Evaluation of QT prolongation in children with cirrhosis and its association with the severity of liver diseases

Summary

Introduction: Prolongation of the QT interval in an electrocardiogram (ECG) is seen in more than 60% of adults with advanced cirrhosis. According to careful research, people with cirrhosis who have their QT intervals prolonged had worse survival rates, more severe disease symptoms, and faster development of their condition. Considering the importance of predicting complications of liver cirrhosis in children and the limited number of studies related to the relationship between prolonged QT and the severity of liver disease in children, in this study, prolonged QT in children with liver cirrhosis and its relationship with the severity of liver disease was investigated. Methods: In the present study, children under 18 years of age with liver cirrhosis were evaluated in the list of liver transplants referred to Abu Ali Sina Organ Transplantation Hospital in Shiraz between 2019 and 2021. QT was calculated based on two pediatric cardiologists‘ 12-lead ECG from liver transplant surgery. Results: In this study, 130 patients with liver cirrhosis with an average age of 7.05±5.34 years were evaluated. The average length of the QT segment was reported as 397±31milliseconds. Only 4 (3%) had a long QT segment in all the studied patients. The comparison of the Meld/Peld criterion and Child criterion in the two groups of regular QT and prolonged QT showed that the mean of both criteria was significantly longer in the standard QT group (P = 0.018, P = 0.038). Also, prolonged QT showed a significant relationship with the cause of liver cirrhosis (P = 0.003). Conclusion: Our study is one of the first to examine the relationship between QT and severity of cirrhosis in children. Based on the results of this study, prolonged QT is associated with severity of liver disease.

Keywords:

