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with chronic hepatitis by Polat et al. [31], who correlated degree of myocardial dysfunction to degree of liver
fibrosis establishing a direct connection between degree of liver injury and heart failure.
DD is traditionally difficult to diagnose on echocardiography alone, and it becomes even more difficult in
infants and children, because parameters are not well defined and can only be inferred. Jang et al.
[4] proposed
myocardial performance index (MPI) (
Fig. 16.6) as yet another adjunct to diagnosing LV diastolic and systolic
dysfunction. In a retrospective review of clinical and Doppler echocardiographic data for 45 consecutive pediatric
LT recipients (median age 15 months), the authors demonstrated that abnormal MPI ( . 0.5 tei index) was seen in
B30% of children listed for transplant, and abnormal MPI values correlated with lactate accumulation at end of
LT, and increased hospital stay post-LT
[4]. In a recently published study on 198 pre-LT patients (median age of
4 years) with cirrhotic ESLD, Junghe et al.
[5] showed that LV end diastolic diameter, LV mass and LVMI was
higher in cirrhotic children as compared to their noncirrhotic children, suggesting a link between liver disease
5.4
R
2
=0.29, p<0.01 R
2
=0.37, p<0.01
Log LVMI (g/m
˄
2.7) Pre-LT
Log LVMI (g/m
˄
2.7) Post-LT
5.1
4.8
4.5
4.2
3.9
5.4
5.1
4.8
4.5
4.2
3.9
-400 -300 -200
Time Pre-LT (days) Time Post-LT (days)
-100 4003002001000-0
FIGURE 16.4 Evolution of LV myocardial index in the peri-transplant period in children with biliary atresia: Figure depicts the progres-
sion and regression of LVMI (g/m
2.7
) before and after. LVMI values were first log transformed and Linear regression analysis was conducted
to determine association. Source: Adapted from Gorgis NM, Kennedy C, Lam F, Thompson K, Coss-Bu J, Arikan AA, et al. Clinical consequences of car-
diomyopathy in children with biliary atresia requiring liver transplantation. Hepatology 2018;69(3):120618.
160
* p<0.01
* p<0.01
PRE-LT 2DE POST-LT 2DE
*
*
120
80
40
0.7
0.5
0.3
RWT
LVMI (g/m
˄
2.7)
FIGURE 16.5 Resolution of pathologic changes in LV geometry after transplant: Figure depicts the differences in LVMI (g/m
2.7
) (top
panel) and RWT (bottom panel) between the pre- and post-LT 2DE in patients with biliary atresia who survived to transplant. Differences in
LVMI and RWT were assessed using Wilcoxon rank sum and Dunn method for joint ranking using Bonferroni adjustment. 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):120618.
254 16. Cardiovascular dysfunction in liver diseases: pediatric perspectives
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and abnormal LV geometry in line with previous reports [2,3]. Abnormalities in LV geometry were significantly
associated with cholestasis and degree of liver fibrosis, further emphasizing the liverheart interaction. These
changes reversed 1 year after transplantation
[5], showing yet again that CCM in children is a consequential but
reversible cardiomyopathy, with liver transplantation as the only current remedy.
Electrocardiographic abnormalities, more specifically pro longation of the QT interval, though not as common
as in adult CCM, were first described in a heterogeneous population of 88 pediatric cirrhotic children by Arikan
et al. and were associated with a B3.66 higher odds of mortality prior to liver transplantation
[32]. Similar to
adults, these electrocardiographic abnormalities reversed after transplantation. In a cohort of cirrhotic children
who were predominantly (B75%) BA, Cho et al.
[33] established a positive association between corrected QT
interval (QTc) and LV chamber size and mass suggesting that repolarization abnormalities in cirrhosis may be in
part contributed by structural alterations in the heart
[33]. In a study of 198 children (median age of 4 years),
Junge et al. also found an association of prolonged QT interval with the diagnosis of liver failure, but found no
difference in the incidence of prolonged QT intervals between those with advanced fibrosis requiring LT (7.5%)
and those with nonadvanced fibrosis requiring LT (11.5%). They, however, found that those with pathologic QTc
had a significantly higher values for serum bilirubin levels, suggesting a yet undefined role for cholestasis in the
pathophysiology of electrocardiographic disturbance
[5].
The clinical relevance of this subtle electrocardiographic abnormality is unknown, as none of the studies or obser-
vations published till date have found any association with prolonged QTc with fatal dysrhythmias, ventricular
tachyarrhythmias or torsade de pointes in children. It could be speculated that fatal dysrhythmias are an effect of high
circulating hydrophobic cardio-toxic bile acids
[34], and that hydrophilic bile acid—ursodeoxycholic acid (ursodiol), a
known choleretic commonly used in children and adults with cholestasis is protective against dysrhythmias
[35].
