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Idiopathic adulthood ductopenia
Jo,rnalofHepatology, 1988: 7:193-199
193
Elsevier HEP 00454
Idiopathic a d u l t h o o d d u c t o p e n i a A cause of chronic cholestatic liver disease and biliary cirrhosis Jurgen Ludwig t, Russell H. Wiesner 2 and Nicholas F. LaRusso 2 1Department of Laboratol3, Medicine and Pathology, Section of Medical Pathology, and 2Division of Gastroenterology and hlternal Medicine, Mayo Clinic and Mayo Foundation, Rochester, MN (U.S.A.)
(Received 5 April 1988) (Accepted 17 May 1988)
Summary We describe three adult patients who had chronic cholestatic liver disease associated with unexplained loss of interlobular bile ducts; two of these patients eventually required orthotopic liver'transplantation. We have named this condition 'idiopathic adulthood ductopenia' because (1) the etiology is unknown, (2) the age of the patients may be the only distinguishing feature between this newly described condition and neonatal or infantile nonsyndromatic paucity of intrahepatic bile ducts, and (3) morphologic demonstration of ductopenia is an indispensable finding. Our three patients, all males, had a negative drug history, absence of antimitochondrial antibodies, normal cholangiographic findings, and no evidence of inflammatory bowel disease_ Idiopathic adulthood ductopenia may be a representation of (1) late onset of infantile paucity of intrahepatic bile ducts, (2) destructive viral cholangitis, and (3) isolated small-duct primary sclerosing cholangitis - that is, 'pericholangitis' unassociated with inflammatory bowel disease.
Introduction
The term 'paucity of intrahepatic bile ducts' [1] and its more recently coined synonym, 'ductopenia' (originally spelled 'ductipenia' [2]), have been used to describe intrahepatic bile duct atresia and related pediatric liver diseases. Collectively, these conditions have been named 'infantile obstructive cho-
langiopathy' [3]. Because of its brevity and convenience, the term 'ductopenia' is also used to describe findings in adult patients - specifically, a decrease in the number of interlobular and septal bile ducts. The best known example of such small-duct biliary disease [4] in adults is the syndrome of primary biliary cirrhosis. In addition, ductopenia has been observed in sarcoidosis, large-duct primary sclerosing chol-
Correspondence: .lurgen Ludwig, M.D., Department of Laboratory Medicine and Pathology, Section of Medical Pathology, Mayo Clinic, Rochester, MN 55905, U.S.A. Tel. : (507) 284 3883.
0168-8278/88/$03.50 © 1988 Elsevier Science Publishers B.V. (Biomedical Division)
194 angitis, some drug-induced liver diseases, graft-versus-host disease, and hepatic allograft rejection [4]. All these conditions appear to be acquired, and immunologic attack often seems to play a major role in the pathogenesis of the lesions. Of lesser importance is the ductopenia after prolonged large-duct biliary obstruction and suppurative cholangitis and the ductopenia that is observed in rare instances of lymphomatous bile duct destruction [5]. In recent years, we have observed ductopenia and its sequelae in several adult patients who did not appear to have any of the above-named conditions. In particular, our patients had no clinical evidence of primary biliary cirrhosis and they had negative tests for antimitochondrial antibodies, no biopsy evidence of florid duct lesions or sarcoid granulomas, no exposure to drugs or hepatotoxic substances that might have caused bile duct destruction, and no evidence of neoplastic disease. They had had no biliary tract surgery but two of the three patients had had cholecystectomy at ages 18 and 38. Cholangiograms had been normal or not diagnostic. Herein, we describe our experience with three of these patients.
J. LUDWIG et al. membranes, moderate mixed inflammatory infiltrates, and ductopenia (Fig_ 1A). Interlobular bile ducts were identified in only three of eight portal tracts. Hepatocytes in the periphery of the regenerative nodules were swollen and contained Mallory bodies (Fig. 1B) as well as many rhodanine-positive copper granules. Florid duct lesions, granulomas, a~-antitrypsin globules, or cholestasis could not be identified. The patient made an uneventful postoperative recovery_ Because of the clinical and biopsy findings, further diagnostic tests were done. Levels of total bilirubin were 0.4 mg/dl, A S T 30 U/l, alkaline phosphatase 198 U/l, and serum albumin 2.9 g/dl. The se-
Case Reports Case 1 A 22-year-old unemployed man with cerebral pal-
sy was admitted to the Mayo Clinic because of massive hemorrhage from large esophageal varices. Angiography showed patent splenic, superior mesenteric, and portal veins, but the spleen was enlarged and the liver shrunken, causing tortuosity of the intrahepatic arteries. Hepatofugal flow through a large umbilical vein was noted. The corrected hepatic wedge pressure was 25 mmHg. Because the bleeding could not be controlled by any other means, an emergency laparotomy was done and an end-to-side portacaval shunt was established. During that procedure, a grossly cirrhotic liver was noted and a biopsy specimen was obtained. Microscopic:ally, the liver showed septal fibrosis, evidence of nodular regeneration, prominent ductu l a r proliferation with hyalinization of basement
Fig. !. Biliary cirrhosis in patient with idiopathic adulthood ductopenia (Case 1). (A) Fibrous septum with remnant of portal tract. Note hepatic artery branches (A) and absence of interlobular bile duct. (H & E, x 120). (B) Periphery of regenerative nodule with swollen hepatocytes and Mallory bodies (arrows). (H & E, x240).
