Pathologic aspects of cirrhosis. A review.

REVIEW ARTICLE B

PATHOLOGIC ASPECTS OF CIRRHOSIS

Pathologic Aspects of Cirrhosis A Review Hans Popper, MD, PhD

THE PERIODIC REEVALUATION OF CIRRHOSIS in reviews such as this shows lingering disagreement about its clinical and pathologic significance. At one extreme, elimination of the term cirrhosis has been recommended 1 because it refers to a form of chronic inflammation for which no specific name is used for other organs. The term, however, has met the test of time, and in a recent book on liver disease 2 cirrhosis occupies the longest chapter. Moreover, its incidence in the Western countries is on the rise.3 This review, emphasizing pathologic problems, covers a) definition and classification to assist in diagnosis; b) etiology, important in therapy when the offending agent can be withdrawn; and c) pathogenesis to help in prevention by identifying the precursor stage.

Definition and Classification Discrepancies prevail in definition and classification between different textbooks and authors. They were only slightly relieved by the Havanna classification.' Recently, the International Association for the Study of the Liver has recommended a standard nomenclature of liver diseases which promises to becomne universally accepted." Its outlines are followed here. Basic Structural Features

Cirrhosis is characterized conventionally by a nodular parenchyma and widespread fibrosis, with hepatocellular necrosis sometimes listed as a third component. Cirrhosis is better described as the result of abnormal reconstruction of the preexisting lobular architecture. The two criteria which correlate best with the functional manifestations are parenchymal nodules and septa which link portal with central canals. Parenchymal nodules are round portions of the parenchyma surrounded by connective tissue which consist of portions of many lobules (Figure IA) or of one lobule (Figure 1B). (Acinus " is the more functional From the Stratton Laboratory for the Study of Liver Disease, Mount Sinai School of Medicine of The City University of New York, New York, New York. Address reprint requests to Dr. Hans Popper, Mount Sinai School of Medicine, Fifth Avenue and 100th Street, New York, NY 10029.

228

Vol. 87, No. 1 April 1977

CIRRHOSIS

229

designation, but since it is not widely used, it will not be applied here.) The parenchymal nodule may display normal architectural arrangements with single-cell hepatocytic plates, particularly when the nodules derive from the dissection of lobules by septa (passive nodules).7 Usually, it shows cytologic and more frequently architectural features of regeneration (regenerative nodule). Cytologic features are foci of enlarged hepatocytes with large, often polyploid, nuclei and multinucleate cells. The architectural features are hepatic plates which are two or more cells thick, as is normal in lower animals and in human embryos and is often maintained until the fifth postnatal year.8 They are recognized by position of nuclei on the sinusoidal surface (Figure 2A). Architectural changes persist longer than cytologic ones because of the long life-span of the hepatocytes. Increases in the width of the plates is associated with greater extension of the hepatocellular surface endowed with perisinusoidal microvilli.9 Architectural regeneration is uniform at the periphery of smaller monolobular nodules but is irregular throughout the multilobular nodules where multicellular plates border on single-cell plates which may be narrowed as a result of pressure (differential regeneration) (Figure 2B). This may be combined with variations in blood distribution. In monolobular nodules the plates converge on a new efferent vessel. In larger nodules, disturbance of blood flow may be reflected in hepatocellular iron in the central rather than in the peripheral zone. In histochemical stains, e.g., for glucose-6-phosphatase, the reaction product varies greatly within one nodule or in different nodules. With predominant hyperplasia, some speak of hyperplastic or adenomatous nodules, which are grossly succulent in appearance and of a uniformly different color from others (Figure 3A). This indicates a different chemical composition and a metabolic regulation independent from that of the entire liver. Nodules not surrounded by connective tissue, as seen in experimental animals on carcinogenic regimens or in nodular regenerative hyperplasia in man,'0',' do not indicate cirrhosis. Septa are connective tissue membranes of various widths.'2 They result from either collapse of preexisting parenchyma or formation of new connective tissue fibers. Septa are wide when they form after extensive collapse of lobular or nodular parenchyma (Figure 5A and B). They cause functional manifestations when they connect central with portal canals and contain vessels permitting short circuits of blood flow (Figure 3B and C). Focal nodules and septa-such as those in focal nodular hyperplasia (hamartoma),'3"l around focal lesions (such as primary and secondary tumors, abscesses, and granulomas), or in subcapsular location as result of

230

POPPER

American Journal of Pathology

subserous inflammation-may be confusing in interpretation of surgical wedge specimens.'5 A question of definition arises if a few nodules and septa are scattered diffusely throughout the liver following arrested chronic hepatitis of various etiology. The term cirrhosis should be applied when they are widespread. Relation of Cirrhosis to Chronic Hepatitis

Cirrhosis is a scarred end-stage of a chronic inflammation of the liver. The precursor stage is often designated as chronic hepatitis, sometimes modified by an etiologic designation. However, the term hepatitis is not always applied in metabolic disorders or in iron overload diseases. If the clinical, functional, and morphologic features of the hepatitis predominate, the diagnosis is chronic hepatitis with cirrhosis (or with transition to cirrhosis). If the features of cirrhosis and particularly its sequelae are in the foreground, the term cirrhosis is conventionally applied. While clinicians and pathologists previously spoke of decompensated cirrhosis in progressive stages. the emphasis is now placed on chronic hepatitis, particularly if the latter is the main target of therapy-symptomatic or withdrawal of the offending agent. In addition to chronic hepatitis without cirrhosis and chronic hepatitis with cirrhosis, there are instances of cirrhosis in which the precursor inflammatory lesion has subsided or is no longer detectable and a scar stage of variable extent is the presenting problem. Functional Effects of Structural Alterations Portal Hypertension

The drainage of blood from the liver is impaired by several factors which contribute in varying degrees to portal hypertension in individual cases.'6 Their clinical importance is identified by radiologic methods, particularly angiography and venography;'7 by measurement of portal pressure in the spleen, through the periumbilical vein, or by a transcutaneously inserted thin needle into the liver; and by measurement of hepatic venous pressure by wedging a catheter. The main factor which produces outflow block is compression of hepatic vein tributaries by regenerative nodules, which is more effective the smaller the nodules,18 or by fibrosis as in alcoholic liver injury.'9 A second factor is perisinusoidal fibrosis, the functional significance of which is difficult to distinguish from the first. The third is arteriovenous anastomoses in septa, which bring hepatic arterial pressure to bear on the portal vein. The fourth is portal tract scarring, and the fifth is the splenomegaly associated with cirrhosis which, accompanied by a


CIRRHOSIS

231

reduced splenic vascular resistance, increases blood flow to the liver while the liver scarring prevents expansion of its vascular bed. The first three factors raise intrasinusoidal pressure with a tendency towards ascites and hepatic failure, whereas the last two are presinusoidal and account particularly for the extrahepatic sequelae of portal hypertension. Any type, however, may cause phlebosclerosis 20 in the trunk and branches of the portal vein and thus create a vicious circle. Hemodynamic Alterations

These alterations result from three factors: a) Diversion of splanchnic blood from the liver by extrahepatic portosystemic anastomoses, which are best evaluated by radiologic procedures. Hepatic arterial flow is, however, increased, and the hepatic artery is enlarged and tortuous.21 b) Diversion of blood reaching the liver from the hepatic parenchyma by anastomoses in the septa between afferent branches of hepatic artery and portal vein and efferent tributaries of the hepatic veins.n'" They are demonstrated by postmortem injection preparations and by radiologic and scanning techniques."4 Their functional significance, originally doubted, has been substantiated by functional studies.2'27 The portal vein flow to the nodular parenchyma is particularly reduced, as is apparent by radiologic study. 17"2 The outflow block in advanced cirrhosis slows or even reverses the portal vein flow.2' c) Reduced efficiency of the intralobular microcirculation, caused by intrasinusoidal inflammatory cells, continuous basement membranes around the sinusoids,2' pericellular fibrosis,31 and lobular distortion. The hemodynamic alterations deprive the body of some of the liver function,' independent of the functional status of the hepatocytes. Hepatic insufficiency may thus develop on a circulatory basis alone. Moreover, intestinal bacteria may bypass the liver. This explains gram-negative bacteremia " or spontaneous peritonitis.' More frequent is endotoxemia, explained by vascular bypass as well as by inadequate function of Kupffer cells,-" which normally destroy such enterogenous toxins. Endotoxemia has been held responsible for many systemic manifestations of cirrhosis " such as hvpotension, leukocytosis, alteration of renal function, and some of the alterations of extrahepatic circulation (including increase of peripheral blood flow, cardiac output, blood volume, ventilation, and reduction of renal perfusion, arterial saturation, and peripheral vascular resistance, as well as vascular changes in the skin). Bacterial and some viral antigens bypassing the liver and reaching the lymphatic system alter the immune status independent of sensitization by hepatocellular antigens. This explains the hypergammaglobulinemia in cirrhosis, and its

232

POPPER


accentuation by shunt operations.38 Bypass also accounts for other systemic manifestations in cirrhosis, such as disturbance of hormone metabolism and faulty hepatic inactivation of gastrin.39 Although increase in peptic ulcers from shunts is not established, they are more frequent in cirrhosis.40 Since the hepatocytes require for their integrity only a fraction of the parenchymal blood flow, some diversion need not significantly impair hepatocellular function. However, if blood flow is further impaired by additional factors, such as gastrointestinal hemorrhage from varices or ulcers, or septicemia, hepatocellular necrosis develops in the center of lobules and nodules preceded by thinning of the plates or by steatosis (Figure 4A). Necrosis is grossly apparent by dark discoloration of the nodular center. This should be distinguished from a diffuse color variation of the nodules. Histologically, eosinophilic necrosis is accompanied by loss of cells replaced by macrophages intermixed with granulocytes. The differential diagnosis of necrosis from other causes is seldom difficult. This necrosis may cause death but, being rare in biopsy specimens, accounts but little for self-perpetuation; it is the morphologic substrate of hepatic failure following shunt operations. The alteration of hepatic circulation is not only the key feature of cirrhosis but also the main target of its therapy and thus justifies the term. Additional features accompany, or are caused by, the altered hepatic circulation. They include: a) reduced functional mass of hepatic parenchyma is recognized even in enlarged livers in which the blood flow may be decreased.4' b) increase of hepatic lymph flow results primarily from postsinusoidal portal hypertension.42 The thoracic duct is engorged and sclerotic 4' and the hepatic lymphatics are dilated.44 Alterations of the serosal surface in association with ascites were visualized in experimental cirrhosis.45 Ascites is caused not only by increased lymph flow but also by excessive exudation from peritoneal capillaries due to sodium sequestration caused by altered hormone metabolism in the liver. Hypoalbuminemia may also play a role. The different contributions of these factors influence therapy of ascites in cirrhosis. c) alteration of the bile flow occurs in two directions. Increased sinusoidal pressure favors excess secretion of bile of reduced concentration.46 In both human and experimental cirrhosis the intrahepatic bile duct system is tortuous and increased in weight.47 Moreover, cholestasis may occur on either a mechanical or a chemical basis. The former results from periductal scarring, especially in the biliary forms. The nature of the latter is not established (intrahepatic cholestasis).48 It is sometimes accentuated

