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396 SECTION VI Gastrointestinal Disease
Fig. 38.2 Endoscopic image of Crohn’s disease demonstrates linear
ulcers in areas of otherwise normal mucosa.
can infrequently result in inflammation of the terminal ileum, called
backwash ileitis, usually when severe disease of the cecum or ascending
colon is present. In many patients with indeterminate colitis, repeated
examination is necessary, or complications may develop that help
identify the disease form.
Several types of radiologic studies can be used to diagnose IBD.
In Crohn’s disease, the most sensitive radiographic test to diagnose
small bowel disease is CT or MR enterography. On traditional small
bowel radiography, segments of edematous bowel appear thickened
next to uninvolved mucosa, a characteristic pattern referred to as cob-
blestoning. Tight, long strictures in the small bowel can be identified
and are called a string sign. Cross-sectional imaging with computed
tomographic (CT) enterography and magnetic resonance enterography (MRE) has replaced traditional small bowel radiography. Crosssectional imaging can identify bowel wall thickening with surrounding
inflammation, as well as intra-abdominal abscesses and fistulas (Figs.
38.3 and 38.4). A characteristic finding on cross-sectional imaging in
Crohn’s disease is infiltration of the mesentery with fat, commonly
known as creeping fat.
Video capsule endoscopy allows for direct visualization of the small
bowel mucosa where erosions or ulcerations of the small bowel may be
found (Fig. 38.5). Patients with known or suspected strictures should
be evaluated for risk of capsule retention before undergoing capsule
endoscopy.
Mucosal biopsies in IBD reveal acute and chronic inflammation with infiltration by plasma cells, neutrophils, lymphocytes, and
eosinophils; focal ulcerations; crypt architectural distortion; and crypt
abscesses (Figs. 38.6 and 38.7). The presence of chronic inflammation
distinguishes IBD from other types of acute self-limited colitis like
enteric infection. In Crohn’s disease, the inflammation is transmural
and more commonly focal. Granulomas are found in 25% to 30% of
histologic specimens in Crohn’s disease. The presence of granulomas is
not required but can assist in making the diagnosis of Crohn’s disease
in the right clinical setting (Fig. 38.8). Granulomas are not diagnostic
because they can be found in many other diseases, such as Behçet’s
disease, tuberculosis, Yersinia infection, gastrointestinal and hepatic
sarcoidosis, and lymphoma.
Fig. 38.3 Computed tomographic enterography shows inflammatory
stricture (arrow) and small bowel wall thickening in a patient with
Crohn’s disease.
Fig. 38.4 Computed tomographic enterography shows extensive
Crohn’s disease with fistula (arrow).
Fig. 38.5 Video capsule endoscopic image shows ulcerated stenosis in
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a patient with Crohn’s disease (arrows).
CHAPTER 38 Inflammatory Bowel Disease
Fig. 38.7 Mucosal biopsy specimen demonstrates crypt branching
and a crypt abscess characteristic of ulcerative colitis (hematoxylin and
eosin stain).
397
Fig. 38.6 Normal colonic mucosa (hematoxylin and eosin stain).
The differential diagnosis of IBD includes infectious colitis, ischemic colitis, radiation enteritis, enterocolitis induced by nonsteroidal
anti-inflammatory drugs, diverticulitis, appendicitis, gastrointestinal
malignancies, and irritable bowel syndrome. In patients with acute onset
of bloody diarrhea, infectious causes that must be excluded with stool
testing include Salmonella enteritidis, Shigella species, Campylobacter
jejuni, Escherichia coli O157, and Clostridioides difficile. Clostridioides
difficile is more common among patients with IBD. Among the infec-
tious causes, Yersinia enterocolitica can mimic Crohn’s disease because
the pathogen causes ileitis, mesenteric adenitis, fever, diarrhea, and
right lower quadrant abdominal pain. Mycobacterium tuberculosis
Fig. 38.8 Colonic biopsy specimen demonstrates a chronic inflamma-
tory infiltrate with a granuloma in a patient with Crohn’s colitis (hematoxylin and eosin stain).
infection, strongyloidiasis, and amebiasis must be excluded in high-risk
populations, because these infections can mimic IBD, and treatment
with corticosteroids can lead to disseminated infection and death.
TREATMENT
Treatment of IBD follows a systematic, standardized, and evidence-based approach. It relies on first identifying the type of IBD,
then categorizing severity of disease, and then identifying a management goal, which now encourages a “treat to target” approach and
focuses on endoscopic improvement and healing. Next, a therapeutic agent is selected incorporating data from well-designed clinical
studies and also patient tolerability and overall safety, convenience,
and preference. Furthermore, the treatment of IBD includes a focus
on employing more aggressive and effective “top down” strategies by
using biologic and newer oral agents earlier in the course in selected
patients with moderate to severe disease. Maximizing the efficacy of
current therapies now includes achieving therapeutic levels of these
drugs when possible in the attempt to achieve endoscopic healing rapidly and thus improve long-term outcomes.
