Harfinddall

50CirrhosisJ. Richard Brown

Definition • 1346Treatment Goals • 1346Epidemiology • 1346Pathophysiology • 1347Clinical Presentation and

Diagnosis • 1348Signs and Symptoms • 1348Diagnosis • 1348

Psychosocial Aspects • 1351

DEFINITION

Cirrhosis is defined as irreversible chronic injury of the livercharacterized by diffuse fibrosis and the formation of regen-erative nodules. Areas of necrosis and regeneration of he-

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 qual-

ity 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 therapeuti-

cally that patients discontinue consumption of all alcohol.

EPIDEMIOLOGY

Although cirrhosis is frequently encountered in medicine, itis difficult to cite an accurate incidence because patientsoften have no symptoms until the later stages of disease.Postmortem data from various hospitals show an incidenceof 3% to 15%. In 1989, cirrhosis was the ninth leading causeof death in the United States.1 Worldwide, the annual deathrate from cirrhosis of all causes is as high as 15 to 40 per100,000 people.2 However, death and hospitalization ratesof patients with chronic liver disease and cirrhosis are onthe decline in the United States. In 1989, chronic liver dis-ease was the underlying cause of death for 26,720 peopleand a contributing cause of death for an additional 14,101people. From 1980 through 1989 the age-adjusted death ratefor chronic liver disease decreased 23%, from 13.5 to 10.4per 100,000 people. Chronic liver disease appeared as the

1346

Therapeutic Plan • 1351Treatment • 1351

Pharmacotherapy • 1351Nonpharmacologic Therapy • 1360

Alternative Therapy • 1360Improving Outcomes • 1361Prognosis • 1361Pharmacoeconomics • 1361Key Points • 1361

patic parenchyma impart the classic glandular or nodularappearance of the liver. Necrosis of hepatocytes leads todeposition of connective tissue, which distorts the vascula-ture and alters the flow of blood through the liver, resultingin portal hypertension. These pathologic changes are the endresult for many types of chronic liver injury.

first diagnosis in an estimated 72,232 hospitalizations in1989 and as a secondary diagnosis in an additional 218,156hospitalizations. From 1980 through 1989 the hospitalizationrate attributed to chronic liver disease and cirrhosis declined44%, from 50.6 to 28.2 per 100,000 people.3 Centers forDisease Control and Prevention data from 2001 reported27,035 deaths, or 9.5 per 100,000. In 2000, 360,000 dis-charges from chronic liver disease and cirrhosis wererecorded. In 2002, chronic liver disease and cirrhosis wasthe 12th leading cause of death in the United States, account-ing for 1.2% of all deaths recorded.4

Table 50.1 lists the relative frequencies of the varioustypes of cirrhosis encountered in the clinical setting. Thelargest percentage is alcohol-related cirrhosis, which occursprincipally in patients between 40 and 60 years of age andis more common in men. (The management of alcoholismis discussed in greater detail in Chapter 58.) In the United

CHAPTER 50 ■ Cirrhosis 1347

TABLE 50.1

Type Frequency (%) Causes

Cirrhosis: Incidence and Causes

Alcohol-associated

Biliary (primary and secondary)

Postnecrotic

CryptogenicMetabolic

60–70

10–15

10–15

10–155–10

Alcohol abuse and protein deficiency inducing fatty changes,inflammation, and scarring of liver

Obstruction of bile flow (e.g., immune complexes, stones, andcarcinoma); often secondary to long-standing bacterial infection

Scarring following massive hepatic necrosis, such as that seen inchronic viral hepatitis, after exposure to hepatotoxic drugs, or inimmune-mediated hepatitis

UnknownExcessive iron (hemochromatosis) or excessive copper (Wilson’s disease)

deposition, �1-antitrypsin deficiency, other inborn errors of metabolism

States, 50% to 90% of these patients have a history of chronicalcoholism. The quantity of ethanol needed to cause cirrhosisis 80 g per day for 5 years. With approximately 11 to 12 gin the average drink, six or seven drinks per day over thisperiod could be considered a factor in the development ofcirrhosis. In developing countries, children often acquirehepatitis B by maternal transmission.1,2,5

PATHOPHYSIOLOGY

Several major types of cirrhosis have been described (Table50.1), but cirrhosis associated with chronic hepatitis C infec-tion is currently the most commonly encountered form inthe United States, followed by alcohol-related cirrhosis.5,6

(Viral hepatitis is discussed further in Chapter 49.) Alcoholicliver disease usually begins with severe fatty changes in theliver (steatosis). In the early stages this fatty infiltration isnot associated with fibrosis and scarring. Later stages aremarked by a prominent inflammation, an increase in fibroustissue, and a progressive shrinkage, nodularity, and harden-ing of the liver.

In experimental animal models, dietary derangements caninduce significant fatty changes in the liver, with subsequentdevelopment of cirrhosis. Therefore, it is often claimed thatdietary indiscretion in alcoholics may be an important under-lying associated cause of cirrhosis. This concept is supportedby the observation that when a chronic alcoholic is hospital-ized and placed on an appropriate diet, excess fat can bemobilized and the liver structure and function may return tonormal. This reversibility is less clear if fibrosis is present.Other evidence implicates alcohol as a direct hepatotoxin.One group of investigators showed development of cirrhosisin baboons that were maintained on a balanced diet but givenlarge daily doses of alcohol.7

Biliary cirrhosis is caused by chronic obstruction of bileflow (cholestasis). Primary biliary cirrhosis (PBC) followslong-standing cholestasis that is generally of unknown ori-

gin, but it may have an underlying immunologic basis withelevated immunoglobulin M (IgM), autoantibodies, and cir-culating complement-fixing immune complexes. The pres-ence of antimitochondrial antibodies is the serologic hall-mark for PBC. Secondary biliary cirrhosis may be causedby bile stones or a tumor obstructing bile flow, leading toan inflammatory reaction and scarring.

Other causes of cirrhosis are related to chronic viral hepa-titis (e.g., chronic hepatitis B), autoimmune hepatitis, andvarious metabolic disorders (Table 50.1). In 10% to 15%of cirrhotic patients, the cause is never determined. This isreferred to as cryptogenic cirrhosis.

The liver has a unique blood supply. The hepatic artery,which supplies oxygen-rich blood, provides approximately20% of the blood supply to the liver. The remaining 80%of the blood supply comes from the portal vein. The portalvein, formed from the confluence of the splenic and mesen-teric veins, provides nutrient-rich blood that comes from thegastrointestinal (GI) tract. A second set of microvasculature(or sinusoids) runs throughout the liver and then rejoins toempty into the hepatic veins and eventually the inferior venacava. The main function of the portal venous system is toact as a pathway for detoxification and metabolism by theliver of substances absorbed from the GI tract. The anatomyof the portal system allows for first-pass (presystemic) me-tabolism of orally administered drugs such as propranolol,verapamil, and morphine.

With the development of cirrhosis, fibrosis, and the for-mation of regenerative nodules, the normal flow of bloodthrough the liver parenchyma is impeded, resulting in a dra-matic rise in the portal venous pressure and that of its tributa-ries. This is referred to as portal hypertension. Blood mayalso be shunted around the liver via collateral veins in thedistal esophagus and gastric fundus. The increase in bloodflow through these normally low-pressure tributaries resultsin engorgement of the submucosal veins, commonly referredto as esophageal and gastric varices.

1348 SECTION XIV ■ Hepatic and Pancreatic Disorders

CLINICAL PRESENTATION ANDDIAGNOSIS

DIAGNOSISThe diagnosis of cirrhosis is usually made based upon clini-cal, laboratory, and radiologic data. Cirrhosis can be con-firmed and staged based on histologic evidence from liverbiopsy.

SIGNS AND SYMPTOMSCirrhosis is insidious in its development and is often asymp-tomatic until the late stages of disease. Up to 50% of allcases are discovered only at postmortem examination. Manypatients seek medical help, complaining of vague, nonspe-cific symptoms such as weight loss, loss of appetite, nausea,vomiting, and ill-defined digestive disturbances. Othersenter the hospital acutely ill with the full syndrome of acutehepatitis (a precursor to cirrhosis). These patients have jaun-dice (bilirubin levels range from 2 mg per deciliter to morethan 40 mg per deciliter), mildly elevated serum alanineand aspartate aminotransferase (ALT and AST) and alkalinephosphatase levels, a low serum albumin level, evidenceof impaired coagulation (prolonged prothrombin time andelevated INR), and right upper quadrant pain. In the laterstages of cirrhosis, patients may have the complications ofcirrhosis: ascites, variceal bleeding, and hepatic encephalop-athy. The clinical manifestations include visible collateralvenous engorgement on the abdominal wall (caput medusa),testicular atrophy, parotid gland enlargement, nail clubbing,skin hyperpigmentation, amenorrhea, jaundice, edema, pal-mar erythema, fetor hepaticus, loss of body hair, spider angi-omas, gynecomastia, ascites, splenomegaly, and musclewasting. Patients can also experience intense pruritus due tohyperbilirubinemia. Hepatocellular carcinoma develops inas many as 10% of subjects with long-standing cirrhosis.

Ascites. Ascites, characterized by the accumulation of pro-tein-rich fluid in the peritoneal cavity, is one of the most

FIGURE 50.1 Mechanisms of ascites develop-ment.

Underfilltheory Cirrhosis Portal hypertension Ascites

Overfilltheory Cirrhosis

Renal Na/H2Oretention

Intravascularblood volume

2 renalNa/H2O retention

↑ Bloodvolume Ascites

Renal Na/H2Oretention

↑ Bloodvolume Ascites

Integrativetheory Cirrhosis

Peripheral arterialvasodilation

↓ Intravascularblood volume

striking features of cirrhosis. Complaints associated with as-cites include a rapidly developing inability to fit into one’sclothes, weight gain, abdominal and low-back pain, gastro-esophageal reflux, and shortness of breath secondary to im-paired diaphragm movement or the development of pleuraleffusions. The amount of fluid in the abdomen can vary froma few liters to 20 liters or more, leading to a large protuberantabdomen and an umbilical hernia. Ascitic fluid is a goodmedium for bacterial growth. Infection of the peritoneal cav-ity can occur spontaneously (spontaneous bacterial peritoni-tis). An unexplained high fever or elevated white blood cellcount is an indication for obtaining a sample of the asciticfluid for bacterial culture or initiating empiric antibiotictherapy.

Several mechanisms have been postulated to explain theformation of ascites (Fig. 50.1), none of which is fully ac-cepted as the definitive answer.8,9 Most agree that disruptionof hepatic architecture and blood flow caused by inflamma-tion, cell necrosis, fibrosis, or obstruction leads to hemody-namic alterations, causing an elevated lymphatic pressurewithin the hepatic sinusoids, which eventually causes exces-sive transudation (weeping) of protein-rich fluid from thesurface of the liver into the peritoneal cavity. According tothe underfill theory, both the lymphatic leakage and highprehepatic venous pressure (portal hypertension) cause a netflow of volume from the vascular space to the peritonealcavity via hydrostatic forces. The high protein content ofthe ascitic fluid may also help to draw fluid out of the vascu-lature. As a result, effective vascular volume throughout thebody decreases, causing secondary sodium and water reten-tion by the kidney. The renin angiotensin system is a majormediator of the sodium and water retention, ultimately caus-ing release of aldosterone from the adrenal gland. Antidi-uretic hormone (ADH) release may also increase. Serumlevels of aldosterone and ADH remain elevated because ofimpaired metabolism secondary to liver failure. These pro-cesses are accentuated by a reduced oncotic pressure withinthe intravascular space due to hypoalbuminemia. A major


inconsistency with the underfill theory is that some patientshave an increased, not decreased, total intravascular volume,and not all patients have demonstrable hyperaldosteronism.

According to the overfill theory, the primary defect inascites formation is excessive renal reabsorption of sodiumand water. As plasma volume expands, ascites results fromoverflow of fluid out of the splanchnic circulation and in-creased pressure in the portal system. This implies that anunknown primary renal stimulus initiates the volume expan-sion. Increased sympathetic activity and a variety of hor-monal substances have been proposed as factors affectingrenal function in cirrhotic patients.10

Schrier et al8 proposed an integration of these two theo-ries, citing a possible systemic intravascular vasodilation thatcauses a relative decrease in effective plasma volume orpressure, followed by excessive renal retention of sodiumand water. Central blood volume has a primary influenceon renal circulation. In cirrhotic patients, there is reducedcirculating volume even in patients who have not yet devel-oped ascites. This volume reduction results from vasodila-tion of the peripheral vascular system. Sensing a shift fromthe central circulation, the kidneys and arterial baroreceptorsactivate vasoconstrictive systems to enhance sodium reab-sorption. The renin-angiotensin-aldosterone system and therelease of vasopressin act to increase central vascular fill-ing.9 It is believed that both intrahepatic hypertension anda primary renal defect are responsible for the early stagesof ascites.7

Hypoalbuminemia, secondary to decreased hepatic syn-thesis and lymphatic leakage into the peritoneum, may fur-ther contribute to accumulation of ascites. A low serum albu-min concentration reduces serum oncotic pressure, whichfavors the flow of fluid from the vasculature into the extra-vascular space. Not all patients with cirrhosis have hypoal-buminemia, but those who do may have both ascites andextensive peripheral edema with a relative systemic hypovo-lemia. Ascites from portal hypertension can be distinguishedfrom other causes (hepatoma, pancreatic ascites, biliary asci-tes) by evaluation of a serum albumin ascites gradient. Thisgradient is calculated by subtracting the ascitic fluid albuminvalue from the serum albumin value. If the value of thegradient exceeds 1.1 g per dL, the patient has portal hyper-tension with 97% certainty.10 Patients often have hypona-tremia from retention of free water, induced by elevatedADH levels. Hypokalemia may develop secondary to hyper-aldosteronism or excessive vomiting.

Gastrointestinal Bleeding. GI hemorrhage occurs inabout one fourth to one third of patients. About one third ofthese patients die of the initial hemorrhage. Even nonfatalGI hemorrhages can be massive. The major cause of GIbleeding associated with cirrhosis is shunting of blood awayfrom the high-pressure portal system to low-pressure collat-erals in the esophagus or gastric fundus (esophageal or gas-tric varices respectively), rectum (hemorrhoids), and otherparts of the GI tract. The increased blood flow causes these

veins to become enlarged and tortuous, which means theycan easily rupture. The risk of bleeding can be compoundedby a coagulopathy from a deficiency of vitamin K–depen-dent clotting factors (II, VII, IX, X). Esophageal varicesaccount for about 50% to 60% of the cases of GI bleedingin patients with cirrhosis, while peptic ulcer disease accountsfor another 25%. The presence of varices in the cirrhoticpatient accounts for a 20% higher 2-year mortality rate anda 30% higher 5-year mortality rate.

Hepatic Encephalopathy. Hepatic encephalopathy is aspectrum of neuropsychiatric abnormalities seen in patientswith liver failure. Other neurologic or metabolic causes ofencephalopathy must be excluded first.

Reversal of the day–night sleep cycle (insomnia or hyper-somnia) usually precedes other symptoms. Other manifesta-tions range from forgetfulness, mental confusion, personal-ity changes, hyperreflexia, asterixis (characteristic flappingof the fingers when the hands are dorsiflexed) to somno-lence, confusion, and coma. Hepatic encephalopathy can bedivided into five stages—stage 0, no abnormality; stage 1,mild impairment (insomnia or hypersomnia, reversal ofsleep pattern); stage 2, moderate impairment (slow respon-siveness, lethargy); stage 3, severe impairment (somnolence,confusion, semistupor); and stage 4, coma (stupor, uncon-sciousness).

As the disease progresses, a characteristic sweet, pungentodor (fetor hepaticus) may be present on the patient’s breath.The cause of the odor is unclear but may be related to exhala-tion of mercaptans.

The diagnosis of hepatic encephalopathy may be compli-cated by other neurologic disorders, including alcohol with-drawal-induced tremors, Wernicke’s disease (mental distur-bances, ataxia, and nystagmus from acute thiaminedeficiency), Korsakoff’s syndrome (psychosis and confabu-lation from chronic thiamine deficiency), and cerebellardamage from chronic alcohol ingestion. The presence of as-terixis is a major differentiating factor.

The pathogenesis of hepatic encephalopathy is not wellunderstood, but it may be related in part to increased arterialand central nervous system (CNS) ammonia levels. No directcause-and-effect relationship has been shown between en-cephalopathy and blood ammonia concentration. Elevationof blood ammonia is seen in 60% to 80% of encephalopathicpatients. When factors that influence ammonia productionare decreased, the patient’s sensorium often clears. Ingestionof a protein-rich (more than 70 g per day) diet or bleedinginto the GI tract (e.g., esophageal bleeding) introduces asource of protein into the intestinal tract. Ammonia is pro-duced in the lower GI tract when these proteins and ureaare metabolized by bacterial enzymatic action. The ammoniais then absorbed into the bloodstream. Normally, the liverconverts the ammonia into glutamine and urea for excretionby the kidney, but when the liver is failing or the blood isbeing shunted away from it, as in advanced cirrhosis, serum


ammonia levels increase and encephalopathy ensues. Hypo-kalemia can also contribute to renal ammonia production.

Hypokalemia should be promptly corrected. It is theo-rized that the cerebrotoxicity of ammonia results from inhibi-tion of oxidative metabolism by the citric acid cycle in thebrain. Alpha-ketoglutarate combines with ammonia to pro-duce high CNS levels of glutamine (a byproduct of ammoniametabolism) while robbing the citric acid cycle of the �-ketoglutarate needed for production of high-energy adeno-sine triphosphate (ATP), impairing brain energy metabo-lism. Cerebrospinal fluid (CSF) glutamine levels are occa-sionally measured to confirm hepatic encephalopathy.

An alternative explanation for the pathogenesis of hepaticencephalopathy concerns derangements in plasma and brainamino acid patterns.11–15 Characteristically, there is a rela-tive elevation in methionine and aromatic amino acid (AAA)levels (e.g., phenylalanine, tyrosine, and tryptophan) and acorresponding relative deficiency in branched-chain aminoacids (BCAA; e.g., valine, leucine, and isoleucine). Thesederangements lead to an imbalance of brain neurotransmit-ters, causing elevated levels of serotonin, octopamine, andphenylethanolamine and a decrease in dopamine and possi-bly norepinephrine. Serotonin is an end product of trypto-phan metabolism, whereas phenylethanolamine and octo-pamine are byproducts of phenylalanine and tyrosinemetabolism.

Although the exact reason for these derangements inplasma and brain amino acids is unknown, a number of ob-servations have been made.9–11 The normal ratio of BCAAsto AAAs is 4:1 to 6:1. In both sepsis and liver failure, cata-bolic states lead to a negative nitrogen balance and preferen-tial use of BCAAs as a source of energy. As ammonia levelsrise, glucagon secretion is stimulated, which in turn stimu-lates hepatic gluconeogenesis to convert amino acids intoglucose for energy. In response to gluconeogenesis, insulinis secreted, which leads to increased uptake and metabolismof BCAAs by skeletal muscle. As liver failure progresses,the liver can no longer store or release glucose in adequateamounts, so greater quantities of BCAAs must be metabo-lized by skeletal muscle for energy.

Simultaneously, the plasma clearance of AAAs and me-thionine, which depends on hepatic metabolism, is dimin-ished. The net result is an alteration of the BCAA:AAAratio. In acute liver failure the AAAs rise dramatically whileBCAAs remain normal. In chronic hepatic disease the AAAsremain abnormally high while BCAA concentrations drop tolow levels, further lowering the BCAA:AAA ratio. Althoughcontroversial, BCAA supplementation is used in an effortto restore the BCAA:AAA ratio. If patients are protein intol-erant, this approach may offer some merit.16

In addition to alterations in amino acid metabolism, thereappears to be a derangement of the blood–brain barrier dur-ing chronic liver disease. In people with hepatic encephalop-athy, there is a selective increase in transport of AAAs acrossthe blood–brain barrier, possibly via an exchange of CSFglutamine (from ammonia metabolism) for AAAs in the

plasma. The arterial concentration of ammonia and otheramines may be accentuated by excessive dietary protein con-sumption, GI hemorrhage (source of protein), overdiuresisleading to dehydration, or other conditions that lead to severeelectrolyte imbalance and metabolic alkalosis.

