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246 15. Cirrhotic cardiomyopathy

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CHAPTER

Cardiovascular dysfunction in liver diseases:

pediatric perspectives

Noelle Gorgis and Moreshwar S. Desai

Pediatric Liver Intensive Care, Department of Pediatrics, Division of Pediatric Critical Care, Texas Children’s Hospital

and Baylor College of Medicine, Houston, TX, United States

Introduction

The far-reaching effects of a dysfunctional liver on remote organs of a human body, including the heart, has long fas-

cinated and perplexed the medical world. Liver gets 25% of the cardiac output directly from the heart, while venous

blood from the liver drains into the right side of the heart. This intricate interdependence leads to a unique liverheart

interaction, where pathologic changes in the heart lead to liver dysfunction, and pathologic changes in the liver lead to

myocardial dysfunction. Liver controls the metabolic environment of the host, and impairment in liver function impairs

cardiac function. Congenital heart diseases such as single ventricle physiology after Fontan procedure for hypoplastic

ventricle, severe pulmonary hypertension, left sided outflow tract obstructive lesions, or acute heart failure with poor

cardiac output adversely impact liver physiology and function and are more commonly seen in infants, children, and

young adults. This chapter will specifically focus on “hepatic cardiopathy” [effects of liver disease (acute, chronic,

acquired and genetic) on the heart] in the pediatric population. Effects of cirrhosis on the heart in adults [adult cirrhotic

cardiomyopathy (CCM)] and “cardiac hepatopathy” (effects of heart failure on liver) have been discussed elsewhere in

this book.

Cardiomyopathy in adults with end-stage cirrhotic liver disease, CCM, has been well studied with established

guidelines to define the disease

[1]. In contrast, cardiomyopathy in children with end-stage liver disease (ESLD)

has yet not been well characterized or defined . Lack of a consistent definition stems from the fact that children

have a wide spectra of cirrhotic and noncirrhotic liver disorders with varying degree of severity and presentation

and often have coexisting congenital heart defects. This diversity makes disease specific parameters hard to

define. Despite these limitations, there is growing body of evidence that cardiomyopathy in pediatric ESLD is

prevalent and equally detrimental to patient outcomes

[25].

In children, cardiac consequences of liver disease c an be classified into six broad primary categories: (1) car-

diovascular consequences of structural congenital heart disease coexisting with liver diseases; (2) cardiovascu-

lar consequences of geometric and functional derangements of the heart as a direct consequence of cirrhotic

ESLD (pediatric CCM); (3) consequences of heart dysfunction associated with inherited metabolic disease and

failure of energy metabolism; (4) cardiovascular dysfunction as a part of multiorgan dysfunction in acute ful-

minant liver failure; (5) pulmonary vascular complications of chronic cirrhosis, portal hypertension and port-

systemic shunts; and, (6) cardiac derangements secondary to chemotherapy agents used in liver cancer and

posttransplant immune-suppressive agents. These six categories of liverheart interactions have been

described in detail below.

247

Cardio-Hepatology.

DOI:

https://t.me/medicina_free

Cardiovascular consequences of structural congenital heart diseases coexisting

with diseases of the liver

Primary liver diseases with concomitant coexisting congenital heart defects though rare are unique to the pedi-

atric population. These structural defects impair myocardial function and further aggravat e the primary liver dis-

ease, occasionally inducing irreversible liver damage and death. Abnormal myocardial physiology often makes

them a poor candidate for a liver transplant and adversely affects quality of life and survival. Severity of the con-

genital heart disease, cardiovascular status, and availability of surgical options to correct the defects often deter-

mine the ultimate fate and survival of the patient rather than the liver disea se itself.

There are three primary liver diseases with coexisting structural heart defects (

Table 16.1): Alagille syndrome

(ALGS), Biliary Atresia Splenic Malformation (BASM), and Abernathy malformation of portal vein [6].

