Hypoxia a case - Thorax · Adiagnostic pneumoperitoneum ... insight into their cause. Case report...

Thorax, 1977, 32, 457-471

Hypoxia and hydrothoraces in a case of livercirrhosis: correlation of physiological, radiographic,scintigraphic, and pathological findingsN. N. STANLEY, A. J. WILLIAMS, C. A. DEWAR, L. M. BLENDIS, AND LYNNE REID

From the Department of Medicine, The Middlesex Hospital, Mortimer Street, London WIN 8A A, theDepartment of Gastroenterology, Central Middlesex Hospital, London NWJO 7NS, and theDepartment of Experimental Pathology, Cardiothoracic Institute, Brompton Hospital, London SW3

Stanley, N. N., Williams, A. J., Dewar, C. A., Blendis, L. M., and Reid, Lynne (1977). Thorax,32, 457-471. Hypoxia and hydrothoraces in a case of liver cirrhosis: correlation of physiological,radiographic, scintigraphic, and pathological findings. A case is reported of liver cirrhosiscomplicated by cyanosis and recurrent right hydrothorax. A diagnostic pneumoperitoneumdemonstrated that direct movement of ascites through a diaphragmatic defect was responsiblefor the hydrothoraces. Pulmonary function tests between episodes of hydrothorax showed severearterial hypoxaemia, a 23% right-to-left shunt, and a reduction in the carbon monoxide transferfactor to less than half of the predicted value. Evidence of abnormal intrapulmonaryarteriovenous communications was obtained by perfusion scanning. At necropsy the centraltendon of the diaphragm showed numerous areas of thinning which were easily ruptured.Injection of the pulmonary arterial tree demonstrated precapillary arteriovenous anastomosesand pleural spider naevi. A morphometric analysis provided quantitative evidence of pulmonaryvasodilatation limited to the intra-acinar arteries, consistent with the effect of a circulatingvasodilator. The scintigraphic and pathological findings suggested that shunting had beengreater in the right than the left lung. Examination of thin lung sections by light microscopyshowed that the walls of small veins were thickened, and electron microscopy showed that thiswas due to a layer of collagen. The walls of capillaries were similarly thickened, which causedan approximately two-fold increase in the minimum blood-gas distance and contributed to thereduction in transfer factor.

Two respiratory complications may dominate theclinical picture in patients with liver cirrhosis.Some are deeply cyanosed due to a complex dis-order of gas exchange. This includes right to leftshunting (Georg et al., 1960), ventilation-perfusioninequality (Cotes et al., 1968) and reduction in thetransfer factor (Stanley and Woodgate, 1972).Gross abnormalities of the pulmonary circulationmay be revealed by perfusion scanning (Stanleyet al., 1972) and during postmortem examinationof the lung vasculature (Berthelot et al., 1966).Other patients develop hydrothoraces which areoften massive, recurrent and unilateral (Frothing-ham, 1942). This paper presents a comparison ofphysiological, isotopic and necropsy findings in a

case of liver cirrhosis with hypoxaemia and re-current hydrothorax and provides some furtherinsight into their cause.

Case report

The patient, a woman of 45 years, was first ad-mitted to the Central Middlesex Hospital in July1973 with a four-week history of jaundice, darkurine, and pale stools. There had been no ab-dominal pain, but her alcohol intake had beenexcessive and she had been treated with methyl-dopa since the diagnosis of mild hypertension oneyear earlier. She had smoked approximately 10cigarettes per day. On physical examination there

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N. N. Stanley, A. J. Williams, C. A. Dewar, L. M. Blendis, and Lynne Reid

was moderate hepatomegaly. Laboratory investiga-tions revealed an obstructive jaundice (serumbilirubin 720 ,umol/l, aspartate transaminase 63IU/ml, and alkaline phosphatase 184 IU/ml) witha negative mitochondrial antibody test. Laparo-tomy revealed no anatomical defect of the biliarysystem and an operative cholangiogram was nor-mal. A liver biopsy showed an advanced micro-nodular cirrhosis. Postoperatively she developedascites, but this resolved after salt restriction andadministration of a diuretic. Her cirrhosis waspresumed to be due to chronic alcoholism. Thecause of the cholestasis was uncertain but waspossibly related to the methyldopa therapy (Tog-hill et al., 1974). After stopping the use of thisdrug her blood pressure remained normal and thejaundice gradually disappeared.She was readmitted in June 1974 with an acute

