ALP & LD - Alkaline Phosphatase and Lactate Dehydrogenase. A longevity study mystery.

Spoiler ... Or maybe it was just an error in the article regarding 'normal' ranges for ALP and LD. Post too long for email.

Summary/post in brief - I’m not sure what the answer is regarding why lab values for ALP and LD were elevated above normal for all participants in a study on longevity. (Murata, et al., 2023) Elevated values might occur in healthy people who are physically active with weight bearing strenuous activity and that would not indicate chronic issues are present in liver or bone as might be expected.

The post wanders a bit in learning more about the lab values and what they may indicate and conversion of the units ukat/L and U/L.

Alkaline phosphatase (ALP or AP) has protective value and low levels are a health negative. It protects against the bacterial endotoxin LPS in the gut and helps prevent inhibition of mineralization of bone and tooth enamel - among other benefits (Rader, 2017)

Lactate dehydrogenase (LD or LDH) is used to convert lactate to pyruvate, reducing risk of metabolic acidic waste accumulating after strenuous exercise when muscle needs rapid energy and glycolysis occurs anaerobically.

Being healthy enough to exercise strenuously into your nineties and above — and getting out there and doing it everyday — may be the answer. My grandma waltzed at her 100th birthday party and was a sturdy farm lady who gardened into nineties. A car accident sometime after the 100th birthday slowed her down and she lived to ~ 104. She was quite strong and swore by Vick’s VapoRub under her nostrils every night. She avoided much salt and spicy foods but produce and meats and eggs were staples. Adequate protein is really important as we age because we need more throughout the day instead of just a big load at dinner.

Photo by Zoe Schaeffer on Unsplash

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A Tweet by Remnant, MD on Twxtter suggested or asked Dr. Jack Kruse if a light-related improvement in metabolism might be an underlying reason why centenarians were found to have elevated Alkaline phosphatase and Lactate dehydrogenase levels in a long term study (AMORIS cohort) on Swedish people and their health. (Murata, et al., 2023)

Remnant | MD, @RemnantMd

Some of the healthiest people in the world have levels of ALP and LDH that are 2-3x higher than the upper limits of 'normal.'

@DrJackKruse What do you make of this? Seems like there is an efficient high-metabolic state (dare I say, light-related) story behind this.

Remnant MD, quote reTweeting his own Tweet:

Medical school teaches us that Alkaline Phosphate and Lactate Dehydrogenase must be in the shaded green range. Swedish study of centenarians disagrees: -each shaded bar is a quartile -blue are centenarians, red non-centenarians [(Murata, et al., 2023)] Note: >80% of 'non-centenarians' live past 80

A screenshot portion of Figure 1, (Murata, et al., 2023).

My replies before seeing the study (it wasn’t linked in the Tweet):

Lactate dehydrogenase generally is increased when there is cell damage/ tissue injury. Strenuous exercise can be a cause of elevated LD https://healthline.com/health/lactate-dehydrogenase-test…

Healthy people exercise more > keeps growth & repair pathways active > anabolic instead of age related increase in catabolism

and

Maybe they have strong bones and do weight bearing activity. https://medicalnewstoday.com/articles/321984#causes-of-abnormal-levels…

elevated ALP

and

Low ALP can be bad. https://hypophosphatasia.com/understanding-alp?gclid=Cj0KCQjwvL-oBhCxARIsAHkOiu06TfxMovGkQWeLdWwC-bDTlHbheThCkrLantBmlZDklqPzECWLBuQaAtwIEALw_wcB…

Info on LD/LDH - Lactate dehydrogenase

Lactate dehydrogenase is an enzyme that is used for anaerobic glycolysis. Lactate is produced by exercising muscle tissue and the LD enzyme recycles it to pyruvate, (preventing increased lactic acid build up). It is present throughout the body and elevated levels can indicate tissue damage to the heart, liver, kidney, skeletal muscle, brain, red blood cells, and lungs - but further testing is needed to pinpoint the location. Strenuous exercise can also cause an increase in LD levels. (Blood Chemistry and CBC Analysis, pp 142-149, Weatherby and Ferguson, 2002, Amazon)

Other replies…

Other replies mention that ALP/AP levels increased on Carnivore diet, @richcollins, Sep 25. Another by @HereticalLipid, Sep 24 states that weight lifting increases ALP and potassium and magnesium intake can also. And @charly_knaller, Sep 24, mentions a reason why low ALP would be bad - it helps breakdown excess purines (adenosine from ATP for example) which are damage signaling and inflammatory in extracellular fluid in excess. It suggests a cell split open and cleanup needs to occur.

Karl Popper‘s Anima, @charly_knaller, Sep 24, “AP hydrolizes extracellular purine nucleotides which are known danger signals.”

