PULMONARY ASPECTS OF LIVER DISEASE
From Liver Disease and Transplant Symposium, presented by the Medical University of South Carolina
Michael Krowka, MD, Professor of Medicine, Vice Chair, Department of Pulmonary and Critical Care Medicine,
Department of Cardiovascular Diseases, Department of Gastroenterology, Mayo Clinic College of Medicine, and
Mayo Clinic Transplant Center, Rochester, MN
| Relationship between liver and lung: quantifying hypoxemia important; portal bed culprit in hepatopulmonary syndrome
(HPS) and in portopulmonary hypertension (PPH); vascular obstruction causes high resistance to portal flow into
liver; splanchnic bed vasodilatation, probably due to nitric oxide and metabolites, results in low-resistance flow circuit;
hyperdynamic circulatory state, ie, high cardiac output and low systemic vascular resistance, affects lungs downstream;
HPS problem of low resistance to flow; PPH problem of high resistance to flow; differ in clinical manifestations; difficult
to predict which patients will have HPS or PPH and when
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| Etiology: HPS—in pulmonary bed, vascular dilatation occurs at precapillary and capillary level; arteriovenous communications
true anatomic shunts; clinical result oxygenation problem resulting in hypoxemia; PPH—vascular obstruction in
pulmonary bed; due to proliferation of endothelium, smooth muscle, fibrosis, in situ thrombosis and clot, plexogenic arteriopathy,
and vasoconstriction; hemodynamic consequences lead to right heart failure and death if untreated
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| HPS-caused hypoxemia: incidence 5% to 10%; normal alveoli and normal capillary bed; main manifestation diffusion-
perfusion defect; because blood vessels dilated, as blood flows past alveoli, O2 does not get to center of blood flow
stream, resulting in excess perfusion for given amount of ventilation and decreased O2 level; uncommonly, true anatomic
shunts seen that bypass alveoli; when supplemental O2 given under increased pressure, O2 reaches dilated blood vessels
and patient responds, since not true anatomic shunt; more capillaries in lungs with HPS than in normal lung; if hypoxemia
severe, PaO2 may be <50 mm Hg; if patient with chronic liver disease has Pa O2 <50 mm Hg, assume HPS until
proven otherwise; good response to 100% O2 , not true shunt; orthodeoxia may exist, ie, oxygenation becomes worse as
patient goes from supine to sitting position; probably related to gravitational effect on cardiac output; platypnea may also
occur, ie, oxygenation even worse when patient stands
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| Diagnostic criteria: chronic liver disease, portal hypertension, arterial hypoxemia (PaO2 <70 mm Hg); alveolar-arterial
(AA) O2 gradient <20 mm Hg abnormal; pulmonary vascular dilatation key; must show oxygenation problem due to dilated
blood vessels; dilation demonstrated noninvasively with contrast echocardiography or lung perfusion scan; contrast
echocardiography— inform cardiologist looking for pulmonary vascular dilatation; infuse agitated saline into peripheral
vein with syringe; should see microbubbles in right atrium and ventricle; should never see anything in left heart; lung
perfusion scan—20-µ particles remain in lung and never pass through to heart; measure uptake over brain; normal shunt
index <5%; quantitate hypoxemia with lung perfusion in patients with defined HPS; contrast echocardiography more sensitive
than lung perfusion scan; unknown whether patients with positive echocardiography and PaO2 of 90 mm Hg have
subclinical condition that may evolve into HPS; pulmonary angiography—rarely used; performed when patient with
severe hypoxemia (PaO2 <50 mm Hg) has PaO2 <300 mm Hg on 100% O2 ; look for arteriovenous malformations
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| Comorbid reasons for hypoxemia: include hepatic hydrothorax, ascites, chronic obstructive pulmonary disease
(COPD), and pulmonary fibrosis; seen in up to one-third of patients; distinguished from HPS by normal lung perfusion
scan
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| Survival: HPS has poor prognosis; study found median survival 4.8 mo in Child class C patients with HPS without liver
transplantation
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| Treatments: no satisfactory medications; steroids, octreotide, garlic all tried, but do not improve oxygenation or long-term
