Biliary Duct Hamartomas: A Systematic Review

Biliary duct hamartomas are benign intrahepatic bile duct lesions. Despite being primarily incidental findings on imaging, these lesions can provide a diagnostic conundrum due to their shared characteristics with malignant tumors. The goal of this systematic review is to offer a thorough clinical profile of biliary duct hamartomas. There were 139 cases of biliary duct hamartomas identified in a structured systematic review of the literature. Patient demographics, clinical presentation, significant laboratory and imaging data, diagnostic modalities, treatment choices, and outcomes were all studied and reported. Biliary duct hamartomas present with mild symptoms and laboratory abnormalities, and while being visible on imaging, the results are non-specific and may require biopsy in case of red flag signs such as weight loss and a progressive increase in the size of the lesion. Furthermore, there are currently no published guidelines for the treatment of biliary duct hamartomas, and many people have had surgery despite the clinically benign nature of these abnormalities. As per the findings of the study, individuals who exhibit signs of malignancy should be investigated further. Eyeballing for red flag symptoms, followed by a specialized imaging scan and invasive treatment, is the three-step approach to biliary duct hamartomas. Since our recommendations include a shift in strategy and do not contradict existing rules, there are likely to be few roadblocks to improvement; the key barriers being technological equipment and image quality. In this study, we intended to pave the way for future research in the field. In our opinion, the next decade will bring a better understanding of the characteristics of biliary hamartomas, disease symptoms, and better recognition of any suspicious features. These indications will aid in reducing the number of unneeded surgical or invasive operations. Finally, the findings of these future studies will allow the medical community to improve and provide the best care possible.


Introduction And Background
Biliary duct hamartomas, often known as 'von Meyenberg complexes,' are benign bile duct malformations [1,2]. These clinically benign lesions are frequently discovered accidentally during imaging or laparotomy and might resemble malignant lesions by presenting with clinical symptoms that may necessitate a lengthy diagnostic workup and even surgical intervention. Because of its rarity and diverse clinical presentation, management of this condition can be challenging [1,3]. As a result, detecting and distinguishing biliary hamartomas from other diseases is critical.
Biliary duct hamartomas are malformations of the tiny interlobular bile ducts caused by the failure of embryonic bile duct involution. Their estimated frequency on autopsy ranges from 0.6% to 5.6% and is around 1% on imaging [4,5]. Although biliary duct hamartomas have been observed in children, they are most common in adults over the age of 35 [1]. Furthermore, polycystic liver and polycystic kidney disease patients are much more likely to have them [6]. They are also more common in individuals with cirrhosis, indicating that environmental exposure plays an important role in their pathophysiology [1,7].
The majority of biliary hamartomas are asymptomatic, however, they might cause fever, jaundice, or abdominal pain. Similarly, even though most patients have a normal clinical exam and lab findings, rare abnormalities in transaminases, alkaline phosphatase, or gamma-glutamyl transferase (GGT) levels have been reported [1]. Even while their clinical history is often benign, as is the case with other ductal plate malformation diseases, biliary hamartomas do pose a minor risk of malignant transition to intrahepatic cholangiocarcinoma or, less commonly, hepatocellular carcinomas [8]. Given the significant variations in care of biliary duct hamartomas and other disorders with similar symptoms, it is critical to adequately define them to aid in correct diagnosis and effective management. Our systematic review seeks to provide a comprehensive clinical picture of biliary duct hamartomas, as well as an up-to-date summary of all cases published in the literature, to identify any prominent and distinctive characteristics.
This article was previously posted to the medRxiv preprint server on April 30, 2021 [9].

Protocol Development and Systematic Review Registration
We developed the protocol for this review per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria after obtaining consensus with all of the reviewers and topic experts. Following protocol preparation and the International Prospective Register of Systematic Reviews (PROSPERO) registration (CRD42021230745), the data search was carried out as described below.

Risk of Bias (Quality) Assessment
The methodological quality and synthesis of case series and case reports as stated by Murad et al. (2018) [10] were used to assess the quality of all included studies (see Tables 1, 2).   According to this technique, four broad viewpoints were employed to assess quality: study group selection, ascertainment of the observed outcome, causation of the observed outcome, and case reporting.

Strategy for Data Synthesis
We utilized Statistical Package for the Social Sciences (SPSS) version 21 (IBM Corp., Armonk, NY, USA) for statistical analysis. Continuous data were expressed as mean ± standard deviation based on the distribution of data, whereas qualitative variables were expressed as frequency and percentages.

Results
There

Patient Demographics
Patients' ages ranged from 17 to 88 years old at the time of diagnosis, with a mean age of 55±13 (mean±SD) years. Males accounted for 63.3% of all reported cases (88 vs 51), suggesting a slight male predominance.

