Genetic mutations esp. in PRSS1, SPINK1, and CFTR genes may occur in hereditary and familial pancreatitis. It may present as recurrent pancreatitis or chronic pancreatitis. Such patients are atGenetic mutations, particularly in the PRSS1, SPINK1, and CFTR genes, can lead to hereditary and familial pancreatitis. This condition may manifest as recurrent or chronic pancreatitis. Patients with these mutations face a 100-fold increased risk of developing pancreatic cancer. a 100-fold increased risk of pancreatic cancer.

1. HEREDITARY AND
FAMILIAL PANCREATITIS
Dr. Ajay Kumar Yadav
DM1 Resident Gastroenterology, NAMS
2081/01/06

2. Layout
HP
and FP
Definitions
and
terminologies
HP
FP
CF
Genes
involved
Clinical stages
TIGARO
Acinus and Duct
anatomy/physiol
ogy

3. Definitions and Terminology
Precision medicine
• Aka personalized or individualized medicine
• origin of disorders disease  targeted therapies minimize dysfunction
and maximize health
Acute Pancreatitis (AP)
• event triggered by sudden pancreatic injury that is followed by sequential
inflammatory responses
Recurrent Acute Pancreatitis (RAP)
• 2 or more episodes of documented AP, separated by at least 3 months
Chronic Pancreatitis (CP)
• process with persistent and progressive pathologic stages that usually
begins as AP or RAP and ends with immune system-mediated destruction of
the pancreas and widespread glandular fibrosis and atrophy

4. Hereditary Pancreatitis (HP)
• refers to RAP or CP in an individual from a family in which the pancreatitis
phenotype appears to be inherited through a disease-causing gene mutation
expressed in an autosomal dominant pattern
Familial pancreatitis (FP)
• refers to pancreatitis from any cause that occurs in a family with an incidence
that is greater than would be expected by chance alone
• may or may not be caused by a genetic defect.
Mendelian syndromes involving the pancreas
• follows classic Mendelian inheritance patterns - AD (e.g., HP) or AR (e.g., CF,
SDS, Johanson-Blizzard syndrome)
Complex pancreatic disorders
• multiple factors must occur together for the phenotype to be expressed, and
may involve 2 or more genes (polygenic disorders), gene-environment
interactions, or a combination of factors.

7. Clinical Stages of Pancreatitis

8. TIGAR-O version 2 Classification of Pancreatitis Etiologies
Smoking
• Never (<100 cigarettes/lifetime) or Ever (>100 cigarettes)
• Past or current smokers
North American Pancreatitis Study II (NAPS2)
• risk of CP occurs only at or above the threshold of 5 alcoholic
drinks per day
• smoking is a/w risk of CP in a dose-dependent fashion that is
independent of alcohol use.
• alcohol + smoking : effects additive and/or multiplicative

9. Pancreatic acinus and duct cell physiology

11. Acinar cell dysfunction/failure
without pancreatitis
• Shwachman-Diamond syndrome
gene mutations (SBDS)
• Johanson-Blizzard syndrome
(UBR1)
Duct Cell-Related Pancreatitis
1. Failure of the duct cells to
generate sufficient bicarbonate-
rich fluid on demand.
2. duct obstruction

12. Trypsinogen
• Cationic trypsinogen (PRSS1 ~65%), Anionic trypsinogen (PRSS2 ~ 30%),
Mesotrypsin (PRSS3, ~5%)
• 2 calcium binding sites, calcium concentration  activation vs inhibition
Gain of
function
mutation
Loss of
function
mutation
SPINK1 p.N34S variant
• present in 1% to 4% of most populations throughout the world
• common in early-onset RAP and CP in children, HP, TP, and alcoholic CP, and is often a
feature of polygenic pancreatitis–associated genotype

