"CARDIAC" OR CONGESTIVE CIRRHOSIS OF LIVER *PAUL KoTuN, M.D., and E. M. HALL, M.D.

(From the Departments of Pathology of the University of Southern California School ofMedicine and the Los Angeles County Hospital, Los Angeles, Calif.)

Cardiac or congestive cirrhosis has long been the subject of confu-sion and controversy. Some seriously question the causal relationshipof chronic passive congestion to the cirrhotic changes found in theliver,1-3 while others doubt that the condition constitutes an entity.We desired further data on the pathogenesis of the lesion and its rela-tionship to various kinds of cardiac disease. What is the extent anddistribution of the hepatic fibrosis in relation to duration of cardiacdecompensation? What part, if any, does mercurial intoxication playin the hepatic fibrosis that accompanies chronic cardiac failure? Itseemed worth while, therefore, to review some of our necropsy recordsat the Los Angeles County Hospital with these questions and conceptsin mind.

METHOD AND MATERIALA review was made of 7,075 consecutive necropsies performed at the

Los Angeles County Hospital over a period of 4 years (1942-46). Allcases with the diagnosis of congestive heart failure were studied. Thosewith all other conditions that may have an association with hepaticfibrosis were eliminated. These included alcoholism, dietary deficien-cies, syphilis, chronic biliary disease, and neoplastic and parasitic dis-eases. There remained 605 cases, which provided our source material.From this group, those cases were selected in which clinically thepatients had had congestive heart failure associated with dependentedema. Seventy-eight per cent of them had been on digitalis for aminimum of 6 months. Bouts of failure alternating with periods ofcompensation were the most constant clinical features encountered.On gross examination the livers were usually smaller and firmer

than the average normal organ. The surface was smooth, pebbled, orfinely granular. The under surface often revealed pebbling or granu-larity when the upper surface was smooth. The cut surface at timesshowed purplish or brownish mottling due to marked chronic passivecongestion but often there was little evidence of chronic congestion.The liver always cut with some increased resistance.

All original microscopic sections were reviewed. All paraffin blockswere freshly cut and stained with Mallory's aniline blue and many

* Presented at the Forty-seventh Annual Meeting of The American Association of Path-ologists and Bacteriologists, Madison, Wisconsin, April Ig, I950.

Received for publication, August 14, 1950.

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KOTIN AND HALL

were stained by van Gieson's method. Microscopic changes of cen-tral lobular hepatic fibrosis were graded I, 2, and 3 plus on the fol-lowing basis.

Histopathologic FeaturesIn those livers in which the fibrosis was slight (i plus), there usually

was marked atrophy of the liver cells about the central veins withdilatation of sinusoids and pooling of blood. The central vein was thick-ened. Reticulum of the sinusoids was definitely thickened in the centralone-third to one-half of the lobule. Architecture of the lobule was onlyslightly disturbed (Fig. i).

In the instances in which the hepatic fibrosis was moderate (2 PIUS),in addition to the fibrous network about the central veins, irregularstar-shaped scars appeared in the mid- or peripheral parts of the lobules.Brush-like bands of fibrous tissue sweeping from central to peripheralareas might replace the star-shaped scars. In a few cases there was adiffuse connective tissue network throughout the lobule with some in-creased thickness of fibers near the center (Fig. 2).

In the more severely affected livers (3 plus), the fibrous tissue net-work about the center of the lobule was coarser and more of the lobulewas involved than in the 2 plus group. Fibrosis in the periphery waseither a network or in the form of fibrous bands. The portal spaceswere usually free but might be slightly enlarged. In the more severegrades within this group the fibrous tissue network involved wholelobules or groups of lobules. Heavier bands of fibers tended to criss-cross here and there. In heavily fibrosed areas periportal spaces mightbe included in the fibrous changes, but in clearer areas these were free,with central fibrous networks present (Figs. 3 and 4).The cases designated as i plus showed very little disturbance of the

hepatic architecture and probably should not be designated as cirrhosis.Cases classified as 2 and 3 plus showed more or less alteration of thelobular pattern due to fibrosis and may justly be classified under theheading of cirrhosis.

RESULTSOf the 6o5 instances of chronic cardiac decompensation, 62 were

found that met the criteria described. Thus io per cent of the patientswith long drawn out cardiac failure developed central and/or intra-lobular fibrosis of the liver. The ages of the patients varied greatly,the extremes ranging from io to 85 years. There was a slight increasein the number of males over females, but the ratio of males to femaleswas the same as in the larger necropsy group.

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CONGESTIVE CIRRHOSIS OF LIVER 563

The kind of organic heart disease resulting in congestive heart fail-ure was tabulated (Text-fig. I).

