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The problem of primary biliary cirrhosis
The American Journal of Medicine VOL.
xxx111
DECEMBER
1962
No. 6
Editorial The
Problem
of Primarv
T
HE clinical syndrome of primary biliary cirrhosis, characterized by long-standing jaundice, itching and skin lesions, all surprisingly well tolerated, has long been recognized. The clinical and laboratory manifestations of this disorder have best been analyzed by Ahrens and co-workers in 1950 [7] and were subsequently also well described by Hoffbauer [2], Sherlock [3] and the French school [4]. The pathologic changes have been particularly well presented by Cameron and Hou [5], who also offered a workable classification. MacMahon and Thannhauser [6,7] designated it pericholangiolitis; they pointed out that it may occur with or without elevated serum cholesterol levels and xanthomatosis. While the criteria of cirrhosis are not fulfilled in the earlier stages, typical cirrhosis eventually develops, ultimately with hepatocellular failure [S]. The concept of this disease as an entity has been opposed primarily on the basis of pathologic investigations of the terminal stage [9,70]. Nevertheless, most clinicians accept the clinical syndrome of primary biliary cirrhosis and consider it, as Sherlock does [3], a form of prolonged obstructive jaundice or, as Albot does [4], as cholestasis without mechanical obstruction to major bile ducts. In intrahepatic cholestasis [77], the clinical and laboratory findings indicate interference with bile flow in the absence of any demonstrable mechanical obstacle. Mechanical obstruction within the liver, diffuse enough to produce jaundice, occurs for the most part in intrahepatic biliary atresia of infancy [;1, rarely in cicatrizing intrahepatic cholangitis [ 721. Most instances of intrahepatic cholestasis with jaun-
J
Biliarv
J
Cirrhosis
dice are not associated with any mechanical obstruction of the biliary tract. Under the conventional microscope, cholestasis is characterized by dilatation of the bile canaliculi, which contain bile casts, predominantly in the centrolobular zone [II]. The effect of the bile on the surrounding liver cells is reflected in “feathery degeneration” [ 731. Histochemically, the characteristic ATPase reaction of the bile canaliculi is focally diminished [ 741. Under the electron microscope, varying dilatation of the bile canaliculi is associated with deformity or loss of their microvilli [ 75,761. The serum alkaline phosphatase activity is increased. These structural and functional findings separate intrahepatic cholestasis from other types of jaundice with increased conjugated bilirubin in the plasma, namely, chronic idiopathic jaundice with pigment (Dubin-Johnson disease) [77] or without pigment (Rotor’s disease) [78,79], which probably reflect an intracellular defect of bilirubin transport. These findings also distinguish intrahepatic cholestasis from jaundice in which only free bilirubin is increased in the plasma, and in which defects of conjugation or uptake of bilirubin by the liver cells [20,27] or excess bilirubin production are responsible. Intrahepatic cholestasis as a defect in the excretion of conjugated bilirubin into the bile, as well as its stagnation in the biliary tract, can be considered a reaction of the liver to injury, induced by various etiologic factors [77,22]. It may be the predominant manifestation of liver disease (in the form of pure cholestasis) found, for instance, in drug jaundice and in some patients with viral hepatitis. It may also be a component of a 807
Editorial variety of diseases in which conspicuous injury to the hepatic cell cytoplasm is present, as in alcoholic hepatitis, most cases of viral hepatitis and many types of cirrhosis. Occasionally, however, pure cholestasis occurs without any recognizable etiologic factor. Primary biliary cirrhosis is frequently cited as an example of such chronic idiopathic cholestasis [3,4]. Several observations obtained by various technics and on different material made in our which appeared at first to be laboratory, unrelated, when correlated, suggested an entirely different concept for primary biliary cirrhosis. When drug-induced hepatic injury with jaundice was studied in autopsy specimens, in which a large field could be examined, intrahepatic bile ducts of medium size occasionally exhibited thickening of the walls, with edema and infiltration by mononuclear cells and eosinophils [23]. This apparently hyperergic cholangitis attracted attention to less conspicuous changes in the smaller bile ducts seen in some of the biopsy specimens, and the changes in both small and medium ducts were interpreted as producing an intrahepatic biliary tract obstruction complicating intrahepatic cholestasis. Several years ago Italian [24] and English [Zfl investigators described a striking proliferation of bile ductules as the result of chronic feeding of alpha-naphthyl-isothiocyanate to rats. Subsequently, Israeli investigators [Z&27] demonstrated that this lesion was preceded by a transient lesion in the intrahepatic bile ducts, characterized by necrosis of the epithelium and thickening of the wall, associated with deep but transient jaundice. Subsequent studies in our laboratory [28] indicated that the peak of jaundice so produced was accompanied by complete cessation of bile flow, while the walls of the intrahepatic bile ducts exhibited excessive swelling; this was seen particularly well with connective tissue stains. Moreover, necrosis in the surrounding tissue suggested local escape of bile. In the meantime, an electron microscopic and histochemical analysis of a large series of cases of primary biliary cirrhosis, obtained from our own and other institutions, was being made. Many of these patients were in early stages of the disease, as judged by history. In the earlier cases particularly a confusing picture was noted in that the ATP’ase reaction of the bile canaliculi
