Cholecystitis

Cholecystitis is an inflammatory disorder of the gallbladder produced by interacting obstructive, mechanical, ischemic, infectious, immune-mediated and metabolic mechanisms. In calculous disease, obstruction of the cystic duct by a gallstone is the principal initiating event; gallbladder distension, impaired emptying and mucosal injury then promote inflammation. Gallbladder stasis also facilitates bacterial colonisation, although bacteriobilia may be a secondary consequence rather than the primary trigger in every patient. ^[3][6]D[7]D

Obstruction, stasis and ischemia

Acalculous cholecystitis (AAC) occurs without gallstones and represents approximately 5–10% of acute cholecystitis in adults. ^[8]D Its pathophysiology is heterogeneous: obstruction may occur without a visible stone, while non-obstructive mechanisms include biliary stasis and ischemic injury. ^[6]D Critical illness can therefore create a vulnerable gallbladder through reduced emptying, systemic hypoperfusion and impaired microvascular perfusion; the resulting distension and ischemia may progress to necrosis or perforation, although the relative contribution of each mechanism varies between patients. ^[6]D[7]D

Portal biliopathy illustrates a different obstructive–ischemic pathway. In extrahepatic portal-vein obstruction with portal cavernoma, enlarged collateral veins can compress the bile ducts from outside, while altered biliary vascularisation can cause ischemic damage. These abnormalities are common on magnetic-resonance cholangiopancreatography (77–100%), but only 5–38% are symptomatic; manifestations may include cholecystitis, jaundice, cholangitis, abdominal pain and cholelithiasis. ^[2]

Gallbladder motility influences stasis and stone-associated inflammation. Bile acids normally modulate postprandial gallbladder contraction, and glucagon-like peptide pathways affect gallbladder motility; altered motility has been investigated as a possible explanation for cholelithiasis and cholecystitis reported with GLP-1- and GLP-2-receptor agonists. ^[10]D These data support impaired emptying as a contributory mechanism, but they do not establish that motility disturbance alone causes cholecystitis in all exposed patients. ^[10]D

Bacterial and infectious mechanisms

Bacterial infection is reported in approximately 50–85% of acute cholecystitis presentations, and bile culture positivity in cholecystitis varies from 20–70%. ^[116]C[3] The gut and biliary tract are closely related, and patients with acute cholecystitis showed enrichment of Akkermansia, Enterobacter and the Escherichia/Shigella group compared with healthy controls in a 16S rRNA study of faecal microbiota. ^[116]C These findings support gut–biliary microbial interaction, but do not prove that each enriched organism causes gallbladder inflammation. ^[116]C

Culture-independent and culture-based observations indicate that microbial communities can be present in diseased gallbladders. In one patient, live organisms resembling Corynebacterium urinapleomorphum, Staphylococcus saprophyticus and Helicobacter pylori were isolated from the gallbladder using culture, microscopy, phylogenetic analysis, urease testing and immunoblotting. ^[15]C Conversely, metagenomic sequencing of bile and stones from cholecystectomy patients found that bacterial diversity did not vary by surgical pathology, indicating that the mere presence or diversity of biliary bacteria is not sufficient to define the inflammatory mechanism. ^[119]D

Mucin may link infection, epithelial injury and stone disease. Gallstone pathogenesis has been associated with mucin hypersecretion and bacterial infection, and gallbladder epithelial tissues express multiple mucin genes, including MUC3, MUC5AC, MUC5B and MUC6. ^[146]D Lipopolysaccharide exposure was also used experimentally to study mucin responses in canine gallbladder epithelial cells, supporting a potential interaction between bacterial products and epithelial mucus biology. ^[146]D

Infectious cholecystitis is not limited to enteric bacteria. Coxiella burnetii is an under-recognised cause of AAC. A 2025 systematic review identified 27 Q-fever-associated cholecystitis cases, including 3 children (11.1%); all occurred during acute Q fever, and one patient subsequently developed recurrent pancreatitis and chronic cholecystitis. Gallbladder PCR was positive in 2/2 (100%) tested cases, whereas immunohistochemistry was negative in all cases, illustrating that tissue staining may be insensitive and that direct molecular detection can be informative. ^[1] COVID-19 has also been reported in association with AAC; proposed biological plausibility includes viral interaction with ACE2-expressing gastrointestinal epithelial cells, although the clinical relationship may also reflect systemic illness and critical-care factors. ^[8]D

Immune, drug-related and metabolic influences

Systemic inflammation, immune dysfunction and altered host response can lower the threshold for gallbladder injury. AAC has been reported as a safety risk after alemtuzumab: eight cases were identified, with four assessed as probable and four as possible drug-related events; all occurred in patients with relapsing-remitting multiple sclerosis, and seven developed AAC during or shortly after treatment. ^[11]D In Wilson disease, patients had a higher incidence and poorer prognosis of cholecystitis, while single-cell analysis showed an altered hepatic innate immune landscape and NK-cell exhaustion as a fundamental associated factor. ^[20]D These observations suggest that immune and metabolic abnormalities can influence susceptibility and outcome, but they do not establish a single causal pathway. ^[20]D

Immune-mediated fibroinflammatory disease can involve the biliary system. IgG4-related disease is characterised by immune-mediated fibroinflammation, commonly affecting the pancreas and bile ducts; classic histopathology remains the diagnostic standard, and glucocorticoids generally produce a marked initial response. ^[9]D Gallbladder inflammation may therefore occur within broader immune-mediated biliary disease rather than through obstruction or infection alone. ^[9]D

Tissue response and related disease biology

Gallbladder inflammation is accompanied by changes in the epithelial and immune microenvironment. Single-cell analysis across gallbladder cancer, cholecystitis, polyps, adenomas and normal tissues demonstrated altered immune landscapes across pathological states, although the strongest immunosuppressive changes were described in cancer. ^[118]D VEGF-A was studied immunohistochemically in advanced gallbladder carcinoma and chronic cholecystitis, reflecting the relevance of angiogenic signalling to gallbladder tissue biology, but these data do not establish VEGF-A as a primary cause of ordinary acute cholecystitis. ^[5] Similarly, differential exosomal RNA profiles have been investigated in gallbladder cancer and xanthogranulomatous cholecystitis, supporting molecular heterogeneity among gallbladder inflammatory and neoplastic conditions without defining a universal mechanism. ^[120]D