Yes, info on alkaline phosphatase, called ALP or AP:

“Alkaline phosphatases are a group of isoenzymes, located on the outer layer of the cell membrane; they catalyze the hydrolysis of organic phosphate esters present in the extracellular space.

Zinc and magnesium are important co-factors of this enzyme.” (StatPearls)

and another Twxtter reply to the original query by Remnant MD:

HereticalLipid, @HereticalLipid, Sep 24", “weight lifting raises ALP, K2 intake does. Mg intake does.”

and another:

Rich Collins, @richcollins, Sep 25, “My ALP doubled on Carnivore. Likely because it’s involved in fat digestion?”

Yes, the alkaline phosphatase enzyme is involved in regulation of fat absorption and bicarbonate secretion:

“Intestinal AP is expressed in villus-associated enterocytes where it regulates fatty acid absorption through secretion of vesicles at both the luminal and basolateral surfaces (41, 42), regulates bicarbonate secretion and duodenal surface pH (43), and has been implicated in the regulation of diet-induced obesity (44, 45) and metabolic syndrome (46, 47) (Figure 1A).” (Rader, 2017)

Bonus benefit: Intestinal alkaline phosphatase (IAP) has a huge protective benefit against gut dysbiosis effects.

IAP protects against the bacterial endotoxin LPS by dephosphorylating the lipid section of the molecule.

But perhaps, the most remarkable function of IAP centers on its protective interactions with the bacterial symbionts that inhabit or invade our enteric system. IAP has been shown to dephosphorylate (detoxify) the lipid A moiety of lipopolysaccharide (LPS), the outer lipid layer of the outer membrane of Gram-negative bacteria (48). In vertebrates, these phosphates are important for binding of LPS to the toll-like receptor 4/MD-2 innate immune receptor complex (49), initiation of NF-kB signaling, and immune response induction (50–52).” (Rader, 2017)

Bonus benefit #2 - ALP prevents inhibition of mineralization of bone and tooth enamel.

AP/ALP, of the non tissue-specific type, also plays a role in preventing inhibition of mineralization, protecting against “softening of bone, bowing and spontaneous breakage of bones, rickets, and tooth (dentin/cementum/enamel) defects (23).” (Rader, 2017)

• Related posts about mineralization of tooth enamel: Teeth; TRP channels that sense pressure, cold, and promote remineralization in teeth with cavities.(Substack) That is a follow-up post to the lengthy What are teeth? (Substack).

• *This post talks about LPS and histamine issues and cordyceps mushrooms may be protective. (Substack)

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If EVERYONE is outside of a ‘normal’ range, then is it truly the normal range for that population?

My thoughts after looking at the study by Murata, et al., 2023, it is odd because the control group and the centenarian group both were outside of the ‘normal’ range for ALP and LD. The centenarian group was slightly more elevated but both groups were not ‘normal’ = this suggests that the lab range stated as ‘normal’ may not literally represent healthy levels.

Supplementary material, Table 1 shows the ranges and units used for ‘normal’ for the lab values:

“Alkaline phosphatase (ukat/L) Liver functioning 0.75 – 1.93 [5]

Lactate dehydrogenase (ukat/L) Liver functioning 2.34 – 4.68 [6]” (Supplementary material, Murata, et al., 2023)

My lab values textbook says the range for alkaline phosphatase is Optimal 70-100 U/L and Alarm ranges below 30 U/L or above 130 U/L, for Standard US or International Units. (Blood Chemistry and CBC Analysis, pp 120, Weatherby and Ferguson, 2002, Amazon) And for Lactate dehydrogenase is - Optimal Range 140-200 U/L, Standard US and International Units are listed as the same. Alarm ranges are below 80 U/L or above 249 U/L. (pp 143, Weatherby and Ferguson, 2002, Amazon)

»Maybe the seeming anomaly in ALP and LD levels is just an error in what the Murata team used as the ‘normal’ ranges. Why are the numbers so different in Murata, et al., 2023 than the numbers in Weatherby and Ferguson, 2002, . . . yet U/L and ukat/L seem like similar units?

“The katal (symbol: kat) is the unit of catalytic activity in the International System of Units (SI) used for quantifying the catalytic activity of enzymes ...” “One katal refers to an enzyme catalysing the reaction of one mole of substrate per second.^{[3][4]” “}10⁻⁶ kat µkat microkatal” (Wikipedia)

This reference pdf solves the puzzle (cmeinfo.com/Laboratory-Units-Conversion-Table.pdf) - U/L is the standard units and ukat/L is the Si units and they are not the same. There needs to be a conversion calculation to make them equivalent.

