© Springer International Publishing Switzerland 2017Kia Saeian and Reza Shaker (eds.)Liver Disordershttps://doi.org/10.1007/978-3-319-30103-7_17
17. Autoimmune Liver Diseases: Primary Sclerosing Cholangitis
Division of Gastroenterology and Hepatology, Medical College of Wisconsin, 8700 West Wisconsin Avenue, Milwaukee, WI 53226, USA
KeywordsBiliary stricturesCholangiocarcinomaCholangitisCholestatic liver diseaseColorectal carcinomaDominant stricturesGallbladder polypsIgG4 cholangiopathyInflammatory bowel diseaseLiver transplantationMELDOnion-skinningOverlap syndromePruritusSmall-duct primary sclerosing cholangitis
Acquired immune deficiency syndrome
Dual energy X-ray absorptiometry
Endoscopic retrograde cholangiography
Fluorescent in situ hybridization
Inflammatory bowel disease
Model for end-stage liver disease
Magnetic resonance cholangiography
Magnetic resonance imaging
Perinuclear antineutrophil cytoplasmic antibodies
Primary sclerosing cholangitis
Percutaneous transhepatic cholangiography
Transjugular intrahepatic portosystemic shunt
United Network for Organ Sharing
Patient Questions and Answers
What is Primary Sclerosing Cholangitis and how did I get it?
Primary sclerosing cholangitis, or PSC for short, is a chronic liver disease that leads to strictures or narrowing of the large and small bile ducts in the liver. The bile ducts are the plumbing of the liver and serve to move products produced in the liver to the small intestine, where they perform functions necessary for survival. While the exact cause of PSC remains unclear, it is frequently classified as an autoimmune disease. This means that it may be the result of an overactive or abnormal immune system . Patients with PSC frequently have other autoimmune disorders with the most common being inflammation of the colon, or colitis. Unfortunately, there is no effective therapy that prevents the progression of PSC and many patients will develop advanced liver disease and possibly cirrhosis which is severe, irreversible scarring of the liver. It is important to recognize that PSC is not associated with alcohol use, specific diets or behaviors. Primary sclerosing cholangitis is not the result of an infection or exposure to other individuals. You cannot transmit PSC to other individuals.
What can I do to treat Primary Sclerosing Cholangitis?
It is important to remember that your PSC is not the result of anything you have done wrong. While not related to alcohol, it is important to avoid alcohol as regular alcohol use can by itself lead to liver damage . As with all chronic liver diseases, you should be checked for immunity or protection to hepatitis A and B. If tests show that you are not protected, you should undergo vaccination. Both of these vaccines are safe and effective. It is important to maintain a healthy diet as patients who are able to accomplish this are better able to tolerate chronic illnesses , including PSC. Because of the strong association with colitis (inflammation of the colon), you should undergo a colonoscopy (a test to examine your colon) unless you have already had one. Primary sclerosing cholangitis can also lead to difficulty absorbing certain vitamins such as vitamin D. When patients have low vitamin D levels it can lead to thinning of the bones, osteoporosis, and possible bone fractures. Because of this, you should undergo a test known as a bone densitometry to determine whether you are at risk for developing bone disease .
There is no specific medicine that has been shown to be effective in slowing the progression of PSC. While it is classified as an autoimmune disorder, it does not respond to medications that are effective against other autoimmune conditions. While you may want to explore alternative or natural therapies such as herbal therapies, I would discourage you from using these substances as they are frequently not regulated by the Food and Drug Administration and in some cases have also been shown to be harmful to the liver. You should always let all of your doctors know of any medicine you are taking, as some medicines may not be as well tolerated by patients with liver disease such as PSC.
Will I need a liver transplant ?