Alagille syndrome

ALGS, first described by Daniel Alagille in 1969 [7], is an autosomal dominant, multisystem disorder caused

by heterozygous mutations in one of the two essential genes regulating the Notch signaling pathway, JAGGED1

(JAG1) and NOTCH2

[8,9]. Clinical features of this syndrome are variable and depend on the phenotypic pene-

trance of the mutation. Approximately 90% of these patients have detectable mutations in JAG1, and B10% have

a detectable mutation in NOTCH2. Based on gene analysis, the overall frequency of ALGS in infants is 1 in 30,000

live births

[10]. Initial diagnosis is based on the presence of intrahepatic cholestasis and at least three other clini-

cal findings such as chronic jaundice, structural cardiovascular disease, ocular abnormalities, skeletal abnormali-

ties, and characteristic facial features

[811].

Congenital cardiovascular defects associated with ALGS

Congenital heart disease is a common feature of ALGS. In a case series of 92 patients with ALGS published in

1999 by Emrick et al.

[12], which included 83 unrelated patients and nine members of the same family, an audible

heart murmur was present in nearly all (B97%) of the children. Abnormal cardiovascular status was the initial

admitting diagnosis in 16 of the 92 (17%) of these children. A majority 49 of 73 (67%) had a stenotic lesion in the

pulmonary vasculature, with peripheral/branch pulmonary artery (PA) stenosis as the most common defect.

Structural intracardiac disease was present in 22 of 92 (24%) of the children. Tetralogy of Fallot (TOF) was pres-

ent in 10 of the total 92 (11%) with ALGS making it the commonest structural congenital defect in these children,

followed by valvular pulmonary stenosis, valvular aortic stenosis, atrial septal defects, and ventricular septal

defects. In this cohort, the overall mortality was 17%, and presence of complex congenital heart disease was pre-

dictive of mortality, and accounted for 15% of all ALGS deaths. Among the heart defects, TOF and TOF with pul-

monary atresia had a high 10-year mortality of 34% and 75%, respectively

[12].

A similar prevalence of right and left sided structural defects was reported in 200 children with ALGS by

McElhinney et al., majority of whom [154 of 200 (77%)] had JAG1 mutation

[13]. In that study, right-sided lesions

[110 of 200 (55%)] were the commonest defects, with branch PA stenosis [70 of 200 (35%)] and TOF [23 of 200

(12%)] being the commonest lesions. Ten of the 23 children with TOF (43%) died from cardiovascular causes.

TABLE 16.1 Structural congenital heart diseases associated with liver diseases in children.

Syndrome Pathology in the liver Pathology in the heart

Alagille syndrome

(ALGS)

Syndromic paucity of intrahepatic bile ducts, cholestasis,

cirrhosis and portal hypertension

Peripheral pulmonic stenosis, Tetralogy Of Fallot,

coarctation of aorta, Aneurysms of basilar, cerebral and

internal carotid artery

Biliary atresia splenic

malformation

syndrome (BASM)

Extrahepatic destruction and obstruction of the biliary

tract (Biliary atresia), cholestasis, cirrhosis, liver failure,

portal hypertension, liver failure, polysplenia, intestinal

malrotation, portal vein anomaly, hepatic artery

anomaly, inferior vena cava interruption situs inversus

ASD, VSD, PDA, TOF, right-sided aortic arch, double

outlet right ventricle, common atrioventricular canal,

dextrocardia, pulmonary stenosis, total anomalous

pulmonary venous return, and hypoplastic left heart

Abernathy

malformation of the

portal vein

Congenital absence of portal vein, congenital

portosystemic shunts, liver nodules, portal hypertension,

hepatic encephalopathy, hepatopulmonary syndrome

Atrial septal defect, ventricular septal defect and Patent

ductus arteriosus

248 16. Cardiovascular dysfunction in liver diseases: pediatric perspectives

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Forty-six (23%) of ALGS required at least one form of cardiac intervention (surgery or a therapeutic right heart

catheterization) and exhibited a 7% mortality among those who did get a cardiac intervention. This study also

found that though JAG1 mutation is associated with defects in the embryonic development of the heart and the

major vessels in humans, there was no correlation between the degree of mutation in JAG1 and the severity of

the cardiovascular defects

[13].