IDIOPATHIC ADULTHOOD DUCTOPENIA rum ceruloplasmin level was 37.5 mg/dl. The copper excretion in the urine was 199 /~g/24 h. Flameless atomic absorption spectrophotometry of hepatic tissue yielded 1380 ktg copper per g dry weight. A slitlamp examination failed to reveal Kayser-Fleischer rings. Other negative findings included tests to detect hepatitis A and B antibodies, and antimitochondrial antibodies. Although the patient had had no symptoms of inflammatory bowel disease, a double-contrast barium enema study was performed. No abnormalities were found_ Endoscopic retrograde cholangiopancreatography (ERCP) revealed prominent tortuosity and crowding of bile ducts in the shrunken liver but no evidence of sclerosing cholangitis_ The extrahepatic bile ducts and the pancreatic duct were normal. The patient's drug history was negative. During the last 7 years, the patient has been maintained on a daily dose of 500 mg o-penicillamine and a low-copper diet_ During the fourth year, another liver biopsy was done; the specimen revealed less inflammation but persistent ductopenia - no interlobular bile ducts could be found in the five portal tracts of this sample. The fibrosis appeared denser than in the first specimen. Periportal feathery degeneration with many Mallory bodies had become a prominent finding and stainable copper was still present, with little change in density. Electron micrographs revealed an increase in the number and size of lipolysosomes. Despite the biopsy evidence of persistent disease, the patient's status has not deteriorated further; the portacaval shunt functions well. Currently, his total serum bilirubin is 4.3 mg/dl (direct, 2.8); the level of AST is 77 U/l, of alkaline phosphatase 329 U/I, and of albumin, 2.1 g/dl. Case 2
A 21-year-old man, a road construction worker, was admitted to the Mayo Clinic with a 4-year history of jaundice, initially associated with right upper quadrant pain. The patient had not received any medications. A cholecystectomy was done at age 18 because of a pigment stone, apparently without complications; no recurrence of stone disease or other damage to the extrahepatic bile ducts was noted. However, mild pruritus developed. The levels of alkaline phosphatase and ALT were reported to be
195 three times the upper limit of normal. An ERCP examination had been done 1 year prior to his admission; it yielded a normal cholangiogram_ A liver biopsy specimen which had been obtained at that time showed moderate periportal hepatitis with some ductular proliferation and mild piecemeal necrosis, hepatocellular and canalicular cholestasis of predominantly periportal distribution, and minimal fatty change. The specimen contained six portal tracts but no interlobular bile ducts could be identified_ Florid duct lesions, granulomas, or al-antitrypsin globules were absent. During evaluation at the Mayo Clinic, levels of total bilirubin were 7.8 mg/dl (direct, 5.4), AST 69 U/l, alkaline phosphatase 433 U/I, and total cholesterol 230 mg/dl (expected, <210). Laboratory findings included a normal prothrombin time and absence of hepatitis A and B antibodies as well as antimitochondrial antibodies. The serum arantitrypsin level was 193 mg/dl. Copper excretion in the urine was 97 fig/24 h but the presence of Wilson's disease was ruled out after determination of serum ceruloplasmin levels, copper-kinetic studies, And slit-lamp examination. An ERCP again yielded a normal cholangiogram (Fig. 2A). The absence of inflammatory bowel disease was confirmed by history, repeated colonic roentgenography, and proctoscopy. A second liver biopsy was done; the specimen again showed cholestatic hepatitis and ductopenia but also evidence of destructive pleomorphic cholangitis as well as destructive fibrous cholangitis (Fig. 2B). A rhodanine stain for copper was strongly positive; the tissue copper level was 1142#g/g dry weight (expected, <35). In an attempt to classify the disease, two more liver biopsies were done during the next 3 years; they revealed decreasing cholestasis but increasing biliary piecemeal necrosis, biliary fibrosis, and ductopenia (Fig. 2C). A total of nine portal tracts were identified and only two contained interlobular bile ducts. The patient developed symptoms of progressive hepatic failure and eventually required orthotopic liver transplantation, which was done at the University of Pittsburgh, 6 years after onset of the disease. The patient is alive and well, 1 year after the transplant procedure.
196 Study of the native liver at the time of transplantation revealed biliary cirrhosis; the organ weighed 1120 g and measured 19 x 15 x 9.5 cm. T h e hilar structures, including the hepatic ducts, were normal. The p a r e n c h y m a was green. The gallbladder was absent. Microscopically, the liver showed fibrosis, nodular regeneration, and a mixture of portal tracts without bile ducts and portal tracts with proliferated ducts as well as focal fibrous cholangitis; much ductular proliferation was present also. The nodules showed severe cholestasis. C o p p e r and copper-associated protein could not be identified. Chemical c o p p e r analysis was not carried out on this specimen_ Electron micrographs confirmed the presence of ductopenia and revealed enlarged lipolysosomes, similar to those observed in other chronic cholestatic liver diseases.
Case 3 A 51-year-old man had been a high school teacher since graduation from college. A t age 38, he had a cholecystectomy because of h y d r o p s of the gallbladder and, at age 48, resection of an a d e n o c a r c i n o m a of the sigmoid colon ( D u k e B). No evidence of inflammatory bowel disease was found but when he had cancer surgery, the liver was noted to be cirrhotic. Biopsy study revealed septal fibrosis, nodular regeneration with feathery d e g e n e r a t i o n of peripheral hepatocytes, and paucity of interlobular bile ducts. Florid duct lesions, granulomas, a l - a n t i t r y p s i n globules, or bile pigment could not be identified. Iron or copper stains were not available. Levels of tissue copper were not d e t e r m i n e d . L a b o r a t o r y data for that time could not be retrieved.
Fig. 2. Normal cholangiogram, cholangitis, and biliary fibrosis in patient with idiopathic adulthood ductopenia (Case 2). (A) Normal endoscopic retrograde cholangiopancreatogram. (B) Destructive fibrous cholangitis in early stage of the disease. Note fibrous collar and degenerative epithelial changes of interlobular bile duct (asterisk). Branches of the hepatic artery (A) and portal vein (V) accompany the damaged duct. (H & E, x240). (C) Biliary fibrosis with 'empty' portal tract, in late stage of the disease. Note absence of bile duct in vicinity of hepatic artery (A) and portal vein branches (V). (Masson trichrome, x 120.)
.I. LUDWIG et al.