An entirely different avenue of research suggests that the�-aminobutyric acid (GABA) benzodiazepine receptor com-plex is involved in the pathogenesis of hepatic encephalopa-thy.17 GABA is the primary inhibitory neurotransmitter inthe CNS. According to this theory, an increase in CNS GA-BAergic neurotransmission may partially account for the be-havioral and electrophysiologic manifestations of encepha-lopathy. This hypothesis is based on the observation that anaccentuation of CNS inhibitory neurotransmitter tone cancause ataxia, sedation, and coma. Although GABA levelsdo not seem to be elevated in patients with encephalopathy,it is speculated that other endogenous or exogenous GABA-like ligands may be involved. Not surprisingly, these patientsalso demonstrate unusual sensitivity to benzodiazepine-likedrugs that elicit GABAergic-like activity.

Other Associated Disorders. Anemia and other hemato-logic disorders commonly accompany cirrhosis. Chronic al-cohol abusers tend to malabsorb folic acid and iron. In addi-tion, their diets may be deficient in both iron and folate. Irondeficiency may be aggravated by a blocking of iron uptakeinto the bone marrow induced by chronic alcoholism and byslow GI bleeding caused by gastritis. Thrombocytopenia andleukopenia may occur because of folic acid deficiency andalcohol-related bone marrow suppression. Hypersplenism,secondary to portal hypertension, may also contribute.

Endocrine disorders are seen in advanced cirrhosis be-cause of the liver’s inability to metabolize the steroid hor-mones of the adrenals and gonads. In men, increased circu-lating estrogen levels cause gynecomastia, testicularatrophy, loss of male-pattern body hair, impotence, spiderangiomas, and palmar erythema.

The concurrent impairment of renal function with hepaticfailure is called hepatorenal syndrome (HRS). HRS developsin about 4% of patients with decompensated cirrhosis andis associated with a poor prognosis; more than 95% of thesepatients die within a few weeks after the onset of azotemia.HRS is characterized by increased renal vascular resistanceand decreased systemic vascular resistance. The complexhemodynamic changes occur in response to vasoactiveagents that produce different effects on the systemic andrenal circulation. The vasoactive agents and systems in-volved in HRS are the renin-angiotensin-aldosterone system,the sympathetic nervous system, ADH, and the renal prosta-glandin and kinin systems.

HRS may occur acutely or progressively. The acute onsetgenerally occurs in patients with end-stage cirrhosis or withother complications such as encephalopathy, bacterial infec-tions, and bleeding. Clinical symptoms include oliguria thatdevelops within a few days, along with a rapid increase inplasma urea and creatinine levels, tense ascites, dilutional


hyponatremia, hypotension, and jaundice. A slower progres-sive type involving other chronic types of renal conditionsassociated with liver disease exhibits a gradual decrease inglomerular filtration rate that may last for several weeks ormonths. These patients may also demonstrate ascites that ispoorly responsive to diuretics.18

PSYCHOSOCIAL ASPECTS

It is generally accepted that more than 90% of Americansdrink alcohol at some time. The social drug clearly is themost widely abused substance in our society. Problems asso-ciated with the chronic use of alcohol are impressive in theirpathologic magnitude and the costs incurred by society. Forthe alcoholic patient with cirrhosis, psychological therapywith consideration for structured rehabilitation should be acomponent of the overall care plan.

THERAPEUTIC PLAN

Management of cirrhosis is largely symptomatic (Table50.2). Patients with complications of cirrhosis such as asci-tes, hepatic encephalopathy, and esophageal varices shouldreceive appropriate treatment. Treatment of chronic hepatitisB or C may slow the progression of disease. Liver transplan-tation should be considered for patients with end-stage liverdisease. Patients and their caregivers should be referred toa transplant center to determine whether liver transplantationwill be a viable option (see Chapter 27).

All patients with liver disease should refrain from furtheralcohol consumption. Other potentially hepatotoxic drugsshould also be discontinued. Acetaminophen-induced hepa-totoxicity may be more common in alcoholic patients dueto compromised nutritional intake and diminished hepaticreserves. Acetaminophen can be safely used, if the dose islimited to less than 2 g per day. The use of aspirin or nonste-roidal anti-inflammatory drugs may worsen gastritis or pre-cipitate GI bleeding or renal dysfunction. Other analgesics,such as narcotics, may lead to profound CNS and respiratorydepression if liver function is severely compromised or thepatient is obtunded. If the patient experiences nausea, anti-emetics may be used with caution. Phenothiazine-type anti-emetics (e.g., prochlorperazine, promethazine) have been as-sociated with cholestasis and can also cause alteredsensorium. Benzodiazepines, sedatives, hypnotics, and otherdrugs that can alter sensorium should be avoided, as theymay worsen or precipitate hepatic encephalopathy.

TREATMENT

PharmacotherapyVitamin Supplementation. Specific vitamin supple-mentation is essential in most cirrhotic patients, especially

those with a recent history of alcohol abuse. Replacementof thiamine at 50 to 100 mg per day along with a balanceddiet may improve mentation, decrease symptoms of nutri-tional polyneuropathy, and improve gait disorders.

Continuation of thiamine therapy beyond 1 or 2 weeksis of questionable value because it is a water-soluble vitaminwhose stores are rapidly replaced. Up to 1 g per day is occa-sionally needed if the patient displays severe nystagmus,Wernicke’s encephalopathy, or oculogyric crisis. Iron re-placement and folic acid supplements may be needed if thepatient is anemic or folate-deficient. Iron deficiency can bedetermined by a blood smear and measurement of serumiron, total iron-binding capacity, and ferritin concentrations(see Chapter 31).

Vitamin K 10 mg subcutaneously daily for 3 days is givenif the prothrombin time/INR is elevated. Lack of responseto vitamin K implies an impaired synthetic capacity thataccompanies vitamin K deficiency from advanced liver dis-ease. If the prothrombin time/INR is not reversed after threeto five doses of vitamin K, further doses should be avoidedbecause there may be a paradoxical lengthening of the pro-thrombin time from excessive vitamin K. This paradoxicaleffect is thought to be a result of consumptive processesinduced by overstimulation of the production of clotting fac-tors, leading to an eventual depletion of the body stores.Vitamin K1, or phytonadione (AquaMephyton), gives amore rapid response when given parenterally than either vi-tamin K3 (menadione) or vitamin K4 (menadiol). Neithermenadione nor menadiol is available in the United States.If giving phytonadione parenterally, the subcutaneous routeis preferred, but it may also be given by very slow intrave-nous infusion in 50 mL of 5% dextrose in water over 15 to20 minutes. Intramuscular injections are contraindicated ifthe patient has a prolonged prothrombin time/INR or isthrombocytopenic because of the possibility of hematomaand other bleeding complications. Because phytonadione isa colloidal suspension, there is a small risk of developmentof fever, chills, and even anaphylactic reactions with rapidintravenous injection. If the patient is malabsorbing fats oris cholestatic, the absorption of fat-soluble vitamins (A, D,E, and K) from the GI tract may be compromised. Subcutane-ous phytonadione would be the preferred route in this setting.Patients should be assessed for signs and symptoms of vita-min deficiency and should receive vitamin supplementationif found deficient (see Chapter 29).

Ascites. Ascites reversal, especially with drug therapy, isa time-consuming process that entails weeks or months ofconservative management including bed rest to decreaseplasma renin release, sodium restriction (500 mg to 2 g per-day), and, in some cases, fluid restriction. Approximately5% of patients have a spontaneous diuresis with bed restalone, 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 fluidrestriction may lead to decreased renal blood flow and prere-


TABLE 50.2

Drug Reason Dose Monitoring Parameters

(continued)

Drugs Used in Cirrhotic Patients

Thiamine

Vitamin K(phytonadione)

Spironolactone

Loop diureticsfurosemide

Vasopressin

Sodium tetradecylsulfate, ethanolamineoleate, or sodiummorrhuate

Propranolol

Lactulose

Neomycin

Reverse or prevent mentalconfusion secondary tothiamine deficiency(Wernicke’s syndrome)and decreaseperipheral neuropathies

Prevent bleedingsecondary to decreasedproduction of factors II,VII, IX, and X (vitaminK–dependent factors)

Diuresis in ascites;specific for antagonismof preexistinghyperaldosteronism

Diuresis in ascites used incombination withspironolactone

Vasoconstrictor foresophageal bleeding

Sclerosing agents foresophageal varicealbleeding

Prevent GI bleeding

Hepatic encephalopathy;converted to acids tolower bowel pH andprevent absorption ofNH3

Hepatic encephalopathy;sterilizes gut to preventbacterial breakdown ofprotein and thusdecreases serum NH3levels

100–200 mg/day,occasionally higher

10 mg/day, not to exceed3 doses

100–400 mg/day,occasionally higher; maybe given as a single dailydose

Start at 40 mg, titrate to 1-kg weight loss per day;occasionally very highdoses (200–600mg/day) needed

0.2–0.4 units/min IVinfusion

0.5–2 mL of 1–1.5%tetradecyl, 5%ethanolamine, or 5%sodium morrhuatesolution in each varixabout 2 cm apart

20–320 mg/day titrated to55–60 bpm resting pulserate if tolerated

20–30 g QID or 300 mLlactulose QS to700–1,000 mL as rectalenema titrated to 3–4 softstools per day

2–6 g/day, orally orrectally

Mental statusDecrease in nystagmus, peripheral

neuropathies; �10 days oftherapy is unwarranted

Hypersensitivity (fever, chills,anaphylaxis, flushing, sweating)

Prothrombin time/INR

Weight (avoid more than 1-kgweight loss per day)

Mental statusSerum K�

Urine Na� and K� (Na� shouldnot exceed K� at therapeuticdoses)

Abdominal girthBlood urea nitrogen (increased in

dehydration)Gynecomastia (prolonged use)Blood pressureSame as spironolactone except

urine electrolytes are of no valuePossible hearing loss with rapid IV

bolus

Rate of GI bleedingSigns of ischemia (chest pain,

elevated blood pressure,bradycardia)

GI crampingSerum Na�

Signs of GI bleedingChest pain, fever, local ulceration

Signs of GI bleedingMental changesVital signs: pulse, blood pressureSigns of congestive heart failure,

bradycardiaSigns of bronchospasmRenal functionMental status, liver flap (asterixis),

diarrhea

Mental status, liver flap (asterixis)Diarrhea, bacterial overgrowthRenal functionSigns of ototoxicity


TABLE 50.2

Drug Reason Dose Monitoring Parameters

aNot recommended for all patients. bInvestigational use only; efficacy unclear.

continued

Rifaximinb

Hepatamine, Hepatic-Aid, andNutihepa

Dopaminea

Colchicinea,b

Cefotaxime,norfloxacina,ciprofloxacin,trimethoprim/sulfamethoxazole

Flumazenila,b

Octreotide

Midodrine

Hepatic encephalopathy;decreases ureaseproducing, bacteria

Hepatic encephalopathy;replace branched-chainamino acids

Hepatorenal syndrome

Anti-inflammatory andantifibrotic effects

Treatment or prevention ofspontaneous bacterialperitonitis

Acute reversal of hepaticencephalopathy

Treat GI bleeding

Hepatorenal syndrome(investigational use)

400 mg orally three timesdaily

Titrate to caloric andnitrogen needs

1–4 �g/kg/min

0.6 mg PO BID or 1 mg POQD 5 days/wk

Norfloxacin 400 mg dailyor 400 mg BID(ciprofloxacin 750 mgweekly, TMP/SMX 1 DSQD, M through F)

0.2–0.4 mg titrated toresponse

50-�g bolus, 50–200-�g/hrinfusion for 5 days

Dosed orally to maintainincrease of 15 mm Hg inmean arterial pressure

Mental status,liver flap (asterixis)

Mental statusSerum ammonia, cerebrospinal fluid

glutamineSerum amino acid levels (branched-

chain: aromatic amino acid ratio)Electrolyte balanceMental status, liver flap (asterixis)Urine outputBlood pressureNausea, abdominal pain, diarrhea

Reduction in incidence of SBP

Reversal of mental obtundation

DiarrheaImprovement in GI bleedingBlood pressureGlomerular filtration rateRenal sodium excretion

nal azotemia. Hospitalization usually is recommended forrefractory patients for the following reasons: intensive edu-cation on medications and diet; close monitoring of serumand urine electrolytes, urea nitrogen, and creatinine; and in-vestigation of the cause of the liver disease.

Diuretics are the cornerstone of drug therapy for the treat-ment of ascites. Diuresis must be slow and controlled tominimize complications. If urinary losses exceed the volumeof fluid reabsorbed from ascites or peripheral edema, volumedepletion with hypotension and renal insufficiency can de-velop. In patients treated with sodium restriction alone, nomore than 300 mL of ascites can be reabsorbed per day.Even with the use of a diuretic, the maximum rate of reab-sorption is 1,440 mL per 24 hours.19,20 Diuresis should belimited to 0.2 to 0.3 kg weight loss per day in those withoutedema and 0.5 to 1 kg per day in patients with edema. Othersallow a slightly more liberal diuresis of 0.75- to 2-kg weightloss per day.20 These recommendations assume that eachliter of volume lost is equivalent to a 1-kg weight loss. Inpatients with concurrent peripheral edema, a greater diuresismay be acceptable for the first 1 to 2 days because peripheraledema equilibrates more readily with the vasculature thandoes ascitic fluid. Other monitoring parameters include urineoutput, changes in abdominal girth, postural blood pressures,blood urea nitrogen, serum creatinine, increase in the urine-

potassium:sodium ratio from pretreatment baseline, andmental status changes.

Although slow diuresis with any diuretic may be accept-able for treating ascites, typically the first diuretic given isspironolactone with or without furosemide. Spironolactoneis a gentle, slow-acting diuretic that antagonizes the effectsof the hyperaldosteronism that exists in many of these pa-tients. In contrast to the small doses of spironolactone thatare used as an adjunct in hypertension and congestive heartfailure, the initial dose for the treatment of ascites is usually50 to 100 mg per day. A 3- to 5-day lag period exists forthe onset and maximum response from spironolactone, sofrequent dose adjustments prior to this time period shouldbe avoided. Doses are titrated upward in 50- to 100-mg incre-ments every 3 to 5 days, with 400 mg per day being requiredin approximately 75% of patients. The delayed onset andlong duration of spironolactone result from the long half-life (approximately 17 to 20 hours) of its active metabolite,canrenone. For patient convenience and to improve compli-ance, once-daily dosing is recommended. Multiple dailydoses are not necessary unless the patient cannot swallowthe necessary number of tablets at one time without gastricdistress.

Other concomitant diuretics such as furosemide offer anadditional mechanism of diuresis. Runyon et al advocated


the use of furosemide initially or early in treatment in a ratioof 40 mg to every 100 mg of spironolactone, given oncedaily in the morning to avoid nocturnal diuresis.21 An addedadvantage of this combined approach is to maintain potas-sium balance in the face of diuresis.

Triamterene (Dyrenium) and amiloride (Midamor) arepotassium-sparing diuretics that have a slightly more rapidonset of action, but they are not specific inhibitors of aldoste-rone. The relative efficacy of these potassium-sparing di-uretics compared to spironolactone has not been evaluatedextensively. They may be useful in patients who developgynecomastia with spironolactone. The new and more selec-tive aldosterone antagonist eplerenone (Inspra) is associatedwith less gynecomastia, but it has not been adequately stud-ied in this patient population.

Besides the general monitoring parameters cited for di-uretic therapy, serum and urine electrolyte levels, especiallypotassium, must be monitored. If hyperaldosteronism ispresent, it is not uncommon to see very little or no urinarysodium excretion and large urinary potassium losses. Onemeasure of having achieved the desired spironolactone doseis a reversal of the urine electrolyte pattern to normal (i.e.,sodium loss greater than potassium loss). Patients with urinesodium:potassium ratios greater than 1 tend to respond tolower doses of spironolactone (100 to 150 mg per day); thosewith ratios less than 1 often need larger doses, averaging400 mg per day.9

Hyperaldosteronism, if present, may also cause a reduc-tion in the serum potassium concentration. Although the useof spironolactone with potassium supplements is usuallycontraindicated in treatment of other diseases because of ahigh risk of inducing hyperkalemia, this combination maybe necessary early in the treatment of ascites, especially ifthe patient has additional GI losses of potassium secondaryto vomiting or diarrhea. Serum potassium must be monitoreddaily to avoid hypokalemia or hyperkalemia. Because thesepatients often are placed on a low-sodium diet, the use ofsalt substitutes that contain potassium use should be discour-aged to further limit the complexity of potassium supplemen-tation in this setting. Long-term use of spironolactone in-creases the risk of gynecomastia, a problem that is commonin cirrhosis independent of diuretic use. Patients should beinformed of this side effect of spironolactone.

High doses of spironolactone alone may not produce thedesired diuresis in some patients or may cause hyperkalemia.In this situation, the addition of more potent diuretics suchas thiazides or loop diuretics may be warranted. Some pa-tients are especially refractory, often requiring severalhundred milligrams per day of furosemide to obtain the de-sired weight loss of 0.5 to 1 kg per day. One drawback tothe use of thiazides and loop diuretics is that they cause asignificant natriuresis, which interferes with the ability tointerpret urine electrolytes. Intravenous furosemide shouldbe avoided if possible because it can decrease glomerularfiltration rates and adds additional unnecessary cost.22 Use ofnonsteroidal anti-inflammatory drugs and COX-2 inhibitors

should be avoided because they may blunt the effects ofdiuretics 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 abdominaldistention, has traditionally been discouraged because of therisk of abdominal perforation and infection. If a large volumeis removed, 15% to 100% (mean 58%) of the fluid mayreaccumulate over the next 24 to 48 hours, leading to tran-sient hypovolemia and the possibility of shock, encephalopa-thy, or acute renal failure.19

More recently, the combination of a therapeutic paracen-tesis with or without intravenous albumin infusion (to main-tain volume in the vascular space) has become an acceptedmode of therapy.23–26 A typical regimen is the removal of4 to 6 L per day via paracentesis, with replacement of 40 to50 g albumin after each paracentesis (approximately 10 to12.5 g of albumin per liter of ascites fluid removed). Paracen-tesis with albumin replacement is superior to diuretic ther-apy; it decreases ascites faster and shortens the hospital staywithout significant worsening of hepatic, renal, or cardiovas-cular function. Single large-volume (about 5 L) paracentesiswithout albumin replacement also appears to be safe in pa-tients with painful, tense ascites,27 but repeated large-volumeparacentesis without albumin replacement may result in hy-ponatremia or renal impairment in some patients.24 Anotherpossible concern is an increased risk of spontaneous bacterialperitonitis secondary to reduced ascitic fluid opsonic activ-ity.21 Arguments about the high cost of albumin are counter-balanced by the decreased length of hospital stay. The useof dextran as a volume expander after paracentesis has beenevaluated as an alternative to albumin.23 It has been shownto help prevent the asymptomatic abnormalities in laboratoryvalues at a lower cost,22 although its use remains controver-sial.28,29 Albumin has also been used without paracentesisin an attempt to increase intravascular volume and inducediuresis. The drawbacks to this treatment are a short durationof response, the risk of inducing variceal hemorrhage, andhigh cost. Generally, treatment with albumin without para-centesis is to be avoided unless all other therapies havefailed. In Europe, ascites recirculation (removal, concentra-tion, and reinfusion of peritoneal fluid) has been found tobe safe and effective.30 The possibility of reaccumulation ofascites after paracentesis necessitates continuation of a low-sodium diet and diuretics.

