Acalculous Cholecystitis

Etiology

Gallbladder dysfunction in the absence of gallstones has a multifactorial etiology. Long periods of fasting, total parenteral nutrition (TPN), and drastic weight loss can all increase the incidence of acute acalculous cholecystitis. Often, other more serious conditions are present. Patients in the intensive care unit (ICU) recovering from major surgeries or other life-threatening ailments, eg, a stroke, heart attack, sepsis, severe burns, and extensive trauma, are all at a higher risk of developing acute acalculous cholecystitis.

Gallbladder stasis can develop due to a lack of gallbladder stimulation by cholecystokinin (CCK), leading to the concentration of bile salts and increased pressure within the gallbladder. The elevated pressure leads to hypoperfusion and ischemia of the gallbladder wall that eventually causes pressure necrosis and perforation if prompt intervention is not initiated. This static condition also increases the seeding and growth of common enteric pathogens, eg, Escherichia coli, Klebsiella, Bacteroides, Proteus, Pseudomonas, and Enterococcus faecalis.[4] 

Individuals with chronic acalculous cholecystitis may have decreased gallbladder emptying or hypokinetic biliary dyskinesia due to a variety of factors, including hormone imbalance, vasculitis, and decreased nerve innervation secondary to conditions such as diabetes. Often, the exact etiology of chronic acalculous cholecystitis is unknown.[5][6] 

Epidemiology

Acute acalculous cholecystitis accounts for 10% of all cases of acute cholecystitis and 5% to 10% of all cases of cholecystitis. Males are more commonly afflicted than females, with a mean age of 50.[7] Despite the close relationship between acute acalculous cholecystitis and critical illness, studies have shown that individuals with underlying vascular disease can develop acute acalculous cholecystitis in the outpatient setting.[8] Rates are increased in HIV and other immunosuppressed patients. These individuals are more susceptible to opportunistic infections, including microsporidia, cytomegalovirus (CMV), Cryptosporidium, and Epstein-Barr Virus (EBV), which can seed and flourish in bile within the gallbladder. Carriers of Giardia lamblia, Helicobacter pylori, and Salmonella typhi are also associated with increased risks of developing cholecystitis.[9][10]

Pathophysiology

The pathogenesis of acute acalculous cholecystitis is complex, with the interplay of several mechanisms. Prolonged fasting and long-term TPN seen in critically ill patients can lead to biliary stasis within the gallbladder due to the lack of CCK stimulation.[11] Stasis of the gallbladder results in the build-up of intraluminal pressure against the gallbladder wall and distention. The gallbladder wall develops an inflammatory reaction, characterized by significant thickening and inflammation of the gallbladder wall. Prolonged biliary stasis can lead to bacterial colonization, contributing to the inflammatory response. If the pressure is not relieved promptly, the gallbladder wall loses its primary source of blood supply from the cystic artery, which is prone to ischemia.[12] Progressive gallbladder wall ischemia will result in necrotic or gangrenous changes. A necrotic gallbladder wall will eventually perforate and stimulate a systemic inflammatory response, followed by sepsis and shock. 

Chronic acalculous cholecystitis usually presents more insidiously. Symptoms are more prolonged and may be less severe. Symptoms may also be more intermittent and vague, although patients can present with signs of acute biliary colic.[9][13] Although acute acalculous cholecystitis is often associated with critical illness, several mechanisms have been reported in patients without critical illness, including gallbladder vasculitis, biliary tree obstruction, and bile acid sequestration.[11]

Acute Acalculous Cholecystitis Types

Acute acalculous cholecystitis can be divided into the following 4 types:

1. Uncomplicated cholecystitis (gallbladder inflammation without necrosis or perforation)
2. Acute suppurative cholecystitis (an inflamed gallbladder with associated purulence)
3. Gangrenous cholecystitis (gallbladder wall necrosis)
4. Perforated cholecystitis (gallbladder wall rupture) [14]

Histopathology

Acute acalculous cholecystitis may present with varying degrees of inflammation, and the findings are similar to those of calculus cholecystitis but without gallstones. The gallbladder wall will be thickened to variable degrees, and there may be adhesions to the serosal surface. Smooth muscle hypertrophy, especially in chronic conditions, is often present. At times, sludge or viscous bile can be seen. These findings can be precursors to gallstone formation due to increased bile salts or stasis.

Various species of bacteria can be present in 11% to 30% of cases. Rokitansky-Aschoff sinuses, also known as adenomyomatosis, are often present in specimens of chronic cholecystitis. These are herniations of intraluminal sinuses from increased intraluminal pressure, possibly associated with ducts of Luschka, which are small aberrant bile ducts found along the gallbladder fossa. The gallbladder mucosa will exhibit varying degrees of inflammation, from mild to moderate ulcerations with gangrenous changes. Extreme situations may show total gangrenous changes of the gallbladder with perforation.[15]

Toxicokinetics

Mild cases of acute acalculous cholecystitis are usually only treated for symptoms of biliary colic, but more severe cases can lead to sepsis and shock. The pressurized, static intraluminal bile can be susceptible to bacterial seeding. Antibiotics are usually ineffective because they do not treat the increased intraluminal pressure and subsequent ischemia. Eventual gallbladder perforation will lead to bile peritonitis and contribute to the body's systemic inflammatory response and sepsis.

