J Forensic Sci, July 2014, Vol. 59, No. 4 doi: 10.1111/1556-4029.12436 Available online at: onlinelibrary.wiley.com

CASE REPORT PATHOLOGY/BIOLOGY

Dorothy E. Dean,1 M.D.; Jennifer M. Jamison,2 M.A., B.S.; and Jason L. Lane,3 M.D.

Spontaneous Rupture of the Gall Bladder: An Unusual Forensic Diagnosis

ABSTRACT: Peritonitis secondary to spontaneous rupture/perforation of the gall bladder is a rare condition overall and is even less common in the forensic population. We report the case of a middle-aged man who died from generalized peritonitis from gall bladder perforation due to acute acalculous cholecystitis. This condition usually occurs in critical patients with systemic illness, and although the exact pathogenesis remains unclear, the development of acalculous cholecystitis appears to be multifactorial. Antemortem diagnosis is reliant upon clinical presentation, laboratory data, and radiologic studies. Surgery and appropriate antibiotics are mainstays of treatment; however, there is an emerging role for minimally invasive procedures. Histopathologic features show significant overlap with the calculous type. Although increasing numbers of acalculous cholecystitis have been diagnosed in the critically ill, the fatal presentation of a perforated gall bladder following an undiagnosed case of acute acalculous cholecystitis is unusual in a nonhospitalized and ambulatory man.

KEYWORDS: forensic science, forensic pathology, extrahepatic biliary tree, gall bladder, spontaneous rupture, acalculous cholecystitis

Acute acalculous cholecystitis (AAC) is an inflammation of the gall bladder in the absence of gallstones. One of the first cases of acalculous cholecystitis was described in 1844 by Duncan (1), following surgery for a strangulated femoral hernia. Upon autopsy of the deceased patient, the gall bladder was gangrenous and perforated, yet no calculi were described. Years later in 1910, Osler described acute noncalculous cholecystitis in his book Practice of Medicine and described five cases in which appendicitis had been the incorrect diagnosis. He wrote that the diagnosis of acalculous cholecystitis was “by no means easy” (2). AAC today continues to be a difficult diagnosis with only 3% of perforated cases diagnosed preoperatively (3). Perforation and gangrene of the gall bladder remain a significant cause of morbidity in these patients. Identification of subtle risk factors without pre-existing gall bladder pathology is crucial, and early detection of perforation and/or gangrene may be prognostic (4). Whereas stone disease constitutes the major cause of cholecystitis, the rare acalculous form of cholecystitis represents 2–15% of acute inflammation but has become increasingly diagnosed in postoperative and intensive care patients (5–9). Of the nontrauma postoperative patients, more than 80% of reported cases of AAC have been of the male gender (10). However, AAC has also been identified in a demographic variety of patients as a result of secondary infection or disease states such as disseminated candidiasis (11,12), hemolytic streptococcal septicemia (6), malaria (13), tuberculosis (14), Salmonella of nontyphoidal and 1 Summit County Medical Examiner’s Office, 85 North Summit Street, Akron, OH 44303. 2 Wright State University Boonshoft School of Medicine, 3640 Colonel Glenn Highway, Dayton, OH 45435. 3 Summa Akron City Hospital, 525 East Market Street, Akron, OH 44304. Received 1 Feb. 2013; and in revised form 10 May 2013; accepted 1 June 2013.

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typhoidal species (15), as well as Epstein–Barr virus (16) and other viral pathogens. Risk factors for AAC include sepsis, surgery (particularly cardiovascular), severe burns, acquired immunodeficiency syndrome, long-term use of total parenteral nutrition, mechanical ventilation, hypotension, transfusions, opiate sedation, and complicated diabetes mellitus (7,17). AAC has been described in patients with end-stage renal disease extensively (7). Additionally, AAC has been described in bone marrow transplant recipients with an incidence rate up to 4% (18). AAC may also develop in patients who have suffered severe trauma (8). We present a case of a man who died from a rupture of the gall bladder following acute and chronic inflammation of the wall without having reported any symptoms to a medical professional. To our knowledge, he had only a short history of nonspecific complaints and none of the risk factors described in the literature. However, he may have been somewhat immunocompromised due to his ethanol abuse. Case Background The Office of the Medical Examiner was notified of the death of a middle-aged man in mid-August of 2010. An investigator from the Medical Examiner’s office and a representative from law enforcement responded to the home in which he was found. This 68-year-old Caucasian man was observed lying supine on the floor in the living room. History obtained from his friend revealed that he reported not feeling well for the previous few days, but did not give specific complaints. He did not seek medical attention and, to our knowledge, did not try any at-home remedies. According to the friends interviewed, this patient was able to ambulate well, eat and vocalize coherently the day before he was found dead. © 2014 American Academy of Forensic Sciences