CIRRHOSIS


233

focally in hyperplastic portions of nodules. Prolonged cholestasis may lead to excess deposition of copper, mainly in periportal distribution,4' e.g., in biliary cirrhosis, in other types of cholestatic cirrhosis, and in that associated with a-l-antitrypsin deficiency.'5 Whether the excess copper deposition contributes to liver cell injury and calls for therapy remains to be established. d) Excess iron storage in periportal hepatocytes develops sometimes spontaneously and more frequently after shunt operation;5' it may be explained by increased arterial blood flow. The actual incidence is controversial, and only rarely do the functional consequences of iron overload become a problem. Cirrhosis is conventionally considered an irreversible scar stage. However, the irreversibility is in dispute. The turnover of collagen fibers suggests the possible regression of septa. Thinning and even disappearance of septa and relobulation of nodules has been observed in experimental studies.5' In man, regression of cirrhosis of iron overload type has been described." Aatomic iand Fucl

aficaton

Establishment of the presence of cirrhosis is clinically far more useful than its classification, which mainly serves epidemiologic comparisons. Except for an etiologic designation there is little agreement,"55J because different pattems may be seen in the same liver and these pattems are not necessarily specific. Moreover, one anatomic form may change into another during the course of the disease, e.g., in alcoholic liver disease micronodular cirrhosis can become macronodular."O Steatosis, though more frequent in some types, may secondarily develop in any. Table 1 lists some of the many terms in use. A simple anatomic classification based on minimal criteria is recommended 5 and lends itself also to morphologic statistical analysis:' 1. Micronodular cirrhosis is characterized by nodules of equal size, up to 3 mm in diameter, associated with septa up to 2 mm in diameter and Table 1 -Examples of Synonyms Used for Anatomic Types of Cirrhosis Recornmended term Mainly micronodular Mainly macronodular Laennec Synonyms Podtnecrotic Portal Regular

Irregular

"Nutltional"

With

Wthout

"postnecrotic"

"posthepatitic"

Japanese A

Japanese B

Extensive collapse

234

POPPER


usually of equal width. The pattern suggests a uniform process (Figure IB). 2. In macronodular cirrhosis the size of the nodules varies; many are more than 3 mm and some up to 3 cm in diameter. They are often composed of many lobules. The irregular septa vary in width and are often broad after collapse of multiple lobules and nodules (Figure IA). The liver may be conspicuously deformed, particularly in the left lobe. This pattern suggests either irregularity of the preceding injury or sustained regeneration. Either form may be found in an enlarged or in a small shrunken organ, without significant correlation to the clinical picture, to the functional parameters, or to the degree of regeneration reflected by the histologic evidence. In addition, an incomplete septal cirrhosis is recognized in which the regeneratory features are not conspicuous in large or smaller nodules, but septa traversing the parenchyma are prominent. Some end blindly and do not link central and portal canals (Figure 4B). The weakness of anatomic classification is illustrated by the frequent use of the term mixed macronodular and micronodular cirrhosis. Functional Classification

A functional classification, useful in staging, should take into consideration63'64 a) degree of development; b) activity indicating tendency towards progression, which depends mostly on the activity of the attendant chronic hepatitis as reflected by hypergammaglobulinemia, and by inflammation and cell necrosis on the border of the parenchyma towards portal tracts and septa (piecemeal necrosis); c) degree of hepatocytic alterations (steatosis, hepatitis, cholestasis) as the basis of presenting hepatic symptoms, indicated by liver function tests; and d) presence of complications (portal hypertension and its sequelae, ascites, hemorrhagic diathesis and encephalopathy). Liver biopsy is required for the evaluation of the first three considerations, although its usefulness in prognosis is limited. Diagnosis of Cirrhosis by Liver Biopsy

This is important because of the unreliability of the clinical and laboratory manifestations and their absence in latent cirrhosis.65 Blind needle liver biopsy is applied widely, particularly where laparoscopy is sparsely used. Despite occasional sampling errors because of cylinders obtained from large nodules with seemingly normal architecture or because of deflection of the needle from portal and septal tissue, the diagnoses based on or supported by liver biopsy have been found reliable in statistical


CIRRHOSIS

235

studies." Sampling errors are more significant in the comparison of repeat biopsy specimens during monitoring of therapy. Connective tissue stains increase the diagnostic accuracy. The following criteria indicate cirrhosis with decreasing certainty: 1) nodules surrounded by septa with or without portal and central canals (in fibrosis a parenchymal portion near portal tracts mav sometimes appear round); 2) hepatic vein tributaries in contact with septa; 3) connective tissue septa linking central with portal canals, particularlv when bent or zigzag; 4) fragmentation of specimens into round pieces surrounded in more than half of their circumference by thin layers of connective tissue; and 5) irregularity of architecture including a) circumscribed variations in size of hepatocytes and thickness of cell plates, b) abnormal spacing of vascular channels, c) excess of hepatic vein tributaries over portal tracts, especially if the latter are small, and d) in adults, paucity of centrolobular lipofuscin pigment in newly formed hepatocvtes. Conditions Resembling Cirrhosis

The proposed criteria exclude some conditions often designated as cirrhosis. They include: A. Precirrhotic stages: 1) precursor stages in biliary cirrhosis, either primarvy or obstructive," in both of which cirrhosis only develops in the latest stages and is thus seen at autopsy, 2) congestive fibrosis before nodule formation and hnking septa have developed," 3) fibrosis from sarcoidosis,70 and 4) central hyaline sclerosis in alcoholic liver injury.71 In the first three, presinusoidal portal hypertension may be a problem, but ascites, if present, is not hepatic. The fourth has sinusoidal portal hvpertension with tendencv to ascites before nodules appear.19 B. Hepatic fibrosis with portal hypertension on presinusoidal basis (in most the flow in the portal vein tributaries is compromised and possibly arterial flow is augmented): 1) Schistosomiasis producing portal lesions on immunologic basis." (In some countries this, the most common form of portal hvpertension in the world, is associated with cirrhosis, possible due to additional causes.) 2) Biliarv dvsplasias, encompassing hamartomatous lesions involving biliarv ductal epithelium, with manv transitions between them, include Meyenberg complexes, hepatic cysts, focal dilatation of the intrahepatic bile ducts (Caroli's disease), choledochal cysts, and congenital hepatic fibrosis. (The last73 resembles cirrhosis because of the excessive portal fibrosis separating nodular portions of normal parenchvma. The uniform separation of hepatic vein tributaries from the fibrotic areas, excess arteries, and bile precipitates in abundant ductules lined by cuboidal regular epithelium in the absence of jaundice are diagnostic criteria.) 3) Hepatic fibrosis associated with exposure to envi-

236

POPPER


ronmental agents such as Thorotrast, inorganic arsenicals, and vinyl chloride leads only exceptionally to cirrhosis. (Both portal and hepatic vein pressure may be elevated. The fibrosis proceeding to angiosarcoma is associated with nodules in which both hepatocytes and sinusoidal cells are hyperplastic but which are not demarcated by connective tissue.74) 4) Reversible pericellular fibrosis from hypervitaminosis A.75 5) Radiation fibrosis. 6) Gaucher's disease.76 and 7) Partial nodular transformation.77 Presinusoidal portal hypertension may cause additional hepatic fibrosis (Banti's syndrome). This is also true for other causes of presinusoidal portal hypertension such as myeloproliferative diseases with splenomegaly, arteriovenous fistulae, and extrahepatic portal vein thrombosis, as well as those designated as idiopathic portal hypertension. C. Acute submassive necrotic hepatitis exhibits, following collapse of necrotic parenchyma, bridges which by dissecting the lobules create a resemblance to cirrhosis, particularly in autopsy specimens. The absence of a roundness of the nodules and, more important, the sharp demarcation of portal tracts seen with connective tissue stains should prevent misdiagnosis (Figure 5A). This is important in legal/medical problems when preexisting disease is claimed in fatal acute hepatic insufficiency. Etiology

In many forms of cirrhosis the etiology can be established or is strongly suspected. But since the same etiologic factor may not cause cirrhosis in another person, additional contributing, mostly host, factors are required. This is similar to the situation in infectious diseases, where doubts about etiology are not as frequently raised. The etiologic features, primarily in the precursor lesions, are the key to an etiologic classification and therefore will here receive emphasis for morphologic differential diagnosis. Treatment by corticosteroids and other antiinflammatory agents may obscure inflammatory features of diagnostic significance; moreover, at autopsy the inflammatory reaction may be subdued. Alcoholic Cirrhosis

It is estimated that only 10 to 30% of alcoholics develop cirrhosis.78 Recently, dose and time dependence was described.79 Studies in baboons have established that ethanol intake even with adequate diet produces cirrhosis.80 This resolves the long-standing argument about the cirrhogenous potential of ethanol. In the early stages, a large micronodular cirrhosis with steatosis prevails, whereas later, large nodules and broad septa predominate.59 The most useful diagnostic feature is the alcoholic


CIRRHOSIS

237

hepatitis,78 initially centrolobular, characterized bv hydropic hepatocytes containing also mans large fat droplets, single-cell necrosis, and intralobular inflammatorv cells, mainlv neutrophilic leukocytes. These hepatocvtes may also contain alcoholic hvalin of Mallorv, finely fibrillar on electron microscopv. It consists of intermediate-sized fibrils.8" They supposedlv result from an antitubulin action of ethanol comparable to that of colchicine.82 Such an effect also explains the retention of proteins normally secreted by the liver even in excess of the retained fat." Excess fibers form in the centrolobular zone with rapid deposition of dense collagen, resulting in early development of postsinusoidal portal hvpertension."9 The centrolobular process extends bridge-like to the portal areas, which then develop inflammation. Proliferated ductules and also arterioles extend into the bridge, which becomes extensively sclerotic with approximation of central and portal zones." Bile ductules in previous central zones account for the term portal cirrhosis in a lesion which begins central. Additional portal-to-portal connections and sometimes massive necrosis of whole lobules account for the disorganization of the lobular architecture which may develop rapidly. In later stages, Mallor-'s hyalin is seen in the peripherv of nodules. The increased incidence of alcoholic hepatitis in recent years and the recognized pathwavs between it and cirrhosis led to the assumption that alcoholic hepatitis is the essential precursor to cirrhosis. This ignores the often insidious development of cirrhosis. However, three-dimensional reconstructions ' as well as newer studies on human and experimental material " suggest a second, slower process of deformation of the liver; namely, formation of septa radiating from the center, from the portal tracts, and within the parenchyma which join and dissect the parenchvma. Pericellular fibrosis is accompanied by only a few acute inflammatorv cells, but by many lipocytes and foci of PAS-positive macrophages within parenchyma and portal tracts, possibly as result of excess extracellular lipids (fat granulomas and fatty cysts). This is consistent with the fibrogenic effect of alcohol 8"'8 and the diffuse pericellular fibrosis in florid cirrhosis. Diagnostic features for alcoholic etiology of cirrhosis are a) alcoholic hvalin (which is diagnostic only if centrolobular, while peripheral deposition occurs in primary biliary cirrhosis and other cirrhoses associated with cholestasis, Wilson's disease, Indian childhood cirrhosis, and hepatocellular carcinoma;89 in disintegrating nodules in any type of cirrhosis, Mallory bodies may be seen); b) large droplet steatosis, c) relative integrity of portal tracts, d) pericellular fibrosis, e) hvpocellular centro/portal bridges, and f) fat deposition wvith or without granulomatous reaction in portal tracts (sometimes pointing to a preceding steatosis, but also caused by intake of mineral oil).

