Changes

July 2021 — reviewed. A literature search was conducted in June 2021 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials published since the last revision of the topic. No changes to clinical recommendations have been made.

Update

Goals

To support primary healthcare professionals to:

• Assess a person with suspected acute cholecystitis.
• Refer a person with suspected acute cholecystitis to secondary care for confirmation of the diagnosis and management.

Outcome measures

Audit criteria

QOF indicators

QIPP - Options for local implementation

No QIPP indicators were found during the review of this topic.

NICE quality standards: Gallstone disease

• Adults with acute cholecystitis have laparoscopic cholecystectomy within 1 week of diagnosis.
• Adults with common bile duct stones causing jaundice have endoscopic retrograde cholangiopancreatography within 72 hours of diagnosis.
• Adults with common bile duct stones who need emergency endoscopic retrograde cholangiopancreatography have it within 24 hours.
• Adults with symptomatic gallstone disease who have not had their gallbladder or gallstones removed are advised to avoid food and drink that triggers their symptoms.

[NICE, 2015]

What is it?

• Acute cholecystitis is an inflammation of the gallbladder. It usually occurs when a gallstone completely obstructs the gallbladder neck or cystic duct [Kimura, 2013; BMJ, 2020].
• Pathological classifications of acute cholecystitis include [Kimura, 2013] [BMJ, 2020]:
  • Oedematous cholecystitis — occurs after 2–4 days of obstruction. The gallbladder tissue is intact histologically, with oedema in the subserosal layer. 
  • Necrotizing cholecystitis — occurs after 3–5 days of obstruction and is characterized by oedematous changes in the gallbladder, with areas of haemorrhage and necrosis. Necrosis does not involve the full thickness of the gall bladder wall. 
  • Suppurative cholecystitis — occurs after 7–10 days of obstruction and is characterized by thickened gallbladder wall with white cell infiltration, intra-wall abscesses, and necrosis. May result in perforation of the gallbladder and a pericholecystic abscess formation. 
  • Chronic cholecystitis — occurs after repeated episodes of mild attacks and is characterized by mucosal atrophy and fibrosis of the gallbladder wall. Acute-on-chronic cholecystitis refers to an acute infection that has occurred in chronic cholecystitis.
• Acalculous cholecystitis is inflammation of the gallbladder which occurs in the absence of gallstones [Balmadrid, 2018] [BMJ, 2020]. It typically occurs in critically ill people due to a combination of risk factors.

What causes it?

• Gallstones account for 90–95% of cases of acute cholecystitis [Indar, 2002] [Kimura, 2013] [BMJ, 2020] [Bloom, 2021]. 
  • Obstruction of the gallbladder neck or cystic duct by a gallstone causes bile to become trapped in the gallbladder, resulting in irritation and increased pressure in the gallbladder. 
  • If the obstruction is partial and of short duration, the person experiences biliary colic, characterized by severe pain and tenderness of the right side of the abdomen and/or back). Acute cholecystitis occurs when the obstruction is complete and prolonged (usually several hours).
  • Trauma caused by the gallstone stimulates the release of prostaglandins, which mediates the inflammatory response. 
  • As the gallbladder becomes more distended and inflamed, blood flow and lymphatic drainage are compromised, leading to mucosal ischemia [Bloom, 2021]. Secondary bacterial infection of the bile may occur [Indar, 2002].
  • Continued inflammation, ischemia, and/or infection can result in necrosis and gallbladder perforation.
• Acalculous cholecystitis (gallbladder inflammation without gallstones) is seen in about 5–14% of people who present with acute cholecystitis [Balmadrid, 2018; BMJ, 2020]. 
  • The exact cause is poorly understood. However, functional cystic duct obstruction is often present and is associated with bile stasis or thickening.
  • It typically occurs in critically ill people due to a combination of risk factors that result in bile stasis (such as trauma, severe systemic illness, and prolonged total parenteral nutrition use) or bile thickening (such as fever and dehydration).
  • Other factors may be involved, such as a predisposition to bacterial colonization of static gallbladder bile.

What are the risk factors?

