Literature Watch
Guarana
2023 Jan 28. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012–.
ABSTRACT
Guarana is an extract of roasted and pulverized seeds of the plant Paullinia cupana which is indigenous to the Amazon Basin and whose major active components are caffeine and other xanthine alkaloids such as theophylline and theobromine. Guarana has been used as a stimulant and tonic to treat fatigue, decrease hunger and thirst and for headaches and dysmenorrhea. In conventional doses, guarana has few side effects and has not been linked to episodes of liver injury or jaundice.
Clopidogrel Therapy and <em>CYP2C19</em> Genotype
2012 Mar 8 [updated 2022 Dec 1]. In: Pratt VM, Scott SA, Pirmohamed M, Esquivel B, Kattman BL, Malheiro AJ, editors. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012–.
ABSTRACT
Clopidogrel (brand name Plavix) is an antiplatelet medicine that reduces the risk of myocardial infarction (MI) and stroke in individuals with acute coronary syndrome (ACS), and in individuals with atherosclerotic vascular disease (indicated by a recent MI or stroke, or established peripheral arterial disease) (1). Clopidogrel is also indicated in combination with aspirin for individuals undergoing percutaneous coronary interventions (PCI), including stent placement.
The effectiveness of clopidogrel depends on its conversion to an active metabolite, which is accomplished by the cytochrome P450 2C19 (CYP2C19) enzyme. Individuals who have 2 loss-of-function copies of the CYP2C19 gene are classified as CYP2C19 poor metabolizers (PM). Individuals with a CYP2C19 PM phenotype have significantly reduced enzyme activity and cannot activate clopidogrel via CYP2C19, which means the drug will have a reduced antiplatelet effect. Approximately 2% of Caucasians, 4% of African Americans, 14% of Chinese, and 57% of Oceanians are CYP2C19 PMs (2). The effectiveness of clopidogrel is also reduced in individuals who are CYP2C19 intermediate metabolizers (IM). These individuals have one loss-of-function copy of CYP2C19, with either one normal function copy or one increased function copy. The frequency of the IM phenotype is more than 45% in individuals of East Asian descent, more than 40% in individuals of Central or South Asian descent, 36% in the Oceanian population, approximately 30% in individuals of African descent, 20–26% in individuals of American, European, or Near Eastern descent, and just under 20% in individuals of Latino descent (2).
The 2022 FDA-approved drug label for clopidogrel includes a boxed warning on the diminished antiplatelet effect of clopidogrel in CYP2C19 PMs (Table 1). The warning states that tests are available to identify individuals who are CYP2C19 PMs, and to consider the use of another platelet P2Y12 (purinergic receptor P2Y, G-protein coupled 12) inhibitor in individuals identified as CYP2C19 PMs.
The 2022 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for clopidogrel recommends that for individuals with ACS or non-ACS indications who are undergoing PCI, being treated for peripheral arterial disease (PAD), or stable coronary artery disease following MI, an alternative antiplatelet therapy (for example, prasugrel or ticagrelor) should be considered for CYP2C19 PMs if there is no contraindication (Table 2) (3). Similarly, CPIC strongly recommends that CYP2C19 IMs should avoid clopidogrel for ACS or PCI but makes no recommendations for other cardiovascular indications (Table 2). For neurovascular indications, CPIC recommends avoidance of clopidogrel for CYP2C19 PMs and consideration of alternative medications for both IMs and PMs if not contraindicated (Table 3) (3).
The Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP) have also made antiplatelet therapy recommendations based on CYP2C19 genotype. For individuals with ACS who undergo PCI, they recommend an alternative antiplatelet agent in PMs, and for IMs they recommend choosing an alternative antiplatelet agent or doubling the dose of clopidogrel to 150 mg daily dose, 600 mg loading dose (Table 4) (4).
Oxycodone Therapy and <em>CYP2D6</em> Genotype
2022 Oct 4. In: Pratt VM, Scott SA, Pirmohamed M, Esquivel B, Kane MS, Kattman BL, Malheiro AJ, editors. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012–.
ABSTRACT
Oxycodone (brand names OxyContin, Roxicodone, Xtampza ER, and Oxaydo), is an opioid analgesic used for moderate to severe pain caused by various conditions for which alternative analgesic treatments are inadequate.(1) Oxycodone exerts its analgesic affects by binding to the mu-opioid receptors (MOR) in the central and peripheral nervous system. While it is an effective pain reliever, this agent also has a high potential for addiction, abuse, and misuse.
