Cystic fibrosis

Overview

Cystic fibrosis is a hereditary condition that causes long-term lung infections and gradually reduces one's capacity to breathe.

Mucous accumulation in the pancreas prevents the release of digestive enzymes that aid in the body's absorption of food and vital nutrients, resulting in malnutrition and poor development. The thick mucus in the liver might clog the bile duct, resulting in liver disease. CF may impair men's capacity to produce children.

Cystic fibrosis definition 

Cystic fibrosis (CF) is a hereditary illness that mostly affects the lungs, although it can also affect the pancreas, liver, kidneys, and gut.  As a result of recurring lung infections, long-term difficulties include difficulty breathing and coughing up mucus. Sinus infections, poor development, fatty stool, clubbing of the fingers and toes, and infertility in most males are further indications and symptoms. Different persons may have varying degrees of symptoms.

CF is a recessive autosomal recessive disorder. It is caused by mutations in both copies of the cystic fibrosis transmembrane conductance regulator (CFTR) protein gene. Those with a single functional copy are carriers, but otherwise appear to be in good health. Sweat, digestive fluids, and mucus are all produced by CFTR. When the CFTR is not working properly, normally thin secretions thicken. A sweat test and genetic tests are used to detect the illness. In various parts of the globe, newborns are screened at birth.

Cystic fibrosis background

Children have been afflicted with cystic fibrosis, which causes them to live shorter lives, since ancient times. These children were thought to be cursed by witches and doomed to die in medieval Europe. "Woe to the youngster who tastes salty from a kiss on the brow, for he is cursed and will soon die," said the curse, which entered folklore. An indication of an approaching sickness with no known cause or remedy was salty skin.

Cystic fibrosis was poorly known until quite recently. Lowe et al. proposed in 1949 that cystic fibrosis is caused by a genetic abnormality resulting from the disease's autosomal recessive inheritance pattern. The presence of high levels of salt in the sweat of cystic fibrosis patients showed a problem with electrolyte transport from the sweat gland.

Chloride was unable to pass through the sweat ducts of these people. Further research led to the conclusion that the defective chloride channel must be located in the apical membranes of the lung surface or the glandular epithelium to explain the respiratory and systemic organ failure seen in cystic fibrosis patients.

Epidemiology

The most common mutation is delta F508, which affects 70% of white CF patients in the United States and two-thirds of all cases worldwide. This is a class 2 mutation that causes aberrant folding of the CFTR protein, causing it to be destroyed prematurely within the Golgi apparatus. Exocrine pancreatic insufficiency and a greater risk of meconium ileus are common side effects of the delta F508 mutation.

Cystic fibrosis causes

A genetic mutation on chromosome 7 causes CF, which is caused by a mutation in the protein transmembrane conductance regulator (CFTR), which works as a transmembrane cAMP-activated chloride channel. In clinical illness, both copies of the gene are altered.

There are over 2000 different mutations in the CFTR gene that can cause disease. These mutations are divided into five classes:

1. Defective protein synthesis
2. Defective protein processing
3. Disordered regulation
4. Defective chloride conductance
5. Accelerated channel turnover

Cystic fibrosis pathophysiology

Class 1 dysfunction is caused by nonsense, frameshift, or splice-site mutations, which cause the mRNA sequence to be terminated prematurely. When the genetic information is not translated into a protein product, the CFTR protein is completely absent, resulting in around 2% to 5% of cystic fibrosis cases.

The CFTR protein undergoes aberrant post-translational processing as a result of Class 2 malfunction. This phase in the protein processing process is critical for the protein's correct intracellular transit. As a result, CFTR cannot be relocated to its proper cellular position.

Protein activity in response to intracellular signaling is decreased in Class 3 malfunction. As a result, there is a completely constructed but non-functional protein channel in the cellular membrane.

When a protein is generated and correctly localized to the cell surface, it is classified as Class 4 dysfunction. The rate of chloride ion flow and the length of channel activation after stimulation, on the other hand, are both lower than normal.

The net decreased concentration of CFTR channels in the cellular membrane as a result of fast degradation by cellular processes is classified as Class 5 dysfunction. Mutations that affect the stability of mRNA as well as mutations that affect the stability of the final CFTR protein are included.

All mutations result in decreased chloride secretion and, as a result, increased salt resorption into the cellular space. Higher sodium reabsorption causes increased water resorption, resulting in thicker mucus discharges on epithelial linings and more viscous exocrine secretions. Mucus plugging with obstructive disorders is caused by thickened mucus discharges in practically every organ system involved. Sinuses, lungs, pancreas, biliary and hepatic systems, intestines, and sweat glands are among the most usually affected organs.