• Gallstones account for 90–95% of cases of acute cholecystitis [Indar, 2002] [Kimura, 2013] [BMJ, 2020] [Bloom, 2021]. 
  • Risk factors for gallstones include increasing age, female gender, obesity, and a low fibre diet. 
  • See the sections on Causes and Risk factors in the CKS topic on Gallstones for more information.
• Acalculous cholecystitis typically occurs in critically ill people due to a combination of factors that result in bile stasis (due to gallbladder hypomotility/dysmotility) or bile thickening (due to dehydration) [Balmadrid, 2018] [BMJ, 2020] [Bloom, 2021].
  • Conditions associated with biliary stasis or thickening include:
    
    • Sepsis.
    • Extensive trauma.
    • Burns.
    • Major surgery.
    • Prolonged fasting or starvation.
    • Prolonged total parenteral nutrition use.
  • Other risk factors for acalculous cholecystitis include:
    • Diabetes, end-stage renal disease, congestive heart failure/coronary artery disease, and peripheral vascular disease.
    • Drug treatments, for example cyclosporin, can decrease bile acid secretion, leading to sludge formation. Ceftriaxone is secreted into bile and can precipitate with calcium, forming biliary sludge.
    • Infection, such as Epstein-Barr virus (EBV) infection. In people who are HIV positive, cholangiopathy due to infection with microsporidia species can occur.

How common is it?

• The estimated overall prevalence of gallstones (the most common cause of acute cholecystitis) is 10–15% in the general population, with some differences across countries [Pisano, 2020].
  • Most people with gallstones are asymptomatic.
  • About 1–3% of people with asymptomatic gallstones become symptomatic each year. Acute cholecystitis occurs in 10–15% of these people [BMJ, 2020; Pisano, 2020].
  • Acute cholecystitis is three times more common in women than in men up to the age of 50 years, and about 1.5 times more common in women than in men thereafter [BMJ, 2020].
• Acalculous cholecystitis accounts for 5–14% of cases of acute cholecystitis [Balmadrid, 2018] [BMJ, 2020]. It typically occurs in critically ill people due to a combination of risk factors.

What are the complications?

• Without treatment, acute cholecystitis may resolve spontaneously within 1–7 days. However, 25–30% of people will require surgery or develop complications, such as [Kimura, 2013; BMJ, 2020; Bloom, 2021]:
  
  • Necrosis of the gallbladder wall (gangrenous cholecystitis).
  • Perforation of the gallbladder — occurs in about 10% of people with acute cholecystitis and has a mortality rate of up to 30% [BMJ, 2020]. 
  • Biliary peritonitis — occurs with the entry into the peritoneal cavity of bile leakage due to various causes, including cholecystitis-induced gallbladder perforation.
  • Pericholecystic abscess — perforation of the gallbladder wall is covered by the surrounding tissues along with the formation of abscesses around the gallbladder.
  • Fistula (between the gallbladder and duodenum) — usually caused by a large gallbladder stone eroding through the wall of the gallbladder into the duodenum. If the stone is large in size, the person can develop gallstone ileus with the stone causing mechanical small bowel obstruction at the ileocecal valve.
  • Jaundice — occurs in up to 10% of people with cholecystitis and may be due to biliary tract inflammation and oedema, pressure from a distended gallbladder, or a stone in the common bile duct or impacted in the gallbladder neck (Mirizzi's syndrome).
  • Sepsis — could develop if there is superimposed bacterial infection.
• The mortality rate of acalculous cholecystitis ranges from 10–50% (which is much higher than the expected 4% mortality observed in people with acute cholecystitis). In people who are critically ill with acalculous cholecystitis and perforation or gangrene, mortality can be as high as 50–60% [Bloom, 2021].

When should I suspect acute cholecystitis?

• Suspect acute cholecystitis if a person presents with:
  • Sudden-onset, constant, severe pain in the upper right quadrant, lasting several hours.
  • Tenderness, with or without guarding, in the right upper quadrant.
• If acute cholecystitis is suspected, assess the person to:
  
  • Identify other symptoms and signs of acute cholecystitis.
  • Identify risk factors for acute cholecystitis and acute acalculous cholecystitis. 
  • Exclude differential diagnoses, such as gallstones and peptic ulcer disease.
  • Identify complications, such as an abscess, perforated gallbladder, sepsis, and jaundice.

How should I assess a person with suspected acute cholecystitis?

