Disorders of water and electrolyte

metabolism

Yu-Hong Jia, Ph.D

Pathophysiological department

Dalian medical university

• Water is an important component of human body.

• Water and dissolved particles (solutes) in it form into body fluid.

• body fluid is the place in which the metabolism of our body is taken place

• Homeostasis of water and electrolyte in the body fluid is very important to normal cell function.

• Electrolyte-Compound that when dissolved in water or another solvent, forms or dissociates into ions (electrically charged particles)– Cations – positively charged

• Na+, K+ , Ca2+, H+

– Anions – negatively charged• Cl-, HCO3

- , PO43-

• Non-electrolytes - Uncharged • Proteins, urea, glucose, O2, CO2

Solutes – dissolved particles

Disorders of water and electrolyte metabolism

• The consequence of diseasei.e. vomit and diarrhea→ dehydration & hyponatre

mia

• Concomitant pathological alteration of diseasei.e. hypertension + hypokalemia→hint? Primary inc

rease of ADS (adrenal cortical tumor)

• Danger threaten to life

Be familiar with and grasp the pathogenesis and changing rule of water and electrolyte disturbance is important for clinical work.

• Water disturbance

– ↑water volume i.e. edema

– ↓water volume i.e. dehydration

• Electrolyte disturbance

– disturbance of Na+, K+, Ca2+, Mg2+

Ⅰ. Body fluid and electrolyte balance

• Body fluids are composed of – Water– Dissolved particles

• Electrolyte• Non-electrolyte

• Its volume, distribution , composition and omsmolality is essential to normal cell metabolism and normal organ function.

1. Body fluid volume

• The total body fluid, or total body water, in a adult man averages approximately 60% of his body weight.– i.e. 60kg body weight

total body fluid is about 36 kg or 36 liter

• Total body fluid can vary with age and sex.

Why women have less water than men if they are the same weight?

The water content of adipose (fat) tissue is less than that of muscle, while women have more adipose tissue at the effect of feminine hormone.

•Fluid compartment are seperated by membranes that are freely permeable to water.•Movement of fluids due to hydrostatic pressure and osmotic pressure

2. Body fluid distribution• Body fluids are distributed in

two distinct area:– intracellular fluid (ICF)

40% body weight– Extracellular fluid (ECF)

20% body weight• Interstitial fluid -15% body weight• Plasma -5% body weight

Transcellular fluid —is a small compartment that represents all those body

fluids which are formed by the secretion of epithelial cell. —is contained within epithelial lined spaces. —includes cerebrospinal, pleural, pericardial, peritoneal,

intraocular, synovial and gastrointestinal fluids.

• Internal environment -extracellular fluid.

• Homeostasis -maintenance of constant conditions in the

internal environment.

3. Body fluid composition

Body Fluid Compartments

3. Body fluid composition

Cation AnionIntracellular fluid K+ Mg2+ PO4

3-

Extracellular fluid Na+ Cl- HCO3-

•ICF and ECF are different in ionic composition.

•Plasma and interstitial fluid are identical in ionic composition. the difference between plasma and interstitial fluid is protein content. Plasma contains a large amount of protein, while the interstitial fluid contains less.

?

?

• Answer to question 1– cell membrane is semipermeable, only water

and small, noncharged molecules can move freely between interstitial and intracellular compartment. Ion can not cross easily.

– All kinds of ionic pump or channel on cell membrane determine the uneven distribution.

• Answer to question 2– Blood capillary wall is permeable to most mole

cules, including water and electrolytes, except for macromolecule, i.e. protein.

4. Body fluid osmolality• Osmosis

– movement of water or solvent across a membrane from a less concentrated solution to a more concentrated solution

• Osmotic pressue– Pull that draws solvent through the membrane to the mor

e concentrated side (or side with solute ). – Determined by the number of particles instead of the mas

s of the solute in the solution.– Can be divided in two types:

• Crystal osmotic pressure: formed by a lot of small molecular weight materials, such as electrolyte, Glucose, BUN and so on.

• Colloid osmotic pressure: formed by large molecular weight materials such as proteins

Figure 7-2

OsmosisWhen a bottle bottomed with a semi-permeable membrane is filled with 3% salt solution and put into a glass of water, the water in the glass will move into the bottle, this phenomenon is call osmosis. Osmosis make the salt solution rising and solution stops rising when weight of column equals osmotic pressure.