The peritoneovenous (LeVeen or Denver) shunt, in useextensively for the past 20 to 25 years, was devised for usein diuretic-refractory ascites.31,32 This type of shunt consistsof a surgically implanted one-way valve in the abdominalwall, an intra-abdominal cannula, and an outflow tube tun-neled subcutaneously from the valve to a vein that emptiesdirectly into the inferior vena cava. As the diaphragm de-scends, the pressure in the intrathoracic veins drops and in-traperitoneal pressure rises. This pressure differential pushesascitic fluid via the shunt into the venous system. The resultsmay be dramatic, with urine output as high as 15 L occurringduring the first 24 hours. Supplemental diuresis with furose-


mide may be needed to prevent vascular overload. However,use of this procedure is limited by such complications asfever, shunt occlusion, hypokalemia, infection, shunt leak,disseminated intravascular coagulopathy, and less often vari-ceal hemorrhage, bowel obstruction, pulmonary edema, andpneumothorax.31 A Veterans Administration Cooperativestudy involving 3,860 patients showed a lack of improve-ment in survival and significant morbidity rates in patientstreated with a peritoneovenous shunt compared with thosetreated with diuretic therapy.32 However, shunting alleviateddisabling ascites more rapidly than medical management did.

A more widely accepted shunting approach is the trans-jugular intrahepatic portosystemic shunt (TIPS). A transjug-ular approach is used to place a stent within the liver thatcreates a low-resistance conduit between a branch of theportal vein and the hepatic vein. Blood will flow directlythrough the TIPS and decompress the portal venous system.Adverse effects of the TIPS include worsened hepatic en-cephalopathy, hepatic ischemia, and bleeding. The value ofthe TIPS in refractory ascites has been evaluated. In thisstudy, the TIPS in combination with medical treatment wasproven superior to medical management alone; however, theTIPS did not improve either survival or the quality of life.33

These relatively aggressive shunting options are generallyreserved for patients with ascites refractory to medical inter-vention.

Spontaneous Bacterial Peritonitis. Spontaneous bacte-rial peritonitis (SBP) is infection of the ascitic fluid in theabsence of an intra-abdominal source (e.g., bowel perfora-tion or abscess). SBP occurs in approximately 30% to 40%of cirrhotic patients.34 Although some patients are asymp-tomatic, commonly observed signs and symptoms includefever, chills, vomiting, abdominal pain or tenderness, de-creased bowel sounds, worsened renal function, and enceph-alopathy. The diagnosis of SBP is made by evaluating asmall sample of the ascitic fluid. A polymorphonuclear cellcount greater than 250 cells per cubic millimeter of asciticfluid or a positive bacterial culture is diagnostic for SBP.35,36

SBP is thought to be the consequence of alterations inthe immune defense of patients with advanced liver disease.It is believed that the gut is the main source of infectingbacteria in SBP; however, hematogenous spread from theurinary or respiratory tract or skin can occur. Bacterial trans-location (passage of bacteria from the lumen of the GI tractto extraintestinal sites such as the peritoneum) is an impor-tant step in the pathogenesis of SBP. Bacterial overgrowthand bowel wall edema from portal hypertension contributeto the translocation of bacteria. Mesenteric lymph nodes andthe hepatic reticuloendothelial filtering system would nor-mally 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 op-sonization and phagocytosis by macrophages further con-tribute to infection of the ascitic fluid.35

Predisposing factors for SBP include a previous episodeof SBP, the severity of underlying liver disease, GI hemor-rhage, and an ascitic fluid total protein concentration of 1 gper dL or less.

Enteric gram-negative bacilli such as Escherichia coliand Klebsiella pneumoniae, and Streptococcus pneumoniaeare the most common organisms seen with SBP. Anaerobicbacteria, Pseudomonas sp, Staphylococcus sp, and fungi arenot common pathogens in SBP. Infection in SBP is usuallymonobacterial. If multiple species of bacteria or anaerobicbacteria are cultured, secondary bacterial peritonitis (e.g.,bowel perforation) should be considered.

Empiric therapy has traditionally been ampicillin or afirst-generation cephalosporin in combination with an ami-noglycoside. More recently, the use of less toxic alternativeagents such as ampicillin/sulbactam, ticarcillin/clavulanate,piperacillin/tazobactam, second- and third-generation cepha-losporins, and quinolones have also resulted in favorableoutcomes. Caution is advised with the use of cefotetan andother cephalosporins with a methylthiotetrazole (MTT) sidechain, which can interfere with vitamin K and cause a hypo-prothrombinemic state. Cefotaxime 2 g every 8 hours is gen-erally accepted as the current drug of choice for SBP.37,38

The antibiotic regimen should be tailored based upon cultureand sensitivity results. Duration of therapy is approximately5 days because of the relatively low inoculum of organismsin the ascitic fluid.39 Administration of intravenous albuminin patients with SBP has been shown to reduce the mortalityrate and decrease the incidence of renal dysfunction.

SBP is associated with significant morbidity and mortal-ity. Recurrence of SBP is common following treatment.Long-term prophylaxis with antibiotics to prevent recurrentSBP has been evaluated in several clinical trials. Norfloxacin400 mg once daily has been used successfully in high-riskpatients. This fluoroquinolone results in a selective intestinaldecontamination that decreases gram-negative bacilli butpreserves the remaining normal flora. Norfloxacin has beenshown to markedly reduce the incidence of SBP in patientswith previous episodes of SBP.40 Twice-daily dosing for thefirst 7 days of a prophylaxis regimen may be needed in pa-tients experiencing a GI hemorrhage.41 Other regimens suchas trimethoprim/sulfamethoxazole 1 double-strength tabletdaily given 5 days per week or ciprofloxacin 750 mg oncea week have been shown to be effective in preventingSBP.42,43 When a fluoroquinolone is chosen, it is importantthat concomitant administration with medications containingdivalent and trivalent cations be avoided to minimize thedrug–drug interaction.

Gastrointestinal Bleeding. Bleeding from esophageal orgastric varices is one of the most feared complications ofportal hypertension. Variceal hemorrhage is a grave sign andmay be difficult to stop. Mortality from a single bleedingepisode is approximately 17% to 57%.44

Varices are portosystemic collateral veins that are dilateddue to portal hypertension. Varices are present in up to 60%of patients with cirrhosis, but bleeding occurs in only about


one third of patients. Factors associated with increased riskofa variceal hemorrhage include continued alcohol consump-tion, poor liver function, and large varices seen on endos-copy.

In the setting of an acute bleed, multiple blood transfu-sions and intravenous fluids may be necessary to maintaincirculatory volume. Balloon tamponade, pharmacologictherapy, and endoscopic intervention are methods to stopbleeding.

Application of direct pressure with a balloon tube (Linton,Minnesota, or Sengstaken Blakemore tube) that can be in-flated in the esophagus and/or stomach can slow bleeding.As the balloon is inflated, the varix is compressed betweenthe balloon and the esophageal wall, slowing or even stop-ping bleeding. While bleeding is stopped in 40% to 80% ofpatients, it is only a temporary measure. This procedure iscomplicated by vomiting, a high risk of aspiration, ischemiaof the esophageal mucosa, perforation, and recurrence ofbleeding as soon as the balloon is deflated.

Endoscopic therapies include sclerotherapy and varicealligation. Injection of sclerosing agents into esophageal vari-ces has revolutionized the care of patients with bleedingvarices.45–50 This approach is considered by many to be thetherapy of choice. The most commonly used sclerosingagents in the United States are sodium tetradecyl sulfate(Sotradecol), ethanolamine oleate (Ethamolin), and sodiummorrhuate (Scleromate). Injection of these agents into ableeding varix leads to an intense inflammatory response,thrombus formation, and cessation of bleeding within 2 to5 minutes. A more permanent fibrotic obliteration of thevessel develops over several days.

Sclerotherapy controls acute variceal bleeding in 90% to95% of patients.45 A single treatment controls bleeding in90% of patients; the remainder may require multiple treat-ments over several weeks.

Success rates are lower in actively bleeding patients thanin those in whom bleeding was controlled initially by moreconservative methods. Failure of therapy is defined as con-tinuation of bleeding after two injections of a sclerosingagent during a single admission.51 Compared with portacavaland splenorenal shunt procedures, sclerotherapy is almostequally effective in stopping bleeding, there is no differencein survival, and there is much lower morbidity.47,48 Prophy-lactic sclerotherapy in patients with endoscopic evidence ofvarices but no history of past or current bleeding is of noclinical benefit.49,50

A 0.5% to 3% solution of tetradecyl sulfate or a premixedsolution of ethanolamine 5% or morrhuate 5% for injectionis used. After the endoscope is passed, approximately 0.5 to2 mL of the sclerosing solution is injected into each varixat points about 2 to 4 cm apart. If bleeding recurs, therapycan be repeated. Although it appears that sclerotherapy iseffective in stopping acute bleeding and preventing rebleed-ing, more than 50% of patients will rebleed, and the long-term mortality is not lower than with conventional therapy.Side effects associated with sclerotherapy include pericardi-

tis, chest pain, dysphagia, pyrexia, cardiac tamponade, for-mation of esophagobronchial or tracheoesophageal fistulas,and local ulcerations.

Following sclerotherapy, prophylaxis with antacids, his-tamine-2 (H2) antagonists, proton pump inhibitors, or sucral-fate may be initiated. Dosing of these drugs is the same asthat recommended for treating peptic ulcer disease or refluxesophagitis (see Chapter 45). Careful monitoring of mentalstatus in those who are treated with cimetidine is warrantedbecause cirrhosis may predispose patients to the mental con-fusion associated with this agent.52 With the available acid-suppressing alternatives, one could make an argument foravoiding cimetidine altogether in this setting. The pharmaco-kinetics of ranitidine may also be altered in cirrhosis, result-ing in its accumulation.53 Sucralfate suspension has beenused to prevent ulcers at the sclerosis site. Investigators usingendoscopy have shown that the drug complex seems to coatthe varices, decreasing ulcer formation.54 The aluminumcomponent of sucralfate may complex with coadministerednorfloxacin or ciprofloxacin, resulting in poor absorption.The importance of divalent and trivalent cations complexingwith quinolones could be questioned in SBP prophylaxisbecause of local intestinal rather than systemic action. How-ever, because the complex does not enter bacteria as well,55

it is prudent to space the administration of these agents evenwith SBP prophylaxis.

A newer endoscopic technique for control of varicealbleeds 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 smallrubber band over a distal varix. A large varix is drawn bysuction aspiration into the end portion of the sleeve, and therubber band is released over the base of the varix. A speciallymodified endoscope that carries a triggering device and rub-ber band on a small sleeve over the objective end of thescope is required. Endoscopic variceal banding therapy hasa control rate of 86% for acute bleeding. It has also beenassociated with a lower complication rate, although the riskof rebleeding may be slightly higher than with sclero-therapy.57,58

Historically, the hormone vasopressin (ADH) was usedto treat bleeding varices before the advent of sclerotherapyand octreotide. Vasopressin decreases portal blood flow andpressure by constricting portal and other splanchnic arteri-oles. This slows or stops bleeding long enough to allowthrombus formation at the site of bleeding in 60% to 80%of patients. The use of this drug is declining and it remainscontroversial because the benefits in terms of morbidity andmortality have never been proven.59 Sclerotherapy has beenshown consistently to be more effective than vasopressin,but vasopressin may be given first to slow bleeding andfacilitate endoscopic visualization of the bleeding varix.

The major limitation to vasopressin therapy is its sideeffects. The intense vasoconstriction decreases cardiac out-put and may cause coronary ischemia. This is especiallyproblematic in patients with coronary artery disease or hy-


pertension; however, ischemic changes have also been re-ported in patients with no prior evidence of ischemic disease.Bradycardia caused by stimulation of the vagus nerve is themost widely observed side effect of vasopressin. It may alsoproduce skin blanching, GI cramping, and even bowel necro-sis. Women may experience uterine pain similar to menstrualcramps. Finally, vasopressin may lead to excess water reten-tion and a dilutional hyponatremia.59

A continuous intravenous infusion starting at 0.2 to 0.4units per minute and direct intra-arterial infusion via a cathe-ter into the superior mesenteric artery at 0.05 to 0.4 unitsper minute have been tried. The maximum recommendedintravenous infusion rate is 0.9 units per minute. Infusionsmay be continued for up to 72 hours, with a slow taperingof the dose over time. The results have been varied, withsome authors claiming up to 50% to 70% effectiveness.59

Others claim poor response and a high incidence of compli-cations, including bleeding from the site of catheter insertionand septicemia.60

A combination of vasopressin infusion and intravenousnitroglycerin (10 to 50 �g per minute titrated according toblood pressure to a maximum of 400 �g per minute)61 orsublingual nitroglycerin (0.6 mg every 30 minutes for 6hours)62 may cause an additional decrease in portal pressure.In the study using intravenous nitroglycerin, there was lessbleeding with combination therapy; in the trial with sublin-gual nitroglycerin, the rate of bleeding cessation was equalto that with vasopressin alone. In both studies, combinationtherapy led to a marked reduction in cardiac complications.

Somatostatin and its analogue, octreotide, have also beenevaluated in controlling variceal bleeding. Somatostatin re-duces portal pressure and blood flow after a bolus dose fol-lowed by continuous intravenous administration. It offers ef-ficacy equal to that of vasopressin, with considerably fewerside effects.63 Its use is limited only by its higher acquisitioncost.47,64 Somatostatin dosing consists of a 250-�g bolus fol-lowed by an infusion of 250 �g per hour. The equally effectivesomatostatin analogue, octreotide, is dosed with a 50-�gbolus and continued as an infusion at a rate of 50 �g per hourfor 5 days. Octreotide is considered the agent of choice in themanagement of acute variceal bleeding used alone and withendoscopic sclerotherapy or banding.65,66

Bleeding from other GI sites, especially bleeding causedby gastritis and peptic ulcer, usually is treated with nasogas-tric suction, H2 receptor antagonists, or proton pump inhibi-tors or hourly antacids.67 Occasionally, 20 units of vasopres-sin, 1 to 2 (4 to 8 mg) ampules of norepinephrine, or ice isused in a gastric lavage to cause localized vasoconstrictionin an attempt to slow bleeding. No evidence documents theselatter maneuvers to be any more effective than tap waterlavage or acid suppression alone; therefore, their use is gen-erally discouraged.

It has been suggested that because propranolol, nadolol,and possibly other nonselective �-adrenergic blockers de-crease portal venous pressure, they may prevent GI bleedingassociated with portal hypertension.68–73 Primary prophy-

laxis is defined as treatment of patients with known varicesbut without a history of active bleeding. Secondary prophy-laxis involves administering the drug after resolution of anacute bleeding episode to prevent subsequent bleeding. Al-though data are limited, overall analysis of the benefit ofprimary therapy is positive.68–70 For example, in the Euro-pean Cooperative study group, after a median dose of 160mg per day (range 40 to 320 mg), 74% of patients in thepropranolol group were free of bleeding after 2 years, com-pared with 39% in the placebo group. Two-year survivalwas 72% in the treated patients and 37% in the untreatedsubjects.70 Propranolol also appears to be a cost-effectiveapproach, with savings between $450 and $14,600 over 5years in 1997 dollars.71

The results for secondary prophylaxis are also encourag-ing but somewhat more complex. Lebrec et al72 showed thatoral propranolol in doses that reduced the heart rate by 25%to a resting rate of 50 to 60 beats per minute led to a signifi-cantly lower frequency of rebleeding than did placebo, dur-ing a 2-year study in chronic alcoholic patients with a historyof esophageal bleeding. Only 21% of patients in the propran-olol group had recurrence of bleeding, compared to 68%in the placebo group. Cumulative survival was 90% in thepropranolol group and 57% in the placebo group. None ofthe patients showed deterioration of hepatic or renal functionwhile taking propranolol. Because propranolol may decreasecardiac output and liver blood flow, patients should be moni-tored closely.

A similar study by Burroughs et al73 failed to confirmthe findings of Lebrec. However, the patients in Burroughset al’s study had more severe liver disease and some hadcirrhosis from causes other than chronic alcoholism. Selec-tive �-blockade with atenolol or metoprolol appears to beless effective than sclerotherapy in arresting acute varicealbleeding.68,69

A follow-up study by Poynard et al74 confirmed the bene-fits of propranolol, with 71% of subjects free of bleeding at1 year and 57% at 2 years. In this study, five factors wereidentified that increased the risk of rebleeding: hepatocellu-lar carcinoma, continued alcohol abuse, lack of suppressionof pulse rate by propranolol, a history of rebleeding, andnoncompliance with drug therapy. Of particular concern, 12of 14 (86%) patients who discontinued �-blocker therapyabruptly had an episode of rebleeding. The time of greatestrisk for rebleeding is within the first 3 to 4 days after stoppingtherapy, but it may occur up to 150 days later.68,69,74–76 Itis not possible to be certain that drug discontinuation is re-sponsible for rebleeding in the delayed rebleeding cases.

A randomized controlled study by Teres et al77 in Barce-lona compared sclerotherapy with propranolol in the preven-tion of rebleeding for varices. Although the incidence ofrebleeding was less with sclerotherapy (26 of 58 subjects)than with propranolol (37 of 58 subjects) titrated to reducethe resting heart rate by 25%, complications were signifi-cantly more common and of greater severity with sclerother-apy. The authors could not recommend either approach onthe basis of the study findings.


Another published trial compared isosorbide-5-mononi-trate with propranolol in long-term follow-up (128 patientsfollowed up over 7 years). Isosorbide-5-mononitrate was aseffective as propranolol in reducing mortality.78 Additionalperspective on this approach was offered in an accompany-ing editorial.79 However, at least one trial comparing isosor-bide mononitrate to nadolol showed a greater risk of bleedingwith the nitrate.80 Currently, �-blockade alone seems moreestablished and safer than nitrates when used alone or whencombined with �-blockade. Because patients with cirrhosisoften have a low blood pressure, �-blockers should alwaysbe used with extreme caution.

Surgical treatment may be needed for patients who haverepeated GI bleeding (especially esophageal varices) orthose who have bleeding that cannot be stopped by the moreconservative measures already described.45 A portacavalshunt involves anastomosis of the portal vein directly to theinferior vena cava, thus bypassing the cirrhotic liver. Thissurgical procedure decreases portal hypertension. Unfortu-nately, these patients often have a poor prognosis becausethe blood that normally flows to the liver for detoxificationand metabolism is now shunted away from the liver. If theysurvive the initial surgery, patients may die of sepsis or de-velop hepatic failure and encephalopathy. The Warren (distalsplenorenal) shunt decompresses the varices by shuntingsplenic blood flow to the renal vein and does not alter hepaticperfusion as much. The TIPS procedure also effectively de-compresses the portal system and is an option in the treat-ment of and prevention of variceal bleeding.

Hepatic Encephalopathy. Clinical manifestations of he-patic encephalopathy should be recognized and addressedpromptly, because most are reversible with appropriate ther-apy.81 If the patient exhibits signs of hepatic encephalopathy(e.g., confusion, drowsiness, asterixis), lactulose is indi-cated, as well as dietary protein restriction to approximately0.8 to 1 g per kilogram per day. Use of CNS depressants(e.g., benzodiazepines, narcotics) should be minimized oravoided; this is especially true of benzodiazepines. Exceptfor cautious use of spironolactone or furosemide, diureticsusually should be withheld at this stage because hypovo-lemia, hypokalemia, and metabolic alkalosis may aggravateencephalopathy.

