Case 4 -
Acute Ischemic Injury with Fibrin Thrombi in Microvasculature
Charles R. Lassman
Geffen School of Medicine at UCLA
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A 31 year old woman, presented to the emergency room with severe cramps and bloody diarrhea. She had
been in good health until two days prior to presentation when she suffered from acute onset of watery
diarrhea and abdominal cramping. After two days, the diarrhea turned bloody and she sought medical
Examination in emergency room was notable for a tender abdomen, which was not felt to require surgical
intervention. The patient was afebrile. Routine laboratory work was unremarkable. The patient was
placed on levafloxacin and sent home; stool cultures were not performed. The patient continued to pass
moderate amounts of blood in her stool and returned to the ER the following day with worsening cramps. A
CT suggested "inflammation and ischemia" of the hepatic flexure and right transverse colon; the patient
was admitted for further evaluation and observation.
On admission stool was sent for culture and analysis and the patient was continued on levafloxacin
with a presumptive diagnosis of acute infectious colitis. Stool cultures were negative for pathogenic
organisms. Severe cramping and bloody diarrhea continued unabated for two more days. Five days after
the onset of symptoms and 4 days after antibiotic treatment was started, colonoscopy was performed and
biopsies were taken.
Colonoscopy demonstrated normal appearing mucosa from the cecum to the proximal transverse colon. The
proximal transverse colon appeared inflamed and markedly edematous with areas of extensive superficial
ulceration. The distal transverse colon appeared less edematous, with less severe ulceration. The
rectum was minimally involved. Biopsies were obtained from the rectum as well as the transverse colon.
Case 4 - Slide 1
Case 4 - Figure 1 - Colonic tissue demonstrating hemorrhage with superficial mucosal necrosis, mild acute inflammation, preservation of deep crypts, reepithelialization of the surface and occasional deep crypt apoptosis. The submucosa demonstrates edema hemorrhage and a mild mixed inflammatory infiltrate (20x, H &E).
Case 4 - Figure 2 - Colonic tissue demonstrating hemorrhage with superficial mucosal necrosis, mild acute inflammation, preservation of deep crypts, reepithelialization of the surface and occasional deep crypt apoptosis. The submucosa demonstrates edema hemorrhage and a mild mixed inflammatory infiltrate (20x, H &E).
Case 4 - Figure 3 - Colonic tissue demonstrating hemorrhage with superficial mucosal necrosis, mild acute inflammation, preservation of deep crypts, reepithelialization of the surface and occasional deep crypt apoptosis. The submucosa demonstrates edema hemorrhage and a mild mixed inflammatory infiltrate (20x, H &E).
Case 4 - Figure 4 - A small fragment of fibrinopurulent exudate with foreign (fecal) material (40x, H&E)
Case 4 - Figure 5 - Deep mucosal capillaries with fibrin thrombi (40x, H &E).
Case 4 - Figure 6 - Colonic tissue demonstrating hemorrhage with superficial mucosal necrosis, mild acute inflammation, preservation of deep crypts and reepithelialization of the surface. (40x, H &E).
Acute inflammatory process of the transverse colon,
probable severe acute infectious colitis, ischemic colitis can not be excluded, less likely, though still
possible is inflammatory bowel disease, specifically Crohn's.
Acute Ischemic injury with fibrin thrombi in microvasculature,
rule out E. coli O157:H7.
Subsequent Clinical History:
Following histologic exam of biopsy
specimens, further clinical history was obtained. Two days prior to the onset of symptoms, the patient
went to her parent's home to house-sit while they were away. She arrived late in the evening, was quite
hungry and found some form of cooked ground meat in the refrigerator. She stated that it tasted bad but
thought it was lamb (she did not like lamb) and was so hungry that she continued to eat it. She later
found out that it was hamburger.
Most fecal E. coli. do not cause
disease in humans; a subset of organisms however elaborate toxins which are responsible for a wide
variety of colonic manifestations. These organisms have been referred to as enterotoxigenic E. coli and those which are associated with bloody diarrhea are referred to as
enterohemorrhagic E. coli. (EHEC). Pathogenesis is due to toxins which are
closely related to those elaborated by Shigella dysinteriae, so called
shiga-like toxins (stx). Numerous shiga-like toxins have been identified and characterized.
Enterohemorrhagic E. coli which elaborate shiga-like toxins have been
referred to as shiga toxin producing E. coli (STEC). Not all STEC and not
all stx are pathogenic; most EHEC associated human disease is caused by organisms elaborating stx 1 and
the stx 2. There are numerous subtypes of stx 2 with differing propensity to cause diarrhea, hemorrhagic
diarrhea and thrombotic microangiopathy (TTP and HUS).
More than 100 serotypes of EHEC have been identified, the most common is O157:H7. The O refers to a
cell surface antigen and H refers to a flagellar antigen. Bloody diarrhea occurs more commonly with this
serotype than with others.
In 1982 an outbreak of bloody diarrhea primarily amongst adults was linked to consumption of
hamburgers at different outlets of the same fast food chain. Cultures for usual Campylobacter, Salmonella, Shigella and Yersinia were negative. E. coli O157:H7 was isolated from stool samples of many of the patients (Riley)
and was thought to be the cause for the outbreak of hemorrhagic colitis.
