Primary Sclerosing Cholangitis: A Diagnostic and Management Dilemma!

Primary Sclerosing Cholangitis (PSC) is a chronic inflammatory condition of the biliary system which results in biliary strictures and obliterating fibrosis [1,2]. Although, the precise etiology of PSC is uncertain, it is thought to be due to conglomerate of genetic predisposition, environmental conditions, an altered biliary mucosa, immune responses, and even cholangiocytes themselves can elicit the onset of disease [3]. The typical features, as seen on magnetic resonance cholangiopancreatography (MRCP), consist of alternating segments of annular strictures with normal duct interspersed; portraying a bead-like appearance of the bile ducts [2]. Because of the patchy and extensive involvement of PSC, liver biopsy is usually not helpful in early phase of disease and the final diagnosis is made with the help of MRCP (1). ERCP has a similar sensitivity to MRCP, but it is invasive, therefore, ERCP is reserved for therapeutic (stenting or dilation) or diagnostic(brushings) procedures [4].

Signs and symptoms of PSC patients are vague, which makes diagnosing it early difficult; patients present with hepatobiliary symptoms such as jaundice, hepatosplenomegaly, pruritus, and frequently test positive for autoimmune markers [1]. Patients with advanced stage of PSC usually have a cholestatic pattern of liver chem istry tests with raised serum gamma glutamyl transferase (GGT), alkaline phosphatase (ALP), and conjugated bilirubin [2]. ALP levels can be normal or fluctuating in some cases, normal levels of ALP shouldn’t discourage clinician to pursue PSC diagnosis [5]. Serum bilirubin is usually normal at the time of diagnosis; however, a rise in serum bilirubin should raise suspicion of advancing disease, dominant biliary stricture, choledocholithiasis or malignancy [1].

Since PSC is known to damage intrahepatic biliary ductules and liver parenchyma and ultimately leads to portal hypertension, liver transplantation is the only treatment proven to improve survival. The progressive course of PSC inevitably leads to malignancy, which is the leading cause of death in these patients [2]. Levels of ALP can be used to monitor the progression of PSC and response to the treatment. Indication for liver transplantation (LT) is based on the recurring episodes of cholangitis, Model for End Stage Liver Disease (MELD) score and ultimately development of CCA [1].

Many times, PSC is diagnosed incidentally on imaging performed for some other purposes and with other existing conditions. PSC has a strong association with inflammatory bowel disease, specifically ulcerative colitis [1]. PSC patients also have a 10-fold increase risk of colorectal carcinoma, an increased risk of developing gallbladder neoplasia and cholangiocarcinoma (CCA) [1]. In a population based study from Netherlands, median survival time until death or LT is estimated to be about 20.6 years. Whereas, literature from the past 25 years from liver transplantation centers or referrals has reported that to be about 9.3 years [6].

Even though PSC is a premalignant condition, duration of its diagnosis has no cumulative effect in the risk of developing cholangiocarcinoma (CCA) [2]. In a patient previously diagnosed with PSC, acute worsening of clinical condition and abnormal serum biochemistries should raise suspicion of an emerging malignancy. Overall, the lifetime prevalence of CCA in PSC patients is 5-10%; 160-fold greater risk than the general population. Generally, 1-2% of PSC patients develop CCA within 3 years of diagnosis [1].

CCA is difficult to diagnose due to several reasons. First of all, differentiating between malignant and benign strictures can be deceiving because of the similar resemblance. Next, the liver panel of initial CCA patients mimics obstructive jaundice [6]. In its earlier stages, CCA grows along the ductal area; a region hard to examine with non-invasive procedures [2]. CCA grows longitudinally, making it harder to visualize on MRCP, which makes the diagnosis even more difficult.

PSC patients have to be assessed regularly for the disease progression and CCA development. Patients are evaluated by signs of clinical worsening, annual imaging and serologic markers. Currently, the screening method suggests annual imaging with magnetic resonance cholangiopancreatography (MRCP) or ultrasound, and serum carbohydrate antigen 19-9 measurements (CA19-9) [2]. MRCP has a 78% and 76% sensitivity and specificity, respectively. However, the sensitivity of MRCP + CA 19-9 value cutoff set at ≥20U/mL, goes up to 100% at the expense of specificity at 38% [7]. An increase in tumor marker CA19-9, dominant strictures and/or rapidly worsening clinical condition are worrying signs and should be further investigated by endoscopic retrograde cholangiopancreatography (ERCP), cholangioscopy and biopsies. However, certain coexisting conditions have to be ruled out. For example, serum CA19-9 elevation can also occur in bacterial cholangitis, which make MRCP adjuvant and necessary. After excluding other causes, CA19-9 levels above 100U/mL has 89% sensitivity for detecting cholangiocarcinoma. Furthermore, CA19- 9 is helpful in monitoring treatment regimens and examining for cancer recurrence [6].

