Cholecystitis (Acute, Suspected)

• Acute right upper quadrant pain is very common as a presenting symptom in hospital emergency departments 1
• Gallstone-related disease (e.g. biliary colic, acute cholecystitis) is the most common cause of acute RUQ pain

• Acute cholecystitis (AC) is caused by gallstones in 90-95% of cases and may be life-threatening when not treated in a timely manner 1
• Calculous AC accounts for 90–95% of cases of AC, secondary to obstruction of the gallbladder by a stone in the cystic duct or the neck of the gallbladder 2. This leads to gallbladder distension and increased intraluminal gallbladder pressure, inducing chemical and eventually ischaemic injury to the gallbladder mucosa, which results in acute cholecystitis.
• If the cystic duct obstruction and mural inflammation persist, this may lead to vascular compromise, wall necrosis and perforation 3
• Acute Acalculous cholecystitis (AAC) is very much less common and mainly a disease of sick ICU patients rather than ambulatory ED patients. The mere failure to visualise a stone on imaging in a patient with an inflamed gallbladder should not necessarily be overcalled as AAC. See pathway ‘Acute Acalculous Cholecystitis’ for further information. Cholecystitis (Acute, Acalculous, Suspected)
• The differential diagnosis of AC is wide and careful consideration of alternative diagnoses is necessary when obtaining a history and performing an examination. These include conditions related to the following 4:
  • Liver – e.g. acute hepatitis, hepatic abscess, hepatic tumour, hepatic laceration
  • Gallbladder and biliary tree – e.g. acute cholecystitis (calculous and acalculous), cholelithiasis with biliary colic, choledocholithiasis and bile duct obstruction, Mirizzi syndrome, cholangitis, carcinoma
  • Pancreas – e.g. acute pancreatitis
  • Bowel – e.g. peptic ulcer disease, small bowel obstruction, gallstone ileus, appendicitis, enteritis/colitis
  • Genitourinary system – e.g. pyelonephritis, nephrolithiasis with renal colic 
  • Non-abdominal causes – e.g. pneumonia, pulmonary infarction, myocardial infarction, musculoskeletal pain
• Up to a third of patients initially suspected of having AC have an alternative diagnosis 2

• Imaging plays a major role in confirming the diagnosis of AC, identifying complications, and detecting alternative diagnoses. The widely used Tokyo Guidelines for acute cholecystitis include imaging findings as a necessary component to making a definitive diagnosis. 5

• Tokyo Guidelines: Diagnostic criteria for Acute Cholecystitis 5, 6
  1. Local (clinical) Signs of Inflammation
     • Murphy’s sign
     • Right upper quadrant (RUQ) mass, pain, or tenderness
  2. Systemic Signs of Inflammation
     • Fever
     • Elevated C-reactive protein (CRP)
     • Elevated White Blood Cell (WBC) count
  3. Imaging Findings
     • Imaging findings characteristic of AC (See US section - US

A definitive diagnosis of AC requires at least one item from each of the three categories (A + B + C)

A suspected diagnosis of AC requires one item from A and one from B

The Tokyo Guidelines also define the severity of disease: 5

• Grade I (Mild) - disease confined strictly to the gallbladder; no organ dysfunction and no criteria of Grade II
• Grade II (Moderate) - any one of: Elevated WBC (>18,000/mm³); palpable tender RUQ mass; complaints >72 hours; or marked local inflammation (gangrenous, emphysematous, abscess)
• Grade III (Severe) - acute cholecystitis accompanied by organ dysfunction (cardiovascular, neurological, respiratory, renal, hepatic, or haematological)

• Despite recent evidence demonstrating that CT is superior to ultrasound (US) in the diagnosis of AC, and can be considered as an alternative first-line in certain scenarios (e.g. patient factors - elderly/obesity, high risk of alternate pathologies, high risk for complications), US is generally the preferred primary imaging test when acute cholecystitis is suspected as it is: 1, 2, 7, 8
  • low cost
  • widely available and easily accessible
  • often available at the point-of-care 
  • does not involve ionising radiation
  • superior to CT in the diagnosis of gallstones which may impact further management
• The commonest findings of AC on US include:
  • gallstones
  • gallbladder distension
  • thickened (i.e. oedematous) gallbladder wall (>3 mm)

  These findings occurred in 59-88% of AC patients in two studies 9, 10.

