SEMINARS IN LIVER DISEASE-VOL.
12. NO. 2, 1992
Human Immunodeficiency Virus-Associated Biliary Tract Disease
Although hepatic parenchymal involvement with opportunistic infections and malignancies has been widely recognized in patients with human immunodeficiency virus (HIV) disease, disease of bile ducts and gallbladder with unique clinical manifestations has not generally been recognized." With increasing frequency, typical and atypical biliary infections and malignancies are being reported among patients with HIV disease. Of course, in approaching patients with the diagnosis of acquired immunodeficiency syndrome (AIDS)-related complex or AIDS who have biliary tract signs or symptoms, the clinician must at the outset be certain that one is not dealing with a routine condition of the bile duct such as postoperative biliary stricture, calculous cholecystitis, choledocholithiasis, or periampullary neoplasm. In approaching patients with HIV disease who have signs and symptoms of biliary tract abnormalities, the same diagnostic and therapeutic approach should be employed as with nonHIV-infected patients. Emphasis must always be given to the search for treatable conditions, especially those that can be ameliorated with minimal intervention.
HISTORICAL PERSPECTIVE Atypical opportunistic infections of the bile ducts and gallbladder were recognized in veterinarians for several Kovatch and Whiteh in 1972 described cryptosporidial cholangitis among juvenile rhesus monkeys. Combined B- and T-cell immunodeficiency in Arabian foals with associated cryptosporidial cholangitis was likewise reported by Snyder et al in 1978.' Many of the cholangiographic abnormalities described in these animals mirror those described subsequently in patients with immunodeficiency. Pitlik et al8.' and Guarda et all0 first described human cryptosporidial infection of the bile ducts in 1983. Each described an AIDS patient with hepatobiliary cryptosporidium largely involving the extrahepatic duct associated with obstruction. No intrahe-
From rhe Gtrsrroenterology Division, Depurttnent of Medicine, Sun Fruncisco General Hospital. Universirv of Cnliforniu, Sun Fruiicisco, Culiforniu. Reprint requests: Dr. Cello, Gastroenterology Division, Department of Medicine, San Francisco General Hospital, 995 Potrero Avenue, San Francisco, CA 94143.
patic disease was reported by them. One of these patients was treated with and responded to operative sphincteroplasty. Pitlik et al first suggested that the source of chronic infection of the bile ducts with Cryptosporidium was a chronically inflamed gallbladder. Blumberg et all' and Kavin et all' in 1984 and 1986, respectively, first reported acalculous cholecystitis in patients with AIDS. One patient had cytomegalovirus (CMV) disease and the second had cytomegalovirus plus Cryptosporidium on pathologic evaluation. Margulis and associate^'^ at New York Hospital in 1986 reported on three patients with a diagnosis of AIDS, who had right upper quadrant pain, increased serum alkaline phosphatase levels, and noninvasive imaging demonstrating dilated ductal systems. Two of their patients underwent endoscopic retrograde cholangiopancreatography (ERCP) sphincterotomy and two required cholecystectomy. Pathologic evaluation demonstrated CMV alone in one patient, Cryptosporidium alone in one patient, and CMV plus Cryptosporidium in one patient. In 1987 Schneiderman et a1'3.'5reported on eight patients with the endoscopic appearance of papillary stenosis and associated intra- or extrahepatic sclerosing cholangitis. Patients presented with predominantly right upper quadrant abdominal pain and associated fever. Mean serum alkaline phosphatase levels of 720 IUiliter together with near normal bilirubin levels were reported. Most patients had prominent bile duct dilation on computed tomography (CT) or ultrasound evaluation prior to ERCP (Fig. 1). All patients underwent successful ERCP sphincterotomy with marked improvement in pain. Four of the patients demonstrated specific histopathologic abnormalities, including two patients with Cryptosporidium and two patients with CMV. Viteri and GreenI6 in 1987 likewise described two patients with bile duct abnormalities presenting with right upper quadrant pain, fever, and an increased serum alkaline phosphatase level. One patient underwent ERCP evaluation, demonstrating diffuse changes of sclerosing cholangitis, and a papillary biopsy, demonstrating CMV inclusions. A liver biopsy on the second patient demonstrated periportal fibrosis, but no CMV or Cryptosporidium. This latter patient had, however, a well-established diagnosis of CMV-associated esophagitis. Gremse et all7 in 1989 likewise described intra- and extrahepatic sclerosing cholangitis and associated papillary stenosis in an immunocompromised, but not HIV-infected, child, with chronic cryptosporidial diarrhea. Once again, ERCP demonstrated a dilated common bile duct with
Copyright O 1992 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, N Y 10016. All rights reserved.
213
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JOHN P. CELLO, M.D.
