Hepatic and Pancreatic Disorders

Cirrhosis

As the liver sustains repeated injury and inflammation over a long time, a process referred to as fibrosis takes place. Fibrosis leads to the replacement of normal liver cells with scar tissue. The function of the remaining normal liver cells is often able to compensate for the initial fibrosis. Once the fibrosis gets severe enough, the structure of the liver cells and blood vessels is altered, and the liver starts to lose the ability to perform its normal functions. This advanced stage is referred to as cirrhosis, also sometimes called end-stage liver disease. The development of cirrhosis is a slow process and patients may not be aware that they have it until complications are present or abnormalities are identified on laboratory examination of liver function tests. Patients with cirrhosis may develop complications such as jaundice, an enlarged spleen, ascites, hepatic encephalopathy (HE), edema, and an increased risk for liver cancer.^4–6 When these complications are present patients are then referred to as having decompensated cirrhosis.⁷

Laboratory abnormalities seen in patients with cirrhosis often include increased or normal AST/ALT (liver function tests), low serum albumin, increased serum bilirubin and prothrombin time (or INR), anemia, and low platelets. Once cirrhosis develops, the damage to the liver is generally considered to be irreversible. Patients may ultimately require a liver transplant as a consequence of cirrhosis.

Variceal Bleeding

Blood entering the liver through the portal vein can usually flow through the sinusoids without much resistance. Once patients develop cirrhosis, the structural changes and presence of scar tissue in the liver cause increased resistance to blood flow within the liver. This limits the ability of blood to flow easily into the liver from the portal vein and leads to a backup of blood flow and increased pressure in the portal vein. This process ultimately results in increased pressure within the portal vein, referred to as portal hypertension. This increased pressure in the portal vein causes a backup of blood flow in the blood vessels in the surrounding area that empty into the portal vein leading to collateral vessel formation. These blood vessels, located mostly in the esophagus or stomach, significantly enlarge and protrude close to the surface. These enlarged vessels are referred to as varices. Approximately 50% of patients with cirrhosis have gastroesophageal varices, and the percentage of patients with varices increases as the liver disease becomes more severe.^5–7

Once varices are present, they can continue to increase in size and may protrude into the center of the esophagus. The most serious (and sometimes even fatal) complication that can occur is bleeding secondary to rupture of the varices. Following an acute bleeding episode, patients are at high risk for rebleeding, with this risk being highest within the first 5 days after the bleeding episode.⁵ Certain drug and nondrug therapies may be used to prevent a first episode of bleeding in patients with varices (referred to as primary prevention) or to prevent future bleeding in patients who have already experienced a variceal bleeding episode (called secondary prevention).

Ascites

By definition, ascites is the presence of fluid in the peritoneal cavity. It is one of the most common complications of cirrhosis and occurs in up to 50% of patients within 10 years of their diagnosis.⁶ The development of ascites is related to both portal hypertension and dilation of the blood vessels that supply the liver and the gastrointestinal (GI) system. This dilation of blood vessels is due to the increased local production of substances such as nitric oxide, which cause the blood vessels to relax and increase blood flow. The shift in blood flow causes the blood volume in the rest of the arterial system to decrease. The body senses this and institutes processes that lead to sodium and water retention to try and maintain arterial blood volume. Since blood flow through the liver is already compromised in cirrhosis, excessive sodium and water retention causes fluid to leak out of the surface of the liver into the peritoneal cavity. The rate of death due to ascites is approximately 44% within 5 years.⁶

