Clinical Vignette 3

Question 1

What the most common manifestations of von Hippel-Lindau (VHL) disease? What is their nature?

Answer 1

Many of the disease manifestations are vascular in nature.– Hemangioblastoma (CNS or retinal angiomas) – Renal cell carcinoma (clear cell type) – Pheochromocytoma (catecholamine secreting tumors that arise from the adrenals) – Multiple tumors are oftentimes seen in a single organ

Question 2

What role does VHL play in the regulation of Hif 1-alpha? What are the consequences of mutations in VHL?

Answer 2

The protein VHL is part of a multi-protein complex that targets selected proteins including Hypoxiainducible factor (Hif)-alpha for degradation via ubiquitylation. Hif-alpha is usually regulated with respect to the cellular oxygen levels (e.g. degraded with normoxia and not degraded with hypoxic conditions). When VHL is dysfunctional, Hif-alpha levels increase in an uncontrolled manner and trigger the production of several vascular promoting actors including VEGF (vascular endothelial growth factor) and PDGF (platelet derived growth factor).

Question 3

What happens to VHL in many cases of renal cell carcinoma that are not associated with inherited von Hippel-Lindau disease?

Answer 3

It is estimated that 60-70% of sporadic clear-cell kidney cancer have spontaneous mutations that lead to inactivation of both VHL alleles. The disease can also be the result of hyper-methylation of the promoter.

Question 4

What are recently approved biologically targeted agents to treat renal cell carcinoma are based on?

Answer 4

The pathophysiology of the VHL mutation. Duh. In particular this means that therapeutics (Sutent + Nexavar) are aiming at regulating VEGF.

Question 5

What are the three core ethical principles relevant to clinical research?

Answer 5

Respect for persons: use dignity, respect their ability to make autonomous decisions Beneficence: Benefits to society should outweigh the risks, risks should be minimizedJustice: there is just distribution of both benefits and risk of research

Question 6

What is the Belmont report?

Answer 6

The document from 1979 outlining ethical principles for clinical research.

Question 7

What are the basic functions of an IRB?

Answer 7

Protect people’s rights and interests
Guard against exploitation of research subjects
Help protect safety of research subjects
Strive for fairness in selection of research participants, equitable distribution of risks and benefits of research

Question 8

Understand the basic mechanisms of nerve conduction.

Answer 8

Electrical transmission of messages from brain to muscles along nerve fibers via action potentials. Cells are depolarized because channels are opened and ions move. Neurotransmitters are released between cells allowing the message to reach its targeted destination.

Question 9

Understand the consequences of demyelination in nerve conduction.

Answer 9

Demyelination = neuronal damageSlower conduction of action potentials because of ↑ membrane capacitance and ↓ membrane resistance. Proliferation of sodium channels along the axon causes the ↓ membrane resistance. Symptoms of MS: Fatigue, Walking impairment, Spasticity, Cognitive impairment, Bladder dysfunction, Pain, Mood instability, Sexual dysfunction

Question 10

Understand how certain therapies might improve nerve function.

Answer 10

Sodium channel blockers, including phenytoin and flecainide, preserve axons in the animal model of MS. K+ channel blockade: Enhances conduction of action potentials in demyelinated axons through inhibition of K+ channels

Question 11

Review the pathophysiology of Diabetic Ketoacidosis (DKA).

Answer 11

Ketones accumulate in the blood as an acid resulting in excess H+This drives the reaction: H+ + HCO3-↔ H2CO3↔ H2O+CO2
Excess CO2 is eliminated through the lungs: Kussmaul respirations
The majority of the K+ is intracellularIn acidosis H+ extracellular is exchanged for K+ intracellularK+ is lost in the urine
Net result is total body K+ depletion in the face of normal or high normal K+ level in the blood

Question 12

Understand the evolution of potassium (K+) during the development and initial treatment of DKA

Answer 12

Complications of treatment of diabetic ketoacidosis include change in potassium levels and cerebral edema. Potassium is mostly intracellular. During the evolution of diabetic ketoacidosis, potassium is exchanged for hydrogen and lost in the urine. Therefore, although serum levels of potassium may be normal or even high normal, the total body levels of potassium are low. Treatment with insulin improves the acidosis and drives the potassium intracellularly resulting in decreasing potassium levels and risk for hypokalemia

Question 13

Describe risk for cerebral edema in DKA.

