pediatric cystic fibrosis: a multi-organ disease...pancreatic insufficiency presents with...

Pediatric Cystic Fibrosis:A Multi-Organ Disease

NASPGHAN Fellows’ Page

CF: Historical Perspectives

First described by Anderson in 1938 (Arch Pediatr Adolesc Med).At that time, median survival was 1 year. Current survival: 32 years of age.Autosomal recessive inheritanceIncidence: 1 in 3000 live white births

Historical Perspectives

Gene was cloned in 1989.Specific defect: 250,000 base pairs on chromosome 7q.Encodes an 1480 AA protein named Cystic Fibrosis Transmembrane Regulator (CFTR).CFTR is primary chloride channel for epithelial cells.> 1000 mutations for CFTR have been described.

Cystic Fibrosis Mutation Database: http://www.genet.sickkids.on.ca/cgi-bin/WebObjects/MUTATION

Historical Perspectives

Most common mutation is 3 nucleotide deletion encoding phenylalanine (F) at position 508.

Hence, ΔF508.

CFTR - NORMAL

Intracellular Region

CFTR(cAMP channel)

Cl-Lumen

H20

Na+H20

Aqueous layer

CFTR - IMPAIRED

Intracellular Region

CFTR(cAMP channel)

Cl-

LumenX

Thickenedsecretions

H2O transportis disrupted

Na+

Increased

Normal:1. Na+ absorption normal2. Cl- secretion normal3. H20 transfer normal

CF:1. Na+ absorption increased2. Cl- secretion decreased3. H20 transfer impaired4. “Thickened secretions”

CFTR

5 classes of CFTR mutations: I – VI – Severe diseaseV – Milder disease

CFTR

Example of CFTR class:ΔF508: A class II mutation with 99% of homozygotes and 72% of heterozygoteshaving pancreatic insufficiency. Why is this important? Normal pancreatic function in CF is associated with improvedlung function.

Survival By Decade

0.5 years in 1940

32.5 yearsIn 2000

Orenstein, et al., J Peds, 2002

Factors Associated With Poor Prognosis

Established factors:Poor physical fitnessResp. infection with P. aeruginosa or B. cepaciaSecond-hand smokePancreatic insufficiencyPoor nutritional statusLack of health insuranceFemale sexNon-CF center care

Probable factors:Genotype (some mutations with less severe disease)Lack of aggressive careNon-usage of inhaled tobramycin or DNaseNon-usage of anti-inflammatory medsSocioeconomic status: i.e., Medicaid patients

Diagnosis

Sweat testingNasal potential differenceDNA screening

Diagnosis

Quantitative analysis of sweat using pilocarpineiontophoresis (“Sweat test”).Range: <40mmol/L – negative40 – 60 mmol/L – borderline>60mmol/L – positiveFalse positives: anorexia nervosa, atopicdermatitis, GSD I, hypothyroidism, adrenal insufficiency.False negatives: Edema, inadequate/inappropriate sweat

Diagnosis

Macroduct® Sweat Collection System

Sweat Chek® SweatCollection System

Nasal PD Measurement

Normal: Low PDResponse to amiloride

CF: High PD“Falling away” responseto amiloride

Amiloride Na+ absorptionXBlocks

DNA Screening

Can detect severe mutations such as the ΔF508.Can detect minor mutations such as 5T variant.Useful to detect CF in patients who are unable to perform sweat test.Can give a general idea as to severity of illness.Can detect less severe CF variants (such as congenital absence of the vas deferens).

Ex. CFTR and 5T variant in Cis.

