Involvement of the gallbladder: Immediately following cholestasis onset, one-half of our patients had sonographic signs of acute (predominantly acalculous) cholecystitis. Within the 1st year after initial injury acute cholecystitis occurred in 69% (11/16) of the patients. Of these, 45% (5/11) required emergency cholecystectomy. The cholecystitis described was mostly an acalculous cholecystitis (10/11). Gallbladder perforation evolved in 2 of these patients—in 1 patient 24 days after the onset of cholestasis. The perforation rate was thus 18% (2/11).
Outcome, Progression, Listing, Need for Transplantation
The data relating to outcome and transplantation are shown in Tables 1 and 3 and Figure 5. After a short course of disease, clinical signs and symptoms of liver cirrhosis appeared within a few months. Most of the patients in our series (12/16) had to be placed on the waiting list for liver transplant within 1 year after the onset of cholestasis. The mean time to listing was 322 ± 257 days (median: 225 days). The mean time from the onset of cholestasis until transplantation was 35 months (median: 42 months). The earliest transplantation was performed 189 days after the onset of cholestasis in a 63-year-old woman who developed cholangiosepsis and multiple organ failure.
If ERC demonstrates PSC-like cholangiographic findings, all types of sclerosing cholangiopathy must be considered in the differential diagnosis. This includes secondary sclerosing cholangitis in critically ill patients (SSC-CIP). With mortality rates of up to 50%, SSC-CIP represents a challenge to gastroenterologists and intensive care specialists.5 Currently, SSC-CIP is still widely underdiagnosed. Early detection of the disease and its complications is crucial to improving the poor prognosis.
In the initial stages of the disease, SSC-CIP must be recognized as a cause of liver failure in ICU patients. In the later stages, SSC-CIP must be differentiated from other types of sclerosing cholangiopathy. This differentiation is necessary with regard to the selection and timing of liver transplantation as SSC-CIP progresses much more rapidly than other cholangiopathies. To enable clinical differentiation, characteristic features of SSC-CIP must be identified.
As its name indicates critical illness is an obligatory precondition for SSC-CIP.2–5 All of our patients had a history of intensive care treatment for a life-threatening event. Although this event often necessitates lengthy intensive care treatment, long-term treatment (>7 days) is not required for the destruction of the bile ducts, as previously believed. Rather, it seems that bile duct damage is a very early event that manifests within the first 5 to 7 days, as evidenced by the early increase of cholestatic enzymes in our series.
There is a trend that the disease affects men more often than women. In addition, SSC-CIP showed a predilection for surgical patients, especially those in whom extensive tissue destruction occurs, such as patients with polytrauma or those undergoing major surgery. The first detectable sign of SSC-CIP was an increase in the liver enzymes—as our data confirm. SSC-CIP was characterized by a cholestatic pattern. In our patients, GGT was the predominant enzyme, which increased earlier and peaked more markedly than ALP. Hyperbilirubinemia occurred in the later stages. Although not specific, these laboratory findings may be helpful in distinguishing SSC-CIP from other causes of elevated liver enzymes in ICU patients, for example, from septicaemia-associated cholestasis, in which a hyperbilirubinemia predominates.6–8
Our data show that SSC-CIP is associated with markedly elevated serum cholesterol. Elevated levels of cholesterol are common in primary biliary cirrhosis (PBC), but occur less frequently in PSC.9,10 In SSC-CIP, the combination of elevated serum-cholesterol and pruritus may reflect disturbed bile acid metabolism.