onset of dyspnoea due to a massive right-sidedhydrothorax. There was also mild ascites andankle oedema. The pleural fluid had the character-istics of a transudate. Its protein concentrationwas 0-25 g/l; light microscopy revealed only meso-thelial cells and bacterial cultures produced nogrowth. A pleural biopsy and bronchoscopyshowed no abnormality. After an initial 1-5 1thoracentesis she was given more intensive diure-tic therapy and the hydrothorax disappeared. InSeptember and November 1974 she had two fur-ther admissions due to recurrent right-sided hydro-thoraces; on both occasions there was acuterespiratory distress. Between these episodes sheexperienced moderate dyspnoea on effort, eventhough physical and radiographic examinationsof the chest were normal. During the Novemberadmission she was noticed to be cyanosed and tohave finger clubbing. There were no abnormalheart sounds and the electrocardiogram was nor-mal. The cyanosis persisted after her chest radio-graph had returned to normal; physiologicalstudies and a lung scan performed at this time aredescribed below.

In January 1975 she had a fourth right-sidedhydrothorax, and one week later, when it hadlargely been absorbed, she was investigated bymeans of a diagnostic pneumoperitoneum. After1 litre of air had been introduced into the peri-toneal cavity she experienced a 'bubbling' sensa-tion behind the sternum which persisted for 45minutes. A chest radiograph two minutes afterperitoneal air injection showed no air above thediaphragm, but another obtained after one hourshowed a large pneumothorax. These findings sug-gested that a pleuroperitoneal communication wasresponsible for the hydrothorax. In an attempt to

prevent its recurrence a pleurodesis was inducedby insufflating iodised talc into the right pleuralspace. After this there was a remission for sixmonths, but in August 1975 she developed a fifthlarge hydrothorax on the right side. Once again itdisappeared after thoracentesis and readjustmentof the diuretic therapy. Her condition graduallydeteriorated thereafter. Six further episodes ofright-sided hydrothorax occurred in the next ninemonths, and moderate oedema, ascites, and en-cephalopathy became intractable features. In May1976 she was readmitted and died in hepatic coma.

Pulmonary function tests

METHODSThe forced expiratory volume in one second andthe forced vital capacity were measured using alow resistance dry spirometer. Intrathoracic gasvolumes were determined by the helium dilutionmethod and the carbon monoxide transfer factor(TF) by the single breath technique (Ogilvie et al.,1957). Arterial 02 tension (Pao2), CO2 tension(Paco2), and pH were measured with appropriateelectrodes (Radiometer E 5046, E 5036 and G297). The 02 and CO2 electrodes were calibratedusing humidified gases of known composition andthe measured Pao2 was corrected for the 02 elec-trode's blood-gas factor (106) which had beendetermined by tonometry. Using standard tech-niques and calculations, described in detail else-where (Stanley and Woodgate, 1971), the alveolar-arterial 02 tension difference (A-ADO2) wasmeasured while she breathed room air. TheA-ADO2 was also measured after 15 minutesbreathing 100% 02 and the true shunt was deter-mined as a percentage fraction of the cardiacoutput assuming an arteriovenous 02 contentdifference of 29 vol %, which was the averagevalue in 12 other cases of cirrhosis with fingerclubbing (Stanley and Woodgate, 1971). Observedvalues were compared with predicted normalvalues for lung volumes and TF given by Cotes(1975), and with gasometric data previously ob-tained by the authors in healthy control subjectsusing the same techniques.

RESULTSPhysiological data obtained in November 1974when no pleural fluid was seen in the chest radio-graph are listed in Table 1. The lung volumeswere normal, which excluded any major restric-tive or obstructive ventilatory defects, but the TFwas very low. Arterial blood analysis showed severehypoxaemia in spite of a respiratory alkalosis. The

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Hypoxia and hydrothoraces in a case of liver cirrhosis

Table 1 Pulmonary function tests

Observed Predicted

Forced expiratory volume in one second (1) 2 5 2-5Forced vital capacity (1) 3-1 3-1Forced expiratory volume in one second 81% 81%

Forced vital capacityTotal lung capacity (1) 4-4 4-7Functional residual capacity (1) 1 9 2-4Residual volume (1) 1-3 1-6Transfer factor (mmol min- kPa) (ml min-'mm Hg) 4-0 (12-1) 8-2 (245)Arterial 0, tension (kPa) (mm Hg) 7-2 (54) 12-2 (92)Arterial CO2 tension (kPa) (mm Hg) 4-1 (31) 5-2 (39)Arterial pH 7-44 7 40Plasma bicarbonate (mmol 1-1) 20 5 24 5Alveolar-arterial 0, tension difference breathing room air (kPa) (mm Hg) 8-0 (60) < 3-3 (