History and Physical

Acute acalculous cholecystitis may present similarly to calculous cholecystitis. Patients typically present with right upper quadrant abdominal pain that worsens with fatty foods, physical exam findings of right upper quadrant tenderness, and a positive Murphy's sign (ie, inspiratory arrest from pain during palpation of the right upper quadrant). Fever, chills, body aches, nausea, vomiting, and food intolerance may also be present. These patients are often already admitted to the ICU for another severe illness or are recovering from extensive surgery. Critically ill patients unable to participate in the physical exam may have fevers of unknown origin or grimacing during abdominal palpation, which should prompt additional testing.

Evaluation

Laboratory Studies

Preliminary laboratory studies typically include a complete blood count, a basic metabolic panel, liver function tests, and lipase levels. Findings of leukocytosis and elevated liver enzymes, including alkaline phosphatase and direct bilirubin, are common.

Ultrasound Imaging

Ultrasound is usually the initial image obtained, as this can be completed at the bedside in a timely fashion and is cost-effective. Gallbladder wall thickening >3 mm, gallbladder wall edema, and pericholecystic fluid are indicative of cholecystitis (see Image. Acalculous Cholecystitis).

Additional Diagnostic Studies

The test of choice for diagnosing acute acalculous cholecystitis in the setting of a normal ultrasound is a hepatobiliary iminodiacetic acid (HIDA) scan, which may be done in conjunction with administration of CCK.[16] A HIDA scan evaluates the function or ejection fraction of the gallbladder. After the radionuclide is administered, CCK is given to stimulate gallbladder emptying.

A calculated ejection fraction of ≤35% may be indicative of hypokinetic functioning of the gallbladder.[17] HIDA scan may also demonstrate no filling of the gallbladder with radiotracer material, indicative of cystic duct obstruction and acute cholecystitis.[6][18] Computed tomography (CT) scans of the abdomen with intravenous contrast may also reveal gallbladder wall thickening, edema, and pericholecystic fluid in the absence of gallstones and sludge. 

Treatment / Management

Stabalization and Antibiotic Therapy

Patients with acute acalculous cholecystitis should receive appropriate fluid resuscitation and broad-spectrum antibiotics that provide coverage for gram-negative rods and anaerobes, ideally after blood cultures have been obtained. Antibiotics alone are usually ineffective as they inadequately penetrate the pressurized gallbladder.[5][19][20] Individuals requiring ICU-level care should be properly stabilized before undergoing operative intervention.(A1)

Percutaneous Cholecystostomy Tube  and Stent Placement

In those patients who are too unstable to undergo surgery, clinicians should consider interventional radiology consultation for percutaneous cholecystostomy tube placement.[21] Percutaneous drainage is often the definitive treatment because acute acalculous cholecystitis has a lower recurrence rate when compared to acute calculous cholecystitis. The cholecystostomy tube can be removed after 3 weeks.[22] After percutaneous drainage and recovery, outpatient tube studies by interventional radiology can confirm patency of the cystic duct before removal. Alternatively, the patient can undergo cholecystectomy between 4 and 8 weeks after tube placement.[23]

Another treatment option is cystic duct stent placement via endoscopic retrograde cholangiopancreatography (ERCP) to decompress the gallbladder and prevent cystic duct obstruction.[24] However, this approach is not as widely available as percutaneous cholecystostomy, and outcomes have not been studied as extensively.

Surgical Management

Laparoscopic cholecystectomy is the preferred definitive approach. However, an open cholecystectomy can also be performed if a contraindication to a minimally invasive approach is identified. Acute acalculous cholecystitis must be addressed fairly urgently because rapid progression and deterioration may result if left untreated. Chronic acalculous cholecystitis is treated similarly to chronic calculous cholecystitis with laparoscopic cholecystectomy. 

A robotic approach should be considered depending on the surgeon's experience. Studies suggest that a robotic approach may be associated with a shorter hospital stay and a lower conversion rate to an open approach when compared with a laparoscopic approach.[25](B3)

Differential Diagnosis

Differential diagnoses that should also be considered when evaluating acalculous cholecystitis include:

• Biliary colic
• Calculous cholecystitis
• Choledocholithiasis
• Cholangitis
• Pancreatitis
• Hepatitis
• Gastritis
• Peptic Ulcer Disease
• Appenditis 
• Mesenteric ischemia

Prognosis

Acute acalculous cholecystitis is a serious illness that has high morbidity and mortality, which is in part due to the critically ill patient population. The reported mortality rate of acute acalculous cholecystitis varies from 30% to 75%.[26][27] Patients who recover also have a long recovery. 

Complications

The following complications are associated with acalculous cholecystitis:

• Perforation of the gallbladder
• Gangrene of the gallbladder
• Sepsis