Unintentional weight loss appears to be a typical feature of SSC-CIP and affected 94% of our patients. This contrasts with reports of weight loss in only 35% to 40% of PSC patients.11 Losing a mean 18 kg, our patients experienced a level of weight loss otherwise seen only in wasting diseases. The reason for this weight loss remains unclear. Conceivably, it might have been associated with the liberation of cytokines in the presence of chronic inflammation of the bile ducts. This is a well-known mechanism in the case of cancer cachexia. In cancer patients, inflammatory mediators such as TNF-alpha can induce changes in lipid metabolism that result in increased lipolysis, hyper-cholesterolemia, and a reduction of total fat mass.12
Cholangiography is mandatory for the diagnosis of SSC-CIP. In clinical practice, the decision to perform endoscopic retrograde cholangiography (ERC) in ICU patients with cholestasis is often based on ultrasound findings of dilated bile ducts. However, this approach delayed the diagnosis in our series since only a few patients had dilated extrahepatic bile ducts. Therefore, despite of the severe and striking initial course of SSC-CIP, it took 3 months (mean) to establish the final diagnosis. Typical ERC findings were biliary casts, destruction of intrahepatic bile ducts, or finally the picture of a “pruned tree.” These 3 different ERC findings occurred consecutively and might reflect distinct stages in the development of the disease. However, overlapping stages have also been observed. Our findings show that SSC-CIP is mainly a disease of the visible intrahepatic bile ducts—the extrahepatic bile ducts were only marginally affected. Biliary cast formation may be considered pathognomonic for SSC-CIP, as suggested by the high proportion of patients with biliary casts in our series. The casts completely fill the bile ducts and may distend them. In all patients initially presenting sonographically distended extrahepatic bile ducts, the first ERC's revealed biliary casts. The occurrence of biliary casts in association with either PSC or IgG4 cholangiopathy has not been described in the literature.
After liver transplantation, the occurrence of biliary casts is a known phenomenon, and an etiological association with ischemic events is assumed.13,14 However, single cases of “biliary cast syndrome” in nontransplant patients have also been described.15–18 This “biliary cast syndrome” in nontransplant patients is presumably not a separate entity, but rather an early stage of SSC-CIP, as supported by some case reports.19,20 In agreement with data from orthotopic liver transplantation we found biliary casts in SSC-CIP only within the first year after the initial event.13 Despite successful initial endoscopic removal, 7 of our patients showed recurrence of the biliary casts at subsequent ERC examinations. Whether these were merely the result of a sliding down of incompletely removed intrahepatic fragments, or whether new casts were formed is not clear.
Complications of SSC-CIP
SSC-CIP carries a high risk for hepatobiliary complications. In 75% of our patients the clinical course was complicated by acute acalculous cholecystitis, gallbladder perforation, cholangitic liver abscess, or cholangiosepsis.
Involvement of the Gallbladder
It seems that the gallbladder epithelium is involved in the pathogenetic process in SSC-CIP. This is underscored by the high rate of acute cholecystitis (in the absence of a cholelithiasis) in the early stage of disease in our series. Acute acalculous cholecystitis (AAC) is a serious and potentially fatal condition. Ischemic necrosis of the gallbladder wall, often extending into the deeper layers, causes a high spontaneous perforation rate, as our data confirm. It is known that acute acalculous cholecystitis shows a predilection to occur in critically ill patients after trauma, burns, or major surgery.21–23 Because acute acalculous cholecystitis has also been observed in association with Schönlein–Henoch purpura, antiphospholipid syndrome and lupus erythematosus, an ischemic pathogenesis for AAC is supposed.24–26 A similar pathogenetic mechanism that could explain the gallbladder involvement is hypothesized for SSC-CIP. In ICU patients, an unexplained cholestasis and the simultaneous appearance of acute acalculous cholecystitis should raise the suspicion of SSC-CIP. Conversely, acute acalculous cholecystitis is not a known phenomenon in patients with PSC or IgG4-associated cholangiopathy.
