Primary sclerosing cholangitis (PSC) is a life-altering condition that impacts the liver. For anyone dealing with PSC, research over the past couple of decades points to ways to mitigate some of the damage.
This article was written in conjunction with a Genetic Lifehacks member who has been on a personal quest to understand the PSC research and help out a family member. He wanted to share his collection of research studies with a wider audience to help others struggling with a PSC diagnosis.
What is primary sclerosing cholangitis (PSC)?
Primary sclerosing cholangitis (or PSC) is a rare condition affecting the bile ducts. Your liver produces bile to break down fats into fatty acids that can be easily absorbed from foods. Bile travels from the liver to the gallbladder via the bile ducts.
It is a one-way street – the liver produces bile that travels to the gallbladder and then is released into the intestines.
In PSC, the bile ducts in and outside the liver have been narrowed and scarred. The duct damage then causes the bile to backflow into the liver. As a result, the liver suffers permanent damage.
For people with PSC, this lifelong condition can result in liver damage to the point of often needing a liver transplant.
What causes primary sclerosing cholangitis?
The definite cause of primary sclerosing cholangitis is still not entirely known. It is often diagnosed around 30-40 years of age and is more common in men.[ref]
Essentially, there is an inflammatory process going on in the bile ducts that damages them. They become narrow and blocked by scar tissue.
PSC is estimated to affect roughly 1 in 100,000 people yearly, and it is more prevalent in northern regions and among non-smokers.[ref] Since most patients will require a liver transplant, the survival rate historically has been only 12- 17 years after a diagnosis.[ref][ref]
Many people with PSC have coexisting autoimmune conditions. Inflammatory bowel diseases (IBD), such as ulcerative colitis or Crohns disease, are reported in about 2/3 of PSC patients. About 25% of PSC patients also have other autoimmune diseases such as type 1 diabetes, rheumatoid arthritis, autoimmune thyroid disease, or psoriasis.[ref] These coexisting conditions may help shed some light on why PSC occurs.
What are the symptoms of PSC?
The early symptoms of PSC include:[ref]
- Jaundice ( yellowing of the eyes/skin)
- Abdominal pain
Often, this disease is diagnosed with routine blood tests (such as elevated levels of alkaline phosphatase) and magnetic resonance imaging of the liver before symptoms appear. Those with an early diagnosis may still feel well for years. Since no cause has been established, doctors are unclear on how this disease will progress for each individual.[ref]
However, as the disease progresses, the symptoms will run the range of a diseased liver. A person can expect to see a fever, chills, night sweats, enlarged liver, enlarged spleen, and weight loss.
Are there any complications to this disease?
Complications of PSC can include bleeding of the veins in the GI tract (variceal hemorrhage), cancer of the bile ducts, colon cancer, or gallbladder cancer.
Numerous novel therapies have been tested in PSC, although there is little proof that they are helpful. For end-stage liver disease brought on by PSC, liver transplantation effectively increases survival. After transplantation, however, PSC may return in about 15 – 20% of cases.
Cholangiocarcinoma (cancer of the bile ducts) is the PSC complication that is most feared. This extremely aggressive tumor is challenging to diagnose, and there are no indicators for early identification. Although liver transplantation with neoadjuvant chemo-irradiation shows promise in certain individuals with cholangiocarcinoma, the results are incredibly dismal.[ref][ref]
Other risk factors:
- Patients with a coexisting IBD disease have an increased risk of colon cancer.[ref]
- There is a chance of developing autoimmune conditions, like autoimmune hepatitis.[ref]
- Other autoimmune diseases that present alongside PSC include sarcoidosis, thyroid disease, and type I diabetes mellitus.[ref]
Theories on the Causes of PSC:
Researchers have several theories as to how and why PSC develops.
1) Aberrant homing theory:
T cells, which are part of our immune system, are thought to be misdirected from the gut to the liver due to altered receptor expression in the liver. This misdirection is referred to as aberrant homing. MadCAM-1 and CCL25 appear to be important actors. MadCAM-1 and CCL25, normally only expressed in the gut, are expressed in the livers of PSC patients leading to inflammation.[ref][ref]
A new study, though, shows that the aberrant T cells are found in all types of liver disease, not just PSC. The authors of the study contend that this new research negates the theory that aberrant T cells are causal for PSC.[ref]
Antibodies against proteins in the body can cause the immune system to attack your own normal cells. One PSC theory is that antibodies drive an immune response that causes liver damage.
