ACID BASE PATHOPHYSIOLOGY AND DISEASE STATES

ACID BASE PATHOPHYSIOLOGY

AND DISEASE STATES

The Four Cardinal Acid Base Disorders

M acidosis

M alkalosis

R acidosis

R alkalosis

Disorder pH pCO2 [HCO3-]

Metabolic Acidosis: The “Anion Gap”

Na+

Cl-

HCO3-

Alb-

[Na+] - ([Cl-] + [HCO3-])

~ 10-12 mM/L

Na+ + Cl- + H+ + HCO3-

Na+ + Cl- + H2CO3

Na+ + Cl- + CO2 + H2O

What happens after HCl addition:

Na+ + Cl-

Metabolic Acidosis: The “Anion Gap”

Na+

Cl-

HCO3-

Alb-

[Na+] - ([Cl-] + [HCO3-])

Na+

Cl-

HCO3-

Alb-

Nl Anion gapM acidosis

Na+ + A- + Cl- + H+ + HCO3-

Na+ + A- + Cl- + H2CO3

Na+ + A- + Cl- + CO2 + H2O

What happens after AH additionwhere “A” is a retained anion:

Na+ + A- + Cl-

Metabolic Acidosis: The “Anion Gap”

Na+

Cl-

HCO3-

Alb-

Na+

Cl-

HCO3-

Alb-

[Na+] - ([Cl-] + [HCO3-])

Nl Anion gapM acidosis

Na+

Cl-

HCO3-

Alb-

A-

High Anion gapM acidosis

Clinician short-hand you should know:

Na+ Cl- BUN K+ HCO3

- creatinine Glucose

140 105 30 4.5 25 1.5

90

140 105 30 Glucose 904.5 25 1.5

141 105 27 Glucose 1004.2 6 1.2

139 113 33 Glucose 1263.7 16 1.4

And now, it’s time for: “Calculate That Gap”

140 -(105 + 25) = 10 = normal

141 - (105 + 6) = 30 = high

139 - (113 + 16) = 10 = normal

Differential Dx of high-anion gap acidosis: "SLUMPED":

SalicylatesLactic acidosisUremiaMethanol intoxicationPaint sniffing (toluene)Ethylene glycol intoxication

DKA or alcoholic ketoacidosis

Usually: mixed respiratory alkalosis & metabolic acidosis (rare: metab pure acidosis)

Toxic at < 5 mEq/l, so no anionic contrib to AG No increase in osmolal gap ([ASA] < 5 mM)

Salicylates - ± Hx aspirin ingestion, nausea, tinnitus, unexplained hyperventilation, noncardiogenic pulmonary edema, elevated prothrombin time

Treatment for salicylate intoxication:

Un-ionized form (protonated) enters the brain and is excreted poorly

So….alkalinize (HCO3 infusion) to maximize renal excretion (dialysis)

Lactic acidosis -

Type A = increased O2 demand or decreased O2 delivery

Type B = Malignancies (lymphoma)Phenformin, metforminhepatic failureacute respiratory alkalosis (salicylates)HAARTcongenital (glycogen storage disease type I)etc

Uremia is indicated by BUN, creatinine(chronicity by kidney size and Hct).

Methanol - presents with ± abdominal pain, vomiting, headache; CT: BL putamen infarctsvisual disturbance (optic neuritis)

Normal retina (left); optic neuritis (right)

Methanol intoxication: neurological effects

Putameninfarcts

Anion gap may be > 50 Osmolal gap > 10 mOsm

No increase in osmolal gap

Paint sniffing (“huffing”)(toluene) may present as eitheranion gap acidosis or normal gap acidosisAnion = hippurate

Ethylene glycol - presents with ± CNS disturbances, cardiovascular collapse, respiratory failure, renal failure

Oxalate crystals (octahedral or dumbell) in urine are diagnostic

Anion gap may be > 50

Osmolal gap > 10 mOsm

“The rotund rodents chew through brake lines and radiator hoses in search of a fix of ethylene glycol…”“Marmots have an amazing ability to handle toxic substances. To tranquilize them, they need the same dose as a bear, and a bear will be down for 40 minutes while a marmot will be back up in 5. If you have to redrug them, it’s really hard to make them unconscious again.”

