{"paper_id":"486fecf8-90bc-43a1-99b3-ceef23ee1e36","body_text":"A meta-analysis of cumulative incidence of hepatocellular carcinoma after the Fontan operation | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A meta-analysis of cumulative incidence of hepatocellular carcinoma after the Fontan operation Sophie Hansen, Richard Gilroy, Ian Lindsay, John R. Doty, Ross A. Butschek, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3706635/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 13 Jun, 2024 Read the published version in Digestive Diseases and Sciences → Version 1 posted 7 You are reading this latest preprint version Abstract Background Hepatic complications are increasingly recognized after the Fontan operation. The development of hepatocellular carcinoma (HCC) is associated with high mortality when diagnosed, but its incidence and risk factors are poorly understood. We conducted a systematic review and meta-analysis of the cumulative incidence of HCC after Fontan and associated risk factors. Methods We searched PubMed, CINAHL, and MEDLINE databases for articles reporting the cumulative incidence of HCC after Fontan operation on March 21, 2023. A single-arm random effects meta-analysis was conducted to assess cumulative incidence at 10-, 20-, and 30-years after Fontan. Meta-analysis of the difference of the medians was used to assess the influence of risk factors on the development of HCC. Results Four studies including a total of 1,320 patients reported cumulative incidence. The cumulative incidence of HCC at 10-, 20-, and 30-years after Fontan was 0% (95% CI 0.00-0.01), 2% (0.01–0.06), and 7% (0.03–0.17) respectively. Seven studies including 6,250 patients reported overall incidence of HCC and associated risk factors. At a median 18.4 (IQR 11.9–24.9) years of follow-up, incidence of HCC was 2% (0.01–0.04). Only use of anticoagulation was associated with a lower risk of HCC (RR 0.3, 95% CI 0.1–0.88). Discussion By 30 years after Fontan, cumulative incidence of HCC is high (7%). Risk of HCC development prior to 10-years post-Fontan is low (0%) and HCC screening can be safely deferred in this population. Screening with ultrasound every 6 months starting 20-years post-Fontan is reasonable, however, further research regarding timing, cost-effectiveness, additional risk factors associated with HCC risk, and different screening modalities is required. liver cancer screening congestive hepatopathy congenital heart disease systematic review Figures Figure 1 Figure 2 Figure 3 Introduction The Fontan procedure is a palliative operation for patients with congenital heart disease and single-ventricle physiology which consists of a series of surgeries to reroute systemic venous return directly into the pulmonary arterial confluence bypassing the subpulmonary ventricle. 1 The resulting nonpulsatile passive venous filling of the pulmonary arterial bed results in increased central venous pressure (CVP), hepatic venous congestion, hypoxia, and ultimately progressive hepatic fibrosis. 2 Fontan-associated liver disease (FALD), marked by hepatic fibrosis, cirrhosis, liver dysfunction, and hepatocellular carcinoma (HCC), is increasingly recognized but is not often clinically apparent. The development of hepatocellular carcinoma (HCC) is one of the most feared complications with high mortality when diagnosed, 3 but its incidence and risk factors are poorly understood. We conducted a systematic review and meta-analysis of the incidence and risk factors for the development of HCC after the Fontan operation. Methods This systematic review and meta-analysis are reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. 4 Selection Criteria We included only those studies published as full-text articles in peer-reviewed journals. Retrospective and prospective cohort studies were included, while cross-sectional studies, case reports, case series, or review articles were excluded. Studies that included only those patients with previously known liver disease or liver lesions were excluded. For the cumulative incidence analysis, studies were required to report cumulative incidence of HCC after the Fontan procedure. For the analysis of HCC risk factors, studies were required to report incidence of HCC and potential risk factors in those with HCC. Data Sources and Search Strategy Our detailed search strategies were designed with input from an experienced medical librarian and can be found in Supplemental Table 1. We searched PubMed, CINAHL, and MEDLINE databases from inception through March 21, 2023 using the search terms (and synonyms) in various combinations: “Fontan procedure”, “liver neoplasms”, and “incidence”. The titles, abstracts, and/or full texts of the resulting studies were screened by two reviewers (S.H. and C.D.) to determine their eligibility. Any disputes were mediated through discussion between the two reviewers. Data Extraction and Quality Assessment Two reviewers (S.H and C.D.) independently extracted the following data from all included studies: authorship, year of publication, country of origin, study design, inclusion/exclusion criteria, diagnostic criteria for HCC or cirrhosis, overall incidence of HCC, cumulative incidence of HCC at 10-, 20-, and 30-years post-Fontan, age at last follow-up or HCC diagnosis, sex, duration of follow-up, time to HCC development, presence of cirrhosis, type of Fontan, MELD score, ejection fraction, central venous pressure (CVP), brain natriuretic peptide (BNP), platelet count, alanine aminotransferase (ALT), total bilirubin, international normalized ratio (INR), anticoagulation status, presence of protein-losing enteropathy (PLE), presence of situs inversus, body mass index (BMI), FIB-4 score, and alpha-fetoprotein (AFP) level. All clinical characteristics were from time of most recent follow-up or at HCC diagnosis. Discrepancies were settled through discussion between the two reviewers. The quality of individual studies were assessed using a modified Newcastle-Ottawa Scale (Supplemental Table 2), awarding a maximum of 7 points (indicating maximal study quality), subdivided by patient selection (0–3 stars), comparability of patient cohorts (0–1 stars), and clinical outcomes and follow-up (0–3 stars). Statistical Analysis The primary outcome of cumulative incidence of HCC at 10-, 20-, and 30-years post-Fontan was meta-analyzed using a single-arm random effects model using the meta package in RStudio (version 1.3.1093). Only one study reported annual incidence or person-years of follow-up, so annual incidence was estimated using the formula: Annual Incidence = -((ln(1 -Cumulative Incidence))/Time). Heterogeneity between studies was quantified using the I 2 statistic (where I 2 > 50% was considered significant heterogeneity). Meta-regression analysis was conducted to evaluate study-level effect of variables on the development of HCC. The median difference between clinical variables in those with and without HCC was meta-analyzed using the “metamedian” package in RStudio as described by McGrath et al. 5 Median-based methods are superior to mean-based methods as the proportion of studies reporting medians increases. 5 The majority of studies reported median as the outcome for variables evaluated, hence median-based methods were used where applicable. All statistical tests were 2-tailed with a significance threshold of p < 0.05. Results The PRISMA flow diagram for study selection is shown in Fig. 1 . The initial database search returned 24 unique publications of which 7 met criteria for inclusion in our meta-analysis. All studies were retrospective cohorts. Six cohorts were derived from consecutive Fontan patients at surgical centers performing the procedure, while one identified patients using an electronic medical record search at a single institution. Two studies only included those patients with a histopathologic diagnosis of HCC, while the remaining studies allowed for imaging findings consistent with HCC (Table 1 ). Table 1 Characteristics of included studies Author/ Year Design Setting Inclusion Criteria Exclusion Criteria Patients (n) Duration follow-up (years [median, IQR]) HCC definition Egbe 2018 19 Retrospective cohort Multicenter Consecutive Fontan patients None 2470 NR Pathology Nandwana 2018 20 Retrospective cohort Single center All Fontan patients identified by EMR search Excluded those without abdominal imaging or age < 18 at time of study 145 NR Imaging findings Wilson 2020 21 Retrospective cohort Multicenter All Fontan patients in Australia/New Zealand Excluded those who did not consent (n = 68) 1620 Mean 12.7 Pathology or imaging findings Yoon 2020 9 Retrospective cohort Single center Consecutive Fontan patients with > 5 years follow-up Excluded those without abdominal imaging 313 18.6 (13.5–23.4) Pathology or imaging findings with elevated AFP Ohuchi 2022 10 Retrospective cohort Single center Consecutive Fontan patients Excluded those without > 6mo follow-up, moved, died, or dropped out before study inception 339 25.6 (13.3–32.1) Pathology Sakamori 2022 22 Retrospective cohort Single center Consecutive Fontan patients Excluded HBsAg + or HCV ab + patients, those without HBsAg or HCV antibody data or data regarding Fontan date/type and those without hepatic imaging post-Fontan 103 19.6 (1.0-37.7) Imaging findings Inuzuka 2023 23 Retrospective cohort Multicenter Consecutive Fontan patients who survived the operation and were discharged