Cystic Fibrosis

A 5-year-old boy presents with recurrent pulmonary infections and failure to thrive. He had meconium ileus shortly after birth. Despite a good appetite, he has poor weight gain. Examination shows digital clubbing, a barrel-shaped chest, bilateral crackles, and wheezing. Sputum culture grows Staphylococcus aureus. Chest X-ray shows hyperinflation. Sweat chloride is ≥60 mmol/L on two occasions, and genetic testing identifies a CF-causing CFTR variant. Diagnosis?

The diagnosis is cystic fibrosis.

1. Definition

Cystic fibrosis is an autosomal recessive multisystem disorder caused by pathogenic variants in the CFTR gene, resulting in abnormal chloride and bicarbonate transport and thick, dehydrated secretions.

2. Pathophysiology

1.      Mutation in the CFTR gene on chromosome 7. F508del is the most common CF-causing variant, although its frequency varies among populations.

2.      The CFTR protein is a cAMP-regulated chloride and bicarbonate channel.

3.      Effects:

1.      Lungs and GI tract

§  Decreased chloride and bicarbonate secretion

§  Thick, dehydrated mucus

§  Impaired mucociliary clearance, obstruction, and recurrent infection

2.      Sweat glands

§  Decreased chloride reabsorption

§  Increased chloride concentration in sweat

3. Clinical Features

3.1 Pulmonary

1.      Recurrent respiratory infections

o    Common organisms include Staphylococcus aureus, Haemophilus influenzae, and Pseudomonas aeruginosa

o    S. aureus is common in younger children, while chronic Pseudomonas infection becomes more prevalent with increasing age and disease severity

2.      Chronic cough and sputum production

3.      Bronchiectasis

4.      Wheezing and obstructive lung disease

5.      Digital clubbing

6.      Chronic sinusitis and nasal polyps

3.2 Gastrointestinal

1.      Meconium ileus in neonates

2.      Pancreatic insufficiency

o    Steatorrhea

o    Fat-soluble vitamin deficiency (A, D, E, K)

3.      Failure to thrive

4.      Distal intestinal obstruction syndrome

5.      CF-related diabetes mellitus

6.      CF-related liver disease

3.3 Other Features

1.      Male infertility commonly due to congenital bilateral absence of the vas deferens

2.      Excess salt loss in sweat, which may cause dehydration and electrolyte abnormalities

4. Diagnosis

Diagnosis requires compatible clinical features or newborn screening findings plus evidence of CFTR dysfunction.

1.      Sweat chloride test

o    ≥60 mmol/L: consistent with CF

o    30 to 59 mmol/L: intermediate and requires further evaluation

o    ≤29 mmol/L: CF is unlikely, although rare exceptions occur

2.      Newborn screening

o    Elevated immunoreactive trypsinogen (IRT)

o    Screening alone does not establish the diagnosis

3.      Genetic testing

o    Identification of two CF-causing CFTR variants provides molecular evidence of CFTR dysfunction

o    Identification of only one CFTR variant does not exclude CF when other evidence of CFTR dysfunction is present

4.      Sputum culture

o    Identifies respiratory pathogens and guides antibiotic therapy

5.      Chest imaging

o    May show hyperinflation, bronchiectasis, mucus plugging, atelectasis, and scarring

6.      Pulmonary function tests

o    Typically show an obstructive pattern

5. Management

5.1 Airway Clearance

1.      Daily airway clearance therapy

2.      Inhaled hypertonic saline may be selectively offered based on individual clinical circumstances

3.      Dornase alfa may be selectively offered based on individual clinical circumstances

5.2 Pharmacologic Therapy

1.      Antibiotics guided by respiratory cultures and clinical infection

2.      Bronchodilators when clinically indicated, such as with bronchospasm or airway hyperreactivity

3.      CFTR modulator therapy is selected according to age, CFTR genotype, and regulatory eligibility

o    Ivacaftor for eligible responsive CFTR variants

o    Combination CFTR modulator therapies for eligible patients

o    Elexacaftor, tezacaftor, and ivacaftor is an important highly effective modulator combination for eligible patients

5.3 Nutritional Support

1.      Pancreatic enzyme replacement therapy for pancreatic insufficiency

2.      Fat-soluble vitamin supplementation (A, D, E, K) as indicated

3.      Individualized nutritional support, with increased caloric intake when needed for catch-up growth

5.4 Preventive Care

1.      Routine age-appropriate immunization, including annual influenza vaccination

2.      Regular monitoring of growth, nutritional status, respiratory microbiology, and lung function

5.5 Advanced Therapy

1.      Lung transplantation may be considered in advanced CF lung disease

6. Key Clinical Insight

In a child with characteristic clinical features, a sweat chloride concentration ≥60 mmol/L establishes the diagnosis of cystic fibrosis.

