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Fatal acute acalculus cholecystitis as an early complication after radiation therapy (acalculous cholecystitis after radiation therapy)
P. Katsinelos, I. Pilpilidis, B. Papaziogas, G. Chatzimavroudis, G. Paroutoglou, K. Mimidis, S. Dimiropoulos, E. Kamperis (Chirurgia, 103 (2): 223-226)

Introduction
Acute acalculus cholecystitis was first described in 1844 by Duncan (1), in which a fatal case of gangrenous cholecystitis occurred following an operative procedure on a femoral hernia. It is not common, representing only 2-12 per cent of all cases of acute cholecystitis in the general population (2). Acute acalculus cholecystitis has been to occure mainly with parenteral nutrition, me-chanical ventilation, use of narcotic analgesics, multiple trauma, hypovolaemic shock, septic shock, visceral ischaemia, bone marrow transplantation, and bacterial, fungal, and parasitic infections (3-15).
Biliary stasis and ischaemia of the gallbladder have been suggested to be the main factors predisposing to acalculus cholecystitis (2, 16, 17). Although, there is increasing evidence of the detrimental role of splachnic ischaemia, it has been generally agreed that the aetiology of acalculus cholecystitis is mul-tifactorial.
We report a patient who developed fatal acute acalculus cholecystitis as an early complication of radiation therapy for metastatic lymphadenopathy along the hepatoduodenal ligament and distal common bile duct. To our best kwnoledge this is the first case of acute acalculous cholecystitis after radiation therapy.

Case report
A 66-year old man was admitted to our department with a 1-day history of high fever (40°C) with chills, nausea, and two episodes of vomiting, two days after the completion of radiotherapy (total dose 1260 rads) for metastatic lymphadeno-pathy along the hepatoduodenal ligament and distal common bile duct. On admission, he appeared restless with temperature 39.5°C, pulse 92 beats/min and blood pressure 135/90 mm/Hg. The abdomen was soft and distended with mild right upper quadrant abdominal tenderness. Bowel sounds were hypoactive. There was no splenomegaly or stigmata of chronic liver disease.
Past medical history revealed two myocardial infarcts, 15 and 9 years ago respectively. After the second infarct, he underwent angioplasty for stenosis of left coronary artery. Furthermore, 11 years ago he was operated for Leriche's disease with aortoiliac bypass.
Two years ago, he underwent a Bilroth II subtotal gastrectomy for adenocarcinoma of the antrum. The histopathological examination, of the resected part of stomach, showed a moderate differentiated adenocarcinoma with metastasis to perigastric lymph nodes. One month ago, he presented with painless obstructive jaundice. Abdominal ultrasonography, computed tomography, and MRI cholangiography showed obstruction of the distal common bile duct. The patient, underwent an exploratory laparotomy which revealed, that the obstruction was caused by enlarged lymph nodes along the hepatoduodenal ligament and pericholedochal area of distal common bile duct. He had an uneventful choledocho-duodenal anastomosis. Histological examination of the resected lymph nodes showed complete occupation from malignant cells similar to those of the operated adenocarcinoma of stomach. Thirty days later received adjuvant radiation for metastatic lymphadenopathy along the hepatoduodenal ligament and distal common bile duct.
On admission to our department, his white blood cell count was 13.800 celss/mm3 with 91% neutrophils. Other measures were as follows: hemoglobin 11.3g/dl hematocrit 33,3%, plateles 470.000/mm3, blood urea nitrogen 53mg/dl, creatinine 1,3mg/dl, sodium 141 mEq/L, potassium 3,9mEq/L, chloride 99mEq/L, bicarbonate 25mEq/L. His total bilirubin level was 1.4 mg/dl with direct bilirubin level of 0.9 mg/dl. His alkaline phosphatase level was 198 IU/L (normal 60-120 IU/L), aspartate aminotransferase 127 IU/L (normal <40IU/L), alanine aminotransferase 141 IU/L (normal <40 IU/L), and normal serum lipase and amylase. Chest radiographs and an electrocardiogram were unremarkable.
Abdominal CT and US showed a dilated gallbladder filled with sludge a thichened gallbladder wall (6 mm), and a dilated common bile duct (10 mm). A presumptive diagnosis of cholecystitis was made and the patient was placed on intravenous piperacilline 1.5 gr every 6 hours, and metrodanizole 500 mg every 8 hours. He underwent exploratory laparotomy two days later, because he continued to be septic and was found to have a distended, tense, inflammed gallbladder without stones. The histological report of resected gall-bladder showed findings of acute acalculus cholecystitis (fig. 1A, 1B). Unfortunately he died 2 days later from uncontrolled sepsis.