• Osmole– Measure of solution’s ability to create osmotic pressur

e & thus affect movement of water– Proportional to the number of osmotic particles formed

in solution– 1 mole of nonionizable substance= 1 osmole.

• 1mole of glucose forms a 1 osmolar solution in 1L water• 1mole of NaCl forms a 2 osmolar solution in 1L water• 1mole of CaCl2 forms a 3 osmolar solution in 1L water

• Osmolality– When the concentration of a solution is expressed in o

smoles per kilogram of water, the osmolar concentration of a solution is referred to as its osmolality.

– 1 osmoles/kg H2O=1 osmoles/L = 1000 milliosmoles/L= 1000 mOSM =1000mmol/L

• In normal condition, the osmolality of plasma = interstitial fluid = intracellular fluid = 280-310 mOsm/ kg or 280-310 mmol/L

• The osmolality is determined mainly by:– in ECF: Na+ and Cl- (80%)

• In clinical practice, serum osmolality can be estimated by doubling serum sodium

– in ICF: K+ (50%)

Because water can move freely through cell membrane and blood capillary wall,

so there is no osmotic disequilibrium among different fluid compartment

hypotonic isotonic hypertonic

Particle concentration compared with intracellular

fluid

fewer same more

Osmolality (mmol/L) <280 280-310 >310

Representative solution 0.45% NaCl 0.9% NaCl 3% NaCl

Distilled water 5% glucose 20% glucose

Response of cell placed in solution

Swell & burst no alteration wrinkle or shrivel

Figure 7-3

•In tissues with high water permiability (such as the kidney proximal tubule), water transport occurs at a much greater rate than would be expected across a pure lipid bilayer.•This transport is in many cases sensitive to mercuric ions and ADH.•Suggest the existence of specialized water channels in cell membrane.

Water transport

Simple diffusion?

Intracellular fluid Interstitial fluid

Lipid

cell

Water

Water channel

bilayer

Method of water transport?

• The first water channel protein, CHIP28 ( later called aquporin-CHIP) was purified by Agre and his colleagues from human erythrocytes in the late 1980s and its cDNA sequence was reported in 1991.

• The Xenopus oocytes introduced with CHIP28 cDNA will swell rapidly and burst in five minutes in hypotonic solution. While the control Xenopus oocytes without aquaporin will be intact.

Aquaporin discovery

Aquaporins,AQPs

•Aquaporins are a family of small, hydrophobic proteins forming water selective channels.

•It located in the animal, plant and microorganism.

• Up to now, 11 mammalian AQPs (AQP0-AQP10) have been identified.

Peter Agre Roderick MacKinnon

2003 Chemistry Nobel Prize

Water Channels

Ⅱ. Mechanism for regulating body fluid and electrolyte balance

1. The sensation of thirst

2. Antidiuretic hormone

3. Aldosterone

4. The natriuretic peptide family

5. The guanylin family

• Conscious desire for water• Major factor that determines fluid intake• Initiated by the osmoreceptors in hypothalam

us that are stimulated by increase in osmotic pressure of body fluids

• Also stimulated by a decrease in the blood pressue through the receptor of baroreceptor.

THIRST

1. The sensation of thirst

The vascular organ of the lamina terminalis (OVLT) contains osmoreceptive neurons – also the subfornical organ (SFO) and the median preoptic n. (MnPO)

Osmoreceptors stimulate AVP secretion and thirst

These cells project to the paraventricular nuclei (PVN) and supraoptic nuclei (SON) to produce AVP secretion

The regulation of thirsty reaction

The stimulus sensed by osmoreceptor:

•Not a change in the extracellular fluid osmolality per se

•But a change in osmoreceptor neuron size or in the some intracellular substance.

Thirst is inhibited by decreased plasma osmolality (OVLT receptors) and by increased blood pressure (hypervolemia)

Thirst is triggered by increased plasma osmolality (OVLT receptors) , decreased plasma volume, and increased plasma Ang which is caused by decⅡreased plasam volume.(angiotensin II in SFO).

Thirst precisely regulate the volume and osmolality of ECF

Two Kinds of Thirst

2. Antidiuretic hormone(ADH)

• Also called arginine vasopressin (AVP).