Patients with ascites may have several liters of fluid present in their peritoneal cavity. This causes patients to develop serious abdominal swelling, which can limit mobility and cause shortness of breath if the fluid presses on the diaphragm and does not allow the lungs to expand normally. Patients often complain of abdominal discomfort and may gain several pounds of weight because of the large amount of fluid that is retained. Patients may also develop hernias due to the increased pressure in the abdominal cavity. The fluid may also become infected with bacteria, leading to the development of spontaneous bacterial peritonitis. Samples of the ascitic fluid may be taken by inserting a needle through the abdominal wall into the peritoneal cavity. This is called paracentesis. Patients who don’t respond to drug treatment for ascites may need paracentesis on a regular basis to remove large amounts of fluid (more than 5 liters) to relieve their symptoms. Alternatively, patients may require placement of a stent, called a TIPS (transjugular intrahepatic portosystemic shunt), to reduce pressure in the portal vein with the hopes of reducing the rate of ascitic fluid production.⁴ The ultimate cure for ascites is liver transplantation.

Hepatic Encephalopathy

Hepatic encephalopathy (HE) is a metabolic disorder that is another common complication of cirrhosis. Patients with HE experience alterations in mental status, consciousness or alertness, behavior, and muscle function. The primary reason patients develop HE is thought to be the accumulation of various substances in the bloodstream that are normally detoxified by the liver. The major substance involved in the development of HE is ammonia. Ammonia is produced by various tissues in the body but is mostly produced in the colon as a byproduct of bacterial protein metabolism. Ammonia enters the bloodstream via the portal vein. The hepatocytes metabolize the ammonia to urea, which is then mostly excreted through the kidney. Some urea does diffuse back into the intestines from the bloodstream, where bacteria convert it back into ammonia. In patients with liver disease, less ammonia is converted into urea, and the excess may enter the central nervous system, leading to significant dysfunction. Other substances may also contribute to the development of HE but to a lesser extent than ammonia. Several additional factors may precipitate HE, and ammonia may sensitize the brain to the effects of these factors. Precipitating factors include excess protein intake, infection, GI bleeding, electrolyte disturbances, acidosis, and drugs that have sedative or central nervous system depressant effects, such as narcotics.⁸

Patients with HE require a lot of focused care. They may appear sleepy or confused and may be unable to cooperate with their caregivers. They may also be unable to perform routine tasks that require fine motor function and be confined to a bed in severe cases. Patients with HE may also have disturbances in their sleep patterns and may exhibit bizarre or aggressive behavior. If untreated, patients may fall into a coma. Fortunately, HE may be reversible with the removal of precipitating factors, restriction of protein intake, and initiation of drug treatment.

Spontaneous Bacterial Peritonitis

Infections are another common complication of cirrhosis. Spontaneous bacterial peritonitis (SBP) is an often-fatal complication, and occurs when bacteria cause infection of the ascitic fluid within the peritoneal cavity.^6,7 Infection is thought to occur by a process known as bacterial translocation, in which bacteria migrate from the intestinal tract into the bloodstream and ultimately end up in the ascitic fluid. This is secondary to the reduced immune system function that develops in patients with cirrhosis, possible bacterial overgrowth in the intestines, and reduced GI motility. Once bacteria enter the ascitic fluid, the dysfunction of the immune system caused by chronic liver disease results in a lack of clearance of the bacteria. The most common bacteria that cause SBP are organisms that normally reside in the intestinal tract, such as Escherichia coli, Klebsiella, or Proteus. Gram positive organisms, such as Staphylococcus or Streptococci, may also be present. Risk factors for the development of SBP include a low ascitic fluid protein, increased serum bilirubin, and the presence of variceal bleeding.^7,8

Patients who develop SBP may have signs or symptoms that include fever, abdominal pain or tenderness, altered mental status, vomiting, or diarrhea. Laboratory values may indicate an elevated white blood cell count in the ascitic fluid or presence of an elevated blood urea nitrogen (BUN) or lowered bicarbonate concentration (acidosis). The diagnosis is ultimately made by performing a paracentesis. The presence of inflammation secondary to SBP may also lead to decreased perfusion of the kidney. Kidney dysfunction is a major concern and is a leading cause of mortality in patients with SBP.⁷ Once patients have SBP they often require lifelong antibiotic treatment to prevent further SBP episodes.