Rheumatic heart disease comprised 33 cases or 53.2 per cent of thewhole group. It totaled 9I per cent, or 2I, of the 23 cases under 50years of age. Mitral stenosis was a finding in 23 of the 33 cases. Un-complicated dilatation of the mitral ring was found in 4 cases. Hyper-

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Text-figure i. Distribution of 62 cases of congestive cirrhosis as to the type of organicheart disease present. Rheumatic cardiopathy comprised over one-half of the entire series.

tensive heart disease was the next largest group. Twenty-two patients(35.5 per cent) constituted this group. Arteriosclerotic heart diseasecomprised only 6 cases or 9.7 per cent. These patients presented noevidence of hypertension. A single case of congestive cirrhosis in afemale, 56 years old, was noted among the 24 patients with congenitalheart disease who died in congestive failure (4.17 per cent). Thelesion was a large interauricular septal defect measuring 3 by 5 cm.Of the 605 patients with chronic decompensation, 7 had chronic con-strictive pericarditis. Three of these developed congestive cirrhosis.Koletsky and Barnebee I found congestive cirrhosis present in 5 of 8cases of chronic constrictive pericarditis. Furthermore, the fibrosiswas greater in this group than in any of the other types of cardiacdisease.

Butt and Simonsen 5 reported considerable quantities of mercurypresent in the liver and kidneys of patients dying of congestive cardiacfailure when mercurial diuretics were administered over a long periodof time. We have, therefore, tried to correlate the quantity of mercu-

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KOTIN AND HALL

rial diuretic administered with the degree of hepatic fibrosis in patientswho received mercurial diuretics. For comparative purposes, medica-tion has been computed as metallic mercury. A definite history ofmercurial therapy was obtained in 46 of our cases. These were classi-fied on the bases of duration of therapy and of quantity of mercuryreceived. Seventeen patients received mercury for a period of 2 yearsor more; ii patients received mercury for more thaun i but less than2 years. The remaining i8 patients received mercury for less than iyear. In each group based on the degree of fibrosis as I, 2, or 3 plus,the known cases receiving mercurial therapy were arranged into groupsthat had (a) less than 5 gm. total mercury; (b) less than io gm. but

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Text-figure 2. Distribution of cases of congestive cirrhosis of each of the three grades ofseverity as to the amount of mercury administered in mercurial diuretics. There was nopositive correlation between the amount of mercury and the intensity of fibrosis.

more than 5 gm., and (c) those receiving over IO gm. The mercurialdiuretics used were salyrgan-theophylline (mersalyl, U.S.P.) and mer-cuhydrin (N.N.R.), both of which contain 39 mg. of mercury per cc.Text-figure 2 displays the results graphically. There appears to be nocorrelation whatsoever between the intake of mercury and the degreeof fibrosis.

COMMENTFrom these data it is evident that hepatic fibrosis of the central

lobular type may be noted as a finding subsequent to passive conges-tion of either short or long duration. The severity of the fibrosis, whilefollowing a loose pattern of relationship to length of decompensationand passive congestion, shows enough variation to make a definiteprediction hazardous as to extent of fibrosis on the basis of duration

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of cardiac failure. Cases having a history of decompensation for Y2 toio years were observed in all grades of fibrosis (Text-fig. 3).With rheumatic heart disease constituting the largest group (53.2

per cent) showing congestive fibrosis of the liver, and hypertensiveheart disease the second (35.5 per cent), these two occur in the sameorder as was reported by Koletsky and Barnebee.4 Arterioscleroticheart disease comprised a lower percentage (9.7 per cent) than mighthave been expected. Seven patients in our series had chronic constric-tive pericarditis but only 3 of these developed congestive cirrhosis.Others 4 have found this condition most effective in producing the moresevere grades of hepatic fibrosis. There was only a single case of con-

DUPATION OF DECOMPENS1ATIONIlTrEIW Of FRBROSIS

Text-figure 3. The intensity of fibrosis in congestive cirrhosis of the liver shows aninconstant relationship to the duration of decompensation.

genital heart disease showing congestive cirrhosis, representing but4.17 per cent of the total number of patients with congenital cardiacanomalies that died in congestive failure.

Wallach and Popper 6 have called attention to the central necrosisand atrophy associated with cases of congestive heart failure, empha-sizing certain characteristics, such as large central veins with widebranches piercing the walls. Although there is marked atrophy of livercells about the centers, these authors indicate that there are no frag-ments or remnants of cells such as are seen in acute hepatic necrosis.This probably is due to the great slowness of the process and theabsence of strong cytotoxic substances. We agree with the featuresdescribed by Wallach and Popper but would remark that in our casesthere was little or no evidence of actual necrosis while atrophy of livercells was a constant feature.

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The fibrosis in the early cases was always more marked about thecentral vein or the center of the lobule. It seems to begin as a thick-ening of the basement membranes of the sinusoids. The sinusoids areconsiderably dilated and filled with blood.