398 SECTION VI Gastrointestinal Disease
TABLE 38.3 Treatment Options
Disease Severity Ulcerative Colitis Crohn’s Disease
Mild Oral and topical 5-ASA
compounds
Budesonide MMX
Moderate Oral and topical 5-ASA
compounds
Oral steroids or
budesonide MMX
Azathioprine, 6-MP
Infliximab, adalimumab,
golimumab
Vedolizumab
Tofacitinib
Ustekinumab
Severe Intravenous steroids
Cyclosporine
Infliximab, adalimumab,
golimumab
Vedolizumab
Tofacitinib
Ustekinumab
Surgery
5-ASA, 5-Aminosalicylic acid; 6-MP, 6-mercaptopurine.
Budesonide EC
Elemental diet
Oral steroids or
budesonide EC
Azathioprine, 6-MP
Methotrexate
Infliximab, adalimumab,
certolizumab pegol
Vedolizumab
Ustekinumab
Intravenous steroids
Methotrexate
Infliximab, adalimumab,
certolizumab vedoli-
zumab
Ustekinumab
Surgery
Patients with mild or moderate disease can be managed as outpatients. Patients with severe or fulminant disease—with abdominal
pain, fever, tachycardia, anemia, and leukocytosis—require hospital
admission and multidisciplinary team management. Because IBD is
a chronic recurrent illness, treatment is centered on controlling the
acute attack with induction of remission, followed by maintenance of
remission. Treatment options for UC and Crohn’s disease are summarized in Table 38.3.
In brief, treatment agents for IBD broadly include nontargeted
immune suppressants such as corticosteroids, topical anti-inflammatories including 5-aminosalicylic acid (mesalamine) and related
agents, antibiotics, and traditional immunomodulators including
thiopurine analogs (azathioprine, 6-MP) that inhibit replication of
inflammatory cells by inducing cell death or apoptosis and methotrexate, which inhibits replication of inflammatory cells by inhibiting cell
division or mitosis.
Newer approved biologic and oral agents work variably by targeting
effector pro-inflammatory cytokines such as TNF-alpha and IL-12/23,
targeting immune cell function such as the JAK-STAT enzyme pathway or inhibiting cell trafficking such as the alpha-4/beta7 adhesion
inhibition.
5-Aminosalicylic Acid (Mesalamine)
The 5-aminosalicylates are given either orally or topically (suppository/enema) or as a combined regimen. They are safe and effective for
treatment (i.e., induction of remission) of mild to moderate UC and
for maintenance of remission. The efficacy of the 5-aminosalicylic acid
(5-ASA) agents in induction or maintenance of remission in Crohn’s
disease has not been demonstrated. This class of anti-inflammatory
medications includes sulfasalazine (Azulfidine) at a dose of 4 to 6 g/day
in divided doses. This drug consists of 5-ASA linked to a sulfapyridine
moiety; the 5-ASA is released after bacterial lysis of the azo bond in the
distal small bowel and colon. Side effects, including headache, nausea,
and skin reactions, require discontinuation of sulfasalazine in about
30% of patients. Reversible oligospermia may occur with sulfasalazine.
Rare serious side effects include pleuropericarditis, pancreatitis, agranulocytosis, interstitial nephritis, and hemolytic anemia may occur with
sulfasalazine and 5-ASA. Patients who take sulfasalazine need folic acid
supplementation.
Derivatives of oral 5-ASA compounds include mesalamine (Pentasa,
4 g/day in divided doses; Delzicol, 2.4 g/day in divided doses; Asacol
HD, 2.4 to 4.8 g/day in divided doses; Lialda, 2.4 to 4.8 g once daily;
Apriso, 1.5 g once a day), olsalazine (Dipentum, 1 to 2 g/day in divided
doses), and balsalazide (Colazal, 6.75 g/day in divided doses; Giazo 3.3
g/day in divided doses). Topical forms of mesalamine (Canasa suppositories, 1000 mg once daily; Rowasa enemas, 4 g once nightly) are
commonly used because of a more favorable side effect profile.
