Type
Incidence
Europe and North America = 0.43–0.85/10,000 live births
East Asia and French Polynesia = 0.86–2.0/10,000 live births
Western Countries = 1/100,000–150,000 live births
Asian Populations = 1/1000 live births
10–65/100,000 live births
Gallbladder duplication and septation [5]
1/3800 live births
Left-sided gallbladder [6]
4/10,000 live births
The most common extrahepatic biliary anatomy involves a right and left hepatic duct, which exit the liver and merge to form a common hepatic duct [1]. The gallbladder, commonly located inferior to and between hepatic lobes IV and V, connects to the common hepatic duct via the cystic duct, which then forms the common bile duct, distally. The common bile duct, a structure that lies anterior to the portal vein and lateral to the proper hepatic artery, courses inferiorly to either join the pancreatic duct before connecting with the second portion of the duodenum or join the second portion of the duodenum directly via the sphincter of Oddi.
The gallbladder serves as a reservoir for bile produced daily by the liver [7]. Bile, produced by hepatocytes and composed primarily of water, bile acids, proteins, phospholipids, cholesterol, and inorganic electrolytes, drains from the liver and empties into the second portion of the duodenum via the common bile duct [8]. In times of fasting, the sphincter of Oddi remains constricted, forcing buildup of bile within the common bile duct and gallbladder [7]. While stored in the gallbladder, bile is concentrated through absorption of water. This process continues until the next meal, whereupon cholecystokinin is released from the duodenum. This hormone serves to stimulate gallbladder contraction and sphincter of Oddi relaxation, thus releasing bile into the second portion of the duodenum to aid in digestion and fat absorption.
Cholecystitis was first described in 1888 by Hutchinson et al. [9], and has since been defined as, “an inflammation of the gallbladder, generally caused by obstruction of the cystic duct [10].” Once obstructed, egress of bile and the mucous continuously produced by the gallbladder is impeded, placing direct outward pressure upon the gallbladder wall. As tension increases, venous and lymphatic outflow become compromised (i.e., edematous cholecystitis; 2–4 days) [11]. Eventually, the wall tension reaches a threshold whereupon arterial inflow becomes compromised, leading to ischemic injury, necrosis (i.e., necrotizing cholecystitis; 3–5 days), intramural abscesses (i.e., suppurative cholecystitis; 7–10 days), and possible perforation. If this process is repeated multiple times, fibrous proliferation replaces much of the wall tissue and the gallbladder mucosa atrophies and contracts (i.e., chronic cholecystitis). Obstruction is most commonly attributable to gallstones [10, 12] (Table 9.2) [13]; however, it may also be due to biliary stasis (e.g., acalculous cholecystitis) [14], cancer [15, 16], volvulus or torsion [17, 18], gallbladder polyps [19], common bile duct cysts [20], scarring (e.g., prior cholecystitis, cholangitis, or pancreatitis, or primary sclerosing cholangitis) [10], or parasites [21]. This process typically remains sterile; however, secondary infection with bacteria, fungi, viruses, and parasites may further complicate the cascade of events.
Types | Prevalence | Formation location | Etiology |
---|---|---|---|
Cholesterol | 85 % within DC | Gallbladder primarily, CBD secondarily | Obesity, female gender, older age, and genetic disorders |
Black pigment | 15 % within DC | Gallbladder primarily, CBD secondarily | Hemolytic disorders and cirrhosis |
Brown pigment | Predominate within East Asia | CBD primarily, intrahepatic bile ducts secondarily | Infection and biliary strictures |
Bacterial Infections
Bacteria have previously been thought to colonize the hepatobiliary tract and contribute to gallstone formation [12, 22]. Prior murine models evaluating this theory, have observed a greater rate of gallstone formation in mice infected with Helicobacter spp. compared to uninfected, genetically identical mice [12, 23]. Hazrah et al., prospectively evaluated the gallstones of 100 consecutive patients [24]. They observed that bacterial colonization was present in 81 % of patients with cholelithiasis and 77 % of patients with gallbladder carcinoma. Bacterial isolates included: Klebsiella spp., Escherichia coli, Pseudomonas spp., Enterococcus spp., Enterobacter spp., Acinetobacter spp., Proteus spp., Staphylococcus aureus, Citrobacter spp., and Salmonella spp. Additionally, Helicobacter spp. have been recovered from gallstones and bile [12, 22, 25]. It is thought that these bacteria either migrate in a retrograde fashion or translocate from the gastrointestinal epithelium. Once present, bacteria firmly attach to the hepatobiliary epithelium and protect themselves from the antibacterial properties of biliary secretions (i.e., bile salts and IgA) via fimbriae and biofilm (i.e., glycocalyx) [26].