Bile acid-myocardial interaction as a potential mechanism of cardiomyopathy
Multiple pathophysiologic mechanisms have been proposed and studied using elegant rodent models of bili-
ary fibrosis, cirrhosis, and portal hypertension. Impaired myocardial membrane receptor function (β-adrenergic,
muscarinic, and cannabinoid receptors), disturbances in the biochemical properties and fluidity of the cardiomyo-
cyte cell membrane (plasmalemma), altered ion channel function (Ca
21
,K
1
,Na
1
/Ca
21
exchanger), increases in
circulating cardio-depressants like carbon monoxide, hem-oxygenase-1, and nitric oxide and increased circulating
inflammatory mediators such as TNFα and NFκB, increased cardiomyocyte apoptosis, deposition of titin, and
FIGURE 16.6 Figure depicting the calculation of Myocardial Performance Index. MPI (Myocardial Performance Index) (Tei), IVCT
(Isovolumic contraction time), IVRT (Isovolumic relaxation time), LVET (LV ejection time). E wave (peak velocity blood flow in early diastole),
A wave (peak velocity flow in late diastole caused by atrial contraction).
255Cardiovascular complications of pediatric cirrhosis
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even a shift in myosin heavy chain isoform from the more powerful α-subtype to the weaker β-isoform, all of
which negatively influence heart rhythm and contractility in rodent models
[22,3639]. Detailed mechanistic
insights into the pathogenesis of CCM can be found in Chapter 15.
Patients with cirrhosis have elevated concentrations of bile acids in their systemic circulation
[4044]. Bile acids
are made by the liver from cholesterol, and, in normal host are mostly contained within the entero-hepatic circulation,
with tightly regulated feedback mechanisms to ensure a stable bile acid pool in the host. Bile acid pool is composed
of cholic acid (CA) and chenodeoxycholic acid (CDCA), which are primary bile acids, and deoxycholic acid (DCA)
and lithocholic acid (LCA), which are secondary bile acids and their tauro and glyco-conjugates. The composition,
concentration, and ratios of primary and secondary bile acids within this circulating pool gets altered when hepato-
cyte is injured. In cirrhosis, there is a blockage or/and destruction of hepatocytes, which promptly affects the well-
coordinated feedback regulation of bile acids and destruction/obs truction of biliary tract interrupts the bile flow.
These events lead to spillage and high levels of bile acids (B10 to 100 fold increases) in the systemic circulation, a
condition called cholestasis/cholanemia
[4044], which then adversely affect remote organ function, including the
heart. The section below focuses on defining a pathologic bile acid-myocardial interaction, as a critical mediator of
myocardial dysfunction seen in cholestatic liver diseases, a term we coin “cholecardia.”
Heart as a target for bile acids
Bile acids have traditionally been viewed as mere “detergents” responsible for aiding digestion and absorption
of dietary fats and lipid-soluble vitamins. However, over the past decade, research in the field of bile acid biol ogy
and discovery of receptors, both on cell membrane [Takeda G protein-coupled receptor 5 (TGR5), also known as
G protein-coupled bile acid receptor 1 (GPBAR1)] and nuclear [Farnesoid X receptor (FXR)] receptors, who have
specific affinity for endogenous bile acids, have ushered a new era for bile acids and raised their profile as potent
circulating signaling molecules with the ability to regulate cell biology, metabolism, and function and exert a
“hormone-like” effect on extrahepatic organs
[4548]. Discovery of bile acid responsive TGR5, FXR, along with
vitamin D receptor, and muscarinic (M2) receptors, in the cardiomyocytes and vascular endothelium of rodents
and humans, makes the heart a target for circulating bile acids
[46,4855].
Clinical evidence of pathologic bile acid-myocardial interaction
In cirrhotic adults and children, plasma concentrations of total bile acids can exceed B100 μmol/L (normal values:
215 μmol/L)
[43,56,57]. Thus, high concentrations of cytotoxic hydrophobic bile acids such as CA, CDCA, LCA,
DCA, and their tauro and glyco-conjugates bathe the cardiomyocytes and the vasculature in humans. These bile acids
have been implicated in some of the abnormalities noted in heart of a cirrhotic patient. Rainer et al.
[34] reported an
association between high serum levels of cytotoxic hydrophobic bile acids mentioned above and low levels of hydro-
philic (and hence less cytotoxic) UDCA in adults suffering from atrial fibrillations. In isolated human atrial myocar-
dium, the same study demonstrated a dose-dependent effect of tauro-CA on heart rhythm
[34].Perhapsthemost
direct evidence of bile acid induced fatal dysrhythmias comes from a series of published reports by Williamson and
Gorelik et al., who have linked total bile acid levels and specifically tauro-CA in placental circulation to premature
births and early fetal deaths in intrahepatic cholestasis of pregnancy
[58]. Through clinical and experimental observa-
tions, this group has established a causative role for tauro-CA (at levels above 40 μmol/L in placenta) to altered cal-
cium dynamics and loss of synchronous beating of cardiomyocytes and development of fetal supraventricular
tachycardia leading to early fetal demise. The relatively less hydrophobic UDCA, by displacing the cytotoxic and
more hydrophobic tauro-CA, mitigates fetal dysrhythmias
[35,54,5962].
In 58 adults with cirrhosis, Voiosu et al. showed a positive correlation between echocardiographic evidence of
hyperdynamic circulation and left atrial volume
[63]. Gorgis et al. [3] showed an association between degree of
cholestasis (high bilirubin levels) and abnormal LV geometry. In summary, pathologic bile acid-myocardial inter-
action is evident in pathologies affecting fetal, pediatric and adult hearts and merits further studies.
