Abstract
Background
Liver cirrhosis is a rare but serious form of liver dysfunction that can lead to severe complications including cardiopulmonary involvement in children.
Objectives
In this study, our aim is to investigate the cardiopulmonary complications in children with cirrhosis by using contrast echocardiography.
Method
In this observational cross-sectional study, all pediatrics diagnosed with cirrhosis were enrolled from 2020 to 2024. Demographic data, weight, height, BMI, z-score, consanguinity, patient’s history, cause of cirrhosis, family history of cirrhosis, laboratory data, abdominal sonography, liver biopsies, and saline contrast echocardiography for arteriovenous malformation (AVM) were evaluated and recorded.
Result
A total of twenty-two children were observed, with 59 % of them being boys. The average age of all the children was 8.43 ± 4.6 years. During the study, it was found that 27.3 % of the patients had mild left ventricular diastolic dysfunction, 13.6 % had mild AVM, and 4.5 % had moderate AVM in the contrast echocardiography. No relationship was found between cardiopulmonary complications with age, sex, and laboratory data. However, there was a significant relationship between moderate AVM diagnosed in contrast echocardiography and nodular formation, as well as a significant relationship between left ventricular enlargement (LVE) and nodular formation. One patient had nodular formation in the liver biopsy concurrent with LVE and moderate AVM. Mild AVM was seen in a patient with severe vascular change and giant cell transformation. Additionally, there was a relationship between contrast echocardiography and BUN, creatinine, and vitamin D levels (all P -values <0.05).
Conclusion
The results of contrast echocardiography are correlated with some complications of cirrhosis and can be used as a method to evaluate cardiopulmonary complications in children with cirrhosis.
Highlights
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Liver cirrhosis is a rare but serious form of liver dysfunction that can lead to cardiopulmonary involvement.
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A total of 22 children were observed, with 59 % of them being boys. The average age of all the children was 8.43 years.
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There was a significant relationship between moderate AVM diagnosed in contrast echocardiography and nodular formation.
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Furthermore, a significant relationship between left ventricular enlargement (LVE) and nodular formation.
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Mild AVM was seen in a patient with severe vascular change and giant cell transformation.
1
Introduction
Liver cirrhosis is the transformation of healthy, normal liver tissue into hard, nodular tissue. Although cirrhosis may remain asymptomatic throughout life, most patients present with hepatic failure after an asymptomatic period. There are several complications associated with cirrhosis, including portal hypertension, ascites, hemorrhage, coagulopathy, and hepatorenal syndrome [ , ]. Cirrhosis is uncommon in children, but its complications have significant effects on the patient’s life. The involvement of the respiratory system in pulmonary hypertension and the involvement of the cardiopulmonary system in the form of hepatopulmonary syndrome is noteworthy in this context [ , ]. The association between chronic liver disease and cardiovascular disease is defined as cirrhotic cardiomyopathy [ ]. Cirrhotic cardiomyopathy includes systolic, diastolic, and electrophysiological abnormalities [ ]. It was observed that in patients with chronic liver disease, abnormal arterial blood gas has occurred in approximately 41 % of patients, and abnormal respiratory function tests were reported in 15 % of patients [ ]. These complications are vital in these patients because they have a direct effect on mortality and morbidity before and after liver transplantation [ ]. The screening test of choice for arteriovenous malformation (AVM) is transthoracic saline contrast echocardiography, which has a sensitivity of up to 98.6 % and a high rate of inter-observer confidence [ , ]. Contrast echocardiography has become the paramount technique for screening and diagnosis because of its availability and noninvasive nature [ ]. However, the gold standard of AVM diagnosis in children is CT angiography, which is not routinely used due to its invasiveness and risks. In this study, we aimed to investigate the correlation between pediatric cirrhosis and cardiopulmonary complications with contrast echocardiography.
2
Method and material
This article is an observational single-center (Mofid Children’s Hospital, Tehran, Iran) cross-sectional study investigating the cardiopulmonary complications in cirrhotic pediatrics from 2020 to 2024 on pediatrics with cirrhosis referred to the hospital. The ethical committee of Shahid Beheshti Medical University approved this study (IR.SBMU.MSP.REC.1398.514).
All pediatrics with cirrhosis diagnoses were referred to the hospital during these times and assessed. The inclusion criterion was cirrhosis involvement; a biopsy and pathological assessment by an expert pathologist confirmed the diagnosis. The exclusion criteria were no consent to enter the study, preexisting cardiac disorder, alagille syndrome patients, and lack of patient data.
