Cystic fibrosis

Vignette says a 5 year old male child presents to the pediatric clinic by his parents due to recurrent pulmonary infections and failure to thrive; His mother reports that he has had several episodes of pulmonary infections requiring hospitalizations in the past; He also had a history of meconium ileus (intestinal obstruction) shortly after birth, which was treated with surgery; The mother states that the child has difficulty gaining weight, despite having a healthy appetite; On examination, he appears thin with digital clubbing and barrel shaped chest; Lung auscultation reveals bilateral crackles and wheezing; Sputum culture shows staphylococcus aureus; Chest x-ray shows mild hyperinflation; Sweat chloride test shows elevated chloride levels (i.e. > 60 mmol/L on two occasions after administration of pilocarpine); Genetic testing shows mutation in CFTR gene; Diagnosis?

Diagnosis is Cystic fibrosis.

Pathophysiology:- Mutation of CFTR gene on chromosome 7 (ΔF 508; deletion of phenylalanine) which codes for CFTR protein; CFTR gene encodes an cAMP-activated chloride channel that secretes chloride in lungs & GI tract and reabsorbs chloride in sweat glands that results in:-

1. Decreased chloride secretion and consequently increased sodium (via epithelial Na+ channels (ENaC)) and water resorption, causes abnormally thick mucus secretions into lungs and gastrointestinal tract.

2. Increased chloride secretion in sweat glands.

Clinical Features:-

1. GI features include meconium ileus (failure to pass stool in the first 24 hours after birth) in infants with abdominal distention; Pancreatic insufficiency with steatorrhea and vitamin A, D, E, and K malabsorption; Recurrent pancreatitis; Diabetes mellitus; Weight loss; Distal intestinal obstruction; Biliary cirrhosis; Failure to thrive.

2. Pulmonary features include recurrent respiratory infections (e.g. S aureus [infancy and early childhood], P aeruginosa [adulthood], allergic bronchopulmonary aspergillosis [ABPA]), chronic bronchitis and bronchiectasis), productive cough, dyspnea, chest pain, chronic sinusitis, nasal polyps, nail clubbing.

3. Infertility in males (due to congenital bilateral absence of vas deferens).

4. Heat exhaustion.

Diagnosis:-

1. Elevated sweat chloride test (i.e. > 60 mmol/L on two occasions after administration of pilocarpine).

2. Increased immunoreactive trypsinogen (newborn screening) due to clogging of the pancreatic duct.

3. CXR shows bronchiectasis (reticulonodular pattern on chest x-ray), Pneumothorax, Scarring, Atelectasis, Hyperinflation.

4. Sputum cultures often grow Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenzae.

5. Genetic testing shows mutation in CFTR gene.

6. Spirometry (i.e. pulmonary function test).

Management:-

1. Chest physiotherapy.

2. Antibiotics for infections.

3. Inhaled bronchodilators (e.g. albuterol, salbutamol).

4. Aerosolized dornase alfa (DNase) (mucolytics, breaks down the massive amounts of DNA in respiratory mucus that clogs up the airways); Inhaled hypertonic saline also facilitates mucus clearance; Aerosolized N-acetyl cysteine (mucolytics, breaks disulfide bonds).

5. Pneumococcal and influenza vaccinations. 

6. Pancreatic enzyme replacement therapy for pancreatic insufficiency; Fat soluble vitamins supplemention (e.g. A, D, E and K).

7. Combination of lumacaftor or tezacaftor (corrects misfolded proteins and facilitates their transport to cell surface) with ivacaftor (opens chloride channels which improves chloride transport).

8. Lung transplantation.

Celiac disease

Vignette says a 34 year old female presents to the gastroenterology clinic with the history of chronic diarrhea, bloating, intermittent abdominal pain and unintentional weight loss over the duration of 6 months; She describes her stool as loose, foul smelling and difficult to flush; She also reports fatigue and generalized weakness; She was previously diagnosed iron deficiency anemia and takes iron supplements; She notes a recent onset of pruritic rash with vesicles on her elbows and knees; On physical examination, her BMI is 21 kg/m2; CBC shows microcytic anemia; Iron studies show ↓ferritin, ↑TIBC, ↓serum iron, ↓% saturation; Serology shows positive anti-tTG, anti endomysial and anti deamidated gliadin antibodies; Small bowel biopsy shows villous atrophy, intra epithelial lymphocytes and crypts hyperplasia; D-xylose test shows decreased D-xylose absorption; Diagnosis?

