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30 Drug Induced Mesenteric and Retroperitoneal Diseases 285
patients with cocaine-induced nonocclusive mesenteric ischemia died, with mortality in these patients resulting from septic shock caused by extensive bowel injury.
Angiotensin Converting Enzyme (ACE)-Inhibitor Induced Visceral Edema
Definition
ACE-inhibitors are widely prescribed medications for a hypertension, coronary
artery disease, heart failure, diabetes, and chronic kidney disease. Common side
effects of these medications include dizziness, headache, diarrhea, and dry cough.
ACE-inhibitors are also known to be the leading cause of drug-induced angioedema
in the United States and in some cases intermittent abdominal pain secondary to
intestinal angioedema.
Epidemiology
Angioedema from ACE-inhibitor therapy is relatively rare and occurs in 0.1 to
0.7% of recipients. However, because they are so commonly prescribed,
ACE-inhibitors account for 20 to 40% of all emergency department visits for
angioedema per year. Compared to the general population, patients of African
descent have a five times higher rate of occurrence of angioedema from
ACE-inhibitor therapy. The Omapatrilat Cardiovascular Treatment vs. Enalapril
(OCTAVE) trial was a prospective study which evaluated over 12,500 patients with
hypertension who were treated with enalapril, an ACE-inhibitor or omapatrilat, an
inhibitor of both neprilysin (neutral endopeptidase, NEP) and ACE. The rate of the
development of angioedema secondary to enalapril over a period of six months was
0.68%.
Patients at Risk
Potential risk factors for developing ACE-inhibitor angioedema include a previous
history of episodes of angioedema, (specifically those related to NSAID use), age
greater than 65 years, intake of aspirin or other NSAIDs, and smoking.
Pathophysiology
ACE-inhibitors prevent the enzyme ACE from metabolizing Angiotensin I to
Angiotensin II. Angiotensin II is responsible for inactivating bradykinin and acts as
a vasoconstrictor by stimulation of angiotensin I and II recept ors. ACE inhibitors
286 S. Burroughs and E. D. Ehrenpreis
Fig. 30.2 Relationship between angiotensin II, ACE-inhibitors, and Bradykinin. Bold text: drugs.
Italicized text: enzymes. ACE: angiotensin-converting enzyme; BK: bradykinin; ARB: angiotensin
II receptor blocker. Modified from: Hurst M, Empson M. Oral angioedema secondary to ACE
inhibitors, a frequently overlooked association: case report and review. N Z Med J 2006; 119:
U1930
affect the signaling and the degradation of bradykinin, as they inhibit Angiotensin II
from inactivating bradykinin. This in turn stimulates the release of nitric oxide and
prostaglandins resulting in vasodilation as bradykinin levels increase. Increased
capillary permeability of the blood vessels may also occur (Fig. 30.2).
Signs and Symptoms
Angioedema is often described at asymmetric, nonpitting swe lling most commonly
affecting nondependent areas of subcutaneous or submucosal tissues. Commonly
affected areas are the lips, tongues and face. Visceral angioedema involving the
mesentery that is associated with ACE-inhibitor use has also been described in a
few case reports and reviews. Signs and symptoms described in these cases include
diffuse abdominal pain, diarrhea, vomiting, anorexia and ascites. Angioedema
30 Drug Induced Mesenteric and Retroperitoneal Diseases 287
Fig. 30.3 Angiotensin converting enzyme inhibitor (ACE)-induced angioedema: coronal view.
With permission from Dr. Abraham Dachman and Dr. Justin Ramirez
Fig. 30.4 a and b Angiotensin converting enzyme inhibitor (ACE)-induced angioedema: axial
views. With permission from Dr. Abraham Dachman and Dr. Justin Ramirez
associated with ACE-inhibitors may appear within a week of starting or increasing
medications, or after years of use.
Laboratory Findings
No definitive laboratory tests exist to diagnose ACE-inhibitor induced angioedema.
Obtaining a complement protein 4 level may be reasonable if there is clinical
suspicion that another cause of bradykinin-mediated angioedema could be present.
Monitoring for resolution of symptoms after discontinuation of ACE inhibitor
confirms the diagnosis.