Demographic data, weight, height, BMI, z-score, consanguinity, patient’s history, cause of cirrhosis, and family history of cirrhosis were taken from patients and their families and recorded. An expert pediatrician performed a complete physical examination to gather additional data. The laboratory data including Alanine transaminase (ALT), Aspartate transaminase (AST), Alkaline phosphatase (ALKP), total bilirubin (Bili T), direct bilirubin (Bili D), albumin (Alb), total protein, Gamma-glutamyl transferase (GGT), Prothrombin time (PT), Partial thromboplastin time (PTT), international normalized ratio (INR), white blood cell count (WBC), hemoglobin (Hb), mean corpuscular volume (MCV), platelet (Plt), calcium (Ca), phosphorus (P), Vitamin D3 level, blood urine nitrogen (BUN), creatinine (Cr), and lactate dehydrogenase (LDH) was measured in admission time and hospitalization.
An expert radiologist performed abdominal ultrasonography to examine the hepatomegaly, splenomegaly, liver echogenicity, size and nodularity, bile ducts and gallbladder, kidneys, and urinary tract in all patients and to evaluate ascites.
Portal hypertension occurs when a condition causes an increase in portal blood flow resistance after the portal vein blood circulation. This condition is one of the most critical complications of liver diseases and cirrhosis, which can lead to several problems. The primary cause of portal hypertension is the increase in intrahepatic vascular resistance due to changes in the liver’s structure and vascular tone caused by liver fibrosis. Portal hypertension can be detected in various ways, with one of the most helpful methods being the discovery of gastroesophageal varices in an Esophagogastroduodenoscopy exam [ ].
An endoscopic evaluation was performed to evaluate gastrointestinal complications, including esophageal varices indicating portal hypertension and hypertensive gastropathy, by an expert gastroenterology specialist.
An echocardiography and a 12‑lead ECG were done for cardiac evaluation. All patients had echocardiograms and complications to assess cardiopulmonary complications. A cardiologist measured the QTc interval in a resting 12‑lead EEG (Cardio Soft GE V6.73 GE Healthcare, Solingen, Germany). The QT measurements were taken in lead II for three beats in a row. QT intervals were observed from the start of the QRS complex to the finish of the T wave. When U waves were present, the nadir between the T and U waves was used to measure the end of the T wave. For the heart rate adjustment, the Bazett formula was implemented (QTc). According to current recommendations, a QTc interval of >440 ms was regarded as extended. Experienced pediatric echocardiography experts performed echocardiography examinations at our center using a standardized procedure. 2D, M-Mode, and Doppler echocardiography were used to examine the anatomy and function of the heart using the usual approach of employing the apical 4-chamber view and the left parasternal long and short-axis views (Philipps IE 33, Amsterdam, Netherlands, with a 12 Hz, 8 Hz, or 5 Hz transducer, depending on age). M-Mode traces were used to assess the diameters of the ventricles at end-diastole and end-systole. The following parameters were measured: left ventricular diastolic function, left ventricular systolic function, tricuspid regurgitation (TR), pulmonic insufficiency (PI), mitral regurgitation (MR), left ventricular enlargement (LVE), left atrial enlargement (LAE), right atrial enlargement (RAE), aortic time velocity integrals (ATVI), and pulmonary hypertension (PHTN). Saline Contrast echocardiography was performed for arteriovenous malformation assessment. The normal pulmonary artery pressure range, which was measured in echocardiography, is <20 mmHg; thus, pulmonary hypertension (PHTN) occurs when this pressure is over 20 mmHg [ ]. The normal ejection fraction (EF) values in children are between 56 and 78 % [ ]. ATVI was measured by a standard 2D Doppler echocardiography based on the American Society of Echocardiography guidelines compared to the QuickOptTM method [ ].
Left ventricular diastolic dysfunction is when the left heart muscle wall becomes stiff due to hypertrophy, patchy fibrosis, and subendothelial edema. This stiffness can affect the ventricle’s ability to fill with blood by changing the relaxation ability of the ventricular muscles. It can also contribute to the development of systolic dysfunction; therefore, cardiac diastolic dysfunction could be the initial problem in any cardiovascular complications, as any disorder in the structure of the myocardium can change the filling pattern of the ventricle. Doppler echocardiography is the most practical way to evaluate ventricular function due to its accessibility and ease of use. In addition to systolic dysfunction, Doppler echocardiography can diagnose ventricular diastolic dysfunction by observing the flow velocities and the ventricle’s filling volume over the cardiac cycle time. Left ventricular enlargement was measured by evaluating left ventricular end-diastolic diameter. If the sum is >10 mm, left ventricular enlargement is present.