liver – cirrhosis – children – long QT – fibrosis

Introduction

Cirrhosis is a chronic liver damage response resulting in regenerating nodules encircled by fibrous bands, leading to portal hypertension and end-stage liver disease [1]. Fibrosis, the collagen scar surrounding or replacing injured tissue, causes liver fibrosis, which advances at varying speeds depending on the liver illness, environmental variables, and host. A more severe form of liver fibrosis, cirrhosis, is accompanied by changes to the hepatic arteries‘ structural integrity, affecting the interchange between hepatic sinusoids and nearby hepatocytes [2–4]. Hepatic stellate cells and mononuclear cells are present in the permeable connective tissue sheets surrounding the hepatic sinuses, while hepatocytes carry out most of the liver‘s tasks. The endothelial cushions are lost in cirrhosis, and the empty space is filled with scar tissue. Cirrhosis is defined histologically by fibrotic vascular septa that link portal ducts to central veins, causing hepatocytic islands to be surrounded by fibrotic septa, but missing a central vein [5]. Liver illnesses have become one of the most prevalent causes of mortality due to increased global prevalence [6]. Cirrhosis occurs widely, but the actual incidence is unclear. In 2017, over 132 million people died due to cirrhosis worldwide, with 170,000 fatalities in Europe annually related to liver cirrhosis [7]. The mortality rate in Iran from liver cirrhosis is rising, with around 5,400 deaths in 2017 [8]. On average, one in every 2,500 live births has a newborn with liver illness, and in the United States, 1 in 250 children aged 12 to 19 years and 1 in 500 children aged 6 to 11 years have chronic hepatitis C virus infection [9]. Cirrhosis in children can be caused by various factors, including Alagille syndrome, familial intrahepatic cholestasis, biliary obstruction, biliary atresia, choledochal cysts, gallstones, bile duct stenosis, deficiencies in bile acid production, and infection. Hepatotropic viruses, hereditary genetic-metabolic illnesses, -1-antitrypsin deficiency, galactosemia, fructosemia, tyrosinemia type 1, mitochondrial hepatopathies, cystic fibrosis, hemochromatosis, Wolman‘s disease, hepatitis B and D, hepatitis C, hepatitis E, Budd-Chiari syndrome, primary sclerosing cholangitis, autoimmune illnesses, poisons, narcotics, and total parenteral feeding are some of the most common causes. Cirrhosis is often caused by persistent viral hepatitis and autoimmune disorders in older children, while biliary atresia and hereditary metabolic abnormalities are the most common causes in infants and young children [10–12]. Cirrhosis has a quiet clinical history before liver failure and portal hypertension develop. It leads to hepatocellular carcinoma, increased intrahepatic resistance, and liver dysfunction. Cirrhosis changes hepatic arteries and portal blood pressure, which are linked to irregular blood flow irregularities. The underlying cause and compensation of cirrhosis determine clinical symptoms. In 40% of cases, individuals may be asymptomatic before experiencing liver failure [5,6,10]. Cirrhosis affects children and teenagers with similar symptoms to adults, including weight loss, anorexia, lethargy, muscular weakness, nausea, and vomiting. Abdominal discomfort can result from gallstones, gastritis, ulcers, liver distension, ascites, and portal hypertension. Diagnosis involves recognizing typical liver disease symptoms, such as spider nevi, visible abdominal circulation, and palmar erythema. Skin symptoms include bruising, face, back telangiectasia, and recurring epistaxis. Physical examination can also diagnose clubbing. Persistent cholestasis can cause severe itching, affecting quality of life. Decompensated cirrhosis can lead to ascites, hepatic encephalopathy, and gastrointestinal bleeding [10,13,14]. Cirrhosis is a severe liver disease characterized by a rise in hepatic venous pressure gradient, which is rarely assessed in children and adolescents. Mortality risk is calculated using albumin levels, Child-Pugh--Turcotte scores, and body mass index. Treatment planning is crucial for etiological categorization, as cirrhosis is the last stage of progressive liver disease. Advances in diagnostic and therapeutic technologies, particularly liver transplant surgery, have significantly improved management in children. About 25% of cardiac output is sent to the liver, which is sensitive to decreased flow. Additionally, the hepatic vein and inferior vena cava lack a valve, causing any rise in venous pressure to be conveyed to the liver‘s sinus bed [10,15,16]. Cirrhosis affects various organs and systems, including cardiovascular, neurological, and autonomic systems. Common cardiovascular symptoms include increased basal output, reduced function, decreased responsiveness, and electrophysiological abnormalities in cirrhosis patients [17,18]. People with liver cirrhosis have high activity levels and hyperdynamic blood flow, resulting in increased cardiovascular output and reduced vascular resistance. This can cause systolic function, diastolic dysfunction, and cardiomyopathy, leading to left ventricular hypertrophy and myocardial remodeling [19–21]. Cardiomyopathy in cirrhotic people is characterized by stress-related loss of contractile response and/or delayed-type diastolic dysfunction with electrophysiological alterations in the absence of established heart illness, according to a working group‘s definition [15]. Reduced cardiac contractility, systolic and diastolic dysfunction, and conduction deficits make up this syndrome, which is frequently found in adults with cirrhosis [17,22], is linked to a greater death rate following liver transplantation [23–25]; this has recently been documented in children. Typically, patients with severe cirrhosis experience rhythm problems (tachycardia, bradycardia). Reduced production might result from an inability to sustain an elevated heart rate. It supports the heart but not to the extent necessary for systemic blood circulation [17,26,27]. The baroreceptor reflex determines the heart‘s electrical stability [15,19–21,28].

It is believed that toxic, metabolic, and immune conditions that impact the sympathetic and parasympathetic components of the autonomic nervous system are the cause of the autonomic nervous system‘s participation in the symptoms of cirrhosis [18,29]. Toxic, metabolic, and immune conditions impact the autonomic nervous system, leading to cirrhosis symptoms. Research in diabetic individuals shows a connection between cardiac autonomic neuropathy and QT prolongation, which is linked to higher all-cause mortality [30–34]. In about 60% of people with advanced cirrhosis, the QT interval on the electrocardiogram (ECG) is prolonged. Interestingly, some research has linked the lengthened QT interval in cirrhosis patients to the severity and development of their conditions to a worse prognosis [35–37]. On the other hand, several studies have noted that prolonged QT is linked to more severe liver dysfunction, but is not linked to a higher death rate [38,39]. The study examines the relationship between prolonged QTc and liver disease severity in children with liver cirrhosis. Most individuals with extended QTc experienced improvement after liver donation, with recovery varying [40]. This finding is significant for predicting liver cirrhosis consequences in children and is consistent with previous studies.