National WildlifeFeb/Mar, 2002

Oxalate crystals

“back of the envelope”

1. Ethanol infusion to compete with alcohol dehydrogenase (dialysis)

OR

2. “Antizol” (fomepizole) (inhibits ADH)load, then 10 mg/kg q12 x 4

Treatment for methanol & ethylene glycol intoxication:

Diabetic ketoacidosis -

Key clinical features are:

type I DM (i.e. no insulin)

a trigger: e.g. sepsis, fracture, stroke

hyperglycemia

ECF vol depletion & renal insufficiency

acetoacetic- and hydroxybutyric- acids

Alcoholic ketoacidosis - key clinical features are recent stopping ingestion of ethanol, hypoglycemia, and contracted ECF (usually due to vomiting)

THE SERUM OSMOLALITY CAN HELP WITH THE DIAGNOSISIN HIGH ANION GAP ACIDOSES

Step 1: Calculate Osm = 2[Na+] + glucose/18 + BUN/2.8

Step 2: Measure Osm (freezing point depression)

3. Osmolal gap (measured - calc) should be ≤ 10

Osm gap due to small, osmotically-active molecules:

mannitol (no acidosis)ethanol (acidosis = AKA)isopropanol (a "drunk" with ketones,

but no acidosis)methanol (acidosis)ethylene glycol (acidosis)

Does metabolic acidosis causehyperkalemia via H+/K+ exchange?

Na+ + Lact- + Cl- + H+ + HCO3-

Na+ + Lact- + Cl- + H2CO3

Lact- HCO3-

Na+ + Cl- + HCO3- (normal HCO3

-,normal gap)

Acute lactic acidosis from seizures(“closed” system”; lactate reabsorbed)

Na+ + Lact- + Cl- (low HCO3-,high gap)

Na+ + Lact- + Cl- + CO2 + H2O

Na+ + Cl- + HCO3-

Time (minutes)

Acute lactic acidosis from seizures(“closed” system”; lactate reabsorbed)

Seizure

[K+]

[HCO3-]

pH

A. Gap

Principles of K+/H+ Exchange:

1. Occurs if anion is impermeable 2. Limited if anion is permeable (“organic”)

K+

H+

Cl-H+

A-

K+

1. GI bicarbonate loss:diarrheavillous adenomapancreatic, biliary, small bowel fistulaeuretero-sigmoidostomyobstructed uretero-ileostomy

Causes of a “normal anion gap”(A.K.A. “hyperchloremic”)

metabolic acidosis

Pancreas

Ileum

Colon

Pancreas

Ileum

Colon

Diarrhea Causes Loss of HCO3-

And a Normal Anion Gap AcidosisAnd Hypokalemia

HCO3-

HCO3-

Cl-

HCO3-

Cl-

K+ HCO3-

Normal Diarrhea

Cl-

Flooding the colon or CCD with HCO3

- instead of Cl- drives K+ secretion

Na+Na+

K+ K+

Cl-

HCO3-

K+

Pancreas

Ileum

Pancreatic fistula or transplant:loss of HCO3

-

Skin orurinary bladder

HCO3-

Cl-

Ileal loop

Obstructed Uretero-ileostomy Causes a Normal Anion Gap Acidosis

Obstructedileal loop

HCO3-Ureter Skin

Cl-

Ileostomy bag

Cl-

The underlying assumption is that NH4+

is excreted and maintains electroneutrality: ([Na+] + [K+] + [NH4

+]) - [Cl-] = 0

Since NH4+ is unmeasured,

a negative urine anion gap indicates NH4

+Cl excretion(i.e. normal renal tubule acidification)

How to differentiate GI HCO3- loss

from renal HCO3- loss?