Corticosteroids
Corticosteroids may be used topically, orally, or intravenously. They
are effective for controlling active inflammatory disease but not for
maintaining remission and should act as a bridge to maintenance therapy. They are not indicated for maintenance therapy. They are indicated for moderate or severe disease in patients with UC for whom
treatment with 5-ASA has failed. The most commonly used agents are
parenteral methylprednisolone for severe/fulminant disease requiring
hospitalization at doses of 45 to 60 mg intravenously daily and for
outpatients, oral prednisone, started in doses between 40 and 60 mg/
day. Patients typically improve rapidly, and the medication is usually
tapered down slowly (i.e., by 5 to 10 mg/week) until discontinuation.
Patients who do not improve after 1 week of oral treatment and those
with more severe disease are best treated in the hospital with intravenous corticosteroids.
Controlled trials have shown that budesonide EC (Entocort EC)
is more effective than placebo or oral 5-ASA and has similar efficacy
to prednisolone for the induction of remission in Crohn’s disease of
the terminal ileum (level of evidence I, A). Entocort EC (9 mg given
once daily as three 3-mg pills) undergoes extensive first-pass hepatic
metabolism and is approved for inducing and maintaining remission
of ileal and ileocolonic Crohn’s disease (level of evidence III, A) with
decreased corticosteroid side effects. Budesonide MMX (Uceris 9 mg
given once daily) has an extended release that targets the colon and is
approved for the treatment of mild to moderate UC but should not
be used as maintenance therapy. Corticosteroids have numerous side
effects with long-term use.
Traditional Immunomodulators
The traditional immunomodulators used in IBD include azathioprine (Imuran) and its active metabolite, 6-mercaptopurine (6-MP)
(Purinethol), as well as methotrexate and cyclosporine. Metabolism of
azathioprine and 6-mercaptopurine is based on the enzyme thiopurine methyl transferase (TPMT). TPMT should be measured in each
patient before starting therapy to determine starting dose to minimize
toxicity and maximize efficacy. Hematologic monitoring for drug toxicity on therapy is essential. Azathioprine and 6-MP are effective therapies for maintaining remission in both Crohn’s disease and UC and
are used primarily as corticosteroid-sparing agents. They have a slow
onset of action (weeks to months) and consequently are not used to
induce remission. Side effects include pancreatitis, nausea, abnormal
liver enzymes, bone marrow suppression, opportunistic infections,
and an increased risk of lymphoma and nonmelanoma skin cancer.
Methotrexate can be used for induction (25 mg subcutaneously
once weekly) and maintenance of remission (15 to 25 mg subcutaneously once weekly) in active Crohn’s disease; the side effect profile
includes bone marrow suppression, mucositis, interstitial pneumonitis, and with long-term use, cirrhosis. Folic acid should be given with
methotrexate to reduce the risk of mucositis. Methotrexate has been
CHAPTER 38 Inflammatory Bowel Disease
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399
studied as a primary treatment for UC and was not found to be effective. Intravenous cyclosporine (2 mg/kg/day given over 24 hours) is
used as a rescue medicine and, in severe UC refractory to intravenous
steroids, as a bridge treatment to one of the above immunomodulators
or biologic agents. Given the potential for both short-term and longterm side effects, as well as the need for close follow-up, patients needing these medications are best managed by gastroenterologists.
Previously used as primary therapy for IBD, azathioprine/6-mercaptopurine and methotrexate are now more commonly used in
combination with newer more effective biologic therapies, especially
anti-TNF agents.
Biologic Agents
Biologics are a class of medications that target specific aspects of the
immune system. The first such agent to be used in IBD was infliximab (Remicade), a chimeric monoclonal antibody to TNF-α, which
has been shown to be effective in the treatment of both moderate to
severe Crohn’s disease, including fistulizing disease, and UC (level of
evidence I, A). Anti-TNF agents that are administered subcutaneously
include adalimumab (Humira) and golimumab (Simponi), which are
fully human monoclonal antibodies, and certolizumab pegol (Cimzia),
which is a humanized anti-TNF antibody Fab fragment. Adalimumab,
certolizumab pegol, and infliximab are indicated for the treatment
of patients with moderate to severe Crohn’s disease. Adalimumab,
infliximab, and golimumab are approved to treat moderate to severe
UC. These agents can be associated with adverse reactions including
infusion reactions (infliximab), delayed-type hypersensitivity reaction,
and with development of anti-drug antibodies resulting in reduced
effectiveness.
Natalizumab (Tysabri), a humanized anti–α4-integrin antibody,
blocks inflammatory cell migration and adhesion and is approved for
the treatment of moderate to severe Crohn’s disease in patients who
have had an inadequate response to, or are unable to tolerate, conventional Crohn’s disease therapies including inhibitors of TNF-α. Due to
its link with progressive multifocal leukoencephalopathy (PML) and
approval of a more gut selective agent, vedolizumab, it is now rarely
used. Vedolizumab (Entyvio), a humanized monoclonal antibody to
α4β7 integrin, is approved for the treatment and maintenance of both
Crohn’s and UC.