ERCP is used for further evaluation upon observing malignant appearing dominant strictures on MRCP. ERCP allows for a definitive diagnosis through direct visualization and collection of tissue sample and allows for therapeutic interventions such as biliary stenting. ERCP by itself has some limitations, because of the disease’s unique course, extracting samples is difficult. ERCP independently has a sensitivity of 30-60% in determining malignant strictures; the rate improves to 90% when ERCP is used in adjunction to MRCP/ ultrasound. In the event of discovering dominant strictures on ERCP, further investigation is recommended, even if cytology is negative. The next step is fluorescence in situ hybridization (FISH) of chromosome 17 on p16, which has a specificity of 88% [6].

To summarize, if PSC patient’s condition suggest malignancy, MRCP & CA19-9 should be considered. Further evaluation is decided using ERCP and completed via cytology, FISH and/or EUS-FNA. On the other hand, if screening procedures show negative outcomes of CCA but a high index of suspicion persists, then MRCP with CA19-9 should be repeated every 3 to 6 months. Overall, patient’s clinical condition along with an experienced physician at cholangiography are the best tools for assessing CCA development [6]

PSC is the most common cause of CCA and the fifth most frequent indication for liver transplant (LT) in the United States. Although many therapeutic interventions have been proposed, none have improved the mortality rate [2]. Currently, LT with neoadjuvant therapy has shown promising results in improving the outcomes [8].

A strict surveillance on the liver function and clinical condition is the initial way of assessing patients for LT. Clinical indications for LT are any complications resulting from advancing liver disease [9]; specifically, uncontrolled pruritus, jaundice, recurrent ascending cholangitis, and/or portal hypertension [1,2]. Generally, LT is only indicated for extrahepatic CCA. However, recent research has been promising for early stages of intrahepatic CCA [10]. Evaluating the liver via surrogate markers has limited the need for biopsy; however, a final exploratory laparotomy is crucial in approving CCA patients to undergo a LT [1,11]. Exploratory laparotomy for staging, and exclusion of extrahepatic diseases by bone scan is very critical component in evaluating patients before surgery. Any metastasis of CCA is a contraindication for LT, therefore it is important that the patient is managed in a timely manner [11].

Many parameters have to be considered before undergoing LT for CCA. The major one being a positive biopsy, or intraluminal brushing of biliary stricture suggesting high possibility of CCA. LT indication includes combination of staging and grading systems. For example, prognostic Mayo Model has been advised, which assesses Primary Sclerosing Cholangitis (PSC) patients nearing CCA development. Another criterion, MELD-Na (modified end stage liver disease- sodium) score, gives an estimate severity of liver disease and 3 months mortality without LT. The guideline is based on patient’s age, serum biochemistries, clinical signs, and staging of the carcinoma. Mayo risk score ≥7.8, bilirubin >6mg/dL and MELDNa score > 15 are the indication for LT assessment and putting on wait list for transplant [12]. Patients treated with neoadjuvant therapy and LT across 12 centers had a 65% recurrence free survival rates [13].

Another alarming signs for listed patient for LT includes CA19-9 levels greater than 100U/ml (after excluding bacterial cholangitis) and malignant strictures. Finally, polysomy on fluorescence in-situ hybridization (FISH), or an explicit mass on cross-sectional imaging are definite indications for LT [9].

Common complications of LT include hepatic artery stenosis, thrombosis, ductopenia, ABO incompatibility, and recurring strictures [2]. Hepatic artery and portal venous complications occur at higher rates in patients with neoadjuvant therapy than in liver transplantation alone [14]. More complications are found among patients with a history of prior cholecystectomy, CA 19-9 greater than 100U/ml and older age [15].

Stenosing of vessels are resolved with dilation and placement of temporary plastic biliary stents through ERCP. Stents are usually reserved for strictures refractory to dilation, as they are associated with higher risks of complications including bacterial cholangitis [16]. ERCP can also be used to treat reoccurring dominant strictures, an early stage of cholangiocarcinoma. It is recommended that posttransplant patients undergo cholangiography or liver biopsy to assess recurrence [17]. Approximately 30%–50% LT patients have reported recurrence of PSC within 10 years [9].

A major issue seen in post-transplant patients is worsening of pre-existing inflammatory bowel disease (IBD). IBD can be managed with azathioprine and cyclosporine. Since the patient’s regimen include immunosuppression therapy, infections should be foreseen and prophylaxis antibiotics may become necessary [9].

Primary Sclerosing cholangitis (PSC) is believed to be due to or combination of genetic predisposition, autoimmune responses and has no cure yet. Current management with the help of secondary bile salts may help in reducing the progression of disease. Early diagnosis is the biggest challenge for a clinician. Common clinical presentation and laboratory findings of other hepatobiliary disorders and difficulties in achieving early diagnosis of CCA leave patients vulnerable. MRCP ± ERCP is helpful in establishing diagnoses of Primary Sclerosing Cholangitis (PSC) and for CCA as well. Many recommendations exist for screening for CCA; astute physician and close monitoring of liver function tests and serum markers (CA19-9) are essential in diagnosing CCA. Liver transplant with neoadjuvant therapy has clearly shown a mortality benefit amongst other treatment; however, it has many shortcomings such as, disease recurrence, transplant related immune issues, and worsening of IBD. In conclusion, early diagnosis of CCA and LT are clearly the best possible way to decrease mortality [18,19].

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