CLINICAL PROGRESS

Respiration and Circulation in Patients with PortalCirrhosis of the Liver

By H. 0. HEINEMANN, M.D.

IT IS generally known that cirrhosis of theliver may be accompanied by marked

changes in the hepatic and splanchnic vascula-ture, which in turn lead to reduced hepaticblood flow, increased portal venous pressure,and the development of collateral vessels per-mitting bypass of the diseased liver.'-7 Lesswell known is the fact that cirrhosis of theliver may also be associated with changes inthe respiratory pattern, the pulmonary vas-culature, and the systemic circulation.8-10Information on this subject is at present in-complete. It may even seem questionable thatimpairment of the function of a single organcan lead to such a varied pathologic pattern.This review attempts to fulfill a dual purpose:first, to draw attention to the above-mentioned,less well known complications of cirrhosis ofthe liver, and, secondly, to present a moreunified concept of the respiration and circula-tion in patients with this disease.

Patients with cirrhosis of the liver mayhyperventilate at rest in the absence of re-duced hemoglobin content of the blood andwithout apparent increase in oxygen consump-tion. This leads to the development of mildrespiratory alkalosis.10 To explain the hyper-ventilation in the face of reduced carbon diox-ide tension and normal, or slightly elevated,pH of the arterial blood, the assumption isoften made that the respiratory center is stim-ulated by ammonia, because the blood level of

From the Department of Medicine, Francis Dela-field Hospital, and the College of Physicians andSurgeons, Columbia University, New York, N.Y.Supported in part by Grant C-2332 from the Na-

tional Cancer Institute, U.S. Public Health Service.

this metabolite is frequently elevated in pa-tients with liver disease." Poor correlation be-tween the ammonia content of arterial bloodand the minute ventilation casts some doubton the significance of ammonia as a respira-tory stimulus and leaves this problem open forfurther investigation.9 Another stimulus thatmust be considered to explain the hyperven-tilation is the low oxygen tension of arterialblood, not infrequently observed in patientswith cirrhosis of the liver. Determination ofthe partial pressure of oxygen in arterial bloodreveals tensions, however, which are not ofthe order of magnitude commonly assumed tobe necessary to increase ventilation,9' 12 andthe mechanism maintaining hyperventilationin the absence of adequate physiologic stimuli(pCO2, pH, and P02) remains, at presentunsatisfactorily explained.The above-mentioned low arterial oxygen

tension, observed in some patients with cir-rhosis of the liver, leads to an increasedgradient in the partial pressure of oxygenbetween the blood and alveolar air.13 Thisgradient is further accentuated by the highalveolar oxygen tension caused by hyperven-tilation. The low arterial oxygen tension incirrhosis of the liver might be due to hypoven-tilation of well-perfused lung tissue, becauseof elevation of the diaphragm secondary toascites, or these patients may have intrinsiclung disease with reduced diffusing capacityfor oxygen. Pulmonary function remainswithin normal limits and unsaturation ofarterial blood persists, however, irrespectiveof the presence or absence of ascites,9 andparacentesis has no apparent effect on ventila-

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tion.14 It is also conceivable that changes inthe hemoglobin molecule, leading to a shift inthe oxygen dissociation curve, may be respon-sible for the hypoxemia in liver disease.15' 16Such a mechanism can similarly be excluded,however, because blood of hypoxemic patientsbecomes fully saturated by equilibration invitro with gas mixtures containing oxygen attensions similar to the ones observed in vivo.9