Overall, cholecystitis is best understood as a final common inflammatory response in which obstruction or impaired emptying, ischemia, microbial exposure and host immune or metabolic factors interact. The initiating pathway differs between calculous disease, AAC, portal biliopathy, infection-associated disease and immune-mediated conditions. ^{[1][2][3][6]D[7]D[8]D[9]D[10]D[11]D[20]D[116]C[119]D[146]D}

History

The history should establish the tempo, localization, and severity of symptoms, while distinguishing acute, chronic, recurrent, and secondary forms of gallbladder inflammation. In emergency-department populations, acute cholecystitis may be difficult to recognize because no single historical symptom or physical finding reliably rules the diagnosis in or out; a combined assessment of symptoms, examination findings, and point-of-care ultrasonography (POCUS) is therefore supported by prospective validation of the Bedside Sonographic Acute Cholecystitis (SAC) Score. ^[135] The Tokyo-guideline studies similarly evaluate acute cholecystitis using a combination of local clinical findings, systemic inflammatory features, and imaging rather than an isolated symptom. ^[134][135]

Pain is usually assessed for right-upper-quadrant localization and associated tenderness. Right-upper-quadrant tenderness was associated with positive hepatobiliary scintigraphy (HIDA) results in a retrospective cohort of patients evaluated for suspected acute cholecystitis. ^[134] The clinical history should also document fever or other systemic symptoms, vomiting, jaundice, prior biliary disease, recent procedures, anticoagulant exposure, and relevant comorbidity; however, the cited studies do not establish a single symptom combination with sufficient accuracy to replace imaging. ^{[134][135][141]C}

Vomiting was reported in 66% (23/35) of dogs with emphysematous cholecystitis, demonstrating that severe gallbladder infection can present with nonspecific gastrointestinal signs; because this evidence is veterinary, it should not be directly extrapolated to human diagnostic frequencies. ^[133] Hemorrhagic cholecystitis is an uncommon complication that may be difficult to diagnose before surgery and has been associated in prior reports with anticoagulation; the clinical presentation may therefore overlap with uncomplicated acute cholecystitis and should prompt attention to bleeding risk, anemia, and anticoagulant use. ^[141]C

The history should include prior conservative treatment for acute cholecystitis and recurrence. In a propensity-score-matched cohort, low skeletal muscle mass and high visceral adiposity were associated with recurrence after conservative management, and recurrent episodes may be more severe than the initial episode. ^[23] Social and nutritional context may also be relevant: a retrospective study of 1,609 emergency general-surgery patients examined residence in low-income, low-access food deserts in relation to acute biliary disease severity and outcomes, although the available abstract does not provide the complete association estimates. ^[29]D

Iatrogenic and unusual causes should be considered. Cholecystitis after yttrium-90 radioembolization was evaluated prospectively using symptoms, imaging, and laboratory parameters, with risk assessment based on gallbladder enhancement on pretreatment technetium-99m-MAA SPECT/CT and management of the cystic artery. ^[144]C Xanthogranulomatous cholecystitis commonly presents clinically as cholecystitis but can be difficult to distinguish from gallbladder carcinoma before surgery. ^[132] In children, eosinophilic cholecystitis and lymphoeosinophilic cholecystitis are histopathologic diagnoses defined by the proportion of inflammatory cells that are eosinophils—more than 90% for eosinophilic cholecystitis and 50–90% for lymphoeosinophilic cholecystitis—so the diagnosis generally cannot be made from history and examination alone. ^[26]C

Physical examination

Examine for right-upper-quadrant tenderness and a sonographic Murphy sign, and assess for guarding, rigidity, abdominal distension, generalized peritonism, fever, jaundice, dehydration, and hemodynamic instability. Right-upper-quadrant tenderness is specifically associated with positive HIDA findings, while the SAC Score combines historical symptoms, physical examination signs, and POCUS findings to improve bedside diagnostic prediction. ^[134][135] Absence of gallbladder-wall changes on an initial POCUS examination should not be used in isolation to exclude acute cholecystitis: gallstones and gallbladder tenderness may occur earlier, whereas wall thickening and pericholecystic fluid can appear later on subsequent imaging. ^[139]

Ultrasound assessment should document gallstones, gallbladder tenderness, wall thickening, pericholecystic fluid, and other secondary findings. Peak systolic cystic-artery velocity of ≥40 cm/s has been proposed as a highly specific independent sonographic marker of acute cholecystitis, although a retrospective emergency-department study evaluated its diagnostic performance alongside other ultrasound parameters rather than establishing it as a stand-alone clinical criterion. ^[28]D Hemorrhagic cholecystitis may have variable ultrasound and CT appearances, including findings that reflect blood within the gallbladder, so unexplained anemia, gastrointestinal bleeding, or atypical intraluminal imaging should increase suspicion. ^[141]C[143]C

Examination should also identify features suggesting complicated or difficult disease, including marked systemic toxicity, peritonism, jaundice, a palpable mass, or severe obesity. In one retrospective cohort of acute cholecystitis, BMI >30 kg/m² was associated with difficult laparoscopic cholecystectomy, although this operative-risk finding does not independently diagnose cholecystitis. ^[140]C Xanthogranulomatous inflammation may similarly create an inflammatory mass that clinically or radiologically resembles malignancy. ^[132]

The cited randomized trials of analgesic blocks and drainage address postoperative pain control or drain use rather than diagnostic history or physical-examination findings; they should not be used to define presenting symptoms or examination criteria. ^[21][22] Likewise, evidence concerning erector spinae plane block addresses pain during percutaneous cholecystostomy in high-risk elderly patients and does not establish diagnostic findings. ^[137] Studies of out-of-hours surgery and pandemic-era care describe management timing and health-system effects, not additional diagnostic examination criteria. ^[136][138]

Clinical spectrum

Cholecystitis comprises a spectrum extending from uncomplicated acute inflammation to purulent, gangrenous, emphysematous, perforated, torsive, and chronic inflammatory forms. Recent studies have particularly emphasized the difficulty of recognizing severe disease before operation and the substantial overlap between inflammatory variants and gallbladder malignancy.^{[34][36][37][51]D} Acute calculous cholecystitis may be categorized clinically and pathologically as simple, purulent, or gangrenous disease; in one cohort, the acute calculous group included 62 simple, 35 purulent, and 33 gangrenous cases.^[153] Histopathologic gangrenous cholecystitis is defined by focal or diffuse necrosis of the gallbladder wall.^[37]

