Biliary disease — biliary colic, acute cholecystitis and ascending cholangitis

Biliary disease is a spectrum defined by where in the biliary tree a gallstone obstructs and how the body responds to that obstruction. The Fellowship candidate must hold three distinct conditions in mind at once — biliary colic (transient cystic duct obstruction, self-limiting), acute cholecystitis (sustained cystic duct obstruction with gallbladder inflammation) and acute (ascending) cholangitis (obstruction of the common bile duct with infection and sepsis) — because the disposition, the urgency and the drug doses diverge sharply across them. The emergency task is to place each patient correctly on the spectrum at the bedside, exclude the lethal mimics, and escalate the obstructed septic patient to urgent biliary drainage before organ failure develops.[1][2]

Definition and classification

Biliary colic is symptomatic uncomplicated gallstone disease: a gallstone transiently impacts the cystic duct or Hartmann pouch during a post-prandial gallbladder contraction, generates visceral pain that typically lasts one to six hours, and then dislodges or passes, so the pain resolves spontaneously and there is no gallbladder inflammation or infection. Acute cholecystitis is sustained obstruction of the cystic duct producing gallbladder wall inflammation — chemical and ischaemic injury first, bacterial superinfection second — with fever, right upper quadrant tenderness and a positive Murphy sign. Roughly 90 per cent is calculous (a stone); about 10 per cent is acalculous, arising in the critically ill, the septic, the burned or the fasting patient on total parenteral nutrition, and carrying a much higher rate of gangrene and perforation. Acute cholangitis is bacterial infection of an obstructed bile duct, classically ascending from the duodenum, producing the systemic inflammatory and septic response that defines this as a medical and procedural emergency.[1][2]

The Tokyo Guidelines (TG18) grade severity consistently across the spectrum. Acute cholecystitis is mild (Grade I) when there is no organ dysfunction and no marked local inflammation, moderate (Grade II) when there is marked local inflammation (gangrene, abscess, pericholecystic gas, perforation) or systemic inflammation that does not respond to initial treatment, and severe (Grade III) when there is organ dysfunction requiring supportive care.[2] Acute cholangitis is graded the same way: severe (Grade III) cholangitis is defined by organ dysfunction — cardiovascular (hypotension requiring vasopressors), neurological (disturbed consciousness), respiratory (oxygen required), renal (oliguria or creatinine over 2 mg/dL), hepatic (INR over 1.5) or haematological (platelet count under 100) — and mandates urgent biliary drainage.[1]

Epidemiology and risk

Gallstones are present in 10 to 15 per cent of adults in Western populations; most remain asymptomatic, but each year roughly 1 to 3 per cent of carriers become symptomatic. About 80 per cent of stones are cholesterol stones, formed when bile becomes supersaturated with cholesterol and nucleation occurs in a sluggish gallbladder; the remainder are pigment stones (black, from haemolysis and cirrhosis; brown, from biliary stasis and bacterial infection of bile). The traditional risk profile is captured, loosely, by the five F's. [1]

The clinically useful risk list runs wider than the mnemonic. Rapid weight loss (including post-bariatric surgery), oestrogen therapy and oral contraceptives, terminal ileal disease (Crohn's, resection) impairing bile-salt reabsorption, cirrhosis, total parenteral nutrition, diabetes mellitus, and the haemoglobinopathies (sickle cell, hereditary spherocytosis, thalassaemia) for pigment stones all raise risk. Certain ethnicities — North American Pima Indians, South Americans, Northern Europeans — have markedly higher gallstone prevalence. A family history roughly doubles individual risk. [1]

Pathophysiology

Cholesterol stones form when bile is supersaturated with cholesterol relative to its bile-salt and phospholipid content, and when gallbladder hypomotility allows nucleation into crystals that aggregate into stones. Pigment stones form when unconjugated bilirubin precipitates — classically from chronic haemolysis (black pigment) or from bacterial deconjugation of bilirubin in an obstructed, infected duct (brown pigment). [1]

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In cholecystitis the obstructed gallbladder becomes inflamed through three overlapping mechanisms: chemical injury from concentrated bile and lysolecithin, ischaemic injury from venous and lymphatic obstruction as the wall distends, and bacterial infection in roughly half (Escherichia coli, Klebsiella, Enterococcus, anaerobes). Untreated, the natural history is progression through gangrene (most often at the fundus, the least vascular part), perforation (localised into a pericholecystic abscess, or free into the peritoneum producing biliary peritonitis), and empyema. In cholangitis the raised intraductal pressure forces bacteria-laden bile into the systemic circulation via the hepatic sinusoids and lymphatics, so bacteraemia is common and septic shock develops quickly: blood cultures are positive in roughly a third of patients. [1]