• Take a detailed history. 
  • Ask about the nature of the pain.
    • A constant pain present for several hours is consistent with acute cholecystitis. The duration of pain can be shorter if the gallstone returns into the gallbladder lumen or passes into the duodenum.
    • The pain is severe, steady, and may radiate to the back.
    • Referred pain from the gallbladder may be felt in the right shoulder or interscapular region.
  • Ask about the presence of other symptoms, such as:
    • Fever/chills — may be present as a symptom of infection. 
    • Nausea  — can occur in conjunction with severe pain and can be a prominent symptom of a stone in the common bile duct.
    • Vomiting — sometimes associated with biliary disease but not specific for cholecystitis. It can be a prominent symptom of a stone in the common bile duct.
    • Anorexia — associated with biliary disease but not specific for cholecystitis.
  • Ask about current or previous episodes of gallstones or biliary colic.
    • Over 90% of people with acute cholecystitis have gallstones. See the CKS topic on Gallstones for more information.
    • About 50% of the people who have had one episode of biliary pain will have another within 12 months.
  • Ask about the presence of risk factors for acalculous cholecystitis, such as recent severe illness or trauma.
• Perform a physical examination.
  • Look for signs of sepsis, such as extreme pain, mottled skin, fever or reduced core temperature, rigors or chills, and/or shortness of breath.
    • Suspect sepsis based on acute deterioration in a person in whom there is clinical evidence or strong suspicion of infection.
    • The person may present with non-specific or non-localized symptoms (such as being acutely unwell with a normal temperature) or there may be severe signs with evidence of multi-organ dysfunction and shock. 
    • If sepsis is suspected, see the section on Management in the CKS topic on Sepsis for more information. 
  • Examine the person's abdomen. Palpate for:
    • Right upper quadrant tenderness.
    • Right upper quadrant mass — a distended, tender gallbladder may be palpable as a distinct mass in 30–40% of people.
    • Presence of Murphy’s sign (inspiration is inhibited by pain on palpitation when the examiner's hand is positioned along the costal margin). Be aware that Murphy's sign is unreliable in older adults and is difficult to elicit in people who are critically ill.
  • Look for other signs of complication, such as:
    
    • Jaundice — occurs in up to 10% of people with cholecystitis and may be due to biliary tract inflammation and oedema, pressure from a distended gallbladder, or a stone in the common bile duct or impacted in the gallbladder neck (Mirizzi's syndrome).
    • Abscess formation and/or gallbladder perforation — the person may present with persistent fever, a palpable mass, severe localized and/or generalized pain/tenderness.
  • Acalculous cholecystitis can present with fever, jaundice, and abdominal tenderness and is usually a diagnosis of exclusion. It often occurs in critically ill people.
• See the section on Management for information on managing people with suspected acute cholecystitis.

What else might it be?

• Differential diagnoses of acute cholecystitis include: 
  • Acute cholangitis — presents with jaundice, fever, chills, and abdominal pain.
  • Acute coronary syndrome — see the CKS topic on Chest pain for more information.
  • Acute pancreatitis — see the CKS topic on Pancreatitis - acute for more information.
  • Appendicitis — see the CKS topic on Appendicitis for more information.
  • Gastrointestinal cancer — see the CKS topic on Gastrointestinal tract (upper) cancers - recognition and referral for more information.
  • Gastro-oesophageal reflux disease — see the CKS topic on Dyspepsia - proven GORD for more information.
  • Hepatitis — see the CKS topics on Hepatitis A, Hepatitis B, and Hepatitis C for more information.
  • Peptic ulcer disease — see the CKS topic on Dyspepsia - proven peptic ulcer for more information.
  • Right lower lobe pneumonia — see the CKS topic on Chest infections - adult for more information.
  • Symptomatic gallstones — see the CKS topic on Gallstones for more information.

Scenario: Management

From age 18 years onwards.

Search strategy

Scope of search

A literature search was conducted for guidelines, systematic reviews and randomized controlled trials on primary care management of acute cholecystitis.

Search dates

October 2016 - April 2021

Key search terms

Various combinations of searches were carried out. The terms listed below are the core search terms that were used for Medline.