before 2011 Excluded those without postoperative cardiac catheterization data (11% of patients) 1117 10.3 (7.3–16.4) Pathology or imaging findings with elevated AFP HCC, hepatocellular carcinoma; IQR, interquartile range; NR, not reported; EMR, electronic medical record; AFP, alpha fetoprotein; HBsAg, hepatitis B surface antigen; HCV, hepatitis C antibody Cumulative Incidence Four studies including a total of 1,320 patients reported cumulative incidence and were included in the meta-analysis for cumulative incidence (Fig. 2 ). The cumulative incidence of HCC at 10-, 20-, and 30-years after Fontan was 0% (95% CI 0.00-0.01), 2% (0.01–0.06), and 7% (0.03–0.17) respectively (Fig. 2 ) corresponding to an estimated annual incidence of 0%, 0.2%, and 0.73% at 10-, 20-, and 30-years, respectively. Heterogeneity was low at 10 and 30 years ( I 2 = 0%), but moderate at 20 years ( I 2 = 67%). On metaregression, only duration of follow-up was significantly associated with HCC incidence (OR 1.31, 95% CI 1.1–1.57). Gender, manner of HCC diagnosis, prevalence of cirrhosis, anticoagulation use, Fontan type, and congenital anatomical diagnosis were not associated with HCC incidence on a study-wide level. Risk Factors for HCC Seven studies including a total of 6,250 patients were included in the analysis of risk factors for HCC. Over a median 18.4 (11.9–24.9) years of follow-up, overall incidence of HCC was 2% (0.01–0.04) (Fig. 3 ). Heterogeneity was high ( I 2 = 89%). Only age at last follow-up or HCC diagnosis, use of anticoagulation, and presence of situs inversus were reported for both those with and without HCC in two or more studies and were able to be used for meta-analysis. Of these, only anticoagulation use was associated with a significantly lower risk of HCC (RR 0.3, 95% CI 0.1–0.88). Sex, duration of follow-up, time to HCC development, presence of cirrhosis, Fontan type, MELD score, ejection fraction, CVP, BNP, platelet count, ALT, total bilirubin, INR, anticoagulation status, presence of PLE, BMI, FIB-4 score, and AFP level were not reported for both HCC and non-HCC groups in more than one study. Study Quality Overall study quality was low (Table 2 ). Only one study was rated 5 of 7 using a modified Newcastle-Ottawa scale. Table 2 Quality assessment of included studies using a modified Newcastle-Ottawa Scale Author/ Year Representativeness Ascertainment of exposure Demonstration that outcome not present Comparability of cohorts Assessment of outcome Follow-up long enough? Adequacy of follow-up Sum Egbe 2018 1 1 0 0 1 0 0 3 Nandwana 2018 0 1 1 0 0 0 0 2 Wilson 2020 1 1 1 0 0 0 0 3 Yoon 2020 0 1 1 0 0 0 0 2 Ohuchi 2022 1 1 0 1 1 1 0 5 Sakamori 2022 0 1 1 1 0 0 0 3 Inuzuka 2023 0 1 1 0 0 0 2 Discussion By 30 years after Fontan, cumulative incidence of HCC is high (7%). At the same time, risk of HCC prior to 10 years post-Fontan is extremely low (0%; 95% CI 0.00-0.01) and screening for HCC can be safely deferred in this population. Unfortunately, beyond 10 years post-Fontan, the ideal timing for HCC screening and those risk factors associated with HCC development that might guide screening remains unclear. The timing of when to start HCC screening is determined by the level of risk for HCC while taking into account age, health, functional status, and cost. Interventions costing less than 50,000 U.S. dollars/year of life gained are generally considered cost-effective. 6 The annual incidence at which HCC screening becomes cost-effective in the Fontan population has not been determined. Non-cirrhotic hepatitis B patients who tend to be younger with less chronic medical comorbidities than those with cirrhosis, in whom the threshold incidence for cost-effective screening is 1.5% per year, 7 may best approximate the Fontan population. In non-cirrhotic hepatitis B, ultrasound and alpha-fetoprotein (AFP) every 6 months is thought to be cost-effective at an annual HCC incidence of > 0.2%. 8 We were unable to directly meta-analyze annual incidence with the data provided. Yoon et al reported an annual incidence of 0.12% over 5875.9 person-years of follow-up, 9 however, incidence increases significantly over time and low annual incidence averaged over a median follow-up of 18.6 years does not necessarily mean screening can be safely deferred in later decades. Ohuchi et al. did break down annual incidence by decade which suggests those over 20 years post-Fontan may benefit from HCC screening (annual incidence 0.43%) and certainly over 30 years in which the reported annual incidence was 8.83% (n = 21 patients). 10 When estimating from meta-analyzed cumulative incidence, annual incidence is 0%, 0.2%, and 0.73% at 10-, 20-, and 30-years respectively which would also support screening 20-years post-Fontan if using cut-offs for non-cirrhotic hepatitis B. Recently published European Association for the Study of the Liver (EASL) guidelines, suggest screening starting 10-years post-Fontan. 11 However, based on our analysis, annual incidence 10–20 years after Fontan is between 0-0.2% and cannot be definitely recommended. Whether there are any risk factors that may be helpful in targeting screening remains to be seen. Of the variables collected, only age at last follow-up or HCC diagnosis, use of anticoagulation, or presence of situs inversus were reported in both HCC and control populations in two or more studies. Of these, only anticoagulation use was significantly associated with a lower risk of HCC (RR 0.3, p-value 0.03). The mechanism by which anticoagulation would reduce HCC risk is unclear and whether those not on anticoagulation require earlier surveillance cannot be assessed in this study. The development of cirrhosis is typically used as the trigger for HCC screening in other forms of chronic liver disease. 7 However, presence of cirrhosis was not reported in both HCC and control groups in more than one study and could not be meta-analyzed in the present study. Yoon et al. did report an annual incidence of HCC of 1.04% in those once cirrhosis was diagnosed which suggest this as another potential trigger to start HCC screening, 9 however, the diagnosis of cirrhosis in Fontan patients is complicated. Traditional methods such as liver surface nodularity on imaging, platelet level, splenomegaly, transient elastography, and even presence of ascites or esophageal varices are not necessarily reliable measures of the presence of cirrhosis in Fontan patients 12 and the definition of cirrhosis used in studies involving the Fontan populations is very heterogeneous. Despite these challenges, non-invasive laboratory assessment of cirrhosis using FIB-4 may be effective in stratifying risk of HCC. Ohuchi et al. reported mean FIB-4 of 1.91 (SD 0.99–3.20) in those with HCC compared to 0.62 (SD 0.4–1.08) in those without HCC (p-value < 0.05). 10 Similarly, Yoon et al. reported an odds ratio of 3.5 (95% CI 1.61–7.64) for HCC risk in those with a FIB-4 ≥ 0.12 vs. < 0.12. 9 Due to different reporting methods, these results were unable to be combined in meta-analysis. Kogiso et al. also report higher FIB-4 levels (mean 1.8, SD 0.53–4.59) in those with HCC compared to those without (mean 0.82, SD 0.15–6.30). 13 This study was not included in the meta-analysis since it only included Fontan patients with previously known liver disease or liver lesions. The best modality for HCC screening in Fontan patients is also unclear. While cross-sectional imaging with MRI or CT certainly have higher sensitivity for identifying all types of liver nodules in FALD, the clinical significance of this is not known. In one prospective study, MRI or CT identified 2 suspicious nodules in 8 patients which were not identified by ultrasound, however, these were not confirmed to be HCC on biopsy. 14 In one systematic review, 9 out of 10 nodules ultimately diagnosed as HCC were visible on ultrasound. 15 Until better data becomes available, screening with ultrasound every 6 months is reasonable. One limitation of the current study is the quality of the included studies (Table 2 ). Studies used a variety of criteria for defining HCC including both imaging and histopathologic findings (Table 1 ). Imaging alone is not sufficient for diagnosing HCC in post-Fontan patients and, while elevated AFP combined with imaging findings is suggestive of HCC, no AFP cut-off levels for accurate diagnosis have been defined. 