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His past medical history is significant for hypertension, gastroesophageal reflux, remote head trauma, and ethanol abuse. He was taking no known medications. Autopsy Findings Examination of the body by the Medical Examiner revealed an ill and poorly nourished-appearing Caucasian man who was 72 inches and 155 pounds. He had some red and red-purple contusions and red abrasions on his head, torso, and limbs, but no severe trauma was detected anywhere on his body. Upon opening the abdominal cavity, the most striking initial feature was the diffuse yellow-green staining of the abdominal viscera and peritoneum without a distinctive odor. Within the abdominal cavity was 1300 mL of slightly viscous, yellow-orange-green purulent-appearing liquid associated with a 1.25-cm rupture of the fundus of the gall bladder. The wall of the gall bladder around the area of rupture was yellow-green, slightly thickened, slightly rolled, and slightly hyperemic. The remainder of the gall bladder wall was yellow-green and appropriately thin. There were no calculi identified. There were no calculi in the gall bladder and in the remainder of the extrahepatic biliary tree or free in the peritoneal cavity. There also were no adhesions. A photograph taken at autopsy shows the discolored abdominal tissue in Fig. 1. The perforation is visible in Fig. 2. Microscopic examination revealed moderately autolyzed tissue, and chronic inflammation consisting of fibrosis of the wall. An intense inflammatory cell infiltrate composed primarily of lymphocytes and some plasma cells was evident. An acute component with neutrophils was present focally. The inflammation extended to the subserosal connective tissue. Bacterial colonies were associated with the inflammation. Bacterial culture of the fluid within

FIG. 1––Bile stained intra-abdominal tissue.

FIG. 2––Perforation of the gall bladder. The white arrow indicates the perforation.

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the gall bladder contained S. aureus (predominating) and E. coli (minor component). The cause of death was determined to be complications of the spontaneous rupture of the gall bladder due to acalculous cholecystitis. Other significant findings were a 480-g heart with a 1.7-cm left ventricular wall thickness and hepatic fibrosis, although not having progressed to cirrhosis. Serum testing for ethyl alcohol was negative, as was an immunoassay screen for drugs of abuse. Discussion The etiology of acalculous cholecystitis appears to be multifactorial, although the exact pathogenesis is still unclear. Various risk factors including those resulting in decreased motility and bile stasis contribute to the formation of “sludge,” a calcium bilirubinate mixture with an increased level of unconjugated bilirubin (19). Bile stasis and the resulting change in chemical composition of the bile have been implicated to cause injury to the gall bladder mucosa due to inflammation and increased prostaglandin production (20,21). Increased inflammatory mediators promote fluid and mucous secretion which increases intraluminal pressure (22,23). By the principle of Laplace (tension = pressure 9 radius), wall tension of the organ is increased. This compromises arterial, lymphatic, and venous flow to and from the gall bladder wall, leaving it susceptible to infection, gangrene and frank necrosis (24). This increased intraluminal pressure, sepsis, an increase in sympathetic tone, and hypotension are fundamental to gall bladder wall ischemia and necrosis (20,25–31), and consequently rupture. Acalculous cholecystitis can be a lethal disease, one which is not often included in the differential diagnosis of the cause of abdominal pain. Gangrene of the gall bladder is prevalent in over 50% of AAC cases, and progression to perforation in AAC can occur rapidly. Gall bladder perforation (GBP) occurs in 10 or more percent of patients with acalculous cholecystitis (32), with the fundus being the most common site, and is considered a surgical emergency (17). When gall bladder perforation occurs and if the patient ultimately expires, the immediate cause of death is usually severe sepsis with multisystem organ failure (33). According to the Niemeier classification of GBP, the patient in this reported case suffered a Type I perforation, which is characterized by generalized peritoneal inflammation (34). Diagnosis of AAC while the patient is still alive is reliant upon clinical presentation, laboratory data, and radiologic findings and can oftentimes be nonspecific in the critically ill patient. Patients with a positive Murphy’s sign (pain elicited with inspiration during palpation of the right upper quadrant of the abdomen, but not on the left side) and/or persistent right upper quadrant pain are suspected to have disease of the gall bladder, although some intensive care patients are unable to localize pain (35). Other symptoms shared with calculous cholecystitis include fever, vomiting, jaundice, high white blood cell count, and increased bilirubin (7,35). Radiologic studies are more definitive and can be used to determine the thickness of the gall bladder wall. Ultrasound can be utilized with a specificity of 90% at 3 mm and 98.5% at 3.5 mm, and sensitivity of 100% at 3 mm and 80% at 3.5 mm wall thickness. Thickening of greater or equal to 3.5 mm is considered diagnostic of acalculous cholecystitis (35). A transverse diameter of 5 cm of the gall bladder has also been considered significant. Additionally, findings of pericholecystic fluid, a sonolucent layer within the gall bladder wall, and the presence of sludge are important (7). CT