Historic evidences of pathologic bile acid-myocardial interaction in animal models
The concept of cholecardia is not new. It has been known for over a century that high concentrations of bile
acids are toxic to the heart. Ro
¨
hrig was the first to document bile acid mediated cardiotoxicity as early as 1863.
He demonstrated that filtered ox bile wh en injected into the jugular veins of rabbits caused bradycardia, while
256 16. Cardiovascular dysfunction in liver diseases: pediatric perspectives
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repeated doses caused cardiac arrest, a phenomenon he described as “cardiac paralysis”[64]. At around the same
time, Landois showed bradycardia induced by bile persisted even a fter denervation of the heart, suggesting a
direct cardio-depressant effect of bile, not influenced by the sympathetic nervous system. Later, Wakim et al. in
1939 extended the observations in dogs and showed that along with whole bile, sodium taurocholate salt pro-
duced hypotension, bradycardia, and rhythm disturbances irrespective of presence and absence of cardiac auto-
nomic nerves
[65]. Joubert in 1978 showed that infusion of CA induced dose-dependent bradycardia resistant to
atropine in a rodent heart [66,67]. These historic clinical and experimental observations [20,6471] were the basis
for further studies which have now cemented an important role for bile acids as mediato rs of myocardial dys-
function seen in cirrhosis
[7275].
Mechanistic insights into bile acid-myocardial interaction
In the late 1980s, Binah et al. were the first to report that tauro-CA reduced slow inward Na
1
and Ca
21
current
while increasing the outward K
1
current, thus reducing the duration of action potential in the isolated rat ventricular
myocytes
[76]. Effects of bile acids on calcium homeostasis and contractility have been studied in vascular endothelial
cells as well as isolated cardiomyocytes and provides support for bile acid mediated vasodilation and contractile dis-
turbance seen in cirrhosis. In human umbilical cells and calf aortic endothelium, Nakajima et al. found DCA and
CDCA and their conjugates activated Ca
21
dependent K
1
current and induced nitric oxide release from cells in a
dose-dependent manner and induced vasodilation
[77]. Kida et al. linked production of nitric oxide in bovine aortic
endothelial cells by bile acids to its agonistic effect on TGR5 mediated activation of Protein kinase B
[52].
Bile acids impair contractility of the cardiomyocytes. Tauro-CA at concentrations of 1001000 μMol/L reduces
the rate and amplitude of contraction of rat neonatal cardiomyocytes in vitro. The effect of tauro-CA can be attrib-
uted to its direct effect on cardiomyocyte membrane depolarization and disruption of calcium dynamics medi-
ated, in part, via acetylcholine muscarinic M2 receptor activation. At extreme doses of 3000 μMol/L, the
cardiomyocytes stop beating and die in cell culture—an observation in line with Ro
¨
hrig’s in 1863 that high
repeated doses of ox bile caused “cardiac paralysis” in rabbits
[35,54,5962].
Zavecz and Battarbee compared the effect of CA on contractility of isolated mouse ventricular strips, and again
found dose-dependent reductions in contractile tension starting as low as 0.1 μmol/L. At a molecular level, they dem-
onstrated that CA exposure decreased cAMP production, and reduced intracellular Ca
21
and sodiumcalcium
exchange activity, all of which are associated with impaired cardiomyocyte contraction
[78].
In a mouse model of liver fibrosis and cholestasis, using electrocardiography, echocardiography, cardiac MRI,
treadmill exercise stress testing, histology and molecular analysis Desai et al. demonstrated hyp ertrophic and
hyperdynamic LV function, poor exercise tolerance, catecholamine insensitivity, bradycardia and prolonged QT
interval, recapitulating many features seen in cirrh otic adults and children. The hearts of the cholestatic mice
showed molecular evidence of pathologic remodeling (activation of stress pathways, reexpression of fetal genes,
accumulation of glycogen in the heart muscle and downregulation of genes mediating fatty acid oxidation (FAO)
and switch in fuel/substrate utilization from fats to glucose for maintain heart function)
[50]. In the same model,
the authors linked functional, structural, and molecular derangements to the cholanemia and showed that resolu-
tion of liver injury and cholestasis and reduction in bile acid levels in mice reversed cardiomyopathy
[79].
Bile acids induce metabolic disturbance in the heart—the concept of cholecardia
In normal state of health, heart relies on energy generated from FAO for its contractile activity and function.
When heart is stressed (injury, pressure, ischemic, or metabolic), it adapts by switching its preferred substrate
from fats to glucose and relies on energy derived from glucose oxidation to sustain its function. In presence of
continuing unrelieved stress or additional external insult, adaptive responses are overwhelmed, compromising
energy production resulting in heart failure
[8083]. Fatty acid and glucose oxidation occurs in the mitochondria.
Bile acids are toxic to the cardiac mitochondria. Toxicity to cardiac mitochondria was dem onstrated by Ferreira
et al., who exposed isolated rat cardiac mitochondria in vitro to LCA, DCA, and CDCA. Even at physiologic
doses, hydrophobic bile acids resulted in decrease in the mitochondrial respiratory ratio and membrane potential,
resulting in activation of mitochondrial permeability transition pore, increased permeability across the mitochon-
drial membrane, and induced mitochondrial swelling and destruction
[8084].