There seems to be a substantial genetic link between PSC and HLA (human leukocyte antigens). Different HLA types are strongly linked to various autoimmune diseases. Twenty-five years ago, researchers discovered a genetic link between PSC and the human leukocyte antigen (HLA) complex on chromosome 6p21.[ref]
For PSC, the association with pANCA antibodies (antineutrophil cytoplasmic antibodies that target a protein called MPO) supports the “autoimmunity” theory.[ref] In addition to pANCA antibodies, autoantibodies to Saccharomyces cerevisiae are also commonly detected. Saccharomyces cerevisiae is a common yeast species used in winemaking and baking. This yeast species is also a common finding in people with IBD.[ref] Another antibody found in IBD and PSC patients is anti-GP2. Glycoprotein 2 (GP2) is secreted from the pancreas along with digestive enzymes.[ref][ref]
3) Bile Transporter Problems: Toxic bile theory
The “toxic bile” theory is based on the idea that bile transporter abnormalities, such as those in CFTR (cystic fibrosis gene) and ABCB4, could cause bile ducts to be chemically damaged by bile acids.[ref] CFTR is a protein that helps regulate salt and water on surfaces in the body, such as the lungs. Mutations in the CFTR gene can cause cystic fibrosis (check your CFTR gene here).[ref] ABCB4 codes for a protein that moves phospholipids across membranes in liver cells.[ref].
The steroid and xenobiotic receptor (SXR), also known as the pregnane X receptor (PXR), is a crucial nuclear receptor that controls bile acid detoxification and alternate excretion pathways. It has been demonstrated that PSC patients with certain genetic SXR/PXR variations experience a more severe illness trajectory. It is consistent with the significance of PXR’s protective actions in cholestasis-related animal models.
4) Leaky gut:
Lastly, a leaky gut could be a factor as well. Leaky gut refers to the intestinal lining becoming more permeable, allowing gut microbes the ability to pass through. The microbes enter the bloodstream and end up in the liver. Early studies in a rat model of intestinal bacterial overgrowth with the “leaky gut” theory (conducted about 20 years ago) suggested that innate immune responses to bacterial metabolites may start a PSC-like pathogenesis.[ref]
While the liver is well-equipped to take care of some bacteria and bacterial components, a leaky gut and the translocation of bacteria to the liver is a driving factor in liver disease, such as NAFLD (non-alcoholic fatty liver disease).[ref]
Primary Sclerosing Cholangitis Genotype Report:
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Many genetic variants and rare mutations have been linked to the risk of primary sclerosing cholangitis. The combination of genetic susceptibility is an important part of developing PSC.[ref] Heritability studies show that siblings of PSC patients are 9-39 times more likely to develop the disease.
The HLA genes code for human leucocyte antigens, which are cell surface proteins involved in how the immune system recognizes foreign pathogens. There is a considerable diversity in HLA variants, which is one way the human population can survive new and varied pathogens. While I’m only listing on HLA type here, multiple HLA alleles are associated with PSC (just not covered in 23andMe or AncestryDNA data).
The HLA-DRB1 gene codes for a part of the innate immune response. The HLA genes vary widely among individuals, and they are a big part of why people can respond differently to various pathogens. The HLA-DRB1 variant below is positive because it decreases susceptibility to several pathogens. On the flip side, the variant below increases the risk of certain autoimmune diseases, including lupus.
Check your genetic data for rs2187668 (23andMe v4, v5; AncestryDNA):
- T/T: likely to carry two copies of DRB1*0301[ref][ref]; increased susceptibility to PSC[ref][ref]
- C/T: likely to carry one copy of HLA-DRB1*0301; increased susceptibility to PSC
- C/C: typical
Members: Your genotype for rs2187668 is —.
In the HLA-B gene region on chromosome 6p21 (top hits on a genome-wide association study):
Check your genetic data for rs3099844 (23andMe v4, v5; AncestryDNA):
- C/C: typical
- A/C: increased risk of PSC
- A/A: >4-fold increased risk of PSC[ref]
Members: Your genotype for rs3099844 is —.
Check your genetic data for rs2844559 (23andMe v4; AncestryDNA):
- C/C: typical
- C/T: increased risk of PSC
- T/T: increased risk of PSC[ref]
Members: Your genotype for rs2844559 is —.
FUT2 Gene: Encoding the enzyme needed for secreting blood type in saliva and mucosa. About 20% of the population carries the variant below and doesn’t secrete their blood type. It alters the mucus lining of the gut and the composition of the gut microbiota.