was normal. Electron microscopically, the bile canaliculi were not dilated and their microvilli were intact, although occasionally excess bile pigment was seen in liver cells. Bile canaliculi were normal even in patients with considerable jaundice. This encouraged us to take another look at these cases with the light microscope, to find centrolobular cholestasis in particular. Surprisingly, it was absent, and the liver cells in the centrolobular zone were normal. Cholestasis was conspicuous only when patients had received anabolic steroid therapy for their pruritus. This regularly increased jaundice in patients with primary biliary cirrhosis [3]; in later stages of primary biliary cirrhosis, even without anabolic steroid therapy, bile stasis was seen, but more so in the lobular periphery. A further light microscopic observation in primary biliary cirrhosis was an alteration of medium-sized intrahepatic bile ducts, which had previously been described [&7,30,37] but now received more thorough study in view of its similarity to the experimental lesions produced by alpha-naphthyl-isothiocyanate. Connective tissue stains reveal swelling of the wall of the bile ducts such as is found in the experimental lesion at the time of cessation of bile flow. Looking back at the experimental lesion, a further similarity is the normal appearance of the bile canaliculi under the electron microscope at the height of jaundice [32]. The lining epithelium of the bile ducts in the human lesion shows proliferation and atypical cells, but the lumens appear only slightly compromised. The infiltrating cells in the duct walls are lymphocytes and plasma cells, in which macroglobulins and, to a slightly lesser degree, 7s gamma globulin can be demonstrated [33]. During this stage of bile duct involvement, in which centrolobular bile stasis is not usual, proliferation of bile ductules is inconspicuous. Ductular proliferation develops later, and the ductules are surrounded by inflammatory cells. Eventually, ductules appear to be destroyed, as described by MacMahon [s]. This stage of ductular destruction is associated with dense fibrosis of the portal tracts, and eventually a thick connective tissue barrier separates the portal tracts from the parenchyma, in which peripheral bile stasis is now noted. These five observations, partly clinicalpathological correlation, partly light microscopic findings, partly fine structural observations by electron microscopy, immunocytoAMERICAN
JOURNAL
OF
MEDICINE
Editorial chemistry and histochemistry, and partly study of experimental models, were each puzzling when first made. When considered together, they seem to fall into place like the pieces of a jigsaw puzzle. The surprising lack of cholestasis in the early stages of primary biliary cirrhosis, even in the presence of jaundice, and the lack of dilatation of bile canaliculi during the time of cessation of bile flow in the icteric stage of alpha-naphthyl-isothiocyanate intoxication, indicate that the cholestatic mechanism, whatever its pathogenesis, is not responsible for jaundice in these instances. It appears rather that regurgitation through the edematous and inflamed intrahepatic bile ducts is the cause of the icterus. This coincides with the clinical observation that in this early stage of primary biliary cirrhosis, when jaundice is absent, there may be markedly increased serum alkaline phosphatase activity and bromsulfalein retention, with severe itching, probably as the result of excess bile acids in the blood, presumably from regurgitation of bile. The intact liver cells may temporarily compensate for the regurgitation by increased bilirubin secretion. This concept would place the initial insult in primary biliary cirrhosis in the intrahepatic bile ducts. Gradual involvement of the smaller bile ductules associated with inflammation is followed by their destruction and by fibrosis, resulting in mechanical obstruction of the proximal intrahepatic biliary tract. After several years this is followed by the characteristic septal cirrhosis, which does not display many of the distinctive features of its evolution. This explains why the pathologist looking at the final stages may not be able to recognize the earlier pathways easily. In the pathogenesis of primary biliary cirrhosis, immunologic processes seem to play a role, as suggested by the presence of macroglobulins in the periductal lymphoid cells. In other disorders macroglobulins were found by immunofluorescence only once, in the liver of a patient with WaldenstrGm’s macroglobulinemia and chronic viral hepatitis [34]. Further support for the immunologic concept is derived from the serologic demonstration of circulating antibodies to ductules, also found in many other liver diseases, and antinuclear antibodies not usually found in liver diseases [35]. Other investigators have demonstrated an unusually high titer of complement-binding antibodies [36] and a level of plasma macroglobulins high VOL.