14. Fig. Trypsinogen and CFTR synthesis in acinar and duct cells,
respectively, with locations of gene mutation effect

16. Hypertriglyceridemia-Associated Gene
Variants
• Nomal level < 150 mg/dL
– Hypertriglyceridemia (HTG)
• mild (150 to 199 mg/dL)
• Moderate (200 to 999 mg/dL)
• severe (1000 to 1999 mg/dL)
• very severe (≥2000 mg/dL)
• The lifetime risk of pancreatitis in pts with severe HTG is about 5% and very
severe about 10% to 20% (general population lifetime risk of about 0.5% to 1%)
• Familial hyperlipidemias, previously classified as Fredrickson Type I, V, and IV,
are often a/w RAP.
• Type 1 hyperlipoproteinemia (Familial chylomicronemia syndrome, FCS)
– AR disorder a/w pathogenic variants in LPL or other genes

17. Fig. Fredrickson Classification of
Hyperlipidemia

18. Hereditary Pancreatitis
• Syndrome of RAP, often leading to
CP, that develops in an individual
from a family in which the
pancreatitis phenotype appears to
be inherited through a disease-
causing gene mutation expressed
in an AD pattern.
• The most common cause (65-81%)
is a gain-of-function mutation in
the cationic trypsinogen gene
(PRSS1)

19.  Acute Pancreatitis (AP)
• An attack of AP typically signals the
onset of disease and beginning of cycle
of RAP
• Median age for onset of disease
– USA: 7 Y (inter-quartile range, 3 to 16;
range <1 to 73).
– EUROPAC study: 10 years for PRSS1
p.R122H and 14 years for PRSS1 p.N29I
• Duration < 7 days
• No of attacks/year: 2 (p.R122H) or 1.4
(p.N29I)
• Penetrance: incomplete ~80%
• Prevention:
Multiple small meals,
avoidance of high-fat meals,
use of anti-oxidants and vitamins
avoid alcohol and smoking
 Chronic Pancreatitis (CP)
• cumulative risk of pancreatic
exocrine failure in EUROPAC study
– 2.0% at age 10 years, 8.4% at age 20,
33.6% at age 40, and 60.2% at age 70

20.  Pain
• RAP/CP  recurrent pain
• most distressing and
debilitating features of HP
• more pain-related
disability/unemployment
and significantly lower QOL
scores
 Diabetes mellitus
• cumulative risk of endocrine failure in
EUROPAC study
– 1.3% at age 10 years, 4.4% at age 20,
8.5 % at age 30, and 47.6% by age 50
 Pancreatic cancer
• Dramatic ↑in incidence of PC
– PC appears to develop about 30 to 40
years after the onset of AP.
• cumulative risk of PC by age 70 was
40% (95% CI 9% to 71%).3

21.  Diagnosis/Genetic testing:
• The discovery of the cationic trypsinogen
gene mutations PRSS1 p.R122H and p.N29I
opened the door to molecular diagnosis.
• Majority (~80%) with an AD pattern of RAP
and CP (and/or DM or PC) will have GOF
PRSS1 mutations
• Mutation-positive individual has a 50%
chance of passing on the mutation to each
child.
• A negative test result in a family with a
known mutation in the PRSS1 gene
essentially eliminates the risk of this
genetic form of pancreatitis
 Treatment
• Treatment options are limited
• Prognosis remains poor despite some
recent advances.
• The most effective approach is
prevention.
– The most effective lifestyle target is
tobacco smoking, which doubles the risk
for PC.
• Pts with HP have 50-fold ↑ed risk of PC than
general population
– Avoid alcohol consumption and fatty
foods.