Oxycodone is metabolized by members of the cytochrome P450 (CYP) enzyme superfamily. The CYP3A4, CYP3A5, and CYP2D6 enzymes convert oxycodone to either less-active (CYP3A4 and CYP3A5) or more-active (CYP2D6) metabolites. Most of the analgesic effect is mediated by oxycodone itself, rather than its metabolites. Variation at the CYP3A4 and CYP3A5 loci leading to altered enzyme activity is rare. A handful of altered-function alleles are known, but there is no documented evidence to support altered oxycodone response in the presence of these variant alleles. The FDA approved drug label for oxycodone cautions that co-medication with CYP3A inhibitors or inducers may lead to altered pharmacokinetics and analgesia, but does not discuss genotype-based recommendations for prescribing (1).
Genetic variation at the CYP2D6 locus has conflicting evidence regarding altered response of individuals to oxycodone therapy. Thus, the Clinical Pharmacogenetics Implementation Consortium (CPIC) has determined that there is insufficient evidence to recommend alterations to standard clinical use based on CYP2D6 genotype (2). Similarly, the Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP) recognizes the drug-gene interaction between CYP2D6 and oxycodone but states that the interaction does not affect analgesia achieved by the medication (3, 4). The PharmGKB online resource reports that drug labels in Switzerland (regulated by Swissmedic) state that CYP2D6 variation can alter oxycodone response (5, 6).
Interactions among drugs from polypharmacy may be further enhanced by genetic variation, but there are no professional recommendations to alter prescribing based on drug-drug-gene interactions. Regardless of genotype, oxycodone is contraindicated in individuals with significant respiratory depression, acute or severe bronchial asthma, known or suspect gastrointestinal obstruction, or known hypersensitivity to the medication (1).
Hepatitis C (HCV) Agents
2022 Feb 7. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012–.
ABSTRACT
The hepatitis C virus (HCV) is a small RNA virus belonging to the family flaviviridae and genus hepacivirus. The virion is approximately 50 nm in diameter and has an outer lipid associated envelop (E1 and E2) and inner nucleocapsid (Core). Within the nucleocapsid is a single molecule of single-stranded RNA of positive polarity approximately 9.5 kilobases in length. The RNA is transcribed into a large polyprotein that is subsequently cleaved into multiple polypeptides, labeled from the 5’ to 3’ end: core, envelope 1 and 2, and nonstructural proteins NS2, NS3, NS4 and NS5A and NS5B. The NS3 region encodes a viral helicase and protease. The NS5A region encodes a polypeptide that is essential for production and maintenance of the replicative complex. The NS5B region encodes a viral RNA dependent, RNA polymerase that is essential for replication. The NS3, NS5A and NS5B regions have been targeted with direct acting antiviral agents.
The initial agents used to treat chronic hepatitis C were interferon alfa, peginterferon and ribavirin. The antiviral activity of interferon and peginterferon is based upon their ability to stimulate interferon stimulated genes (ISGs) that have endogenous antiviral activities. Ribavirin is a nucleoside analogue that potentiates the effects of interferon against hepatitis C by as yet undefined mechanisms. Until 2010, the standard therapy of chronic hepatitis C was the combination of peginterferon and ribavirin given for 24 or 48 weeks. This combination led to sustained clearance of HCV and remission in disease in 40% to 50% of patients. Response rates were higher with certain HCV genotypes, so that response rates in patients with genotypes 2 and 3 were as high as 70% to 80%. Importantly, these remissions in disease have been shown to represent cure of the chronic viral infection, in that long term follow up demonstrated lack of HCV replication and resolution of disease activity in over 98% of patients. The shortcomings of peginterferon-ribavirin therapy were significant, most importantly the poor tolerance and side effects of this regimen. Thus, a high proportion of patients was intolerant or had contraindications to treatment. In 2010, three HCV-specific protease inhibitors were approved for use and introduced into practice: boceprevir, telaprevir and simeprevir. All three of these were specific to genotype 1 HCV and had little or no activity against genotypes 2 or 3 or the lesser common genotypes 4, 5 and 6. Triple therapy with peginterferon, ribavirin and a HCV-specific protease inhibitor (boceprevir, telaprevir or simeprevir) increased the response rate in patients with chronic hepatitis C, genotype 1 from 40%-45% to 65%-75%. A persistent difficulty, however, was the continued need to combine these agents with peginterferon and the considerable side effects which were worsened by these protease inhibitors.
