Morphologic Alterations Precede Functional Hepatic Impairment as Determined by 13C-Methacetin Liver Function Breath Test in Adult Fontan Patients

Objectives: Fontan-associated liver disease (FALD) is the most common end-organ dysfunction affecting up to 70–80% of the Fontan population. The clinical significance of FALD is incompletely understood and no unambiguous correlation between hepatic function and FALD severity has been established. In this study, we sought to evaluate maximal liver function capacity with liver maximum function capacity test (LiMAx®) in adult Fontan patients.Methods: Thirty-nine adult Fontan patients (median age: 29.4 years [IQR 23.4; 37.4], median follow-up after Fontan operation: 23.9 years [IQR 17.8;26.4]) were analyzed in a cross-sectional observational study using LiMAx® test (Humedics GmbH, Berlin, Germany), laboratory testing, transient elastography (TE) and hepatic ultrasound. The LiMAx® test is based on the metabolism of 13C-methacetin, which is administered intravenously and cleaved by the hepatic cytochrome P4501A2 to paracetamol and 13CO2, which is measured in exhaled air and correlates with maximal liver function capacity.Results: Maximal liver function capacity assessed by LiMAx® test was normal in 28 patients (>315 μg/h*kg) and mildly to moderately impaired in 11 patients (140–314 μg/h*kg), while no patient displayed severe hepatic impairment (<139 μg/kg*h). No correlation was found between maximal liver function capacity and hepatic stiffness by TE (r2 = −0.151; p = 0.388) or the presence of sonographic abnormalities associated with FALD (r2 = −0.204, p = 0.24). There was, however, an association between maximal liver function capacity and the laboratory parameters bilirubin (r2 = −0.333, p = 0.009) and γ-glutamyl transferase (r2 = −0.367; p = 0.021). No correlation was detected between maximal liver function capacity and the severity of FALD (r2 = −0.235; p = 0.152).Conclusion: To the best of our knowledge, this is the first study to evaluate maximal liver function capacity using LiMAx® test in Fontan patients, which is a useful complementary diagnostic instrument to assess chronic hepatic injury. Maximal liver function capacity was preserved in most of our adult Fontan patients despite morphologic evidence of FALD. Moreover, maximal liver function capacity does not correlate with the extent of FALD severity evaluated by sonography or laboratory analysis. Thus, the development and progression of FALD in Fontan patients is not a uniform process and diagnostics of chronic hepatic injury during follow-up should encompass various modalities.

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Impact of the Fontan Operation on Organ Systems

Cardiovascular & Haematological Disorders - Drug Targets ◽

10.2174/1871529x19666190211165124 ◽

2019 ◽

Vol 19 (3) ◽

pp. 205-214

Author(s):

Miriam Michel ◽

Manuela Zlamy ◽

Andreas Entenmann ◽

Karin Pichler ◽

Sabine Scholl-Bürgi ◽

...

Keyword(s):

Systematic Study ◽

Fontan Operation ◽

Gastrointestinal System ◽

Adjunct Treatment ◽

Organ Systems ◽

Fontan Surgery ◽

Fontan Patients

: In patients having undergone the Fontan operation, besides the well discussed changes in the cardiac, pulmonary and gastrointestinal system, alterations of further organ systems including the hematologic, immunologic, endocrinological and metabolic are reported. As a medical adjunct to Fontan surgery, the systematic study of the central role of the liver as a metabolizing and synthesizing organ should allow for a better understanding of the pathomechanism underlying the typical problems in Fontan patients, and in this context, the profiling of endocrinological and metabolic patterns might offer a tool for the optimization of Fontan follow-up, targeted monitoring and specific adjunct treatment.

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Abstract 15268: Development of a Reliable Means of Assessment of Liver Function After the Fontan Operation: Dual Cholate Clearance Assay

Circulation ◽

10.1161/circ.142.suppl_3.15268 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Yuli Y Kim ◽

Greg Everson ◽

Steve Helmke ◽

Jessica Carducci ◽

Andrew C Glatz ◽

...