Clinical presentation

Biliary colic presents as severe, gripping right upper quadrant or epigastric pain that begins an hour or two after a meal (classically a fatty meal, through cholecystokinin release), builds to a plateau over minutes to an hour, lasts one to six hours, and then gradually resolves as the stone dislodges. Nausea and vomiting are common. The patient is afebrile, may be writhing during the attack, and is entirely well and non-tender between attacks — the resolution of pain and the absence of fever distinguish it from cholecystitis. Presentation atypical or referral pain to the right scapular tip or interscapular area is common. [1]

Acute cholecystitis begins like colic but the pain does not resolve — it persists beyond six hours, and fever, anorexia, nausea and right upper quadrant tenderness develop. The classic bedside sign is Murphy sign: the examiner's hand is placed at the costal margin in the right upper quadrant, the patient is asked to breathe in deeply, and the sign is positive when inspiration is arrested by pain as the inflamed gallbladder contacts the examining hand; the same manoeuvre on the left is negative. The sensitivity is high but it falls in the elderly, the diabetic and the chronically ill. Mild jaundice may occur from concomitant common-duct stones or from Mirizzi syndrome, but frank jaundice should always raise the question of cholangitis. [1]

Acute cholangitis presents with the Charcot triad — right upper quadrant pain, fever (often with rigors) and jaundice — in roughly 50 to 70 per cent of cases. The full Reynolds pentad adds hypotension and a depressed conscious level and marks severe, suppurative disease. Presentation in the elderly or diabetic is frequently atypical: confusion may be the dominant feature, pain minimal, and fever absent, so any septic patient with obstructive liver enzymes and biliary dilation has cholangitis until proven otherwise. Hypotension, oliguria, a raised lactate and a falling conscious level herald septic shock and demand immediate resuscitation and urgent biliary drainage. [1]

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Differential diagnosis

Right upper quadrant pain overlaps with several lethal and several benign mimics, and the first task is to exclude a perforation, an inferior myocardial infarction, a septic source in the biliary tree and acute pancreatitis before attributing the picture to simple colic. [1]

Other considerations include hepatic abscess (continuing fever, right pleuritic pain, a collection on imaging, often in the immunocompromised or post-biliary-sepsis patient), pyelonephritis or nephrolithiasis (pain radiating to the groin, urinalysis, no jaundice), Fitz-Hugh-Curtis syndrome (perihepatitis from pelvic inflammatory disease — the young woman with RUQ pleuritic pain), acute appendicitis (especially in pregnancy where the appendix is displaced upward), and Mirizzi syndrome (a stone impacted in the cystic duct or Hartmann pouch compressing the common hepatic duct, producing obstructive jaundice with an intact common duct). [1]

Bedside assessment

Begin with airway, breathing and circulation — the patient with ascending cholangitis may be in established septic shock within the first hour of presentation. Give oxygen, attach monitoring, establish two large-bore intravenous cannulae, and obtain intravenous access for fluid and vasoactive drugs. A focused history establishes the pain pattern (onset after food, duration, persistence or resolution), the presence of fever, rigors, jaundice, dark urine and pale stools, and the risk factors (family history, recent weight loss, oestrogen use, known gallstones, haemoglobinopathy). Examination looks for jaundice, the scratch marks of chronic pruritus, right upper quadrant tenderness, a positive Murphy sign, guarding or peritonism (perforation), and signs of chronic liver disease. In the older or diabetic patient, explicitly assess the conscious level and the haemodynamics for the early features of Reynolds pentad. An explicit screen for organ dysfunction — oxygen saturation, respiratory rate, blood pressure, urine output, conscious level and lactate — determines whether this is a ward, high-dependency or intensive-care admission, and whether biliary drainage is an emergency rather than an urgent task. [1]