IDIOPATHIC ADULTHOOD DUCTOPENIA
197
During the next 3 years, the patient d e v e l o p e d itching, jaundice, and ascites. W h e n he was referred to the Mayo Clinic for liver transplantation, laboratory studies of serum samples revealed total bilirubin 24.3 mg/dl (direct, 14.4), A S T 72 U/I, alkaline phosphatase 933 U/I, and albumin 1.7 g/dl. The p r o t h r o m bin time was 13.5 s. Negative studies included determination of serum ceruloplasmin, hepatitis A and B serology, and tests to detect antimitochondrial antibody. The patient's drug history prior to the discovery of liver disease was negative. Proctoscopy and double-contrast colon r o e n t g e n o g r a p h y failed to reveal any abnormalities. E R C P was not done. The patient d e v e l o p e d a bleeding d u o d e n a l ulcer and later, spontaneous bacterial peritonitis and E. coli septicemia. The creatinine level rose to 1_8 mg/ml. Because the patient's liver function and general status continued to d e t e r i o r a t e , o r t h o t o p i c liver transplantation was done. The excised liver weighed 2035 g and measured 28 × 18 x 12_5 cm. Biliary cirrhosis with p r o m i n e n t scarring was noted. Microscopically, the regenerative nodules showed much cholestasis in their periphery, with feathery d e g e n e r a t i o n of hep-
atocytes, Mallory bodies, and m o d e r a t e c o p p e r deposition. DUctopenia again was noted; among 20 randomly selected portal tracts, only three contained interlobular bile ducts. A few cholangiectases were also identified. Mild to m o d e r a t e hepatocellular hemosiderosis was another microscopic feature. D e t e r mination of tissue copper levels by flameless atomic absorption s p e c t r o p h o t o m e t r y yielded 2189 ktg/g dry weight (expected, >35). The patient has recovered well. Except for a transient lobular hepatitis of unknown cause, the allograft has functioned well during an 8-month followup period.
Discussion We have coined the name 'idiopathic a d u l t h o o d d u c t o p e n i a ' ( I A D ) for the condition described in these three patients because (1) the etiology is unknown, (2) a d u l t h o o d may be the only distinguishing feature between I A D and neonatal or infantile nonsyndromatic paucity of intrahepatic bile ducts, and
TABLE 1 DIAGNOSTIC FEATURES OF IDIOPATHIC ADULTHOOD DUCTOPENIA Method of study
Obligatory findings
Facuhative findings
Morphologic
Ductopenia, defined as absence of interlobular bile ducts in at least 50% of small portal tracts
Presence of granulomatous Nongranulomatous destructive cholangitis, ductular proliferation, cholangitis (florid duct lesions); biliary piecemeal necrosis, other , histiocytosis X, lymphoma, or other neoplastic diseases; neutrophilic types of cholestasis, Mallory suppurative or nonsuppurative bodies, copper deposition, cholangitis biliary fibrosis or cirrhosis
Exclusion criteria
Clinical
Adulthood (may include late adolescence)
Jaundice; ascites; other symptoms related to cirrhosis and hepatic failure
History of infantile obstructive cholangiopathy; evidence of inflammatory bowel disease; (possibly exposure to some drugs and chemicals)
Biochemical
Elevated levels of alkaline phosphatase
Direct hyperbilirubinemia, hypertransaminasemia, hypoalbuminemia
Presence of antimitochondrial antibodies
Radiologic
Essentially normal cholangiogram and double-contrast colon roentgenogram or, preferably, normal colonoscopic findings
Abnormalities of large bile ducts that could be associated with small-duct disease; evidence of inflammatory bowel disease
198 (3) the presence of ductopenia is indispensable for the diagnosis. We prefer the term 'ductopenia' [2] because it is shorter than its older synonym, 'paucity of intrahepatic bile ducts' [1]. Our criteria for the diagnosis of I A D are compiled in Table 1. The crucial finding, ductopenia, requires morphologic study because the affected bile ducts are too small for cholangiographic demonstration. By convention, the diagnosis of ductopenia is considered confirmed if interlobular and septal bile ducts cannot be identified in at least 50% of the portal tracts [6]. Of course, such a percentage is only meaningful if a sufficient number of portal tracts can be reviewed. Similar to the practice in other small-duct diseases, it appears desirable to study at least 20 portal tracts [7], which often can be done only if a wedge specimen or consecutive needle biopsy specimens are available. Duct counts are based on experience with control specimens which show that 70-80% of all interlobular arteries are accompanied by a bile duct [8]. Proliferation of cholangioles (ductular proliferation) [4] should be disregarded in this context. The ductopenia and related microscopic findings in patients with IAD generally are indistinguishable from those in the syndrome of primary biliary cirrhosis (PBC) and in other small-duct liver diseases [4]. The only exception is the absence of granulomatous cholangitis in IAD. This type of cholangitis is considered an exclusion criterion for l A D because granulomatous duct lesions are near-diagnostic for PBC and for the rare cases of chronic cholestasis of sarcoidosis [5]. Exclusion criteria for l A D still need to be refined. For instance, we would consider adults of all ages possible candidates for the diagnosis of IAD, but we are not sure whether adolescents should be included also. One of our patients fulfilled all criteria of I A D but the case was not reported here because the first episode of cholestatic liver disease occurred at age 13. It appears possible that in this age group an overlap exists between l A D and infantile nonsyndromatic paucity of intrahepatic bile ducts; presence of this latter condition is considered an exclusion criterion, together with all other manifestations of infantile obstructive cholangiopathy [3]. Similarly, patients with
J. LUDWIG et al. evidence of inflammatory bowel disease should not be considered to have I A D because of the likely association between chronic ulcerative colitis or, rarely, Crohn's colitis, and small-duct primary sclerosing cholangitis (PCS) [9]. The relationship between I A D and adverse drug effects is difficult to discern. Approximately 15 drugs have been incriminated as a cause of destructive cholangitis but the evidence has been weak in most instances. Use of the drug may have been coincidental or it may have in some way aggravated a previously asymptomatic disease [4]. Nevertheless, if cholestatic liver disease closely follows exposure to drugs such as phenothiazines, an adverse drug effect should be considered. Another exclusion criterion for the diagnosis of I A D is the absence of antimitochondrial antibodies because of their strong association with PBC_ Finally, normal cholangiograms, normal proctoscopic findings, and normal colon roentgenograms or, preferably, normal colonoscopic studies, are required to rule out the presence of PSC and inflammatory colon disease, respectively. In our case 3, ERCP had not been done but the absence of PSC was confirmed during orthotopic liver transplantation and after study of the native liver_ The incidence of I A D cannot be determined at present. The authors are aware of six likely additional cases from their consultation practice. Unfortunately, these patients could not be completely reevaluated or, in one instance, failed to meet our age requirements. Published evidence suggests that other authors have observed IAD, particularly Galambos et al. [10] and possibly Nakanuma et al. [11]. Familial IAD also may have been observed [12]. Based on these experiences, it appears likely that some cases of antimitochondrial-antibody-negative PBC, particularly when they occur in men, are examples of IAD. The etiology of IAD, by definition, is unknown. However, three pathogenetic mechanisms should probably be considered - namely, (1) late manifestation of 'infantile' nonsyndromatic paucity of intrahepatic bile ducts, (2) destructive viral cholangitis, and (3) isolated small-duct PSC ('pericholangitis')_ The preponderance of young patients among puta-
IDIOPATHIC ADULTHOOD DUCTOPENIA tive cases of I A D (our cases 1 and 2; patients of Haratake et al. [12]) suggests that in s o m e instances the c o n d i t i o n i n d e e d r e p r e s e n t s a late m a n i f e s t a t i o n of infantile obstructive c h o l a n g i o p a t h y [3]. H o w e v e r , if n o n s y n d r o m a t i c paucity of i n t r a h e p a t i c bile ducts
199 large-duct i n v o l v e m e n t [9], a n d large-duct P S C occurred in the a b s e n c e of i n f l a m m a t o r y bowel disease [18] and w i t h o u t small-duct PSC. B e c a u s e the presence of i n f l a m m a t o r y bowel disease traditionally has
m a y r e m a i n latent for such a long period, classic Alagille's s y n d r o m e [13] s o m e t i m e s should also m a n i f e s t
been used as a selection criterion for the study of 'pericholangitis' or s m a l l - d u c t PSC [9], it is not surprising that cases of isolated small-duct PSC have n o t
itself in late adolescence or early a d u l t h o o d . W e are not aware of such cases.