Use the urinary anion gap

A positive urine anion gap ~ no NH4+Cl excretion

(i.e. low renal tubule acidification)

Normal acidotic: closed circlesDiarrhea: closed triangles

Type 1 or IV RTA: open circles

Battle et al, NEJM 1988

2. Ingestions & infusionsammonium chloridehyperalimentation (arginine/lysine-rich)

3. Renal bicarbonate (or equivalent) lossproximal RTAdistal RTAtype IV RTAearly renal failureacetazolamidehydrated DKA

Causes of a “normal anion gap”(A.K.A. “hyperchloremic”)

metabolic acidosis

Proximal RTA (“Type II”)

HCO3- (1) Na+

(3) HCO3-H+

CO2 H2O+

H+

Na+

Na+

HCO3-

glucoseamino acidsuratephosphate

DefectiveNa+ - dependentresorption =Fanconi’sSyndrome

Inheritance Gene Geneproduct

Clinicalfeatures

Genetically-Defined Proximal RTAs

Autosomalrecessive

SLC4A4 NBC1 Prox RTAcorneal Ca++

pancreatitis

Autosomalrecessive

CA2 CarbonicAnhydraseII

ProximalOrdistalOr“hybrid” RTA;osteopetrosis;cerebral Ca++

HCO3- in

moles/time

filtered

GFR x [HCO3-]plasma = “filtered load of HCO3

-”

HCO3- Tm

UHCO3V

Type II Renal Tubular Acidosis (“Proximal RTA”)

NewHCO3

Tm

UHCO3V

Type II Renal Tubular Acidosis (“RTA”)

HCO3-

Net acid excretion =urinary NH4

+

+urinary “titratable acid” (H2PO4

-)-

urinary HCO3-

H+

NH4+

NH3+

HCO3-

+

H2CO3

HPO4-- +H2PO4

-

Not titratable;need to measure

Present inProx RTA

Titratableacid

Flooding ofCCD with

HCO3- exceeds

its resorptive capacity;

HCO3- becomes

“a poorly resorbed anion”

Na+

K+

Na+

K+

Principal cell

a IC cell

IC cell

HCO3-

Cl-

HCO3-

Cl-

Cl-

H+ATP

ADP + Pi

H+ATP

ADP + Pi

Cl-

pHmin = 5

HCO3-

Glomerulus

Proxtubule

CCD

How Diarrhea and Proximal RTA Are Alike

Pancreas

Ileum

ColonK+ HCO3

-

HCO3-

HCO3-

K+ HCO3-

Urine pH in proximal RTA

Fractional excretionof HCO3

- in proximal RTA

Diminished proximal resorption of HCO3-

Plasma [HCO3-] 10-15 mEq/L

Urine pH depends on plasma [HCO3-] & GFR

relative to proximal HCO3- Tm

Fractional HCO3- excretion high (15-20%)

at nl plasma [HCO3-]

Plasma [K+] reduced, worsens with HCO3- therapy

Dose of daily HCO3- required: 10-15 mEq/kg/d

Non-renal: rickets or osteomalacia

Features of Proximal Renal Tubular Acidosis (“Type II”)

3. Renal bicarbonate (or equivalent) lossproximal RTAdistal RTAtype IV RTAearly renal failureacetazolamidehydrated DKA

Causes of a “normal anion gap”(A.K.A. “hyperchloremic”)

metabolic acidosis

Distal RTA

Na+

K+

Na+

K+

Principal cell

a IC cell

IC cell

HCO3-

Cl-

HCO3-

Cl-

Cl-

H+ATP

ADP + Pi

H+ATP

ADP + Pi

Cl-

Aldosterone

amphotericin

Auto-immune

Hypo-kalemia

indistal RTA:

H + nolonger shunts

Na +

current soK+ must

do so

Na+

K+

Na+

K+

Principal cell

a IC cell

IC cell

HCO3-

Cl-

HCO3-

Cl-

Cl-

H+ATP

ADP + Pi

H+ATP

ADP + Pi

Cl-

Aldosterone

Urine pH in distal RTA

Fractional excretionof HCO3

- in distal RTA

Diminished distal H+ secretion (autoimmune)or backleak of secreted H+ (ampho-B)

