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Hepatobiliary complications
> Neonatal cholestasis
CFTR is expressed in cholangiocytes and participates in bile secretion. Neonatal cholestasis is characterized by conjugated hyperbilirubinemia (conjugated or direct bilirubin >1.0 mg/dL or >20% of the total bilirubin level), with a reported prevalence of 2% to 5.7% in infants with CF. 46.47L _
Cholestasis may be the first hepatic manifestation of CF and is due to obstruction of the extrahepatic bile ducts. It is associated with MI and the use of total parenteral nutrition. 48
Infants with cholestasis may present with jaundice, acholic stools, hepatomegaly, splenomegaly, and abnormal laboratory findings, including hypoalbuminemia, conjugated hyperbilirubinemia, and elevation of serum transaminases, alkaline phosphatase, and glutamyl transferase (GGT).
These patients should also be evaluated for other causes of neonatal cholestasis, including biliary atresia, choledochal cyst, progressive familial intrahepatic cholestasis, endocrinologic and metabolic disorders, Alagille syndrome, and infections.
The long-term sequelae of cholestasis in CF infants are not entirely clear, although most cases appear to resolve within the first year of life, with very rare cases of liver failure. 46,49 Additional studies are needed to determine whether neonatal cholestasis in CF leads to the development of multilobular cirrhosis in the future.
Management is primarily supportive care, with close monitoring of growth and fat-soluble vitamin levels. It has been postulated that ursodiol produces a benefit by improving bile flow and accelerating normalization of laboratory values; however, its use is not recommended to prevent cirrhosis in CF. fifty
> Transaminitis
CFTR is not expressed in hepatocytes; However, liver injury can occur in CF patients due to proximity to cholangiocytes (which may be inflamed) and/or increased intestinal permeability. 51 Transient elevation of serum aspartate aminotransferase (AST) and alanine transaminase (ALT) is seen in up to 50% of infants and young children with CF and often normalizes by 2 to 3 years of age.
It is critical to use age-appropriate normative values for AST, ALT, and GGT because they vary among infants, older children, and adults. No correlation has been observed between intermittent transaminitis and the progression of focal biliary cirrhosis or portal hypertension. 23 However, persistent elevation of AST, ALT, or GGT warrants further investigation. 52
In the neonatal period, these elevations may also be due to concurrent medications, infections, parenteral nutrition, genetic, metabolic, and immune-mediated diseases. The involvement of pediatric gastroenterology and/or hepatology specialists may help assess the need for more extensive and/or invasive evaluation based on liver function and/or the degree of potential liver injury.
> Gallbladder involvement
Infants with CF may have microgallbladder and cholelithiasis.
Microgallbladder is usually an asymptomatic finding with a reported prevalence of 5% to 45% in adult and pediatric patients with CF. 47 It is believed to be due to atresia or stenosis of the cystic duct leading to macroscopic atrophy of the gallbladder. As this is a benign finding, no intervention is indicated, although care should be taken to exclude biliary atresia, which is also associated with microgallbladder.
Cholelithiasis is reported in 3% to 35% of adult and pediatric patients with CF. 47 Stones in CF are composed of calcium bilirubinate, which cannot be dissolved by ursodiol. 53 Fat malabsorption in CF leads to increased colonic absorption of unconjugated bilirubin, which combines with calcium and results in the formation of calcium bilirubinate stones. This is further exacerbated by bile stasis due to thick bile. Some patients are at increased risk of developing stones, especially those with the Gilbert syndrome-associated UGT 1 A 1 mutation , which leads to increased levels of unconjugated bilirubin. 54
> Pancreatic complications: Exocrine pancreatic insufficiency
The pancreas is one of the earliest and most frequently affected organs in CF. CF patients are often divided into those with intact or impaired exocrine pancreatic function. Pancreatic injury results from decreased ductal secretion of chloride and bicarbonate and premature activation of pancreatic enzymes, leading to obstructive destruction of acinar tissue with fat replacement, ductal dilation, and fibrosis.
In the pancreas of pig models with CF, a greater expression of profibrotic and proinflammatory genes and the complement cascade is found. 55 Exocrine pancreatic insufficiency (EPI) is common in CF, being present in 60% of infants diagnosed through CN, but by one year of age, 90% of infants have evidence of EPI. 56 Individuals with 2 severe CFTR mutations of classes I to III tend to have EPI at birth, whereas those with mild CFTR mutations of classes IV to VI often have preserved pancreatic function at birth.