• exp Cholecystitis, Acute/
• (acute ADJ cholecystitis).tw.
• Acute acalculous cholecystitis.ti,ab
• Acute cholecystitis.kw

Sources of guidelines

• National Institute for Health and Care Excellence (NICE)
• Scottish Intercollegiate Guidelines Network (SIGN)
• Royal College of Physicians
• Royal College of General Practitioners
• Royal College of Nursing
• NICE Evidence
• World Health Organization
• Guidelines International Network
• TRIP database
• Agency for Healthcare Research and Quality
• Institute for Clinical Systems Improvement
• National Health and Medical Research Council (Australia)
• Royal Australian College of General Practitioners
• British Columbia Medical Association
• Canadian Medical Association
• Alberta Medical Association
• Michigan Quality Improvement Consortium
• Singapore Ministry of Health
• National Resource for Infection Control
• RefHELP NHS Lothian Referral Guidelines
• Medline (with guideline filter)
• Driver and Vehicle Licensing Agency
• NHS Health at Work (occupational health practice)

Sources of systematic reviews and meta-analyses

• The Cochrane Library:
  • Systematic reviews
  • Protocols
  • Database of Abstracts of Reviews of Effects
• Medline (with systematic review filter)
• EMBASE (with systematic review filter)

Sources of health technology assessments and economic appraisals

• NIHR Health Technology Assessment programme
• The Cochrane Library:
  • NHS Economic Evaluations
  • Health Technology Assessments
• Canadian Agency for Drugs and Technologies in Health
• International Network of Agencies for Health Technology Assessment

Sources of randomized controlled trials

• The Cochrane Library:
  • Central Register of Controlled Trials
• Medline (with randomized controlled trial filter)
• EMBASE (with randomized controlled trial filter)

Sources of evidence based reviews and evidence summaries

• Bandolier
• Drug and Therapeutics Bulletin
• TRIP database
• Central Services Agency COMPASS Therapeutic Notes

Sources of national policy

• Department of Health
• Health Management Information Consortium (HMIC)

Patient experiences

• Healthtalk
• BMJ - Patient Journeys

Sources of medicines information

The following sources are used by CKS pharmacists and are not necessarily searched by CKS information specialists for all topics. Some of these resources are not freely available and require subscriptions to access content.

• British National Formulary (BNF)
• electronic Medicines Compendium (eMC)
• European Medicines Agency (EMEA)
• LactMed
• Medicines and Healthcare products Regulatory Agency (MHRA)
• REPROTOX
• Scottish Medicines Consortium
• Stockley's Drug Interactions
• TERIS
• TOXBASE
• Micromedex
• UK Medicines Information

Stakeholder engagement

Our policy

The external review process is an essential part of CKS topic development. Consultation with a wide range of stakeholders provides quality assurance of the topic in terms of:

• Clinical accuracy.
• Consistency with other providers of clinical knowledge for primary care.
• Accuracy of implementation of national guidance (in particular NICE guidelines).
• Usability.

Principles of the consultation process

• The process is inclusive and any individual may participate.
• To participate, an individual must declare whether they have any competing interests or not. If they do not declare whether or not they have competing interests, their comments will not be considered.
• Comments received after the deadline will be considered, but they may not be acted upon before the clinical topic is issued onto the website.
• Comments are accepted in any format that is convenient to the reviewer, although an electronic format is encouraged.
• External reviewers are not paid for commenting on the draft topics.
• Discussion with an individual or an organization about the CKS response to their comments is only undertaken in exceptional circumstances (at the discretion of the Clinical Editor or Editorial Steering Group).
• All reviewers are thanked and offered a letter acknowledging their contribution for the purposes of appraisal/revalidation.
• All reviewers are invited to be acknowledged on the website. All reviewers are given the opportunity to feedback about the external review process, enabling improvements to be made where appropriate.

Stakeholders

• Key stakeholders identified by the CKS team are invited to comment on draft CKS topics. Individuals and organizations can also register an interest to feedback on a specific topic, or topics in a particular clinical area, through the Getting involved section of the Clarity Informatics website.
• Stakeholders identified from the following groups are invited to review draft topics:
  • Experts in the topic area.
  • Professional organizations and societies (for example, Royal Colleges).
  • Patient organizations, Clarity has established close links with groups such as Age UK and the Alzheimer’s Society specifically for their input into new topic development, review of current topic content and advice on relevant areas of expert knowledge.
  • Guideline development groups where the topic is an implementation of a guideline.
  • The British National Formulary team.
  • The editorial team that develop MeReC Publications.
• Reviewers are provided with clear instructions about what to review, what comments are particularly helpful, how to submit comments, and declaring interests.

