Disorders of potassium metabolism

Yu-Hong Jia, Ph.DDepartment of pathophysiologyDalian medical university

Potassium function

• Participates in many metabolic processes, e.g. regulation of protein and glycogen synthesis.

• Maintain osmotic and acid-base balance between intra- and extra- cell.

• Maintain resting membrane potential (RMP) of cellular membrane.

Ⅰ. Normal potassium metabolism

K+

Na+ATPase

K+

H+K+ ch

anne

l

140-160 mmol/L4.2±0.3mmol/L

50-200mmol/day K+ ingestion

Kidneycolon

skin

(90%)

insulin

β-adrenergic agonist

ECF [K+]

K+: 50-55mmol/kg B.W

toxin (Ba)

acid-base state

Pump-leak

① free filtration

② reabsorption (90% of filtered potassium)

③secretion or reabsorption (in normal diet, secretion is major)

K+

K+

K+

Proximal tubule &Henle’s loop

Distal tubule & Collecting duct

Three elements for achieving potassium secretion:

1. Na+-K+-ATPase on basolateral membrane

2. Permeability of luminal membrane to K+

3. Electrochemical gradient from blood to tubular lumen

ATPaseNa+

K+

K+ channel

K+

Principal cell

Basolateral membrane

luminal membrane

peritubular interstitial

tubular lumen

K+

factors affecting renal secretion of K+

•↑the activity of Na+-K+-ATPase in principle cells;

•↑luminal membrane permeability to K+

•↑the activity of Na+-K+-ATPase

•↑luminal membrane permeability to potassium

•↓K+ concentration gradient between interstitial fluid and tubular cell →↓K+ counterflow into the interstitial fluid

•↑urinary flow rate→ rapidly remove the K+ secrected by tubular cells→↓ the K+ concentration in tubular lunmen→↑K+ concentration gradient across luminal membrane→↑ K+ secretion

•Increased H+ concentration inhibits Na+-K+-ATPase in principle cells →↓ K+ secretion, on the contrary, ↓H+ concentration→↑K+ secretion

•aldosterone（ ADS）• Extracellular K+ concentration

• Urinary flow rate

•Acid-base state

↑

↑ ↑K+ secretion

↑K+ secretion

↑K+ secretion

K+

Na+ATPase

K+

H+K+ ch

anne

l

140-160 mmol/L4.2±0.3mmol/L

50-200mmol K+ ingestion

Kidneycolon

skin

(90%)

insulin

β-adrenergic agonist

ECF [K+]

50-55mmol/kg B.W

ADS

ECF K+ concentration

Urinary flow rate

acid-base state

toxin drug

acid-base state

Ⅱ. Disorders of potassium metabolism

Classification of Disorders of potassium metabolism:

• Hypokalemia– Serum potassium concentr

ation <3.5mmol/L1. Etiology and pathogenesis

(1). ↓Potassium intake(2). Potassium shift from extracell

ular to intracellular fluid(3). ↑potassium excretion

• Hyperkalemia– Serum potassium concent

ration >5.5mmol/L1. Etiology and pathogenesei

(1). ↑Potassium intake(2). Potassium shift from intrace

llular to extracellular fluid

(3). ↓potassium excretion

hypokalemia, hyperkalemia Potassium deficit

Hypokalemia,

normal serum potassium

Hypokalemia: etiology and pathogenesis

(3). ↑K+ excretion

•Unable to eat, i.e. coma, digestive tract obstruction

•Fasting, i.e. after operation of digestive tract

(1). ↓K+ intake

(2). ↑K+ shift from ECF to ICF

•Use of some drug, i.e. insulin, β-adrenergic agonist

•Toxin poisoning, i.e. barium

•Alkalosis

•Familial hypokalemic periodic paralysis

•Via kidney

•Via gastrointestinal tract

•Via skin

Familial hypokalemic periodic paralysis

• A rare inherited disorder with autosomal dominant trait.

• Characteristic feature: recurrent episodes of muscle weakness accompanied with hypokalemia, automatically relieved without treatment.

• Mechanism: related with mutation of genes coding for skeletal muscle L-type calcium channel, sodium channel αsubuint, or potassium channel accessory subunit.

Excessive renal loss of potassium

• Use of certain diuretic agents i.e. acetazolamide and furosemide.