Keyword(s):

Liver Function ◽

Fontan Operation ◽

Hepatic Clearance ◽

Severity Index ◽

Hepatic Function ◽

Shunt Fraction ◽

Impaired Liver Function ◽

Impaired Liver ◽

Fontan Patients ◽

Normal Controls

Introduction: Currently there is no biomarker or test to accurately measure liver function in Fontan-associated liver disease. The dual cholate test (HepQuant SHUNT) is a noninvasive, flow-dependent assay measuring hepatic clearance of a bile acid, cholate, and may serve as a useful measure of liver function in the Fontan. We aim to measure cholate clearance in a cohort of Fontan patients and compare to normal controls. Methods: Single center, prospective pilot study of Fontan patients ≥ 18 years. Hepatic clearance of orally administered d4-cholate and intravenously administered 13C-cholate were measured in peripheral venous samples after 5, 20, 45, 60, and 90 minutes. Portal hepatic filtration rate (HFR), systemic HFR, shunt fraction (systemic HFR/portal HFR), and disease severity index (DSI) were calculated. Decline in HFRs and increase in shunt fraction or DSI is indicative of impaired liver function. Two-sided t-tests were used to compare values between Fontans and controls. Results: Twelve Fontan patients were enrolled (33% female, median age 29.9 [range 23.6 - 41.0] years). Median total bilirubin was 0.8 (range 0.3-2.1) mg/dL, AST 30.5 (range 16-55) U/L, ALT 32 (range 11-53) U/L, alkaline phosphatase 87 (range 42-191) U/L and platelets 177 (range 130-428) 10 3 /μL. Mean cardiac index was 3.0 ± 0.5 L/min/m 2 . Cholate clearance was lower in Fontans compared to controls (Figure). Mean portal HFR (mL/min/kg) in Fontans was lower than controls (15.1 ± 10.9 vs 29.1 ± 9.0; p<0.001) as well as systemic HFR (3.7 ± 1.3 vs 6.5 ± 1.5; p<0.001) whereas shunt fraction (%) was not (29.2 ± 11.4 vs 24.1 ± 7.5; p=NS). DSI was higher in Fontans compared to controls (19.4 ± 6.1 vs 9.2 ± 3.4; p<0.001). Conclusions: Fontan patients demonstrate reduced hepatic function compared to normal controls but there is considerable variability. Future studies using the dual cholate test will examine the relationship between liver and cardiac function, as well as risk of adverse clinical outcome, in the Fontan.

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Managing adult Fontan patients: where do we stand?

European Respiratory Review ◽

10.1183/16000617.0091-2016 ◽

2016 ◽

Vol 25 (142) ◽

pp. 438-450 ◽

Cited By ~ 16

Author(s):

Paul Clift ◽

David Celermajer

Keyword(s):

Quality Of Life ◽

Life Expectancy ◽

Fontan Operation ◽

Adult Survivors ◽

Late Complications ◽

Therapeutic Interventions ◽

Palliative Procedure ◽

Fontan Patients

The Fontan operation is performed as a palliative procedure to improve survival in infants born with a functionally univentricular circulation. The success of the operation is demonstrated by a growing adult Fontan population that exists with this unique physiology. Late follow-up has demonstrated expected and unexpected sequelae, and has shown multisystem effects of this circulation. This review discusses the challenges of managing the late complications in terms of understanding this unique physiology and the innovative therapeutic interventions that are being investigated. The challenge remains to maintain quality of life for adult survivors, as well as extending life expectancy.

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Lithium Carbonate in the Treatment of Graves’ Disease with ATD-Induced Hepatic Injury or Leukopenia

International Journal of Endocrinology ◽

10.1155/2015/694023 ◽

2015 ◽

Vol 2015 ◽

pp. 1-7 ◽

Cited By ~ 4

Author(s):

Rendong Zheng ◽

Kemian Liu ◽

Kun Chen ◽

Wen Cao ◽

Lin Cao ◽

...

