Download Intro to PSC A to Z

Introduction to PSC:
From A to Z
David N. Assis, MD
Assistant Professor of Medicine
Yale University
I have no disclosures relevant to this
presentation.
Primary Sclerosing Cholangitis (PSC)
A heterogeneous, idiopathic, inflammatory
disorder of the bile ducts, frequently
associated with inflammatory bowel
disease (IBD) of the colon, resulting in
strictures of the intrahepatic and/or
extrahepatic bile ducts.
What is bile and what does it do?
• Bile is made in the liver which has a variety
of important functions:
– Helps to digest food
– Carries waste products from the liver to the
intestine
– Contains bile acids, which are hormones that
help regulate metabolism
• Bile flows out of the liver through bile ducts
NIH.
In PSC…
• The bile in PSC is more toxic than normal
– Increase in harmful bile acids
• There is inflammation along the walls of
the bile ducts
– Caused by bile acids and also immune cells
attracted to the bile ducts
• Over time, this results in scars (strictures)
of the biliary tree
Netter’s Gastroenterology. 2nd Edition. 2010.
Researchgate.
Primary vs. Secondary
Sclerosing Cholangitis
– Primary if the cause is not known
– Secondary if a specific cause is known
– Causes of Secondary Sclerosing Cholangitis:
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Vascular injury
Cancer
Infectious
Inherited
Iatrogenic (surgical errors)
Categories of PSC (Variants)
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Large duct PSC
Small duct PSC
PSC – Autoimmune Hepatitis Overlap
Autoimmune sclerosing cholangitis (kids)
IgG4 related sclerosing cholangitis
Large Duct PSC
• Classic form of the disease
• Majority of patients have this type
– Bile duct strictures can be found by imaging
such as MRI or endoscopy (ERCP)
– More commonly men
– Strongly associated with IBD (80%)
• Usually ulcerative colitis
• Often causes no symptoms (asymptomatic)
• Involves the entire colon
Small Duct PSC
• The injury is limited to the microscopic bile
ducts seen on liver biopsy
• 10% of all PSC patients
• Similar patient population as large duct PSC
• Often associated with colitis
• Usually does not progress to large duct PSC
• May have a better outcome vs. large duct PSC
Autoimmune Sclerosing Cholangitis
• Found in some children with PSC
• More inflammatory than adult PSC
• May respond to immune suppressing
medications
PSC-Autoimmune Hepatitis
Overlap
• 5-10% of patients with PSC
• Clinical features of PSC but also
inflammation in the liver tissue
(autoimmune hepatitis)
• May start with one and later develop the
other
• The hepatitis responds to immune
suppressing medications
IgG4 related Sclerosing
Cholangitis
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Rare!
High blood levels of immunoglobulin G4 (IgG4)
IgG4 positive plasma cells seen in the tissue
Associated with autoimmune pancreatitis
Presents with large duct scars (strictures) that
look like typical large duct PSC
• Responds very well to steroids and scars
improve
Epidemiology of PSC
• Incidence
– 1 to 1.5 cases per 100,000 person-years
• Prevalence
– 6 to 16 cases per 100,000 inhabitants
• More common in North America & Northern Europe
• Men > Women
• Any age
• Approximately 32,000 Americans have PSC
– Definition of Rare Disease in the US: <200,000
patients at any given time.
Where does PSC come from?
• Multiple mechanisms involved
Immune System
Self-reacting lymphocytes
Inflammation
Bile Acids
Toxic Injury
Inflammation
PSC
Liver-Gut Axis
Altered Microbiome
Colitis
Genetics
HLA
Possible causes of PSC
• Various genes have been found that
can increase the risk of PSC
• Variations in the HLA molecule
– Presents fragments of protein to the
immune system
• Abnormal genes account for less than
20% of the overall risk of PSC
PSC and Genetic Associations
• Integration of Genetics and Environment?
Karlsen et al. J Hepatol 2015;62:S6–S14.
Environmental risk factors
• Not well understood!
• Smoking is protects against ulcerative
colitis, and this is also seen in patients who
have both PSC and colitis
• Two independent studies have suggested a
negative association between coffee
consumption and PSC.
Lammert et al Clin Gastroenterol Hepatol 2014; 12:1562-8.
Autoimmune
• PSC is an autoimmune disease
• The immune system loses “tolerance to self”
• Lymphocytes (white cells) are attracted to bile
ducts (why?)