• Primary and secondary aldosteronism

• Alkalosis• Renal tubular acidosis• Magnesium deficit

↑Urinary flow rate

↓ECF volume→ secondary ADS increase

K+

H+alkalosis

Renal tubular acidosis (RTA)

• Acidosis caused by renal tubular dysfunction.– Type RTA: distal renal tubular acidosis, cauⅠ

sed by reduced H+ secretion in the distal nephron

– Type RTA: proximal renal tubular acidosis, Ⅱcaused by impaired reabsorption of HCO3

- in the proximal tubule.

Hypokalemia: etiology and pathogenesis

(3). ↑K+ excretion

•Unable to eat, i.e. coma, digestive tract obstruction

•Fasting, i.e. after operation of digestive tract

(1). ↓K+ intake

(2). ↑K+ shift from ECF to ICF

•Use of some drug, i.e. insulin, β-adrenergic agonist

•Toxin poisoning, i.e. barium

•Alkalosis

•Familial hypokalemic periodic paralysis

•Via kidney

•Via gastrointestinal tract

•Via skin

Use of certain diuretic agents, Primary and secondary aldosteronismAlkalosis, Renal tubular acidosis, Magnesium deficit

Excessive gastrointestinal loss of K+ —vomit, diarrhea, gastric suction

• Direct K+ loss through gastrointestinal juice• Gastrointestinal juice loss→ extracellular fluid vo

lume decrease→ ADS secretion increase→ renal excretion of K+ increase

• vomiting→ gastric acid (HCl) loss → alkalosis is resulted in →K+ shift into cells via H+-K+ exchange and increased renal excretion of K+

Hypokalemia: etiology and pathogenesis

(3). ↑K+ excretion

•Unable to eat, i.e. coma, digestive tract obstruction

•Fasting, i.e. after operation of digestive tract

(1). ↓K+ intake

(2). ↑K+ shift from ECF to ICF

•Use of some drug, i.e. insulin, β-adrenergic agonist

•Toxin poisoning, i.e. barium

•Alkalosis

•Familial hypokalemic periodic paralysis

•Via kidney

•Via gastrointestinal tract

•Via skin

Use of certain diuretic agents, Primary and secondary aldosteronismAlkalosis, Renal tubular acidosis, Magnesium deficit

Vomit, dirrhea, gastric suction

Heavy sweat in hot environment

Hyperkalemia: etiology and pathogenesis

(3). ↓K+ excretion

•Rapid intravenous infusion of KCl or potassium salt of penicillin

(1). ↑K+ intake

(2). ↑K+ shift from ICF to ECF•Deficiency of insulin, i.e. diabetes mellitus

•β-adrenergic antagonist

•acidosis

•Cell injury, i.e. trauma, hemolysis

•Familial hyperkalemic periodic paralysis

•Glomerular filtration rate decrease, i.e. oliguric stage of renal failure

•Renal tubular secretion of K+ decrease

•↓ADS, i.e. adrenal cortical insufficiency ( Addison disease)

•acidosis

Familial hyperkalemia periodic paralysis

• A rare inherited disorder with autosomal dominant trait.

• A sudden increase in serum potassium concentration and muscle paralysis

2. Alterations of metabolism and function

– Dysfunction related with abnormal resting membrane potential

– Damage related with cellular metabolism dysfunction

– Effect on acid-base balance

Electrical gradient

Chemical gradient

• Permeability RMP negative value↓ → ↓ i.e. normal -90mv → -70mv

• Extracellular K+ concentration [K+]e

RMP negative value ↓ → ↑ ↑ → ↓

K+ ----

-++++

+

Na+ATPase

140-160mmmol/L4.2±0.3mmol/L

Resting membrane potential (RMP)

Excitable cell

•Cell membrane permeability to K+

•K+ transmembrane concentration gradient

RMP≈ ﹣59.5lgIntracellular K+ concentrationextracellular K+ concentration

•Action potential

is a wave of depolarization and repolarization that moves across a cell membrane

•Threshold potential

The critical value of depolarization that can provoke action potential.

hypokalemia

(1). Effects on neuromuscular irritability: ↓– skeletal muscle: flabbiness, w

eakness and even paralysis– smooth muscle: abdominal di

stention, vomit, even paralytic ileus.

