Lecture 16: Metabolic Acidosis Flashcards
What is blood pH determined by?
The ratio of HCO3-/pCO2*0.03 (since it is part of Henderson-Hasselbalch)
What does “osis” mean?
It describes a process (how we got to a certain state) but does NOT tell us the pH of the blood
Can be respiratory/metabolic acidosis/alkalosis
Example: a respiratory disorder = one type of process
Kidney dysfunction = another type of process that can lead to acidemia
Describe the underlying cause of the problem
What is a mixed process mean?
When there are multiply underlying disorders, each of which can cause a change in blood pH
Example: body is capable of having a metabolic alkalosis, metabolic acidosis and EITHER, a respiratory acidosis or alkalosis at the SAME time! So three processes in one
Metabolic acidosis = decreased HCO3-
Metabolic alkalosis = increased HCO3-
Respiratory acidosis = increased pCO2
Respiratory alkalosis = decreased pCO2
What does “emia” mean?
Indicated the blood pH
Acidemia pH < 7.35
Alkalemia pH > 7.45
However does not tell us how we got there
What are causes of metabolic metabolic acidosis?
All causes lead to fall in serum bicarb and increased in [H+] accumulation
- Loss of base (bicarb) from body
- due to renal or GI
- Failure of kidneys to generate sufficient new bicarb and excrete endogenous acid
- Increased generation of endogenous organic acids
- Addition of exogenous acid (or something that generates an acid)
What is the anion gap?
The gap between positive and negative ions
Anion gap = unmeasured anions – unmeasured cations
Unmeasured anions = proteins, organic acids and PO4/SO4
Unmeasured cations = K, Ca and Mg
Anion gap = Na – Cl – HCO3-
Thus unmeasured anions – unmeasured cations = Na-Cl-HCO3-
Normal anion gap values: 10-12 mEq/L
What happens when you add HCl or lose HCO3-, two potential processes that lead to metabolic acidosis?
Adding HCl will increase Cl- concentration (teal bar on right will increase)
Losing HCO3- will decreased the blue bar on the right proportional to teal bar change
Anion gap stays the same
Lost bicarb replaced by chloride
Na stays the same
This is an example of normal anion gap metabolic acidosis
What are the characteristics of normal anion gap metabolic acidosis?
When chloride concentration makes up for the loss of bicarb Primary problem is twofold: i. loss of bicarb ii. gain of HCl aka Hyperchloremic metabolic acidosis
What are the causes of normal anion gap metabolic acidosis?
- Renal causes
- GI tract causes
- Addition of HCl and/or NH4Cl (basically anything that can exchange H+ excretion for Cl- accumulation)
What are the renal causes of normal anion gap metabolic acidosis?
Leads to loss of bicarb or abnormal retention of acid
- Renal tubular acidosis (RTA)
- Carbonic anhydrase inhibitors
- Kidney failure (reduced GFR, acute or chronic, mild or moderate)
- Mineralocorticoid deficiency/resistance
- Drugs (cause acidosis by inhibiting effect/synthesis of aldosterone)
What are the drugs that can cause normal anion gap metabolic acidosis?
- Sprionolactone/eplerenone
- NSAIDs
- triamterene
- amiloride
- trimethoprim
- Cyclosporine
- Tacrolimus (calcineurin inhibitors)
What are the GI causes of normal anion gap metabolic acidosis?
- Diarrhea
- Uretero-enterostomy or obstructed ileal conduit
- Drainage of pancreatic or biliary secretions
- Small bowel fistula
How does high anion gap come about?
Not by loss of bicarb or by increase of HCl
Rather this is due to Addition or retention of Organic Acids!
Thus, high anion gap metabolic acidosis is due to addition of non-Cl containing acid to plasma
-this is because adding an organic acid will reduce bicarb (because the two cancel out)
-however, since organic acid wont have Cl- conjugate base, Cl- level does not increase commensurately with bicarb decrease, thereby increasing the anion gap
What makes up the majority of the unmeasured anion value? Significance?
Albumin
In a nutritionally deprived individual, hypoalbuminemia may be present (less albumin than normal)
-this thus lowers the patient’s value for “normal” anion gap to 3 or 4 (instead of 10)
-thus, if a hypoalbuminemia patient has an anion gap of 10, this indicates the presence of additional organic acids (or a high anion gap metabolic acidosis), since the patient should normally have gap of 3-4
Thus, when measuring anion gap of malnourished patient, make sure to use a “corrected” anion gap
What are the causes of high anion gap metabolic acidosis?
