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Articles

Prevalence and Reversibility of the HepatopulmonarySyndrome After Liver Transplantation

The Cleveland Clinic ExperienceJAMES K. STOLLER, MD; PAUL A. LANGE, MD; MARY KAY WESTVEER, RN; WILLIAM D. CAREY, MD;

DAVID VOGT, MD; and J. MICHAEL HENDERSON, MD, Cleveland, Ohio

To ascertain the prevalence and reversibility of the hepatopulmonary syndrome, we reviewed thecases of 98 patients undergoing liver transplantation at the Cleveland (Ohio) Clinic Foundation fromJune 1988 through July 1992 and identified 4 patients with clinically recognized hepatopulmonary syn-drome (prevalence 4%). All 4 patients ultimately had complete reversal of their disorder. As reviewedherein, the prevalence of the hepatopulmonary syndrome in the current series is lower than in previ-ous reports, possibly reflecting a dependence on its clinical recognition in this series rather than theuse of routine screening tests. This report confirms previous experience that the hepatopulmonarysyndrome may be reversible after transplantation.(Stoller JK, Lange PA, Westveer MK, Carey WD, Vogt D, Henderson JM: Prevalence and reversibility of the hepatopul-monary syndrome after liver transplantation-The Cleveland Clinic experience. West J Med 1995; 163:1 33-1 38)

T he hepatopulmonary syndrome is characterized by a

triad of impaired arterial oxygenation, hepatic dys-function, and the presence of intrapulmonary vasculardilatations." Clinical features include dyspnea, ortho-deoxia, tachypnea, cyanosis, and digital clubbing.

Despite earlier impressions that the hepatopulmonarysyndrome is irreversible and that it is a contraindicationto liver transplantation (because posttransplantation hy-poxemia could exacerbate graft failure),3', recent obser-vations suggest that the syndrome can resolve after livertransplantation."'l In the context that the pathogenesis ofthe hepatopulmonary syndrome remains unknown, how-ever, predicting reversal after liver transplantation cur-

rently remains impossible.This study was undertaken to assess the frequency and

time course of the reversal of the hepatopulmonary syn-

drome following liver transplantation. Because overallestimates of the prevalence of the syndrome vary widely,another goal of this research was to examine its preva-

lence among liver transplantation candidates referred tothe Cleveland (Ohio) Clinic Foundation.

Patients and MethodsTo identify patients with the hepatopulmonary syn-

drome before undergoing liver transplantation and alsothe group in whom posttransplantation reversibility couldbe assessed, we reviewed retrospectively the roster of allpatients undergoing liver transplantation at the ClevelandClinic Foundation from June 1988 through July 1992.Over this 49-month period, 98 patients underwent livertransplantation at our institution. The subjects of the cur-

rent report are the 4 patients in whom the hepatopul-monary syndrome was suspected (and subsequently con-

firmed) by their managing physicians. Although routinescreening for the syndrome-by the physiologic assess-

ment of shunt fraction, by imaging using technetium Tc99m-labeled macroaggregated albumin or contrast-enhanced echocardiography, or both-was not part of ourroutine pretransplantation evaluation protocol until afterthe current study was completed (November 1993), our

previously reported experience with a patient whose he-patopulmonary syndrome and associated digital clubbingreversed after liver transplantation heightened our suspi-cion for the syndrome."

The following criteria were used for diagnosing thehepatopulmonary syndrome in this series:

* Impaired oxygenation, defined as an elevated alve-olar-arterial oxygen gradient (PAO2 - Pao,) for age (usinga maximal normal age-specific value of PAO2 - Pao2 as

age *4 + 4);* The presence of chronic liver dysfunction; and* Evidence of a right-to-left shunt, based on the re-

sults of radionuclide scans using ssmTc-macroaggregatedalbumin, contrast-enhanced echocardiography, or both.