EPI evolves during the first year of life, with some children regaining function, therefore the status of this condition should be evaluated at regular intervals. 6 Patients with intact exocrine pancreatic function have a significantly longer mean life expectancy compared to those with EPI, although their pancreatic function is not completely normal and may deteriorate over time.
Endocrine function is preserved early in life, but in many individuals with EPI, islet function is affected and islets may be gradually lost. Approximately 20% of adolescents and 50% of adults develop CF-related diabetes. 57
EPI presents with symptoms of fat malabsorption, including steatorrhea, abdominal pain, bloating, flatulence, and poor weight gain. Fat malabsorption worsens in the setting of low duodenal pH, abnormal pancreatic bicarbonate secretion, and bile precipitation, further exacerbating the absorption of fats and fat-soluble vitamins. 58
Assessing the function of the exocrine pancreas is challenging due to its anatomical inaccessibility and high reserve capacity. That is, fat malabsorption may not occur until the functional capacity of the exocrine pancreas is less than 10%.
There are both direct and indirect methods to diagnose EPI. 59,60 The most sensitive method is through the direct pancreatic stimulation test. However, it is not commonly used in infants due to its invasiveness, complexity, and cost. It is more common to use indirect tests of pancreatic function. Among them, the measurement of fecal elastase is the most common.
It is a simple, non-invasive and reproducible test, and the use of exogenous enzymes (which are of porcine origin) do not interfere with the performance of the test. Babies, even if they are premature, are expected to show levels within the normal range for an adult by 2 weeks of age.
Fecal elastase values greater than 200 µg/g are considered normal, between 100 and 200 µg/g are suspicious for IPE, and below 100 µg/g often indicate IPE. Caution should be used when interpreting this test in the case of a large volume of stool, as the results may be diluted. 61
Fecal elastase values should be interpreted within the clinical context because EPI may be present with values greater than 200 µg/g and enzyme supplementation may not be necessary in those with fecal elastase levels within the range of 100 to 200 µg/g.
Management of EPI includes TREP, close monitoring, and repletion of fat-soluble vitamins. TREP should be initiated in infants known to have 2 CFTR mutations associated with EPI, laboratory evidence of EPI, or symptoms of malabsorption. 6 TREP comes in multiple formulations, including enteric-coated capsules, non-enteric-coated tablets, and cartridge.
The most common formulation of TREP is the delayed-release enteric-coated capsule. Inside each capsule are beads containing digestive enzymes, which are covered by an enteric coating that dissolves in the small intestine. To administer enzymes to infants, open the capsule and mix the contents in a small amount of acidic foods at room temperature (such as applesauce) and offer them on a spoon. Contents should not be mixed with formula, breast milk or medications.
Enzymes should not be crushed or chewed. Before starting feeding, the caregiver should ensure that all beads have been swallowed by closely examining the baby’s mouth. The enzymes can be irritating to babies in the first month of use and cause mouth sores, skin irritation, and diaper rash, and/or cause areolar injury in breastfeeding mothers.
For those receiving continuous feedings, RELiZORB is an in-line digestive cartridge that contains a fixed microbial lipase, which hydrolyzes fats in enteral formulas as the formula passes through the cartridge before it is ingested by the child. This immobilized lipase formulation is currently approved by the US Food and Drug Administration (FDA) for children 5 years and older. Although it is used in babies, data on this practice are limited. An alternative option for continuous feeding is Viokace, a non-enteric-coated pancrelipase tablet that is ground to a fine powder and added to the diet to predigest nutrients before infusion.
It is preferable to oral administration of enteric-coated pancrelipase before continuous infusion and in cases where the fixed microbial lipase cartridge cannot be used. 62 For complete dissolution of enzymes, by predigesting the formula with enzymes, prolonged mixing and/or the addition of bicarbonate may be necessary. Nutritionists, pharmacists and/or gastroenterologists can provide advice as needed.
