Cystic Fibrosis

A 5 year old male child is brought to the pediatric clinic due to recurrent pulmonary infections and failure to thrive. His mother reports multiple hospitalizations for respiratory infections. He had meconium ileus shortly after birth, requiring surgical intervention. Despite a good appetite, he has poor weight gain. On examination, he appears thin, with digital clubbing and a barrel shaped chest. Lung auscultation reveals bilateral crackles and wheezing. Sputum culture grows Staphylococcus aureus. Chest x ray shows hyperinflation. Sweat chloride is ≥60 mmol/L on two occasions. Genetic testing reveals a CFTR mutation. Diagnosis?

Diagnosis is Cystic fibrosis.

1. Definition

Cystic fibrosis is an autosomal recessive disorder caused by mutations in the CFTR gene, leading to abnormal chloride transport and viscous secretions affecting multiple organs.

2. Pathophysiology

1. Mutation in the CFTR gene on chromosome 7, most commonly ΔF508
2. The CFTR protein is a cAMP regulated chloride channel
3. Effects:
1. Lungs and GI tract
• Decreased chloride secretion
• Increased sodium and water absorption via ENaC
• Leads to thick, dehydrated mucus
2. Sweat glands
• Decreased chloride reabsorption
• Leads to increased chloride concentration in sweat

3. Clinical Features

3.1 Pulmonary

1. Recurrent respiratory infections
• Early: Staphylococcus aureus, Haemophilus influenzae
• Later: Pseudomonas aeruginosa
2. Chronic productive cough
3. Bronchiectasis
4. Wheezing and dyspnea
5. Digital clubbing
6. Chronic sinusitis and nasal polyps

3.2 Gastrointestinal

1. Meconium ileus in neonates
2. Pancreatic insufficiency
• Steatorrhea
• Fat soluble vitamin deficiency (A, D, E, K)
3. Failure to thrive
4. Distal intestinal obstruction syndrome
5. CF related diabetes mellitus
6. Hepatobiliary disease, including biliary cirrhosis

3.3 Other Features

1. Male infertility due to congenital bilateral absence of vas deferens
2. Salt loss leading to heat intolerance and dehydration

4. Diagnosis

1. Sweat chloride test
• ≥60 mmol/L on two separate occasions is diagnostic
2. Newborn screening
• Elevated immunoreactive trypsinogen
3. Genetic testing
• Confirms CFTR mutation
4. Sputum culture
• Common organisms: S aureus, Pseudomonas, H influenzae
5. Chest imaging
• Hyperinflation, bronchiectasis, atelectasis, scarring
6. Pulmonary function tests
• Obstructive pattern

5. Management

5.1 Airway Clearance

1. Chest physiotherapy
2. Inhaled hypertonic saline
3. Dornase alfa, reduces mucus viscosity

5.2 Pharmacologic Therapy

1. Bronchodilators such as albuterol
2. Antibiotics for acute and chronic infections
3. CFTR modulators (genotype specific)
• Ivacaftor, improves channel function
• Lumacaftor or tezacaftor, improve protein folding
• Elexacaftor tezacaftor ivacaftor combination, most effective for ΔF508 mutation

5.3 Nutritional Support

1. Pancreatic enzyme replacement therapy
2. Fat soluble vitamin supplementation (A, D, E, K)
3. High calorie diet

5.4 Preventive Care

1. Influenza and pneumococcal vaccination

5.5 Advanced Therapy

1. Lung transplantation in advanced disease

6. Key Clinical Insight

Child with recurrent pulmonary infections, failure to thrive, meconium ileus, and elevated sweat chloride strongly suggests cystic fibrosis

7. Exam Level Pearls

1. ΔF508 is the most common mutation
2. Meconium ileus is a classic neonatal presentation
3. Sweat chloride ≥60 mmol/L confirms diagnosis
4. Early infection with Staphylococcus, later Pseudomonas
5. Pancreatic insufficiency leads to fat soluble vitamin deficiency

Celiac disease

A 34-year-old female presents with a 6-month history of chronic diarrhea, bloating, intermittent abdominal pain, and unintentional weight loss. She describes her stools as loose, foul-smelling, and difficult to flush, suggestive of steatorrhea. She also reports fatigue and generalized weakness and has a known history of iron deficiency anemia for which she is taking supplements. Recently, she developed a pruritic vesicular rash over her elbows and knees consistent with dermatitis herpetiformis. On evaluation, her BMI is 21 kg/m². Laboratory investigations reveal microcytic anemia with iron studies showing decreased ferritin, increased TIBC, low serum iron, and reduced transferrin saturation. Serologic testing is positive for anti-tTG (IgA), anti-endomysial, and anti-deamidated gliadin antibodies. Small bowel biopsy demonstrates villous atrophy, intraepithelial lymphocytosis, and crypt hyperplasia, and the D-xylose test shows decreased absorption. These findings are consistent with a diagnosis of celiac disease. Diagnosis?