Bile acid induced dysregulation in energy metabolism as a critical mediator of myocardial dysfunction in cir-
rhosis was demonstrated in a genetic mouse model of high circulating bile acids—mouse lacking both Fxr and
257Mechanistic insights into bile acid-myocardial interaction
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Shp, genes responsible for bile acid homeostasis. In this double knockout mouse, Desai, Mathur, et al. [85] recapit-
ulated pathogenic cardiac features seen in experimental and clinical cirrhosis. Single and repeated injections of
tauro-CA and LCA mimicked the cardiac effects in wild-type mice, while direct perfusion of tauro-CA through
isolated whole heart using ex vivo Langendorff apparatus decreased contractile force, and impaired fatty acid
and glucose oxidation. Further, using in vivo and in vitro gene analysis and overexpression experiments, the
authors showed that bile acid mediated suppression of peroxisome-proliferator-activated receptor gamma coacti-
vator 1-alpha (Pgc1α)—the master regulator of cell energy metabolism was responsible for suppression of genes
regulating FAO. Both overexpression of Pgc1α in cardiomyocytes and administration of a bile acid-binding agent,
cholestyramine, reduced the detrimental effects of hydrophobic bile acids on cardiac gene expression and func-
tion, convincingly supporting role of bile acids in metabolic derangements in heart, a syndrome they coined “cho-
lecardia”
[85] (Fig. 16.7).
Implications for intensive care management and liver transplantation
Takentogether,studiesinchildrenwithcirrhosisand ESLD of varied etiologies clearly demonstrate the
presence of distinct pathophysiologic alterations in the heart as a direct consequence of an abnormal failing
liver. CCM in children increases perioperative mortality, increases postoperative hospital and ICU length
of stay, increases need for perioperative mechanical ventilation, vasoactive medications and need for dialy-
sis
[25,30,32,33,86,87]. Thus, however sparse and sporadic, these studies consistently show that CCM is a
deleterious comorbidity in children irrespective of the etiology of cirrhosis adversely impacts peri-LT out-
comes and healthcare delivery in children with liver diseases. It is also clear, that similar to adults, there is
as yet no cure for this cardiomyopathy, except a liver transplant, which is the only intervention that has
shown to reverse cardiac pathology. CCM in children is now rapidly emerging as consequential reversible
cardiomyopathy
[88].
Cardiovascular consequences of inherited metabolic liver failure and failure of energy metabolism
Some of the earliest scientific literature discussing hepato-cardiac interactions are found in case reports of chil-
dren who died from various then unnamed inborn errors in metabolism. The clinical presentations and postmor-
tem autopsy descrip tions detail the devastating degree of severe multiple-organ failure and the unforgiving
rapid decline of liver and heart functions to early death that was the unfortunate reality of the time. With the
advent of molecular and genomic medicine, advanced diagnostic testing and newborn screenings, those once
nearly uniformly fatal diseases now account for 10%15% of pedi atric LT and carry a 1-year post-LT survival
rates approaching 90%
[89,90]. Although only an estimated 5% of children diagnosed with an inborn error have
an associated cardiomyopathy
[91], these patients have a significantly higher rate of mortality (B54%) within a
FIGURE 16.7 The concept of cholecardia: Bile acid (yellow hexagons) excess leads to suppression of the master energy regulator PGC1α and
induces decreased heart rate, rhythm abnormalities, activation of stress response kinases and suppression of fatty acid oxidation. Reduction in
circulating bile acids using bile acid-binders such as cholestyramine, replenishes PGC1α and restores normal cardiac function.
258 16. Cardiovascular dysfunction in liver diseases: pediatric perspectives
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year especially in those diagnosed with hypertrophic cardiomyopathy [92]. Below is a detailed description of car-
diovascular consequences of key inherited storage disorders and inborn error in energy metabolism who present
to the hepatologists and geneticists for liver transplantation in children.
Hereditary hemochromatosis
Hereditary hemochromatosis is a systemic disease of impaired iron metabolism secondary to a mutation in
the HFE gene. Hereditary hemochromatosis is autosomal recessive and has a prevalence of 1 in 200 to 500
among Caucasian populations of European ancestry. Though this is a genetic defect, clinical manifestations
appear at 4060 years of age, late in adulthood. Patients present with multiorgan dysfunction including car-
diac, hepatic, endocrine, and neurological from diffuse iron deposition. Cirrhosis coexists with characteristic
endocrinopathies, which include diabetes mellitus, diabetes insipidus, hypopituitarism, hypogonadism, and
increased skin pigmentation. Cardiac involvement includes a dilated or a hypertrophic type of cardiomyopa-
thy that can quickly progress to restrictive cardiomyopathy and arrhythmia. The severity of heart failure and
arrhythmia correlates with extent of myocardial iron deposition, which gives the heart a rusty brown color
on autopsy. Phlebotomy, iron chelation therapy, and active surveillance for hepatocellular carcinoma are the
primary strategies in management of hereditary hemochromatosis. Liver transplantation, though an option
for advanced disease is rarely offered in hepatocellular carcinoma due to genetic hemochromatosis because
of dismal post-LT outcomes
[93,94].