Sinus illness develops when the viscosity of the discharge rises, obstructing the sinus Ostia. Here, other processes are frequently present. Ciliary dysfunction, higher inflammatory mediators, and increased bacterial colonization with infections like Pseudomonas aeruginosa are just a few of the symptoms. Sinus secretion clearance is reduced as a result of this condition. Chronic sinusitis develops as a result, and subsequent structural damage may develop.

Lung illness is characterized by mucous production that has thickened. It's crucial to remember that a CF patient's lungs are normal in the womb, at birth, and after birth. Following infection and the accompanying inflammatory response, disease develops as a cascade effect. The obstructive lung disease clinical picture is caused by mucus blockage in the bronchioles. An ideal habitat for bacterial development is generated within the airways as a result of blockage. Bronchiectasis develops, as does thick, purulent sputum output.

The synthesis of neutrophil interleukin-8 from epithelial cells, which acts as a secretagogue and increases mucous secretion, is part of the inflammatory response, producing a positive feedback loop of mucous secretion with the persistence of inflammation, infection, and structural damage. As a result of this cascade, the airways become obstructed, leading in lung ventilation failure. In people with CF, poorly treated pulmonary symptoms are the leading cause of death.

The blockage of the pancreatic ductules by thicker secretions is a major cause of pancreatic symptoms of CF. The pancreatic exocrine glands are stimulated to secrete pancreatic enzymes into the luminal area of the small intestines when gastric contents enter into the proximal duodenum. This procedure is hampered by increased viscosity of excretions and occlusion of the pancreatic ductules.

Due to a decrease in sodium bicarbonate composition, the net pH of the secretions decreases, resulting in less neutralization of the acidic stomach chyme. The chyme's lower pH effectively destroys any pancreatic enzymes that make it into the intestinal lumen. As a result, intestinal chyme is not digested enzymatically in the intestines, resulting in pathognomonic oily stools, colicky abdominal pain, and nutrient malabsorption from diets. Vitamins A, D, E, and K, which are fat-soluble, are particularly low.

Furthermore, because these enzymes target pancreatic tissues, autodigestion of the pancreas may occur. Pancreatitis is the effect of this. When imprisoned pancreatic enzymes begin to degrade the islets of Langerhans, this can lead to endocrine pancreatic failure in severe, chronic cases. The long-term effects of this spectrum of disease are similar to type 1 diabetes.

The biliary and hepatic systems are not spared by increased secretion viscosity. Secretions may obstruct the biliary ductules. It's possible to develop obstructive cirrhosis and post-hepatic hyperbilirubinemia. As a result of the elevated hepatic portal vein pressures, esophageal varices, splenomegaly, and hypersplenism may develop. Gallbladder disease is more common as part of this CF presentation, with gallstones affecting up to 15% of people with cystic fibrosis.

Sweat glands provide an interesting contrast to all other tissues with CFTR channels in that the chloride flow is reversed. Sweat glands normally transport chlorine from the extracellular to the intracellular region. As a result, salt and water are reabsorbed into the body from sweat gland tissues. However, if the chloride channel fails to reabsorb chloride, sodium is lost onto the skin surface, resulting in fluid loss. This is what causes cystic fibrosis' pathognomonic salty skin. Hyponatremic dehydration can occur in prolonged or warm conditions, or in more severe situations.

Other interactions of CFTR have been proposed in addition to its role as a chloride transport protein. CFTR is part of a multiprotein assembly at the apical plasma membrane, where three of its amino acids, threonine, arginine, and leucine, serve to anchor the protein to a region known as PDZ-type receptors. Multiple intracellular signaling proteins linked with the plasma membrane have been shown to have PDZ domains.

Other transporters, ion channels, receptors, kinases, phosphatases, signaling molecules, and cytoskeletal components are all linked to CFTR in this way. In vitro and in vivo, these interactions between CFTR and its binding proteins have been demonstrated to be crucial in controlling CFTR-mediated transepithelial ion transport. These intimate ties appear to allow CFTR to have a role in epithelial cells that goes beyond that of an ion channel.

While the function of CFTR is still unknown, animal studies have shown that it is linked to inflammatory reactions, maturational processing, non-chloride ion transport, and intracellular signaling. These other interacting proteins may operate as modifiers of the cystic fibrosis phenotype, explaining why similar genotypic patients with CF have such a wide range of clinical severity.

Cystic fibrosis symptoms

Meconium ileus, persistent neonatal jaundice, and early lung infection are common in newborns with CF. Failure to thrive and poor weight gain in infants and children with CF, anemia, undescended testicles in boys, recurrent sinopulmonary infections, and a distal intestine obstructive syndrome with or without pancreatic insufficiency are also possible symptoms. Although individuals may not display clinical signs and symptoms until later, the usual age of diagnosis is 6 to 8 months.

Exacerbations of one or more symptoms are common in adults with CF. Chronic bronchitis, abnormal pulmonary function tests, bronchiectasis, atypical asthma, allergic bronchopulmonary aspergillosis, and infection with Pseudomonas aeruginosa are all lung symptoms of CF.