Acute and gangrenous cholecystitis

Gangrenous cholecystitis is a severe complication of acute cholecystitis characterized by gallbladder-wall necrosis and risk of sepsis and other complications.^{[34][37][152]} Preoperative recognition is difficult because conventional clinical and imaging findings may not reliably distinguish gangrenous from nongangrenous disease.^[34][36] Multicenter predictive studies have therefore evaluated combinations of demographic, clinical, laboratory, and imaging variables rather than relying on a single finding; one explainable machine-learning model used 20 preoperative variables, while another incorporated plain and contrast-enhanced CT.^[36][34] In a multicenter CT study of 1,228 patients, a self-supervised model was developed to identify gangrenous disease preoperatively, and a separate multicenter model was developed from 1,246 patients to distinguish xanthogranulomatous cholecystitis from gallbladder cancer.^[34][50]D

Systemic inflammatory and nutritional indices may help stratify severity, although their retrospective evidence base does not establish them as standalone diagnostic tests. Evaluated markers include the neutrophil-to-lymphocyte, platelet-to-lymphocyte, monocyte-to-lymphocyte, systemic immune-inflammation, systemic inflammatory response, aggregate inflammation, and prognostic nutritional indices.^[152][153] A retrospective study of 435 patients specifically assessed aggregate inflammation, systemic immune-inflammation, and systemic inflammatory response indices for predicting gangrenous evolution of acute lithiasic cholecystitis.^[152] Reported predictors of gangrenous disease and its complications should be interpreted in the context of the study population and local diagnostic pathways.^[37]

Emphysematous cholecystitis

Emphysematous cholecystitis is a rare, severe variant of acute cholecystitis caused by gas-forming infection and is identified by gas within the gallbladder or surrounding tissues on ultrasonography or CT.^[133] In a retrospective series of 35 dogs diagnosed between 2000 and 2024, commonly reported signs included vomiting (23/35; 66%); the study also evaluated laboratory findings, ultrasonography, CT, bile cytology, bacterial culture and susceptibility, histopathology, treatment, and outcomes.^[133] These veterinary findings should not be directly generalized to human patients, but they reinforce that emphysematous disease may present nonspecifically and requires imaging confirmation.^[133]

In human practice, emphysematous cholecystitis has been evaluated in older and medically complex populations using cholecystectomy, percutaneous cholecystostomy, or medical management.^[147]C A 10-year single-center study compared these three strategies and assessed hospital stay, complications, conversion to cholecystectomy after drainage, and mortality.^[147]C Diabetes is a clinically relevant susceptibility factor for severe infection because chronic hyperglycemia impairs neutrophil chemotaxis, oxidative burst, and complement activation and may compromise tissue perfusion through vascular disease.^[35]D

Xanthogranulomatous and plasma-cell-rich variants

Xanthogranulomatous cholecystitis is an uncommon chronic inflammatory variant characterized by marked fibrosis and infiltration of macrophages and foamy histiocytes.^[49]D[151]C It can closely mimic thick-walled gallbladder carcinoma on clinical assessment and CT, MRI, or 18F-FDG PET/CT, creating a major preoperative diagnostic dilemma.^[49]D In a multicenter study of 1,246 patients, a machine-learning model using clinical, imaging, and laboratory variables achieved an area under the curve of 0.94 in internal validation and 0.88 in external testing for differentiating xanthogranulomatous cholecystitis from gallbladder cancer.^[50]D Dense inflammatory adhesions make surgery technically difficult, and conversion from laparoscopic to open surgery is more frequent than in routine gallbladder disease.^[38]

Plasma-cell-rich chronic cholecystitis includes lymphoplasmacytic cholecystitis and IgG4-related cholecystitis.^[151]C Lymphoplasmacytic cholecystitis has historically been associated with primary sclerosing cholangitis, whereas IgG4-related cholecystitis occurs within IgG4-related disease and is commonly associated with autoimmune pancreatitis; approximately 25–32% of patients with autoimmune pancreatitis demonstrate concomitant IgG4-related cholecystitis.^[151]C

Rare mechanical and complicated forms

Gallbladder torsion is a rare, life-threatening emergency that disproportionately affects older adults and may be obscured by multimorbidity or age-related anatomic changes.^[154]D Symptoms can mimic acute cholecystitis; sudden severe right-upper-quadrant pain, nausea, and vomiting, together with a markedly distended gallbladder, gallstones, and pericholecystic fluid, should raise suspicion, although imaging may be nondiagnostic and confirmation may occur only at laparoscopy.^[154]D Gangrenous disease may be unsuitable for immediate surgery in patients with major comorbidity; in a retrospective series, endoscopic transpapillary gallbladder drainage was assessed in 29 patients with CT-defined gangrenous cholecystitis and 62 without gangrene.^[53]D Percutaneous cholecystostomy is likewise used for patients considered unsuitable for early cholecystectomy, but mortality after drainage is influenced by baseline clinical severity and radiologic disease burden.^[148]

Operative implications

Severe inflammation, gangrene, emphysematous infection, xanthogranulomatous fibrosis, and delayed presentation can increase operative difficulty and the likelihood of conversion from laparoscopic to open surgery.^{[38][48]D[149]} In a cohort of 4,535 laparoscopic cholecystectomies, conversion predictors were assessed using demographic, clinical, laboratory, radiologic, operative, and histopathologic data; published conversion rates generally range from 2–15%, with conversion associated with increased operative time, morbidity, and hospital stay.^[149] A separate study of 259 patients evaluated patient- and health-system-related predictors of severe operative findings, defined as a Parkland Grading Scale score of ≥3, including the effect of a 48-hour treatment window.^[48]D Robotic and laparoscopic cholecystectomy have both been compared for acute cholecystitis in acute-care surgery services, including a retrospective cohort of 322 patients, while single-incision laparoscopic approaches have been studied mainly for benign gallbladder disease and technical difficulty rather than as defining clinical variants.^[128]C[150]

Scope of the evidence

The supplied updated literature focuses predominantly on acute cholecystitis (AC), particularly operative difficulty, drainage selection, perforation, severity assessment, and emerging imaging technologies. It does not provide a new, validated replacement for the conventional clinical, laboratory, and imaging evaluation of suspected cholecystitis. Diagnostic decisions should therefore distinguish confirmation of AC from assessment of severity, complications, operative risk, and suitability for immediate intervention. The available evidence is heterogeneous: comparative robotic studies are observational, and several drainage and diagnostic-technology studies are retrospective or single-center investigations. ^{[59][156][157]C[159]C[162]}

