Familial and Hereditary Pancreatitis
Pancreatitis is a complex condition with multiple potential causes. When pancreatitis occurs in multiple closely related individuals, it warrants further investigation, which may include genetic counselling and/or genetic testing. The diagnosis of hereditary or familial pancreatitis should include the collection of a 3-generation family history and evaluation for other causes of pancreatitis in the family (e.g., gallstones, heavy alcohol use, cystic fibrosis). Genetic testing may help determine the presence of hereditary pancreatitis or familial pancreatitis in a family. Although they sound similar, there are important differences between these two diagnoses.
While pancreatitis can occur as a result of medications, infections, trauma, autoimmune disease or lifestyle factors, pancreatitis can also happen as a result of genetics.
Hereditary pancreatitis is a genetic condition that’s characterized by recurrent episodes of inflammation of the pancreas that often progresses to chronic pancreatitis in early adulthood. Unlike most other forms of pancreatitis, patients with hereditary pancreatitis usually start to experience symptoms of acute pancreatitis in childhood. These episodes can be characterized by an acute attack of abdominal pain, nausea, fever or vomiting. Clinically, hereditary pancreatitis is defined as (1) recurrent acute or chronic pancreatitis in ≥2 individuals in ≥2 generations of a family or (2) pancreatitis in an individual with a known disease-causing variant in the PRSS1 gene.
According to the U.S. National Library of Medicine, the persistent inflammation damages the pancreas and reduces function. Individuals with hereditary pancreatitis have an increased risk to develop pancreatic cancer, which is believed to be from prolonged inflammation in the pancreas. Patients with hereditary pancreatitis have a 40% lifetime risk of developing pancreatic cancer, though estimates in the literature range from 7.2% to 40% at age 70 years.
Hereditary pancreatitis is a rare and aggressive form of pancreatitis that typically presents in childhood. However, families with hereditary pancreatitis have substantial variability in age of onset, severity, and more. A diagnosis of hereditary pancreatitis requires (a) demonstration of a clear pattern of autosomal dominant inheritance in a family and/or (b) finding a known disease-causing variant in the PRSS1 gene. This presentation of disease in a family should be consistent with autosomal dominant inheritance – i.e. two or more individuals with recurrent acute or chronic pancreatitis across two or more generations of a family.
The gene most commonly related to a hereditary pancreatitis diagnosis is PRSS1. Under normal circumstances, PRSS1 provides the body with instructions to make an important digestive enzyme. This enzyme is referred to as trypsinogen in its inactive form and trypsin in its activated form; variants in PRSS1 may cause trypsinogen to activate prematurely, causing damage to the tissue of the pancreas. However, some families with hereditary pancreatitis don’t yet have an identifiable genetic cause.
Causes of Hereditary Pancreatitis
Variants in the PRSS1 gene are the primary cause of hereditary pancreatitis. However, not all families with hereditary pancreatitis have an identifiable genetic cause in the PRSS1 gene. It’s estimated that between 60% to 85% of people with hereditary pancreatitis have an identifiable genetic cause. Variants in other genes, some of which are not yet identified, can cause hereditary pancreatitis in those who do not have a disease-causing variant in PRSS1.
The PRSS1 genes give instructions for making the enzyme cationic trypsinogen, which is produced in the pancreas and aids in the digestion of food.
The U.S. National Library of Medicine explains: “Some PRSS1 gene mutations that cause hereditary pancreatitis result in the production of a cationic trypsinogen enzyme that is prematurely converted to trypsin while it is still in the pancreas. Other mutations prevent trypsin from being broken down. These changes result in elevated levels of trypsin in the pancreas. Trypsin activity in the pancreas can damage pancreatic tissue and can also trigger an immune response, causing inflammation in the pancreas.”
For reasons that remain unknown, not all individuals with a disease-causing variant in PRSS1 develop hereditary pancreatitis. The chance of developing pancreatitis due to a variant in the PRSS1 gene has been estimated to be approximately 80%.
Familial pancreatitis is used to describe families with a higher incidence of pancreatitis than expected by chance. A diagnosis of familial pancreatitis requires at least two or more first- or second-degree family members with idiopathic pancreatitis not attributed to obstructive or environmental causes. Additional causes of pancreatitis that should be ruled out include PRSS1-hereditary pancreatitis and a CFTR-related disorder. Idiopathic refers to the unknown etiology, or cause, of the pancreatitis attacks. To rule out other causes, your healthcare provider may ask questions about your lifestyle behaviors, medications you’ve been on, and other details about your life. Genetic testing may be indicated to look for genetic variants associated with familial and/or hereditary pancreatitis.
The Distinction Between Hereditary and Familial Pancreatitis
The distinction between hereditary and familial pancreatitis is important to determine the cause of pancreatitis in a family and the risk to other family members. Ultimately, the risk for family members to develop pancreatitis depends on both the presentation of pancreatitis within the family and the presence of known genetic contributions.
Although genetic variants are expected to contribute to pancreatitis in hereditary and familial pancreatitis kindreds, not all families have a known genetic cause due to limitations in testing and research. Still, avoiding certain lifestyle behaviours like drinking alcohol or smoking cigarettes may reduce the severity of attacks or slow the progression of chronic pancreatitis even in individuals with genetic forms of pancreatitis. Speak to your healthcare provider if you have questions surrounding your diagnosis or the diagnosis of a loved one.
How Genetic Testing for Diseases Can Impact Treatment
Genetic testing involves examining your genes for changes that may or may not cause illness or disease. The results of a genetic test allow your doctors to make better targeted treatment decisions for your disease.
Patient Story: Meaghan’s Story
My journey with pancreatitis began in 1993 when I was 8 years old and hospitalized at the Children’s Hospital of Philadelphia (CHOP) for acute pancreatitis. Just a few months before that, my older sister had her first attack of pancreatitis and about a year before that, my dad was finally diagnosed and treated after years of suffering through pain. Thankfully, I had immediate access to the incredible doctors and surgeons at CHOP and a lot of family knowledge about this condition.