Ustekinumab, a monoclonal antibody against the P40 subunit of
IL-12 and IL-23, is approved for the induction and maintenance of
remission in moderate to severe Crohn’s and UC.
Tofacitinib, an oral small molecule that inhibits Janus kinase
(JAK) enzymes, is approved for treatment of moderate to severe UC
in patients intolerant of or who have not responded to anti-TNFs.
Because of the potent effects these biological drugs and oral agents
have on the immune system, careful patient selection and monitoring
for complications are necessary. Reactivation of latent tuberculosis and
other serious infections have been reported with the anti-TNF agents.
Other rare but serious complications include non-Hodgkin’s lymphoma, exacerbation of congestive heart failure, abnormal complete
blood count (CBC) and liver function test results, venous thrombosis,
and demyelinating disease. Natalizumab is associated with rare cases
of progressive multifocal leukoencephalopathy caused by the human
JC virus.
Future biologic agents with alternative mechanisms of action are
being developed. These include several selective IL-23 inhibitors such
as risankizumab, mirikizumab, guselkumab, and brazikumab. These
biologics selectively target the P19 subunit of the interleukin-23 (IL-
23) cytokine, thus being more selective than ustekinumab (Stelara),
which inhibits the P40 components of both IL-12 and IL-23. A theoretical advantage of IL-23 selectivity is thought to be reduced potential
side effects related to targeting of IL-12, including risk of carcinogenesis suggested in some animal studies.
Additional JAK inhibitors (filgotinib, upadacitinib) are being examined for their role in treatment of IBD. Etrolizumab, a beta7 inhibitor, and ontamalimab, a MadCAM-1 ligand inhibitor, are inhibitors
of cell trafficking that are in clinical trials. Ozanimod (RPC1063), an
oral agent that acts as a selective agonist and modulator of sphingosine
phosphate receptor subtypes 1 and 5, thus inhibiting lymphocyte trafficking to sites of inflammation, is also being tested for its efficacy in
UC and Crohn’s disease.
The availability of these biologic agents has changed the approach
to the management of IBD. The emphasis now has shifted from treating symptoms alone and maintaining clinical remission to treating
to a target of endoscopic remission. Endoscopic remission or mucosal healing (as it is typically referred to) is defined as the absence of
mucosal ulceration or erosion. The finding of ulceration in the lining of the bowel is associated with higher likelihood of disease flare
in asymptomatic patients. Achieving endoscopic remission has been
associated with better long-term patient outcomes including longer
sustained clinical remissions, lower rates of hospitalization and, in
some studies, lower rates of surgery. In this paradigm, after a therapy
has been started, an asymptomatic patient will undergo an evaluation
6 to 9 months later to look for evidence of endoscopic remission or
ongoing intestinal inflammation. If persistent or significant disease
is present, then treatment is typically optimized or changed to try to
achieve endoscopic remission. This treat to target approach continues
to undergo further study.
Other Agents
Other agents for the treatment of IBD include antibiotics, probiotics,
antidiarrheal agents, bile salt resin binders, and nutritional support.
Although used widely in the past for luminal Crohn’s, antibiotics
are now less commonly employed in routine treatment of patients with
luminal Crohn’s disease. Current use of antibiotics in active Crohn’s
is largely limited to treatment of pyogenic complications and in perianal disease. Metronidazole may prevent postoperative recurrence in
some patients with luminal Crohn’s but adverse effects typically limit
its usefulness. There is some evidence for the efficacy of a novel enteric
form of rifaximin in mild to moderately active luminal Crohn’s disease. The role of antibiotics in UC is unclear, and further studies are
required. However, intravenous antibiotics may be used in the initial
treatment of severe, toxic, or fulminant colitis when infection is a concern. Antibiotics are useful to treat bacterial overgrowth that can be
associated with Crohn’s disease.
Probiotics are viable nonpathogenic organisms considered to be
food products that after ingestion may prevent or treat intestinal diseases and have been explored in the treatment of IBD. There is some
evidence for their efficacy in pouchitis (see later) and UC but no clear
benefit in Crohn’s disease has been noted thus far. Additional studies
are ongoing.