Lactulose is a synthetic disaccharide of galactose andfructose that is neither absorbed nor hydrolyzed in the smallbowel. It is degraded by colonic bacteria to lactic, acetic,and formic acid, thus lowering the pH of the colonic con-tents. The effect of lactulose was originally attributed toreplacement of proteolytic bacteria such as E. coli, Proteus,and Bacteroides with organisms such as Lactobacillus thatthrive in a more acidic medium and lack urease and otherenzymes that are used in the production of ammonia. How-ever, most investigators have not found a marked change inthe colonic flora and have attributed the effects of lactulosesolely to the change in pH of the colonic contents. As thecolon becomes more acidic, this favors the conversion from

ammonia to ammonium. Ammonium is a charged particleand is not absorbed. There may also be back-diffusion ofammonia from the blood to the intestinal lumen under acidicpH conditions. Regardless of which mechanisms are in ef-fect, lactulose therapy results in a decrease in arterial ammo-nia levels.82

Each 15 mL of lactulose oral liquid contains 10 g lactu-lose; it is usually given in a dose of 30 to 40 mL three orfour times daily (approximately 45 to 90 g per day). Reten-tion enemas of 300 mL of lactulose syrup diluted with 700mL of tap water can also be used.83 The onset of effect byeither route is 12 to 48 hours, with an endpoint of two orthree loose stools daily and an improvement in mental capac-ity. The success rate with lactulose has been reported to bearound 85%. Patient tolerance can be improved by dilutingthe drug in water, fruit juice, or carbonated beverages. Pa-tients may require prolonged therapy to prevent recurrenceof symptoms.

The most common complaints of patients treated withlactulose are nausea (because of the sweet taste of the drug),gaseous distention, bloating, belching, or diarrhea caused byosmotic effects in the bowel. Diarrhea may account for partof the therapeutic effects of lactulose by flushing out tox-ins,84 but compared with sorbitol, lactulose is more effectivein treating the encephalopathy, indicating that other mecha-nisms are working such as decreasing ammonia levels. Ex-cessive diarrhea may lead to dehydration and electrolyte ab-normalities such as hypernatremia. Patients should beclosely monitored during lactulose therapy to avoid thesefluid and electrolyte abnormalities.

Neomycin, an alternative to lactulose, is an aminoglyco-side antibiotic that kills the urease-producing bacteria in thecolon, 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 2to 4 g per day. For patients who cannot take medicationsorally, a retention enema of 2 to 4 g in 200 mL of salinethickened with methylcellulose may be used twice a day.

One well-controlled study failed to show a clear superior-ity of neomycin (83% effective) or lactulose (90% effective)in treating acute encephalopathy. For long-term use, lactu-lose has the potential advantage of less toxicity, but it isconsiderably more expensive.85 The possibility that steriliza-tion of the gut by neomycin might decrease the effectivenessof 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 theGI tract, approximately 1% to 3% of a dose is absorbed.79

Neomycin can cause nephrotoxicity and ototoxicity in pa-tients on chronic therapy.88,89 Most of these patients hadbeen taking neomycin for at least 8 months and had coexist-ing renal dysfunction. An auditory test should be performedat baseline and annually to assess for hearing impairment.

Other oral antibiotics that have been evaluated with somesuccess include metronidazole, vancomycin, and rifaximin,a derivative of rifamycin.81


There are multiple approaches to the management of he-patic encephalopathy. Avoiding the use of drugs that canalter sensorium is of paramount importance. Lactulose istypically the drug of choice. Neomycin or rifaximin are alter-natives for patients who are intolerant to lactulose or inwhom the effects of lactulose are waning. Dietary interven-tions such as protein restriction and avoiding large proteinloads are also useful.

Therapeutic Value of �-Aminobutyric Acid Antagonists.Some investigators believe that endogenous or exogenousGABAergic-like compounds that stimulate the GABA–ben-zodiazepine receptor complex in the brain may be responsi-ble for symptoms of encephalopathy.17,90 Preliminary datasuggest that the benzodiazepine antagonist flumazenil maybe valuable in both short-term and long-term managementof hepatic encephalopathy.

In 14 subjects, 71% showed short-term improvement insymptoms after intravenous administration of flumazenil.91

Arousal was greatest in patients with deeper coma (stage IIIor IV encephalopathy). Although response was rapid, theduration of effect was only 1 to 2 hours. The usual dose was0.2 to 0.4 mg, with some subjects receiving up to 10 doses.

A single case report describes the long-term use of oraltherapy.92 A patient given 25 mg twice daily experiencedcomplete reversal of symptoms for 14 months. Previously,this patient had experienced 12 episodes of coma over a2-year period. Discontinuation of the drug led to a recurrenceof symptoms within 48 hours.

A randomized double-blind placebo-controlled crossovertrial from Canada showed a significant clinical improvementin 5 of 11 (45%) patients with hepatic coma receiving fluma-zenil in the initial treatment phase and 1 of 2 (50%) in thecrossover phase of the study. The authors concluded thatthe agent is efficacious and safe for reversing neurologicsymptoms in cirrhotic patients with hepatic coma.93 Thistrial has been criticized.94 A recent analysis of this approachhas also shown efficacy, but it is short-lived and not associ-ated with mortality reduction. Thus, the use of a benzodiaze-pine receptor antagonist in these patients remains investiga-tional and controversial95 and is not the standard of care.

Therapeutic Value of Corticosteroids. Cirrhotic pa-tients with biopsy-proven alcoholic hepatitis may benefitfrom the anti-inflammatory effects of corticosteroid therapy.The beneficial effect may be related to the corticosteroid’sinhibition of cytokine production.

The efficacy of steroids in treating liver disease remainscontroversial. Clinical trials have shown conflicting resultswith regard to mortality. A meta-analysis of the randomizedtrials was completed to determine the efficacy of steroidson short-term mortality in patients with alcoholic hepatitis.The combined data indicated that steroids provide a protec-tive efficacy of 27% in patients with hepatic encephalopathy.This figure increased in patients without active GI bleeding.Among subjects without hepatic encephalopathy, steroidshad no protective efficacy. These data suggest that only pa-

tients with severe disease would benefit from steroid ther-apy. Patients with severe disease are defined as those withhepatic encephalopathy or a discriminant function higherthan 32 [discriminant function � 4.6 (Patient’s prothrombintime � control prothrombin time) � bilirubin]. Patientswith severe disease who have active GI bleeding or needtreatment for active infection should be excluded from ste-roid therapy.96

Prednisolone is the most studied and appears to be thepreferred corticosteroid. The typical dosing regimen is 40mg per day for 4 weeks and is then tapered over 2 to 4weeks.97 Overall, the available data on this subject are lessthan consistent in their conclusions and outcomes. TheAmerican College of Gastroenterology consensus positionon steroid use in hepatitis related to alcohol was recentlypublished.98

Hepatorenal Syndrome

Therapeutic Value of Vasoactive Agents. HRS is the de-velopment of renal failure in patients with cirrhosis. Dopa-mine and norepinephrine are important neurotransmitters inthe CNS, the periphery, and the kidneys. Some of the neuro-logic manifestations of hepatic failure, and HRS, may becaused by accumulation of other �-hydroxylated phenyleth-ylamines such as octopamine and serotonin. These com-pounds may replace normal transmitters and act as false neu-rotransmitters in sympathetic nerve terminals. Precursors offalse neurotransmitters, such as phenylalanine and tyrosine(Fig. 50.2), are produced from protein in the gut by bacterialamino acid decarboxylases. Normally, these precursors aremetabolized rapidly in the liver by monoamine oxidase, al-lowing norepinephrine that is formed elsewhere in the bodyto predominate. When hepatic function is impaired or whenblood is shunted away from the liver, these false neurotrans-mitters may replace normal transmitters. Systemically, thismay lead to lowered peripheral vascular resistance andshunting of blood away from the kidney. Similarly, asterixisand other signs of hepatic encephalopathy might result fromdisplacement of transmitters such as dopamine and norepi-nephrine in the basal ganglia and other areas in the brain.

FIGURE 50.2 Synthetic pathway of neurotransmitters. Mono-amine oxidase (MAO) action occurs mainly in the liver and isdepressed in hepatic disease and shunting.


If the displacement of normal central and peripheral trans-mitters by less active amines can account for hepatic comaand its cardiovascular complications, then the restoration ofnormal transmitter stores might restore normal function. Forhospitalized patients, this is accomplished with low-dose in-fusions 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 pressurewithin the first 24 hours of dopamine treatment is a poorprognostic sign. Because dopamine does not cross theblood–brain barrier, encephalopathy will not improve. How-ever, as shown in Figure 50.2, dopamine is also a precursorto norepinephrine, which may help to restore natural neuro-transmitter balance.

Use of the alpha agonist midodrine in combination withoctreotide has also shown efficacy in reducing mortality inHRS.100 Although not universally effective, this combina-tion is becoming established as a trial modality to offer pa-tients with this often fatal complication. There is no struc-tural abnormality of the kidneys in HRS; rather, it is mostlikely due to humoral imbalances from liver failure. HRS isassociated with a mortality rate that approaches 100%. Whilemany therapeutic methods have been tried to improve renalfunction, most have either a minor or a temporary effect,with the exception of liver transplantation.

Pharmacotherapy of Primary Biliary Cirrhosis. Col-chicine, a drug with both anti-inflammatory and antifibroticproperties, has been evaluated as a potential disease-modify-ing agent. In one study, 57 patients with biopsy-proven PBCwere treated with 0.6 mg colchicine twice daily or pla-cebo.101 The colchicine-treated patients had a significant im-provement in biochemical parameters (serum bilirubin andaminotransferase levels) but no difference in histologic pro-gression when compared to placebo. A second group of in-vestigators conducted a randomized, double-blind, placebo-controlled trial of colchicine, 1 mg per day, 5 days per week,in 100 patients with cirrhosis caused by alcohol abuse or ahistory of hepatitis.102 Median survival was 3.5 years in theplacebo group and 11 years in the colchicine-treated patients,while deaths from liver failure were 24% in the placebogroup and 15% in the treatment group. Side effects in bothtrials were mild, consisting primarily of nausea, abdominalpain, and diarrhea. Although these results are encouraging,flaws in the study design and the small number of subjectstreated prevent widespread endorsement of colchicine ther-apy at this time.

Numerous other drugs have been tried in treating PBC,including penicillamine, chlorambucil, azathioprine, cyclo-sporine, corticosteroids, and methotrexate.103 Each of thesetherapies is based on the hope that anti-inflammatory orimmunomodulating effects may alter the disease process.Cyclosporine showed modest improvement in symptoms,enzyme levels, and histologic findings in a controlled trialof PBC. However, toxicity with this drug is a limiting factorin therapy. Sequestration of copper by penicillamine mayhave a therapeutic effect, but most of the trials with these

drugs have been limited by a small sample size without ade-quate controls, and the improvement obtained has been onlymarginal. At this time, none of these drugs can be recom-mended.

A controlled, multicenter trial with ursodeoxycholic acidalso showed improvement in symptoms, enzyme levels, andhistologic findings in some patients, but there was little ef-fect in patients with advanced disease.104 Ursodiol may beeffective in slowing the progression of PBC and may de-crease the need for transplantation.105 Ursodiol (ursodeoxy-cholic acid) is a naturally occurring bile acid with cholereticproperties. The dose of ursodiol in the treatment of PBC is13 to 15 mg per kilogram per day given in four divideddoses.

NONPHARMACOLOGIC THERAPYIt is imperative to provide adequate nutritional support inpatients with liver disease. Positive nitrogen balance mustbe established without exacerbating hepatic encephalopathy.Diets high in BCAAs and low in AAAs and methioninemay help to restore normal amino acid balance and reduceencephalopathy.13–15,106 HepatAmine is an 8% amino acidsolution that contains more BCAAs than standard parenteralamino acid solutions. The ratio of BCAAs to AAAs in Hepat-Amine is 37:1, compared to 5:1 with crystalline amino acidsolutions. The indications for use and the efficacy of thisspecial amino acid formulation are debated. The expenseand questionable efficacy have limited its use to select pa-tients with life-threatening encephalopathy refractory to con-ventional therapy. An amino acid screen can be used to as-sess the BCAA:AAA ratio in patients. The cost of an aminoacid screen is approximately equal to 1 day’s therapy withHepatAmine.

For the awake patient without central venous access, ther-apy with enteral nutrition is preferred. One such dietary sup-plement is Nutrihep, a calorically dense product with a highcalorie to nitrogen ratio that helps maintain protein utiliza-tion for lean muscle mass in liver disease. This product pro-vides a 50:50 ratio of aromatic and branch amino acids. Useof oral BCAAs has been limited because of its questionableefficacy, its expense, and its disagreeable taste. The Ameri-can Society of Parenteral and Enteral Nutrition (ASPEN)has published guidelines for nutritional supplementation inpatients with liver disease.107 Growth hormone resistancehas also been associated with the protein catabolic state seenin cirrhosis. From the limited data available, it appears thattreatment with growth hormone can improve nitrogen utili-zation.108 In addition, because Helicobacter pylori has strongurease activity, there is evidence that supports treatment. Ifpresent, H. pylori eradication can reduce hyperammo-nemia.109

ALTERNATIVE THERAPY

The use of herbal supplements and other alternative remedieshave become popular in patients with liver disease. The natu-


rally occurring whole extract of the milk thistle (Silybummarianum) is known as silymarin. This flavonoid complexhas been shown to have a liver-protective effect in experi-mental models of hepatotoxicity from acetaminophen,ethanol, carbon tetrachloride, and phenylhydrazine. Use ofsilymarin has been popularized by the lay press and internetsources, with some scientific validation of efficacy. Sily-marin has been found to prevent lipid peroxidation, changesin the phospholipid composition of membranes, and hepaticglutathione depletion. It also appears to normalize hepaticfunction markers in patients with alcoholic liver disease.This positive effect may be attributed to an isomer of thesilymarin complex, silibinin, on inhibiting leukotriene for-mation by Kupffer cells.110 There is the potential for sily-marin to inhibit the activity of cytochrome P-450 3A4(CYP3A4) and P-glycoprotein. Studies have confirmed thisinhibitory effect, but the clinical significance has yet to beconclusively shown.111,112 Caution is thus advised when itis used with any drugs that are substrates for CYP3A4 orP-glycoprotein.

Zinc deficiency is observed in patients with chronic liverdisease, and zinc sulfate is often given to reverse this defi-ciency. Zinc may also improve dysgeusia and thus improveappetite. Zinc supplementation has also been suggested toimprove cirrhosis-related hepatic encephalopathy, but out-comes data are inconclusive.113

IMPROVING OUTCOMES

The outcome for patients with cirrhosis depends on the stageof disease and the presence of complications. Once the diag-nosis of liver disease has been established, consumption ofalcohol should stop. If the patient continues to drink alcohol,the prognosis is poor. Adherence to a low-sodium, protein-restricted diet is important in minimizing the formation ofascites and maintaining adequate nitrogen balance. Compli-ance with the prescribed medical regimen is critical in themanagement of the complications arising from cirrhosis. Amultidisciplinary approach can improve the outcome of thiscomplex disease. It is also important to develop a rapportwith family members and other caregivers to ensure theirsupport of the treatment plan and lessen the risk of noncom-pliance and recidivism.

PROGNOSIS

In a series of 1,155 patients with cirrhosis from a variety ofcauses, the over-5-year survival was about 40%.114 Thecauses of death were liver failure in 49%, hepatocellularcarcinoma in 22%, bleeding in 14%, HRS in 8%, and othercauses. Patients who entered the study with compensatedcirrhosis (absent or mild symptoms) became symptomaticat a rate of 10% per year. Survival was higher in this groupof patients (54% at 6 years). Patients who entered the study

with symptoms already present (ascites, history of bleeding,or encephalopathy) had a survival of only 21% at 6 yearsand a much higher incidence of hepatocellular carcinoma.The severity of disease can be classified according to varioussystems. The Child-Pugh score and the Model for EndstageLiver Disease (MELD) score can be used to assess surgicalrisk and short- and long-term mortality in patients with cir-rhosis.115–118 Given the irreversible nature of cirrhosis andthe high morbidity and mortality, liver transplantation maybe an option for select patients with end-stage liver disease.

PHARMACOECONOMICS

The management of cirrhosis can have a major economicimpact, primarily because of the chronicity and progressivenature of the disease. Patients who do not abstain from alco-hol and do not adhere to their diet and drug therapy can beexpected to have multiple hospital admissions as the diseaseprogresses. Management of patients with end-stage liver dis-ease is expensive. The preventive approaches discussed inthis chapter, such as SBP prophylaxis, diuretics, treatmentof hepatic encephalopathy, vitamin supplementation, and di-etary modification, are cost-effective and must be imple-mented early in the care plan.

KEY POINTS

■ In the United States, cirrhosis is the 12th most com-mon cause of death in people over age 40

■ Despite extensive investigation, no effective drug ther-apy has been found to reverse cirrhosis

■ Discontinuation of alcohol intake in patients withproven cirrhosis is of the utmost importance. Use ofnaltrexone in an effort to decrease craving may provevaluable in this setting119

■ Although therapy for cirrhosis focuses mainly on symp-tom management, other forms of chronic liver disease,such as viral hepatitis and autoimmune hepatitis, canbe successfully treated

■ Portal hypertension, a complication of cirrhosis, canmanifest as ascites, hepatic encephalopathy, esophagealvarices, and hepatorenal syndrome

■ Although the fibrosis from advanced cirrhosis is irrever-sible, it is estimated that 70% or more of liver tissuemust be destroyed before the body is unable to elimi-nate drugs and toxins via the liver.120 Unfortunately, itis difficult to tell which patients have reached thisstage of involvement. Practitioners should always beaware of the potential inability of patients with ad-vanced liver disease to metabolize various drugs nor-mally cleared by the liver, and should adjust doses ac-cordingly

■ Limited pharmacokinetic dosing research and guidanceare available for the aging liver and the diseased


liver.121,122 Dose reductions continue to be made empir-ically because data quantifying the degree of adjust-ment necessary in liver disease generally are unavail-able

SUGGESTED READINGS

Carithers RL Jr. Liver transplantation. Liver Transplant 6:122–135,2000.

Gerber T, Schomerus H. Hepatic encephalopathy in liver cirrhosis: patho-genesis, diagnosis and management. Drugs 60:1353–1370, 2000.

Gines P, Arroyo V. Hepatorenal syndrome. J Am Soc Nephrol 10:1833–1839, 1999.

Mowat C, Stanley AJ. Spontaneous bacterial peritonitis: diagnosis, treat-ment and prevention. Aliment Pharmacol Ther 15:1851–1859, 2001.

Runyon BA. AASLD Practice guideline: management of adult patientswith ascites due to cirrhosis. Hepatology 39:1–16, 2004.

Sharara AI, Rockey DC. Gastroesophageal variceal hemorrhage. N EnglJ Med 345:669–681, 2001.

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92. Ferenci P, Grimm G, Meryn S, et al. Successful long-term treat-ment of portal-systemic encephalopathy by benzodiazepine antago-nist flumazenil. Gastroenterology 96:240–243, 1989.

93. Pomier LG, Giguere JF, Lavoie J, et al. Flumazenil in cirrhotic pa-tients in hepatic coma. Hepatology 19:32–37, 1994.

94. Sterling R, Shiffman M, Schubert M. Flumazenil for hepatic coma:the elusive wake-up call? Gastroenterology 107:1204–1205, 1994.

95. Goulenok C, Bernard B, Cadranel J, et al. Flumazenil vs. placeboin hepatic encephalopathy in patients with cirrhosis: a meta-analy-sis. Alimentary Pharmacol Ther 16:361–372, 2002.

96. Imperiale T, McCullough A. Do corticosteroids reduce mortalityfrom alcoholic hepatitis? Ann Intern Med 113:299–307, 1990.

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99. Chan TYK. Beneficial effects of low-dose dopamine in cirrhosisand renal insufficiency. Ann Pharmacother 29:433, 1995.

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101. Bodenheimer H, Schaffner F, Pezzullo J. Evaluation of colchicinetherapy in primary biliary cirrhosis. Gastroenterology 95:124–129,1988.