Radionuclide scans using ssmTc-macroaggregated al-bumin were done using standard techniques.2' Specifi-cally, after the administration of 4 mCi of `9mTc-macroaggregated albumin (mean particle diameter, 20 to50 ,um), scans were taken over the kidney and brain to de-tect particles bypassing the pulmonary capillaries (thesmaller diameter [8 to 15 ,um] of which would trap the

From the Departments of Pulmonary and Critical Care Medicine, Gastroenterology, and General Surgery, Cleveland Clinic Foundation, Cleveland, Ohio.Reprint requests to James K. Stoller, MD, Pulmonary and Critical Care Medicine, A-90, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195.

134IM Auut19-o 6,N.2LvrTasIntto-oleeta

macroaggregated albumin particles). The appearance ofradionuclide in the brain, kidneys, or both denotes thequalitative presence of a right-to-left shunt.

Contrast-enhanced surface echocardiography was per-

formed using standard echocardiographic techniques(Sonos-1000, HP-77020A, Hewlett Packard, Andover,Massachusetts). Contrast consisted of microbubbles (60to 90 ,um) created by administering a hand-agitated salinesolution or indocyanin intravenously. The appearance ofmicrobubbles or contrast in the left atrium or the left ven-tricle (or both) three to six cardiac cycles after their ap-

pearance in the right atrium denotes an intrapulmonaryright-to-left shunt.22", Transesophageal echocardiographywas not routinely performed.'" As previously reported,one of the four patients underwent pulmonary angiogra-phy and was found to have a type 1 angiographic pattern(diffuse, "spongy" vascularity)."215

Other tests included arterial blood gas measurements,both while the patient was breathing room air (eitherstanding or supine as indicated) or after the patient hadbreathed 100% oxygen. The shunt fraction was deter-mined by obtaining an arterial blood specimen after the pa-

tient breathed 100% oxygen through a tight-fitting facemask for at least 20 minutes. The shunt fraction was calcu-lated according to a published nomogram that assumes an

arteriovenous oxygen content difference of 5 mg per dl.?'Orthodeoxia was defined as a decline in room-air

arterial oxygen tension of 10 mm of mercury or more

when the patient was standing (versus the baseline seatedor supine value). The room-air PAO2 - Pao2 gradient was

calculated according to a standard formula using a respi-ratory quotient value of 0.8. Age-specific normal valueswere calculated using the formula age . 4 + 4.27

Static pulmonary function tests included spirometryand the measurement of lung volumes and steady-statediffusing capacity. This spirometry was done using a

pneumotachygraph-based spirometer (Model TL, Spin-naker, and Excel, Cybermedic, Inc, Boulder, Colorado)without inhaled bronchodilators. We recorded the highestspirometric values based on three acceptable spirometrymaneuvers, as defined by American Thoracic Society cri-teria.' Predicted values for the forced expiratory volumein 1 second and the forced vital capacity were based on

published predictive equations.' Lung volumes were de-termined by helium dilution using published predictive

equations.30 With the patient seated, the lungs' diffusingcapacity for carbon monoxide was measured using a

single-breath technique and comparing with predictednormal values.3

ResultsOf 98 cases of liver transplantation reviewed, 4 pa-

tients were suspected clinically by their managing physi-cians of having the hepatopulmonary syndrome. In eachpatient, further pretransplantation evaluation confirmedthe presence of the syndrome, yielding a prevalence ofclinically suspected hepatopulmonary syndrome of 4%(4/98) in this series. Patient 1 was the subject of an earlierreport from our group."

Characteristics of these four patients with the he-patopulmonary syndrome who subsequently underwentliver transplantation are summarized in Table 1. Theirmean age was 33.5 years (range, 5 to 52). All patients hadlimited exercise tolerance and digital clubbing. Cuta-neous spider angiomata were noted in three patients. Or-thodeoxia was present in one of the two patients forwhom matched supine and standing room-air arterialblood gas values were available.