22. Familial Pancreatitis
• Initial symptoms occur at a young age
(<20 years)
• more likely a/w strong genetic risk.
• AD transmission generally d/t GOF
PRSS1 mutations
• AR transmission a/w CFTR mutations
and/or SPINK1 mutations, or more
complex genotypes (SDS, Johanson-
Blizzard Syndrome)
 Schwachman-Diamond
Syndrome (SDS)
• rare AR disorder a/w mutations in the
SBDS gene.
– results in pancreatic acinar cell defect with
markedly reduced zymogen synthesis and
PI rather than susceptibility to pancreatitis.
– Lack of SBDS expression also affects
myeloid differentiation and increases risk
for BM failure and AML
• characterized by EPI with hematologic
abnormalities (e.g., cyclic neutropenia),
skeletal defects, and short stature.
• Severe cases of SDS present in infancy
with malabsorption, FTT, or recurrent
infections.

23. Pancreatic insufficiency:
• The MPD and islets are normal
• Extensive fatty replacement of the pancreatic
acinar tissue
Hematologic manifestations:
• Cyclic neutropenia (2/3rd
)
• N/N anemia (~80%)
• Pancytopenia (worst prognosis)
• MDS (1/3rd
)
• AML (10-25%)
Growth and development:
• Most pts remain below 3rd
percentile for height
and weight.

24. Treatment:
 Multidisciplinary approach
• PERT
• Supplementation with fat soluble
vitamins, MCTG
• High calorie diet
• Febrile neutropenia
• Appropriate antibiotics
• Chronic use of G-CSF (2-3
mcg/kg every 3 days) for
recurrent invasive bacterial
and/or fungal infections
• HSCT: only curative therapy for
severe AA or MDS/AML

25. Johanson-Blizzard
Syndrome
• rare AR syndrome linked to
mutations in the ubiquitin-
ligase E3 (UBR1) gene.
• characterized by PI and
growth restriction, with
lipomatous transformation
of the pancreas rather than
AP
• No hematologic
abnormalities as in SDS
Pearson Marrow-Pancreas Syndrome
• rare AD mtDNA breakage syndrome
characterized by refractory
sideroblastic anemia with EPI
• EPI results from fibrosis rather
than fatty replacement of acinar
cells, as in SDS, and is more likely
to be a/w DM
• Other affected organ systems include
• Kidney (tubulopathy,
aminoaciduria, FA)
• Liver (hepatomegaly, cholestasis)
• Endocrine (DM, adrenal
insufficiency)
• Neuromuscular system, and
• Heart
• Biochemical analysis
• Lactic acidosis, lactic/pyruvic
aciduria, low palsma citrulline and
arginine

26. Iverson syndrome (asplenia with
cystic liver, kidney, and pancreas)
Congenital absence of pancreatic
lipase
Colipase deficiency
SPINK1 deficiency
Enterokinase deficiency

27. Cystic Fibrosis
• m/c lethal genetic defect of white
populations (1/2500 to 1/3200 live
births).
AR, CFTR mutation
• The incidence of CF is lower in children
of African, Native American, Asian, East
Indian, or MEA backgrounds.
• Median age at death is about 30 years.
• Clinical features:
 > 60% of CF pts diagnosed by NBS in the
USA
 Minimally symptomatic or asymptomatic

28. Chronic infections with P.
aeruginosa, Staph aureus
EPI: 85-90%, secretion of lipase
and trypsin < 10%
Pancreas is shrunken, cystic,
fibrotic, and fatty
ILH spared until late
Glucose intolerance (30-75%),
CSDM (10%)
Meconium ileus
Uncoplicated
Complicated (IO, volvulus, atresia,
necrosis, perforation, peritonitis,
giant meconium pseudocyst
Micro-GB (23%)
GB sludge/stone (8%)
White bile
Secretion of bicarbonate through
CFTR is critical to sperm and
infertility can occur
Cancer risk
Esophagus, SI, LI, stomach,
hepatobiliary tract, panctreas, or
rectum
↑ed risk of ALL, testicular cancer

30. Fig. Uncomplicated meconium ileus characteristically
demonstrates a. narrow distal ileum with a beaded
appearance caused by b. waxy, gray pellets of inspissated
meconium, beyond which the c. colon is unused (microcolon)
Fig. DIOS in pts of CF

31. CFTR molecule
• regulated ion channel
• expressed on epithelial cells in the respiratory system, sweat glands, GIT mucosa,
biliary epithelium, pancreatic duct cells, and other locations.

