Usefulness of Liver Stiffness on Ultrasound Shear-Wave Elastography for the Evaluation of Central Venous Pressure in Children With Heart Diseases

Eiko Terashi; Yoshihiko Kodama; Ayako Kuraoka; Yuichi Ishikawa; Makoto Nakamura; Koichi Sagawa; Shiro Ishikawa

doi:10.1253/circj.CJ-18-1313

Abstract

Background: Liver stiffness on ultrasound shear-wave elastography (SWE) reflects central venous pressure (CVP) in adult patients with heart failure, but the association of liver stiffness on SWE with CVP in pediatric patients is not clear. The present study evaluated whether liver stiffness on SWE is useful as a non-invasive indicator of CVP in pediatric patients.

Methods and Results: Liver stiffness was measured using ultrasound SWE in 79 patients aged <20 years with congenital heart diseases. None of the patients was found to have liver disease. Correlations between liver stiffness and other clinical variables, including CVP, were analyzed. CVP was the only factor independently and significantly correlated with liver stiffness in multivariate analysis. However, variables related to hepatic fibrosis did not correlate with liver stiffness.

Conclusions: Liver stiffness on ultrasound SWE is useful as a non-invasive indicator of CVP in children with heart diseases.

Ultrasound shear-wave elastography (SWE) is being widely used for the non-invasive measurement of tissue stiffness.¹^,² Its use is prevalent in the field of hepatology, and the quantitative stiffness of the liver is known to correlate with the degree of fibrosis.³^–⁷ In the field of adult cardiology, liver stiffness is known to reflect central venous pressure (CVP).⁸^–¹²

In patients after the Fontan procedure, SWE of the liver is reportedly useful for identifying hepatic fibrosis.¹³^–¹⁵ However, the association between SWE findings of the liver and CVP among children with heart diseases has not been clarified. In children, because vascular access is limited, the evaluation of CVP has mainly relied on classic indices such as body weight and skin edema. Therefore, clarification of the relationship between liver stiffness on SWE and CVP in children might change the practice of pediatric heart care and intensive care.

In this study, we measured liver stiffness using ultrasound SWE in children with heart diseases to evaluate whether it is useful as a non-invasive indicator of CVP in this population.

Methods

Study Subjects

This study was approved by the Institutional Review Board of Fukuoka Children’s Hospital and informed consent was obtained appropriately. Ultrasound SWE was performed in 79 patients aged <20 years with congenital heart diseases who underwent cardiac catheterization between August 2017 and August 2018. The medical records of the patients were reviewed to retrieve information about the diagnosis and previous treatments.

Ultrasound SWE

SWE of the liver was performed just before catheterization in the same room using Logic S8 equipment (GE Healthcare, Chicago, IL, USA). The fasting time was at least 4 h in all cases. SWE was performed 10 times on the right lower lobe of the liver to a depth of 2–4 cm from the liver surface while the patient was upright. In some cases of situs inversus or if the size of the right lobe was inadequate, the left lobe was used. The size of the SWE box was 3.0×1.5 cm and the region of interest was 1.25 cm in diameter. Thick and obvious vessels were excluded from the region of interest. The patients included infants and toddlers for whom breath holding was difficult, so all examinations were performed during a motionless period of respiration while free breathing. The median of 10 measurements was used for analysis.

Statistical Analysis

Continuous variables are expressed as mean±standard deviation. Categorical variables are expressed as number (percentage). Pearson›s correlation coefficient and multiple regression models were used to evaluate the correlations between liver stiffness on SWE and other variables in the univariate and multivariate analyses, respectively. A 2-sided P-value <0.05 was considered to indicate statistical significance. All statistical analyses were performed using JMP Pro 13 software (SAS Institute Inc., Cary, NC, USA).