238

POPPER


Cirrhosis Following Viral Hepatitis

It is disputed whether and with what frequency viral hepatitis leads to cirrhosis 9 which is often macronodular. Recent evidence supports this evolution in Type B and in Type not-A-not-B, but not in Type A hepatitis. It is seen more frequently in older people and particularly in the presence of abnormal Y-globulins. It appears to be rare in the younger drug addicts despite their lack of hygiene. The etiology is difficult to prove even if histologic manifestations of viral hepatitis are present because of their lack of specificity. Components of hepatitis antigen or antibodies in serum or liver 91 are strong indicators but do not provide absolute evidence. Whether other infections such as syphilitic or parasitic disease cause cirrhosis is not established. Chemically (Drug) Induced Cirrhosis

An example of predictable-meaning dose-dependent-drug reactions is cirrhosis which follows prolonged methotrexate treatment, a risk accepted in malignant tumors including lymphoma, but unacceptable in nonmalignant diseases such as psoriasis. The precursor fibrosis can be recognized more readily by biopsy than by hepatic function tests.92 The lesion shows steatosis, hyperplasia of hepatocytes with eosinophilic cytoplasm, predominant portal involvement, and sparsity of inflammation. Cirrhosis following intoxication by poisons is rare in man. Nonpredictable drug reactions 3 producing chronic hepatitis such as after prolonged intake of the laxative oxyphenisatin,94 the antihypertensive drug amethyldopa,96 and the antibacterial nitrofurantoin," and possibly, the antituberculous isoniazid 9' entail the risk of cirrhosis whereas drugs producing massive necrosis, such as halothane and monoamine oxidase inhibitors, seldom cause it. Obstructive Biliary Cirrhosis

This follows prolonged extrahepatic biliary obstruction.68 Biliary infection is of questionable significance. At the onset the lesion is predominantly periportal. A focal biliary cirrhosis develops in adolescents with cystic fibrosis following obstruction of dilated bile ductules by inspissated PAS-positive material.98 Congestive Cirrhosis

Prolonged cardiac failure, particularly in tricuspid insufficiency and constrictive pericarditis, results in septal extensions of the mainly centrolobular fibrosis to the portal tracts and eventually can lead to cirrhosis.69 It also follows hepatic vein disease (Budd-Chiari syndrome) including congenital webs in the major hepatic veins."


N

CIRRHOSIS

239

Hepa cirdmis

Whether malnutrition alone produces cirrhosis in man remains in doubt despite the major importance of nutritional factors 100 contributing to cirrhosis from other causes. Three conditions with suggestive malnutritional features are associated with histologic lesions identical to alcoholic hepatitis and cirrhosis: a) intestinal bvpass operation for obesitv,"'0 b) severe steatosis mainly in obese women with diabetes or on estrogen therapv,"02 and c) abetalipoproteinemia.'03 In the first two, however, incidental alcohol abuse has not been totallv excluded. Cirrhsis From Iron Overlad (I

1)uchdomatis)

The iron overload may result from an inbom error (primary hemochromatosis) or from acquired alterations of the iron metabolism such as faulty red cell formation (blood dyscrasias), chronic liver disease, or excess iron supply in blood transfusions, medications, alcoholic beverages, and cooking utensils.5-",' Cirrhosis fullv develops only in genetically determined anemias (thalassemia '0 and pvridoxine-dependent anemia 106). It is probable that excess iron storage damages the hepatocytes and stimulates fibrogenesis.'O0 Most iron overload cirrhoses show little inflammation. The architectural pattern varies although micronodular features are common. Iron overload as sole cause of cirrhosis can be distinguished only in early stages when iron excess precedes fibrosis and the diagnosis becomes a problem at autopsy.'07 Cirthsis on HereditaryB

Most cirrhoses of this type are the result of inborn errors of metabolism (in addition to hemachromatosis). Wilson's disease reveals transition from chronic hepatitis to cirrhosis with excess copper demonstrable in hepatocytes in variable distribution and frequent vacuolated glycogen nuclei.'"6 The diagnosis, however, depends on the demonstration of abnormalities of copper metabohism.'09 a-l-Antitrvpsin deficiency is suggested by PAS-positive, diastase-resistant globules of variable sizes, up to 4 j in diameter, in hepatocvtes close to portal tracts and septa, and also in ductules and macrophages.5 "'0 The septa may have a hvalinized core. The definitive diagnosis depends upon immunologic demonstration of the serum protease inhibitor in the liver or of its decrease in the serum."' Many homozygotes (rarely heterozygotes) develop usuallv transient neonatal cholestasis, a few develop cirrhosis in childhood, and even fewer develop cirrhosis later in life 112 that is associated with emphysema "1 and tendency to carcinoma formation."0 It seems to be the most frequent cause of childhood cirrhosis. The defect involves either synthesis of a protein form not readilv transported or, less probably, a defect in glv-

240

POPPER


cosyltransferase essential for secretion of the protein.114 Galactosemia," 5 glycogenosis Type IV,"16 tyrosinemia,117 and hereditary fructose intolerance 118 produce infantile cirrhosis preceded by steatosis and are identified by the enzyme defect. Many other instances of infantile fatty cirrhosis may belong to this group but have enzyme defects that are yet to be discovered. Other hereditary familial cirrhoses are of unknown nature: a) cirrhosis with Osler's hereditary hemorrhagic telangiectasia,119 in which the hepatic scar tissue contains dilated vessels, and b) familial cirrhosis of various types, usually juvenile. 120 The role of genetic factors in cirrhosis of any etiology is not established. The evidence is either anecdotal or based on blood group studies suggesting predominance of Type A.121 Multifactonal Cirrhosis

In any type of cirrhosis there may be several causative factors and some deserve listing: 1) inflammatory bowel disease, particularly chronic ulcerative colitis, in which pericholangitis, nutritional disturbances and incidental transfusional hepatitis may be responsible for 2 to 5% of patients having cirrhosis; 122 2) alcohol abuse and viral hepatitis; 113 and 3) congestive heart failure superimposed on an alcoholic cirrhosis. Cirrhosis of Unknown Etiolog

Some cirrhoses of unknown etiology have a characteristic morphologic evolution. 1. Cryptogenic cirrhosis is the common form of cirrhosis without known etiology 124 but with a similarity to cirrhosis of hepatitis. Since the discovery of hepatitis B antigen, many cases have been transferred to the viral hepatitis group, particularly in developing countries.125-127 One subgroup, more frequent in women at the beginning and end of their reproductive period, has excessive hypergammaglobulinemia associated with abnormal serologic reactions, immune markers (smooth muscle or nuclear antibodies, LE reaction), HLA antigens,128 and systemic manifestations, and is designated by many terms, including lupoid hepatitis.129,130 2. Primary biliary cirrhosis is the fourth and last stage of an evolution starting with chronic nonsuppurative destructive cholangitis.67"31 The manifestations of the latter, often still seen in the cirrhotic stage, are the most reliable diagnostic criterion in addition to the paucity of bile ducts. Cirrhosis in sarcoidosis may resemble primary biliary cirrhosis.132 Whether the alterations of the immune reactivity or of the bile acid metabolism are primary or secondary remains to be established. This is also true for the rare cholestatic cirrhoses in children, including Byler's disease.'33'134

Vol.87,No. 1 April 1977

CIRRHOSIS

241

3. Indian childhood cirrhosis after a toxic hepatitis between the ages of 1 and .3 has a noncharacteristic end-stage with abundant Mallory's hvalin.'35 4. Obstrujetive infantile cholangiopathy ''""3 covers neonatal giant-cell hepatitis and intrahepatic or extrahepatic biliarv atresia and hvpoplasia. sometimes terminating in cirrhosis with features of a chronic biliarv obstruction. Some of the children have a-1-antitrypsin deficiency.'37 Anatomic Clustering of Etologic Forms

The cirrhoses commonly seen in adults at autopsy form groups w%hich are the basis of most anatomic classification systems: a) mainly mixed macronodular and micronodular cirrhosis related to viral hepatitis, nonpredictable reactions to drugs, and cryptogenic forms; b) fatty, usually hepatomegalic, cirrhosis with micronodular pattern following alcohol abuse, intestinal bypass operations, and prolonged methotrexate therapy; and c) the usually deep green livers of primary and obstructive biliary cirrhosis. Paftogenesis Despite the often known etiology, the pathogenesis of cirrhosis is a puzzle in almost all forms. This includes the committed precursor stage which separates the tendency to morphologic restitution from progression to the life-threatening disease, sometimes arrested with scarring. This stage identifies the patient at risk.32 Since with almost all known etiologies only a fraction of cases reach the committed precursor stage, host factors enter the pathogenesis. While cirrhosis usuallv develops slowlyr and insidiouslv. the transition in both alcoholic and viral hepatitic forms may be rapid,.' as short as 5 months. Hepatocellular necrosis, inflammation, regeneration, and fibrosis are the main processes, all of which are interrelated.

Heptolar Neois Causative factors, topography, and extent permit classification of hepatocellular injury progressing to necrosis in cirrhosis. It is the substrate of the presenting abnormalities of hepatic test results. Causative factors are: 1) Direct action of the offending agent or its metabolites, exemplified by ethanol, other chemical toxins, and metals. Their effects can be distinguished by characteristic appearance including the associated inflammatonr reaction. 2) Immunologic hepatocellular injury, now increasinglv substantiated. In hepatitis B the surface component of the antigen incorporated in the cell membrane is attacked by sensitized lymphocytes

242

POPPER


in cooperation with circulating antibodies.139 "40 Lipoproteins of the hepatocytic cell membrane are the target of cell-mediated immune attack by processes still to be clarified.14' Thus, exogenous or endogenous hepatocellular membrane antigens may be involved in hepatocellular necrosis and the associated inflammation.142 An altered immune status may prevent the clearing of the cells containing such antigens and thus render the process chronic. 143,144 Also in alcoholic liver disease, immune processes against either altered hepatocytic membrane components 14 or the filamentous aggregates of alcoholic hyalin 146 are incriminated. This explains features of chronic hepatitis not characteristic of alcoholic liver injury and the occasional perpetuation after alcohol withdrawal. 3) Anoxic injury caused by disturbance of the circulation inherent in cirrhosis and by encircling fibrosis of hepatocytes. 4) Cholestatic liver injury,48 reflected in feathery degeneration and often localized in portions of a nodule. The frequent destruction of the entire nodules is produced by a combination of the last two. 5) Enzyme deficiency in inborn errors of metabolism may account for steatosis or necrosis. Rappaport's acinus concept 6 assists in evaluation of the extent of necrosis. He assumes that a simple liver acinus arranged around a triangular terminal portal tract forms part of a lobule, with its periphery designated as Zone 3; the central vein is localized here. At least three such simple acini combine to form a complex acinus which includes a sleeve of parenchyma around the preterminal portal tract. Several such complex acini with their supporting structures form acinar agglomerates. This arrangement, demonstrated also by vital microscopy, determines parenchymal blood flow and oxygen concentration, with Zone 1 around the portal tracts receiving first both portal vein and hepatic arterial blood. Zone 3, farthest away, is most susceptible to injury because of reduced oxygen tension and enhanced formation of metabolites in the microsomal biotransformation system which is more concentrated in this zone. Glucuronization is more effective in Zone 1 and assists in detoxification. Injury in Zone 3 is initially pericentral if only one acinus is involved and subsequently becomes starfish-shaped by connecting central fields. It eventually extends towards the portal tracts between acini. This creates bridges which the classic nomenclature designate as portocentral. Acinar remnants regenerate to become nodules. The acinar concept also facilitates the understanding of the topography of necrosis which may be followed by collapse and fibrosis. The necrosis may thus be 1) focal; 2) in Zone 1 (central), eventually assuming the starfish shape; 3) in Zone 3 (periportal) leading to apparent enlargement of the portal tracts and, if extensive, creating portoportal "bridges" al-


