 10,000 12,000 16,000 18,000 20,000 20,000 8,000 4,500 4,000 10,000 16,000 20,000 10,000 20,000 4,500 12,000 18,000 20,000 12,000
Protease
30,000 12,500 30,000 30,000 60,000 180,000 70,000 30,000 60,000 20,000 18,750 37,500 75,000 37,500 25,000 30,000 37,500 39,000 48,000 58,500 65,000 75,000 45,000 25,000 12,000 30,000 48,000 44,000 37,500 75,000 25,000 39,000 58,500 65,000 24,000
Amylase
30,000 12,500 30,000 30,000 60,000 180,000 70,000 30,000 60,000 20,000 16,600 33,200 66,400 33,200 20,000 30,000 33,200 39,000 48,000 58,500 65,000 66,400 40,000 20,000 12,000 30,000 48,000 56,600 33,200 66,400 20,000 39,000 58,500 65,000 24,000
Rapid Release Cotazym Donnazyme Ku-Zyme HP Panokase Pancreatin 4x USP Viokase Viokase 8 Viokase 16 Delayed-Release Capsules Cotazym-S Creon 5 Minimicrospheres Creon 10 Minimicrospheres Creon 20 Minimicrospheres Encron 10 Lipram 4500 Lipram-PN10 Lipram-CR10 Lipram-UL12 Lipram-PN16 Lipram-UL18 Lipram-UL20 Lipram-CR20 Pancrebarb MS-8 Pancrease Pancrease MT-4 Pancrease MT-10 Pancrease MT-16 Pancrease MT-20 Pancron 10 Pancron 20 Ultrase Ultrase MT12 Ultrase MT18 Ultrase MT20 Zymase
a These products, available before passage of the 1938 Food, Drug, and Cosmetic Act, are not approved by the FDA and cannot be considered pharmaceutically or therapeutically equivalent.11 b PC, pancreatin; PL, pancrelipase. c C, capsule; MS, enteric-coated microspheres; MT, enteric-coated microtablets; P, powder; T, tablet.
1383
Administer enteric-coated pancreatic extract preparation (approximately 28,000 U lipase per meal). If unsuccessful
Increase dosage. If unsuccessful
Decrease fat intake to 5075 g/day (normal American diet, 100 g/day), or use smaller, more frequent meals. If unsuccessful
Add an H2 receptor antagonist or proton pump inhibitor. If unsuccessful
Try a different enzyme preparation. If unsuccessful
FIGURE 51.5 Treatment of steatorrhea.
Consider an alternative diagnosis.
tion of the enteric coating. Different products may not be bioequivalent, and changes in regimen should not be made without consulting a physician or pharmacist.84 Problems that may be encountered with enzyme-replacement therapy, especially at high doses, include abdominal pain, oral and perianal irritation, nausea, vomiting, diarrhea, and rare hypersensitivity. There have also been reports of hyperuricosuria, although this appears to be more common in cystic fibrosis patients receiving very high doses of pancreatic enzymes. Finally, patient compliance is often less than optimal due to the administration of large numbers of capsules, gastrointestinal distress, and expense.13,70 The overall safety and tolerability of pancreatic extracts, however, appears to be good.113
IMPROVING OUTCOMES
This patient population presents challenges, particularly if there is continued alcohol consumption. Substance abuse programs may help to establish and maintain abstinence, and referral to a pain clinic may be warranted. A multidisciplinary team approach should improve patient outcomes, although evidence for this approach is only anecdotal. One physician should manage narcotic analgesics.83 Quality of life data are sparse, and much of the data has been collected in patients who have undergone surgical intervention.3,85,115 A more global study was recently conducted in Germany.116 In this study, patients with chronic pancreatitis reported lower quality of life in all areas surveyed. As one might expect, chronic pain, pancreatic diarrhea, and unemployment were particularly problematic. There are also data to suggest that the development of insulin-requiring diabetes has a significant negative impact on quality of life.115 Improving therapeutic outcomes will almost certainly contribute to improved quality of life for patients with chronic pancreatitis.
FUTURE THERAPIES
Chronic pancreatitis is a heterogeneous disease state, and it is likely that response to a therapeutic modality depends, at least in part, upon the etiology and clinical course of the disease in a particular patient. This has not been addressed to date in clinical trials, since the study populations generally reflect the heterogeneity of the population at large. Defining which patient subgroup may benefit from a particular therapy will help to guide treatment. Gene therapy, although years from clinical application, may prevent or reverse pancreatic damage in certain patients.1,111,114
PHARMACOECONOMICS
To date, no studies have been published evaluating the economic impact of chronic pancreatitis or its therapy. This
1384
information will be needed to refine emerging therapeutic algorithms.
SUGGESTED READINGS
Meier R, Beglinger C, Layer P, et al. Consensus statement: ESPEN guidelines on nutrition in acute pancreatitis. Clin Nutr 21:173183, 2002. Mitchell RMS, Byrne MF, Baillie J. Pancreatitis. Lancet 361: 14471455, 2003. Nathens AB, Curtis JR, Beale RJ, et al. Management of the critically ill patient with severe acute pancreatitis. Crit Care Med 32:25242536, 2004.
KEY POINTS
