Continuing Education Activity

The diagnostic criteria for small-duct primary sclerosing cholangitis (SDPSC) included biochemical features of chronic cholestasis with unknown etiology, normal cholangiogram, liver histology compatible with PSC. SDPSC is more common in males with an average age of 38 years old. This activity reviews the evaluation and management of SDPSC and highlights the role of interprofessional team members in collaborating to provide well-coordinated care and enhance patient outcomes.

Objectives:

• Identify the small duct primary sclerosing cholangitis in the etiology of chronic cholestasis.
• Describe the pathophysiology of small duct primary sclerosing cholangitis.
• Summarize the prognosis of small duct primary sclerosing cholangitis compares to large duct primary sclerosing cholangitis.
• Explain the importance of SDPSC diagnosis and how it affects to improving care coordination among the interprofessional team when distinguishing SDPSC from large duct primary sclerosing cholangitis (LDPSC).

Introduction

Primary sclerosing cholangitis (PSC) is an uncommon cholestatic liver disease characterized by the inflammation and fibrosis of intra- and extra-hepatic biliary ducts. It has an incidence of 0.9 to 1.3 cases per 100000 in the United States.[1] After recruiting of endoscopic retrograde cholangiopancreatography (ERCP) in the early 1970s, it revealed that ‘classical’ primary sclerosing cholangitis (PSC) appears as multiple strictures in the intra- and extra-hepatic biliary tree.[2] However, the ERCP is not diagnostic for the detection of the small intra-hepatic biliary strictures.[3] Then, in 1985, this question raised by Ludwig that whether the small bile ducts might be involved in PSC.[4] Pathological studies in 1991 led to the coining of the term small duct PSC (SDPSC). [5] Later, SDPSC was defined in the patients with inflammatory bowel disease and chronic cholestasis, who have normal cholangiogram with liver biopsy diagnostic for PSC.[6]

Etiology

The etiology of small duct primary sclerosing cholangitis (SDPSC), also referred to as 'pericholangitis,' is unknown. However, with consideration of SDPSC as a subtype of PSC, dietary exposure, infection, toxins, and autoimmunity can be the initial insults.[7] Naess et al. investigated the genetic association between the patients of SDPSC and LDPSC. They concluded HLA-DRB1*13:01 and B*08 alleles were significantly associated with SDPSC. Also, SDPSC, when associated with IBD, is genetically similar to LDPSC and represent milder version or early stages of LDPSC. However, when SDPSC does not correlate with IBD, they were genetically dissimilar to LDPSC.[8]

Epidemiology

The male predominance observed in large duct pathology was confirmed in the small duct patients with inflammatory bowel disease, although not in the group of patients without IBD, where females predominated.[9] A study by Bjornsson et al. on 83 patients with small-duct PSC showed 51 males (61.5%) and 32 females (38.5%). This study reported the median age at the time of small duct PSC diagnosis was 38 years. It reported no significant ethnicity consistency.[10] In a study by Singal et al. on 25 patients with SDPSC, the mean age of diagnosing was 37 years old, with a male to female ratio of 13:12.[11] The study by Charatcharoenwitthaya et al. on forty-two patients with SDPSC was confirmed the male dominance.[12] Heikius et al., in a Finnish study, evaluated the prevalence of SDPSC in IBD patients. After studying 237 unselected patients with IBD, they reported the prevalence of PSC was 11%. Of these patients, 11.5% had the small-duct variant.[13] Among adults with PSC, 75% have involvement of both small and large ducts, 15% small ducts only, and 10% large ducts only. Small duct PSC typically presents with an insidious onset of symptoms or with end-stage liver disease.[7]

Pathophysiology

Small duct PSC is considered as a subtype of PSC. Generally, PSC divides into four subgroups due to similarity:

1. Classic PSC (intrahepatic and extrahepatic strictures on cholangiography)
2. Intrahepatic PSC (intrahepatic strictures on cholangiography)
3. Extrahepatic PSC (extrahepatic stricture on cholangiography)
4. Small duct PSC (normal on cholangiography).[14] 