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and MRI have also been utilized in the diagnosis of AAC with similar if not improved accuracy, compared with ultrasound (35,36). Diagnosis is difficult. A patient with a gall bladder perforation may present with generalized peritonitis, intramural or intraluminal gas, intraperitoneal free air, or ascites (17,37). Additionally, Madl et al. (4) suggested that an elevated serum alkaline phosphatase can be useful in distinguishing between acalculous cholecystitis and frank perforation. Although the exact pathophysiology leading to gall bladder perforation is unknown, a higher percentage of segmented neutrophils (80% or greater) and older age have been associated with an increased risk of perforation (37,38). Historically, the treatment for AAC has been surgical intervention, which allows inspection of the gall bladder and resection if gangrene or perforation is present (31). Additionally, pericholecystic fluid collections can be drained and other pathology that may mimic acute cholecystitis may be identified and managed if the diagnosis of AAC is incorrect. Percutaneous cholecystostomy is also now established as a potentially lifesaving, minimally invasive alternative (39,40) and controls AAC in 85–90% of patients (41–43). Antibiotic therapy is an important adjunct in cases of AAC, but does not substitute for proper drainage. The most common bacteria isolated from bile in acute cholecystitis are E. coli, Klebsiella spp., and Enterococcus faecalis; therefore, antibiotic therapy should be directed against these organisms accordingly (35). The histopathologic features of AAC and those of acute calculous cholecystitis (ACC) were studied by Laurila et al. (5). This group of researchers systematically evaluated multiple histologic features without knowledge of the type of disease the patients had. All gall bladders came from surgical patients. There were no autopsy specimens studied; therefore, postmortem changes (autolysis) were not considered. The type and extent of inflammation, epithelial degeneration, necrosis, and other histologic features were noted. The material from two patients (one each in the AAC and the ACC group) was too necrotic for histologic grading, leaving 33 patients with AAC, 27 patients with ACC, and 14 control patients with grossly normal-appearing gall bladders. Although inflammation in all layers was more commonly observed in the gall bladders taken from patients who had cholelithiasis than patients without, the gall bladders from the acalculous group were inflamed with the same population of cells: neutrophils, mononuclear cells, and eosinophils. The authors found that patients without gall stones had significantly fewer neutrophils in the epithelium, in the lamina propria, and on the peritoneal surface than did the patients with stones. The patients without stones also had fewer mononuclear cells in the subserosal fat and the peritoneal surface than did the patients with stones. Eosinophils were less common in the subserosal fat layer in the tissue of patients without stones than with stones. As a group, control gall bladders contained inflammatory cells throughout all layers. There was significantly less epithelial degeneration, less bile infiltration, and less necrosis of smooth muscle in the gall bladders of patients without stones than with stones. There was no significant difference in epithelial necrosis between the two study groups and none found in the control group. There was also no difference in the presence of capillary thromboses between the two groups. Based on these histopathologic changes, these authors concluded that AAC is largely a consequence of a critical systemic