Peripheral vascular defects in ALGS

Along with pulmonary vessels, peripheral vascular involvement is equally common, often neglected and pro-

foundly consequential in overall management of children with ALGS. Abnormalities in peripheral vasculature

justify the alternative name for ALGS, “arterio-hepatic dysplasia.” In an extensive retrospective chart review of 268

children with ALGS, Kamath et al.

[11] found a 9% (25 of 268) prevalence of peripheral vascular abnormalities

within the cohort. Sixteen children had documented structural vascular abnormality: basilar artery aneurysms

(n 5 2), internal carotid artery anomalies (n 5 7), one each had a middle cerebral artery aneurysm and Moyamoya

disease. Aortic aneurysms were seen in (n 5 3), while coarctation was seen in two of the children. Of those who

had undocumented vascular abnormality, nine had intracranial events which required intervention. Vascular

events accounted for 34% of the mortality all ALGS in this cohort

[11].

Biliary atresia splenic malformation syndrome

Biliary atresia (BA) is a condition in infants where extrahepatic bile ducts are scarred/not developed, leading

to obstructed bile flow, cholestasis, and cirrhosis. BA is the leading indication for LT in children worldwide

[14].

Approximately 15%20% of all BA are associated with one or more major malformation/defect, placing them in

a special category of “syndromic” BA. This group has been further subdivided into those with laterality defe cts

(B10% of all syndromic BA), which primarily includes splenic abnormalities such as polysplenia and ectopic

spleen, and those without laterality defects but with at least one structural defect (B6% of all syndromic BA).

Cardiovascular abnormalities were common (70%80%) in both the syndromic groups. Common cardiac lesions

included aortic arch abnormalities, coarctation of aorta, atrial septal defects, patent ductus arteriosus, patent fora-

men ovale, PA stenosis, pulmonary valvular stenosis, TOF, transposition of the great vessels, and ventricular sep-

tal defects

[1517]. Though infants with BASM present at a much younger age, their long-term prognosis is poor

because often the cardiovascular morbidity is severe enough to mask the diagnosis or prevent a Kasai porto-

enterostomy or a definitive transplant. The mortality in children with BASM is higher than those with nonsyn-

dromic BA, and lethal uncorrectable cardiac lesions has been reported to be the primary cause for the observed

low survival in children with BASM

[15,17].

Heart defects associated with Abernathy malformation of portal vein

Abernethy malformatio n, described in 1793 by John Abernathy, is an extremely rare splanchnic vascular mal-

formation, characterized by congenital absence of the portal vein (CAPV), diversion of portal flow, congenital

portosystemic shunts, and liver nodules. This condition is often as sociated with congenital cardiac diseases

including atrial septal defect, patent foramen ovale, ventricular septal defects, and patent ductus arteriosus.

Along with septal defects, congenital stenosis of the aortic valve and PA valve is also observed in a number of

patients with CAPV and can cause tricuspid regurgitation, increased right-sided pressures and eventually further

worsen liver congestion and portosystemic shunts

[6].

Implications of coexisting congenital heart diseases for liver transplantation

Indications for LT in ALGS include severe pruritus, synthetic dysfunction, portal hypertension, and growth

failure. In a systematic review on ALGS syndrome, by Kamath et al. report that 15%47% of patients undergo

LT at the median age of 46 years, with a survival between 70% and 90% among those who received a liver

transplant with a mean follow-up of 4.2 years (range 0.712.3 years). Most of the deaths occurred within first

30 days post-LT and were related to surgical complications [hepatic vessels (21%) and biliary (16%)] and surpris-

ingly not related to inherent cardiovascular defects

[12,18,19]. The frequency of complex cardiac anomalies how-

ever was lower in the group that were listed for LT and those who eventually obtained a LT than the general

ALGS population (5% vs 13%), suggesting that those with severe uncorrectable heart defects may have never

249Cardiovascular consequences of structural congenital heart diseases coexisting with diseases of the liver

III. Cardiovascular system in liver failure

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been considered as LT candidates. With advancements in pediatric cardiac surgical care, heart defects can be

fixed, and data show that ALGS with heart defects have a comparable outcome to those without. Overall, the

1-year survival rate was modestly lower for the ALGS patients versus the BA patients. Vascular, CNS, and renal

complications were increased in the ALGS patients after LT, and this multisystem involvement may attribute to

the lower post-LT survival rate in ALGS than BA

[10]. There are no reported heart transplants or combined

heartliver transplants in children with ALGS.