Comorbidities
An underlying comorbidity was identified in 48.9% of the 139 documented cases. Cancer was the most often reported comorbidity, with 12.9% of patients reporting it. Among these, gastrointestinal cancers (esophageal tumors, gastric cancer, common bile duct cancer, and colorectal cancer) were the most prevalent, accounting for 12 out of 18 or 66.7% of all underlying malignancies. Comorbid cancers of the breast, prostate, lung, and thyroid were also reported.
Viral hepatitis was found in 8.6% of the patients in this study, with hepatitis B accounting for seven of the 12 cases (58.3%) and hepatitis C accounting for five of the 12 cases (41.7%). Furthermore, 8.6% of patients had underlying hypertension, and 5% had type 2 diabetes. Tobacco usage (4.3%), alcohol use (3.6%), hemochromatosis (1.4%), and tuberculosis (1.4%) were among the other comorbidities noted.

Clinical Presentation
Only 36% of the patients in this study were symptomatic, whereas the vast majority (almost 2/3 of them) were asymptomatic at the time of presentation. Abdominal pain was the most prevalent presenting symptom among those who were symptomatic, with 22.3% of patients reporting abdominal pain ranging from nonspecific abdominal discomfort to localized epigastric or right hypochondrial pain. Fever (18%), weight loss (14%), and jaundice (14%) were other frequently mentioned symptoms. Clinical symptoms that were less often described were abdominal distension and upper and lower gastrointestinal haemorrhage. The interval between the onset of symptoms and presentation varied amongst studies, ranging from one day to 10 years.
Although clinical exams were recorded inconsistently, a positive Murphys' sign and right hypochondrial soreness to palpation were prevalent among patients who had a physical exam (nine out of 26 or 34.6%), particularly among those who arrived with abdominal pain. Hepatomegaly and splenomegaly were seen in a limited percentage of individuals with documented physical examinations (19.2% and 13.6%, respectively).

Laboratory Findings
Laboratory data, mostly alanine or aspartate transaminases (ALT/AST), were recorded for 66 of the 139 patients in this study. Around 33.3 % of the 66 individuals showed increased transaminase levels to some degree. The levels of gamma-glutamyl transferase (GGT) and alkaline phosphatase (ALP) were measured in 71 individuals, with 42.2 percent (30 of 71) having high GGT or ALP. Bilirubin levels were measured in 60 people in the research, with 15 (25%) having hyperbilirubinemia. Other documented laboratory abnormalities include hypoalbuminemia, increased C-reactive protein (CRP), and hematologic abnormalities such as anaemia, leukocytosis, leukopenia, and thrombocytopenia.
Tumor marker information was recorded for 42 of the 139 patients. The great majority of patients (85.7 percent) had no tumour marker elevations. Carbohydrate antigen 19-9 (CA 19-9), a tumor marker linked with gastrointestinal malignancies, particularly pancreatic malignancies [89,91], was found to be high in four patients (9.5%). One patient (2.4 percent) had high levels of alpha-fetoprotein (AFP), a tumor marker linked to liver and testicular malignancies [91,92]. One patient also had a rise in CEA, a tumor marker related to malignancies in numerous organ systems, including the gastrointestinal system [91].
This review included studies that used both T1-weighted and T2-weighted MRI images. T1 hypo-intensity was found in 96.3% of the 81 T1-weighted scans for suspected lesions, whereas T1 hyper-intensity was seen in 3.7%. In contrast, T2 hypo-intensity was found in 6.2% of the 80 T2-weighted scans for benign lesions, whereas T2 hyper-intensity was seen in 93.8%.
Forty-one MRI scans used contrast, with 41.5 % of them reporting contrast enhancement. Several individuals had magnetic resonance cholangiopancreatography (MRCP), which revealed hepatic lesions or cysts that had no relationship to the biliary network. On imaging, however, three of these individuals had dilated biliary ducts, which were discovered by ultrasonography. In one case, the CT scan also indicated dilated biliary ducts. The MRI revealed a similar result in four patients.

Lesion Characteristics
The size and location of the lesions of interest were reported on radiography for 44.6% and 48.2% of the patients, respectively. The average size of the lesions was 1 cm in 53.2% of the cases. Twenty-two of the 67 lesions (32.8%) were uniformly distributed across the liver, whereas 21 of the 67 (31.3%) were limited to a single segment. Only two lesions were on the surface of the liver in the right lobe (16 vs 6). They were frequently diagnosed intraoperatively as grey or white nodular lesions, with some cases indicating a cystic component.