Beta Blockers for Prevention of Variceal Bleeding

Beta-adrenergic antagonists (often referred to as “beta blockers”) are traditionally used for patients with cardiovascular conditions such as high blood pressure, heart failure, heart attack, or rapid heart rate (as discussed in Chapters 15 and 16). However, in patients with cirrhosis, beta blockers are used for the prevention of variceal bleeding. Beta blockers work by inhibiting the actions of epinephrine and norepinephrine at the beta-receptor. Stimulation of beta₁ (β₁) receptors causes increases in heart rate and blood pressure, while stimulation of beta₂ (β₂) receptors causes relaxation of the smooth muscles in the airways and in the blood vessels in the GI system. The stimulation of the beta₂ receptor causes the blood vessels in the GI system to dilate, therefore increasing blood flow to the portal vein.

Beta blockers are thought to prevent variceal bleeding by reducing heart rate and cardiac output (β₁ effects), therefore reducing the amount of blood that is pumped to the GI system and portal vein. This results in reductions in portal vein pressure. They also prevent the dilation of the blood vessels in the GI system (β₂ effects), causing these blood vessels to constrict and further reduce blood flow to the portal vein. To have these favorable effects, the use of agents that block both β₁ and β₂ receptors, also referred to as “nonselective” beta blockers, is required. The most commonly used nonselective beta blockers are propranolol, carvedilol, and nadolol. Beta blockers that only target the β₁ receptor, such as atenolol or metoprolol, are less effective and therefore are not recommended for the prevention of variceal bleeding. Patients who are candidates for the use of beta blockers for primary prevention are those with advanced cirrhosis and “high-risk varices,” which are either small varices that have certain characteristics, called red wale marks (seen during endoscopy), or any patient with medium or large varices. Any patient who experiences an episode of variceal bleeding should receive a nonselective beta blocker for secondary prevention of a future episode.

Beta blockers can significantly reduce the rate of variceal bleeding. Propranolol is typically started at a low dose of 20 mg orally twice daily or 10 mg orally 3 times daily. A typical starting dose for nadolol is 40 mg once daily. The goal is to reduce the heart rate by at least 25% from baseline to a goal of 55–60 beats/minute. Once patients reach the maximum effective dose, they may be switched to long-acting formulations that are given once daily to improve adherence.

Unfortunately, beta blockers may be associated with many side effects, including fatigue, low blood pressure and heart rate, shortness of breath, lightheadedness, nausea, insomnia, and sexual dysfunction. Increases in blood sugar or potassium levels may also occur. Patients with asthma, those with diabetes who experience frequent hypoglycemia, those with peripheral vascular disease or preexisting low heart rate should not receive beta blockers. For patients who cannot tolerate beta blockers, the preferred method of prevention is endoscopic variceal ligation. This procedure involves placing rubber bands around the varices during endoscopy, which cause the varices to become necrotic and die.

Diuretics for Management of Ascites and Edema

Diuretics are medications that work by increasing fluid and sodium loss through the kidney. The main role of diuretics in patients with cirrhosis is the treatment of ascites and edema (leg and ankle swelling). The main goals of diuretic therapy are to reduce patient symptoms and remove an adequate amount of fluid and sodium. Prior to starting diuretics, patients should restrict their intake of sodium to less than 2,000 mg/day. This will help to prevent further formation of ascites and edema; however, these restrictions are very difficult to follow for most patients.

