Learning Objectives
- Explain the epidemiology of hereditary pancreatitis
- Describe the typical presentation and disease progression of patients with
hereditary pancreatitis
- Review the mode of inheritance and the genes involved with hereditary pancreatitis
- Review the pathophysiology and diagnosis of hereditary pancreatitis
- Create a plan for genetic counseling of family members for patients with
hereditary pancreatitis
- Discuss the treatments for chronic and hereditary pancreatitis
Pretest Questions
- What percentage of childhood chronic pancreatitis cases are believed to
have a primary hereditary component?
a. 1%
b. 5%
c. 10%
d. 20-25%
e. 40-50%
- What is the mode of inheritance seen in hereditary pancreatitis?
a. autosomal dominant
b. autosomal recessive
c. X-linked dominant
d. X-linked recessive
- Which of the following gene(s) is believed to have the mutations that lead
to recurring pancreatitis in patients with hereditary pancreatitis?
a. LKB1 (STK11)
b. HFE
c. PRSS1
d. BMPR1A and SMAD4
e. P53
- What is the main function of the gene that is often mutated in hereditary
pancreatitis
a. tyrosine kinase receptor
b. trypsinogen
c. ion transport channel
d. H2 receptor protein
e. pepsin
- What, if any, is the increase risk for pancreatic cancer in patients with
hereditary pancreatitis compared to the general population?
a. none, they have the same risk as the general population
b. 2 fold increase
c. 50 fold increase
d. 1000 fold increase
e. All patients with hereditary pancreatitis will get pancreatic cancer
Answers: 1) d, 2) a, 3) c, 4) b, 5) c
Case Study
A mother and father bring an eight year old female child to the emergency
department. They are concerned because she has been having a moderate
amount of abdominal pain over the last few days. At first, they believed
she had a virus, however, the pain has become worse and the child is refusing
to eat. The patient has had frequent mild cases of abdominal pain before
but they have all resolved without complication. The parents are concerned
because this pain appears to be much worse than previous episodes. The
patient states, “My belly hurts and I feel I am going to throw up.” The
child has no other significant medical or surgical history. She is up
to date on all immunizations and has received frequent well child visits. She
attends school and is doing well. Her mother and father are both young. Family
history is significant for frequent abdominal pain in the mother and maternal
grandmother who recently passed away from cancer. The mother is unsure
of the type but believes it was pancreatic. The mother states she has
been in the hospital before on several occasions for abdominal pain. She
has been told she has had pancreatitis on several occasions but has never been
told the cause. She and her husband drink one to two alcoholic beverages
per week. The father and the patient’s younger sibling are both
in good health. On physical exam you notice a child that appears
in moderate to severe pain. Vital signs are significant for a mild fever
but are stable. The child has severe pain to palpation over the mid epigastrum
with guarding. Bowel sounds are absent. You order a CT scan and
standard labs. The CT scan shows pancreatic stranding consistent with
chronic pancreatitis. A consult to the gastroenterology service is placed
and an ERCP is performed. A pancreatic duct stricture and stone are present. The
duct is dilated and stented and the stone is removed. The patient’s
pain resolved over the next few days.
Explain the epidemiology and prevalence of Hereditary Pancreatitis:
There are many diseases leading to chronic pancreatitis such as cystic fibrosis
and alpha-1 antitrypsin deficiency. However, there are subsets of patients
who have chronic pancreatitis with no known etiology. These patients
are diagnosed with idiopathic pancreatitis. A subset of these patients
will have a family history of chronic pancreatitis, and several studies have
found a genetic link in chronic pancreatitis families. It is difficult
to estimate the incidence and prevalence of the disease due to its similarity
in presentation to other causes of chronic pancreatitis. It is estimated
that of childhood cases of chronic pancreatitis (CP), idiopathic CP accounts
for approximately 40% to 60%, and hereditary pancreatitis (HP) accounts for
approximately 20% to 25% (1). Using the childhood population is useful
since it avoid the confounding variable of alcohol which predisposes patients
to chronic pancreatitis in older populations. Gender distribution
appears to be equal. To date, approximately 100 families and 600 individuals
have been reported.