b e e n described in the literature. O u r Case 2 showed m a n y features of small-duct PSC.
D e s t r u c t i o n of small bile ducts a p p e a r s to occur in s o m e bacterial [14,15] a n d , m o r e c o m m o n l y , in viral infections [16,17]. It is c o n c e i v a b l e that destructive
W e believe that the r e c o g n i t i o n of l A D will lead to the identification of m o r e p a t i e n t s who do n o t fit into the currently accepted categories of small-duct dis-
viral cholangitis, for instance, in acute or c h r o n i c vi-
eases_ O n c e the i n c i d e n c e and n a t u r a l history of I A D have b e e n elucidated, we will be closer to successful
ral n o n - A , n o n - B hepatitis [17], m a y be severe e n o u g h to result in s y m p t o m a t i c d u c t o p e n i a . O u r Case 3 might b e l o n g in this category. Finally, smallduct PSC w i t h o u t large-duct i n v o l v e m e n t and without e v i d e n c e of i n f l a m m a t o r y bowel disease might cause I A D , c o n s i d e r i n g that all o t h e r possible combin a t i o n s of these c o n d i t i o n s have b e e n d o c u m e n t e d that is, small-duct PSC has b e e n f o u n d in patients with c h r o n i c ulcerative colitis, in the a b s e n c e of
References 1 Sharp HL, Carey JB Jr, White JG, Krivit W. Cholestyramine therapy in patients with a paucity of intrahepatic bile ducts. J Pediatr 1967; 71: 723-736. 2 P6rez-Soler A. The inflammatory and atresia-inducing disease of the liver and bile ducts. Monogr Pediatr 1976; 8: 1-245. 3 Landing BH. Considerations of the pathogenesis of neonatal hepatitis, biliary atresia and choledochal cyst. The concept of infantile obstructive cholangiopathy. Prog Pediatr Surg 1974; 6:113-139. 4 Ludwig J. New concepts in biliary cirrhosis. Semin Liver Dis 1987; 7: 293-301. 5 Ludwig J, Czaja A J, Dickson ER, et al. Manifestations of nonsuppurative cholangitis in chronic hepatobiliary diseases: morphologic spectrum, clinical correlations and terminology. Liver 1984; 4:105-116. 6 Balistreri WF. Neonatal cholestasis. Lessons from the past, issues for the future [Foreword]. Semin Liver Dis 1987; 7 (2). 7 Ludwig J, Wiesner RH, Batts KP, et al. The acute vanishing bile duct syndrome (acute irreversible rejection) after orthotopic liver transplantation. Hepatology 1987; 7: 476-483. 8 Nakanuma Y, Ohta G. Histometric and serial section observations of the intrahepatic bile ducts in primary biliary cirrhosis. Gastroenterology 1979; 76: 1326-1332. 9 Wee A, Ludwig J. Pericholangitis in chronic ulcerative colitis: primary sclerosing cho[angitis of the small bile ducts?
studies of etiology a n d , e v e n t u a l l y , t r e a t m e n t trials.
Acknowledgment W e t h a n k Dr. A.J. D e m e t r i s , D e p a r t m e n t of Pathology, U n i v e r s i t y of Pittsburgh, for allowing us to review the native liver of the p a t i e n t described in Case 2. Ann Intern Med 1985; 102: 581-587. 10 Galambos JT, Brooks WS Jr. Atypical biliary cirrhosis - or sclerosing cholangitis. J Clin Gastroenterol 1980; 2: 43-52. 11 Nakanuma Y, Ohta G, Takeshita H, et al. Florid duct lesions and extensive bile duct loss of the intrahepatic biliary tree in chronic liver diseases other than primary biliary cirrhosis. Acta Pathol Jpn 1983; 33:1095-1104. 12 Haratake J, Horie A, Ishii N, Okuno F. Familial intrahepatic cholestatic cirrhosis in young adults. Gastroenterology 1985; 89: 202-209. 13 Alagille, D, Odi~vre M, Gautier M, Dommergues JP_ Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental and sexual development, and cardiac murmur. J Pediatr 1975; 86: 63-71. 14 Vyberg M, Poulsen H. Abnormal bile duct epithelium accompanying septicemia. Virchows Arch Pathol Anat 1984; 402: 451-458. 15 Ishak KG, Rogers WA. Cryptogenic acute cholangitis - association with toxic shock syndrome. Am J Clin Pathol 1981; 76:619-626 16 Finegold MJ, Carpenter RJ. Obliterative cholangitis due to cytomegalovirus: a possible precursor of paucity of intrahepatic bile ducts. Hum Pathol 1982; 13: 662-665. 17 Schmid M, Pirovino M, Altorfer J, et al. Acute hepatitis non-A, non-B; are there any specific light microscopic features? Liver 1982; 2: 61-67. 18 LaRusso NF, Wiesner RH, Ludwig J, MacCarty RL. Primary sclerosing cholangitis. N Engl J Med 1984; 310: 899-903.