33,
DECEMBER
1962
for a disease other than Waldenstriim’s macroglobulinemia [37]. While the nature of the immunologic insult is not clearly established [38], it could be a peculiar immunologic reaction involving the triggered perhaps by common bile ducts, diseases such as drug reactions, viral hepatitis and possibly bacterial cholangitis in the course of biliary tract disease. This hypothesis places the emphasis in the pathogenesis of primary biliary cirrhosis upon an immunologic reaction rather than a distinctive etiologic agent. Surgical biopsy specimens of the earlier lesions are readily diagnostic since they show the characteristic bile duct abnormality. It is usually not present in the small core of the needle biopsy specimen, but absence of histologic centrolobular cholestasis in a jaundiced patient with pruritus, high alkaline phosphatase activity and bromsulfalein retention is very suggestive of primary biliary cirrhosis, even in the absence of visible jaundice. By thus linking together what initially appeared to be unrelated observations, this concept of the nature and progression of primary biliary cirrhosis was evolved, but its pathogenesis and etiology remain obscure.
HANS POPPER, EMANUEL
RUBIN,
M.D., M.D.
and FENTON SCHAFFNER, M.D. Department of Pathology The Mount Sinai Hospital New York, New York REFERENCES 1. AHRENS, E. H., JR., PAYNE, M. A., KUNKEL, H. G., EISENMENGER, W. J. and BLONDHEIM, S. H. Primary biliary cirrhosis. Medicine, 29: 299, 1950. 2. HOFFBAUER, F. Primary biliary cirrhosis. Observations on the natural course of the disease in 25 women. Am. J. Digest. Dis., 5: 348, 1960. 3. SHERLOCK, S. Primary biliary cirrhosis (chronic intrahepatic obstructive jaundice). Gastroenterolog~, 37: 574, 1959. 4. ALBOT, G. La cholostase intrahtpatique chronique. Arch. mal. app. dzgest., 46: 177, 1957. 5. CAMERON, R. and Hou, P. C. Biliary Cirrhosis. Springfield, Ill., 1962. Charles C Thomas. 6. MACMAHON. H. E. and THANNHAUSER. S. J. Xanthom&ous biliary cirrhosis (a clinical syndrome). Ann. Znt. Med., 30: 121, 1949. 7. MACMAHON, H. E. Biliary cirrhosis. Differential features of the five types. Lab. Invest., 4: 243,1955. 8. WATSON, C. J. and HOFFBAUER, F. W. The problem of prolonged hepatitis withjiparticular reference to the cholangiolitic type and to the development of cholangiolitic cirrhosis of the liver. Ann. Znt. Med., 25: 195, 1946.