Diagnostic imaging and emerging tools

Artificial-intelligence (AI)-assisted imaging has been evaluated for abdominal infections including cholecystitis, appendicitis, and pneumoperitoneum. A systematic review and meta-analysis identified 11 eligible studies and pooled diagnostic-performance measures, but the supplied abstract does not report pooled sensitivity, specificity, or evidence that AI should replace clinician-interpreted imaging. AI should therefore be regarded as an investigational or adjunctive tool rather than a stand-alone diagnostic standard. ^[156]

Near-infrared fluorescence cholangiography using indocyanine green has been compared with conventional white-light laparoscopic imaging in patients with gallstone disease and cholecystitis. The integrative review included randomized controlled trials and systematic reviews with meta-analyses, and was designed to synthesize intraoperative visualization and identification of biliary anatomy. This technology is relevant to operative anatomical clarification, but it is an intraoperative adjunct and does not establish the diagnosis of AC before surgery. ^[155]

Computed tomography (CT) may also contribute to complication assessment and risk stratification. In patients with gallbladder perforation, CT-derived body-composition measures—including skeletal muscle index, intramuscular adipose tissue content, and the visceral-to-subcutaneous fat ratio—were investigated in relation to perforation subtype, treatment selection, and mortality. These measures are prognostic and exploratory; they should not be interpreted as diagnostic criteria for AC or perforation without corroborating clinical and radiological findings. ^[164]

Severity, complications, and prognostic workup

The workup should specifically assess whether AC is complicated by gallbladder perforation, contained perforation, emphysematous infection, or systemic deterioration because these findings may alter drainage and operative strategies. EUS-guided gallbladder drainage (EUS-GBD) is traditionally considered contraindicated in perforated cholecystitis, although prospective and retrospective cohorts have examined selected patients with contained or frank perforation. In a prospective cohort of 23 patients with contained perforation, underlying malignancy was frequent, affecting 87.0% of patients, underscoring the need to evaluate for malignancy when perforation or atypical anatomy is present. ^[158] A separate retrospective series assessed high-risk patients with perforated cholecystitis treated with electrocautery-enhanced lumen-apposing metal stents, reporting technical and clinical success as primary outcomes, but the supplied evidence does not establish routine EUS-GBD for all perforations. ^[129]C

Emphysematous cholecystitis is a severe variant characterized in a veterinary retrospective series through clinical findings, laboratory values, ultrasonography or CT, bile cytology, culture and susceptibility testing, and histopathology. Because this evidence concerns dogs, it should not be extrapolated directly to human diagnostic thresholds or management. ^[133]

Hypoglycemia has been studied as a prognostic marker in human acute calculous cholecystitis. A retrospective cohort evaluated hypoglycemia alongside clinical variables, Tokyo classification, American Society of Anesthesiologists status, intensive-care admission, treatment, and mortality. The study’s premise was that hypoglycemia may identify mortality risk even among patients with lower Tokyo classifications; it does not establish hypoglycemia as a diagnostic test for AC. ^[160]

Workup when immediate cholecystectomy is unsuitable

For patients at elevated operative risk, diagnostic assessment should define whether gallbladder drainage is required and identify the anatomy relevant to percutaneous, transpapillary, or transmural access. A network meta-analysis of 17 trials involving 2,254 patients compared percutaneous gallbladder drainage (PTGBD), EUS-GBD, and endoscopic transpapillary gallbladder drainage (ETGBD). PTGBD and EUS-GBD had higher technical-success rates than ETGBD, although treatment ranking must be interpreted in the context of differing anatomy, expertise, and patient selection. ^[67]

A multicenter Western cohort demonstrated substantial variation in EUS-GBD practice and examined lumen-apposing-metal-stent adverse events, recurrent biliary disease, recurrent AC, and all-cause mortality. ^[157]C In high-risk patients with cirrhosis, a multicenter comparative study evaluated EUS-GBD versus percutaneous drainage, including technical success, clinical success, and device- or catheter-related adverse events. ^[159]C These data support individualized multidisciplinary assessment rather than a universal drainage route.

Workup for operative planning and interval treatment

If inflammation prevents safe achievement of the critical view of safety, subtotal cholecystectomy is recognized as a bailout strategy. A systematic review and meta-analysis evaluated subtotal versus total cholecystectomy and fenestrating versus reconstituting subtotal techniques, with analyses of safety, effectiveness, and patient factors affecting risk. ^[58] Long-term counseling should include the possibility of remnant cholecystitis: a population-based cohort of 2,682 patients quantified this outcome after subtotal cholecystectomy and evaluated subsequent completion surgery. ^[163]

Timing and prior drainage should be documented because they affect operative planning. A randomized trial of 100 patients compared early laparoscopic cholecystectomy within 72 hours with interval surgery after 6–8 weeks; early surgery had a longer mean operative time but a shorter total hospital stay. ^[126]C After percutaneous cholecystostomy, a systematic review and meta-analysis compared early versus late interval cholecystectomy using perioperative complications, operative duration, blood loss, postoperative length of stay, and catheter-related complications as outcomes. ^[123] Another meta-analysis compared interval cholecystectomy after PTGBD, EUS-GBD, or ETGBD, focusing on operative outcomes and the anatomical effects of each drainage method. ^[66]

Robotic assistance may be considered during operative planning, but it is not a diagnostic modality. Evidence comparing robotic and laparoscopic emergency cholecystectomy remains observational and heterogeneous, with no randomized emergency-setting trials in the systematic review. ^[59] Retrospective cohorts reported comparisons across acute-care services and across grades of AC, while another study examined robotic interval cholecystectomy after gallbladder drainage; these studies do not establish superiority or alter the diagnostic workup. ^{[128]C[162][165]}

Initial supportive care and treatment strategy

Management should be individualized according to disease severity, operative risk, symptom duration, and response to initial treatment. Early laparoscopic cholecystectomy (ELC) remains the operative standard evaluated against delayed or interval surgery in adults with acute cholecystitis (AC). The 2026 meta-analysis included randomized trials comparing index-admission ELC with delayed laparoscopic cholecystectomy performed ≥4 weeks after conservative management, while a separate randomized trial compared surgery within 72 hours with interval surgery after 6–8 weeks of conservative treatment. ^[122][126]C In the latter trial, ELC was associated with a shorter total hospital stay than interval surgery (6.50 versus 10.80 days), although operative time was longer (95.47 versus 73.69 minutes). ^[126]C