Plasma [HCO3-] may be below 10 mEq/L

Urine pH always > 5.5

Fractional HCO3- <3% at nl plasma [HCO3

-]

Plasma [K+] reduced

Dose of daily HCO3- required: 1-2 mEq/kg/d

Non-renal: nephrocalcinosis, renal stones

Features of Classic Distal Renal Tubular Acidosis (“Type I”)

Inheritance Gene Geneproduct

Clinicalfeatures

Genetically-Defined Type I Distal RTAs-1

Autosomalrecessive

SLC4A1 AE1 (G710D)V850)

Acute illnessor growthfailure inchildhood± deafness

Autosomaldominant

SLC4A1 AE1(A858DR589SR589H)

Milder;Hearing is OK

Inheritance Gene Geneproduct

Clinicalfeatures

Genetically-Defined Type I Distal RTAs-2

Autosomalrecessive

ATP61 58 kDasubunit:vacuolarH+ATPase

Distal RTA;sensori-neural hearingloss

Autosomalrecessive

ATP6N1B 116 kDasubunit:vacuolarH+ATPase

Distal RTA;no hearingloss

3. Renal bicarbonate (or equivalent) lossproximal RTAdistal RTAtype IV RTAearly renal failureacetazolamidehydrated DKA

Causes of a “normal anion gap”(A.K.A. “hyperchloremic”)

metabolic acidosis

Hyporenin-hypo

aldosteronism

Na+

K+

Na+

K+

Principal cell

a IC cell

IC cell

HCO3-

Cl-

HCO3-

Cl-

Cl-

H+ATP

ADP + Pi

H+ATP

ADP + Pi

Cl-

Aldosterone

Diabetesis the maincause

Urine pH generally < 5.5as if the H+ gradient is OK but the H+ “throughput” is poor

Plasma [HCO3-] usually above 15 mEq/L

Major problem: hyperkalemiasuppresses ammoniagenesis

Hypoaldosteronism(“Type IV RTA”)

Total Body K+ Excess Decreases Proximal Tubule Acidification and Ammoniagenesis

via Intracellular Alkalosis

2. Total body K+ excess

K+

3. K+ entryinto proximal tubule cells

HCO3- (1) Na+

(3) HCO3-H+

CO2 H2O+

H+

Na+

H+

4. Alkalinization of prox tubule cellby K+/H+ exchange

1. Failed CCD K+ secretion

“Voltage” typeHyperkalemicDistal RTA

Na+

K+

Na+

K+

Principal cell

a IC cell

IC cell

HCO3-

Cl-

HCO3-

Cl-

Cl-

H+ATP

ADP + Pi

H+ATP

ADP + Pi

Cl-

Aldosterone

ObstructionSickle CellAmilorideTrimethoprimPentamidine“PHA”

Urine pHLasix +

amiloride

Lasix

Urine pH generally > 5.5as if the H+ gradient is poor AND the H+ “throughput” is poor

Plasma [HCO3-] usually above 15 mEq/L

Again: hyperkalemiasuppresses ammoniagenesis

“Voltage type” Hyperkalemic Distal RTA

Inheritance Gene Geneproduct

Clinicalfeatures

Genetically-Defined Hyperkalemic Distal RTAs-1

Autosomaldominant

MLR Mineralo-corticoidreceptor

PHA* I:Hyperkalemicdistal RTA

* “PHA” = Pseudohypoaldosteronism

Inheritance Gene Geneproduct

Clinicalfeatures

Genetically-Defined Hyperkalemic Distal RTAs-1

Autosomalrecessive

SNCC1A aENaC PHA I

Autosomalrecessive

SNCC1B ENaC PHA I

Autosomalrecessive

SNCC1G ENaC PHA I

Aldosterone deficiency or resistance (“voltage”)