810
Editorial
9. GALL, E. A. Posthepatitic, postnecrotic, and nutritional cirrhosis. A pathologic analysis. Am. J. Path., 36: 241, 1960. 10. Case record of Massachusetts General Hospital No. 21-1962. New England J. Med., 266: 666, 1962. 11. POPPER, H. and SZANTO, P. B. Intrahepatic cholestasis (“cholangiolitis”). Gastroenterology,31 : 683, 1956. 12. KLEMPERER, P. Chronic intrahepatic obliterating cholangitis. J. Mt. Sinai Hosg., 4: 279, 1937. 13. WEISBROD,F. G., SCHIFF, L., GALL, E. A., CLEVELAND, F. P. and BERMAN,J. R. Needle biopsy of the liver. m. Experiences in the differential diagnosis of jaundice. Gastroenterology, 14: 56, 1950. 14. GOLDFISCHER,S., ARIAS, I. M., ESSNER, E. and NOVIICOFP, A. B. Cytochemical and electron microscopic studies of rat liver with reduced capacity to transport conjugated bilirubin. J. Exper. Med., 115: 467, 1962. 15. SCHAFFNER, F. and POPPER, H. Morphologic studies of cholestasis. Gastroenterology, 37: 565,1959. 16. SASAKI, H. and ICHIDA, F. Electron microscopic studies of cholestasis. Ann. Rep. Inst. Vzrus Res., Kyoto Unrv., 4: 172, 1961. 17. DUBIN, I. N. Chronic idiopathic jaundice. A review of 50 cases. Am. J. Med., 24: 268, 1958. 18. ROTOR, A. B., MANAHAN, L. and FLORENTIN, A. Familial nonhemolytic jaundice with direct van den Bergh reaction. Acta med. phtlififiinas, 5: 37, 1948. 19. SCHIFF,L. and BILLING,B. H. Congenital defects in bilirubin metabolism as seen in the adult. Gastroenterology, 37: 595, 1959. 20. SCHMID,R. and HAMMAKER,L. Glucuronide formation in patients with constitutional hepatic dysfunction (Gilbert’s disease). New England J. Med., 260: 1310, 1959. 21. ARIAS, I. M. The transport of bilirubin in the liver. In: Progress in Liver Diseases, vol. 1. Edited by Popper, H. and Schaffner, F., New York, 1961. Grune & Stratton. 22. CAROLI, J., PARAF, A. and ETBv~, J. La cholestase intrahtpatique aigue et subaigue. Arch. mal. app. digest., 46: 229, 1957. 23. POPPER, H. VIII. Potential drug toxicity to the liver. Clin. Pharmacol. @ Therap., 3: 385, 1962. 24. LOPEZ, M. and MAZZANTI, L. Experimental investigations on alpha-naphthyl-isothiocyanate as a hyperplastic agent of the biliary ducts in the rat. J. Path. @ Bact., 69: 243, 1955. 25. MCLEAN, M. R. and REES, K. R. Hyperplasia of
26.
27.
28.
29.
30. 31.
32.
33.
34.
35.
36.
37.
38.
bile ducts induced by alpha-naphthyl-isothiocyanate; experimental biliary cirrhosis free from biliary obstruction. J. Path. B Bact., 76: 175, 1958. ELIAKIM, M., EISNER, M. and UNGAR, H. Experimental intrahepatic obstructive jaundice following ingestion of alpha-naphthyl-isothiocyanate. Bull. Res. Council, Israel, 8E: 7, 1959. UNGAR, H., MORAN, E., EISNER,M. and ELIAKIM,M. Rat intrahepatic biliary tract lesions from alphanaphthyl-isothiocyanate. Arch. Path., 73; 427, 1962. GOLDFARB,S., SINNER,E. J. and POPPER, H. Experimental cholangitis due to alpha-naphthyl-isothiocyanate (ANIT). Am. J. Path., 40: 685,1962. RUBIN, E., SCHAFFNER,F. and POPPER,H. Localization of the basic injury in primary biliary cirrhosis. J. A. M. A., in press. MOSCHCOWITZ,E. Morphology and pathogenesis of biliary cirrhosis. Arch. Path., 54: 259, 1952. K~~HN,H. A., MUELLER,W. and PFISTER,R. eber chronische Cholangiolitis und ihre Beziehung zur primlren biliaren Cirrhose. Ztschr. klin. Med., 154: 462,. 1957. RUBIN, E., GOLDFARB, S. and SCHAFFNER,F. Two sites of intrahepatic cholestasis. Fed. Proc., 21: 303, 1962. PARONETTO,F., SCHAFFNER,F., KOFFLER, D. and POPPER, H. Immunologic observations in primary biliary cirrhosis. In preparation. COHEN, S., SOLOMON, A., PARONETTO, F. and POPPER, H. Subacute hepatitis in a patient with Waldenstrom’s macroglobulinemia. Am. J. Med., in press. PARONETTO, F., SCHAFPNER, F. and POPPER, H. Immunocytochemical reaction of serum of patients with hepatic diseases with hepatic structures. Proc. Sot. Exper. Biol. d Med., 106: 216, 1961. MACKAY, I. R. Primary biliary cirrhosis showing a high titer of autoantibody. Report of a case. New England J. Med., 258: 185, 1958. DEICHER,H. R. G., HOLMAN, H. R. and KUNKEL,H. Anti-cytoplasmic factors in the sera of patients with systemic lupus erythematosus and certain other diseases. Arthritis B Rheumat., 3: 1, 1960. POPPER, H. Possible role of immune processes in self-perpetuation of liver disease, p. 303. In: Mechanism of Cell and Tissue Damage Produced by Immune Reactions. Second International Symposium on Immunopathology. Edited by Graber, P. and Miescher, P. Benno Schwabe & Co.