• ADH is produced in neuron cell bodies in supraoptic and paraventricular nuclei of the Hypothalamus, and stored in posterior pituitary.

• Physiological function– Promote the reab

sorption of water in the collecting duct.

• Mechanism?

The signal pathway following V2 receptor stimulation by ADH

AC: adenylate cyclase; BLM: basolateral membrane; AM:

apical membrane; V2: vasopressin receptor; PKA: protein k

inase A

tubule

ADH feedback regulation mechanism

Stimulus for secretion of ADH:•An increase as small as 2% in osmolality of ECF •Decrease of arterial pressure•Decrease of blood volume•angiotenⅡ•Emotion stress and pain

ADH is more sensitive to the change of osmotic pressure. 1-2% change of osmotic pressure will change the production of ADH.

At first, when blood volume is not markedly decrease, ADH will not be increased.

When blood volume is decreased >10%, ADH will be increased At this time, the decrease of blood volume may be life-threatening.

ADH released

BP/Blood volume

+Stretch receptor

+

Plasma osmotic pressure

+Osmoreceptor

+

Plasma osmotic pressure

-Osmoreceptor

-?

maintenance of body fluid volume has priority over maintenance of body fluid osmolality.

3. Aldosterone• Hormone secreted fro

m the zona glomerulosa cells of adrenal cortex

• Stimulates kidneys– Retain sodium

• Retain water

– Secrete potassium

Mechanism of aldosterone effect

Principal cells

Renin

Ang Ⅰ

Ang Ⅱ Adrenal gland

The renin-angiotensin-aldosterone system

4. The natriuretic peptide family• Four peptides of this family have been identified, including:

– Atrial natriuretic peptide (ANP)– Brain natriuretic peptide (BNP)– C-type natriuretic peptide (CNP)– Urodilatin

• release• Function:

– Diuretic and natriuretic actions

• Mechanism of diuresis and natriuresis– Three natriuretic peptide receptors termed NPR1, NPR2, and NP

R3 (or NPR-A, NPR-B and NPR-C)– NPR-A/B are membrane-bound, guanylyl cyclase-coupled recepte

ors, and mediate ANP functional effects– NPR-C lacks guanylyl cyclase domain and acts to clear circulating

natriuretic peptide.

Atrial Natriuretic Peptide: Release

•Acute ANP release from cardiac atria

–Atrial distension

–Acute ECF volume expansion

•Saline infusion

•Delivery at the end of pregnancy

–Congestive Heart Failure

•Chronic Increase in ANP Synthesis

–Atrial and Ventricular hypertrophy/stretch

Atrial Natriuretic Peptide (ANP)

(causes afferent arterial vasodilation and relaxes mesangial cells)

(inhibits sympathetic output from cardiovascular center)

NPR-A/B Mediates ANP Functional EffectsNPR-C is Clearance Mechanism

Levin et al., NEJM (1998) 339:321-328

Action of atrial natriuretic peptide at target cells

PDE: phosphodiesterase

5. The guanylin family

• Types and distribution– Include guanylin, uroguanylin, lymphoguanylin and exogenous p

eptide toxin produced by enteric bacteria– Guanylin, uroguanylin - highly expressed in gastrointestinal tract– Lymphoguanylin – kidney, myocardium and lymphoid-immune sy

stem• Function

– In gastrointestinal tract, stimulate epithelial secretion of Cl- and HCO-, causing enhanced secretion of fluid and electrolyte into the intestinal lumen.

– in kidney, increase excretion of Na+, Cl-, K+ and water.• Mechanism of above functions

– These peptides bind to and activate cell-surface receptors that have intrinsic guanylate cyclase (GC) activity.

An endocrine axis involving uroguanylin released from the GI tract into the circulation may link the digestive system with the kidney as o

ne means of influencing body sodium balance

↑RAAS ↑Uroguanylin released from GI

Sodium oral intake

Renal excretion of Sodium

Sodium balance

Increased decreased

- +

• Guanylin binding to the extracellular side of the receptor causes activation of guanylyl cyclase at the intracellular side of the receptor and further synthesis of cGMP in intestinal epithelial cells, which further leads to biological effect.