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51PancreatitisJennifer W. Beall and Paula A. Thompson

Anatomy • 1365Physiology • 1366

Overview of Exocrine Function • 1366Secretion of Water and Electrolytes • 1366Enzymes • 1367Regulation of Exocrine Function • 1368

ACUTE PANCREATITIS • 1368Definition • 1368Etiology • 1369Epidemiology • 1369Pathophysiology • 1370Clinical Presentation and Diagnosis • 1371

Signs and Symptoms • 1371Diagnosis and Clinical Findings • 1371Laboratory Tests • 1371Pancreatic Enzymes • 1371Imaging • 1371Assessing Severity • 1371Complications • 1371

Psychosocial Aspects • 1373Therapeutic Plan • 1374Treatment Goals: Acute

Pancreatitis • 1374Treatment • 1374

General Supportive Measures • 1374Nutrition • 1375

Pancreatic inflammatory disease may be classified as eitheracute or chronic based on the reversibility of the functionaland structural changes that arise within the gland. Althoughthese are usually treated as discrete clinical entities, theymay actually be part of a continuum of pancreatic disease.1,2

Following an acute attack of pancreatitis, the pancreas willusually recover normal exocrine and endocrine function andmorphology once the underlying cause of acute inflamma-tion is eliminated. While most attacks have a mild, self-limited course, severe disease complicated by multiple organsystem failure and life-threatening infection may develop.Although pancreatic necrosis can result in transient or, occa-sionally, permanent impairment of gland function and struc-ture, acute pancreatitis rarely progresses to chronic dis-ease.3,4

In contrast, the persistent inflammation from chronic pan-creatitis is associated with a permanent and often progressiveloss of pancreatic exocrine and endocrine function, and irre-versible structural damage. Recurrent exacerbations of pan-creatitis, which frequently complicate chronic disease, arevirtually impossible to distinguish clinically from discreteattacks of acute pancreatitis.4,5

1365

Analgesia • 1375Antibiotics • 1375Correcting Biliary Tract Disease • 1375

Alternative Therapies • 1376Future Therapies • 1376Improving Outcomes • 1376Pharmacoeconomics • 1376

CHRONIC PANCREATITIS • 1376Definition • 1376Epidemiology • 1377Pathophysiology • 1377Clinical Presentation and

Diagnosis • 1378Signs and Symptoms • 1378Diagnosis and Clinical Findings • 1378

Psychosocial Aspects • 1379Therapeutic Plan • 1379Treatment Goals: Chronic

Pancreatitis • 1379Treatment • 1379

Pharmacotherapy • 1379Future Therapies • 1383Improving Outcomes • 1383Pharmacoeconomics • 1383

Reliable incidence and prevalence data are difficult toobtain. The incidence of both acute and chronic forms variesconsiderably among geographic areas as a consequence ofdifferences in regional environmental and genetic factors.5,6

Both acute and chronic pancreatitis will be discussed aftera brief review of pancreatic anatomy and physiology. Anunderstanding of normal structure and function is necessarybackground for this discussion.

ANATOMY

The adult pancreas is a flattened and elongated gland, usuallyranging from 12 to 20 cm in length and weighing 70 to 110g. It is lobular, like the salivary glands, and its lack of afibrous capsule makes it soft in texture. The pancreas liesretroperitoneally, the head nestled within the curve of theduodenum as it exits the stomach and the tail extendingobliquely to the left (Fig. 51.1).7,8

Blood is supplied to the pancreas by the celiac and supe-rior mesenteric arteries, and the blood ultimately drains intothe hepatic portal vein. The lymphatic vessels draining the


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 andpancreatoduodenal lymph nodes. Sympathetic innervation ispredominately through splanchnic neurons synapsing in theceliac plexus, and parasympathetic innervation is derivedfrom the vagus nerve.7,8

The pancreas contains exocrine (about 80%) and endo-crine (about 2%) tissue. The remaining 18% of the gland isductular. The secretory unit of the exocrine pancreas is theacinus (Latin for ‘‘berries in a cluster’’). Each acinus con-sists of 20 to 50 pyramid-shaped cells surrounding a centrallumen. The acini are connected to the main pancreatic ductthrough a network of interconnecting ductules. The islets ofLangerhans (pancreatic islets) make up the endocrine pan-creas and are composed of four major cell types, each appar-ently secreting a single hormone. Approximately 50% to80% of the islet cell mass is comprised of � cells, whichsecrete insulin. Glucagon, somatostatin, and pancreatic poly-peptide are secreted by � cells, � cells, and PP cells, respec-tively. Insulin and glucagon are critical in the regulation ofcarbohydrate metabolism (see Chapter 40). In addition tothe systemic effects exerted by each of these hormones, theyalso play a role in the regulation of pancreatic exocrine secre-tion. Insulin may potentiate the actions of stimulatory fac-tors, while glucagon, somatostatin, and pancreatic polypep-tide exert inhibitory effects.7

PHYSIOLOGY

Overview of Exocrine FunctionPancreatic exocrine function is complex and incompletelyunderstood. During the course of a day, the pancreas cansecrete 1 to 2.5 liters of isosmotic alkaline fluid containingover 20 enzymes and proenzymes (zymogens). This fluid,commonly termed ‘‘pancreatic juice,’’ is produced by acinarand ductular cells. The acinar cells synthesize and secretethe digestive enzymes. Proximal ductular cells, termed cen-troacinar cells, extend into the lumen of the acinus and areprimarily responsible for secretion of water and electrolytes.The intralobular ductules draining the acini coalesce withinterlobular ductules, ultimately emptying into the main pan-creatic duct. The main pancreatic duct and the common bileduct enter the duodenum at the ampulla of Vater (hepatopan-creatic ampulla). The sphincter of Oddi (sphincter of thehepatopancreatic ampulla) regulates flow from bothducts.9–11

SECRETION OF WATER AND ELECTROLYTESThe principal cations of pancreatic juice are sodium andpotassium, which are secreted at fixed concentrations similarto their plasma concentrations. The principal anions are bi-

CHAPTER 51 ■ Pancreatitis 1367

FIGURE 51.2 Relationship between ion concentra-tion in pancreatic juice and secretory flow rate.(Reprinted with permission from Pandol S, Pan-creatic physiology. In: Sleisenger MH, FordtranJS. Gastrointestinal Disease: Pathophysiology,Diagnosis, Management. 5th ed. Philadelphia:WB Saunders, 1993:1586.)

carbonate and chloride, which vary reciprocally in concen-tration, maintaining the sum of the two fairly constant atapproximately 150 mEq per liter (Fig. 51.2). Bicarbonate issecreted by the centroacinar cells, whereas secretions fromthe acinar cells are rich in chloride. The relative concentra-tion of each reaching the duodenum depends on the amountsecreted and the exchange of bicarbonate for chloride in theductules. The concentration of bicarbonate, physiologicallythe most important of the electrolytes, increases with increas-ing flow rates. Flow rates range from a basal level of 0.2 to0.3 mL per minute to 4 mL per minute during stimulation.At maximal rates of secretion, bicarbonate concentration ap-proaches 120 mEq per liter, and the pH of the resultingpancreatic juice is approximately 8.3. This alkalinity buffersthe acidic chyme delivered to the duodenum from the stom-ach and maintains a pH that is optimal for the functioningof pancreatic enzymes. Other ions present in pancreatic juiceinclude calcium and trace amounts of magnesium, zinc,phosphate, and sulfate. Water enters the ductules passivelydown the concentration gradient established by the activetransport of solute, maintaining iso-osmolality.9–11

ENZYMESProtein represents up to 10% of pancreatic juice, and over90% of this protein consists of digestive enzymes and proen-zymes.9–11 These enzymes are synthesized in the rough en-doplasmic reticulum of the acinar cells and are stored insecretory vesicles (zymogen granules) prior to their releaseby exocytosis. There are four major categories of enzymes,corresponding to the four classes of organic compoundsfound in food: proteins, carbohydrates, lipids, and nucleicacids (Table 51.1). The proteases and phospholipases aresecreted as inactive zymogens that become active in the in-testinal lumen through the action of enterokinase producedby the duodenal mucosa. Enterokinase cleaves a small frag-

ment of trypsinogen to form active trypsin, which can thenactivate other zymogens, including additional trypsinogenmolecules.

The pancreas is protected from autolysis not only by se-cretion of proteolytic enzymes in zymogen form, but alsoby the presence of trypsin inhibitor, which binds to trypsinin a 1:1 ratio, rendering it inactive. This protein is present

TABLE 51.1

ProteolyticTrypsinogenEnterokinase, Trypsin trypsinChymotrypsinogenTrypsin chymotrypsinProelastaseTrypsin elastaseProcarboxypeptidase ATrypsin carboxypeptidase AProcarboxypeptidase B Trypsin carboxypeptidase B

Amylolytic�-Amylase

LipolyticLipaseProcolipaseTrypsin colipase [cofactor essential for optimallipase activity]Prophospholipase A2

Trypsin phospholipase A2

Carboxylesterase lipaseNucleolytic

Deoxyribonuclease (DNAse)Ribonuclease (RNAse)

(Adapted from Pandol SJ. Pancreatic physiology and secretorytesting. In: Feldman M, Sleisenger MH, Scharschmidt BF.Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis,Management. 6th ed. Philadelphia: WB Saunders, 1998:871.)

Major Digestive Enzymes Secreted by thePancreas


in sufficient quantity to protect against small amounts oftrypsin, which may become active in the ductules, but itsactivity is insignificant in the duodenal lumen.9,10,12

REGULATION OF EXOCRINE FUNCTIONA discussion of all the putative regulatory factors of pan-creatic exocrine function, both neural and hormonal, is be-yond the scope of this text. The roles of secretin, cholecysto-kinin (CCK), and cholinergic neurons in pancreaticsecretions have been well established and will be reviewedbriefly.

Secretin, a peptide hormone released from the mucosa ofthe duodenum and jejunum, stimulates bicarbonate andwater secretion, primarily in response to the presence of acidin the small intestine. The pH threshold for secretin releaseis 4.5. The presence of bile salts and some fatty acids withinthe intestinal lumen can also trigger secretin release. In addi-tion to its effect on bicarbonate, secretin may cause a weakstimulation of pancreatic enzyme release.9–11

CCK, also a peptide hormone secreted by the mucosa ofthe small bowel, causes the release of an enzyme-rich juicefrom the pancreas. Production of CCK occurs when aminoacids or fatty acids enter the duodenum. Intravenous admin-istration of CCK also stimulates enzyme release, while pan-creatic response is substantially reduced by the administra-tion of CCK antagonists. The combined release of secretinand CCK potentiates the pancreatic response, increasing bi-carbonate and volume secretion.9–11

Inhibitory mechanisms are less well understood thanstimulatory ones. Intravenous infusions of amino acids orglucose inhibit pancreatic function, probably due at least inpart to the release of glucagon and somatostatin from isletcells. Pancreatic polypeptide may also decrease exocrinefunction by modulating cholinergic pathways, although thephysiologic significance of this has not been delineated. Thepresence of lipids in the colon inhibits CCK-stimulated pan-creatic output, possibly acting through a mediator called pep-

A C U T E P A N C R E A T I T I SA C U T E P A N C R E A T I T I S

DEFINITION

Acute pancreatitis is an acute inflammatory process of thepancreas with variable involvement of other regional tissuesor remote organ systems.15 The inflammation may remainlocalized in the pancreas or may involve tissues elsewhere.16

Approximately 80% of patients have interstitial pancreatitis,which is characterized by interstitial edema resulting frominflammatory cells, yet there is no destruction to the architec-ture of the gland.17–20 The remaining patients develop necro-tizing pancreatitis, with diffuse or focal areas of nonviable

tide YY.9–11,13 A negative feedback loop has also been hy-pothesized whereby trypsin in the intestinal lumeninactivates a CCK-releasing peptide, decreasing CCK re-lease and pancreatic enzyme secretion.9,10,12,14 Increasingour understanding of these inhibitory mechanisms may helpto guide the development of effective therapeutic modalitiesfor pancreatitis.

Phases of Pancreatic Secretion. Pancreatic functioncan best be described in terms of interdigestive (fasting) anddigestive (postprandial) periods. Digestive secretion can befurther subdivided into cephalic, gastric, and intestinalphases. The pancreas is not quiescent between meals, butrather displays a basal secretion that is cyclical. Althoughoverall secretion is low, there are fluctuations that parallelchanges in gastrointestinal motility.9–11

Vagal nerves mediate the cephalic phase, in which pan-creatic secretion can be stimulated by the sight, smell, ortaste of food. In sham feeding experiments (patients chewfood without swallowing it), pancreatic enzyme secretionincreased to approximately 50% of the maximal secretionelicited by intravenous CCK. Gastric acid production is alsostimulated during this phase, triggering secretin release,which increases bicarbonate and enzyme secretion. The gas-tric phase begins when food enters the stomach. Gastric dis-tention causes increased pancreatic secretion, mediatedthrough a gastropancreatic vagovagal reflex. The most im-portant phase is triggered when chyme enters the small intes-tine. This intestinal phase is regulated by the hormones secre-tin and CCK and by enteropancreatic vagovagal reflexestriggered by volume or hyperosmolality in the gut. Duringall phases of pancreatic secretion, it is the interplay of neuraland hormonal factors that result in the coordinated responseof the pancreas to feeding.9–12

This brief overview of normal anatomy and physiologyshould serve to clarify the subsequent discussions of acuteand chronic pancreatitis.

pancreatic parenchyma and large areas of peripancreatic fatnecrosis.16,18 Thrombus is also common in acute necrotizingpancreatitis.

Acute pancreatitis can also be classified clinically as mildor severe.16 Although interstitial pancreatitis may be associ-ated with serious systemic toxicity, its clinical course is usu-ally mild, with minimal organ dysfunction and a resultantmortality of less than 2%. In contrast, the mortality of severeacute pancreatitis, involving organ failure or local complica-tions such as abscess or pseudocyst, is 10% to 30%.17,18

Severe pancreatitis is most often the clinical expression ofpancreatic necrosis.


ETIOLOGY

Acute pancreatitis is associated with many other disease pro-cesses and events (Table 51.2). Biliary tract stone diseaseand ethanol abuse account for 60% to 80% of acute boutsof pancreatitis, with the incidence of each depending on thepatient population being evaluated.6,17 Women tend to havepancreatitis as a result of biliary tract stone disease, whereasethanol abuse is more often associated with pancreatitis inmen.6,17 A number of miscellaneous causes account for 10%to 15% of pancreatitis attacks, with another 10% to 15% ofcases classified as idiopathic.17,21 However, recent studiessuggest that up to two thirds of idiopathic cases may becaused by biliary microlithiasis.6

EPIDEMIOLOGY

The incidence of acute pancreatitis varies widely and de-pends on the incidence of precipitating factors in a popula-tion.6 The incidence of acute pancreatitis in the United Statesis thought to range from 54 to 238 episodes per 1 millionpeople per year.22 Disease incidence has been extensivelystudied in the United Kingdom and appears to have increased10-fold from the 1960s to the 1980s.21 This may reflect anincrease in alcohol abuse and diagnostic advances.

Cholelithiasis increases a patient’s relative risk of devel-oping acute pancreatitis; however, the condition develops inonly a few patients with this condition.23 Biliary pancreatitismay be associated with recurrent episodes of acute disease,but chronic pancreatitis is rare. In contrast, many patientswith alcoholic pancreatitis have consumed large amounts ofalcohol for many years before the initial onset of symptoms.Pancreatitis in an alcoholic patient was previously thoughtto be an acute exacerbation of chronic pancreatitis. However,despite continued abuse of alcohol, not all will progress fromacute to chronic disease.6,15,21 Because clinical pancreatitisdevelops in only 5% of alcoholics, unidentified factors mustaffect susceptibility to pancreatic injury.21

Gallstones are the most common obstructive cause ofacute pancreatitis, but inflammation may also result fromother lesions that interfere with the flow of pancreatic juicethrough the ductal system. Thus, pancreatitis may result fromductal strictures, sphincter of Oddi dysfunction, or tumorsof the pancreas, ampulla, or duodenum.3,21 Blunt trauma tothe abdomen may also cause pancreatitis by disrupting thepancreatic ductal system. Similarly, pancreatitis can occuras a postoperative complication of procedures that involvemanipulation of the pancreas or during endoscopic retro-grade cholangiopancreatography (ERCP), in which a side-viewing endoscope is passed into the duodenum and a cathe-ter introduces a radiopaque contrast medium into the pan-creatic duct. Certain viral, parasitic, and bacterial infectionsmay also precipitate acute attacks. Other causes of acutepancreatitis include penetrating duodenal ulcer, vascularcompromise, hypertriglyceridemia, and various toxins.3,6,21

TABLE 51.2Obstruction

GallstonesSphincter of Oddi spasm or stenosisPeriampullary or pancreatic tumorsPeriampullary duodenal diverticulaPancreas divisum with accessory duct obstruction

InfectionParasitic: ascariasis, clonorchiasisViral: Coxsackie B virus, mumps, rubella, Epstein-Barr

virus, cytomegalovirus, varicella, hepatitis A, hepatitis BBacterial: Mycoplasma sp, Legionella sp, Salmonella sp,

Shigella sp, Mycobacterium tuberculosis, Campylobacter spToxins

AlcoholDrugs (see Table 51.3)Scorpion venomOrganophosphate insecticides

TraumaPostoperativeEndoscopic retrograde cholangiopancreatographyEndoscopic sphincterotomyCoronary artery bypassBlunt abdominal trauma

MetabolicHypertriglyceridemiaHypercalcemia

VascularVasculitisAtherosclerotic emboliHypoperfusion

MiscellaneousIdiopathicHereditary pancreatitisCystic fibrosisPenetrating duodenal ulcerInflammatory bowel diseaseHypothermia

(Data from Mitchell RMS, Byrne MF, Baille J. Pancreatitis. Lancet361:1447–1455, 2003; Steer ML, Waxman I, Freedman S.Chronic pancreatitis. N Engl J Med 332:1482–1490, 1995; andOwyang C, Levitt MD. Chronic pancreatitis. In: Yamada T. Textbookof Gastroenterology. 2nd ed. Philadelphia: JB Lippincott,1995:2061.)

Causes of Acute Pancreatitis


Debate continues about the association of acute pancreati-tis with pancreas divisum, a congenital abnormality in whichthe dorsal and ventral pancreatic ducts fail to fuse. Becausepancreas divisum is a common anatomic abnormality withan overall incidence of about 7%, it may be an incidentalfinding in many patients with idiopathic pancreatitis.6,21

More than 85 drugs have been associated with acute pan-creatitis, although the frequency of drug-induced diseasegenerally is low.24–36 Because scattered case reports makeup the bulk of the literature on drug-induced pancreatic dis-ease, it usually is difficult to link drugs with pancreatic in-flammation conclusively. Mallory and Kern25 classifieddrugs into three categories based on the clinical evidenceimplicating them in the development of acute pancreatitis:definite, probable, and questionable. The association is con-sidered definite when drug therapy results in abdominal paincombined with hyperamylasemia that resolves when therapyis discontinued or recurs when the drug is reintroduced(Table 51.3). Because drug-induced acute pancreatitis can-not be distinguished clinically from that induced by othercauses, it should be considered when other causes of diseasehave been ruled out.

PATHOPHYSIOLOGY

The inflammation and necrosis of acute pancreatitis beginas an autodigestive process initiated by the inappropriateactivation and release of proteolytic and lipolytic enzymesinto the interstitium of the organ. The activation of trypsino-gen to trypsin within the acinar cells is the initial step in thepathogenesis of acute pancreatitis.3 Trypsin can then activateother pancreatic proteases, including elastase, chymotrypsin,and carboxypeptidase, and phospholipase A2, which thencontribute to acinar cell inflammation. Elastase causes vas-cular damage by dissolving the elastic fibers of blood ves-sels. Chymotrypsin augments this vascular damage and theresulting edema, and phospholipase A2 destroys acinar cellmembranes. These pancreatic enzymes, after damaging aci-nar cells, leak into the interstitium, causing local inflamma-tion. Lipase is also liberated from peripheral acinar cells,resulting in peripancreatic fat necrosis. The kinin and com-plement systems are activated by trypsin, leading to the re-lease of vasoactive peptides, which cause vasodilation,increased vascular permeability, and accumulation of leuko-cytes.17 In severe disease, pancreatic enzymes, vasoactivepeptides, and other toxic factors extravasate from the pan-creas into peripancreatic spaces and the peritoneal cavity,causing a widespread chemical irritation.18 These materialsmay also reach the systemic circulation through retroperito-neal lymphatic and venous circulation to contribute to sys-temic complications, including shock, respiratory failure,and renal failure.18

Factors in acute pancreatitis that contribute to the trans-formation from a local inflammatory process into a multior-gan illness are not entirely understood. The contribution of

Data from references 25–35.