A symptom-onset threshold of 7 days should not automatically mandate postponement. An international retrospective analysis specifically evaluated ELC performed within versus beyond 7 days because evidence supporting a rigid seven-day rule was considered lacking. ^[127] In high-risk patients stratified according to Tokyo Guidelines 2018, a retrospective series of early laparoscopic cholecystectomy reported no in-hospital deaths and no significant difference in major complications between high- and low-risk groups; major complications occurred in 6.0% and 5.1%, respectively. Grade 3 disease was independently associated with overall complications (adjusted OR 3.12, 95% CI 1.03–21.47). ^[130]C

Antibiotic use

For mild-to-moderate AC treated with emergency laparoscopic cholecystectomy, routine prolonged postoperative antibiotics have not demonstrated a statistically significant reduction in infection. A multicenter, double-blind randomized trial compared intravenous cefazolin for three days during hospitalization followed by oral antibiotics for four days after discharge with placebo in this population. ^[88] A 2026 systematic review and meta-analysis similarly found infectious complications in 9% (84/889) of antibiotic-treated patients versus 12% (106/895) of controls, without a significant benefit (OR 0.78, 95% CI 0.58–1.07; I²=0%); surgical-site infections were also not significantly reduced. ^[124] These findings support antimicrobial stewardship and avoidance of routine extended courses in appropriately selected mild-to-moderate cases, while the cited studies do not establish management for severe infection, perforation, abscess, or uncontrolled sepsis. ^[88][124]

Drainage for patients unsuitable for immediate surgery

Percutaneous cholecystostomy (PC) is used as temporizing treatment in high-risk patients who do not respond adequately to conservative management, with cholecystectomy later considered as definitive treatment. ^[91][123] The optimal interval between PC and interval cholecystectomy remains uncertain: a 2026 systematic review identified 12 retrospective studies involving 1,032 patients and compared early with late interval surgery using 1-month and 8-week cutoffs, assessing perioperative, operative, length-of-stay, and catheter-related outcomes. ^[123] A multicenter retrospective cohort also assessed major complications defined as Clavien–Dindo grade ≥III after cholecystectomy following PC. ^[91] After percutaneous transhepatic gallbladder drainage, a separate study analyzed the interval to laparoscopic cholecystectomy as a continuous variable using restricted cubic splines, focusing on technical difficulty and the risk of bailout surgery rather than relying solely on arbitrary time categories. ^[131]

Endoscopic ultrasound-guided gallbladder drainage (EUS-GBD) is described as a drainage option for high-surgical-risk patients with AC. A retrospective series evaluated electrocautery-enhanced lumen-apposing metal stents in patients with AC complicated by gallbladder perforation, a condition often considered a contraindication to endoscopic treatment; technical success, clinical success, and adverse events were assessed. ^[129]C

Preventing bile duct injury and managing the difficult gallbladder

When inflammation or distorted anatomy prevents safe achievement of the critical view of safety, subtotal cholecystectomy (STC) is a guideline-supported bailout strategy. A contemporary systematic review and meta-analysis evaluated STC outcomes, including comparisons with total cholecystectomy and fenestrating versus reconstituting techniques. ^[58] Fenestrating and reconstituting STC should therefore be regarded as distinct technical approaches whose safety trade-offs must be considered in the individual case. ^[58]

Completion cholecystectomy may be required after STC for persistent or recurrent symptoms, residual gallbladder disease, or acute cholecystitis. A 48-study meta-analysis including 1,225 patients found that common indications were symptomatic cholelithiasis (55.8%) and AC (19.8%); the pooled interval to completion surgery was 47 months, laparoscopy was used in 75.6%, open surgery in 15.6%, and symptom resolution occurred in 92.5%. ^[60] These data support referral to experienced hepatobiliary surgeons when completion surgery is contemplated. ^[60]

Indocyanine-green fluorescence cholangiography has been evaluated as an adjunct to conventional white-light laparoscopic cholecystectomy in AC. A propensity-score-matched analysis examined bailout procedures and other surgical outcomes, reflecting its proposed role in improving biliary-anatomy visualization and identifying failure to achieve the critical view of safety. ^[125]

Operative and postoperative adjuncts

Ultrasonic dissection and electrocautery are the principal dissection methods used during laparoscopic cholecystectomy for AC. An updated systematic review and meta-analysis of randomized trials compared operative time, hospital stay, blood loss, and intraoperative and postoperative complications between these techniques. ^[62] Robotic assistance may improve visualization and instrument dexterity, but the available emergency AC evidence remains observational and heterogeneous, with no randomized comparative trials in the systematic review. ^[59] Retrospective acute-care cohorts likewise reported comparisons between robotic and laparoscopic surgery, including a 322-patient series (107 robotic and 215 laparoscopic cases) and a single-center study assessing outcomes across all grades of AC; these studies do not establish robotic superiority. ^[128]C[162]

Postoperative analgesia can be supplemented with regional anesthesia. In a randomized trial of laparoscopic cholecystectomy, ultrasound-guided T7–11 intercostal nerve block was compared with subcostal transversus abdominis plane block using 40 mL of 0.3% ropivacaine, with tramadol requirement at 24 hours as the primary endpoint and pain scores, time to rescue analgesia, and satisfaction as secondary outcomes. ^[21] Port selection may also influence wound morbidity, although the available randomized evidence involved obese patients with chronic calculous cholecystitis rather than AC: a 5-mm versus 10-mm umbilical port trial evaluated port-site hernia, pain, operative time, and patient and surgeon satisfaction. ^[65]

Procedure-related cholecystitis

Postprocedural cholecystitis is a recognized complication after covered self-expandable metal stent placement for distal malignant biliary obstruction. A systematic review and meta-analysis compared covered with uncovered stents, evaluating cholecystitis, pancreatitis, stent migration, and tumor ingrowth; stent position relative to the cystic-duct orifice was clinically relevant to the prevention of cholecystitis. ^[85]

Overall prognosis

Acute cholecystitis is usually survivable when promptly diagnosed and treated, but reported mortality remains approximately 0.6%–6.0%, with risk concentrated in patients with severe disease, advanced age, major comorbidity, organ dysfunction, or treatment failure ^[160]. Tokyo grade III disease identifies a particularly high-risk group, although prognostic discrimination may be limited because grade III represents only a minority of patients who die ^[160]. In a retrospective cohort, hypoglycaemia was investigated as an additional mortality marker, suggesting that readily available biochemical variables may improve risk assessment beyond Tokyo grade alone ^[160].