The most common diuretic regimen used in the treatment of ascites is the combination of furosemide and spironolactone.^6,7 Furosemide is a potent loop diuretic that causes rapid excretion of water and sodium from the kidney. Furosemide is typically started at an oral dose of 40 mg once daily in the morning.⁶ It is also available as an intravenous (IV) preparation that can be used in hospitalized patients with severe ascites and edema, or in patients who cannot swallow. IV doses range from 20–80 mg and may be repeated several times throughout the day. Spironolactone is a potassium-sparing diuretic that works synergistically with furosemide. While its diuretic effects are much weaker than furosemide, spironolactone also has favorable effects on blocking the effects of aldosterone, the main hormone that leads to excessive sodium and water retention in patients with cirrhosis. It also helps to offset the loss of potassium that occurs with furosemide. A typical starting dose of spironolactone is 100 mg once daily in the morning, given in combination with 40 mg furosemide.⁶

Once diuretic therapy is started urine output should be monitored to ensure effectiveness. Most patients will also be weighed daily to mark fluid loss. The use of furosemide may cause excessive loss of sodium and potassium, so these laboratory values are usually monitored closely. Furosemide may also cause increases in ammonia production in the kidney, which may precipitate HE. Spironolactone use may be associated with elevated blood concentrations of potassium. In addition, male patients may experience painful breast swelling, called gynecomastia, because spironolactone may cause reduced effects of testosterone in the body. If the patient experiences gynecomastia an alternate potassium-sparing diuretic, such as amiloride, may be substituted, although this drug may be less effective and is more costly.

For patients who are acutely symptomatic from massive ascites or those who are unresponsive to diuretic therapy, removal of fluid by performing periodic paracentesis may be needed. Paracentesis, while faster at removing fluid than diuretics, is only a symptomatic intervention and does not address the underlying process that leads to formation of ascites. Removal of large quantities of fluid (> 5 L) via paracentesis may cause shifting of fluid from the bloodstream back into the peritoneal cavity. This may reduce blood flow to the kidney, leading to kidney failure. IV albumin may be administered in this setting to help prevent kidney failure. Ultimately, patients may need a liver transplant or placement of a TIPS shunt to alleviate ascites.

Lactulose for Treatment and Prevention of Hepatic Encephalopathy

As discussed earlier, the major substance thought to contribute to the development of HE is ammonia. Thus, therapies that are effective at managing HE are those that reduce blood concentrations of ammonia. One such drug is the nonabsorbable sugar lactulose. Lactulose is available as a solution that contains 10 g lactulose/15 mL (tablespoon) or as 10-g or 20-g powder packets that can be dissolved in water. When ingested orally lactulose is not absorbed—it remains in the intestine and is broken down by bacteria in the colon to acetic acid and lactic acid. This makes the environment of the colon more acidic. Ammonia (the chemical designation is NH₃) in the acidified colon is converted to a charged form called ammonium ion (NH₄⁺) that cannot pass back through the intestine into the bloodstream. Additionally, lactulose acts as a laxative and causes increased frequency of bowel movements. This leads to excretion of ammonia in the stool, which ultimately reduces blood ammonia concentrations and improves the symptoms of HE. A typical starting dose of lactulose is 20–30 g (30–45 mL) every 1–2 hours until one-two soft bowel movements occur. Once this happens the dose is reduced to maintain two to three bowel movements a day. A typical maintenance dose is 10–20 g (15–30 mL) orally two or three times a day.

Lactulose therapy is commonly used for both acute and chronic management of HE. Since lactulose is a laxative, the main adverse effect seen in practice is diarrhea. Doses may be reduced in patients who experience more than two to three bowel movements daily. Patients may have difficulty with adherence to lactulose therapy because of the need to have frequent bowel movements. Diarrhea may lead to dehydration in severe cases, as well as loss of potassium through the GI tract. Lactulose may also cause abdominal cramping and distension, as well as flatulence. Lactulose tastes very sweet, which may not be appealing to some patients.

Antibiotics for Prevention and Treatment of Spontaneous Bacterial Peritonitis and Hepatic Encephalopathy

Antibiotics have various roles in the management of the complications of chronic liver disease, including both prevention and treatment of SBP and HE. These drugs are discussed extensively in Chapter 27 but will be introduced here in context. For patients who have not had a prior episode of SBP, antibiotics may be prescribed on a chronic basis to select patients to prevent a first episode (primary prevention). Antibiotics also reduce the rate of development of SBP and improve rates of survival in the setting of acute variceal bleeding.