33. Fig. CF and CFTR-RD Diagnostic Guidelines
False positive sweat
chloride test
• Malnutrition
• Medications
• Inadequate
sweating
Abnormal CFTR
function
• Nasal potential
difference
(NPD)
• Intestinal
current
measurement
(ICM)
NPD and ICM are quantitative biomarkers of CFTR activity in the respiratory and
intestinal epithelium that can be used to define a threshold between ‘CFTR-normal
activity’ and ‘CFTR dysfunction’.

34. Fig. Diagnostic algorithm of CF

35. Fig. Nasal potential difference (NPD) measurement. A. Schematic illustration of the setup. B. Measurement instruments: A/D converter PowerLab 4/26, Bioamplifier BMA-200,
ISO-Z Headstage. C. Custom made nasal catheter, produced by Marquat ® . D. View showing the placement and attachment of the catheter. E. NPD tracing in a cystic fibrosis (CF)
patient. F. NPD tracing in a healthy control subject. NPD baseline is more negative in CF than in controls; the change in NPD towards positive values is more pronounced in CF than
in controls after blocking sodium channels with amiloride; the NPD in CF changes barely or not at all in CF after stimulation of cystic fibrosis transmembrane conductance regulator
(CFTR) chloride channels with zero-chloride solution and isoprenaline, but changes markedly toward negative values in controls; NPD changes to more negative values in both CF
and controls after stimulation of alternative chloride channels with ATP.

36. CF Foundation International
consensus committee
recommendations on the
diagnosis of CF
• presumptive diagnosis of CF can
be made in a patient with a
positive NBS and 2 CF mutations
from the CFTR2 mutation list
(http://cftr2.org/) or s/s of CF or
meconium ileus, but the
diagnosis must be confirmed
with a positive sweat chloride
test (>60 mmol/L).
• The guidelines classified
patients who did not have CF
into 2 groups:
• CFTR-related metabolic
syndrome (CRMS) and
• CFTR-related disease
(CFTR-RD)

37. Management of Cystic Fibrosis (CF)
Treatment of Pancreatic Dysfunction
• Multivitamin preparation, Fat soluble vitamins A, D, E, and K supplements, plus
• Pancreatic enzyme replacement therapy (PERT) for pts with EPI.
Nutritional Management
• Ideally, an age-appropriate diet that is 1.1 to 2 times the reference calorie intake,
with adequate PERT provided (and with gastric acid suppression, if indicated) to
achieve as normal a fat balance as possible
• Enteral tube feeding
• About 10% of CF patients require supplemental tube feeding.
• Very lowfat, elemental formulas without enzyme supplements by
continuous infusion

38. Treatment of CFTR functional variants with targeted drug therapy
• First targeted therapy: VX-770 or ivacaftor (Kalydeco)
• directed at the third most common CF-causing mutation, p.G551D.
• In phase II and III clinical trials VX-770 improved predicted FEV1, ↓ed sweat chloride
concentration, and ↓ed the frequency of pulmonary exacerbations
• VX-770 was FDA-approved for use in patients with a variety of mutations that cause gating
dysfunction in CFTR.
• This population does not include patients carrying the most common disease-causing variant,
CFTR p.F508del.
• The issue was approached by combining VX-770 with VX-809 (lumacaftor), a
small molecule that facilitates CFTR folding.
• The combination results in a partial rescue of p.F508del CFTR function.
• Clinical trials of the combination therapy showed improved clinical outcomes in patients
homozygous for p.F508del CFTR and the therapy was approved by the FDA

42. References
• Sleisenger and Fordtran’s Gastrointestinal and
Liver Disease 11th Edition
• Yamada’s Textbook of Gastroenterology 7th
Edition