Antidiarrheal agents and bile salt resin binders have no effect on
IBD inflammation but can be used as adjuncts for management of
diarrhea in patients with IBD, but antidiarrheal agents should be used
cautiously during exacerbations of colitis because they may precipitate
toxic megacolon. The main role of antidiarrheal medications involves
controlling diarrhea in patients who have undergone previous resections. Patients with Crohn’s disease who have had less than 100 cm of
terminal ileum removed can develop a bile salt malabsorptive state,
during which bile salts enter the colon and cause a secretory diarrhea.
Bile salt resin binders such as cholestyramine are an effective treatment
in these cases. When patients have undergone one or more extensive resections amounting to more than 100 cm of ileum, the bile salt
400 SECTION VI Gastrointestinal Disease
pool is depleted and fat malabsorption develops. These patients may
require a low-fat diet supplemented with medium-chain triglycerides
and antidiarrheal agents, but bile salt resin binders should not be used.
Nutritional support is an important adjunctive aspect in the management of IBD. However, the role of nutrition as a primary treatment
has been limited to patients with small bowel Crohn’s disease, especially in children. These patients may achieve and maintain remission
with total parenteral nutrition or elemental diets after prolonged periods (at least 4 weeks) and potentially avoid the need for corticosteroids. Many patients with Crohn’s disease or UC experience weight
loss during exacerbations of their illness and need caloric supplements.
Vitamins and minerals can be given orally as a multivitamin with folic
acid. Vitamin B12 should be supplemented parenterally in patients who
have extensive ileal disease or an ileal resection. Patients taking corticosteroids require supplemental calcium and vitamin D, and individuals
with extensive small bowel involvement can also develop malabsorption of fat-soluble vitamins (A, D, E, and K), iron, and, rarely, trace
minerals. A low-fiber diet may be necessary in patients with active
disease or strictures. There is some observational evidence to suggest
effectiveness of the specific carbohydrate diet (SCD) in patients with
IBD but it is very restrictive in nature; therefore, it is not being widely
recommended until further research becomes available.
More studies on diet as a treatment for IBD are needed.
Complementary and alternative medicines are used frequently by
patients with IBD and it is important that treating clinicians ask about
their use.
Surgical Management
Surgical intervention is indicated for patients with complications such
as obstruction, perforation, fibrotic stricture, massive gastrointestinal
hemorrhage, or toxic megacolon or who are not responsive to medical treatment. The other main indication for surgical treatment is the
presence of dysplasia or cancer. For patients with UC, regardless of the
extent of disease, the entire colon must be removed. Historically, the
initial operation for UC was a total proctocolectomy and Brooke ileostomy, but ileal pouch–anal anastomosis has become the procedure of
choice in most patients. In this operation, the colon is removed and the
small bowel is constructed into a reservoir (ileal pouch) that is anastomosed to the anus or a short segment of the rectum, allowing defecation
through the anus. Complications include the development of inflammation of the rectum (cuffitis) or pouch (pouchitis), fecal incontinence,
reduced fertility, and need for reoperation. Surgery is not curative in
Crohn’s disease. Many surgical procedures in patients with Crohn’s disease are performed to manage complications of the disease, including
segmental resection, stricturoplasty, fistulectomy, and abscess drainage.
PROGNOSIS
Approximately two thirds of patients with UC have at least one relapse
in the 10 years after their diagnosis. About 20% to 30% of patients with
extensive UC will require colectomy within their lifetime. Only 5% of
individuals with proctitis undergo colectomy by 10 years after diagnosis. In contrast, more than 60% of Crohn’s patients require surgery
within the 10 years after their diagnosis although these data are based
on patients treated in the pre-biologic era. The rate of recurrence in
Crohn’s disease is high, with 70% of patients having an endoscopic
recurrence within 1 year after surgery and 50% having a symptomatic recurrence within 4 years. Predictors of a severe course in Crohn’s
disease include stricturing or penetrating disease and perianal disease.
The risk for colon cancer is increased in patients with UC, and its
magnitude is related to the extent and duration of disease. The colon
cancer risk is increased 10- to 20-fold after 8 to 10 years of disease in
pancolitis, and after 15 to 20 years in left-sided colitis. The cumulative
incidence of colorectal cancer is 2.5% after 20 years and 7.6% after
30 years of disease. Proctitis is not associated with an increased risk
of colorectal cancer. In colonic Crohn’s disease, the risk of colorectal
cancer is equivalent to that in patients with UC of similar extent and
duration. Patients with isolated small bowel Crohn’s disease are not at
increased risk for colorectal cancer. The rates of small bowel carcinoma
and lymphoma are increased in patients with Crohn’s disease but the
absolute risk is very low.