Plasma [HCO3-] usually above 15 mEq/L

Urine pH depends:generally < 5.5 in hypoaldosteronismgenerally > 5.5 in voltage defect

Fractional HCO3- excretion <3% at nl

plasma [HCO3-]

Plasma [K+] elevated

Dose of daily HCO3- required: 1-3 mEq/kg/d

Non-renal: none

Features of the Hyperkalemic Distal RTAs

Normal Gap Acidosis With Nl Creatinine

Urinary anion gapNegative

(high NH4+)

GI HCO3- loss

Proximal RTAacetazolamide

Positive(low NH4

+)

Urine pH& plasma [K+]

Urine pH < 5.5 & high[K+]

Hypo-aldosteronismRTA(type IV)

Urine pH > 5.5 & low/nl[K+]

Distal RTA(“Type I”):secretory or

gradient defect

VoltageDefect

Urine pH > 5.5 & high[K+]

2. Ingestions & infusionsammonium chloridehyperalimentation (arginine/lysine-rich)

3. Renal bicarbonate (or equivalent) lossproximal RTAdistal RTAtype IV RTAearly renal failureacetazolamidehydrated DKA

Causes of a “normal anion gap”(A.K.A. “hyperchloremic”)

metabolic acidosis

Excretion of the Daily Acid Load is Decreased inChronic Renal Failure (CRF) or

Distal Renal Tubular Acidosis (dRTA)

Kim et al, AJKD 1996

Chronic Renal Failure dRTA Acid-loaded controls

2. Ingestions & infusionsammonium chloridehyperalimentation (arginine/lysine-rich)

3. Renal bicarbonate (or equivalent) lossproximal RTAdistal RTAtype IV RTAearly renal failureacetazolamidehydrated DKA

Causes of a “normal anion gap”(A.K.A. “hyperchloremic”)

metabolic acidosis

Renal handling of acetoacetatein the dog

Schwab and Lotspeich 1954

Self-inhibitionof absorption

Renal handling of acetoacetateAnd -OH butyrate in the rat

Ferrier et al, 1992

Endogenous levels:Good resorption

Elevated levels:Poor resorption

Self-inhibitionof absorption

Na+ + AcAc- + Cl- + H+ + HCO3-

Na+ + AcAc- + Cl- + H2CO3

Na+ + AcAc- + Cl- + CO2 + H2O

Na+ + Cl-

Renal loss of filtered AcAc-

Pathophysiology of normal anion gap acidosisin diabetic ketoacidosis

Dumping of keto-anions with hydration in DKA

Adrogué 1984

DKAs admitted hydrated have non-anion gap acidosis

Adrogué 1984

The Four Cardinal Acid Base Disorders

M acidosis

M alkalosis

R acidosis

R alkalosis

Disorder pH pCO2 [HCO3-]

Vomiting

H+ loss

Plasma pHand HCO3

Distal K+

secretionK+ depletion

High HCO3 Tm

NH3/NH4+

secretion

CCD HCO3

resorption

Renal HCO3

resorption

H+/K +

ATPase

pCO2

K+ loss, K + intake

Vomiting

High HCO3 Tm

CCD HCO3

resorption

Renal HCO3

resorption

H+ loss

Plasma pHand HCO3

Distal K+

secretionK+ depletion

NH3/NH4+

secretion

H+/K +

ATPase

pCO2

K+ loss, K + intake

Na+ loss

ECFvolume

Sympathetic tone

GFR

GFR x PHCO3

Renin

Local Ang II

Systemic Ang II

Aldosterone

Low filtered HCO3 load

Na+ loss

ECFvolume

Sympathetic tone

GFR

GFR x PHCO3

Renin

Local Ang II

Systemic Ang II

Aldosterone

Vomiting

High HCO3 Tm

CCD HCO3

resorption

Renal HCO3

resorption

H+ loss

Plasma pHand HCO3

Distal K+

secretionK+ depletion

NH3/NH4+

secretion

H+/K +

ATPase

pCO2

K+ loss, K + intake

Low filtered HCO3 load

Chloride loss TGfeedback

Distalchloridedelivery

CCD HCO3

Secretion( IC cell)