Investigations

Send blood for a full blood count (leukocytosis in cholecystitis and cholangitis), urea and electrolytes, liver function tests, coagulation, C-reactive protein, amylase or lipase (to exclude pancreatitis), glucose and a venous lactate. The liver function tests are the diagnostic pivot: a predominantly obstructive picture (raised bilirubin, alkaline phosphatase and gamma-glutamyl transferase) with right upper quadrant pain and fever points to a biliary source, while very high aspartate aminotransferase and alanine aminotransferase (in the hundreds or thousands) with obstructive change is "gallstone hepatitis" — a stone lodged at the ampulla — and may precede clinical pancreatitis. Take blood cultures before antibiotics in any febrile or septic patient; they are positive in roughly a third of cholangitis. Check a lipase to exclude pancreatitis, and obtain an ECG and troponin in any older patient with epigastric or right upper quadrant pain to exclude an inferior myocardial infarction. [1]

Abdominal ultrasound is the first-line imaging test for all three conditions. It identifies gallstones (echogenic foci with acoustic shadowing), measures gallbladder wall thickening over 3 mm, detects pericholecystic fluid, elicits a sonographic Murphy sign (maximal tenderness over the sonographically identified gallbladder), and measures the common bile duct diameter (normally up to about 6 mm in the adult, increasing by roughly 1 mm per decade after 60). A duct over 7 mm with jaundice suggests choledocholithiasis. Ultrasound is operator-dependent and limited by bowel gas, but it is fast, bedside-available and radiation-free. Magnetic resonance cholangiopancreatography (MRCP) is the non-invasive test of choice for the common-duct stone when ultrasound is equivocal or the duct is dilated. Computed tomography is reserved for the complicated picture — suspected perforation, empyema, gas in the gallbladder wall (emphysematous cholecystitis), or when the diagnosis is unclear — and for the patient in whom pancreatitis is also suspected. A HIDA scan (hepatobiliary iminodiacetic acid scintigraphy) is the gold standard for suspected acalculous cholecystitis: non-filling of the gallbladder confirms cystic duct obstruction even when no stone is seen. [1]

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Severity grading — the Tokyo Guidelines

The Tokyo Guidelines 2018 (TG18) provide the diagnostic criteria and severity grading used worldwide and in the Fellowship exam.[1][2] The diagnostic criteria for acute cholecystitis require one local sign (Murphy sign, right upper quadrant mass, pain or tenderness), one systemic sign (fever, raised inflammatory marker, raised white cell count) and confirmatory imaging (ultrasound, CT or HIDA). The criteria for acute cholangitis require evidence of systemic inflammation, cholestasis (raised bilirubin, ALP, GGT) and biliary obstruction (dilated duct, stone, stricture) or imaging confirming the cause. Charcot triad alone is no longer required to diagnose, but its presence strongly supports the diagnosis.

For cholecystitis the same three grades apply: mild disease has no organ dysfunction and no marked local complication and settles with supportive care; moderate disease has marked local inflammation (gangrene, abscess, emphysematous change, perforation) and needs early cholecystectomy; severe disease has organ dysfunction demanding intensive care and cholecystostomy or cholecystectomy once stabilised. The operational point for the emergency clinician is identical across both conditions: organ dysfunction defines the severe patient, and the severe patient needs urgent biliary drainage. [1]

Immediate management and resuscitation

The management diverges sharply by diagnosis. Biliary colic is managed with analgesia (paracetamol 1 g orally, or a non-steroidal such as diclofenac 75 mg intramuscularly or ibuprofen 400 mg orally, with an opioid such as morphine 5 to 10 mg intravenously for severe pain), an antiemetic (ondansetron 4 mg intravenously or metoclopramide 10 mg intravenously), and discharge with surgical outpatient follow-up for an elective laparoscopic cholecystectomy. The patient must be warned of the return precautions — new fever, persistent pain, jaundice or dark urine, all of which signal progression to cholecystitis or cholangitis. [1]

Acute cholecystitis is admitted. Give nothing by mouth, establish intravenous access, give intravenous fluids (a balanced crystalloid such as Hartmann solution or Plasma-Lyte, 1 to 1.5 mL per kilogram per hour, titrated to urine output), and provide analgesia (morphine 2.5 to 5 mg intravenously titrated, or fentanyl 50 to 100 micrograms intravenously) and an antiemetic (ondansetron 4 mg intravenously). Start antibiotics as soon as cultures are drawn — the Tokyo Guidelines first-line regimen for mild to moderate disease is ceftriaxone 2 g intravenously once daily plus metronidazole 500 mg intravenously every eight hours.[3] For severe disease, penicillin allergy, or where local resistance is high, escalate to piperacillin-tazobactam 4.5 g intravenously every eight hours, or a carbapenem (meropenem 1 g intravenously every eight hours) in the septic or previously-instrumented patient. The antibiotics cover the typical biliary flora — the Gram-negative aerobes Escherichia coli, Klebsiella and Enterobacter, the Enterococci, and the anaerobes (Bacteroides, Clostridium) when disease is severe or there has been previous biliary surgery.