Surveillance for dysplasia and colon cancer among patients with
UC and Crohn’s disease colitis should be performed by colonoscopy
8 to 10 years after the onset of symptoms. Surveillance examinations
are performed every 1 to 3 years. Proctitis does not require endoscopic
surveillance, but colonoscopy should be performed 8 years after diagnosis to look for evidence of proximal spread of the disease. Patients
with IBD and PSC appear to have a particularly increased risk for
colon cancer, and yearly surveillance is recommended after the initial
diagnosis of PSC. UC associated with PSC may have minimal or no
symptoms, so all patients with PSC should undergo colonoscopy with
biopsy to look for evidence of UC. The classic approach for UC surveillance has been to take a minimum of 33 “random” mucosal biopsy
samples during the colonoscopic examination, in addition to targeted
samples of visible lesions. The use of chromoendoscopy (spraying of
the colon surface with indigo carmine or methylene blue dye during
colonoscopy) increases the detection of dysplastic lesions in patients
with UC and has replaced the performance of random biopsies in
some societal guidelines. Polypoid dysplasia entirely removed by polypectomy in the colon can be managed with continued surveillance
colonoscopy. Colectomy is indicated in patients with unresectable dysplasia or evidence of colorectal cancer.
As understanding of the etiologic and pathophysiologic aspects of
IBD increases, major advances in diagnosis and treatment are anticipated. These will be based on better use of molecular, genetic, and
serologic tests to differentiate among the subtypes of disease; earlier
and more targeted use of biologic agents to manage inflammation; and
improvements in the detection and prevention of colorectal cancer in
those at risk.
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39
Diseases of the Pancreas
David R. Lichtenstein, Pushpak Taunk
ACUTE PANCREATITIS
Definition and Epidemiology
Acute pancreatitis is an acute inflammatory process of the pancreas
that may also involve peripancreatic tissues and remote organ systems.
It is one of the leading causes of hospitalization for patients with gastrointestinal disorders in the United States, with more than 275,000
admissions annually. This translates into an overall incidence of 5 to 30
cases per 100,000 people in the general population. The aggregate cost
of acute pancreatitis is more than $2.6 billion per year and the overall
case fatality is roughly 5%. Approximately 80% of patients admitted
with acute pancreatitis have mild, self-limited disease.
Pathology
The pancreas is located in the retroperitoneum and has exocrine and
endocrine functions (Fig. 39.1) derived from the pancreatic acinus and
the pancreatic islet, respectively. As an exocrine gland, the pancreas
participates in normal digestion and nutrient absorption. The enzymes
secreted by the pancreas digest starch (i.e., amylase), fats (i.e., lipase),
and protein (i.e., trypsin and other proteolytic enzymes). Within acinar
cells, proteolytic digestive enzymes are synthesized and packaged separately in the Golgi region into condensing vacuoles and transported in
an inactive form referred to as zymogens to the apical portions of the
cell. When stimulated, they are discharged into the central ductule of
the acinus by exocytosis.
Normal physiology involves secretion of inactive enzymes into
the duodenum, where they are converted to an active form by enterokinase, a brush border enzyme secreted by small bowel enterocytes. Trypsinogen conversion to active trypsin is the trigger enzyme
that subsequently converts the other zymogens to active enzymes
(E-Fig 39.1).
The pathogenesis of acute pancreatitis remains incompletely understood. Based on experimental models, the initiating event appears to
involve intra-acinar activation of trypsin from trypsinogen, resulting
in acute intracellular injury, pancreatic autodigestion, and the potential for profound systemic complications after activated enzymes are
leaked into the bloodstream. The acinar cell injury results in a systemic
inflammatory response that involves multiple cytokines, including
platelet activating factor, tumor necrosis factor-α (TNF-α), and various interleukins. Initiating events may include obstruction of the pancreatic duct (e.g., gallstones, pancreatic tumor), overdistention of the
pancreatic duct (e.g., from endoscopic retrograde cholangiopancreatography [ERCP]), reflux of biliary or duodenal juices into the pancreatic duct, changes in permeability of the pancreatic duct, ischemia of
the organ, and toxin-induced cholinergic hyperstimulation (Fig. 39.2).
During the initial hospitalization for acute pancreatitis, reasonable
attempts to determine the cause are appropriate, particularly those that
may affect acute management. The cause of acute pancreatitis is readily
identified in 70% to 90% of patients after an initial evaluation consisting of the history, physical examination, focused laboratory testing,
and routine radiologic studies. Gallstones account for 45%, alcohol for
35%, miscellaneous causes for 10%, and idiopathic causes for 10% to
20% of acute pancreatitis cases (Table 39.1).