12, NUMBER 2, 1992
FIG. 1. Computed tomography scan of the abdomen. Markedly dilated intrahepatic ducts (left side greater than right side) are noted (arrows) in a patient with high-grade papillary stenosis.
characteristic features of sclerosing cholangitis. Prompt improvement in pain and dramatic decrease in abnormal liver function tests occurred following ERCP sphincterotomy. Additional reports in the literature have noted profound abnormalities of the biliary tree among patients with AIDS.
FIG. 3. Papillary stenosis and extrahepatic biliary sclerosis. The catheter has been passed selectively into the narrowed distal bile duct (arrows), which measures 8 mm in diameter (a bubble of air has likewise been introduced into the duct). The main duct is irregular in contour as well.
Among 40 patients with AIDS-associated bile duct abnormalities, we have defined four different, but related forms of HIV-associuted cholungiopathy. '' These include:
Pclpillury stenosis, defined as a common bile duct diameter greater than 8 mm, distal 2 to 4 mm tapering of the common bile duct with marked retention of contrast beyond 30 minutes (Figs. 2, 3). Sclrrosing cholangitis, characterized by focal strictures and dilations of the intra- and extrahepatic bile ducts (Figs. 4 through 8).
FIG. 2. Papillary stenosis. The main common bile duct is larger in diameter than the endoscope (that is more than 12 mm). Normal intrahepatic ducts are noted.
FIG. 4. lntrahepatic sclerosing cholangitis, mild. Subtle irregularities of the intrahepatic ducts are shown with irregular focal stricturing. The extrahepatic duct is normal.
CLINICAL SPECTRUM OF DISEASE
Downloaded by: University of British Columbia. Copyrighted material.
SEMINARS IN LIVER DISEASE-VOLUME
FIG. 5. Intra- and extrahepatic sclerosing cholangitis, mild. Irregular contours of the intra- and extrahepatic ducts are shown. Disease is more severe in the left ductal system. The extrahepatic duct is "beaded" in Contour with subtle serrations.
3.
Combined papillarj~stenosis and intra- and extrahepatic sclerosing cholangitis (Fig. 3 ) . 4. Long, extrahepatic bile duct strictures with lengths in excess of 1 to 2 cm in patients without prior common bile duct exploration or documented chronic pancreatitis (Fig. 9). In addition to the features just noted, the common bile duct in patients with HIV cholangiopathy often has a "beaded" mucosal pattern suggestive of intramural submucosal infiltration and edema (Figs. 5 , 6 ) . The left duc-
FIG. 6. Early intra- and extrahepatic sclerosing cholangitis, same patient as in Figure 5. The irregular serrated mucosa (arrows) of the common hepatic and bile ducts is noted. Small focal debris is also noted in the right main bile duct.
FIG. 7. Moderately severe intra- and extrahepatic sclerosing cholangitis. Both intra- and extrahepatic ducts are markedly irregular with irregular caliber and focal stricturing.
tal system is disproportionately more severely involved with intrahepatic ducts having irregular sacculations often containing what appears to be intraductal debris or shredded sloughed mucosa (Fig. 6 ) . The ducts are markedly irregular and there is a pruning of the smaller intrahepatic bile ducts. The cholangiographic features of AIDS-associated cholangiopathy do differ from those of idiopathic sclerosing cholangitis. In most patients with the latter condition, the common bile duct is irregularly
FIG. 8. Severe intrahepatic sclerosing cholangitis. A balloon catheter (arrow) has been passed and inflated to occlude the proximal common hepatic duct to allow for complete filling of the intrahepatic ducts. Marked irregularities of the duct contour are noted.
Downloaded by: University of British Columbia. Copyrighted material.
BILIARY TRACT DISEASE AND HIV-CELLO
SEMINARS IN LIVER DISEASE-VOLUME
TABLE 2.
12, NUMBER 2, 1992
AlDS Cholangiopathy*
Frciture
N u m b ~ rof'Patienrs
Cytomegalovirus ( C M V ) Cr!pto.sporidium Mycobacterium avium CMV and Crvprosporidium Kaposi's sarcoma Lymphoma Inflammation only Total
FIG. 9. Long extrahepatic bile duct stricture. An irregularly t a p e r e d distal d u c t is n o t e d ( b e t w e e n t h e arrows) with m a r k e d proximal bile d u c t dilation. P o s t m o r t e m histopathologic e x a m ination n o t e d cytomegalovirus inclusions throughout t h e distal bile d u c t m u c o s a .
