Download recurrent episodes of acute pancreatitis in a cystic fibrosis carrier

The West London Medical Journal 2010 Vol 2 No 2 pp 1- 6
RECURRENT EPISODES OF ACUTE
PANCREATITIS IN A CYSTIC FIBROSIS CARRIER
Diwanji S[∗1], Bedi R[1], Vatliya M[1], Singh H[1] , Arnold J[2]
ABSTRACT
We report a case of 40 year old Caucasian gentleman, who presented with
recurrent episodes acute pancreatitis over a year and a half.
He was found to be positive for ΔF508 mutation (Heterozygote) on Cystic
fibrosis carrier screen CDSL 0412721.
In spite, of the repeated attacks of acute pancreatitis he did not develop
any chronic complications to it nor was any aetiological agent implicated,
making them most likely due to defective cystic fibrosis transmembrane
receptor (CFTR) gene status.
CASE SUMMARY:
A 40 year old Caucasian gentleman presented with episodes of acute
abdomen over a period of a year and a half which were diagnosed to be acute
pancreatitis. All the attack had similar presentation of acute epigastric and
central abdominal pain which radiated to the back. In all there were five
episodes.
He did lose a considerable amount weight after first episode (five
kilograms in 2 months). During the first attack, amylase levels were 1600
units, and during rest of the four attacks it was between 1000-2400 units. An
ultrasound of abdomen revealed two stones in the gall bladder, with no
common bile duct dilatation. There were diffuse fatty liver changes. Rest of
the scan did not reveal any abnormality. After the second attack of acute
pancreatitis, he underwent a laparoscopic cholecystectomy. A MRI scan of
abdomen failed to reveal any pathology. There is no history of alcohol intake.
Liver enzymes were within normal limits (including AST: ALT ratio and
GGT).
The patient had a history of being a carrier for ΔF508 mutation
(Heterozygote) on Cystic fibrosis carrier screen CDSL 0412721in June 2004.
∗
Address for correspondence: Dr Diwanji SN, Post Graduate Centre, Ealing Hospital,
Uxbridge Road, Southall, Middlesex UB1 3HW.
1
Clinical Fellow in Medicine, Post Graduate Centre, Ealing Hospital, London.
2
Consultant Gastroenterologist, Ealing Hospital, London.
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He had been investigated for infertility and as a result we found out that he
has fibrosis of vas deferens. His vitamin D levels were quite low (26 nmol/L).
He did not have any fat malabsorption, diabetes mellitus or recurrent
respiratory infections.
He is a known case of gastro oesophageal reflux disease (GORD) and a
recent upper GI endoscopy revealed small hiatus hernia and reactive
gastropathy.
He also has dyslipidemia with high serum cholesterol and LDL levels.
(Serum cholesterol 6 and LDL 3.90)
DISCUSSION
Cystic fibrosis an autosomal recessive disease, the most common
genetic defect of the white population, seen in about 1 in 2500 to 1 in 3500
live births.(1,2) Although, cystic fibrosis affect a number of organs but our
patient surprisingly had only pancreatic manifestations due to CFTR gene
mutation and not respiratory complications. CFTR gene is the most important
molecule for regulating the pancreatic duct cell function- generating the
bicarbonate rich pancreatic juice that helps to neutralize the acidic chime
coming from stomach and flushing digestive enzymes out of the pancreas.(2)
Thus CFTR molecule is relevant to the pancreatic disease when either its
function or regulation of its function is altered by various gene mutations.
The overall clinical picture in an individual case depends on the nature of
combined CFTR mutation, genetic background in which the defective genes
operate and environmental factors.(3) About 70% of white patients with cystic
fibrosis have a three base pair deletion of phenylalanine coding codon 508
(∆F508), although more than 1300 mutation have been reported.(2)
Sometimes in patients with cystic fibrosis may not have any pancreatic
complications. This is due to the reason that mutations such as R117 markedly
reduce the chloride conductance without affecting the bicarbonate
secretion.(4) On the other hand, like in our patient mutation affecting the
bicarbonate transport can put patient at risk to recurrent pancreatitis without
affecting the chloride dependent organs (respiratory features).(5)
The functional consequence of CFTR mutations depends on the combined
effects of both CFTR alleles, and the severity of the phenotype depending on
the mildest mutation.(6)
Recurrent acute pancreatitis requires, at minimum, a partially functioning
pancreas and is therefore seen in some cases of cystic fibrosis with pancreatic
sufficiency and atypical cystic fibrosis. Many of these features of cystic
fibrosis cannot be explained by variations in CFTR sequence. Instead this
features are caused by specific environmental factors (bacterial colonization,
tobacco smoke and nutritional status) or modifier genes.(3,7) In 1998 two
groups demonstrated that CFTR mutations were very common in idiopathic
and alcoholic chronic pancreatitis thus some of the more than 1300
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RECURRENT EPISODES OF ACUTE PANCREATITIS IN A CYSTIC FIBROSIS
CARRIER
Class
Mutation
Defect
01
02
03
04
05
W1282X
∆F508
G551D
R117H
IVS8-5T
Synthesis
Maturation
Activation
Conductance
Abundance
Pancreatic
dysfunction
Severe
Severe
Severe
Mild
Mild
If a class I through III mutation, or some class IV mutation, is
combined with wild type CFTR or a benign polymorphism the