Keyword(s):

Liver Function ◽

Blood Cells ◽

Hepatic Injury ◽

Clinical Effect ◽

Radioiodine Therapy ◽

White Blood Cells ◽

Lithium Carbonate ◽

Graves Disease ◽

Blood Cell Count

Objective. GD with ATD-induced hepatic injury or leukopenia occurs frequently in clinical practice. The purpose of the present study was to observe the clinical effect of lithium carbonate on hyperthyroidism in patients with GD with hepatic injury or leukopenia.Methods. Fifty-one patients with GD with hepatic injury or leukopenia participated in the study. All patients were treated with lithium carbonate, in addition to hepatoprotective drugs or drugs that increase white blood cell count. Thyroid function, liver function, and white blood cells were measured. Clinical outcomes were observed after a 1-year follow-up.Results. After treatment for 36 weeks, symptoms of hyperthyroidism and the level of thyroid hormones were improved and liver function, and white blood cells returned to a normal level. Twelve patients (23.5%) obtained clinical remission, 6 patients (11.8%) relapsed after withdrawal, 25 patients (49.0%) received radioiodine therapy, and 8 patients (15.7%) underwent surgical procedures after lithium carbonate treatment.Conclusion. Lithium carbonate has effects on the treatment of mild-to-moderate hyperthyroidism caused by GD, and it is particularly suitable for patients with ATD-induced hepatic injury or leukopenia.

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Impact of the cardio-hepatic syndrome on outcomes after transcatheter mitral valve edge-to-edge repair

European Heart Journal ◽

10.1093/eurheartj/ehab724.2217 ◽

2021 ◽

Vol 42 (Supplement_1) ◽

Author(s):

L Stolz ◽

M Orban ◽

N Karam ◽

E Lubos ◽

M Wild ◽

...

Keyword(s):

Liver Function ◽

Cox Regression ◽

Cox Model ◽

Hepatic Function ◽

Gamma Glutamyl Transferase ◽

Prognostic Impact ◽

Laboratory Parameters ◽

Glutamyl Transferase ◽

The Impact

Abstract Background The prognostic value of impaired liver function in the presence of moderate-to-severe and severe mitral regurgitation (MR), also called cardio-hepatic syndrome (CHS), for outcomes in patients undergoing transcatheter edge-to-edge repair (TEER) has not been studied yet. Purpose In this work, we aimed at identifying the prognostic impact of the CHS on two-year all-cause mortality in patients undergoing TEER compared to established risk factors. Furthermore, we evaluated the change in hepatic function after TEER. Methods Hepatic function was assessed by laboratory parameters of liver function (bilirubin, gamma glutamyl transferase [GGT], alkaline phosphatase [AP], aspartate and alanine aminotransferase [AST and ALT]). We defined CHS as elevation of at least two out of three laboratory parameters of hepatic cholestasis (bilirubin, GGT, AP). The impact of CHS on two-year mortality was evaluated using a proportional hazards Cox model. The change in hepatic function after TEER was evaluated by repeat laboratory testing at follow-up. Results We included 1083 patients who underwent TEER for highly symptomatic primary or secondary MR at four high volume academic European centers between 2008 and 2019. In 66.4% of patients, we observed elevated levels of either bilirubin, GGT or AP. CHS was present in 23% of patients and showed strong association with a reduced two-year survival (52.9% vs. 87.0% in patients without CHS, p<0.01). In a multivariate Cox regression model, CHS was identified as a strong and independent predictor of increased two-year mortality (hazard ratio 1.49, p=0.03). In patients with successful MR reduction ≤2+ (90.7% of patients), parameters of hepatic function significantly improved from baseline to follow-up (−0.2 mg/dl for bilirubin; −21 U/l for GGT, respectively, p<0.01), while they did not in case of residual postprocedural MR >2+. Conclusions CHS can be observed in up to 25% of patients undergoing TEER and is associated with impaired two-year survival rates. Successful TEER is associated with decreased levels of hepatic enzymes at follow-up evaluation. FUNDunding Acknowledgement Type of funding sources: None. Cardio-hepatic syndrome TEER

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Noninvasive Assessment of Liver Stiffness in Patients Undergoing the Fontan Procedure

World Journal for Pediatric and Congenital Heart Surgery ◽

10.1177/2150135120935418 ◽

2020 ◽

Vol 11 (5) ◽

pp. 572-577 ◽

Cited By ~ 1

Author(s):

Sachin Talwar ◽

Vasubabu Gudala ◽

Raja Joshi ◽

DM Shalimar ◽

Kumble Seetharama Madhusudhan ◽

...