The pretransplantation physiologic features of thesefour patients are summarized in Table 2. Among the threepatients with available measurements of diffusing capac-

ity, values were uniformly low (mean, 51.6% predicted;range, 34% to 64% of predicted). Similarly, among thethree patients with available room-air arterial blood gas

values, the PAO2 - Pao2 gradients were elevated in allthree (mean value, 58.1 mm of mercury; range, 43 to 66mm of mercury). In the fourth patient, the pretransplanta-tion Pao2 with the patient receiving 6 liters of transtra-cheal oxygen was 45 mm of mercury. The mean

pretransplantation shunt fraction was 18.7% in the threepatients studied (range, 18% to 20%).

As shown in Figure 1, the hepatopulmonary syndromeresolved in all four patients following liver transplanta-tion. The reversal of the right-to-left shunt was demon-strated by a return to normal shunt fraction measurementsin three patients following liver transplantation and, in pa-tient 2, who was 5 years old, by less invasive contrast-enhanced echocardiography. The mean posttransplanta-tion shunt fraction was 4.5% (range, 3.5% to 5.1%). Theinterval over which the hepatopulmonary syndrome was

TABLE 1.-Characteristics of Patients With the Hepatopulmonary Syndrome Undergoing Liver Transplantation

Age at Digital TransplontationPotient Trarnsiantation Sex Diag,osis C0bb tog Orthodeoxia' Date

1 . 38 F Primary biliary Yes No 6/1 2/88cirrhosis

2 ........ 5 F Postnecrotic cirrhosis Yes NA 7/201903 .......... 52 M Laennec's cirrhosis Yes NA 61/28/914 ........ 39 F Autoimmune chronic Yes Yes 7/29/92

active hepatitisNA = daa nol a\valab?le

*Orthodeoxia is defined as i de(tF ne i- te Pa: E e a',tl :he patiert oreatnih ' cor air oIt0 mm of rmercrn r' s.;prc to -tandcin.

134 WJM, August 1995-Vol 163, No. 2 Liver Transplantation Stoller et al

Liver Transpiantation-Stoller et al 1 35

documented to resolve ranged from 1 to 8 months, whenposttransplantation assessments were done.

Figure 2 depicts the change in the PAO, - Pao, gradi-ent values before and after transplantation in all three pa-tients while they were breathing room air. While patient 4was receiving 6 liters of transtracheal oxygen beforetransplantation, the Pao, was 45 mm of mercury; aftertransplantation the PAO, - Pao, gradient was 29.7 mm ofmercury. In the absence of demonstrable right-to-leftshunting after liver transplantation to suggest persistenthepatopulmonary syndrome, persistent elevation of thePAO, - Pao, gradient was thought to indicate othercauses of abnormal oxygenation, such as persistentventilation/perfusion mismatching.

DiscussionThe current study elicited the following findings:* The prevalence of clinically suspected hepatopul-

monary syndrome was 4% among this group of livertransplant recipients.

* The hepatopulmonary syndrome was uniformly re-versible following liver transplantation in the four pa-tients in whom it was detected in this series.

* The time to detected reversal of the hepatopul-monary syndrome was one to eight months in this series.

The estimated prevalence of the hepatopulmonarysyndrome of 4% in the current series is lower than otheravailable estimates, which range from 13% to 47%3.32Specifically, a group of 40 liver transplant candidateswere systematically screened for the hepatopulmonarysyndrome.32 The investigators noted that 13% (5 of 38) ofthese patients had echocardiographic evidence of intra-pulmonary vascular dilatations, the hallmark of the syn-drome. In another series, 53 liver transplant candidateswere studied, and evidence of intrapulmonary right-to-left shunting was demonstrated in 25 (47%) by contrast-enhanced echocardiography.2Y That our prevalenceestimate is lower than that of others probably reflects thedependence on the clinical recognition of the hepatopul-monary syndrome in the current series rather than system-

atic screening with contrast-enhanced echocardiographyor radionuclide scans, as was undertaken in the two otherseries cited. Evidence of intrapulmonary right-to-leftshunting by contrast-enhanced echocardiography hasbeen shown in patients lacking clinical features of thehepatopulmonary syndrome such as orthodeoxia, platyp-nea, or both.2 Furthermore, it has been observed thatcontrast-enhanced echocardiograms positive for right-to-left intrapulmonary shunting in 10% of cirrhotic patientswith Pao, values exceeding 70 mm of mercury suggest a

