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Gastroenteritis-Associated Hyperamylasemia
Prevalence and Clinical Significance
Shomron Ben-Horin, MD;
Zvi Farfel, MD;
Meir Mouallem, MD
Arch Intern Med. 2002;162:689-692.
ABSTRACT
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Background Serum amylase levels can be elevated in various pathological conditions.
However, acute gastroenteritis has not been widely recognized as a cause for
hyperamylasemia.
Patients and Methods We conducted a retrospective study of amylase results for all patients
hospitalized or discharged from the emergency department with a diagnosis
of gastroenteritis from April through November 1999. Patients with other possible
medical causes for elevated amylase levels were excluded. We also compared
the clinical and laboratory parameters of hyperamylasemic vs normoamylasemic
hospitalized patients with gastroenteritis.
Results A total of 1041 patients with acute gastroenteritis were identified.
Serum amylase levels were determined in 701 patients and were abnormally elevated
in 66 of them. In 15 patients, other possible causes of hyperamylasemia were
present, and these patients were excluded. The mean serum amylase level among
the remaining 51 patients (7.4% of the remaining 686 patients with gastroenteritis)
was 1.32 of the upper normal level, with a range of up to 2.2 times the upper
normal range. Clinicians tended to admit more hyperamylasemic patients than
normoamylasemic patients (10 of 51 vs 65 of 635; P
= .03, 1 sided). However, the course of gastroenteritis in the hospitalized
hyperamylasemic patients did not differ significantly from that in the hospitalized
normoamylasemic patients, as judged by the clinical signs and symptoms, laboratory
results, length of hospital stay, and need for antibiotics.
Conclusions Gastroenteritis is associated with a mild to moderate elevation of serum
amylase levels in a significant portion of patients and should be included
in the differential diagnosis of hyperamylasemia. Such elevation, however,
does not seem to bear clinical significance in terms of the severity of disease.
INTRODUCTION
ELEVATED SERUM amylase levels have long been recognized as a useful
marker for pancreatic inflammation. There are several other clinical conditions
in which hyperamylasemia is present, however, such as salivary gland disorders,
gastrointestinal perforation or infarction, renal failure, and macroamylasemia.
Although gastroenteritis is not widely considered as a cause of hyperamylasemia,
several reports have documented elevated amylase levels in patients with gastroenteritis
of specific pathogenesis. However, to our knowledge, the prevalence of hyperamylasemia
among nonselected patients with acute gastroenteritis and the impact of elevated
serum amylase levels on disease course have not been hitherto studied.
PATIENTS AND METHODS
Patients with any abdominal complaint who come to the emergency department
in our medical center usually have their blood drawn for a "surgical routine,"
which includes determination of amylase levels. We retrospectively examined
amylase values in all patients who were discharged from the emergency department
or who were admitted to the hospital with a diagnosis of gastroenteritis during
8 months in 1999 (April-November). Amylase values were determined in all patients
by the 2-point rate test using slide spectrophotometry (Vitros500; Johnson
& Johnson, Raritan, NJ) with a wavelength of 540 nm. Patients with elevated
amylase values were further evaluated. The normal range of amylase levels
in our laboratory is 30 to 300 IU/L, determined as the range of 2 SD of the
mean, thereby allowing for 2.5% of above-normal results in the reference population.1 In our study, patients were considered to have hyperamylasemia
only when their amylase values were higher than 318 IU/L, which is the value
at 3 SD of the normal population. By choosing this higher cutoff point, we
limited the expected incidental results above this value to only 1% of reference
population.1 Patients with a known pancreatic
abnormality (such as chronic pancreatitis or pancreatic tumor), patients with
known risk factors for pancreatitis (such as alcohol abuse or ingestion of
potential pancreaticotoxic drugs), patients with renal failure, and patients
with salivary gland disorders were also excluded, as were patients with hemolytic
blood samples and patients with a known biliary tract disease or elevated
direct bilirubin levels. A single patient with celiac disease was also excluded,
because several case reports indicate the occurrence of hyperamylasemia in
this disease.2 We then compared epidemiological,
clinical, and laboratory parameters of the hospitalized patients who had gastroenteritis
and hyperamylasemia with those who had normal amylase values. We also reviewed
the files of all patients who were admitted during the study period with an
emergency department provisional diagnosis of acute pancreatitis to see if
this diagnosis was altered to gastroenteritis at discharge. Statistical analysis
was performed by  2 test with Yates correction or by t test, as appropriate.
RESULTS
A total of 1041 patients were seen in the emergency department with
a diagnosis of acute gastroenteritis from April 1999 through November 1999.