Keyword(s):

Liver Injury ◽

Transient Elastography ◽

Early Recognition ◽

Fontan Procedure ◽

Fontan Operation ◽

Liver Stiffness ◽

Shear Wave Elastography ◽

Noninvasive Methods ◽

Over Time

Background: Hepatic derangements and liver injury following the Fontan operation (FO) may progress in some cases to hepatic fibrosis (HF) and cirrhosis. The respective roles of transient elastography (TE) or FibroScan, shear wave elastography (SWE), and aspartate transaminase to platelet ratio index (APRI) in assessing liver stiffness (LS) and possible liver injury in these patients are unclear. Methods: Thirty-nine patients (31 males), mean age 11.8 ± 5.7 years, median 11 years (interquartile range: 7-14.7 years), undergoing the FO between November 2017 and December 2018 were included. Liver stiffness and HF assessment was done with TE, SWE, and APRI in the preoperative period and postoperatively at 3-, 6-, and 12-month interval. Results: The LS values increased over time (postoperative values at 3, 6, and 12 months) as compared to preoperative values by both FibroScan and SWE. The change in liver stiffness measurement (LSM) was statistically significant: LSM0 to LSM3 ( P ≤ .0001), LSM0 to LSM6 ( P ≤ .0001), and LSM0 to LSM12 ( P = .001). Similarly, significant changes were observed on SWE: SWE0 to SWE3 ( P ≤ .0001), SWE0 to SWE6 ( P ≤ .0001), and SWE0 to SWE12 ( P = .001). There was no significant change in the APRI values over time. Conclusion: Noninvasive methods such as FibroScan and SWE may be of use to assess LS in follow-up of patients undergoing the FO for early recognition of hepatic changes.

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(AVK) Anti Vitamin K Treatment In patients with Fontan Surgery

Blood ◽

10.1182/blood.v116.21.4397.4397 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4397-4397

Author(s):

Maria Stefania Infante ◽

Cristina Pascual Izquierdo ◽

Fernando Carretero Lopez ◽

Jose Manuel Sanchez Ramirez ◽

Ana Maria Rodriguez Huerta ◽

...

Keyword(s):

Pediatric Patients ◽

Fontan Operation ◽

Thrombotic Event ◽

Bleeding Complications ◽

Target Range ◽

Group A ◽

Group B ◽

Fontan Surgery ◽

Fontan Patients

Abstract Abstract 4397 OBJECTIVES Thrombotic events have been reported as a major cause of morbidity after the Fontan procedure. There is no consensus about the type and duration of postoperative anticoagulation prophylaxis, due to the high risk of bleeding complications, the difficulties in monitoring and the questionable therapeutic compliance in children. In spite of the lack of long term prospective studies in this situation, the ACCP has recommended in their guidelines OAT following Fontan or Glenn operation for at least 6 months. This has also been our practice in our institution during the period of study. AIM OF THE STUDY To analyze the efficacy and complications of OAT in our pediatric patients after undergoing the Fontan operation. METHODS Retrospective chart review of all the children treated with OAT in our institution between 1995 and 2009. All patients were treated initially with acenocumarol 0,2 mg/kg, except the Fontan patients, who received 0,1 mg/kg. Target INR was 2–3 for all patients. The Mann-Whitney test was used to compare the rate of complications, and the percentage of visits out of target INR between the Fontan patients and the rest of the cohort. RESULTS There were 61 children (26 female/35 males) aged between 1 month and 17 years, who received OAT with a range of follow up between 4 months and 14 years: 27 after Fontan operation (Group A), an 34 for other reasons (Group B: n=13 non prothetic valve cardiopathy, n=21 treatment of thromboembolic disease). The average follow-up was similar in both groups (median of 6.5 months in group A vs.7.5 months in group B). There were few complications: 1 mild epistaxis and 1 thrombotic event in group B, and none in group A. There were no differences in the proportion of controls in normal range between both groups; there was a moderate proportion of controls outside the target range of INR, with higher distribution below the range than above the range. The median dose used to achieve the target INR was 0.3 mg/kg/d in Group A and 0.4 mg/kg/d in Group B. CONCLUSIONS Oral Anticoagulant therapy is safe and effective in pediatric patients,with very low rates of thrombotic or hemorragic complications including those undergoing the Fontan surgery. There were not any differences between both groups in any of the analizyed parameters. Disclosures: No relevant conflicts of interest to declare.