Neonatal hemochromatosis
Although neonatal hemochromatosis is now classified as Gestational Alloimmune Liver Disease (GALD) and
not an inborn error of metabolism, it is listed here for completion and convenience. Neonatal hemochromatosis
(or GALD) presents with severe acute liver failure soon after birth that can progress to multiorgan failure and
death. Similar to hereditary hemochromatosis, it is characterized by widespread iron deposition and extrahepatic
siderosis; however, unlike genetic hemochromatosis, the pathophysiology is thought to be secondary to severe
hepatic damage from maternal antibodies and not a metabolic derangement. Because maternal alloantibody pres-
ence is transient, successful supportive medical therapy, which includes exchange transfusions, intravenous
gamma globulin infusions, iron chelation agents, and antioxidants, are now successfully used to avoid LT
[95].
Glycogen storage diseases
Glycogen storage diseases (GSD), are a heterogeneous group of disorders with enzymatic defects in glycogen
metabolism. GSD typically have an autosomal recessive inheritance with an incidence of 1 in 50,000 children
[90].
Of the twelve established types, seven are characterized by hepatic enzyme defects—types III (glycogen debran-
cher enzyme) and IV (branching enzyme). Type III and IV GSD can have both liver and cardiac involvement.
GSD II or Pompe
´
disease on the other hand primarily effects the cardiac muscle and is typically not associated
with liver failure and therefore will not be addressed here.
The presentations of both GSD III and IV are variable, both in symptoms and age of onset, which can range
from neonatal to adolescent. Both can present in infancy with symptoms characteristic of impaired hepatic glyco-
genolysis, including failure to thrive, generalized weakness, muscle wasting, and hepatomegaly. Initial laboratory
workup demonstrates hypoglycemia, metabolic/lactic acidosis, elevated liver enzymes, hyperuricemia and ele-
vated creatinine kinase. LV hypertrophy with variable progression to symptomatic hypertrophic cardiomyopathy
are the most commonly associated cardiac abnormal ities and often manifests later in life
[96,97]. While available
data on the incidence are limited and based primarily on smaller case series, myocardial involvement is report-
edly between 30% and 80% in GSD III
[96,97]. Prior to onset of symptoms, electrocardiography and bedside echo-
cardiography may show evidence of LV hypertrophy. Histopatholgy shows periodic acid-Schiff positive diffuse
myocardial glycogen deposits, vacuolation of cardiomyocytes and the atrioventricular node, muscle fibrosis, and
myocardial disarray
[96,97]. Although outcome data are sparse, the American College of Metabolic Genetics and
Genomics cu rrently recommends obtaining serial echocardiograms every 1 to 2 years to screen for signs of ven-
tricular hypertrophy or dysfunction in specifically in GSD IIIa
[96,97].
259Cardiovascular consequences of inherited metabolic liver failure and failure of energy metabolism
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Wilson disease
Wilson disease, an autosomal recessive disorder of copper me tabolism is prevalen t in 1:30,000 persons.
Copper accumulates systemically beginning in the liver due to disruptions or mutations of the ATP7B gene, a
transporter responsible for the biliary elimination of excess copper
[98100]. In children, it usually presents later
in adolescence, with either an acute, subacute, or chronic form of liver disease. Acute presentation of Wilson dis-
ease carries the highest risk of mortality and is associated with fulminant hepatic failure, renal failure, and sys-
temic hemolysis. Additional extrahepatic findings include ocular, neuropsychologic, endocrine, skeletal along
with cardiac involvement
[101]. Cardiac abnormalities in Wilson disease are more commonly subclinical but may
occur in up to 30% of patients. Arrhythmias, hypertrophic cardiomyopathy, interstitial fibrosis, small vessel, and
perivascular vasculitis are seen clinically and on autopsy. Severity of cardiac dysfunction has not been found to
correlate with severity of Wilson disease or the extent of copper deposition
[102,103]. Current practice is to
actively list, support, and transplant all patients with fulminant Wilson disease.
Tyrosinemia type 1
Tyrosinemia type I is a disorder of tyrosine metabolism caused by mutation in the gene that transcribes the
enzyme fumaryl-acetoacetase. Patients with tyrosinemia present in early infancy with progressive liver injury,
which if uncorrected, can then lead to liver failure. Tyrosinemia also predisposes children to hepatocellular carci-
noma, renal dysfunction and hypophosphatemic rickets. Current medical management of tyrosinemia type 1
involves the use of nitisinone, which prevents formation of toxic intermediaries like fumarylacetoacetate and mal-
eylacetoacetate. Liver transplantation is reserved only for severe cases of tyrosinemia type 1 who are resistant to
medical management or those with hepatocellular carcinoma. Though liver is the primary organ affected, heart is
also involved in this genetic condition. A study in 20 children with tyrosinemia type 1 in 1987 reported a 30%
(6/20) prevalence of asymmetric and symmetric LV hypertrophy. The study also showed that cardiomyopathy
resolved in five of the six children with a median interval of 3.6 years and resolves with nitisinone therapy and
transplantation
[87,104106]
Primary hyperoxaluria type 1
Type 1 primary hyperoxaluria is a rare genetic disorder, caused by a deficiency of hepatic alanine glyoxy-
late aminotransferase, an enzyme which facilitates the conversion of glyoxylate to glycine. This then results
in accumulation of large amounts of oxalates in the systemic circulation and the tissue. Organs i nvolved in
systemic oxalosis are the kidneys (renal stones, ox alate crystals, and renal failure), brain, musculoskeletal,
peripheral nervous system, and the heart. Heart involvement in uncorrected systemic oxalosis becomes evi-
dent in adulthood. In a study conducted in 93 patients with hyperoxaluria (median age of presentation 5 40
years), dyspnea, palpitations, chest pains, and syncopal events were the commonest presenting symptoms.
