PSC-Related Blog

Often times, there is an abundance of information in scientific journals that may contain useful information to patients, yet is inaccessible to many due to excessive medical jargon. This blog series is designed to benefit patients by summarizing important PSC research in simple terms so that patients and caregivers can understand what these important articles are saying without having specialized knowledge.

TITLE: “PRIMARY SCLEROSING CHOLANGITIS – A COMPREHENSIVE REVIEW”

AUTHORS: TOM KARLSEN, TRINE FOLSERAAS, DOUGLAS THORBURN, AND METTE VESTERHUS

This paper provides a comprehensive review of what we know about PSC.  The aims of this study/presentation are to:

• Provide a comprehensive review of PSC research status
• Emphasize developments related to patient stratification and disease behavior
• Survey advances made in our understanding of PSC pathogenesis (causes)
• Summarize the ongoing efforts to develop an effective therapy based on these insights

INTRODUCTION

In the introduction, the authors of this article provide a brief history of our current understandings of PSC.  Below are the key points:

• PSC patients have an increased risk of cholangiocarcinoma (bile duct cancer)
• The only cure for PSC is liver transplantation, and PSC recurs in some transplanted patients
• The relationship of PSC and IBD (Inflammatory Bowel Disease) has inspired several areas of research
• The cause for development of PSC is unknown, but there are several theories about what causes PSC:
  • Defects in one’s protection against bile acid (which is a toxic substance)
  • Leakage of harmful, pro-inflammatory specimen from microbiome (where lots of micro-organisms live in your body)
  • Movement of T-cells (a type of immune cell) originating in gut to liver, causing damage in the liver
• The actual cause is very complex and involves many factors working together

EPIDEMIOLOGY

In this section, the authors share information about the epidemiology of PSC – the frequencies and patterns for PSC and the causes and risk factors in specified populations.

• With an estimated 30,000 PSC patients in the U.S., PSC meets the definition of a rare disease (affecting less than 200,000 people nationally.)
• Studies have shown increasing incidence worldwide
  • This may be due to MRCP vs ERCP as a diagnostic tool; however, clinical features of newly diagnosed patients are stable over time, so earlier diagnosis may not explain the higher incidence
  • Prevalence of PSC is hampered by a lack of ICD-10 code (international code used to identify a disease)
• The typical PSC patient is a 30-40-year-old male (but the disease affects a wide variety of ages)
  • PSC affects approximately 8% of patients with IBD and often runs a subclinical course in female patients and Crohn’s disease.
• In 25% of cases, patients may have other autoimmune diseases in addition to PSC and IBD
• PSC patients have an increased risk of biliary cancer and colorectal cancer
  • Half of cholangiocarcinoma cases are diagnosed within the first year of PSC diagnosis
  • Colonoscopies should be performed regularly as PSC-IBD patients have a 5x greater risk of colorectal cancer
• Pancreatic cancer and hepatocellular cancer can also occur with PSC
• Increased frequencies of gallbladder abnormalities have been found in PSC patients
  • Gallstones found in 25% of patients with PSC
  • Gallbladder cancer frequency of ~3% in PSC population

AETIOLOGY AND PATHOGENESIS (CAUSE OF DISEASE)

Aetiology is the cause, set of causes, or manner of causation of a disease or condition. Pathogenesis describes the development of a disease and the chain of events leading to that disease.

This section discusses the different factors found in the development of PSC.  The authors state that the information we have about the causes of PSC is incomplete and contradictory; it is this lack of understanding about PSC pathogenesis that hinders the development of effective treatments.