Affected Systems

1) Pulmonary disease2) Gastrointestinal disease3) Pubertal delay (malnutrition)4) Fertility: Azoospermia (98% of CF males);

females with decreased fertility rate.5) CF-related diabetes mellitus6) Osteopenia / osteoporosis7) Psychological factors / HRQOL

GI AspectsPancreatic insufficiency (more commonly exocrine, but also endocrine)PancreatitisCholelithiasisCommon bile duct stenosisLiver disease (neonatal cholestasis, non-alcoholic fatty liver disease, fibrosis, cirrhosis)Distal intestinal obstructive syndrome (DIOS)Fibrosing colonopathyClostridium difficile enterocolitisSmall intestinal bacterial overgrowthGastroesophageal reflux diseaseGastrointestinal cancer (in adult CF patients)

Pulmonary Disease

Pulmonary Disease

Upper tract disease: Sinusitis is universal.Nasal polyps are common (generally, mucous retention cysts due to glandular dysfunction).Lower tract disease: Chronic infection occurs early in life and is progressive.Disease characterized by bacterial colonization and viscous secretion / obstruction.Can have an RAD component.Respiratory failure is the leading cause of death in CF patients.

Left maxillarysinusitis

Typical findings:1. Atelectasis2. Infiltrates3. Hyperinflation

www.googleimages.com

Pulmonary Disease

Initial infecting organism is S. aureus.Progresses to P. aeruginosa over time.Other bacteria: H. influenzae, Burkholderia cepacia, MAC.

Other comorbid conditions worsening lung function:

1) Pneumothorax 5-8% of CF patients2) Hemoptysis (mild to life-threatening)3) ABPA (10% of CF patients). This is not invasive disease.

Pneumothorax

Pulmonary Disease

Burkholderia cepacia1) Originally isolated as soil flora. 9 distinct species

known as “B. cepacia complex.”2) Easily transmitted between CF patients led to

cessation of CF camps.MAC complex1) In soil, drinking water, aerosolized mist (showers).2) Cough, bronchiectasis, cavitation of lungs3) Prevalence rate 4-19%.4) Persistent isolation of MAC from sputum is

indicative of infection and should be treated.

Pulmonary Disease

Treatment:Primary treatment is prevention of progressive airway disease.“Colds” are generally treated aggressively with antibiotics to prevent progression to bacterial disease.Anti-inflammatory airway inflammation: corticosteroids, ibuprofen, inhaled antibiotics (tobramycin; Tobi nebs®)Serial PFTs are essential.

Pulmonary Disease

Obstructive airway prevention: mechanical vest, Flutter valve®, positive pressure masks.Inhaled alpha dornase (Pulmozyme®): DNase that reduces sputum viscosity by cleaving neutrophil-derived DNA.Pulmonary exacerbations: Generally require 14 days of oral / inhaled / IV antibiotics (home or in-patient).CF patients have increased volume of distribution and increased clearance of antibiotics higher dosing levels.

Pulmonary Disease

Pseudomonas aeruginosa colonization:Patients with CF given 250mg azithromycin (Wt < 40 kg) or 500mg azithromycin (Wt > 40 kg) or placebo (3X per week)Followed therapeutic response for 168 days.FEV1, patient weight, and # of pulmonary exacerbations decreased in the azithromycin group.Azithromycin associated with clinical improvement in CF patients 6 yrs old or older with P. aeruginosainfection.

Saiman, et al. JAMA 2003; 290: 1749-1756

Pulmonary Disease

Saiman, et al. JAMA 2003; 290: 1749-1756

GI Disease and Nutrition

Nutrition

Dietician consultation is essential.Adult energy requirements: 120-150% RDA30-45% of diet as high-fat supplementation (↑ calories; ↓ CO2 load)REE: 7.2% higher in CF patients than controls (esp. in females and severe disease mutations)Increased risk of fatty acid deficiency (linoleicand docosahexaenoic acid).

Nutrition

MCT / glucose polymer polymer supplementationFrequent vitamin and electrolyte levelsEssential fatty acid supplementationPancreatic enzyme supplementationGrowth hormone: Potentially useful to increase IGF-1 (anabolic peptide) to improve lean body mass, increase growth rate, decrease lung disease.Hardin, et al., J Peds, 2001: Daily GH injections improved weight, lung studies, and decreased hospitalizations and antibiotic usage.