Amylase results were available for 701 (67.0%) of these patients. Sixty-six
patients (9.4%) had elevated amylase values. Fifteen patients were excluded
after the application of the exclusion criteria previously described, leaving
51 patients (7.4%) with gastroenteritis-related elevated amylase levels out
of 686 patients with gastroenteritis and available amylase results. The average
amylase level among the hyperamylasemic patients was 396 IU/L (x1.32
of upper normal level), with a range of 319 to 657 IU/L (up to x2.2
of upper normal value). Amylase values were available for 13 of the 51 patients
within 1 month of current hospital referral, and were normal in all of them.
The lipase value was available for only 1 patient with hyperamylasemia, and
was elevated as well.
Overall, 75 (10.9%) of the 686 patients with gastroenteritis who were
seen at the emergency department were hospitalized. There was a significant
tendency to admit more patients with gastroenteritis and elevated amylase
levels (10/51, 19%), compared with patients with normal amylase values (65/635,
10.2%; P = .03, 1-sided). Hyperamylasemic patients
did not differ significantly in their age and sex from normoamylasemic patients
(Table 1). Several parameters
were examined to find out whether the clinical course of gastroenteritis differed
between patients with normal and elevated amylase levels (Table 1). No difference was found in reported subjective symptoms
of abdominal pain, vomiting, and diarrhea or in the type of stool reported
(watery vs mucous or bloody). The percentage of patients with temperatures
above 37.8°C was also similar in the 2 groups. No difference was found
in the laboratory parameters studied, which included the presence of leukocytosis
(white blood cell count, >11 000/mm3[>11.0 x 109/L]), electrolyte abnormalities, and determination of albumin levels,
as well as elevated urea levels, reflecting the degree of dehydration. Stool
culture results were available for 26 of the 75 hospitalized patients; 23
of the 26 stool samples were collected from normoamylasemic patients. Two
of these 23 cultures were positive for organisms (1 for Shigella flexneri, and 1 for Shigella species);
however, the numbers are too small for statistic analysis. The length of hospital
stay, the percentage of patients treated with antibiotics, and the percentage
of patients who underwent abdominal x-ray examination were similar in the
2 groups. The results of the abdominal x-ray examination, which were interpreted
as either normal or as revealing nonspecific dilation of small-bowel loops,
were also similar in both groups (data not shown). In addition, we identified
84 patients who were admitted during the study period with an emergency department
diagnosis of acute pancreatitis. In 14 of the 84 patients, the evaluation
during hospitalization yielded different diagnoses, such as biliary colic
or other gastrointestinal disorders. In none of the patients was the diagnosis
changed to gastroenteritis at discharge.
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Clinical and Laboratory Features of Hyperamylasemic vs Normoamylasemic
Patients With Gastroenteritis
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COMMENT
Amylase is found in several tissues, most notably the pancreas and the
salivary glands. The finding of elevated serum amylase levels most commonly
reflects pancreatic inflammation or injury. However, hyperamylasemia can result
from several other acute abdominal events, such as intestinal perforation,
ischemia, or infarction. Other well-recognized causes of elevated serum amylase
levels include salivary gland disorders; tumors such as ovarian and lung carcinomas;
renal failure, which causes reduced amylase clearance; and macroamylasemia.3 In most of these conditions, the amylase level is
only moderately elevated.4 Whether the level
of hyperamylasemia can be relied on to differentiate between pancreatitis
and other disorders has been a matter of controversy. In general, however,
when the clinical circumstances are suggestive of pancreatitis, a cutoff point
of more than 3 times the upper normal amylase value has been shown to be highly
specific for pancreatic inflammation.4-5
Measurement of lipase levels, pancreatic isoenzymes of amylase, and urine
excretion of amylase are additional biochemical aids to diagnosis.3 Gastroenteritis is generally not considered a cause
of hyperamylasemia and is not mentioned in the differential diagnosis of hyperamylasemia
in standard gastroenterological or surgical textbooks.6-7
Our study shows for the first time, to our knowledge, that a substantial number
(about 7.4% in our series) of patients with gastroenteritis have a mild to
moderate increase in serum amylase levels. In all 13 patients who were examined
within a month after the gastroenteritis episode, amylase levels were found
to be normal, showing the temporal association between gastroenteritis and
hyperamylasemia. The fact that amylase values in our series did not exceed
2.2 times the upper normal value should be interpreted cautiously, as inclusion
of patients in this retrospective study was based on emergency department
diagnosis of acute gastroenteritis. Thus, it could be assumed that some patients
with gastroenteritis and higher amylase levels were not diagnosed by the emergency
department physician as having acute gastroenteritis but rather as having
suspected pancreatitis, and were therefore not included in this study population.
However, such misrepresentation is unlikely in light of our finding that in
none of the 84 patients admitted during the study period with suspected pancreatitis
was the diagnosis changed to gastroenteritis at discharge.