Electrocardiography showed LV hypertrophy and rhythm disturbance in the form of a bundle branch block
and atrioventricular block. Echocardiographic abnormalities included increased LVMI, left atrial enlarge-
ment, pulmonary hypertension, and DD
[87,107110]. The presence of cardiac abnormalities correlated with
plasma oxalate levels and severity of renal dysfunction. Combined liver and kidney transplant resolved sys-
temic oxalosis and reversed the cardiovascular abnormalities
[111].
Propionic acidemia
Propionic academia is an equally rare inherited disorder of branched chain amino acid metabolism, where
there is a high circulating level of propionic acid which arises form deficiency of the enzyme, pro pionyl coen-
zyme A carboxylase. Children with this disease frequently develop electrocardiographic abnormalities, specifi-
cally prolongation of the corrected QT (QTc) interval, and dilated cardiomyopathy. LT reduces risks for
metabolic decompens ation and brain injury and is advised before serious irreversible brain injury occurs.
Dysrhythmias and cardiomyopathy have been found to reverse post-LT
[112114].
260 16. Cardiovascular dysfunction in liver diseases: pediatric perspectives
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Homozygous familial hypercholesterolemia
Homozygous familial hypercholesterolemia (HFH) is a rare disorder, caused by mutation in the gene for
the low-density lipoprotein (LDL) receptor. The absence of the LDL receptor or inability of the receptor to
bind to LDL leads to pathologic elevations of serum cholesterol (often .1000 mg/dL) and triglyceride levels.
Hypercholesterolemia and hypertriglyceridemia are often severe and resistant to medical therapies and puts
the children at high risk for atherosclerosis and coronary artery disease. Since a m ajority (70%) of the LDL
receptors are present in the liver, liver transplantation is the only treatment option to reduce the levels of cir-
culating cholesterol. The most lethal comorbid consequence of HFH is myocardial infarction and death. HFH
though rare, with incidence of 1 in a million children, is the leading cause of childhood myocardial infarction
and death before age 20 if uncorrected. Children with d rug resistant hypercholesterolemia should be trans-
planted before coronary artery disease develops. These children should have a cardiology consultation and a
coronary angiogram before listing. If coronary artery disease is present, a combined liverheart transplant
may be considered. LT has been shown to normalize cholesterol levels and prevents coronary artery disease
and heart failure
[115,116].
Disorders of inborn error in energy metabolism
Disorders of mitochondrial FAO are inherited in an autosomal recessive manner and have an estimated prevalence
between 1:5000 and 1:10,000 births
[117]. They include defects in (1) the carnitine cycle, (2) beta oxidation, and (3) elec-
tron transfer. As fatty acids are the body’s primary fuel source used by all tissues but especially highly metabolically
active ones such as the heart, brain, and muscles, FAO disorders often present clinically during periods of stress or
fasting with signs of cardiomyopathy, myopathy, and/or encephalopathy with liver dysfunction. Findings on labora-
tory workup include hypoketotic hypoglycemia, metabolic acidosis, hyperammonemia, elevated creatinine kinases,
and myoglobinuria. Patients can present anywhere between neonatal to adult years depending on enzyme activity.
The transfer of long chain fatty acids across the mitochondrial membrane for beta oxidation requires the essential
cofactor carnitine and a system of transporter and enzymatic proteins. Defects in the carnitine cycle enzymes—carni-
tine palmitoyl transferase II or carnitine acylcarnitine translocase or in the carnitine transporter are associated with
cardiac dysfunction. Primary carnitine deficiency (PCD; autosomal recessive; 1:40,000), seen in individuals who inherit
a genetic defect in the carnitine transporter, is associated with dilated cardiomyopathy and arrhythmias including
brady-arrhythmia, atrioventricular block, or ventricular fibrillation. Children with PCD can present in overt heart fail-
ure or lethal arrhythmia. EKG is notable for tall peaked T waves in the mid-cordial leads and a shortened QT interval.
A large globular heart with endocardial lipid deposits and ventricular fibrosis are seen on cardiac histopathology.
Timely diagnosis of carnitine deficiency is critical, as initiation of supplemental high-dose L-carnitine has excellent
benefit in reversing pathogenic myocardial changes before becoming irreversible
[118,119].