Currently, data on the optimal dose of TREP in infants are lacking, and recommendations are based on dosing for older children. The dose of TREP should be adequate to ensure nutrient absorption and growth, but not too high to prevent the development of fibrosing colonopathy, an adverse effect of TREP, which historically occurs at doses greater than 6,000 lipase units/kg per dose. meal. 63
Older guidelines from the Cystic Fibrosis Foundation suggested a starting dose of 2,000 to 5,000 lipase units per meal; However, these guidelines were extrapolated from older patients who received a maximum daily dose and may be insufficient for rapidly growing infants. 6.64
Recent prescribing practices have reported average TREP doses of 1,882 lipase units/kg per meal (range, 492–3727 lipase units/kg per meal) between birth and 6 months of age and an average of 1,842 lipase units/kg per meal. /kg per meal (range, 313–3612 lipase units/kg per meal) between 6 months and 12 months of age. 65
Overall, it is recommended to start TREP with 3000 to 6000 lipase units per feeding, with dose adjustments based on the volume/type of feeding and the baby’s symptoms and growth, in close consultation with a dietitian and gastroenterologist specialized in CF.
If TREP is maximized and malabsorption is still present, gastric acid suppression with PPIs may be considered, which work by reducing the acidity of the duodenum, thereby improving enzyme release and fat absorption. Enzymes should be stored in a cool, dry place and expiration dates should be checked regularly. Only FDA-approved enzymes should be used, and not over-the-counter formulations. 66
Nutritional complications
> Lack of growth
Malnutrition is a cause of significant morbidity in CF and can be attributed to increased energy loss, increased energy needs, and inadequate nutritional intake.
Fat malabsorption is the primary cause of energy loss, which is further exacerbated by dysbiosis, intestinal inflammation, and low pancreatic bicarbonate secretion.
Because of persistent lung inflammation and frequent infections, children with CF often have higher energy needs. Additionally, patients with EPI have higher energy expenditures at rest. 67,68 Optimizing nutrition in childhood is paramount, given the countless studies that establish the link between better nutrition and better long-term pulmonary outcomes.
The researchers found that infants with CF and pancreatic insufficiency who met weight-for-age z-scores by age 2 were more likely to maintain better body mass index and height z-scores until age 12, while than infants who were not, were more likely to exhibit suboptimal growth in childhood. eleven
Additionally, those who regained their birth weight-for-age z-score within 2 years of CF diagnosis had better lung function at 6 years of age compared with children who did not. 69 Lung function was found to be significantly decreased in children whose weight-for-age measurement at 3 years of age was below the 5th percentile compared to children whose weight-for-age measurement was above the 75th percentile. 12
Treatment of growth failure in CF requires a multidisciplinary team, which may include specialists in pulmonology, gastroenterology/hepatology, endocrinology, nutrition, nursing, social work, psychology, feeding therapy, and speech pathology.
The recommended intake is 110% to 200% of the energy needs of a patient of that healthy age, with the goal of reaching the 50th percentile of weight for height at 2 years of age. 66 There may be exceptions to the 50th percentile target, but in these cases, targets should be carefully considered by the entire team and should ensure that there is adequate growth and nutritional reserve for times of increased energy demand and decreased intake ( e.g., acute infections).
Breast milk is the preferred nutrition source, given its association with higher weight and length z-scores compared to formula-fed infants, and its positive impacts on the fecal microbiome and long-term lung health. 40,70 For formula-fed infants, there is limited evidence comparing standard formulas with hydrolyzed protein formulas containing medium-chain triglycerides.
Current recommendations are to use standard infant formula. 71 Calorie density can be increased by fortifying breast milk, concentrating formula, or supplementing with fat or carbohydrates. For babies who cannot grow adequately on oral intake, enteral tube feeding may be necessary. Early and frequent discussions about enteral tube feeding should be held to normalize this intervention and not see it as a failure of caregivers. Children with evidence of EPI should be treated with TREP as discussed in the previous section.
It is important to ensure that families have adequate access to food for nursing mothers and formula for babies. Screening for food insecurity and referrals should be made to community resources such as the Special Supplemental Nutrition Program for Women, Infants and Children and the Supplemental Nutrition Assistance Program.
As patients live longer and do better with CF modulating therapy, it is important to note the increasing occurrence of overweight and obesity in children with CF, which has been reported at 15% and 8%, respectively. , in children from 2 to 18 years old. 72 Although previous nutritional guidelines had focused on a diet rich in calories, protein and fat, there is now a shift towards a healthy, balanced diet.
