SYMPOSIUM: NEONATOLOGY
Hepatopulmonary syndrome
in children-an update
Akash Deep
Bipin Jose
Anil Dhawan
Abstract
Hepato-pulmonary syndrome (HPS) is an uncommon complication of liver
disease. It can be acute or chronic and occur with or without portal hyper-
tension. The reported frequency of HPS in patients with liver disease
ranges between 4% and 32%. It occurs as a result of vasodilatation of
the pulmonary vasculature which is most likely to be mediated by nitric
oxide (NO). Three components are essential to the definition of HPS: 1.
liver disease, 2. intra-pulmonary vascular dilatation (IPVD) and 3.
impaired oxygenation. .Disease severity is determined by quantifying
the degree of oxygenation impairment. Contrast enhanced echocardiogra-
phy (CE-TTE) and Tc-99 labeled macro-aggregated albumin lung scan with
uptake in brain are the gold standard investigations to diagnose HPS and
plan management. Clinical features which are characteristic of HPS
include orthodeoxia and platypnea in the presence of liver disease.
Although there are anecdotal reports on the use of several drugs in the
medical management of HPS, none have been shown to result in either
sustained improvement in oxygenation or reduce mortality. Liver trans-
plantation is possible and no longer considered to be contraindicated
in HPS. However it is important to carefully select and prioritize patients
with HPS for liver transplantation for optimum results.
Keywords de-oxygenation; hepato-pulmonary syndrome; liver failure;
orthotopic liver transplantation
Introduction
As the liver disease progresses, other organ systems become
affected including the kidneys, the heart and lungs. Pulmonary
complications or pulmonary manifestations of liver disease can
be due to a number of contributing factors which might not be
always pulmonary in origin. They include immunosuppression
secondary to malnutrition which frequently leads to infectious
complications and massive ascites and pleural effusions in
advanced portal hypertension. Two distinct pulmonary vascular
syndromes are well described in children with liver disease e
porto-pulmonary hypertension and hepato-pulmonary syn-
drome. An awareness of these complications is vital when
assessing children with liver disease.
The term hepato-pulmonary syndrome (HPS) was coined in
1977 by Kennedy and Knudson. HPS results in de-oxygenation of
Akash Deep MD FRCPCH is Director of PICU, King’s College Hospital,
London, UK. Conflict of interests: none.
Bipin Jose MD MRCPCH is a Clinical Fellow in Paediatric Intensive Care,
King’s College Hospital, London, UK. Conflict of interests: none.
Anil Dhawan MD FRCPCH is Professor and Director of Paediatric Hepatology,
King’s College Hospital, London, UK. Conflict of interests: none.
PAEDIATRICS AND CHILD HEALTH --:-
Please cite this article in press as: Deep A, et al., Hepatopulmonary syndrome in children-an update, Paediatrics and Child Health (2015), http://
dx.doi.org/10.1016/j.paed.2015.02.002
arterial blood induced by intrapulmonary vascular dilatation
(IPVD) secondary to liver disease. The prevalence of HPS ranges
between 4 and 32% in adult liver cirrhosis patients and is re-
ported in 9e20% of children with liver disease. The changes in
pulmonary vasculature may be diffuse or focal. HPS typically
includes a triad of arterial de-oxygenation, intrapulmonary
vascular dilatation and liver disease. The presence of portal hy-
pertension is not mandatory for the development of HPS and it
can co-exist in patients even with pre and post hepatic causes of
liver failure. The survival of patients with established HPS
without liver transplantation is poor as there are no effective
medical therapies. This review provides current state of the art of
insights into aetiopathogenesis and management of HPS with a
particular focus on the post-operative care of children following
liver transplantation.
Pathogenesis and physiology
Changes in pulmonary vasculature secondary to liver disease are
fundamental to development of HPS. The aetiology of end stage
liver disease in paediatric patients is diverse. In our institute
which is a supra-regional referral centre for paediatric liver dis-
eases, the most common single aetiology is biliary atresia. Our
experience is that the severity of HPS is only weakly correlated
with the degree of liver dysfunction. HPS is typified by vasodi-
latation of pulmonary capillaries and this is accompanied by
varying degrees of pleural and pulmonary arterio-venous com-
munications (shunts). The abnormally dilated pulmonary capil-
laries can be diffuse (Type 1) or more focal (Type 2). Capillary
dilation leads to hypoxaemia either as a result of alveolar
ventilation-perfusion mismatch or a diffusion-perfusion defect or
through pulmonary vascular shunts.
