Gallbladder angiodysplasia: a literature review

Introduction: Angiodysplasia is a vascular lesion responsible for 6% of lower gastrointestinal bleeding cases. It is generally located in the cecum and ascending colon in elderly patients. Angiodysplasia of the gallbladder is a rare condition. The main objective of this literature review was to summarize the demographics, clinical signs and symptoms, gross findings, histopathology, immunohistochemistry, treatment, and follow-up of patients with gallbladder angiodysplasia. Methods and materials: The authors searched PubMed, ScienceDirect, and Google Scholar using relevant keywords. The search was performed in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, using appropriate keywords. The case reports included were those dealing exclusively with human subjects, were published in the English language, and had free, full-text, public access. Data was extracted and case reports were evaluated. Results: Of the 1097 studies initially identified, 3 (0.27%) were analyzed. There were two females (66.6%) and one male (33.3%). The mean age of presentation was 47.6 years. The most common presenting complaint was colicky right upper abdominal pain in two cases (66.6%). Elective cholecystectomy was performed in only two cases (66.6%). In one case (33.3%), petechiae were diffusely present in the gastric mucosa and patchy in the gallbladder, duodenum, jejunum, ileum, cecum, and ascending colon on autopsy. Histopathological findings were consistent with gallbladder angiodysplasia in all three cases (100%). On immunohistochemistry CD-34, CD-31, and D2-40 were positive in only one case. Conclusions: Despite conflicting data, histological and immunohistochemical analyses play major roles in the diagnosis of gallbladder angiodysplasia. Nonetheless, further clinical studies are required to provide universal guidelines for the treatment and diagnosis of angiodysplasia of the gallbladder.


Introduction
Blood vessels are vital integrative structures of all tissues; therefore, their abnormality may be the cause of a variety of clinical disorders.Angiodysplasia is a clinically or endoscopically defined entity that is histologically determined to be a vascular malformation according to the most recent WHO classification of digestive system malignancies [1] .This type of lesion is distinguished by defective submucosal and mucosal blood vessels bordered with normal endothelium and surrounded by sparse or no smooth muscle and unrelated to any genetic, cutaneous, or systemic disease [2,3] .There are multiple systems for angiodysplasia classification.One classification system is based on the location, size, and number of angiodysplastic lesions [4] .The gastrointestinal (GI) site is an extensively documented location of angiodysplasia [5,6] .According to size, it is classified as minute (< 2 mm in diameter), intermediate (2-5 mm), or large ( > 5 mm).According to the number of lesions, they are classified as unique (n = 1), multiple (n = 2-10); or diffuse (n > 10) [4] .Another system uses endoscopic findings to classify angiodysplasia into type 1: angioectasias; type 2: Dieulafoy's lesions; type 3: pulsatile red protrusion with surrounding venous dilatation; and type 4: other lesions not classified into any of the above categories [7] .
Angiodysplasia is a rare condition that mostly affects the GI tract and can manifest as an asymptomatic condition or bleeding from the GI tract.It is most commonly present in patients with a history of aortic stenosis, liver cirrhosis, pulmonary disease, renal failure, and von Willebrand disease [2] .Both lower GI tract, for example, the colon or upper GI tract, for example, the stomach and duodenum are the most prevalent sites of angiodysplaisa [5,8] .There are cases of angiodysplasia of the appendix, minor papilla, and proximal bile duct that have been reported in the English literature [8][9][10] ; however, angiodysplasia of the gallbladder is uncommon, and only three cases have been reported thus far [3,11,12] .
The incidence of gallbladder angiodysplasia cannot be predicted owing to its rarity.The most common presenting complaint is colicky right upper quadrant pain.Imaging usually reveals concomitant gallstones.On gross inspection, no macroscopic changes are usually observed.The characteristic histopathological findings of gallbladder angiodysplasia include gall bladder surface denudation/ulceration, widened mucosal folds, disorganized veins and arteries, and the presence of large dilated vessels in the serosa extending through the muscular layer onto the submucosa and mucosa [13] .Immunohistochemistry shows positivity for CD-34, CD-31, and podoplanin (D2-40) monoclonal antibodies.Elective cholecystectomy is the preferred treatment of choice, with a good prognosis [3,11,12] .
To the best of our knowledge, there has been no comprehensive review of gallbladder angiodysplasia.This literature review aimed to summarize the demographics, clinical signs and symptoms, gross findings, histopathology, immunohistochemistry, treatment, and follow-up of cases of gallbladder angiodysplasia.

Methodology
PubMed, Google Scholar, and ScienceDirect were used to investigate the cases of gallbladder angiodysplasia.We collected all relevant reports electronically by entering (gallbladder angiodysplasia) OR (gallbladder angiodysplasias).The search cut-off date for the databases was 21 May 2023.

Inclusion and exclusion criteria
We searched broadly for studies with a larger sample size, but could only find case reports related to gallbladder angiodysplasia.We only included human subjects with English language.We excluded studies that were not in English or that did not use humans as subjects.

