B Phillips, C Perry
cystic, fibrosis, medicine, surgery
B Phillips, C Perry. Quick Review: Cystic Fibrosis. The Internet Journal of Internal Medicine. 2000 Volume 3 Number 1.
CF is the
most common lethal genetic disease among Caucasians with an Incidence in the
United States of 1:2000 among whites; incidence is approximately 1:17000 among
African-Americans; it is very rare among Orientals. CF is the major cause of
severe chronic lung disease in children and is responsible for most exocrine
pancreatic insufficiency during early life. It is inherited as an Autosomal
Recessive Trait with a carriage percentage of approximately 5%; heterozygotes
are not clinically affected. Twenty percent of patients in the US are Adults.
[ Mucoviscidosis; Fibrocystic Disease of the Pancreas; Pancreatic Cystic Fibrosis]
an inherited disease of the exocrine glands, primarily affecting the GI and Respiratory systems, and usually characterized by the triad of chronic obstructive pulmonary disease, exocrine pancreatic insufficiency, and abnormally high sweat electrolytes.
CF is the
According to Nelson's,
In general, the CF gene is most prevalent in Northern and Central Europeans and their descendents.
The basic underlying defect has yet to be identified but
It is known that the CF gene is localized to the long arm of Chromosome 7 (Dr. Francis Collins, U. of M - and you thought they only had a good football team) with a large domain encoding for approximately 1500 amino acids - called the “COVERT - CF Transmembrane Receptor”. This receptor is thought to act like a Membrane Regulator or an Anion Pump/Channel.
The most common gene mutation results in the deletion of a Phenylalanine residue at amino acid 508 (referred to as Delta-F 508); however, there are many more less-common mutations that have been identified throughout affected patients.
With this disease, even with the lack of a clear underlying defect, there has been 4 fundamental steps involved in the pathophysiologic process:
Failure to Clear Mucus Secretions
A Paucity of Water in Mucus Secretions
An Elevated Salt Content of Sweat and other Serous Secretions
Chronic Infection limited to the Respiratory Tract.
Current research is showing that the first three are related to the genetic mutation (and to each other) and that the fourth factor of Infection is a Secondary Event. A summary of the proposed process involves the Sodium and Chloride Channels within apical membranes. These are present and functional - compared to controls, but have an altered regulation of their activity ! The product of the COVERT Gene is thought to be involved in this “altered regulation” and affects “key phosphorylation steps” in cAMP-dependent and C-kinase pathways that up-regulate and down-regulate the activity of sodium channels (which makes the channel defective in establishing the “normal” potential difference across epithelial surfaces).
A “unifying pathogenetic scheme” for the clinically-observable lung dysfunction is as follows (per Nelson's):
Nearly all exocrine glands are affected !! However, the degree of severity and general distribution varies from patient to patient. Involved glands can be grouped into 3 types:
Those that become Obstructed by Viscid or Solid Eosinophilic Material in the Lumen (e.g. pancreas, intestinal glands, intrahepatic bile ducts, gallbladder, and submaxillary glands)
Those that produce an Excess of Histologically-Normal Secretions (e.g. tracheobronchial and Brunnuer's Glands)
Those that are Normal Histologically but Secrete Excessive Na and Cl (e.g. sweat, parotid, and the small salivary glands)
This summary and division into “groupings” is helpful (at least to us) in trying to correlate the clinical findings with the pathophysiologic process; if one can explain the sign or symptom as related to one of the above groups then the course of disease can be rationalized and - hopefully understood ! For example, in women
Current evidence suggests that, at time of birth, the lungs are
Pulmonary disease becomes initiated by diffuse obstruction of the smaller airways by the abnormally-thick mucus (the kind that turned our “wise and thoughtful” Clerkship Coordinator off of Pulmonology!).
This obstruction leads to
Death usually results from a combination of Respiratory Failure and Cor Pulmonale !
Symptoms and Signs
Varied in type and number!
The earliest possible sign is present at birth and affects 7 - 10 % of infants:
This is due to obstruction of the ileum by viscid meconium and is often associated with volvulus, perforation, or atresia.
In the Newborn, the
Pancreatic insuffiency is present in 85-90% of patients with
50% of patients present with pulmonary manifestations consisting of
As the disease progresses, there are noticeable intercostal retractions, use of accessory muscles of respiration, a barrel-chest deformity, digital clubbing, and cyanosis. Upper Respiratory Tract involvement includes
Teenagers may have retarded growth, delayed onset of puberty, and a declining tolerance for exercise.
Pulmonary Complications in adolescents and adults include:
RHF (secondary to the Pulmonary HTN).
In 3% of patients, Insulin-requiring Diabetes develops; 4-5% will develop Multinodular Biliary Cirrhosis with Varices and Portal Hypertension (one of my favorite subjects - all of the various sequelae that are possible - and probable - make it a fascinating topic!!). Chronic and or recurrent abdominal pain may be related to Intussusception, Pancreatitis, GERD, Gallbladder disease, or episodes of partial Intestinal Obstruction secondary to abnormally-viscid fecal material.