strictured and rarely exceeds 4 to 5 mm in diameter. In idiopathic sclerosing cholangitis, moreover, the entire duct tends to be involved and there is usually no "beading" of the mucosa. In addition, among patients with idiopathic sclerosing cholangitis there are rare dilated segments, virtually no intraductal debris, but an associated paucity of intrahepatic bile ducts. The combination of papillary stenosis and sclerosing cholangitis has been found in over half our patients with HIV cholangiopathy. Pure sclerosing cholangitis, papillary stenosis, and long extrahepatic bile duct strictures are less frequently encountered and, when combined, equal the remaining nearly 50% of patients with AIDS-associated cholangiopathy. Table I compares the clinical features of AIDS pa-
tients with subsequently confirmed bile duct abnormalities with those who had normal bile ducts on ERCP. The mean age of our 40 patients with AIDS cholangiopathy was 36 2 1.2 years. Patients had the diagnosis of AIDS for nearly I year and most presented with right upper quadrant pain. The remainder of our patients with subsequently confirmed bile duct abnormalities presented with fever and jaundice together with abnormal biochemical tests of hepatocellular function. Twenty-eight of 38 patients had abnormal ultrasonographic findings, including dilated intra- or extrahepatic bile ducts, thickened bile duct wall, and distal tapering of the common bile duct. Twelve of 17 patients who underwent CT scans had abnormal CT findings consisting largely of dilated intra- or extrahepatic bile ducts. These two features, namely, abnormal ultrasound and CT findings, distinguished the patients with AIDS cholangiopathy from patients with similar clinical presentation in whom ERCP subsequently confirmed normal bile ducts. However, it should be noted that nearly one third of patients with confirmed abnormal bile ducts had normal noninvasive imaging studies. As mentioned earlier, the most remarkable abnormality detected on prior biochemical testing was marked elevation of the alkaline phosphatase to a mean of 750 IUlliter or five times the upper limits of normal. Serum transaminasc levels were only moderately abnormal. Although there were a few patients with hyperbilirubinemia, the mean serum bilirubin was 1.5 mgldl. As anticipated, most patients had mild hypoalbuminemia, leukopenia, and anemia.
TABLE 1. AlDS Cholangiopathy*t Abnormal Ducts
(11 =
401
Norn~cilDucts f n
=
I I1
Mean age (yr) AIDS duration (mo) Right upper quadrant pain Abnormal ultrasound Abnormal CT Alkaline Phosphatase (IUIL) Alamine amino-transferase (IUiL) Bilirubin (mgidl) Albumin *AIDS: acquired immunodeficiency syndrome; CT: computed tomography; NS: difference not significant; t i SEM
11
Vc!ire
Downloaded by: University of British Columbia. Copyrighted material.
"Ampullary biopsy at endoscopic retrograde cholangiopancreatography, surgical pathology, or postmortem.
planation remains elusive. It is possible that the biliary ductular epithelium is a target organ for HIV infection. Previously, bowel epithelium has been noted to harbor HIV, and the possibility remains that the HIV itself distorts or destroys bile duct epithelium or submucosa. It is also possible that there is a stereotypic pattern of injury in the bile duct and that a similar pattern of injury occurs from a multitude of pathogens and malignancies. Moreover, it could be that all the cholangiopathic findings are due to CMV or Cryptosporidium and that the patients without specific histopathologic diagnosis have CMV or Cryptosporidiutn undetected because of sampling error or the limited number of postmortem evaluations. Another possibility could invoke an ulcerative colitis-like ductal sclerosis, possibly related to persistent portal bacteremia in AIDS patients, who so frequently have intractable diarrhea and associated enteritis. Furthermore, a unique HLA haplotype, HLA-DRw52a, might be associated with an immunologic response to a ubiquitous possibilities unproven or agent in these patients.?"ther untested include copper hepatotoxicity, an unidentified viral infection, enhanced HLA class I1 antigens on bile duct epithelial cells, or circulating immune complexes. I t also remains undetermined whether there are unique biliary manometric abnormalities in AIDS patients with or without cholangiopathic abnormalities. Clearly, additional intensive investigations will be necessary to define the etiology of HIV-associated cholangiopathy. FIG. 10. Ampullary biopsy following sphincterotomy in a patient with AIDS-associated cholangiopathy. Two classic cytomegalovirus inclusion cells (arrows) are noted within the ampullary mucosal epithelial cells.
THERAPY For those patients presenting with moderate to severe right upper quadrant pain, together with cholangiographic abnormalities of papillary stenosis, an ERCP sphincterotomy should be performed. In our study, dramatic improvement in pain scores occurred; however, there was no substantial change in serum alkaline phosphatase, bilirubin, or transaminase levels." In a handful of patients undergoing repeat ERCP evaluation following sphincterotomy, progressive intrahepatic sclerosing cholangitis has been noted. Among 40 patients with cholangiopathy, only 18 had a specific histopathologic diagnosis based on ampullary biopsy and surgical pathologic findings or postmortem evaluation. The histopathologic findings in these 40 patients is shown in Table 2. The single most commonly identifiable histopathologic feature on ampullary biopsy was CMV alone or in combination with Cryptosporidum (Fig. 10). Twenty-two patients had acute and chronic inflammatory changes in the periampullary area or periductal region on histopathologic examination.