16 Including HCC patients diagnosed with imaging alone runs the risk of overestimating HCC incidence. Two studies included only patients with biopsy-proven HCC (Table 1 ). Only one of these reported cumulative incidence of HCC, but including only these two studies in a sensitivity analysis of HCC overall incidence did not change estimates (0.02, 95% CI 0.01–0.04). Another source of heterogeneity is the inclusion/exclusion criteria used. The majority of studies included consecutive patients who underwent Fontan at a single center, however one identified patients using ICD codes (Table 1 ). Several studies excluded those without abdominal imaging regardless of follow-up time which may either result in under- or overestimating HCC incidence depending on the characteristics of those excluded. Limited duration of follow-up was also a limitation for most studies. Of all included studies, only Ohuchi et al had a median follow-up > 20 years (Table 1 ). Duration of follow-up was the only variable associated with HCC risk at a study-wide level on metaregression (OR 1.31, 95% CI 1.1–1.57) while controlling for gender, manner of HCC diagnosis, prevalence of cirrhosis, anticoagulation use, Fontan type, and congenital anatomical diagnosis, indicating short duration of follow-up as a shortcoming for most included studies. Many studies also reported only clinical characteristics of those with HCC and not of the control population without HCC which limited our ability to assess risk factors associated with HCC. In summary, risk of HCC in post-Fontan patients is low in the first decade after the Fontan procedure and HCC screening can be safely deferred during this period. After this, HCC risk increases with each decade that passes, with an estimated annual incidence of 0.2% and 0.73% at 20- and 30-years post-Fontan respectively. Using annual incidence cut-offs for non-cirrhotic hepatitis B, screening with ultrasound and AFP every 6 months would become cost-effective 20-years post-Fontan, however due to difference between the hepatitis B and Fontan populations, this cannot be recommended with certainty in the Fontan population. In addition, improvements in patient care and evolving life expectancy and quality of life in the Fontan population may complicate assessment of cost-effectiveness of HCC screening. 17 , 18 Future studies should report annual HCC incidence by decade post-Fontan, incidence by method of diagnosis (pathology or imaging), and report risk factors such as FIB-4 and MELD-Xi in the control population to help delineate when HCC screening becomes appropriate in those 10–30 years post-Fontan. Abbreviations AFP, alpha fetoprotein; ALT, alanine aminotransferase; BMI, body mass index; BNP, brain natriuretic peptide; CI, confidence interval; CVP, central venous pressure; HCC, hepatocellular carcinoma; INR, international normalized ratio; MELD, model for end-stage liver disease; OR, odds ratio; PLE; protein-losing enteropathy; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-analyses; RR, risk ratio Declarations Acknowledgments: Thank you to Brianna Patterson, medical librarian, who assisted in database search and manuscript acquisition. Declarations: The authors have no conflicts of interest to declare. Ethics approval: This systematic review and meta-analysis are reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. The Intermountain IRB has confirmed that no ethics approval is required. Author contributions: Sophie Hansen, Richard Gilroy, Christopher J. Danford: study concept and design. Sophie Hansen and Christopher J. Danford: data extraction and analysis. All authors: manuscript preparation and critical manuscript review Financial support and sponsorship: none Conflicts of interest: nothing to report References Fontan F, Baudet E. Surgical repair of tricuspid atresia. Thorax . 1971;26(3):240-248. doi:10.1136/thx.26.3.240 Simonetto DA, Yang H yin, Yin M, et al. Chronic passive venous congestion drives hepatic fibrogenesis via sinusoidal thrombosis and mechanical forces. Hepatology . 2015;61(2):648-659. doi:10.1002/hep.27387 Rodriguez De Santiago E, Téllez L, Guerrero A, Albillos A. Hepatocellular carcinoma after Fontan surgery: A systematic review. Hepatology Research . 2021;51(1):116-134. doi:10.1111/hepr.13582 Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ . 2021;372:n71. doi:10.1136/bmj.n71 McGrath S, Sohn H, Steele R, Benedetti A. Meta-analysis of the difference of medians. Biom J . 2020;62(1):69-98. doi:10.1002/bimj.201900036 Laupacis A, Feeny D, Detsky AS, Tugwell PX. How attractive does a new technology have to be to warrant adoption and utilization? Tentative guidelines for using clinical and economic evaluations. CMAJ . 1992;146(4):473-481. Marrero JA, Kulik LM, Sirlin CB, et al. Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology . 2018;68(2):723-750. doi:10.1002/hep.29913 Bruix J, Sherman M, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology . 2011;53(3):1020-1022. doi:10.1002/hep.24199 Yoon JS, Lee DH, Cho EJ, et al. Risk of Liver Cirrhosis and Hepatocellular Carcinoma after Fontan Operation: A Need for Surveillance. Cancers (Basel) . 2020;12(7). doi:10.3390/cancers12071805 Ohuchi H, Hayama Y, Nakajima K, Kurosaki K, Shiraishi I, Nakai M. Incidence, Predictors, and Mortality in Patients With Liver Cancer After Fontan Operation. J Am Heart Assoc . 2021;10(4):e016617. doi:10.1161/JAHA.120.016617 Téllez L, Payancé A, Tjwa E, et al. EASL-ERN position paper on liver involvement in patients with Fontan-type circulation. J Hepatol . 2023;79(5):1270-1301. doi:10.1016/j.jhep.2023.07.013 Munsterman ID, Duijnhouwer AL, Kendall TJ, et al. The clinical spectrum of Fontan-associated liver disease: results from a prospective multimodality screening cohort. Eur Heart J . 2019;40(13):1057-1068. doi:10.1093/eurheartj/ehy620 Kogiso T, Sagawa T, Taniai M, et al. Risk factors for Fontan-associated hepatocellular carcinoma. PLoS One . 2022;17(6):e0270230. doi:10.1371/journal.pone.0270230 Téllez L, Rodríguez de Santiago E, Minguez B, et al. Prevalence, features and predictive factors of liver nodules in Fontan surgery patients: The VALDIG Fonliver prospective cohort. J Hepatol . 2020;72(4):702-710. doi:10.1016/j.jhep.2019.10.027 Yao J V., Sood S, Lokan J, Murugasu A, Grigg L, Zentner D. Hepatic adenoma masquerading as a hepatocellular carcinoma in a patient with a Fontan procedure on the oral contraceptive pill. Intern Med J . 2021;51(4):613-615. doi:10.1111/imj.15267 Wells ML, Hough DM, Fidler JL, Kamath PS, Poterucha JT, Venkatesh SK. Benign nodules in post-Fontan livers can show imaging features considered diagnostic for hepatocellular carcinoma. Abdom Radiol (NY) . 2017;42(11):2623-2631. doi:10.1007/s00261-017-1181-9 Kasparian NA, Kovacs AH. Quality of Life and Other Patient-Reported Outcomes Across the Life Span Among People With Fontan Palliation. Can J Cardiol . 2022;38(7):963-976. doi:10.1016/j.cjca.2022.04.025 Hedlund E, Lundell B. Fontan circulation has improved life expectancy for infants born with complex heart disease over the last 50 years but has also resulted in significant morbidity. Acta Paediatr . 2022;111(1):11-16. doi:10.1111/apa.16023 Egbe AC, Poterucha JT, Warnes CA, et al. Hepatocellular Carcinoma After Fontan Operation: Multicenter Case Series. Circulation . 2018;138(7):746-748. doi:10.1161/CIRCULATIONAHA.117.032717 Nandwana SB, Olaiya B, Cox K, Sahu A, Mittal P. Abdominal Imaging Surveillance in Adult Patients After Fontan Procedure: Risk of Chronic Liver Disease and Hepatocellular Carcinoma. Curr Probl Diagn Radiol . 2018;47(1):19-22. doi:10.1067/j.cpradiol.2017.04.002 Wilson TG, Iyengar AJ, Hardikar W, Sood S, d’Udekem Y. Prevalence of hepatocellular carcinoma in the entire Fontan population of Australia and New Zealand. JTCVS Tech . 2020;2:128-130. doi:10.1016/j.xjtc.2020.03.008 Sakamori R, Yamada R, Tahata Y, et al. The absence of warfarin treatment and situs inversus are associated with the occurrence of hepatocellular carcinoma after Fontan surgery. J Gastroenterol . 2022;57(2):111-119. doi:10.1007/s00535-021-01842-8 Inuzuka R, Nii M, Inai K, et al. Predictors of liver cirrhosis and hepatocellular carcinoma among perioperative survivors of the Fontan operation. Heart . 2023;109(4):276-282. doi:10.1136/heartjnl-2022-320940 Additional Declarations No competing interests reported. Supplementary Files Supplementalmaterial.docx Cite Share Download PDF Status: Published Journal Publication published 13 Jun, 2024 Read the published version in Digestive Diseases and Sciences → Version 1 posted Editorial decision: Revision requested 06 Apr, 2024 Reviews received at journal 09 Mar, 2024 Reviewers agreed at journal 17 Feb, 2024 Reviewers invited by journal 17 Feb, 2024 Editor assigned by journal 14 Feb, 2024 Submission checks completed at journal 13 Feb, 2024 First submitted to journal 04 Dec, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-3706635\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Research Article\",\"associatedPublications\":[],\"authors\":[{\"id\":272919775,\"identity\":\"efd7d061-38d5-4ba1-9c02-c4cd11747f5c\",\"order_by\":0,\"name\":\"Sophie Hansen\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"University of Utah\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Sophie\",\"middleName\":\"\",\"lastName\":\"Hansen\",\"suffix\":\"\"},{\"id\":272919776,\"identity\":\"97ecc2c8-2baa-4fd2-bcc5-5ef0b4acb551\",\"order_by\":1,\"name\":\"Richard Gilroy\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Intermountain Medical Center\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Richard\",\"middleName\":\"\",\"lastName\":\"Gilroy\",\"suffix\":\"\"},{\"id\":272919777,\"identity\":\"41b01d2f-5221-4293-bdbc-f8611f8d91fb\",\"order_by\":2,\"name\":\"Ian Lindsay\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"University of Utah\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Ian\",\"middleName\":\"\",\"lastName\":\"Lindsay\",\"suffix\":\"\"},{\"id\":272919778,\"identity\":\"025e2ad1-a49a-4c16-81ad-619245207c03\",\"order_by\":3,\"name\":\"John R. Doty\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Intermountain Medical Center\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"John\",\"middleName\":\"R.\",\"lastName\":\"Doty\",\"suffix\":\"\"},{\"id\":272919779,\"identity\":\"7dc898fc-d78b-474e-b3e0-8cafde623735\",\"order_by\":4,\"name\":\"Ross A. Butschek\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Intermountain Medical Center\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Ross\",\"middleName\":\"A.