288 S. Burroughs and E. D. Ehrenpreis
Imaging
Visceral angioedema can be appreciated on computed tomography. Findings
include dilated bowel loops, thickened mucosal folds, mesenteric edema, perihepatic fluid, ascites, or small intestinal “doughnut” or “stacked coin” appearance.
Most reported cases of ACE inhibitor-induced intestinal angioedema involve the
small bowel with circu mferential thickening of the small bowel wall, ascites and
incomplete small bowel obstruction (see Figs. 30.3 and 30.4a, b).
Discontinuation of ACE-inhibitors is the primary treatment of ACE-inhibitor
induced angioe dema. After discontinuation, angioedema usually resolves within 24
to 72 hours. H1 and H2 histamine blocker and, corticosteroids are commonly used
treatments for angioedema. In severe cases, intramuscular or subcutaneous epinephrine is administered.
Drug Induced Retroperitoneal Fibrosis
Definition, Description, and Epidemiology
The retroperitoneum is the anatomical space that lies between the posterior parietal
peritoneum and anterior to the transversalis fascia. The organs within the
retroperitoneal space include the adrenal glands, kidneys, ureters, aorta, inferior
vena cava, pancreas, esophagus, ascending and descending colon, rectum, and anal
canal. The primary drug-induced disease in this region is retroperitoneal fibrosis.
Retroperitoneal fibrosis is a disease process characterized by progressive inflammation and fibrosi s of connective and adipose tissue in the retroperitoneal space.
This inflammatory process generally originates inferior to the level of the aortic
bifurcation near the sacral promontory and then covers the retroperitoneum with
extension bilaterally along the aorta and inferior vena cava. It was first known as
Ormond’s disease, in the idiopathic, likely autoimmune form, and is uncommon,
with an occurrence of 1 in 200,000 patients. With an overall male predominance of
2–3 to 1, retroperitoneal fibrosis usually presents in the fifth and sixth decades of
life.
Pathophysiology
Retroperitoneal fibrosis has been linked to paraneoplast ic syndromes and may occur
as the result of severe retroperitoneal inflammation in acute pancreatitis. At least
two thirds of retroperitoneal fibrosis are considered idiopathic. However, several
medications have also been implicated as causes of retroperitoneal fibrosis
(Table 30.2).
Methysergide, an ergot derived prescription medication used for the prophylaxis
of migraine and cluster headaches, is a serotonin antagonist and has clearly been
30 Drug Induced Mesenteric and Retroperitoneal Diseases 289
Table 30.2 Medications
associated with drug induced
retroperitoneal fibrosis
Methysergide
Ergotamine
Hydralazine
Beta-adrenergic blocking agents
shown to be linked to the development of retroperitoneal fibrosis with lengthy use.
The estimated incidence of methysergide-induced retroperitoneal fibrosis is 1 in
5,000 treated patients. While the main mechanism is unknown, it has been
hypothesized that methysergide has profibrotic-reactive activities. In these patients,
methysergide enhances myofibroblast proliferation and overproduction of extracellular matrix components such as collagen, fibronectin, tenascin,
glycosaminoglycans.
Other pharmacologic agents such as ergotamine, hydralazine, and
Beta-adrenergic blocking agents, (both nonselective and Beta-1 selective), have
also been implicated in the development of retroperitoneal fibrosis by similar
mechanisms.
Diagnosis, Physical Findings and Laboratory Findings
Presenting symptoms of retroperitoneal fibrosis are usually the result of gradual
compression of structures within the retroperitoneal space, especially the ureter. The
most common individual symptom of retroperitoneal fibrosis is a dull, constant pain
localized to the back or flank, radiating to the lower abdomen. Other symptoms
which may be present are nausea, diarrhea, fever, and weight loss, as well as
hypertension. Laboratory abnormalities may include leukocytosis, elevated erythrocytic sedimentation rate, and elevated alkaline phosphatase levels. As the disease progresses, and there is further compression of the retroperitoneal structures,
most commonly the ureters, azotemia, renal insufficiency, and possible renal failure
can be seen. Lymphatics and venous obstruction can also occur secondary to
compression and result in edema, specifically of the lower extremities. Arterial
insufficiency can be seen with symptoms such as leg claudication secondary to aorta
involvement. Rarely this disease process involves the duodenum, common bile
duct, or colon resulting in obstruction.