According to the Pediatric ASE Guidelines, the assessment of left ventricular (LV) function and dimensions should be based on age- and body surface area (BSA)-indexed z-scores rather than fixed cutoffs such as LVEF 60 % or LV diameter of 10 mm, which are arbitrary. Systolic dysfunction is defined as LVEF <55 %, with global longitudinal strain (GLS) less negative than −18 % serving as a more sensitive marker. LV dilation is diagnosed when LV end-diastolic dimension (LVEDD) or LV end-systolic dimension (LVESD) z-score exceeds +2.0. For diastolic dysfunction, key echocardiographic markers include an E/A ratio adjusted for age, an E/e’ ratio > 14, left atrial volume indexed to BSA (z-score > 2), and abnormal tissue Doppler indices (e.g., septal e’ velocity < 10 cm/s). The cutoff values for the isovolumetric relaxation time (IVRT) and E/A ratio in pediatrics are 57 ms and 0.75–1.5 ms, respectively. If a patient’s IVRT and E/A ratio are abnormal, they are considered to have mild left ventricular diastolic dysfunction [ ].
An expert pediatrician performed agitated saline contrast echocardiography to inspect the cardiopulmonary shunt and evaluate arteriovenous malformations (AVM). This method involves injecting 5 to 10 ml of agitated saline into a peripheral vein for a patient in the left lateral decubitus position after placing an intravenous line and performing heart imaging with 2-dimensional echocardiography in the four-chamber apical view. The agitated saline includes microbubbles, which are visible by echocardiography and can be used to detect AVM [ ].
This study used contrast echocardiography to grade cardiopulmonary shunts. Shunts were classified as mild, moderate, or severe based on the opacification of the cardiac left-sided chambers through a semi-quantitative analysis of contrast echocardiography [ ]; normal, no bubbles; mild, occasional filling with <20 bubbles; moderate, moderate filling; severe, complete opacification [ ]. To ensure the accuracy of the intrapulmonary shunt assessment, we confirm that the patent foramen ovale (PFO) was removed in all patients, as the PFO can act as an alternative pathway for right-to-left shunting.
A professional liver pathologist used the ISHAK fibrosis score to analyze the staging of the liver cirrhosis histopathology and different types of pathological images [ ].
All patients underwent a liver biopsy and cirrhosis. Portal fibrosis, inter portal fibrosis, interface hepatitis microvesicular stenosis, bile duct damage, giant cell transformation, nodular formation, and focal necrosis were investigated.
Fine needle biopsy of the liver is a commonly used procedure to investigate the presence of liver nodules and cellular changes in patients with liver disease. These nodules are usually benign and different from liver nodules associated with hepatocellular carcinoma (HCC). Benign hepatic nodular lesions include macro regenerative nodules (MRN), dysplastic nodules (DN), focal nodular hyperplasia (FNH), and liver cell adenoma (LCA), which signify changes in the liver cells and structure. Liver cirrhosis is defined as advanced hepatic fibrosis and developing hepatocellular nodules, such as regenerative nodules, dysplastic, and neoplastic nodules [ , ].
Finally, all data were recorded and analyzed to investigate the relationship between cirrhosis complications and cardiopulmonary involvement.
3
Statistical analysis
Mean, standard deviation, median, amplitude, frequency, and percentage were used to describe the data. We used chi-square and Fisher exact tests to compare the relationships between the variables. All analyses were performed using SPSS 25.0 statistical software. In these analyses, P < 0.05 is considered as statistically significant.
4
Results
In this cross-sectional study, a total of 22 children were examined, including 9 girls (41 %). The mean age and mean age at diagnosis were 8.43 ± 4.6 years and 4.78 ± 4.54 years, respectively. On average, children were born with a weight of 3.08 ± 0.58 kg, and BMI and Z -score were 18.6 ± 4.94 and 0.24 ± 1.65, respectively.