Acute cholangitis is a resuscitation and drainage emergency. Apply the sepsis six within the first hour: oxygen, two large-bore cannulae, give a 20 to 30 mL per kilogram crystalloid bolus (balanced crystalloid) titrated to mean arterial pressure and urine output, take blood cultures and a lactate before antibiotics, give broad-spectrum antibiotics within the hour (ceftriaxone 2 g intravenously plus metronidazole 500 mg intravenously, or piperacillin-tazobactam 4.5 g intravenously for severe disease), start a noradrenaline infusion for refractory septic shock (titrated to mean arterial pressure over 65 mmHg), and catheterise to monitor urine output. Broad-spectrum antibiotics alone do not relieve the obstruction — the definitive treatment of severe cholangitis is urgent biliary decompression by ERCP, ideally within 12 hours of grade III disease and within 24 to 48 hours of grade II. ERCP achieves sphincterotomy, stone extraction and stent placement across the obstruction, and reduces mortality dramatically. When ERCP fails or is unavailable, percutaneous transhepatic biliary drainage (PTBD) or surgical drainage are the fallback. [1]

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Definitive management and disposition

Biliary colic is referred for an elective laparoscopic cholecystectomy; surgery can be delayed safely, but recurrence is common and roughly 1 to 3 per cent of colic patients develop cholecystitis, cholangitis or pancreatitis each year. A patient with one attack is counselled to return immediately if fever, persistent pain or jaundice develop. [1]

Acute cholecystitis is managed with admission, antibiotics and early laparoscopic cholecystectomy within 72 hours of symptom onset. The Cochrane review of early versus delayed cholecystectomy for acute cholecystitis found that early surgery reduced complications, shortened hospital stay and did not increase conversion to open operation compared with a delayed cholecystectomy weeks later.[4] The 72-hour window matters because beyond it the inflammatory adhesions become dense and the conversion rate rises. For the high-risk surgical candidate — severe comorbidity, advanced age, or the acalculous patient in intensive care — a percutaneous cholecystostomy drains the obstructed gallbladder and deflates the sepsis, with cholecystectomy deferred or avoided entirely. Antibiotics are continued until the systemic inflammation resolves (typically five to seven days) and the patient is fit for surgery.

Acute cholangitis is managed by resuscitation, antibiotics and urgent ERCP. Grade III (severe) cholangitis goes to intensive care with the biliary drain as the central intervention; Grade II is drained early (within 24 to 48 hours); Grade I may settle on antibiotics alone but most centres drain to remove the source. After drainage and recovery, the gallbladder is removed electively if it still contains stones, to prevent recurrence. Acalculous cholecystitis in the critically ill is managed by percutaneous cholecystostomy as the first intervention. Emphysematous cholecystitis (gas in the gallbladder wall, classically in the diabetic older man from Clostridium or gas-forming Gram-negatives) is treated with broad-spectrum antibiotics covering anaerobes and an emergency cholecystectomy because of the high rate of gangrene and perforation. [1]

Complications and pitfalls

Gallbladder complications include gangrene (ischaemic necrosis, most often at the fundus), perforation (localised into a pericholecystic abscess or free into the peritoneum causing biliary peritonitis), empyema (a gallbladder filled with pus — effectively an abscess, treated with drainage), and emphysematous cholecystitis. Biliary-duct complications include cholangitis and gallstone pancreatitis (a stone obstructing the ampulla, often after passing through the cystic duct). Two rarer phenomena are exam favourites: Mirizzi syndrome, in which a stone impacted in the cystic duct or Hartmann pouch externally compresses the common hepatic duct to cause obstructive jaundice, and gallstone ileus, in which a large stone erodes through a cholecystoduodenal fistula and lodges at the terminal ileum causing small-bowel obstruction — the Rigler triad of pneumobilia, small-bowel obstruction and an ectopic gallstone on imaging makes the diagnosis. [1]