The most common antibiotics used for SBP prevention in patients with acute variceal bleeding are third-generation cephalosporins, such as ceftriaxone 1 g IV every 24 hours.^6,7 Alternatively, systemic antibiotic therapy with ciprofloxacin or levofloxacin may be considered. There is concern, however, for an increase in potential adverse effects with these agents.

Patients who develop an acute episode of SBP are typically hospitalized and require systemic IV antibiotic treatment as initial therapy for a total of 5 days. This is usually a third-generation cephalosporin, such as ceftriaxone, often in combination with IV albumin. Albumin where indicated based on lab values, is thought to prevent the development of kidney failure in patients with SBP.^6,7 More broad-spectrum antibiotics, such as piperacillin/tazobactam or meropenem, may be required if the patient has a previous history of SBP or develops the infection during hospitalization. Ciprofloxacin and levofloxacin may be options in patients with serious penicillin allergies; however, the potential for serious adverse effects needs to be considered. Aminoglycoside antibiotics, such as gentamicin or tobramycin, should be avoided, as they can cause serious injury to the kidney. The antibiotics should also be dose-adjusted properly for the patient’s kidney function.

Once patients recover from an acute episode of SBP they typically receive lifelong oral antibiotic therapy to prevent further episodes (secondary prevention), unless there is a significant improvement in their liver disease over time. The antibiotic used should preferably be one that is poorly absorbed and thus targets the bacteria in the GI tract, although systemically absorbed antibiotics are also routinely used and are effective. The choice of antibiotic may be made based on several factors, including cost, presence of allergies, frequency of administration, and potential for drug interactions and adverse effects. Recent guidelines recommend norfloxacin or ciprofloxacin daily as preferred agents. Trimethoprim/sulfamethoxazole, one double-strength tablet given once daily for 5–7 days per week, is often prescribed as a starting regimen. The use of antibiotics for treatment or prevention of SBP may be associated with adverse effects. These are discussed in Chapter 27.

The other main use for antibiotics in patients with cirrhosis is the treatment and prevention of HE. Antibiotics are considered therapeutic alternatives to lactulose.^7,8 This is based on the fact that a large proportion of ammonia is produced by the bacteria that normally live in the colon. By reducing the number of bacteria, the amount of ammonia that is produced and absorbed into the systemic circulation is significantly reduced, thus improving symptoms of HE. Antibiotics may also be combined with lactulose in patients who do not completely respond to appropriate doses of lactulose. Similar to prevention of SBP, antibiotics that are poorly absorbed can be used for the treatment of HE. The most widely studied antibiotic for HE is neomycin 3–6 g daily orally in divided doses. When taken orally, less than 1% of an oral dose of neomycin is absorbed. Nevertheless, there is concern for kidney dysfunction with long-term use and thus, its use has largely fallen out of favor.

Rifaximin has become the most common antibiotic used for HE. When taken orally, only about 0.5% (about 1/200^th of the dose) is absorbed; thus, its effects are localized to the GI tract. Unlike neomycin, rifaximin is not associated with kidney or hearing dysfunction. Overall, it may be better tolerated than lactulose. Rifaximin’s main role is for the prevention of recurrent episodes of HE, often in combination with lactulose. The recommended rifaximin dose is 550 mg orally twice daily.

Octreotide for Acute Variceal Bleeding

As mentioned, acute variceal bleeding is associated with significant morbidity and mortality in patients with cirrhosis. When patients develop acute variceal bleeding, the treatment is typically a combination of direct therapies administered via endoscopy, such as endoscopic variceal ligation or sclerotherapy (injection of an irritating substance into the bleeding varices that causes local inflammation and coagulation). In addition, drugs that cause constriction of the vessels in the intestinal system may also help to reduce blood flow into the portal vein. This may reduce acute bleeding. Octreotide is a drug that constricts the intestinal blood vessels in this setting. It is thought to act by reducing the release of substances that cause dilation of GI blood vessels and is administered as an initial IV bolus dose of 50 mcg, followed by a continuous infusion of 50 mcg/hour IV for a total of 2–5 days. Potential adverse effects of octreotide include nausea, headache, dizziness, low calcium, and increased or decreased blood glucose.