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Assessment of Liver Stiffness in Pediatric Fontan Patients Using Transient Elastography

Canadian Journal of Gastroenterology and Hepatology ◽

10.1155/2016/7125193 ◽

2016 ◽

Vol 2016 ◽

pp. 1-7 ◽

Cited By ~ 19

Author(s):

Becky Chen ◽

Richard A. Schreiber ◽

Derek G. Human ◽

James E. Potts ◽

Orlee R. Guttman

Keyword(s):

Transient Elastography ◽

Liver Stiffness ◽

Noninvasive Method ◽

Demographic Information ◽

Fontan Surgery ◽

Fontan Patients ◽

Age And Sex ◽

Patients Acceptance

Background. Hepatic fibrosis is a potential complication following Fontan surgery and heralds long-term risk for cirrhosis. Transient elastography (TE) is a rapid, noninvasive method to assess liver fibrosis by measuring liver stiffness.Objectives. To compare liver stiffness and liver biochemistries in pediatric Fontan patients with age- and sex-matched controls and to determine patients’ acceptance of TE.Methods. Patients were recruited from British Columbia Children’s Hospital. Twenty-two Fontan patients (15 males) were identified. Demographic information and cardiac data were collected. TE was measured using size-appropriate probes.Results. The median age of the Fontan cohort was 13.7 (5.9–16.8) years. Time from Fontan surgery to TE was 9.6 (1.0–12.9) years. The median Fontan circuit pressure was 13 (11–14) mmHg. TE values were higher in Fontan patients versus controls (18.6 versus 4.7 kPa,p<0.001). There was no association between TE values and patient age (r=0.41,p=0.058), time since Fontan surgery (r=0.40,p=0.062), or median Fontan circuit pressure (CVP) (r=0.35,p=0.111). Patients found TE to be nonpainful, convenient, and safe.Conclusions. TE is feasible to assess liver stiffness in children following Fontan surgery. Pediatric Fontan patients have markedly elevated liver stiffness values. TE may have important utility in liver care follow-up of pediatric Fontan patients.

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Abstract 16359: Incidence of Fontan Associated Liver Disease and Its Impact on Mortality in Patients With Single Ventricle Physiology

Circulation ◽

10.1161/circ.142.suppl_3.16359 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Carlos Guerrero ◽

judith Therrien ◽

Aihua Liu ◽

Liming Guo ◽

Masaki Kodaira ◽

...

Keyword(s):