AMERICAN
JOURNAL
OF
MEDICINE
xxx111
DECEMBER
1962
No. 6
Editorial The
Problem
of Primarv
T
HE clinical syndrome of primary biliary cirrhosis, characterized by long-standing jaundice, itching and skin lesions, all surprisingly well tolerated, has long been recognized. The clinical and laboratory manifestations of this disorder have best been analyzed by Ahrens and co-workers in 1950 [7] and were subsequently also well described by Hoffbauer [2], Sherlock [3] and the French school [4]. The pathologic changes have been particularly well presented by Cameron and Hou [5], who also offered a workable classification. MacMahon and Thannhauser [6,7] designated it pericholangiolitis; they pointed out that it may occur with or without elevated serum cholesterol levels and xanthomatosis. While the criteria of cirrhosis are not fulfilled in the earlier stages, typical cirrhosis eventually develops, ultimately with hepatocellular failure [S]. The concept of this disease as an entity has been opposed primarily on the basis of pathologic investigations of the terminal stage [9,70]. Nevertheless, most clinicians accept the clinical syndrome of primary biliary cirrhosis and consider it, as Sherlock does [3], a form of prolonged obstructive jaundice or, as Albot does [4], as cholestasis without mechanical obstruction to major bile ducts. In intrahepatic cholestasis [77], the clinical and laboratory findings indicate interference with bile flow in the absence of any demonstrable mechanical obstacle. Mechanical obstruction within the liver, diffuse enough to produce jaundice, occurs for the most part in intrahepatic biliary atresia of infancy [;1, rarely in cicatrizing intrahepatic cholangitis [ 721. Most instances of intrahepatic cholestasis with jaun-
J
Biliarv
J
Cirrhosis
dice are not associated with any mechanical obstruction of the biliary tract. Under the conventional microscope, cholestasis is characterized by dilatation of the bile canaliculi, which contain bile casts, predominantly in the centrolobular zone [II]. The effect of the bile on the surrounding liver cells is reflected in “feathery degeneration” [ 731. Histochemically, the characteristic ATPase reaction of the bile canaliculi is focally diminished [ 741. Under the electron microscope, varying dilatation of the bile canaliculi is associated with deformity or loss of their microvilli [ 75,761. The serum alkaline phosphatase activity is increased. These structural and functional findings separate intrahepatic cholestasis from other types of jaundice with increased conjugated bilirubin in the plasma, namely, chronic idiopathic jaundice with pigment (Dubin-Johnson disease) [77] or without pigment (Rotor’s disease) [78,79], which probably reflect an intracellular defect of bilirubin transport. These findings also distinguish intrahepatic cholestasis from jaundice in which only free bilirubin is increased in the plasma, and in which defects of conjugation or uptake of bilirubin by the liver cells [20,27] or excess bilirubin production are responsible. Intrahepatic cholestasis as a defect in the excretion of conjugated bilirubin into the bile, as well as its stagnation in the biliary tract, can be considered a reaction of the liver to injury, induced by various etiologic factors [77,22]. It may be the predominant manifestation of liver disease (in the form of pure cholestasis) found, for instance, in drug jaundice and in some patients with viral hepatitis. It may also be a component of a 807