Diagnosis is Celiac disease.

1. Definition

Celiac disease is a chronic autoimmune disorder triggered by dietary gluten, resulting in immune-mediated inflammation and damage of the small intestinal mucosa, leading to malabsorption and systemic manifestations.

2. Etiology / Associations

1. Triggered by gluten (wheat, barley, rye)
2. Strong association with HLA-DQ2 and HLA-DQ8
3. Multifactorial: genetic, environmental, and immune factors
4. Associated with other autoimmune diseases (e.g., type 1 diabetes)

3. Pathophysiology

1. Gluten → gliadin peptides
2. Deamidation by tissue transglutaminase (tTG)
3. Binding to HLA-DQ2/DQ8 → T-cell activation
4. Immune-mediated injury causes:
• Villous atrophy
• Crypt hyperplasia
• Intraepithelial lymphocytosis
5. ↓ intestinal surface area → malabsorption (iron, fat, vitamins)

4. Clinical Features

4.1 Gastrointestinal Features

1. Chronic diarrhea
2. Steatorrhea (foul-smelling, bulky stools)
3. Bloating, abdominal discomfort
4. Weight loss
5. Constipation (may occur)

4.2 Extraintestinal Features

1. Iron deficiency anemia (most common)
2. Fatigue
3. Dermatitis herpetiformis (pathognomonic)
4. Osteopenia / osteoporosis
5. Neurologic symptoms (e.g., peripheral neuropathy, ataxia)
6. Infertility, menstrual irregularities

5. Diagnosis

5.1 Initial Test

• Anti-tTG IgA + total IgA level
• If IgA deficiency → use IgG-based tests

5.2 Serology

1. Anti-tTG IgA → most sensitive
2. Anti-endomysial antibody → most specific
3. Anti-deamidated gliadin antibodies

5.3 Confirmatory Test

• Small bowel (duodenal) biopsy:
1. Villous atrophy
2. Crypt hyperplasia
3. Intraepithelial lymphocytosis

5.4 Additional Findings

1. Iron deficiency anemia
2. ↓ D-xylose absorption
3. ↑ stool fat (steatorrhea)

Important Diagnostic Rule

• Testing should be performed while the patient is on a gluten-containing diet (to avoid false-negative results)

6. Differential Diagnosis

1. Non-celiac gluten sensitivity
2. Irritable bowel syndrome (IBS)
3. Inflammatory bowel disease (IBD)
4. Lactose intolerance
5. Small intestinal bacterial overgrowth (SIBO)
6. Tropical sprue
7. Giardiasis
8. Pancreatic insufficiency

7. Management

7.1 First-Line

• Strict lifelong gluten-free diet

7.2 Dietary Avoidance

• Avoid: wheat, barley, rye
• Ensure avoidance of cross-contamination

7.3 Supportive Care

1. Correction of nutritional deficiencies
• Iron, folate, vitamin B12, calcium, vitamin D
2. Dietitian-guided nutritional counseling
3. Monitor serologic markers for adherence

7.4 Special Treatment

• Dapsone for dermatitis herpetiformis

8. Complications

1. Malnutrition
2. Osteoporosis
3. Infertility
4. Neurologic complications
5. Enteropathy-associated T-cell lymphoma (EATL)
6. Small intestinal adenocarcinoma

9. Key Clinical Insight

A patient with chronic diarrhea + iron deficiency anemia + dermatitis herpetiformis strongly suggests celiac disease

10. Key Exam Points

1. Anti-tTG IgA = best initial test
2. Check total IgA level
3. Biopsy confirms diagnosis
4. Associated with HLA-DQ2/DQ8
5. Causes malabsorption → steatorrhea
6. Dermatitis herpetiformis = pathognomonic
7. Must be on gluten-containing diet before testing
8. Improves with gluten-free diet
9. Risk of T-cell lymphoma (EATL)

Multiple Sclerosis

A 32 year old female presents to the neurology clinic with a history of intermittent neurological symptoms over the past 18 months. She reports episodes of numbness, tingling, and mild weakness in her left leg that typically last about a week and resolve spontaneously. She notes that her symptoms worsen with heat exposure and after physical exertion. Over the past few months, she has also developed blurry vision in her right eye associated with pain on eye movement, along with urinary urgency and occasional incontinence. On examination, her vital signs are normal. Neurologic examination reveals mild weakness in the left leg with a motor strength of 4 out of 5, decreased sensation to light touch and vibration in the same limb, and hyperreflexia with an extensor plantar response on the left side. Cranial nerve examination shows decreased visual acuity in the right eye with a relative afferent pupillary defect, while fundoscopic examination is normal. Magnetic resonance imaging of the brain and spinal cord demonstrates multiple T2 and FLAIR hyperintense lesions in the periventricular regions. Cerebrospinal fluid analysis reveals oligoclonal IgG bands, and visual evoked potentials show delayed conduction in the right eye. What is the most likely diagnosis?