During an obstructive process of the hepatobiliary system (e.g., acute cholecystitis), upregulation of inflammatory markers result in leaky capillaries and a permeable epithelium, which resultantly allow colonized bacteria to gain access to the systemic circulation [22, 26].
Of patients who develop acute cholecystitis complicated by bacterial infection, the most common etiology is gallstones (85 %) and the most common isolates include Escherichia coli, Klebsiella spp., and Enterococcus faecalis [12, 14] (Table 9.3) [12, 14]. Patients usually present with complaints of epigastric pain (diffuse, visceral) that migrate toward the right upper quadrant (focal, somatic) as time progresses [10]. This is typically associated with nausea, vomiting, anorexia, and fever. Additionally, a prior history of biliary colic (i.e., intermittent, postprandial abdominal pain with meals high in fat) may be reported. This clinical picture may be complicated in areas of poor sanitation and/or immunosuppressed patients, such as that seen with critical illness (medical or surgical), transplant, immunosuppressant medication, AIDS, hepatitis, liver cirrhosis, malignancy, or diabetes, all conditions that may predispose patients to additional, opportunistic pathogens [12, 14] (Table 9.3) [12, 14, 27–42]. While patients may present with complaints similar to the ones described above (i.e., right upper quadrant pain, nausea, vomiting, anorexia, and fever), the clinical picture may often be varied and nondescript owing to patient acuity and critical illness [10]. In these scenarios, a high suspicion for acalculous cholecystitis must be maintained given the increased frequency of gallbladder gangrene (50 %), emphysema (45 %), perforation (10 %), and patient mortality (30 %) [10, 14].
Table 9.3
Bacterial infections complicating acute cholecystitis and antimicrobial therapy
Bacteria | Antimicrobial treatment |
---|---|
Non–immunosuppressed | |
β-Lactam/β-lactamase inhibitor or | |
Carbapenem | |
or | |
Second- or third-generation cephalosporin | |
or | |
Quinolones | |
β-Lactam/β-lactamase inhibitor or | |
Carbapenem | |
or | |
Second- or third-generation cephalosporin | |
or | |
Quinolones | |
β-Lactam/β-lactamase inhibitor or | |
carbapenem | |
or | |
Second- or third-generation cephalosporin | |
or | |
Fluoroquinolone | |
Immunosuppressed | |
Pseudomonas putida [27] | β-Lactam/β-lactamase inhibitor |
or | |
Third- or fourth-generation cephalosporin | |
or | |
Monobactam | |
or | |
Fluoroquinolone | |
or | |
Carbapenem | |
or | |
Aminoglycoside and β-lactam | |
Moellerella wisconsensis [28] | Tetracycline |
or | |
Aminoglycoside | |
or | |
β-Lactam | |
or | |
Fluoroquinolone | |
or | |
Folate-pathway inhibitor | |
or | |
Chloramphenicol | |
or | |
Nitrofurantoin | |
Penicillin G | |
Fluoroquinolone | |
– Typhi | or |
– Enterica | Third-generation cephalosporin |
Brucella spp. [32] | Doxycycline |
and | |
Streptomycin | |
or | |
Rifampin | |
Isoniazid | |
– Tuberculosis | and |
– Bovis | Rifampin |
and | |
Pyrazinamide | |
and | |
Ethambutol | |
Haemophilus parainfluenzae [36] | Ampicillin |
or | |
Clarithromycin | |
or | |
Doxycycline | |
or | |
Cotrimoxazole | |
Coxiella burnetii [37] | Doxycycline |
Staphylococcus aureus [38] | Nafcillin |
or | |
Vancomycin | |
Leptospira interogans [39] | Penicillin G |
or | |
Ampicillin | |
Vibrio cholerae [40] | Cephalothin |
or | |
Tetracycline | |
or | |
Aminoglycoside | |
or | |
Trimethoprim/sulfamethoxazole | |
Campylobacter jejuni [41] | Ofloxacin |
Edwardsiella tarda [42] | β-Lactam |
or | |
Cephalosporins | |
or | |
Aminoglycosides | |
or | |
Oxyquinolones |
Fungal Infections