survival; transjugular intrahepatic portosystemic shunt (TIPS) not advised for hypoxemia; in Abernathy syndrome or
malformation, ligation can be performed; in children (ligation of communication improves hypoxemia); balloon cavoloplasty
to open hepatic vein in patients with noncirrhotic portal hypertension due to obstruction (rare in United States)
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| Liver transplantation: best treatment; normalization of oxygenation occurs in most cases, regardless of degree of hypoxemia;
time to resolution depends on severity of hypoxemia; mortality significant; severe hypoxemia formerly contraindication
for liver transplantation; now liver transplantation indicated for HPS in children and adults; mortality risk—
highest in patients with PaO2 <50 mm Hg and brain uptake > 20% on lung perfusion scan; these patients require prolonged
intubation, mechanical ventilation, and prolonged hospital stay; liver transplants not denied due to HPS alone, but
transplant denied for comorbidities, eg, diabetes, coronary disease ; speaker’s data—liver transplantation for HPS leads
to 70% 5-yr survival; in control patients with HPS and no transplant 5-yr survival 20%; PaO2 <60 mm Hg, higher priority
for transplantation in United States
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| PORTOPULMONARY HYPERTENSION
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| Clinical presentation: diagnosis of liver disease; exertional dyspnea main complaint; late manifestations include chest
pain, chest pressure, syncope, and abnormal chest x ray; hemodynamic patterns of liver disease—hyperdynamic circulatory
state most common; small group of patients have vasoconstriction and vasoproliferation (PPH); right heart catheterization
shows elevated mean pulmonery artery pressure (PAP), ie, pulmonary hypertension; pattern of high cardiac
output, low calculated resistance, and low wedge pressure characteristic of PPH; pressure of right ventricle very high; as
patients worsen cardiac output decreases
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| Diagnostic criteria: with or without cirrhosis; pulmonary artery hypertension determined by right heart catheterization;
most important criteria mean PAP >25 mm Hg and calculated pulmonary vascular resistance >240 (dyn sec)/cm5 ; wedge
pressure of 15 mm Hg soft criterion no longer used by speaker; >1200 patients screened with echocardiography—
those with right ventricular systolic pressure >50 mm Hg received right heart catheterization; one-third did not have PPH
(had excess volume state or hyperdynamic state); two-thirds had PPH; transpulmonary gradient (difference between
mean PAP and pulmonary artery occlusion pressure) elevated in all patients with true PPH; normal mean PAP ≈25 mm
Hg; in PPH, very high PAP (>50 mm Hg)
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| Pathology: more than vasoconstriction; PA contains clot, fibrosis, platelet aggregates with proliferation, and plexogenic
change, ie, new vessels growing out of pulmonary vessel wall, with obstruction and medial hypertrophy; obstructive process
can be reversible with newer medications; liver correlates of PPH— seen ≈5% of time in liver transplantation centers;
occurs in children and adults; no correlation with portal hemadynamics, Child-Turcotte-Pugh class, or with
modeling end stage liver disease (MELD) score; abdominal vascular shunts seen in many patients; after portocaval
shunts, PPH found in 30% of patients; 83% frequency of spontaneous splenorenal shunts in patients with PPH
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| Treatments: 1) prostacyclins; intravenous (IV) 24-hr infusion, subcutaneous 24 hr, inhaled and oral forms; 2) endothelin
receptor antagonists (oral) and 3) phosphodiesterase inhibitors (oral); all vasodilate; all may be vasomodulators, ie, allow
remodeling of pulmonary vascular bed; adverse effects in liver disease—prostacyclins worsen thrombocytopenia and
increased doses lead to massive splenomegaly; phosphodiesterase inhibitors increase nitric oxide (already associated with
portal hypertension); endothelin receptor antagonists cause hepatic toxicity, so use in patients with hepatic dysfunction
questionable; β-blockers lead to undesirable decreases in cardiac output; warfarin (Coumadin) contraindicated; transplantation
results in marked fluid changes and may lead to acute right heart strain; IV epoprostenol—gold standard for PPH;
in catheterization laboratory, changes observed in pulmonary vascular resistance; improvement observed over many