Answer 13

Cerebral edema is the major cause of death in pediatric cases of diabetic ketoacidosis. Because brain capillaries are more permeable to water than glucose the osmotic pressure forces water into the skull. Not good. It results from shifts of fluids during the treatment of diabetic ketoacidosis. Preventing significant morbidity and mortality requires careful monitoring for changes in metal status and prompt treatment with mannitol. Mannitol does not cross the blood brain barrier and therefore acts as an osmotic load to pull free water from the brain and decrease edema and pressure.

Question 14

Review insulin release.

Answer 14

Glucose enters the ß-cell through the GLUT-2 transporter.Glucose is then phosphorylated by glucokinase ultimately causing the ratio of ATP to ADP to increase. This serves as a signal to close the potassium channels. Closure of this potassium channel depolarizes the membrane, opening the voltage dependent calcium channel, allowing an influx of calcium. Calcium causes exocytosis of insulin containing secretory granules. Insulin then travels to the liver and increases formation of glycogen, decreases gluconeogensis and lipolysis and travels to the muscle allowing glucose to enter the cell.

Question 15

Understand the key clinical features of cholera infection.

Answer 15

Voluminous watery feces (rice water) with bits of mucus, vomiting, severe and rapid dehydration.

Question 16

Understand the role of cholera toxin A and B and the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) in cholera infection.

Answer 16

Cholera toxin (A subunit is active site, B is transport unit). Binds to cell, creates cAMP, which goes to activate CFTR channel, lots of Cl- flows into intestines followed by Na+ and water.

Question 17

Understand the physiology behind oral rehydration therapies.

Answer 17

Rehydrating solutions help replace stool loss. This works because there are solute coupled sodium transporters in the lumen of the intestines (Na+ + glucose) etc. Need Na+:Glucose ratio of 1:1 to 1:1.4 to take advantage of transporters maximally. Too much glucose will lead to more diarrhea.

Question 18

List causes of hyperkalemia.

Answer 18

1. Muscle cell death. 2. Redistribution in which potassium is shifted out of cells. 3. Impaired renal potassium secretion from drugs and/or reduced GFR. 4. High potassium foods. Foods that are high in potassium include avocados, tomatoes, potatoes, citrus, prunes and bananas.

Question 19

Know signs and symptoms of hyperkalemia.

Answer 19

Hyperkalemia is often asymptomatic. It can present as muscle weakness. EKG changes show peaked T waves and shortened QT intervals progressing to lengthening of PR and QRS intervals and ultimately sine waves.

Question 20

Know which foods are high in potassium.

Answer 20

Foods that are high in potassium include avocados, tomatoes, potatoes, citrus, prunes and bananas.

Question 21

Know why certain people are more susceptible to hyperkalemia.

Answer 21

They have reduced kidney function and thus a reduced ability to excrete potassium. Such people are usually on an ACE inhibitor which can impair potassium excretion. This can also occur in individuals with diabetes for many years. Longstanding diabetes can kill the juxtaglomerular cells in the kidney that produce rennin. Thus diabetics often have decreased levels of aldosterone and aldosterone is important for renal excretion of potassium. A person who takes beta blockers is at risk as well.

Question 22

List causes of hypokalemia.

Answer 22

Pseudohypokalemia from leukocytosis. This happens when the serum is left at room temperature for a while before analysis causing the WBCs to take up potassium. Redistribution. Factors which shift potassium into cells such as insulin excess or beta adrenergic stimulation can cause hypokalemia.Non-renal losses from the skin (excess sweating) or GI tract (diarrhea) can result in hypokalemia. Renal causes of hypokalemia include: a. Drugs that cause potassium wasting such as thiazide and loop diuretics, antifungal medications such as amphotericin and chemotherapy agents such as cisplatin. b. Hyperaldosteronism (excess aldosterone) can also lead to low blood potassium levels by causing the kidneys to excrete potassium. c. Intrinsic renal defects such as defects in sodium or chloride channels can cause hypokalemia. d.Finally, magnesium depletion can lead to hypokalemia. This should be suspected in cases where aggressive potassium repletion does not result in significant increases in serum potassium levels.

Question 23

Know signs and symptoms of hypokalemia.

Answer 23

Hypokalemia can cause increased blood pressure through vasoconstriction. More seriously it can lead to ventricular arrhythmias. Hypokalemia can result in impaired muscle contraction and, if it is severe enough, even paralysis. It can also lead to renal tubulointerstitial fibrosis and renal cyst formation. Hypokalemia can cause problems in patients with liver disease as low serum potassium leads to increased renal ammonia production which can worsen hepatic encephalopathy.