Ⅲ. Disorders of water and sodium metabolism

Water Steady State• Amount Intake = Amount Eliminated

To eliminate waste produced by metabolism, at least 500ml of urine must be excreted everyday.

disorders

Sodium is the primary cation in the extracellular fluid→ sodium content determine the osmolality in ECF → while osmolality gradient across cell membrane is the driving force of water movement → so disturbance of sodium is always accompanied with water disturbance.

• Sodium and water disturbances often occur at the same time and will be discussed to

gether in this chapter.

Classification of disorders of water and sodium metabolism

ECF volume

HypervolemiaNormovolemia Hypovolemia

Disorders of water metabolism with

normal serum sodium concentration

Hypovolemic hyponatremia

(Hypotonic dehydration)

Isotonic dehydration

Hypovolemic hypernatremia

(Hypertonic dehydration)

Normal

Hypervolemic hyponatremia

(Water intoxication)

Edema

Hyponatremia

Hypernatremia

Dehydration: an excessive loss of body fluid.

Serum sodium concentration

Normovolemic hyponatremia

(SIADH, Rest osmostat)

Normovolemic hypernatremia (Upward resetting of hypothalamus osm

olar set-point)

Hypervolemic hypernatremia (Sodium intoxic

ation)

(<130mmol/L)

(130-150mmol/L)

(>150mmol/L)

1. Hypovolemic hypernatremia

The dehydration in which the water loss is in excess of salt loss and the remaining ECF of the body is hypertonic (serum Na+ >150mmol/L, plasma osmotic pressure> 310mmol/L) is termed of hypertonic dehydration.

Hypertonic dehydration

Concept:

Characteristics:

—Loss of water more than sodium—Serum Na+ >150mmol/L—Plasma osmotic pressure> 310mmol/L

Etiology and pathogenesis

• Causes of hypertonic dehydration: water loss is more than sodium loss

(1). Water intake

(2). Water loss

•Environmental water deficit, i.e. desert

•Difficulty in drinking, i.e. esophageal tumor, coma

•Impaired thirst, i.e. CNS disease

•Via gastrointestinal tract

•Via skin

•Via lung

•Via kidney

i.e. diarrhea and vomitting

i.e. ↑environmental and body temperature

i.e. diabetes insipidus, Osmotic diuresis

↓

↑

Diabetes Insipidus

Central diabetes insipidus is characterized by decreased secretion of antidiuretic hormone (ADH) that results in polyuria and polydipsia by diminishing the patient's ability to concentrate urine.

Nephrogenic diabetes insipidus is characterized by a decrease in the ability to concentrate urine due to a resistance to ADH action in the kidney.

Osmotic diuresis

Increased blood glucose

↑Glomerular filtration of glucose

↑Osmotic pressure of renal tubular fluid

↓Water reabsorption

Osmotic diuresis

H2O reabsorption

↑glucose filtration

Osmotic diuresis

↑Osm

olality

-

Alterations of metabolism and function

1. hyperosmolality of ECF →stimulate thirst mechanism →thirst ↑Ingestion

of water↑ECF volume

↓ECF osmolality2. Hyperosmolality of ECF → stimulate secretion of ADH →↑renal tubular reabsorption of water → decrease of urinary volume & increase of urinary concentration

3. Hyperosmolality of ECF →water shift from intracellular to extracellular compartment

↑ECF volume

↓ECF osmolality

↑ECF volume

↓ECF osmolality

ICF

Inte

rstit

ial f

luid

plas

ma

The relative volume change of ICF, interstitial fluid and plasma.

→cell dehydration and shrinkage

Alterations of metabolism and function (continued)

4. Early stage, change of blood volume not obvious→ADS not increase→Na+ reabsorption not increase

↑ADH →H2O reabsorption increase

↑Urinary sodium

Late state, decrease of blood volume →increase of ADS → Na+ reabsorption increase →↓urinary sodium

5. Brain cell dehydration→ CNS dyfunction, such as twitching, somnolence, coma

6. hypovolemia→ reduced blood pressure, elevation in body temperature

Principles of Therapy:

Treating the primary disease

Supplying 5%-10% Glucose

Adding a small amount of NaCl solution

Adding K+ properly

2. Hypovolemic hyponatremia

The dehydration in which the salt loss is in excess of water loss

and the remaining ECF of the body is hypotonic (Serum Na+

<130mmol/L, Plasma osmotic pressure< 280mmol/L) is termed of

hypertonic dehydration.