months; vascular remodeling occurs; bosentan—endothelin receptor A and B antagonist; does not cause hepatotoxicity
in patients with Child class A disease; decreases pulmonary and portal pressures (at least transiently); minimal adverse
effects on liver enzymes; ambrisentan—endothelin A selective antagonist; less hepatotoxicity anticipated; phosphodiesterase
inhibitors—with sildenafil (eg, Viagra), 3 mo of improvement; after 3 mo, condition worsens; could be part of
combination therapy; no hepatic or gastrointestinal bleeding
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| Liver transplantation and PPH: 35% mortality; 65% of patients first diagnosed with PPH in operating room at time of
transplantation; even when candidates for transplantation screened for PPH (of 66 patients, 30 found to have PPH and denied
transplantation), mortality still 36% in transplant patients; intraoperative death due to right heart failure; PPH treatment
poorly administered; long-term survival—with or without pretransplantation treatment for PPH, improvement in hemodynamics
seen with different regimens; epoprostenol—therapy to transplantation; treatment goal pressures <35 mm Hg; in 8-
case series, patients with PPH awaiting liver transplantation treated 2 to 15 mo; 2 died on waiting list, 4 successfully transplanted,
and 2 required additional treatment with sildenafil or bosentan
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| Summary: with liver transplant complete resolution and improvement possible; PPH may develop after successful transplantation
for reasons unknown; survival unchanged in patients with PPH treated with prostacyclin alone; improved survival
in transplant recipients treated with IV prostacyclin; regimen of vasodilator or vasomodulator pretransplantation
leads to better outcomes; patients can develop pulmonary hypertension after transplant; right ventricle key to which patients
do well (must decrease thickness)
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| PULMONARY EVALUATION BEFORE LIVER TRANSPLANTATION
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| Screening: for HPS, PPH, hepatic hydrothorax, α1 -antitrypsin (AAT) deficiency and smoking-related conditions; primary
biliary cirrhosis— granulomas in lungs and organizing pneumonitis; ringed lesions; linear infiltrate on bottom of lungs
(noncaseating granulomas); assessment of arterial oxygenation required; conducted with patient at rest; HPS—finger
pulse oximetry (easiest); radial arterial blood gas (ABG; most definitive); oximetry may overestimate prevalence of HPS;
current screening program—everyone in liver transplantation program receives resting ABG while breathing room air;
if PaO2 <70 mm Hg, perform contrast echocardiography and if positive, quantitate degree of HPS with lung perfusion
scan; then look at response to 100% O2 ; every patient receives Doppler echocardiography to estimate right ventricular
systolic pressure; ask cardiologist to look for pulmonary hypertension; if no tricuspid regurgitant flow, examine right
ventricular size and function; if normal, continue and observe; repeat echocardiography at 12 mo if patient has not received
transplant; pulmonary hypertension—varying criteria for right heart catheterization; by Mayo Clinic criteria
right ventricula (RV) systolic pressure >50 mm Hg reasonable cutoff
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| Treatment algorithm: for patients with RV systolic pressure >50 mm Hg, categorize at right heart catheterization; if
mean PAP <35 mm Hg proceed to liver transplantation; PAP> 50 mm Hg, contraindication for transplantation (initiate or
modify therapy for PPH); if PAP between 35 mm Hg and 50 mm Hg, transplant candidacy depends on individual risk, including
pulmonary vascular resistance and comorbidities
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| Hepatic hydrothorax: perform thoracentesis for diagnostic and therapeutic purposes; diagnostic when pain, fever or neoplasm
(hepatocellular carcinoma) present; therapeutic thoracentesis done under ultrasonographic guidance; ≤ 2 L removed
at one time; removal of >2L leads to shifts of mediastinum that cause coughing, shortness of breath, and pain;
some patients have no clinical ascites but substantial pleural effusions; fluids flow through defects in diaphragn with negative
pressures; chylous effusions (transudates) found in ≈20% of hepatic hydrothorax cases; measure triglycerides in
fluid (may be milky to white); whether fluid exudate or transudate management same; nasal continuous positive airway