Laboratory Findings which are helpful in distinguishing CF may begin with the Newborn Screening Test; a meconium examination looking for the abnormally-large amount of serum protein (especially albumin); however, this screening does NOT detect 10-15% of patients with normal or near-normal pancreatic function - thus it is not recommended as a universal screen.
Since 85-90% of patients will have some degree of pancreatic insufficiency, the duodenal fluid will be abnormally viscid and show an absence (or decrease) in enzyme activity and [HCO3-]. Stool Trypsin and Chymotrypsin are usually diminished or absent [a serum concentration of “immunoreactive trypsin” is being studied as a possible screening test in newborns].
Approximately 40% of patients will show a diabetic oral glucose tolerance reponse secondary to a delayed insulin release. Fasting blood levels of the carotenoids, vitamins A and E (possibly D and K - since absorption would be seriously affected, but D and K were not specifically mentioned as being diminished; direct assays of vitamins D and K may not be required - just by looking at the expected outcomes of their respective deficiencies would be a clinical guide to their possible deficiency: vitamin D - leading to a “Rickets”-type picture if long-term; vitamin K- leading to abnormal values in PTT and Bleeding Time).
Chest x-ray findings may be helpful in diagnosing CF with the earliest findings being Hyperinflation and Bronchial Wall Thickening. Subsequent changes include areas of infiltrate, atelectasis, and hilar lymphadenopathy. With further progression comes segmental or lobar atelectasis, cyst formation, bronchiectasis, and pulmonary artery enlargement with RVH.
Characteristic findings of CF include: “branching” and “finger-like opacifications” (which are due to mucoid impaction in the dilated bronchi. PFT's reveal hypoxemia, reduction in the Forced Vital Capacity, ratio of FEV1/FVC, and an increase in residual volume (with subsequent increase in the RV/TLC ratio).
Unfortunately there is no reliable test for prenatal diagnosis or for heterozygote detection. With the recent discovery of linkage markers for the CF Gene, families with a previously-affected child can undergo karyotype and genetic evaluation with prenatal evaluations !
CF is usually diagnosed in infancy or early-childhood; 10 % of patients do not become detected until adolescence or early adulthood. The diagnosis is suggested by the above clinical signs and symptoms without alternative explanations and then gets confirmed by demonstrating an elevation of Na and CL concentrations in the sweat. The ONLY reliable test is the:
Quantitative Pilocarpine Iontophoresis Sweat Test
The test works by pharmacologically stimulating localized sweating and then collecting the amount of sweat secreted; measurements of electrolytes are determined and NA or Cl values > 60 mEq/L confirms the diagnosis given a suggestive clinical picture or positive family history. It is estimated, that less than 1:1000 patients with CF will have a sweat chloride less than 50 mEq/L. False-negative tests are rae but can occur in the presence of edema, hypoproteinemia, or with inadequate quantities of sweat. It must be remembered that a small subset of patients (labeled
Course of CF
Largely determined by the degree of Pulmonary Involvement and varies greatly from patient to patient. However, deterioration is inevitable.
Prognosis has improved over the past few decades and is said to be mainly due to the widespread aggressive treatment before the onset of irreversible pulmonary changes.
Median Survival is 20 yrs of age.
Long-term survival is better for males compared to females.
One of the most important factors in this disease is the quality of Supportive Treatment - trying to make this condition more tolerable for both the patient and family (in my opinion, one of the most important responsibilities of the physicians, nurses, physical therapists, counselors, and social workers - the disease is progressive and non-curable. Most patients are able to work or attend school until shortly before death.
Genetic counseling must be considered for “at-risk” families !
The ultimate goals of therapy include:
Adequate Nutritional Status
Prevention or Aggressive therapy of Pulmonary Complications
Encouragement of Physical Activity
Provision of Adequate Psychosocial Support.
Diet therapy includes: sufficient calories and protein to promote normal growth and development (suggestion is to exceed the RDA requirements by 50%; a high-normal fat intake to increase the caloric density; multivitamins in double the recommended concentrations; supplemental Salt in times of increased sweating. Prophylaxis against respiratory infections includes the maintenance of Pertusis and Measles Immunity and annual Influenza vaccination. Since there has been no reported increase in the morbidity or mortality from Pneumococcal Infections, pneumococcal vaccine is
Obstruction (in the uncomplicated Meconium Ileus or in the “
Treatment of Pulmonary infections includes the prevention of Airway Obstruction and subsequent control of infection. At the first sign of pulmonary involvement,
Surgery may be indicated for the following:
Localized Bronchiectasis or medically-”resistant” Atelectasis
Bleeding form Esophageal Varices (secondary to Portal HTN)
Intestinal Obstruction (due to Volvulus or an Intussusception that can not be medically reduced, or that is not reducible by Barium Enema)
In symptomatic outpatients, bacterial pathogens in the respiratory tree should be treated with effective drugs as determined by C&S. For
Combinations of an Aminoglycoside with an anti-pseudmonas penicillin are commonly used by the IV route; some of the newer cephalosporins do carry anti-
Bradley J. Phillips, MD Dept. of Trauma & Critical Care Medicine CCM 2707 One Boston Medical Center Place. Boston, MA 02118 Tel: (617) 638-6406 Fax: (617) 638-6452 Email: firstname.lastname@example.org