The link between eating habits formed in early childhood and the risk of obesity later in life is well established. 73 Therefore, it is recommended that clinicians work closely with families and the CF team to establish early healthy eating patterns and tailor the individual nutrition plan for the child.
> Micronutrient deficiencies
Fat-soluble vitamin deficiencies. CF patients are at high risk of developing fat-soluble vitamin (A, D, E, K) insufficiency due to EPI and fat malabsorption. Patients with hypoalbuminemia or elevated alkaline phosphatase at diagnosis may also be at increased risk. 6
Given the high prevalence of fat-soluble vitamin deficiencies and their important clinical impact, serum levels of vitamins A, D, E, and K should be measured periodically. Of note, the international normalized ratio (INR) rather than serum vitamin K should be measured to assess vitamin K levels. In the first 12 months of life, daily dosage guidelines are as follows: 1,500 IU of vitamin A, 40 to 50 IU of vitamin E, 400 IU of vitamin D and 0.3 to 0.5 mg of vitamin K. 71
Zinc deficiency. Zinc deficiency occurs due to fat malabsorption and improves when TREP is provided. Low zinc levels are associated with growth problems, increased risk of infection, and eye complications. It is generally not recommended to obtain plasma zinc concentration in an infant because zinc deficiency may occur along with plasma zinc in the normal range. Instead, it is recommended to proceed with a trial of zinc supplementation at a dose of 1 mg elemental zinc/kg per day for 6 months in patients who are failing to thrive despite adequate caloric intake and a dose of Optimized TREP. 71
Sodium deficiency. Babies with CF are at increased risk of developing sodium deficiency due to excessive sweat losses, intestinal malabsorption, and inflammation. Additionally, human milk and infant formulas often do not provide adequate amounts of sodium. Additional sodium may be needed in high temperature environments and in infants experiencing vomiting and diarrhea.
Sodium deficiency is associated with poor growth and can cause anorexia, vomiting, irritability, and weakness due to hyponatremic hypochloremic dehydration. To avoid this, it is recommended that babies in the first 6 months of life receive a dose of one-eighth of a teaspoon of table salt per day (corresponding to 12.5 mEq of sodium), and in the following six months, a quarter of teaspoon of salt per day (25.2 mEq of sodium), without exceeding a daily dose of 4 mEq/kg. 6.71
Due to the inaccuracy of this method, sodium chloride solutions that can be dispensed more accurately are available in pharmacies. Serum sodium levels should not be obtained since this measurement does not accurately reflect total body sodium deficiency. A more precise assessment of sodium level is made through the urinary sodium/creatinine ratio.
The changing landscape of CF
> CFTR modulating therapy
CF management is evolving with the development of CFTR modulators and their increasing use in young children. Current types of FDA-approved CFTR modulators include enhancers and correctors, and additional stabilizers and amplifiers are being developed. If given early, these medications have the potential to slow or even reverse the progression of CF. This was demonstrated by the ARRIVAL study, which involved children aged 12 to 24 months who were given ivacaftor and found to have increased fecal elastase concentrations at week 24 of treatment, suggesting an exocrine pancreatic function. preserved. 74
Currently, the approved modulators in infancy are ivacaftor (for infants ≥ 4 months with certain mutations) and lumacaftor/ivacaftor (for infants 1 year and older who are homozygous for the F508del mutation). The newest CFTR modulator, elexacaftor/tezacaftor/ivacaftor, is approved for children ≥ 2 years of age.
