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-


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-


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


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”)



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


Non-renal: nephrocalcinosis, renal stones

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


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


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



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


Again: hyperkalemiasuppresses ammoniagenesis

“Voltage type” Hyperkalemic Distal RTA


Clinicalfeatures

Genetically-Defined Hyperkalemic Distal RTAs-1

Autosomaldominant

MLR Mineralo-corticoidreceptor

PHA* I:Hyperkalemicdistal RTA

* “PHA” = Pseudohypoaldosteronism


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”)


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

Fractional HCO3- excretion <3% at nl

plasma [HCO3-]

Plasma [K+] elevated


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+]




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




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


M acidosis

M alkalosis

R acidosis

R alkalosis


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+


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+


NH3/NH4+

secretion

H+/K +

ATPase

pCO2

K+ loss, K + intake


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+


NH3/NH4+

secretion

H+/K +

ATPase

pCO2

K+ loss, K + intake


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


M acidosis

M alkalosis

R acidosis

R alkalosis


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


M acidosis

M alkalosis

R acidosis

R alkalosis


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

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ACID BASE PATHOPHYSIOLOGY AND DISEASE STATES