Based on the collected data, consanguinity was found for 3 patients, and two patients (9.1 %) had a history of liver disorder in their families. Also, the most common cause of cirrhosis was autoimmune hepatitis, which was observed in 7 (31.8 %) children ( Table 1 ).
| N (%) | |||
|---|---|---|---|
| Consanguinity | 3 (13.6 %) | ||
| Family History | 2 (9.1 %) | ||
| Cause | Extrahepatic | 1 (4.5 %) | |
| Autoimmune hepatitis | 7 (31.8 %) | ||
| Congenital fibrosis | 2 (9.1 %) | ||
| GSD IV | 2 (9.1 %) | ||
| biliary atresia | 5 (22.7 %) | ||
| PFIC III | 1 (4.5 %) | ||
| Choledochal cysts | 1 (4.5 %) | ||
| PTLD | 1 (4.5 %) | ||
| Budd–Chiari syndrome | 2 (9.1 %) | ||
| Mean SD | Median (range) | ||
| Age | 8.43 ± 4.6 year | 8.5 (7 month,16 year) | |
| Diagnosis Age | 4.78 ± 4.54 year | 3.5 (1 month, 14 year) | |
| Body Weight (kg) | 3.08 ± 0.58 | 3 (2.1,4.8) | |
| Weight (kg) | 27.09 ± 16.88 | 21.15 (5.8, 60) | |
| Height (cm) | 115.55 ± 34.67 | 118 (62, 170) | |
| BMI (kg.m 2) | 18.6 ± 4.94 | 17.5 (12.5, 33.3) | |
| BMI Z score | 0.24 ± 1.65 | 0.5 (−2.9, 3) | |
Different types of liver echogenicity were evaluated. Seven patients (31.8 %) had Coarse echogenicity, 1 (4.5 %) had increased echogenicity, 2 (9.1 %) had heterogeneous, and 2 (9.1 %) had coarse + heterogeneous echogenicity. The liver sizes of 9 (40.9 %) children were larger than normal; one child had a smaller liver size than normal, and the rest were normal. Also, one child had liver nodularity out of the total number of patients.
In abdominal sonography, 6 (27.3 %) of these 22 children had mild ascites, and one had moderate ascites. Fourteen (63.6 %) had increased Spleen size. One patient had increased renal echogenicity, one had hydronephrosis, and one had calcification in the kidney (4.5 % for everyone). Three (13.6 %) children had bile duct obstruction, 5 (22.7 %) had bile duct wall thickness, and 3 (13.6 %) children had bile duct stones.
In the endoscopic evaluation, eleven children also had esophageal varices (50 %), of which 4 (23.5 %) had grade I, 4 (23.5 %) had grade II, and finally 3 (17.6 %) had grade III. Hypertensive gastropathy was seen in 4 (23.5 %) of patients.
Table 2 presents the results of cardiac complications in ECG and saline contrast echocardiography. Eighteen (81.8 %) patients had pulmonary arterial mean pressure below 20 mmHg; the rest were between 20 mmHg and 40 mmHg. Twenty (90.9 %) patients had left ventricular (LV) systolic function above 60 %, and the rest were between 50 % and 60 %. The LV diastolic function was examined, and 16 children (72.7 %) had good LV diastolic function, and the rest had mild dysfunction based on IVRT and E/A ratio. Also, 3 (13.6 %) had mild AVM, and 1 (4.5 %) had moderate AVM in the saline contrast echocardiography. The mean pulse rate, QTc, MPI, and ATVI were 99 ± 20, 0.38 ± 0.05, 0.15 ± 0.06, and 21 ± 6, respectively.
| Cut-off values | N (%) | ||
|---|---|---|---|
| PHTN | <20 mmHg | 18 (81.8 %) | |
| 20–40 mmHg | 4 (18.2 %) | ||
| LV systolic Function | >60 % | 20 (90.9 %) | |
| 50–60 % | 2 (9.1 %) | ||
| LV diastolic Function | Good | 16 (72.7 %) | |
| Mild | 6 (27.3 %) | ||
| Contrast echocardiography | AVM mild | 3 (13.6 %) | |
| AVM moderate | 1 (4.5 %) | ||
| PI | 18 (81.8 %) | ||
| MR | 2 (9.1 %) | ||
| LVE | 5 (22.7 %) | ||
| LAE | 3 (13.6 %) | ||
| RAE | 1 (4.5 %) | ||
| Mean SD | Median (range) | ||
| Pulse rate | 99 ± 20 | 100 (58, 140) | |
| QTc | 0.38 ± 0.05 | 0.39 (0.26, 0.45) | |
| ATVI | 21 ± 6 | 20 (15, 33) |
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