Fig. 1 Monochromephotograph of a posteriorcolour scan of the trunk afterthe intravenous injection of99-technetium-labelledalbumin macro-aggregates. Theright lung (RL) has taken upfewer of the particles than theleft lung (LL), and theirpassage through abnormalintrapulmonary arteriovenouscommunications to the systemiccirculation is demonstrated bythe high count rates over thekidneys (K).

veins indicates the presence of arteriovenous ana-stomoses. After vascular injection the lungs wereinflated through the trachea with 10% formolsaline at a pressure of 4 5 kPa (45 cm H20) untilthe pleura was tense. After fixation the lungs wereradiographed and the preacinar arterial size wasassessed by measuring on the radiograph the inter-nal diameter of the largest artery in the lower lobeat 10 equal intervals along its axial pathway fromthe hilum to the periphery. Eight blocks of tissuewere then taken from each lung using a stratifiedrandom sampling technique (Dunnill, 1962), and

4 ,tm sections were cut and stained with Verhoff'selastic van Gieson. After a general histologicalassessment, a quantitative microscopic analysis ofthe small vessels was performed. The average dia-meters of arteries adjacent to respiratory bron-chioles and alveolar ducts were calculated. Asanother index of vessel size population countswere done on arteries less than 300 ,um in diameter(Hislop and Reid, 1972), whereby the relative in-cidence of muscular, partially muscular, and non-muscular vessels was determined in relation toarterial diameter. The total numbers of filled

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arteries and alveoli were also counted in a unitarea and expressed as a ratio of number of arteriesto number of alveoli. Control data were obtainedusing the lungs of four individuals who had diedwithout liver or lung disease. For further studyof small intra-acinar vessels random samples weretaken from the injected lungs and embedded inAraldite. Using an LKB III ultramicrotome andglass knives, 1 ,um sections were cut, which werestained with toluidine blue in 1% borax andstudied by light microscopy.The lung tissue which had been obtained soon

after death for electron microscopy was fixed in2 5% glutaraldehyde in cacodylate buffer for 2hours, postfixed in 1% osmium tetroxide, dehy-drated, and embedded in Araldite. Pale gold sec-tions were cut and stained with methanolic uranylacetate followed by lead citrate (Reynolds, 1963).

MACROSCOPIC AND RADIOGRAPHIC APPEARANCESDuring vascular injection many abnormal pleuralvessels resembling cutaneous spider naevi werefilled with the micropaque gelatin, as shown inFig. 2. The naevi were more numerous over theright than the left lung and provided a strikingcontrast with the vessel-free appearance of the

pleural surface after vascular injection of normallungs. There was no reflux of injected materialfrom the pulmonary veins at the hilum, suggestingthat no major arteriovenous anastomoses werepresent. Likewise no arteriovenous communica-tions or filling of large veins were visible on theradiographs; these also showed that the preacinararterial diameter was normal.

LIGHT MICROSCOPYThe lung architecture appeared normal and nodirect communications were seen between largearteries and veins. Nonetheless injected materialwas visible in some of the small veins, especiallyin the right lung, which were identified by theirperipheral position in connective tissue of theinterlobular septa and by the absence of an ac-companying airway (Fig. 3). The venous fillingdemonstrated the existence of arteriovenous ana-stomoses and was not observed in any of thecontrol lungs; its limitation to the small veins sug-gested that the anastomoses were at precapillarylevel. Another abnormality was dilatation of allintra-acinar arteries, and this was more pronouncedin the right lung, as shown by the results in Table2. Statistical comparisons showed that in each lung

Fig. 2 Macroscopic appearance of the right lung's pleural surface showing numerousspider naevi filled with micropaque gelatin.

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Fig. 3 Photomicrograph of a lungsection showing injection materialfilling an artery (A) adjacent to analveolar duct and also a small vein (V)in an interlobular septum. The venousfilling indicates the presence ofintrapulmonary arteriovenousanastomoses (Elastic van GiesonX55).

Table 2 Diameter (,gm) of small arteries categorisedby adjacent airway

Adjacent airway Left lung Right lung Control lungs

Respiratory 265 ± 100 321 + 120 178 + 30bronchiole (n = 28) (n = 49) (n = 55)

Alveolar duct 155 ±50 165 +56 88 ±17(n =51) (n = 64) (n = 95)

Values given as mean ±SD.

the mean arterial diameters measured at respira-tory bronchiolar or alveolar duct level were sig-nificantly greater than in control lungs (P


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Fig. 4 Arterial population counts. Percentagefractions of muscular (M), partially muscular(PM), and non-muscular (NM) vessels within arterialpopulations grouped by diameter are shown for thenormal lung (upper panel) and each of the patient'slungs (lower panel). Note the rightward shift of thecurves in the patient's lungs, which affects her rightmore than her left lung. This indicates that thetransition between each structural type of vessel isoccurring at an abnormally large diameter due topulmonary vasodilatation.