The role of immune-mediated mechanisms in the PSC patients has support from the association of human leukocyte antigen (HLA) and non-HLA haplotypes, and the presence of autoantibodies in serology.[15] Also, the association between IBD and PSC can be explained by different hypotheses. The leaky gut hypothesis described bacteria or bacterial components and products passing the inflame bowel wall and enter the portal venous system, which results in concomitant initiation of an inflammatory reaction focused on portal fields.[16] The gut lymphocyte homing hypothesis arose to justify the association of PSC in inactive IBD patients. This hypothesis assumes that CCR9+ α4β7+ memory T lymphocytes primed persist in the inflamed gut and entering into an enterohepatic circulation, which can be the trigger for portal inflammation in PSC through abnormally expressed adhesion molecules in the gut and liver.[17]

Histopathology

Except for extrahepatic PSC, LDPSC, SDPSC, and intrahepatic PSC have similar liver histology features, described as nonsuppurative cholangitis, periductal fibrosis, ductular reaction, and ductopenia. However, in extrahepatic PSC, the histology features are nondiagnostic or nonspecific features of cholestasis, particularly in early-stage disease.[14] Liver Biopsy findings classically reported as an “onion skin” appearance, which includes non-suppurative cholangitis, ductular reaction, ductopenia, and periductal fibrosis. However, this classic finding is present in almost 10% of liver biopsies. Furthermore, histology alone is not enough for making the diagnosis of PSC.[18] Other diseases such as IgG4-associated cholangiopathy, ductopenic rejection following a liver transplant, and acquired immune deficiency syndrome also can have similar histopathology, which seen in PSC.[19] The main reason for liver biopsy in large-duct PSC patients is to exclude other diseases, determine the stage of PSC, and diagnose small-duct PSC.[20]

History and Physical

The specific diagnostic criteria in small duct PSC are still challenging, particularly whether the existence of IBD is a requirement for the diagnosis or not. The detail definition has varied from study to study. Generally, IBD is not a mandatory criterion for small duct PSC.[21] The diagnostic criteria for small-duct PSC included biochemical features of chronic cholestasis with unknown etiology, normal cholangiogram, liver histology compatible with PSC.[22] The diagnosis criteria for large-duct PSC are the same as small-duct PSC, except for the findings of bile duct strictures and dilations (“string of beads”), which are the typical features of LDPSC.[10] Data from the studies showed that abnormal liver biochemistries are the most common cause of presentation. However, clinical symptoms or signs are not uncommon with abdominal pain, fatigue, pruritus, and weight loss are the most common presentations.[11][23] The data from Bjornsson et al. revealed a strong correlation between small duct PSC and IBD. From the 83 patients with small duct PSC, approximately 81% of patients had colitis which is including ulcerative colitis (78%), Crohn’s colitis (21%), and collagenous colitis (1%). However, this study concluded there is no difference existing in the outcome (defined as died or underwent liver transplantation) between small duct PSC either with ulcerative colitis or with Crohn’s colitis.[10] Also, it seems that Crohn’s colitis related to small-duct PSC more than large-duct PSC.[24]

Evaluation

Laboratory tests - In most patients, liver biochemical tests usually show elevation of the serum alkaline phosphatase. The serum aminotransferases are generally less than 300 international unit/L. The serum albumin concentration may be low in patients with active inflammatory bowel disease, although in early-stage PSC is often normal.[25] Elevation of serum immunoglobulin G4 (IgG4), which is a marker of autoimmune pancreatitis, has been reported in patients with PSC.[26][27][26] Other known etiology of chronic cholestasis require exclusion by appropriate laboratory tests, clinical evaluation, imaging, and histologic criteria. The following etiologies, such as autoimmune hepatitis, primary biliary cirrhosis (PBC), drug-induced liver disease, chronic viral liver disease, alcoholic hepatitis, and HIV infection, should rule out by laboratory tests and history. Furthermore, pancreatic disease and gall stone should exclude by ultrasound examination.[10]

Cholangiography - It is helpful for the evaluation of affected biliary radicles greater than 100 micro millimeters. Various options such as Endoscopic retrograde cholangiopancreatography (ERCP), magnetic resonance cholangiopancreatography (MRCP), or percutaneous transhepatic cholangiography (PTC) are available to obtain cholangiograms. However, being noninvasive and accurate makes MRCP as the preferred test of choice to distinguish SDPSC from LDPSC.[11][28][29][30] Small duct primary sclerosing cholangitis involves biliary calibers less than 100 micro millimeters, which lead to normal cholangiogram.[11] However, cumulative follow-up data by Bjornsson et al. reported that nineteen (22.9%) of SDPSC progress to large duct PSC after a median of 7.4 years.[10]