• Other US findings in AC include pericholecystic fluid, pericholecystic fat echogenicity 11, gallbladder sludge, US Murphy’s sign 9, 10, tensile gallbladder fundus sign 9 and cystic artery velocity =/> 4cm/sec 9

• However, no single  imaging finding (or combination of findings) is definitive for the diagnosis of AC. For example, gallbladder wall thickening can be seen with many other causes of right upper quadrant pain, including hepatitis, chronic cholecystitis, cirrhosis, congestive heart failure. Similarly, pericholecystic fluid is also relatively insensitive.
• In the diagnosis of AC, sensitivities and specificities of US range from about 61-80% and 79-94% respectively 10, 12-18
• In limited evidence, there does not appear to be any consistent significant difference in diagnostic accuracy whether US is performed by radiologists, surgeons or ED physicians 13
• With regard to adjunct US techniques, investigations are appearing in the literature on the use of various Doppler techniques and contrast enhanced ultrasound (CEUS) in AC and other biliary conditions with early evidence showing improvements in the sonographic evaluation of these conditions 19, 20
• There are case reports of CEUS aiding the diagnosis of gangrenous cholecystitis and perforation in AC 21, 22

• A chest radiograph is useful to exclude thoracic causes for RUQ pain, and an erect chest radiograph may demonstrate free gas under the diaphragm if there is a perforated intra-abdominal hollow viscus (e.g. from a perforated peptic ulcer) 10
• However, plain abdominal radiography, although often performed, is of limited utility in acute RUQ pain and is not recommended as there is limited evidence supporting its routine use
• The presence of a radio-opaque gallstone on plain x-rays is non-specific and may be incidental to the patient’s presentation; it is estimated that 10–15% of the general population has asymptomatic cholelithiasis 2. Conversely, the absence of a stone on plain radiography does not exclude AC, as the majority of gallstones are non-radio-opaque.

The Tokyo Guidelines indicate that a definitive diagnosis of AC requires at least one item from each of the three following categories (A + B + C). 

Tokyo Guidelines: Diagnostic criteria for Acute Cholecystitis 5, 6

 A. Local (clinical) Signs of Inflammation

• Murphy’s sign
• Right upper quadrant (RUQ) mass, pain, or tenderness

B. Systemic Signs of Inflammation

• Fever
• Elevated C-reactive protein (CRP)
• Elevated White Blood Cell (WBC) count

 C. Imaging Findings

• Imaging findings characteristic of AC (See US section -US)

The Tokyo Guidelines indicate that a suspected diagnosis of AC requires one item from A and one from B of the following:

Tokyo Guidelines: Diagnostic criteria for Acute Cholecystitis 5, 6

A. Local (clinical) Signs of Inflammation

• Murphy’s sign
• Right upper quadrant (RUQ) mass, pain, or tenderness

B. Systemic Signs of Inflammation

• Fever
• Elevated C-reactive protein (CRP)
• Elevated White Blood Cell (WBC) count

 C. Imaging Findings

• Imaging findings characteristic of AC (See US section -US)

In studies in recent years, CT has been shown to be equivalent or superior to US in the diagnosis of AC, with sensitivities and specificities of 55-85% and 81-94% respectively 10, 15-17

• Typical CT findings of AC include (10):
  • gallstones 
  • gallbladder distention (>4 cm transverse)
  • gallbladder wall thickening (>3 mm) 
  • pericholecystic stranding
  • pericholecystic fluid 
• Other findings include hyperaemia of the adjacent liver parenchyma, cystic duct enhancement 23, and tensile fundal gallbladder wall 24
• CT has the advantage over US as better showing alternative causes to AC of RUQ symptoms 17 as well as showing complications of AC (e.g. perforation, abscess formation) 2
• For the purposes of evaluating AC or RUQ pain, CT should be performed with intravenous contrast, unless contraindicated
• Dual-energy CT may improve sensitivity over conventional CT in diagnosing AC and gangrenous AC 25 and may improve sensitivity for gallstones compared to conventional CT 26-29
• Despite CT’s increased accuracy over US, the latter remains the preferred primary imaging in suspected clinically uncomplicated AC. US provides advantages of low cost, ready access (including point-of-care), and lack of ionising radiation.
• CT is recommended as an alternative first-line investigation to US when:
  • there is reasonable clinical suspicion of alternate pathology
  • where complications (e.g. gangrenous gallbladder, perforation and pericholecystic abscess or fistula formation) are suspected clinically
  • dependent on local practice and availability
• CT is recommended as second-line investigation when:
  • US is technically unsuccessful (for example due to obesity or bowel gas)
  • US is equivocal, suspicious of AC by Tokyo Criteria, or negative but clinical suspicion of AC remains
  • Initial US suggests an alternative diagnosis to AC and/or complications of AC requiring clarification