Alveolar ventilation-perfusion (V/Q) mismatch results from
normal ventilation of parts of the lung with ‘over-perfused’
dilated capillaries. Any pulmonary vascular shunts facilitate
rapid exit of blood into pulmonary veins before it is adequately
oxygenated. This shorter exit time is augmented by the lack of
hypoxic vasoconstriction in pulmonary vasculature secondary to
HPS. These dilated capillaries may also have thickened walls
which restrict the diffusion of oxygen across the alveolus to
equilibrate with RBC’s in the centre of capillaries: a diffusion-
perfusion defect.
V/Q mismatch and shunts predominate in the early stages of
HPS where the hypoxaemia is mild (PaO2 more than 60e80 mm
of Hg in room air), while more severe hypoxaemia (PaO2 less
than 60 mm of Hg) usually also has a component of abnormal gas
exchange. A diagrammatic representation of the various patho-
physiological mechanisms leading to hypoxaemia is given in
Figure 1.
Nitric oxide (NO) is the most widely implicated substance in
the development of pulmonary vasodilatation. There are high
levels of NO in exhaled air in children and adults with HPS which
normalize following liver transplantation. NO is endogenously
synthesized from L-arginine and it induces vasodilation by guanyl
cyclase mediated cGMP activation of myosin light chain of
vascular smooth muscles. Microvascular endothelial changes in
pulmonary vasculature due to hyperdynamic flow result in
increased endothelial nitric oxide (via eNO synthase) as well as
inducible nitric oxide (via iNO synthase) from pulmonary
1 Ó 2015 Published by Elsevier Ltd.
 SYMPOSIUM: NEONATOLOGY
Figure 1 Physiology of vasodilation and hypoxaemia in HPS.
macrophages. This is accompanied by selective proliferation of
endothelin-B (ETB) receptors through which NO acts to mediate
vasodilatation.
NO alone is an unlikely trigger for pulmonary vasodilation.
eNO is also increased in inflammatory states like asthma and
most researchers believe that increased NO is only the trigger for
a series of events that lead to eventual permanent vasodilation. It
is likely that several agents including haem-oxygenase (HO),
carbon monoxide (CO) and prostaglandins are involved in the
eventual vasodilation seen in HPS.
A central role for hepatic macrophages (Kupffer cells) and the
inflammatory mediators released from them like TNF-a in the
pathogenesis of HPS is suggested by its prevention in rat models
by treatment with pentoxifylline; (a TNF-a inhibitor). Moreover,
in animal models that undergo common bile duct ligation
(CBDL); bacterial translocation and macrophage accumulation
was prevented with norfloxacin which also transiently delayed
the iNO production and onset of HPS.
Natural history
There are no specific data available in the paediatric population.
However, untreated HPS in adults has a poor prognosis. Median
survival in adult liver patients with HPS is 11 months compared to 41
months in cirrhotic patients without HPS. Over a median period of
2.5 years the reported mortality rate in HPS ranges from 41 to 63%,
the leading cause of which is hemorrhagic shock from GI bleeding.
Clinical features
It is important to suspect and screen all liver disease patients for
HPS who complaint of dyspnoea particularly platypnea (short-
ness of breath that is relieved by lying down). Platypnea occurs
because ventilation perfusion mismatch worsens whilst erect. A
fall in more than 5% in oxygen saturations or a fall of more than
4 mmHg of PaO2 when patient shifts from supine to upright
position is defined as orthodeoxia and is considered as a specific
sign of HPS (although it probably only occurs in 25% of pa-
tients). There is also a good clinical correlation with clubbing and
HPS. A good starting point in the evaluation of HPS is to do pulse
oximetry in ambient air with the child lying and sitting.
Diagnosis and investigations
Documenting arterial hypoxaemia is the earliest step in screening
and diagnosis of HPS. A recent study has highlighted the clinical
PAEDIATRICS AND CHILD HEALTH --:-
Please cite this article in press as: Deep A, et al., Hepatopulmonary syndrome in children-an update, Paediatrics and Child Health (2015), http://
dx.doi.org/10.1016/j.paed.2015.02.002
utility of using pulse oximetry with target saturation of 97% as a
screening tool with 100% sensitivity and high specificity in
detecting hypoxaemia (PaO2 less than 70 mm of Hg). A more
accurate description of the degree of hypoxaemia comes from
arterial partial pressure of oxygen (PaO2) in upright position and
calculation of Alveolar-arterial pressure gradient (Aea) DO2. In
2004 European Respiratory Society Task force classified HPS
based on the degree of hypoxaemia in arterial blood gas; Mild
(PaO2 80 mmHg), Moderate (PaO2 60 and less than 80
mmHg), Severe (PaO2  50 and less than 60 mmHg) and very
severe (less than 50 mmHg). Recommended cut off values for
diagnosis of HPS are PaO2 80 mmHg and (Aea) DO2 more than
15 mmHg in children. A diagnostic algorithm on the approach to
dyspnoea in liver disease patients is shown in Figure 2.