CIRRHOSIS

243

though they actually represent only a widening of the portal tract system; and 4) confluent with subdivisions such as a) extensive focal necrosis, b) portocentral bridging,'47 and c) massive or submassive elimination of all or most hepatocytes of a lobule. The forms of necrosis mentioned in points 1, 2, 3, and 4a allow restitution with normal regeneratory capacity except when thev are so severe that parenchymal areas are disjoined from normal blood supply and undergo transformation to nodules. By contrast, in points 4b and 4c, restitution is impossible because of collapse. Short circuits between afferent and efferent blood supply develop if sinusoids are transformed to veins and arterioles grow into the collapsed bridge. Collapse mav be primary, after necrosis of lobules (Figure 5A), or secondary, if involving nodules. The former shows normal spacing of central and portal canals and histologically a sharp border between preformed portal tracts with thick collagenous bundles and collapsed parenchyma with wavy collagenous membranes; secondary collapse shows abnormal vascular spacing and persistence of small parenchymal nodules and histologicallv no demarcation of the original portal tracts are seen (Figure 5B). Primary collapse involving significant parts of the liver, such as the left lobe or extensive subeapsular areas, is more frequent after viral hepatitis or in crvptogenic cirrhosis, while in alcoholic cirrhosis scattered and irregularly outlined areas of secondary collapse are common.' lnfanwnabo

Inflammation in cirrhosis may be a) a reaction to hepatocvtic injurv and stimulated bv breakdown products of dead cells or shed portions of surviving cells (apoptosis '¶), b) an immunologic process, and c) a result of stimulation by the offending agent. The location of the inflammation determines the evolution. Portal inflammation characterizes chronic persistent hepatitis 15""1' which has little tendencv to progression except if associated with lymph follicles or bile duct injury.152 Periportal inflammation may represent a spilling over of exudate into Zone 1. It becomes significant if a sleeve of parenchvma in this zone becomes necrotic to cause an apparent widening of the portal tracts in which scattered trapped hepatocytes persist, often in acinar or rosette arrangement. They may act as a nidus for continued inflammation on immunologic basis, particularly if they proliferate. Increased arterial blood supply to Zone 1 may accentuate the immunologic reaction and explain the zone's vulnerability. Formation of a new limiting plate demarcating the necrotic portion of Zone 1 from the remaining parenchyma creates the impression of widened portal tracts. Connective tissue stains

244

POPPER


distinguish this incorporation of collapsed Zone 1 parenchyma as observed in chronic active (or aggressive) hepatitis 150 from enlargement of the portal tract itself as seen in chronic persistent hepatitis or in early biliary disease. Intralobular inflammation is related to liver cell injury except in primary biliary cirrhosis; renewal of hepatocytes usually permits restitution except when exposed antigens persist in the cell membrane. Inflammation with confluent necrosis, both in porto/central bridging or in the massive form, has the most prognostic significance. When in massive or bridging collapse all hepatocytes with the accompanying inflammatory reaction are removed, either a narrow bridging septum or a broad area of collapse develops; both these have little functional consequence even if the latter is extensive.1"3 Cirrhosis seems not to follow single bouts of massive necrosis. By contrast, incomplete collapse with persisting hepatocytes surrounded by lymphocytes reflect a trend to progression, as observed in follow-up studies on chronic active hepatitis.147'154 Inflammation surrounds actively proliferating ductules or hepatocytes in pseudoductular arrangement. In this setting, segmented leukocytes need not indicate a bacterial infection. Thus, persisting hepatocytes in a collapsed zone or proliferating ductules are mechanisms for the spread of inflammation through the parenchyma. Histologic evaluation of the inflammation in cirrhosis and in its precursor stages is at present the most reliable indicator of prognosis. Inflammation is also the target of therapy by steroids or other "immunosuppressive" agents.155 Regeneration

Both reduced function and death of hepatocytes stimulate proliferation of a) hepatocytes either as nodules or as pseudoductules (Figure 5A), b) ductules, and c) sinusoidal cells. Hepatocellular regeneration restores lost parenchyma, but where parenchymal portions are disconnected from portal venous blood supply, they may become irregular and hyperplastic. This may reflect not only altered hemodynamics but also changed supply of hepatotrophic substances in the pancreatic blood, which contains hormones of which insulin and glucagon are examples.'56 Better information about their mechanism may assist in regulating abnormal regeneration. Age, nutrition (particularly vitamins), and anemia influence regeneration. The functional capacity of the nodular regenerates is not established. Most information derives from analysis of neoplastic nodules in animals on carcinogenic diets 157 in which DNA synthesis is far more active than in cirrhotic nodules.'58 The smooth endoplasmic reticulum is usually in-


CIRRHOSIS

245

creased, and microsomal biotransformation of drugs is therefore barely inhibited in stable cirrhosis despite the bypass of blood. The greater susceptibility to psychopharmaceuticals in cirrhosis is therefore not explained by hepatic processes. Nodules grow and, to conclude from experimental animal studies,1" this may be followed by ingrowing of bile ducts as well as branches of hepatic arterv and portal vein, to form portal tracts which initiallv are small (Figure 5C). Eventually, full relobulization occurs which may be followed by inflammatory reactions within nodules otherwise seen outside them. The conflict between growth and degeneration of regenerates determines the evolution. Hepatocvtes also proliferate in ductular patterns, which can be distinguished from ductules only by electron microscopy.'6° The functional capacitv of these structures is unknown but is probably low. Ductules proliferate by sprouting and appear plate-like on three-dimensional reconstructions."'1 The stimulus for their proliferation in any liver disease is unknown but may be intraluminal factors which also illicit the periductular inflammation.162 Formation of a continuous basement membrane around these ductules and hepatocellular pseudoductules3 also stimulates fibrosis. Sinusoidal cells proliferate in some nodules. They mav induce fibrosis and mav develop into angiosarcoma as observed after exposure to environmental agents 7 and also in experimental cirrhosis, e.g., from dimethvlnitrosamine.1" The frequent association of hepatocellular carcinoma with cirrhosis raises the question whether carcinoma results from independent action of carcinogens or from abnormal regeneration in cirrhosis. Cancers in man without cirrhosis have been occasionally observed in association with etiologic factors of cirrhosis such as alcohol abuse or viral hepatitis. Carcinoma without cirrhosis in animals can be induced bv carcinogenic agents with cirrhogenous potential. There is morphologic evidence for carcinomatous transformation of abnormal regeneration in cirrhosis. Cancer appears to be more frequent in the macronodular type 1'16 and in alcoholics who have ceased to drink,'" perhaps because of their long survival. Hepatocarcinogenesis has been explained bv successive formation of consecutivelv altered cell populations 167 and these are seen in large multilobular cirrhotic nodules; "nodules in nodules" form which are a recognized precursor of experimental cancers.1" This includes areas of small cells, of highlv basophilic hepatocvtes, or of multicellular plates.'" Moreover, groups of dvsplastic cells with multiple, often polvpoid nuclei are sometimes found,170 especially in cirrhosis associated with carcinoma. The question whether many patients with cirrhosis would eventually

246

POPPER


develop carcinoma without additional carcinogenic factors (e.g., ubiquitous ones) if they were to live long enough remains to be resolved. Fibrosis

Excess hepatic connective tissue results from collapse (passive septa) or from formation of new fibers (active septa).3" Collapse induces additional fiber formation. Connective tissue consists of a matrix of glycoproteins and proteoglyeans, many sulfated, and scleroproteins of which collagen is the most important in the liver. Little is known about hepatic elastin. Collagen differs from most other proteins by a posttranslational hydroxylation of peptide-bound proline and lysine. The responsible intracellular enzymes, prolyl or lysyl hydroxylases, thus characterize collagen synthesis 31,171 and are otherwise involved only in the synthesis of a collagenlike compound of complement Clq.172 Human liver contains about three times as much collagen as rat liver, and the collagen concentration of rat cirrhosis equals that of normal human liver.173 Differences in the gene product permits distinction of four types of collagen.174 Type I, characteristic of skin, tendon, and bone, is present in the liver as thick collagen bundles in portal tracts and Glisson's capsule as well as around hepatic vein tributaries. It is demonstrated by the aniline blue and Van Gieson connective tissue stains and by double refraction with simple polarizing methods (Figure 6A and B). It is physically dense and has a tendency to contract and shrink. Type II is found in hyalin cartilage and not in liver tissue. Type III, rich in hydroxyproline, is in embryonal tissues and vessels and is the reticulum demonstrated by silver impregnation in the lobular parenchyma and also in portal and central canals (Figure 6C). Type IV, rich in cysteine and glycoproteins, represents basement membranes which cannot be demonstrated by conventional light microscopy but are visualized by electron microscopy although devoid of the characteristic periodicity of the other species of collagen. They, form a continuous layer around vessels, capillaries, ducts, and ductules in the normal liver. Immunologic techniques permit visualization of the first three types,1731676 and visualization of basement membranes is currently being developed. Procollagen is synthesized in the cell as a helical monomer chain with globular extensions at both ends. These are cleaved during the secretion by the cell and almost all collagen is deposited in the interstitial tissue as triple helical chains. This cleavage may not take place in the basement membrane collagens 177 or when other collagens are rapidly synthetized. The cleaved globular portions are immunogenic, and their demonstration in the serum may become a clinical parameter of fibrogenesis.'78 It has


CIRRHOSIS

247

long been assumed that the cell responsible for synthesis of both collagen and matrix substances is the fibroblast. However, evidence now exists that other cells also have the potential for collagen synthesis."7' Vascular myoblasts are an example w and even liver cells form some species of collagen,'a' possibly basement membranes. In the liver, perisinusoidal cells contain many small fat droplets with vitamin A fluorescence I" but are devoid of phagosomes (Ito cells or lipocytes).`""` They are considered resting precursors of fibroblasts.'" Transitional forms between fibroblasts and lipocytes have been demonstrated in experimentally increased fibrogenesis and have been associated with formation of Type III collagen (reticulum).'a Since lipocytes are concentrated in hepatic necrosis, their stimulation may account for some pathologic hepatic fibrogenesis. Excess fibers form in the liver in several locations:' 1) In portal tracts, associated with increase of typical fibroblasts. 2) Around damaged hepatocytes within the parenchyma, particularly near portal tracts and septa. When hepatocellular organelles are altered and the microvilli are sparse or missing, collagen bundles form an almost continuous layer as a pericellular coat, while normally only an occasional fibril bundle is in a groove of the hepatocyte. Moreover, continuous basement membranes develop around damaged hepatocytes in contact with excess collagen bundles. 3) Around proliferated bile ductules, again in contact with their basement membranes, which may be conspicuously thickened. 4) Around capillaries, more numerous in cirrhosis, and around veins, in septa. 5) Around macrophages containing excess stored material, particularly iron; this is one cause of excess fibrogenesis in iron storage diseases. Several processes are involved in parenchymal fibrogenesis. "" The first is a commirtment of cells to form both collagen and rmatix substances. Little is known about the regulation and rate of this synthesis and whether the same cell forms several components. One fibroblast may form collagen I and III.`" Perisinusoidal cells take up radioactive proline as precursor of collagen hydroxyproline,`9"" when lipocytes are also transformed to fibroblasts."7 The presence of both macrophages and lymphocytes suggests their participation in this process. Cultured lymphocytes from patients with chronic hepatitis release, on stimulation by autologous liver, lymphokinins that enhance fibroblastic activity.'" Ethanol administration to rats increases hepatic prolyl hydroxylase activity and fibrosis,"'" tentatively explained by increased formation of lactate from pyruvate. But, aside from this direct stimulation of fibrogenesis, the most important factor in fibrogenesis is hepatocellular injury3' and the inflammation caused by it, as illustrated by fibrosis-stimulating factors in the liver during carbon tetrachloride intoxication."'