ETIOLOGY Several etiologic factors for HIV-associated cholangiopathy have been suggested, although a definitive ex-
FUTURE PROSPECTS In addition to endoscopic sphincterotomies for those patients with AIDS-associated papillary stenosis, there have been a few isolated reports of patients undergoing balloon dilation or endoscopic or percutaneous stent placement for bile duct obstructions. Chemotherapy is appropriate in patients with Kaposi's sarcoma or lymphoma involving the bilc duct. The potential efficacy of bile salt therapy such as ursodeoxycholic acid or anti-CMV therapies (such as ganciclovir) have yet to be reported, although we have treated a handful of patients with these agents and have noted modest improvement in intrahepatic bile duct abnormalities over a short period of follow-up time.
REFERENCES Glascow BJ, Anders K , Layfield CJ, et al: Clinical and pathologic findings of the liver in the acquired immune deficiency syndrome (AIDS). Clin Pathol 83:582-588. 1985. Caccamo P. Pervez N K . Marchevsky A: Primary lymphoma of the liver in the acquired immunodeficiency syndrome. Arch Pathol Lab Med 110:553-555, 1986. Nakanuma Y. Liew CT, Peters RL, et al: Pathologic features of the liver in acquired immune deficiency syndrome (AIDS). Liver 6: 158-166, 1986. Lebovics E. Thung SN. Schaffner F, et al: The liver In the acquired immunodeficiency syndrome: A clinical and histologic study. Hepatology 2:293-298, 1985. Schneiderman DJ, Arenson DM, Cello JP, et al: Hepatic disease in patients with the acquired immune deficiency syndrome (AIDS). Hepatology 7:925-930, 1987.
Downloaded by: University of British Columbia. Copyrighted material.
BILIARY TRACT DISEASE AND HIV-CELLO
6. 7. 8.
9. 10.
II.
12.
13.
14.
15.
SEMINARS IN LIVER DISEASE-VOLUME Kovatch RM, White JD: Cryptosporidiosis in two juvenile rhesus monkeys. Vet Pathol 9:426-440, 1972. Snyder SP, England JJ, McChesney AE: Cryptosporidiosis in immunodeficient Arabian foals. Vet Pathol 15: 12- 17, 1978. Pitlik S,Fainstein V, Garza D, et al: Human cryptosporidiosis: Spectrum of disease: Report of six cases and review of the literature. Arch Intern Med 143:2269-2275, 1983. Pitlik S, Fainstein V, Rios A, et al: Cryptosporidial cholecystitis. (Letter.) N Engl J Med 308:967, 1983. Guarda LA, Stein SA, Clearly KA, Ordonez NG: Human cryptosporidiosis in the acquired immune deficiency syndrome. Arch Pathol Lab Med 107:562-566, 1983. Blumberg RS. Kelsey P, Perrone T, et al: Cytomegalovirusand cryptosporidium-associated acalculous gangrenous cholecystitis. Am J Med 76:l 118-1 123, 1984. Kavin H. Jonas RB, Chowdhury L, Kabins A: Acalculous cholecystitis and cytomcgalovirus infection in the acquired immunodeficiency syndrome. Ann Intern Med 104:53-54, 1986. Margulis SJ. Honig CL, Soave R, et al: Biliary tract obstruction in the acquired immunodeficiency syndrome. Ann Intern Med 105:207-210, 1986. Schneiderman DJ, Cello JP, Laing FC: Papillary stenosis and sclerosing cholangitis in the acquired immunodeficiency syndrome. Ann Intern Med 106:546-549. 1987. Dolmatch BL. Laing FC, Cello JP et al: AIDS-related cholangitis: Radiographic findings in nine patients. Radiology 163:313-316, 1987.
12, NUMBER 2, 1992
Viteri AL, Greene JF: Bile duct abnormalities in the acquired immune deficiency syndrome. Gastroenterology 92:20142108, 1987. Gremse DA, Bucuvalas JC, Bongiovanni GL: Papillary stenosis and sclerosing cholangitis in an immunodeficient child. Gastroenterology 96: 1600-1603, 1989. Ccllo JP: Acquired immunodeficiency syndrome cholangiopathy: Spectrum of disease. Am J Med 86539-546, 1989. Kaplan LD, Kahn J, Jacobson M, et al: Primary bile duct lymphoma in the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 110:161-162, 1989. Bruggen JT, Cello JP, Chernoff DN, et al: Unusual biliary tract disease in a patient with AIDS--clinical pathological conference. Gastroenterol Int 1 : 3 3 4 0 , 1988. Radin DR, Cohen H, Halls JM: Acalculous inflammatory disease of the biliary tree in acquired immunodeficiency syndrome: CT demonstration. J Comput Assist Tomogr 11:775778, 1987. lannuzzi C, Belghiti J, Erlinger S, et al: Cholangitis associated with cholecystitis in patients with acquired immunodeficiency syndrome. Arch Surg 125:1211-1213, 1990. Prochazka EJ, Terasaki PI, Park MS. et al: Association of primary sclerosing cholangitis with HLA-DRw52a. N Engl J Med 322: 1842-1844. 1990.