 

Methods

The study is a cross-sectional study designed to investigate the relationship between long QT in children with liver cirrhosis and severity of the liver disease.

The study population of children under 18 with liver cirrhosis is in the list of liver transplants who visited Abu Ali Sina Organ Transplantation Hospital in Shiraz between 2019 and 2021.

Inclusion criteria were aged fewer than 18 years, having liver cirrhosis, and being on the liver transplant list.

Exclusion criteria included conduction abnormalities or recent myocardial infarction (within the past 30 days) in ECG and cases with familial blood cholesterol.

Data collection

In order to collect data, a pre-designed form including the following items was used:

1.
demographic information (age and gender);

2.
information related to the history of liver disease (cause of cirrhosis, use of beta-blocker drugs);

3.
current evaluations of patients measured twice by two pediatric cardiologists, including QTc in 12-lead ECG, serum sodium level, international normalized ratio (INR), creatinine, total bilirubin, serum albumin, weight in kilograms, end-stage liver disease score (PELD), end-stage liver disease score model (MELD), and Child-Pugh QTc.

 

In this study, according to European regulatory guidelines and Goldenberg et al., QTc >450 milliseconds for men and QTc >470 milliseconds for women were considered abnormal. Also, mild QT (451–470 milliseconds in men, 471–490 milliseconds in women), moderate (471–490 ms in men, 510–491 ms in women), and severe (more than 490 ms in men, more than 510 ms in women).

Laboratory information was obtained within 90 days of baseline ECG (as part of routine outpatient care of patients).

Ethical approval was made by Shiraz University of Medical Sciences, and the information of individuals and their outcomes were kept confidential (IR.SUMS.MED.REC.1399.169).

 

Statistical methods

This study used descriptive statistics of average, standard deviation, number, percentage, etc. Moreover, the independent t-test and, if necessary, the Mann-Whitney and Pearson correlation coefficient tests were used to measure the relationship between different parameters. In order to interpret and analyze the data, SPSS23 software was used. The p-value was considered less than 0.05.

 

Results

In this study, 130 patients with liver cirrhosis with an average age of 7.05±5.34 years were evaluated, the youngest was one years old, and the oldest patient was 17 years old. Of these, 63 (48.5%) were girls, and 67 (51.5%) were boys.

This study‘s most common cause of cirrhosis was Wilson‘s disease, seen in 21.5%. After that, biliary atresia and Progressive familial intrahepatic cholestasis were in the following positions (Tab. 1).

In our study, 30 patients (23.1%) died. The most common cause of death was sepsis and multiple organ failure (Tab. 2).

The QT segment‘s average length was 397±31 milliseconds. Only 4 (3%) had a long QT segment in all of the studied patients. QT prolongation was mild in 3 patients (75%) and moderate in 1 patient (25%) (Graph 1).

In this study, the mean of the Meld/Peld criterion was 22.4±17.9, and the mean of the Child criterion was 8.9±2.5 (Tab. 3).

The comparison of the Meld/Peld criterion and Child criterion in the two groups of regular QT and prolonged QT showed that the average of both criteria is significantly longer in the standard QT group. Also, long QT did not show a significant relationship with gender. Beta-blocker use was not significantly associated with QT prolongation.

 

 

Tab. 1. Causes of liver cirrhosis in all patients included in the study.
Tab. 1. Příčiny jaterní cirhózy u všech pacientů zařazených do studie.

Characteristic                                                              Percent		Number
Wilson	21.5	28
allagy la syndrome	1.5	2
autoimmune hepatitis	3.8	5
biliary atresia	20.8	27
bode-Kiari	0.8	1
- Karoli	1.5	2
congenital fibrosis of the liver	0.8	1
crigler-carpenter	3.8	5
hepatocellular carcinoma	2.3	3
hepatoblastoma	1.5	2
hypercholesterolemia	2.3	3
hyperexalure	1.5	2
intrahepatic cholestasis	0.8	1
liver fibrosis	0.8	1
liver mass	0.8	1
liver necrosis	1.5	2
metabolism	0.8	1
neonatal hepatitis	0.8	1
progressive familial intrahepatic cholestasis	15.4	20
primary sclerosing cholangitis	0.8	1
tyrosenemia	6.9	9
of unknown origin	9.2	12

 

Tab. 2. Cause of death in the patients present in the study.
Tab. 2. Příčina smrti u pacientů přítomných ve studii.