Results

A total of 79 patients were enrolled in the present study. Their characteristics are shown in Table 1: 45 patients had biventricular diseases, such as transposition of the great arteries and tetralogy of Fallot, and none had liver diseases; 34 patients had previously undergone the Fontan procedure using an extracardiac conduit without fenestration and most of them were administered warfarin, aspirin, and an angiotensin-converting enzyme inhibitor or β-blocker according to the institutional policy for Fontan management. The major issues among the Fontan patients included a history of tachyarrhythmia in 5 patients and bradyarrhythmia, which required pacemaker implantation, in 3 patients. All of the Fontan patients routinely underwent morphological assessment of the liver using abdominal ultrasound, and no patient was diagnosed with liver cirrhosis. Additionally, we did not identify any significant elevation among the Fontan patients compared with the biventricular patients in the average level of type IV collagen (232.4±96.9 vs. 190.6±152.4, P=0.20), type III procollagen peptide (0.50±0.16 vs. 0.65±0.68, P=0.44), and Mac-2 binding protein glycosylation isomer (41.3±48.7 vs. 27.7±17.8, P=0.10), which have been reported to reflect hepatic fibrosis.¹⁶^–²¹

Table 1. Patients’ Characteristics

Total no. of patients	79
Age (years)	10.3±4.9
Female sex	37 (46.8)
Diagnosis
Biventricular disease	45 (57.0)
TGA (after the Jatene procedure)	13 (16.5)
TOF (after total repair)	12 (15.2)
VSD (before closure)	5 (6.3)
ASD (before closure)	2 (2.5)
Valvular AS	2 (2.5)
Other	11 (24.4)
Fontan physiology	34 (43.0)
TA	5 (6.3)
HLHS	5 (6.3)
PAIVS	1 (1.3)
uAVSD	5 (6.3)
ccTGA	3 (3.8)
Other SV	15 (19.0)
Heart rate (beats/min)	84.0±21.8
Systolic blood pressure (mmHg)	107.4±14.0
Mean blood pressure (mmHg)	76.7±12.0
Hemoglobin level (g/dL)	13.8±1.9
Platelet count (×10³/μl)	25.0±8.1
AST level (IU/L)	27.3±8.8
ALT level (IU/L)	20.9±11.8
γGTP level (IU/L)	33.1±28.4
Creatinine level (mg/dL)	0.5±0.2
Total bilirubin level (mg/dL)	1.0±0.7
Total bile acid level (μmol/L)	4.4±5.8
Brain natriuretic peptide level (pg/mL)	57.5±196.3
Type IV collagen level (ng/mL)	203.9±130.8
Type III procollagen peptide level (ng/mL)	32.7±33.1
M2BPGi level (μg/mL)	0.6±0.5
Central venous pressure (mmHg)	5.7±3.5
Cardiac index (L/min/m²)	3.1±0.9
Oxygen saturation (%)	95±4.4
Ejection fraction (%)	62.1±8.8

Data are presented as number (%) of patients and mean±standard deviation. γGTP, γ-glutamyl transpeptidase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ccTGA, congenitally corrected transposition of the great arteries; HLHS, hypoplastic left heart syndrome; M2BPGi, Mac-2 binding protein glycosylation isomer; PAIVS, pulmonary atresia with intact ventricular septum; SV, single ventricle; TA, tricuspid atresia; TGA, transposition of the great arteries; TOF, tetralogy of Fallot; uAVSD, unbalanced atrioventricular septal defect; VSD, ventricular septal defect.

In the univariate analysis, age, heart rate, platelet count, γ-glutamyl transpeptidase and total bilirubin levels, CVP, and cardiac index significantly correlated with liver stiffness (Table 2). On the other hand, indicators of hepatic fibrosis, such as type IV collagen, type III procollagen peptide, and Mac-2 binding protein glycosylation isomer, did not show significant correlations with liver stiffness. The subsequent multivariate analysis revealed that CVP was the only factor that independently and significantly correlated with liver stiffness, among all the factors identified in the univariate analysis. This relatively strong correlation between CVP and liver stiffness (Figure 1) was noted even in the subgroups of patients with biventricular disease (Figure 2A) and those who underwent the Fontan procedure (Figure 2B).