Acute and chronic pancreatitis have historically been considered distinct clinical entities that are often, although not always, alcohol-related. Acute pancreatitis is an autodigestive process characterized by inflammation, edema, and necrosis, while chronic pancreatitis is the result of poorly understood processes leading to irreversible loss of functional tissue. In acute pancreatitis, it is important to establish the severity of the attack so that appropriate therapy can be instituted and the patients risk for developing complications evaluated. With chronic pancreatitis, care is directed toward pain relief and managing declining endocrine and exocrine function. In both, therapy remains almost exclusively supportive. Although there have been recent advances in our understanding of pathophysiology and treatment, much remains unclear Controlled clinical trials are needed to assess the role of medical therapy directed at the underlying pathogenesis of acute and chronic pancreatic disease. Acute Pancreatitis: The mortality associated with acute pancreatitis ranges from 5% to 10% The most common causes of acute pancreatitis are alcohol and gallstones Patients with severe acute pancreatitis should be identified early in the course of the disease and will likely require intensive care, including fluid replacement and nasojejunal feeding. Pain management with an opioid analgesic is usually required Antibiotic prophylaxis is not recommended in cases of acute pancreatitis Patients should be assessed throughout the course of an acute attack for the development of complications such as organ failure and infection Therapy for acute pancreatitis is supportive. Future therapies will be directed at curtailing the inflammatory process Chronic Pancreatitis: Most cases of chronic pancreatitis are alcoholrelated and are usually progressive and irreversible The clinical course of chronic pancreatitis varies widely, complicating the diagnosis and therapy Treatment of chronic pancreatitis is directed at managing pain, steatorrhea, diabetes, and other complications Future trials of chronic pancreatitis should stratify patients by etiology or clinical course, compare treatment regimens, determine the cost-effectiveness of therapy, and assess patients quality of life
REFERENCES
1. Mitchell RMS, Byrne MF, Baille J. Pancreatitis. Lancet 361: 14471455, 2003. 2. Stevens T, Conwell DL, Auccaro G. Pathogenesis of chronic pancreatitis: an evident-based review of past theories and recent developments. Am J Gastroenterol 90:22562270, 2004. 3. Fosmark CE. Chronic pancreatitis. In: Feldman M, Sleisenger MH, Scharschmidt BF. Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management. 6th ed. Philadelphia: WB Saunders, 1998:809. 4. Steer ML, Waxman I, Freedman S. Chronic pancreatitis. N Engl J Med 332:14821490, 1995. 5. Owyang C, Levitt MD. Chronic pancreatitis. In: Yamada T. Textbook of Gastroenterology. 2nd ed. Philadelphia: JB Lippincott, 1995:2061. 6. Gorelick FS. Acute pancreatitis. In: Yamada T. Textbook of Gastroenterology. 2nd ed. Philadelphia: JB Lippincott, 1995:2064. 7. Magee DJ, Burdick JS. Anatomy, histology, embryology, and developmental anomalies of the pancreas. In: Feldman M, Sleisenger MH, Scharschmidt BF. Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management. 6th ed. Philadelphia: WB Saunders, 1998:871. 8. Simeone DM, Mulholland MW. Pancreas: anatomy and structural anomalies. In: Yamada T, ed. Textbook of Gastroenterology. 4th ed. Philadelphia: Lippincott Williams & Wilkins, 2003:20132026. 9. Pandol SJ. Pancreatic physiology and secretory testing. In: Feldman M, Sleisenger MH, Scharschmidt BF. Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management. 6th ed. Philadelphia: WB Saunders, 1998:871. 10. Owyang C, Williams JA. Pancreatic secretion. In: Yamada T. Textbook of Gastroenterology. 2nd ed. Philadelphia: JB Lippincott, 1995:361. 11. Valenzuela JE, Pancreatic physiology. In: Valenzuela JE, Reber HA, Ribet A. Medical and Surgical Diseases of the Pancreas. New York: Igaku-Shoin, 1991:1. 12. Lebenthal E, Rolston DDK, Holsclaw DS. Enzyme therapy for pancreatic insufficiency: present status and future needs. Pancreas 9: 112, 1994. 13. Chey WY. Regulation of pancreatic exocrine secretion. Int J Pancreatol 9:720, 1991. 14. Owyang C, Louie DS, Tatum D. Feedback regulation of pancreatic enzyme secretion: suppression of cholecystokinin release by trypsin. J Clin Invest 77:20422047, 1986. 15. DiMagno EP, Chari S. Acute pancreatitis. In: Feldman M, Sleisenger MH, Scharschmidt BF. Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management. 6th ed. Philadelphia: WB Saunders, 1998:913. 16. Bradley EL. A clinically based classification system for acute pancreatitis. Arch Surg 128:586590, 1993. 17. Marshall JB. Acute pancreatitis: a review with an emphasis on new developments. Arch Intern Med 153:11851198, 1993. 18. Banks PA. Acute pancreatitis: medical and surgical management. Am J Gastroenterol 89(Suppl):S7885, 1994. 19. DiMagno EP. Treatment of mild acute pancreatitis. In: Bradley EL. Acute pancreatitis: diagnosis and therapy. New York: Raven, 1994: 261263. 20. Topazian M, Gorelick FS. Acute pancreatitis. In: Yamada T. Textbook of Gastroenterology. 2nd ed. Philadelphia: JB Lippincott, 1995:2026. 21. Steinberg W, Tenner S. Acute pancreatitis. N Engl J Med 330: 11982010, 1994.