illness which ultimately affects the integrity of the gall bladder wall, whereas ACC is a local disease of the gall bladder. Although there is an interesting distinction in the type and location of inflammation, bile infiltration, and mucosal necrosis between groups of patients, these histologic differences between groups cannot be used as criteria to distinguish AAC from ACC in any one patient. The only criterion remains the presence or absence of calculi. In conclusion, although increasing numbers of acalculous cholecystitis have been diagnosed in the critically ill, the fatal presentation of a perforated gall bladder following an undiagnosed case of AAC is unusual in a nonhospitalized and ambulatory man. We present this rare case of a 68-year-old man with an uncommon disease with no known history of many of the risk factors associated with AAC. Acknowledgments The authors would like to thank Dr. Lisa J. Kohler and Dr. Raymond E. Clarke for their general support and encouragement in our academic pursuit. References 1. Duncan J. Femoral hernia; gangrene of the gallbladder; extravasation of bile; peritonitis; death. North J Med 1844;2:151–3. 2. Osler W. The principles and practice of medicine. New York, NY: Appleton, 1910. 3. Stefanidis D, Sirinek KR, Bingener J. Gallbladder perforation: risk factors and outcome. J Surg Res 2006;131(2):204–8. 4. Madl C, Grimm G, Mallek R, Schneeweiss B, Druml W, Laggner AN, et al. Diagnosis of gallbladder perforation in acute acalculous cholecystitis in critically ill patients. Intensive Care Med 1992;18(4): 245–6. 5. Laurila JJ, Ala-Kokko TI, Laurila PA, Saarnio J, Koivukangas V, Syrjala H, et al. Histopathology of acute acalculous cholecystitis in critically ill patients. Histopathology 2005;47(5):485–92. 6. Rosai J. Rosai and Ackerman’s surgical pathology, 10th edn. Maryland Heights, MO: The C.V. Mosby Company, 2011. 7. Stevens PE, Harrison NA, Rainford DJ. Acute acalculous cholecystitis in acute renal failure. Intensive Care Med 1988;14(4):411–6. 8. Imhof M, Raunest J, Rauen U, Ohmann C. Acute acalculous cholecystitis in severely traumatized patients: a prospective sonographic study. Surg Endosc 1992;6(2):68–71. 9. Imhof M, Raunest J, Ohmann C, Roher HD. Acute acalculous cholecystitis complicating trauma: a prospective sonographic study. World J Surg 1992;16(6):1160; discussion 1166. 10. Barie P. Acalculous and postoperative cholecystitis. In: Barie PS, Shires GT, editors. Surgical intensive care. Boston, MA: Little Brown, 1993;837–57. 11. Hiatt JR, Kobayashi MR, Doty JE, Ramming KP. Acalculous candida cholecystitis: a complication of critical surgical illness. Am Surg 1991;57 (12):825–9. 12. Mandak JS, Pollack B, Fishman NO, Furth EE, Kochman ML, Acker MA, et al. Acalculous candidal cholecystitis: a previously unrecognized complication after cardiac transplantation. Am J Gastroenterol 1995;90 (8):1333–7. 13. Khan FY, El-Hiday AH. Acute acalculous cholecystitis complicating an imported case of mixed malaria caused by plasmodium falciparum and plasmodium vivax. Int J Infect Dis 2010;14(Suppl 3):e217–9. 14. Vallejo AE. Acute tuberculous cholecystitis. Gastroenterology 1950;16 (2):501–4. 15. McCarron B, Love WC. Acalculous nontyphoidal salmonellal cholecystitis requiring surgical intervention despite ciprofloxacin therapy: report of three cases. Clin Infect Dis 1997;24(4):707–9. 16. Lagona E, Sharifi F, Voutsioti A, Mavri A, Markouri M, Attilakos A. Epstein-barr virus infectious mononucleosis associated with acute acalculous cholecystitis. Infection 2007;35(2):118–9. 17. Goenka U, Majumder S, Banerjee P, Kapoor N, Nandi S, Sethy PK, et al. Spontaneous perforation of acalculous gall bladder presenting as acute abdomen. J Emerg Med 2012;43(4):637–40.

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34. Niemeier OW. Acute free perforation of the gall-bladder. Ann Surg 1934;99(6):922–4. 35. Barie PS, Eachempati SR. Acute acalculous cholecystitis. Gastroenterol Clin North Am 2010;39(2):343–57. 36. Sood B, Jain M, Khandelwal N, Singh P, Suri S. MRI of perforated gall bladder. Australas Radiol 2002;46(4):438–40. 37. Tsai MJ, Chen JD, Tiu CM, Chou YH, Hu SC, Chang CY. Can acute cholecystitis with gallbladder perforation be detected preoperatively by computed tomography in ED? correlation with clinical data and computed tomography features. Am J Emerg Med 2009;27(5):574–81. 38. Wang AJ, Wang TE, Lin CC, Lin SC, Shih SC. Clinical predictors of severe gallbladder complications in acute acalculous cholecystitis. World J Gastroenterol 2003;9(12):2821–3. 39. Granlund A, Karlson BM, Elvin A, Rasmussen I. Ultrasound-guided percutaneous cholecystostomy in high-risk surgical patients. Langenbecks Arch Surg 2001;386(3):212–7. 40. Davis CA, Landercasper J, Gundersen LH, Lambert PJ. Effective use of percutaneous cholecystostomy in high-risk surgical patients: techniques, tube management, and results. Arch Surg 1999;134(7):727–31; discussion 731-2. 41. Akhan O, Akinci D, Ozmen MN. Percutaneous cholecystostomy. Eur J Radiol 2002;43(3):229–36. 42. Lee MJ, Saini S, Brink JA, Hahn PF, Simeone JF, Morrison MC, et al. Treatment of critically ill patients with sepsis of unknown cause: value of percutaneous cholecystostomy. AJR Am J Roentgenol 1991;156 (6):1163–6. 43. vanSonnenberg E, D’Agostino HB, Goodacre BW, Sanchez RB, Casola G. Percutaneous gallbladder puncture and cholecystostomy: results, complications, and caveats for safety. Radiology 1992;183(1):167–70. Additional information and reprint requests: Dorothy E. Dean, M.D. Summit County Medical Examiner’s Office 85 North Summit Street Akron, OH 44303 E-mail: [email protected]

Spontaneous rupture of the gall bladder: an unusual forensic diagnosis.

Peritonitis secondary to spontaneous rupture/perforation of the gall bladder is a rare condition overall and is even less common in the forensic popul...
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