Imaging
CT scan is the imaging of choice for the diagnosis of retroperitoneal fibrosis.
Retroperitoneal fibrosis is seen as a periaortic soft tissue mass of variable thickness
that envelops the retroperitoneal structures with obliteration of the plane between
these structures and the adjacent psoas musculature (Figs. 30.5, 30.6 and 30.7).
290 S. Burroughs and E. D. Ehrenpreis
Fig. 30.5 Coronal contrast-enhanced CT image demonstrates confluent soft tissue encasing the
infrarenal abdominal aorta and bilateral common iliac arteries (oval). The infrarenal IVC is
thrombosed (arrowheads)
Fig. 30.6 Axial CT image at the level of the bilateral common iliac arteries shows the
retroperitoneum completely replaced by abnormal soft tissue (oval) with additional thrombus in
the left gonadal vein (arrow)
Magnetic resona nce imaging (MRI) is also being more frequently used to define
the staging clearly, particularly using T2-weighted imaging.
Intravenous pyelogram is also used to define retroperitoneal fibrosis. Classic
findings that have been described include delayed excretion of contrast material
with hydronephrosis, ureteral narrowing and medial deviation of the ureters at the
L4–L5 level, (as opposed to lateral deviation found in retroperitoneal neoplasms). It
is important to note, however, that medial deviation of the ureters is not a constant
finding in patients with retroperitoneal fibrosis.
30 Drug Induced Mesenteric and Retroperitoneal Diseases 291
Fig. 30.7 Axial CT image at
the level of the kidneys again
shows abnormal
retroperitoneal soft tissue
encasing the aorta and IVC
(Asterix). Images courtesy of
Dr. Abraham Dachman
Histologic Findings
As the disease progresses, abundant collagen disposition and fibrous scarring
occurs. Grossly, it will appear as woody, white, and fibrous plaque. Microscopically, features include abundant lymphocytes, plasma cells, and macrophages
interspersed with fibroblasts and collagen bundles.
Treatments
The goal of treatment for patients with retroperitoneal fibrosis includes establishing
the diagnosis, relieving the obstruction, and preventing progression of the disease.
Medications that are causative for retroperitoneal fibrosis are discontinued. Corticosteroids, implemented in early, active inflammatory stage of retroperitoneal fibrosis,
have been shown to be effective.Other immunosuppressivedrugs, such as azathioprine
and cyclophosphamide, also have been used with success. Symptoms caused by
venous obstruction are best treated nonoperatively, with elevation and elastic support
of the leg eventually resulting in the development of collateral circulation.
Surgical
Surgical management of retroperitoneal fibrosis involves removing obstruction,
often involving the ureter utilizing ureterolysis with intraperitoneal transposition of
the urete rs. Other maneuvers described to prevent recurrence of the ureteral
obstruction include rapping the ureters in omental fat or interposing retroperitoneal
fat between the ureters and the fibrosis.
Prognosis
In patients with idiopathic retroperitoneal fibrosis without renal compromise and
effective ureterolysis, the prognosis is excellent with long-term success rates
exceeding 90%.
292 S. Burroughs and E. D. Ehrenpreis
Drug Induced Pancreatitis
Introduction
Acute pancreatitis is a condition in which the pancreas becomes inflamed and is
often clin ically characterized as epigastric abdominal pain with elevated levels of
amylase and lipase. In some cases, inflammation of the mesentery may occur as a
consequence of acute pancreatitis (See Chap. 16, Pancreatitis). A number of conditions are known to cause acute pancreatitis, with gallstones and alcohol abuse
accounting for most cases. Drug-induced pancreatitis is the cause of up to 2% of
patients with acute pancreatitis.
A number of medications have been associated with acute pancreatitis with
timing of onset varying, from immediately upon drug administration, to several
months. Since causative medications are usually identified in case reports and small
cases studies, the likelihood of evidence for ca usation is classified based on timing
of exposure and relationship to use and discontinuation of the drug (Table 30.3).
A listing of drugs demonstrating the greatest potential for causing acute pancreatitis
are shown in Table 30.4.
