Chronic Cholecystitis

Etiology

Under normal conditions, bile produced in the liver flows through the hepatic ducts into the common hepatic duct. Bile may then enter the gallbladder through the cystic duct for storage or continue through the common bile duct into the duodenum through the ampulla of Vater. After food ingestion, particularly after high-fat meals, cholecystokinin stimulates gallbladder contraction. The gallbladder releases bile through the cystic duct and common bile duct into the duodenum, where bile facilitates fat emulsification and absorption.[1] Chronic cholecystitis occurs when intermittent obstruction of the cystic duct develops, usually because of gallstones. The condition is more commonly seen in patients with recurrent biliary colic or recurrent episodes of acute cholecystitis that have not been treated with cholecystectomy. Some patients have mild chronic symptoms and may not seek medical care until symptoms worsen.

Epidemiology

The epidemiology of chronic cholecystitis generally parallels that of cholelithiasis. Gallstone disease is very common.[2] Approximately 10% to 20% of the global population will develop gallstones during their lifetime, and about 80% of gallstones are asymptomatic.[3] Each year, more than 500,000 cholecystectomies are performed in the US for gallbladder disease.

The incidence of gallstone formation increases with age. Furthermore, obesity increases the likelihood of gallstones, especially in women, due to increased biliary cholesterol secretion. Risk also increases with drastic weight loss or fasting because of biliary stasis.[4][5] Notably, gallstones are associated with hormones. Results from studies showed that estrogen increases bile cholesterol and decreases gallbladder contractility. Women of reproductive age or who use estrogen-containing contraceptives have a 2-fold increase in gallstone formation compared with men. Additionally, people with chronic illnesses such as diabetes mellitus also have an increased risk of gallstone formation and reduced gallbladder wall contractility due to neuropathy.[6]

Pathophysiology

Occlusion of the cystic duct or malfunction of gallbladder emptying mechanics is the underlying pathology of this disease. More than 90% of cases of chronic cholecystitis are associated with gallstones.[2] Gallstones cause intermittent obstruction of bile flow through the cystic duct, leading to inflammation and edema of the gallbladder wall. Occlusion of the common bile duct, such as by neoplasms or strictures, can also lead to bile stasis, which can cause gallstone formation.[7]

Researchers have proposed that lithogenic bile leads to increased free radical–mediated damage from hydrophobic bile salts. This process, together with reduced mucosal protection due to lower prostaglandin E2 levels, results in a continuous inflammatory state. When cholecystokinin receptors in the smooth muscle are affected, gallbladder contraction is impaired, leading to stasis and worsening of the permissive environment in which lithogenic bile promotes inflammation.[8]

Histopathology

The gallbladder wall may be thickened to variable degrees, and adhesions may involve the serosal surface. In some cases, extensive fibrosis may cause the gallbladder to appear shrunken. Smooth muscle hypertrophy may be present and more pronounced in prolonged chronic conditions. Additionally, calcium bilirubinate or cholesterol stones are most common and can range in size from sand-like particles or sludge to stones that completely fill the gallbladder lumen. These stones may be multiple or single. Interestingly, normal-appearing bile can also be present. Finally, various bacterial species can be found in 11% to 30% of cases.

Rokitansky-Aschoff sinuses are present or accentuated in 90% of chronic cholecystitis specimens. Rokitansky-Aschoff sinuses represent herniations of intraluminal sinuses from increased pressure, possibly associated with the ducts of Luschka. Furthermore, the mucosa may exhibit varying degrees of inflammation. T lymphocytes are the predominant cells, followed by plasma cells and histiocytes. Moreover, metaplastic changes may be present. Notably, hypertrophy of the muscularis mucosa is usually present, with varying degrees of mural fibrosis and elastosis. A variant in which calcium deposition and hyaline fibrosis lead to diffuse thinning of the gallbladder wall is called hyalinizing cholecystitis. The brittle consistency and hyperdense appearance on advanced imaging also give hyalinizing cholecystitis the name porcelain gallbladder (see Image. Porcelain Gallbladder).[9]

History and Physical

Patients with symptomatic chronic cholecystitis usually present with dull right upper quadrant abdominal pain or epigastric pain that may radiate around the waist to the midback or right scapular tip. High-fat foods may exacerbate the pain, but the classic prolonged postprandial pain of acute cholecystitis is less common. Nausea and occasional vomiting also accompany concerns about increased bloating and flatulence.

