1. Primary and Secondary Causes of Diffuse Gallbladder Wall Thickening: A Pictorial Essay
Oliver Ayres MBBS 1,2
Steven Knox MBBS 1,3
Khimseng Tew MBBS, FRANZCR 1,4
Sarah Constantine MBBS, FRANZCR 1,5
1. The Queen Elizabeth Hospital, Adelaide, Australia.
2. Flinders Medical Centre, Adelaide, Australia.
3. The Royal Adelaide Hospital, Adelaide, Australia.
4. Australian Radiology Clinics, Adelaide, Australia.
5. Dr Jones and Partners, Adelaide, Australia.

2. ANATOMY OF THE GALLBLADDER AND ITS WALL
The gallbladder is a pear-shaped hollow viscus that serves as a repository for bile. It is usually 7 to10cm long, 2.5cm wide, has a wall thickness of less than 3mm and has an average volume of 30 to 50ml 1.
The gallbladder wall consists of (from internal to external); a mucosal lining (which has a single layer of columnar cells), a fibromuscular layer, a layer of subserosal fat (which has arteries, veins, lymphatics, nerves and paraganglia) and a peritoneal covering (except for the surface attached to the visceral surface of the liver). Unlike the rest of the gastrointestinal tract, the gallbladder wall lacks a muscularis mucosae and submucosa. Small tubular channels (ducts of Luschka) are sometimes found buried within the gallbladder wall adjacent to the liver and communicate with the intrahepatic biliary tree. Out-pouching of the gallbladder mucosa may penetrate into and through the muscle wall (Rokitansky-Aschoff sinuses) and are thought to represent acquired herniations 2.
A normal gallbladder with its Phrygian cap folded inwards 2
Low power microscopic view of the normal gallbladder wall

3. IMAGING OF THE GALLBLADDER
The thickness of the gallbladder wall depends upon the degree of gallbladder distension and pseudo-thickening can occur in the post prandial state. Dedicated imaging for gallbladder wall thickness assessment should occur in the fasted patient, ideally for 8 to12 hours 1, which promotes physiologic distension.
The gallbladder is usually located close to the skin surface, hence Ultrasound (US) has traditionally been the modality of choice for evaluating gallbladder disease. Ultrasound allows fast non-invasive real-time assessment. It is portable and has good sensitivity and specificity in demonstrating gallstones and gallbladder wall inflammation 1,3.
On ultrasound (right), the normal gallbladder wall appears as a thin echogenic line. It is usually measured between the gallbladder lumen and the hepatic parenchyma (right). Transcutaneous measurement of gallbladder wall thickness by ultrasound is typically within 1mm of intraoperative measurements in 92.5% of patients and 1.5mm in 100% 4. Ultrasound assessment of gallbladder wall thickness is limited in obese individuals due to increased beam attenuation, degrading image quality.
Ultrasound
Computed tomography (CT) is often the first choice examination in the evaluation of an acute abdomen. In this setting, CT will often demonstrate gallbladder wall thickening. The normal gallbladder wall on CT appears as a thin rim of soft-tissue density that enhances after contrast injection (left).
Non contrast CT
Post contrast CT

4. CLASSIFICATION OF DIFFUSE GALLBLADDER WALL THICKENING
Magnetic Resonance Imaging (MRI) has assumed an increasing role as an adjunct modality for gallbladder imaging, primarily in patients who are incompletely assessed with ultrasound 1. T2 weighted sequences (usually fast spin echo with respiratory gating) are optimal for evaluating gallbladder the wall, the biliary system and adjacent soft-tissue structures 1. On T2 weighted images the gallbladder wall has low signal intensity and is conspicuous against the bright visceral fat. On T1 weighted images, the gallbladder wall has intermediate signal intensity and enhances uniformly after the administration of gadolinium-based contrast material. The wall adjacent to the liver cannot be identified as a separate structure on T2 or T1. Normal bile appears uniformly bright on T2 and varies in signal intensity according to its concentration on T1.
Post contrast fat sat T1
T1 MRI
T2 MRI axial
T2 MRI coronal
CLASSIFICATION OF DIFFUSE GALLBLADDER WALL THICKENING
Traditionally the finding of a diffusely thick-walled gallbladder has been regarded as proof of primary gallbladder disease. Gallbladder wall thickness greater than 3mm on ultrasound is a hallmark feature of acute cholecystitis 5. It is now well known, however, that the finding of diffuse gallbladder wall thickening is commonly due to a variety of disorders not directly related to intrinsic gallbladder disease 3,6-8, with extrinsic (non biliary) causes more common than intrinsic causes 9. In patients who have secondary gallbladder involvement associated with wall thickening, cholecystectomy is unwarranted and the gallbladder wall will usually return to normal after correction of the extrinsic cause.
Correlation of the clinical presentation, laboratory analysis and imaging findings should allow classification of gallbladder wall thickening as either due to primary gallbladder disease or to secondary gallbladder involvement.
The following slides will show examples of the imaging findings in a variety of intrinsic and extrinsic conditions that can cause diffuse gallbladder wall thickening.