Table 2. Correlations Between Liver Stiffness on Shear-Wave Elastography and Other Variables

Variable	Univariate analysis		Multivariate analysis
Variable	R	P value	SE	P value
Age	0.246	0.029	0.008	0.416
Heart rate	0.303	0.007	0.002	0.326
Systolic blood pressure	0.078	0.496
Mean blood pressure	0.979	0.114
Hemoglobin level	0.132	0.246
Platelet count	0.391	<0.001	0.004	0.202
AST level	0.095	0.405
ALT level	0.135	0.235
γGTP level	0.561	<0.001	0.001	0.177
Creatinine level	0.132	0.246
Total bilirubin level	0.374	<0.001	0.043	0.263
Total bile acid level	0.115	0.965
Brain natriuretic peptide level	0.182	0.108
Type IV collagen level	0.106	0.366
Type III procollagen peptide level	0.087	0.463
M2BPGi level	0.175	0.301
Central venous pressure	0.776	<0.001	0.010	<0.001
Cardiac index	0.445	<0.001	0.038	0.478
Oxygen saturation	0.134	0.244
Ejection fraction	0.104	0.367

Abbreviations as in Table 1.

Figure 1.

Significant correlation between liver stiffness on SWE and CVP in all patients (<20 years old). CVP, central venous pressure; SWE, shear-wave elastography.

Figure 2.

Significant correlations between liver stiffness on SWE and CVP in patients with biventricular diseases (A) and those who underwent the Fontan procedure (B). Abbreviations as in Figure 1.

Discussion

In this study, we showed that ultrasound SWE of the liver was useful for the evaluation of CVP in children, including those with biventricular disease and those with Fontan circulation. Our findings are valuable, as reports on the use of ultrasound SWE in children with heart diseases, especially biventricular circulation, are limited.

The usefulness of ultrasound SWE in the field of adult cardiology is already known. Liver stiffness is known to reflect CVP,⁸^–¹⁰ which is reversed by treatment of congestion,⁸^,¹² so SWE can be used to evaluate the sufficiency of treatment. Although estimating cardiac output and congestion is crucial in the treatment of heart failure, quantitative measurement of CVP is sometimes difficult, because invasive procedures, such as Swan–Ganz catheter insertion, are usually required. Because SWE is a non-invasive procedure, it is preferable, especially for pediatric patients in whom invasive procedures have high risks, such as occlusion of large vessels and respiratory failure associated with sedation.

In the field of pediatric cardiology, ultrasound SWE has often been reported as an evaluation tool for hepatic fibrosis after the Fontan procedure.¹³^–¹⁵^,²²^–²⁴ However, it is not known whether liver stiffness after the Fontan procedure truly reflects the degree of hepatic fibrosis, because these patients have high venous pressure to some degree, which may result in increased stiffness. Some previous studies have shown a relationship between liver stiffness and fibrosis severity according to the blood sample score among Fontan patients.¹⁴^,¹⁵ However, it is not clear whether the fibrosis score, which is frequently used in adult patients with liver diseases, can be applied in Fontan patients. Kutty et al reported a substantial correlation between the degree of histological fibrosis and liver stiffness on ultrasound SWE among 10 patients after the Fontan procedure.¹³ On the other hand, some studies have reported significant increase in liver stiffness immediately after the Fontan procedure,²⁵^,²⁶ and it should be noted that liver stiffness reflects venous congestion to some extent. The present study revealed a significant correlation between liver stiffness and CVP in patients after the Fontan procedure as well as biventricular repair. We also revealed no significant relationships between liver stiffness and serum indices of hepatic fibrosis such as type IV collagen, type III procollagen peptide, and Mac-2 binding protein glycosylation isomer. Although the histological data of the patients were not assessed, we believe that liver stiffness on SWE is useful as an index of CVP rather than as an index of hepatic fibrosis in children with heart diseases.

Study Limitations

First, as this was an observational cross-sectional study, the reversibility of liver stiffness was not investigated. Therefore, it remains unclear whether ultrasound SWE is useful for the evaluation of temporal changes in CVP. Second, histological data on hepatic fibrosis were lacking in this study, and the poor correlation between hepatic fibrosis and liver stiffness was derived only from the serum indices of fibrosis. Further studies are required to address these limitations and confirm the present findings.

Conclusions

Liver stiffness on ultrasound SWE may be a useful non-invasive indicator of CVP in children with heart diseases, including those with biventricular disease and those with Fontan circulation.

Grants

None.

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