Figure 1A
Figure 1B

Discussion
Acute acalculus cholecystitis (AAC) is a disorder with an increased incidence in critically ill patients and those recovering from trauma or non-biliary tract surgery (4). Compared with acute calculus cholecystitis, AAC tends to have a more fulminant course, frequently associated with gangrene, perforation and empyema. The nonspecific nature of the symptoms, signs, and laboratory findings often results in delays in diagnosis and treatment and contributes to its high morbidity and mortality (2, 4, 18). The pathophysiology of acute acalculus cholecystitis is ill defined and appears to be multifactorial. Several mecha-nisms have been proposed, including systemic sepsis with release of media-tors, generalized or localized ischemia, and biliary stasis (2, 4, 7). Glenn and Becker19 noticed the common histologic features of AAC are intensive wall injury with necrosis of blood vessels in the muscularis and serosa of the gall-bladder. In animals, these lesions can be caused by activation of factor X-II dependent pathways. Therefore it was suggested that tissue breakdown from surgery or trauma liberated a substance associated with factor XII that affects the gallbladder wall. In another study, platelet-activating factor was found to induce acute cholecystitis associated with systemic stress through a prostaglandin - mediated pathway. Ischemia, generalized or localized, may play an important role in the pathogenesis of AAC (21). Experimental animal studies (20, 22, 23) causing ischemia and reperfusion of the gallbladder emphasized the potential role of ischemia in the pathogenesis of AAC. Angiographic studies showed that in contrast to patients with acute calculus cholecystitis, in which gallbladder specimens exhibited arterial dilatation and venous filling, the prominent features of AAC are arterial occlusion and absent venous filling. Numerous radiographic modalities have been utilized to confirm the diagnosis of acute acalculus cholecystitis. Those used most commonly are ultrasonography (US), computed tomography, radionuclide cholescintigraphy and morphine cholescintigraphy (24).
The gross pathologic acute changes induced in the gastrointestinal tract by radiation therapy occur during and immediately after irradiation, involve abnormal epithelial cell proliferation and maturation associated with a decrease in crypt cell mitosis (25). In addition, hyperemia, edema, and extensive inflammatory cell infiltration of the mucosa occur. Crypt abscesses, consisting of acute inflammatory cells, eosinophils, and sloughed epithelial cells, may be present. Such ulceration may be diffuse or localized, depending on the area and the extent of exposure (26).
The relationship between the onset of acalculous cholecystitis and radiation therapy in this patient appears clear. One possible explanation is that radiation resulted in acute inflammation, vasulitis, and necrosis of gallbladder's wall. The reduced motility of gallbladder due to adhesions from prior surgeries and generalized atherosclerosis of our patient, contributed in postradiation injury of gallbladder. It is known that specific factors increasing the risk of radiation to gastrointestinal tract include a history of prior abdomina surgeries (with resultant adhesions), diabetes, pelvic inflammatory disease, cardiovascular disease, extremely low body weight, combined chemotherapy and radiation therapy, and underlying vascular compromise of the intestine. (26) The major protective mechanism for the gastointestinal tract is its motility. (26)
The most frequent physical and laboratory findings of AAC are fever, right upper quadrant pain, leukocytosis and hyperbilirubinemia (24). However, they are nonspecific in the setting of critical ilness and as Kalliafas et al. (2) reported, 20 per cent of their patients had normal liver function tests. The non specific clinical and laboratory findings, in our patient, resulted a delay of four days between starting of symptoms of AAC and operation. This was a critical time for our patient, who eventually developed uncontrolled sepsis and died, despite of the administration of broad spectrum antibiotics.
In conclusion, the fatal outcome of acute acalculous cholecystitis, in our patient, underscore the significance of early diagnosis and operation. A recent radiation therapy in gallbladder's area indicates a high index of suspicion for development of acute acalculous cholecystitis, and therefore to recommend surgical intervention before complication (perforation, necrosis) develop.

References
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