Varying mechanisms have been proposed for drug-induced pancreatitis. These
include an immunologic reaction as seen with sulfonamides, 6-mercaptopurine, and
aminosalicylates; ischemia as seen with diuretics such as furosemide and azathioprine; intravascular thrombosis as seen with estrogen; direct toxic effect as seen
Table 30.3 Classifi cation
system for drug-induced acute
pancreatitis
Class Ia drugs
At least 1 case report with positive rechallenge, excluding all
other causes, such as alcohol, hypertriglyceridemia, gallstones,
and other drugs
Class Ib drugs
At least 1 case report with positive rechallenge; however, other
causes, such as alcohol, hypertriglyceridemia, gallstones, and
other drugs were not ruled out
Class II drugs
At least 4 cases in the literature
Consistent latency (>75 percent of cases)
Class III drugs
At least 2 cases in the literature
No consistent latency among cases
No rechallenge
Class IV drugs
Drugs not fitting into the earlier-described classes, single case
report published in medical literature, without rechallenge
Reused with permission from Badalov N, Baradarian R,
Kadirawel I, et al. Drug-Induced Acute Pancreatitis: An
Evidence-Based Review. Clin Gastroenterol Hepatol 2007;
5:648. Copyright © 2007 AGA Institute
30 Drug Induced Mesenteric and Retroperitoneal Diseases 293
Interleukin-2
Ketoprofen
Lovastatin
Mefenamic acid
Nitrofurantoin
Octreotide
Oxyphenbutazone
Adrenocorticotrophic hormone
Ampicillin
Bendroflumethiazide
Benazepril
Alendronate
Atorva statin
Carbamazepine
Captopril
Betamethasone
Capecitabine
Cisplatin
Colchicine
Cyclophosphamide
Ceftriaxone
Chlorthalidone
Cimetidine
Clarithromycin
Cyclosporin
Cyproheptadine
Danazol
Diazoxide
Diclofenac
Diphenoxylate
Doxorubicin
Gold
Hydrochlorothiazide
Indomethacin
Interferon/ribavirin
Irbesartan
Isotretinoin
Ethacrynic acid
Famciclovir
Finasteride
Ketorolac
Lisinopril
Metolazone
Fluvastatin
Gemfibrozil
5-fluorouracil
Metformin
Minocycline
Mirtazapine
Naproxen
Paclitaxel
Ponatinib
Prednisone
Prednisolone
Penicillin
(continued)
Table 30.4 Summary of drug-induced acute pancreatitis based on drug class
Class Ia Class Ib Class II Class III Class IV
Acetaminophen
Chlorohiazide
Clozapine
Didanosine
Erythromycin
All-trans-retinoic acid
Amiodarone
Azathioprine
Clomiphene
Dexamethasone
Cannabis
a-methyldopa
Carbimazole
Azodisalicylate
Bezafibrate
Estrogen
L-asparaginase
Pegaspargase
Propofol
Tamoxifen
Ifosfamide
Lamivudine
Losartan
Lynestrenol/methoxyethinylestradiol
6-mercaptopurine
Meglumine
Methimazole
Nelfinavir
Norethindronate/mestranol
Codeine
Cytosine
Arabinoside
Dapsone
Enalapril
Furosemide
Isoniazid
Mesalamine
Metronidazole
Omeprazole
Premarin
Trimethoprimsulfamethazole
Pentamidine
Pravastatin
Procainamide
Pyritonol
Simvastatin
Stibogluconate
Sulfamethoxazole
Sulindac
Tetracycline
Valproic acid
294 S. Burroughs and E. D. Ehrenpreis
Phenophthalein
Propoxyphene
Ramipril
Ranitidine
Rifampin
Risperidone
Ritonavir
Roxithromycin
Rosuvastatin
Sertraline
Strychnine
Tacrolimus
Vigabatrin/lamotrigine
Vincristine
Class Ia Class Ib Class II Class III Class IV
Table 30.4 (continued)
Adapted from Badalov N, Baradarian R, Kadirawel I, et al. Drug-Induced Acute Pancreatitis: An Evidence-Based Review. Clin Gastroenterol Hepatol 2007;
5:648. Copyright © 2007 AGA Institute