248

POPPER


The second factor is extracellular deposition and maturation of collagen associated with cross linkage between the helical a-chains, facilitated by copper-dependent enzymes. Eventually the maturing collagen loses its extractability by salt and acids which permits separation of old from newly formed collagen. This maturation may proceed to a hyalinization with reduction of matrix substances and cells. Newly formed collagen is Type III (reticulum), but dense collagen Type I is deposited subsequently to varying degrees."9' This is prominent in the septa and appears to be accelerated in alcoholic liver injury. The deposition of dense collagen around sinusoids which are transformed into veins furthers the bypass of blood. The deposition of collagen and its maturation is enhanced around surfaces with reduced fluid exchange like basement membranes, damaged hepatocytes, and loaded macrophages, as well as by reduced oxygen tension, which explains the preferential deposition in Zone 3 of Rappaport. The increase of constituents of collagen and proteoglyeans 196 in blood or urine in actively fibrosing conditions such as chronic active hepatitis suggests an increased turnover of these substances and an uneconomic utilization. 171,188 The third process is breakdown of senescent collagen, which depends on the action of mesenchymal cells such as macrophages and fibroblasts. They form enzymes degrading matrix mucopolysaccharides and their activity is increased in CCI-induced fibrosis. Irreversible CCI4-induced fibrosis is associated with an excess of one type of mucopolysaccharide, chondroitin sulfate C, for which, in contrast to the other types, degrading enzymes are sparse.197 Macrophages produce collagenases 198 which cleave collagen more effectively when the matrix is degraded. Collagen fragments can also be phagocytosed. In irreversible experimental fibrosis the life-span of some of the collagen is prolonged. Irreversibility is, therefore, promoted by deposition of chondroitin sulfate C, by hyalinization preventing access of cells, by paucity of cells, and by eventual obliteration of vessels in the septa. 171,188 Progression of fibrosis and cirrhosis depends thus on several factors besides direct stimulation. The main factor is hepatocytic injury with inflammation resulting in collapse and fibrogenesis. Persisting hepatocytes undergoing necrosis stimulate sustained inflammation and fibrogenesis. This is associated with the production of continuous basement membranes around hepatocytes and with proliferation of ductules providing a second route for the spread of inflammation. Either active or passive septa create a bypass which disturbs the circulation. Formation of hard and contracting Type I collagen in the septa contributes to portal hypertension and around bile ducts creates an intrahepatic mechanical cholestatic


CIRRHOSIS

249

component as seen in biliary cirrhosis.-I Thus a vicious circle is established in that hepatocellular injury and the associated inflammation produce pericellular fibrosis interfering with cellular nutrition and septa disturbing hemodynamics. This, in turn, induces additional liver cell injury. The current studies on hepatic fibrosis are expected to contribute both to diagnosis and therapy. Liver biopsy reveals only a static picture, but it is today the clinical tool to monitor fibrogenesis, which is not reflected in the current hepatic tests. Determination of constituents of collagen and matrix substances and enzymes acting on them may eventually provide practical diagnostic parameters. There is no rational therapy for hepatocellular necrosis except withdrawal of the offending agent. Antiinflammatory therapy by steroids and other immunosuppressive agents is the mainstay in therapy of chronic active hepatitis. It might inhibit fibrogenesis, but since the mesenchymal cells which this therapy suppresses are essential in fiber breakdown, it may also inhibit fiber removal. This might explain its ineffectiveness once cirrhosis has developed. Antifibroblastic therapy has been tried in experimental and clinical cirrhosis using proline analogs which interfere with collagen synthesis, colchicine which inhibits collagen secretion, and lathyritic agents and penicillamine which decrease cross linking.7' Concluding Remas This review has focused on the unsolved rather than the solved problems of cirrhosis. Agreement seems to have been reached about definition and anatomic or functional classification schemes. In etiology the main problem, aside from the cryptogenic form, is the evaluation of the host processes; e.g., genetic susceptibility, which is the reason why the known factors cause cirrhosis only in some persons. The mechanism of chronicity remains the major unsolved problem in pathogenesis. The recent upsurge in the study of hepatic fibrogenesis may generate answers perhaps even more readily than immunologic studies and may eventually provide specific serologic diagnostic tests and antifibroblastic therapy. Refemces 1. Himsworth HP: The Liver and Its Diseases. Cambridge, Mass., Harvard University Press, 1947 2. Conn HO: Cirrhosis. Diseases of the Liver, Fourth edition, Edited by L Schiff. Philadelphia, J. B. Lippincott Company, 1975, pp 833-939 3. Martini GA, Bode C.: The epidemiology of cirrhosis of the liver. Skandia International Symposia: Alcoholic Cirrhosis anid Other Toxic Hepatopathias. Edited by A Engel, T Larsson, Stockholm, Nardiska Bokhandelns F5rlag, 1970, pp.315-35 4. Report of the Board of Classification and Nomenclature of Cirrhosis of the Liver.

250

5.

6. 7.

8. 9. 10. 11. 12. 13. 14.

15. 16. 17. 18. 19.

20. 21. 22. 23. 24. 25. 26.

POPPER


Fifth Pan-American Congress of Gastroenterology, La Habana, Cuba, January 20-27, 1956. Gastroenterology 31 :213-216, 1956 Leevy CM, Popper H, Sherlock S (criteria committee): Diseases of the Liver and Biliary Tract: Standardization of Nomenclature, Diagnostic Criteria, and Diagnostic Methodology, Fogarty International Center Proceedings, No. 22, DHEW Publication No (NIH) 76-725. Washington, DC, US Government Printing Office, 1976 Rappaport AM: The microcirculatory acinar concept of normal and pathological hepatic structure. Beitr Pathol 157:215-243, 1976 Rubin E, Popper H: The evolution of human cirrhosis deduced from observations in experimental animals. Medicine 46:163-183, 1967 Morgan JD, Hartroft WS: Juvenile liver: Age at which one-cell-thick plates predominate in the human liver. Arch Pathol 71:86-88, 1961 Phillips MJ, Steiner JW: Electron microscopy of liver cells in cirrhotic nodules. I. The lateral cell membranes. Am J Pathol 46:985-1005, 1965 Steiner PE: Nodular regenerative hyperplasia of the liver. Am J Pathol 35:943-953, 1959 Knowles DM II, Kaye GI, Godman GC: Nodular regenerative hyperplasia of the liver. Gastroenterology 69:746-751, 1975 Popper H, Elias H: Histogenesis of hepatic cirrhosis studied by the three-dimensional approach. Am J Pathol 31:405441, 1955 Benz EJ, Baggenstoss AH: Focal cirrhosis of the liver: Its relation to the so-called hamartoma (adenoma, benign hepatoma). Cancer 6:743-755, 1953 Soirensen, TIA, Almersjo 0: Focal nodular hyperplasia of the liver: Five cases. Scand J Gastroenterol 11:97-101, 1976 PetrelliM, Scheuer PJ: Variation in subcapsular liver structure and its significance in the interpretation of wedge biopsies. J Clin Pathol 20:743-748, 1967 Popper H: The pathology of portal hypertension. Surgery of the Liver, Pancreas and Biliary Tract. Edited by JS Najarian, JP Delaney. Miami, Symposia Specialists, 1975, pp 577-591 Okuda K, lio M: Radiological Aspects of the Liver and Biliary Tract: X-Ray and Radiosotope Diagnosis. Tokyo, Igaku Shoin Ltd., 1976 Baggenstoss AH: Postnecrotic cirrhosis: Morphology, etiology and pathogenesis. Progress in Liver Diseases. Vol I. Edited by H Popper, F Schaffner. New York, Grune & Stratton, 1961, pp 14-38 Reynolds TB, Hidemura R, Michel H, Peters R: Portal hypertension without cirrhosis in alcoholic liver disease. Ann Intern Med 70:497-506, 1969 Krenz G, Meyer WW: Strukturveraenderungen der Pfortaderwand bei Lebercirrhose: Untersuchungen am entfalteten Venenrohr. Frankfurt Z Pathol 75:375484, 1966 Takahashi T, Tezuka F: Hepatic arteries and arterial circulation in liver cirrhosis. Tohoku J Exp Med 113:113-128, 1974 Popper H, Elias H, Petty DE: Vascular pattern of the cirrhotic liver. Am J Clin Pathol 22:717-729, 1952 Mitra SK: Hepatic vascular changes in human and experimental cirrhosis. J Pathol Bacteriol 92:405-414, 1966 Horisawa M, Goldstein G, Waxman A, Reynolds T: The abnormal hepatic scan of chronic liver disease: Its relationship to hepatic hemodynamics and colloid extraction. Gastroenterology 71:210-213, 1976 Shalden S, Chiandussi L, Guevara L, Caesar J, Sherlock S: The estimation of hepatic blood flow and intrahepatic shunted blood flow by colloidal heat denatured human serum albumin labelled with I"'3. J Clin Invest 40:1346-1354, 1961 Huet P-M, Marleau D, Lavoie P, Viallet A: Extraction of 12-Ialbumin microaggregates from portal blood: An index of functional portal blood supply in cirrhotics. Gastroenterology 70:74-81, 1976