Fungal infections of the hepatobiliary system are rare and usually indicative of disseminated illness [43]. Of patients who develop acute cholecystitis complicated by fungal infection, the most common etiology is acalculous cholecystitis [14]. The prevalence of acalculous cholecystitis is greatest within critically ill (medical or surgical) patients exposed to cardiac/vascular surgery, trauma, burns, prolonged parenteral nutrition, and multisystem failure [14, 44]. Additionally, diabetics, cancer patients, and patients with human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS) may develop acalculous cholecystitis without critical illness. Similar to above, patients may present with right upper quadrant pain, nausea, vomiting, anorexia, and fever. However, symptoms may be skewed or absent altogether. Thus, the clinical picture along with exam findings become paramount. For example, one should not disregard culture results yielding Coccidioides immitis in the southwestern region of the United States or Histoplasma capsulatum in the Ohio and Mississippi river valleys of the United States or Central and South America as contaminants [43, 45]. Fungal pathogens previously linked to acute cholecystitis are provided in Table 9.4 [43, 45].
Table 9.4
Fungal infections complicating acute cholecystitis, characteristic features, and antifungal treatment
Fungi | Characteristic features | Antifungal treatment |
---|---|---|
Pneumocyctis carinii [45] | – 39 % hepatobiliary involvement in AIDS patients | Pentamidine |
– Diagnosed using silver stain | ||
– 19 % hepatobiliary involvement in AIDS patients | Amphotericin B | |
– Identified by cryptococcal antigen latex agglutination test | or | |
– Cerebral spinal fluid should be tested in all cases | Fluconazole | |
– Diagnosed using India ink or Gomori’s silver stain | or | |
Fluconazole | ||
and | ||
Flucytosine | ||
Coccidioides immitis [43] | – Endemic to Southwestern United States | amphotericin B |
– Serum IgM antibodies may be detected | or | |
Fluconazole | ||
or | ||
Itraconazole | ||
– 16 % hepatobiliary involvement in AIDS patients | Amphotericin B | |
– Endemic to Ohio and Mississippi River Valleys of the United States | or | |
– Endemic to Central and South America | Itraconazole | |
– Diagnosed using periodic acid-Schiff, Wright’s, or Giemsa stains | ||
Candida albicans [43] | – Rare | Amphotericin B |
– Bull’s-eye appearance on abdominal imaging | ||
– Invasive mycelia demonstrated on silver stains |
Viral Infections
Similarly, viral infections of the extrahepatic biliary system are rare and indicative of disseminated illness. While acalculous cholecystitis is thought to be the most common cause of cholecystitis in this population, additional factors may play a role. For example, in a case report detailing acute acalculous cholecystitis associated with acute hepatitis B virus infection, Unal et al., theorized that extrahepatic complications of the virus (i.e., polyarteritis nodosa) may also be responsible [46]. They suggest that increased viral replication gives rise to immune complex accumulation in the walls of small-to-medium diameter arteries. Likewise, in a case report examining hepatitis B-related polyarteritis nodosa, Takeshita et al., discovered necrotizing vasculitis in the biopsy specimen of a gallbladder wall removed for alithiasic cholecystitis [47]. Thus, in addition to the common signs and symptoms of acute cholecystitis, hepatitis B patients may also present with bilateral wrist and ankle erythema, edema, and pain. A cell-mediated immunologic response has also been proposed as a mechanism contributing to cholecystitis in patients with hepatitis A [48]. Dengue fever increases vascular permeability, plasma and protein leakage, and serous effusion resulting in gallbladder wall thickening [49]. It is thought that the extent of gallbladder wall thickening is associated with disease severity and progression of dengue fever. In addition to the common signs and symptoms of acute cholecystitis, dengue fever patients may also present with biphasic fever, skin rash, headache, retro-orbital pain, photophobia, cough, vomiting, myalgia, arthralgia, leukopenia, thrombocytopenia, and lymphadenopathy. Viral pathogens previously linked to acute cholecystitis are provided in Table 9.5 [43, 46–54].