193
Elsevier HEP 00454
Idiopathic a d u l t h o o d d u c t o p e n i a A cause of chronic cholestatic liver disease and biliary cirrhosis Jurgen Ludwig t, Russell H. Wiesner 2 and Nicholas F. LaRusso 2 1Department of Laboratol3, Medicine and Pathology, Section of Medical Pathology, and 2Division of Gastroenterology and hlternal Medicine, Mayo Clinic and Mayo Foundation, Rochester, MN (U.S.A.)
(Received 5 April 1988) (Accepted 17 May 1988)
Summary We describe three adult patients who had chronic cholestatic liver disease associated with unexplained loss of interlobular bile ducts; two of these patients eventually required orthotopic liver'transplantation. We have named this condition 'idiopathic adulthood ductopenia' because (1) the etiology is unknown, (2) the age of the patients may be the only distinguishing feature between this newly described condition and neonatal or infantile nonsyndromatic paucity of intrahepatic bile ducts, and (3) morphologic demonstration of ductopenia is an indispensable finding. Our three patients, all males, had a negative drug history, absence of antimitochondrial antibodies, normal cholangiographic findings, and no evidence of inflammatory bowel disease_ Idiopathic adulthood ductopenia may be a representation of (1) late onset of infantile paucity of intrahepatic bile ducts, (2) destructive viral cholangitis, and (3) isolated small-duct primary sclerosing cholangitis - that is, 'pericholangitis' unassociated with inflammatory bowel disease.
Introduction
The term 'paucity of intrahepatic bile ducts' [1] and its more recently coined synonym, 'ductopenia' (originally spelled 'ductipenia' [2]), have been used to describe intrahepatic bile duct atresia and related pediatric liver diseases. Collectively, these conditions have been named 'infantile obstructive cho-
langiopathy' [3]. Because of its brevity and convenience, the term 'ductopenia' is also used to describe findings in adult patients - specifically, a decrease in the number of interlobular and septal bile ducts. The best known example of such small-duct biliary disease [4] in adults is the syndrome of primary biliary cirrhosis. In addition, ductopenia has been observed in sarcoidosis, large-duct primary sclerosing chol-
Correspondence: .lurgen Ludwig, M.D., Department of Laboratory Medicine and Pathology, Section of Medical Pathology, Mayo Clinic, Rochester, MN 55905, U.S.A. Tel. : (507) 284 3883.
0168-8278/88/$03.50 © 1988 Elsevier Science Publishers B.V. (Biomedical Division)
194 angitis, some drug-induced liver diseases, graft-versus-host disease, and hepatic allograft rejection [4]. All these conditions appear to be acquired, and immunologic attack often seems to play a major role in the pathogenesis of the lesions. Of lesser importance is the ductopenia after prolonged large-duct biliary obstruction and suppurative cholangitis and the ductopenia that is observed in rare instances of lymphomatous bile duct destruction [5]. In recent years, we have observed ductopenia and its sequelae in several adult patients who did not appear to have any of the above-named conditions. In particular, our patients had no clinical evidence of primary biliary cirrhosis and they had negative tests for antimitochondrial antibodies, no biopsy evidence of florid duct lesions or sarcoid granulomas, no exposure to drugs or hepatotoxic substances that might have caused bile duct destruction, and no evidence of neoplastic disease. They had had no biliary tract surgery but two of the three patients had had cholecystectomy at ages 18 and 38. Cholangiograms had been normal or not diagnostic. Herein, we describe our experience with three of these patients.
J. LUDWIG et al. membranes, moderate mixed inflammatory infiltrates, and ductopenia (Fig_ 1A). Interlobular bile ducts were identified in only three of eight portal tracts. Hepatocytes in the periphery of the regenerative nodules were swollen and contained Mallory bodies (Fig. 1B) as well as many rhodanine-positive copper granules. Florid duct lesions, granulomas, a~-antitrypsin globules, or cholestasis could not be identified. The patient made an uneventful postoperative recovery_ Because of the clinical and biopsy findings, further diagnostic tests were done. Levels of total bilirubin were 0.4 mg/dl, A S T 30 U/l, alkaline phosphatase 198 U/l, and serum albumin 2.9 g/dl. The se-
Case Reports Case 1 A 22-year-old unemployed man with cerebral pal-
sy was admitted to the Mayo Clinic because of massive hemorrhage from large esophageal varices. Angiography showed patent splenic, superior mesenteric, and portal veins, but the spleen was enlarged and the liver shrunken, causing tortuosity of the intrahepatic arteries. Hepatofugal flow through a large umbilical vein was noted. The corrected hepatic wedge pressure was 25 mmHg. Because the bleeding could not be controlled by any other means, an emergency laparotomy was done and an end-to-side portacaval shunt was established. During that procedure, a grossly cirrhotic liver was noted and a biopsy specimen was obtained. Microscopic:ally, the liver showed septal fibrosis, evidence of nodular regeneration, prominent ductu l a r proliferation with hyalinization of basement
Fig. !. Biliary cirrhosis in patient with idiopathic adulthood ductopenia (Case 1). (A) Fibrous septum with remnant of portal tract. Note hepatic artery branches (A) and absence of interlobular bile duct. (H & E, x 120). (B) Periphery of regenerative nodule with swollen hepatocytes and Mallory bodies (arrows). (H & E, x240).