\",\"lastName\":\"Butschek\",\"suffix\":\"\"},{\"id\":272919780,\"identity\":\"989e1fd2-8797-473e-af32-733df2135b4d\",\"order_by\":5,\"name\":\"Christopher J. Danford\",\"email\":\"data:image/png;base64,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\",\"orcid\":\"\",\"institution\":\"Intermountain Medical Center\",\"correspondingAuthor\":true,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Christopher\",\"middleName\":\"J.\",\"lastName\":\"Danford\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2023-12-04 19:14:08\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-3706635/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-3706635/v1\",\"draftVersion\":[],\"editorialEvents\":[{\"content\":\"https://doi.org/10.1007/s10620-024-08470-1\",\"type\":\"published\",\"date\":\"2024-06-13T15:19:21+00:00\"}],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":51189875,\"identity\":\"4a26020f-8731-45ea-aac8-9b1c89e4bbea\",\"added_by\":\"auto\",\"created_at\":\"2024-02-15 16:52:14\",\"extension\":\"jpg\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":69528,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003ePRISMA flow diagram of study selection\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Figure1.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-3706635/v1/83c3fb33655103c5dc5afa17.jpg\"},{\"id\":51189878,\"identity\":\"7816c2bb-94d8-41de-98f6-421f2cd79aa9\",\"added_by\":\"auto\",\"created_at\":\"2024-02-15 16:52:15\",\"extension\":\"jpg\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":152030,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eForest plots demonstrating cumulative incidence of hepatocellular carcinoma at 10-, 20-, and 30-years post Fontan procedure\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Figure2.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-3706635/v1/96468b97b580fbbe7961a384.jpg\"},{\"id\":51189876,\"identity\":\"9e8e51e1-b500-4b27-97d4-0dd897ca562f\",\"added_by\":\"auto\",\"created_at\":\"2024-02-15 16:52:14\",\"extension\":\"jpg\",\"order_by\":3,\"title\":\"Figure 3\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":66466,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eForest plot demonstrating overall incidence of HCC in the post-Fontan population over a median 18.4 (IQR 11.9-24.9) years of follow-up\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Figure3.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-3706635/v1/74e11ffe8134f91f7fae5d0e.jpg\"},{\"id\":58823122,\"identity\":\"9e0c0e6c-60f9-49d1-b4bb-8602553cdb75\",\"added_by\":\"auto\",\"created_at\":\"2024-06-21 16:53:38\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":811080,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-3706635/v1/f4fc1663-877c-4ec1-abb4-e448cb4cc1a3.pdf\"},{\"id\":51189877,\"identity\":\"deaa21ca-03e7-4825-a110-0638fce6e06e\",\"added_by\":\"auto\",\"created_at\":\"2024-02-15 16:52:15\",\"extension\":\"docx\",\"order_by\":7,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":16123,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Supplementalmaterial.docx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-3706635/v1/b79b95800783b9394a56327c.docx\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"A meta-analysis of cumulative incidence of hepatocellular carcinoma after the Fontan operation\",\"fulltext\":[{\"header\":\"Introduction\",\"content\":\"\\u003cp\\u003eThe Fontan procedure is a palliative operation for patients with congenital heart disease and single-ventricle physiology which consists of a series of surgeries to reroute systemic venous return directly into the pulmonary arterial confluence bypassing the subpulmonary ventricle.\\u003csup\\u003e\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e\\u003c/sup\\u003e The resulting nonpulsatile passive venous filling of the pulmonary arterial bed results in increased central venous pressure (CVP), hepatic venous congestion, hypoxia, and ultimately progressive hepatic fibrosis.\\u003csup\\u003e\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e\\u003c/sup\\u003e Fontan-associated liver disease (FALD), marked by hepatic fibrosis, cirrhosis, liver dysfunction, and hepatocellular carcinoma (HCC), is increasingly recognized but is not often clinically apparent. The development of hepatocellular carcinoma (HCC) is one of the most feared complications with high mortality when diagnosed,\\u003csup\\u003e\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e\\u003c/sup\\u003e but its incidence and risk factors are poorly understood. We conducted a systematic review and meta-analysis of the incidence and risk factors for the development of HCC after the Fontan operation.\\u003c/p\\u003e\"},{\"header\":\"Methods\",\"content\":\"\\u003cp\\u003eThis systematic review and meta-analysis are reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement.\\u003csup\\u003e\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e\\u003c/sup\\u003e\\u003c/p\\u003e \\u003cdiv id=\\\"Sec3\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eSelection Criteria\\u003c/h2\\u003e \\u003cp\\u003eWe included only those studies published as full-text articles in peer-reviewed journals. Retrospective and prospective cohort studies were included, while cross-sectional studies, case reports, case series, or review articles were excluded. Studies that included only those patients with previously known liver disease or liver lesions were excluded. For the cumulative incidence analysis, studies were required to report cumulative incidence of HCC after the Fontan procedure. For the analysis of HCC risk factors, studies were required to report incidence of HCC and potential risk factors in those with HCC.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec4\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eData Sources and Search Strategy\\u003c/h2\\u003e \\u003cp\\u003eOur detailed search strategies were designed with input from an experienced medical librarian and can be found in Supplemental Table\\u0026nbsp;1. We searched PubMed, CINAHL, and MEDLINE databases from inception through March 21, 2023 using the search terms (and synonyms) in various combinations: \\u0026ldquo;Fontan procedure\\u0026rdquo;, \\u0026ldquo;liver neoplasms\\u0026rdquo;, and \\u0026ldquo;incidence\\u0026rdquo;. The titles, abstracts, and/or full texts of the resulting studies were screened by two reviewers (S.H. and C.D.) to determine their eligibility. Any disputes were mediated through discussion between the two reviewers.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec5\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eData Extraction and Quality Assessment\\u003c/h2\\u003e \\u003cp\\u003eTwo reviewers (S.H and C.D.) independently extracted the following data from all included studies: authorship, year of publication, country of origin, study design, inclusion/exclusion criteria, diagnostic criteria for HCC or cirrhosis, overall incidence of HCC, cumulative incidence of HCC at 10-, 20-, and 30-years post-Fontan, age at last follow-up or HCC diagnosis, sex, duration of follow-up, time to HCC development, presence of cirrhosis, type of Fontan, MELD score, ejection fraction, central venous pressure (CVP), brain natriuretic peptide (BNP), platelet count, alanine aminotransferase (ALT), total bilirubin, international normalized ratio (INR), anticoagulation status, presence of protein-losing enteropathy (PLE), presence of situs inversus, body mass index (BMI), FIB-4 score, and alpha-fetoprotein (AFP) level. All clinical characteristics were from time of most recent follow-up or at HCC diagnosis. Discrepancies were settled through discussion between the two reviewers. The quality of individual studies were assessed using a modified Newcastle-Ottawa Scale (Supplemental Table\\u0026nbsp;2), awarding a maximum of 7 points (indicating maximal study quality), subdivided by patient selection (0\\u0026ndash;3 stars), comparability of patient cohorts (0\\u0026ndash;1 stars), and clinical outcomes and follow-up (0\\u0026ndash;3 stars).\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec6\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eStatistical Analysis\\u003c/h2\\u003e \\u003cp\\u003eThe primary outcome of cumulative incidence of HCC at 10-, 20-, and 30-years post-Fontan was meta-analyzed using a single-arm random effects model using the \\u003cem\\u003emeta\\u003c/em\\u003e package in RStudio (version 1.3.1093). Only one study reported annual incidence or person-years of follow-up, so annual incidence was estimated using the formula: Annual Incidence = -((ln(1 -Cumulative Incidence))/Time). Heterogeneity between studies was quantified using the I\\u003csup\\u003e\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e\\u003c/sup\\u003e statistic (where I\\u003csup\\u003e2\\u003c/sup\\u003e\\u0026thinsp;\\u0026gt;\\u0026thinsp;50% was considered significant heterogeneity). Meta-regression analysis was conducted to evaluate study-level effect of variables on the development of HCC. The median difference between clinical variables in those with and without HCC was meta-analyzed using the \\u0026ldquo;metamedian\\u0026rdquo; package in RStudio as described by McGrath et al.\\u003csup\\u003e\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e\\u003c/sup\\u003e Median-based methods are superior to mean-based methods as the proportion of studies reporting medians increases.