Being a non-secretor or carrier of one copy of the variant significantly influences the biliary bacterial composition and fungal (Candida) infections of the bile. The effect of FUT2 on bacterial colonization of the gastrointestinal tract has now been more fully investigated in relation to Crohn’s disease, with interesting results showing that FUT2 is an important host genetic factor influencing host-microbial diversity.[ref][ref]
Check your genetic data for rs601338 (23andMe v4, v5; AncestryDNA (some)):
- G/G: blood type secretor
- A/G: blood type secretor; increased risk of Candida infections in the bile ducts, increased episodes of cholangitis, increased risk of dominant stenosis
- A/A: non-secretor of blood type; increased risk of Candida infections in the bile ducts, increased episodes of cholangitis, increased risk of dominant stenosis[ref]
Members: Your genotype for rs601338 is —.
SLCO1B1 gene: encodes a transporter protein known as OATP1B1. This transporter protein is mainly found in the liver and regulates the uptake of natural compounds, such as …. , and drugs, such as statins, in the liver.
Check your genetic data for rs4149056 (23andMe v4, v5; AncestryDNA):
- T/T: typical
- C/T: reduced breakdown of some drugs[ref]; slightly decreased risk of PSC[ref]
- C/C: reduced breakdown of some drugs;[ref][ref][ref][ref]; slightly decreased risk of PSC[ref]
Members: Your genotype for rs4149056 is —.
PNPLA3 gene: patatin-like phospholipase-3 enzyme, strongly linked in genetic studies to a significant increase in NAFLD risk. This enzyme interacts with the retinol form of vitamin A.
Check your genetic data for rs738409 I148M(23andMe v4):
- C/C: typical risk of NAFLD
- C/G: increased liver fat, increased risk of NAFLD, and increased severity of fibrosis; in PSC, increases the risk of fibrosis and fibrosis progression by 3-fold[ref]
- G/G: increased liver fat[ref]; 3.5x increased risk of NAFLD[ref][ref][ref]; in PSC, increases the risk of fibrosis and fibrosis progression by 3-fold[ref]
Members: Your genotype for rs738409 is —.
NR1I2 gene: encodes the pregnane x receptor that helps to protect against bile-acid-induced liver damage
Check your genetic data for rs1054190 (23andMe v4; AncestryDNA):
- C/C: typical
- C/T: typical survival time
- T/T: reduced median survival time in PSC[ref]
Members: Your genotype for rs2844559 is —.
MMP3 gene: matrix metalloproteinase-3 is involved in the remodeling of collagen.
Check your genetic data for rs650108 (AncestryDNA)
- G/G: increased risk of tendinopathies (high-level athletes)[ref]; increased risk of progression and need for liver transplant in PSC patients[ref]
- A/G: typical risk
- A/A: typical risk
Members: Your genotype for rs650108 is —.
TNF gene: encode the TNF-alpha inflammatory cytokine
Check your genetic data for rs1800629 -308A/G (23andMe v4, v5; AncestryDNA):
- A/A: Higher TNF-alpha levels. > 3-fold increased risk of primary sclerosing cholangitis[ref] Also, increased risk of: ulcerative colitis[ref] celiac disease[ref] (note – must have HLA type also), septic shock[ref], diabetic foot ulcers[ref], asthma[ref], Hashimoto’s thyroiditis[ref], skin infections[ref], periodontitis[ref], asthma[ref] in children, COPD[ref], stroke[ref], gum disease[ref], heart disease[ref]; nasal polyps[ref]
- A/G: somewhat higher TNF-alpha levels, 3-fold increased risk of primary sclerosing cholangitis[ref]
- G/G: typical, better response to high protein/low carb diet
Members: Your genotype for rs1800629 is —.
MMEL1 gene: encodes the Membrane metallo-endopeptidase-like 1 protein
Check your genetic data for rs3748816 (23andMe v4, v5; AncestryDNA):
- A/A: typical risk
- A/G: decreased relative risk of PSC
- G/G: decreased relative risk of PSC[ref]
Members: Your genotype for rs3748816 is —.
Genome-wide association studies have identified other variants (not covered in 23andMe or AncestryDNA) likely contributing to PSC.
Primary sclerosing cholangitis is a serious, life-altering disease. You should discuss any dietary or supplement changes with your doctor.
The rest of this article is for Genetic Lifehacks members only. Consider joining today to see the rest of this article.
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Autoimmune Diseases: Genetics plus Triggers
A list of articles for an in-depth look at the background science, research studies, and genetic variants related to the triggers of autoimmune diseases.
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Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and also an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.