An important advance in therapy of hepatitis C came in 2013 with the approval of an HCV specific RNA polymerase inhibitor, sofosbuvir. Sofosbuvir not only increased the response rate when combined with peginterferon and ribavirin, but also allowed for interferon-free treatment when combined with ribavirin, HCV protease inhibitors or a new class of agents that antagonized HCV NS5A activity. In 2014, all-oral HCV specific antiviral regimens were approved that yielded response rates in excess of 95% in patients with genotype 1. Furthermore, successful therapy required only 8 to 12 weeks of treatment in most patients and were extremely well tolerated. These all-oral regimens revolutionized therapy of hepatitis C, allowing treatment of virtually all patients regardless of severity of illness or co-morbid conditions with few side effects and durations of therapy of 8, 12 or 24 weeks. Other all oral regimens, including treatments for the less common genotypes of hepatitis C began to become available in 2015, 2016 and 2017. The several classes of agents that are combined in either a two-, three- or four-drug regimens include HCV RNA polymerase inhibitors (nucleoside and nonnucleoside), HCV NS5A antagonists and the HCV protease inhibitors. Several of these drug combinations have been formulated as single tablet or co-packaged regimens. These combination products made therapy easier to apply, but also resulted in the withdrawal of less successful agents, including boceprevir, telaprevir, daclatasvir, simeprevir and the four-drug combination of ombitasvir, dasabuvir, paritaprevir and ritonavir (Viekira Pak). Most currently used regimens are given for 8 to 12 weeks and yield response rates of 98% or more (Epclusa, Mavyret and Zepatier). Widespread application of these therapies to patients with chronic hepatitis C will likely decrease the morbidity and mortality of this disease and make significant inroads into decreasing the burden of chronic liver disease, cirrhosis, and hepatocellular carcinoma worldwide.
Diuretics
2021 Oct 13. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012–.
ABSTRACT
Diuretics constitute a large family of medications that increase urine flow and induce urinary sodium loss and are widely used for therapy of hypertension, congestive heart failure, and edematous states. Diuretics in current use (and the year of their approval for use in the United States) include chlorothiazide (1958), hydrochlorothiazide (1959), bendroflumethiazide (1959), spironolactone (1960), chlorthalidone (1960), methyclothiazide (1961), polythiazide (1961), triamterene (1964), furosemide (1966), ethacrynic acid (1967), metolazone (1973), bumetanide (1983), indapamide (1983), amiloride (1986), acetazolamide (1986), torsemide (1993), and eplerenone (2002). Diuretics are typically classified as thiazide diuretics (bendroflumethiazide, chlorothiazide, chlorthalidone, hydrochlorothiazide, indapamide, metolazone and polythiazide), loop diuretics (bumetanide, ethacrynic acid, furosemide, and torsemide), and potassium-sparing agents (amiloride, eplerenone, spironolactone, and triamterene). The carbonic anhydrase blockers acetazolamide (1986) and methazolamide (1959) are also diuretics, but are more commonly used for the therapy of glaucoma.
Diuretics are some of the most frequently used medications in medicine and are usually well tolerated. Common side effects are those that are caused by the diuresis and mineral loss such as weakness, dizziness, electrolyte imbalance, low sodium and potassium. Diuretics have not been associated with an appreciable increased rate of serum aminotransferase elevations and have rarely been associated with clinically apparent liver injury. Isolated case reports of idiosyncratic hepatotoxicity due to diuretics have been published, but there have been virtually no case series on individual diuretics or even whole class of drugs. The case reports that have been published provide only a very general pattern of injury that has not provided a clear clinical signature or suggestion that hepatotoxicity is a class effect among the thiazides and the loop diuretics. Switching from one diuretic to another has not been reported in any systematic fashion. Most information on hepatotoxicity is available on the commonly used diuretics which include (and the number of prescriptions filled in 2007 for each): hydrochlorothiazide (45 million), furosemide (37 million), triamterene (21 million), spironolactone (8 million), and metolazone, bumetanide, indapamide and torsemide (1 to 2 million each). Diuretics implicated in rare cases of drug induced liver injury include hydrochlorothiazide, acetazolamide, amiloride, spironolactone and triamterene.
