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much salt, too little soda: cystic fibrosis.Sheng
Li Xue Bao. 2007 Aug 25;59(4):397-415.
Cystic fibrosis
(CF) of the pancreas is the most widely accepted name of the most
common fatal inherited single gene defect disease among Caucasians.
Its incidence among other races is thought to be significantly less,
but mutations in the gene have been reported in most, if not all,
major populations. This review is intended to give general concepts of
the molecular as well as physiological basis of the pathology that
develops in the disease. First, an overview of the organ pathology and
genetics is presented, followed by the molecular structure of the gene
product (cystic fibrosis transmembrane conductance regulator, CFTR),
its properties, functions, and controls as currently understood.
Second, since mutations appear to be expressed primarily as a defect
in electrolyte transport, effects and mechanisms of pathology are
presented for two characteristically affected organs where the
etiology is best described: the sweat gland, which excretes far too
much NaCl ("salt") and the pancreas, which excretes far too little
HCO3(- )("soda"). Unfortunately, morbidity and mortality in CF develop
principally from refractory airway infections, the basis of which
remains controversial. Consequently, we conclude by considering
possible mechanisms by which defects in anion transport might
predispose the CF lung to chronic infections.
Review of the
abdominal manifestations of cystic fibrosis in the adult patient.Radiographics.
2006 May-Jun;26(3):679-90.
Cystic
fibrosis is a common inherited fatal disease. As the life expectancy
of affected individuals continues to increase with advances in disease
management, this disease is no longer limited to the pediatric
population. Currently, 40% of patients with cystic fibrosis are
adults. In addition, patients may not present until adulthood and
frequently have extrapulmonary symptoms. Abdominal manifestations are
common and affect multiple organ systems. Hepatobiliary manifestations
include fatty infiltration of the liver, gallbladder abnormalities,
bile duct abnormalities, focal biliary fibrosis, and multinodular
cirrhosis. Manifestations in the pancreas include acute pancreatitis,
fatty replacement, calcifications, cysts, duct abnormalities, and
carcinoma. Gastrointestinal manifestations include gastroesophageal
reflux, peptic ulceration of the gastric and duodenal mucosa, distal
intestinal obstruction syndrome, intussusception, appendicitis,
fibrosing colonopathy, pneumatosis intestinalis, rectal mucosal
prolapse, malignancies, and pseudomembranous colitis. Renal
manifestations include nephrolithiasis, as well as secondary renal
complications such as interstitial nephritis due to antibiotic therapy
and amyloidosis. Awareness of these manifestations is important to
successfully guide management of cystic fibrosis in adult patients.
Cystic
fibrosis diabetes in adult. Ann
Endocrinol (Paris). 2005;66(4):347-54.
Cystic
fibrosis is an autosomal recessive disorder affecting about 1/3500
case in France. The disease, that affects all epithelia, is
responsible for pulmonary tract infections but also pancreas, gut,
liver and genital tract abnormalities. It is linked to CFTR gene
mutations, inducing unusually high increase of sodium chloride in
sweat, used to track down the illness. deltaF508 CFTR mutation,
encountered in 70% of cases, is nearly always associated to pancreatic
insufficiency with early-onset lung attack. Around 10% of cystic
fibrosis cases, whatever the age, are complicated with partially
insulinopenic diabetes, favored by pancreatic fibrosis, while one
third of patients shows glucose intolerance. After 20 years old, one
third of patients suffers from diabetes and one half after 30 years.
Diabetes diagnosis is difficult, and requires the fulfillment of oral
glucose tolerance test (OGTT). One glycemia greater or equal to 2 g/l,
two hours after a 75 g glucose load, established diabetes diagnosis.
Indeed, fasting blood glucose and glycated hemoglobin appear as poor
diagnosis markers. Despite histological arguments in favor of the
mainly mechanical islet disturbances, an increased prevalence of
anti-islets auto-antibodies and an increased frequency of HLA DR3/DR4
have been reported in cystic fibrosis population with glucose
tolerance troubles. Also, glucose metabolism is influenced by specific
factors linked to cystic fibrosis (infection, malnutrition,
steroids...). In reason of the silent phase of diabetes, systematic
tracking down of diabetes with a yearly OGTT is recommended, all the
more so that hyperglycemia appears as a worsening factor of cystic
fibrosis. The efficacy of oral anti-diabetic drugs has not been
evaluated on large studies. By contrast, some studies argue for
insulin therapy as soon as diabetes appears, insulin improving
respiratory and nutritional prognosis. In conclusion, the aim of
treatment of cystic fibrosis is to prevent the lung function decline
by controlling inflammation and infection, to implement endo- and
exo-crine pancreas insufficiency, and to improve nutritional status.
Cystic
fibrosis: recent structural insights.J
Cyst Fibros. 2004 Aug;3 Suppl 2:91-4.
Cystic
fibrosis (CF) is a debilitating human disease caused by mutations in
the cystic fibrosis transmembrane conductance regulator (CFTR) gene.
The recently solved crystal structures of the murine CFTR nucleotide
binding domain (NBD) provide insight into the molecular basis of
several CF-causing mutations. In addition, the NBD structures reveal
several unexpected findings that may have implications concerning CFTR
function. In this mini-review, we discuss the key structural features
of ATP Binding Cassette (ABC) transporter NBDs, as well as highlight
how structural information has aided our understanding of the
ATP-regulated solute transport cycle
Inspissation of pancreatic zymogen material in cystic fibrosis.Ultrastruct
Pathol. 2003 Sep-Oct;27(5):323-35.