Early cholecystectomy generally reduces the cumulative burden of illness and hospitalisation. In a randomised trial of 100 patients with acute calculous cholecystitis, early laparoscopic cholecystectomy within 72 hours required longer operative time than interval surgery at 6–8 weeks (95.47 versus 73.69 minutes), but resulted in a shorter total hospital stay (6.50 versus 10.80 days) ^[126]C. A prospective cohort evaluating a proactive emergency laparoscopic strategy in complex disease—including symptom duration of at least 7 days, advanced age, severe inflammation, and Tokyo grades II/III—examined whether emergency treatment could be safely extended to patients traditionally considered technically difficult ^[83]D. Similarly, a retrospective study of early laparoscopic cholecystectomy found no in-hospital deaths and a 5.6% rate of major complications; major complication rates were similar in Tokyo high- and low-risk groups, although grade III disease independently increased the odds of overall complications (adjusted OR 3.12) ^[130]C. These findings support early surgery in appropriately selected high-risk patients, but are not proof that all patients should undergo immediate operation because most evidence remains observational and centre-specific ^[83]D[130]C.

Outcomes after difficult or subtotal cholecystectomy

When the critical view of safety cannot be achieved, subtotal cholecystectomy is a guideline-supported bailout intended to reduce major bile-duct injury ^[58]. The contemporary systematic review evaluated outcomes of subtotal versus total cholecystectomy and compared fenestrating with reconstituting techniques; interpretation should account for the predominantly non-randomised evidence base and technique-dependent trade-offs ^[58]. Long-term surveillance is important because residual gallbladder or cystic-duct tissue can remain symptomatic. In a population-based cohort of 2,682 patients undergoing subtotal cholecystectomy for acute cholecystitis, longitudinal incidence of remnant cholecystitis, subsequent completion surgery, and related outcomes were specifically assessed ^[163].

Completion cholecystectomy is usually performed for recurrent symptoms or remnant stones. A meta-analysis of 1,225 patients found that symptomatic cholelithiasis accounted for 55.8% of indications and acute cholecystitis for 19.8%; the median interval from the initial operation to completion surgery was 47 months ^[60]. Laparoscopy was used in 75.6% and an open approach in 15.6%, while symptom resolution was achieved in 92.5% ^[60]. These data indicate that completion surgery can provide durable symptom relief, although delayed reoperation may be technically demanding and should be undertaken in experienced hepatobiliary units ^[60].

High-risk patients managed with drainage

For patients unfit for immediate surgery, gallbladder drainage may control the acute episode but does not necessarily eliminate future biliary risk. A systematic review and meta-analysis compared early versus late interval cholecystectomy after percutaneous cholecystostomy, examining perioperative complications, operative duration, blood loss, postoperative length of stay, and catheter-related complications; subgroup analyses used 1 month and 8 weeks as timing thresholds ^[123]. The available evidence comprised 12 retrospective studies, so the optimal interval remains uncertain and vulnerable to selection bias ^[123].

Drainage modality may influence later surgery. A network meta-analysis of 2,254 patients from 17 trials found that percutaneous drainage and EUS-guided drainage had higher technical success than endoscopic transpapillary drainage ^[67]. A separate meta-analysis compared operative outcomes after interval cholecystectomy following percutaneous, EUS-guided, or transpapillary drainage, but the evidence remains comparative and heterogeneous rather than definitive ^[66]. In Western multicentre practice, EUS-guided gallbladder drainage with a lumen-apposing metal stent was used in patients unsuitable for immediate surgery, with outcomes assessed for stent-related adverse events, recurrent biliary disease, recurrent acute cholecystitis, and all-cause mortality ^[157]C. EUS-guided drainage has also been studied in high-risk patients with gallbladder perforation, a condition traditionally viewed as a contraindication, and in cirrhosis patients unsuitable for surgery, where it was compared with percutaneous drainage for clinical success and long-term device- or catheter-related adverse events ^[129]C[159]C. These approaches may provide durable non-operative management in selected patients, but require specialist expertise and long-term monitoring ^{[129]C[157]C[159]C}.

In octogenarians with moderate-to-severe cholecystitis and concomitant cholangitis who underwent percutaneous cholecystostomy followed by ERCP, subsequent cholecystectomy was compared with non-operative management using overall survival, recurrent biliary events, and procedure-related complications as outcomes ^[166]. Decisions should therefore incorporate life expectancy, functional status, recurrence risk, and operative risk rather than age alone ^[166].

Robotic surgery and long-term expectations

Robotic cholecystectomy has not yet demonstrated a consistent prognostic advantage over laparoscopy. A systematic review of emergency robotic surgery included 1,142 cases, 28.7% involving acute cholecystitis; overall conversion was 9.1%, complications were similar to laparoscopy (13.2% versus 14.7%; P=0.21), and mean blood loss was lower with robotic surgery (85 versus 120 mL) ^[61]. However, the acute-cholecystitis-specific systematic review found that comparative evidence was entirely observational, heterogeneous, and lacked randomised trials ^[59]. Single-centre studies likewise reported equivalent outcomes between robotic and laparoscopic cholecystectomy across all acute cholecystitis grades and evaluated feasibility in acute-care services ^[162][128]C. Robotic interval cholecystectomy after drainage has also been compared retrospectively with laparoscopy, but cost and uncertain clinical benefit remain important limitations ^[165].

The management of acute cholecystitis has undergone a significant paradigm shift over the last two decades, moving from a conservative 'cool-down' approach to early surgical intervention. This transition has been driven by high-quality evidence demonstrating that early laparoscopic cholecystectomy (LC) reduces hospital stay and prevents recurrent biliary events without increasing surgical morbidity. Furthermore, the management of high-risk surgical candidates—those previously managed exclusively with percutaneous cholecystostomy (PC)—is currently being refined through rigorous multicenter trials.