TABLE 51.3Definite Association

AmiodaroneAngiotensin-converting

enzyme inhibitorsAsparaginaseAzathioprineCodeineCytarabineDidanosineEstrogensFurosemideIsoniazidLosartanMercaptopurineMesalamineMetronidazolePentamidineSulfonamidesSulindacTetracyclineThiazidesValproic acid

Probable AssociationBumetanideChlorthalidoneCimetidineClarithromycinClozapineCorticosteroidsEthacrynic acidIfosfamideKetorolacMethyldopaPhenforminProcainamide

SalicylatesSulfasalazineZalcitabine

Questionable AssociationAcetaminophenAmpicillinCarbamazepineCholestyramineCisplatinClonidineColchicineCyclosporineCyproheptadineDiazoxideDiphenoxylateErgotamineErythromycinGold compoundsIndomethacinInterleukin-2IsotretinoinKetoprofenMefenamic acidMetolazoneNaproxenNitrofurantoinOpiatesOxyphenbutazonePhenolphthaleinPiroxicamPropoxypheneRanitidineTryptophan

Agents Associated with Acute Pancreatitis

leukocytes and their products in amplifying pancreatic in-flammation into a generalized systemic inflammatory re-sponse has been recognized.3,37 Neutrophils, macrophages,and monocytes invade the inflamed pancreas and releasedestructive mediators such as elastase, phospholipase A2,platelet activating factor, nitric oxide, oxygen free radicals,and cytokines.3 The inflammatory cytokines, particularly in-terleukin-1, interleukin-6, and tumor necrosis factor, appear


to be important systemic mediators of acute pancreatitis.37

Cytokines are produced not only locally, but also systemi-cally in sites such as the spleen, liver, and lung, where theyhave been linked to organ dysfunction. Circulating levels ofcytokines are higher in patients with severe acute pancreati-tis, and these levels can be predictive of disease severity,end-organ failure, and mortality.38,39 Consequently, cyto-kine antagonism may prove beneficial in treating patientswith acute pancreatitis. Furthermore, impairment of the pan-creatic microcirculation by the deleterious effects of leuko-cyte products on the vascular endothelium appears to be animportant mechanism in pancreatic necrosis.40

The mechanism by which pancreatic enzymes becomeprematurely activated within the gland to initiate the cascadeof events that causes acute pancreatitis is unknown. Pro-posed mechanisms focus on biliary tract stone disease, pos-tulating that reflux of hepatic bile or duodenal contents intothe pancreatic ductal system may activate enzymes withinthe pancreatic parenchyma.3,6 More recently, investigatorshave proposed that activation of trypsin may occur within thepancreatic acinar cell rather than in the ductal or intercellularspace.3,21 Obstruction in the pancreatic duct could disturbthe normal events that maintain segregation of lysosomalenzymes, including cathepsin B, from digestive enzymes,thus allowing them to mix intracellularly. Cathepsin B canconvert trypsinogen to trypsin, which could then activate theremaining digestive zymogens. The mechanism of ethanol-induced pancreatitis is not understood but may include relax-ation or spasm of the sphincter of Oddi, obstruction of smallpancreatic ductules with proteinaceous plugs, or direct toxiceffects of ethanol or one of its metabolites.3,6,20

The pathogenesis of drug-induced pancreatic injury hasnot been elucidated, but it does not appear to differ substan-tially from that of acute pancreatitis induced by other causes.Possible mechanisms include pancreatic ductal constriction,immune suppression, arteriolar thromboses, direct cellulartoxicity, hepatic production of free radicals, and osmotic ormetabolic effects.26


Signs and SymptomsThe classic presentation of acute pancreatitis consists of ab-dominal pain, nausea, and vomiting; however, a patient’ssymptoms and physical findings may vary with the severityof disease.15 The abdominal pain is usually located in theepigastrium or diffusely throughout the upper abdomen.3

Pain is usually sudden in onset and peaks within 10 to 30minutes.41 Pain may be severe, and it is most commonlydescribed as a steady, dull, or boring pain that often radiatesto the back. Patients may move about continually in searchof a comfortable position, with little relief.6,15 Pain resolvesover 1 to 3 days in mild cases but may last many days toweeks during severe attacks. Painless pancreatitis has been

reported infrequently. Nausea and vomiting are almost invar-iably present and are usually preceded by the onset of pain.Epigastric tenderness is a consistent finding on abdominalexamination, as is abdominal distention. Bowel sounds oftenare diminished but not absent. Fever in the range of 100� to102�F is seen in most patients as the pyrogenic productsof pancreatic injury enter the circulation. Tachycardia andhypotension progressing to circulatory shock can occur insevere cases as a result of hypovolemia caused by vomiting,hemorrhage, and fluid sequestration within the retroperito-neal space. Circulating kinins and cytokines contribute tothis circulatory instability through vasodilatory effects andincreased vascular permeability.17 Disorientation, delirium,or hallucinations are sometimes observed, although most pa-tients present without changes in mental status.3

DIAGNOSIS AND CLINICAL FINDINGSThe diagnosis of acute pancreatitis is based on careful clini-cal evaluation of the patient, laboratory tests, and radio-graphic imaging. Mild cases of acute pancreatitis often repre-sent a diagnostic dilemma because symptoms may benonspecific and pancreatic enzyme levels and imaging stud-ies are often virtually normal.17 Occasionally, acute pancre-atitis must be distinguished from other processes that presentwith abdominal pain and hyperamylasemia, such as acutecholecystitis or appendicitis, intestinal ischemia or infarc-tion, perforated gastric or duodenal ulcer, intestinal obstruc-tion, ectopic pregnancy, and common bile duct obstruc-tion.41

LABORATORY TESTSLeukocytosis, ranging from 10,000 to 25,000 cells per cubicmillimeter, is a common finding during routine laboratoryevaluation of patients with acute pancreatitis.3,17 Hypergly-cemia, transient hypertriglyceridemia, and hypoalbumi-nemia also are common. Liver function tests often revealmild hyperbilirubinemia and elevated serum alkaline phos-phatase and transaminase levels, which tend to be more pro-nounced with biliary pancreatitis. Hypovolemia may resultin hemoconcentration, as evidenced by elevated hematocrit,blood urea nitrogen, and serum creatinine levels.

PANCREATIC ENZYMESElevation of the serum amylase level has remained centralto the diagnosis of acute pancreatitis since its first associationwith the disease in 1929.17,21 The pancreas and salivaryglands account for most of the serum amylase activity inhealthy people. The serum amylase level typically rises rap-idly (from the normal range of 35 to 118 IU per liter) duringthe initial hours of an attack and then declines over the fol-lowing 3 to 10 days.3,6 The sensitivity of the test may becompromised if patients do not present early in the courseof the disease. Furthermore, the test lacks specificity becausehyperamylasemia is associated with a variety of nonpan-creatic conditions, including diseases of the biliary tract, in-testines, female genitourinary tract, lungs, prostate, and sali-


vary glands.42 Generally, patients with biliary pancreatitispresent with a more marked hyperamylasemia than do pa-tients with alcohol-related disease.17,42 The measurement ofserum amylase isoenzymes has been largely abandoned be-cause most nonpancreatic abdominal diseases that simulatepancreatitis are associated with increased pancreatic ratherthan nonpancreatic amylase levels.42

In contrast, serum lipase is derived almost exclusivelyfrom the pancreas (normal range 2.3 to 20 IU per deciliter).Thus, it is more specific for acute pancreatitis and remainsnormal in a variety of conditions associated with elevationsof serum amylase, including salivary gland disease, gyneco-logic disorders, and macroamylasemia associated with renalinsufficiency.3 However, hyperlipasemia may also occur innonpancreatic acute abdominal conditions.6,42 Althoughserum lipase typically parallels amylase in onset of eleva-tion, lipase elevation persists longer, thus enhancing its diag-nostic utility in patients who present several days after theonset of symptoms.

In summary, elevations in serum amylase and lipase ac-tivity support the diagnosis of acute pancreatitis. The assaysare widely available and can be performed rapidly and relia-bly at low cost.42 Values of serum amylase and lipase greaterthan three times the upper limit of normal are characteristicof acute pancreatitis and rarely occur in nonpancreatic condi-tions.3 The magnitude of increase in serum amylase and li-pase activity has no prognostic value and does not correlatewith the severity of the acute attack.41 Furthermore, dailymeasurement of pancreatic enzymes has little value in as-sessing a patient’s progress or prognosis.3 The use of otherpancreatic enzymes, such as immunoreactive trypsinogen,chymotrypsin, elastase, and phospholipase A2, as markersfor acute pancreatitis does not appear to provide any diagnos-tic advantage over the determination of serum amylase andlipase activity. In addition, measuring the urinary amylaselevel and the amylase:creatinine clearance ratio offers littlebenefit in improving diagnostic accuracy. However, a rapidassay of urinary trypsinogen 2 may prove to be a reliabletest in the future.17,20,42

IMAGINGRadiographic studies play an important role in confirming thediagnosis of pancreatitis and provide important etiologic andprognostic information. Although abdominal radiography isnot considered diagnostic, it has several uses in this setting.42

Most importantly, it may help to exclude nonpancreatic dis-eases that may mimic pancreatitis, including bowel obstruc-tion and perforated viscus. The primary role of ultrasonogra-phy is in evaluating the biliary tract for stones, dilation, orobstruction.42 Guidelines from the American College of Gas-troenterology recommend performing an abdominal ultra-sound within 24 to 48 hours of hospitalization for the initialepisode of acute pancreatitis.41 Computed tomography (CT)is useful for excluding other serious intra-abdominal condi-tions, but its utility early in an acute attack is controversial.41

Dynamic contrast-enhanced CT scan, the best test for identi-

fying pancreatic necrosis, should be performed after the first3 days in patients with severe acute pancreatitis to distinguishinterstitial from necrotizing disease.41

ASSESSING SEVERITYMultiple clinical criteria systems have been developed toassess the severity and prognosis of acute pancreatitis. Pre-dictors of severity allow early identification of patients withthe greatest likelihood of developing severe pancreati-tis.16,17,41 Ranson et al developed 11 prognostic criteria thatcan be measured 48 hours after hospital admission to assessthe severity of an acute attack (Table 51.4).41,43 The AcutePhysiology and Chronic Health Evaluation II (APACHE II)is another list of clinical and laboratory values used to assesspatients with acute pancreatitis that can be calculated withinhours of admission and at daily intervals thereafter6,21,44

(Table 51.5). Severe acute pancreatitis is characterized bythree or more Ranson criteria or at least eight APACHE IIpoints.16 According to recent guidelines, the APACHE IIscore should be generated on the day of admission.41 After48 hours, the APACHE II or Ranson score may be used tofollow the course of the patient with pancreatitis.41

COMPLICATIONSThe clinical course of acute pancreatitis is uncomplicated inapproximately 80% of attacks. Thus, most patients withacute pancreatitis have mild disease that resolves promptlywith conservative therapy.17–19 The remaining patients de-

Nonbiliary BiliaryPancreatitis Pancreatitis

On AdmissionAge (years) �55 �70White cells/mL �16,000 �18,000Glucose (mg/dL) �200 �220Lactate dehydrogenase �350 �400

(LDH) (IU/L)Aspartate aminotransferase �250 �250

(AST) (IU/L)Within 48 Hours of Admission

Decrease in hematocrit (points) �10 �10Increase in blood urea

nitrogen (mg/dL) �5 �2Calcium (mg/dL) �8 �8PaO2 (mm Hg) �60 —Base deficit (mEq/L) �4 �5Fluid deficit (L)a �6 �4

a Input minus output.(From Ranson JHC. Etiological and prognostic factors in human acutepancreatitis: a review. Am J Gastroenterol 77:633–638, 1982.)

TABLE 51.4 Ranson’s Prognostic Criteria


Temperature Serum sodiumHeart rate Serum potassiumMean arterial pressure Serum creatinineRespiratory rate HematocritOxygenation White blood countArterial pH Glasgow Coma Scale scoreAge points Chronic health assessment points

(Adapted from Agarwal N, Pitchumoni CS. Assessment of severity inacute pancreatitis. Am J Gastroenterol 86:1385–1391, 1991.)

TABLE 51.5 APACHE II Variables

velop severe disease that is usually the clinical expression ofpancreatic necrosis.16 Although the mortality of interstitialpancreatitis remains low (�less than 2%), necrotizing pan-creatitis has a mortality ranging from 10% (sterile necrosis)to 30% (infected necrosis).18

Acute pancreatitis may be complicated by either localor systemic events (Table 51.6). Local events include thedevelopment of acute fluid collections in or near the pan-creas, occurring early in the course of 30% to 50% of at-tacks.45 Acute fluid collections lack a well-defined wall and

LocalNecrosis (sterile or infected)Pancreatic fluid collection (sterile or infected)PseudocystAbscessPancreatic ascitesBlood vessel rupture or thrombosisBowel necrosis, obstruction, perforationIleusFistula

SystemicShockRenal failurePulmonary insufficiency (including adult respiratory distress

syndrome)CoagulopathyGastrointestinal hemorrhageEncephalopathyRetinopathyHypocalcemiaHyperglycemia

(Compiled from Steer ML, Waxman I, Freedman S. Chronicpancreatitis. N Engl J Med 332:1482–1490, 1995; and OwyangC, Levitt MD. Chronic pancreatitis. In: Yamada T. Textbook ofGastroenterology. 2nd ed. Philadelphia: JB Lippincott, 1995:2061.)

TABLE 51.6 Complications of Acute Pancreatitis

regress spontaneously in 50% of cases.45 Fluid collectionsmay also progress to become pseudocysts or abscesses. Apseudocyst is a collection of pancreatic juice enclosed by awell-defined wall of fibrous tissue forming 4 or more weeksafter the onset of an acute attack.45 Approximately 40% ofthese acute pseudocysts resolve within 6 weeks.45 Pseu-docysts may be clinically silent or they may cause severeabdominal pain and elevation of pancreatic enzymes. Pan-creatic abscess, another late-developing complication, is acircumscribed intra-abdominal collection of pus containinglittle or no pancreatic necrosis.45 The term pancreatic ab-scess is also used to describe infection within a pseudocyst.In contrast, the development of pancreatic necrosis is anearly event appearing within the first 4 days of an acuteattack. Necrosis can be found in approximately 20% of acutepancreatitis cases and is necessary for the subsequent devel-opment of infection. Pancreatic infection, which occurs in30% to 50% of patients, usually develops in the second tothird week of illness.41 Infectious complications account for80% of deaths from acute pancreatitis.6,16,17

Severe acute pancreatitis may be complicated by multipleorgan system failure, which most commonly involves thecardiovascular, renal, and pulmonary systems.6,21 Organfailure is the most important indicator of the severity of acutepancreatitis.16,18 Cardiovascular decompensation, the resultof hypovolemia and vasodilation caused by circulating vaso-active peptides and cytokines, is associated with morbidityand mortality. Acute renal failure is a consequence of hypo-volemia and decreased renal perfusion. Pulmonary compli-cations vary from mild arterial hypoxemia, usually detectedduring the first 2 days of an attack, to adult respiratory dis-tress syndrome, the result of pulmonary parenchymal injurycaused by circulating inflammatory mediators.3 Systemiccomplications related to organ failure are responsible fordeath early in the course of acute pancreatitis.


There have been few studies evaluating the psychosocialaspects of acute pancreatitis. These studies have primarilyassessed patients with severe disease, whose quality of lifeis most likely to be affected. Even patients who recover froman acute attack can have long-term complications, such asdiabetes, recurrent disease, and continued abdominal pain.46

Another important factor in quality of life after severe pan-creatitis is the role of alcohol, which can affect quality oflife and mortality beyond the disease state. Up to 72% ofthose patients who had alcohol-induced pancreatitis will de-crease their alcohol intake after their disease episode. Thistype of positive change could improve a patient’s quality oflife overall. When compared with population control groups,most patients who have recovered from an attack of severeacute pancreatitis rate their physical and mental health equiv-alent to that of the controls.47


THERAPEUTIC PLAN

In the absence of effective specific therapy for the underlyingdisease process, the treatment of acute pancreatitis remainslargely supportive. In patients with mild disease, principlesof management include eliminating oral intake, maintainingadequate hydration with intravenous fluid, and providingparenteral analgesia.21,41 With standard conservative ther-apy, the majority of cases of acute pancreatitis subside within3 to 10 days.17 In contrast, severe acute pancreatitis almostinvariably warrants treatment in an intensive care unit. Quan-tification of the attack severity with the APACHE II systemor Ranson’s criteria is an important early step.22,41 A dy-namic contrast-enhanced CT scan should be performed inpatients with severe acute pancreatitis, as evidenced by thedevelopment of organ failure, to detect necrotizing pancre-atitis (Fig. 51.3).41 In the absence of clinical improvement,a CT-guided percutaneous aspiration should be performedto detect infected necrosis, which necessitates surgical de-bridement.41 Patients must be reassessed and monitoredthroughout the attack for the development of complications,particularly organ failure and infection. In addition, eliminat-ing factors that precipitated the acute attack may improvethe patient’s course and prevent recurrence of disease.17,21

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 MeasuresAcute pancreatitis may be associated with severe intravascu-lar volume contraction and hypovolemia that result fromexudation of protein-rich fluid into the inflamed peripancrea-tic retroperitoneum and peritoneal cavity. In addition, vol-ume losses are incurred through vomiting, hemorrhage, andnasogastric suction. The primary goal of therapy early in thecourse of acute pancreatitis is to replace intravascular vol-ume and electrolytes to avoid cardiovascular compromiseand renal failure. Aggressive fluid resuscitation may alsosupport the pancreatic microcirculation, limiting the devel-opment of necrosis. Volume replacement with crystalloidsolutions is adequate for most patients, but intravenous col-loids may be needed if protein-rich fluid losses are massive.

Severe

MildAssessseverity

(first few days)

Acutepancreatitis

Necrotizingpancreatitis

Interstitialpancreatitis

Surgicaldebridement

Percutaneousaspiration

Supportivecare

CT scan

Sterile

Improvement

Infection

Deterioration

FIGURE 51.3 Algorithm for the management of acute pancreati-tis. (Adapted with permission from Banks PA. Practice guide-lines in acute pancreatitis. Am J Gastroenterol 92:384, 1997.)

Potassium, calcium, and magnesium losses may also neces-sitate intravenous replacement. Hyperglycemia should bemanaged with insulin as needed. Clinical status, vital signs,and appropriate laboratory and radiographic studies shouldbe reassessed frequently. Severe acute pancreatitis for whichaggressive fluid resuscitation and maximal supportive careare needed should be managed in the intensive care setting.The complicated course of severe disease often necessitatescontinuous hemodynamic and arterial blood gas monitoring,as well as intensive management of cardiovascular, pulmo-nary, renal, and septic complications.

