pulmonary disorders in cirrhosis
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PulmonaryHepatic vascular Disorders; R. Rodrguez-Roisin, M.J. Krowka, Ph. Herve, M.B. Fallonz, on behalf ofthe ERS Task Force; Eur Respir J 2004; 24: 861880
The hepatopulmonary syndrome; D.T. Palma, M.B.Fallon; Journal of Hepatology 45; (2006): 617625
Portopulmonary hypertension and hepatopulmonarysyndrome: a clinician-oriented overview; Mateo Porres-
Aguilar, Jose T. Altamirano, Aldo Torre-Delgadillo,Michael R. Charlton and Andres Duarte-Rojo; Eur RespirRev 2012; 21: 125, 223233
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Diagnostic criteria:
Hepatic dysfunction or portal hypertension Widened alveolar-arterial oxygen gradient (A-aPO2) (15
mmHg in patients 64 years of age) +/- hypoxemia
Intrapulmonary vasodilatation
Alveolar-arterial O2 gradient = PAO2 - PaO21.25PaCO2At sea level when breathing room air (FiO2 = 0.2), the PAO2is 150 mmHg
Above combination is so unique that it supports thediagnosis of HPS even in the presence of associated chroniccardiopulmonary diseases
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ERS Task Force staging system based on PaO2: PaO2 80 mmHg mild HPS PaO2 60-79 mmHg - moderate HPS PaO2 50-59 mmHg - severe HPS
PaO2
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Cirrhosis irrespective of aetiology (mostcommon)
Portal hypertension in the absence ofcirrhosis
Acute and chronic hepatitis in the absenceof portal hypertension
Congenital disorders without liver injury inwhich either hepatic venous blood flowdoes not reach the lung or portal venousblood reaches the IVC without passingthrough the liver
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The primary structural disturbance is diffuse orlocalised dilatation of the pulmonary pre-capillary and post-capillary vessels. Lesscommonly, pleural and pulmonary AV
communications may be present
Vasodilatation is assumed to result fromexcessive vascular production of vasodilators,particularly NO. However, the mechanism ofincreased endogenous NO production and itsrelationship to the liver disease remainsuncertain
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There are three intrapulmonary determinants ofarterial deoxygenation and all may contributeto HPS:
Alveolar V/Q mismatch (main mechanism)
due to lung regions in which alveoli arenormally ventilated but overperfused
Increased intrapulmonary shunt
Diffusion impairment of oxygen
Individual contribution by each mechanismmay varying according to HPS severity; all three
can coexist in severe and very severe HPS
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Insidious onset dyspnea (most common symptom)Early exertional dyspnoea may evolve into dyspnoea atrest as hypoxaemia progresses
Platypnea and orthodeoxia (decrease in PaO2 5% or4 mmHg from the supine to upright position)Result from a gravitational increase in blood flowthrough dilated vessels in the lung basesThe sensitivity of orthodeoxia for HPS is relatively low, but
increases in cases of severe HPSWhile orthodeoxia is observed in a variety of conditions,it is highly specific for HPS in the setting of liver disease
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Cyanosis, polycythaemia, clubbing Spider angiomata (but are frequently seen
in cirrhotic patients without HPS also)
Extrapulmonary complications of right toleft pulmonary communications, such ascerebral abscesses or ICH may occur
HPS may be an important factor thatinfluences the progression of liver disease.Mortality is usually due to complications ofhepatic disease, as opposed to a primaryrespiratory event
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Widened A-aPO2 +/- hypoxemia Pulse oximetry
A simple, non-invasive screening test for hypoxemiaCaution must be exercised in the interpretation, as pulseoximetry may overestimate oxygenation in nearly one
half of patients with cirrhosis
ABGPerformed at rest in the sitting position, while breathingroom air
In HPS, ABGs reveal an elevated age-adjusted A-aPO2with or without hypoxemiaSince patients with advanced liver disease usuallyhyperventilate, hypocapnia and respiratory alkalosis arecommon
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Intrapulmonary vasodilatation Contrast echocardiography
Transthoracic microbubble contrastechocardiography is the preferred screening test
While up to 40% of patients with cirrhosis have apositive contrast echocardiogram, only a subset ofthese patients have sufficient vasodilatation to causeabnormal gas exchange and fulfill criteria forhepatopulmonary syndrome
Transoesophageal echocardiography with contrastenhancement may be superior, being more sensitiveand with the ability to visualize the passage ofmicrobubbles through an interatrial pathway versusmicrobubble entrance into the left atrium from thepulmonary veins
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99mTc-Macroaggregated albumin scanIn the presence of shunting, a fraction of themacroaggregated albumin passes into the systemiccirculation and then, scintigraphy reveals uptake in other
organs in addition to the lung
This test allows quantification of the shunt, unlike CE-TTE.This also makes it useful in defining the contribution of HPSto gas exchange abnormalities in hypoxemic patients withboth HPS and intrinsic cardiopulmonary disease
Sensitivity of MAA scan is lower than that of CE-TTEIt is also less specific since it is not possible to differentiatebetween intracardiac and intrapulmonarycommunications
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Pulmonary angiography
Not routinely utilized since it is expensive, invasive and hasa low sensitivity for detecting intrapulmonary
vasodilatationThere are 2 types of angiographic patterns:
Type I pattern - normal angiography or diffuse vasculardilatations
Type II pattern - focal arteriovenous communications