Vol.87,No. 1 April 1977

CIRRHOSIS

251

27. Gross G, Perrier CV: Intrahepatic portasystemic shunting in cirrhotic patients. N Engl J Med 293:1046-1047, 1975 28. Burchell AR, Moreno AH, Panke WF, Nealon TF: Hemodynamic variables and prognosis following portocaval shunts. Surg Gynecol Obstet 138:359-369, 1974 29. Moreno AH, Burchell AR, Reddy RV, Steen JA, Panke WF, Nealon TF Jr: Spontaneous reversal of portal blood flow: The case for and against its occurrence in patients with cirrhosis of the liver. Ann Surg 181:346-358, 1975 30. Schaffner F, Popper H: Capillarization of hepatic sinusoids in man. Gastroenterology 44:239-242, 1963 31. Popper H, Undenfriend S: Hepatic fibrosis: Correlation of biochemical and morphologic investigations. Am J Med 49:707-721, 1970 32. Popper H: Cirrhosis. Liver. Edited by SJ Saunders, J Terblanche, London. Pitman Press, 1973, pp 240-251 ,33. Ginsberg MD: Spontaneous group B streptococcal bacteremia complicating hepatic cirrhosis. Am J Dig Dis 13:1065-1071, 1968 ,34. Conn HO, Fessel JM: Spontaneous bacterial peritonitis in cirrhosis: Variations on a theme. Medicine 50:161-197, 1971 35. Maderazo EG, Ward PA, Quintiliani R: Defective regulation of chemotaxis in cirrhosis. J Lab Clin Med 85:621-30, 1975 ,36. Nolan JP: The role of endotoxin in liver injury. Gastroenterology 69:1346-1356, 1975 37. Liehr H, GrOn M: Endotoxine und RES-Funktion in der Pathogenese von Lebererkrankungen. Intemist 17:1-7, 1976 38. Pnrtz H, Bjomeboe M, Johansen TS, ()rskov F: The influence of portosystemic shunt operation on immunoglobulins and Escherichia coli antibodies in patients with cirrhosis of the liver. Acta Med Scand 196:109-112, 1974 .39. Lauritsen KB, Rehfeld JF, Christiansen LA, Juhl E, Stadil F: Serum-gastrin in cirrhosis. Scand J Gastroenterol 11:33--34, 1976 40. Orloff MJ, Chandler JG, Alderman Sj, Keiter JE, Rosen H: Gastric secretion and peptic ulcer following portacaval shunt in man. Ann Surg 170:515-527, 1969 41. Bircher J, Blankart R, Halpem A, Hacki W, Laissue J, Preisig R: Criteria for assessment of functional impairment in patients with cirrhosis of the liver. Eur J Clin Invest 3:72-85, 1973 42. Witte MH, Witte CL, Dumont AE: Progress in liver disease: Physiological factors involved in the causation of cirrhotic ascites. Gastroenterology 61:742-750, 1971 43. Borchard F, Borchard H, Huth F: Beitrag zur lvmphvascularen Sklerose des Ductus thoracicus: Morphometrische Untersuchungen von 88 Fillen. Beitr Pathol 146:145-161, 1972 44. Ludwig J, Linhart P, Baggenstoss HA: Hepatic lymph drainage in cirrhosis and congestive heart failure. Arch Pathol 86:551-562, 1968 45. Bhathal PS, Hurlev JV: An electron microscope study of the production of ascites in acute dimethyl nitrosamine (DMN)induced liver injurv. J Pathol 111:103-116, 1973 46. Donovan AJ, Child MA, Masto AS: The effect of hepatic venous obstruction on the rate of flow of bile. Surg Gvnecol Obstet 134:89-93, 1972 47. NMasuko K, Rubin E, Popper -H: Proliferation of bile ducts in cirrhosis. Arch Pathol 78:421-431, 1964 48. Popper H, Schaffner F, Denk H: Molecular pathology of cholestasis. The Hepatobiliarv System: Fundamental and Pathological Mechanisms. Edited by W Tavlor. New York, Plenum Press, 1976 49. Fleming CR, Dickson ER, Baggenstoss AH, McCall JT: Copper and primarv biliarv cirrhosis. Gastroenterology 67:1182-1187, 1974 50. Ishak KG, Jenis EH, Marshall ML, Bolton BH, Battistone GC: Cirrhosis of the liver associated with alpha-1-antitrypsin deficiency. Arch Pathol 94:445-455, 1972

252

POPPER


51. Barry M: Iron and the liver. Gut 15:324-334, 1974 52. Takada A, Porta EA, Hartroft WS: The recovery of experimental dietary cirrhosis. I. Functional and structural features. Am J Pathol 51:929-957, 1967 53. Takada A, Porta EA, Hartroft WS: The recovery of experimental dietary cirrhosis. II. Turnover changes of hepatic cells and collagen. Am J Pathol 51:959-976, 1967 54. Powell LW, Kerr JFR: Reversal of "cirrhosis" in idiopathic haemachromatosis following long-term intensive venesection therapy. Aust Ann Med 19:54-57, 1970 55, Baggenstoss AH, Stauffer MH: Posthepatitic and alcoholic cirrhosis: Clinicopathologic study of 43 cases of each. Gastroenterology 22:157-180, 1952 56. Gall EA: Posthepatitic, postnecrotic and nutritional cirrhosis: A pathologic analysis. Am J Pathol 36:241-271, 1960 57. Yoshida T: Cirrhosis of the live'r in Japan. Jap J Med 3:1-14, 1964 58. MacSween RNM, Scott AR: Hepatic cirrhosis: A clinicopathologic review of 320 cases. J Clin Pathol 26:936-942, 1973 59. Rubin E, Krus S, Popper H: Pathogenesis of postnecrotic cirrhosis in alcoholics. Arch Pathol 73:288-299, 1962 60. Meister HP, Szanto PB, Schoolman H: Quantitative-morphologic evaluation of postnecrotic cirrhosis. Virchows Arch [Pathol Anat] 336:447-464, 1963 61. Ludwig J, Elveback LR: Parenchyma weight changes in hepatic cirrhosis: A morphometric study and discussion of the method. Lab Invest 26:338-343, 1972 62. Kaneda M, Takahashi T: Histometrical analysis of hepatic parenchyma in normal and cirrhotic livers. Tohoku J Exp Med 100:201-225, 1970 63. Popper H, Orr W: Current concepts in cirrhosis. Scand J Gastroenterol 6:203-222, 1970

64. Winkel P, Juhl E, Tygstrup N, The Copenhagen Study Group for Liver Diseases (CSL): The clinical significance of classifications of cirrhosis: A comparison between conventional criteria and numerical taxonomy. Scand J Gastroenterol 11:33-40, 1976 65. Ludwig J, Garrison CO, Baggenstoss AH: Latent hepatic cirrhosis: A study of 95 cases. Am J Dig Dis 15:7-14, 1970 66. Scheuer PJ: Liver biopsy in the diagnosis of cirrhosis. Gut 11:275-278, 1970 67. Rubin E, Schaffner F, Popper H: Primary biliary cirrhosis. Chronic nonsjjppurative destructive cholangitis. Am J Pathol 46:387-407, 1965 68. Doehlert CAJ, Baggenstoss AH, Cain JC: Obstructive biliary cirrhosis and alcoholic cirrhosis: Comparison of clinical and pathologic features. Am J Clin Pathol 25:902-914, 1955 69. Sherlock S: The liver in heart failure. Relation of anatomical, functional and circulatory changes. Br Heart J 13:273-293, 1951 70. Klatskin G, Yessner R: Hepatic manifestations of sarcoidosis and other granulomatous diseases: A study based on histologic examination of tissue obtained by needle biopsy of the liver. Yale J Biol Med 23:207-248, 1950 71. Edmondson HA, Peters RL, Reynolds TB, Kuzma OT: Sclerosing hyalin necrosis of the liver in the chronic alcoholic: A recognizable clinical syndrome. Ann Intern Med 59:646-673, 1963 72. Warren KS: Hepatosplenic schistosomiasis Mansoni: An immunologic disease. Bull NY Acad Med 51:545-550, 1975 73. Fauvert R, Benhamou JP: Congenital hepatic fibrosis. The Liver and Its Diseases. Edited by F Schaffner, S Sherlock, CM Leevy. New York, Intercontinental Medical Book Corporation, 1974, pp 283-288 74. Popper H, Maltoni C, Selikoff IJ, Squire RA, Thomas LB: Comparison of neoplastic hepatic lesions in man and experimental animals. Cold Spring Harbor Conferences on Cell Proliferation, Vol 4, Origins of Human Cancer. New York, Cold Spring Harbor Laboratory (In press)


CIRRHOSIS

253

75. Hruban Z, Russell RM, Boyer JL, Glagov S, Bagheri SA: Ultrastructural changes in livers of two patients with hvpervitaminosis A. Am J Pathol 76:451-468, 1974 76. Fellows KE, Grand RJ, Colodnv AH, Orsini EN, Crocker AC: Combined portal and vena caval hypertensions in Gaucher disease: The value of preoperative venography. Pediatrics 87:739-743, 1975 77. Glassen M, Elster K, Pesch HJ, Demling L: Portal hypertension caused by partial nodular transformation of the liver. Gut 11:245-249, 1970 78. Galambos JT: Alcoholic hepatitis.' pp 255-267 79. Lelbach WK: Epidemiology of alcoholic liver disease. Progress in Liver Diseases, Vol V. Edited by H Popper, F, Schaffner, New York, Grune & Stratton, 1976, pp 494-515 80. Lieber CS, DeCarli LM, Rubin E: Sequential production of fatty liver, hapatitis, and cirrhosis in sub-human primates fed ethanol with adequate diets. Proc Natl Acad Sci USA 72:437-441, 1975 81. Wiggers KD, French SW, French BA, Carr BN: The ultrastructure of Mallory body filaments. Lab Invest 29:652-658, 1973 82. French SW, Sim JS, Burbige E, Denton T: Alcoholic hepatitis. Hepatology: Research and Clinical Issues, Vol 3. New York, Plenum Publishing Corporation (In

press) 83. Baraona E, Leo MA, Borowsky SA, Lieber CS: Alcoholic hepatomegalv: Accumulation of protein in the liver. Science 190:794-795, 1975 84. Gerber MA, Popper H: Relation between central canals and portal tracts in alcoholic hepatitis: A contribution to the pathogenesis of cirrhosis in alcoholics. Hum Pathol 3:199-207, 1972 85. Popper H, Szanto PB, Elias H: Transition of fatty liver into cirrhosis. Gastroenterology 28:183-192, 1955 86. Popper H: The pathogenesis of alcoholic cirrhosis." 87. Feinman L, Lieber CS: Fibrogenic effect of alcohol in rat liver: Role of diet. Science 179:406-407, 1973 88. Chen TSN, Leevy CM: Collagen biosynthesis in liver disease of the alcoholic. J Lab Clin Med 85:10(-112, 1975 89. Gerber MA, Orr W, Di,nk H, Schaffner F, Popper H: Hepatocellular hyalin in cholestasis and cirrhosis: Its diagnostic significance. Gastroenterology 64:89-98, 1973 90. Sherlock S: Viral hepatitis and cirrhosis. Clinics in Gastroenterology, V'ol IV. Cirrhosis. Edited by H Popper. London, W. B. Saunders Company, Ltd., 1975, pp 281-296 91. Shikata T: Australia antigen in hepatoma and cirrhosis tissue. Tumor Res 8:127-130, 1973 92. Nvfors A, Poulsen H: Liver biopsies from psoriatics related to methotrexate therapy. II. Findings before and after methotrexate therapy in 88 patients: A blind study. Acta Pathol Microbiol Scand [A] 84:262-270, 1976 93. Perez V, Schaffner F, Popper H: Hepatic drug reactions. Progress in Liver Diseases, Vol IV. Edited by H Popper, F Schaffner. New York, Grune & Stratton, 1972, pp 597-625 94. Reynolds TB, Peters RL, Yamada S: Chronic active and lupoid hepatitis caused by a laxative oxyphenisatin. N Engl J Med 285:813-820, 1971 95. Maddrey WC, Boitnott JK: Severe hepatitis from methyldopa. Gastroenterology 68:351 -360, 1975 96. Fagrell B, Strandberg I, Wengle B: A nitrofurantoin-induced disorder simulating chronic active hepatitis: A case report. Acta Med Scand 199:237-239, 1976 97. Black M, Mitchell JR, Zimmerman HJ, Ishak KG, Epler GR: Isoniazid-associated hepatitis in 114 patients. Gastroenterology 69:289-302, 1975

