# Clinical Cases: Cell Membrane Physiology ## Case 1: Cystic Fibrosis - CFTR Channel Dysfunction ### Clinical Image ![Cystic Fibrosis](case_01_image.jpg) *Source: [Wikimedia Commons - Cystic fibrosis](https://commons.wikimedia.org/wiki/File:Cystic_fibrosis01.jpg) - CC BY-SA 3.0* ### Patient Presentation A 6-month-old male infant is brought to the pediatric clinic by his parents due to failure to thrive, recurrent respiratory infections, and foul-smelling, greasy stools. The parents report that the child was diagnosed with meconium ileus at birth requiring surgical intervention. They also noticed that his skin tastes unusually salty when they kiss him. ### Demographics - Age: 6 months - Sex: Male - Ethnicity: Caucasian ### Chief Complaint Failure to thrive, recurrent respiratory infections, and steatorrhea ### Physical Examination - Weight: 5.8 kg (below 3rd percentile) - Length: 62 cm (10th percentile) - Digital clubbing: Early changes noted - Respiratory: Scattered crackles bilaterally, mild tachypnea - Abdomen: Mildly distended with palpable stool in right lower quadrant - Skin: Normal turgor, slightly salty taste noted on examination ### Workup - Sweat chloride test: 85 mEq/L (diagnostic; normal <30 mEq/L) - Genetic testing: Homozygous for F508del mutation in CFTR gene - Chest X-ray: Hyperinflation with peribronchial thickening - Stool elastase: <100 mcg/g (indicates pancreatic insufficiency) - Sputum culture: Staphylococcus aureus ### Diagnosis Cystic Fibrosis with pancreatic insufficiency and early pulmonary disease ### Treatment 1. Pancreatic enzyme replacement therapy (PERT) with meals 2. Fat-soluble vitamin supplementation (A, D, E, K) 3. High-calorie, high-fat diet 4. Airway clearance therapy (chest physiotherapy) 5. Nebulized hypertonic saline 6. CFTR modulator therapy (elexacaftor/tezacaftor/ivacaftor for eligible genotypes) 7. Prophylactic antibiotics as needed 8. Multidisciplinary care at a CF center ### Physiological Principles Demonstrated - **CFTR as a chloride channel**: The CFTR protein functions as a chloride channel in epithelial cell membranes. The F508del mutation causes misfolding and degradation of the channel protein, preventing its insertion into the cell membrane. - **Chloride and water transport**: Without functional CFTR, chloride cannot be secreted into the airway lumen. Water follows chloride osmotically; therefore, reduced chloride secretion leads to dehydrated, thick mucus that cannot be cleared effectively. - **Sweat gland physiology**: In sweat glands, CFTR normally reabsorbs chloride (and sodium follows). Dysfunctional CFTR leads to elevated sweat chloride, the basis for the diagnostic sweat test. - **Secondary active transport**: CFTR dysfunction also affects ENaC (epithelial sodium channel) regulation, further altering ion and water balance across epithelia. --- ## Case 2: Hyperkalemia - Membrane Potential Disturbance ### Clinical Image ![ECG in Hyperkalemia](case_02_image.jpg) *Source: [Wikimedia Commons - ECG in hyperkalemia](https://commons.wikimedia.org/wiki/File:ECG_in_hyperkalemia.svg) - CC BY-SA 3.0* ### Patient Presentation A 68-year-old male with a history of chronic kidney disease (CKD stage 4), type 2 diabetes mellitus, and hypertension presents to the emergency department with generalized weakness, fatigue, and palpitations that began this morning. He ran out of his prescribed medications, including furosemide and sodium polystyrene sulfonate, one week ago and has been eating his usual diet including bananas and orange juice daily. ### Demographics - Age: 68 years - Sex: Male - Past Medical History: CKD stage 4, Type 2 DM, HTN ### Chief Complaint Generalized weakness, fatigue, and palpitations ### Physical Examination - Blood pressure: 158/94 mmHg - Heart rate: 52 bpm (bradycardic) - Temperature: 36.8C - Respiratory rate: 16/min - General: Alert but appears fatigued - Cardiovascular: Bradycardic, irregular rhythm, no murmurs - Neurological: Decreased deep tendon reflexes, mild proximal muscle weakness - Extremities: 1+ bilateral lower extremity edema ### Workup - Serum potassium: 7.2 mEq/L (severely elevated; normal 3.5-5.0) - Serum creatinine: 4.8 mg/dL (elevated from baseline of 3.5) - BUN: 68 mg/dL - Glucose: 186 mg/dL - ECG: Peaked T waves, prolonged PR interval (0.24s), widened QRS (0.14s) ### Diagnosis Severe hyperkalemia with ECG changes in the setting of acute-on-chronic kidney disease ### Treatment 1. Immediate cardiac monitoring 2. IV calcium gluconate 1g for cardiac membrane stabilization (immediate effect) 3. IV regular insulin 10 units with D50W to shift potassium