Editorial variety of diseases in which conspicuous injury to the hepatic cell cytoplasm is present, as in alcoholic hepatitis, most cases of viral hepatitis and many types of cirrhosis. Occasionally, however, pure cholestasis occurs without any recognizable etiologic factor. Primary biliary cirrhosis is frequently cited as an example of such chronic idiopathic cholestasis [3,4]. Several observations obtained by various technics and on different material made in our which appeared at first to be laboratory, unrelated, when correlated, suggested an entirely different concept for primary biliary cirrhosis. When drug-induced hepatic injury with jaundice was studied in autopsy specimens, in which a large field could be examined, intrahepatic bile ducts of medium size occasionally exhibited thickening of the walls, with edema and infiltration by mononuclear cells and eosinophils [23]. This apparently hyperergic cholangitis attracted attention to less conspicuous changes in the smaller bile ducts seen in some of the biopsy specimens, and the changes in both small and medium ducts were interpreted as producing an intrahepatic biliary tract obstruction complicating intrahepatic cholestasis. Several years ago Italian [24] and English [Zfl investigators described a striking proliferation of bile ductules as the result of chronic feeding of alpha-naphthyl-isothiocyanate to rats. Subsequently, Israeli investigators [Z&27] demonstrated that this lesion was preceded by a transient lesion in the intrahepatic bile ducts, characterized by necrosis of the epithelium and thickening of the wall, associated with deep but transient jaundice. Subsequent studies in our laboratory [28] indicated that the peak of jaundice so produced was accompanied by complete cessation of bile flow, while the walls of the intrahepatic bile ducts exhibited excessive swelling; this was seen particularly well with connective tissue stains. Moreover, necrosis in the surrounding tissue suggested local escape of bile. In the meantime, an electron microscopic and histochemical analysis of a large series of cases of primary biliary cirrhosis, obtained from our own and other institutions, was being made. Many of these patients were in early stages of the disease, as judged by history. In the earlier cases particularly a confusing picture was noted in that the ATP’ase reaction of the bile canaliculi
was normal. Electron microscopically, the bile canaliculi were not dilated and their microvilli were intact, although occasionally excess bile pigment was seen in liver cells. Bile canaliculi were normal even in patients with considerable jaundice. This encouraged us to take another look at these cases with the light microscope, to find centrolobular cholestasis in particular. Surprisingly, it was absent, and the liver cells in the centrolobular zone were normal. Cholestasis was conspicuous only when patients had received anabolic steroid therapy for their pruritus. This regularly increased jaundice in patients with primary biliary cirrhosis [3]; in later stages of primary biliary cirrhosis, even without anabolic steroid therapy, bile stasis was seen, but more so in the lobular periphery. A further light microscopic observation in primary biliary cirrhosis was an alteration of medium-sized intrahepatic bile ducts, which had previously been described [&7,30,37] but now received more thorough study in view of its similarity to the experimental lesions produced by alpha-naphthyl-isothiocyanate. Connective tissue stains reveal swelling of the wall of the bile ducts such as is found in the experimental lesion at the time of cessation of bile flow. Looking back at the experimental lesion, a further similarity is the normal appearance of the bile canaliculi under the electron microscope at the height of jaundice [32]. The lining epithelium of the bile ducts in the human lesion shows proliferation and atypical cells, but the lumens appear only slightly compromised. The infiltrating cells in the duct walls are lymphocytes and plasma cells, in which macroglobulins and, to a slightly lesser degree, 7s gamma globulin can be demonstrated [33]. During this stage of bile duct involvement, in which centrolobular bile stasis is not usual, proliferation of bile ductules is inconspicuous. Ductular proliferation develops later, and the ductules are surrounded by inflammatory cells. Eventually, ductules appear to be destroyed, as described by MacMahon [s]. This stage of ductular destruction is associated with dense fibrosis of the portal tracts, and eventually a thick connective tissue barrier separates the portal tracts from the parenchyma, in which peripheral bile stasis is now noted. These five observations, partly clinicalpathological correlation, partly light microscopic findings, partly fine structural observations by electron microscopy, immunocytoAMERICAN