pressure (CPAP) can reduce hepatic hydrothorax; liver transplantation definitive treatment; no increase in postoperative
complications; pleural effusions after transplantation are exudates; no satisfactory answer for cause; TIPS—resolves
problem in ≈58% of patients; 30-day survival 75% (determined by whether transplant available); TIPS may cause acute
increase in cardiac index (usually sustained) and acute increase in pulmonary vascular resistance (transient); TIPS not
recommended in pulmonary hypertension; chest tube not recommended for hepatic hydrothorax (outcomes unfavorable)
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| AAT deficiency: transplant candidates screened for α1 genotype and α1 level; phenotype less accurate than genotype;
most severe deficiency presentation below diaphragm cirrhosis and hepatocellular carcinoma; above diaphragm, pulmonary
emphysema and bronchiectasis; no role for α1 -proteinase inhibitor (Prolastin) therapy in liver patients; experience
with liver transplantation in AAT-deficient patients suggests lung problems continue to progress; α1 protein synthesized
in liver and binds 1 to 1 with neutrophil elastase; in smokers, receptor does not fit into neutrophil elastase, so effect of
AAT deficiency exacerbated, especially in lungs; in liver, hepatocytes become engorged α1 protein due to protein misfolding;
cirrhosis in ZZ patients 20%, emphysema 50% to 60%, panniculitis, skin problems in few patients; predictors of
mortality lung problems, sepsis, hepatomas, variceal bleeding, hemorrhaging after liver transplants; abnormal phenotype
(S or Z) in 15% to 20% of liver transplant candidates; of patients with ZZ abnormality who never smoke, one-half to one-
third develop respiratory abnormality
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| Smoking: complete pulmonary function testing for current smokers or former smokers who quit within last few years; tobacco
use and abuseafter tliver transplant substantial problem; 40% alcoholic cirrhotic patients resume smoking after
transplantation; increased frequency of ear nose, throat, and lung cancers; hepatic artery complications in ≈9.7% of
smokers after transplantation; 2-yr smoking abstinence leads to outcomes similar to those of nonsmokers; Mayo Clinic
does not perform transplantation anyone actively smoking; do serum and urinary cotinine studies to confirm no smoking
3 mo before transplantation
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| MELD priority: HPS higher priority if PaO2 <60 mm Hg breathing room air in sitting position; MELD score increased to
allow transplantation within 3 mo; MELD exception for PPH—if mean PAP >35 mm Hg, recommend minimum 12 wk
of FDA-approved medication, with goal of decreasing pressure and vascular resistance levels to 35 mm Hg and 400
dynesec/cm-5 respectively, with satisfactory right-heart function; assign MELD score of 26, and proceed to transplantation
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Suggested Reading
Arqueda MR et al: Utility of pulse oximetry screening for hepatopulmonary syndrome. Clin Gastroenterol Hepatol
5:749, 2007; Ashfaq M et al: The impact of portopulmonary hypertension on survival following liver transplantation. Am
J Transplan 7:1258, 2007; Aucejo F et al: Pulmonary hypertension after liver transplantation in patients with antecedent
hepatopulmonary syndrome: a report of 2 cases and review of literature. Liver Transplant 12:1278, 2006; Barst RJ: A review
of pulmonary arterial hypertension: role of ambrisentan. Vasc Health Risk Manag 3:11, 2007; Barth F et al: Efficacy
and safety of bosentan in Child C cirrhosis with portopulmonary hypertension and renal insufficiency. Eur J
Gastroenterol Hepatol 18:1117, 2006; Fallon MB et al:. Model for end-stage liver disease (MELD) exception for
hepatopulmonary syndrome. Liver Transplant 12:S105, 2006; Fix OK, et al: Long-term follow-up of portopulmonary hypertension:
effect of treatment with epoprostenol. Liver Transplant 13:875, 2007; Golbin JM, Krowka MJ: Portopulmonary
hypertension. Clin Chest Med 28:203, 2007; Halank M et al:. Portopulmonary syndrome. J Gastroenterol
41:837,2006; Hoeper MM, et al: Bosentan therapy for portopulmonary hypertension. Eur Respir J 25:502, 2005;
Jiminez C et al: Incidence and risk factors for development of lung tumors after liver transplantation. Transplant Int
20:57, 2007; Krowka MJ et al: Model for end-stage liver disease (MELD) exception for portopulmonary hypertension.
