From clinical observations, male patients with gallstone disease seem to have a higher threshold for pain caused by biliary stones than their female counterparts. Perhaps this is one of the reasons that underlay the male preponderance seen in the acute calculous cholecystitis group in this study.
Our study showed that the fasting GBV increased in two age groups in non-gallstone subjects, i.e. from age 20 to 40 years and 60 to 80 years; especially the former period. In accordance with this differential increase in GBV in specific periods, the occurrence of gallstones reached its plateau between 40 and 80 years of age (from 15% before 40 years old to 42.5% after 40 years, P = 0.0027, Table ).
The gallbladder is a hollow visceral elastic organ. Its actual maximal fasting volume under in vivo physiological conditions is difficult to measure. Measuring methods include in vivo ultrasonography, nuclear scintigraphy, CT and in vitro post-cholecystectomy saline-filling measurement. hepatobiliary iminodiacetic acid scintigraphy is seldom used clinically except to demonstrate cystic duct obstruction in acute cholecystitis patients, due to its isotope radioactivity. On the other hand, in vitro post-cholecystectomy saline-filling measurement is the most accurate gold standard for measuring GBV. In contrast, abdominal ultrasonography is the most convenient examination for measuring GBV. However, the accuracy and precision depend greatly on the operators’ individual experiences. CT represent the more uniform, constantly used and easier method for diagnosis of gallstone diseases and for measuring GBV. These are the reasons why we adopted abdominal ultrasonography, CT and in vitro post-cholecystectomy saline-filling measurement in the present study.
GBV can have clinical and therapeutic implications and reflect pathophysiological mechanisms of gallstone diseases. The clinical and therapeutic implications of increased GBV lie in the cystic duct obstruction in acute calculous cholecystitis. The dilatation of the gallbladder is due to stones being trapped in the spiral valve of Heist. The onset of painful dilatation of the gallbladder is acute and is caused by the stones irritating the gallbladder mucosa, and the pressure exerted by the dilated gallbladder on the visceral nerve endings distributed over the entire gallbladder wall. Early dilatation of the gallbladder due to undrained mucus secretions also predisposes to compromised local blood circulation to the mucosa and the gallbladder wall, which leads to impaired absorption of water and electrolytes, which further aggravates the dilatation[10-12
]. GBV can usually reach up to 3.4 times the normal size. The vicious cycle of undrained mucus secretions and impaired absorption of water and electrolytes, coupled with chemical irritation by lysozyme, cytokines and chemokines, sometimes causes gangrene and/or perforation in 15% and 1.5%, respectively, of patients with acute calculous cholecystitis[2
In our study, the fasting GBV was larger in gallstone patients with acute cholecystitis than with chronic cholecystitis (Table ). Furthermore, local gallbladder wall necrosis/abscess was associated with further increases in GBV (Table ). It is possible that gallbladder decompression might prevent gangrene/empyema and perforation and make it easier to manipulate the gallbladder during cholecystectomy.
Gallbladder contraction is known to result from long-standing chronic cholecystitis and has the smallest GBV. The anatomical characteristics make it a difficult challenge to perform laparoscopic cholecystectomy safely.
The fasting GBV was larger in gallstone patients with chronic cholecystitis than that in non-gallstone subjects (28.77 ± 15.00 cm3
= 85, vs
16.77 ± 15.75, n
= 240, P
< 0.0001), which indicated possible pathophysiological mechanisms of weaker gallbladder contractility in gallstone patients with chronic cholecystitis, which was confirmed in our second study. In 2000, Portincasa proposed that larger GBV predisposes to bile stasis[6
Weaker gallbladder contractility in gallstone patients with chronic cholecystitis might provide a suitable micro-milieu for cholesterol monohydrate micro-crystals to grow into larger gallbladder stones, by preventing them from expulsion from the gallbladder lumen, when the gallbladder contracts in response to cholecystokinin (CCK) secreted from duodenum I cells stimulated by proteins and lipids in ingested food[8
In our second study, we measured fasting and postprandial GBV of 65 patients with gallstones and chronic cholecystitis and 53 healthy subjects, by abdominal ultrasonography and calculated the gallbladder EF. The average EF of patients with gallstones and chronic cholecystitis was lower than that of the healthy subjects. The difference in EF was statistically significant (Table ).