These considerations leave shunting ofvenous blood into the systemic circulation asa third possibility to explain the hypoxemiaof liver disease. The presence of such venous-to-arterial shunts is made likely by the factthat administration of 100 per cent oxygendoes not abolish either the increased gradientfor oxygen tension between alveolar air andarterial blood, nor the hypoxemia in patientswith marked unsaturation.8' 17 In adults withportal cirrhosis, in contrast to patients withso-called juvenile cirrhosis,* these shunts areapparently not located between the pulmonaryarteries and pulmonary veins.'8' 19 Abnormalvascular channels, which could account forextrapulmonary shunting of venous blood intothe systemic circulation, have been docu-mented by Calabresi and Abelman,20 whodemonstrated communications between theportal vascular bed and the pulmonary veinsvia periesophageal and mediastinal veins. Thevolume of portal venous blood entering thesystemic circulation per unit of time mustdepend on the available pressure gradient be-tween the portal and pulmonary veins andmay, therefore, vary considerably during therespiratory cycle because of the unusual loca-tion across the diaphragm.tUnpublished observations indicate that cir-

rhosis of the liver may in some instances beassociated with changes in the pulmonaryarteries (vasculitis?) and an elevated pul-monary artery pressure. The underlying

*Rydell and Hoffbauer'8 observed arteriovenousanastomoses between the pulmonary artery and thepulmonary vein in a patient with juvenile cirrhosis.

tThe so-called shunt equation cannot be applied tocalculate the volume of blood flowing through thesevascular communications because the oxygen contentof portal blood is not readily measurable.n

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mechanism is at present not understood. Butthe question arises whether there is a relation-ship between the pulmonary hypertension andthe fact that metabolites, originating from thegastrointestinal tract, have direct access to thepulmonary arteries via acquired or surgicallyinduced anastomoses of portal vein to venaeava. It is tempting to compare this situationwith the pulmonary hypertension in patientswith the carcinoid syndrome, where serotoninescapes hepatic inactivation because of over-production or metastases beyond the liver andthen affects the pulmonary vessels. At present,however, there is no evidence to suggest thatthe changes in the pulmonary arteries, oc-casionally observed in patients with cirrhosisof the liver, are due to a specific metabolitesuch as serotonin.-*

Patients with cirrhosis of the liver mayhave unexplained cardiac hypertrophy. Lun-seth, Olmstead, and Abboud23 reported suchcardiomegaly in 12 out of 108 autopsies onpatients with portal cirrhosis, an incidence of11 per cent. Coronary artery disease and hy-pertension are generally considered to be lesscommon in these patients.24 To account for thisabnormality, one has therefore to considerother mechanisms. One possibility would bethat portal cirrhosis is associated with aspecific type of myocardial disease. Such amechanism is not unlikely because microscopicexamination of the myocardium in the patientsstudied by Lunseth, Olmstead, and Abboud23and others25 revealed an unusual type ofdiffuse fibrosis, often only in portions of asingle muscle fiber.Predominant right ventricular hypertrophy

is another characteristic feature of the cardio-megaly in patients with cirrhosis of the liver.This may be due to the occasionally observedincreased pulmonary artery pressure. It isalso known that patients with cirrhosis of theliver may have a high cardiac output at rest,irrespective of the presence or absence of col-lateral circulation, portocaval shunt, anemia,*The serotonin content in blood of patients with

cirrhosis of the liver is reported to be lower than innormal subjects.9

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or nutritional deficiencies.8 26-28 Such persist-ent elevation of the cardiac output couldaccount for cardiac hypertrophy. The increasein cardiac output is not associated with in-creased oxygen consumption and is thereforedifferent from the circulatory pattern ob-served in the so-called hypermetabolic state.The rise in cardiac output is similar to thechange noted in patients with arteriovenousfistulae29' 30 and thiamine deficieney.31 Allthese syndromes have in common a reductionof the peripheral resistance.