Persistent rhinosinusitis, chronic post-nasal drip, nasal polyposis, and panopacification of the paranasal sinuses are all symptoms of CF. Pancreatic insufficiency, recurrent pancreatitis, and early-onset diabetes are all pancreatic symptoms. Focal biliary cirrhosis, cholelithiasis, periportal fibrosis, liver cirrhosis, portal hypertension, and variceal hemorrhage are all hepatobiliary symptoms. Kyphoscoliosis, osteopenia/osteoporosis, and arthropathy are musculoskeletal manifestations. Iron deficiency anemia or chronic illness anemia with splenomegaly are hematologic symptoms.

Nephrolithiasis, nephrocalcinosis, hyperoxaluria, and hypocitraturia are all nephrogenic symptoms. "Salty sweat," "digital clubbing," and cyanosis are some of the dermatological signs. Acrodermatitis enteropathica owing to zinc deficiency and scaly dermatitis due to fatty acid deficiency are two more dermatologic diseases caused by malabsorption. Finally, males with missing vas deferens may be sterile, whereas females with thicker cervical mucus may have lower fertility.

Cystic fibrosis diagnosis

Newborns in the United States are checked for cystic fibrosis as part of a routine newborn screening panel. Prenatal ultrasonography may reveal meconium peritonitis, intestinal dilatation, or the absence of a gallbladder in some cases of CF. Prenatal CF carrier screening is frequently used as a result of such findings.

To diagnose CF, the following criteria must be met:

Suspicion for Cystic Fibrosis

1. Sibling with cystic fibrosis
2. Positive newborn screen
3. Clinical symptoms consistent with CF in 1 or more organ systems

• Chronic sinopulmonary disease
• Gastrointestinal or nutritional abnormalities
• Salt loss syndromes
• Obstructive azoospermia

Evidence of CFTR Dysfunction

1. Elevated sweat chloride 2 than 60 mEq/L on two occasions
2. Two disease-causing CFTR mutations
3. Abnormal nasal potential difference

A sweat chloride test is the first step in the diagnostic process. A second sweat chloride test is recommended if the results are normal but the patient is still experiencing symptoms. If the test results are abnormal, DNA testing is recommended. Expanded DNA analysis is recommended if one or more CFTR mutations are discovered. The discovery of two CF-related mutations, on the other hand, confirms the diagnosis of cystic fibrosis.

When screening babies with meconium ileus for CF, the immunoreactive trypsinogen (IRT) test, a pancreatic enzyme, boosts sensitivity and specificity. IRT monitoring can be linked to the severity of CF, and when it decreases below detectable levels, it may suggest that pancreatic enzyme replacement is required.

Depending on the presenting symptoms, additional diagnostics may be required. Hyperinflation, bronchiectasis, abscesses, and atelectasis can all be detected using a chest radiograph. Panopacification of the paranasal sinuses can be seen on sinus radiography.

In neonates with meconium ileus, abdominal imaging may be beneficial. Microbiology is frequently positive for Haemophilus influenzae, Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia, Escherichia coli, or Klebsiella pneumoniae in bronchoalveolar lavage.

Pulmonary function testing is an important technique for assessing and monitoring the disease state and progression in people with cystic fibrosis. The most common pulmonary function test is spirometry. After a maximal inhalation, it measures the volume of air released during a vigorous and full expiration. The most important variables given are the total exhaled volume, also known as the forced vital capacity (FVC), the volume exhaled in the first second, also known as the forced expiratory volume in one second (FEV1), and their ratio (FEV1/FVC). These numbers can be used to figure out how well the lungs are ventilating.

To obtain an expected normal value, these data are compared to an expected normal for age, height, and gender. The measured number is then converted to a percent of normal, with 100 percent equaling normal. A low FVC and/or a normal or high FEV1 may suggest restrictive lung disease. Obstructive pulmonary disease with airway trapping is indicated by a low FEV1 and a high FVC. With low FEV1 values corresponding to the severity of the disease, air trapping patterns are expected in cystic fibrosis.

Cystic fibrosis treatment

When left untreated, cystic fibrosis is a systemic disease with far-reaching consequences for both quality and quantity of life. As a result, treatment should be centered on improving function in order to prevent acute sickness. Maintaining lung function by aggressively controlling respiratory infection and cleaning mucus from airways, maximizing nutritional status with pancreatic enzyme supplements and multivitamins, and finally managing any other health concerns that may occur should all be part of this plan. This is best accomplished with the help of a multidisciplinary team of cystic fibrosis specialists.