Traditionally, it has been standard practice to eliminateoral intake of food and liquids early in an acute attack tominimize pancreatic exocrine secretion and halt the auto-digestive process. Nasojejunal feedings have been shown tobe equally effective compared to total parenteral nutrition


(TPN) without some of the more serious complications seenwith TPN and are preferred over TPN. Although it may bereasonable to restrict fat and protein intake to limit pancreaticstimulation, there is little evidence to support the benefit ofa low-fat, low-protein diet.3 Nasogastric suction has not beenshown to improve the clinical course of mild to moderatepancreatitis,47,48 but it is appropriate therapy for patientswith severe nausea and vomiting or significant abdominaldistention and ileus.6,17,19,21

NUTRITIONIn 2002 the European Society for Clinical Nutrition andMetabolism (ESPEN) published a consensus article on the useof nutritional strategies in acute pancreatitis.49 There areseveral risks from parenteral nutrition in a patient with acutepancreatitis, such as catheter-related sepsis, hyperglycemia,suppression of the immune system, and bacterial transloca-tion resulting from a breakdown of the barrier the intestinalmucosa provides. There was no difference in outcomes in pa-tients with acute pancreatitis who received either nasojejunalfeedings or TPN. Disadvantages of TPN include sepsis andhyperglycemia, which can be a result of overfeeding. In addi-tion, TPN costs four times more than nasojejunal feedings.49

An important part of therapy for acute pancreatitis is en-teral nutrition early in the disease. Not only does this helpto preserve body mass, but it also maintains the integrity ofthe structure and prevents the loss of function of the gastroin-testinal tract. Even hypocaloric feedings can be beneficial,as noted by McClave et al.49 Eighty-two percent of patientsin this study who received nasojejunal feedings met theircaloric goal, in contrast with 96% of TPN patients. Despitethe number of patients not receiving adequate caloric intake,the patients receiving nasojejunal feedings showed no differ-ence in terms of infections or length of stay compared toTPN patients.

Similar results have been seen in patients with severepancreatitis. Improvements in systemic inflammatory re-sponses were seen in patients who received nasojejunal feed-ings, compared to patients receiving TPN, who showed littleimprovement.50

Oral feedings may be restarted once pain is under controland the pancreatic enzymes have returned to normal levels.The initial diet should consist mainly of carbohydrates andprotein, with fats being instituted gradually over 3 to 6 days.49

ANALGESIANarcotic analgesics are usually needed to control the severeabdominal pain that often accompanies acute pancreatitis.Transient elevations in serum amylase and lipase that oftenfollow the administration of opiates should not preclude theiruse, because these effects do not appear to be detrimentalto the disease course. Therapy is commonly initiated withmeperidine administered parenterally at regular intervals indoses of 50 to 100 mg because it reportedly causes lessspasm of the sphincter of Oddi than morphine and its deriva-tives.17 However, because there is little evidence to suggest

a clinically significant difference in the degree of sphincterspasm produced by any particular opiate, efficacy should bethe primary guide for analgesic treatment of these patients.3

ANTIBIOTICSInfection is a serious complication in severe acute necrotiz-ing pancreatitis: mortality rates are reported to be approxi-mately 20% to 30% in this patient population.51 Even thoughinfection has emerged as an important cause of death in acutepancreatitis, the role of prophylactic antibiotics remains tobe firmly established. Early studies evaluating the use ofantibiotics in patients with mild disease failed to show anyclinical benefit; therefore, they are not recommended.52 Onestudy suggested that imipenem reduced the incidence of pan-creatic infections, but the incidence of organ failure and themortality rate were not affected.53 Prophylactic cefuroximehas been shown to reduce mortality but not to decrease theincidence of infection.54 It is appropriate to initiate empiricantibiotic therapy in patients with pancreatic necrosis con-firmed by dynamic contrast-enhanced CT scan and clinicalevidence of infection or a deteriorating clinical condition.The presence of infected necrosis should be confirmed witha CT-guided percutaneous needle aspiration of fluid fromnecrotic areas for Gram stain and culture (Fig. 51.3).18,41

Pathogens most often isolated from infected necrosis includeEscherichia coli, Klebsiella pneumoniae, Enterococcus sp,Staphylococcus aureus, Pseudomonas aeruginosa, Proteusmirabilis, Enterobacter aerogenes, and Bacteroides fragilis,presumably originating in the colon.55 The possibility thatinfection results from a fungal source cannot be ruled out,as fungi are found in the intestine as normal flora and theopportunity for superinfection exists with prophylactic anti-biotics.56 An estimated 10% of cases of acute necrotic pan-creatitis are thought to involve fungal organisms. There areno clear recommendations for prophylactic antifungal ther-apy in severe acute pancreatitis. Antibiotics that can achievebactericidal concentrations in pancreatic tissue, such as thefluoroquinolones, metronidazole, and imipenem, should beused.18,52,55 Once infection develops in the necrotic pan-creas, surgical debridement is mandatory.41

CORRECTING BILIARY TRACT DISEASEVirtually all clinicians agree that removing residual biliarytract stones is necessary to prevent recurrent attacks of bili-ary pancreatitis. However, the optimal timing of stone re-moval and the choice between endoscopic and surgical treat-ment are subjects of continuing debate. Early ERCP (within72 hours of admission) is recommended for patients withgallstone pancreatitis who have evidence of biliary sepsis ororgan failure.3,41 Stones in the common bile duct should beremoved and a sphincterotomy performed.41 Otherwise, itappears that either surgical or endoscopic procedures forbiliary duct clearance should be performed before dischargefrom the hospital once pancreatic inflammation has re-solved.6,17


ALTERNATIVE THERAPIES

There are few studies of alternative therapies in acute pancre-atitis. Based on the observation that serum antioxidants aredepleted in acute pancreatitis and the correlation between theamount of depletion and severity of pancreatitis, antioxidanttherapy (N-acetylcysteine, ascorbic acid, and sodium selen-ite given intravenously along with alpha-tocopherol and�-carotene given via a nasogastric tube) in patients withsevere acute pancreatitis has been investigated. Althoughantioxidant levels returned to normal, there did not appearto be any additional benefit from this therapy.57 Some benefithas been shown from including glutamine in TPN formula-tions for acute pancreatitis; however, TPN is no longer apreferred therapy.58

FUTURE THERAPIES

Although medical treatment of acute pancreatitis is currentlysupportive, major goals in the future should include limitingsystemic complications and preventing pancreatic necro-sis.41 Attempts at inflammatory mediator antagonism havefocused on activated pancreatic enzymes; however, the de-structive products of leukocytes, including elastase, phos-pholipase A2, platelet activating factor, nitric oxide, and cy-tokines, have not been addressed in prospective, randomizedtrials. Preliminary studies with the platelet activating factorantagonist lexipafant have demonstrated that a therapeuticwindow exists for cytokine antagonism.59,60 Animal studieshave also shown that colloidal hemodilution may improvethe pancreatic microcirculation and minimize necrosis.3

Well-designed, controlled, prospective studies are warrantedto establish the value of these medical therapies. Additionalstudies are also needed to determine the optimal use of pro-phylactic antibiotics for improving mortality in patients withpancreatic necrosis.

C H R O N I C P A N C R E A T I T I SC H R O N I C P A N C R E A T I T I S

DEFINITION

Chronic pancreatitis is generally defined as an inflammatorydisease process leading to irreversible damage to pancreaticstructure and function. All patients experience fibrosis andloss of exocrine tissue, and many lose endocrine function aswell. The clinical course may consist of recurrent acute at-tacks, which are difficult to distinguish from acute pancreati-tis, or chronic symptoms that usually, but not inevitably,progress. Students of medical history are referred to Pitchu-

IMPROVING OUTCOMES

Early identification of severe acute pancreatitis should en-hance patient outcomes.41 Formalized scoring systems andclinical evidence of organ failure can assist the clinician inthis regard. Severe disease almost invariably warrants man-agement in an intensive care unit for aggressive cardiovascu-lar and pulmonary support. Patients must be reassessed andmonitored throughout the attack for complications, particu-larly organ failure and infection. When infection is sus-pected, pharmacists should assist in selecting and monitoringappropriate antibiotic therapy. Invasive procedures such assurgical debridement of infected necrosis and endoscopic orsurgical removal of gallstones also are important for optimiz-ing patient outcome.41 Cytokine antagonism may eventuallyhave a role in reducing the morbidity and mortality of severeacute pancreatitis.37

In addition, eliminating factors that precipitated the acuteattack may improve the patient’s course and prevent recur-rence of disease.17,21 Pharmacists can assist in identifyingdrug-induced pancreatitis and recommend therapeutic alter-natives for the offending agent. Because alcoholic pancreati-tis is associated with chronic pancreatic damage, substanceabuse counseling should be offered to support the patient’sefforts to abstain.6,21

PHARMACOECONOMICS

Although data about the economic impact of acute pancreati-tis are sparse, experts have recognized the resource demandsof intensive care management in severe disease.61 Becausesurvivors of severe acute pancreatitis report excellent qualityof life, these substantial costs may be justified.61 As disease-specific therapies, such as cytokine antagonists, becomeavailable, their contribution to cost containment must be ana-lyzed.

moni’s review of chronic pancreatitis from the first descrip-tion of the pancreas in 300 BC to the present.62

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 Mar-seilles-Rome system, which distinguishes three types.63 The


first type, chronic calcifying pancreatitis, is the most com-mon, accounting for more than 95% of cases.64 It usuallyresults from alcohol abuse and is characterized by intraductalprotein plugs and, often, calcified stones. The second type,chronic obstructive pancreatitis, is relatively uncommon andoccurs as a result of obstruction of the main pancreatic ductby tumor, stricture, or congenital abnormalities. This typeis notable in that protein plugs and stones are absent, anddamage may be reversible in part when the obstruction isalleviated. The third type, chronic inflammatory pancreatitis,is characterized by fibrosis, infiltration by monocytes, andatrophy of exocrine tissue. This form has been associatedwith autoimmune disease.

A more recent classification is the TIGAR-O system.2,65

This system proposes that there are several risk factors thatmay interact with each other to predispose patients to pan-creatic disease. As a result, this system better addresses thecomplexity and heterogeneity of chronic pancreatitis.

Toxic-metabolic. This classification includes alcohol, themost common etiology of chronic pancreatitis in theUnited States and other developed countries. However,only 10% to 20% of alcoholics develop chronic pancre-atitis.66

Idiopathic. Up to 30% of patients have no identifiable riskfactors for the development of chronic pancreatitis.

Genetic. Several genes have been identified that seem topredispose patients to developing pancreatic disease.

Autoimmune. Although this has been thought to be rare, itmay account for some of the cases of ‘‘idiopathic’’chronic pancreatitis.

Recurrent and severe acute pancreatitis. Although histori-cally acute pancreatitis and chronic pancreatitis havebeen regarded as discrete clinical entities, it is nowthought that severe acute pancreatitis may cause perma-nent damage to the gland.

Obstructive. Obstruction of the main pancreatic duct byneoplasms, stenosis, or other mechanisms can causechronic pancreatic damage.

In summary, the precise etiology of chronic pancreatitisis poorly understood and the subject of ongoing debate.2

Multiple factors may be involved. The role of genetic predis-position has not yet been elucidated, although several geneticmutations have been associated with some forms of chronicpancreatitis. Ethanol abuse is involved in most cases ofchronic pancreatitis, particularly in Western countries, ac-counting for approximately 70% of reported cases. Althougha relatively small percentage of alcoholics actually developclinical symptoms of chronic pancreatitis, as many as 45%show evidence of the disease at autopsy (approximately 50times the incidence in nondrinkers).5 A tropical form alsoexists in some Afro-Asian countries; malnutrition and per-haps dietary toxins are presumed to play a role.67,68 Otherpotential etiologic factors include trauma, hyperparathyroid-ism/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: earlyand late onset. Although gallstone disease may coexist withchronic pancreatitis, cholelithiasis does not appear to predis-pose a patient to this disease.3–5,62,70–72

EPIDEMIOLOGY

As mentioned previously, the incidence and prevalence dataare meager and specific to geographic area. Prevalence esti-mates range from 0.03% to 5%, and the incidence may ap-proximate 3 to 9 per 100,000 inhabitants per year. Men aresubstantially more likely to be affected than women.3–5,62

PATHOPHYSIOLOGY

Over the past several decades, numerous theories have beenadvanced in an attempt to explain the complex pathogenesisof chronic pancreatitis. Although each may describe a pieceof the puzzle, none adequately accounts for all findings. Thismay be due in part to the heterogeneity of the disease, asevidenced by the classification systems discussed previ-ously.2,3

Alcohol-related injury to the pancreas is perhaps thebest understood process. Ethanol is metabolized in pan-creatic acinar cells by both oxidative and nonoxidativepathways. Ethanol, its metabolites, and the resulting in-crease in oxidative stress may all contribute to increasedlocal levels of digestive enzymes and an increased riskof autodigestion. This results in inflammation and therelease of proinflammatory cytokines. Although transform-ing growth factor-� has received much attention in recentyears, other mediators may include platelet-derived growthfactor, interleukin-1 and interleukin-6, and tumor necrosisfactor-�. These mediators in turn activate pancreatic stel-late cells that synthesize collagen and fibronectin, leadingto fibrosis.2,73,74

A related theory that has been widely accepted in thepast proposes that alcohol changes the nature of pancreaticsecretions, predisposing to the formation of protein plugsand stones, leading to ductal obstruction. In the presenceof alcohol, the absolute amount of protein in pancreaticsecretions increases, facilitating the formation of proteinplugs, particularly in the smaller ductules. GP2, a 97-kilodalton protein that is analogous to the renal cast proteinuromodulin, has been isolated from ductal plugs and mayplay a role in their formation.75 The resulting obstructioncan lead to inflammation and fibrosis, and protein plugsact as a nidus for the formation of calcium carbonatestones.3–5 In addition, there is decreased secretion of lith-ostatine, also known as pancreatic stone protein, whichnormally inhibits the formation of insoluble calcium saltsin the ductules. Hence, a deficiency of this protein mayallow increased precipitation of calcium salts, exacerbating


obstruction, inflammation, and fibrosis.3–5,76 Stones, how-ever, are not found in all cases of alcoholic pancreatitis,and this process may not play a central role in the patho-genesis.2

However, alcohol-related injury is only one piece of thepuzzle. A better understanding of the pathogenesis ofchronic pancreatitis may lead to strategies for disease mitiga-tion or prevention.


Signs and SymptomsPain and maldigestion are the hallmarks of chronic pancre-atitis, although a significant number of patients also de-velop diabetes mellitus, pseudocysts, or jaundice.3,5,70,77

The causes of pain have not been delineated, but increasedintraductal and parenchymal pressure, ischemia, pseu-docyst, obstruction of the bile duct, or inflammation, espe-cially in and around the pancreatic nerves, may be in-volved.3,5,78–84 Pain may also be caused by extrapancreaticcomplications such as biliary stricture or duodenal steno-sis.3,5,84 This pain, sometimes accompanied by nausea andvomiting, is similar to that of acute pancreatitis. It isepigastric and often described as deep and penetrating,with a characteristic radiation to the back. Relief may beobtained by leaning forward from a sitting position, andpain is usually aggravated by eating. This pain with eating,in addition to maldigestion and malabsorption, contributesto the weight loss often observed in these patients.3,5,82

Up to 20% of patients may be pain-free, but this is morecommonly the case with idiopathic rather than alcoholicpancreatitis.4,5,62,73,85

Loss of exocrine function occurs in all cases of chronicpancreatitis, but it may remain subclinical until fairly latein the disease. Malabsorption does not manifest itself untilless than 10% of pancreatic secretory function remains.1,84

Lipase activity decreases relatively more than proteaseactivity; therefore, steatorrhea presents earlier and is usu-ally more severe than azotorrhea.3,5,84,86,87 Although somedecrease in absorption of carbohydrates and fat-solublevitamins does occur, symptoms rarely develop.5,84,87 Bicar-bonate secretion also declines with disease progres-sion.64,84,88

The following scenario summarizes the clinical course ofa representative patient. He is an alcoholic who began todrink heavily at age 20 and who started to experience attacksof pain by age 30. Abdominal radiographs showed calcifica-tion of the pancreas. At 40 years of age, pancreatic insuffi-ciency had progressed to the point that steatorrhea was trou-blesome, and he developed glucose intolerance. He was deadat 50, probably from complications of alcoholism rather thanpancreatitis per se.3,4,84,89 Major predictors of mortality ap-pear to be the age at diagnosis (the older the patient, the

worse the prognosis), smoking, and drinking.90 Chronic pan-creatitis is also associated with an increased risk of pan-creatic cancer.91–93

DIAGNOSIS AND CLINICAL FINDINGSA diagnosis of chronic pancreatitis is generally straightfor-ward in an alcoholic patient with recurrent bouts of epigastricpain and evidence of calcification of the pancreas by radiog-raphy. The diagnosis is made more difficult, however, if thepatient is without pain, or if a distinction is sought betweenchronic pancreatitis and either recurring acute pancreatitisor pancreatic cancer. Physical examination and routine labo-ratory tests are of limited utility, since the results are usuallywithin normal limits. Even serum amylase and lipase levelsare generally normal, although they may be elevated duringacute exacerbations or decreased late in the disease. Imagingtechniques and pancreatic function tests provide the mostuseful diagnostic tools.3–5 They are presented below in ap-proximately the order in which they should be consideredbased on effectiveness, invasiveness, and expense. A reviewof diagnostic criteria and methodologies has been recentlypublished.91

Imaging Studies. Radiography can reveal calcifications(usually diagnostic for chronic pancreatitis) and displace-ment of the stomach or duodenum, indicating the presenceof a pseudocyst. Ultrasonography usually shows calcifica-tions, pancreatic enlargement, and pseudocysts, althoughCT is superior at detecting pseudocysts and can revealdilated pancreatic ducts as well as pancreatic enlargementand calcifications. ERCP is the most sensitive procedurefor viewing changes in the ductal system and is currentlyconsidered the gold standard of imaging; however, thereis the risk of causing pancreatitis.1,3,5,94,95 Newer tech-niques such as magnetic resonance cholangiopancreatogra-phy (MR-CP) and endoscopic ultrasonography (EUS) aregaining popularity.3,94

Pancreatic Function Tests. Pancreatic function testsmay be used if imaging studies are inconclusive. These tests,which can be classified as direct or indirect, have been re-viewed extensively.3,5,96–99 Direct tests, including the secre-tin-pancreozymin and Lundh tests, are invasive, requiringintubation of the duodenum. In the secretin-pancreozymintest, usually considered the gold standard for measuring pan-creatic secretory function, a patient is given intravenous se-cretin and CCK, and the subsequent increase in secretion ismeasured. The Lundh test is similar, with pancreatic secre-tion measured after the ingestion of a test meal.

Indirect tests measure markers of pancreatic function inthe blood, urine, breath, or stool. Indirect tests are of limitedusefulness due to their relative lack of sensitivity early inthe course of chronic pancreatitis. Examples of indirect testsinclude measurement of fat or chymotrypsin in stool samplesand measuring urinary excretion of para-aminobenzoic acid(PABA) after hydrolytic cleaving of PABA from NBT-PABA by chymotrypsin in the intestine (bentiromide test).


A combination of imaging studies and pancreatic functiontests may be necessary for a definitive diagnosis of chronicpancreatitis, particularly early in the disease (Table 51.7).


Many patients develop chronic pancreatitis as a result ofalcoholism. This patient population can be very difficult tomanage. If the patient is still actively drinking, every effortshould be made to convince him or her to abstain. Unfortu-nately, however, this may not slow the course of the disease.4

Alcoholics may also be at increased risk for addiction toopioid analgesic agents, complicating pain management.Treatment regimens and follow-up need to be tailored toindividual patient profiles.