Alkaline phosphatase

• Conventional units: U/L

• Conversion factor: 0.0167

• SI units: µkat/L

• Reference Range (Conventional Units): 30-120

• Reference Range (SI Units): 0.5-2.0

• (cmeinfo.com/Laboratory-Units-Conversion-Table.pdf)

That is helpful but relooking at the Murata, et al., graph shows that the midpoint for the non-centenarians and centenarians was around 3 ukat/L for ALP which is high whether in SI units or converted to Conventional units = 180 U/L. The Alarm Range for ALP is anything above 130 U/L per (Blood Chemistry and CBC Analysis, pp 120, Weatherby and Ferguson, 2002, Amazon).

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More speculation based on it not being just an error in the reported ranges.

The screenshot in the earlier Tweet is only one section of a larger figure - all the other blood parameters did mostly fall within the current range of ‘normal’ for both control and experimental group. See Figure 1, screenshot further below. (Murata, et al., 2023)

Maybe the centenarian group were more active with weight bearing exercise that stimulates bone mineralization and had adequate magnesium and zinc and their slightly elevated alkaline phosphatase was protecting them from any LPS being produced in their guts.

The authors point out that the non-centenarians were frequently 80 years old so we are comparing data about older adults, not younger groups. Age 64-74 is the youngest cohort, 75-84, and 85-99, are the two older groups, with data lines for males and females of each age group. “Normal” lab values for middle age adults may truly be different than for adults aged 64 to 99. Zinc deficiency becomes more common as an increased amount is needed to maintain thymus function and current recommendations do not reflect that increased need.

Low zinc would likely be associated with low alkaline phosphatase. ‘Low Alkaline Phosphatase (ALP) In Adult Population an Indicator of Zinc (Zn) and Magnesium (Mg) Deficiency’, (Ray, et al., 2017).

‘Low Alkaline Phosphatase (ALP) In Adult Population an Indicator of Zinc (Zn) and Magnesium (Mg) Deficiency’, (Ray, et al., 2017)

The bars in red tones in the next image are the non-centenarians and Glucose, Creatinine, Uric acid, ALAT, and GGT seem more likely to be elevated in the non-centenarians and ALP and LD were more elevated for the non-centenarians than for the centenarians. (Murata, et al., 2023) The odd thing is that both groups were totally out of the range considered ‘normal’, suggesting that those lab ranges for ALP and LD are not normal for the Swedish population. Is that true for all of the Swedish population, or all people, or all people on modern diets? We don’t know.

I shrank the Figure 1 to show the overview - the green colored area of each square represents the current ‘normal’ range for the lab value.

All of the values are mostly within ‘normal’ and similar between the two groups except for ALP and LD, first two squares on the third row. The Top row: TC, Glucose, Creatinine, Uric Acid; Second row: ALAT, ASAT, Albumin, GGT; Last two of third row: Iron, TIBC.

I shrank Figure 1, (Murata, et al., 2023), to show the overview - the green colored area of each square represents the current ‘normal’ range for the lab value. All of the values are mostly within ‘normal,’ similarly so between the two groups except for ALP and LD, the first two squares in the third row. Top row: TC, Glucose, Creatinine, Uric Acid; Second row: ALAT, ASAT, Albumin, GGT; Last two of third row: Iron, TIBC. The bars in red tones are the non-centenarians and Glucose, Creatinine, Uric acid, ALAT, GGT, and TIBC seem more likely to be elevated in the non-centenarians and ALP and LD were more elevated for the non-centenarians than for the centenarians. The odd thing is that both groups were totally out of the range considered ‘normal’, suggesting it isn’t normal for the Swedish population.

In Figure 1, Glucose, creatinine, Uric acid, and GGT seem to be elevated more in the non-centenarian group than in centenarian group. And the ALP and LD are more elevated in the non-centenarian group too, just both groups are out of the ‘normal range’.

TC (Total Cholesterol) was more likely to be elevated in both groups, slightly higher in the non-centenarian group, but closer to similar than Glucose, Uric acid, Creatinine and GGT. The ALAT, ASAT, Albumin, Iron and TIBC values were all within normal range, with the ALAT and TIBC slightly higher for the non-centenarian group. A little low iron is present in the non-centenarian group.

Background info on lab values from the Inflammation Mastery book by Dr. Vasquez.

(*newer 4th Ed. available now ichnfm.org! As one giant book or a two volume set, which I now realize I also bought Vol 1, so now I just need Vol 2. These are good texts once adjusted to the style. Dr. Vasquez goes for excellence rather than brevity and may achieve both if you consider condensing 25 books of info into one place is ‘brief’ when condensed into less than 1000 pages.)