Older adults and frailty

Age and comorbidity should not automatically preclude early cholecystectomy. In a Swedish national cohort of 12,481 patients aged ≥70 years, hospitals with different cholecystectomy practices were compared to estimate the effect of operative management on mortality and gallstone-related healthcare use over the index admission and 1- and 3-year follow-up periods.^[167] In octogenarians with moderate-to-severe cholecystitis and concurrent cholangitis who had undergone percutaneous cholecystostomy followed by ERCP, subsequent cholecystectomy was compared with non-operative follow-up for survival, recurrent biliary events, and procedure-related complications.^[166] These observational data support individualized assessment rather than age alone determining treatment, while recognizing that selection bias may influence comparisons between operative and non-operative groups.^[167][166]

Sarcopenia may identify particularly vulnerable patients. In a radiological study of gallbladder perforation, skeletal muscle index, intramuscular adipose tissue content, and the visceral-to-subcutaneous fat ratio were assessed on CT at the L3 level in relation to perforation subtype, treatment preference, and mortality.^[164] Body composition assessment may therefore complement conventional severity and anesthetic-risk evaluation, although the study was retrospective and focused on patients who had already developed perforation.^[164]

High surgical risk and drainage strategies

For patients unfit for immediate surgery, gallbladder drainage may be performed percutaneously or endoscopically. In a statewide analysis of 8,112 emergency-department admissions across 40 hospitals, 990 patients (12%) underwent percutaneous cholecystostomy; age and clinical severity were the strongest factors associated with its use, with additional associations reported for sex and insurance status.^[168] The variation in use indicates that institutional practice and patient characteristics both influence selection of percutaneous drainage.^[168]

EUS-guided gallbladder drainage using a lumen-apposing metal stent is increasingly used in patients unsuitable for immediate surgery.^[157]C A multicenter Western cohort involving 18 centers evaluated patient- and procedure-related factors associated with LAMS-related adverse events, recurrent biliary disease, recurrent acute cholecystitis, and all-cause mortality; the study also highlighted heterogeneity in current practice.^[157]C In high-risk patients with cirrhosis, a multicenter comparative study assessed EUS-guided drainage versus percutaneous drainage for technical success, clinical success, and short- and long-term adverse events, including biliary, catheter-related, and device-related events.^[159]C These approaches should be selected by a multidisciplinary team according to surgical risk, anatomy, endoscopic expertise, coagulopathy, ascites, and anticipated need for definitive gallbladder treatment.^[159]C[157]C

Cirrhosis and perforated cholecystitis

Cirrhosis increases the complexity of both operative and drainage decisions. In cirrhotic patients considered unfit for surgery, EUS-guided drainage with LAMS and percutaneous drainage were directly compared in a multicenter cohort, with outcomes reported using both intention-to-treat and clinical-success analyses.^[159]C The evidence is observational; it supports EUS-guided drainage as a potential alternative to percutaneous catheter drainage in selected expert centers, but does not establish universal superiority.^[159]C

Gallbladder perforation has traditionally been viewed as a contraindication to EUS-guided drainage, particularly when contamination is uncontrolled.^{[158][129]C[169]C} Nevertheless, prospective and retrospective cohorts have examined EUS-guided drainage in contained perforation, defined in one study as Niemeier type 2.^[158] The prospective cohort included 23 patients, representing 39.7% of that center’s overall EUS-guided drainage cohort, and reported a high prevalence of underlying malignancy (87.0%); a contemporaneous cohort with intact gallbladder walls was used for exploratory comparison.^[158] A separate multicenter pilot study of 22 patients with radiologically confirmed Niemeier type II perforation reported 100% technical and clinical success, with three adverse events.^[169]C Another tertiary-center series evaluated electrocautery-enhanced LAMS in high-risk patients with perforation, using technical and clinical success as primary outcomes and adverse events as safety outcomes.^[129]C These findings suggest feasibility in carefully selected, contained perforations, but they are based on small, mostly retrospective cohorts and should not be extrapolated to free perforation or uncontrolled peritonitis.^{[158][129]C[169]C}

Timing and technically difficult disease

Early laparoscopic cholecystectomy remains appropriate when the patient can tolerate surgery. In a randomized trial of 100 patients with acute calculous cholecystitis, surgery within 72 hours was compared with interval surgery after 6–8 weeks of conservative management; early surgery had a longer mean operative time but a shorter total hospital stay.^[126]C An international retrospective cohort specifically evaluated early laparoscopic cholecystectomy performed ≤7 versus >7 days after symptom onset, addressing whether the conventional seven-day threshold should determine delay.^[127] In patients classified as high risk by Tokyo Guidelines 2018, early laparoscopic cholecystectomy was evaluated in 126 patients; there was no in-hospital mortality, and major complications occurred in 5.6%, without a significant difference between high- and low-risk groups.^[130]C

For patients initially treated with percutaneous transhepatic gallbladder drainage, the interval to laparoscopic cholecystectomy was analyzed as a continuous variable using restricted cubic splines, with bailout surgery as the principal marker of operative difficulty.^[131] Interval surgery should therefore be individualized rather than determined by an arbitrary cutoff alone.^[131] Subtotal cholecystectomy remains an accepted bailout strategy for a difficult gallbladder, but a population-based analysis of 2,682 patients found that subsequent remnant cholecystitis and completion surgery remain relevant long-term considerations.^[163]

Recurrent disease, metabolic risk, and operative approach

A nationwide Swedish study compared early cholecystectomy for recurrent versus first-time cholecystitis, using 30-day complications as the primary outcome and assessing whether recurrent presentation increased operative risk.^[103]D GLP-1 receptor agonist exposure in adults with type 2 diabetes was evaluated against matched controls for gallstones, cholecystitis, pancreatitis, ERCP, and cholecystectomy, with analyses stratified by GLP-1 receptor agonist exposure characteristics.^[161] Hypoglycemia was studied as an independent predictor of mortality in acute calculous cholecystitis, including patients with lower Tokyo severity grades, because mortality is not confined to Tokyo grade 3 disease.^[160]

Robotic cholecystectomy has been compared with laparoscopic surgery in acute-care cohorts, including analyses across acute cholecystitis severity grades and a study of 322 patients treated between 2023 and 2026.^[128]C[162] A separate study examined robotic versus laparoscopic interval cholecystectomy after percutaneous or endoscopic drainage.^[165] Current evidence is retrospective and does not establish a consistent outcome advantage for robotic surgery; approach should therefore reflect surgeon expertise, resources, urgency, and patient-specific anatomy.^{[128]C[162][165]}