• Cholescintigraphy uses 99mTc-hepatic iminodiacetic acid (generically referred to as a HIDA scan)
• The patient receives an IV administration of 99mTc-hepatic iminodiacetic acid compound, an agent that has rapid uptake by the liver and excretion in the bile
• Normally, visualisation of contrast within the common bile duct, gallbladder, and small bowel occurs within 30 to 60 minutes. When the gallbladder is not visualised within 60 minutes, delayed images (at 3-4 hours) or morphine augmentation is obtained.
• Failure of the gallbladder to fill within 60 minutes from administration of the tracer indicates obstruction of the cystic duct (the primary event in most patients with AC). False positives can occur, mostly due to cystic duct obstruction induced by chronic inflammation and chronic cholecystitis, or due to hepatic dysfunction and prolonged fasting.  False negatives may also occur but are uncommon, since most patients with AC have obstruction of the cystic duct. When they occur, they may be due to incomplete cystic duct obstruction. 
• The hallmark of AC (calculous as well as acalculous) is persistent gall bladder non-visualisation 30 minutes post-morphine or on delayed (3-4 hours) images
• HIDA scans are generally regarded as the most accurate imaging test in suspected AC with sensitivities up to 96% 2, 16, 18, 30 and moderate to high specificity
• However, the use of HIDA scans for suspected AC is limited in practice due to:
  • Extra-biliary causes of symptoms will not be detected
  • Longer examination time compared to US or CT
  • Poor liver function may cause inadequate excretion of the radiopharmaceutical agent
  • Serum bilirubin levels > 340-500 µmol/L may lead to unreliable results 
  • Optimisation with reduction of false positives requires fasting for at least 4 hours, selective use of a sincalide analogue, or a fatty meal prior to the test (the latter of which may be poorly tolerated) to induce emptying of the gallbladder prior to administration of the radiopharmaceutical agent 2
  • Failure to visualise the gallbladder after 1 hour post-agent injection may require morphine administration to induce Sphincter of Oddi contraction (morphine-augmented cholescintigraphy) to permit backfilling of the gallbladder or delayed imaging 1
  • Previous biliary sphincterotomy may result in low resistance to bile flow, leading to preferential excretion of the tracer into the duodenum without filling the gallbladder
  • In many institutions there is limited access to nuclear medicine services
• In summary, although HIDA scans are highly accurate in the diagnosis of AC, their use is limited to those patients in whom US and/or CT is equivocal i.e. as a problem-solver

• See pathway ‘Cholecystitis (Acute, Acalculous, Suspected)’ for the role of HIDA scans in that scenario Cholecystitis (Acute, Acalculous, Suspected)

• MRI (with or without IV contrast) is highly sensitive and specific in AC
• In a meta-analysis comparing US, CT, HIDA, and MRI, MRI had the highest sensitivity and specificity (91% and 93% respectively). 16. However, the overall evidence base for MRI is relatively limited compared to other modalities. It is also a high-cost examination with limited access.

• Typical findings of AC on MRI include:
  • Gallstones (often impacted in the gallbladder neck or cystic duct)
  • Gallbladder wall thickening (>3 mm)
  • Gallbladder wall oedema
  • Gallbladder distention (diameter >40 mm)
  • Pericholecystic fluid or stranding
  • Fluid around the liver
• MR Cholangiopancreatography (MRCP) is highly accurate in demonstrating concomitant choledocholithiasis 1, which can influence the timing and method of treatment in patients presenting with AC
• MRI can provide information on biliary anatomy that may be surgically relevant at laparoscopic cholecystectomy 31
• MRI is also useful in the diagnosis of complications of AC 2 such as gangrenous, emphysematous, and perforated cholecystitis
• In addition, Diffusion Weighted imaging may help distinguish acute from chronic cholecystitis 32, 33
• MR cholangiography using hepatobiliary MR contrast agents such as Gd-EOB-DTPA can demonstrate cystic duct patency or otherwise with high sensitivity. 34, 35 This is analogous to the mechanism of HIDA scanning in the context of suspected AC.
• Due to the lack of ionising radiation, MRI may be preferable to CT or HIDA scan in children, young adults and pregnant women
• In summary, MRI has excellent accuracy for AC, and may be beneficial in identifying concomitant choledocholithiasis, complications, and defining biliary anatomy preoperatively. Its high cost, time, and restricted access limit its use as a second-line investigation to select patient groups, particularly if US/CT are equivocal.