• Alkaline phosphatase can be elevated due to vitamin D deficiency, bone lesions, metabolic bone disease, and hepatopathy — congestive liver disease. Consider zinc deficiency and malnutrition for low values. (p 30 and 109, Inflammation Mastery, Vasquez, 2014, ichnfm.org)

• GGT is reduced in hypothyroidism possibly reflecting reduced protein synthesis in general. GGT is a possible biomarker for oxidative stress and xenobiotic exposure (*manmade chemicals/environmental pollutants, (citing Lim et al., 2007; p 31, Vasquez, 2014) Hepatobiliary obstruction and other liver problems are likely with elevated values. Minor elevation may be seen with autoimmune SLE or hyperthyroidism. ALP may be elevated with liver or bone conditions, while GGT will not be affected by bone conditions. (p 31, Vasquez, 2014, ichnfm.org)

• Creatinine - likely renal failure is the cause of elevated levels in older age groups. Excessive dietary protein intake can also cause elevated creatinine. It is likely to be low with sarcopenia, protein deficiency or malabsorption. (p 32, Vasquez, 2014)

• Glucose - elevated with diabetes, type 1 or , Cushing’s disease, hyperthyroidism, acromegaly, pheochromocytoma, and glucagonoma. 9p 8, Vasquez, 2014, ichnfm.org)

I would add that low magnesium can be a factor in elevated glucose and oxidative stress or vitamin D deficiency.

In my replies I suggested that strenuous exercise might be a factor leading to elevated ALP and LD levels instead of only chronic illness of liver or bone — but that doesn’t explain why both groups having fairly similar ‘elevations’. Although, ALP was more likely to be very elevated in the non-centenarian group.

What might effect most of a nation’s people? The food, air, and water supply. Medications commonly used and type of topical products used may also be relevant to public health along with other cultural selfcare routines or traditional practices — they may have protective value or add specific risks. Vitamin D deficiency is quite common now, especially in countries that use glyphosate. Magnesium deficiency is also very common in modern diets and can add to risk of vitamin D deficiency.

• Uric acid can be elevated in gout which also may occur with hyperhomocysteinemia, but levels of uric acid were not found to be directly linked to homocysteine levels in a study on patients with gout. (Agilli, et al., 2014)

• TIBC — total iron-binding capacity. Elevated values may be seen when microscopic bleeding is present. TIBC would be above 350 or 62.7 micromol/dL and total serum iron would be low, below 50 or 8.96 micromol/dL. (p 163, Weatherby and Ferguson, 2002, Amazon)

Disclaimer: This information is being provided for educational benefits within the guidelines of Fair Use and is not intended to provide individual health guidance.

Reference List

(Agilli, et al., 2014) Agilli M, Aydin FN, Cayci T, Kurt YG. The relationship between homocysteine and uric acid levels in gouty patients. J Korean Med Sci. 2014 Sep;29(9):1328. doi: 10.3346/jkms.2014.29.9.1328. PMID: 25246756; PMCID: PMC4168191.

(Di Virgilio, Sarti, Coutinho-Silva, 2020) Di Virgilio F, Sarti AC, Coutinho-Silva R. Purinergic signaling, DAMPs, and inflammation. Am J Physiol Cell Physiol. 2020 May 1;318(5):C832-C835. doi: 10.1152/ajpcell.00053.2020. Epub 2020 Mar 11. PMID: 32159362. https://www.facebook.com/groups/ifmntcotfullcourse/

(Murata, et al., 2023) Murata, S., Ebeling, M., Meyer, A.C. et al. Blood biomarker profiles and exceptional longevity: comparison of centenarians and non-centenarians in a 35-year follow-up of the Swedish AMORIS cohort. GeroScience (2023). https://doi.org/10.1007/s11357-023-00936-w https://link.springer.com/article/10.1007/s11357-023-00936-w Figure 1: https://link.springer.com/article/10.1007/s11357-023-00936-w/figures/1

(Rader, 2017) Rader, B.A., Alkaline Phosphatase, an Unconventional Immune Protein, Frontiers in Immunology, Vol 8, 2017, DOI=10.3389/fimmu.2017.00897 https://www.frontiersin.org/articles/10.3389/fimmu.2017.00897/full

(Vasquez, 2014) Vasquez, A., Naturopathic Rheumatology and Integrative Inflammology, Edition. 3.5, A Colorful Guide Toward Health and Vitality and Away from the Boredom, Risks, Costs, and Inefficacy of Endless Analgesia and Pharmacoimmunosuppression, InflammationMastery.com, International College of Human Nutrition and Functional Medicine, Barcelona, Spain, 2014. *There is now a Fourth Edition: https://www.ichnfm.org/inflammation-mastery-4th-edition. This is a useful book - I would buy the 4th Edition if I had known about it, and may yet as he says he updated the fibromylagia and migraine and gut dysbiosis sections. **I did buy Vol 1 of the 4th Ed. without realizing. So now I just need Vol 2 to get the remaining updates.

(Weatherby and Ferguson, 2002) Weatherby, D., Ferguson, S., Blood Chemistry and CBC Analysis; Clinical Laboratory Testing from a Functional Perspective, Bear Mountain Publishing, 2002, Jacksonville, OR. (Amazon)