Secondary sclerosing cholangitis after long-term treatment in an Intensive care unit: clinical presentation, endoscopic findings, treatment, and follow-up

• Introduction
• Patients and Methods
• Statistical Analysis
• Results
• Discussion
• References

Background and Study Aims: We present ten patients who developed secondary sclerosing cholangitis following long-term treatment in an intensive care unit (ICU) between 1999 and 2004.
Patients and Methods: Ten consecutive patients who had no evidence suggestive of pre-existing hepatobiliary disease were admitted to an ICU because of trauma (n = 5), intracerebral hemorrhage (n = 3), or nonabdominal postsurgical complications (n = 2). All the patients had required treatment with long-term ventilation, catecholamines, total parenteral nutrition, and several antimicrobial agents.
Results: Cholestasis was first noted within 11 days after the initial insult. Endoscopic retrograde cholangiopancreatography (ERCP), performed after a median follow-up of 69 days, revealed multifocal stricturing and beading of the intrahepatic bile ducts, and attenuation of the peripheral branches. In all the patients, the bile ducts were partially filled by black-pigmented thrombotic material. All the patients underwent endotherapy, which comprised sphincterotomy and removal of the occluding material, in an attempt to improve biliary drainage; the treatment had to be repeated in seven of the ten patients. After a median follow-up period of 21 months, despite transient clinical improvement following endotherapy, complete recovery has not been achieved in any of the patients and so far one patient has had to undergo orthotopic liver transplantation as a result of end-stage liver disease.
Conclusions: The development of secondary sclerosing cholangitis in patients who have received long-term treatment in an ICU is a rare event of unknown pathophysiology, but patients demonstrate characteristic findings on ERCP. It is not known whether endotherapy can delay the progress of the condition in the long term.

Introduction

Secondary sclerosing cholangitis is a rare clinical entity within the broad spectrum of ”vanishing bile duct syndrome“ disorders and is associated with significant morbidity and a poor prognosis, often progressing to secondary biliary cirrhosis and the need for orthotopic liver transplantation [1]. In recent years, the pathology and pathogenesis of bile duct loss have been studied extensively and a number of mechanisms that result in the histomorphologic appearance of ductopenia have been characterized [2]. Recently, a new variant of secondary sclerosing cholangitis, a condition that occurs after septic shock and long-term treatment in an intensive care unit (ICU), has been added to the list of disorders that make up the vanishing bile duct syndrome [3].

We present here another series of ten patients without pre-existing hepatobiliary disease who developed rapid-onset secondary sclerosing cholangitis after long-term treatment in an ICU. This report focuses on the clinical presentation, the characteristic endoscopic findings prior to and after endoscopic treatment, and the clinical outcome on follow-up.

Patients and Methods

More than 800 endoscopic retrograde cholangiopancreatography (ERCP) procedures, mainly therapeutic, are performed annually in the endoscopy unit of the Department of Medicine II, HSK Wiesbaden, a referral center for endotherapy. Patients in the hospital’s ICU are seen regularly by an experienced gastroenterologist and patients with potential indications for ERCP (e. g. severe cholestasis with hyperbilirubinemia, bacterial cholangitis, or common bile duct stones) are evaluated by an interdisciplinary team, with management decisions based on the general health status and prognosis of the individual patient.

Between 1999 and 2004, ten consecutive patients (five men, five women; median age 55, range 41 - 78) were retrospectively identified as suffering from secondary sclerosing cholangitis associated with ICU treatment. They had all previously been healthy, immunocompetent, and nonalcoholic individuals, all negative for viral hepatitis, and showed no evidence suggestive of pre-existing bile duct abnormalities or hepatobiliary disease. Only one patient had a past history of cholecystectomy (for cholecystolithiasis). None of the patients showed elevation of total bilirubin levels or serum alkaline phosphatase levels prior to their admission or on the initial laboratory tests in the ICU. The causes for admission to the ICU were trauma (n = 5, all road traffic accidents), intracerebral hemorrhage (n = 3), and nonabdominal postsurgical complications (one patient had had a Zenker diverticulotomy and one patient had had a cerebral meningioma removed). During their time in the ICU all the patients had required long-term mechanical ventilation (median duration 28 days, range 18 - 39 days). As part of the intensive treatment regimens, all the patients had received catecholamines, total parenteral nutrition, and several antimicrobial drugs. The median follow-up period after the initial insult was 21 months (range 3 - 54 months).