Results
After a comprehensive search of PubMed, Science Direct, and Google Scholar, we found 1097 articles, of which there were 200 duplicates.Duplicates were removed via Zotero, 897 records were reviewed, and 894 were discarded based on the inclusion/ exclusion criteria.The final screening yielded three case reports that were included in this review.This is illustrated in Figure 1.

Sex distribution
There were two females (66.6%) and one male (33.3%), as shown in Table 1.

Age
The mean age was 47.6 years at the time of presentation, as shown in Table 1.

Ethnicity
Ethnicity was not mentioned in any case (Table 1).

Chief complaint
The most common presenting complaint was colicky right upper abdominal pain in two cases (66.6%), as seen in Table 1.

Site of angiodysplasia
The gallbladder was the most common site of angiodysplasia in all three cases (100%).Angiodysplasia of the stomach, duodenum, and colon was present in only one case (33.3%) (Table 1).

Pre-existing condition
There were no reports of any pre-existing medical conditions in any case.

Previous history of GI bleeding
There was no history of GI bleeding in any case, as shown in Table 1.

Imaging
On imaging gallstones were found in only two cases (66.6%), as seen in Table 1.

Surgical procedure
Elective cholecystectomy was performed in only two cases (66.6%), as shown in Table 1.

Gross findings
In two cases (66.6%), there were no macroscopic findings on the gallbladder upon gross examination.In one case (33.3%), petechiae were diffusely present in the gastric mucosa and patchy distribution in the gallbladder, duodenum, jejunum, ileum, cecum, and ascending colon on autopsy, as shown in Table 1.

Immunohistochemistry
On immunohistochemistry CD-34, CD-31, and D2-40 were positive in only one case.In the other two cases, immunohistochemistry was not performed, as shown in Table 2.

Follow-up
Two cases (66.6%) upon follow-up were healthy postoperative cholecystectomy.Only one patient (33.3%) died of fatal cardiac arrest, as seen in Table 1.

