Microangiopathic Hemolytic Anemia Is a Late and Fatal Complication of Gastric Signet Ring Cell Carcinoma: A Systematic Review and Case-Control Study.

BACKGROUND: Microangiopathic hemolytic anemia (MAHA) is a rare paraneoplastic syndrome that has been reported in patients with gastric signet ring cell carcinoma (SRCC). Clinical and prognostic features of MAHA in this setting have been poorly described. MATERIALS AND METHODS: We conducted a systematic review in 8 databases of gastric SRCC complicated by MAHA and performed a case-control study assessing factors associated with survival in patients with gastric SRCC and MAHA in our pooled cohort compared with age-, sex-, and stage-matched cases of gastric SRCC from the Surveillance, Epidemiology, and End Results (SEER) database. Descriptive analyses were performed and multivariable Cox-proportional hazards regression modeling was used to determine factors associated with overall survival. RESULTS: All identified patients (n = 47) were symptomatic at index presentation, commonly with back/bone pain, and dyspnea. Microangiopathic hemolytic anemia was the first manifestation of gastric SRCC in 94% of patients. Laboratory studies were notable for anemia (median 7.7 g/dL), thrombocytopenia (median 45.5 × 103/µL), and hyperbilirubinemia (median 2.3 mg/dL). All patients with MAHA had metastatic disease at presentation, most often to the bone, bone marrow, and lymph nodes. Median survival in patients with gastric SRCC and MAHA was significantly shorter than a matched SEER-derived cohort with metastatic gastric SRCC (7 weeks vs 28 weeks, P < .01). In multivariate analysis, patients with MAHA were at significantly increased risk of mortality (HR 3.28, 95% CI 2.11-5.12). CONCLUSION: Microangiopathic hemolytic anemia is a rare, late-stage complication of metastatic gastric SRCC and is associated with significantly decreased survival compared with metastatic gastric SRCC alone.

Liver chemistries in glycogenic hepatopathy associated with type 1 diabetes mellitus: A systematic review and pooled analysis.

BACKGROUND & AIMS: Glycogenic hepatopathy (GH) in type 1 diabetes-mellitus (T1DM) is characterized by hepatomegaly and perturbations of liver chemistries (LC) that have not been well studied. Furthermore, misdiagnosis with other hepatic complications of T1DM, such as nonalcoholic fatty liver disease, has been described. We perform a systematic review of biopsy-proven GH reports in T1DM patients to identify LC patterns. METHODS: A systematic review identified reports of biopsy-proven GH in patients with T1DM. We excluded GH with other liver diseases, Mauriac syndrome, or GH without T1DM. Two reviewers screened and extracted studies and assessed their methodological quality. LC elevation magnitude, AST-to-ALT ratio, R-ratio to designate hepatocellular, cholestatic or mixed pattern of hepatic injury, and evolution of transaminases after glycemic control were analyzed. RESULTS: A total of 192 patients were included, with median age of 20 years, 73% adults, 66% females, median duration of T1DM before diagnosis 10 years, median adult body mass index 21 kg/m2 , median HbA1c 12%, at least one episode of diabetic ketoacidosis 70%, and hepatomegaly 92%. ALT and AST showed moderate-to-severe elevation in 78% and 76%, respectively, AST/ALT >1 in 71% and hepatocellular to mixed pattern of hepatic injury in 81%. Transaminase improvement with glycemic control was the rule, regardless of other factors in multilinear regression analysis. CONCLUSION: GH tends to have AST-predominant elevation with a median of 13 times the upper normal limit and R-ratio >2, which may distinguish it from other etiologies of AST-predominant LC elevation, and in the appropriate clinical context, may obviate invasive tests.

Normal liver stiffness and influencing factors in healthy children: An individual participant data meta-analysis.