Cardiovascular consequences of acute liver failure
Pediatric Acute Liver Failure (PALF) is a rare but potentially catastrophic disease process with rapid progres-
sion of multisystem organ involvement and death. According to the PALF registry B 55% children with acute
liver failure survive with native liver, B35%40% of children need an urgent liver transplant, while B5% of chil-
dren with acute liver failure die while waiting for a transplant
[120,121]. Though primary myocardial injury and
acute heart failure are not very common in ALF, subtle evidence of damage to the cardiomyocytes and LV stress
has been shown in some adult studies. In 187 adults enrolled in the US ALF study group, 74% of patients had a
modest elevation in troponin I ( . 0.1 ng/mL), and this was associated with higher odds (OR of 3.88) of develo p-
ing advanced hepatic encephalopathy, and higher odds of death (OR 5 4.69)
[122]. Acute myocardial injury in
acute liver failure has not been reported in children; however, the heart is involved as a part extrahepatic organ
involvement and rapid deterioration is seen in fulminant liver necrosis. Direct myocardial damage may also be
seen in viral (CMV, herpes, EBV) mediated liver failure.
Implications for intensive care management and liver transplantation
Maintaining hemodynamic stability in a child with fulminant ALF and preventing irreversible life threatening
complications is a major challenge for hepatologists and intensivists alike. In children with hemodynamic
261Cardiovascular consequences of acute liver failure
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imbalance, circulatory shock and inflammation potentiate the toxic effects of hyperammonemia on the astrocytes,
and directly contribute to worsening hepatic encephalopathy and cerebral edema
[123]. Hypovolemia is often
present in children with ALF when they arrive in the emergency center or the ICU, and fluid resuscitation to
reverse the hypovolemic shock often results in LV stress and pulmonary edema. The systemic release of toxic
mediators and cytokines by the rapidly dying and necrotic hepatocytes, compounded by the inability of the liver
to clear them leads to vasodilatory shock. Vasoplegia with hypotension refractory to fluids are treated with vaso-
constrictors, preferably alpha adrenergic agents (norepinephrine/noradrenaline), and vasopressin
[124,125].As
adrenal insufficiency can occur in ALF, hydrocortisone may be beneficial as the next step in reversing shock
[126,127]. Multiorgan failure in the setting of ALF is ominous, as not only does the hepatocyte destruction further
exacerbate with heart failure and poor cardiac output, but also the hemodynamic instability puts the recipient at
high risk for a major surgical intervention such as a LT. Though current pediatric sepsis guidelines
[128] suggest
the use of extracorporeal membrane oxygenation for fluid, vasopressor and steroid nonresponsive shock, the out-
comes for use of extra-corporeal membrane oxygenation in ALF are dismal
[129131]. In children needing hemo-
dynamic support in ALF or acute on chronic liver failure, we and others have reported modest success with
early institution of total plasmapheresis, high flux continuous renal replacement therapy, and albumin dialysis
with charcoal adsorption in the form of molecular adsorbent recirculation system, a combination therapy we
term hybrid extracorporeal therapy
[132,133].
Cardiovascular consequences of chronic cirrhosis, portal hypertension, and portosystemic shunts
Pulmonary vascular pathology, though more common in adults with cirrhosis, is also seen in children espe-
cially those who have chronic unresolved cirrhosis, extrahepatic portal vein obstruction, portal vein agenesis and
thrombosis, or congenital portosystemic shunts. Pulmonary vascular reverse remodeling as a direct consequence
of liver disease is seen in two conditions: Hepatopulmonary syndrome (HPS) and portopulmonary hypertension
(PoPH), both of which affect the cardiac health and transplant status in children
[134137]. Both these topics are
covered in a separate chapter. This chapter will focus on effects of HPS and PoPH on children.
Hepatopulmonary syndrome
HPS in children is defined, similar to adults as a triad of (1) hypoxemia (demonstrated by low arterial oxygen-
ation, desaturation, and an alveolar—arterial gradient of $ 15 mmHg); (2) intrapulmonary vascular dilatation ;
and (3) presence of advanced cirrhotic liver disease, hepatic or extrahepatic portal hypertension, or congenital
portosystemic shunts.
[134,137]
Prevalence of HPS in children varies anywhere from B9% to as high as B30%. The prevalence for BA is
B9%, to B30% in cirrhosis not secondary to BA. The initial diagnosis of HPS in children is oxygen saturations
less than 96% on room air, arterial partial pressure of oxygen on arterial blood gas of less than 70 mmHg on
room air at sea level. Further to confirm HPS, chest roentgenogram (to rule out parenchymal disease), pulse
oximetry on higher oxygen support and a detailed contrast-enhanced transthoracic echocardiogram with agitated
saline to diagnose intrapulmonary vascular dilation and shunting. A positive contrast-enhanced transthoracic
echocardiogram, evidenced by appearance of mi crobubbles in the left side of the heart $ 3 cardiac cycles after
microbubbles appear in the right heart following 10 mL of agitated saline in the peripheral venous system is con-
sidered diagnostic of intrapulmonary shunting. To further confirm HPS, either a CT scan with contrast angiogra-
phy and/or a right-sided catheterization may be beneficial to rule out correctable causes of severe desaturation
and a prerequisite for transplant
[134,137].
Implications of HPS for intensive care management and liver transplantation
HPS is a debilitating consequence in children with chronic cirrhosis. Medical therapies are still experimental.