NOTE:

1. Detailed review of the imaging findings in the various complications of AC (see below) is beyond the scope of this article but the reader is referred to the reviews by Maddu et al (2021) 36 and Sandomenico et al (2022) 37
2. Recent articles suggest that a CT- and biomarker-based scoring system can help in the early identification of complicated cholecystitis 38

Complications of Acute Calculous Cholecystitis 2, 36, 37

Worrisome US findings for complicated AC include:

• Gallbladder wall abnormalities (striations, asymmetrical wall thickening, gas in the gallbladder wall, loss of sonoreflectivity and/or contrast enhancement, interruption of continuity of the gallbladder wall, etc)
• Intraluminal findings (sloughed mucosa, haemorrhage and/or abnormal gas)
• Pericholecystic changes (pericholecystic fluid and/or abscess formation)
• Visualisation of a pericholecystic or intrahepatic fluid collection/abscess

For most complications of AC, suspected clinically or on US, the preferred imaging investigation is CT.

• Gangrenous Cholecystitis (GC)

The incidence of GC in various studies is reported to be 2-38%. It is due to transmural inflammation and ischemic necrosis of the gallbladder wall and carries a higher mortality rate than standard AC, ranging from 15-50%. Risk factors for GC include advanced age, male sex, and diabetes. Subsequent perforation is reported to occur in up to 10% of patients with GC. CT findings for gangrenous cholecystitis include gas in the wall or lumen, intraluminal membranes, and irregular or absent wall enhancement 39. There is early evidence that CEUS can aid in the diagnosis of gangrenous cholecystitis and perforation in AC 21, 22.

• Perforation.

The incidence of gallbladder perforation in AC is 2-11% and is associated with a high risk of morbidity. Predisposing factors are comorbidities such as malignancy, drugs (e.g. corticosteroids), diabetes mellitus, and heart diseases. Haemorrhagic, gangrenous, and emphysematous cholecystitis may all lead to perforation of the gallbladder.

Perforation may occur freely into the peritoneal cavity, produce walled-off peri-cholecystic or intrahepatic abscesses, or fistula formation (cholecysto-enteric, cholecysto-colic or into an adjacent part of the biliary system).

• Emphysematous Cholecystitis (EC)

EC is a severe variant occurring in 1% of AC cases. Unlike the majority of cases of AC, this does not result from cystic duct obstruction by calculi, but from ischaemic insult to the gallbladder wall, subsequent gallbladder necrosis, and secondary infection by gas-forming organisms.  The disease predominantly affects diabetic, elderly or immunocompromised patients, and progresses rapidly with a high mortality rate. It is related to infection of the gallbladder wall by gas-forming organisms. There is a significant risk of perforation and a higher mortality than other forms of AC. The hallmark finding of EC is the presence of gas within the gallbladder wall, best diagnosed on CT though occasionally visible on US or even X-ray (rarely).

• Cholecystoenteric/colic fistula – see above
• Gallstone ileus/Bouveret syndrome

The passage of a gallstone from cystic duct or gallbladder through the common bile duct or through a fistula (see above) may result in impaction of the stone in the small bowel (or less commonly the duodenum – Bouveret’s syndrome) causing obstruction.

• Haemorrhagic cholecystitis

Haemorrhagic cholecystitis is uncommon (3.5% of patients with AC) and is more likely to occur in patients with comorbidities such as renal failure, coagulopathy, diabetes, and in patients on anticoagulation and anti-platelet agents. It is due to transmural inflammation, leading to mucosal infarction, necrosis, and haemorrhage due to bleeding from small vessels in the wall.