Downloaded by: University of British Columbia. Copyrighted material.
218
12. NO. 2, 1992
Human Immunodeficiency Virus-Associated Biliary Tract Disease
Although hepatic parenchymal involvement with opportunistic infections and malignancies has been widely recognized in patients with human immunodeficiency virus (HIV) disease, disease of bile ducts and gallbladder with unique clinical manifestations has not generally been recognized." With increasing frequency, typical and atypical biliary infections and malignancies are being reported among patients with HIV disease. Of course, in approaching patients with the diagnosis of acquired immunodeficiency syndrome (AIDS)-related complex or AIDS who have biliary tract signs or symptoms, the clinician must at the outset be certain that one is not dealing with a routine condition of the bile duct such as postoperative biliary stricture, calculous cholecystitis, choledocholithiasis, or periampullary neoplasm. In approaching patients with HIV disease who have signs and symptoms of biliary tract abnormalities, the same diagnostic and therapeutic approach should be employed as with nonHIV-infected patients. Emphasis must always be given to the search for treatable conditions, especially those that can be ameliorated with minimal intervention.
HISTORICAL PERSPECTIVE Atypical opportunistic infections of the bile ducts and gallbladder were recognized in veterinarians for several Kovatch and Whiteh in 1972 described cryptosporidial cholangitis among juvenile rhesus monkeys. Combined B- and T-cell immunodeficiency in Arabian foals with associated cryptosporidial cholangitis was likewise reported by Snyder et al in 1978.' Many of the cholangiographic abnormalities described in these animals mirror those described subsequently in patients with immunodeficiency. Pitlik et al8.' and Guarda et all0 first described human cryptosporidial infection of the bile ducts in 1983. Each described an AIDS patient with hepatobiliary cryptosporidium largely involving the extrahepatic duct associated with obstruction. No intrahe-
From rhe Gtrsrroenterology Division, Depurttnent of Medicine, Sun Fruncisco General Hospital. Universirv of Cnliforniu, Sun Fruiicisco, Culiforniu. Reprint requests: Dr. Cello, Gastroenterology Division, Department of Medicine, San Francisco General Hospital, 995 Potrero Avenue, San Francisco, CA 94143.
patic disease was reported by them. One of these patients was treated with and responded to operative sphincteroplasty. Pitlik et al first suggested that the source of chronic infection of the bile ducts with Cryptosporidium was a chronically inflamed gallbladder. Blumberg et all' and Kavin et all' in 1984 and 1986, respectively, first reported acalculous cholecystitis in patients with AIDS. One patient had cytomegalovirus (CMV) disease and the second had cytomegalovirus plus Cryptosporidium on pathologic evaluation. Margulis and associate^'^ at New York Hospital in 1986 reported on three patients with a diagnosis of AIDS, who had right upper quadrant pain, increased serum alkaline phosphatase levels, and noninvasive imaging demonstrating dilated ductal systems. Two of their patients underwent endoscopic retrograde cholangiopancreatography (ERCP) sphincterotomy and two required cholecystectomy. Pathologic evaluation demonstrated CMV alone in one patient, Cryptosporidium alone in one patient, and CMV plus Cryptosporidium in one patient. In 1987 Schneiderman et a1'3.'5reported on eight patients with the endoscopic appearance of papillary stenosis and associated intra- or extrahepatic sclerosing cholangitis. Patients presented with predominantly right upper quadrant abdominal pain and associated fever. Mean serum alkaline phosphatase levels of 720 IUiliter together with near normal bilirubin levels were reported. Most patients had prominent bile duct dilation on computed tomography (CT) or ultrasound evaluation prior to ERCP (Fig. 1). All patients underwent successful ERCP sphincterotomy with marked improvement in pain. Four of the patients demonstrated specific histopathologic abnormalities, including two patients with Cryptosporidium and two patients with CMV. Viteri and GreenI6 in 1987 likewise described two patients with bile duct abnormalities presenting with right upper quadrant pain, fever, and an increased serum alkaline phosphatase level. One patient underwent ERCP evaluation, demonstrating diffuse changes of sclerosing cholangitis, and a papillary biopsy, demonstrating CMV inclusions. A liver biopsy on the second patient demonstrated periportal fibrosis, but no CMV or Cryptosporidium. This latter patient had, however, a well-established diagnosis of CMV-associated esophagitis. Gremse et all7 in 1989 likewise described intra- and extrahepatic sclerosing cholangitis and associated papillary stenosis in an immunocompromised, but not HIV-infected, child, with chronic cryptosporidial diarrhea. Once again, ERCP demonstrated a dilated common bile duct with
Copyright O 1992 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, N Y 10016. All rights reserved.