THERAPEUTIC PLAN

Chronic pancreatitis is usually progressive and, with the pos-sible exception of the obstructive form, irreversible. Treat-ment, therefore, is directed at managing the pain, maldiges-tion, and other complications that arise from this disease.When a patient presents for medical treatment, assessment of

TREATMENT GOALS: CHRONIC PANCREATITIS

Pain is the symptom that commonly brings patients to the attention of the medical com-munity. Alleviation of this pain is an important goal of therapy. In addition, both exo-crine and endocrine insufficiency must be appropriately managed. Treating exocrine in-sufficiency will be discussed in this chapter, while insulin insufficiency is covered inChapter 40. Diabetes develops in 40% to 80% of chronic pancreatitis patients, usuallylate in the course of the disease.3,5 One key difference between type 1 diabetes mellitusand pancreatic diabetes should be mentioned, however: in chronic pancreatitis, there isloss of glucagon as well as insulin secretion, leading to diabetes that is very hard tocontrol, or ‘‘brittle.’’3

■ Control pain using analgesics, enzyme replacement, and endoscopic and surgical treat-ment

■ Manage maldigestion and malabsorption through enzyme replacement■ Manage diabetes

TREATMENT

PharmacotherapyPain. The pain of chronic pancreatitis, which may be epi-sodic or persistent, is a poorly understood phenomenon,complicating decisions about therapy. The lack of controlledclinical trials makes it difficult to define treatment strategies.As a result, there has not been a universally accepted stan-dard of care for these patients. Warshaw et al sought toaddress this in their review of pain management,98 and they

Imaging TechniquesPlain abdominal radiographyUltrasonographyComputed tomographyMagnetic resonance cholangiopancreatographyEndoscopic retrograde cholangiopancreatographya

Pancreatic Function TestsDirect tests: measurement of pancreatic exocrine secretions

Secretin-pancreozymin testa

Lundh testIndirect tests: measurement of enzyme action

Bentiromide (NBT-PABA) testFecal chymotrypsin concentrationFecal fat analysis

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

TABLE 51.7 Selected Diagnostic Tests for ChronicPancreatitis

symptoms and prior medication use is an important startingpoint. In particular, narcotic use and potential for addictionshould be evaluated.

proposed an algorithm for the treatment of pain in chronicpancreatitis (Fig. 51.4).99

Abstinence from alcohol may reduce pain in up to 50%of patients, but the majority will require some form of anal-gesia.79,82,85,87 Having patients keep a log of their pain mayaid in assessment.98 Salicylates, nonsteroidal anti-inflamma-tory drugs, or acetaminophen should be tried initially, per-haps in conjunction with a low-fat diet.98 Adjunctive therapywith tricyclic antidepressants or selective serotonin reuptakeinhibitors may prove beneficial in some patients, althoughevidence of efficacy is merely anecdotal.81,83,85,98


No response

No response

Surgery chosen

Small ducts

Consider nerve ablation in controlled setting

Pancreatic resection

Large ducts

Surgical drainage

Pseudocyst, biliarystricture, duodenal

stenosis, peptic ulcerdisease, 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 andfill out quality-of-life questionnaire

Discuss with patient watchful waiting vs. narcotic analgesics andrisk of addiction vs. benefits and risks of surgery

Patient with chronic pancreatitis and pain

CT � ERCP � EUS � upper endoscopy or upper GI

8 week trial of high-dose pancreatic enzymes (in tablet form) � acid suppression

Consider trial of endoscopic therapy

Endoscopic therapy not performed or no response

FIGURE 51.4 Guideline for treatment of pain in chronic pancreatitis. BS, biliary stricture; CT, com-puted tomography; DS, duodenal stenosis; ERCP, endoscopic retrograde cholangiopancreatogra-phy; EUS, endoscopic ultrasonography; PS, pseudocyst; PUD, peptic ulcer disease. (Reprinted withpermission from Warshaw AL, Banks PA, Fernandez-del Castillo C. AGA technical review on treat-ment of pain in chronic pancreatitis. Gastroenterology 115:763–764, 1998.)


Enzyme replacement therapy, which will also be discussedfor the treatment of maldigestion, may help to alleviate pain,especially in patients with nonalcoholic chronic pancreati-tis.3,7,72,82–84,98 Clinical trial data have not always shown ef-fectiveness, however.3,73,84,98,100 It is presumed that the pres-ence of exogenous proteases in the duodenum suppressespancreatic function through a negative feedback mechanism.This mechanism involves degradation of a CCK-releasingpeptide by trypsin in the duodenum, inhibiting the release ofCCK.3,14,98,101 Enzymes contained in nonenteric-coatedpreparations may be more reliably delivered to the duodenumthan enzymes from enteric-coated dosage forms, since the lat-ter are sometimes released in more distal portions of the smallintestine. This is due to the relatively low duodenal pH causedby decreased bicarbonate secretion in chronic pancreati-tis.63,88 As a result, nonenteric preparations may be more ef-fective at suppressing CCK release and reducing pain.1,3,72,98

In theory, the addition of an H2-receptor antagonist or a protonpump inhibitor could decrease acid-stimulated pancreatic se-cretion and diminish pain, but this has not been demonstrated.These agents are frequently tried due to their ease of use andrelative safety.84,98

Other agents may also have utility in the control of pain.Octreotide, a somatostatin analogue, has not consistentlydemonstrated efficacy in chronic disease,1,84,98 but it mayhave a role in the management of pancreatic pseu-docysts102,103 and in decreasing complications after pan-creatic surgery.104 Antioxidant therapy may also prove bene-ficial, since patients with chronic pancreatitis seem to bedeficient in endogenous antioxidants.3,84,98 Further study isrequired before specific recommendations can be made,however.

For patients still experiencing pain, the choices remainingare opioid analgesics and interventional therapy. Unfortu-nately, there are no well-defined criteria for making thisdecision. Opioid analgesics may prove very effective, al-though there is a very real risk of addiction, particularly inthis patient population.73,84,98,105 Refer to Chapter 64 for adiscussion of these agents.

Despite maximum medical management, up to 30% ofpatients still experience pain.89 This pain may diminish, or‘‘burn out,’’ over time as the pancreas becomes progres-sively more fibrotic, but this phenomenon may not occur inas many patients as was once thought.3,73,98 Approximatelyhalf of chronic pancreatitis patients will require endoscopicor surgical intervention to control pain, although this maynot reliably improve qualify of life.1

Endoscopic treatment may be effective for stenosis, stric-tures, or stones. Stent placement relieves intraductal pressureand pain in many patients, although there is a risk of ductalinjury. Patients may also experience pain relief with theelimination of intraductal pancreatic stones by lithotripsy orpancreatic duct sphincterotomy. Improvement is reported in50% to 85% of patients undergoing endoscopic therapy, butmany questions remain.3,95,98,106

Surgery is usually reserved for the patients with intracta-ble pain. The procedure of choice for patients with dilatedducts (larger than 6 or 7 mm) is surgical drainage with aprocedure called lateral pancreaticojejunostomy. For pa-tients with small duct disease, surgical denervation and pan-creatic resection are options. These procedures have beenreviewed extensively.3,72,98,107–109

Maldigestion/Malabsorption. Patients with docu-mented weight loss and steatorrhea should receive treatmentfor maldigestion. Two types of pancreatic enzyme replace-ment preparations are currently available. Pancreatin is de-rived from freeze-dried porcine or bovine pancreases andcontains at least 2 USP units of lipase and 25 USP unitseach of protease and amylase per milligram. Pancrelipase,extracted from porcine pancreases, is more potent, contain-ing 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 avail-able. While rapid-release forms more reliably deliver pro-teases to the upper duodenum, where they may exert a nega-tive feedback inhibitory effect, they expose lipase to the acidenvironment of the stomach. Lipase is pH labile, maximallyactive at pH 8 and irreversibly inactivated at pH less than4. Enteric-coated microspheres, which dissolve at approxi-mately pH 5.6 to 6.0, better protect lipase from gastric acid-ity, but enzyme release may be delayed. While rapid-releaseforms are preferable for pain control, enteric-coated productsare more effective in the treatment of steatorrhea.1,72,84

Since lipid malabsorption and steatorrhea are the primaryclinical problems associated with pancreatic insufficiency,the dose of lipase to be delivered to the duodenum is a para-mount concern. Maximal postprandial delivery of lipasefrom a normal pancreas is 140,000 units per hour for 4 hours.Supplying 5% to 10% of this will significantly decrease ste-atorrhea; therefore, the enzyme supplement should usuallyprovide approximately 30,000 (25,000 to 40,000) units overa 4-hour period, although regimens should be individualizedfor each patient.3,70,84,109–111

Efficacy of therapy can be assessed by monitoring the fatcontent of stools. If steatorrhea persists, another agent canbe added to increase gastric pH in an attempt to increase thedelivery of active lipase to the duodenum. Agents that maybe useful include H2-receptor antagonists and proton pumpinhibitors.12,73,84,108,112

Even with careful management of supplements, however,the elimination of steatorrhea is very difficult.12,109 Researchinto other forms of enzyme replacement therapies, includingbacterial lipase and bioengineered human gastric lipase, areongoing.109,110 Figure 51.5 presents one possible approachto enzyme replacement therapy for steatorrhea.

Patients should be counseled to take supplements justbefore or with meals. The microspheres/microtablets con-tained in capsules should not be crushed, but they may bemixed with soft food such as applesauce, if necessary. ThepH of the food should be below 5 to avoid premature dissolu-


Enzyme Content (USP Units)

Producta Formulationb Dosage Formc Lipase Protease Amylase

Rapid ReleaseCotazym PL C 8,000 30,000 30,000Donnazyme PC T 1,000 12,500 12,500Ku-Zyme HP PL C 8,000 30,000 30,000Panokase PL T 8,000 30,000 30,000Pancreatin 4x USP PC T 12,000 60,000 60,000

8x USP PC T 22,500 180,000 180,000Viokase PL P 16,800 70,000 70,000Viokase 8 PL T 8,000 30,000 30,000Viokase 16 PL T 16,000 60,000 60,000

Delayed-Release CapsulesCotazym-S PL MS 5,000 20,000 20,000Creon 5 Minimicrospheres PL MS 5,000 18,750 16,600Creon 10 Minimicrospheres PL MS 10,000 37,500 33,200Creon 20 Minimicrospheres PL MS 20,000 75,000 66,400Encron 10 PL MS 10,000 37,500 33,200Lipram 4500 PL MS 4,500 25,000 20,000Lipram-PN10 PL MS 10,000 30,000 30,000Lipram-CR10 PL MS 10,000 37,500 33,200Lipram-UL12 PL MS 12,000 39,000 39,000Lipram-PN16 PL MS 16,000 48,000 48,000Lipram-UL18 PL MS 18,000 58,500 58,500Lipram-UL20 PL MS 20,000 65,000 65,000Lipram-CR20 PL MS 20,000 75,000 66,400Pancrebarb MS-8 PL MS 8,000 45,000 40,000Pancrease PL MS 4,500 25,000 20,000Pancrease MT-4 PL MT 4,000 12,000 12,000Pancrease MT-10 PL MT 10,000 30,000 30,000Pancrease MT-16 PL MT 16,000 48,000 48,000Pancrease MT-20 PL MT 20,000 44,000 56,600Pancron 10 PL MS 10,000 37,500 33,200Pancron 20 PL MS 20,000 75,000 66,400Ultrase PL MS 4,500 25,000 20,000Ultrase MT12 PL MT 12,000 39,000 39,000Ultrase MT18 PL MT 18,000 58,500 58,500Ultrase MT20 PL MT 20,000 65,000 65,000Zymase PL MS 12,000 24,000 24,000

a These products, available before passage of the 1938 Food, Drug, and Cosmetic Act, are not approved by the FDA and cannot be consideredpharmaceutically or therapeutically equivalent.11

b PC, pancreatin; PL, pancrelipase.c C, capsule; MS, enteric-coated microspheres; MT, enteric-coated microtablets; P, powder; T, tablet.

TABLE 51.8 Some Commercial Pancreatic Enzyme Preparations


FIGURE 51.5 Treatment of steatorrhea.

Increase dosage.

If unsuccessful

If unsuccessful

If unsuccessful

Administer enteric-coated pancreatic extract preparation(approximately 28,000 U lipase per meal).

Decrease fat intake to 50–75 g/day (normal American diet, 100 g/day),or use smaller, more frequent meals.

Add an H2 receptor antagonist or proton pump inhibitor.

If unsuccessful

Try a different enzyme preparation.

If unsuccessful

Consider an alternative diagnosis.

tion of the enteric coating. Different products may not bebioequivalent, and changes in regimen should not be madewithout consulting a physician or pharmacist.84

Problems that may be encountered with enzyme-replace-ment therapy, especially at high doses, include abdominalpain, oral and perianal irritation, nausea, vomiting, diarrhea,and rare hypersensitivity. There have also been reports ofhyperuricosuria, although this appears to be more commonin cystic fibrosis patients receiving very high doses of pan-creatic enzymes. Finally, patient compliance is often lessthan optimal due to the administration of large numbers ofcapsules, gastrointestinal distress, and expense.13,70 Theoverall safety and tolerability of pancreatic extracts, how-ever, appears to be good.113

FUTURE THERAPIES

Chronic pancreatitis is a heterogeneous disease state, and itis likely that response to a therapeutic modality depends, atleast in part, upon the etiology and clinical course of thedisease in a particular patient. This has not been addressedto date in clinical trials, since the study populations generallyreflect the heterogeneity of the population at large. Definingwhich patient subgroup may benefit from a particular ther-apy will help to guide treatment. Gene therapy, althoughyears from clinical application, may prevent or reverse pan-creatic damage in certain patients.1,111,114

IMPROVING OUTCOMES

This patient population presents challenges, particularly ifthere is continued alcohol consumption. Substance abuseprograms may help to establish and maintain abstinence, andreferral to a pain clinic may be warranted. A multidiscipli-nary team approach should improve patient outcomes, al-though evidence for this approach is only anecdotal. Onephysician should manage narcotic analgesics.83

Quality of life data are sparse, and much of the data hasbeen collected in patients who have undergone surgical inter-vention.3,85,115 A more global study was recently conductedin Germany.116 In this study, patients with chronic pancreati-tis reported lower quality of life in all areas surveyed. Asone might expect, chronic pain, pancreatic diarrhea, and un-employment were particularly problematic. There are alsodata to suggest that the development of insulin-requiringdiabetes has a significant negative impact on quality oflife.115 Improving therapeutic outcomes will almost certainlycontribute to improved quality of life for patients withchronic pancreatitis.

PHARMACOECONOMICS

To date, no studies have been published evaluating the eco-nomic impact of chronic pancreatitis or its therapy. This


information will be needed to refine emerging therapeuticalgorithms.

KEY POINTS

■ Acute and chronic pancreatitis have historically beenconsidered distinct clinical entities that are often, al-though not always, alcohol-related. Acute pancreatitisis an autodigestive process characterized by inflamma-tion, edema, and necrosis, while chronic pancreatitis isthe result of poorly understood processes leading to ir-reversible loss of functional tissue. In acute pancreati-tis, it is important to establish the severity of the attackso that appropriate therapy can be instituted and the pa-tient’s risk for developing complications evaluated.With chronic pancreatitis, care is directed toward painrelief and managing declining endocrine and exocrinefunction. In both, therapy remains almost exclusivelysupportive. Although there have been recent advancesin our understanding of pathophysiology and treatment,much remains unclear

■ Controlled clinical trials are needed to assess the roleof medical therapy directed at the underlying pathogen-esis 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 willlikely require intensive care, including fluid replace-ment and nasojejunal feeding. Pain managementwith an opioid analgesic is usually required

❍ Antibiotic prophylaxis is not recommended in casesof acute pancreatitis

❍ Patients should be assessed throughout the course ofan acute attack for the development of complica-tions such as organ failure and infection

❍ Therapy for acute pancreatitis is supportive. Futuretherapies will be directed at curtailing the inflamma-tory process

Chronic Pancreatitis:❍ Most cases of chronic pancreatitis are alcohol-

related 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 man-

aging pain, steatorrhea, diabetes, and other complica-tions

❍ Future trials of chronic pancreatitis should stratifypatients by etiology or clinical course, compare treat-ment regimens, determine the cost-effectiveness oftherapy, and assess patients’ quality of life

SUGGESTED READINGS

Meier R, Beglinger C, Layer P, et al. Consensus statement: ESPENguidelines on nutrition in acute pancreatitis. Clin Nutr 21:173–183,2002.

Mitchell RMS, Byrne MF, Baillie J. Pancreatitis. Lancet 361:1447–1455, 2003.

Nathens AB, Curtis JR, Beale RJ, et al. Management of the critically illpatient with severe acute pancreatitis. Crit Care Med 32:2524–2536,2004.

REFERENCES

1. Mitchell RMS, Byrne MF, Baille J. Pancreatitis. Lancet 361:1447–1455, 2003.

2. Stevens T, Conwell DL, Auccaro G. Pathogenesis of chronic pan-creatitis: an evident-based review of past theories and recent devel-opments. Am J Gastroenterol 90:2256–2270, 2004.

3. Fosmark CE. Chronic pancreatitis. In: Feldman M, Sleisenger MH,Scharschmidt BF. Gastrointestinal and Liver Disease: Pathophysiol-ogy, Diagnosis, Management. 6th ed. Philadelphia: WB Saunders,1998:809.

4. Steer ML, Waxman I, Freedman S. Chronic pancreatitis. N Engl JMed 332:1482–1490, 1995.

5. Owyang C, Levitt MD. Chronic pancreatitis. In: Yamada T. Text-book of Gastroenterology. 2nd ed. Philadelphia: JB Lippincott,1995:2061.

6. Gorelick FS. Acute pancreatitis. In: Yamada T. Textbook of Gastro-enterology. 2nd ed. Philadelphia: JB Lippincott, 1995:2064.

7. Magee DJ, Burdick JS. Anatomy, histology, embryology, and devel-opmental anomalies of the pancreas. In: Feldman M, SleisengerMH, Scharschmidt BF. Gastrointestinal and Liver Disease: Patho-physiology, Diagnosis, Management. 6th ed. Philadelphia: WBSaunders, 1998:871.

8. Simeone DM, Mulholland MW. Pancreas: anatomy and structuralanomalies. In: Yamada T, ed. Textbook of Gastroenterology. 4thed. Philadelphia: Lippincott Williams & Wilkins, 2003:2013–2026.

9. Pandol SJ. Pancreatic physiology and secretory testing. In: Feld-man M, Sleisenger MH, Scharschmidt BF. Gastrointestinal andLiver Disease: Pathophysiology, Diagnosis, Management. 6th ed.Philadelphia: WB Saunders, 1998:871.

10. Owyang C, Williams JA. Pancreatic secretion. In: Yamada T. Text-book of Gastroenterology. 2nd ed. Philadelphia: JB Lippincott,1995:361.

11. Valenzuela JE, Pancreatic physiology. In: Valenzuela JE, ReberHA, Ribet A. Medical and Surgical Diseases of the Pancreas. NewYork: Igaku-Shoin, 1991:1.

12. Lebenthal E, Rolston DDK, Holsclaw DS. Enzyme therapy for pan-creatic insufficiency: present status and future needs. Pancreas 9:1–12, 1994.

13. Chey WY. Regulation of pancreatic exocrine secretion. Int J Pan-creatol 9:7–20, 1991.

14. Owyang C, Louie DS, Tatum D. Feedback regulation of pancreaticenzyme secretion: suppression of cholecystokinin release by tryp-sin. J Clin Invest 77:2042–2047, 1986.

15. DiMagno EP, Chari S. Acute pancreatitis. In: Feldman M,Sleisenger MH, Scharschmidt BF. Gastrointestinal and Liver Dis-ease: Pathophysiology, Diagnosis, Management. 6th ed. Philadel-phia: WB Saunders, 1998:913.

16. Bradley EL. A clinically based classification system for acute pan-creatitis. Arch Surg 128:586–590, 1993.

17. Marshall JB. Acute pancreatitis: a review with an emphasis on newdevelopments. Arch Intern Med 153:1185–1198, 1993.

18. Banks PA. Acute pancreatitis: medical and surgical management.Am J Gastroenterol 89(Suppl):S78–85, 1994.

19. DiMagno EP. Treatment of mild acute pancreatitis. In: Bradley EL.Acute pancreatitis: diagnosis and therapy. New York: Raven, 1994:261–263.

20. Topazian M, Gorelick FS. Acute pancreatitis. In: Yamada T. Text-book of Gastroenterology. 2nd ed. Philadelphia: JB Lippincott,1995:2026.

21. Steinberg W, Tenner S. Acute pancreatitis. N Engl J Med 330:1198–2010, 1994.

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