The thiazide and loop diuretics are discussed as a class; the other diuretics as individual agents. Selected references are given together at the end of this introductory section.
Covid-19 Vaccines
2021 May 3. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012–.
ABSTRACT
The Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV-2) is the cause of the pandemic of coronavirus disease (COVID-19) that was first detected in December 2019 in Wuhan, China and subsequently spread globally. By March 2020, COVID-19 was declared a global pandemic and within a year it accounted for more than 100 million cases and 2 million deaths. Also, within a year of its detection, vaccines against SARS-CoV-2 were developed using several methodologies including mRNA-, adenoviral vector- and recombinant DNA-technology. Several of these vaccines have been evaluated in large, placebo-controlled trials and found to be both safe and effective. Adverse events have been mild-to-moderate local reactions and transient systemic symptoms such as fatigue, nausea and headache. No hepatic specific adverse events have been described, although rare reports of thrombotic thrombocytopenia have occurred with the adenoviral based vaccines that sometimes involve portal or hepatic vein thromboses and some degree of liver dysfunction.
Vanzacaftor, Tezacaftor and Deutivacaftor
2025 Jan 15. Drugs and Lactation Database (LactMed®) [Internet]. Bethesda (MD): National Institute of Child Health and Human Development; 2006–.
ABSTRACT
No information is available on milk or infant serum levels of vanzacaftor or deutivacaftor. Information from mother-infant pairs with elexacaftor, ivacaftor and tezacaftor indicates that tezacaftor has low levels in milk and infant serum. Deutivacaftor is a deuterated form of ivacaftor that has slower clearance, a longer half-life and greater maternal exposure. Transient mild elevations in bilirubin and liver enzymes during maternal therapy have been reported in breastfed infants whose mothers were taking another combination product containing tezacaftor and ivacaftor. Enzyme levels tended to normalize during continued breastfeeding. Until more data are available, monitoring of infant bilirubin and liver enzymes might be advisable during breastfeeding with maternal vanzacaftor, tezacaftor and deutivacaftor therapy.[1] Congenital cataracts in breastfed infants has been reported in the infants of mothers who took drugs of this class during pregnancy. Examination of breastfed infants for cataracts has been recommended.[2] Anecdotal evidence indicates that these types of drugs in breastmilk may moderate cystic fibrosis in breastfed infants.
Codeine
2021 Aug 16. Drugs and Lactation Database (LactMed) [Internet]. Bethesda (MD): National Library of Medicine (US); 2006–.
ABSTRACT
Maternal use of codeine during breastfeeding can cause infant drowsiness, central nervous system depression and possibly even death, with pharmacogenetics possibly playing a role.[1,2] Newborn infants seem to be particularly sensitive to the effects of even small dosages of narcotic analgesics. Once the mother's milk comes in, it is best to provide pain control with a nonnarcotic analgesic and limit maternal intake of oral codeine to 2 to 4 days at a low dosage with close infant monitoring, especially in the outpatient setting.[2-4] If the baby shows signs of increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties, or limpness, a physician should be contacted immediately.[5] Excessive sedation in the mother often correlates with excess sedation in the breastfed infant. Following these precautions can lower the risk of neonatal sedation.[6] Numerous professional organizations and regulatory agencies recommend that other agents are preferred over codeine or to avoid codeine completely during breastfeeding;[7-11] however, other opioid alternatives have been studied less and may not be safer.[12,13]
Dihydrocodeine
2021 Jun 21. Drugs and Lactation Database (LactMed) [Internet]. Bethesda (MD): National Library of Medicine (US); 2006–.
ABSTRACT
Maternal use of oral narcotics during breastfeeding can cause infant drowsiness, central nervous system (CNS) depression and even death. Like codeine, pharmacogenetics probably plays a role in the extent of CNS depression. Newborn infants seem to be particularly sensitive to the effects of even small dosages of narcotic analgesics. Dihydrocodeine possibly caused severe respiratory depression in one newborn infant whose mother was taking the drug for cough. Once the mother's milk comes in, it is best to provide pain control with a nonnarcotic analgesic and limit maternal intake of hydromorphone to a few days at a low dosage with close infant monitoring. If the baby shows signs of increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties, or limpness, a physician should be contacted immediately. Because there is little published experience with dihydrocodeine during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.