5. INTRINSIC GALLBLADDER DISEASE
ACUTE CHOLECYSTITIS
Gallbladder wall thickening in acute cholecystitis (below) is usually in the range of 5 to12mm 6. Gallbladder wall thickening, however, is a non-specific finding that should be supported by other imaging findings as well as clinical signs and symptoms (such as an obstructing gallstone, hydropic gallbladder, sonographic Murphy’s sign, pericholecystic fluid or fat inflammation, and hyperaemia of the gallbladder wall on Power Doppler imaging) 10. The presence of striations within the gallbladder wall in the setting of acute cholecystitis suggests gangrenous changes 6.
Most cases of acute cholecystitis are associated with gallstones causing obstruction at the gallbladder neck leading to chemical irritation from concentrated bile.
Acute acalculous cholecystitis mainly occurs in critically ill patients and it is thought to be caused by cholestasis as a result of increased bile viscosity due to fasting and medications 3. Biliary sludge is usually present in acute acalculous cholecystitis. The diagnosis of acalculous cholecystitis can be difficult in such patients, as often there are concurrent conditions that can contribute to gallbladder wall thickening.
Ultrasound
Post contrast CT
T2 MRI
T1 MRI

6. INTRINSIC GALLBLADDER DISEASE
CHRONIC CHOLECYSTITIS
Chronic cholecystitis is used to describe the low-grade inflammation and fibrosis that occurs with transient obstruction. Gallstone disease causes repeat episodes of acute and subacute cholecystitis. In chronic cholecystitis, the gallbladder wall can be thick and its capacity can be low. Imaging studies may be normal. On nuclear medicine biliary studies (HIDA / DISIDA scan), there can be delayed filling by biliary agents as well as poor gallbladder contractility after cholecystokinetic challenge (e.g. fatty meal or cholecystokinin).
Xanthogranuloma on
low power microscopy 11
Arrows – Xanthogranuloma
Star – Gallbladder lumen
Arrows – Xanthogranuloma
Star – Gallbladder lumen
Ultrasound
Post contrast CT
T2 MRI1
T1 MRI1
Xanthogranulomatous cholecystitis (above) is a variant of chronic cholecystitis that is characterised by a lipid-laden inflammatory process associated with marked gallbladder wall thickening. The pathogenesis is not well understood but it may be caused by blockage of the Rokitansky-Aschoff sinsuses, leading to inspissation of bile, rupture of bile and subsequent inflammation resulting in scarring. Nodules in the thickened wall represent foci of xanthogranulomatous inflammation. These appear hypoechoic on ultrasound and hypodense on CT. Xanthogranulomatous cholecystitis can mimic cancer both on imaging and pathologically.
A porcelain gallbladder (below) is a rare disorder in which chronic cholecystitis produces mural calcification. It has an associated increased risk of gallbladder carcinoma 5.
X-ray
Post contrast CT
Ultrasound

7. INTRINSIC GALLBLADDER DISEASE
GALLBLADDER CARCINOMA
Gallbladder carcinoma is the 5th most common malignancy of the gastrointestinal tract and is found incidentally in 1 to 3% of cholecystectomy specimens 3. Diffuse mural thickening is an uncommon imaging presentation of gallbladder carcinoma as it is more commonly seen as a mural based polypoid intraluminal lesion or an infiltrating mass replacing the gallbladder. Secondary imaging findings such as invasion of adjacent structures, biliary obstruction and liver or porta hepatis lymph node metastases aid in differentiating carcinoma from acute or chronic cholecystitis.
Post contrast CT
Ultrasound
Ultrasound
T1 MRI1
T2 MRI1
Post contrast T11

