Case of the Week - January 13, 2005

45 yo White Male admitted 12/05

• With c/o nausea, non-bloody emesis and yellow discoloration of his skin for several days
• Denies fevers, chest pain, shortness of breath
• Notes occasional coughing productive of thick, clear sputum

A Few Labs …

• WBC - 8.0
• Hgb - 11.2
• Plt - 316
• PTT - 134
• Inr > 11
• Na⁺ - 136
• Cl^- -97
• BUN - 11
• K⁺ - 3.7
• HCO₃ - 30
• Cr - 0.61
• Glucose - 125
• LDH - 294
• Lactate - 3.6
• Alb - 3.3
• Ast - 156
• Alt - 102
• Alp - 1142
• GGT - 745
• Bili Total - 10.6

10/12/05

And a bit more information …

• Hx of multiple admissions for productive cough, fevers, shortness of breath since infancy
• Recent respiratory cultures positive for Staph and Pseudomonas
• Hx of diarrhea and weight loss for several years
• Insulin Dependent Diabetes
• Recent liver biopsy with focal non-bridging portal fibrosis

Diagnosis: Cystic Fibrosis

• Most common fatal autosomal recessive dz in Caucasian populations
• Frequency 1 in 2000-3000 live births
• Caused by mutation in CF transmembrane conductance regulator protein
• Over 1250 different known mutations

Clinical Features:

• Due to derangement of chloride transport in exocrine tissues
• Leads to thick, viscous secretions in lungs, pancreas, liver, intestine, reproductive tract
• > 40% present with respiratory symptoms
  • 29% with FTT
  • 24% steatorrhea
  • 19% meconium ileus
• ~7 % present > age 18
• < 10% diagnosed based on newborn screening

Respiratory Manifestations:

• Persistent, productive cough
• Multiple acute exacerbations
• 90-100% with sinus disease, 10-20% with nasal polyps
• PFTs with obstructive pattern
• Hyperinflation on CXR
• Develop upper lobe and central bronchiectasis
• Colonization of airways with Staph, H flu, Pseudomonas

Colonization:

• Colonization with Staph, H flu initially
• Most become colonized with Pseudomonas
  • Mucoid phenotype
  • Associated with accelerated decline in lung function
  • Due to impaired clearance specifically of Pseudomonas
  • CFTR gene transfer to respiratory epithelial cells of patients with CF show decreased binding of Pseudomonas

Radiographic Manifestations:

• Hyperinflation with flattening of diaphragm and prominent retrosternal space
• Upper lobe predominance initially
• Tram Tracking
• Peribronchial cuffing
• Small nodules

GI Manifestations:

• Pancreatic insufficiency
• Malabsorption
• Chronic idiopathic pancreatitis
• Meconium ileus
• Distal ileal obstruction syndrome
• Biliary disease

Biliary Disease:

• In 2-5% of patients
• Develop focal biliary cirrhosis
• Due to thickened bile
• Present with symptomatic portal hypertension
• More commonly find asymptomatic liver disease at autopsy or incidental elevated alkaline phosphatase and lobular hepatomegaly
• Ursodeoxycholic acid may arrest progression
• Also develop cholethiasis in ~12%

Other Manifestations:

• Infertility
• Pseudotumor cerebri
• Musculoskeletal disorders
  • Osteopenia and osteoporosis
  • Hypertrophic osteoarthropathy

Diagnostic Testing:

• Sweat Chloride Test
• Molecular Diagnosis
• Nasal Potential Difference
• Newborn Screening
• Examination for azoospermia
• Measurement of pancreatic enzymes
• 72 h fecal fat measurement

Sweat Chloride Test:

• Gold Standard
• With collection of sweat with pilocarpine iontophoresis then determination of chloride concentration
  • > 60 meq/L considered positive for CF
  • Must collect at least 50 mg within 45 minutes
  • False negative in patients with hypoproteinemic edema and concurrent use of steroids
• 1-2% of patients with CF have a normal sweat test

Molecular Diagnostics:

• Usually by direct mutation analysis
• As screen for 20-30 of the most common mutations
  • Will identify ~90% of CF chromosomes
• Can also do linkage analysis for prenatal diagnosis or to detect carrier status

Newborn Screening:

• Most infants with CF will have elevated immunoreactive trypsin (IRT)
• Will detect 95% of newborns with CF
• Levels fall rapidly by 8 weeks
• Screening programs have not shown improved survival or morbidity
• Have shown better lung function and growth in children diagnosed by screening
• Not mandatory in US; on state by state basis

CF Diagnosis in Adulthood:

• More likely to have inconclusive sweat tests
• May require multiple tests
• May need nasal potential testing
• Often with uncommon mutations
• Disease manifestations often mild
• Most with variable lung disease
• Some with single organ disease
  • Congenital absence of vas deferens
  • Pancreatitis
• More likely to have pancreatic sufficiency
• Majority diagnosed in childhood will reach adulthood
  • Average life expectancy ~28
  • >95% die from pulmonary complications
• Issues:
  • Transfer of care to Adult Pulmonologists?
  • End-of-life care?
  • Transplantation?
  • With regards to genetic testing, insurance?
  • With regards to family?

Case Concluded:

• Coagulopathy corrected with Factor Novo 7
• Patient remained alert, orientated throughout hospital course
• Treated with dornase, IV antibiotics including aztreonam and nebulized tobramycin due to emerging resistance in previous Pseudomonas cultures
• Sputum cultures grew Moderate Staph aureus, Moderate Pseudomonas fluorescens, putida, mendocina
• LFTs resolved
• Underwent outpatient ERCP and simultaneous bronchoscopy while intubated. Results pending.

References:

• Gilljam et al, “Clinical Manifestations of Cystic Fibrosis Among Patients with Diagnosis in Adulthood,” Chest 2004; 126; 1215-1224.
• Katkin, Julie P., “Clinical Manifestations and Diagnosis of Cystic Fibrosis,” uptodate.com

Disclaimer:  This information is intended solely for resident review of presented cases which may or may not be pathologically proven. Information is derived from a number of published sources of varying reliability and does not represent original research from the institution. It is not intended to be comprehensive and should therefore not substitute for careful review of the literature.