The pathogenesis of hyperamylasemia in our patients is not clear. One
possible cause of elevated amylase values in these patients is direct involvement
of the pancreas in the infectious inflammatory process that affected the intestine.
There are several reports suggesting pancreatic damage during infectious gastroenteritis.
In a prospective study of 188 patients with Campylobacter
jejuni enteritis, Pitkanen et al8 reported
a rate of 6% of complicating pancreatitis as determined by elevation of amylase
and lipase levels. However, lipase levels were not measured in all patients;
the degree of elevated amylase levels at which pancreatitis was diagnosed
was not specified; and imaging studies were not reported to have been performed.
In another prospective study of 47 patients with Salmonella enteritis, 62% of patients were diagnosed as having concurrent pancreatitis
based on elevated amylase and lipase levels.9
However, in a prospective study of 147 cases of acute gastroenteritis, in
which Salmonella was the causative agent in 51 patients
and Campylobacter in 22, there were no cases of pancreatitis.10 Mild elevation of amylase levels was found in only
4 patients, 1 with Salmonella and none with Campylobacter.10 These conflicting
results have led to a dispute regarding the incidence of pancreatitis in infectious
gastroenteritis.11 Only a few case reports
adequately document the concomitant occurrence of pancreatitis with infectious
gastroenteritis through detailed clinical course and an elevation of amylase
and/or lipase levels of more than 3 times the normal values, along with imaging
studies.12-15
Altogether, only 4 patients have been so described: 2 with Campylobacter enteritis, 1 with typhoid, and 2 with rotavirus.12-15 While
the postulated mechanism is direct invasion of pancreatic parenchyma by the
pathogen,9 no proof by direct tissue visualization
or cultivation of pathogen has been available so far.
An alternative mechanism to explain the elevated amylase levels in patients
with gastroenteritis was offered by some investigators based on the long-observed
barrier dysfunction of the intestinal mucosa during infectious diarrhea, as
well as in other inflammatory diseases of the gut, a state referred to as leaky gut.16-17
Gnadinger et al11 described 2 patients with Salmonella enteritis and elevated amylase and lipase levels,
without ultrasonographic evidence of pancreatitis. Increased intestinal permeability
for chromium 51–labeled EDTA was demonstrated in both patients. The
authors concluded that rather than "true" pancreatitis, mucosa inflammation
causes increased permeability, or a state of leaky gut, which in turn causes
increased reabsorption of pancreatic enzymes from the intestinal lumen into
the blood stream. It is therefore possible that the elevated amylase levels
in our patients reflect increased lumen amylase absorption through an inflamed
and defective mucosal barrier, rather than direct pancreatic involvement by
the inflammatory process.
The course of gastroenteritis as manifested by duration of hospital
stay, need for antibiotics, and clinical symptoms and laboratory results was
similar in patients with elevated or normal amylase levels in our study. This
similarity in the clinical course is consistent with the findings of a previous
small-scale retrospective study of elevated pancreatic enzyme levels in patients
with gastroenteritis.18 Our study revealed
that the hospitalization rate was almost twice as high among patients with
gastroenteritis and hyperamylasemia (10/51, 19%) than among patients with
gastroenteritis and normal amylase levels (65/635, 10.2%; P = .03, 1-sided), probably owing to clinicians' concern over the elevated
amylase values. However, the similarity in the clinical course of gastroenteritis
in normoamylasemic and hyperamylasemic patients argues against the need for
hospitalizing patients with gastroenteritis and mild to moderate elevations
of serum amylase levels, unless indicated by other clinical parameters.
Finally, one should recognize the limitation of our study, which is
based on a retrospective analysis. A controlled prospective study, which will
preferably include serum lipase measurement and appropriate imaging studies
for all patients, is required to confirm our findings.
CONCLUSIONS
Gastroenteritis should be included in the differential diagnosis of
mild to moderate hyperamylasemia. The pathogenesis of this hyperamylasemia
is not clear, but may result either from pancreatic involvement in the inflammatory
process or from increased absorption of pancreatic enzymes from the gut lumen
owing to increased permeability of the intestinal mucosa. The clinical course
of patients with gastroenteritis and mild to moderate hyperamylasemia does
not differ significantly from that of normoamylasemic patients.
AUTHOR INFORMATION
Accepted for publication July 30, 2001.
Corresponding author and reprints: Shomron Ben-Horin, MD, Department
of Medicine F, Sheba Medical Center, Tel Hashomer 52621, Israel (e-mail: m_bhorin{at}Netvision.net.il).
From the Departments of Medicine F (Dr Ben-Horin) and E (Drs Farfel
and Mouallem), Sheba Medical Center, Tel Hashomer, Israel, and Sackler School
of Medicine, Tel-Aviv University, Tel Aviv, Israel.
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