JOURNAL
OF
MEDICINE
Editorial chemistry and histochemistry, and partly study of experimental models, were each puzzling when first made. When considered together, they seem to fall into place like the pieces of a jigsaw puzzle. The surprising lack of cholestasis in the early stages of primary biliary cirrhosis, even in the presence of jaundice, and the lack of dilatation of bile canaliculi during the time of cessation of bile flow in the icteric stage of alpha-naphthyl-isothiocyanate intoxication, indicate that the cholestatic mechanism, whatever its pathogenesis, is not responsible for jaundice in these instances. It appears rather that regurgitation through the edematous and inflamed intrahepatic bile ducts is the cause of the icterus. This coincides with the clinical observation that in this early stage of primary biliary cirrhosis, when jaundice is absent, there may be markedly increased serum alkaline phosphatase activity and bromsulfalein retention, with severe itching, probably as the result of excess bile acids in the blood, presumably from regurgitation of bile. The intact liver cells may temporarily compensate for the regurgitation by increased bilirubin secretion. This concept would place the initial insult in primary biliary cirrhosis in the intrahepatic bile ducts. Gradual involvement of the smaller bile ductules associated with inflammation is followed by their destruction and by fibrosis, resulting in mechanical obstruction of the proximal intrahepatic biliary tract. After several years this is followed by the characteristic septal cirrhosis, which does not display many of the distinctive features of its evolution. This explains why the pathologist looking at the final stages may not be able to recognize the earlier pathways easily. In the pathogenesis of primary biliary cirrhosis, immunologic processes seem to play a role, as suggested by the presence of macroglobulins in the periductal lymphoid cells. In other disorders macroglobulins were found by immunofluorescence only once, in the liver of a patient with WaldenstrGm’s macroglobulinemia and chronic viral hepatitis [34]. Further support for the immunologic concept is derived from the serologic demonstration of circulating antibodies to ductules, also found in many other liver diseases, and antinuclear antibodies not usually found in liver diseases [35]. Other investigators have demonstrated an unusually high titer of complement-binding antibodies [36] and a level of plasma macroglobulins high VOL.
33,
DECEMBER
1962
for a disease other than Waldenstriim’s macroglobulinemia [37]. While the nature of the immunologic insult is not clearly established [38], it could be a peculiar immunologic reaction involving the triggered perhaps by common bile ducts, diseases such as drug reactions, viral hepatitis and possibly bacterial cholangitis in the course of biliary tract disease. This hypothesis places the emphasis in the pathogenesis of primary biliary cirrhosis upon an immunologic reaction rather than a distinctive etiologic agent. Surgical biopsy specimens of the earlier lesions are readily diagnostic since they show the characteristic bile duct abnormality. It is usually not present in the small core of the needle biopsy specimen, but absence of histologic centrolobular cholestasis in a jaundiced patient with pruritus, high alkaline phosphatase activity and bromsulfalein retention is very suggestive of primary biliary cirrhosis, even in the absence of visible jaundice. By thus linking together what initially appeared to be unrelated observations, this concept of the nature and progression of primary biliary cirrhosis was evolved, but its pathogenesis and etiology remain obscure.