Liver Transplant 20:S114 2006; Krowka MJ:. Hepatopulmonary syndrome and portopulmonary hypertension: implications
for liver transplantation. Clin Chest Med 26:587-597, 2005; Murray KF, Carithers RL: AASLD Practice Guidelines:
Evaluation of the patients for liver transplantation. Hepatology 41:1407-1432, 2005; Provencher S et al:
Deleterious effects of beta-blockers on exercise capacity and hemodynamics in patients with portopulmonary hypertension.
Gastroenterology.130:120, 2006; Reichenberger F et al: Sildenafil treatment for portopulmonary hypertension. Eur
Respir J 28:563, 2006; Rodriguez-Roisin R et al: Pulmonary-hepatic vascular disorders: report of a Task force. Eur
Respir J 24:861, 2004; Sussman N et al: Successful liver transplantation following medical management of portopulmonary
hypertension: a single-center series. Am J Transplant 6:2177, 2006; Swanson KL et al: Natural history of hepatopulmonary
syndrome. Hepatology 41:1122, 2005; Vatter H, Seifert V:. Ambrisentan, a non-peptide endothelin receptor
antagonist. Cardiovasc Drug Rev 24:63, 2006; Xiol X et al: Liver transplantation in patients with hepatic hydrothorax.
Transplant Int 18(6):672 2005.
Educational Objectives
| The goal of this program is to improve the screening, diagnosis, and management of the pulmonary aspects
of liver diseases. After hearing and assimilating this program, the clinician will be better able to:
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 | 1. Perform screening for pulmonary disorders in liver transplant candidates.
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| 2. Diagnose hepatopulmonary syndrome and portopulmonary hypertension.
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| 3. Choose appropriate therapy for managing portopulmonary hypertension.
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| 4. Manage hepatic hydrothorax.
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| 5. Describe the impact of smoking, α1 antitrypsin deficiency, hepatopulmonary syndrome and portopulmonary
hypertension on liver transplantation outcomes.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee
to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest.
Any identified conflicts were resolved to ensure that this education al activity promotes quality in health care and not a proprietary
business or commercial interest. For this program, the following has been disclosed: Dr. Krowka is a consultant for Gilead Sciences
Inc and United Therapeutics. The planning committee reported nothing to disclose.
Acknowledgements
Dr. Krowka spoke in North Charleston, SC, at the Liver Disease and Transplant Symposium, presented February 17, 2007, by
the Medical University of South Carolina College of Medicine, MUSC Liver Service, Division of Gastroenterology and Hepatology,
Liver Transplant Program,and Office of Continuing Medical Education, and cosponsored by the Office of Continuing Nursing
Education, College of Nursing. The Audio-Digest Foundation thanks the speaker and the Medical University of South Carolina
for their cooperation in the production of this program.
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