Nutrition

Chitkara, Clin Perspect Gastroenterol, 2000

Gastrointestinal Disease

Pancreatic insufficiencyFibrosing colonopathyGERDRectal prolapseMeconium ileus / DIOSRectal prolapseHepatobiliary disease (focal biliary cirrhosis)Malnutrition / fat-soluble vitamin deficiencyCancer


Pancreatic insufficiencyOver 80% of CF patients require pancreatic enzyme replacement.↑ gastric acid secretion↓ duodenal bicarbonate / enzyme secretionSome residual lipase function exists (gastric lipase).


Testing for pancreatic insufficiency:1) 72 hour fecal fat collection2) Stool trypsin / chymotrypsin3) Breath testing4) Secretin / CCK stimulation with duodenal

intubation for pancreatic enzyme collection (“Gold Standard”).

5) Fecal pancreatic elastase 1


Pancreatic insufficiencyPresents with steatorrhea, weight loss, fat-soluble vitamin deficiency.Symptoms are present only when exocrine function < 1% of normal.CAREFUL!!! Pancreatitis can occur in patients with residual exocrine function.CFTR mutations are found 11X more frequently in patients with chronic idiopathic pancreatitis.


Pancreatic insufficiencyEnzyme replacement: 500 – 2000 U lipase/kg/meal or up to 10,000 U/kg/day.Enteric-coated microspheres are preferred (ex. Creon® and Pancrease®).Side effects of replacement: oral / anal irritation, hypersensitivity rxn., hyperuricosuria.


Pancreatic insufficiencyAcid suppression enhances enzyme replacement (esp. PPIs).Use of fat-soluble vitamins (ex. ADEK®, Vitamax®)High-calorie feeds (oral / NG / G-tube)

Fibrotic pancreas

Pancreatic Fibrosis


Pre-CCK infusion Post-CCK infusion

CCK Stimulation Test


Fibrosing colonopathy:Leads to colonic strictures with high dosing of pancreatic enzymes.Young children at increased risk.Risk associated with dosing > 10,000 U/kg/day.

Lewis, et al., J Peds, 1999

Submucosal expansion

due to ECM, smooth

muscle hyperplasia

and increased adipocytes.

Thick mucosaBE with narrow

colon


DIOSDISTAL INTESTINAL OBSTRUCTION SYNDROMEUp to 50% of CF infants present with meconium ileus and half of these infants require surgical resection.Older children / adults present with meconium ileus equivalent or DIOS


DIOSDue to undigested food residues, disturbed motility, inadequate enzyme replacement, fecal stasis / dehydration.Can cause:

1) Abdominal pain2) Bowel obstruction3) Intussusception4) Volvulus


DIOSFindings include a palapable cecal mass.Abdominal X-ray: “Bubbly” fecal material in TI / cecum region.Treatment options: Consider acute and preventative care.

DIOS treatment options

Chitkara, Clin Perspect Gastroenterol, 2000

Meconium Ileus


D.I.O.S.


Hepatobiliary diseaseIncreasing problem as patient life span increases.Incidence in CF: 10% of infants, 72% of adults.No specific CFTR mutation correlation is noted.However, familial clusters are common.Myriad of diseases are described.


Hepatobiliary disease:Focal biliary cirrhosis multilobular cirrhosisNeonatal cholestasisMicrogallbladderCholelithiasisBile duct stricturesGallstones / common bile duct stonesSteatosis / steatohepatitisPortal hypertension

End stage liver disease

Gallstones in an Infant with CF

Lenaerts, et al. J Pediatrics (143), 2003.

Percentage of CF patients who developliver disease as age progresses:


Hepatobiliary diseaseUrsodeoxycholic acid – choleretic that delays progression of disease.β blockade, sclerotherapy, bandingEnd-stage treatments: hepatic shunts, TIPPS, liver transplantationFeigelson, et al. Arch Dis Child, 1992: Percentage of cirrhosis in CF patients with liver disease is 7%.Annual US with Doppler flow

Focal Biliary Cirrhosis

Hypoechogenicity in liver

Focal Biliary Cirrhosis

Multilobular Cirrhosis


Rectal prolapse occurs in 1-2% of UNTREATED CF patients by age 3.