Discussion
Angiodysplasia is an uncommon lesion that is mainly located in the GI tract and may present with no symptoms or bleeding.They tend to occur most commonly in older people of both sexes [2] ; however, in our review, angiodysplasia of the gallbladder was reported with a mean age of 47.6 years comparatively younger as opposed to angiodysplasia of the GI tract, which primarily occurs in older patients aged greater than 60 years.In our review, only one patient reported by Yudt et al. (1994) had age greater than 60 years (78 years old male) but he also had concomittent angiodysplasia of the rest of the GI tract (stomach, duodenum, and colon) in addition to gallbladder angiodysplasia.This patient presented with symptoms of obscure GI bleeding as shown in Table 2 and had a fatal outcome; however, the rest of the two patients were young female with ages 29 and 36 with the findings of solitary gallbladder angiodysplasia.Both females presented with symptoms of cholecystitis and concomitant gallstones, and gallbladder angiodysplasia was an incidental histopathological finding.Both female patients showed excellent outcomes after laparoscopic cholecystectomy.In all three patients in our review, there was no history of GI bleeding or other concomitant disorders, such as a history of aortic stenosis, liver cirrhosis, pulmonary disease, renal failure, or von Willebrand disease, which are quite prevalent in patients with other GI angiodysplasia [2] .The significant difference between males and females at the age of onset, symptoms at presentation, severity of symptoms, and other concomitant findings such as gallstones only in females apparently shows that the etiology of gallbladder angiodysplasia might differ according to sex, but we cannot comment on anything related to etiology based on the sample size (n = 3) with no mention of ethnicity, genetic analysis, or immunohistochemistry.
The pathogenesis of gallbladder angiodysplasia is unknown; however, several authors [3,11] have hypothesized it based on the possible pathophysiology of angiodysplasia of the GI tract, particularly in the right colon and cecum.To understand the possible pathogenesis of gallbladder angiodysplasia, we must understand the proposed pathogenesis of angiodysplasia of the GI tract.In angiodysplasia of the GI tract (right colon and cecum) chronic, partial, intermittent, and low-grade obstruction of the submucosal veins, particularly where they penetrate the circular and longitudinal muscle layers of the colon, is a direct cause of ectasia.During muscular contraction and distention of the cecum and right colon, obstruction occurs repeatedly for several years.Because vein pressure is lower than arterial pressure, veins can be occluded, while arterial pressure maintains arterial inflow.Eventually, repeated episodes of transiently elevated pressure within a submucosal vein result in dilation and tortuosity of the vessel, as well as the venules and capillaries of the mucosal units discharging into it.As the capillary rings dilate, the precapillary sphincters lose competency, resulting in minor arteriovenous communication.The latter is responsible for the ʻearly filling of veinsʼ, which are the angiographic hallmarks of these lesions.A sustained increase in blood flow through this arteriovenous communication can result in alterations in the arteries supplying the area and in the extramural veins discharging it, based on Laplace's law, which relates the wall tension to the luminal dimension and transmural pressure difference in a cylinder such that the wall tension equals the pressure difference multiplied by the cylinder radius.In the case of the colon, as hypothesized by Boley et al. [14] , wall tension refers to intramural tension, pressure difference is the difference between the bowel lumen and peritoneal cavity, and the cylinder radius is the radius of the right colon; therefore, in bowel segments with the greatest diameter, such as the right colon, wall tension is the greatest, and hence, there is a high prevalence of angiodysplasia in the right colon.
To answer the question related to the pathogenesis of gallbladder angiodysplasia, Kok et al. (2011) hypothesized that gallbladder angiodysplasia can also result from distension and contraction of the gallbladder, similar to other GI angiodysplasia (colonic vascular ectasias), ultimately resulting in intermittent obstruction of vessels that penetrate the muscular wall.This occlusion ultimately results in focal dilatation and tortuosity of the overlying mucosal vessels [3,13] ; however, these findings are only based on a pure hypothesis.To explain the pathogenesis with certainty, we need to study the molecular genetics of gallbladder angiodysplasia in both males and females to provide definitive clues related to the elaborate mechanisms of its onset.
What causes gallstones concomitant with gallbladder angiodysplasia?To answer this question Ivan et al. [11] hypothesized that vascular abnormalities in the gallbladder can deform the muscular wall, resulting in decreased motility, which can be involved in the development of gallstones.Consequently, Ivan et al. proposed that gallbladder angiodysplasia could be a risk factor for the development of cholelithiasis in younger female patients, and may even be the primary cause.Furthermore, the possibility of a causal relationship between gallbladder angiodysplasia and gallstones may provide new insights into the pathophysiology of cholecystolithiasis, although the extreme rarity [13] of angiodysplasia of gallbladder angiodysplasia may be a limiting factor for future research.
Histopathological examination of the angiodysplasia of the gallbladder revealed focal ulceration of the mucosa as well as focal expansion of the mucosal folds due to the deposition of foamy histiocytes.Moderate chronic inflammatory cell infiltration was also observed.The muscle layer was typically hypertrophied and exhibited characteristics consistent with chronic cholecystitis, which is a unique feature of gallbladder angiodysplasia.The presence of massive dilated arteries in the serosa, spreading through the muscular layer onto the submucosa and mucosa, is the most remarkable aspect of gallbladder angiodysplasia, similar to other GI angiodysplastic lesions.However, on gross examination, there were no macroscopic findings of any lesions, as shown in Table 1 [3,11,12] .
Only one case reported by Švagelj et al. (2020) had findings of positive results for CD-31, CD-34, and podoplanin (D2-40) (Table 2).We propose that some of the important differentials that should be considered while interpreting the positive results of CD-31, CD-34, and D2-40 in suspected gallbladder angiodysplasia should be vascular lesions such as angiosarcoma and Kaposi sarcoma [11,13] .Angiosarcoma of the gallbladder seems to have a worse prognosis than angiodysplasia of the gallbladder [15] , and Kaposi sarcoma of the gallbladder is an AIDS-defining illness.None of the reported cases of gallbladder angiodysplasia had HIV/AIDs [16] .Švagelj et al. [11] + ve + ve + ve Kok and Telisinghe [3] ------------Yudt et al. [12] ------------Laparoscopic cholecystectomy was performed for the treatment of gallbladder angiodysplasia, as evident from the cases described by Ivan et al. and Kenneth et al., and it seems to be therapeutic.There were no technical difficulties encountered by the surgeons in both cases during the procedure and it seems that the prognosis of GI angiodysplasia is better than that of GI angiodysplasia and we can hypothesize that the reason for a good prognosis can be a younger age at presentation, no other concomitant disorders and timely surgical intervention; however, to comment on it with certainty, we need a large sample size with results from much larger observational studies.

Limitations
The current literature review has its limitations; to date, only case reports related to gallbladder angiodysplasia are available.There is a dearth of large observational studies that can provide authentic data.Case reports by design lack internal validity, and any conclusion drawn from them needs to be verified by observational studies and clinical trials, which was certainly not possible with only three case reports with a sample size (n = 3).The small sample size and significant heterogeneity among the patient data significantly reduced the power of our analysis.Second, the ethnicity of the patients was missing from all the case reports.It is important to mention the ethnicity of patients because it helps in evaluating the prevalence of the disease in a particular population.Therefore, future studies must include complete demographic characteristics and genetic prevalence.

Conclusion
Our study reviewed all cases of gallbladder angiodysplasia in the English literature and summarized their main features.Angiodysplasia of the gallbladder is a rare condition.Despite the scarcity of available data, histological and immunohistochemical analyses appear to play a major role in the diagnosis of angiodysplasia of the gallbladder.Nonetheless, further clinical studies are required to provide universal guidelines for the treatment and diagnosis of angiodysplasia of the gallbladder.Our review is important in the sense that it provides an overview of the currently available literature and provides insight into important diagnostic markers, treatment strategies, and outcomes of patients with gallbladder angiodysplasia.

Figure 1 .
Figure 1.Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).

Table 1
Summary of case reports of angiodysplasia of gallbladder.