BACKGROUND & AIMS: Although transient elastography (TE) is used to determine liver stiffness as a surrogate to hepatic fibrosis, the normal range in children is not well defined. We performed a systematic review and individual participant data (IPD) meta-analysis to determine the range of liver stiffness in healthy children and evaluate the influence of important biological parameters. METHODS: We pooled data from 10 studies that examined healthy children using TE. We divided 1702 children into two groups: ≥3 years (older group) and < 3 years of age (younger group). Univariate and multivariate linear regression models predicting liver stiffness were conducted. RESULTS: After excluding children with obesity, diabetes, or abnormal liver tests, 652 children were analysed. Among older children, mean liver stiffness was 4.45 kPa (95% confidence interval 4.34-4.56), and increased liver stiffness was associated with age, sedation status, and S probe use. In the younger group, the mean liver stiffness was 4.79 kPa (95% confidence interval 4.46-5.12), and increased liver stiffness was associated with sedation status and Caucasian race. In a subgroup analysis, hepatic steatosis on ultrasound was significantly associated with increased liver stiffness. We define a reference range for normal liver stiffness in healthy children as 2.45-5.56 kPa. CONCLUSIONS: We have established TE-derived liver stiffness ranges for healthy children and propose an upper limit of liver stiffness in healthy children to be 5.56 kPa. We have identified increasing age, use of sedation, probe size, and presence of steatosis on ultrasound as factors that can significantly increase liver stiffness.

Range of Normal Liver Stiffness and Factors Associated With Increased Stiffness Measurements in Apparently Healthy Individuals.

BACKGROUND & AIMS: Transient elastography (TE) is a noninvasive technique used to measure liver stiffness to estimate the severity of fibrosis. The range of liver stiffness measurements (LSMs) in healthy individuals is unclear. We performed a systematic review to determine the range of LSMs, examined by TE, in healthy individuals and individuals who are susceptible to fibrosis. METHODS: We collected data from 16,082 individuals, in 26 cohorts, identified from systematic searches of Embase, Ovid MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews for studies of liver stiffness measurements. Studies analyzed included apparently healthy adults (normal levels of liver enzymes, low-risk alcohol use patterns, and negative for markers of viral hepatitis). The presence of diabetes, hypertension, dyslipidemia, or steatosis, based on ultrasound examination, was known for most participants. We performed a meta-analysis of data from individual participants. The cohort was divided into 4 groups; participants with a body mass index <30 kg/m2 were examined with the medium probe and those with a body mass index ≥30 kg/m2 were examined with the extra-large probe. Linear regression models were conducted after adjusting for potential confounding factors of LSMs. We performed several sensitivity analyses. RESULTS: We established LSM ranges for healthy individuals measured with both probes-these did not change significantly in sensitivity analyses of individuals with platelets ≥150,000/mm3 and levels of alanine aminotransferase ≤33 IU/L in men or ≤25 IU/L in women. In multivariate analysis, factors that modified LSMs with statistical significance included diabetes, dyslipidemia, waist circumference, level of aspartate aminotransferase, and systolic blood pressure at examination time. Significant increases in LSMs were associated with the metabolic syndrome in individuals examined by either probe. Diabetes in obese individuals increased the risk of LSMs in the range associated with advanced fibrosis. CONCLUSIONS: In a systematic review and meta-analysis of data from individual participants, we established a comprehensive set of LSM ranges, measured by TE in large cohorts of healthy individuals and persons susceptible to hepatic fibrosis. Regression analyses identified factors associated with increased LSMs obtained by TE with the medium and extra-large probes.

Incidence, Admission Rates, and Economic Burden of Adult Emergency Visits for Chronic Pancreatitis: Data From the National Emergency Department Sample, 2006 to 2012.

INTRODUCTION: Chronic pancreatitis (CP) is a common reason for emergency department (ED) visits, but little research has examined ED use by patients with CP. MATERIALS AND METHODS: The Nationwide Emergency Department Sample (2006 to 2012) was interrogated to evaluate trends in adult ED visits for a primary diagnosis of CP (International Classification of Disease, 9th revision, Clinical Modification code: 577.1), the rates of subsequent hospital admission, and total charges. A survey logistic regression model was used to determine factors associated with hospitalization from the ED. RESULTS: We identified 253,753 ED visits with a primary diagnosis of CP. No significant trends in annual incidence were noted. However, the ED-to-hospitalization rates decreased by 3% per year (P<0.001) and mean ED charges after adjusting for inflation increased by 11.8% per year (P<0.001). Higher Charlson comorbidity index, current smoker status, alcohol use, and biliary-related CP were associated with hospitalization. In hospitalized patients, length of stay decreased by 2.2% per year (P=0.003) and inpatient charges increased by 2.9% per year (P=0.004). CONCLUSIONS: Patient characteristics associated with higher risk of hospitalization from the ED deserve further attention.

Systematic review of acute pancreatitis associated with interferon-α or pegylated interferon-α: Possible or definitive causation?