Albumin

Albumin is one of the primary circulating proteins in the bloodstream and is a major product of the liver. One of albumin’s main functions is to help maintain the appropriate amount of fluid in the bloodstream by virtue of its osmotic effects. In advanced liver disease, the ability of the liver to produce albumin is significantly reduced. As the blood concentration of albumin becomes lower, fluid that is normally retained in the bloodstream leaks into the tissues, causing edema. Additional fluid may leak into the peritoneal cavity, worsening ascites. Likewise, blood flow to vital organs, such as the kidney, may be reduced as blood volume decreases. Therefore, administration of IV albumin has a role in patients with cirrhosis who are at high risk for kidney dysfunction, such as those with SBP and those patients who are undergoing large-volume paracentesis. In these settings IV infusions of albumin are thought to help maintain blood volume and possibly bind inflammatory substances.

In SBP an IV dose of 25% albumin 1.5 g/kg given on day 1, followed by 1 g/kg on day 3 given in conjunction with IV antibiotics has been shown to reduce the incidence of kidney impairment.⁶ In patients who undergo paracentesis, fluid may shift from the bloodstream back into the peritoneal cavity. This may reduce perfusion (blood flow) to the kidney and cause kidney failure. This typically does not happen unless more than 5 L is removed at any one time. Albumin infusions can help maintain blood volume and prevent this shift of fluid following paracentesis. Recommendations are to use 6–8 g albumin/liter of fluid removed in patients who have 5 or more liters removed at one time.^6,7 Albumin is well tolerated, with allergic reactions occurring very rarely.

Nonpharmacologic

The management of patients with acute pancreatitis mostly involves removal of the cause and treatment of symptoms. Most patients require hospitalization. Oral intake may be withheld to prevent stimulation of the pancreas. Oxygen and IV fluid administration may be required if the patient has difficulty breathing or appears dehydrated.^9,10 For patients with gallstone-induced pancreatitis, performance of an endoscopy with a procedure to remove the gallstone from the biliary tract is sometimes required. In some instances, the gallstone will pass out of the biliary tract by itself. Formation of abscesses or pseudocysts may require surgical drainage and antibiotic therapy.

Pharmacologic Treatments

Since abdominal pain is often the most common symptom patients have, the use of IV analgesics is often required. Intravenous acetaminophen may be added to supplement pain control.¹⁰ Narcotics, discussed extensively in Chapter 5, are the most commonly used medications in this setting. Examples include morphine, hydromorphone, and fentanyl. The use of patient-controlled analgesia for administration may be preferred, as patients often require frequent doses. Potential adverse effects include sedation, nausea, itching, constipation, and respiratory depression. Patients with acute pancreatitis often have nausea and vomiting, so antiemetic drugs are usually required. Examples include promethazine, prochlorperazine, or ondansetron. IV or rectal (suppository) administration is often required. For patients who are in the intensive care unit, the administration of acid-suppressive drugs, such as histamine-receptor antagonists or proton pump inhibitors, is required to prevent GI bleeding. Patients who develop pancreatic necrosis with infection may need broad-spectrum IV antibiotics such as imipenem, meropenem, or doripenem.

Since many cases of acute pancreatitis are associated with chronic alcohol use, hospitalization and cessation of alcohol use is required. During this time patients are at risk for alcohol withdrawal. Many hospitals have protocols that are used to screen for and manage alcohol withdrawal. This involves frequent monitoring of the patient’s mental status and vital signs. Haloperidol may need to be administered for treatment of delirium or mental status changes. Patients may develop alcohol withdrawal seizures. Benzodiazepine drugs such as alprazolam, diazepam, or chlordiazepoxide are frequently administered to relieve most symptoms of alcohol withdrawal. Patients are also given IV multivitamins, folic acid, and thiamine to prevent complications related to deficiencies in vitamins. If the offending cause of the acute episode is removed, the patient should ultimately recover and be able to go home.