disparity between the anatomic evidence of right-to-leftshunt and physiologic evidence of venous admixture.32Discordance was also reported recently between the re-

sults of contrast-enhanced echocardiography and physio-logic shunt studies in 60 liver transplant candidates.33 Ofthe 26 patients with discordant results (such as positiveechocardiographic study for intrapulmonary right-to-leftshunt but shunt less than 5%), 12 (20%) had positivecontrast-enhanced echocardiograms but normal shuntstudies and 14 (23%) had positive shunt studies but nor-mal echocardiograms.

Figure 1-.The graph depicts the results of shunt fraction beforeand after liver transplantation in the 3 patients in whom bothmeasurements were available. Shunt fractions decreasedmarkedly in all 3 patients. The range of time between shunt as-sessments was 1 month in patient 1 to 8 months in patient 4.

TABLE 2.-Pretransplantation Physiologic Measurements

FEV, FEW TlC. 3 -:. ;). p . - a~ St r. C^r5;C,Patient Predicted r!VC, G Prectec-d;,Pre;h[ted vf Prerca(- a,nerccrrraCt Ccno

I ............... 68 78 74 64 62 43 18 Intrapulmonaryright-to-leftshunt present

2 .NA NA NA NA 36 66.5 NA Intrapulmonaryright-to-leftshunt present

3 .64...... 64 67 86 57 43 66 18 Intrapulmonaryright-to-leftshunt present

4 ......... 59 77 NA 34L NA, NA 20 NAD - atHL. 3a C jc1s rIv Or' e r s r- ro o. - - :.. = -rCe3, .era Te . c-e a > A.cota .nc capacitv.

c-.rctec fr -the'umug oi- ee.

3,DO,, : r! ' -- 3:C.. , s . u < i . 3 C: W:3s.r.erdaci. o .t, e

25

20 - Patient 1A - Patient 3

.. 15 *- Patient4

0a. 10

Ds5

0 T A

Before Transplant After Transplant

WJM, August 1995-Vol 163, No. 2 Liver Transplantation-Stoller et al 1 35

No. 2 Liver Transplantation-Stoller et al

70'

60

E 530

a- 20 - ~~Patient 1A-Patient 2

0- Patient 3

Before Transplant After Transplant

Figure 2.-The graph shows the results of the alveolar-arterialoxygen gradient (PA02 - Pao2) taken with the patient breathingroom air in the 3 patients in whom both measurements wereavailable. The inean PA02 - Pao2 decreased after liver transplanta-tion from 58.1 to 33.4 mm of mercury, but remained abnormallyelevated.

In the context that some persons may have evidenceof intrapulmonary vascular dilatation with little impair-ment of gas exchange, we suspect that systematic screen-ing of the 98 patients in this series would have detectedadditional patients whose hepatopulmonary syndromewas more clinically subtle than in the 4 patients reportedhere. To address this suspicion, current practice at the

Cleveland Clinic Foundation is to evaluate all prospective

liver transplantation candidates with two-dimensional

surface contrast-enhanced echocardiography and shunt

determinations done with the patient breathing 100%

oxygen. Transesophageal echocardiography, which we

have used to identify the site of intrapulmonary vascular

dilatation by localizing contrast bubbles in specific pul-

monary veins,24 has not been performed routinely. Simi-

larly, until the therapeutic relevance of distinguishing

between a type (diffuse "spiderlike" vessels) and a type

2 (discrete vascular changes) angiographic pattern is bet-

ter understood, we have reserved the use of pulmonary

angiography for standard indications-suspected pul-

monary embolism or large arteriovenous malformations.