IDIOPATHIC ADULTHOOD DUCTOPENIA rum ceruloplasmin level was 37.5 mg/dl. The copper excretion in the urine was 199 /~g/24 h. Flameless atomic absorption spectrophotometry of hepatic tissue yielded 1380 ktg copper per g dry weight. A slitlamp examination failed to reveal Kayser-Fleischer rings. Other negative findings included tests to detect hepatitis A and B antibodies, and antimitochondrial antibodies. Although the patient had had no symptoms of inflammatory bowel disease, a double-contrast barium enema study was performed. No abnormalities were found_ Endoscopic retrograde cholangiopancreatography (ERCP) revealed prominent tortuosity and crowding of bile ducts in the shrunken liver but no evidence of sclerosing cholangitis_ The extrahepatic bile ducts and the pancreatic duct were normal. The patient's drug history was negative. During the last 7 years, the patient has been maintained on a daily dose of 500 mg o-penicillamine and a low-copper diet_ During the fourth year, another liver biopsy was done; the specimen revealed less inflammation but persistent ductopenia - no interlobular bile ducts could be found in the five portal tracts of this sample. The fibrosis appeared denser than in the first specimen. Periportal feathery degeneration with many Mallory bodies had become a prominent finding and stainable copper was still present, with little change in density. Electron micrographs revealed an increase in the number and size of lipolysosomes. Despite the biopsy evidence of persistent disease, the patient's status has not deteriorated further; the portacaval shunt functions well. Currently, his total serum bilirubin is 4.3 mg/dl (direct, 2.8); the level of AST is 77 U/l, of alkaline phosphatase 329 U/I, and of albumin, 2.1 g/dl. Case 2
A 21-year-old man, a road construction worker, was admitted to the Mayo Clinic with a 4-year history of jaundice, initially associated with right upper quadrant pain. The patient had not received any medications. A cholecystectomy was done at age 18 because of a pigment stone, apparently without complications; no recurrence of stone disease or other damage to the extrahepatic bile ducts was noted. However, mild pruritus developed. The levels of alkaline phosphatase and ALT were reported to be
195 three times the upper limit of normal. An ERCP examination had been done 1 year prior to his admission; it yielded a normal cholangiogram_ A liver biopsy specimen which had been obtained at that time showed moderate periportal hepatitis with some ductular proliferation and mild piecemeal necrosis, hepatocellular and canalicular cholestasis of predominantly periportal distribution, and minimal fatty change. The specimen contained six portal tracts but no interlobular bile ducts could be identified_ Florid duct lesions, granulomas, or al-antitrypsin globules were absent. During evaluation at the Mayo Clinic, levels of total bilirubin were 7.8 mg/dl (direct, 5.4), AST 69 U/l, alkaline phosphatase 433 U/I, and total cholesterol 230 mg/dl (expected, <210). Laboratory findings included a normal prothrombin time and absence of hepatitis A and B antibodies as well as antimitochondrial antibodies. The serum arantitrypsin level was 193 mg/dl. Copper excretion in the urine was 97 fig/24 h but the presence of Wilson's disease was ruled out after determination of serum ceruloplasmin levels, copper-kinetic studies, And slit-lamp examination. An ERCP again yielded a normal cholangiogram (Fig. 2A). The absence of inflammatory bowel disease was confirmed by history, repeated colonic roentgenography, and proctoscopy. A second liver biopsy was done; the specimen again showed cholestatic hepatitis and ductopenia but also evidence of destructive pleomorphic cholangitis as well as destructive fibrous cholangitis (Fig. 2B). A rhodanine stain for copper was strongly positive; the tissue copper level was 1142#g/g dry weight (expected, <35). In an attempt to classify the disease, two more liver biopsies were done during the next 3 years; they revealed decreasing cholestasis but increasing biliary piecemeal necrosis, biliary fibrosis, and ductopenia (Fig. 2C). A total of nine portal tracts were identified and only two contained interlobular bile ducts. The patient developed symptoms of progressive hepatic failure and eventually required orthotopic liver transplantation, which was done at the University of Pittsburgh, 6 years after onset of the disease. The patient is alive and well, 1 year after the transplant procedure.
196 Study of the native liver at the time of transplantation revealed biliary cirrhosis; the organ weighed 1120 g and measured 19 x 15 x 9.5 cm. T h e hilar structures, including the hepatic ducts, were normal. The p a r e n c h y m a was green. The gallbladder was absent. Microscopically, the liver showed fibrosis, nodular regeneration, and a mixture of portal tracts without bile ducts and portal tracts with proliferated ducts as well as focal fibrous cholangitis; much ductular proliferation was present also. The nodules showed severe cholestasis. C o p p e r and copper-associated protein could not be identified. Chemical c o p p e r analysis was not carried out on this specimen_ Electron micrographs confirmed the presence of ductopenia and revealed enlarged lipolysosomes, similar to those observed in other chronic cholestatic liver diseases.
Case 3 A 51-year-old man had been a high school teacher since graduation from college. A t age 38, he had a cholecystectomy because of h y d r o p s of the gallbladder and, at age 48, resection of an a d e n o c a r c i n o m a of the sigmoid colon ( D u k e B). No evidence of inflammatory bowel disease was found but when he had cancer surgery, the liver was noted to be cirrhotic. Biopsy study revealed septal fibrosis, nodular regeneration with feathery d e g e n e r a t i o n of peripheral hepatocytes, and paucity of interlobular bile ducts. Florid duct lesions, granulomas, a l - a n t i t r y p s i n globules, or bile pigment could not be identified. Iron or copper stains were not available. Levels of tissue copper were not d e t e r m i n e d . L a b o r a t o r y data for that time could not be retrieved.
Fig. 2. Normal cholangiogram, cholangitis, and biliary fibrosis in patient with idiopathic adulthood ductopenia (Case 2). (A) Normal endoscopic retrograde cholangiopancreatogram. (B) Destructive fibrous cholangitis in early stage of the disease. Note fibrous collar and degenerative epithelial changes of interlobular bile duct (asterisk). Branches of the hepatic artery (A) and portal vein (V) accompany the damaged duct. (H & E, x240). (C) Biliary fibrosis with 'empty' portal tract, in late stage of the disease. Note absence of bile duct in vicinity of hepatic artery (A) and portal vein branches (V). (Masson trichrome, x 120.)
.I. LUDWIG et al.