Pain Management

Once patients develop chronic pancreatitis, drug treatment is used primarily to relieve symptoms, promote nutrient absorption, and treat diabetes. Chronic abdominal pain is the most common symptom that patients experience. Patients initially may experience intermittent episodes of intense abdominal pain. These episodes eventually increase in frequency and ultimately progress to continuous pain. Analgesics are commonly used for the management of pain in patients with chronic pancreatitis. The initial use of nonnarcotic medications, such as acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs), is usually preferred. Unfortunately, most patients will not get adequate relief with these drugs.

Narcotics are often required to manage chronic pain. Patients should receive scheduled medications around the clock, with additional doses of short-acting drugs for episodes of breakthrough pain. Morphine or oxycodone are commonly used and are available in both long-acting preparations that may require less frequent dosing and short-acting versions that can be used for breakthrough pain. Fentanyl is available as a patch that is administered once every 3 days (72 hours), but there is no corresponding oral preparation. Methadone is another oral option for long-term management. Less potent narcotics, such as tramadol, may also be tried. The use of long-term narcotics may be associated with dependence, constipation, nausea, and delayed gastric emptying. Patients may develop tolerance to narcotics, which may require increases in dosing over time. Patients may ultimately require nerve blocks to manage pain. The use of pancreatic enzymes may help to reduce pain as well as improve maldigestion and nutritional status.

Pancreatic Enzymes

One of the major complications of chronic pancreatitis is malnutrition. This is directly related to the loss of pancreatic enzyme secretion, or PEI. Lack of pancreatic enzyme activity in the GI tract leads to the inability to digest nutrients, a process known as maldigestion. Maldigestion leads to undigested food and nutrients being present within the GI tract in forms that cannot be absorbed. This is referred to as malabsorption. Normally, digestion of carbohydrates and starches starts upon ingestion, as amylase enzymes present in the saliva begin to break down these molecules. Other enzymes present in the intestinal tract break the molecules into smaller pieces that are readily absorbed in the small intestine. Protein digestion begins in the stomach following exposure to pepsin and gastric acid. Enzymes present in the intestinal wall further break the proteins into smaller molecules to be absorbed. The amylase and protease enzymes that are normally secreted by the pancreas contribute to this digestive process, but as pancreatic function declines, loss of pancreatic amylase and protease does not substantially impair the absorption of carbohydrates and proteins as these other digestive processes can compensate.

Unlike carbohydrates and proteins, up to 90% of fat absorption is facilitated by pancreatic lipases, and loss of pancreatic function significantly affects fat digestion. When pancreatic lipase falls too low, as happens in patients with chronic pancreatitis, fat cannot be digested and absorbed. This leads to loss of fat in the stool and the development of steatorrhea, as well as impaired absorption of fat-soluble vitamins. Another major contributor to maldigestion is the loss of pancreatic bicarbonate secretion. Pancreatic enzymes are normally secreted into the duodenum and require a local pH of least 5 in the GI tract to function properly. At a pH of below 5 pancreatic enzymes are inactivated and destroyed by the acid environment. Bicarbonate secretion from the pancreas normally helps neutralize the acidic contents of the stomach and allows the pancreatic enzymes to function appropriately. Since patients with chronic pancreatitis not only have a lack of enzymes but also a loss of bicarbonate secretion from the pancreas, the digestive and absorptive processes are shifted to further down in the small intestine, leading to faster passage of nutrients through the GI tract and further malabsorption.