Gallstone Pancreatitis
Among patients with gallstones, the incidence of acute pancreatitis
is about 0.17% per year. Gallstones increase the relative risk of pancreatitis 25- to 35-fold. Gallstone pancreatitis is more common in
women than men. It is theorized that gallstone passage causes transient obstruction of the pancreatic duct, precipitating acute pancreatitis. Acute gallstone pancreatitis should be suspected when associated
with a transient elevation in liver-associated enzymes, particularly alanine aminotransferase (ALT) levels greater than 150 IU/L. Most stones
pass spontaneously from the ampulla and do not require intervention
(discussed later).
Alcoholic Pancreatitis
Acute alcoholic pancreatitis is the second most common cause of pancreatitis in the United States. Approximately 10% of individuals with
an alcohol use disorder develop attacks of pancreatitis that are indistinguishable from other forms of acute pancreatitis. Prolonged alcohol
use (four to five drinks daily over a period of more than 5 years) is
required for alcohol-associated pancreatitis. The type of alcohol does
not affect risk, and binge drinking in the absence of long-term, heavy
alcohol use infrequently precipitates acute pancreatitis. Alcoholics
with acute pancreatitis most commonly have underlying chronic disease. However, some have true acute alcoholic pancreatitis because
not all patients progress to chronic pancreatitis, even with continued
alcohol use. The mechanism of pancreatic injury, the genetic and environmental factors that influence its development in alcoholics, and the
reason only a small proportion of alcoholics develop pancreatitis are
unclear (see “Chronic Pancreatitis”).
Hypertriglyceridemia
Hypertriglyceridemia is the third most identifiable cause of pancreatitis, and serum triglyceride levels greater than 1000 mg/dL may
precipitate attacks of acute pancreatitis. Patients may have lactescent
(milky) serum owing to increased concentrations of chylomicrons.
Both primary and secondary disorders of lipoprotein metabolism are
associated with hypertriglyceridemic pancreatitis. Although the exact
pathogenesis of hypertriglyceridemic pancreatitis is unclear, the release
of free fatty acids by lipase may damage pancreatic acinar cells or capillary endothelium. The main treatment modalities for initial management of hypertriglyceridemia are apheresis with therapeutic plasma
402
ENTEROCYTES
GUT LUMEN
Trypsinogen
B
2
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CHAPTER 39 Diseases of the Pancreas
402.e1
Enterokinase
Trypsin
E-Fig. 39.1 Mechanism of proenzyme activation in the intestinal lumen.
(Modified from Solomon TE: Exocrine pancreas: pancreatitis. In the
Undergraduate teaching project in gastroenterology and liver disease,
unit 24, Bethesda, Md., 1984, American Gastroenterological Association.)
Tr ypsinogen
Chymotrypsinogen
Proelastase
Procarboxypeptidases A and
Prophospholipase A
Tr ypsin
Chymotrypsin
Elastase
Carboxypeptidases A and B
Phospholipase A
2
CHAPTER 39 Diseases of the Pancreas
Minor
ampulla
Dorsal duct
pancreas
(Wirsung)
ampulla
bile duct
interstices of pancreas
Death
Progression
xtrapancreatic
estations)
Bile reflux
Ethanol
T
Other causes
403
Major
Pylorus
Common
Fig. 39.1 Normal anatomy of the pancreas.
Ventral duct
(Santorini)
Head of
10. Acute respiratory distress syndrome11. Intractable shock
Tail of
pancreas
exchange and insulin. Lowering serum triglyceride levels to less than
200 mg/dL can prevent pancreatitis and is typically done with a combination of diet and medications.
Drug-Related Pancreatitis
Drugs appear to cause fewer than 5% of all cases of acute pancreatitis,
although hundreds of medications have been implicated. The drugs
most strongly associated with acute pancreatitis are azathioprine,
6-mercaptopurine, didanosine, valproic acid, angiotensin-converting-enzyme inhibitors, eluxadoline, and mesalamine. Though there
are several potential pathogenic mechanisms of drug-induced pancreatitis, the most common is a hypersensitivity reaction. This tends
to occur 4 to 8 weeks after starting the drug and is not dose related.
On re-challenge with the drug, pancreatitis recurs within hours to
days. The second mechanism is the presumed accumulation of a toxic
metabolite that may cause pancreatitis, typically after several months
of use. Pancreatitis caused by drugs is usually mild and self-limited.