BACKGROUND: Acute pancreatitis (AP) associated with interferon-α or pegylated interferon-α (AP-IFN) has been described, although the causal relation certitude remains elusive. Some recent studies suggest definite causality, although the relation is grouped in class III of Badalov classification of drug-induced AP. OBJECTIVES: Perform systematic review of AP-IFN and assess causality. METHODS: Two reviewers independently evaluated the data and quality of studies extracted from multiple databases on March 13, 2017. Studies selection was based on a priori criteria. Naranjo scale, and Badalov classification were applied to determine causality. RESULTS: We identified 16 studies that reported AP-IFN with a total of 23 patients. Fifteen studies had moderate to good methodological quality. The frequency of AP-IFN was 7/3450 (0.2%). The median age of patients was 50 years. In most cases IFN was used for chronic hepatitis C. The latency between IFN and diagnosis of AP was (>30 days). AP was mild or moderately severe and improved with supportive management. No mortality was observed. Re-challenge was done in 5 patients and resulted in AP recurrence in 3 cases. Twenty-one cases were classified as probable and 2 cases as definitive according to Naranjo scale. Evaluations of studies confirm a status Ia for AP-IFN according to Badalov classification. CONCLUSION: AP-IFN is rare and has a probable or definite causal relation according to Naranjo scale. The evidence supports a class Ia of Badalov classification. Hypertriglyceridemia is not a contributing factor. IFN-induced AP is usually mild or moderately severe, and responds favorably to supportive management.

Acute liver failure caused by hepatitis E virus genotype 3 and 4: A systematic review and pooled analysis.

BACKGROUND & AIMS: Acute liver failure caused by hepatitis E virus genotype 3 and 4 has been rarely described. Because of the presence of a short golden therapeutic window in patients with viral acute liver failure from other causes, it is possible that early recognition and treatment might reduce the morbidity and mortality. We performed a systematic review and pooled analysis of acute liver failure caused by hepatitis E virus genotype 3 and 4. METHODS: Two reviewers appraised studies after searching multiple databases on June 12th, 2017. Appropriate tests were used to compare hepatitis E virus genotype 3 vs 4, suspected vs confirmed genotypes, hepatitis E virus-RNA positive vs negative, and to discern important mortality risk factors. RESULTS: We identified 65 patients, with median age 58 years (range: 3-79), and a male to female ratio of 1.2:1. The median bilirubin, ALT, AST and alkaline phosphatase (expressed by multiplication of the upper limit of normal) levels were 14.8, 45.3, 34.8 and 1.63 respectively. Antihepatitis E virus IgG, antihepatitis E virus IgM and hepatitis E virus-RNA were positive in 84%, 91% and 86% of patients respectively. The median interval from symptoms onset to acute liver failure was 23 days, and 16 patients underwent liver transplantation. Final outcome was reported in 58 patients and mortality was 46%. Age was a predictor of poor prognosis in multivariate analysis. No important differences were found between patients infected with genotype 3 vs 4, patients with confirmed vs suspected genotypes, or patients with positive vs negative RNA. CONCLUSION: Acute liver failure caused by hepatitis E virus genotype 3 and 4 is rare, similar between genotypes, occurs commonly in middle-aged/elderly patients and has a very high mortality. Age is predictive of poor prognosis in multivariate analysis.

Frequency and prognosis of acute pancreatitis associated with fulminant or non-fulminant acute hepatitis A: A systematic review.