The common pitfalls invert good care. Treating persistent fever and tenderness as biliary colic misses cholecystitis. Drawing blood cultures after antibiotics lowers the yield and removes the microbiological guide. Delaying ERCP in severe cholangitis while waiting for the gastroenterology review kills patients — organ dysfunction mandates drainage within hours. Missing an inferior myocardial infarction in the older patient with epigastric pain and gallstones is avoided by an ECG on every such patient. Missing acalculous cholecystitis in the intensive-care patient with sepsis of unknown source is avoided by ultrasound (and HIDA when the picture is equivocal) in any ventilated patient with new fever and right upper quadrant collection. Overlooking emphysematous cholecystitis in the diabetic delays emergency surgery. [1]

Prognosis and disposition

Biliary colic is benign — discharge with elective surgical referral and return precautions. Acute cholecystitis settles on antibiotics and early cholecystectomy in over 95 per cent of cases; mortality is under 1 per cent in the otherwise well, rising in the elderly and the acalculous intensive-care patient. Acute cholangitis carries a mortality that rises sharply with severity — modern series report overall mortality around 2 to 5 per cent but up to 10 to 30 per cent in severe disease with organ dysfunction, and the single intervention that transforms outcome is timely biliary drainage.[1] Disposition follows severity: biliary colic to home; mild to moderate cholecystitis to a surgical ward with a plan for early cholecystectomy; severe cholecystitis or any cholangitis with organ dysfunction to high-dependency or intensive care with the drainage pathway activated.

Special populations

Pregnancy: biliary colic and cholecystitis are common in pregnancy because of the oestrogen-driven rise in biliary cholesterol. The first episode of colic is managed conservatively; recurrent symptomatic disease or cholecystitis in the second trimester is treated with laparoscopic cholecystectomy, which is safe in pregnancy and preferable to the risks of progression to pancreatitis or preterm labour from ongoing sepsis. The elderly present atypically — confusion rather than localised pain, minimal fever, an unremarkable white cell count — and tolerate untreated sepsis poorly; a high index, early imaging and early drainage are essential. Acalculous cholecystitis is more common in this group. The critically ill patient (sepsis, burns, major surgery, trauma, prolonged fasting, total parenteral nutrition) develops acalculous cholecystitis from gallbladder ischaemia and stasis; ultrasound or HIDA confirms, and percutaneous cholecystostomy is the first intervention. The diabetic is at particular risk of emphysematous cholecystitis and of severe, rapidly progressive infection. Children with gallstones usually have an underlying cause — haemolytic disease (sickle cell, spherocytosis), a biliary anomaly, or total parenteral nutrition — and are managed along the same algorithm. [1]

Evidence and regional guidelines

The contemporary framework is the Tokyo Guidelines 2018 (TG18), which unified the diagnostic criteria and severity grading for acute cholecystitis and cholangitis, codified the antibiotic regimens by severity, and formalised the timing of biliary drainage (urgent for severe, early for moderate).[1][2][3] The practice-defining surgical evidence is the Cochrane review of early versus delayed laparoscopic cholecystectomy for acute cholecystitis, which established that surgery within the first 72 hours reduces complications and length of stay without raising the conversion rate.[4] The WSES 2022 guidelines for acute calculous cholecystitis reinforce the same principles, and the NICE (United Kingdom) guideline on gallstone disease endorses early laparoscopic cholecystectomy and risk-stratifies the surgical candidate. Across all guidelines, the three fixed points are: biliary colic is managed electively; acute cholecystitis is admitted, given antibiotics and operated early; and acute cholangitis is resuscitated, given antibiotics and drained urgently.

Resuscitation and drainage pathways

The two time-critical pathways — cholangitis and cholecystitis — converge on the same principle: relieve the obstruction. The flowcharts below encode the Tokyo Guidelines 2018 initial management sequence and the Surviving Sepsis Campaign hour-1 bundle.[5][6]

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Pharmacology in depth — antibiotic selection

The biliary tree is colonised by enteric Gram-negatives and enterococci, with anaerobes joining when disease is severe, gangrenous or post-instrumentation. The Tokyo Guidelines 2018 stratify empiric therapy by severity, local resistance and allergy.[3] The aim is to cover Escherichia coli, Klebsiella, Enterobacter and Enterococcus, adding anaerobic cover (Bacteroides, Clostridium) for severe, complicated or healthcare-associated infection.

