Alpha-1 Antitrypsin Deficiency, CF😍

Mnemonic for Antitrypsin deficiency

• Tryp (α1 AT) poi
• Lovely (Liver, lungs) trip with child (children) for 14 (Chr 14) days

• Pizza (PIZZ) kazhichu, Pasta (PAS +ve) kazhichu

• But child ullond dive (Diastase resistant) cheythilla

• Sarpathina kandu (SERPINA gene)

Cystic Fibrosis

Amylase is raised in all of the following conditions except :

• Inheritance: Autosomal recessive

• Defect:
• CFTR gene on chromosome 7 (p or q)
• commonly Delta F508 mutation
• → due to deletion of phenylalanine at 508th position.

• M/c class of mutation
• CLASS 2 Trafficking

PATHOPHYSIOLOGY

• CFTR = ATP-gated Cl⁻ channel
• Normally:
• secretes Cl⁻ in lungs/GI & reabsorbs Cl⁻ in sweat glands

• Phe508 deletion → misfolded protein → improper trafficking → less Cl⁻ (and H2O) secretion → ENaC overactivity → ↑ Na⁺/H₂O reabsorption → mucus dehydration → abnormally thick mucus secreted into lungs/GI tract
• Mucoviscidosis: Thick mucus secretions throughout the body.
• There is no defect in the cilia.

Gastrointestinal Tract Features

• Normal Meconium Passage: 
• Within 24 hours after birth.

• Meconium ileus (newborns):
• 10-15% patients.
• Impaction of thick meconium in ileum → intestinal obstruction at ileum → delayed passage of meconium & abdominal distension → Virtually diagnostic of CF
• Contrast enema
• shows microcolon + filling defects.
• Distended small intestine (d/t obstruction) proximal to terminal ileum.

• Constipation (Older children):
• Distal Intestinal Obstruction Syndrome (DIOS).

• Pancreatic Insufficiency (85% cases):



• Acini is affected → secrete enzymes with thick, sticky mucus → obstructs the pancreatic ducts → prevent flow of digestive enzymes
• Initially exocrine → Later endocrine.
• Exocrine Features:
• Steatorrhea
• Vitamin A, D, E, K deficiency
• Endocrine Features (2nd decade):
• Diabetes mellitus

Differential Diagnosis (D/D)

• Ano-rectal malformations

• Hirschsprung's disease

Respiratory Tract Features

• Bilateral nasal polyps

• Recurrent infections by catalase positive organisms:
• < 16 yrs: Staphylococcus aureus (M/C) → in early childhood.
• > 16 yrs: Pseudomonas:
• In late childhood/adults.
• Causes mucoid secretions → Forms biofilm → Antibiotic resistance.
• Burkholderia cepacia:
• ↑ risk of death.
• Mnemonic: Buckingham Palace Sheppoi in microbiology
• H. influenzae type B.

Other Features

• Biliary Tract:
• Thick biliary secretions → Bile outflow obstruction → Biliary cirrhosis/neonatal cholestasis.

• Genitourinary Tract:
• Males: Failure of Wolffian duct development → Azoospermia → Infertility.
• absence of B/L vas deferens / seminal vesicle
• spermatogenesis may be unaffected
• Females: ↓ Fertility rate.

• Sweat Glands:
• Inactive CFTR protein → ↑ loss of Na⁺/Cl⁻ in sweat (↓ Reabsorption).
• Salty skin (on kissing).
• Frosting of skin.
• Predisposed to hyponatremic hypochloremic metabolic alkalosis.
• ↑ in sweat Cl⁻ test.

Investigations

 

• X-ray:
• "Soap-bubble" appearance (AKA Neuhauser sign)
• Microcolon: Meconium has not reached the colon.
• NO Air fluid levels.
• Ground glass appearance.

Sweat Chloride Test

• Confirmatory for Cystic Fibrosis.

• Elevated chloride levels in sweat.

• Pilocarpine Iontophoresis:
• Pilocarpine administered into skin via electrodes;
• Sweat collected for Cl⁻ levels processing.

DIAGNOSIS

Clinical

• Positive for any one of the following
• Typical clinical features (respiratory/gastrointestinal/genitourinary).
• History of CF in a sibling (Autosomal Recessive - AR).

Laboratory

• Any 1 positive lab test confirms CF:
• Sweat chloride concentrations
• ≥ 60 mEq/L on separate days.
• Pilocarpine iontophoresis
• Identification of CF mutations.
• Abnormal trans epithelial nasal potential difference.

Associated with:

• Metabolic alkalosis (contraction alkalosis)
• Hyponatremic hypochloremic metabolic alkalosis.

• Hypokalemia

• ↑ Immunoreactive trypsinogen (newborn screening)
• due to clogging of pancreatic duct.

Management of Cystic Fibrosis

• Gastrograffin Enema:
• Contrast enema
• Water soluble.
• Mixes with meconium.
• Forms a bulk to loosen the meconium.

• Bishop Koop Surgery:
• Indicated if not responsive to enema
• Ileostomy performed to manually irrigate the bowel.

• CF → ↑↑ immunoreactive Trypinogen (newborn screening) → Bishop Koop → New house (Neuhauser)

• Koch Appi idunilla → call Bishop (Bishop Koop) → Bishop told its because of New House’s (Neuhauser) Door (Dornase α)

TREATMENT

• Airway clearance:
• Chest physiotherapy,
• Mucolytics → Inhaled DNase
• Human recombinant DNAse.
• Human dornase alfa.
• hypertonic saline

• Infections:
• Azithromycin (prophylaxis), other antibiotics

• Prophylaxis for Pseudomonas infection 
  (3 times a week, decreases colonization):
• Inhaled Tobramycin/Aztreonam.
• Oral Azithromycin.

• Pancreas:
• Enzyme replacement

CFTR modulators:

• TRIKAFTA:
• Elexacaftor + Tezacaftor + Ivacaftor 
• Alexa Tessa Ivani

• Potentiators
• open CFTR
• Ivacaftor

• Correctors
• help folding and trafficking
• Lumacaftor, tezacaftor, Elexacaftor

• Ivan (Ivacaftor) Pottan (Potentiator) anu → Correct cheyyan Luma (Lumacaftor) Teacher (Tezacaftor) ne vilikku

Meconium ileus

Causes

1. Prematurity

2. Hypothyroidism

3. Cystic Fibrosis
• Present with other features of CF
• Soap bubble appearance
• NO AIR FLUID LEVEL (dry thick impacted meconium)
• Bishop Koop surgery
• Stippled calcification d/t inspissated stools

4. Hirschsprung disease
• present within 48hrs,
• abdominal distension and bilious vomiting
• On per rectal examination
• On removal of finger
• Sudden expulsion of meconium d/t transient dilatation

5. Anorectal malformation

6. Lazy Left colon syndrome
• Infant of Diabetic mother
• d/t ↓ gut motility → delayed passing of meconium