- Diabetic ketoacidosis
- Alcoholic ketoacidosis
- Lactic acidosis
- Toxic ingestions
-methanol, ethylene glycol (antifreeze), diethylene glycol - Fasting ketoacidosis
- Pyroglutamic acidosis
- Toluene intoxication (glue sniffing)
- Kidney failure (reduced GFR, acute or chronic, more advanced stages)
Pretty much anything that adds an acid that does not generate Cl- as a conjugate base
What is the significance of determining the anion gap?
Helps determine what type of acidosis patient has
Normal vs high anion gap metabolic acidosis
What are the characteristics of acidosis with reduced GFR?
Characterized by fewer normally functioning nephrons
Leads to reduced GFR
Reduced GFR and less nephrons = less filtration/excretion of organic acids + reduced ammoniagenesis
-reduced ammoniagenesis caused by increased serum potassium concentration
ECF volume expansion (from inability to excrete) will also decrease aldosterone synthesis, thereby reducing distal acidification
-why?
Can lead to BOTH normal and high anion gap metabolic acidosis
How does reduced GFR lead to acidosis?
Mild to moderate kidney failure = retention of acid and failure of bicarb reabsorption/generation
-normal anion gap
Advanced kidney failure = reduced filtration and retention of sulfuric/phosphoric acids
-high anion gap
What decreases as a result of reduced GFR?
- Reduced NH4+ synthesis due to hyperkalemia
- Decreased proximal tubule HCO3 reabsorption due to ECF volume expansion and effects on Na/H exchange
- Decreased distal H secretion due to hypoaldosteronism
What is renal tubular acidosis?
An acidosis that occurs when there is NORMAL kidney function (or kidney function is not so severely impaired as to cause metabolic acidosis)
Composed of 3 different types
1. Proximal (Type II)
-defect in HCO3 reabsorption
2. Distal (Type I)
-defect in acid excretion (HCO3 regeneration)
3. Distal Hyperkalemic (type IV)
-defect in acid excretion (ammoniagenesis, acid excretion)
All RTAs are NORMAL ANION GAP metabolic acidoses
What is the defect in Proximal RTA?
Defect in HCO3 reabsorption
What is the defect in distal RTA?
Defect in acid excretion and thus less HCO3 regeneration
What is the defect in distal hyperakalemic RTA?
Defect in acid excretion due to decrease in ammonia genesis and less responsiveness to aldosterone
Characterized by inability of collecting duct to secrete both H and K
Defined by a high plasma potassium concentration
Distal and proximal RTA have low to normal K concentrations
How does hypoaldosteronism lead to defect in K and H secretion in the principal cells of the collecting ducts?
Aldosterone increases ENaC expression, thereby taking up Na+ into the cell
Since Na leaves the lumen and travels to bloodstream, the luminal fluid becomes more negative
Since luminal fluid becomes more negative, H+ and K+ can travel down its apical gradient (intracellularly to extracellulary) to replace the charge lost by Na
Thus, when you have no aldosterone, Na is secreted and H and K remain inside the cell, since there is no electrogenic gradient
In rodents, it was also observed that aldosterone upregulates apical proton pumps in intercalated cells
-so theoretically, lack of aldosterone means less apical proton pumps
How does hyperkalemia fuck up ammoniagenesis?
Since K travels from ECF to ICF, it will then mean the cell’s H+ will have to go from ICF out to ECF in order to counteract K influx
Thus K influx = increased pH
Increased pH = impairment of enzymes involved in ammoniagenesis (which takes a glutamine and breaks that shit down twice to alphaketoglutarate)
What are the characteristics of Proximal RTA?
Caused by decreased capacity of proximal tubule to reabsorb HCO3
Result = increase in fractional excretion of HCO3
Decreases threshold at which HCO3 reabsorption plateaus
Normally, there is a threshold at which HCO3 reabsorption can no longer increase, despite the plasma HCO3…however normally, this threshold is 25 HCO3 mEq/L…in proximal PTA, the threshold is 19 HCO3 mEq/L…this means less bicarb is reabsorbed
Urine pH is LOW for proximal RTA patients since the ability to acidify urine is determined by distal nephron
-is high at first but will eventually be low pH at steady state
What happens when you have an initial GFR load that is above the threshold of bicarb reabsorption (situation on the right hand side)?