overall function of CFTR is reduced by up to 50% but the
phenotype is usually normal because more than 90% of overall
function must be lost before clinical features appear.(6)
known CFTR gene sequence variant can cause milder disease (atypical cystic
fibrosis) or pancreas specific injury or can be a part of a more complex
trait.(8,9,10) In early onset idiopathic pancreatitis, this factor may be a
heterozygous SPINK1 mutation but stronger environmental factors such as
alcoholism and smoking may be causative.(5)
In adult population, presenting symptoms of cystic fibrosis include
pulmonary disease, nasal polyps, liver disease, recurrent pancreatitis and
chronic pancreatitis. Although the prevalence of CFTR mutation in patients
with these common disorders is much lower than in those presenting with
pancreatic insufficiency or meconium ileus.(2) Acute recurrent pancreatitis is
rare complication in CFTR mutation (around 1% have it) and much rarer to be
a presenting feature which are both there in our patient.(2,11)
The pathogenesis of these episodes is not entirely clear. It is thought that
as a result of dysfunction of the chloride channel mediated by the cAMP
protein (CFTR), alters the composition of pancreatic juice, and decrease the
concentrations of chloride and bicarbonate and volume of water.(12) In these
conditions, with an acid and pancreatic juice hyper concentrated, favours the
precipitation of protein content and pancreatic ductal obstruction. These
patients, therefore, may be particularly susceptible to certain environmental
factors such as fatty foods, alcohol and viral infections. (13)
In the course of the disease, the patients with acute pancreatitis secondary
to cystic fibrosis, after several episodes, can progress to chronic pancreatitis
with duct dilatation.(14) Although the management of acute pancreatitis
secondary to cystic fibrosis does not differ, the importance of diagnosis lies in
the possibility of genetic counselling. Hence all young patients with recurrent
acute pancreatitis due to unknown causes must be ruled out.
CF-related liver disease (CFLD) occurs in up to 30% of people with CF.
(15) However, it is only a significant clinical problem in a minority of
individuals. For most there is an abnormality of liver function tests and in
some of these, some fatty changes in the liver. In a minority of patients,
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cirrhosis develops with secondary pulmonary portal hypertension.(15) The
pathophysiology of the condition is related to obstruction of small biliary
calculi and it is likely that modifier genes in addition to CFTR dysfunction
play an important part in this process. Screening for liver disease is taken in
most CF centres with annual assessment of liver transaminases, gamma
glutamyl transferase (γ GT), and alkaline phosphatase. (16)
Fat-soluble vitamin deficiency is common in people with CF.(17) Vitamin
deficiency rarely causes clinical deficiency syndromes though eye problems
have been demonstrated in individuals with low vitamin A concentrations.(18)
Neurological complications with peripheral neuropathy have also been
demonstrated in vitamin E deficient patients.(19)
CF-related bone disease (CFRBD) is an important systemic complication.
CFRBD is very similar to osteoporosis with low bone mass and micro
architectural deterioration of bone tissue.(20) This leads to an increase in bone
fragility and increases the susceptibility to fracture. In general the prevalence
of CF-related bone disease is reported as at around 30 to 35% of adults.(21)
The pathophysiology of low BMD in people with CF has not been entirely
determined but there is evidence of increased bone absorption and decreased
bone formation.(22) Osteoclasts express CFTR, and several recent studies
suggest that CFTR dysfunction contributes to the development of
CFRBD.(23) It is difficult to determine the relative importance of many of
these risk factors, but evidence increasingly points to systemic inflammation
as being one of the most important drivers of low BMD. Proinflammatory
cytokines such as interleukin (IL)-1, IL-6, and tumour necrosis factor-α
stimulate Osteoclasts numbers.(24) Several interventions are likely to be very
beneficial in preventing the development of CFRBD.
In a large study of 38,000 persons with cystic fibrosis there was a
significant risk of increase in tumours of the digestive tract but not an increase
in the risk of cancer in relation to the general population for all types of
cancer.(25) These cancers tend to occur in the third decade of life and
involved the tumours of the small and large intestine, stomach, liver, biliary
tract, pancreas and the rectum. Their pathogenesis is uncertain and pancreatic
cancer can be due to chronic inflammation as observed with other cases of
chronic pancreatitis. These risks are important to keep in mind due to
increasing life expectancy on patients with cystic fibrosis.
CONCLUSION
The case report illustrates the need to rule out cystic fibrosis in the
patients with recurrent acute pancreatitis in whom aetiology is unknown.
The life expectancy in people with cystic fibrosis is improving, and hence
it is vital to bear in mind the complications like related carcinoma and other
complications.
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RECURRENT EPISODES OF ACUTE PANCREATITIS IN A CYSTIC FIBROSIS
CARRIER
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