BACKGROUND: Acute pancreatitis (AP) in patients with fulminant viral hepatitis is well recognized and its mortality depends on the severity of hepatitis rather than pancreatitis. Acute pancreatitis associated with non-fulminant acute hepatitis A (AHA) has been rarely described, and is considered to have a benign course with good response to conservative management. OBJECTIVE: To perform a systematic review of the frequency and prognosis of AP associated with fulminant or non-fulminant AHA. RATIONALE: An increasing number of reports describe AP associated with AHA. Some life-threatening complications related to AP may occur, and death has been reported. In addition, it is possible that early diagnosis of these cases may help in reducing the morbidity and mortality. DATA SOURCES: Ovid Medline In-Process & Other Non-Indexed Citations, Ovid MEDLINE, Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, Scopus, Google Scholar, and reference lists of relevant articles. STUDY SELECTION: All available studies discussing AP associated with fulminant or non-fulminant AHA. DATA EXTRACTION AND ASSESSMENT: Two blinded independent observers extracted and assessed the frequency of AP associated with AHA based on large studies including all cases of AHA observed during a prolonged period of time, diagnosis of AHA based on anti-HAV IgM, diagnosis of fulminant hepatitis (FH) based on the American Association for the study of Liver Diseases (AASLD) position paper, diagnosis of AP based on the American College of Gastroenterology (ACG) guidelines, diagnosis of AP associated with AHA based on Makharia's association, and diagnosis of AP severity based on the Revision of the Atlanta Classification (RAC). We have developed a tool for risk of bias assessment of case reports and case-series and applied it to the included studies. RESULTS: The frequency of reported AP associated with AHA is 0-0.1%. Thirty-eight publications with a total of 54 patients meeting the inclusion criteria have been published. Twenty-two studies had a low risk for bias, 10 had moderate risk and 6 had high risk. Patients originated from all continents but most of them were from Asia. The median age at diagnosis was 16 years (range: 2-81) with a male to female ratio of 2. The median interval between the onset of jaundice and onset of AP pain was 4 days (range: 0-30). AP was severe in 9% of patients. The median hospital stay for AP was 8 days (range: 3-35). Most cases occur in patients without FH (94%). Mortality was reported in 2 patients (3.7%). CONCLUSION: Acute pancreatitis associated with AHA is rare with an estimated frequency of 0-0.1%. Fifty-four documented cases, mostly in Asian patients, have been reported. The median age of patients is 16 years with a M/F ratio of 2. Acute pancreatitis occurs less than one week after the onset of jaundice and mostly in patients without FH. Acute pancreatitis in this setting is severe in 9% of patients with a mortality rate similar to all other causes of AP.

Frequency and prognosis of acute pancreatitis associated with acute hepatitis E: A systematic review.

BACKGROUND: The association of acute pancreatitis (AP) with viral hepatitis is well known, and is usually attributed to HAV, HBV, or HCV. AP related to acute hepatitis E (AHE) has been rarely described, and the typical profile is that of a young male, residing in an endemic area, presenting with mild to moderate pancreatitis, and improving with conservative management. RATIONALE: An increasing number of reports describe AP associated with AHE. Some life-threatening complications related to AP may occur, and death has been reported. In addition, it is possible that early diagnosis of these cases may help in reducing the morbidity and mortality. OBJECTIVE: Perform a systematic review to study cases of AP associated with AHE and to assess their prognosis. DATA SOURCES: PubMed, EMBASE, Scopus, and the Cochrane library. STUDY SELECTION: All available studies discussing AP associated with AHE. DATA EXTRACTION AND ASSESSMENT: Two blinded independent observers extracted and assessed the studies for diagnosis of AHE based on serological and/or molecular techniques, diagnosis of fulminant hepatitis based on the American Association for the study of Liver Diseases (AASLD) position paper, diagnosis of AP based on the American College of Gastroenterology (ACG) guidelines, diagnosis of AP associated with AHE based on Makharia's association, and diagnosis of AP severity based on the Revision of the Atlanta Classification (RAC). RESULTS: Thirteen case reports and 4 case series were found with 55 patients meeting the inclusion criteria. All patients originated from Southern Asia or had a recent travel to that area. The mean age at diagnosis was 28 years with a male to female ratio of 18:1. The mean interval between the onset of jaundice and the onset of AP pain was 10 days. AP was mild or moderately severe in 45 patients (82%), and severe in 10 patients (18%). Mortality was reported in 2 patients (3.6%). CONCLUSION: Fifty-five cases of acute pancreatitis associated with AHE are reported in the literature. Acute pancreatitis in this setting is severe in approximately one fifth of patients with an overall mortality rate similar to all other causes of AP.

Making the case for the development of a vaccination against hepatitis E virus.

Hepatitis E virus (HEV) infection is a global problem that affects 20 million individuals, and cause acute hepatitis in 3.5 million, with approximately 70,000 deaths worldwide per year. While the acute disease is generally self-limited, however, it may progress to fatal fulminant liver failure in certain individuals. Contaminated water supplies disseminate this virus through the faecal-oral route, and swine is thought to be its zoonotic reservoir. Attempts have been made to develop effective HEV vaccines, and two candidates have undergone successful clinical trials. In this review, we discuss HEV epidemiology, genotypes, microbiological structure, as well as the most recent advances in vaccination developments.

Verrucous esophageal carcinoma is a unique indolent subtype of squamous cell carcinoma: a systematic review and individual patient regression analysis.