8. INTRINSIC GALLBLADDER DISEASE
ADENOMYOMATOSIS
Adenomyomatosis is a benign condition of unknown aetiology that is characterised by epithelial proliferation, muscular hypertrophy (up to 5 times normal thickness) and intramural diverticula (Rokitansky-Aschoff sinsuses). It is an incidental finding on 9% of cholecystectomy specimens 3. It requires no specific treatment.
Gallbladder involvement in adenomyomatosis can be may be focal, segmental or diffuse. Segmental involvement can be circumferential in the body of the gallbladder causing annular constriction and an “hourglass” appearance of the gallbladder. Focal involvement is the most common manifestation. It is seen as crescentic or rounded wall thickening usually at the fundus. Focal adenomyomatosis presenting as a discrete mass is known as an adenomyoma.
On imaging, adenomyomatosis can be difficult to distinguish from acute cholecystitis and gallbladder carcinoma. The Rokitansky-Aschoff sinuses may contain cholesterol crystals, which give the “comet tail” reverberation artefact on ultrasound. Reveberation artefacts can also be caused by intramural gas in emphysematous cholecystitis. Adenomyomatosis is usually associated with focal or generalised gallbladder wall thickening. Adenomyomatosis may show the “rosary sign” on CT and MRI (due to enhancing mucosal epithelium within intramural diverticula surrounded by a non-enhancing hypertrophied muscle layer) and this sign can help distinguish adenomyomatosis from acute cholecystitis and gallbladder carcinoma. Absence of uptake on nuclear medicine PET scans (18-FDG) can help in distinguishing an adenomyoma from gallbladder malignancy.
Left: Macroscopic view of Rokitansky-Aschoff sinuses in the gallbladder wall 12.
Right: Low power microscopic view of adenomyomatosis showing a Rokitansky-Aschoff sinus containing inspissated bile and surrounding muscular hypertrophy 13.

9. Rokitansky- Aschoff sinuses Reveberation artefacts Focal type
ADENOMYOMATOSIS
Oral cholecystogram12
Ultrasound
Post contrast CT
Ultrasound
Rokitansky- Aschoff sinuses
Reveberation artefacts
Focal type
Segmental (annular) type
Post contrast CT
T2 MRI14
T2 MRI14
Post contrast T114
Combined diffuse and segmental (annular) types with gallstones showing “rosary” sign at fundus
Diffuse type with gallstones
Combined diffuse and segmental (annular) types with gallstones

10. INTRINSIC GALLBLADDER DISEASE
CHOLESTEROLOSIS OR “STRAWBERRY” GALLBLADDER
Cholesterolosis is a condition of unknown aetiology in which cholesterol is deposited in the gallbladder wall. The disease process is associated with cholesterol stones in about half of patients. Most patients do not show thickening of the gallbladder wall on imaging studies. A small percentage of patients with this condition will show cholesterol polyps. Polyps can be detected with ultrasound as small (<10mm), immobile, usually multiple smooth mural projections that do not shadow. The cholesterol polyp has a single layer of epithelium and is attached to the gallbladder by a delicate stalk.
Cholesterolosis often coexists with adenomyomatosis, although they are unrelated. It can be difficult to distinguish between the two processes. Cholesterolosis does not demonstrate the generalised gallbladder wall thickening and “rosary” sign (on CT and MRI) seen with adenomyomatosis. Absence of uptake on nuclear medicine PET scans (18-FDG) can help in distinguishing small cholesterol polyps from gallbladder malignancy.
Low power microscopic view of Cholesterolosis
Cholesterolosis with cholesterol polyp 12
Ultrasound

11. EXTRINSIC DISEASE WITH GALLBLADDER INVOLVEMENT
SYSTEMIC DISEASE
Gallbladder wall thickening can result from many systemic diseases such as right heart failure, liver cirrhosis, alcoholic liver disease, hypoalbuminemia, ascites, sepsis, multiple myeloma and acute myeloid leukaemia. The mechanism that leads to gallbladder wall oedema in these conditions is uncertain, but it is likely due to combination of elevated portal venous pressure and decreased intravascular osmotic pressure.
Ultrasound
Post contrast CT
Ultrasound
Malignant ascites
Hypoalbuminaemia
Appendicitis
Ultrasound
Post contrast CT
T2 weighted MRI
Right heart failure
Liver cirrhosis with ascites