• The link with variations in HLA molecule is
likely significant
Liver-Gut Axis
• The liver continuously receives blood
coming from the intestines
• Carries bacterial products, toxins, nutrition
• Abnormalities in the intestine might trigger
inflammation in the liver
– Abnormal composition of the microbiome
(organisms living in the intestines)
– Are these bacteria causing PSC or responding
to the different cause?
Toxic Bile
• Increase in toxic bile acids will harm the
surface of the bile ducts
Beuers et al Hepatology 2010.
Diagnosis of PSC
• Cholestasis
– Difficulty in moving bile out of the liver
– Results in inflammation of biliary and liver tests
– Alkaline Phosphatase (ALP), Gamma GT (GGT)
• Strictures
– By ERCP (endoscopic retrograde
cholangiopancreatography)
– By MRI
• Typical liver biopsy findings (only 30%)
• Lack of evidence of Secondary Sclerosing Cholangitis
Clinical Features of PSC
• Early stages
– Most (but not all) patients are asymptomatic
– Cholestatic tests may be the only indication of disease
– Strictures may exist
– Little to no scars in the liver itself
• Advanced stages
– Cholestasis with symptoms
– Significant amount of scars in the liver itself (Cirrhosis)
– Portal Hypertension (increased pressure in the veins of
the abdomen)
– Jaundice, weight loss, abdominal pain, ascites (fluid in
the abdomen), intestinal bleeding
Symptoms of PSC
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Itching (pruritus)
Fatigue
Abdominal pain
Cholangitis
Mineral bone deficiency
Itching (Pruritus) in PSC
• Can be devastating! Excoriations
• If sudden onset, verify that there is no
blockage of the bile ducts
• Best medication:
– Cholestyramine 4 g 20 minutes before meals
– Cannot take other medications with it
• Refractory cases: rifampin, naltrexone,
selective serotonin reuptake inhibitors, and
plasmapheresis.
Bacterial Cholangitis
• Sudden pain, fever, chills, jaundice
• Infection of the biliary ducts, often due
to blockage from a stricture
• Requires antibiotics and possibly an
ERCP to open a blockage
Mineral Bone Disease
• Lack of normal bile flow in the intestine
prevents absorption and processing of
vitamins
– A, D, E, K
– Can contribute to risk of osteoporosis
Maintaining Bone Health in
PSC
• DEXA scan at presentation and every 1-3
years
• Regular Exercise
• Good nutrition
• Minimize/eliminate alcohol intake
• Calcium: 1000 - 1500 mg/day
• Vitamin D: 800 - 1000 IU/day
• Bisphosphonates in setting of osteoporosis
Malignancy Risks in PSC
• Cholangiocarcinoma
– Cumulative risk of cholangiocarcinoma at
10 years, 20 years, and 30 years of 6%,
14%, and 20%.
– Recommendation for yearly imaging
• Colorectal adenocarcinoma
– Need yearly colonoscopy
• Gallbladder carcinoma
Drugs for PSC
• As of now, there is no proven
pharmacotherapy for the treatment of
PSC that is able to reduce disease
progression or improve mortality.
Drug Development
• Clear need for improvement in outcomes!
Mendes et al. Hepatology 2008;47:1241-7.
Ursodiol
AASLD:
In adult patients with PSC, we recommend against the use
of UDCA as medical therapy (1A).
EASL:
The limited data base does not yet allow a specific
recommendation for the general use of UDCA in PSC.
Hepatology. 2010;51:660-78.
J Hepatol. 2009;51:237-67.
Procedures in PSC?
• For blockages with infection or
dominant strictures
• Dominant Strictures
– A narrowing with a diameter of 1.5 mm or
less in the common bile duct or 1 mm or
less in the hepatic duct
– As high as 50% in PSC.
Procedures in PSC
• Short-term stenting or dilation for
dominant strictures can lead to
significant improvement in symptoms
• However, doing this to prevent
symptoms could increase the potential
for bacterial cholangitis and the
formation of biliary abscesses
Liver Transplant
• Patients with signs of decompensated
cirrhosis (failing liver) need to be
evaluated and listed for liver transplant
– Deceased Donor transplant
– Living Donor transplant
• PSC can recur after liver transplant (30%)
Summary
• PSC is a challenging disease
• Several categories and association with
other diseases (IBD)
• Gradual progression in many (but not
all) patients
• There is an urgent need for new
therapies