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Cirrhosis

TABLE 50.1 Cirrhosis: Incidence and Causes

SECTION XIV Hepatic and Pancreatic Disorders

CLINICAL PRESENTATION AND DIAGNOSIS

SIGNS AND SYMPTOMS

Intravascular blood volume Overfill theory

2 renal Na/H2O retention Renal Na/H2O retention Blood volume

Peripheral arterial vasodilation Blood volume

Intravascular blood volume

FIGURE 50.1 Mechanisms of ascites development.

Renal Na/H2O retention

SECTION XIV Hepatic and Pancreatic Disorders

SECTION XIV Hepatic and Pancreatic Disorders

TABLE 50.2 Drugs Used in Cirrhotic Patients

10 mg/day, not to exceed 3 doses

Hypersensitivity (fever, chills, anaphylaxis, flushing, sweating) Prothrombin time/INR

100400 mg/day, occasionally higher; may be given as a single daily dose

Loop diuretics furosemide

Diuresis in ascites used in combination with spironolactone

Vasoconstrictor for esophageal bleeding

Sodium tetradecyl sulfate, ethanolamine oleate, or sodium morrhuate

Sclerosing agents for esophageal variceal bleeding

TABLE 50.2 continued

Hepatamine, Hepatic-Aid, and Nutihepa

Colchicinea,b Cefotaxime, norfloxacina, ciprofloxacin, trimethoprim/ sulfamethoxazole Flumazenila,b Octreotide Midodrine

Anti-inflammatory and antifibrotic effects Treatment or prevention of spontaneous bacterial peritonitis

SECTION XIV Hepatic and Pancreatic Disorders

SECTION XIV Hepatic and Pancreatic Disorders

SECTION XIV Hepatic and Pancreatic Disorders

SECTION XIV Hepatic and Pancreatic Disorders

SECTION XIV Hepatic and Pancreatic Disorders

SECTION XIV Hepatic and Pancreatic Disorders

CHRONIC PANCREATITIS 1376 Definition 1376 Epidemiology 1377 Pathophysiology 1377

SECTION XIV Hepatic and Pancreatic Disorders

SECRETION OF WATER AND ELECTROLYTES

TABLE 51.1 Major Digestive Enzymes Secreted by the

SECTION XIV Hepatic and Pancreatic Disorders

REGULATION OF EXOCRINE FUNCTION

TABLE 51.2 Causes of Acute Pancreatitis

SECTION XIV Hepatic and Pancreatic Disorders

TABLE 51.3 Agents Associated with Acute Pancreatitis

DIAGNOSIS AND CLINICAL FINDINGS

CLINICAL PRESENTATION AND DIAGNOSIS

SECTION XIV Hepatic and Pancreatic Disorders

TABLE 51.4 Ransons Prognostic Criteria

55 16,000 200 350 250

TABLE 51.5 APACHE II Variables

TABLE 51.6 Complications of Acute Pancreatitis

SECTION XIV Hepatic and Pancreatic Disorders

Assess severity (first few days) Severe CT scan

TREATMENT GOALS: ACUTE PANCREATITIS

CORRECTING BILIARY TRACT DISEASE

SECTION XIV Hepatic and Pancreatic Disorders

SECTION XIV Hepatic and Pancreatic Disorders

DIAGNOSIS AND CLINICAL FINDINGS

CLINICAL PRESENTATION AND DIAGNOSIS

TABLE 51.7 Selected Diagnostic Tests for Chronic

Currently considered gold standards. (1,3,69)

SECTION XIV Hepatic and Pancreatic Disorders

Patient with chronic pancreatitis and pain

Medical (PUD), surgical (PS, BS, DS), or endoscopic (PS) therapy

Consider trial of endoscopic therapy

Endoscopic therapy not performed or no response