The natural history of PSC is highly variable. Some patients present at a young age and have an aggressive course leading to the need for liver transplantation, while others will carry a diagnosis of PSC for many years and not require liver transplantation or die from this condition. Since PSC is a progressive disease and there is no known effective medical therapy, it will be important that you follow-up with a hepatologist or liver doctor on a regular basis even if you do not have any symptoms. During these visits you will be asked about symptoms as well as undergo a physical exam and blood tests that will allow your hepatologist to determine the overall status of the PSC and when a liver transplant evaluation should be considered. Your hepatologist may determine that a repeat examination of your bile ducts is necessary, particularly if there is suspicion that a cancer has developed in the bile ducts. Cancer of the bile ducts is known as cholangiocarcinoma. You should have an ultrasound of the liver and gallbladder every year as there in an increased risk of developing both liver and gallbladder cancer. You should contact your physicians immediately if you experience symptoms including jaundice or yellowing of the eyes and skin, worsening itching throughout your body which is most noticeable at night, fever, weight loss, and abdominal pain which most commonly occurs in the area over your liver.
Autoimmune Liver Diseases: Primary Sclerosing Cholangitis
Primary sclerosing cholangitis (PSC) is a chronic condition characterized by inflammation, fibrosis, and obliteration involving the intra- as well as extrahepatic bile ducts . Initially described in 1924 and once considered a rare condition, the condition can no longer be considered rare as advancements in cholangiography have led to more frequent diagnosis. While the etiology remains elusive, it is commonly classified as an autoimmune liver disease and other immune-mediated conditions, most notably inflammatory bowel disease, are frequently concurrently encountered. Genetic predisposition also appears to play a contributory role based on the finding of associated as well as protective haplotypes. Complications of PSC are both nonspecific and associated with chronic cholestatic liver disease as well as those specific to PSC. The natural history is highly variable with the potential for progression to cirrhosis, end-stage liver disease, and the need for liver transplantation. Patients with PSC are also at an increased risk for the development of cholangiocarcinoma as well as colorectal, gallbladder, and hepatocellular carcinoma. Despite the evaluations of multiple pharmacologic agents, there is currently no medical therapy that has been shown to alter the timeline to death or the need for liver transplantation. Liver transplantation is the only effective therapy for long-term survival in those who develop complications of end-stage liver disease and is associated with excellent long-term results. Variants of PSC include small-duct PSC, overlap PSC and autoimmune hepatitis, and immunoglobulin G cholangiopathy.
Various epidemiological studies have placed the incidence of PSC from 0.9 to 1.31 cases per 100,000 person-years and the prevalence at 8.5 to 13.6 cases per 100,000 persons [1, 2]. There is, however, significant regional variability which supports the theory of genetic predisposition playing a role. Sixty to 70 % of affected patients have underlying inflammatory bowel disease (IBD) , more frequently chronic Ulcerative Colitis than Crohn Disease with colonic involvement [3, 4]. The IBD is typically diagnosed several years prior to PSC . In addition, while associated with IBD, the two disorders’ activity level and progression do not necessarily correlate. Approximately two-thirds of those affected with PSC are male with the median age at diagnosis of approximately 37 .
While the exact etiology of PSC remains unknown, it appears that both genetic and immunologic factors play prominent roles.
An immune mechanism is supported by the findings of serum autoantibodies in a large number of those with PSC, the most common being perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) which are found in up to two-thirds of patients. Other autoantibodies occasionally encountered include antinuclear and anti-smooth muscle antibodies . Additionally, hypergammaglobulinemia is common, as is the association with other autoimmune disorders, most notably inflammatory bowel disease.
Other potential etiol ogies that may play minor roles in PSC include infectious causes, toxin exposure, and vascular complications.
The association of PSC with IBD has led to the theory that damaged colonic mucosa leads to translocation of bacteria that enter the blood stream and bile ducts. The failure to identify specific organisms, the absence of portal phlebitis, failure of antibiotics or colectomy to alter the natural history and the fact that not all patients with PSC have IBD argues against an infectious etiology.
Toxin exposure as a cause of PSC is based on the theory that imbalances between hydrophilic and hydrophobic bile acids, such as lithocolic acid, can lead to biliary epithelial damage and strictures. Other toxic agents that have been evaluated include iron and copper, both of which are shown to be elevated in many patients with PSC. Elevated iron and copper levels, however, are nonspecific findings and can be associated with both hepatocellular and cholestatic disorders.