Cholangitic Episodes/Cholangiosepsis/Liver Abscesses
In our patients, the clinical course of disease was complicated by recurrent episodes of bacterial cholangitis. In SSC-CIP, these episodes may be secondary events explainable by the presence of multifocal intrahepatic biliary strictures due to extensive destruction of segmental and subsegmental bile ducts. Furthermore, as a result of the duct damage peripheral bile duct branches can lose their connection to the central ducts and become “excluded” bile ducts. The elimination of a biliary obstruction is a prerequisite for successful antibiotic treatment of cholangitis. Unfortunately in SSC-CIP this drainage is frequently inadequate since peripheral, “excluded” ducts often can no longer be reconnected by endoscopic means. The remaining obstruction impairs the penetration of antibiotics into bile, limits the effectiveness of the treatment, and increases the risk of cholangiosepsis. In the absence of drainage the mortality rate of cholangitis is high, as is known from the pre-ERC era.27–30 This problem is reflected by our data, showing a high rate of cholangiosepsis, and among these patients a high fatality rate. Two of 3 patients died from cholangiosepsis despite intensive therapeutic efforts while still on the transplant waiting list. Furthermore, the stagnation of bile flow also promotes cholangitic liver abscesses—almost 19% of our patients developed this complication.
Progression/Need for Transplantation
Two aspects contributed to the short latency between the onset of cholestasis and the need for transplantation observed in our SSC-CIP cases. First, the clinical and histology data indicate that the liver fibrosis progressed unusually quickly over a period of a couple of months. This rapid and extensive fibrotic response may be explainable by the large extent of initial cholangiocyte destruction of the intrahepatic bile ducts.31 Second, on account of the risk of cholangiosepsis, transplantation is urgently needed in cases with irreversible destruction of bile ducts and recurrent severe cholangitis. Two patients of our series died of cholangiosepsis while still on the transplant waiting list; another patient with cholangiosepsis and multiple organ failure had to be transplanted 195 days after the initial event. Median liver transplantation-free survival was only 44 months (mean 40 months) in our patients, compared to 89 to 112 months in other fibrosing cholangiopathies such as PSC, and 72 months in “classical” infective SSC.32–34 In view of the more rapid disease progression, patients with SSC-CIP require closer monitoring than patients with other forms of fibrosing cholangiopathy and an early cooperation with a transplantation center should be initiated.35,36
Survival After Liver Transplantation
It was assumed earlier that patients with secondary sclerosing cholangitis had a poor outcome after liver transplantation.33,37 Our findings refute this. Eight of the 9 transplanted patients are alive and in a good state of health. Only 1 female patient, who underwent simultaneous liver and lung transplantation, died from pulmonary complications. The resulting 1-year survival rate of 85% and 3-year survival rate of 83% correspond well with the survival rates for OLT in alcoholic liver cirrhosis.
The limitations of the present study are its retrospective nature and the recruitment of the patients from a transplantation center. Patients with an initially severe course who did not live long enough to be listed, as also those with a milder course and no liver transplantation, were not included in the study. Further larger clinical studies can build on and consolidate our results. Prospective studies with a control group, which makes it possible to perform complex statistics generating P values would be needed to validate our observations.
Frequency of SSC-CIP
The actual prevalence of SSC-CIP remains unknown and is also not adequately reflected in our data (due to selection bias, as mentioned above). Overall, 0.61% of all liver transplantations performed at our center were due to SSC-CIP. Similar rates have been observed, for example, in patients with hemochromatosis (0.7% of all OLT at our center). For PSC the figure was 6.2% in our center, indicating that SSC-CIP is 10 times rarer than PSC.
Despite some similarities with other sclerosing cholangiopathies, SSC-CIP shows characteristic features that allow for discrimination of SSC-CIP from other entities. In particular, the occurrence of biliary casts in patients with equivocal findings of sclerosing cholangiopathy in ERC is suggestive of SSC-CIP and excludes PSC and IgG4 cholangiopathies. Last but not least, the fatal outcome of the complications of SSC-CIP could be prevented by better recognition of the disease and its natural history.
The authors wish to thank Peter Palm, Berlin, for the graphic design in Figure 2 and H. Niggemann for statistical analysis.
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