Cardiovascular complications of pediatric cirrhosis

Cirrhosis is the common ultimate outcome of long-standing ongoing hepatocyte injury, cellular response to the

damage and regeneration that is secondary to a wide spectrum of illnesses whether congenital/inherited or acquired,

inflammatory, or infiltrative.

Table 16.2 enumerates key pediatric diseases that lead to cirrhotic ESLD in children.

Correlation between cirrhosis and cardiomyopathy had been recognized as early as the 1960s

[20,21]. Over the

last couple of decades, however, the appreciation of this cardiomyopathy as a direct consequence of cirrhosis has

grown substantially. The role played by the hepato-cardiac interactions in adult cirrhotic patients and its adverse

effects on quality of life and surgical outcomes are coming to prominence

[22,23]. The emerging role and impor-

tance of CCM as a distinct disease entity can be credited in large part, to the monumental body of work pro-

duced by experts

[1,2227] in the field of CCM. In adults, CCM, per consensus in 2005, was defined as a chronic

cardiac dysfunction characterized by impaired cardiac contractility (systole) in response to stress (either induced

by catecholamine/exerci se/surgical) and altered diastolic relaxation with electrophysiological abnormalities in

patients with cirrhosis and no known inherent heart disease

[22,23]. The 2005 consensus definition has been fur-

ther refined in 2019 after inclusion of recent advances in cardiac scanning modalities.

Table 16.3 enumerates the

2019 current guidelines that can be used to diagnose adult CCM

[1]. Pathophysiologic mechanisms and clinical

outcomes of adult CCM are detailed elsewhere. This chapter will only focus on pediatric CCM and will discuss

what is currently known based on current data and the inferences draw n from studies that have tried to charac-

terize this disease in children with cirrhotic ESLD.

Studies into the prevalence and clinical consequences of pediatric CCM (pCCM) are, quite literally, decades

behind that in adults. There is a plethora of reasons for the lack of pediatric data on this topic, mainly stemming

from the inherent limitations to evaluating parameters of systolic and diastolic dysfunction (DD) in children,

with no set parameters and values for infants, children and adolescents

[28,29] all of which greatly limit the abil-

ity to extrapolate the adult criteria. Additionally, many of the pediatric disorders that result in ESLD are diverse

and often associated with congenital heart disease, or infiltrative diseases, or inherited metabolic and mitochon-

drial diseases that hamper the ability to assess for coexisting CCM. Regardless of these limitations, the adverse

impact of CCM on outcomes in the pediatric population necessitated an exp loration, using initial framework

extrapolated from established criteria used in pediatric population with congenital or acquired cardiomyopathies.

Data that have emerged over the last 10 years, though sporadic, confirm that pediatric CCM exists, has detrimen-

tal consequences to children with cirrhosis, adversely impacts peri-LT outcomes, and resolves after liver trans-

plantation

[25], similar to that in adults. Studies evaluating CCM have been conducted in children with BA as

well as children with heterogeneous cirrhotic diseases. These are mostly focused on abnormalities in echocardiog-

raphy, probably because invasive tests like cardiac catheterizations and stress challenges are often not feasible in

infants and children, while cardiac magnetic resonance imaging (MRI) requires anesthesia and sedation.