Intra-pulmonary vascular dilatation (IPVD) can be confirmed
by two investigations: 1. contrast enhanced echocardiography
Hepatic disease with dyspnea/cyanosis
SpO 2 < 80%
Contrast enhanced echocardiography
+/– MAA SCAN
Confirmed HPS
Positive CEE Positive CEE
and SpO2 ≥ 60%, and SpO2 < 60%, and/or
shunt fraction < 6% shunt fraction > 6%
Mild HPS, follow up Listing for transplantation
MAA, macro-aggregated albumin scan;
CEE, contrast-enhanced echocardiography
Figure 2 Proposed diagnostic algorithm for HPS in children (King’s College
Hospital practice).
2 Ó 2015 Published by Elsevier Ltd.
 SYMPOSIUM: NEONATOLOGY
(CEE) using agitated saline with microbubbles and 2.
Technitium-99 labeled macro aggregated albumin (MAA) scan.
Transthoracic echocardiography with agitated saline bubbles as
contrast works on the principle that the bubbles from saline
bolus injected into the proximal vein will appear in the right
ventricle but normally not in the left atrium as they are filtered in
pulmonary vessels. In contrast in HPS, the dilated pulmonary
vessels will permit the micro bubbles to reach the left atrium
usually in 3e5 cardiac cycles. Their appearance in the left side of
heart after three cardiac cycles is taken as a positive test for
IPVD. If the bubbles make their way to the left side in less than
three cardiac cycles, it is suggestive of intracardiac shunting.
Compared to MAA scan CEE is more sensitive and can differ-
entiate between intracardiac and intrapulmonary shunts. MAA
scan on the other hand is more specific and can reliably quantify
the shunt fraction. Normally the Tc99 tagged albumin particles
measuring 20e50 m is filtered in pulmonary capillaries; but in
IPVD they pass downstream to get lodged in capillary beds of
brain where they can be measured by quantitative brain imaging.
A shunt fraction in brain compared to lungs of more than 6% is
highly specific for HPS even with co-existing lung diseases.
Differential diagnosis
Advanced liver disease-associated pulmonary or pleural com-
plications form part of differential diagnosis of hepatopulmonary
syndrome. Portopulmonary hypertension (PPHTN) is character-
ized by presence of both pulmonary and portal hypertension
with or without liver disease. Right heart catheterization is often
required to characterize the pulmonary arterial and venous hy-
pertension and in established cases pulmonary vasodilatory
treatment has a definite role.
Prognosis and treatment considerations
Adults with HPS have a high mortality rate (see above in Natural
history). Our institutional experience with children shows that
the factors which adversely determine the outcome in paediatric
patients receiving liver transplantation include mean PaO2 less
than 50 mm of Hg and pre-transplant oxygen requirement (SpO2
less than 78% in room air). The shunt fraction documented in
non-survivors was significantly higher than survivors (32.8% vs
18.9%).
Whilst unproven, medical treatment of HPS is targeted at in-
hibition of nitric oxide synthesis. Methylene blue an inhibitor of
NO, had shown some improvement in acute oxygenation but did
not have any long term effects on gas exchange or mortality.
Disappointingly selective pulmonary inhibition of NO production
by inhaled N(G)-nitro-L-arginine methyl ester (L-NAME) did not
result in clinical benefit. Clinical trials of norfloxacin (hoping to
achieve GI decontamination, prevention of bacterial trans-
location and endotoxemia as a strategy for decreasing TNF-a
mediated inducible NO synthesis) vasoconstrictors like somato-
statin analogues and prostaglandin inhibitors like indomethacin
in HPS have all been disappointing and none of these strategies
have shown significant clinical benefit in humans.
Embolization of large pulmonary arterio-venous fistulas can
be used as a bridging strategy for preparing patients with severe
hypoxaemia before liver transplantation. Coil embolization of
multiple discrete arterio-venous fistulae has been shown to be
PAEDIATRICS AND CHILD HEALTH --:-
Please cite this article in press as: Deep A, et al., Hepatopulmonary syndrome in children-an update, Paediatrics and Child Health (2015), http://
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beneficial in refractory hypoxaemia 6 months after liver trans-
plantation. The various mediators and their antagonists used in
the management of HPS are summarized in Table 1.