Our finding that the hepatopulmonary syndrome was

universally reversible following liver transplantation in

this series is also at odds with existing observations. Table

3 reviews the frequency with which intrapulmonary shunt-

ing caused by the hepatopulmonary syndrome lessened or

reversed following liver transplantation in available series

and indicates that 52% complete reversal and 43% partial

abatement occurTed.8"10-19324-40 Although some reports do

demonstrate failure of the hepatopulmonary syndrome to

resolve or to lessen at all following liver transplantation

(Table 3), we suspect that "publication bias"4' has inflated

rABLE 3. co . LK Recrs Roc:du. Rev.-ers0cirlni pruvement

cii i 1~iri"If OL

Silv.ermanwr e' al, 108 T: 50 atriVF eov yin1Pi),S:a!zc71et Qi 8 .. -SP: 00Stanley aid SS J 9.1"L2 . 0I00 tafttE.,r liver recoverv)(Che et a':, 'I1 084...... C r, vm.S 0 T: 100 (a fterl!ver recovery)Ja'e alJ8 .0~ 1 00 vidth somatostati anialoguIe

Shij'o et ai, 1 910 .... 0 r :0 fter liver, recovervEnIssoncla,000 .h 6~~~~~~~~C.T: 83>:P: I17

Krowlka- etal, 990 ......r...... n( ' U

Mvev s ct al, 1 K19. 0

Stoller et 99o . 100D)i,ac rta o n 7; T: 33

IcCioCoI:s1t 0 .....t 1C C~Irn T: 100

Cacdrarnjl eta'. .... ' r (1"c -1 1I00 after miedilcal therapy-

Fri0'In~~~~~~~T 0

Barrv- it Li'. ..1 ..1... ..ST 28: P: 72S Ccr y,(Cii ..P:5 50; T 501t aSak ,I av 3 ......a. To . rCrni : 00

Schyarcher' u ~I, 013.. 4,o.,:,'r J! Ci~\T: 100Y511ne1 "lii)LC) . . 1. I,.0i: , P: 100 ipMioSImlprovement)

To! a2......32... Parti,a I im1provement: 43Tir;,a;: improvemnent: 52

136 WJM, August 1995-Vol 163, No. 2 Liver Transplantation-Stoller et al

WIM,-, Auc--.Iust ----

the prevalence of reported reversibility, especially becausethe concept that the hepatopulmonary syndrome can be re-

versed has gained recognition only over the past severalyears (since 1989). Because no large series evaluating thereversibility of hepatopulmonary syndrome after livertransplantation is available, case reports or small case se-

ries of patients with the hepatopulmonary syndrome fail-ing to improve after liver transplantation seem lessnewsworthy and, therefore, less likely to be submitted or

accepted for publication. To the extent that the 4 patientsin this report with reversible hepatopulmonary syndromerepresent only a fraction of all such patients among our 98liver transplant recipients, we suspect that our data mayoverestimate the frequency with which the hepatopul-monary syndrome reverses after liver transplantation.

Finally, our observation that the hepatopulmonary syn-

drome resolved within eight months after liver transplan-tation is consistent with observations by others.'0-20 Aspresented in Table 4, some reports document improvementin the shunt fraction within days of liver transplantation,whereas others show more delayed resolution (2 to 14months). Because none of the available series has done

testing for the hepatopulmonary syndrome at frequent,predetermined intervals following transplantation, some ofthe splay in the observed time course of resolution may re-

flect managing physicians' decisions to defer postopera-tive testing for the syndrome until patients were beyondthe immediate postoperative period. Also, in the absenceof a specified posttransplantation protocol for retesting forthe syndrome, clinicians are likely to reassess only whenclinical improvement is evident enough to justify the in-convenience, expense, and morbidity of repeated testing.In patient 1 in the current series (whose case was reportedpreviously"), the resolution of clinical features of the he-patopulmonary syndrome was evident within 37 days af-ter liver transplantation (that is, by the resolution of digitalclubbing and a reduction in shunt fraction), but was in-complete by the second postoperative day (based on thepersistence of a positive contrast-enhanced echocardio-gram at 34 hours).