Urine will have so much bicarb, that distal tubule is unable to reabsorb it and the pH will actually start out high
However, since there is less bicarb reabsorption at this point, there will be less bicarb volume filtered over time (which is case C in the figure), thus there will be less bicarb in the urine and closer to the threshold
In case B, body reaches a steady state, and only enough bicarb is secreted such that all of it can be reabsorbed in the distal tubule and the urine pH remains acidic (5.5)
-if you notice in case B, bicarb filtration is 15 mmole/L vs 26 mmole/L of normal patient
What are the mechanisms that lead to deficiency of proximal RTA to reabsorb bicarb?
Giving acetazolamide (carbonic acid anhydrase inhibitor)
Carbonic anhydrase II genetic mutation
Mutation in Na/HCO3 cotransporter gene (isolated proximal RTA)
Fanconi Syndrome
What is Fanconi’s syndrome?
Disease of proximal renal tubules When glucose, amino acids, uric acid, phosphate and bicarb are passed into urine instead of being reabsorbed Caused by a shitload of things such as i. tetracycline ii. tenofovir iii. lead poisoning iv. cystinosis v. Wilson disease vi. Lowe’s syndrome vii. hereditary fructose intolerance viii. multiple myeloma etc. (more causes listed on slide 15) Cystinosis is most common cause in children Multiple myeloma is common in adults of no drugs are present
What is cystinosis?
A lysosomal storage disease characterized by abnormal accumulation of amino acid cysteine
Can effect the transporters in proximal renal tubule thereby impairing reabsorption
Most common cause of Fanconi syndrome in children
How can you tell the difference between proximal and distal RTA?
Proximal RTA = low pH of URINE after steady state is reached
Distal RTA = high pH of URINE
-this is because if distal nephron is fucked, one cannot acidify urine well
What are the mechanism through which proximal tubule secretes H+?
- H+ ATPase
2. Na/H apical channel
What is the mechanism through which bicarb is absorbed in proximal tubule?
Carbonic acid is broken down by carbonic anhydrase leads to H2O and CO2, which diffuse into the cell and leave cell to bloodstream as bicarb (in Na/bicarb symporter)
What are the key characteristics of distal RTA?
In contrast with RTA, the problem is with H+ secretion and excretion in the distal nephron
Impairment of acidification of final urine
Reabsorption of distal RTA thus has the same or higher reabsorption threshold than normal
Thus there is no defect in bicarb reabsorption
Classic feature of distal RTA: no matter what the serum bicarb, you have high urine pH (because not able to secrete H+)
What is the pathophysiology of Type 1 distal RTA?
- Defect in apical H+/ATPase
- defect in apical H/K ATPase
- rare
- due to toxins/contaminants like vanadium
- H+ backleak
- caused by amphotericin
- drugs that disrupt membrane integrity
- Carbonic anhydrase II deficiency
- genetic, associated with proximal RTA
- defect in basolateral Cl/HCO3 cotransporter
What are the key features of having a Type 1
Distal RTA due to defect in H ATPase?
Most common defect in pump present in alpha intercalated cells
Acquired and genetic
Genetic = growth defects and kidney stone
Associations
Acquired = associations with Sjogrens
What is the K balance in proximal and distal RTA?
Variable K concentration but usually a bit low
What is the mechanism of hypokalemia in proximal/distal RTA?
Mild hyperaldosteronism due to loss of Na w/ HCO3 and NaCl (due to acidosis) causing mild hypovolemia
Increased distal nephron delivery of Na and bicarb stimulates K secretion
Defect in H/K ATPase reducing K reabsorption (distal RTA)
Increased membrane K permeability (amphotericin B, distal RTA)
What happens if you give someone with proximal RTA sodium bicarb, what will happen?
Bicarb will just be excreted in the urine and won’t be reabsorbed
In a distal RTA, extra bicarb will be reabsorbed and more effective of a treatment
What is the clinical difference between distal RTA and proximal RTA?
The total acid burden with distal RTA is much greater because there is no factor to diminish bicarb excretion
Proximal RTA can adjust its bicarb excretion, since it has normally functioning distal components
What is the difference in treatment between distal RTA and proximal RA?
Proximal RTA = higher doses of sodium bicarb in order to maintain normal levels of serum bicarb since there will be a high rate of urinary loss
Distal RTA = LOWER doses of sodium bicarb since most of it gets reabsorbed by the functioning proximal tubule
What are the key characteristics of hyperkalemic distal RTA?