lagen (Fig. 7). As a result of these changes theminimum blood-gas distance was increased up to096 (+0 11 SEM) ,m compared with 053(+0-04) um in normal lung sections (P

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(c)Fig. 5 Photomicrographs of I gum sections: (a) Small artery showing normal wall thickness(injected lung); (b) Small vein with its wall thickened by amorphous material internal to the elasticlamina (injected lung); (c) Similar thickening is seen in walls of some capillaries containing red bloodcells (uninjected lung) (Toluidine blue X570).

ported by Kravath et al. (1971), and not in fourothers including the present case (Berthelot et al.,1966; Karlish et al., 1967; Silverman et al., 1968).Therefore shunting is rarely attributable tochannels between large vessels remote from a gasexchanging surface, except possibly in children;more usually it reflects small precapillary anasto-moses within the acinus. These may developthrough dilatation of some normal capillaries toprecapillary diameter or alternatively by the open-ing of anatomic precapillary anastomoses, whichmay exist in a non-functioning form in the normallung (Tobin, 1966; Niden and Aviado, 1956). Allintra-acinar vessels are capable of gas exchangedue to the proximity of alveolar gas (Staub, 1961),but °2 uptake is thought to be very slow in pre-capillaries (Sackner et al., 1964) and anastomosesat this level are likely to behave as shunts evenin hyperoxia. Not all hypoxic cases have pre-capillary anastomoses when studied at necropsy(Berthelot et al., 1966), but arterial unsaturation inliver cirrhosis may also be caused by ventilation-perfusion inequality without shunting (Cotes et al.,

1968), perhaps on the basis of airway closure dueto peribronchial oedema (Ruff et al., 1971). It hasalso been postulated that incomplete blood-gas°2 equilibration (partial shunting) may occur atcapillary level, since the intra-acinar vascular dis-order may cause extreme variation in diffusion-perfusion ratios (Schomerus et al., 1975).

Regional variation in shuntingIt was of additional interest that shunting appearedto be greater in the right than in the left lung.This conclusion was based on both lung scanappearances and pathological findings but was alsoconsistent with physiological observations that thePao2 rose when she lay on the left side and duringpartial collapse of the right lung after the diag-nostic pneumoperitoneum. Presumably gravita-tional effects in left lateral recumbency and thepresence of a right-sided pneumothorax improvedgas exchange by causing preferential perfusion ofthe more efficient left lung. The possibility ofleaving a permanent pneumothorax as a thera-peutic manoeuvre was considered but discarded

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466 N. N. Stanley, A. J. Williams, C. A. Dewar, L. M. Blendis, and Lynne Reid

Fig. 6 Electron micrograph showing thickened wall of a small vein (external diameter 40 gin).The thickening is due to collagen (co) interspersed with some fine filaments. Elastin (e) isalso present. Other features include a red blood cell (rbc), endothelium (end), basementmembrane (bm), part of a fibroblast (fb), and elastic lamina (el) (X 18 750).

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(1)Fig. 7 (a) Electron micrograph of an alveolar wall showing capillaries (cap) wi.th red blood cells(rbc). Note the thickening of the capillary walls (X5250). (b) Higher power view showing that thethickening largely consists of collagen (co). Endothelium (end), basement membrane (bm),alveolar space (alv), and epithelial cell debris (epf) are also indicated (X22 500).

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because, in spite of the increased arterial satura-tion, the respiratory stimulus of lung deflationmade her more breathless. Uneven distribution ofintrapulmonary shunting has previously beennoted in a cyanosed patient with active chronichepatitis whose perfusion scan and pulmonaryangiogram suggested relative localisation of intra-pulmonary shunts to the left lower lobe (Stanleyet al., 1972). Regional variation in the size anddensity of arteriovenous anastomoses may alsoexplain the differences betwen lobes in the timefor injected material to cross the pulmonaryvascular bed in the case reported by Karlish et al.(1967).