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Drainage and source control

Definitive treatment of any obstructed biliary tree is to relieve the obstruction. The modality depends on where the stone sits, the patient's stability, and what is locally available.[1][5]

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Landmark trial evidence

The Fellowship candidate must be able to quote the trials that define modern biliary practice — the diagnostic and severity framework (Tokyo Guidelines), the timing of surgery (Cochrane), the resuscitation standard (Surviving Sepsis Campaign) and the contemporary synthesis of grey areas.[1][2][3][4][6][7]

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High-yield bedside and exam pearls

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Exam pearls

• The spectrum in one line: colic is transient cystic duct obstruction and self-limiting; cholecystitis is sustained obstruction with fever and a positive Murphy sign; cholangitis is an obstructed infected duct with Charcot triad or Reynolds pentad.
• Charcot triad is right upper quadrant pain, fever (often with rigors) and jaundice; Reynolds pentad adds hypotension and confusion. The full pentad marks severe suppurative cholangitis.
• Murphy sign is inspiratory arrest on right upper quadrant palpation — high sensitivity for cholecystitis, lower in the elderly and diabetic.
• Ultrasound criteria: stones, wall over 3 mm, pericholecystic fluid, sonographic Murphy, gallbladder distension. A common duct over 6 to 7 mm with jaundice suggests a retained stone.
• Antibiotics for cholecystitis and mild cholangitis: ceftriaxone 2 g IV daily plus metronidazole 500 mg IV every eight hours (TG18 first line). Escalate to piperacillin-tazobactam 4.5 g IV every eight hours for severe disease.
• Acute cholecystitis: admit, NBM, fluids, analgesia, antibiotics, and early laparoscopic cholecystectomy within 72 hours — the Cochrane evidence shows fewer complications and shorter stay, no rise in conversion.
• Severe cholangitis is defined by organ dysfunction and is treated with urgent ERCP within hours, not a routine gastroenterology review.
• Antibiotics do not cure an obstructed infected duct — drainage is the definitive treatment.
• Gallstone hepatitis — AST and ALT in the hundreds or thousands with obstructive change — is a stone at the ampulla, and may precede pancreatitis.
• Emphysematous cholecystitis (gas in the wall, usually diabetic) needs broad-spectrum antibiotics covering anaerobes and emergency cholecystectomy.
• Always do an ECG in epigastric or right upper quadrant pain in the older patient — inferior myocardial infarction is the lethal mimic.
• Mirizzi syndrome and gallstone ileus (Rigler triad of pneumobilia, small-bowel obstruction, ectopic gallstone) are the classic exam rarer presentations. [1]

Exam practice

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Red flags

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References

1. [1]Kiriyama S, Kozaka K, Takada T, et al. Tokyo Guidelines 2018: diagnostic criteria and severity grading of acute cholangitis (with videos) J Hepatobiliary Pancreat Sci, 2018.PMID 29032610
2. [2]Yokoe M, Hata J, Takada T, et al. Tokyo Guidelines 2018: diagnostic criteria and severity grading of acute cholecystitis (with videos) J Hepatobiliary Pancreat Sci, 2018.PMID 29032636
3. [3]Gomi H, Solomkin JS, Takada T, et al. Tokyo Guidelines 2018: antimicrobial therapy for acute cholangitis and cholecystitis J Hepatobiliary Pancreat Sci, 2018.PMID 29090866
4. [4]Gurusamy KS, Davidson C, Gluud C, Davidson BR. Early versus delayed laparoscopic cholecystectomy for people with acute cholecystitis Cochrane Database Syst Rev, 2013.PMID 23813477
5. [5]Miura F, Okamoto K, Takada T, et al. Tokyo Guidelines 2018: initial management of acute biliary infection and flowchart for acute cholangitis J Hepatobiliary Pancreat Sci, 2018.PMID 28941329
6. [6]Evans L, Rhodes A, Alhazzani W, et al. Executive Summary: Surviving Sepsis Campaign: International Guidelines for the Management of Sepsis and Septic Shock 2021 Crit Care Med, 2021.PMID 34643578
7. [7]Fugazzola P, Podda M, Tian BW, et al. Clinical update on acute cholecystitis and biliary pancreatitis: between certainties and grey areas EClinicalMedicine, 2024.PMID 39469538