(1). Effects on neuromuscular irritability: ↑→↓– skeletal muscle: prick, sting,

abnormal sense→ weakness, paralysis

hyperkalemia

Irritability (excitability)

• the ability to produce action potential• determined by the difference between RMP and the thre

shold potental, and state of sodium channel– Difference increase → irritability ↓– Difference diminish → irritability↑ – Difference overly diminish→irritability↓

Neuromuscular cell

RMP (negtive value)

Difference (between RMP and threshold potential)

irritability

hypokalemia ↑ ↑ ↓

hyperkalemia ↓ ↓ ↑→↓

hypokalemia

(2). Effects on the heart• alterations of myocardial

electrophysiology– Irritability: ↑– Conductivity: ↓– Contractility: ↑– Automaticity: ↑

• Alterations of electrocardiogram– prolonged P-R interval, wid

en QRS wave– Depressed S-T segment– Flattened T wave

• Arrhythmia– i.e. sinus tachycardia

(2). Effects on the heart• alterations of myocardial

electrophysiology– Irritability: ↑→↓– Conductivity: ↓– Contractility: ↓– Automaticity: ↓

• Alterations of electrocardiogram– prolonged P-R interval, wid

en QRS wave– Peaking of T wave

• Arrhythmia– i.e. sinus bradycardia

hyperkalemia

• Irritability (excitability)

• determined by the difference between RMP and the threshold potental, and state of sodium channel– Difference increase → irritability ↓– Difference diminish → irritability↑ – Difference overly diminish→irritability↓

• A special point about the effect of hypokalemia on the heart:– Hypokalemia reduces the permeability of cardiac cell membr

ane to K+, but not the permeability of neuromuscular cells membrane to K+.

heart RMP (negtive value)

Difference (between RMP and threshold potential)

irritability

hypokalemia ↓ ↓ ↑hyperkalemia ↓ ↓ ↑→↓

• conductivity

• Determined by the depolarization velocity and amplitude of phase 0 of action potential, and the depolarization velocity is determined by the difference between RMP and threshold potential.– Difference increase → conductivity ↑– Difference diminish → conductivity ↓

heart RMP (negtive value)

Difference (between RMP and threshold potential)

conductivity

hypokalemia ↓ ↓ ↓hyperkalemia ↓ ↓ ↓

• contractility

• Determined by Ca2+ inward flow which is inhibited by K+ in the extracellular fluid.

heart Ca2+ inward flow contractilityhypokalemia ↑ ↑hyperkalemia ↓ ↓

• automaticity

• Attributed to the automatic depolarization of cardiac rhythmic cell at the phase 4 of action potential.

• The automatic depolarization is caused by a net inward current which make membrane depolarization till threshold.

• The net inward current is mainly composed of degressive outward potassium current and progressive inward sodium current.

heart Membrane Permeability to K+

Net inward current

automaticity

hypokalemia ↓ ↑ ↑hyperkalemia ↑ ↓ ↓

• P wave – atria depolarize• QRS wave – ventricles de

polarize phase 0• T wave — ventricles repol

arize phase 3– Outward K+ current

• S-T segment — ventricles repolarize phase 2– Inward Ca2+ current– Outward K+ current

• P–R interval — from start of atria depolarization to start of QRS complex

Comparation between action potential and normal electrocardiogram

• A— atria action potential

• V— ventricle action potential

• Hypokalemia:– ↓conductivity→ prolonged P-R interval, widen QRS wave– ↓Membrane permeability to K+

• Hyperkalemia:– ↓conductivity→ prolonged P-R interval, widen QRS wave– ↑Membrane permeability to K+

ventricles repolarize phase 3 accelerate Peaking of T wave

ventricles repolarize phase 3 prolong

ventricles repolarize phase 2 inward calcium current accelerate

Depressed S-T segment

Flattened T wave

hypokalemia

(3). Effects on acid-base balance– alkalosis– Paradoxical aciduria

(3). Effects on acid-base balance– acidosis– Paradoxical alkaline

urine

hyperkalemia

↓[K+]ECFH+-K+ exchange ↓[H+]ECF

↑[H+]ICF↑Renal excretion of H+

aciduriaK+ shift out of cellsH+ shift into cells

alkalosis

(Paradoxical aciduria)

↑[K+]ECFH+-K+ exchange ↑[H+]ECF

↓[H+]ICF↓Renal excretion of H+

Alkaline urineK+ shift into cellsH+ shift out of cells

acidosis

(Paradoxical alkaline urine)

hypokalemia

(4). Damage related with metabolism dysfunction– polyuria– Renal tubulointerstitial damage