Hypotonic dehydration

Concept:

Characteristics:—Loss of sodium more than water—Serum Na+ <130mmol/L—Plasma osmotic pressure< 280mmol/L

•Via gastrointestinal tract

•Via skin

•Body fluid accumulation in the third space

Etiology and pathogenesis

• Hypotonic dehydration almost all appear after inappropriate therapy, that is after excessive loss of water and salt, only water but not salt is given.

1. Loss of sodium via kidney

• inappropriate long-term use of diuretics

•Adrenocortical insufficiency

•Renal disease

•Renal tubular acidosis

2. Loss of sodium via extra-kidney

furosemide→inhibit Na+ reabsorption by Henle’s loop ascending branch

→ ↓ADS → ↓renal Na+ reabsorptionChronic interstitial nephritis → impairment of medullary interstitium and dysfunction of Henle’s loop →↑urinary Na+ excretion

A decrease in H+ excretion in the collecting duct causes the dysfunction of H+-Na+ exchange → ↑urinary sodium excretion

Vomitting, diarrhea

Serious perspiration, burn

peritonitis→ascites

Alterations of metabolism and function

1. hypoospmolality of ECF →inhibit thirst mechanism →no thirst

2. Early stage, hypoosmolality of ECF → inhibit secretion of ADH →↓renal tubular reabsorption of water → polyuria and & urinary dilution

late stage, blood volume seriouly decreased →↑ADH → oliguria

3. Hypoosmolality of ECF →water shift from extracellular to intracellular compartment → ECF volume further decrease

The relative volume change of ICF, interstitial fluid and plasma.ICF In

ters

titia

l flu

id

plas

ma

Decrease skin turgor, postural hypotension, tachycardia, shock

Alterations of metabolism and function (continued)

5. If sodium loss via kidney→↑urinary sodium

If sodium loss via extra-kidney, decrease of blood volume →increase of ADS → Na+ reabsorption increase →↓urinary sodium

4. Water movement into cells → Brain cell swelling→ CNS dyfunction, such as nausea, vomiting, twitching, confusion, lethargy, stupor and coma.

Principles of Therapy:

Treating the primary disease

Supplying 5%Glocose normal saline or 0.9% NaCl solution

3. Isotonic dehydration

Concept:

Characteristics:

—Loss of water identicle to sodium—Serum Na+ : 130-150mmol/L—Plasma osmotic pressure: 280-310mmol/L

• The dehydration in which the salt loss is identical to water loss and the remaining ECF of the body has the normal osmolality is termed of isotonic dehydration

Causes:

Vomiting, diarrhea, hemorrhage and loss of body fluid through burned area.

Influences:

Reduced ECF volume initiates a series of adaptive response, including thirst, ADH and ADS release.

Isotonic dyhydration

Hypertonic dehydration

Hypotonic dehydration

Insensible water loss

Treated inappropriately with pure water

4. Hypervolemic hyponatremia

Concept:

Characteristics:

—Serum Na+ < 130mmol/L—Plasma osmotic pressure < 280mmol/L

• A hyponatremia with increased extracellular fluid volume, always associated with increased total body sodium and total body water, but the increase of water is greater than that of sodium.

• When hypotonic ECF is excessively increased, this disorder is also termed water intoxication.

Etiology and pathogenesis

(1). Excessive water intake

(2). Decreased Water loss

•Tap water enema

•Psychotic drinking

•Excessive intravenous infusion of hypotonic solution

•Acute renal failure

•Over secretion of ADH caused by phobia, pain, hemorrhage, shock and trauma

Over retention of hypotonic fluid in the body

which exceed the ability of renal excretion of water

In general, water intoxication mostly occurred in patient with acute renal failure and infused inappropriately at the same time.

Alterations of metabolism and function

• Hypoosmolality of ECF

• Hypervolemia of ECF

water movement into cells cell swelling

Signs and symptoms of brain cell swelling

Elevated blood pressure, blood dilution

5. normovolemic hyponatremia

Concept:

Characteristics:

—Serum Na+ < 130mmol/L—Plasma osmotic pressure < 280mmol/L

• A hyponatremia with almost normal extracellular fluid volume.