Vascular injury to the hepatic artery has long been associated with biliary strictures in liver transplant recipients; however, examination of the hepatic vasculature in PSC has failed to demonstrate damage either to the hepatic artery, portal vein, or hepatic vein.
The clinical presentation of patients affected by PSC is highly variable. At one end of the spectrum is the asymptomatic patient who is diagnosed based on cholestatic hepatic biochemistries obtained in the setting of IBD. The majority of patients with PSC will be diagnosed when presenting with symptoms that lead to further investigation. The most common presenting symptoms are pruritus, jaundice, right upper quadrant abdominal pain and acute cholangitis. Unfortunately, some patients will present with advanced liver disease manifested by weight loss, ascites, hepatic encephalopathy, portal hypertensive bleeding, or cholangiocarcinoma .
The majority of patients with PSC will demonstrate cholestasis on hepatic biochemistries. Alkaline phosphatase values greater than 2.5-fold normal values are seen in the majority of patients. As a result, elevated alkaline phosphatase values which are confirmed to be of biliary origin should result in a thorough evaluation and consideration for PSC. Total bilirubin values are elevated in over 50 % of affected patients and 90 % demonstrate a two to threefold elevation in alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Serum iron and copper values are frequently elevated, but as previously mentioned, are nonspecific and therefore not helpful for diagnostic purposes. Despite the finding of p-ANCA autoantibodies in the majority of PSC patients, their presence is nonspecific and should not be utilized to make a diagnosis of PSC. This is in contrast to other autoimmune hepatic disorders such as autoimmune hepatitis and primary biliary cirrhosis where serum autoantibodies play a pivotal role in diagnosis.
The diagnosis of PSC is m ade based on the classic cholangiographic findings of diffuse strictures with intervening areas of normal appearing bile ducts leading to the so-called “beading.” Seventy-five percent of strictures involve both the intra and extrahepatic bile ducts, with 15 % having strictures limited to the extrahepatic system. The cystic duct and gallbladder are involved in approximately 15 % of patients and a smaller number have pancreatic duct involvement [11–13]. Dominant strictures, defined as a diameter less than 1.5 mm in the common bile duct and less than 1.0 mm in the hepatic duct, are present in approximately half of PSC patients. Pseudodiverticula, particularly in the common bile duct are occasionally seen. While initially used as exclusionary criteria in PSC patients, the presence of biliary stones are now well-recognized as a common finding and frequent cause of cholangitis. There are three current modalities that can be used to image the biliary system. Endoscopic retrograde cholangiography (ERC) allows direct biliary visualization as well as also providing the opportunity to perform cytologic analysis, stricture dilation, removal of stones, and biliary stenting. Potential complications of ERC include bleeding, cholangitis, and pancreatitis . Percutaneous hepatic cholangiography (PTC) also allows direct access to the biliary system but has similar complications to ERC and requires experienced radiologists as intrahepatic bile ducts are generally not dilated in PSC. The test of choice when attempting to make a diagnosis of PSC is the magnetic resonance cholangiography (MRC). The noninvasive nature of MRC limits complications and is more cost-effective than ERC or PTC. These advantages must be weighed against the fact that MRC unlike ERC and PTC does not offer the opportunity to perform biliary brushings for cytology nor intervene therapeutically. Magnetic resonance cholangiography also lacks sensitivity compared to ERC when assessing for peripheral bile duct changes. Once a diagnosis of PSC is established, there is no indication for further instrumentation of the biliary system unless there is a change in the p atient’s clinical status.
Liver biopsy at the present is not felt to be necessary to establish a diagnosis of PSC, nor to determine disease severity. Liver biopsy should be considered in all patients suspected of having small-duct PSC or overlap syndrome with autoimmune hepatitis. The classic finding when a liver biopsy is performed in PSC patients is the concentric fibrosis (onion-skinning ) involving the periductal region. This lesion, however, is observed in only a minority of patients . Additionally, biopsy sampling variation may fail to detect these lesions in patients who otherwise have classic cholangiographic findings.