Several shortcomings of the current study are evident.Like most available series, pretransplantation screeningfor the hepatopulmonary syndrome was not uniform inthis series, so that underdetection of the syndrome is

TABLE 4.-Time to Reso/utio0n of th!e Hepotopimlonor1 Spidro!me FoHioo m Liver T-rosoio/mo;oion AslaIbe Series

Starzl eta, 1 968 .... 3 <20 mo \led 85-88L \R 50 \R Decreased shlnIr1(5 r

innmeaiate!' n 2 at' e-'sano afte 10 da jrtsMe

Eriksson et a, 990 .. 6 1 8-45 lixed 78 8§ \R 4.3 \R F0lc\u-U!p 2-12 o 2 pat 'ltsb vj r sFl .J[ltf 1 i9 F *0 r ciCr 2

shr a 1ev' w eeks

Stoller et al, 1990 ............ 1 39 Primarv biliar\yr 62 290 18 \R Normai shlnlit rac ion (5.1c:rrnosis at 37 davs

Dimand et ai, 1991 ............ 3 1 3-53 o soecif ed 50.3§ 289§ NR Presen' Decreased shl! nL and offsuJpplemental 0 a. 3-4 !. o

Levin et al, 991 ............ 1 1I Bii arv\ arresia 4 .8 NR \R La3qe 6 mo resou'ji or oS Urn: 8moc improve-lert fn 0satLfrato'-

MSlcCloskey et al, 1991 ..... 1 17 Crvptogenic 41 115 NR 30 9 mo: Pao 79 mm of mercurvcirrhosis and 3°, sfluilt

LaBerge et al, 1992 ........... 2 12, 14 Biliarv atresia 52§ 233§ 35 PresenL improved exercise toLerarce at3 mo, n-mal 5ClJt stLoC% at

rmoBarv et a!, 1993 .. 7 R lxe NR \R 24.5 \R F o ov:s-uc i ter.al 3-18 mo:

snunt fraction irproved o 14:'as a groLip

Itasaka et a', 1 993 ........... 1 1 3 Cr ptogen:c 42 41 7 52' 48 Resolution of shunt a; 165 oarscirrhosis after transplantation

Schns,varzenherg et al, 1993 . 1 1 8 -Antit,vlpsin 34 57 \R Large At 14 mo: Pac 116 mm ofdeficiercv rrecus arc !0o shurt

Scot: e: al, 1 993 ............. 6 \R Cot soecired 35-71- 350-460= NR 1 2-1 9 3 oa:ier: oromot rezo onof sh.,.n:; 3 patients: iong Post-ope ative courSe, bt 5hucresoiled

'9.::Q.

,............_.__...'.

Z

WJM, August 1995-Vol 163, No. 2 Liver Transplantation-Stoller et al 1 37

1 38 WJM, August 1995-Vol 163, No. 2 Liver Transplantation-Stoller et al

likely. Similarly, the timing of posttransplantation retest-ing for the hepatopulmonary syndrome was not uniform,so that our understanding of the frequency of reversal ofthe syndrome and of the time frame over which reversaloccurs is incomplete. Finally, the small number of pa-tients having the reversal of the hepatopulmonary syn-drome in this and other series precludes a clearunderstanding of pretransplantation clinical features asso-ciated with the reversibility of the syndrome. Indeed, inthe absence of a better understanding about predicting re-versibility of the syndrome, a firm recommendation to dotransplantation in all patients with the hepatopulmonarysyndrome is not possible. Nonetheless, bolstered by theobservation that the syndrome can reverse following livertransplantation, it is reasonable to consider this procedurefor patients whose hepatopulmonary syndrome is the ma-jor debilitating feature'1 and who are otherwise deemed tobe candidates for liver transplantation. To address theaforementioned shortcomings, we are currently prospec-tively evaluating liver transplantation candidates referredto our institution, in which patients are routinely assessedfor the hepatopulmonary syndrome as part of their pre-transplantation evaluation.

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