254

POPPER


98. Roberts WC: The hepatic cirrhosis of cystic fibrosis of the pancreas. Am J Med 32:324-328, 1962 99. Horisawa M, Yokoyama T, Juttner H, Reynolds TB: Incomplete membranous obstruction of the inferior vena cava: Hemodynamic measurements and correction by balloon niembranotomy and surgical resection. Arch Surg 111:599-602, 1976 100. Patek AJ Jr, Toth IG, Saunders MG, Castro GAM, Engel JJ: Alcohol and dietary factors in cirrhosis: An epidemiological study of 304 alcoholic patients. Arch Intern Med 135:1053-1057, 1975 101. Peters RL, Gay T, Reynolds TB: Post-jejunoileal-bypass hepatic disease: Its similarity to alcoholic hepatic disease. Am J Clin Pathol 63:318-331, 1975 102. Thaler H: Die Fettleber und ihre pathogenetische Beziehung zur Lebercirrhose. Virchows Arch [Pathol Anat] 335:180-210, 1962 103. Partin JS, Partin JC, Schubert WK, McAdams AJ: Liver ultrastructure in abetalipoproteinemia: Evolution of micronodular cirrhosis. Gastroenterology 67:107-118, 1974 104. Powell LW, Kerr JFR: The pathology of the liver in hemochromatosis. Pathobiology Annual 1975. Edited by HL Ioachim. New York, Appleton-CenturyCrofts, 1975, pp 317-337 105. Risdon RA, Barry M, Flyn DM: Transfusional iron overload: The relationship between tissue iron concentration and hepatic fibrosis in thalassaemia. J Pathol 116:83-95, 1975 106. Hathway D, Harris JW, Stenger RJ: Histopathology of the liver in pyridoxine responsive anemia. Arch Pathol 83:175-179, 1967 107. Kent G, Schneider KA: Cirrhosis and iron overload.7" pp 314-327 108. Sternlieb I: Evolution of the hepatic lesion in Wilson's disease (hepatolenticular degeneration)." pp 511-525 109. Sternlieb I, Scheinberg IH: Radiocopper in diagnosing liver disease. Semin Nucl Med 2:176-188, 1972 110. Erikson S, Hagerstrand I: Cirrhosis and malignant hepatoma in alpha1-antitrypsin deficiency. Acta Med Scand 195:451458, 1974 111. Sharp HL: The current status of alpha1-antitrypsin, a protease inhibitor in gastrointestinal disease. Gastroenterology 70:611-621, 1976 112. Odievre M, Martin J-P, Hadchouel M, Alagille D, Thaler MM: Alpha1-antitrypsin deficiency and liver disease in children: Phenotypes, manifestations, and prognosis. Pediatrics 57:226-231, 1976 113. Gordon HW, Dixon J, Rogers JC, Mittman C, Lieberman J: Alphar-antitrypsin (A1AT) accumulation in livers of emphysematous patients with AjAT deficiency. Hum Pathol 3:361-370, 1972 114. Weiser MM, Lamont JT, Walker WA: Editorial: Alpha1-antitrypsin deficiency: A defect of secretion. N Ehgl J Med 292:205-206, 1975 115. Smetana HF, Olen E: Hereditary galactose disease. Am J Clin Pathol 38:3-25, 1962 116. Sidbury JB Jr, Mason J, Burns WB, Ruebner BH: Type IV glycogenosis: Report of a case proven by characterization of glycogen and studied at necropsy. Bull Johns Hopkins Hosp 111:157-181, 1962 117. Weinberg AG, Mize CE, Worthen HG: The occurrence of hepatoma in the chronic form of hereditary tyrosinemia. J Pediat 88:434-438, 1976 118. Perheentupa J, Pitkanen E, Nikkila EA, Somersalo 0, Hakosalo J: Hereditary fructose intolerance: A clinical study of four cases. Ann Paediat Fenn 8:221-235, 1962 119. Feizi 0: Hereditary hemorrhagic telangiectasia presenting with portal hypertension and cirrhosis of the liver. Gastroenterology 63:660-664, 1972 120. Iber FL, Maddrey WC: Familial hepatic diseases with portal hypertension with or


CIRRHOSIS

255

without cirrhosis. Progress in Liver Diseases, Vol II. Edited by H Popper, F 121. 122. 123. 124. 125. 126. 127.

Schaffner. New York, Grune & Stratton, 1965, pp 290-302 Wewalka VF: Die Blutgruppen bei Lebercirrhosen. Blut 6:261-266, 1960 Kern F: Hepatobiliary disorders in inflammatory bowel disease." pp 575-589 Pettigrew NM, Goudie RB, Russell RI, Chaudhuri AKR: Evidence for a role of hepatitis virus B in chronic alcoholic liver disease. Lancet 2:724-725, 1972 Stone WD, Islam NRK, Paton A: The natural history of cirrhosis: Experience with an unselected group of patients. Q J Med 37:119-132, 1968 Morrow RH Jr, Sai FT, Barker LF: Australia antigen and hepatitis in Accra, Ghana. Br Med J 4:389-41, 1971 Anthony PP, Vogel CL, Sadikali F, Barker LF, Peterson MR: Hepatitis-associated antigen and antibody in Uganda: Correlation of serological testing with histopathology. Br Med J 1:403-406, 1972 Chainuvati T, Viranuvatti V, Pongpipat D: Relationship of hepatitis B antigen in cirrhosis and hepatoma in Thailand: An etiological significance. Gastroenterology

68:1261-1264, 1975 128. Mackay IR: The concept of autoimmune liver disease. Bull NY Acad Med 52:453-465, 1976 129. Sherlock S: Chronic hepatitis. Gut 15.581-597, 1974

130. Soloway RD, Summerskili WHJ, Baggenstoss AH, Schoenfield LJ: "Lupoid" hepatitis, a nonentity in the spectrum of chronic active liver disease. Gastroenterology 63:458-465, 1972 131. Sherlock S: Primary biliary cirrhosis." pp 559-574 132. Rudzki C, Ishak KG, Zimmerman HJ: Chronic intrahepatic cholestasis of sarcoidosis. Am J Med 59:373-87, 1975 133. Landing BH: Protracted obstructive jaundice in infancy with emphasis on neonatal hepatitis, biliary atresia, and choledochal cyst. The Liver: Normal and Abnormal Functions, Part B. Edited by FF Becker. New York, Marcel Dekker, Inc., 1975, pp 821-849 134. De Vos R, De WoUf-Peeters C, Desmet V, Eggermont E, Van Acker K: Progressive intrahepatic cholestasis (Byler's disease): Case report. Gut 16:043-950, 1975 135. Ramalingaswami V, Nayak NC: Liver disease in India. Progress in Liver Diseases, Vol III. Edited by H Popper, F Schaffner. New York, Grune & Stratton, 1970, pp 222-235 136. Thaler MM: Cryptogenic liver disease in young infants.' pp 476-493 137. Hadchouel M, Gautier M: Histopathologic study of the liver in the early cholestatic phase of alpha-1-antitypsin deficiency. J Pediat 89:211-215, 1976 138. Krieg D, Weigl E: Epidemiologische Untersuchungen zum Problem der posthepatitischen leberzirrhose. Acta Hepatosplen 16-25-34, 1969 139. Edgington TS, Chisari FV: Immunological aspects of hepatitis B virus infection. Am J Med Sci 270:213-227, 1975 140. Gudat F, Bianchi L Sonnabend W, Thiel G, Aenishaenslin W, Stadler GA: Pattern of core and surface expression in liver tissue reflects state of specific immune response in hepatitis B. Lab Invest 32:1-9. 1975 141. Hopf U, Meyer zum Baschenfelde K-H, Arnold W: Detection of a liver-membrane autoantibody in HB,Ag-negative chronic active hepatitis. N Engl J Med 294:578-582, 1976 142. Paronetto F, Popper H: Two immunologic reactions in the pathogenesis of hepatitis? N Engl J Med 294:606-607, 1976 143. Dudley FJ, Fox RA, Sherlock S: Relationship of hepatitis-associated antigen (H.A.A.) to acute and chronic liver injury. Lancet 2:1-3, 1971 144. Galbraith RM, El Sheik N, Portmann B, Eddleston ALWF, Williams R, Parsons V, Bewick M, Ogg CS: Immune response to HBsAg and the spectrum of liver lesions

256

POPPER


in HBsAg-positive patients with chronic renal disease. Br Med J 1:1495-1497, 1976 145. Zinneman HH: Autoimmune phenomena in alcoholic cirrhosis. Am J Dig Dis 20:337-345, 1975 146. Zetterman RK, Luisada-Opper A, Leevy CM: Alcoholic hepatitis: Cell-mediated immunological response to alcoholic hyalin. Gastroenterology 70:382-384, 1976 147. Boyer JL, Klatskin G: Pattern of necrosis in acute viral hepatitis: Prognostic value of bridging (subacute hepatic necrosis). N Engl J Med 283:1063-1071, 1970 148. Popper H, Schaffner F: Hepatic cirrhosis, a problem in communication. Isr J Med Sci 4:1-7, 1968 149. Kerr JFR, Wyllie AH, Currie AR: Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26:239-257, 1972 150. De Groote J, Gedigk P, Popper H, Scheuer PJ, Thaler H, Wepler W, Desmet VJ, Korb G, Poulsen H, Schmid M, Uehlinger E: A classification of chronic hepatitis. Lancet 2:626-628, 1968 151. Dietrichson 0: Chronic persistent hepatitis: A clinical, serological, and prognostic study. Scand J Gastroenterol 10:249-255, 1975 152. Popper H, Schaffner F: Chronic hepatitis: Taxonomic, etiologic and therapeutic problems.79 pp 531-558 153. Karvountzis GG, Redeker AG, Peters RL: Long term follow-up studies of patients surviving fulminant viral hepatitis. Gastroenterology 67:870-877, 1974 154. Baggenstoss AH, Soloway RD, Summerskill WHJ, Elveback LR, Schoenfield LJ: Chronic active liver disease: The range of histologic lesions, their response to treatment, and evolution. Hum Pathol 3:183-198, 1972 155. Summerskill WHJ: Chronic active liver disease reexamined: Prognosis hopeful. Gastroenterology 66:450-464, 1974 156. Starzl TE, Porter KA, Kashiwagi N, Putnam CW: Portal hepatotrophic factors, diabetes mellitus and acute liver atrophy, hypertrophy and regeneration. Surg Gynecol Obstet 141:843-858, 1975 157. Farber E: Hyperplastic liver nodules. Meth Cancer Res 7:345-375, 1973 158. Rubin E, Masuko K, Goldfarb S, Zak FG, Popper H: Role of cell proliferation in hepatic carcinogenesis. Proc Soc Exp Biol Med 115:381-384, 1964 159. Popper H: Experimentelle Leberzirrhose. Verhandlungen der Deutschen Gesellschaft fOir innere Medizin, 82 Band. Munich, Verlag J.F. Bergmann KG (In press) 160. Sasaki H, Schaffner F, Popper H: Bile ductules in cholestasis: Morphologic evidence for secretion and absorption in man. Lab Invest 16:84-95, 1967 161. Jorgenson M: A sterological study of intrahepatic bile ducts. II. Bile duct proliferation in some pathological conditions. Acta Pathol Microbiol Scand [A]81:663-669, 1973 162. Popper H, Schaffner F, Barka T: Has proliferation of bile ductules clinical significance? Acta Hepatosplen 9:129-139, 1962 163. Adamson RH: Long-term administration of carcinogenic agents to primates. Medical Primatology. Edited by El Goldsmith, J Moor-Jankowski. Basel, S. Karger, 1972, pp 216-225 164. Purtilo DT, Gottlieb LS: Cirrhosis and hepatoma occurring at Boston City Hospital (1917-1968). Cancer 32:458462, 1973 165. Shikata T: Primary liver carcinoma and liver cirrhosis. Hepatocellular Carcinoma. Edited by K Okuda, RL Peters. New York, John Wiley & Sons, 1976, pp 53-71 166. Lee Fl: Cirrhosis and hepatoma in alcoholics. Gut 7:77-85, 1966 167. Farber E: Pathogenesis of liver cancer. Arch Pathol 98:145-148, 1974 168. Popper H, Sternberg SS, Oser BL, Oser M: The carcinogenic effect of Aramite in rats: A study of hepatic nodules. Caner 13:1035-1046, 1960 169. Peters RL: Pathology of hepatocellular carcinoma."' pp 107-168


