Keywords
Cholecystokinin - cholescintigraphy - fatty meal - gallbladder ejection fraction -
hepatobiliary imaging - milk
Introduction
Hepatobiliary imaging plays an important role in the evaluation and management of
many patients with gastrointestinal symptoms and abdominal pain. It is estimated that
approximately 30,000–90,000 patients/year undergo cholecystectomy with the diagnosis
of acalculous cholecystitis.[1] The ease of performing laparoscopic cholecystectomy might have inflated the true
incidence of this diagnosis. It has also been reported that cholecystectomies have
only 50%–75% success rate in eliminating the symptoms.[2],[3] Epidemiological studies found that cholecystectomies for functional cholecystitis
are 4–80 times more common in the United States than in Norway, Sweden, Poland, and
Australia.[4] This raises the question that many of these cholecystectomies might be unnecessary.
Since the first description of the possible accurate evaluation of gallbladder contractility
using a phantom and small number of patients after cholecystokinin (CCK) administration
by Krishnamurthy et al. in 1981,[5] this test has gained wide acceptance as the routine standard test for evaluating
gallbladder contractility. Subsequent studies and Cochrane review[6] have established the cutoff value for abnormal gallbladder ejection fraction (GBEF)
of <35% as abnormal and indicates decreased gallbladder contractility. Different methods
of administration of CCK have been proposed as the acceptable mean to produce reliable
results for the evaluation of gallbladder contractility. These include slow infusion
of CCK over 30 or 60 min to mimic the physiologic excretion of CCK in the body in
response to eating[7],[8] versus the short intravenous infusion over 3 min.[8]
Fatty meals are increasingly utilized to evaluate gallbladder contractility, with
the increasing shortage of CCK in the United States. The examples of acceptable fatty
meals include fatty drinks, for example, Ensure or Pediasure or an in-house prepared
fatty meal.[9],[10],[11],[12] We also noticed in one patient who underwent a hepatobiliary scan with CCK and had
an abnormal GBEF <35% had returned in few months for a repeat hepatobiliary scan ordered
by a different physician, with no interval intervention for his continued abdominal
pain, during a time of shortage of CCK. We repeated the scan with half-and-half milk
(HHM) instead of CCK, and surprisingly, the GBEF calculation was normal in the same
patient. Previous studies have been conducted using regular milk with well-established
gallbladder emptying response times and time-activity curves in normal men and women
have been published.[13] Thus, we decided to conduct a prospective study to compare GBEF in the same patients
after CCK administration and HHM ingestion.
In this study, we compared the effect of CCK and HHM administered in the same patient
on gallbladder contractility with follow-up on clinical outcomes of the patients.
Methods
After obtained approval of this study protocol from the University of Texas-McGovern
Medical School's Institutional Review Board, we prospectively and consecutively included
patients that meet the inclusion criteria into the study. This study included 50 patients
who underwent hepatobiliary scan using 5–6 mCi of Tc-99m mebrofenin with CCK administration
and demonstrated a reduced GBEF of <35%. CCK was administered at the end of 1 h of
continuous dynamic imaging at a dose of 0.02 μg/kg as a slow intravenous injection
over 3 min. After consenting to be included in the study which was performed in approximately
10–15 min, these patients were administered 8 ounces of cold HHM (Oak Farms) which
contained 28 g of fat. A waiting period of 10 min after the ingestion of the milk
was followed by repeat of 30 min dynamic imaging of the upper abdomen at 1 min/frame
rate. The GBEF was recalculated using the same computer analysis program used for
calculating the GBEF after CCK stimulation.
Data were collected, including the patients' demographics, clinical symptoms, findings
from other imaging modalities, pain medications, and the GBEF with CCK and HHM stimulation.
In addition, data regarding the reproduction of pain during CCK or HHM administration
were obtained. The patients were contacted at 6 months to follow-up on their symptoms,
particularly abdominal pain, any procedures, or change of medications. The abdominal
pain was evaluated using a pain scale from 0 to 10 for all patients before the hepatobiliary
scan and at 6 months follow-up.
Statistical analysis
Distributions of continuous variables were verified to be normal using the Kolmogorov–Smirnov
test. Continuous variables were summarized as mean and standard deviation. Increase
in GBEF was evaluated by the paired t-test. We reported two-sided P values, and P
< 0.05 was considered as statistically significant.