Ivacaftor
2021 Apr 19. Drugs and Lactation Database (LactMed) [Internet]. Bethesda (MD): National Library of Medicine (US); 2006–.
ABSTRACT
Information from one maternal-infant pair with ivacaftor and lumacaftor indicates that maternal ivacaftor therapy produce low levels in milk. An international survey of cystic fibrosis centers found no adverse effects in breastfed infants of mothers taking these drugs. A task force respiratory experts from Europe, Australia and New Zealand found that these drugs are probably safe during breastfeeding.[1] One breastfed infant had transient elevations in bilirubin and liver enzymes during maternal therapy that could not definitively be attributed to the drugs in breastmilk. Until more data are available, monitoring of infant bilirubin and liver enzymes might be advisable during breastfeeding with maternal ivacaftor therapy. Examination of breastfed infants for cataracts has also been recommended.[2]
Tezacaftor and Ivacaftor
2021 Apr 19. Drugs and Lactation Database (LactMed) [Internet]. Bethesda (MD): National Library of Medicine (US); 2006–.
ABSTRACT
Information from one maternal-infant pair with ivacaftor and lumacaftor indicates that maternal ivacaftor therapy produce low levels in milk. An international survey of cystic fibrosis centers found no adverse effects in breastfed infants of mothers taking these drugs. A task force respiratory experts from Europe, Australia and New Zealand found that these drugs are probably safe during breastfeeding.[1] One breastfed infant had transient elevations in bilirubin and liver enzymes during maternal therapy that could not definitively be attributed to the drugs in breastmilk. Until more data are available, monitoring of infant bilirubin and liver enzymes might be advisable during breastfeeding with maternal tezacaftor and ivacaftor therapy. Examination of breastfed infants for cataracts has also been recommended.[2]
Lumacaftor and Ivacaftor
2021 Apr 19. Drugs and Lactation Database (LactMed) [Internet]. Bethesda (MD): National Library of Medicine (US); 2006–.
ABSTRACT
Information from one maternal-infant pair with ivacaftor and lumacaftor indicates that maternal ivacaftor therapy produce low levels in milk. An international survey of cystic fibrosis centers found no adverse effects in breastfed infants of mothers taking these drugs. A task force respiratory experts from Europe, Australia and New Zealand found that these drugs are probably safe during breastfeeding.[1] One breastfed infant had transient elevations in bilirubin and liver enzymes during maternal therapy that could not definitively be attributed to the drugs in breastmilk. Until more data are available, monitoring of infant bilirubin and liver enzymes might be advisable during breastfeeding with maternal lumacaftor and ivacaftor therapy. Examination of breastfed infants for cataracts has also been recommended.[2]
Diagnostic Tests for Diabetes Mellitus
2025 Feb 7. In: Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, de Herder WW, Dhatariya K, Dungan K, Hofland J, Kalra S, Kaltsas G, Kapoor N, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, Levy M, McGee EA, McLachlan R, New M, Purnell J, Sahay R, Shah AS, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000–.
ABSTRACT
In this chapter, indications for screening for diabetes mellitus are reviewed. Criteria for diagnosis are fasting plasma glucose ≥ 126 mg/dl (7.0 mmol/l) or random glucose ≥200 mg/dl (11.1 mmol/l) with hyperglycemic symptoms, hemoglobin A1c (HbA1c) ≥6.5%, and oral glucose tolerance testing (OGTT) 2-h glucose ≥200 mg/dl (11.1 mmol/l) after 75 g of glucose. One-step and two-step strategies for diagnosing gestational diabetes using pregnancy-specific criteria as well as use of the 2-h 75-g OGTT for the postpartum testing of women with gestational diabetes (4-12 weeks after delivery) are described. Testing for other forms of diabetes with unique features are reviewed, including the recommendation to use the 2-h 75 g OGTT to screen for cystic fibrosis-related diabetes and post-transplantation diabetes, fasting glucose test for HIV positive individuals, and genetic testing for monogenic diabetes syndromes including neonatal diabetes and maturity-onset diabetes of the young (MODY). Elevated measurements of pancreatic islet autoantibodies (e.g., to the 65-KDa isoform of glutamic acid decarboxylase (GAD65), tyrosine phosphatase related islet antigen 2 (IA-2), insulin (IAA), and zinc transporter (ZnT8)) suggest autoimmune type 1 diabetes (vs type 2 diabetes). IAA is primarily measured in youth. The use of autoantibody testing in diabetes screening programs is recommended in first degree relatives of an individual with type 1 diabetes or in research protocols. C-peptide measurements can be helpful in identifying those who have type 1 diabetes (low or undetectable c-peptide) from those who may have type 2 or monogenic diabetes. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.