12. EXTRINSIC DISEASE WITH GALLBLADDER INVOLVEMENT
DIRECT SPREAD FROM EXTRA-CHOLECYSTIC INFLAMMATION
Direct spread of primary inflammation, or less commonly an immunologic reaction, may extend to the region of the gallbladder and result in gallbladder wall thickening. The most common pathologies are hepatitis (including viral causes), pancreatitis, pyelonephritis and systemic viral infections (EBV, HIV). Hepatitis is the most common cause of increased gallbladder wall thickening due to extra-cholecystic inflammation and the thickening can be extensive 7. In viral hepatitis, viruses excreted into the biliary system may cause mild pericholecystic inflammation.
Ultrasound
T2 MRI
Post contrast CT
Pancreatitis
Drug induced hepatitis
NON-BILIARY MALIGNANCY
Contiguous spread of malignancy may also extend to involve the gallbladder wall, resulting in diffuse or focal thickening. Secondary neoplastic infiltration may rarely cause segmental wall thickening. Metastatic disease tends to produce focal rather than diffuse gallbladder wall thickening.
Post contrast T1
Post contrast CT
Lymphoma
Lymphoma

13. CONCLUSION REFERENCES
Gallbladder wall thickness may be related to either intrinsic (primary) or extrinsic (secondary) conditions affecting the gallbladder. Secondary extrinsic causes are more common than primary gallbladder pathologies 6. Systemic illness and extra-cholecystic inflammation are the two main groups of secondary causes. Ultrasound is the imaging modality of choice for initial assessment of gallbladder wall thickness. CT and MRI are less sensitive but can show gallbladder wall thickening often as an incidental finding in the investigation of unexplained abdominal signs and symptoms. Correlation with the clinical presentation, laboratory analysis and imaging findings should allow classification of gallbladder wall thickening as either due to primary gallbladder disease or to secondary gallbladder involvement. Caution is therefore urged in making the diagnosis of acute cholecystitis on the basis of increased wall thickness alone.
REFERENCES
Catalano O, Sahani D, Kalva S, Cushing M, Hahn P, Brown J, Edelman R. MR Imaging of the Gallbladder: A Pictorial Essay. Radiographics ;
Cotran, Kumar, Collins. Pathologic Basis of Disease 6th Ed. Philadelphia 1999: WB Saunders.
Vriesman A, Engelbrecht M, Smithuis R, Pulaert J. Diffuse Gallbladder Wall Thickening: Differential Diagnosis. AJR 2007; 188:
Engel J, Deitch E, Sikkema W. Gallbladder Wall Thickness: Sonographic Accuracy and Relation to Disease. AJR 1980; 134:
Dahnert W. Radiology Review Manual 5th Ed. Philadelphia 2003: Lippincott Williams & Wilkins.
Teefey S, Baron R, Bigler S. Sonography of the Gallbladder. Significance of Striated (Layered) Thickening of the Gallbladder Wall. AJR 1991; 156:
Shlaer W, Leopold G, Scheible F. Sonography of the Thickened Gallbladder Wall: A Nonspecific Finding. AJR 1981; 136:
Ralls P, Quinn M, Juttner H, Halis J, Boswell W. Gallbladder Wall Thickening: Patients without Intrinsic Gallbladder Disease. AJR ;
Middleton, W. General and Vascular Ultrasound. Philadelphia 2007: Mosby Elsevier.
Eisenberg R. Clinical Imaging: an atlas of differential diagnosis 4th Ed. Philadelphia 2003: Lippincott Williams & Wilkins.
Levy A, Murakata L, Abbott R, Rohrmann C. From the Archives of the AFIP. Benign Tumours and Tumorlike Lesions of the Gallbladder and Extrahepatic Bile Ducts: Radiologic-Pathologic Correlation. Radiographics 2002; 22:
Berk R, van der Vegt J, Lichtenstein J. The Hyperplastic Cholecystoses: Cholesterolosis and Adenomyomatosis. Radiology 1983; 146:
Boscak A, Al-Hawary M, Ramburgh S. Best Cases from the AFIP. Adenomyomatosis of the Gallbladder. Radiographics ;
Haradome H, Ichikawa T, Sou H, Yoshikawa T, Nakamura A, Araki T, Hachiya J. The Pearl Necklace Sign: An Imaging Sign of Adenomyomatosis of the Gallbladder at MR Cholangeopancreatography. Radiology 2003; 227:80-88.
Lewandowski B, Winsberg F. Gallbladder Wall Thickness Distortion by Ascites. AJR 1981; 137:
Handler S. Ultrasound of Gallbladder Wall Thickening and Its Relation to Cholecystitis. AJR ;