Liver biopsy - The most specific histologic finding in SDPSC is the "onion skin" pattern, which describes as fibrous obliteration and concentric replacement of connective tissue in small bile ducts.[20] Although, this classic finding histology alone is not enough for making a diagnosis of SDPSC.[18]

Liver ultrasound - Ultrasound findings are commonly used to rule out a secondary cause of chronic cholestasis, such as pancreatic disease and gallbladder abnormalities.[10]

Treatment / Management

There are no reported data in the literature regarding specific treatment for SDPSC. Charatcharoenwitthaya et al. .evalute the effect of ursodeoxycholic acid (UDCA) in 42 patients with SDPSC and follow the liver disease progression (cirrhosis, liver transplantation) and liver biochemistries for 24.9 years. They reported UDCA therapy might not delay disease progression but improves the liver biochemistries.[12] However, liver transplant in SDPSC patients who present with end-stage liver disease has longer transplantation-free survival than large duct PSC (13 years vs. ten years, respectively).[10]

Differential Diagnosis

Intrinsic or Extrinsic Compressive Causes (Either Benign or Malignant)

• Cholangiocarcinoma
• Mirizzi syndrome
• Compressive lymphadenopathy
• Portal hypertensive biliopathy
• Diffuse intrahepatic malignancy
• Postoperative strictures
• Chronic pancreatitis

Infectious Causes

• AIDS cholangiopathy (e.g., Cryptosporidium parvum, cytomegalovirus)
• Recurrent pyogenic cholangitis (also known as oriental cholangio-hepatitis)
• Helminthic infection (e.g., Clonorchis, Opisthorchis, Ascaris)

Ischemic Causes

• Posttransplant non-anastomotic strictures
• Postintraarterial chemotherapy
• Postradiation therapy

Immunologic Causes

• IgG4-associated cholangiopathy
• Eosinophilic cholangitis
• Mast cell cholangiopathy
• Histiocytosis X
• Systemic vasculitis
• Hepatic allograft rejection
• Primary biliary cholangitis

Congenital and/or Idiopathic Causes

• Choledochal cysts (e.g., Caroli disease)
• Progressive familial intrahepatic cholestasis [14]

Prognosis

In contrast to patients with large duct PSC, Small duct PSC has had less research, and usually, the studies compare its prognosis with large duct PSC. Large duct PSC is associated with progression of fibrosis to cirrhosis, end-stage liver disease, and liver transplantation. These patients have an elevated risk of malignancy, particularly cholangiocarcinoma, hepatocellular carcinoma, and colorectal dysplasia and adenocarcinoma in the presence of IBD.[31] Colorectal cancer (CRC) in PSC patients with IBD is approximately a 5-fold higher compared to IBD alone.[32] The most threatening neoplastic complication of PSC is cholangiocarcinoma, which was an estimated annual incidence of 1% and a lifetime occurrence of 15% in patients with PSC.[33]

Small duct PSC, compared to large duct PSC, seems to be more benign. The results of the study by Bjornsson et al. presented the natural history of 33 patients with small duct PSC and 260 patients with large duct PSC over a mean follow-up of approximately nine years. In this study, only 4 (12%) of the 33 patients with small duct PSC died or required liver transplantation versus 122 (47%) of the 260 patients with large duct PSC.[22] The Mayo Clinic's study has confirmed these findings. In this study, Angulo et al. found that the median survival without liver transplantation was 29.5 years in patients with small duct PSC (n = 18) versus only 17 years in the large duct PSC group (n = 36). Survival in the small duct PSC group was similar to that expected in the white US population; however, the large duct PSC group was lower.[23]

A minority of patients with small duct PSC eventually develop cholangiographic evidence of large-duct PSC. In the Bjornsson et al. study, cholangiography was repeated in 19 (58%) of the 33 patients with SDPSC. Only four patients (12%) developed large-duct PSC, with typical intrahepatic and/or extrahepatic changes on cholangiography.[22] In the Angula et al. study, 5 of the 18 patients with SDPSC underwent repeat cholangiography because of worsening liver biochemistry. Of these patients, 3 (17% of the total) developed typical cholangiographic features of large-duct PSC.[23] The study by Broom et al.,4 out of 32(12%) patients developed features of large duct PSC after a median time of 72 months. Two of the four patients had only intrahepatic changes, and one of them had developed cirrhosis. In the other two, the cholangiogram was compatible with intra- and extrahepatic biliary tree involvement.[9]