intracellularly 4. Nebulized albuterol to promote intracellular potassium shift 5. Sodium bicarbonate if acidemic 6. Sodium polystyrene sulfonate (Kayexalate) or patiromer for potassium elimination 7. Consider emergent hemodialysis if refractory 8. Dietary potassium restriction education 9. Medication reconciliation and adherence counseling ### Physiological Principles Demonstrated - **Resting membrane potential**: The resting membrane potential (-70 to -90 mV) depends on the potassium gradient across the cell membrane. Normal intracellular K+ is ~140 mEq/L while extracellular is ~4 mEq/L. - **Nernst equation**: The equilibrium potential for potassium (E_K = -94 mV) approaches zero as extracellular potassium rises, depolarizing the resting membrane potential. - **Effect on excitability**: Elevated extracellular K+ reduces the K+ gradient, partially depolarizing cardiac myocytes. This inactivates sodium channels, reducing excitability and slowing conduction. - **ECG manifestations**: Progressive hyperkalemia causes peaked T waves (rapid K+ repolarization), prolonged PR interval (slowed atrial conduction), widened QRS (slowed ventricular conduction), and eventually sine wave pattern leading to ventricular fibrillation or asystole. - **Na+/K+-ATPase**: Insulin stimulates the Na+/K+-ATPase, actively pumping potassium into cells and temporarily lowering serum levels. Beta-2 agonists like albuterol have a similar effect. - **Calcium and membrane stabilization**: Calcium gluconate increases the threshold potential, widening the gap between resting and threshold potentials, protecting against arrhythmias without changing serum potassium. --- ## Case 3: Digoxin Toxicity - Na+/K+-ATPase Inhibition ### Clinical Image ![Digoxin Toxicity ECG](case_01_image.jpg) *Source: Clinical case illustration - Na+/K+-ATPase inhibition mechanism* ### Patient Presentation A 78-year-old female with a history of atrial fibrillation and heart failure with reduced ejection fraction (HFrEF) presents with nausea, vomiting, visual disturbances (seeing yellow-green halos around lights), and confusion over the past two days. She recently started taking a new medication for her arthritis (ibuprofen) prescribed by another physician. ### Demographics - Age: 78 years - Sex: Female - Past Medical History: Atrial fibrillation, HFrEF (EF 35%), CKD stage 3 ### Chief Complaint Nausea, vomiting, visual disturbances, and confusion ### Physical Examination - Blood pressure: 110/68 mmHg - Heart rate: 44 bpm (bradycardic) - Temperature: 36.5C - General: Confused, oriented to person only - Cardiovascular: Irregularly irregular rhythm, now with long pauses - Neurological: Mild disorientation, visual complaints of yellow-green halos ### Workup - Serum digoxin level: 3.8 ng/mL (toxic; therapeutic 0.8-2.0 ng/mL) - Serum potassium: 5.8 mEq/L (elevated) - Serum creatinine: 2.1 mg/dL (increased from baseline 1.4) - ECG: Atrial fibrillation with complete heart block and slow ventricular escape rhythm, ST segment "scooping" (digoxin effect) ### Diagnosis Digoxin toxicity precipitated by NSAID-induced acute kidney injury and drug interaction ### Treatment 1. Discontinue digoxin immediately 2. Discontinue ibuprofen 3. Digoxin immune Fab (Digibind) for life-threatening arrhythmias 4. Correct electrolyte abnormalities (avoid giving calcium) 5. Temporary pacing if symptomatic bradycardia persists 6. IV fluids for AKI management 7. Supportive care for GI and neurological symptoms 8. Drug interaction education upon discharge ### Physiological Principles Demonstrated - **Na+/K+-ATPase function**: The Na+/K+-ATPase maintains electrochemical gradients by pumping 3 Na+ out and 2 K+ in per ATP hydrolyzed. This pump consumes ~30% of cellular ATP at rest. - **Digoxin mechanism**: Cardiac glycosides like digoxin inhibit the Na+/K+-ATPase, increasing intracellular Na+. This reduces the gradient driving the Na+/Ca2+ exchanger (NCX), leading to less calcium extrusion and higher intracellular calcium, enhancing contractility. - **Toxicity mechanism**: Excessive Na+/K+-ATPase inhibition causes dangerous intracellular calcium overload, leading to delayed afterdepolarizations, triggered activity, and arrhythmias. Hyperkalemia worsens toxicity by further impairing the pump. - **Drug interactions**: NSAIDs reduce renal blood flow and GFR, decreasing digoxin clearance (digoxin is renally eliminated) and precipitating toxicity. - **Antidote mechanism**: Digoxin immune Fab (Digibind) binds free digoxin in the bloodstream, preventing it from binding to the Na+/K+-ATPase and allowing redistribution from tissues.