GWAS – Genome Wide Association Studies

• GWAS have identified 23 genome-wide risk areas (loci) that indicate autoimmune processes may be central to the development of PSC
• The main outcome of PSC genetic studies is the positioning of PSC as an autoimmune disease
• There are high hopes that these identified genes will provide clues to PSC pathogenesis
  • It is possible to generate hypotheses for how the individual identified genes are involved in PSC and these hypotheses provide a great opportunity for further research

Bile Acid Defects and Movement of T-Cells from Gut to Liver

• A broad avenue of research in the bile acid field has developed in close relationship with therapeutic developments.
  • Active features in the outer layer of the bile ducts of PSC patients are likely factors in developing fibrosis and subsequent cirrhosis
  • The wide-spread prescription of UDCA (Ursodiol) has inspired research into the mechanisms of action behind the potential protective effects of bile acid interventions
  • Research on norUDCA shows that this drug appears to enhance general resistance to bile acid induced biliary injury
  • Further research on bile is needed
• It is currently unknown whether the gut-liver connection in PSC is caused by exposure to a similar trigger at both sites, or by the recruitment of T-cells that have been primarily activated in the gut to the liver
  • It has been suggested that there is cross-talk between cholangiocytes and T-cells facilitating their recruitment to the portal areas
  • There is currently limited human data supporting the occurrence of simple “leakage” of bacterial components in PSC
• The role of the gut in PSC development is not yet defined and the interplay between the bacteria in the gut (gut microbiota}, the immune system and bile acid physiology are rapidly growing research fields.
  • Research is showing that microbial diversity is compromised in diseases like PSC
  • Genetic discoveries to date substantiate the involvement of gut bacteria and may lead to new therapies

DIAGNOSTIC DEFINITIONS

Magnetic resonance cholangiopancreatography (MRCP) is now used to make diagnosis of PSC (see picture on the right).

• This technique is preferred since it is non-invasive and more cost effective
• There are many different types of PSC

IgG4-Associated Cholangitis

• IgG4-associated cholangitis (IAC) is different than PSC with elevated IgG4
• IAC can be treated with corticosteroids
• PSC patients with elevated IgG4, on the other hand, are less responsive and have a form of the disease that may progress more quickly

Small-duct PSC

• Diagnosis of this disease is made if an MRCP shows bile ducts characteristic of PSC and the patient has clinical and biochemical abnormalities as well
• Not known if this is less severe version of PSC, an early stage of PSC, or a totally different disease compared to large-duct PSC
• If IBD is not present, then Primary Biliary Cholangitis (PBC) and Secondary Sclerosing Cholangitis should also be explored

Autoimmune hepatitis in patients with PSC

• Features of this are present in 7-14% of patients with PSC
• Higher activity seen in younger patients
• Immunosuppressive therapy is suggested for treatment although literature regarding treatment outcomes is scarce

STRATIFICATION (SEPARATION) AND PROGNOSTICATION (A MARKER FOR INDICATION OF OUTCOME)

• PSC is progressive (develops from a mild form to more severe form over time)
• Patients without symptoms at diagnosis have shown to have a better prognosis than patients with symptoms
• PSC is highly variable
• There are currently no established prognostic tools that can predict outcome in patients

Clinical Risk and Histology

• Several attempts have been made to develop a prognostic model
• PSC specific revised Mayo risk score is most widely used
• Many other models that use invasive means, so not as prevalent
• Further studies are warranted to clarify the relevance of alkaline phosphatase (ALP) to record treatment response
• Biopsies are not performed routinely because they can have adverse outcomes and are invasive

Noninvasive Tests

• The Enhanced Liver Fibrosis (ELF) test has been shown to be a strong indicator of clinical outcome
• Tailoring a specific liver fibrosis marker panel for PSC may help us better predict PSC outcomes
• Liver stiffness measurement by transient elastography (a form of imaging) has been used as an assessment of liver fibrosis (scarring of tissue) in many chronic liver diseases
• Transient elastography is promising as a clinical endpoint in PSC (presented by International PSC Study Group (IPSCSG)

CLINICAL EVENTS AND PATIENT MANAGEMENT

This section describes the clinical aspects of managing PSC patient care.  The authors delve into specific clinical events and best practices for treating them. Key points made are:

• The clinical experience of the physician is critical in treatment of disease due to its complexity
• Symptoms and Quality of Life
  • Fatigue, pain, and itchy skin are the most common symptoms
  • Limited studies on quality of life on patients with PSC
• Bacterial Cholangitis
  • Cholangitis (infection of liver’s bile ducts) can occur frequently in patients with PSC but symptoms can vary
  • Antibiotics are typically effective
  • Some patients may require antibiotics to be readily available in case cholangitis develops
  • Recurring cholangitis may be debilitating for patients, but is not associated with worse prognosis, so additional MELD points are not warranted
• Dominant Strictures
  • A stricture is the narrowing of bile ducts detected by endoscopic retrograde cholangiopancreatography (ERCP)
  • Balloon dilation has been the most widely used method to deal with strictures
• Cholangiocarcinoma
  • Diagnosis dependent on tumor marker CA19-9, different types of imaging, and tests on biopsies (a part of tissue removed)
  • CA19-9 lacks sensitivity (low levels may be seen in advanced CCA) and specificity (elevated levels may be seen with cholangitis or other malignancies)
  • MRI may visualize early features of CCA, but difficulties in distinguishing inflammatory, benign and malignant lesions are an issue
  • Combined MRI/MRC has highest sensitivity and is preferred for detecting small lesions
  • Lack of accurate diagnostic modalities for detection of early stages CCA and insufficient treatment strategies of advanced CCA currently restrict the ability to perform effective CCA surveillance
  • Chemotherapy can improve progression-free and overall survival but median survival time of metastatic cholangiocarcinoma is 1 year
• Cirrhosis
  • Cirrhosis (when liver stops functioning due to long-term damage) cannot be delayed and is the inevitability of PSC
  • The usefulness of Ursodiol has been debated
  • High dose Ursodiol (28-30 mg/kg/day) has been shown in some studies to be harmful
  • There is no evidence against low-dose Ursodiol (13-15 mg/kg/day)
• Liver Transplantation
  • The Model of End-stage Liver Disease (MELD) is used to determine priority for liver transplants although there may be variations depending on the region
  • PSC patients have 2nd best life expectancy after transplantation when compared to other primary liver diseases
  • Immunosuppression is used to prevent rejection of transplanted organ
  • PSC is most common disease to recur after transplantation
• IBD and colorectal neoplasia in PSC
  • Currently no evidence of harm associated with therapies for IBD
  • Yearly colonoscopies are recommended for patients diagnosed with PSC-IBD due to the increased risk of colorectal cancer
  • Surgery may be required for management of IBD
• Osteoporosis
  • Bone mineral density tests are recommended at diagnosis and regular intervals due to increased risk of metabolic bone disease
  • Vitamin D and calcium may be used as supplements for patients with PSC
• Cause of Death
  • Most frequent causes of PSC-related death are cholangiocarcinoma (32%), liver failure (15%), transplant-related complications (9%), and colorectal cancer (8%)

SUMMARY AND FUTURE DIRECTIONS

• PSC is a complex disease despite many advances in recent years
• Lack of effective therapies have made invasive treatments the only methods of disease management
• Additional risks for other diseases (IBD and other cancers) affect quality of life
• Diagnostic tools to measure disease activity are still in infancy
• There are currently a number of clinical trials in progress and their outcomes may help to determine which principal approaches are likely to be most effective.
• Ongoing clinical trials in PSC target different mechanistic compartments (e.g. bile acid therapies, anti-fibrotics, biologics, antibiotics) and may provide proof of concept for future development of effective therapies.
• Implementation of biomarkers and advances in imaging will address current limitations in diagnosis, surveillance and treatment of PSC
• The unmet needs of PSC patients make it one of the remaining major challenges in hepatology
• Lots of challenges, but also lots of enthusiasm for research and to find a cure

I hope this summary of Karlsen et al.’s 20-page paper in Lancet was useful. If you are interested in learning more, then please read the original paper as it is very interesting and informative.

Mahesh

Mahesh is a PSC patient who is currently pursuing an undergraduate degree at Rice University in Texas. Mahesh has a keen interest in better understanding PSC and in helping others who are grappling with this disease by providing them with actionable information.