Research is underway on premature termination codon readthrough medications and gene therapy for class I mutations in cases where CFTR transcription is altered and not amenable to current therapies. For those with CFTR mutations where there is no data on the ability of their mutations to respond to CFTR modulators, in vitro testing can be performed using nasal or intestinal samples before the patient undergoes a test. Often referred to as “typing therapies,” these tests have been shown to correlate with clinical endpoints and enable a personalized medicine approach in CF. 75
Current data on the use of modulators during pregnancy and their effects on the fetus are limited. For this reason, the US FDA has designated a category B label for CFTR modulators during pregnancy. The literature has been limited to animal models and patient case reports and has so far been reassuring, with the majority reporting successful pregnancies and healthy babies without significant modulator-related complications. 76.77
Interestingly, in some reports, in utero exposure was associated with resolution or prevention of the disease in the fetus. Szentpetery et al. 78 reported a case of a pregnant woman carrying F508del who started treatment with elexacaftor/tezacaftor/ivacaftor at 32 weeks of gestation to treat the MI of her F508del homozygous fetus. The infant was born at 36 weeks of gestation without complications and without evidence of MI. 78 Fortner et al. 79 reported a case of a homozygous F508del infant born to a mother receiving CFTR modulating therapy. The serum TIS concentration was normal, suggesting normal pancreatic function. 79
Furthermore, the presence of modulators in breast milk has been demonstrated in both animal models and case reports. 80 In humans, Trimble et al. 80 reported the presence of lumacaftor/ivacaftor in maternal and infant plasma, umbilical cord blood and breast milk (low level), in a woman who received modulatory therapy during pregnancy and lactation, as well as a healthy baby without complications related to the modulator. Nash et al. 81 reported the results of an international survey of CF center physicians on the use of modulators during pregnancy and breastfeeding and found no modulator-related complications in the 27 exposed infants.
A few cases of cataract development as a modulator-related side effect have been reported in pediatric patients and in animal studies. 82 The development of cataracts has been reported in rats 7 to 35 days old exposed to ivacaftor at 0.25 times the maximum recommended human dose, although rats given normal typical human doses did not develop cataracts or other congenital anomalies. 82
In light of these reports, it is recommended that pediatric patients receiving CFTR modulators and infants exposed to CFTR modulators in utero or via breast milk undergo ophthalmologic examinations to evaluate for the presence of cataracts. More data are needed to understand the safety or risk to babies born to people taking CFTR modulators.
To that end, the MAYFLOWERS study is an ongoing observational study that prospectively evaluates the impact of modulators on the health of women with CF and their babies. Until more information is obtained, pregnant patients with CF need to be counseled about the unknown effects of these medications on the fetus/infant and should carefully weigh this against the potential risk to their health if the modulators are discontinued during pregnancy or breastfeeding. Decision making should be shared between the family and the CF care team.
> Global burden of CF disease
Although these advances are transforming care for some CF patients, they are also highlighting growing health disparities in this disease. Although it has historically been considered a disease of white patients, it is important to recognize that CF can affect any ethnic or racial group.
Those who are not of non-Hispanic white origin may have different distributions of CFTR mutations, miss genetic testing, have delays in care, and may not be eligible for modulators, creating important disparities in health care. 83 Furthermore, CF is a global disease and is not limited to the Western world.
Although NC is performed universally in the United States, it is not widely implemented in many parts of the Middle East, Africa, Latin America, and Eastern Europe. 84 Unfortunately, in many parts of the world where infant mortality due to malnutrition and infectious diseases is common, the diagnosis of CF is not even considered. More information is needed regarding CFTR mutations in these areas and to develop therapies for rare mutations, which may not be amenable to current modular CFTR therapies. 2.9
Conclusion
Since early intervention has a significant impact on long-term outcomes in patients with CF, it is crucial that physicians are able to recognize, accurately diagnose, and rapidly refer these patients to CF care centers.
It is hoped that this review will provide a framework for recognizing and treating the most common gastrointestinal manifestations in newborns with CF.
CF research and clinical care is a rapidly dynamic and evolving field. Although this review reflects current knowledge to date, recommendations are likely to change in the coming years with the development of new diagnostic and treatment guidelines.
Comment
Meconium ileus, exogenous pancreatic insufficiency, and growth retardation are usually the first gastrointestinal manifestations in neonates, although this disease can present a wide variety of manifestations during this period.
Timely diagnosis and early intervention in cystic fibrosis are imperative to optimize long-term pulmonary and gastrointestinal outcomes. Professionals must be familiar with the characteristics of the disease to reach an early diagnosis, control symptoms, and work in a multidisciplinary manner to implement the best possible treatment according to the circumstances, also facilitating access to health resources.
Although neonatal screening is essential in the early diagnosis of CF, it has the limitation of not being universal and may miss less common CFTR mutations, creating health disparities. Knowing these mutations can help predict the severity of the patient’s disease and their possible response to modulatory therapy.
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