Heredity
Hereditary causes of pancreatitis include mutations in the genes
encoding cationic trypsinogen (PRSS1), pancreatic secretory trypsin
inhibitor (serine protease inhibitor Kazal type 1 [SPINK1]), cystic
fibrosis transmembrane conductance regulator (CFTR), chymotrypsin
rauma
1. Damage to
ductal epithelium
2. Leakage of
digestive juices
3. Activation of
proteolytic, lipolytic,
or other enzymes in
9. Vasodilation, vascular
permeability, shock,
acute renal failure
4. Capillary and
lymphatic injury
5. Capillary and
lymphatic obstruction
8. Activation of
kallikrein system
7. Progression of
injury (largely
e
in clinical
manif
6. Acinar cell injury
and necrosis; release
and activation of
digestive enzymes
and cell proteins
Fig. 39.2 The pathophysiology of acute pancreatitis is not fully understood, but as the schematic shows, a
cascade of events seems likely, beginning with the release of toxic substances into the parenchyma and ending
with shock and death. Damage to the ductal epithelium or acinar cell injury may result from bile reflux, increased
intraductal pressure, alcohol, or trauma. (Modified from Grendell JH: The pancreas. In Smith LH Jr, Thier SO,
editors: Pathophysiology: the biological principles of disease, ed 2, Philadelphia, 1985, WB Saunders, p 1228.)
404 SECTION VI Gastrointestinal Disease
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TABLE 39.1 Causes of Acute Pancreatitis
Obstruction
Gallstones
Tumors: ampullary or pancreatic tumors
Parasites: Ascaris or Clonorchis species
Developmental anomalies: pancreas divisum, choledochocele, annular pancreas
Periampullary duodenal diverticula
Hypertensive sphincter of Oddi
Afferent duodenal loop obstruction
Toxins
Ethyl alcohol
Methyl alcohol
Scorpion venom: excessive cholinergic stimulation causes salivation, sweating, dyspnea, and cardiac arrhythmias; seen mostly in the West Indies
Organophosphorus insecticides
Drugs
Definite associations (documented with rechallenges): azathioprine or 6-mercaptopurine, valproic acid, estrogens, tetracycline, metronidazole, nitrofurantoin,
pentamidine, furosemide, sulfonamides, methyldopa, cytarabine, cimetidine, ranitidine, sulindac, dideoxycytidine
Probable associations: thiazides, ethacrynic acid, phenformin, procainamide, chlorthalidone, l-asparaginase
Metabolic Disorders
Hypertriglyceridemia, hypercalcemia, end-stage renal disease
Trauma
Accidental: blunt trauma to the abdomen (e.g., car accident, bicycle)
Iatrogenic: postoperative, endoscopic retrograde cholangiopancreatography
Infectious Diseases
Parasitic: ascariasis, clonorchiasis
Viral: mumps, rubella, hepatitis A, hepatitis B, hepatitis C, coxsackievirus B, echovirus, adenovirus, cytomegalovirus, varicella virus, Epstein-Barr virus, human
immunodeficiency virus
Bacterial: mycoplasma, Campylobacter jejuni, tuberculosis, Legionella species, leptospirosis
Vascular Disorders
Ischemia: hypoperfusion (e.g., postcardiac surgery) or atherosclerotic emboli
Vasculitis: systemic lupus erythematosus, polyarteritis nodosa, malignant hypertension
Idiopathic Disorders
Accounts for 10–30% of patients with pancreatitis
Up to 60% have occult gallstone disease (e.g., biliary microlithiasis, gallbladder sludge)
Less common causes: sphincter of Oddi dysfunction, mutations in the cystic fibrosis transmembrane regulator
Miscellaneous Disorders
Penetrating peptic ulcer
Crohn’s disease of the duodenum
Pregnancy-associated disorders
Pediatric associations: Reye’s syndrome, cystic fibrosis
Autoimmune pancreatitis
C (i.e., caldecrin) (CTRC), the calcium-sensing receptor (CASR), and
claudin-2. Aside from acute pancreatitis, mutations in these genes may
cancer. The decision to pursue genetic testing is one that should be made
only with the advice and involvement of an experienced counselor.
increase the risk of development of diabetes and pancreatic cancer.
The role of genetic testing in idiopathic acute pancreatitis is controversial. Diagnosis of these genetic disorders contributes little to direct management because specific therapy is unavailable. Similarly, inadvertent
disclosure of the results of genetic testing protects patients’ health care
life insurance. However, identification of an underlying genetic cause may
obviate the need for further testing, allow more informed family planning,
and enable better surveillance for complications, including pancreatic
Neoplasia
Primary pancreatic ductal adenocarcinoma, ampullary tumors, metastasis to the pancreas, and intraductal papillary mucinous neoplasms
are uncommon causes of acute pancreatitis. The mechanism of pan-
These causes should be considered for patients older than 40 years.
Pancreatitis has been reported in up to 10% of patients with pancreatic
cancer (see Chapter 58).
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