It is conceivable that cardiomegaly, perhapsin combination with degenerative changes inthe myocardium, may lead to cardiac failure.No adequate information, however, is availableon the incidence of such a complication inpatients with cirrhosis of the liver. Dyspneaand cough, frequently noted in these patients,is usually ascribed to the elevated diaphragmbecause of ascites and the higher susceptibilityto respiratory infections.32 Peripheral edemais as frequent as ascites in these patients andmay occur irrespective of the presence orabsence of fluid in the abdomen.32 Hvdro-thorax may develop, most commonly in asso-ciation with ascites. Pulmonary infections orleakage of ascitic fluid into the pleural cavityis usually implicated as a cause. If heart fail-ure, indeed, complicates cirrhosis of the liver,it may be difficult to detect because most synmp-toms can also be ascribed to the underlyingdisease. Measurement of venous pressure andthe response to a cardiotonic regimen may behelpful in differentiating the cause of fluidretention. Furthermore coincidence of cir-rhosis of the liver and heart failure does notimply a causal relationship, because both con-ditions have a high incidence in the same agegroup. However, 2 well-documented cases ofhigh output failure have been reported in theliterature.8' 18 Emphasis, therefore, on highoutput failure as a potential complication ofcirrhosis of the liver seems justified and maylead to more frequent recognition.The increased cardiac output in patients

with cirrhosis of the liver is presumably dueto decreased peripheral resistance and the re-sulting increased peripheral blood flow. These

changes in the hemodynamic pattern areclinically discernible by the increased pulsepressure,33 flushed palms, and capillary pulsa-tionS.8' 34' 35 The mechanism responsible for thereduction in peripheral resistance is unknown.It has been postulated that either increasedproduction or diminished inactivation of vaso-active substances is involved. Such a substance,originating from the area drained by thesplanchnic vessels and normally inactivatedby the liver, could escape hepatic inactivationand gain access to the systemic circulation viacollateral vessels. Increased levels of circulat-ing estrogen35 have also been implicated as acause for both the development of palmarerythema (peripheral vasodilatation) and theappearance of arterial spiders.

Cirrhosis of the liver is occasionallyaccompanied by hypertrophic osteoarthrop-athy,Y' 34, 36 The cause of clubbing remains un-known, but it has been postulated that thisabnormality is related to increased peripheralblood flow, increased cardiac output,37 orshunting of venous blood into the systemic cir-culation, changes also observed in patientswith portal cirrhosis of the liver. But hyper-trophic osteoarthropathy is apparently moreoften observed in patients with biliary cir-rhosis,8 where such a hemodynamic patternseems not to occur..Patients with cirrhosis of the liver have

frequently an enlarged total blood volume.38 41This is mainly due to an increase in the plasmafraction, the red cell mass being within nor-mal limits. This leads to lowering of the hema-tocrit level, a fact that should be taken intoconsideration if the anemia of liver disease isto be evaluated. A normal hematocrit valuein patients with cirrhosis of the liver, in theface of an elevated blood volume, representsa rise in red cell mass. It is conceivable thathypoxemia, if present, may stimulate red cellproduction and induce a relative or absolutepolycythemia. Two such patients with cirrho-sis of the liver and secondary polycythemiahave been reported in the literature.8' 18 Themechanism causing the rise in plasma volumeis unknown. But a similar hypervolemia isobserved in other conditions associated with

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decreased peripheral resistance, such as ar-teriovenous fistulas,42 thiamine deficiency,31' 43

and pregnancy.44 Reduction of the peripheralresistance, due to whatever mechanism, nmayconceivably initiate a cycle of events that ulti-mately leads to an increased plasma vol-ume. 45' 46From the foregoing review, one can con-

clude that cirrhosis of the liver may be accom-panied by marked changes in the respiratorypattern, pulmonary vasculature, and systemiccirculation. Information about the incidenceof these changes and their relationship to thestages of the disease and the type of cirrhosisis at present not available. Most observers havelimited their studies to individual phenomena,such as the cardiac output, in selectedpatients. Rydell and Hoffbauer,15 on the otherhand, performed a careful study in a singlepatient with so-called juvenile cirrhosis andwere able to define a disease entity charac-terized by hypoxemia, secondary polycythe-mia, high cardiac output, heart failure, and,apparently in contrast to adults with portalcirrhosis, multiple intrapulmonary arterio-venous fistulas. Comparable studies are notavailable in adults with cirrhosis of the liver.Such observations are necessary, however, be-fore a similar disease entity can be confidentlydescribed for portal cirrhosis. As a workinghypothesis for future studies, one can separatethe changes observed in adults with portal cir-rhosis into 3 different groups.