Bolton 7 produced chronic passive congestion of the liver in dogs bynarrowing the inferior vena cava between the liver and heart. Henoted dilatation of the sinusoids with "pooling of blood" in the centralparts of the lobule. He believed that stasis with consequent anoxemiawas responsible for the central fibrosis thus produced. In time, in-crease in periportal connective tissue was noted as well.That stasis exists in the livers of these patients with consequent

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Text-figure 4. When the weights of the livers were compared with the degree of fibrosis,it was found that the liver shows progressive decrease in weight as intensity of fibrosisincreases.

anoxemia is generally accepted. Anoxia of tissues in the central zonesof the liver lobules is most probably the cause of liver cell atrophy andof proliferation of the more hardy connective tissues. As the processadvances, in time all of the sinusoids in a given lobule may dilate, fol-lowed by increased reticular supporting tissue. With recurring boutsof cardiac decompensation over the years, spider-like scars and closelymeshed networks of fibrous tissue develop, finally involving the entireintralobular parenchyma. The periportal connective tissues also arestimulated in many of the livers and probably for the same reason, ageneral hepatic tissue anoxia (Text-fig. 4). We are well aware thatnutritional deficiencies exist in patients with chronic cardiac failure.Chronic congestion of the gastro-intestinal tract together with nausea

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CONGEPTIVE CIRRHOSIS OF LIVER 567

from digitalis therapy tends to reduce materially the food intake. Ifthis is a factor in congestive cirrhosis, the reaction in the liver is quitedifferent from that seen in dietary deficiencies due to alcohol.

In spite of the parenteral administration of considerable quantitiesof mercurial diuretics in 46 patients who had hepatic fibrosis of thecongestive type, no correlation was noted between quantities of mer-cury given and degrees of fibrosis.

SUMgARYA review of 7,075 consecutive necropsies performed at the Los Ange-

les County Hospital during I942-46 was undertaken as a clinicopatho-logic study of cardiac cirrhosis. Sixty-two cases of cardiac cirrhosiswere found among 605 cases of decompensation.Ten per cent of patients with chronic cardiac decompensation de-

veloped hepatic fibrosis. Rheumatic heart disease comprised 53.2 percent of the 62 cases. Hypertensive heart disease was present in 35.5per cent and arteriosclerotic heart disease in only 9.7 per cent. Threepatients with hepatic fibrosis had constrictive pericarditis.

Livers showing congestive cirrhosis may be of normal size but areusually smaller than normal. The surface is often pebbled or finelygranular and they cut with increased resistance. Microscopically thereis often central atrophy of marked degree with a thickened reticularnetwork in the central one-third or one-half of the lobule correspond-ing to the atrophied areas. In more advanced cases the fibrous net-work or brush-like bands occupy progressively greater amounts of theintralobular parenchyma. The central veins usually are thickened, attimes to a marked degree.The duration of cardiac decompensation varied from 4 months to

30 years and showed no constant correlation with the degree of fibrosis.Recurrent bouts of decompensation seemed to be more effective inproducing hepatic fibrosis. Anoxia due to stasis associated with chronicpassive congestion of the liver is considered to be the most likely causeof hepatic fibrosis. No correlation was noted between the quantity ofmercury administered in mercurial diuretics and the degree of fibrosis.

REFERENCESi. McCartney, J. S. Cardiac cirrhosis. (Abstract.) Am. J. Path., I949, 25, 769-

770.2. Lambert, R. A., and Allison, B. R. Types of lesion in chronic passive congestion

of the liver. Bull. Johns Hopkins Hosp., I9I6, 27, 350-356.3. Menne, F. R., and Johnston, T. W. Cirrhosis of the liver; its character and inci-

dence in 65oo autopsies. Northwest Med., I933, 32, 129-I37.

568 KOTIN AND HALL

4. Koletsky, S., and Barnebee, J. H. "Cardiac" or congestive cirrhosis. Pathologicand clinical aspects. Am. J. M. Sc., I944, 207, 42I-430.

Butt, E. M., and Simonsen, D. G. Mercury and lead storage in human tissues.With special reference to thrombocytopenic purpura. Am. J. Clin. Path., I950,20, 7I6-723.

6. Wallach, H. F., and Popper, H. Central necrosis of the liver. Arch. Path., I950,49, 33-42.

7. Bolton, C. The pathological changes in the liver resulting from passive venouscongestion experimentally produced. J. Path. & Bact., I9I4-I5, I9, 258-264.

DESCRIPTION OF PLATES

PLATE 10I

FIG. I. Photomicrograph of the liver of a Caucasian male, 78 years old, showingcentral lobular atrophy of hepatic cells with dilated sinusoids and thickenedstroma. Some central veins are obliterated, others show fibrous thickening.Spider-like spread of connective tissue from central to periportal areas (i plus).Mallory-Heidenhain stain. X 125.

FIG. 2. Photomicrograph of the liver of a Caucasian male, 85 years of age. Thisshows minimal fibrosis with central atrophy of liver cells and dilatation of sinu-soids. Central veins and sinusoidal basement membranes are thickened. Someperiportal fibrosis is present (i or 2 plus). Mallory-Heidenhain stain. X 125.

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FIG. 3. Photomicrograph of the liver of a Caucasian female, 39 years old. Thefibrosis here is markedly increased about the central vein and throughout thelobule (3 plus). Mallory-Heidenhain stain. X I25.

FIG. 4. Photomicrograph of the liver of a Caucasian male, I6 years of age. Heavybands of fibrous tissue pass from one lobule to another involving the intralobularhepatic tissue (3 plus). Mallory-Heidenhain stain. X I25.

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PLATE 102