Diagnostic evaluation

For adults, children, and pregnant people with suspected acute cholecystitis or cholangitis, the 2024 Infectious Diseases Society of America (IDSA) guideline update provides recommendations for diagnostic imaging, risk assessment, and microbiological evaluation using the GRADE framework. ^[107] The 2022 American College of Radiology (ACR) Appropriateness Criteria for right-upper-quadrant pain emphasize that gallstone-related acute cholecystitis is a leading diagnostic consideration, while hepatic, pancreatic, gastroduodenal, and musculoskeletal disorders may produce similar symptoms. ^[109] The ACR document addresses ultrasound, computed tomography, magnetic resonance imaging, and other imaging approaches for biliary disease and its complications, while also considering alternative diagnoses such as pancreatitis, peptic ulcer disease, ascending cholangitis, liver abscess, hepatitis, and painful hepatic neoplasms. ^[109]

Tokyo Guidelines 2018 (TG18) grading remains an important framework for describing acute cholecystitis severity and informing treatment selection. ^{[108][112][172]} However, retrospective studies have evaluated simplified or adjunctive risk tools: age-based stratification separated patients aged <65 years, 65–79 years, and ≥80 years, while monocyte distribution width was investigated as a potential predictor of severe disease. ^[112][172] These tools should be interpreted as supportive evidence rather than replacements for comprehensive clinical assessment, because the cited studies were retrospective and/or single-center investigations. ^[112][172]

Initial treatment and operative timing

Laparoscopic cholecystectomy remains the standard or gold-standard treatment for acute cholecystitis in the cited surgical literature. ^{[83]D[113][176][177]C} A prospective cohort from a national emergency center evaluated a proactive emergency laparoscopic cholecystectomy protocol for complex acute cholecystitis, including patients with symptom duration of ≥7 days, advanced age, or severe inflammation corresponding to TG18 grade II/III. ^[83]D Retrospective evidence also compared early surgery within 1 week, intermediate surgery at 1–6 weeks, and delayed surgery after that interval with respect to postoperative quality of life. ^[171] A multidisciplinary protocol combined with surgical audit was specifically evaluated as a method for improving the early-cholecystectomy rate and other treatment indicators. ^[176]

For patients classified as high risk under TG18, a 2026 retrospective analysis of early laparoscopic cholecystectomy reported no in-hospital mortality and no significant difference in major complications between high- and low-risk groups; grade 3 cholecystitis was independently associated with overall complications. ^[130]C These findings support individualized consideration of early surgery in selected high-risk patients but do not eliminate the need for careful assessment of physiological reserve, disease severity, and operative difficulty. ^[130]C[172]

High-risk, critically ill, or unfit-for-surgery patients

The SICUT guideline addresses patients with acute cholecystitis who are high risk, critically ill, or temporarily or definitively unfit for surgery. ^[108] It was developed through systematic literature review and expert-panel discussion and provides 15 statements concerning procedures that may postpone or prevent surgery in this population. ^[108] Percutaneous cholecystostomy is described as a less invasive option for selected patients with severe comorbidity who are unsuitable for surgery or general anesthesia. ^[113] The cited cohort evaluated patients managed with percutaneous cholecystostomy alone and patients subsequently undergoing elective or emergency cholecystectomy. ^[113]

After percutaneous transhepatic gallbladder drainage, the optimal interval before laparoscopic cholecystectomy remains uncertain. ^[131] A retrospective study analyzed the interval as a continuous variable using restricted cubic-spline methods and assessed its relationship with technical difficulty and the need for bailout surgery. ^[131] Consequently, timing after drainage should be individualized rather than based solely on an arbitrary cutoff. ^[131]

Difficult cholecystectomy and operative safety

TG18 describes bailout procedures for difficult cholecystitis. ^[173][174]C Magnetic resonance cholangiopancreatography findings were retrospectively assessed for their ability to predict conversion from laparoscopic cholecystectomy to bailout procedures. ^[173] Fundus-first laparoscopic cholecystectomy, proposed by TG18 as a bailout approach, was evaluated in patients with severe cholecystitis; its use was associated with study-specific differences in surgical outcomes, but the evidence was retrospective. ^[174]C The Parkland Grading Scale has also been retrospectively compared with the Tokyo Guidelines grading system as a predictor of operative difficulty and postoperative complications. ^[175]

Near-infrared fluorescent cholangiography was prospectively studied during emergency laparoscopic cholecystectomy performed 24–72 hours after symptom onset in patients with ASA physical-status scores 0–3 and clinically and radiologically diagnosed acute cholecystitis. ^[111] Intraoperative indocyanine-green fluorescence was also evaluated in a 2025 single-center case-control study as a roadmap for identifying biliary anatomy during emergent surgery, with the objective of improving operative safety and reducing bile-duct injury. ^[177]C These studies provide supportive but not definitive evidence for routine use across all disease-severity groups. ^[111][177]C

COVID-19 and endoscopic resources

The 2025 Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) guideline update addresses urgent and elective appendectomy or cholecystectomy in patients with active COVID-19 infection. ^[105] Following systematic review and interdisciplinary-panel assessment, it issued conditional recommendations supporting either operative or nonoperative management for COVID-positive patients with appendicitis or cholecystitis. ^[105]

The 2024 American Society for Gastrointestinal Endoscopy guideline provides a GRADE-based framework for therapeutic endoscopic ultrasound in biliary disorders. ^[106] Its recommendations include EUS-guided biliary drainage versus percutaneous transhepatic biliary drainage after failed ERCP, EUS-guided hepaticogastrostomy versus choledochoduodenostomy for distal malignant obstruction after failed ERCP, and EUS-directed transgastric ERCP versus laparoscopic-assisted or enteroscopy-assisted ERCP. ^[106] These resources are principally relevant when cholecystitis is accompanied by biliary obstruction or other complex biliary-tract disease rather than uncomplicated gallbladder inflammation. ^[106]

Antimicrobial and microbiological considerations

TG18-based empirical antibiotic selection is influenced by disease severity, and prior endoscopic sphincterotomy may identify patients at increased risk for multidrug-resistant organisms in bile cultures. ^[170] A 2026 propensity-weighted analysis examined whether intraoperative bile culture improved outcomes or guided antibiotic management in patients undergoing cholecystectomy; its findings questioned the clinical utility of routine culture in that setting. ^[178] Antibiotic decisions should therefore incorporate severity, healthcare exposure, prior procedures, local resistance patterns, and microbiological results when clinically indicated. ^[170][178]