In one of the studies looking specifically at children with BA (n 5 40; median age 5 8 months) and end-stage cir-

rhotic liver disease who were listed for liver transplantation, Desai et al. found B 60% prevalence of structural

and/or functional abnormalities in routine pretransplant echocardiography

[2]. Compared to controls, children

with BA had significant increase in multiple echocardiographic parameters, notably left ventricle wall thickness

(23% increase), left ventricular (LV) mass indexed (LVMI) to body surface area (51% increase), and LV shortening

fraction (8% increase). Children with BA had abnormalities in LV geometry. LV geometry on echocardiography

was classified as: (1) normal geometry (where LVMI is normal) (# 110 g/m

2.7

) and Relative wall thickness (RWT) is

normal (#0.41 cm); (2) concentric remodeling (where LVMI is normal and RWT is increased); (3) concentric hyper-

trophy (where both LVMI and RWT are increased); and (4) eccentric hypertrophy (where LVMI is increased and

RWT is normal). Using these parameters, the study found 37% of the children with BA listed for LT had concentric

remodeling, 20% had concentric hypertrophy and 5% had eccentric hypertrophy (

Fig. 16.1). Though underpowered

for effect of mortality, the study found that infants with abnormal echocardiography had longer stays in the inten-

sive care unit (ICU) (median, 6 vs 4 days) and the hospital (21 vs 11 days) compared with infants who had normal

250 16. Cardiovascular dysfunction in liver diseases: pediatric perspectives

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echo reports in the perioperative period. On univariate analysis, the length of hospital and ICU stay correlated with

LV mass index. Autopsies (

Fig. 16.2) performed on the children who died demonstrated cardiomegaly, hypertro-

phy of the left ventricles, and subendocardial fibrosis in both right and left ventricles

[2].

To further characterize and define pCCM in the BA population, Gorgis et al.

[3] studied a separate cohort of

69 patients with BA who were listed for LT and reported a cutoff value of LVMI $ 95 g/m

2.7

which indepen-

dently had a higher sensitivity and specificity for peri-LT death and other serious adverse events compared to

TABLE 16.2 Common etiologies of pediatric end-stage cirrhotic liver diseases.

Disorders of the biliary tract, biliary malformations and cholestasis Biliary atresia

Alagille syndrome

Bile duct stenosis

Choledochal cyst

Congenital hepatic fibrosis

Caroli disease

Progressive familial intrahepatic cholestasis:1,2 and 3

Inflammatory disorders of the liver and biliary duct Autoimmune hepatitis

Primary sclerosing cholangitis

Genetic and inherited metabolic disorders of the liver Alpha-1-antitrypsin deficiency

Cystic fibrosis

Galactosemia

Glycogen storage disease type III and IV

Gaucher disease

Hepatic porphyrias

Hereditary hemochromatosis

Mitochondrial hepatopathies

Niemann-Pick disease type C

Sarcoidosis

Tyrosinemia type I

Wilson disease

Bile Acid synthesis defects

Infectious diseases of the liver and the biliary tract Ascending cholangitis

Chronic hepatitis A, B, C, delta virus and E

Herpes simplex virus

Cytomegalovirus

Rubella

Schistosomiasis

Drugs and toxin induced liver injury Hepatotoxic drugs (isoniazid, methotrexate)

Natural toxins (mushrooms)

Organic solvents

Total parenteral nutrition

Acquired infiltrative diseases and cancer Fatty liver disease

Hepatocellular carcinoma

Langerhans cell histiocytosis

Gestational alloimmune liver disease

Liver infiltration in hematologic diseases

Zellweger (cerebro-hepato-renal) syndrome

251Cardiovascular complications of pediatric cirrhosis

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the Pediatric End Stage Liver Disease (PELD) score (Fig. 16.3), the current score used by UNOS to stratify chil-

dren on the LT waitlist. Those with high LVMI had longer peri-LT ICU and hospital stays, and more days on the

ventilator, vasopressors, and dialysis. Furthermore, the authors also showed that LVMI increased over time till

transplant and then decreased over time after transplant (

Fig. 16.4), indicating that transplanting early may halt

pathologic remodeling of the heart. Additionally, in line with adult findings, abnormalities in LVMI and RWT

resolved after transplant proving that structural aberrations in the heart in cirrhosis though detrimental are

reversible (

Fig. 16.5) [3].

