WBR246

Author	[[PageAuthor::Gerald Chi (Reviewed by Yazan Daaboul, M.D.)]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Pathophysiology
Sub Category	SubCategory::Pulmonology
Prompt	[[Prompt::A 5-year-old boy is brought to the physician's office for routine evaluation. The patient was diagnosed with a congenital disease immediately after birth and has been followed up by his physician ever since. The patient's genetic analysis reveals a homozygous deletion of three nucleotides coding for phenylalanine at amino acid position 508. Which of the following pathophysiological changes in this patient does not result in clinical manifestations at his present age?]]
Answer A	AnswerA::Reduced chloride secretion by the sweat duct
Answer A Explanation	[[AnswerAExp::Reduced chloride absorption in sweat ducts is observed in patients with CF. In the absence of chloride flow in cystic fibrosis, sodium ions do not flow through ENaC despite upregulation of the ENaC channel, leading to greater salt and water loss. As such, patients' skin tastes salty. A chloride sweat test, which detects the concentration of salt on the patient's skin, is a diagnostic test of CF.]]
Answer B	AnswerB::Reduced chloride secretion by the intestinal epithelium
Answer B Explanation	AnswerBExp::Reduced chloride secretion with augmented sodium absorption results in water retention in the intestinal epithelium of patients with CF. Colonic manifestations of CF, such as recurrent constipations, are often evident during childhood.
Answer C	AnswerC::Decreased insulin release from the islets of Langerhans
Answer C Explanation	[[AnswerCExp::The thickened secretions from the pancreas block the exocrine movement of the digestive enzymes into the duodenum and result in irreversible damage to the pancreas. This causes atrophy of the exocrine glands and progressive fibrosis. The observed delay for pancreatic fibrosis to develop accounts for the delayed damage to the endocrine pancreas, whose manifestations often appear at an advanced stage of the disease. The median age at diagnosis of cystic fibrosis-related diabetes (CFRD) is 18-21 years.]]
Answer D	AnswerD::Loss of migration of neurons to submucosa and muscularis propria of the colon
Answer D Explanation	[[AnswerDExp::During normal fetal development, cells from the neural crest migrate into the colon to form Auerbach's plexus and Meissner's plexus. In Hirschprung's disease, the migration is not complete, and part of the colon lacks these nerve bodies that regulate the activity of the colon. The affected segment of the colon cannot relax and may result in meconium ileus.]]
Answer E	AnswerE::Reduced transepithelial chloride conductance of the airway cells
Answer E Explanation	[[AnswerEExp::The "high salt" hypothesis suggests that patients with CF have a reduced transepithelial chloride conductance of the airway cells, which results in high salt concentrations in the surface liquid of the airways. Pulmonary manifestations of CF, including airway plugging and recurrent pulmonary infections, are often evident during early childhood.]]
Right Answer	RightAnswer::C
Explanation	[[Explanation::Cystic fibrosis (CF) is an autosomal recessive genetic disorder that affects the lungs, pancreas, liver, and intestine. It is characterized by abnormal transport of chloride and sodium across an epithelium, leading to thick, viscous secretions. CF is caused by mutation of the gene CFTR (cystic fibrosis transmembrane conductance regulator) which encodes a member of the ATP-binding cassette (ABC) transporter superfamily. ABC proteins transport various molecules across extra- and intra-cellular membranes. The encoded protein functions as a chloride channel and controls the regulation of other transport pathways. ΔF508 is the most common type of mutation within the CFTR gene. The mutation is a deletion of the three nucleotides that comprise the codon for phenylalanine (F) at position 508. Individuals with the CFTRΔF508 mutation produce an abnormal CFTR protein that lacks this phenylalanine residue. This protein does not escape the endoplasmic reticulum for further processing and fails to be translocated to the epithelial surface, rendering epithelial membranes relatively impermeable to chloride ions. In sweat ducts, there is decreased absorption of chloride through CFTR with decreased absorption of sodium through epithelial sodium channel (ENaC) which results in production of hypertonic sweats. In the gastrointestinal tract, there is decreased secretion of chloride through CFTR with increased absorption of sodium through ENaC which leads to production of dehydrated mucus. In the airways, the absence of functional CFTR causes upregulation of the ENaC channel which further decreases salt and water secretion by reabsorbing sodium ions. As such, the respiratory complications in cystic fibrosis are not solely caused by the lack of chloride secretion, but instead by enhanced reabsorption of sodium and water. Cystic fibrosis is a multisystem disease that affects epithelial cells of virtually all organs. It is characterized by excessive salt loss via sweat glands, meconium ileus, bilious vomiting, intestinal obstructionm, malabsorption, steatorrhea, chronic pulmonary infections that result in pulmonary fibrosis, cardiac arrhythmias, pancreatic insufficiency, and male infertility (bilateral congenital vas deferens). Clinical manifestations often occur early during the course of the disease, and patients may develop clinical features of CF as early as day 1 of birth (e.g. meconium ileus). The thickened secretions from the pancreas block the exocrine movement of the digestive enzymes into the duodenum and result in irreversible damage to the pancreas. This causes atrophy of the exocrine glands and progressive fibrosis. The observed delay for pancreatic fibrosis to develop accounts for the delayed damage to the endocrine pancreas, whose manifestations often appear at an advanced stage of the disease. The median age at diagnosis of cystic fibrosis-related diabetes (CFRD) is 18-21 years. Educational Objective: The thickened secretions from the pancreas block the exocrine movement of the digestive enzymes into the duodenum and result in irreversible damage to the pancreas. This causes atrophy of the exocrine glands and progressive fibrosis. The observed delay for pancreatic fibrosis to develop accounts for the delayed damage to the endocrine pancreas, whose manifestations often appear at an advanced stage of the disease. The median age at diagnosis of cystic fibrosis-related diabetes (CFRD) is 21 years. References: Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med. 2005;352:1992-1991. Ntimbane T, Comte B, Mailhot G, et al. Cystic fibrosis-related diabetes: From CFTR dysfunction to oxidative stress. Clin Biochem Rev. 2009;30(4):153-77. First Aid 2015 page 84.]]
Approved	Approved::Yes
Keyword	WBRKeyword::Cystic fibrosis, WBRKeyword::High salt hypothesis
Linked Question	Linked::
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