The natural history of PSC is highly variable and while it is a progressive disease, the rate of progression per year varies significantly in individual patients. Multiple studies have attempted to determine the time period from diagnosis to the need for liver transplantation or death and estimates range from 7 to 18 years from presentation [4, 15, 16]. Much of this variability is associated with the fact that some patients present early in their disease course without symptoms but have abnormal liver biochemistries, while others’ initial presentation may be a complication of advanced disease with portal hypertension or cholangiocarcinoma.
Various prognostic models have been utilized in an attempt to predict future outcomes but their value is questionable in this clinical setting due the highly variable nature of PSC. The most common employed of these prognostic models is one proposed by the Mayo Clinic and utilizes the following variables; total bilirubin, age, presence or absence of variceal bleeding, serum albumin, and aspartate aminotransferase values .
Primary Sclerosing Cholangitis Variants
Small-Duct Primary Sclerosing Cholangitis
Small-duct PSC is chara cterized by cholestatic biochemistries with a normal cholangiogram. Liver biopsy is essential in this group for diagnostic purposes and may demonstrate the periductal damage and onion-skinning previously described. Small-duct PSC represents approximately 10 % of all PSC cases. Small-duct PSC patients may have symptoms but a greater percentage are asymptomatic when compared to large-duct PSC. Approximately 10–15 % of those with small-duct PSC will progress to large-duct PSC, typically over 5–10 years. Patients with small-duct PSC have a better long-term prognosis with fewer complications when compared to their large-duct counterparts [18, 19].
Overlap Syndrome with Autoimmune Hepatitis
Between 1 and 17 % of patients with PSC will also have an overlap syndrome with autoimmune hepatitis [20–22]. These patients will present with a hepatocellular injury as well as cholestasis and have detectable antinuclear antibodies and anti-smooth muscle antibodies. Immunoglobulin G elevations, as in classical autoimmune hepatitis, are typically seen. Liver biopsy should therefore be performed in all patients with PSC who have aminotransferase values greater than five times the upper limit of normal or IgG values greater than two times the upper limit of normal. Liver biopsy demonstrates histologic findings of both conditions; the periductal “onion-skinning” damage seen in PSC and the interface hepatitis and prominent plasma cell infiltration which is classically described in autoimmune hepatitis. The autoimmune hepatitis component unlike the PSC component is responsive to immunosuppression, with the most common agents utilized being corticosteroids and azathioprine. Patients with overlap PSC and autoimmune hepatitis may progress more rapidly than those affected by PSC alone due to the combination of the hepatocellular and cholestatic components.
Primary Sclerosing Cholangitis in Association with Autoimmune Pancreatitis
Autoimmune pancreatitis is a manifestation of a systemic disorder affecting multiple organs and is associated with an elevated serum immunoglobulin G4 (IgG4). Histology of the pancreas shows a predominantly lymphocyte and plasma cell infiltrate. Pancreatic abnormalities include lesions that are frequently difficult to differentiate from malignancy as well as pancreatic duct strictures. A subset of these patients will have biliary strictures similar to those seen in PSC occasionally in the absence of pancreatic abnormalities, a condition occasionally referred to as IgG4 cholangiopathy . Those with IgG4 cholangiopathy tend to have a more aggressive disease course compared to those with PSC and normal IgG4 values [23, 24]. Primary sclerosing cholangitis associated with elevated IgG4 levels are frequently responsive to corticosteroid therapy and it is recommended to measure IgG4 levels in all newly diagnosed PSC patients .
Secondary Sclerosing Cholangitis
There are various conditions that can affect the biliary system and produce findings that mimic the strictures seen in PSC. Prior to making a diagnosis of PSC these secondary causes must be carefully looked for and eliminated as potential etiologies. Secondary causes include congenital biliary tract disorders such as biliary atresia and Caroli’s Disease, AIDS cholangiopathy, ischemic strictures, biliary malignancies such as cholangiocarcinoma not associated with PSC, previous biliary injuries as a result of surgery and chemical exposure to toxins such as fluxoridine, a pyrimidine analogue infused via the hepatic artery in patients with metastatic colon cancer to the liver .