Table 9.5
Viral infections complicating acute cholecystitis, characteristic features, and antiviral treatment
Virus | Characteristic features | Antiviral treatment |
---|---|---|
Cytomegalovirus [54] | – Found throughout the world | Valganciclovir |
– Transmitted via organ transplant or exchange of bodily fluids | ||
– Patients may present with mononucleosis-like syndrome, pneumonitis, retinitis, gastroenteritis, hepatitis, or central nervous system infection, or may be asymptomatic | ||
– Found throughout the world | Lamivudine | |
– History of parenteral exposure or unprotected sexual contact | ||
– Polyarteritis nodosa most common extrahepatic manifestation (bilateral wrist and ankle erythema, edema, and pain) | ||
– Found throughout the world | Supportive care | |
– Transmitted by fecal-oral route | or | |
– Potential association with cell-mediated immunologic response | Vaccine in patients with concomitant chronic liver disease | |
– Self-limiting | ||
– Worldwide condition spread through tropical and subtropical zones (i.e., South-East Asia, the Pacific, East and West Africa, the Caribbean, and the Americas) | Supportive care | |
– Primarily near regions of explosive population growth and inadequate public health systems | (No vaccine available) | |
– Transmitted by infected female Aedes mosquitoes | ||
– Extent of gallbladder wall thickening associated with disease severity and progression of dengue fever | ||
– Symptoms may include biphasic fever, skin rash, headache, retro-orbital pain, photophobia, cough, vomiting, myalgia, arthralgia, leukopenia, thrombocytopenia, and lymphadenopathy | ||
– Self-limiting | ||
– May present as infectious mononucleosis (i.e., fever, pharyngitis, cervical lymphadenopathy, and hepatosplenomegaly) | Supportive care | |
– Self-limiting |
Parasitic Infections
Parasitic infections are commonly endemic to underdeveloped or developing countries lacking adequate sanitation, potable water, and vector control [21, 55–62]. Their association with acute cholecystitis may involve a combination of HIV/AIDS, direct hepatobiliary obstruction secondary to heavy parasitic load, and/or biliary stasis secondary to malabsorptive diarrhea and dehydration. Parasitic pathogens previously linked to acute cholecystitis are provided in Table 9.6 [21, 55–63].
Table 9.6
Parasitic infections complicating acute cholecystitis, characteristic features, and antiparasitic treatment
Parasites | Characteristic features | Antiparasitic treatment |
---|---|---|
Microsporidiosis [55] | – Prevalent worldwide | Albendazole |
Enterocytozoon bieneusi | – Frequent enteric infection among patients with AIDS | |
Enterocytozoon intestinalis | – Symptoms include diarrhea and weight loss | |
– Diagnosed using special stains, light microscopy, and immunohistochemical/molecular techniques | ||
– Worldwide distribution; however, most prevalent in the developing countries of India, China, Asia, South Africa, and Latin America | Pyrantel | |
– Infection via ingestion of embryonated eggs | or | |
– Symptoms include stunting of linear growth, reduced cognitive function, and malnutrition | Mebendazole | |
or | ||
Albendazole | ||
or | ||
Levamisole | ||
– Most prevalent in sub-Saharan Africa and South Asia | Chloroquine | |
Plasmodium vivax | – Mosquito-borne illness | or
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