Results
A total of 50 patients were prospectively included in our study, 19 males and 31 females,
with a mean age of 48.6 ± 14.7 years. Nineteen of these patients were Caucasian, 13
African American, 4 Asian, and 14 others. All patients had an abnormal GBEF after
CCK with an average of 14.7% ± 8.5% (range 0%–33%). The recalculated average GBEF
after HHM administration was 30.7% ± 20.8% (range 0%–88%). The average increase in
GBEF of all the patients with the administration of HHM after CCK was 16.0% ± 22.2%
(range 0%–88%). The increase in GBEF after HHM was statistically significant with
P < 0.001.
The GBEF changed from abnormal (GBEF <35%) to normal (GBEF >35%) in 17 out of the
50 patients (34%), with an average increase in their GBEF of 39.2% ± 18.5% (P < 0.01).
Examples of patients with a significant change of GBEF with HHM are demonstrated in
[Figure 1] and [Figure 2]. The remaining 33 patients had an increase in their GBEF at an average 4.1% ± 12.4%
(P = 0.07) but remained abnormal [Figure 3]. We have also observed a more physiologic response with a gradual smooth continued
drop in the time-activity curves after HHM stimulation than with CCK stimulation [Figure 4].
Figure 1 The same patient sequential images and time activity curve of the gallbladder after
cholecystokinin administration (a) with a calculated gallbladder ejection fraction
20% and after half and half milk administration (b) with a calculated gallbladder
ejection fraction 51%
Figure 2 Significant change in gallbladder ejection fraction in the same patient from abnormal
27% after cholecystokinin stimulation (a) to normal 88% after half and half milk stimulation
(b)
Figure 3 Unchanged abnormal gallbladder ejection fraction in a patient after cholecystokinin
stimulation (a) calculated as 12% and after half and half milk stimulation (b) calculated
as 4%
Figure 4 Comparison of the time-activity curve and gallbladder contractility in the same patient
after cholecystokinin (a) showing a brief mild contraction followed by relaxation
when the cholecystokinin effect fades versus after half-and-half milk (b) showing
smooth gradual increasing gallbladder contraction
Only one patient had pain after CCK administration and was one of those who changed
their GBEF from abnormal to normal after drinking milk. Another patient had abdominal
pain after milk ingestion, and her GBEF remained abnormal with both CCK and HHM.
Clinical outcome was available in 47 patients, and 3 patients were lost to follow-up.
The follow-up interval was 6 months in 45 patients and 6–12 months in 2 patients.
The outcome of the two groups of patients, those with no change in their GBEF after
HHM and those with normalized GBEF after HHM ingestion is summarized in [Table 1].
Table 1 The outcome of the patients with abnormal gallbladder ejection fraction both with
cholecystokinin and half-and-half milk and those with abnormal gallbladder ejection
fraction after cholecystokinin but normal with half and half milk
When focusing on the group of patients with abnormal GBEF after CCK but normal after
HHM (17 patients; 34%), 2 underwent cholecystectomy with improvement of their pain
that may represent the rate of false-negative rate (12%) if HHM is to be used as the
standard stimulus for hepatobiliary imaging. On the other hand, 8 patients (50%) were
appropriately diagnosed with other disorders and were pain free after the treatment
for these disorders but would have been considered as false positives if CCK was to
be used as the only stimulus for gallbladder contractility. These eight patients were
appropriately treated for H-Pylori gastritis (1 patient), kidney stones (1 patient),
inflammatory bowel disease (1 patient), gastroesophageal reflux disease/gastritis
(GERD) (2 patients), pancreatitis (1 patient), hyperparathyroidism (1 patient), and
fatty liver (1 patient). Thus, the sensitivity, specificity, and positive predictive
and negative predictive values of HHM-simulated hepatobiliary imaging are 92.6%, 57.1%,
80.6%, and 80.0%, respectively. Five patients did not improve despite a different
diagnosis and treatment than chronic cholecystitis and/or gallbladder dyskinesia or
they were not diagnosed with any definite diagnosis. They remain undetermined if they
are false-negative studies with HHM versus not responding to the treatment for these
different diagnoses or they are misdiagnosed. Two of these patients had GERD/gastritis;
one had elevated liver enzymes; one with chronic pancreatitis; and one with fatty
liver.