Cystic Fibrosis
2001 Mar 26 [updated 2022 Nov 10]. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2022.
ABSTRACT
CLINICAL CHARACTERISTICS: Cystic fibrosis (CF) is a multisystem disease affecting epithelia of the respiratory tract, exocrine pancreas, intestine, hepatobiliary system, and exocrine sweat glands. Morbidities include recurrent sinusitis and bronchitis, progressive obstructive pulmonary disease with bronchiectasis, exocrine pancreatic deficiency and malnutrition, pancreatitis, gastrointestinal manifestations (meconium ileus, rectal prolapse, distal intestinal obstructive syndrome), liver disease, diabetes, male infertility due to hypoplasia or aplasia of the vas deferens, and reduced fertility or infertility in some women. Pulmonary disease is the major cause of morbidity and mortality in CF.
DIAGNOSIS/TESTING: The diagnosis of CF is established in a proband with:
Elevated immunoreactive trypsinogen on newborn screen, signs and/or symptoms suggestive of CF, or family history of CF; AND
Evidence of an abnormality in cystic fibrosis transmembrane conductance regulator (CFTR) function: sweat chloride ≥60 mmol/L on sweat chloride testing, biallelic CFTR CF-causing pathogenic variants, or nasal transmembrane epithelial potential difference measurement consistent with CF.
MANAGEMENT: Treatment of manifestations – targeted therapy: CFTR modulator therapy is available for individuals with responsive CFTR variants.
Supportive care: Newborns: management by a CF specialist or CF care center; airway clearance instruction; encouraging feeding with breast milk; routine vaccinations; contact precautions with every encounter; antibiotics for bacterial suppression and treatment; nutrition management; pancreatic enzyme replacement; nutrient-dense food and supplements; fat-soluble vitamin supplements; laxative treatment as needed with surgical management for bowel obstruction; and salt and water supplementation.
After the newborn period: airway clearance; pulmonary treatment (bronchodilator, hypertonic saline, dornase alfa, airway clearance, inhaled corticosteroids and/or long-acting beta agonist, and aerosolized antibiotic); standard treatments for pneumothorax or hemoptysis; double lung transplant for those with advanced lung disease; routine vaccinations including influenza; contact precautions; antibiotics for bacterial suppression and treatment; antibiotics and/or surgical intervention for nasal/sinus symptoms; nutrition management; pancreatic enzyme replacement; nutrient-dense food and supplements; fat-soluble vitamin supplements; laxative treatment as needed with surgical management for bowel obstruction; standard treatments for gastroesophageal reflux disease; oral ursodiol for biliary sludging/obstruction; liver transplant when indicated; management of CF-related diabetes mellitus by an endocrinologist; assisted reproductive technologies (ART) for infertility; salt and water supplementation; standard treatments for associated mental health issues.
Surveillance: Frequent assessment by a CF specialist to monitor for new or worsening manifestations; pulmonary function testing frequently after age five years; chest x-ray or chest CT examination to assess for bronchiectasis every two years or as needed; cultures of respiratory tract secretions at least every three months; non-tuberculosis mycobacterium culture and serum IgE annually or as indicated; annual CBC with differential; annual ENT assessment; monitoring growth and GI manifestations at each visit; fecal elastase as needed; annual serum vitamin A, D, E, and PT (as a marker of vitamin K); annual liver function tests; annual random glucose, annual two-hour glucose tolerance test beginning at age ten years; DXA scan as needed in adolescence; infertility assessment as needed; annual electrolytes, BUN, and creatinine; annual assessment of depression and anxiety.
Agents/circumstances to avoid: Environmental smoke, exposure to respiratory infections, dehydration.
Evaluation of relatives at risk: Molecular genetic testing of at-risk sibs (if the pathogenic variants in the family are known) or sweat chloride testing of at-risk sibs (if the pathogenic variants in the family are not known) to identify as early as possible those who should be referred to a CF center for initiation of early treatment.
GENETIC COUNSELING: CF is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a CFTR pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the CFTR pathogenic variants have been identified in an affected family member, targeted heterozygote testing for at-risk relatives and prenatal/preimplantation genetic testing for CF are possible.
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