First, communications between the portalvascular bed and either the pulmonary veinsor the venae eavae may (a) permit venousblood to enter the systemic circulation andcause hypoxemia or (b) may allow intestinalmetabolites to escape hepatic inactivation andgain direct access to the systemie circulation.

Secondly, metabolites escaping hepatic in-activation may be responsible for the changesin the pulmonary vessels, pulmonary hyper-tension, reduced peripheral resistance, andhyperventilation.

Finally, reduction of the peripheral resist-ance leads to a rise in cardiac output and per-haps also the plasma volume. The increasedcardiac output may eventually cause cardiacCirculation, Volume XXII, July 1960

hypertrophy and heart failure, a complicationdifficult to recognize in older patients in whomheart disease may occur independently andfluid retenition and dyspnea can be attributedto the underlying disease.

AcknowledgmentThe author wishes to express his appreciation to

Dr. A. P. Fishman for his suggestions and helpfulcriticism.

AddendumSinlce this paper was subnmitted for publication,

another well-documented example of arterial hypoxe-mia in cirrhosis of the liver has been described byRodman and associates.47

Summario in InterlinguaEs generalmente cognoscite que cirrhosis del hepate

pote esser accompaniate de mareate alterationes in levasculatura hepatic e splanchnic e que isto, de su

parte, resulta in un reduction del fluxo hepatic desanguine, in un augmento del tension venose portal,e in le disveloppamento de vasos collateral que per-mitte le circuition del hepate morbide. Es minus bencognoscite que cirrhosis del hepate pote etiam esserassociate con alterationes del respiration, del vascula-tura pulmonar, e del circulation major. Le presentearticulo ha le duple objectivo de (1) signalar lesupra-mentionate, minus ben cognoscite complicationesde cirrhosis del hepate e (2) presentar un plus unli-ficate conception del respiration e del circulation itipatientes con ille disordine.

In summation de su argumento e como base profutur studios, le autor presenta le hypothese que lealterationes observate in patientes adulte con cirrhosisportal pote esser separate in tres differente gruppos.

1. Communicationes inter le vasculatura portal e, cleun latere, le venas pulmonar o, del altere latere, levenas cave pote resultar in (a) le entrata de sanguine'venose in le circulation major con le effecto de hypox-emia o (b) le non-inactivation de metabolitos intes-tinal per le hepate e le consequente transition directede ille metabolitos a in le circulation major.

2. Metabolitos que escappa al inactivation per lehepate pote devenir respoaisabile pro alterationes ile vasos pulmonar, pro hypertension pulmonar, prole reduction del resistentia peripheric, e pro hyper-ventilation.

3. Le reduction del resistentia peripheric resulta inun augmento del rendimento cardiac e forsan etiamdel volumine de plasma. Le augmentate rendimentocardiac pote, in le curso del tempore, devenir le causade hypertrophia cardiac e disfallimento del corde-un complication que es difficile a identificar in pa-tientes de etates plus avantiate, proque in tales le

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disveloppamento de morbo cardiac pote esser un oc-currentia independente e le retention de liquido ele presentia de dyspnea pote esser interpretate comoattribuibile al morbo subjacente.

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, I

Medical EponymsBy ROBERT W. BUCK., M.D.

The true worth of an experimiienter consists in his pursuing not onlv wvhat he seeks inhis experimuent, but also what be did not seek.-CLAUDE BERNARTD. (Subm11itted by H. M1.Alarvin, M.D.)

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H. O. HEINEMANNRespiration and Circulation in Patients with Portal Cirrhosis of the Liver

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 1960 American Heart Association, Inc. All rights reserved.

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