As previously noted, pulmonary illness is the leading cause of death among cystic fibrosis patients. As a result, having a low diagnostic and intervention threshold for pulmonary sickness exacerbations is critical. A pulmonary exacerbation is when lung function deteriorates as a result of an infection. Shortness of breath, tiredness, a strong cough, and a fever are common symptoms. During an episode, pulmonary function testing will deteriorate from baseline. Any serious illness should require admission to a hospital that specializes in cystic fibrosis care.

Two main goals should be pursued while dealing with pulmonary illness: treating the infection and improving oxygenation. Antibiotic therapy should have broad spectrum coverage against P. aeruginosa since it frequently causes infectious etiologies. However, a sputum culture and sensitivity profile for the pathogens present should be obtained. According to CF guidelines, each pathogenic bacteria cultivated from respiratory secretions should be treated with at least one antibiotic, and P. aeruginosa infections should be treated with two antibiotics.

Oral antibiotics may be effective for mild exacerbations, but intravenous medicine is required for more severe exacerbations. When an intravenous option is available, inhaled antibiotics are not indicated. Inhaled bronchodilators such as albuterol and ipratropium bromide should be used to help with ventilation and oxygenation. Breathed dornase alfa or inhaled hypertonic saline are used in conjunction with chest physiotherapy to enhance airway secretion clearance. Anti-inflammatory drugs, such as glucocorticoids, are also used to aid in the opening of blocked airways.

The work of breathing should be maximized, with nasal cannula oxygen being used as necessary. To overcome airway trapping, bilevel positive airway pressure (BiPAP) breathing may be required. Intubation with mechanical ventilation is a possibility, although it should be avoided if at all possible, and only utilized when respiratory failure is imminent.

Regular pancreatic enzymes, fat-soluble vitamins (A, D, E, K), mucolytics, bronchodilators, antibiotics, and anti-inflammatory medications are all part of CF patients' long-term supportive therapy.

A novel family of drugs called as CFTR modulator therapy aims to repair the malfunction produced by the mutant gene by increasing the production, intracellular processing, or function of the CFTR protein. Each drug is designed to treat a unique ailment caused by a distinct gene mutation. Ivacaftor is used to treat class 3 dysfunctions in which the major abnormality is a mutation at G551D.

It works by attaching to the faulty CFTR protein on the cell surface and opening the chloride channel, restoring the protein's proper function. This was the first drug to target the protein channel directly rather than addressing the symptoms of CF. Patients over the age of six should take 150 mg every 12 hours by mouth. Younger patients should be given weight-based dose, with those weighing less than 14 kg receiving 50 mg by mouth every 12 hours and those weighing more than 14 kg receiving 75 mg every 12 hours.

Lumacaftor is a chaperone molecule that is responsible for transporting the faulty CFTR protein from internal compartments to the cell surface. As a result, delta F508 homozygous mutant genotypes benefit from it. When used alone, this drug has little clinical benefit.

Despite considerable advances in medication therapy for CF, the disease process continues to progress, and without surgical intervention, the lungs will eventually collapse prematurely due to the disease burden. End-stage lung illness is best treated with a lung transplant. The transplant's timing is influenced by a number of factors.

Diet and Exercise

To compensate for malabsorption, people with CF should eat a high-fat diet and take supplemental fat-soluble vitamins. Patients with CF are also recommended to eat a high-calorie diet to maintain a healthy weight and treat the chronic inflammation and infections that are typical in their condition. Women should consume 2500 to 3000 calories per day, while males should consume 3000 to 3700 calories per day, according to the Cystic Fibrosis Foundation.

Those who live in hot areas or who engage in activities that produce perspiration should include more sodium in their diet. Oral feedings are preferred, however enteral (tube) feedings should be attempted if the intake does not match metabolic demand as measured by ongoing BMI declines. Gastric tube feedings or jejunal tube feedings are the most common options. Following exacerbations of sickness, multiple control studies of enteral nutrition in people with CF have shown benefit in the form of improved or neutral lung function, which is directly related to BMI.

Despite this, no randomized studies of enteral nutrition in CF patients have been conducted to far. When oral or enteral nutrition fails to meet metabolic needs, parenteral nutrition may be considered. Parenteral feeding has been related to a higher risk of sepsis, so it should be taken with caution. Exercise is recommended for CF patients to maintain and support lung function.

Differential Diagnosis

• Asthma
• Bronchiolitis
• Bronchiectasis
• Celiac disease
• Nutritional considerations in failure to thrive
• Pediatric Aspergillosis
• Primary ciliary dyskinesia
• Sinusitis

Prognosis

Patients with cystic fibrosis (CF) are expected to live into their fourth decade before necessitating lung transplantation. The median survival after lung transplantation is 8.5 years.

Conclusion 

Cystic fibrosis is a hereditary disease. A defective gene influences the transport of salt and water in and out of cells, which causes it. This, combined with recurring infections, can cause a buildup of thick, sticky mucus in the body's tubes and passageways, especially in the lungs and digestive system.