\\u003csup\\u003e\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e\\u003c/sup\\u003e The majority of studies reported median as the outcome for variables evaluated, hence median-based methods were used where applicable. All statistical tests were 2-tailed with a significance threshold of \\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05.\\u003c/p\\u003e \\u003c/div\\u003e\"},{\"header\":\"Results\",\"content\":\"\\u003cp\\u003eThe PRISMA flow diagram for study selection is shown in Fig.\\u0026nbsp;\\u003cspan class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e. The initial database search returned 24 unique publications of which 7 met criteria for inclusion in our meta-analysis. All studies were retrospective cohorts. Six cohorts were derived from consecutive Fontan patients at surgical centers performing the procedure, while one identified patients using an electronic medical record search at a single institution. Two studies only included those patients with a histopathologic diagnosis of HCC, while the remaining studies allowed for imaging findings consistent with HCC (Table\\u0026nbsp;\\u003cspan class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e).\\u003c/p\\u003e\\n\\u003cdiv class=\\\"gridtable\\\"\\u003e\\n\\u003ctable id=\\\"Taba\\\" border=\\\"1\\\"\\u003e\\u003ccaption\\u003e\\n\\u003cp\\u003eTable 1\\u003c/p\\u003e\\n\\u003cp\\u003eCharacteristics of included studies\\u003c/p\\u003e\\n\\u003c/caption\\u003e\\n\\u003cthead\\u003e\\n\\u003ctr\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eAuthor/\\u003c/p\\u003e\\n\\u003cp\\u003eYear\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eDesign\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eSetting\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eInclusion Criteria\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eExclusion Criteria\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ePatients (n)\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eDuration follow-up (years [median, IQR])\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eHCC definition\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003c/tr\\u003e\\n\\u003c/thead\\u003e\\n\\u003ctbody\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eEgbe 2018\\u003csup\\u003e19\\u003c/sup\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eRetrospective cohort\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eMulticenter\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eConsecutive Fontan patients\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eNone\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e2470\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eNR\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ePathology\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eNandwana 2018\\u003csup\\u003e20\\u003c/sup\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eRetrospective cohort\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eSingle center\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eAll Fontan patients identified by EMR search\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eExcluded those without abdominal imaging or age\\u0026thinsp;\\u0026lt;\\u0026thinsp;18 at time of study\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e145\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eNR\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eImaging findings\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eWilson 2020\\u003csup\\u003e21\\u003c/sup\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eRetrospective cohort\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eMulticenter\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eAll Fontan patients in Australia/New Zealand\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eExcluded those who did not consent (n\\u0026thinsp;=\\u0026thinsp;68)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e1620\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eMean 12.7\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ePathology or imaging findings\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eYoon 2020\\u003csup\\u003e9\\u003c/sup\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eRetrospective cohort\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eSingle center\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eConsecutive Fontan patients with \\u0026gt;\\u0026thinsp;5 years follow-up\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eExcluded those without abdominal imaging\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e313\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e18.6 (13.5\\u0026ndash;23.4)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ePathology or imaging findings with elevated AFP\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eOhuchi 2022\\u003csup\\u003e10\\u003c/sup\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eRetrospective cohort\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eSingle center\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eConsecutive Fontan patients\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eExcluded those without \\u0026gt;\\u0026thinsp;6mo follow-up, moved, died, or dropped out before study inception\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e339\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e25.6 (13.3\\u0026ndash;32.1)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ePathology\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eSakamori 2022\\u003csup\\u003e22\\u003c/sup\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eRetrospective cohort\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eSingle center\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eConsecutive Fontan patients\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eExcluded HBsAg\\u0026thinsp;+\\u0026thinsp;or HCV ab\\u0026thinsp;+\\u0026thinsp;patients, those without HBsAg or HCV antibody data or data regarding Fontan date/type and those without hepatic imaging post-Fontan\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e103\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e19.6 (1.0-37.7)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eImaging findings\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eInuzuka 2023\\u003csup\\u003e23\\u003c/sup\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eRetrospective cohort\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eMulticenter\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eConsecutive Fontan patients who survived the operation and were discharged before 2011\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eExcluded those without postoperative cardiac catheterization data (11% of patients)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e1117\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e10.3 (7.3\\u0026ndash;16.4)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ePathology or imaging findings with elevated AFP\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003c/tbody\\u003e\\n\\u003c/table\\u003e\\n\\u003c/div\\u003e\\n\\u003cp\\u003eHCC, hepatocellular carcinoma; IQR, interquartile range; NR, not reported; EMR, electronic medical record; AFP, alpha fetoprotein; HBsAg, hepatitis B surface antigen; HCV, hepatitis C antibody\\u003c/p\\u003e\\n\\u003cdiv id=\\\"Sec8\\\" class=\\\"Section2\\\"\\u003e\\n\\u003ch2\\u003eCumulative Incidence\\u003c/h2\\u003e\\n\\u003cp\\u003eFour studies including a total of 1,320 patients reported cumulative incidence and were included in the meta-analysis for cumulative incidence (Fig.\\u0026nbsp;\\u003cspan class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e). The cumulative incidence of HCC at 10-, 20-, and 30-years after Fontan was 0% (95% CI 0.00-0.01), 2% (0.01\\u0026ndash;0.06), and 7% (0.03\\u0026ndash;0.17) respectively (Fig.\\u0026nbsp;\\u003cspan class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e) corresponding to an estimated annual incidence of 0%, 0.2%, and 0.73% at 10-, 20-, and 30-years, respectively. Heterogeneity was low at 10 and 30 years (\\u003cem\\u003eI\\u003c/em\\u003e\\u003csup\\u003e2\\u003c/sup\\u003e\\u0026thinsp;=\\u0026thinsp;0%), but moderate at 20 years (\\u003cem\\u003eI\\u003c/em\\u003e\\u003csup\\u003e2\\u003c/sup\\u003e\\u0026thinsp;=\\u0026thinsp;67%). On metaregression, only duration of follow-up was significantly associated with HCC incidence (OR 1.31, 95% CI 1.1\\u0026ndash;1.57). Gender, manner of HCC diagnosis, prevalence of cirrhosis, anticoagulation use, Fontan type, and congenital anatomical diagnosis were not associated with HCC incidence on a study-wide level.\\u003c/p\\u003e\\n\\u003c/div\\u003e\\n\\u003cdiv id=\\\"Sec9\\\" class=\\\"Section2\\\"\\u003e\\n\\u003ch2\\u003eRisk Factors for HCC\\u003c/h2\\u003e\\n\\u003cp\\u003eSeven studies including a total of 6,250 patients were included in the analysis of risk factors for HCC. Over a median 18.4 (11.9\\u0026ndash;24.9) years of follow-up, overall incidence of HCC was 2% (0.01\\u0026ndash;0.04) (Fig.