Cystic
fibrosis is characterized by the elaboration of abnormal, thick,
tenacious mucus resulting in obstructive disease in sites such as the
lung and pancreas. In the pancreas, acinar plugs of mucus have been
reported as the earliest recognizable morphologic lesion in cystic
fibrosis. Since mucus is not normally elaborated within the pancreatic
lobular tissue, the mechanism of accumulation of mucus in acini is
enigmatic. To investigate this phenomenon, well-preserved autopsy
pancreatic tissue was studied ultrastructurally. This study
demonstrated very prominent mucous metaplasia in these diseased
organs. Acinar plugs, though, developed before mucous metaplasia.
Subsequent histochemical study was performed, which demonstrated that
the early acinar plugs exhibited the same staining properties as
zymogen granules and were distinct from the staining pattern of mucus
in pancreatic tissue of cystic fibrosis patients. These findings,
then, indicate that zymogen material, not mucus, becomes inspissated
in the acini of the pancreas in early cystic fibrosis, and that
subsequent mucous metaplasia occurs as the obstruction and exocrine
atrophy progress.
Fatty
replacement of the pancreas in a patient with asymptomatic pulmonary
cystic fibrosis.J
Radiol. 2003 Apr;84(4 Pt 1):409-11.
The authors
report the case of a 26-year-old woman with hepatomegaly, who had
recurrent and progressive nausea and abdominal pain. Computed
tomography and magnetic resonance imaging demonstrated fatty
replacement of the entire pancreas resulting from cystic fibrosis. The
pulmonary disease was totally asymptomatic. Fatty replacement of the
pancreas is the most frequent pattern in older patients with cystic
fibrosis. This pattern correlates with pancreatic exocrine
dysfunction.
New insights
into the pathogenesis of cystic fibrosis.Scand
J Gastroenterol Suppl. 1990;178:17-25.
Cystic
fibrosis (CF) is the most frequent inheritable disease with a lethal
course during childhood. The characteristic high viscosity of the
mucoid secretion products in the lungs, pancreas, and gut cause
plugging and secondary damage of these organs. In the past 20 years
effective treatment of intestinal obstruction in the neonatal period
and the infections of the lungs has improved the prognosis
significantly. Many patients will reach adulthood in the near future.
In the past 10 years new insights into the cause of the disease
changed diagnostic procedures and, it is to be hoped, soon also
treatment. The first development was the estimation of brush-border
enzymes in amniotic fluid. With this method prenatal diagnosis is
possible in the 17th-18th week of pregnancy. The recent discovery of
the gene on chromosome 7 and its structure is the most important
breakthrough. At the same time the process of Cl- transport across the
mucosal membrane of many types of epithelium was subject to
investigation by several laboratories. We have studied the transport
of ions in the small and large intestines of CF patients. The effect
of all three types of intracellular signal transfer is abnormal,
although the second messengers themselves (cAMP, cGMP, and Ca2+) are
present. Evidence is found for K+ instead of Cl- secretion after
addition of secretagogues.
Carcinoembryonic antigen, alpha 1-antitrypsin, and alpha-fetoprotein
in the pancreas of patients with cystic fibrosis.Arch
Pathol Lab Med. 1989 Oct;113(10):1142-6.
The
ductular accumulation of "abnormal mucus" is the key histologic
feature in cystic fibrosis. This material is periodic acid-Schiff
positive and diastase resistant, suggesting that it is glycoprotein in
nature. We used the avidin-biotin-peroxidase method to identify this
material using antibodies to the serum glycoproteins carcinoembryonic
antigen, alpha 1-antitrypsin, and alpha-fetoprotein on paraffin
sections of pancreas obtained from a total of 21 patients: 9 with
cystic fibrosis, 5 with chronic pancreatitis, and 7 controls. The
control patients had normal pancreatic histologic findings, no alpha
1-antitrypsin or alpha-fetoprotein was demonstrated, and only the
ductular epithelium reacted weakly for carcinoembryonic antigen. The
pancreas in pancreatitis showed fibrosis, acinar atrophy, and ectasia
of the ducts that contained only a small amount of periodic
acid-Schiff-positive material. This material reacted weakly for
carcinoembryonic antigen and alpha 1-antitrypsin. The appearance of
the pancreas in cystic fibrosis was similar to that in chronic
pancreatitis. However, the ducts contained a greater amount of
periodic acid-Schiff-positive material, mostly in the form of globules
that reacted strongly for carcinoembryonic antigen and alpha
1-antitrypsin and weakly for alpha-fetoprotein, as did the ductular
epithelium. This study shows that the periodic acid-Schiff-positive
material in cystic fibrosis contains at least the three serum
glycoproteins and that the accumulation may represent a possible
defect in cellular synthesis, assembly, or transport of glycoproteins
in the ducts.
Incidence and
management of surgical pathology in children with cystic fibrosis of
the pancreas.Cir
Pediatr. 1989 Apr;2(2):72-5.
This report
reviews 110 children of ages ranging from 2 months to 17 years, with a
diagnosis of cystic fibrosis, and analyzes the surgical treatments
they have undergone. In our series, meconium ileus shows an higher
occurrence (20%) than the reported by the literature. No direct
relationship could be established between the existence of meconium
ileus and a more severe affectation of cystic fibrosis. Rectal
prolapse occurred in 10% of the patients, and only 4% underwent
surgical treatment. Three children with appendicitis developed a
periappendiceal abscess due to delayed diagnosis and 2 other were
operated upon for meconium ileus equivalent. From 7 patients with
gastroesophageal reflux, 5 were treated non-operatively and 2 required
corrective surgery. Fifty five patients out of the 110 (45%) underwent
different surgical procedures.
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