Patient engagement

Clarity Informatics has enlisted the support and involvement of patients and lay persons at all stages in the process of creating the content which include:

• Topic selection
• Scoping of topic
• Selection of clinical scenarios
• First draft internal review
• Second draft internal review
• External review
• Final draft and pre-publication

Our lay and patient involvement includes membership on the editorial steering group, contacting expert patient groups, organizations and individuals.

Evidence exclusion criteria

Our policy

Scoping a literature search, and reviewing the evidence for CKS is a methodical and systematic process that is carried out by the lead clinical author for each topic. Relevant evidence is gathered in order that the clinical author can make fully informed decisions and recommendations. It is important to note that some evidence may be excluded for a variety of reasons. These reasons may be applied across all CKS topics or may be specific to a given topic.

Studies identified during literature searches are reviewed to identify the most appropriate information to author a CKS topic, ensuring any recommendations are based on the best evidence. We use the principles of the GRADE and PICOT approaches to assess the quality of published research. We use the principles of AGREE II to assess the quality of published guidelines.

Standard exclusions for scoping literature:

• Animal studies
• Original research is not written in English

Possible exclusions for reviewed literature:

• Sample size too small or study underpowered
• Bias evident or promotional literature
• Population not relevant
• Intervention/treatment not relevant
• Outcomes not relevant
• Outcomes have no clear evidence of clinical effectiveness
• Setting not relevant
• Not relevant to UK
• Incorrect study type
• Review article
• Duplicate reference

Organizational, behavioural and financial barriers

Our policy

The CKS literature searches take into consideration the following concepts, which are discussed at the initial scoping of the topic.

• Feasibility
  • Studies are selected depending on whether the intervention under investigation is available in the NHS and can be practically and safely undertaken in primary care.
• Organizational and Financial Impact Analysis
• Studies are selected and evaluated on whether the intervention under investigations may have an impact on local clinical service provision or national impact on cost for the NHS. The principles of clinical budget impact analysis are adhered to, evaluated and recorded by the author. The following factors are considered when making this assessment and analysis.
  • Eligible population
  • Current interventions
  • Likely uptake of new intervention or recommendation
  • Cost of the current or new intervention mix
  • Impact on other costs
  • Condition-related costs
  • In-direct costs and service impacts
  • Time dependencies
• Cost-effectiveness or cost-benefit analysis studies are identified where available. 

We also evaluate and include evidence from NICE accredited sources which provide economic evaluations of recommendations, such as NICE guidelines. When a recommended action may not be possible because of resource constraints, this is explicitly indicated to healthcare professionals by the wording of the CKS recommendation.

Declarations of interest

Our policy

Clarity Informatics requests that all those involved in the writing and reviewing of topics, and those involved in the external review process to declare any competing interests. Signed copies are securely held by Clarity Informatics and are available on request with the permission of the individual. A copy of the declaration of interest form which participants are asked to complete annually is also available on request. A brief outline of the declarations of interest policy is described here and full details of the policy is available on the Clarity Informatics website. Declarations of interests of the authors are not routinely published, however competing interests of all those involved in the topic update or development are listed below. Competing interests include:

• Personal financial interests
• Personal family interest
• Personal non-financial interest
• Non-personal financial gain or benefit

Although particular attention is given to interests that could result in financial gains or losses for the individual, competing interests may also arise from academic competition or for political, personal, religious, and reputational reasons. An individual is not obliged to seek out knowledge of work done for, or on behalf of, the healthcare industry within the departments for which they are responsible if they would not normally expect to be informed.

Who should declare competing interests?

Any individual (or organization) involved in developing, reviewing, or commenting on clinical content, particularly the recommendations should declare competing interests. This includes the authoring team members, expert advisers, external reviewers of draft topics, individuals providing feedback on published topics, and Editorial Steering Group members. Declarations of interest are completed annually for authoring team and editorial steering group members, and are completed at the start of the topic update and development process for external stakeholders.

Competing interests declared for this topic:

None.