Clinical trials targeting nitric oxide and carbon monoxide which are the key mediators of vasodilation and HPS,
inhibitors of angiogenesis, vasoconstrictors such as somatostatin and indomethacin and have been disappointing
with no clear benefit in humans . Invasive procedures such as transjugular intrahepatic portosystemic shunting to
lower portal pressures, ligation of congenital shunts, or coiling of intrapulmonary vasodilated vessels have lim-
ited efficacy. There is a general consensus that LT alone will reverse the pathophysiology of HPS and the
262 16. Cardiovascular dysfunction in liver diseases: pediatric perspectives
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pulmonary vasodilation will regress in time post- LT. There is also an agreement that without LT, children with
HPS will progress to further desaturation and death. Currently, progressive hypoxemia (PaO
2
, 60 mmHg) not
responding to medical management is an indication for LT, but severe hypoxemia can be considered a relative
contraindication. Though data in pediatric HPS is limited, severe hypoxemia and desaturation (pretransplant
PaO
2
, 45 mmHg) has been shown to increase mortality and morbidity posttransplant and is now considered a
relative contraindication for LT
[136,137].
Portopulmonary hypertension
The Pediatric Task Force of the 6th World Symposium on Pulmonary Hypertension (Nice, France; 2018) pro-
posed to modify the definition for PH in children as mean PA pressures . 20 mmHg and pulmonary vascular
resistance $ 3 Wood Units to be consistent with adults
[138]. In accordance with the taskforce recommenda-
tions, PoPH in children is now defined as pulmonary arterial hypertension (mean PA pressures . 20 mmHg;
pulmonary vascular resistance $ 3 Wood units), without any evidence of LV compromise (PA wedge
pressure ,15mmHg)inthepresenceofportalhypertension.Potential mechanisms for PoPH are imbalance in
the vasoconstrictors and vasodilators in presence of portosystemic shunting. An injured liver fails to filter and
eliminate vasoactive mediators and metabolites which then reach systemic circulation and the PA leading to
pulmonary arterial vasoconstriction and hypertension. Another theory proposed is that increased cardiac out-
put seen in ESLD and portosystemic shunting causes increased flow through the PA, thereby increasing shear
stress, resistance, and pressure within the artery a nd arterioles over time, ultimately leading to reverse hyper-
trophy and fibrosis of the vascular tissue
[135].
Prevalence of PoPH in children is not well studied, but is considered less than HPS. A systematic review pub-
lished by Ecohard et al.
[139] indicates that B0.5% of children with portal hypertension and B1% of children
with cirrhotic ESLD have PoPH. Conversely, B78% of children with PoPH had end-stage cirrhotic liver disease
and B22% had congenital portosystemic shunting
[139]. Detailed two-dimensional (2D) echocardiography is a
good initial screening test of every child with cirrhosis listed for liver transplantation. If the surrogate markers of
pulmonary hypertension on the echocardiogram are abnormal (high tricuspid valve regurgitation (TR) velocity,
abnormal right ventricle contractility, abnormal septal wall motion during systole or diastole), then a hemody-
namic right-sided catheterization is recommended by the American Association for Study of Liver Diseases to
further evaluate the candidacy of the child
[140].
Implications of PoPH for intensive care management and liver transplantation
Survival among children with PoPH is poor without medical management. Medicines are targeted to reduce
pulmonary arterial hypertension, and at the same time alleviating portal hypertension. As no formal clinical trials
have been conducted specifically for children with PoPH, current therapies deployed in children with PoPH
have been extra polated from data gathered in adults with PoPH and children with isolated pulmonary arterial
hypertension
[141]. Endothelin receptor antagonists like bosentan, ambrisentan, and macitentan have been used
to reduce PA pressures but medication induced hepatotoxicity limits its wide spread use. Phosphodiesterase-5
inhibitors, such as sildenafil, tadalafil, and vardenafil, have been used to lower the pulmonary vascular resistance
and PA pressures to optim ize transplant candidacy. Surgical or interventional radiologic intervention is often
indicated to close congenital shunts to prevent further increases in flow and PA pressures.
PoPH in children has a significantly high mortality. Liver transplantation in children with high PA pressures is also
linked to high mortality
[137]. In a review conducted by Ecohard-Dugelay et al., out of 98 children with PoPH, B20%
underwent transplant of the liver, at a median age of 12 years (2.540 years) with a majority of cases before age of 18.
Early postoperative mortality was high (30%) and attributed to right heart failure post-LT. Only those who showed
proof of reduction in the PA pressures with medical therapy pre-LT showed a higher survival and successful outcome
post-LT
[139]. Thus, though the indications and contraindications for LT in PoPH are not absolute, high (mean
PAP . 40 mmHg), with right ventricular dysfunction (obtained by hemodynamic catheterization) refractory to medical
therapy should be considered a contraindication to listing a child for a liver transplantation. Overall goal remains early
identification of PoPH in cirrhosis or those with congenital shunts, so that pulmonary vasodilators and other aggressive
medical management can be started early to achieve successful outcomes post-LT. Electrocardiograms and routine echo-
cardiograms are good and reliable initial screening tools to detect PoPH. Cardiac catheterization, however, may be
essential to estimate true PA pressures and response to therapy before listing a child for LT. PoPH resolves post-LT
simultaneous to resolution of portal hypertension. Pulmonary vasodilators should be weaned gradually post-LT while
actively monitoring right ventricular physiology
[137].
263Cardiovascular consequences of chronic cirrhosis, portal hypertension, and portosystemic shunts
III. Cardiovascular system in liver failure
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