Describe the typical presentation and disease progression of patients
with hereditary pancreatitis:
Many people who have the disease
will develop symptoms before age 5 and most will have symptoms before age 20. The median age
of onset is 10-13 years with bimodal pattern at 1 to 6 and 18 to 24 years of age (2). Patients
with HP tend to present earlier than patient with idiopathic chronic pancreatitis. One review
found 63% percent of chronic pancreatitis patients have had 5 or more emergency department visits or
hospitalizations, and 56% had 5 or more episodes of documented pancreatitis before the diagnosis of
HP was made (3). Children who are symptomatic will present with abdominal pain, nausea, vomiting, and
anorexia. Pain in children is usually not chronic as found with adults. The pain will
usually reoccur, but due to the vague symptomology in this age population, the diagnosis is difficult
to make. In children, the pain is often sudden in onset and accompanied by decreased bowel sounds. Adults
will tend to have a similar presentation to chronic pancreatitis including chronic pain. Many
will be depended on opioid pain medication. One study found 52% were taking narcotic analgesic
agents on a chronic basis (3). Pancreatic insufficiency is common with bulky stools. Insulin
dependent diabetes is common. Calcification, pseudocysts formation, necrosis, and infection will
all tend to develop with older age. Eventually, many of these patients will de diagnosed
with pancreatic cancer. Pancreatic cancer prevalence is 50-60 times greater in HP patients than
in the general population (1).
Review the mode of inheritance and the genes involved with hereditary
pancreatitis:
Hereditary pancreatitis is believed to be inherited in an autosomal dominant
manner, however some data would suggest other patterns. It has an 80%
penetrance in the next generation. One study has shown approximately
3.4% of the analyzed 5,600 genes from pancreatic RNA had deregulated expression
in CP patients suggesting a genetic link (4). Although several mutations
have already been found, there are other possible genetic deformities that
could play a role in the pathogenesis of HP.
One of the genes that received the most attention is PRSS1, also referred to
as serine protease 1, a trypsinogen gene that is responsible for one of the
most secreted proteins of the pancreas. The gene is located on the long
arm of chromosome 7 in an area of the chromosome known to contain numerous
trypsinogen genes. Although there are a number of different mutations
associated with this gene, the R122H and N29I mutations have been found in
a number, but not all, of CP patients.
The SPINK1, or PSTI, gene may also play a role in normal pancreatic function
by inactivating trypsin activity. It is located on chromosome 5. A
mutation on this gene called N43S has also been found in CP patients, many
of whom lack the PRSS1 mutants. 25%-40% of patients with idiopathic CP
carry N34S on one or both alleles. There are other possible genetic deformities
that could also play a role in the pathogenesis of HP.
The CFTR gene and the mutations associated with cystic fibrosis have a well
documented affect on the pancreas. The pancreas’ ability to secrete
enzymes and bicarbonate due to mutations in ion and water transport across
membranes can lead to retention of pancreatic enzymes and digestion of the
pancreas.
Review the pathophysiology and diagnosis of hereditary pancreatitis:
Mutations of the PRSS1 gene have been associated with chronic pancreatitis. Many
of the mutant proteins are susceptible to autoactivation and resists autolysis
compared to other trypsinogens proteins. The R122H mutation is believed
to make activated trypsin resistant to hydrolytic inactivation and allowing
continued digestion of the pancreas and associated enzymes. It is also
possible increased autoactivation may play a role in R122H pathophysiology. The
N29I mutation is also associated with increased autoactivation as well as resistant
degradation, although there are several conflicting studies on the exact mechanism
of action. One study has found CP patients have a significant difference
in genotypes corresponding to high TGF-(beta)1 producer phenotypes. Since
TGF-(beta)1 is associated with production and regulation of the extracellular
matrix, excess TGF-(beta)1 may be associated with fibrogenesis seen in CP (5).
Genetic disposition for pancreatitis patients who consume large amounts of
alcohol in an area on continuing study. One model, the SAPE model, attempts
to explain why some patients who consume large amounts of alcohol have CP while
others do not (6). Patients who consume large amounts of alcohol may
put the acinar cells under stress. Under stressful conditions cytokines,
adhesion molecules, activated neutrophils, lymphocytes, and monocytes, and
pancreatic stellate cells are released into the pancreas. After the acute
inflammatory phase, a late phase follows where anti-inflammatory proteins,
including TGF-(beta)1 are released. Any genetic predisposition to an
over inflammatory or insufficient anti-inflammatory response in conjunction
with repeated stress of the pancreas could lead to fibrosis and CP.
The diagnosis of HP is based on clinical suspicion. A physician must
be able to rule out other common causes of pancreatitis in patients who present
repeat episodes such as with alcohol abuse, gallstones, and hypertriglyceridemia. Radiology,
blood test for pancreatic inflammation, and stool studies for fat should all
be used in the diagnostic process. Physicians should have a strong suspension
for children who present with recurring pancreatitis or malabsorption not responding
to treatment. A few laboratories can test for the most common mutations known
to cause hereditary pancreatitis.