Type IV RTA
Hyperkalemia and metabolic acidosis is caused by Type IV RTA
Hyperkalemia and metabolic acidosis is caused by hypoaldosteronism
How does hyperkalemia contribute to metabolic acidosis?
Because hyperkalemia reduces ammoniagenesis, reabsorption of ammonium in TAL, and secretion of ammonium in collecting ducts
What are the causes of hyperkalemic distal RTA?
- Mineralocorticoid deficiency
Primary due to adrenal insufficiency, inherited disorders or drugs
Hyporeninemic hypoaldosteronism
-diabetes, tubulointerstitial kidney diseases, NSAIDs - Mineralocorticoid resistance
Due to PHA-1 (pseudohypoaldosteronism type I)
-autosomal dominant mineralocorticoid receptor defect - Distal nephron tubular dysfunction
- PHA-2
What are drugs that can lead to hyperkalemic distal RTA?
- heparin (inhibits aldosterone synthesis)
- Angiotensin II inhibitors
- NSAIDs
- amiloride, trimethroprim, triamterene
- cyclosporine and tacrolimus (interfere with Na/K ATPase)
- spironolactone and eplerenone
What is PHA-2?
Pseudohypoaldosteronism type 2
Aka Gordon’s Syndrome or Familial Hyperkalemic HTN
Due to mutations in genes that encode kinases, resulting in uncontrolled activation of Na/Cl symporters in DCT
-increase Na reabsorption = downregulation of aldosterone = hyperkalemia and metabolic acidosis
What does aspirin do to acid-base balance?
Can cause respiratory alkalosis because aspirin stimulates hyperventilation
Can cause metabolic acidosis because it can uncouple oxidative phosphorylation
Anion gap alteration due to salicylate anion, ketosis (altered glucose metabolism and hypoglycemia) as well as L-lactic acid production
What are the endogenous compounds that can cause a metabolic acidosis?
Ketoacidosis
Lactic acidosis
Increases anion gap
What are the exogenous compounds that can cause a metabolic acidosis?
- methanol
- ethylene glycol
- diethylene glycol
- Toluene
- Aspirin
What are the characteristics of lactic acidosis?
Occurs when lactate > 5mM
H-pyruvate + NaDH + H H-lactate + NAD+
Pyruvate is product of glycogen, glucose and alanine MET
-lactic acid levels reflect NADH/NAD ratio
Has two types:
i. Type A
ii. Type B
Also there are two types of lactic acid
L-lactic acid = product of metabolism
D-lactic acid = product of bacterial metabolism (due to short bowel syndrome or bowel obstruction)
What are the features of Type A lactic acidosis?
Most common type of lactic acidosis
Caused by hypoxia, sepsis, severe anemia, CO poisoning, hypotension
What are the features of Type B lactic acidosis?
Due to compromised metabolism of lactate in the absence of overt hypoxia leading to excess production of lactate and/or decreased conversion back to pyruvate
Caused by liver disease, thiamine deficiency, alcohol ingestion, mitochondrial toxins, malignancy (tumor lysis syndrome), seizures, inborn errors of metabolism
Also caused by drugs like metformin and nucleoside reverse transcriptase inhibitors
What are the key features of ketoacidosis?
Occurs in absence of insulin
Also occurs in starvation and alcoholics
Can be caused by release of catecholamines as well (makes sense since cortisol inhibits insulin effects)
Absence of insulin = unregulated metabolism of FFA = acetyl CoA = acetoacetic acid + beta (OH) butyric acid
What happens to fat metabolism in insulin deficiency?
Insulin deficiency = promotion of lipolysis (stimulation of lipase)
Increases FFA delivery to liver
What is the predominant ketoacid that accumulates in alcoholic ketoacidosis?
Beta-hydroxy butyrate
Ethanol is metabolized to acetaldehyde and acetic acid by alcohol DH
CYP450 pathway in fetuses (when enzymes are yet to be produced)
How do non-acidic toxic ingestions lead to high anion gap metabolic acidosis?
If the breakdown products of the toxins are acidic
Formic acid from methanol
Oxalic acid from ethylene glycol for instance (see above)
What is the therapy for methanol and ethylene glycol poisonings?
Give them ethanol!
Since ethanol binds to alcohol dehydrogenase (the enzyme that breaks down all three molecules) with 100x more affinity than other 2
Fomepizole, an ADH inhibitor is also commonly used
What is the osmolar gap?