• Portal vein thrombosis and cystic artery pseudo-aneurysm

• Up to a third of patients initially suspected of having AC have an alternative diagnosis 2
• The differential diagnosis of AC is wide and careful consideration of alternative diagnoses is necessary when obtaining a history and performing an examination. These include conditions related to the following 4:
  • Liver – e.g. acute hepatitis, hepatic abscess, hepatic tumour, hepatic laceration
  Gallbladder and biliary tree – e.g. acute cholecystitis (calculous and acalculous), cholelithiasis with biliary colic, choledocholithiasis and bile duct obstruction, Mirizzi syndrome, cholangitis, carcinoma
  • Pancreas – e.g. acute pancreatitis
  • Bowel – e.g. peptic ulcer disease, small bowel obstruction, gallstone ileus, appendicitis, enteritis/colitis
  • Genitourinary system – e.g. pyelonephritis, nephrolithiasis with renal colic 
  • Non-abdominal causes – e.g. pneumonia, pulmonary infarction, myocardial infarction, musculoskeletal pain
• Further investigation and management will be guided by the most likely alternative diagnosis.Acute Abdomen (Non-Traumatic, Overview)

Treatment of AC 2, 40 

• Initial medical treatment for AC includes antibiotics, analgesics, and fluid and electrolyte support
• Early laparoscopic cholecystectomy (LC) is preferred when clinically and technically feasible 41, 42
• A number of publications have indicated the superiority of early LC over delayed LC, if feasible 43-47
• Laparoscopic cholecystectomy, if available and technically feasible, is the preferred option compared to open cholecystectomy due to earlier return of bowel function, less post-operative pain, shorter hospital stays, decreased wound complications, and decreased overall cost
• In difficult cases, laparoscopic cholecystectomy may be converted to an open approach
• Ultrasound may predict the degree of difficulty of laparoscopic cholecystectomy (LC), and thus the likelihood of conversion to an open cholecystectomy (OC). 48-51
  • Typically, the following findings predict a difficult LC or need to convert to OC:
    • Duration of symptoms for greater than 3 days
    • Severe acute cholecystitis on ultrasound with the following features:
      • Gallbladder wall thickening (>4-5 mm). 
      • Pericholecystic fluid/exudate/oedema or abscess adjacent to the gallbladder
      • Difficulty identifying anatomical structures within Calot’s triangle
      • Impacted stone(s) in Hartmann’s pouch or the cystic duct neck
    • In addition, abnormally increased BMI 52, 53 and elevated C-Reactive Protein 53 have been shown to be risk factors
• Patients with severe cholecystitis and/ or significant comorbidities that preclude a safe early surgical procedure may be treated with a holding percutaneous cholecystostomy (PC), under imaging guidance followed by interval cholecystectomy and/or stone extraction when the patient is fitter
• A 2023 meta-analysis (54) found that in patients with acute calculous cholecystitis who were poor surgical candidates, PC as a bridging procedure prior to LC led to significantly lower rates of post-operative complications, post-operative biliary leakage, intraoperative blood loss, operative time, and conversion to open and subtotal cholecystectomy than in emergency laparoscopic cholecystectomy alone
• Before removal of PC, drainage cholangiography should be done 40
• Cholecystostomy may also be performed laparoscopically or under endoscopic US guidance 55
• In unstable patients and those with severe comorbidities, other options for gallbladder drainage are: (a) endoscopic trans-papillary gallbladder drainage (ETGBD) and (b) endoscopic ultrasound-guided trans-gallbladder drainage (EUSGBD)
• Patients with concomitant choledocholithiasis may be treated with a single-stage procedure (LC and common bile duct exploration) or a two-stage procedure: endoscopic retrograde cholangiography with sphincterotomy and stone removal followed by LC)

The 2018 Tokyo Guidelines 56 recommend treatment according to severity:

• For Grade 1 (mild) – early LC in surgically fit patients
• For Grade 2 (moderate) – commence antibiotics and supportive care before urgent LC in surgically fit patients. Otherwise, percutaneous cholecystostomy +/- delayed elective LC. 
• For Grade 3 (severe) – commence antibiotics and supportive care and either perform LC or gallbladder drainage based on performance status and clinical condition. If it is determined that the patient cannot withstand surgery, conservative treatment with early biliary drainage should be considered if it is not possible to control the gallbladder inflammation.