When severe cholestasis and/or cholangitis was suspected, the patients were evaluated by ultrasound and ERCP. Endoscopic treatment included biliary sphincterotomy and instrumental exploration of the bile duct using a balloon catheter or basket if indicated. The endoscopic treatment was repeated if indicated by the findings at ERCP, the clinical outcome, or the results of laboratory tests, or when ductal clearance at the first endoscopy had been incomplete.

Statistical Analysis

Laboratory data before and after endoscopic treatment were analyzed using the nonparametric Wilcoxon rank sum test (SPSS Software), with subsequent Bonferroni’s correction to adjust significance levels for multiple comparisons. A corrected P-value of less than 0.05 was considered to be significant.

Results

Cholestasis was first noted after a median time of 6.5 days (range 4 - 11 days) following the initial insult and showed marked progression. ERCP was performed after a median of 69 days after the injury or insult (range 42 - 126 days). Table [1] summarizes the total bilirubin, alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), serum alanine transaminase (ALT), and serum aspartate transaminase (AST) levels in the individual patients prior to ERCP. Routine ultrasound in the ICU revealed biliary sludge in the gallbladder in eight out of the ten patients, but no dilatation of either the common bile duct or the intrahepatic ducts.

ERCP showed multifocal stricturing and beading involving the intrahepatic bile ducts in all ten patients. Only the intrahepatic bile ducts were involved in six patients; in the remaining four patients the right and/or left hepatic ducts were also involved. In all the patients, the common bile duct was normal in appearance or was only slightly dilated. Figure [1] shows radiographs that were typical of the spectrum of findings of the patients’ endoscopic retrograde cholangiograms.

Interestingly, in all the patients we found occluding masses filling the biliary tree. Attempted endotherapy consisted of endoscopic extraction of the occluding masses and improvement of bile duct drainage. In addition, ursodeoxycholic acid treatment was started in all patients in an effort to improve bile flow. Endoscopic sphincterotomy was performed in all patients, followed by instrumental bile duct exploration. Masses of black-pigmented thrombotic material were extracted with a balloon catheter or with a basket, and this was followed by flush cleaning with saline (Figure [2]). Endotherapy was completed during one session in three of the ten patients; in seven patients two to three further endoscopic retrograde cholangiographic sessions were necessary to complete the endotherapy.

Prior to endotherapy the patients showed steady clinical deterioration, with increasingly abnormal liver function tests. After endotherapy this stopped, and a significant biochemical improvement (P < 0.05) was noted in all patients, accompanied by clinical improvement. Laboratory indices of cholestasis decreased (by 32 % for bilirubin, by 27 % for ALP, and by 21 % GGT); C-reactive protein was reduced by 39 % and the leukocyte counts were lowered by 30 %. The ALT levels fell by 25 % and the AST levels by 30 % (Table [2]).

The median duration of follow-up was 21 months, ranging from 3 months to 54 months (Table [1]). Patient 1 progressed to end-stage liver disease and underwent orthotopic liver transplantation 45 months after the initial insult. Patient 8 died as a result of incidentally diagnosed pulmonary cancer. In eight of the ten patients the progressing secondary sclerosing cholangitis was left as the main problem during their recovery from the initial injury or illness. Despite wide variations in follow-up time, these patients now appear to be in a slowly progressive but still relatively stable condition, without any signs of acute liver failure. Their laboratory indices remain constantly elevated, however, and the long-term prognosis has still to be established.

To date, five of the patients have experienced recurrent episodes of cholangitis during follow-up. These patients were treated with antibiotics and repeat endoscopic retrograde cholangiography has confirmed the initial diagnosis of secondary sclerosing cholangitis with predominant intrahepatic involvement but without dominant strictures. This pattern of disease is not considered to be amenable to further endoscopic or percutaneous transhepatic treatment.