Pulmonary arterial dilatationThe morphometric analysis has provided the firstquantitative evidence that the pulmonary arterialtree is dilated in liver cirrhosis, which had beensuggested by Berthelot et al. (1966). Similar datahave been obtained in cases of fulminant hepaticfailure (Williams et al., 1976). The increasedcalibre of small peripheral rather than largecentral arteries contrasts with the picture in left-to-right shunting due to congenital heart defects,where large arteries dilate more than the smallones (Hislop et al., 1975). This supports the beliefthat a circulating vasoactive substance is primarilyresponsible for the pulmonary arterial changes inliver disease rather than passive distension to ac-commodate an increased blood flow. Pleural spidernaevi and precapillary anastomoses within the lungare presumably other manifestations of the pul-monary vasodilatation. Possible vasoactive sub-stances responsible for the circulatory changes inliver failure include reduced ferritin (Shorr et al.,1951), histamine (Martini et al., 1970), vasoactiveintestinal peptide (Said and Mutt, 1970), brady-kinin, and prostaglandins (Seymour et al., 1976).Identifying the most important among these mightassist in therapy if an appropriate pharmacologicalblocker could be given. Regarding the effect ofhistamine, trials of histamine H1- and H2-receptorantagonists did not cause significant changes inour patient's Pao2.

Vascular basis of reduced TFA reduction in TF is a consistent finding inhypoxic cases of liver cirrhosis (Cotes et al., 1968;Stanley and Woodgate, 1972). It occurs in alltypes of chronic liver disease and not just in caseswith a history of alcoholism or smoking, whichmay be independent causes of a reduced TF(Emirgil et al., 1974; Van Ganse et al., 1972). Itsaetiology has previously been obscure but, in our

patient, might be explained by the thickening ofthe blood-gas barrier, which must have slowedthe rate of carbon monoxide diffusion across thealveolar-capillary membrane. We have since dis-covered mural thickening of capillaries and smallveins, associated with arterial dilatation, in twoother patients who died of primary and secondarybiliary cirrhosis respectively, but not in 12 casesof fulminant hepatic failure reported elsewhere(Williams et al., 1976). Possibly the thickening wasa consequence of long-standing transmission ofabnormally high pressures to capillaries and veinsdue to arterial dilatation, analogous to the pro-gressive arterialisation of vessels distal to peri-pheral arteriovenous fistulae (Petrovsky andMilonov, 1967). Focal intimal thickening of ve-nous walls was also noted in two cases with smallpulmonary arteriovenous fistulae described byHales (1956), including one without liver disease.Alternatively, the venous and capillary changesmay represent a response to some unidentifiedtoxin or product of inflammation. Further studieswill be necessary to assess their nature andphysiological significance.

HEPATIC HYDROTHORAXCharacteristics and aetiologyIn a study of 200 consecutive cases of cirrhosis,pleural effusions were found in 6% (Johnston andLoo, 1964). Although sometimes small and bi-lateral, the effusions are frequently massive andunilateral with the right side involved morefrequently than the left. Frothingham (1942) re-ported a patient with massive recurrent effusionswho needed 211 thoracenteses with the removal of467 litres of fluid for the relief of dyspnoea. Thefluid has the characteristics of a transudate. Vari-ous factors may contribute to the formation ofhepatic hydrothoraces. Small effusions may bethe result of excessive pleural transudation due tohypoalbuminaemia (Higgins et al., 1947), hyper-tension in the azygos vein (Morrow et al., 1958),increased pressure in a thoracic duct overloadedby drainage of ascites (Dumont and Mulholland,1960), and passage of ascites through diaphragmlymphatics (Johnston and Loo, 1964). However,the sudden accumulation of a large, unilateraleffusion is now thought to be caused by directmovement of ascites under pressure across smalldefects in the diaphragm. Openings in the dia-phragm can usually be demonstrated by means ofa diagnostic pneumoperitoneum (Williams, 1950;Lieberman et al., 1966) and have been observedat necropsy in several cases (Emerson and Davies,1955; Lieberman and Peters, 1970). The defectsare probably created by the rupture of congenital

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0 1 2 3 4 5 6 7 8 9 10 11 12mm

Fig. 8 Thoracic surface of transilluminated diaphragm showing areas ofthinning within the central tendon.

sites of weakness. Although no openings werefound post mortem in our patient's diaphragm,there were many weak areas within the centraltendon which might have ruptured under moderatestress (Fig. 8).

TherapyThe formation of a hepatic hydrothorax decom-presses the abdomen, which may allow a dia-phragmatic opening to heal (Lieberman andPeters, 1970). Therefore thoracentesis should bereserved for diagnosis and relief of dyspnoea. sinceit may re-establish a large transdiaphragmatic pres-sure gradient and prevent healing. The principalaim of therapy should be the elimination ofascites because this is the source of the hydro-thorax. Often conventional medical treatment issufficient, but sometimes large hydrothoraces maybe a recurrent problem in spite of the intensiveuse of diuretics. Unfortunately, the potential valueof chemical pleurodesis in such instances cannotbe judged from the results in the present case,since failure to produce a long-lasting remissioncould be explained by an inadequate pleuralreaction to the sclerosing agent.

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