Diagnosis is Celiac disease.

Celiac disease is an autoimmune condition characterized by immune-driven inflammation of the small intestine in response to the ingestion of gluten diet (i.e. Intolerance to gluten diet).

Presents with chronic diarrhea, bloating, abdominal discomfort, dermatitis herpetiformis (pruritic vesicular rash on extensor surfaces), weight loss, vitamin and mineral deficiencies in adults; Associated with HLA-DQ2, HLA-DQ8.

Diagnosis:-

1. CBC shows microcytic anemia (as celiac disease is associated with IDA).

2. Iron studies show ↓ferritin, ↑TIBC, ↓serum iron, ↓% saturation.

3. Serology shows anti-tTG, anti endomysial and anti deamidated gliadin antibodies.

4. Biopsy shows villous atrophy, intra epithelial lymphocytes and crypts hyperplasia.

5. Stool examination with sudan stain detects fat in stools.

6. The D-xylose test is abnormal.

Management:-

1. Gluten free diet; Avoid food containing wheat, barley and rye.

2. Supplementation of vitamins and minerals to address deficiencies.

2. Dapsone is used to treat dermatitis herpetiformis.

Multiple sclerosis

Vignette says a 32 year old female presents to the neurology clinic with intermittent episodes of limb weakness and sensory disturbances in her left leg over the past 18 months; She reports numbness and tingling in her left leg, along with mild weakness for 7 days and her symptoms are particularly worse in hot climate, and after exercise; Over the past few months, she also reports of blurry vision in her right eye, with pain on eye movements and also urinary incontinence; Vital signs are normal; Examination findings show:-
Motor:- Mild weakness with MRC grade of 4/5 in the left leg and 5/5 in the right leg.
Sensory:- Decreased sensation to light touch and vibration in the left leg.
Reflexes:- Hyperreflexia in the left leg with positive Babinski sign on the left leg.
Cranial nerves:- Decreased visual acuity in the right eye with positive relative afferent pupillary defect (RAPD) in the right eye. Fundoscopic examination is normal.
MRI of the brain and spinal cord shows multiple hyperintense lesions (i.e. demyelinating lesions) within the periventricular areas on T2/FLAIR images; CSF analysis shows IgG oligoclonal bands; Visual evoked potential shows delayed latency in the right eye; Diagnosis?

Diagnosis is Multiple sclerosis (i.e. relapsing remitting multiple sclerosis).

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system.

Types:-

1. Relapsing remitting type (MC type)

2. Primary progressive type

3. Secondary progressive type

Presents with fatigue, sensory deficits, motor weakness, autonomic disturbances, cranial nerve deficits, and visual disturbances (e.g. optic neuritis, INO); Higher prevalence in individuals residing in the northern part (due to vitamin D deficiency); Associated with Uhthoff's phenomenon (i.e. symptoms worse in heat), Lhermitte's sign (i.e. radicular pain in legs with neck flexion); Urinary incontinence (i.e. urge incontinence).

Optic neuritis is the first presenting symptom of multiple sclerosis; Presents with vision loss, pain with eye movements, RAPD or Marcus gunn pupil, color vision deficiency and Uhthoff’s phenomenon. Fundoscopy is normal in the acute phase but shows optic disc pallor in the chronic phase.

Diagnosis:-

1. MRI of the brain and spinal cord shows multiple hyperintense lesions (i.e. demyelinating lesions) within the periventricular, juxtacortical and infratentorial areas on T2/FLAIR images i.e. multiple sclerotic plaques (demyelinating lesions) within the periventricular, juxtacortical and infratentorial areas.

2. CSF analysis shows IgG oligoclonal bands.

3. Visual evoked potential tests.

Management:-

1. Acute attacks are managed with high dose corticosteroids (e.g. IV methylprednisolone).

2. Disease-modifying therapies are the mainstay of treatment of relapsing-remitting MS;

Disease modifying drugs are:-

a. Interferon-beta

b. Fingolimod

c. Natalizumab (associated with progressive multifocal leukoencephalopathy due to JC virus reactivation)

d. Glatiramer

e. Rituximab

3. Symptomatic measures are gabapentin for neuropathic pain, baclofen for spasticity, oxybutynin (muscarinic cholinergic antagonist) for urge incontinence, SSRIs for major depression disorder and modafinil for fatigue.

4. Supportive measures are exercise, avoid excessive heat, smoking cessation, and vitamin D supplementation.