BACKGROUND AND AIMS: Verrucous esophageal carcinoma (VEC) is a rare malignancy that presents a diagnostic challenge. We aim to characterize the clinical and genomic features, tumor behavior, and treatment outcomes of VEC to guide clinical practice. METHODS: We performed a systematic review of the literature and identified additional cases from Massachusetts General Hospital records and The Cancer Genome Atlas (TCGA). We obtained individual VEC patient data and analyzed publicly available clinicogenomic data from TCGA. We performed a regression analysis comparing cases of VEC to esophageal squamous cell carcinoma (ESCC) to identify factors influencing survival. RESULTS: A total of 135 patients were reported in 82 publications, and four unpublished cases from Massachusetts General Hospital (median age 65 years, 69% males, 48% smokers, 33% consumed alcohol). Symptoms were present at diagnosis in 95% of patients, most commonly dysphagia and weight loss. Median symptom onset to diagnosis time was 11.5 months with frequent misdiagnosis as Candida esophagitis. Among VEC cases with pathologic staging, lymph node metastases were rare (5%) compared to ESCC (40%). VEC was genomically characterized by enrichment of SMARCA4 missense mutations and a lack of pathogenic TP53 mutations. Despite its diagnostic elusiveness, in a multivariate regression analysis, VEC was detected at earlier stages (p = < 0.001) compared to ESCC, and advanced stage was the only significant factor affecting survival (p = 0.013). CONCLUSIONS: VEC is a rare, clinically and genomically distinct subtype of ESCC. Recognition and diagnosis of this lesion may allow the pursuit of curative and less morbid treatment strategies.

The neglected hepatitis C virus genotypes 4, 5 and 6: an international consensus report.

Abstract Hepatitis C virus (HCV) genotypes 4, 5 and 6 represent >20% of all HCV cases worldwide. HCV-4 is mainly seen in Egypt, where it represents 90% of all HCV cases. Antischistosomal therapy was the main cause of contamination there, followed by procedures performed by informal providers and traditional healers such as dental care, wound treatment, circumcision, deliveries, excision and scarification. It is also highly prevalent in sub-Saharan Africa and in the Middle East. In Europe, its prevalence has recently increased particularly among intravenous drug users and in immigrants. HCV-5 is mainly found in South Africa, where it represents 40% of all HCV genotypes, but four pockets of HCV-5 were found in France, Spain, Syria and Belgium and sporadic cases were found elsewhere. The mode of transmission is mainly iatrogenic and transfusion. HCV-6 is found in Hong Kong, Vietnam, Thailand and Myanmar and also in American and Australian from Asian origin. The response to treatment in HCV-4 is intermediate between HCV-1 and HCV-2 and HCV-3. A sustained viral response is achieved in 43-70% with pegylated interferon and ribavirin. It is higher in Egyptians than Europeans and Africans and is negatively related to insulin resistance and to the severity of fibrosis. It increases to >80% with 24 weeks of therapy only if a rapid virological response is achieved. In HCV-5, a sustained virological response is achieved in >60% with 48 weeks of therapy. HCV-6 is also considered an easy-to-treat genotype, leading to a response in 60-85% of cases.

Peer Review Bias: A Critical Review.

Various types of bias and confounding have been described in the biomedical literature that can affect a study before, during, or after the intervention has been delivered. The peer review process can also introduce bias. A compelling ethical and moral rationale necessitates improving the peer review process. A double-blind peer review system is supported on equipoise and fair-play principles. Triple- and quadruple-blind systems have also been described but are not commonly used. The open peer review system introduces "Skin in the Game" heuristic principles for both authors and reviewers and has a small favorable effect on the quality of published reports. In this exposition, we present, on the basis of a comprehensive literature search of PubMed from its inception until October 20, 2017, various possible mechanisms by which the peer review process can distort research results, and we discuss the evidence supporting different strategies that may mitigate this bias. It is time to improve the quality, transparency, and accountability of the peer review system.

Acute pancreatitis associated with intravenous administration of propofol: evaluation of causality in a systematic review of the literature.