The symptoms often occur in the evening or at night, and are usually present for weeks to months in contrast to the abrupt, severe presentation of acute cholecystitis. Symptoms may gradually worsen, or episodes may increase in frequency. Furthermore, fever and tachycardia are rare. Older adults with cholecystitis may present with nonspecific symptoms, and they are at risk of progression to acute or complicated disease, such as cholecystoduodenal fistula formation. Clinicians need a high index of clinical suspicion to diagnose this condition in this population.

Evaluation

Laboratory testing is neither specific nor sensitive for diagnosing chronic cholecystitis. Leukocytosis and abnormal liver function test results may be absent in these patients, unlike in acute disease. However, basic laboratory testing, including a metabolic panel, liver function tests, and a complete blood count, should be performed. Cardiac testing, including electrocardiography and troponin testing, should be considered in the appropriate clinical setting.

The diagnostic test of choice when chronic cholecystitis is suspected clinically is right upper quadrant ultrasonography. This noninvasive study, which is readily available in most facilities, can accurately evaluate for a thickened gallbladder wall or signs of inflammation. Right upper quadrant ultrasonography also aids in evaluating gallstones or sludge. Computed tomography with intravenous contrast usually reveals cholelithiasis, increased bile attenuation, and gallbladder wall thickening. The gallbladder itself may appear distended or contracted; however, pericholecystic inflammation and fluid collection are usually absent in chronic disease.[10] A distended gallbladder and increased enhancement of adjacent hepatic tissue favor findings of acute cholecystitis, whereas hyperenhancement of the gallbladder wall is more commonly seen in chronic disease.[11] Given the overlap in findings between acute and chronic cholecystitis, ultrasonography and CT are generally sufficient to confirm the diagnosis.[12] 

An MRI study is a useful alternative in patients who are unable to undergo a CT scan due to radiation concerns or renal disease.[13] The diagnostic test of choice to confirm chronic cholecystitis is hepatobiliary scintigraphy (HIDA) with cholecystokinin. The most common scintigraphic findings are delayed gallbladder visualization (between 1 and 4 hours) and delayed increase in biliary-to-bowel transit time.[14] The tracer is injected intravenously and concentrates in the gallbladder. Cholecystokinin is then administered, and the percentage of gallbladder emptying (ejection fraction) is calculated. An ejection fraction less than 35% at the 15-min cutoff is considered evidence of a dyskinetic gallbladder and is suggestive of chronic cholecystitis.

Treatment / Management

The preferred treatment for chronic cholecystitis is elective laparoscopic cholecystectomy. Laparoscopic cholecystectomy has a low morbidity rate and can be performed as an outpatient surgical procedure. An open cholecystectomy is rarely required but can be used when laparoscopic cholecystectomy cannot be performed. Endoscopic retrograde cholangiopancreatography is usually performed when choledocholithiasis is suspected. Patients with suspected choledocholithiasis usually undergo endoscopic retrograde cholangiopancreatography before elective cholecystectomy.

Patients who are not surgical candidates or who prefer not to undergo a surgical procedure can be closely observed and treated conservatively. A low-fat diet can help reduce the frequency of symptoms. In patients with symptomatic cholelithiasis, Results from studies showed that the use of ursodeoxycholic acid or ursodiol reduced the rates of biliary colic and acute cholecystitis.[15] However, the literature on its role in chronic cholecystitis is limited. The treatment of asymptomatic patients with incidentally detected chronic cholecystitis depends on patient characteristics. Asymptomatic patients with no radiographic or clinical concerns for malignant neoplasm can also be closely monitored with follow-up imaging. Patients who are high-risk surgical candidates and progress to acute cholecystitis may have additional options. Patients can be evaluated for percutaneous cholecystostomy tubes when critically ill or unable to tolerate surgical intervention.[16](B3)