Diagnosis, Management, and Outcome
The majority of the patients in this study had biopsies as part of the diagnostic process. The pathologic diagnosis of benign bile duct hamartoma was found in 69.6% of the 112 instances for which biopsy findings were available. In 8.9% of instances, the pathologic diagnosis was bile duct hamartoma with partial malignant alterations, and in 21.4% of cases, the biopsy material was determined to be consistent with malignancy.
The proportion of patients classified radiologically with a malignancy was comparable to the pathology results when considering the final diagnosis provided in each instance; 26.6% of patients were diagnosed with some sort of malignancy, while 73.3% were determined to have a benign diagnosis.
The management strategies used in each case differed significantly. Around 59% of patients with a recorded treatment method had some sort of surgical intervention, the most prevalent of which was partial hepatectomy. Other individuals had cholecystectomies or liver transplants. Prior to the final procedure, 42.7% of patients that received surgical management got a biopsy. In comparison, 36.1% of patients got supportive treatment. Furthermore, 24.4% of patients who underwent surgical intervention were diagnosed with cancer, the most common of which was cholangiocarcinoma (14/20; 70%). A small proportion of cases (4.8%) had postmortem lesions, with two individuals being diagnosed with cancer (2/7; 28.6%).
Overall, the patients in this study had satisfactory results. Of the 116 instances documented patient outcomes, 107 cases (92.2%) stated that the patients were alive at the time of publication, and nine cases (7.8%), including those describing lesions discovered on autopsy, indicated that the patients were deceased at the time of publication. There were no outcomes in the remaining 23 cases.

Discussion
Our systematic review included 82 studies on the incidence of biliary duct hamartomas. In these studies, 139 people with biliary duct hamartomas presented with symptoms or were identified incidentally on imaging, after surgery, or after a malignant transformation.
Their ages varied from 17 to 88 years, with the average patient age being 55 ±13 (mean±SD) years. In our evaluation, the age range was considerably greater than in another study, which reported biliary duct hamartomas detected in individuals above the age of 35 on average [7]. Male dominance was also discovered (88 male patients vs 51 female patients). This conclusion contrasted with one that found female preponderance for this condition [7].
Approximately half of the patients with malignancies had comorbid conditions, with gastrointestinal malignancies being the most prevalent (12.9 %), followed by chronic viral hepatitis B and C (8.6 %). This study supports earlier findings that biliary hamartomas are not always congenital, but can also be acquired as a result of viral inflammation caused by hepatitis B and C [3]. It's worth noting, however, that this higher incidence might be attributable to selection bias since individuals with chronic liver illness are more likely to receive abdominal imaging.
Multiple investigations [1,89] have found that the majority of the patients were asymptomatic (64%). Abdominal discomfort was the most prevalent symptom reported by patients, followed by fever, weight loss, and jaundice. However, 41 symptomatic patients (82%) were identified with biliary duct hamartomas, whereas nine symptomatic patients (18%) had malignancies (cholangiocarcinoma, hepatocellular carcinoma and metastatic cancer). These symptoms have also been reported in other investigations [91,92].
A third of the 66 patients in our study showed high transaminases, while a quarter had hyperbilirubinemia. These increases can point to two possibilities: derangement in tests might be caused by a big lesion obstructing the biliary network, or the derangement could be caused by transient damage to the lesion [93]. Forty-two out of 139 patients (85.7 %) were found to have normal tumor markers. This was consistent with previously published research [3][4][5][6]. However, there were a few cases when CA 19-9, AFP, and CEA levels were increased. This is unlikely to be unique to biliary hamartomas, as increased tumor markers are linked to a variety of cancers and may also be present in situations with underlying liver cirrhosis, portal hypertension, and jaundice [86]. As a result, the significance of tumor markers in biliary duct hamartomas remains debatable.
Ultrasonography revealed a number of common features. The lesions were mostly hypoechogenic (80%) and smaller than 1 cm in diameter (53.2%). This is an intriguing observation, as one research found that smaller lesions are hyperechogenic due to acoustic reflection from tightly apposed walls [41]. As a result, our data support the hypothesis that ultrasonography characteristics for biliary duct hamartomas are usually nonspecific [94,95]. On CT scan, the lesions were predominantly hypointense. According to a few studies, these lesions grow clearer rather than enhance with contrast (32.5%), which is a puzzling feature that might lead to a malignancy diagnosis [96,97]. On MRI, the majority of the lesions exhibited hypointense and hyperintense signals on T1 and T2-weighted images, as reported earlier [96,97]. Contrast enhancement was found in 41.5% of the lesions, which might be attributed to the compressed liver parenchyma around the masses [78].
Biliary duct hamartomas were mostly detected on the liver's surface (32.8%), however, they might sometimes be restricted to a segment (31.5%). The right lobe had a greater involvement than the left. It is unknown what causes the differences in lobe participation. However, the diffuse distribution of nodules on the surface of the liver was considered a trait indicative of a benign form of biliary duct hamartomas [96].
The biopsy is the best diagnostic tool and was performed on 112 patients. Despite the fact that the majority of the patients (73.3%) had benign bile duct hamartomas, 59.9% of them underwent some form of surgical procedure as part of their treatment. Surgical therapy may not be necessary until red flag signs, such as weight loss or a rise in the size of the lesion, are observed. Given the benign nature of the lesion, regular surveillance is not indicated in individuals with stable biliary hamartomas. This would save money and eliminate the need for invasive treatments.
As stated in several studies, the results were usually positive, with many patients living long-term unless they had additional illnesses that might potentially worsen their health in the long run [1,93]. This is true for hamartomas in all organ systems; lungs, small bowel, and pancreatic hamartomas have all been documented to have generally positive outcomes [97][98][99]. Aside from the small chance of malignancy, biliary hamartomas are a benign disorder with no known long-term consequences. As a result, in asymptomatic patients, no intervention is necessary [1].
Bile duct hamartomas are benign lesions that are lined with bile duct epithelium and are frequently dilated due to bile collections in their lumen. The vast majority of cases manifest as non-enhancing, hypoattenuating lesions ( Figure 2). The stromal characteristics of these lesions differ, as does the presence of cystic dilatations of intrahepatic bile ducts covered by a single layer of cuboidal cells with fibrous stroma between them ( Figure 3). Biliary duct hamartomas pose a diagnostic challenge due to their similar appearance to malignant tumors [3]. As a result, the goal of this study is to give common clinical symptoms, laboratory tests, and imaging results that can help diagnose biliary hamartomas in individuals with atypical hepatic lesions.  This image is used here in the article with written consent from the patient's legal guardian.