IDIOPATHIC ADULTHOOD DUCTOPENIA
197
During the next 3 years, the patient d e v e l o p e d itching, jaundice, and ascites. W h e n he was referred to the Mayo Clinic for liver transplantation, laboratory studies of serum samples revealed total bilirubin 24.3 mg/dl (direct, 14.4), A S T 72 U/I, alkaline phosphatase 933 U/I, and albumin 1.7 g/dl. The p r o t h r o m bin time was 13.5 s. Negative studies included determination of serum ceruloplasmin, hepatitis A and B serology, and tests to detect antimitochondrial antibody. The patient's drug history prior to the discovery of liver disease was negative. Proctoscopy and double-contrast colon r o e n t g e n o g r a p h y failed to reveal any abnormalities. E R C P was not done. The patient d e v e l o p e d a bleeding d u o d e n a l ulcer and later, spontaneous bacterial peritonitis and E. coli septicemia. The creatinine level rose to 1_8 mg/ml. Because the patient's liver function and general status continued to d e t e r i o r a t e , o r t h o t o p i c liver transplantation was done. The excised liver weighed 2035 g and measured 28 × 18 x 12_5 cm. Biliary cirrhosis with p r o m i n e n t scarring was noted. Microscopically, the regenerative nodules showed much cholestasis in their periphery, with feathery d e g e n e r a t i o n of hep-
atocytes, Mallory bodies, and m o d e r a t e c o p p e r deposition. DUctopenia again was noted; among 20 randomly selected portal tracts, only three contained interlobular bile ducts. A few cholangiectases were also identified. Mild to m o d e r a t e hepatocellular hemosiderosis was another microscopic feature. D e t e r mination of tissue copper levels by flameless atomic absorption s p e c t r o p h o t o m e t r y yielded 2189 ktg/g dry weight (expected, >35). The patient has recovered well. Except for a transient lobular hepatitis of unknown cause, the allograft has functioned well during an 8-month followup period.
Discussion We have coined the name 'idiopathic a d u l t h o o d d u c t o p e n i a ' ( I A D ) for the condition described in these three patients because (1) the etiology is unknown, (2) a d u l t h o o d may be the only distinguishing feature between I A D and neonatal or infantile nonsyndromatic paucity of intrahepatic bile ducts, and
TABLE 1 DIAGNOSTIC FEATURES OF IDIOPATHIC ADULTHOOD DUCTOPENIA Method of study
Obligatory findings
Facuhative findings
Morphologic
Ductopenia, defined as absence of interlobular bile ducts in at least 50% of small portal tracts
Presence of granulomatous Nongranulomatous destructive cholangitis, ductular proliferation, cholangitis (florid duct lesions); biliary piecemeal necrosis, other , histiocytosis X, lymphoma, or other neoplastic diseases; neutrophilic types of cholestasis, Mallory suppurative or nonsuppurative bodies, copper deposition, cholangitis biliary fibrosis or cirrhosis
Exclusion criteria
Clinical
Adulthood (may include late adolescence)
Jaundice; ascites; other symptoms related to cirrhosis and hepatic failure
History of infantile obstructive cholangiopathy; evidence of inflammatory bowel disease; (possibly exposure to some drugs and chemicals)
Biochemical
Elevated levels of alkaline phosphatase
Direct hyperbilirubinemia, hypertransaminasemia, hypoalbuminemia
Presence of antimitochondrial antibodies
Radiologic
Essentially normal cholangiogram and double-contrast colon roentgenogram or, preferably, normal colonoscopic findings
Abnormalities of large bile ducts that could be associated with small-duct disease; evidence of inflammatory bowel disease
198 (3) the presence of ductopenia is indispensable for the diagnosis. We prefer the term 'ductopenia' [2] because it is shorter than its older synonym, 'paucity of intrahepatic bile ducts' [1]. Our criteria for the diagnosis of I A D are compiled in Table 1. The crucial finding, ductopenia, requires morphologic study because the affected bile ducts are too small for cholangiographic demonstration. By convention, the diagnosis of ductopenia is considered confirmed if interlobular and septal bile ducts cannot be identified in at least 50% of the portal tracts [6]. Of course, such a percentage is only meaningful if a sufficient number of portal tracts can be reviewed. Similar to the practice in other small-duct diseases, it appears desirable to study at least 20 portal tracts [7], which often can be done only if a wedge specimen or consecutive needle biopsy specimens are available. Duct counts are based on experience with control specimens which show that 70-80% of all interlobular arteries are accompanied by a bile duct [8]. Proliferation of cholangioles (ductular proliferation) [4] should be disregarded in this context. The ductopenia and related microscopic findings in patients with IAD generally are indistinguishable from those in the syndrome of primary biliary cirrhosis (PBC) and in other small-duct liver diseases [4]. The only exception is the absence of granulomatous cholangitis in IAD. This type of cholangitis is considered an exclusion criterion for l A D because granulomatous duct lesions are near-diagnostic for PBC and for the rare cases of chronic cholestasis of sarcoidosis [5]. Exclusion criteria for l A D still need to be refined. For instance, we would consider adults of all ages possible candidates for the diagnosis of IAD, but we are not sure whether adolescents should be included also. One of our patients fulfilled all criteria of I A D but the case was not reported here because the first episode of cholestatic liver disease occurred at age 13. It appears possible that in this age group an overlap exists between l A D and infantile nonsyndromatic paucity of intrahepatic bile ducts; presence of this latter condition is considered an exclusion criterion, together with all other manifestations of infantile obstructive cholangiopathy [3]. Similarly, patients with
J. LUDWIG et al. evidence of inflammatory bowel disease should not be considered to have I A D because of the likely association between chronic ulcerative colitis or, rarely, Crohn's colitis, and small-duct primary sclerosing cholangitis (PCS) [9]. The relationship between I A D and adverse drug effects is difficult to discern. Approximately 15 drugs have been incriminated as a cause of destructive cholangitis but the evidence has been weak in most instances. Use of the drug may have been coincidental or it may have in some way aggravated a previously asymptomatic disease [4]. Nevertheless, if cholestatic liver disease closely follows exposure to drugs such as phenothiazines, an adverse drug effect should be considered. Another exclusion criterion for the diagnosis of I A D is the absence of antimitochondrial antibodies because of their strong association with PBC_ Finally, normal cholangiograms, normal proctoscopic findings, and normal colon roentgenograms or, preferably, normal colonoscopic studies, are required to rule out the presence of PSC and inflammatory colon disease, respectively. In our case 3, ERCP had not been done but the absence of PSC was confirmed during orthotopic liver transplantation and after study of the native liver_ The incidence of I A D cannot be determined at present. The authors are aware of six likely additional cases from their consultation practice. Unfortunately, these patients could not be completely reevaluated or, in one instance, failed to meet our age requirements. Published evidence suggests that other authors have observed IAD, particularly Galambos et al. [10] and possibly Nakanuma et al. [11]. Familial IAD also may have been observed [12]. Based on these experiences, it appears likely that some cases of antimitochondrial-antibody-negative PBC, particularly when they occur in men, are examples of IAD. The etiology of IAD, by definition, is unknown. However, three pathogenetic mechanisms should probably be considered - namely, (1) late manifestation of 'infantile' nonsyndromatic paucity of intrahepatic bile ducts, (2) destructive viral cholangitis, and (3) isolated small-duct PSC ('pericholangitis')_ The preponderance of young patients among puta-
IDIOPATHIC ADULTHOOD DUCTOPENIA tive cases of I A D (our cases 1 and 2; patients of Haratake et al. [12]) suggests that in s o m e instances the c o n d i t i o n i n d e e d r e p r e s e n t s a late m a n i f e s t a t i o n of infantile obstructive c h o l a n g i o p a t h y [3]. H o w e v e r , if n o n s y n d r o m a t i c paucity of i n t r a h e p a t i c bile ducts
199 large-duct i n v o l v e m e n t [9], a n d large-duct P S C occurred in the a b s e n c e of i n f l a m m a t o r y bowel disease [18] and w i t h o u t small-duct PSC. B e c a u s e the presence of i n f l a m m a t o r y bowel disease traditionally has
m a y r e m a i n latent for such a long period, classic Alagille's s y n d r o m e [13] s o m e t i m e s should also m a n i f e s t
been used as a selection criterion for the study of 'pericholangitis' or s m a l l - d u c t PSC [9], it is not surprising that cases of isolated small-duct PSC have n o t
itself in late adolescence or early a d u l t h o o d . W e are not aware of such cases.