\\u0026nbsp;\\u003cspan class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e). Heterogeneity was high (\\u003cem\\u003eI\\u003c/em\\u003e\\u003csup\\u003e2\\u003c/sup\\u003e\\u0026thinsp;=\\u0026thinsp;89%). Only age at last follow-up or HCC diagnosis, use of anticoagulation, and presence of situs inversus were reported for both those with and without HCC in two or more studies and were able to be used for meta-analysis. Of these, only anticoagulation use was associated with a significantly lower risk of HCC (RR 0.3, 95% CI 0.1\\u0026ndash;0.88). Sex, duration of follow-up, time to HCC development, presence of cirrhosis, Fontan type, MELD score, ejection fraction, CVP, BNP, platelet count, ALT, total bilirubin, INR, anticoagulation status, presence of PLE, BMI, FIB-4 score, and AFP level were not reported for both HCC and non-HCC groups in more than one study.\\u003c/p\\u003e\\n\\u003c/div\\u003e\\n\\u003cdiv id=\\\"Sec10\\\" class=\\\"Section2\\\"\\u003e\\n\\u003ch2\\u003eStudy Quality\\u003c/h2\\u003e\\n\\u003cp\\u003eOverall study quality was low (Table\\u0026nbsp;\\u003cspan class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e). Only one study was rated 5 of 7 using a modified Newcastle-Ottawa scale.\\u003c/p\\u003e\\n\\u003cdiv class=\\\"gridtable\\\"\\u003e\\n\\u003ctable id=\\\"Tab2\\\" border=\\\"1\\\"\\u003e\\u003ccaption\\u003e\\n\\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 2\\u003c/div\\u003e\\n\\u003cdiv class=\\\"CaptionContent\\\"\\u003e\\n\\u003cp\\u003eQuality assessment of included studies using a modified Newcastle-Ottawa Scale\\u003c/p\\u003e\\n\\u003c/div\\u003e\\n\\u003c/caption\\u003e\\n\\u003cthead\\u003e\\n\\u003ctr\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eAuthor/\\u003c/p\\u003e\\n\\u003cp\\u003eYear\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eRepresentativeness\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eAscertainment of exposure\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eDemonstration that outcome not present\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eComparability of cohorts\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eAssessment of outcome\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eFollow-up long enough?\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eAdequacy of follow-up\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eSum\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003c/tr\\u003e\\n\\u003c/thead\\u003e\\n\\u003ctbody\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eEgbe 2018\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e1\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e1\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e1\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e3\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eNandwana 2018\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e1\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e1\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e2\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eWilson 2020\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e1\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e1\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e1\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e3\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eYoon 2020\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e1\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e1\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e2\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eOhuchi 2022\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e1\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e1\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e1\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e1\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e1\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e5\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eSakamori 2022\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e1\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e1\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e1\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e3\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eInuzuka 2023\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e1\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e1\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e2\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003c/tbody\\u003e\\n\\u003c/table\\u003e\\n\\u003c/div\\u003e\\n\\u003c/div\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cp\\u003eBy 30 years after Fontan, cumulative incidence of HCC is high (7%). At the same time, risk of HCC prior to 10 years post-Fontan is extremely low (0%; 95% CI 0.00-0.01) and screening for HCC can be safely deferred in this population. Unfortunately, beyond 10 years post-Fontan, the ideal timing for HCC screening and those risk factors associated with HCC development that might guide screening remains unclear.\\u003c/p\\u003e \\u003cp\\u003eThe timing of when to start HCC screening is determined by the level of risk for HCC while taking into account age, health, functional status, and cost. Interventions costing less than 50,000 U.S. dollars/year of life gained are generally considered cost-effective.\\u003csup\\u003e\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e\\u003c/sup\\u003e The annual incidence at which HCC screening becomes cost-effective in the Fontan population has not been determined. Non-cirrhotic hepatitis B patients who tend to be younger with less chronic medical comorbidities than those with cirrhosis, in whom the threshold incidence for cost-effective screening is 1.5% per year,\\u003csup\\u003e\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e\\u003c/sup\\u003e may best approximate the Fontan population. In non-cirrhotic hepatitis B, ultrasound and alpha-fetoprotein (AFP) every 6 months is thought to be cost-effective at an annual HCC incidence of \\u0026gt;\\u0026thinsp;0.2%.\\u003csup\\u003e8\\u003c/sup\\u003e\\u003c/p\\u003e \\u003cp\\u003eWe were unable to directly meta-analyze annual incidence with the data provided. Yoon et al reported an annual incidence of 0.12% over 5875.9 person-years of follow-up,\\u003csup\\u003e\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e\\u003c/sup\\u003e however, incidence increases significantly over time and low annual incidence averaged over a median follow-up of 18.6 years does not necessarily mean screening can be safely deferred in later decades. Ohuchi et al. did break down annual incidence by decade which suggests those over 20 years post-Fontan may benefit from HCC screening (annual incidence 0.43%) and certainly over 30 years in which the reported annual incidence was 8.83% (n\\u0026thinsp;=\\u0026thinsp;21 patients).\\u003csup\\u003e\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e\\u003c/sup\\u003e When estimating from meta-analyzed cumulative incidence, annual incidence is 0%, 0.2%, and 0.73% at 10-, 20-, and 30-years respectively which would also support screening 20-years post-Fontan if using cut-offs for non-cirrhotic hepatitis B. Recently published European Association for the Study of the Liver (EASL) guidelines, suggest screening starting 10-years post-Fontan.\\u003csup\\u003e\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e\\u003c/sup\\u003e However, based on our analysis, annual incidence 10\\u0026ndash;20 years after Fontan is between 0-0.2% and cannot be definitely recommended.\\u003c/p\\u003e \\u003cp\\u003eWhether there are any risk factors that may be helpful in targeting screening remains to be seen. Of the variables collected, only age at last follow-up or HCC diagnosis, use of anticoagulation, or presence of situs inversus were reported in both HCC and control populations in two or more studies. Of these, only anticoagulation use was significantly associated with a lower risk of HCC (RR 0.3, p-value 0.03). The mechanism by which anticoagulation would reduce HCC risk is unclear and whether those not on anticoagulation require earlier surveillance cannot be assessed in this study.\\u003c/p\\u003e \\u003cp\\u003eThe development of cirrhosis is typically used as the trigger for HCC screening in other forms of chronic liver disease.\\u003csup\\u003e\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e\\u003c/sup\\u003e However, presence of cirrhosis was not reported in both HCC and control groups in more than one study and could not be meta-analyzed in the present study. Yoon et al. did report an annual incidence of HCC of 1.04% in those once cirrhosis was diagnosed which suggest this as another potential trigger to start HCC screening,\\u003csup\\u003e\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e\\u003c/sup\\u003e however, the diagnosis of cirrhosis in Fontan patients is complicated. Traditional methods such as liver surface nodularity on imaging, platelet level, splenomegaly, transient elastography, and even presence of ascites or esophageal varices are not necessarily reliable measures of the presence of cirrhosis in Fontan patients\\u003csup\\u003e\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e\\u003c/sup\\u003e and the definition of cirrhosis used in studies involving the Fontan populations is very heterogeneous.\\u003c/p\\u003e \\u003cp\\u003eDespite these challenges, non-invasive laboratory assessment of cirrhosis using FIB-4 may be effective in stratifying risk of HCC. Ohuchi et al. reported mean FIB-4 of 1.91 (SD 0.99\\u0026ndash;3.20) in those with HCC compared to 0.62 (SD 0.4\\u0026ndash;1.08) in those without HCC (p-value\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05).