To help correct maldigestion and malabsorption, pancreatic enzymes can be orally administered with ingested nutrients. This goal of pancreatic enzyme replacement is to simulate the normal digestive process as closely as possible by delivering the enzymes to the duodenum in close proximity to ingested nutrients.¹² This ultimately allows the patient to properly digest and absorb nutrients. Oral pancreatic enzyme replacement products are derived from pig pancreatic enzymes (also called pancrelipase) and, much like human enzymes, contain lipases, amylase, and protease. They are available as capsules containing enteric-coated mini-microspheres or micro-tablets, or as immediate-release tablets. Pancreatic enzyme products are discussed in depth in Chapter 19, as they relate to cystic fibrosis.

When initiating pancreatic enzyme replacement therapy for patients with chronic pancreatitis, approximately 40,000–50,000 units of lipase activity should be provided per standard adult meal.¹² In children, 500–2,500 units/kg of lipase activity per meal can be used. One-half the standard dose is often used for snacks. Therefore, capsules containing the appropriate amount of lipase activity should be used for each dose. Patients often require more than one capsule per meal. For instance, an adult patient requiring 40,000 units per meal could use two 20,000-unit capsules.

Once pancreatic enzyme therapy is initiated, the patient is monitored for reductions in steatorrhea and improvement in weight gain. Steatorrhea may be significantly reduced or even go away completely in some patients. The patient’s enzyme dose can be adjusted based on the improvement in steatorrhea and the amount of weight gained. Pancreatic enzyme products are generally well tolerated. Patients may experience diarrhea or constipation from the enzymes. At very high doses blood concentrations of uric acid may be elevated. Doses above the recommended maximum daily dose of 10,000 units/kg/day or 2,500 units/kg per meal have been associated with inflammation and scarring of the inside of the intestinal tract, a condition known as fibrosing colonopathy. This adverse effect is rare if doses are kept below this amount. If the patient is on an appropriate dose of enzymes and is not responding by gaining weight or having fewer symptoms related to steatorrhea, this may be potentially due to the pH in the duodenum being too low for the enteric-coated enzyme products to be released. In this case, the addition of an acid-suppressive drug, such as a proton pump inhibitor or histamine₂-receptor antagonist (as described in Chapter 20), may be added to the patient’s regimen.¹²

One last effect that may be achieved by the use of pancreatic enzymes is pain relief. Pain in patients with chronic pancreatitis is thought to be partially due to continuous stimulation of the pancreas by a substance called cholecystokinin. A protein that causes release of cholecystokinin is secreted in the small intestine. This protein is normally destroyed by proteases that are released by the pancreas, so patients who lack proteases, such as those with chronic pancreatitis, are unable to slow the release of cholecystokinin. To restore the process of slowing cholecystokinin release, pancreatic enzymes must be delivered to the duodenum in their active, uncoated form. This necessitates the use of non-enteric-coated products. Thus, non-enteric-coated products may be used for patients with severe pain who have not responded to other medications. If non-enteric-coated products are used, administration of an acid-suppressive drug is required to help minimize destruction of the enzymes by gastric acid. It may not be practical to use non-enteric-coated enzymes, as enteric-coated products generally require administration of fewer capsules and generally result in better symptom improvement and weight gain.

Fat-Soluble Vitamins

Since a major component of chronic pancreatitis involves maldigestion and malabsorption of fat, patients are at risk for fat-soluble vitamin deficiency. Vitamin preparations that deliver adequate amounts of vitamins A, D, E, and K are required. This may be accomplished though the administration of tablet, capsule, or liquid formulations that are designed specifically to provide higher amounts of these vitamins (Medication Table 23-1; Medication Tables are located at the end of the chapter). These products also often contain other substances, such as B vitamins, folic acid, selenium, and coenzyme Q10. Liquid or chewable formulations may be preferred for children and patients who have difficulty swallowing. Some products are formulated to include different forms of some of the fat-soluble vitamins or may be formulated in a dose form that may enhance absorption. Since products differ in content in formulation, substitution of one for another may not be possible.