CIRRHOSIS

257

170. Anthony PP: Precursor lesions for liver cancer in humans. Cancer Res 36:2579-2583, 1976

171. Popper H, Becker K (editors): Collagen Metabolism in the Liver. New York, Stratton Intercontinental Medical Book Corporation, 1975 172. Shelton E, Yonemasu K, Stround RM: Ultrastructure of the human complement component QQ Proc Natl Acad Sci USA 69f65-8, 1972 173. Kent G, Fels IG, Dubin A, Popper H: Collagen content based on hydroxyproline determinations in human and rat livers: Its relation to morphologically demonstrable reticulum and collagen fibers. Lab Invest 8:48-56, 1959 174. Miller EJ, Matukus VJ: Biosynthesis of collagen: The biochemist's view. Fed Proc 33:1197-1204, 1974 175. Hahn E, Timpl R, Miller EJ: The production of specific antibodies to native collagens with the chain composition (alpha-I-(I)), (alpha-1(II)) and (alpha1(I)2). J Immunol 113:421-42, 1974 176. Nowack H, Gay S, Wick G, Becker J, Timpl R: Preparation and use in immunohistology of antibodies specific for type I and type III collagen and procollagen. J Immunol Methods 12:117-124, 1976 177. Minor RR, Clark CC, Strause EL, Koszalka TR, Brent RL, Kefalides NA: Basement membrane procollagen is not converted to collagen in organ cultures of parietal yolk sac endoderm. J Biol Chem 251:1789-1794, 1976 178. Goldberg B, Taubman MB, Radin A: Procollagen peptidase: Its mode of action on the native substrate. Cell 4:45-50, 1975 179. Langness U, Udenfriend S: Collagen biosynthesis of nonfibroblastic cell lines (prolyl hydroxylase). Proc Natl Acad Sci USA 71:50-51, 1974 180. Ross R, Glomset JA: Atherosclerosis and the arterial smooth muscle cell: Proliferation of smooth muscle is a key event in the genesis of the lesions of atherosclerosis. Science 180:1332-1339, 1973 181. Sakakibara K, Saito M, Umeda M, Enaka K, Tsukada Y: Native collagen formation by liver parenchymal cells in culture. Nature [New Biol] 262:316-318, 1976 182. Chung E, Rhodes RK, Miller EJ: Isolation of three collagenous components of probable basement membrane origin form several tissues. Biochem Biophys Res Commun 71:1167-1174, 1976 183. Wake K: Development of vitamin A-rich lipid droplets in multivesicular bodies of rat liver stellate cells. J Cell Biol 63:683-691, 1974 184. Ito T: Recent advances in the study of the fine structure of the hepatic sinusoidal wall: A review. Gunma Rep Med Sci 6:119-163, 1973 185. Bronfenmajor S, Schaffner F, Popper H: Fat-storing cells (lipocytes) in human liver. Arch Pathol 82:447-453, 1966 186. Schnack H, Stockinger L, Wewalka F: Adventitious connective tissue cells in the space of Disse and their relation to fibre formation. Rev Int Hepatol 17:855-60, 1967 187. Kent G, Gay S, Inouye T, Bahu R, Minick OT, Popper H: Vitamin A-containing lipocytes and formation of type III collagen in liver injurv. Proc Natl Acad Sci USA 73:3719-3722, 1976 188. Popper H Kent G: Fibrosis in chronic liver disease." pp 315-331 189. Gay S, Martin GR, Miller PK, Timpl R, Kuhn K: Simultaneous synthesis of type I and type III collagen by fibroblasts in culture. Proc Natl Acad Sci USA 73:4037-4040, 1976 190. McGee JO, Patrick RS: The role of perisinusoidal cells in hepatic fibrogenesis: An electron microscopic study of acute carbon tetrachloride liver injury. Lab Invest 26:429-440, 1972 191. McGee JO, Patrick RS, Rodger MC, Luty CM: Collagen proline hydroxylase activity and 'S sulphate uptake in human liver biopsies. Gut 15:260-267, 1974

258

POPPER


192. Chen T, Zetterman R, Leevy CM: Sensitized lymphocyte and hepatic fibrogenesis. Gastroenterology 65:532-53, 1973 193. Mezey E, Potter JJ, Maddrey WC: Hepatic collagen proline hydroxylase activity in alcoholic liver disease. Clin Chim Acta 68:313-320, 1976 194. McGee JO, O'Hare RP, Patrick RS: Stimulation of the collagen biosynthetic pathway by factors isolated from experimentally-injured liver. Nature [New Biol] 243:121-123, 1973 195. Rojkind M, Martinez-Palomo A: Increase in type I and type III collagens in human alcoholic liver cirrhosis. Proc Natl Acad Sci USA 73:539-543, 1976 196. Risteli J, Kivirikko KI: Activities of prolyl hydroxylase, lysyl hydroxylase, collagen galactosyltransferase and collagen glucosyltransferase in the liver of rats with hepatic injury. Biochem J 144:115-122, 1974 197. Hutterer F: Degradation of mucopolysaccharides by hepatic lysosomes. Biochim Biophys Acta 115:312-319, 1966 198. Fujiwara K, Sakai T, Oda T, Igarashi S: The presence of collagenase in Kupffer cells of the rat liver. Biochem Biophys Res Commun 54:531-537, 1973 199. Kent G, Gay S, Inouye T, Popper H: Types I and III collagen in experimental liver injury. Gastroenterology 71:915, 1976

*1'

A

B

I7 -4 ;

;-

.

-

r

,

'.

dA_

IeA-Macronodular crrhosKs. The nodules cnsist of mulpe lobules and exhibit tributaries of "pac veins (arrows). (MaloYs aniline blue, x 30) B-Micronodular cirrhosis. The nodules do not show lobular architecture. (H&E, x 40)

A

B

~ ~ ,,3tiit'#-

~

J_

0 %

.N

W

"i

'.

Figure 2A-Two-cell-thick cell plates in multilobular nodule revealing a portal tract (arrow). Note position of nuclei on the sinusoidal surface of hepatocytic plates. (H&E, x 100) Inset-Twocell-thick plates (H&E, x 250). B-Different degrees of regeneratory activity in a cirrhotic nodule (H&E, x 100).

*g-N;PHr *'..7s

4A.:

I- .

Fe" 3A--Hyperpastic

or "adenomatous" nodule. Note variations of cytoplasm of hepatocytes showing basophilia in the upper part and small droplet steatosis in right lower part of figure. (H&E, x 40) B-Septa of variable density containing vessels and connecting central with portal canals in alcoholic cirrhosis (Mallory's aniline blue, x 40). C-Close-up of septum containing vessels (Mallorys aniline blue, x 100).

A

_

Figure 4A-Centronodular steatosis, necrosis, and hemorrhage in cirrhosis following hemorrhage from esophageal varices (Mallory's aniline blue, x 40). -Incomplete septal cirrhosis. Note blind ending of septa (arrows) (Mallory's aniline blue, X 40)

AIL_

--

-

N

nw.

wkl-., 40

O

.%

.j

'

a

.0

§61

1.

.-

"k

..

.

'l-

.-Op -,iF 1

'7 -Fpso ow%-.4-

.

.

-

.;90-4

1h~

Figure 5A-Primary collapse of lobular parenchyma with sharp border or original vascular spaces recognized by thick collagenous bundles. Note pseudoductular proliferation of hepatocytes in the collapsed parenchyma. (Mallory's aniline blue, x 100) B-Secondary collapse of nodular parenchyma. Note irregular spacing of vascular structures and persisting small hepatocellular nodule. (Mallory's aniline blue, x 40) C-Small portal tract structure without apparent artery or vein in relobulization of cirrhosis (H&E, x 100).

A

~ ~ ~ b,#s I~~~~~~~~~~~~~~~~~~I

-07

~

~~

I~~~b

~

~

~~~~4

44 "

B

B~~~ t

I iqC

'if

.444 y

a ~~~A~~~4

Figure 6A-Double-refractive collagen, Type I, in septa of alcoholic cirrhosis (H&E, polarized light, x 100). B-Dense collagen bundles, Type I, in septum of alcoholic cirrhosis (H&E, x 200). C-Alcoholic hepatitis with increased silver-impregnated black reticulum fibers (Type IlIl collagen) around hepatocytes. Note scat-

tered brown thicker collagen bundles (Type I) between arrows. (Silver impregnation, x 240)

Pathologic aspects of skull base tumors.

Pathologic aspects of bronchiolitis obliterans organizing pneumonia.

A Comprehensive Review of Portosystemic Collaterals in Cirrhosis: Historical Aspects, Anatomy, and Classifications.

Clinical aspects of hepatosplenic schistosomiasis: a contrast with cirrhosis.

Regenerating nodules of liver cirrhosis: MR imaging with pathologic correlation.

Clinical and pathologic considerations of the qualitative and quantitative aspects of lupus nephritogenic autoantibodies: A comprehensive review.

Cystic ameloblastoma: a clinico-pathologic review.

Gastrointestinal lipomas: a radiologic and pathologic review.

Cytogenetic and pathologic aspects of Ewing's sarcoma and neuroectodermal tumors.

Regenerating nodules in hepatic cirrhosis: MR findings with pathologic correlation.

EMMPRIN in gynecologic cancers: pathologic and therapeutic aspects.

Alcoholic liver disease: pathologic, pathogenetic and clinical aspects.

Statistical aspects of bioequivalence--a review.

Enucleation of giant hemangiomas of the liver. Technical and pathologic aspects of a neglected procedure.

Hyperhidrosis: a review of its psychological aspects.

Subclinical hypothyroidism: a review of neuropsychiatric aspects.

Immunological aspects of endometriosis: a review.

Health aspects of chloroform--a review.

Quantitative aspects of reactive gliosis: a review.

Psychiatric aspects of brain tumors: A review.

Environmental aspects of Cryptosporidium species: a review.

Noninvasive diagnosis of cirrhosis: a review of different imaging modalities.

Pathologic changes following chronic exposures to halothane: a review.

Abdominal injuries -- surgical aspects: a review.