\\u003csup\\u003e10\\u003c/sup\\u003e Similarly, Yoon et al. reported an odds ratio of 3.5 (95% CI 1.61\\u0026ndash;7.64) for HCC risk in those with a FIB-4\\u0026thinsp;\\u0026ge;\\u0026thinsp;0.12 vs. \\u0026lt; 0.12.\\u003csup\\u003e9\\u003c/sup\\u003e Due to different reporting methods, these results were unable to be combined in meta-analysis. Kogiso et al. also report higher FIB-4 levels (mean 1.8, SD 0.53\\u0026ndash;4.59) in those with HCC compared to those without (mean 0.82, SD 0.15\\u0026ndash;6.30).\\u003csup\\u003e\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e\\u003c/sup\\u003e This study was not included in the meta-analysis since it only included Fontan patients with previously known liver disease or liver lesions.\\u003c/p\\u003e \\u003cp\\u003eThe best modality for HCC screening in Fontan patients is also unclear. While cross-sectional imaging with MRI or CT certainly have higher sensitivity for identifying all types of liver nodules in FALD, the clinical significance of this is not known. In one prospective study, MRI or CT identified 2 suspicious nodules in 8 patients which were not identified by ultrasound, however, these were not confirmed to be HCC on biopsy.\\u003csup\\u003e\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e\\u003c/sup\\u003e In one systematic review, 9 out of 10 nodules ultimately diagnosed as HCC were visible on ultrasound.\\u003csup\\u003e\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e\\u003c/sup\\u003e Until better data becomes available, screening with ultrasound every 6 months is reasonable.\\u003c/p\\u003e \\u003cp\\u003eOne limitation of the current study is the quality of the included studies (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e). Studies used a variety of criteria for defining HCC including both imaging and histopathologic findings (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e). Imaging alone is not sufficient for diagnosing HCC in post-Fontan patients and, while elevated AFP combined with imaging findings is suggestive of HCC, no AFP cut-off levels for accurate diagnosis have been defined.\\u003csup\\u003e\\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e\\u003c/sup\\u003e Including HCC patients diagnosed with imaging alone runs the risk of overestimating HCC incidence. Two studies included only patients with biopsy-proven HCC (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e). Only one of these reported cumulative incidence of HCC, but including only these two studies in a sensitivity analysis of HCC overall incidence did not change estimates (0.02, 95% CI 0.01\\u0026ndash;0.04).\\u003c/p\\u003e \\u003cp\\u003eAnother source of heterogeneity is the inclusion/exclusion criteria used. The majority of studies included consecutive patients who underwent Fontan at a single center, however one identified patients using ICD codes (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e). Several studies excluded those without abdominal imaging regardless of follow-up time which may either result in under- or overestimating HCC incidence depending on the characteristics of those excluded.\\u003c/p\\u003e \\u003cp\\u003eLimited duration of follow-up was also a limitation for most studies. Of all included studies, only Ohuchi et al had a median follow-up \\u0026gt;\\u0026thinsp;20 years (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e). Duration of follow-up was the only variable associated with HCC risk at a study-wide level on metaregression (OR 1.31, 95% CI 1.1\\u0026ndash;1.57) while controlling for gender, manner of HCC diagnosis, prevalence of cirrhosis, anticoagulation use, Fontan type, and congenital anatomical diagnosis, indicating short duration of follow-up as a shortcoming for most included studies. Many studies also reported only clinical characteristics of those with HCC and not of the control population without HCC which limited our ability to assess risk factors associated with HCC.\\u003c/p\\u003e \\u003cp\\u003eIn summary, risk of HCC in post-Fontan patients is low in the first decade after the Fontan procedure and HCC screening can be safely deferred during this period. After this, HCC risk increases with each decade that passes, with an estimated annual incidence of 0.2% and 0.73% at 20- and 30-years post-Fontan respectively. Using annual incidence cut-offs for non-cirrhotic hepatitis B, screening with ultrasound and AFP every 6 months would become cost-effective 20-years post-Fontan, however due to difference between the hepatitis B and Fontan populations, this cannot be recommended with certainty in the Fontan population. In addition, improvements in patient care and evolving life expectancy and quality of life in the Fontan population may complicate assessment of cost-effectiveness of HCC screening.\\u003csup\\u003e\\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e\\u003c/sup\\u003e Future studies should report annual HCC incidence by decade post-Fontan, incidence by method of diagnosis (pathology or imaging), and report risk factors such as FIB-4 and MELD-Xi in the control population to help delineate when HCC screening becomes appropriate in those 10\\u0026ndash;30 years post-Fontan.\\u003c/p\\u003e\"},{\"header\":\"Abbreviations\",\"content\":\"\\u003cp\\u003eAFP, alpha fetoprotein; ALT, alanine aminotransferase; BMI, body mass index; BNP, brain natriuretic peptide; CI, confidence interval; CVP, central venous pressure; HCC, hepatocellular carcinoma; INR, international normalized ratio; MELD, model for end-stage liver disease; OR, odds ratio; PLE; protein-losing enteropathy; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-analyses; RR, risk ratio\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eAcknowledgments:\\u003c/strong\\u003e Thank you to Brianna Patterson, medical librarian, who assisted in database search and manuscript acquisition.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eDeclarations:\\u003c/strong\\u003e The authors have no conflicts of interest to declare.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eEthics approval:\\u0026nbsp;\\u003c/strong\\u003eThis systematic review and meta-analysis are reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. The Intermountain IRB has confirmed that no ethics approval is required.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAuthor contributions:\\u003c/strong\\u003e Sophie Hansen, Richard Gilroy, Christopher J. Danford: study concept and design. Sophie Hansen and Christopher J. Danford: data extraction and analysis. All authors: manuscript preparation and critical manuscript review\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eFinancial support and sponsorship:\\u0026nbsp;\\u003c/strong\\u003enone\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConflicts of interest:\\u003c/strong\\u003e nothing to report\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\n\\u003cli\\u003eFontan F, Baudet E. Surgical repair of tricuspid atresia. \\u003cem\\u003eThorax\\u003c/em\\u003e. 1971;26(3):240-248. doi:10.1136/thx.26.3.240\\u003c/li\\u003e\\n\\u003cli\\u003eSimonetto DA, Yang H yin, Yin M, et al. Chronic passive venous congestion drives hepatic fibrogenesis via sinusoidal thrombosis and mechanical forces. \\u003cem\\u003eHepatology\\u003c/em\\u003e. 2015;61(2):648-659. doi:10.1002/hep.27387\\u003c/li\\u003e\\n\\u003cli\\u003eRodriguez De Santiago E, T\\u0026eacute;llez L, Guerrero A, Albillos A. Hepatocellular carcinoma after Fontan surgery: A systematic review. \\u003cem\\u003eHepatology Research\\u003c/em\\u003e. 2021;51(1):116-134. doi:10.1111/hepr.13582\\u003c/li\\u003e\\n\\u003cli\\u003ePage MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. \\u003cem\\u003eBMJ\\u003c/em\\u003e. 2021;372:n71. doi:10.1136/bmj.n71\\u003c/li\\u003e\\n\\u003cli\\u003eMcGrath S, Sohn H, Steele R, Benedetti A. Meta-analysis of the difference of medians. \\u003cem\\u003eBiom J\\u003c/em\\u003e. 2020;62(1):69-98. doi:10.1002/bimj.201900036\\u003c/li\\u003e\\n\\u003cli\\u003eLaupacis A, Feeny D, Detsky AS, Tugwell PX. How attractive does a new technology have to be to warrant adoption and utilization? Tentative guidelines for using clinical and economic evaluations. \\u003cem\\u003eCMAJ\\u003c/em\\u003e. 1992;146(4):473-481.\\u003c/li\\u003e\\n\\u003cli\\u003eMarrero JA, Kulik LM, Sirlin CB, et al. Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases. \\u003cem\\u003eHepatology\\u003c/em\\u003e. 2018;68(2):723-750. doi:10.1002/hep.29913\\u003c/li\\u003e\\n\\u003cli\\u003eBruix J, Sherman M, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. \\u003cem\\u003eHepatology\\u003c/em\\u003e. 2011;53(3):1020-1022. doi:10.1002/hep.24199\\u003c/li\\u003e\\n\\u003cli\\u003eYoon JS, Lee DH, Cho EJ, et al. Risk of Liver Cirrhosis and Hepatocellular Carcinoma after Fontan Operation: A Need for Surveillance. \\u003cem\\u003eCancers (Basel)\\u003c/em\\u003e. 2020;12(7). doi:10.3390/cancers12071805\\u003c/li\\u003e\\n\\u003cli\\u003eOhuchi H, Hayama Y, Nakajima K, Kurosaki K, Shiraishi I, Nakai M. Incidence, Predictors, and Mortality in Patients With Liver Cancer After Fontan Operation. \\u003cem\\u003eJ Am Heart Assoc\\u003c/em\\u003e. 2021;10(4):e016617. doi:10.1161/JAHA.120.016617\\u003c/li\\u003e\\n\\u003cli\\u003eT\\u0026eacute;llez L, Payanc\\u0026eacute; A, Tjwa E, et al. EASL-ERN position paper on liver involvement in patients with Fontan-type circulation. \\u003cem\\u003eJ Hepatol\\u003c/em\\u003e. 2023;79(5):1270-1301. doi:10.1016/j.jhep.2023.07.013\\u003c/li\\u003e\\n\\u003cli\\u003eMunsterman ID, Duijnhouwer AL, Kendall TJ, et al. The clinical spectrum of Fontan-associated liver disease: results from a prospective multimodality screening cohort. \\u003cem\\u003eEur Heart J\\u003c/em\\u003e. 2019;40(13):1057-1068. doi:10.1093/eurheartj/ehy620\\u003c/li\\u003e\\n\\u003cli\\u003eKogiso T, Sagawa T, Taniai M, et al. Risk factors for Fontan-associated hepatocellular carcinoma. \\u003cem\\u003ePLoS One\\u003c/em\\u003e. 2022;17(6):e0270230. doi:10.1371/journal.pone.0270230\\u003c/li\\u003e\\n\\u003cli\\u003eT\\u0026eacute;llez L, Rodr\\u0026iacute;guez de Santiago E, Minguez B, et al. Prevalence, features and predictive factors of liver nodules in Fontan surgery patients: The VALDIG Fonliver prospective cohort. \\u003cem\\u003eJ Hepatol\\u003c/em\\u003e. 2020;72(4):702-710. doi:10.1016/j.jhep.2019.10.027\\u003c/li\\u003e\\n\\u003cli\\u003eYao J V., Sood S, Lokan J, Murugasu A, Grigg L, Zentner D. Hepatic adenoma masquerading as a hepatocellular carcinoma in a patient with a Fontan procedure on the oral contraceptive pill. \\u003cem\\u003eIntern Med J\\u003c/em\\u003e. 2021;51(4):613-615. doi:10.1111/imj.15267\\u003c/li\\u003e\\n\\u003cli\\u003eWells ML, Hough DM, Fidler JL, Kamath PS, Poterucha JT, Venkatesh SK. Benign nodules in post-Fontan livers can show imaging features considered diagnostic for hepatocellular carcinoma. \\u003cem\\u003eAbdom Radiol (NY)\\u003c/em\\u003e. 2017;42(11):2623-2631. doi:10.1007/s00261-017-1181-9\\u003c/li\\u003e\\n\\u003cli\\u003eKasparian NA, Kovacs AH. Quality of Life and Other Patient-Reported Outcomes Across the Life Span Among People With Fontan Palliation. \\u003cem\\u003eCan J Cardiol\\u003c/em\\u003e. 2022;38(7):963-976. doi:10.1016/j.cjca.2022.04.025\\u003c/li\\u003e\\n\\u003cli\\u003eHedlund E, Lundell B. Fontan circulation has improved life expectancy for infants born with complex heart disease over the last 50 years but has also resulted in significant morbidity. \\u003cem\\u003eActa Paediatr\\u003c/em\\u003e. 2022;111(1):11-16. doi:10.1111/apa.16023\\u003c/li\\u003e\\n\\u003cli\\u003eEgbe AC, Poterucha JT, Warnes CA, et al. Hepatocellular Carcinoma After Fontan Operation: Multicenter Case Series. \\u003cem\\u003eCirculation\\u003c/em\\u003e. 2018;138(7):746-748. doi:10.1161/CIRCULATIONAHA.117.032717\\u003c/li\\u003e\\n\\u003cli\\u003eNandwana SB, Olaiya B, Cox K, Sahu A, Mittal P. Abdominal Imaging Surveillance in Adult Patients After Fontan Procedure: Risk of Chronic Liver Disease and Hepatocellular Carcinoma. \\u003cem\\u003eCurr Probl Diagn Radiol\\u003c/em\\u003e. 2018;47(1):19-22. doi:10.1067/j.cpradiol.2017.04.002\\u003c/li\\u003e\\n\\u003cli\\u003eWilson TG, Iyengar AJ, Hardikar W, Sood S, d\\u0026rsquo;Udekem Y. Prevalence of hepatocellular carcinoma in the entire Fontan population of Australia and New Zealand. \\u003cem\\u003eJTCVS Tech\\u003c/em\\u003e. 2020;2:128-130. doi:10.1016/j.xjtc.2020.03.008\\u003c/li\\u003e\\n\\u003cli\\u003eSakamori R, Yamada R, Tahata Y, et al. The absence of warfarin treatment and situs inversus are associated with the occurrence of hepatocellular carcinoma after Fontan surgery. \\u003cem\\u003eJ Gastroenterol\\u003c/em\\u003e. 2022;57(2):111-119. doi:10.1007/s00535-021-01842-8\\u003c/li\\u003e\\n\\u003cli\\u003eInuzuka R, Nii M, Inai K, et al. Predictors of liver cirrhosis and hepatocellular carcinoma among perioperative survivors of the Fontan operation. \\u003cem\\u003eHeart\\u003c/em\\u003e. 2023;109(4):276-282. doi:10.1136/heartjnl-2022-320940\\u003c/li\\u003e\\n\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":false,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":true,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"digestive-diseases-and-sciences\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"ddsj\",\"sideBox\":\"Learn more about [Digestive Diseases and Sciences](http://link.springer.com/journal/10620)\",\"snPcode\":\"10620\",\"submissionUrl\":\"https://submission.nature.com/new-submission/10620/3\",\"title\":\"Digestive Diseases and Sciences\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"stoa\",\"reportingPortfolio\":\"Springer Hybrid\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":false},\"keywords\":\"liver cancer, screening, congestive hepatopathy, congenital heart disease, systematic review\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-3706635/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-3706635/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003ch2\\u003eBackground\\u003c/h2\\u003e \\u003cp\\u003eHepatic complications are increasingly recognized after the Fontan operation. The development of hepatocellular carcinoma (HCC) is associated with high mortality when diagnosed, but its incidence and risk factors are poorly understood. We conducted a systematic review and meta-analysis of the cumulative incidence of HCC after Fontan and associated risk factors.\\u003c/p\\u003e\\u003ch2\\u003eMethods\\u003c/h2\\u003e \\u003cp\\u003eWe searched PubMed, CINAHL, and MEDLINE databases for articles reporting the cumulative incidence of HCC after Fontan operation on March 21, 2023. A single-arm random effects meta-analysis was conducted to assess cumulative incidence at 10-, 20-, and 30-years after Fontan. Meta-analysis of the difference of the medians was used to assess the influence of risk factors on the development of HCC.\\u003c/p\\u003e\\u003ch2\\u003eResults\\u003c/h2\\u003e \\u003cp\\u003eFour studies including a total of 1,320 patients reported cumulative incidence. The cumulative incidence of HCC at 10-, 20-, and 30-years after Fontan was 0% (95% CI 0.00-0.01), 2% (0.01\\u0026ndash;0.06), and 7% (0.03\\u0026ndash;0.17) respectively. Seven studies including 6,250 patients reported overall incidence of HCC and associated risk factors. At a median 18.4 (IQR 11.9\\u0026ndash;24.9) years of follow-up, incidence of HCC was 2% (0.01\\u0026ndash;0.04). Only use of anticoagulation was associated with a lower risk of HCC (RR 0.3, 95% CI 0.1\\u0026ndash;0.88).\\u003c/p\\u003e\\u003ch2\\u003eDiscussion\\u003c/h2\\u003e \\u003cp\\u003eBy 30 years after Fontan, cumulative incidence of HCC is high (7%). Risk of HCC development prior to 10-years post-Fontan is low (0%) and HCC screening can be safely deferred in this population. Screening with ultrasound every 6 months starting 20-years post-Fontan is reasonable, however, further research regarding timing, cost-effectiveness, additional risk factors associated with HCC risk, and different screening modalities is required.\\u003c/p\\u003e\",\"manuscriptTitle\":\"A meta-analysis of cumulative incidence of hepatocellular carcinoma after the Fontan operation\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2024-02-15 16:52:09\",\"doi\":\"10.21203/rs.3.rs-3706635/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0},{\"type\":\"decision\",\"content\":\"Revision requested\",\"date\":\"2024-04-06T22:03:53+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2024-03-09T16:38:55+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"71ec8aeb-ac84-4f17-a799-9b4d3584fcd5\",\"date\":\"2024-02-17T17:48:13+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewersInvited\",\"content\":\"\",\"date\":\"2024-02-17T15:26:56+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorAssigned\",\"content\":\"\",\"date\":\"2024-02-14T22:55:00+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"checksComplete\",\"content\":\"\",\"date\":\"2024-02-13T14:20:51+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"submitted\",\"content\":\"Digestive Diseases and Sciences\",\"date\":\"2023-12-04T18:59:47+00:00\",\"index\":\"\",\"fulltext\":\"\"}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"digestive-diseases-and-sciences\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"ddsj\",\"sideBox\":\"Learn more about [Digestive Diseases and Sciences](http://link.springer.com/journal/10620)\",\"snPcode\":\"10620\",\"submissionUrl\":\"https://submission.nature.com/new-submission/10620/3\",\"title\":\"Digestive Diseases and Sciences\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"stoa\",\"reportingPortfolio\":\"Springer Hybrid\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":false}}],\"origin\":\"\",\"ownerIdentity\":\"187e9db1-48d1-4826-b4ee-9e860a837d6e\",\"owner\":[],\"postedDate\":\"February 15th, 2024\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"published-in-journal\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2024-06-21T15:19:21+00:00\",\"versionOfRecord\":{\"articleIdentity\":\"rs-3706635\",\"link\":\"https://doi.org/10.1007/s10620-024-08470-1\",\"journal\":{\"identity\":\"digestive-diseases-and-sciences\",\"isVorOnly\":false,\"title\":\"Digestive Diseases and Sciences\"},\"publishedOn\":\"2024-06-13 15:19:21\",\"publishedOnDateReadable\":\"June 13th, 2024\"},\"versionCreatedAt\":\"2024-02-15 16:52:09\",\"video\":\"\",\"vorDoi\":\"10.1007/s10620-024-08470-1\",\"vorDoiUrl\":\"https://doi.org/10.1007/s10620-024-08470-1\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-3706635\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-3706635\",\"identity\":\"rs-3706635\",\"version\":[\"v1\"]},\"buildId\":\"-HB7Z8yhvgn0wM9Nzuekk\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}