Discussion

The diagnostic criteria for sclerosing cholangitis, both primary and secondary, focus on the biochemical profile (demonstrating the degree of cholestasis), and the characteristic cholangiographic findings [1] [4], and they were met in all of our patients. Prompted by severe cholestasis in these patients, we performed endoscopic retrograde cholangiography and in all cases the findings were characteristic of sclerosing cholangitis, with multifocal stricturing, beading, and attenuation of the small bile ducts [5]. Interestingly, we observed that the abnormalities were predominantly intrahepatic and that the common bile duct was not strictured or dilated. Recently, Engler et al. [3] described a series of patients with secondary sclerosing cholangitis occurring after septic shock, with a similar pattern of radiographic findings: eight out of the nine patients in that series had presented with severe intrahepatic stenoses and attenuation of the small bile ducts without any irregularities in the common bile duct [3].

A striking and constant finding in our patients was the black pigmented material that filled the biliary tree. This looked as if it could be necrotic material originating from a rapidly progressing sclerosing cholangitis with sequestration and disintegration of the bile duct system. Similar bile duct sequestration has already been described, caused by ischemic-type biliary lesions after liver transplantation [6].

Despite the characteristic clinical and endoscopic retrograde cholangiographic presentation of sclerosing cholangitis, there is a wide range of theories on its pathogenesis. For the well-defined clinical entity of primary sclerosing cholangitis, immune-mediated damage of the bile ducts has been suggested [4]. In contrast, several pathological processes can mimic the clinical and radiographic features of primary sclerosing cholangitis, and extensive investigation in recent years has identified several potential mechanisms that can lead to secondary sclerosing cholangitis [1] [2] [7] [8] [9] [10].

Rather than invoking a single new pathological trigger, a combination of toxic mechanisms already confirmed as being involved in the pathogenesis of sclerosing cholangitis might have contributed to the secondary sclerosing cholangitis in our patients, showing an overlap with the recently described variant of secondary sclerosing cholangitis occuring after septic shock [3]. The common feature in both series of patients was shock, which sensitized the hepatobiliary system [11]. In addition, all of our patients required total parenteral nutrition, which is known to impair bile flow and so lead to cholestasis and steatosis [12]. However, such a constellation of factors is present in most of the patients treated in an ICU, but only a very small minority of patients progress to secondary sclerosing cholangitis. There must therefore be additional mechanisms at play. There is increasing evidence of a genetic predisposition to cholestatic drug reactions [13]. It might be speculated that the secondary sclerosing cholangitis in our patients was initiated by cumulative hepatotoxic effects in the course of intensive treatment regimens in individuals genetically predisposed to cholestatic drug reactions.

A remarkable finding of our study was that performing endotherapy to improve the bile duct drainage halted the initially rapid deterioration, resulting in a significant clinical and biochemical improvement in all patients. Presumably, endotherapy with sphincterotomy and extraction of the material occluding the distal biliary tree was effective in alleviating the additional bacterial cholangitis which is well established as a factor in persistent primary and secondary sclerosing cholangitis [1] [2] [14] [15]. However, once established, sclerosing cholangitis leads to slow and often irreversible destruction of the walls of the biliary system, resulting in bile duct loss, biliary cirrhosis, and, ultimately, the need for orthotopic liver transplantation [1] [2]. Patient 1 who had the longest follow-up of our ten patients has already progressed to end-stage liver disease and has had a liver transplant. Despite the initial clinical improvement brought about by endotherapy in our patients, the long-term prognosis is still unknown.

Together with the recent paper by Engler et al. [3], this report represents the first description of progressive secondary sclerosing cholangitis in previously healthy individuals who were suffering from a severe insult leading to shock and long-term treatment in an ICU. Although cholestasis occurs frequently in patients in the ICU setting, the progression to secondary sclerosing cholangitis represents a rare clinical entity. The reasons for this progression and the pathogenesis of secondary sclerosing cholangitis in these patients remain obscure. The hallmark of diagnosis is the characteristic constellation of findings on endoscopic retrograde cholangiography. In the initial phase of the pathological process endotherapy leads to clinical and biochemical improvement. The long-term outlook appears to be one of slowly progressive disease, and if a patient develops end-stage liver disease, the ultimate treatment is orthotopic liver transplantation.