Endoscopic alternatives, such as cystic duct stent placement or transduodenal gallbladder drainage, offer additional options for patients who are unable to undergo a surgical procedure.[17][18] These procedures remain less widely available than percutaneous cholecystostomy. Results from recent studies showed promise in patients who are poor surgical candidates, but long-term outcomes require further investigation.[19](B3)

Differential Diagnosis

Other common medical conditions can mimic the presentation of chronic cholecystitis. Common clinical features of these disorders are as follows:

• Acute cholecystitis: Continuous, severe right-sided abdominal pain lasting at least 6 hours, with fever, nausea, and vomiting in an ill-appearing patient, is suggestive of acute cholecystitis.[20]
• Gallbladder cancer: Chronic abdominal symptoms associated with weight loss or other constitutional symptoms should raise suspicion for a neoplasm. Imaging and histology are helpful in making a definitive diagnosis.[21]
• Peptic ulcer disease: The presence of epigastric abdominal pain and early satiety should raise suspicion for peptic ulcer disease. Alarm symptoms include weight loss, anemia, melena, or dysphagia. Please see StatPearls' companion reference, "Peptic Ulcer Disease," for further information.
• Gastroesophageal reflux disease: A burning sensation in the epigastrium or retrosternal region may be associated with regurgitation of food material.
• Gastric cancer: The presence of alarm symptoms of peptic ulcer disease, persistent vomiting, evidence of a malignant neoplasm, or other risk factors should raise concern for gastric cancer.[22]
• Myocardial infarction: In cases of inferior wall or right ventricular ischemia, the presenting symptoms may be epigastric pain with nausea and vomiting. Other cardiac symptoms, such as dizziness or shortness of breath, or risk factors for coronary ischemia should prompt further evaluation.[23]
• Mesenteric ischemia: Acute mesenteric ischemia presents with severe acute abdominal pain, and the chronic variant typically presents with postprandial pain. Advanced age, risk factors for atherosclerosis, blood in the stool, and weight loss are concerning features.[24]
• Mesenteric vasculitis: Ongoing abdominal symptoms unexplained by standard evaluation and other features consistent with systemic vasculitis may suggest this relatively underrecognized but dangerous condition. Please see StatPearls' companion reference, "Mesenteric Vasculitis," for further information.

Prognosis

Most uncomplicated cases of chronic cholecystitis have an excellent outcome. In many cases, supportive treatments can help with symptoms. Most recognized cases are treated with elective cholecystectomy to prevent future complications. Surgical treatment is considered safe for patients who are appropriate surgical candidates. The outcomes of surgical treatment for chronic cholecystitis are not as well studied as those for acute cholecystitis, but outcomes are likely as good as, if not better than, those for acute cholecystitis. In general, laparoscopic cholecystectomy has a morbidity rate as low as 1.6% and a mortality rate as low as 0.08%.[25]

Complications

Disease progression or worsening infection can lead to acute cholecystitis. Gallstones also occasionally erode through the gallbladder wall into the duodenum and become impacted in the terminal ileum, presenting as a cholecystoduodenal fistula with gallstone ileus. Rarely, the patient may develop emphysematous cholecystitis due to gas-forming organisms such as Clostridium spp, Escherichia coli, and Klebsiella species. Emphysematous cholecystitis is most common in patients with diabetes mellitus and carries a high mortality rate.

The relationship between chronic cholecystitis and gallbladder cancer is controversial. Although results from studies showed that chronic inflammation was associated with an increased risk of cancer,[26] the data are limited. Additionally, xanthogranulomatous cholecystitis is a variant of chronic cholecystitis in which ongoing inflammation leads to extensive thickening and fibrosis that extend locally beyond the gallbladder wall. In this severe variant, complications such as abscesses and fistulas are more common. Xanthogranulomatous cholecystitis is considered a premalignant condition. A porcelain gallbladder tends to be asymptomatic in most cases. The association with malignant neoplasm is again controversial, but the consensus is that a porcelain gallbladder carries a slightly increased risk of cancer.[27]