Discussion
Our study has shown that using HHM results in better gallbladder contractility than
using CCK injection over 3 min. Thirty-four percent of the patients demonstrated an
increase in their GBEF from below normal limits after CCK injection to the normal
limit after HHM stimulation (≥35%). We have also observed a more gradual and continuous
slow contractility of the gallbladder after HHM stimulation with a steady smooth decline
of the time-activity curve suggestive of a more physiologic response than with CCK
injection [Figure 4].
The diagnosis of chronic acalculous cholecystitis has been previously questioned by
Lillemoe[1] since it is found in only 5%–15% of over 600,000 cholecystectomies performed every
year in the US. This points out the magnitude of possible unnecessary cholecystectomies
performed based on this diagnosis. To date, the only available test to make this diagnosis
is hepatobiliary scintigraphy with CCK stimulation. Hence, clearly, there are many
false-positive results when CCK is used as a stimulus with hepatobiliary scan. In
another large study by Eckenrode et al., cholecystectomies were performed based on patients' symptoms rather than their
hepatobiliary scan results, and they recorded the resolution of pain in 66% of patients
with positive hepatobiliary scans and 77% of patients with negative hepatobiliary
scans in patients with typical biliary colic symptoms versus 64% of patients with
positive hepatobiliary scans and 43% of patients with negative hepatobiliary scans
in patients with atypical symptoms.[14] CCK was used as a stimulus in their study during hepatobiliary scans and they suggested
that hepatobiliary scans are over-utilized in the management of patients with biliary
dysfunction.
Another study by Goussous et al. compared the reproduction of pain between the two groups of patients who underwent
hepatobiliary scans, one stimulated with CCK and another stimulated with fatty meal
in form of one can of Ensure Plus.[15] They found no difference in the average GBEF between the two groups, but there was
a higher reproduction of pain in the group stimulated with CCK (61%) versus fatty
meal (30%), which they conclude is an important predictor of good response to cholecystectomy.
Morris-Stiff et al. has also reported in a large study that the reproduction of pain during stimulated
hepatobiliary scan is superior to GBEF in predicting the resolution of symptoms after
cholecystectomy.[16] In our study, only one patient had pain after CCK stimulation and his GBEF actually
normalized after stimulating gallbladder contractility with HHM, suggesting that the
pain is likely a side effect of CCK stimulation rather than a true indication of gallbladder
motility dysfunction. Furthermore, only one patient in our study had pain after HHM
stimulation and her GBEF remained abnormal. Interestingly, the number of patients
who experienced pain both after CCK and after HHM stimulation in our study are very
low, suggesting that pain cannot be used as an indication for cholecystectomy or a
predictor for relief after cholecystectomy.
The strength of our study is the design as a prospective study with consecutive enrollment
of patients, and only three patients lost to follow-up at 6 months. Many studies have
been published in the literature about CCK stimulated hepatobiliary imaging, but they
were mostly retrospective studies.[17],[18],[19] Limitation of our study that HHM was administered after CCK administration which
may raise the question if we are double stimulating the gallbladder with two stimuli
one after the other, CCK followed by HHM. Most likely, the effect of CCK should have
weaned off by the time we administered HHM since the interval between CCK administration
and milk administration is approximately 45 min while the half-life of CCK in the
blood is only 2.5 min.[20] Thus, HHM was administered after almost 18–20 half-life of CCK effect. In addition,
it is a well-established routine practice in hepatobiliary imaging to administer CCK
30 min before initiation of the hepatobiliary scan in patients who have been fasting
for longer than 24 h to clear their gallbladder from any sludge knowing that 30 min
is long enough interval to prevent any interference of CCK premedication with the
accuracy of the hepatobiliary scan.
Most importantly, all the patients enjoyed the cold HHM and had no difficulty of drinking
the whole glass of 8 oz, especially after fasting for the test.
Conclusion
In conclusion, our study demonstrated that HHM is a superior and more accurate stimulus
for gallbladder contractility and calculation of GBEF. It also suggests better outcomes
for the management of gallbladder dysfunction, although our results did not reach
statistical significance. However, the difference between the mean GBEF after HHM
was significantly higher than with CCK with P < 0.001.
Thus, we recommend the use of HHM as the standard stimulus for HIDA scans to diagnose
gallbladder motility dysfunction. This will also eliminate the difficulties in performing
hepatobiliary scans in the face of CCK frequent shortages in the US.