213
Downloaded by: University of British Columbia. Copyrighted material.
JOHN P. CELLO, M.D.
12, NUMBER 2, 1992
FIG. 1. Computed tomography scan of the abdomen. Markedly dilated intrahepatic ducts (left side greater than right side) are noted (arrows) in a patient with high-grade papillary stenosis.
characteristic features of sclerosing cholangitis. Prompt improvement in pain and dramatic decrease in abnormal liver function tests occurred following ERCP sphincterotomy. Additional reports in the literature have noted profound abnormalities of the biliary tree among patients with AIDS.
FIG. 3. Papillary stenosis and extrahepatic biliary sclerosis. The catheter has been passed selectively into the narrowed distal bile duct (arrows), which measures 8 mm in diameter (a bubble of air has likewise been introduced into the duct). The main duct is irregular in contour as well.
Among 40 patients with AIDS-associated bile duct abnormalities, we have defined four different, but related forms of HIV-associuted cholungiopathy. '' These include:
Pclpillury stenosis, defined as a common bile duct diameter greater than 8 mm, distal 2 to 4 mm tapering of the common bile duct with marked retention of contrast beyond 30 minutes (Figs. 2, 3). Sclrrosing cholangitis, characterized by focal strictures and dilations of the intra- and extrahepatic bile ducts (Figs. 4 through 8).
FIG. 2. Papillary stenosis. The main common bile duct is larger in diameter than the endoscope (that is more than 12 mm). Normal intrahepatic ducts are noted.
FIG. 4. lntrahepatic sclerosing cholangitis, mild. Subtle irregularities of the intrahepatic ducts are shown with irregular focal stricturing. The extrahepatic duct is normal.
CLINICAL SPECTRUM OF DISEASE
Downloaded by: University of British Columbia. Copyrighted material.
SEMINARS IN LIVER DISEASE-VOLUME
FIG. 5. Intra- and extrahepatic sclerosing cholangitis, mild. Irregular contours of the intra- and extrahepatic ducts are shown. Disease is more severe in the left ductal system. The extrahepatic duct is "beaded" in Contour with subtle serrations.
3.
Combined papillarj~stenosis and intra- and extrahepatic sclerosing cholangitis (Fig. 3 ) . 4. Long, extrahepatic bile duct strictures with lengths in excess of 1 to 2 cm in patients without prior common bile duct exploration or documented chronic pancreatitis (Fig. 9). In addition to the features just noted, the common bile duct in patients with HIV cholangiopathy often has a "beaded" mucosal pattern suggestive of intramural submucosal infiltration and edema (Figs. 5 , 6 ) . The left duc-
FIG. 6. Early intra- and extrahepatic sclerosing cholangitis, same patient as in Figure 5. The irregular serrated mucosa (arrows) of the common hepatic and bile ducts is noted. Small focal debris is also noted in the right main bile duct.
FIG. 7. Moderately severe intra- and extrahepatic sclerosing cholangitis. Both intra- and extrahepatic ducts are markedly irregular with irregular caliber and focal stricturing.
tal system is disproportionately more severely involved with intrahepatic ducts having irregular sacculations often containing what appears to be intraductal debris or shredded sloughed mucosa (Fig. 6 ) . The ducts are markedly irregular and there is a pruning of the smaller intrahepatic bile ducts. The cholangiographic features of AIDS-associated cholangiopathy do differ from those of idiopathic sclerosing cholangitis. In most patients with the latter condition, the common bile duct is irregularly
FIG. 8. Severe intrahepatic sclerosing cholangitis. A balloon catheter (arrow) has been passed and inflated to occlude the proximal common hepatic duct to allow for complete filling of the intrahepatic ducts. Marked irregularities of the duct contour are noted.
Downloaded by: University of British Columbia. Copyrighted material.
BILIARY TRACT DISEASE AND HIV-CELLO
SEMINARS IN LIVER DISEASE-VOLUME
TABLE 2.