H&E: Hematoxylin and eosin
The large number of patients allowed for a detailed study of the clinical, diagnostic, and prognostic aspects of biliary duct hamartomas, which is a key strength of this research. One possible drawback is publication bias; instances with substantial or atypical symptoms or those linked with malignant transformation are more likely to be published in the literature than cases with clinically insignificant symptoms.

Conclusions
Biliary duct hamartomas are benign tumors of the intrahepatic bile ducts that can produce mild symptoms and test abnormalities. However, while symptoms, clinical exam findings, and raised liver enzymes are all valuable markers, they are not specific and may not be diagnostic of biliary duct hamartomas. As a result, imaging methods are critical for diagnosing and treating them. Even though regular monitoring is not indicated due to their benign nature, imaging findings for biliary duct hamartomas are often non-specific, necessitating biopsy, especially in situations with red flag symptoms such as weight loss and a gradual increase in lesion size.
Patients with symptoms suggestive of malignancy should be investigated further, as per the findings of the review. This three-step process of looking for red flag symptoms, a specific imaging scan, and invasive therapy is more of a paradigm change in how bile duct hamartomas are approached. As previously stated, because our recommendations entail a shift in approach rather than contradicting existing norms, there are likely few hurdles to improvement; the key roadblocks are technical equipment and image quality.
There are currently no standard treatment guidelines for biliary duct hamartomas, and even though these malformations are clinically benign, many patients have received surgery. More research is needed in several areas to identify the best strategy to manage this rare disorder, with the ultimate objective of delivering the greatest care to these patients. One of these areas is the development of new and improved guidelines for determining the usage of invasive vs non-invasive approaches to treating biliary duct hamartomas. These guidelines would necessitate additional research, including observational studies, case series, and hospital surveys on imaging, as well as data on imaging modalities. Diagnostic modalities, the kind of modality necessary for benign or malignant lesions in biliary duct hamartomas, and the specificity of each type of modality for the lesions being treated are all factors to take into account. It is crucial to define the features of the lesion more precisely to rule out the possibility of malignancy in biliary duct hamartomas. This distinction would require more precise and clear imaging techniques, which are heavily reliant on the resolution and quality of images generated by various devices. It's possible that in the future, we'll have access to more specific technological advancements that will allow us to better visualize bile duct hamartomas.
This study was done to give insight into the present diagnosis and care of individuals with biliary duct hamartomas while keeping the disease's potential evolution in mind. We also intended to pave the way for further research in this area. In our opinion, the next decade will provide a deeper understanding of biliary hamartomas' characteristics, disease symptoms and processes, and a clearer detection of any suspicious features. Using these cues will drastically reduce the number of unneeded surgical or invasive operations. Ultimately, the findings of all future research will enable the healthcare community to modify and provide the best standards of practice.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.