Na+ loss

ECFvolume

Sympathetic tone

GFR

Filtered HCO3

Renin

Local Ang II

Systemic Ang II

Vomiting

High HCO3 Tm

CCD HCO3

resorption

Renal HCO3

resorption

H+ loss

Plasma pHand HCO3

Distal K+

secretionK+ depletion

NH3/NH4+

secretion

H+/K +

ATPase

pCO2

K+ loss, K + intake

Low filtered HCO3 load

Chloride loss TGfeedback

Distalchloridedelivery

CCD HCO3

secretionAldosterone

DIFFERENTIAL DIAGNOSIS OF METABOLIC ALKALOSIS USING URINE Cl

Normal Urine [Cl-]

MineralocorticoidismRAS, aldosteronism11-DH deficienciesBartter’s

Diuretics (early)

Severe K+ depletion

Diuretics (late)

Low Urine [Cl-]

VomitingNG suction

Posthypercapnia

Low Cl- intake

Cystic fibrosis

The Four Cardinal Acid Base Disorders

M acidosis

M alkalosis

R acidosis

R alkalosis

Disorder pH pCO2 [HCO3-]

Minuteventilation

pCO2 pO2

Centralchemoreceptorsventilation

Carotid &aortic bodies

20 40 60 4080120

The Drives to Ventilation: CO2 and O2

Causes of Respiratory Acidosis

Chronic

10 mm Hg pCO2 3.5 mEq/L HCO3

-

Acute

10 mm Hg pCO2 1 mEq/L HCO3

-

Asthma

Pulmonary edema

Cardiac arrest

Drug overdose

Sleep apnea

Chronic ObstructivePulmonary Disease(COPD)

Neuromuscular (e.g.Lou-Gehrig’s)

Obesity/Pickwickian

NH4+NH4

+

Na+

Chronically Elevated pCO2 StimulatesFormation of New HCO3

- by Ammoniagenesis

H+H+

Na+

NH3NH3NH4

+

HCO3-

Glutamine NH3 + CO2 + H2O

Glutaminase

Proximal tubule

204060pCO2 isobars

HCO3-

pH

25

7.40

Acute vs Chronic Respiratory Acidosis

The Four Cardinal Acid Base Disorders

M acidosis

M alkalosis

R acidosis

R alkalosis

Disorder pH pCO2 [HCO3-]

Causes of Respiratory Alkalosis

Chronic

10 mm Hg pCO2 3-5 mEq/L HCO3

-

Acute

10 mm Hg pCO2 2 mEq/L HCO3

-

Fear

Pain

Acid-base exams…

Anxiety

Altitude; Psychosis

Sepsis; Stiff lungs

Liver failure

Salicylates

Pregnancy

Neurological

Iatrogenic (wrongventilator setting)

HCO3- in

moles/time

filtered

GFR x [HCO3-]plasma = “filtered load of HCO3

-”

HCO3- Tm

UHCO3V

Chronic Reduction in pCO2 Lowers HCO3- Tm

NewHCO3

Tm

UHCO3V

145 95 303.5 25 1.8

RA-ABG: 7.50 /pCO2 33 /pO2 105

EXTRA CREDIT:WHAT IS THE ACID-BASE DISTURBANCE?

3. But the pCO2 is too low for a normal HCO3-

= respiratory alkalosis

This is the “Triple Ripple”

1. Anion gap is high (20) = addition oforganic acid (“footprints”)

2. pH is high = alkalosismust be superimposed on Anion Gap acidosisbut respiratory alkalosis would lower HCO3

-

so must be metabolic alkalosis (vomiting?)

End of Patho-Physiology Section(Acid-Base Part 2)

OR

NH4+

NH4+ undergoes counter-current

multiplication-1

Descending limb

Ascending limb

Counter-Current Multiplication

1. At the start: all cups have 10 pennies;2. All new incoming cups have 10 pennies