Measured by Posm = 2Na + BUN/2.8 + glucose/18
Normally the measured Posm > calculated Posm by 5-10 mosm/L
What is the significance of an osmolar gap?
Indicates likely presence of an osmotically active particle present in the blood but is not part of equation shown above
Example: ethanol
Ethanol intoxication is MOST COMMON increased osmolar gap
Can also be caused by methanol and methylene glycol
What happens to anion gap and osmolar gap as you progress from early to late methanol intoxication?
Early on, osmolar gap > anion gap for methanol intoxication
Later on, Anion gap > osmolar gap for methanol intoxication
Anion gap = breakdown products being effective osmoles
Occurs because methanol gets metabolized
What is the concept of (delta anion gap/delta bicarb)?
Refers to the phenomenon in which anion gap increases the SAME amount that bicarb falls in response to simple organic acidosis
What is (delta)(delta) mean?
Refers to the change in anion gap
What is the significance of a mismatch between delta, delta and bicarb?
May be a clue that there is more than one acid-base disturbance
So if change of anion gap does NOT match change of bicarb, then it signifies the presence of a mixed process
Theory is that for every acid added, it is buffered by one bicarb so serum bicarb should fall in paralle with increased anion gap
What are the clinical features of metabolic acidosis?
- hyperventilation
-kussmaul respiration
-respiratory compensation - Hemodynamic compromise (vasodilatation)
-blood vessels cant retain tone - Hyperkalemia
- Musculoskeletal manifestations (chronic)
Acute acidosis is harmful because of underlying cause
Chronic acidosis can lead to impaired growth and muscle development in children
-chronic acidosis can also cause osteopenia due to bone buffering and muscle catabolism
-release of calcium from bone = hypercalcuria, kidney stones
What are the two components of body that maintain acid-base homeostasis?
- lung
2. kidneys
What is compensation?
A process that corrects for primary defect
Example: lowered pH from metabolic acidosis can lead to lowering the pCO2 in lungs
Or kidneys can increase/decrease bicarb generation to account for respiratory acid-base disturbance
What are the key characteristics about compensation?
- It is NOT second disorder
- never perfect
- no such thing as overcompensation
- if there is overcompensation, then that signifies a possible second primary process going on
Metabolic acidosis = hyperventilation = decrease pCO2
Metabolic alkalosis = hypoventilation = increased pCO2
Respiratory acidosis = increased plasma bicarb reabsorption and increased H/K reabsorption)
Respiratory alkalosis = decrease plasma bicarb and decrease renal H and becarb reabsorption)
How does one predict compensation?
Winter’s formula
Expected pCO2 = 1.5 * bicarb + 8 (within +/- 2)
What does it mean if you get undercompensation?
There must be an additional acid-base disorder (respiratory alkalosis additionally)
Superimposed hyperventilation
What does it mean if you get overcompensation?
No such thing as overcompensation
There must be an additional acid-base disorder (respiratory acidosis perhaps)
What happens to NH3 production in chronic metabolic acidosis?
Increased glutamine uptake by PT cells, muscle release of glutamine and metabolism of glutamine
Can be due to upregulation of N/H exchanger, H-ATPase, H-K ATPase
If your patient with a metabolic acidosis has pCO2 that is lower than predicted by Winter’s formula, you conclude that?
The patient had a second acid-base disorder called respiratory alkalosis
What is the therapy for metabolic acidosis?
- Treat underlying cause
- oral or IV NaHCO3 or an equivalent such as citrate
-desired delta bicarb * 50% body weight in kg = amount of sodium bicarb given
Chronic therapy = use bicarb to stabilize pH
Acute therapy = not necessary to normalize pH or bicarb…focus is on keeping blood pH above 7.2 through respiratory or bicarb treatment
Underlying process > pH in terms of importance
What are the risks of giving NaHCO3 for acute metabolic acidosis?
- hypernatremia and volume overload
- hyperkalemia (if given as hypertonic bolus)
- CO2 generation
- CSF acidosis due to CO2 diffusion across blood brain barrier
- Overshoot alkalosis
- as organic acid gets metabolized (lactic acid and ketoacidosis)
- Hyperventilation will also raise pH
What is overshoot alkalosis?
Occurs when you administer sodium bicarb in patients with lactic acidosis or ketoacidosis
Patient metabolizes lactate/ketones and generates bicarbs endogenously
Bicarb is also added exogenously (as treatment)
Thus endogenous vs exogenous bicarb = alkalemia