Competing interests: None

References

• 1 Amor A, Chapoutot C, Michel J. et al . Secondary sclerosing cholangitis.  Presse Med. 1995;  24 948-952
  PubMedSearch in Google Scholar
• 2 Nakanuma Y, Tsuneyama K, Harada K. Pathology and pathogenesis of intrahepatic bile duct loss.  J Hepatobiliary Pancreat Surg. 2001;  8 303-315
  CrossrefPubMedSearch in Google Scholar
• 3 Engler S, Elsing C, Flechtenmacher C. et al . Progressive sclerosing cholangitis after septic shock: a new variant of vanishing bile duct disorders.  Gut. 2003;  52 688-693
  CrossrefPubMedSearch in Google Scholar
• 4 Lazaridis K N, Wiesner R H, Porayko M K. et al . Primary sclerosing cholangitis. In: Schiff ER, Sorrell MF, Maddrey WC (eds) Schiff’s diseases of the Liver. 8th edn. Philadelphia; Lippincott-Raven 1999: 649-669
  Search in Google Scholar
• 5 Li-Yeng C, Goldberg H I. Sclerosing cholangitis: broad spectrum of radiographic features.  Gastrointest Radiol. 1984;  9 39-47
  CrossrefPubMedSearch in Google Scholar
• 6 Abou-Rebyeh H, Veltzke-Schlieker W, Radke C. et al . Complete bile duct sequestration after liver transplantation, caused by ischemic-type biliary lesions.  Endoscopy. 2003;  35 616-620
  Thieme ConnectPubMedSearch in Google Scholar
• 7 Scheppach W, Druge G, Wittenberg G. et al . Sclerosing cholangitis and liver cirrhosis after extrabiliary infections: report on three cases.  Crit Care Med. 2001;  29 438-441
  PubMedSearch in Google Scholar
• 8 Mohi-ud-din R, Lewis J H. Drug- and chemical-induced cholestasis.  Clin Liver Dis. 2004;  8 95-132
  CrossrefPubMedSearch in Google Scholar
• 9 Tanaka Y, Koshiyama H, Nakao K. et al . Rapid progress of acute suppurative cholangitis to secondary sclerosing cholangitis sequentially followed-up by endoscopic retrograde cholangiography.  Endoscopy. 2001;  33 633-635
  Thieme ConnectPubMedSearch in Google Scholar
• 10 Richardet J P, Lons T, Sibony M. et al . Secondary sclerosing cholangitis and chemo-embolization with lipiodol.  Gastroenterol Clin Biol. 1994;  18 168-171
  PubMedSearch in Google Scholar
• 11 Moore F A. The role of the gastrointestinal tract in postinjury multiple organ failure.  Am J Surg. 1999;  178 449-453
  CrossrefPubMedSearch in Google Scholar
• 12 Quigley E, Marsh M, Shaffer J, Markin R S. Hepatobiliary complications of total parenteral nutrition.  Gastroenterology. 1993;  104 286-301
  CrossrefPubMedSearch in Google Scholar
• 13 Velayudham L S, Farrell G C. Drug-induced cholestasis.  Expert Opin Drug Saf. 2003;  2 287-304
  CrossrefPubMedSearch in Google Scholar
• 14 Deviere J. Therapeutic endoscopy and primary sclerosing cholangitis.  Endoscopy. 1996;  28 576-577
  PubMedSearch in Google Scholar
• 15 Stiehl A, Rudolph G, Sauer P. et al . Efficacy of ursodeoxycholic acid treatment and endoscopic dilation of major duct stenosis in primary sclerosing cholangitis: an 8-year prospective study.  J Hepatol. 1997;  26 560-566
  CrossrefPubMedSearch in Google Scholar