References

1.      Farrell PM, White TB, Ren CL, et al. Diagnosis of cystic fibrosis: consensus guidelines from the Cystic Fibrosis Foundation. J Pediatr. 2017;181S:S4-S15.e1. doi:10.1016/j.jpeds.2016.09.064.

2.      Lahiri T, Hempstead SE, Brady C, et al. Clinical practice guidelines from the Cystic Fibrosis Foundation for preschoolers with cystic fibrosis. Pediatrics. 2016;137(4):e20151784. doi:10.1542/peds.2015-1784.

3.      Mall MA, Burgel PR, Castellani C, et al. Cystic fibrosis. Nat Rev Dis Primers. 2024;10:53. doi:10.1038/s41572-024-00538-6.

Celiac disease

A 34-year-old woman presents with a 6-month history of chronic diarrhea, bloating, intermittent abdominal pain, and unintentional weight loss. Her stools are loose, foul-smelling, and difficult to flush, suggesting steatorrhea. She also reports fatigue and generalized weakness and has iron deficiency anemia. Recently, she developed a pruritic vesicular rash over the elbows and knees, consistent with dermatitis herpetiformis. Laboratory investigations show microcytic iron deficiency anemia. Serologic testing is positive for anti-tissue transglutaminase (tTG) IgA, anti-endomysial antibodies, and anti-deamidated gliadin peptide antibodies. Duodenal biopsy demonstrates villous atrophy, crypt hyperplasia, and increased intraepithelial lymphocytes. The D-xylose test shows decreased absorption. Diagnosis?

The diagnosis is celiac disease.

1. Definition

Celiac disease is a chronic immune-mediated enteropathy triggered by dietary gluten in genetically susceptible individuals, resulting in small intestinal mucosal injury, malabsorption, and intestinal and extraintestinal manifestations.

2. Etiology / Associations

1.      Triggered by gluten in wheat, barley, and rye

2.      Strongly associated with HLA-DQ2 and HLA-DQ8

3.      Results from interaction between genetic, environmental, and immune factors

4.      Associated with other autoimmune disorders, including type 1 diabetes mellitus and autoimmune thyroid disease

3. Pathophysiology

1.      Gluten is digested into gliadin peptides

2.      Tissue transglutaminase (tTG) deamidates gliadin peptides

3.      Deamidated gliadin binds to HLA-DQ2 or HLA-DQ8, causing T-cell activation

4.      Immune-mediated mucosal injury leads to:

o    Villous atrophy

o    Crypt hyperplasia

o    Increased intraepithelial lymphocytes

5.      Reduced intestinal absorptive surface leads to malabsorption of iron, fat, calcium, and vitamins

4. Clinical Features

4.1 Gastrointestinal Features

1.      Chronic diarrhea

2.      Steatorrhea, with bulky, greasy, foul-smelling stools

3.      Abdominal bloating and pain

4.      Weight loss

5.      Constipation may occur in some patients

4.2 Extraintestinal Features

1.      Iron deficiency anemia, a common presentation

2.      Fatigue and weakness

3.      Dermatitis herpetiformis

o    Intensely pruritic grouped papules and vesicles, typically involving extensor surfaces such as the elbows and knees

o    Characteristic cutaneous manifestation of celiac disease

4.      Osteopenia and osteoporosis

5.      Neurologic manifestations, including peripheral neuropathy and ataxia

6.      Infertility and menstrual abnormalities

5. Diagnosis

5.1 Initial Test

1.      Anti-tTG IgA with a total serum IgA level

2.      If IgA deficiency is present, use IgG-based testing, such as IgG deamidated gliadin peptide or IgG tTG antibodies

5.2 Serology

1.      Anti-tTG IgA

o    Preferred initial serologic test in most adults

2.      Anti-endomysial IgA

o    Highly specific

o    Useful mainly in selected or diagnostically equivocal cases rather than as routine confirmation when a validated tTG-IgA assay is available