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Liver transplantationLiver transplantation is the only establishedeffective therapy for HPSTotal resolution or significant improvementoccurs in >85% of patients. Length of time forarterial hypoxemia to normalize aftertransplantation is variable and may be >1 yearMorbidity may be higher after OLT in severe HPSThe observation that HPS increases mortality and
that transplant outcomes may worsen in casesof advanced HPS has led to the policy in UScenters of increasing priority for OLT in patientswith HPS and significant hypoxemia
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Coil embolisationIn type II HRS, arteriovenous communications areanatomically stable and may not regress after LTxand the patients may be at risk of cerebral
embolism and/or abscess. They may be amenableto treatment with coil embolisation
It has been suggested that in patients with verysevere hypoxaemia the response to 100% oxygenbreathing should be assessed, and if PaO2
improves to
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Medical therapies
There are currently no effectivemedical therapies for HPS
Rx that have been studiedaspirin,norfloxacin, garlic powder, methyleneblue
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Supportive therapies
Continuous long-term O2 therapy in
patients with PaO2
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Algorithm: Mild HPS (PaO2 80 mmHg) ABG should be
measured at least once a year to detect anyabnormal PaO2 change and if symptoms appear
Moderate HPS (PaO2 60-79 mmHg) - ABG should bemeasured at least once a year to detect anyabnormal PaO2 change and if symptoms appear. IfPaO2 progressively deteriorates in a symptomaticpatient, then OLT can be considered
Severe HPS (PaO2 50-59 mmHg) - consideration ofOLT is vital Very severe HPS (PaO2
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Diagnostic criteria:
Portal hypertension with or without hepaticdisease
PAHmPAP 25 mmHg at rest with anormal / decreased pcwp (240 dyn/s/cm5 (>3 Wood units)
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Staging based on mPAP at rest:
mPAP 25-34 mmHg - mild PPHTN
mPAP 3544 mmHg - moderate PPHTN
mPAP 45 mmHg - severe PPHTN
Presence or severity of portopulmonaryhypertension does not appear to correlatewith the severity of underlying liver disease orseverity of portal hypertension
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Vasoconstriction and obstruction in thesmall pulmonary arteries occur due to dueto intimal and medial smooth muscleproliferation and fibrosis and in situthrombosis
Increase in vasoconstrictor and
vasoproliferative substances (e.g. ET-1,serotonin) and decrease in vasodilatorsubstances (e.g. NO, prostacyclin) mediatein these processes
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Imbalances in the factors occur as a result of: Increased blood flow in chronic liver disease causes
pulmonary vascular wall shear stress, which can triggerthe dysregulation of numerous mediators
Portosystemic shunts and defective hepatic
metabolism may allow the shunting of vasoactivesubstances from the splanchnic to the pulmonarycirculation
Portosystemic shunts and decreased phagocyticcapacity of the liver, allow circulating bacteria andbacterial endotoxins from the gastrointestinal tract to
enter the pulmonary circulation. This causes recruitmentof pulmonary interstitial macrophages which whenactivated, release numerous factors
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Other supportive Ix
CXR - enlarged central pulmonary arterieswith peripheral pruning, RA and RV
enlargement ECGP pulmonale, RVH, RAD, RBBB
ABG - may show mild-to-moderatehypoxaemia, increased AaPO2 anddecreased PaCO2
Pulmonary function tests - reduced DLCO
BNP - marker of right ventricular stress
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Important distinctions in PPHTN managementcompared to idiopathic PAH: Oral anticoagulation is traditionally not
recommended due to the increased risk of
gastrointestinal hemorrhage CCBs are contraindicated as they canproduce mesenteric vasodilation that canworsen portal hypertension and asresponders are few
Beta blockers are associated withdeterioration of exercise capacity andpulmonary hemodynamics due to theirnegative inotropic and chronotropic effects
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Life style measures
Avoid activities that impose heavyphysical stress and valsalva manoeuvre
Stop smoking Avoid high altitudes
Reduce dietary salt intake
Avoid pregnancy
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Supportive therapy Diuretics - reduce RV volume overload, reduce
hepatic congestion, relieve peripheral edema
Overdiuresis should be avoided as this will
further reduce the RV output Continuous long-term O2 therapy in patients with
PaO2
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Specific therapyHave been studied in PPHTN to some extentbut mostly extrapolated from their use in
idiopathic PAH
Phosphodiesterase-5 Inhibitors (e.g. sildenafil)
Endothelin Receptor Antagonists ( bosentan,sitaxentan, ambrisentan)Risk of transaminitis is present; could beconsidered more safely in extrahepatic portalhypertensionBosentan has been used safely in ChildPughclass A cirrhosis
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Balloon atrial septostomy / RV assistdevice
Indicated as a palliative procedure ifconventional measures fail
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HPS PPHTN
Clinical features Cyanosis, clubbing No cyanosis
Evidence of PHT and RVF
ECG None RBBB
RAD
RVHABG Moderate-to-severe hypoxaemia No/mild hypoxaemia
CXR Normal Cardiomegaly
Hilar enlargement
CEE Always positive Usually negative (unless ASD /
PFO exist)
99mTcMAA shunting index 6%
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