Pre-transplant workup and investigations
The pre-transplant workup includes nutritional, hepatic, cardio-
pulmonary, renal and special consideration for ensuring pre-
transplant immunizations in children. Children with end stage
liver disease are usually at a higher risk for malnutrition as their
energy requirements on an average is 20e80% higher because of
the hyper catabolic state. It has been shown that aggressive
nutritional support prior to transplantation increases the chance
for better graft survival. It is recommended for all patients un-
dergoing liver transplantation to have a 2-D echo evaluation to
assess the right ventricular function and pressures. Patients with
auto immune hepatitis, primary sclerosing cholangitis and bile
salt excretory pump disease should be informed in advance
about the likelihood of having a disease recurrence. Pre-
transplant renal dysfunction in children is usually assessed
with cystatin-C and clinically graded using the RIFLE (Renal
Dysfunction, Injury, Failure, Loss and End stage renal disease)
criteria. All immunizations as per the national protocol should be
completed well before the transplantation in anticipation of the
immunosuppressive state thereafter. Immunological assessment
for EpsteineBarr virus and cytomegalovirus should be made pre-
transplant as patients who are naı̈ve to these viruses can develop
post transplant viraemia if the donor is immunologically positive.
Liver transplantation and post transplant care
Liver transplantation is the only definitive treatment for HPS.
Careful selection of patients for liver transplantation is important
to maximize the survival. In author’s experience the median time
for liver transplantation from diagnosis is 6.5 months. In patients
undergoing liver transplantation although the immediate peri-
operative mortality risk is high; the five year survival can be
compared with those without HPS. Most important predictors of
poor outcome in liver transplant patients include PaO2 less than
50 mm of Hg and MAA scan showing a shunt fraction of more
than 20%, in whom the mortality is as high as 60%(35). The best
outcome is in patients with PaO2 more than 60 mm of Hg, and it
tends to get worse with PaO2 less than 50 mm of Hg. The patients
with severe pre-operative hypoxaemia (less than 50 mm of Hg)
could be considered for OLT with caution.
Hypoxaemia does not resolve immediately after trans-
plantation and can sometimes take up to 12 months. There are
Proposed mediators and their antagonists used in
medical management of HPS
Proposed mediator Antagonist(inhibitor) used in treatment
Nitric oxide Methylene blue, N(G)-nitro-L-arginine methyl
ester (L-NAME)
Bowel endotoxins Norfloxacin(antibiotics)
TNF-a Pentoxifylline
Prostaglandins Indomethacin
Table 1
3 Ó 2015 Published by Elsevier Ltd.
 SYMPOSIUM: NEONATOLOGY

several studies reporting mortality of up to 30% in the first 12 reports of very low mortality in HPS patients who are even in the
months but survival rate can be as good as 93%(26). Important severely hypoxaemic category. Interestingly, there is a recent
causes of immediate post-operative mortality include sepsis, report of HPS resolution in a patient who was treated with
multi-organ dysfunction, opportunistic pulmonary infection, mycophenolate for other reasons and the decision for trans-
complications related to bile duct leak or hepatic artery throm- plantation was suspended. This opens a new arena for discussion
bosis. Important surgical complications in the post-operative and invites more scope for researchers to continue the search
period on follow up include hepatic arterial thrombosis and for a medical solution for this rare but life threatening
biliary strictures. It is important to monitor and maintain hae- complication. A
moglobin at around 10 mg/dl during the post-operative period as
polycythaemia increases the risk for hepatic artery thrombosis.
FURTHER READING:
Another important concern during the pre and post-operative
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tion (ECMO); most commonly the veno-venous type is reported
to be beneficial. However there is not enough data on the use of
ECMO in HPS patients post liver transplant. Acute, late acute and Learning points
chronic rejection can occur in patients who need escalation of
immunosuppression or even re-transplantation. De-novo hepa- C Hepatopulmonary syndrome (HPS) should be considered in the
titis and post transplant lympho-proliferative disease are also differential diagnosis of any child with liver disorder with unex-
reported as long term complications in these patients. plained hypoxia and cyanosis.
C Hepatopulmonary syndrome is caused by vasodilatation of pul-
Future direction and prevention of HPS in liver disease patients monary vessels likely mediated by nitric oxide.
C Ventilation-perfusion mismatch is the predominant mechanism for
As liver transplantation is the only definitive treatment that is hypoxaemia in hepato-pulmonary syndrome.
offered to HPS patients presently; future directions are more C Liver transplantation has become a suitable option for treating
centralized around providing better pre and post transplant care. patients with hepatopulmonary syndrome.
With more specialized post-operative care there have been case

PAEDIATRICS AND CHILD HEALTH --:- 4 Ó 2015 Published by Elsevier Ltd.

Please cite this article in press as: Deep A, et al., Hepatopulmonary syndrome in children-an update, Paediatrics and Child Health (2015), http://
dx.doi.org/10.1016/j.paed.2015.02.002