12, NUMBER 2, 1992
AlDS Cholangiopathy*
Frciture
N u m b ~ rof'Patienrs
Cytomegalovirus ( C M V ) Cr!pto.sporidium Mycobacterium avium CMV and Crvprosporidium Kaposi's sarcoma Lymphoma Inflammation only Total
FIG. 9. Long extrahepatic bile duct stricture. An irregularly t a p e r e d distal d u c t is n o t e d ( b e t w e e n t h e arrows) with m a r k e d proximal bile d u c t dilation. P o s t m o r t e m histopathologic e x a m ination n o t e d cytomegalovirus inclusions throughout t h e distal bile d u c t m u c o s a .
strictured and rarely exceeds 4 to 5 mm in diameter. In idiopathic sclerosing cholangitis, moreover, the entire duct tends to be involved and there is usually no "beading" of the mucosa. In addition, among patients with idiopathic sclerosing cholangitis there are rare dilated segments, virtually no intraductal debris, but an associated paucity of intrahepatic bile ducts. The combination of papillary stenosis and sclerosing cholangitis has been found in over half our patients with HIV cholangiopathy. Pure sclerosing cholangitis, papillary stenosis, and long extrahepatic bile duct strictures are less frequently encountered and, when combined, equal the remaining nearly 50% of patients with AIDS-associated cholangiopathy. Table I compares the clinical features of AIDS pa-
tients with subsequently confirmed bile duct abnormalities with those who had normal bile ducts on ERCP. The mean age of our 40 patients with AIDS cholangiopathy was 36 2 1.2 years. Patients had the diagnosis of AIDS for nearly I year and most presented with right upper quadrant pain. The remainder of our patients with subsequently confirmed bile duct abnormalities presented with fever and jaundice together with abnormal biochemical tests of hepatocellular function. Twenty-eight of 38 patients had abnormal ultrasonographic findings, including dilated intra- or extrahepatic bile ducts, thickened bile duct wall, and distal tapering of the common bile duct. Twelve of 17 patients who underwent CT scans had abnormal CT findings consisting largely of dilated intra- or extrahepatic bile ducts. These two features, namely, abnormal ultrasound and CT findings, distinguished the patients with AIDS cholangiopathy from patients with similar clinical presentation in whom ERCP subsequently confirmed normal bile ducts. However, it should be noted that nearly one third of patients with confirmed abnormal bile ducts had normal noninvasive imaging studies. As mentioned earlier, the most remarkable abnormality detected on prior biochemical testing was marked elevation of the alkaline phosphatase to a mean of 750 IUlliter or five times the upper limits of normal. Serum transaminasc levels were only moderately abnormal. Although there were a few patients with hyperbilirubinemia, the mean serum bilirubin was 1.5 mgldl. As anticipated, most patients had mild hypoalbuminemia, leukopenia, and anemia.
TABLE 1. AlDS Cholangiopathy*t Abnormal Ducts
(11 =
401
Norn~cilDucts f n
=
I I1
Mean age (yr) AIDS duration (mo) Right upper quadrant pain Abnormal ultrasound Abnormal CT Alkaline Phosphatase (IUIL) Alamine amino-transferase (IUiL) Bilirubin (mgidl) Albumin *AIDS: acquired immunodeficiency syndrome; CT: computed tomography; NS: difference not significant; t i SEM
11
Vc!ire
Downloaded by: University of British Columbia. Copyrighted material.
"Ampullary biopsy at endoscopic retrograde cholangiopancreatography, surgical pathology, or postmortem.
planation remains elusive. It is possible that the biliary ductular epithelium is a target organ for HIV infection. Previously, bowel epithelium has been noted to harbor HIV, and the possibility remains that the HIV itself distorts or destroys bile duct epithelium or submucosa. It is also possible that there is a stereotypic pattern of injury in the bile duct and that a similar pattern of injury occurs from a multitude of pathogens and malignancies. Moreover, it could be that all the cholangiopathic findings are due to CMV or Cryptosporidium and that the patients without specific histopathologic diagnosis have CMV or Cryptosporidiutn undetected because of sampling error or the limited number of postmortem evaluations. Another possibility could invoke an ulcerative colitis-like ductal sclerosis, possibly related to persistent portal bacteremia in AIDS patients, who so frequently have intractable diarrhea and associated enteritis. Furthermore, a unique HLA haplotype, HLA-DRw52a, might be associated with an immunologic response to a ubiquitous possibilities unproven or agent in these patients.?"ther untested include copper hepatotoxicity, an unidentified viral infection, enhanced HLA class I1 antigens on bile duct epithelial cells, or circulating immune complexes. I t also remains undetermined whether there are unique biliary manometric abnormalities in AIDS patients with or without cholangiopathic abnormalities. Clearly, additional intensive investigations will be necessary to define the etiology of HIV-associated cholangiopathy. FIG. 10. Ampullary biopsy following sphincterotomy in a patient with AIDS-associated cholangiopathy. Two classic cytomegalovirus inclusion cells (arrows) are noted within the ampullary mucosal epithelial cells.