•Malignant tumors, i.e. pancreatic, duodenal and prostatic carcinoma, leukemia

•Cerebral disorders, i.e. infection, trauma

•Pulmonary diseases i.e. tuberculosis, pneumonia, lung abscesses

Etiology and pathogenesis

1. syndrome of inapproriate ADH secrection (SIADH)

2. reset osmostat syndrome.

SIADH

• Although this disorder is called normovolemic, in fact the ECF volume is slightly increased.

SIADH→↑ADH →↑renal reabsorption of water

ECF volume expansion diluted serum sodium

↑GFR

↓Reabsorption of sodium at proxi

mal tubule

↑ ANP↓ADS

natriuresis

↑Water excretion

slight

-

Alterations of metabolism and function

hyponatremia→ water shifting into cells→ brain cell edema→ CNS dysfunction

6. hypervolemic hyperatremiaConcept:

causes:

—Iatrogenically over infusion of salt solusion, i.e. infusion of hypertonic salt solution to correct the hypotonic dehydration

—Primary sodium retention, i.e. primary hyperaldosteronism

Is a disorder in which extracellular fluid volume expansion and hypernatremia coexist.

Alterations of metabolism and function:

• hyperosmolality of ECF→ thirst, ↑ADH

• hypervolemia→ circulating overload, hypertension, edema

7. normovolemic hypernatremiaCharacteristics:• serum sodium concentration is increased, while extracellular fluid volume is normal.

Etiology and pathogenesis:

upward resetting of osmolar set-point

Osmoreceptor insensitive to osmotic stimulus

Only osmotic pressure is obviously higher than normal level

Thirst, ADH secretion

Baroreceptor, stretchreceptor

Change of blood volume or pressure

Hypothalamus disease

abnormal

normal

Normal: >150mmol/L

Abnormal: >160mmol/L

150-160mmol/L

[Na+]

hypernatremia normovolemia

Effects of hypernatremia on the brain. Brain shrinkage withinminutes of development of hypertonicity.Rapid adaptation infew hrs. Rapid correction results in cerebral edema

Effects of hyponatremia on the brain and adaptive responses.Brain swelling occurs in minutes of developing hypotonicity, Partial restoration in hrs, normalization of brain vol in days.Overly aggressive correction of Na can lead to irreversible braindamage

Application Problem 1

•Michael has recently started working outdoors in the hot weather to earn money for his tuition. After a few days he experienced headaches, low blood pressure and a rapid heart rate. His blood sodium was down to 125 meq/L. The normal is 144 meq/L. How do you explain this?

Answer to Problem 1

• Michael lost sodium by perspiration. The low sodium in his blood allowed fluid to move into cells by osmosis. Lack of fluid lowered his blood pressure to give him a headache. The increased heart rate was his bodies way of trying to increase blood pressure.

MILLIEQUIVALENT (mEq)

• Unit of measure for an electrolyte

• Describes electrolyte’s ability to combine & form other compounds

• Equivalent weight is amount of one electrolyte that will react with a given amount of hydrogen

• 1 mEq of any cation will react with 1 mEq of an anion

Electrochemical Equivalence

• Equivalent (Eq/L) = moles x valence

• Monovalent Ions (Na+, K+, Cl-):– 1 milliequivalent (mEq/L) = 1 millimole

• Divalent Ions (Ca++, Mg++, and HPO42-)

– 1 milliequivalent = 0.5 millimole

Osmotic Concentration

• Proportional to the number of osmotic particles formed: Osm/L = moles x n (n, # of particles in solution)

• Assuming complete dissociation:– 1mole of NaCl forms a 2 osmolar solution in 1L– 1mole of CaCl2 forms a 3 osmolar solution in 1L

• Physiological concentrations:– milliOsmolar units most appropriate– 1 mOSM = 10-3 osmoles/L

e.g. 1 M NaCl = 2 M Glu in Osm/L

Classification of disorders of water and sodium metabolism

ECF volume

HypervolemiaNormovolemia Hypovolemia

Disorders of water & sodium metabolism with normal serum

sodium concentration

Hypotonic dehydration

Isotonic dehydration

Hypertonic dehydration

Normal

Water intoxication

Edema

Hyponatremia

Hypernatremia

Dehydration: an excessive loss of body fluid.

Serum sodium concentration

SIADH

Rest osmostat

Upward resetting of hypothalamus osmolar

set-point

Sodium intoxication

(<130mmol/L)

(130-150mmol/L)

(>150mmol/L)