Developmental stages of acute cholecystitis
From our observations on the GBV changes during the development of acute cholecystitis from a chronic inflammatory state, we hypothesize that there are three stages based on GBV and pathological changes. These correspond to the three stages of severity of acute cholecystitis proposed by Miura et al[13
] at the Tokyo International Consensus Meeting in 2007.
Early (clinical) stage
In the early (clinical) stage of acute cholecystitis, which corresponds to mild (grade I) severity in the Tokyo consensus meeting, the mechanical effect of cystic duct obstruction causes an increase in GBV (from 28.77 ± 15.00 cm3, n = 85, to 54.16 ± 35.17 cm3, n = 44, P < 0.0001). No acute inflammatory leukocyte infiltration is observed, but chronic inflammatory reactions, such as subserosal fibrous tissues, and infiltration of lymphocytes, plasma cells, and macrophages beneath the columnar epithelium and Rokitansky-Aschoff sinus in the muscular layer are present, as revealed by pathological examinations. The early (clinical) stage of acute cholecystitis comprises about 44.4% (44/99). Early laparoscopic cholecystectomy is suggested by the Tokyo guidelines.
Second (pathological) stage
In the second (pathological) stage of development, which corresponds to the moderate severity (grade II) stage of the Tokyo guidelines, the GBV does not change significantly. However, pathological findings of acute immunoreactive and inflammatory responses appear in the gallbladder. These include leukocyte infiltration throughout the tissues, local flattening and denuded mucosal folds, and tissue edema. It comprises about 43.4% (43/99). Early laparoscopic or open cholecystectomy is suggested by the Tokyo guidelines. If a patient has serious local inflammation that makes early cholecystectomy difficult, then percutaneous or operative drainage of the gallbladder is recommended. Elective cholecystectomy can be performed after improvement of the acute inflammatory process.
Late (complicated) stage
If the condition goes untreated or is unresolved by treatment, the late (complicated) stage ensues, which corresponds to the severe (grade III) organ dysfunction stage of the Tokyo guidelines. In this stage, GBV further increases (Table ). Besides the pathological findings of acute immunoreactive and inflammatory responses, local gallbladder wall necrosis (gangrene), abscess and/or even perforations occur. Organ dysfunctions appear. It comprises about 12.2% (12/99). Appropriate organ support in addition to medical treatment for patients with organ dysfunction is suggested by the Tokyo guidelines. Management of severe local inflammation by percutaneous gallbladder drainage and/or cholecystectomy is needed. Biliary peritonitis due to perforation of the gallbladder is an indication for urgent cholecystectomy and drainage. Elective cholecystectomy may be performed after improvement of the acute illness by gallbladder drainage[13
Zhu et al[14
] have found that the amount of gallbladder CCK receptor is lower in patients with gallstones who have poor gallbladder contraction. Choi has found that FGF15 knockout mice have a gallbladder that is completely devoid of bile, and administration of recombinant FGF15 or FGF19 restores the GBV[8,15
]. Whether gallstone patients with poor gallbladder contraction and increased GBV have lower levels of CCK receptor and/or lower FGF19 gene expression is worth further investigation.
Different kinds of diet predispose humans to different gallstone diseases. At present, we have no data concerning how the diet consumed by the gallstone patients was different from that consumed by the normal population. If the diet differs, it is worthwhile investigating whether the diet predisposes the patients to gallstone diseases through its effect on GBV.
There is a limitation to this study. The gallstone patients were not subgrouped into those with cholesterol and pigment stones. Therefore, the findings of Masclee[3-5
] and Portincasa[6
] could not be investigated in this study.
In summary, we found that the fasting GBV increased in two periods in non-gallstone subjects, i.e. from age 20 to 40 years and 60 to 80 years. In accordance with these age preferences, the occurrence of gallstones reached its peak between 40 and 80 years of age. Moreover, we found that gallstone formation was associated with poorer gallbladder contractility and larger fasting and postprandial GBV Also, GBV increased as acute cholecystitis progressed. Therefore, gallbladder decompression is mandatory to prevent gangrene and/or empyema of gallbladders.