Others have investigated cardiac abnormalities in heterogeneous groups of cirrhotic children beyond those

with BA. In a cohort of 52 children, (median age 8 years) consisting of 60% cryptogenic cirrhosis and 20% chronic

hepatitis, Fattouh et al.

addition to plasma Brain Natriuretic Peptide (BNP) concentrations. On echocardiography, they found that

TABLE 16.3 New (2019) proposed consensus guidelines to diagnose

adult cirrhotic cardiomyopathy [1].

New 2019 proposed guidelines

Systolic dysfunction (any 1)

1. LVEF ,50%

2. Absolute GLS value ,18% or .22%

Diastolic Dysfunction (at least 3)

1. Septal e

velocity , 7 cm/s

2. E/e

ratio .15

3. LAVI .34 mL/m

4. TR jet velocity . 2.8 m/s in absence of portopulmonary hypertension

Other supportive criteria*

1. Electrocardiographic abnormalities

2. Prolonged QTc

3. LA enlargement

4. Increased LV mass

5. Increased BNP, Pro-BNP, Troponin I, Galectin-3 and soluble ST-2

6. Abnormal contrast-enhanced cardiac MRI

*These require further research and validation.

NORMAL

CR (Thick heart)

CH (Thick and Heavy)

EH ( Dilated and Heavy)

LVM I < 110 g /ht

2.7

LVMI >110 g/ht

2.7

RWT < 42 mm RWT ≥ 42 mm

2/40=5%

8 / 40 = 20%

15 / 40 = 37%

FIGURE 16.1 Characterization of LV geometry in children with biliary atresia: Based on relative wall thickness (RWT), and LV mass index

(LVMI) values obtained on routine 2 dimensional echocardiography, 37% had a normal LV geometry; 37% had concentric remodeling (CR,

thick heart); 20% had concentric hypertrophy (CH, thick and heavy); and, 5% had eccentric hypertrophy (EH, Dilated and heavy). Arrows

indicate the progression of pathologic remodeling from a normal to EH.

252 16. Cardiovascular dysfunction in liver diseases: pediatric perspectives

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cirrhotic children had a significantly larger left atrium, right atrium, right ventricle, and PA diameters and LV

posterior wall thickness. The investigators evaluated E/A ratio (ratio of peak velocity of blood flow across

mitral/tricuspid valve in early diastole (E) to peak velocity flow across mitral/tricuspid valve in late diastole (A)

caused by atrial contraction) and isovolumetric relaxation time (IVRT) and found that these surrogate markers of

DD were prolonged in cirrhotic children compared with control. Increased myocardial stiffness, hypertrophy,

edema, and fibrosis was speculated as the cause of this DD. Plasma BNP concentrations were also significantly

higher in cirrhotic patients than controls, suggesting stress on the LV

[30]. DD was also demonstrated in children

FIGURE 16.2 Cardiac histopathology from autopsies in infants with biliary atresia: Representative sections of Right and Left ventricles

showing mild to moderate degree of endocardial fibrosis (double headed arrow). Lower panel depicts mild Left ventricular hypertrophy as evi-

denced by thickened myocytes with thinned and elongated nuclei (black arrow). Also note presence of bilirubin pigmentation (purple arrow).

Source: Adapted from Desai MS, Zainuer S, Kennedy C, Kearney D, Goss J, Karpen SJ. Cardiac structural and functional alterations in infants and chil-

dren with biliary atresia, listed for liver transplantation. Gastroenterology 2011;141(4):126472.

1.0

0.8

0.6

0.4

0.2

0.0

0.0 0.2 0.4 0.6

LVMI AUC= 0.88, p<0.01

PELD AUC= 0.59, p NS

1-specificity

Sensitivity

0.8 1.0

FIGURE 16.3 LVMI as a predictor of peri-transplant mortality in children with biliary atresia in comparison to PELD score: Figure depicts

a higher Area Under Curve (AUC) for the association of LVMI with peri-LT death compared to the PELD score. Source: Adapted from Gorgis

NM, Kennedy C, Lam F, Thompson K, Coss-Bu J, Arikan AA, et al. Clinical consequences of cardiomyopathy in children with biliary atresia requiring liver

transplantation. Hepatology 2018;69(3):120618.

253Cardiovascular complications of pediatric cirrhosis

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