HANS POPPER, EMANUEL
RUBIN,
M.D., M.D.
and FENTON SCHAFFNER, M.D. Department of Pathology The Mount Sinai Hospital New York, New York REFERENCES 1. AHRENS, E. H., JR., PAYNE, M. A., KUNKEL, H. G., EISENMENGER, W. J. and BLONDHEIM, S. H. Primary biliary cirrhosis. Medicine, 29: 299, 1950. 2. HOFFBAUER, F. Primary biliary cirrhosis. Observations on the natural course of the disease in 25 women. Am. J. Digest. Dis., 5: 348, 1960. 3. SHERLOCK, S. Primary biliary cirrhosis (chronic intrahepatic obstructive jaundice). Gastroenterolog~, 37: 574, 1959. 4. ALBOT, G. La cholostase intrahtpatique chronique. Arch. mal. app. dzgest., 46: 177, 1957. 5. CAMERON, R. and Hou, P. C. Biliary Cirrhosis. Springfield, Ill., 1962. Charles C Thomas. 6. MACMAHON. H. E. and THANNHAUSER. S. J. Xanthom&ous biliary cirrhosis (a clinical syndrome). Ann. Znt. Med., 30: 121, 1949. 7. MACMAHON, H. E. Biliary cirrhosis. Differential features of the five types. Lab. Invest., 4: 243,1955. 8. WATSON, C. J. and HOFFBAUER, F. W. The problem of prolonged hepatitis withjiparticular reference to the cholangiolitic type and to the development of cholangiolitic cirrhosis of the liver. Ann. Znt. Med., 25: 195, 1946.
810
Editorial
9. GALL, E. A. Posthepatitic, postnecrotic, and nutritional cirrhosis. A pathologic analysis. Am. J. Path., 36: 241, 1960. 10. Case record of Massachusetts General Hospital No. 21-1962. New England J. Med., 266: 666, 1962. 11. POPPER, H. and SZANTO, P. B. Intrahepatic cholestasis (“cholangiolitis”). Gastroenterology,31 : 683, 1956. 12. KLEMPERER, P. Chronic intrahepatic obliterating cholangitis. J. Mt. Sinai Hosg., 4: 279, 1937. 13. WEISBROD,F. G., SCHIFF, L., GALL, E. A., CLEVELAND, F. P. and BERMAN,J. R. Needle biopsy of the liver. m. Experiences in the differential diagnosis of jaundice. Gastroenterology, 14: 56, 1950. 14. GOLDFISCHER,S., ARIAS, I. M., ESSNER, E. and NOVIICOFP, A. B. Cytochemical and electron microscopic studies of rat liver with reduced capacity to transport conjugated bilirubin. J. Exper. Med., 115: 467, 1962. 15. SCHAFFNER, F. and POPPER, H. Morphologic studies of cholestasis. Gastroenterology, 37: 565,1959. 16. SASAKI, H. and ICHIDA, F. Electron microscopic studies of cholestasis. Ann. Rep. Inst. Vzrus Res., Kyoto Unrv., 4: 172, 1961. 17. DUBIN, I. N. Chronic idiopathic jaundice. A review of 50 cases. Am. J. Med., 24: 268, 1958. 18. ROTOR, A. B., MANAHAN, L. and FLORENTIN, A. Familial nonhemolytic jaundice with direct van den Bergh reaction. Acta med. phtlififiinas, 5: 37, 1948. 19. SCHIFF,L. and BILLING,B. H. Congenital defects in bilirubin metabolism as seen in the adult. Gastroenterology, 37: 595, 1959. 20. SCHMID,R. and HAMMAKER,L. Glucuronide formation in patients with constitutional hepatic dysfunction (Gilbert’s disease). New England J. Med., 260: 1310, 1959. 21. ARIAS, I. M. The transport of bilirubin in the liver. In: Progress in Liver Diseases, vol. 1. Edited by Popper, H. and Schaffner, F., New York, 1961. Grune & Stratton. 22. CAROLI, J., PARAF, A. and ETBv~, J. La cholestase intrahtpatique aigue et subaigue. Arch. mal. app. digest., 46: 229, 1957. 23. POPPER, H. VIII. Potential drug toxicity to the liver. Clin. Pharmacol. @ Therap., 3: 385, 1962. 24. LOPEZ, M. and MAZZANTI, L. Experimental investigations on alpha-naphthyl-isothiocyanate as a hyperplastic agent of the biliary ducts in the rat. J. Path. @ Bact., 69: 243, 1955. 25. MCLEAN, M. R. and REES, K. R. Hyperplasia of
26.
27.
28.
29.
30. 31.
32.
33.
34.
35.
36.
37.
38.
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