THERAPY For those patients presenting with moderate to severe right upper quadrant pain, together with cholangiographic abnormalities of papillary stenosis, an ERCP sphincterotomy should be performed. In our study, dramatic improvement in pain scores occurred; however, there was no substantial change in serum alkaline phosphatase, bilirubin, or transaminase levels." In a handful of patients undergoing repeat ERCP evaluation following sphincterotomy, progressive intrahepatic sclerosing cholangitis has been noted. Among 40 patients with cholangiopathy, only 18 had a specific histopathologic diagnosis based on ampullary biopsy and surgical pathologic findings or postmortem evaluation. The histopathologic findings in these 40 patients is shown in Table 2. The single most commonly identifiable histopathologic feature on ampullary biopsy was CMV alone or in combination with Cryptosporidum (Fig. 10). Twenty-two patients had acute and chronic inflammatory changes in the periampullary area or periductal region on histopathologic examination.
ETIOLOGY Several etiologic factors for HIV-associated cholangiopathy have been suggested, although a definitive ex-
FUTURE PROSPECTS In addition to endoscopic sphincterotomies for those patients with AIDS-associated papillary stenosis, there have been a few isolated reports of patients undergoing balloon dilation or endoscopic or percutaneous stent placement for bile duct obstructions. Chemotherapy is appropriate in patients with Kaposi's sarcoma or lymphoma involving the bilc duct. The potential efficacy of bile salt therapy such as ursodeoxycholic acid or anti-CMV therapies (such as ganciclovir) have yet to be reported, although we have treated a handful of patients with these agents and have noted modest improvement in intrahepatic bile duct abnormalities over a short period of follow-up time.
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BILIARY TRACT DISEASE AND HIV-CELLO
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SEMINARS IN LIVER DISEASE-VOLUME Kovatch RM, White JD: Cryptosporidiosis in two juvenile rhesus monkeys. Vet Pathol 9:426-440, 1972. Snyder SP, England JJ, McChesney AE: Cryptosporidiosis in immunodeficient Arabian foals. Vet Pathol 15: 12- 17, 1978. Pitlik S,Fainstein V, Garza D, et al: Human cryptosporidiosis: Spectrum of disease: Report of six cases and review of the literature. Arch Intern Med 143:2269-2275, 1983. Pitlik S, Fainstein V, Rios A, et al: Cryptosporidial cholecystitis. (Letter.) N Engl J Med 308:967, 1983. Guarda LA, Stein SA, Clearly KA, Ordonez NG: Human cryptosporidiosis in the acquired immune deficiency syndrome. Arch Pathol Lab Med 107:562-566, 1983. Blumberg RS. Kelsey P, Perrone T, et al: Cytomegalovirusand cryptosporidium-associated acalculous gangrenous cholecystitis. Am J Med 76:l 118-1 123, 1984. Kavin H. Jonas RB, Chowdhury L, Kabins A: Acalculous cholecystitis and cytomcgalovirus infection in the acquired immunodeficiency syndrome. Ann Intern Med 104:53-54, 1986. Margulis SJ. Honig CL, Soave R, et al: Biliary tract obstruction in the acquired immunodeficiency syndrome. Ann Intern Med 105:207-210, 1986. Schneiderman DJ, Cello JP, Laing FC: Papillary stenosis and sclerosing cholangitis in the acquired immunodeficiency syndrome. Ann Intern Med 106:546-549. 1987. Dolmatch BL. Laing FC, Cello JP et al: AIDS-related cholangitis: Radiographic findings in nine patients. Radiology 163:313-316, 1987.
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Viteri AL, Greene JF: Bile duct abnormalities in the acquired immune deficiency syndrome. Gastroenterology 92:20142108, 1987. Gremse DA, Bucuvalas JC, Bongiovanni GL: Papillary stenosis and sclerosing cholangitis in an immunodeficient child. Gastroenterology 96: 1600-1603, 1989. Ccllo JP: Acquired immunodeficiency syndrome cholangiopathy: Spectrum of disease. Am J Med 86539-546, 1989. Kaplan LD, Kahn J, Jacobson M, et al: Primary bile duct lymphoma in the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 110:161-162, 1989. Bruggen JT, Cello JP, Chernoff DN, et al: Unusual biliary tract disease in a patient with AIDS--clinical pathological conference. Gastroenterol Int 1 : 3 3 4 0 , 1988. Radin DR, Cohen H, Halls JM: Acalculous inflammatory disease of the biliary tree in acquired immunodeficiency syndrome: CT demonstration. J Comput Assist Tomogr 11:775778, 1987. lannuzzi C, Belghiti J, Erlinger S, et al: Cholangitis associated with cholecystitis in patients with acquired immunodeficiency syndrome. Arch Surg 125:1211-1213, 1990. Prochazka EJ, Terasaki PI, Park MS. et al: Association of primary sclerosing cholangitis with HLA-DRw52a. N Engl J Med 322: 1842-1844. 1990.
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