C. Jaeger, M. D.

Third Medical Department and Policlinic · University of Giessen and Marburg

Rodthohl 6 · 35385 Giessen · Germany

Fax: +49-641-99-42759

Email: clemens.jaeger@innere.med.uni-giessen.de

References

• 1 Amor A, Chapoutot C, Michel J. et al . Secondary sclerosing cholangitis.  Presse Med. 1995;  24 948-952
  PubMedSearch in Google Scholar
• 2 Nakanuma Y, Tsuneyama K, Harada K. Pathology and pathogenesis of intrahepatic bile duct loss.  J Hepatobiliary Pancreat Surg. 2001;  8 303-315
  CrossrefPubMedSearch in Google Scholar
• 3 Engler S, Elsing C, Flechtenmacher C. et al . Progressive sclerosing cholangitis after septic shock: a new variant of vanishing bile duct disorders.  Gut. 2003;  52 688-693
  CrossrefPubMedSearch in Google Scholar
• 4 Lazaridis K N, Wiesner R H, Porayko M K. et al . Primary sclerosing cholangitis. In: Schiff ER, Sorrell MF, Maddrey WC (eds) Schiff’s diseases of the Liver. 8th edn. Philadelphia; Lippincott-Raven 1999: 649-669
  Search in Google Scholar
• 5 Li-Yeng C, Goldberg H I. Sclerosing cholangitis: broad spectrum of radiographic features.  Gastrointest Radiol. 1984;  9 39-47
  CrossrefPubMedSearch in Google Scholar
• 6 Abou-Rebyeh H, Veltzke-Schlieker W, Radke C. et al . Complete bile duct sequestration after liver transplantation, caused by ischemic-type biliary lesions.  Endoscopy. 2003;  35 616-620
  Thieme ConnectPubMedSearch in Google Scholar
• 7 Scheppach W, Druge G, Wittenberg G. et al . Sclerosing cholangitis and liver cirrhosis after extrabiliary infections: report on three cases.  Crit Care Med. 2001;  29 438-441
  PubMedSearch in Google Scholar
• 8 Mohi-ud-din R, Lewis J H. Drug- and chemical-induced cholestasis.  Clin Liver Dis. 2004;  8 95-132
  CrossrefPubMedSearch in Google Scholar
• 9 Tanaka Y, Koshiyama H, Nakao K. et al . Rapid progress of acute suppurative cholangitis to secondary sclerosing cholangitis sequentially followed-up by endoscopic retrograde cholangiography.  Endoscopy. 2001;  33 633-635
  Thieme ConnectPubMedSearch in Google Scholar
• 10 Richardet J P, Lons T, Sibony M. et al . Secondary sclerosing cholangitis and chemo-embolization with lipiodol.  Gastroenterol Clin Biol. 1994;  18 168-171
  PubMedSearch in Google Scholar
• 11 Moore F A. The role of the gastrointestinal tract in postinjury multiple organ failure.  Am J Surg. 1999;  178 449-453
  CrossrefPubMedSearch in Google Scholar
• 12 Quigley E, Marsh M, Shaffer J, Markin R S. Hepatobiliary complications of total parenteral nutrition.  Gastroenterology. 1993;  104 286-301
  CrossrefPubMedSearch in Google Scholar
• 13 Velayudham L S, Farrell G C. Drug-induced cholestasis.  Expert Opin Drug Saf. 2003;  2 287-304
  CrossrefPubMedSearch in Google Scholar
• 14 Deviere J. Therapeutic endoscopy and primary sclerosing cholangitis.  Endoscopy. 1996;  28 576-577
  PubMedSearch in Google Scholar
• 15 Stiehl A, Rudolph G, Sauer P. et al . Efficacy of ursodeoxycholic acid treatment and endoscopic dilation of major duct stenosis in primary sclerosing cholangitis: an 8-year prospective study.  J Hepatol. 1997;  26 560-566
  CrossrefPubMedSearch in Google Scholar

C. Jaeger, M. D.

Third Medical Department and Policlinic · University of Giessen and Marburg

Rodthohl 6 · 35385 Giessen · Germany

Fax: +49-641-99-42759

Email: clemens.jaeger@innere.med.uni-giessen.de