3.      Deamidated gliadin peptide antibodies

o    Useful in selected patients, particularly those with IgA deficiency

5.3 Confirmatory Test

1.      Upper endoscopy with multiple duodenal biopsies remains the standard confirmatory approach for most adults

2.      Recommended sampling includes at least four biopsies from the distal duodenum and two from the duodenal bulb, because mucosal involvement may be patchy

3.      Typical histologic findings include:

o    Villous atrophy

o    Crypt hyperplasia

o    Increased intraepithelial lymphocytes

4.      A no-biopsy diagnostic pathway may be considered in selected adults younger than 45 years when:

o    IgA anti-tTG is ≥10 times the upper limit of normal

o    Serologic positivity is confirmed on a second independent blood sample

o    The patient remains on a gluten-containing diet

o    There are no concerning features suggesting an alternative diagnosis

o    The decision is made in an appropriate specialist setting

5.4 Additional Findings

1.      Iron deficiency anemia

2.      Other nutritional deficiencies may include folate, vitamin B12, vitamin D, and calcium deficiency

3.      Increased fecal fat may occur with significant malabsorption

4.      Reduced D-xylose absorption may indicate small intestinal mucosal disease but is not routinely used in modern celiac disease diagnosis

5.      HLA-DQ2/DQ8 testing is not routinely required

o    Its major value is its high negative predictive value in diagnostically uncertain cases

o    Absence of both HLA-DQ2 and HLA-DQ8 makes celiac disease very unlikely

5.5 Dermatitis Herpetiformis

1.      Diagnosis is confirmed by direct immunofluorescence of uninvolved perilesional skin

2.      The characteristic finding is granular IgA deposition in the dermal papillae, sometimes extending along the dermoepidermal junction

Important Diagnostic Rule

Serologic testing and duodenal biopsy should be performed while the patient is consuming a gluten-containing diet, because gluten restriction can produce false-negative results.

6. Differential Diagnosis

1.      Non-celiac gluten sensitivity

2.      Irritable bowel syndrome

3.      Inflammatory bowel disease

4.      Lactose intolerance

5.      Small intestinal bacterial overgrowth

6.      Tropical sprue

7.      Giardiasis

8.      Pancreatic exocrine insufficiency

7. Management

7.1 First-Line

1.      Strict lifelong gluten-free diet

7.2 Dietary Avoidance

1.      Avoid wheat, barley, and rye

2.      Prevent gluten cross-contamination

3.      Dietitian-guided nutritional counseling is recommended to ensure dietary adequacy and adherence

7.3 Supportive Care

1.      Identify and correct nutritional deficiencies

o    Iron

o    Folate and vitamin B12 when deficient

o    Calcium and vitamin D

o    Other micronutrients as indicated

2.      Monitor clinical response, nutritional status, and celiac serology

3.      Assess bone health when clinically indicated

7.4 Dermatitis Herpetiformis

1.      A gluten-free diet is the definitive long-term treatment

2.      Dapsone provides rapid relief of pruritus and skin lesions but does not treat the underlying intestinal disease

3.      Before systemic dapsone therapy, assess:

o    G6PD status

o    Complete blood count

o    Liver function

o    Renal function

4.      Laboratory monitoring is required during therapy because adverse effects may include hemolysis, methemoglobinemia, agranulocytosis, and hypersensitivity reactions

8. Complications

1.      Malnutrition and micronutrient deficiencies

2.      Osteopenia and osteoporosis

3.      Infertility and adverse reproductive outcomes

4.      Neurologic complications

5.      Refractory celiac disease

6.      Enteropathy-associated T-cell lymphoma

7.      Small intestinal adenocarcinoma

9. Key Clinical Insight

In this patient, positive celiac serology together with characteristic duodenal histology establishes the diagnosis of celiac disease.

References

1.      Rubio-Tapia A, Hill ID, Semrad C, et al. American College of Gastroenterology Guidelines Update: Diagnosis and Management of Celiac Disease. Am J Gastroenterol. 2023;118(1):59-76. doi:10.14309/ajg.0000000000002075.

2.      Al-Toma A, Zingone F, Branchi F, et al. European Society for the Study of Coeliac Disease 2025 Updated Guidelines on the Diagnosis and Management of Coeliac Disease in Adults. Part 1: Diagnostic Approach. United European Gastroenterol J. 2025;13(10):1855-1886. doi:10.1002/ueg2.70119.

3.      Reunala T, Hervonen K, Salmi T. Dermatitis herpetiformis: an update on diagnosis and management. Am J Clin Dermatol. 2021;22(3):329-338. doi:10.1007/s40257-020-00584-2.