Lactate metabolism, Warburg effect, malignancy

References

Chapter 19, Part 12

Metabolic acidosis  June 14, 2023

References

Chapter 19, Part 2

Roger mentioned MELAS syndrome MELAS syndrome: Clinical manifestations, pathogenesis, and treatment options

Josh mentioned this blog on lactate- Understanding lactate in sepsis & Using it to our advantage

We discussed the Warburg effect The Warburg Effect: How Does it Benefit Cancer Cells? - PMC and here’s a case from skeleton key- Skeleton Key Group Case #28: Mysterious Acidosis in Cancer - Renal Fellow Network

Otto Warburg won the Nobel Prize in Physiology and Medicine in 1931 for describing how animal tumors produce large quantities of lactic acid (Wikipedia)

Joel calls it the Lactate saline reflex, but the accepted term of art is Lacto-Bolo reflex The origins of the Lacto-Bolo reflex: the mythology of lactate in sepsis

Buffer agents do not reverse intramyocardial acidosis during cardiac resuscitation.

Josh mentioned this article the BICAR-ICU Sodium bicarbonate therapy for patients with severe metabolic acidaemia in the intensive care unit (BICAR-ICU): a multicentre, open-label, randomised controlled, phase 3 trial - The Lancet

Roger shared 3 quotes to make the point that there has been little movement in our knowledge the past 40 years:

Bicarbonate does not improve hemodynamics in critically ill patients who have lactic acidosis. A prospective, controlled clinical study from Cooper in the Annals

Lactic Acidosis and Bicarbonate Therapy | Annals of Internal Medicine from Robert Hollander

Lactic acidosis from Nick Madias

Josh mentioned the use of sodium bicarbonate for CKD Eubicarbonatemic Hydrogen Ion Retention and CKD Progression - Kidney Medicine  (Madias) Bicarbonate therapy for prevention of chronic kidney disease progression (from Wesson),  Sodium Bicarbonate Prescription and Extracellular Volume Increase: Real‐world Data Results from the AlcalUN Study

Amy’s VoG on metabolic acidosis/KDIGO guidelines

Very nice JASN review that describes the mechanisms of how metabolic acidosis leads to CKD progression

First description by THE Dr. Bright

1930 Lancet description of benefit

2009 RCT that the 2012 KDIGO guidelines sort of based their 2b recommendations off of

2020 BiCARB Study

2021 META Analysis

We discussed methanol toxicity : Case Study: Methanol Poisoning from Adulterated Liquor | Food Safety, Acute methyl alcohol poisoning: a review based on experiences in an outbreak of 323 cases and josh poking at the osmolar gap: PulmCrit- Toxicology dogmalysis: the osmolal gap and shared these guidelines: METHANOL | extrip-workgroup and Roger loves this: Urine fluorescence using a Wood's lamp to detect the antifreeze additive sodium fluorescein: a qualitative adjunctive test in suspected ethylene glycol ingestions

From China to Panama, a Trail of Poisoned Medicine - The New York Times (diethylene glycol) . The Accidental Poison That Founded the Modern FDA - The Atlantic

Outline: Chapter 19 Metabolic Acidosis

Etiologies and Diagnosis

Lactic Acidosis

Pyruvate → lactate (LDH; NADH → NAD+)

Normal production: 15–20 mmol/kg/day

Metabolized in liver/kidney → pyruvate → glucose or TCA

Normal lactate: 0.5–1.5 mmol/L; acidosis if > 4–5 mmol/L

Causes:

↑ production: hypoxia, redox imbalance, seizures, exercise

↓ utilization: shock, hepatic hypoperfusion

Malignancy, alcoholism, antiretrovirals

D-lactic acidosis

Short bowel/jejunal bypass

Glucose → D-lactate (not metabolized by LDH)

Symptoms: confusion, ataxia, slurred speech

Special assay needed

Tx: bicarb, oral antibiotics

Treatment

Underlying cause

Bicarb controversial: may worsen intracellular acidosis, overshoot alkalosis, ↑ lactate

Target pH > 7.1; prefer mixed venous pH/pCO2

Ketoacidosis (Chapter 25 elaborates)

FFA → TG, CO2, H2O, ketones (acetoacetate, BHB)

Requires:

↑ lipolysis (↓ insulin)

Hepatic preference for ketogenesis

Causes:

DKA (glucose > 400)

Fasting ketosis (mild)

Alcoholic ketoacidosis

Poor intake + EtOH → ↓ gluconeogenesis, ↑ lipolysis

Mixed acid-base (vomiting, hepatic failure, NAGMA)

Congenital organic acidemias, salicylates

Diagnosis:

AG, osmolar gap (acetone, glycerol)

Ketones: nitroprusside only detects acetone/acetoacetate

BHB can be 90% of total (false negative)

Captopril → false positive

Treatment:

Insulin +/- glucose

Renal Failure

↓ excretion of daily acid load

GFR < 40–50 → ↓ ammonium/TA excretion

Bone buffering stabilizes HCO3 at 12–20 mEq/L

Secondary hyperparathyroidism helps with phosphate buffering

Alkali therapy controversial in adults

Ingestions

Salicylates

Symptoms at >40–50 mg/dL

Early: respiratory alkalosis → Later: metabolic acidosis

Treatment: bicarb, dialysis (>80 mg/dL or coma)

Methanol

Metabolized to formic acid → retinal toxicity

Osmolar gap elevated

Tx: bicarb, ethanol/fomepizole, dialysis

Ethylene glycol

→ glycolic/oxalic acid → renal failure

Same treatment + thiamine/pyridoxine

Other

Toluene, sulfur, chlorine gas, hyperalimentation (arginine, lysine)

GI Bicarbonate Loss

Diarrhea, bile/pancreatic drainage → loss of alkaline fluids

Ureterosigmoidostomy → Cl-/HCO3- exchange in colon

Cholestyramine → Cl- for HCO3-