Diagnosis is Relapsing remitting multiple sclerosis.

1. Definition

Multiple sclerosis is a chronic immune mediated demyelinating disease of the central nervous system, characterized by inflammation, demyelination, gliosis, and neuroaxonal injury, with dissemination in time and space.

2. Types

1. Relapsing remitting multiple sclerosis, most common
2. Secondary progressive multiple sclerosis
3. Primary progressive multiple sclerosis

Additional categories:
4. Clinically isolated syndrome
5. Radiologically isolated syndrome

3. Etiology and Risk Factors

1. Exact cause is unknown
2. Immune dysregulation involving T cells, B cells, and macrophages
3. Environmental factors:
1. Higher latitude
2. Vitamin D deficiency
3. Epstein Barr virus infection
4. Smoking
4. Genetic association with HLA-DRB1*1501

4. Pathophysiology

1. Immune mediated destruction of myelin and oligodendrocytes
2. Formation of demyelinating plaques in:
1. Periventricular regions
2. Juxtacortical or cortical regions
3. Infratentorial regions
4. Spinal cord
3. Lesions often form around small veins
4. Active lesions show gadolinium enhancement
5. Chronic disease leads to axonal loss and gliosis

5. Clinical Features

1. Sensory symptoms such as paresthesia and vibration loss
2. Motor weakness, spasticity, hyperreflexia
3. Optic neuritis
4. Brainstem and cerebellar signs such as diplopia, ataxia, and vertigo
5. Bladder dysfunction, especially urgency and incontinence
6. Fatigue
7. Cognitive and mood disturbances

Characteristic signs:

1. Uhthoff phenomenon, worsening with heat
2. Lhermitte sign, electric shock sensation on neck flexion

6. Optic Neuritis

1. Subacute monocular vision loss
2. Pain with eye movement
3. Relative afferent pupillary defect
4. Color vision impairment
5. Fundoscopy may be normal in acute retrobulbar optic neuritis

7. Diagnosis

Diagnosis is based on clinical findings supported by MRI, CSF, and evoked potentials, with exclusion of alternative diagnoses.

7.1 MRI

1. T2 hyperintense lesions in:
1. Periventricular
2. Juxtacortical or cortical
3. Infratentorial
4. Spinal cord
2. Lesions may appear as Dawson fingers
3. Active lesions show gadolinium enhancement
4. Spinal cord lesions are typically short segment

7.2 CSF

1. Oligoclonal IgG bands
2. Increased IgG index

7.3 Evoked Potentials

1. Delayed conduction, especially visual evoked potentials

7.4 Additional Evaluation

1. Vitamin B12, TSH, ESR, ANA
2. AQP4-IgG and MOG-IgG when atypical features are present

8. Disease Course

8.1 Relapsing Remitting MS

1. Most common type
2. Episodes develop over days to weeks
3. Last more than 24 hours
4. Partial or complete recovery

8.2 Secondary Progressive MS

1. Gradual worsening after relapsing phase

8.3 Primary Progressive MS

1. Progressive disability from onset

9. Management

9.1 Acute Relapse

1. IV methylprednisolone 500 to 1000 mg daily for 3 to 7 days
2. Plasma exchange if steroid refractory

9.2 Disease Modifying Therapy

1. Interferon beta
2. Glatiramer acetate
3. Dimethyl fumarate
4. Fingolimod
5. Natalizumab
6. Ocrelizumab, especially important in progressive disease
7. Mitoxantrone, limited use due to toxicity

9.3 Symptomatic Treatment

1. Baclofen for spasticity
2. Gabapentin for neuropathic pain
3. Oxybutynin for bladder dysfunction
4. Modafinil for fatigue

9.4 Supportive Care

1. Exercise and rehabilitation
2. Avoid heat exposure
3. Smoking cessation
4. Vitamin D supplementation

10. Key Clinical Insight

Young female with relapsing neurologic deficits involving different CNS regions, optic neuritis, Uhthoff phenomenon, and characteristic MRI findings strongly suggests multiple sclerosis

11. Exam Level Pearls

1. Dissemination in time and space is required for diagnosis
2. Periventricular plaques and Dawson fingers are classic MRI findings
3. Optic neuritis with RAPD is a key presentation
4. Uhthoff phenomenon is characteristic of MS
5. Oligoclonal bands support diagnosis and may satisfy dissemination in time