Create a plan for genetic counseling of family members for patients
with hereditary pancreatitis:
The following
are recommendations for screening for HP from the Consensus Committees of the
European Registry of Hereditary Pancreatic Diseases, Midwest Multi-Center Pancreatic
Study Group, International Association of Pancreatology (7). The
committees recommend pre and post-test counseling as well as informed consent
of all patients undergoing genetic testing.
The indication for cationic trypsinogen (PRSS1) gene mutation analysis in
a symptomatic adult patient should be any of the following:
- Recurrent (2 or more separate, documented episodes with hyper-amylasaemia)
attacks of acute pancreatitis for which there is no explanation
- Unexplained (idiopathic)chronic pancreatitis
- A family history of pancreatitis in a first-degree (parent, sib, child),
or second-degree (aunt, uncle, grandparent) relative
- For patients with pancreatitis eligible for a research protocol
The indications for testing in asymptomatic persons include enhanced counsling,
and the person must have a first-degree relative with a defined HP gene mutation.
The person should be over 16 years of age and able to make an independent and
fully informed decision.
The guidelines for symptomatic children are as follows:
- An episode of documented pancreatitis of unknown etiology and severe enough
to require hospitalization
- Two or more documented episodes of pancreatitis of unknown etiology
- An episode of documented pancreatitis occurring in a child where a relative
is known to carry an HP mutation
- A child with recurrent abdominal pain of unknown etiology where the diagnosis
of HP is a distinct clinical possibility
- Chronic pancreatitis of unknown etiology, where the diagnosis of HP is
a distinct clinical possibility
The committees gave no specific recommendations on prenatal tesing.
What are the available treatments for patients with hereditary pancreatitis?
Treatment mimics the care given to a patient with chronic pancreatitis (8).
- Patients should be advised to avoid alcohol, discontinue smoking, and to
eat small meals that are low in fat.
- Pancreatic enzyme supplements relieve pain in some patients, are generally
safe, and are thus a reasonable next step for patients with continued pain.
Treatment may be more likely to be successful in those without involvement
of large ducts and those with idiopathic pancreatitis.
- Treatment for steatorrhea is restriction of fat intake (to less than 20
g per day).
- Pain control with short courses of opioids and amitriptyline has been found
to be effective. Long-acting opioids are preferred over short-acting.
- Nerve blocks, ERCP to relieve obstruction, or surgery can be considered
for patients who continue to have pain despite appropriate pain medication.
- Screening for cancer has been debated and some studies have suggested screening
with CT every year for patients over 40 (2). However, the optimal screening
strategy has not been defined, and it is unknown whether early detection
of cancer at a resectable stage is possible. There are no data on pancreatectomy
as a prophylactic measure to reduce the mortality from pancreatic cancer
(3).
Patient Resources
The National Pancreas Foundation
www.pancreasfoundation.org
National Digestive Diseases Information Clearinghouse
(NDDIC)
http://digestive.niddk.nih.gov/ddiseases/pubs/pancreatitis/index.htm
References
- Witt H, Becker M. Genetics of chronic pancreatitis. Journal of Pediatric
Gastroenterology & Nutrition. 34(2):125-36, 2002 Feb.
- Mossner J, Teich N. Genetic disorders in pancreatitis: Implications in
the pathogenesis of acute and chronic pancreatitis. Surgery. 132(3):421-3,
2002 Sep.
- Choudari C, Nickl N, Fogel E, et al. Hereditary pancreatitis: clinical
presentation, ERCP findings, and outcome of endoscopic therapy. Gastrointestinal
Endoscopy. 56(1):66-71, 2002 Jul
- Friess H, Ding J, Kleeff J, Liao Q, et al Identification of disease-specific
genes in chronic pancreatitis using DNA array technology. Annals of Surgery.
234(6):769-78; discussion 778-9, 2001 Dec.
- Bendicho M, Guedes J, Silva N, et al. Polymorphism of cytokine genes (TGF-beta1,
IFN-gamma, IL-6, IL-10, and TNF-alpha) in patients with chronic pancreatitis.
Pancreas. 30(4):333-6, 2005 May
- Whitcomb DC. Genetic predisposition to alcoholic chronic pancreatitis. Pancreas.
27(4):321-6, 2003 Nov.
- Ellis I, Lerch M, Whitcomb D. Consensus Committees of the European Registry
of Hereditary Pancreatic Diseases, Midwest Multi-Center Pancreatic Study
Group, International Association of Pancreatology. Genetic testing for hereditary
pancreatitis: guidelines for indications, counselling, consent and privacy
issues. Pancreatology. 1(5):405-15, 2001.
- Freedman S. Treatment of chronic pancreatitis. www.uptodate.com. Last
revision Apr 26, 2005.
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