Characteristic                                                               Percent		Number
pneumonia	1.6	2
respiratory distress syndrome	0.8	1
convulsions	0.8	1
encephalopathy	0.8	1
multiple organ failure	7.0	9
initial failure	3.1	4
bloody	2.3	3
sepsis	6.2	9

 

Tab. 3. Descriptive statistics report of practical factors in evaluating the severity of liver cirrhosis and Child criteria and Meld/Peld criteria.
Tab. 3. Popisná statistika praktických faktorů při hodnocení závažnosti jaterní cirhózy a Childova kritéria a Meld/Peld kritéria.

Characteristic          The least             The most            Standard             Average deviation
weight	6.5	100.0	18.5	24.9
albumin	2.0	5.3	0.7	3.4
INR	1.0	8.75	1.7	2.5
creatinine	0.1	5.7	0.8	0.6
sodium	123	151	4.4	138.2
PELD/MELD	0.0	199.0	17.9	22.4
Child criterion	5.0	19.0	2.5	8.9

 

 

Discussion

Despite the importance of chronic liver diseases and cirrhosis in children, studies in this field are limited, and long QT is one of the factors associated with the severity of disease in adults. The studies that deal with this issue in children are minimal, and only one study has addressed this issue; therefore, in the present study, the prevalence of long QT in children with liver cirrhosis and its relationship with the severity of liver disease was investigated. Based on the results of this study, long QT was associated with higher Child-Pugh and Meld/Peld. However, beta-blocker use did not show a relationship with long QT. Our study observed a long QT in only 3% of patients. This value is lower than Fishberger et al.‘s study, where long QT was observed in 18% [41]. In previous studies in adults with cirrhosis, long QT was reported in more than half of the patients [42–44]. Adults appear to have a higher prevalence of a long QT interval. In our study, Child-Pugh and Meld/Peld were higher in patients with a long QT. This finding is consistent with the study‘s results by Hajiani et al. In Hajiani‘s study, 5% of Chappeld class A, 40% of Child class B and 70% of Child-Pugh class C patients had a long QT [45]. In the study of Hela et al., the average QTc in Child-Pugh class 3 was significantly longer than in classes 1 and 2 [46]. In the study by Haji Aghamohammadi et al., a long QT was significantly related to Child-Pugh [47]. The study by Eve et al. showed that Child-Pugh, MELD score, and ALBI score were significantly higher in the group with a long QTc than the group without a long QTc [42]. Unlike these studies and our study, research of Siompanidis et al. showed no significant relationship between long QT and Child-Pugh score, although the length of the QT segment was longer in patients with cirrhosis than in the control group [48]. In the study of Biselli et al., a long QT was considered a predictor of mortality [49]. According to Kim et al.‘s study, QT prolongation was significantly associated with mortality [43]. In Koshi et al.‘s study, a long QT segment was associated with a 5-fold risk of cardiac arrest and ventricular arrhythmias within 30 days of liver transplantation [50]. According to Eve‘s study, long QT intervals may be associated with portal hypertension, acute UGIB, ascites, and myocardial dysfunction [42]. In this study, we faced some limitations. First, the number of patients studied was relatively small, making the results less accurate. Second, patients needing a transplant were evaluated; other patients were not evaluated in this study. Thirdly, the causes of death related to cirrhosis were not separated from other causes, and fourthly, the long-term prognosis and condition of patients after receiving the transplant were not evaluated. However, our study is one of the first to examine the relationship between QT and the severity of cirrhosis in children. Based on the results of this study, prolonged QT is associated with the severity of liver disease. In the future, a multicenter prospective study is suggested to investigate the role of QT in children with liver cirrhosis.