Cumulative follow-up data by Bjornsson et al. reported that nineteen (22.9%) of SDPSC progress to large duct PSC after a median of 7.4 years. In this study, no progression to cholangiocarcinoma was reported except one patient who first developed to large duct PSC. Also, they indicated small duct PSC has longer transplantation-free survival than large -duct PSC(13 years vs. ten years, respectively). SDPSC recured in two patients after liver transplantation.[10] Singal et al. were revealed the data in 25 patients with SDPSC after 17 months of follow up. They did not report malignancy or progression to large duct PSC after the follow-up. However, Two patients developed to end-stage liver disease. One of these two underwent a liver transplant, and the other one with long-standing severe ulcerative colitis died due to sepsis before it could be transplanted.[11]

Charatcharoenwitthaya et al. reported that patients with concomitant of SDPSC and IBD have a better prognosis compare to SDPSC without IBD. Also, they concluded IBD associated with SDPSC had a lower prevalence of pancolitis compared to IBD in patients with large-duct PSC.[12]

Complications

• Progression to LDPSC, then possibly increased risk of cholangiocarcinoma.[10] In contrast to LDPSC, there was no reported cholangiocarcinoma in isolated SDPSC.
• Fat-soluble vitamin deficiencies (A, D, E, and K)[34]
• Metabolic bone disease(osteopenia/osteoporosis rather than osteomalacia)[35]
• Liver cirrhosis and portal hypertension[10]
• Hepatocellular carcinoma in patients with cirrhosis[9]
• Recurrence after liver transplant[10]

Deterrence and Patient Education

Small duct primary sclerosing cholangitis (SDPSC) is a chronic cholestatic disorder described by inflammation and fibrosis of biliary calibers <100 micro millimeters.[11] SDPSC is a rare disease with an unclear prevalence due to limited studies. SDPSC commonly affects males with a median age at diagnosis of 38 years. There is a significant association(81%) with inflammatory bowel disease.[10]

Most patients do not have any symptoms and usually detect by abnormal liver tests. However, in symptomatic patients, abdominal pain, fatigue, pruritus, and weight loss are the most common complaints.[11] For diagnosis of SDPSC, patients need to have abnormal liver enzyme tests with unknown etiology, normal cholangiogram, liver biopsy(histology compatible with PSC).[22] The prognosis of SDPSC is less clear than the large duct PSC. However, studies suggested better prognosis in terms of longer liver transplantation-free survival.[10] IBD (inflammatory bowel disease), fat-soluble vitamin deficiencies (A, D, E, and K), metabolic bone disease (osteopenia/osteoporosis rather than osteomalacia), liver cirrhosis, hepatocellular carcinoma in patients with cirrhosis, and recurrence after liver transplant are the most common complications reported in the literature.[35][10][9] No specific treatment is available for SDPSC. One study reported ursodeoxycholic acid (UDCA) therapy may not delay disease progression but can improve the liver biochemistries.[12]

Enhancing Healthcare Team Outcomes

Small duct primary sclerosing cholangitis (SDPSC) is a rare disease with an unclear prevalence due to limited studies. The rarity of SDPSC causes challenges in diagnosis. The diagnostic criteria for small-duct PSC included biochemical features of chronic cholestasis with unknown etiology, normal cholangiogram, liver histology compatible with PSC.So, health professionals should be aware of etiologies that can cause abnormal liver enzymes and try to rule out them by choosing the correct laboratory or imaging tests. After excluding known causes of chronic cholestasis, patients should evaluate by cholangiogram (MRCP preferred) and liver biopsy to distinguish SDPSC from LDPSC. The study by Bjornsson et al. revealed the difference in prognosis between SDPSC and LDPSC. They concluded SDPSC has longer transplantation-free survival than LDPSC (13 years vs. ten years, respectively). Also, in this study, cholangiocarcinoma did not occur in SDPSC patients except one patient who already progressed to LDPSC.SDPSC can recur even after liver transplantation.[10] [Level3]

In terms of improving outcomes and treatments, no data is available. Only one study evaluated the effect of ursodeoxycholic acid (UDCA) in SDPSC patients which did not show the delay in the progression of the disease, despite improvement in liver enzymes.[12]