GERD: 20% of CF patients report reflux-type symptoms.50% of CF patients with significant respiratory disease have esophagitis.Treatment is same as “normal” GERD population.


MalignancyIncreased risk of GI tumors in CF patients.Peaks at the 3rd decade of life.Involvement: Esophagus, small / large intestine, stomach, hepatobiliary, pancreas, rectumAny adolescent / adult CF patient with chronic abdominal complaints needs evaluation for occult malignancy.

CF-Related Diabetes

CF-related Diabetes Mellitus

30-40% of CF patients have glucose intolerance.Frank diabetes occurs in 2.5 – 7.6% of CF patients.Mean onset age: 20 yearsPrimary mechanism Progressive pancreatic fibrosis with β cell loss.

CF-related Diabetes Mellitus

Solomon et al., J Peds, 2003Evaluated 355 adolescent CF patients in Toronto for glucose intolerance.2.7% of patients had CF-related DM.17% had impaired glucose intolerance by OGTT.Hgb A1C did not correlate with OGTT.Screen CF patients with OGTT?

Renal Disease

Renal Disease

Increased risk of urolithiasis due to:HyperoxaluriaHypercalcuriaHyperuricosuriaDiabetes leads to UTIs stone formation

Why? Vitamin D deficiency, TI disease, change of colonic microflora…

Renal Disease

E. Coli induced urolithiasis / emphysematous cystitis in a CFpatient (Upadhyay, et al. JAMA 2004; 292: 1953-1954.

Osteopenia / Osteoporosis

Osteoporosis

In general, all CF children develop osteopeniavery early in life.Multitude of reasons: Pancreatic insufficiency, increased energy requirements, poor caloric intake, steroids, increased fecal calcium losses.Measurement: ↓ calcium,↑PTH, ↓ 25-OH-D

Osteoporosis

Treatment considerations:1. Annual Dexa scanning2. Annual serum markers3. Calcium supplementation4. Exercise5. Nutrition6. Bisphosphonates (osteoclast inhibitor)

Osteoporosis in an adolescent CF Patient

Z-score at L1 –2.8 S.D. ; L2 -2.5 S.D.

What Does the Future Hold?

Future Therapies?

Improvement of transplant functionGene therapyTransport of intact CFTR to cell membraneImprove ion transport of already impaired CFTR

1) UTP analogues ↑ chloride transport through non CFTR channels.

2) Amiloride ↓s Na absorption into CF cells.Enhancement of naturally-occurring α-helical cationic antimicrobial peptides in CF lungs

Future Therapies?

Wilschanski, et al., NEJM (248): 2003Aminoglycosides can suppress premature termination of stop codons.CF patients with ΔF508 mutations received gentamicin nasal drops for 14 days.Nasal potential difference was reduced. Staining for CFTR on nasal epithelial cells showed increased uptake.

Mouse neg. control ΔF508 pre-gent ΔF508 post-gent

Wilschanski, et al., NEJM (248): 2003

Curcumin?

Derived from curry. See NEJM (351); 2004The ΔF508 variant has abnormal CFTR because “chaperone proteins” grab CFTR prior to do proceeding to the cell membrane.Chaperones send CFTR for early degradation.Chaperone proteins are dependent on intracellular calcium.Curcumin ↓ intracellular Ca with no cell toxicity.Mouse models for CF: Mice treated with curcuminhave increased survival overall.

Treatment Plan

The CF patient requires a multi-discipline team approach (pulmonary, GI, RT, nutritionist, social worker, etc.).Designated CF centers have been shown to improve survival.2 national databases: CFF and ESCFHowever, the PCP is an integral component for CF care (screening, negotiating complex care, vaccinations, etc.)

Thank you!

Questions or comments: [email protected]

pediatric cystic fibrosis: a multi-organ disease...pancreatic insufficiency presents with...

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