b e e n described in the literature. O u r Case 2 showed m a n y features of small-duct PSC.
D e s t r u c t i o n of small bile ducts a p p e a r s to occur in s o m e bacterial [14,15] a n d , m o r e c o m m o n l y , in viral infections [16,17]. It is c o n c e i v a b l e that destructive
W e believe that the r e c o g n i t i o n of l A D will lead to the identification of m o r e p a t i e n t s who do n o t fit into the currently accepted categories of small-duct dis-
viral cholangitis, for instance, in acute or c h r o n i c vi-
eases_ O n c e the i n c i d e n c e and n a t u r a l history of I A D have b e e n elucidated, we will be closer to successful
ral n o n - A , n o n - B hepatitis [17], m a y be severe e n o u g h to result in s y m p t o m a t i c d u c t o p e n i a . O u r Case 3 might b e l o n g in this category. Finally, smallduct PSC w i t h o u t large-duct i n v o l v e m e n t and without e v i d e n c e of i n f l a m m a t o r y bowel disease might cause I A D , c o n s i d e r i n g that all o t h e r possible combin a t i o n s of these c o n d i t i o n s have b e e n d o c u m e n t e d that is, small-duct PSC has b e e n f o u n d in patients with c h r o n i c ulcerative colitis, in the a b s e n c e of
References 1 Sharp HL, Carey JB Jr, White JG, Krivit W. Cholestyramine therapy in patients with a paucity of intrahepatic bile ducts. J Pediatr 1967; 71: 723-736. 2 P6rez-Soler A. The inflammatory and atresia-inducing disease of the liver and bile ducts. Monogr Pediatr 1976; 8: 1-245. 3 Landing BH. Considerations of the pathogenesis of neonatal hepatitis, biliary atresia and choledochal cyst. The concept of infantile obstructive cholangiopathy. Prog Pediatr Surg 1974; 6:113-139. 4 Ludwig J. New concepts in biliary cirrhosis. Semin Liver Dis 1987; 7: 293-301. 5 Ludwig J, Czaja A J, Dickson ER, et al. Manifestations of nonsuppurative cholangitis in chronic hepatobiliary diseases: morphologic spectrum, clinical correlations and terminology. Liver 1984; 4:105-116. 6 Balistreri WF. Neonatal cholestasis. Lessons from the past, issues for the future [Foreword]. Semin Liver Dis 1987; 7 (2). 7 Ludwig J, Wiesner RH, Batts KP, et al. The acute vanishing bile duct syndrome (acute irreversible rejection) after orthotopic liver transplantation. Hepatology 1987; 7: 476-483. 8 Nakanuma Y, Ohta G. Histometric and serial section observations of the intrahepatic bile ducts in primary biliary cirrhosis. Gastroenterology 1979; 76: 1326-1332. 9 Wee A, Ludwig J. Pericholangitis in chronic ulcerative colitis: primary sclerosing cho[angitis of the small bile ducts?
studies of etiology a n d , e v e n t u a l l y , t r e a t m e n t trials.
Acknowledgment W e t h a n k Dr. A.J. D e m e t r i s , D e p a r t m e n t of Pathology, U n i v e r s i t y of Pittsburgh, for allowing us to review the native liver of the p a t i e n t described in Case 2. Ann Intern Med 1985; 102: 581-587. 10 Galambos JT, Brooks WS Jr. Atypical biliary cirrhosis - or sclerosing cholangitis. J Clin Gastroenterol 1980; 2: 43-52. 11 Nakanuma Y, Ohta G, Takeshita H, et al. Florid duct lesions and extensive bile duct loss of the intrahepatic biliary tree in chronic liver diseases other than primary biliary cirrhosis. Acta Pathol Jpn 1983; 33:1095-1104. 12 Haratake J, Horie A, Ishii N, Okuno F. Familial intrahepatic cholestatic cirrhosis in young adults. Gastroenterology 1985; 89: 202-209. 13 Alagille, D, Odi~vre M, Gautier M, Dommergues JP_ Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental and sexual development, and cardiac murmur. J Pediatr 1975; 86: 63-71. 14 Vyberg M, Poulsen H. Abnormal bile duct epithelium accompanying septicemia. Virchows Arch Pathol Anat 1984; 402: 451-458. 15 Ishak KG, Rogers WA. Cryptogenic acute cholangitis - association with toxic shock syndrome. Am J Clin Pathol 1981; 76:619-626 16 Finegold MJ, Carpenter RJ. Obliterative cholangitis due to cytomegalovirus: a possible precursor of paucity of intrahepatic bile ducts. Hum Pathol 1982; 13: 662-665. 17 Schmid M, Pirovino M, Altorfer J, et al. Acute hepatitis non-A, non-B; are there any specific light microscopic features? Liver 1982; 2: 61-67. 18 LaRusso NF, Wiesner RH, Ludwig J, MacCarty RL. Primary sclerosing cholangitis. N Engl J Med 1984; 310: 899-903.