Acute pancreatitis (AP) associated with intravenous administration of propofol has been described with unknown causal relation. We therefore assessed this causality in a systematic review. Multiple databases were searched on 16 August 2017; studies were appraised and selected by two reviewers based on a priori criteria. Propofol causality was evaluated with the Naranjo scale and Badalov classification. We identified 18 studies from 11 countries with a total of 21 patients, and the majority had adequate methodological quality. The median age was 35 years (range, 4-77) and 10 (48%) were males. Overall, propofol was administrated in 8 patients as sedative along with induction/maintenance of anesthesia in 13 patients; median dose was 200 mg, with intermediate latency (1-30 days) in 14 (67%). Serum triglycerides were >1000 mg/dL in four patients. Severe AP was observed in four patients (19%). AP recurrence occurred in one out of two patients who underwent rechallenge. Mortality related to AP was 3/21(14%). Propofol was the probable cause of AP according to the Naranjo scale in 19 patients (89%). Propofol-induced AP has a probable causal relation and evidence supports Badalov class Ib. Hypertriglyceridemia is not the only mechanism by which propofol illicit AP. Propofol-induced AP was severe in 19% of patients with a mortality rate related to AP of 14%. Future research is needed to delineate whether this risk is higher if combined with other procedures that portend inherent risk of pancreatitis such as endoscopic retrograde cholangiopancreatography.

Volvulus of the ileal pouch-anal anastomosis: a meta-narrative systematic review of frequency, diagnosis, and treatment outcomes.

BACKGROUND: Proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the surgical procedure of choice for medically refractory ulcerative colitis and familial adenomatous polyposis. While rare, a pouch volvulus can occur. We aimed to determine the frequency, presentation, and management approach of pouch volvulus in patients with IPAA. METHODS: A systematic search of published literature was performed by a medical reference librarian on 10 August 2018 and two independent reviewers identified relevant publications, extracted data, and assessed the methodological quality based on a validated tool. A retrospective review of the Mayo Clinic electronic medical records identified one case of pouch volvulus between January 2008 and August 2018. RESULTS: The frequency of pouch volvulus from one large published study reporting long-term outcomes of IPAA was 0.18% (3/1,700). A total of 22 patients (18 ulcerative colitis) were included (median age 32 years, 73% females). Median time to volvulus after IPAA was 36 months while median interval to volvulus diagnosis from symptom onset was 24 hours. Abdominal pain was the most commonly reported symptom (76%). The diagnosis was made primarily by abdominal computed tomography (13/17 patients, 76%). Endoscopic treatment was successful in 1 of 11 patients (9%). Surgery was performed in 20 patients and pouch-pexy and pouch excision were the most frequent surgical operations. A redo IPAA was performed in five patients (25%). CONCLUSION: Pouch volvulus is a rare but serious complication of IPAA and should be suspected even in the absence of obstruction symptoms. Endoscopic treatment often fails and surgery is effective when performed early.

Methodological quality and synthesis of case series and case reports.

Case reports and case series are uncontrolled study designs known for increased risk of bias but have profoundly influenced the medical literature and continue to advance our knowledge. In this guide, we present a framework for appraisal, synthesis and application of evidence derived from case reports and case series. We propose a tool to evaluate the methodological quality of case reports and case series based on the domains of selection, ascertainment, causality and reporting and provide signalling questions to aid evidence-based practitioners and systematic reviewers in their assessment. We suggest using evidence derived from case reports and case series to inform decision-making when no other higher level of evidence is available.

Peribiliary cysts: a systematic review and proposal of a classification framework.

OBJECTIVE: Peribiliary cysts are usually benign, although severe complications and mortality may occur, and they may be confounded with other diseases. No classification delineating their different characteristics exists. DESIGN: We performed a systematic review of the frequency and clinical manifestations of peribiliary cysts. Two reviewers identified studies after searching multiple databases on 2 August 2017. RESULTS: These cysts were prevalent in cirrhosis (9%). A total of 135 patients were reported in 72 papers with sufficient clinical data (10 countries, 65% from Japan, median age 63 years (range: 4-88), and 80% were males). Symptoms were present in 70%. Misdiagnosis occurred in 40%, and 33% underwent therapeutic misadventures. Cysts were solitary in 10%. Obstructive features and cholangitis were observed in 36% and 12.5%, respectively. Cysts progression was observed in 37.5% over a median of 18 months. Mortality was 24%, mostly due to cirrhosis. A classification framework is proposed, wherein type I includes hepatic, type II extrahepatic and type III mixed hepatic and extrahepatic cysts, each having distinct features. Specifically, type II was more frequent in females, solitary, without cirrhosis, presenting with obstructive jaundice, more difficult to diagnose and required more surgical interventions (all p<0.05). CONCLUSION: Although rarely studied in the literature, peribiliary cysts were frequent in studies designed to evaluate their prevalence, and were mostly asymptomatic. Inaccurate diagnosis, therapeutic misadventures, cysts progression and cysts-related complications are frequent. In a novel classification framework based on location, extrahepatic peribiliary cysts have distinct characteristics and require a special approach for diagnosis and management.