Infectious Considerations in Complicated Acute Cholecystitis


Type

Incidence

Biliary atresia [1, 2]

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

Choledochal cysts [1, 3]

Western Countries = 1/100,000–150,000 live births

Asian Populations = 1/1000 live births

Gallbladder agenesis [1, 4]

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.


Table 9.2
Types of gallstones [13]





























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


CBD common bile duct, DC developed countries



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, 2742]. 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

Nonimmunosuppressed

Escherichia coli [12, 14]

β-Lactam/β-lactamase inhibitor or

Carbapenem

or

Second- or third-generation cephalosporin

or

Quinolones

Klebsiella spp. [12, 14]

β-Lactam/β-lactamase inhibitor or

Carbapenem

or

Second- or third-generation cephalosporin

or

Quinolones

Enterococcus faecalis [12, 14]

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

Actinomyces spp. [29, 33]

Penicillin G

Salmonella spp. [14, 30, 31]

Fluoroquinolone

 – Typhi

or

 – Enterica

Third-generation cephalosporin

Brucella spp. [32]

Doxycycline

and

Streptomycin

or

Rifampin

Mycobacterium [34, 35]

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

Cryptococcus neoformans [43, 45]

– 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

Histoplasma capsulatum [43, 45]

– 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


AIDS acquired immunodeficiency syndrome


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, 4654].


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

Hepatitis B [43, 46, 47]

– 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)

Hepatitis A [48, 50]

– 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

Flavivirus [49, 51]

– 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

Epstein–Barr [52, 53]

– 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, 5562]. 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, 5563].


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

Ascaris lumbricoides [21, 56]

– 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

Malaria [58, 63]

– Most prevalent in sub-Saharan Africa and South Asia

Chloroquine

Plasmodium vivax

– Mosquito-borne illness

or

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Jun 9, 2017 | Posted by in Uncategorized | Comments Off on Infectious Considerations in Complicated Acute Cholecystitis

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