Liver Disease ◽

Fontan Operation ◽

Population Based ◽

Cumulative Probability ◽

P Value ◽

Logrank Test ◽

Long Term Follow Up ◽

The Impact ◽

Fontan Patients

Introduction: Data on the burden of clinically significant Fontan associated liver disease (FALD) and its relationship to mortality is scant. We performed a retrospective cohort study to assess the incidence of FALD and its association with mortality. Methods: Data source was the Quebec Congenital Heart Disease (CHD) Database, a population-based cohort of over 100,000 CHD patients followed from 1983-2017. Fontan patients surviving longer than 30 days post-Fontan were identified, each were matched to 20 VSD patients on age and sex. The Fontan-VSD cohort were used to assess the association between Fontan and the risk of developing FALD. The VSD cohort served as “Non-exposed to Fontan” group. FALD was defined as at least one hospitalization due to liver disease. Kaplan-Meier curves were used to estimate and compare the cumulative probability of 1) developing FALD between Fontan and VSD patients; and 2) mortality between Fontan patients w/o FALD. Results: A total of 512 Fontan patients and 10,232 VSD patients were included. The cumulative probability of developing FALD at 10 and 25 years of follow-up was higher in Fontan patients (13.0% and 37.1%, respectively), compared to 0.7% and 2.0% for VSD patients respectively (p-value <0.0001-Logrank test). In Fontan patients with FALD, the cumulative probability of mortality by 5 years after the diagnosis of FALD was 12.6%, 11 times higher than the risk in Fontan Patients without FALD (Figure) . Calendar year of Fontan operation was found to be an important predictor of developing FALD. Conclusions: This is the first study documenting the impact of FALD on mortality, using a large cohort with long-term follow up. The findings support the use of well-defined surveillance protocols to identify potential precipitants of FALD before liver disease becomes irreversible.

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Abstract 2972: Permanent Atrial Pacing Lead Implantation Route After Fontan Operation

Circulation ◽

10.1161/circ.116.suppl_16.ii_664 ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Kazuhiro Takahashi ◽

Frank Cecchin ◽

Elizabeth B Fortescue ◽

Charles I Berul ◽

Mark E Alexander ◽

...

Keyword(s):

Thromboembolic Event ◽

Sinus Node ◽

Fontan Operation ◽

Atrial Pacing ◽

Retained Foreign Body ◽

Pacing Lead ◽

Fontan Surgery ◽

Skin Erosion ◽

Fontan Patients

Background: Atrial pacing is commonly used for sinus node dysfunction (SND) after Fontan surgery. The preferred route of lead implant has been debated. We compare procedural and clinical outcomes of transvenous (TV) and epicardial (Epi) atrial lead implants in this population. Methods: All Fontan patients having an atrial lead implant without other associated surgery between 1992 and 2007 were studied. Demographics, pacing lead performance data and procedural outcome were retrospectively analyzed. Results: 78 patients (22 TV and 56 Epi) had 90 leads implanted (25 TV/ 65 Epi). Mean follow-up was 3.3±4.1 yrs (TV) and 4.4±3.6 yrs (Epi). TV leads were implanted in older patients (mean age: 23.9 vs. 13.8 yrs, p<0.001), at longer interval after Fontan surgery (mean: 15.1 vs. 5.7 yrs, p<0.001). Indication for TV was more likely to be SND, while Epi pacing was indicated for AV block. Pacing modes were exclusively AAI/AAI-T in TV and mostly DDD in Epi leads. Acute complication occurred in 2/25 (8%) of TV (pneumothorax n=1, skin erosion n=1) and 12/65 (19%, p=0.23) of Epi implants (effusions n=5, heart failure n=1, retained foreign body n=1, pneumothorax n=1, hematoma n=1, disconnection n=1, sepsis n=1, blood loss n=1). Median hospital stay was shorter in TV (2.0 vs 4.5 days, p=0.03). All TV patients and 43 Epi (77%) were anticoagulated. At follow-up, pocket infection occurred in one Epi patient. No clinical thromboembolic event was observed in either group. 3 TV leads failed in 2 patients (9%), while 12 Epi leads failed in 10 patients (18%); however, mean duration of freedom from lead failure was not significantly different (TV 9.9 vs. Epi 8.0 yrs, P=ns). The mean energy threshold was lower at implant for TV leads (0.9 vs 2.2 μJ, P=0.049), but similar for both leads on follow-up (1.2 vs 2.6 μJ, P=0.35). Atrial sensing was unchanged over time for TV (2.2 to 2.0 mV, P=ns), but significantly decreased in Epi (3.4 to 2.4 mV, p=0.006). Conclusions: Transvenous atrial pacing leads may be placed in Fontan patients with lower procedural morbidity than epicardial leads, and equivalent expectation of lead performance and longevity. Although the thromboembolic event rate appears low in anticoagulated patients with both lead types, the present study design cannot fully address this important issue.

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