Around the same time Karmali et al. reported the isolation of a filtratable substance from stool
samples of children with HUS in Toronto. The substance was toxic to cultured Vero cells (a cell line
derived from epithelial cells of the African green monkey). These toxins were referred to as verotoxins
and the E. coli which produced them were referred to as verotoxin producing
E. coli (VTEC). Various serotypes of E. coli were isolated from the stool
samples of these children with HUS and E. coli O157:H7 was seen in two of
eight children. Verotoxin producing E. coli was thought to be a causative agent in some cases of
In 1983 O'Brien reported that the verotoxin activity of the E. coli
O157:H7 could be neutralized by antibodies to Shiga toxin. Vero toxin producing E. coli are now recognized to be enterohemorrhagic E.
coli (EHEC) and the verotoxins are recognized to be the shiga-like toxins.
Since then sporadic cases and outbreaks of E. coli O157:H7 have been
reported. The most recent being the spinach borne illness in the fall of 2006 which resulted in
approximately 200 infections, 3 deaths and 31 cases of kidney failure and the more recent Taco Bell
outbreak with another approximately 200 infections (and counting).
The main sources of contamination have been undercooked ground beef, unpasteurized milk, unpasteurized
apple juice, raw vegetables, water, swimming in contaminated ponds, and human to human contact.
Infection is more common in warm weather months, and the symptoms are more severe in children and in the
The bacteria can be isolated from as many as 80% of cattle in the United States. They are not
pathogenic to the bovine host as pathogenesis requires attachment of the bacterium to epithelial cells
through a highly specific receptor which the cattle lack. It has been suggested that forage fed cattle
have a lower rate of infection than grain fed cattle and that forage feeding for 1 week prior to
slaughter can markedly reduce the chance of contaminated meat.
The bacteria attach to enterocytes, colonize and
elaborate a toxin. Receptors for toxin on epithelial and endothelial cells may be upregulated by the
immune response to bacterial colonization. The toxin is internalized by epithelial cells, and more
importantly endothelial cells. Once internalized, the toxin irreversibly blocks protein synthesis
resulting in cell death. Endothelial cell death results in thrombosis of small vessels, primarily
capillaries and arterioles. If the toxin becomes widely distributed HUS or TTP may occur.
The incubation period is 1-8 days, generally 3-5.
The first manifestation in many patients is watery diarrhea with severe cramping. In more severe cases
there is progression to blood streaked diarrhea or hemorrhagic colitis. Patients are generally afebrile
but suffer from severe cramps and vomiting. Between 5 and 10% of children with hemorrhagic colitis
associated with E. coli O157:H7 will then develop HUS or TTP. A smaller
percentage of adults develop HUS or TTP. HUS may occasionally develop in the context of mild colonic
disease. There is currently no way to predict which patients will develop systemic disease.
Thrombocytopenia and the presence of schistocytes on a peripheral smear indicate the development of HUS.
In patients for whom bloody diarrhea has resolved for 2-3 days, and for whom evidence of thrombotic
microangiopathy has not developed, HUS will most likely not develop.
Antibiotics have not been demonstrated to be of benefit for either hemorrhagic colitis or for
preventing the onset of HUS. They may in fact be contraindicated as there is some evidence that they
increase the risk of development of HUS.
Histology and Diagnosis:
There are a few studies reporting the histology
of hemorrhagic colitis associated with E. coli O157:H7. Colonoscopy is
generally not performed unless disease is severe and or there is confounding clinical information to
suggest IBD, ischemia or some other form of colitis. Resection specimens due to necrosis or perforation
are reflective of severe disease. The histologic features are nonspecific and may be suggestive of
ischemic and or infectious colitis. Findings are patchy, however the right colon is more frequently
involved. When severe the entire colon may be affected. Mild injury is limited to the mucosa but when
severe there may be full thickness necrosis resulting in perforation.
Griffin et al. described a combination of infectious and ischemic histologic features in 11 patients
(19 biopsies and one resection). All had edema and hemorrhage of the lamina propria. Fourteen
specimens (9 patients) had histology indicative of ischemia as characterized by superficial necrosis with
preservation of the deeper crypts. In only 10 specimens (7 patients) were fibrin/platelet thrombi
identified in mucosal capillaries. Ten specimens (6 patients) demonstrated deep crypt apoptosis. Focal
active colitis with neutrophilic infiltration of crypts and the lamina propria and with crypt abscesses,
typical of infectious, acute self limited colitis was seen in 10 specimens (5 patients). Poorly formed
pseudomembranes were seen in 5 specimens (4 patients). Material form 5 patients showed only ischemic
changes, four showed a mixed pattern and one showed an infectious without ischemic changes.
In 2003 Murray and Patterson reported the pathologic changes in colonic specimens from eight pediatric
patients with hemorrhagic colitis and HUS from a 1993 outbreak in the northwest USA. The study is
weighted towards those with quite severe colonic disease. There was one patient with biopsy material
only, there were 4 subtotal colectomies, two left hemicolectomies and two autopsies. They confirmed many
of the previously described findings and reported more significant left sided disease than has been
reported for adults with hemorrhagic colitis secondary to E. coli O157:H7.
Routine cultures are insufficient for diagnosis. Culture must be performed on MacConkey sorbitol agar
and routine media, the sorbitol negative colonies are then tested with serum for O157 and H7 antigens.
Cultures are less likely to be positive late in the course of illness and in patients treated with
Su et al. have reported the use of a monoclonal antibody which can be used on paraffin embedded tissue
sections. In a retrospective study, 10 sections from 2 patients with culture positive E. coli O157:H7 hemorrhagic colitis were positive with strong staining of the
exudates overlying the area of ulceration. Interestingly 3 of 11 cases diagnosed as ischemic colitis
were also positive. Staining was negative or equivocal for IBD (8 cases) and pseudomembranous colitis
(3). This stain may therefore be helpful in identifying cases of E. coli
O157:H7 associated hemorrhagic colitis.
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