Bile can serve as a reservoir for funghi, making them harder to treat

CrumblingCookie

@Mauritio Serum iron has been at the top of ref. range since almost forever.
Serum ferritin used to be low between 30-60 but to my probable detriment I had received four i.v. iron treatments four years back due to persistent anemia and ever since ferritin has been above 120 (-240).
Only when I stumbled upon copper Morley's high-tier references did I see that serum ferritin is another essential lie and sort of like serum liver enzymes: In general it shouldn't be floating about freely in any significant amount.

@sunsunsun Such combos are def worth a thought!
All I can report is that TUDCA or taurine without antifungals had been making things significantly worse. Perhaps it did release fungi from a biliary reservoir and could turn out differently when combined with antifungals at the same time.
Similar to how some dietary sugar can be a good complement to antifungals as the thereby enhanced metabolism of yeasts raises their susceptibility to antifungals. Just like we need bacteria to not be in a dormant but replicative state to be harmed by ABx.
I may want to try TUDCA again in this context. Have also been thinking of pinning some i.m. thiamine or taking it orally for the same reasons. Yet only once I'm feeling sufficient confidence wrt the effectivity of the antifungal treatment!

yerrag

@CrumblingCookie

I live in Manila, Philippines. I apologize for giving the wrong impression that treating for fungus is common after a round of antibiotics. It depends on the attending physician, and the one that took care of my mom delayed my mom's discharge by giving her antifungals after the antibiotics treatment.

I felt it was odd because it seemed to worsen my mom's condition. I felt fungus is not well understood by doctors. It's hit or miss.

I think that practicing solely germ theory detracts from a better understanding of fungus, given that pleomorphism in terrain theory allows for the idea that bacteria can change into fungus.

Mauritio

@sunsunsun yeah I think so too and minimizing intake first. I stopped using my iron cast pan about 6 weeks ago. Had another blood test on Friday so we'll see if ferritin is still high.

Taurine always makes my cholestasis worse for some reason. It is constipating.
TUDCA I should give another try.

CrumblingCookie

@sunsunsun
The Japanese had found increased susceptibility to severe fungi infetion and mortality thereof in liver injuries. Additional transferrin negated the extra mortality from liver injury in rodent studies.
I.e., liver injuries lead to less transferrin (and UIBC (unbound iron binding capacity) and TIBC (total iron binding capacity) and it is that decrease of transferrin which enhances fungal infections.
https://pubmed.ncbi.nlm.nih.gov/2960898/
https://pubmed.ncbi.nlm.nih.gov/2975353/

Copper (and retinol) are therefore very essential in prevention of fungal infections.
Not sure about any treatment efficacy after infection has already occured, though. Surely more free iron will stimulate fungal growth - but does iron restriction assist when aiming for fungal eradication from tissues?

I have been trying to raise my ceruloplasmin (and thus functional transferrin) by regular copper intake since late last year.

Also, in this paper from 2000 a strong clinical distinction was suggested between acute disseminated candidiasis and chronic disseminated candididiasis: Again, in CDC, there's typically no candidemia and whereas ADC involves several organ system, CDC predominantly befalls the spleen and liver. Typical findings are hepatosplenomegaly, and focal hepatic lesions by ultrasound imaging and recurrent fevers although I reckon the presentation of the latter two will be subject to the mentioned individual immunological response and existence of an even more latent phenotype of CDC (as abundantly shown in other publications in this thread).
Interestingly, cultures and histophathology of liver biopsies again frequently failed to detect fungi proven to be present by clinical signs and PCR of liver biopsies (no positive fungi PCR in healthy control group).

In this 1992 publication intrabiliary Amphotericin B was successfully used in a child after (typical) failure of priorly administred systemic AmB to clear the biliary infection. Good for her. Yet only downstream of the hepatic tumor she had been hospitalized for.

Mossy

@CrumblingCookie said in Bile can serve as a reservoir for funghi, making them harder to treat:

Copper (and retinol) are therefore very essential in prevention of fungal infections.

I have been trying to raise my ceruloplasmin (and thus functional transferrin) by regular copper intake since late last year.

Do you think consuming beef liver would be enough to help with this?

LucH

@Mossy said in Bile can serve as a reservoir for funghi, making them harder to treat:

Do you think consuming beef liver would be enough to help with this?

In prevention, yes. Not when contaminated.
Copper (Cu):
in beef liver (3 oz.): 12 400 mcg
in chicken pan-fried (3 oz.): 455 mcg
in seeds the best options include sesame seeds, almonds, sunflower seeds, and cashews. A 1-ounce serving of these crunchy seeds can supply around 0.5 to 0.9 milligrams of copper.
In pumpkin seeds 1,34 mg per 100 g. 1 tbsp is 7.44 g and brings 99 mcg Cu. => I put 1 big tsp in my smoothie with pomegranate.

Ceruloplasmin is a protein your liver makes. It helps copper circulate throughout your body and plays an important role in making the iron that you get from food ready to move from your intestines to organs like your spleen. You need copper to help maintain energy and bone health.
So, no direct need for blood or liver needs but well for SOD enzyme. Copper is required for sod enzyme in infection control. Cu and Zn are required for superoxide dismutase enzymes. Interaction between HD take (+/ 1/10 Cu/Zn).
And Yes, retinol is also required in the immune process (interaction with A D K). I take 2x/wk. 5 000 UI (retinyl palmitate).

Mauritio

@CrumblingCookie said in Bile can serve as a reservoir for funghi, making them harder to treat:

but does iron restriction assist when aiming for fungal eradication from tissues?

I suspect so. At least on the sense that lower iron will make fungi more susceptible to anti-fungal treatment.

"The SC5314-strain and oral isolates showed enhanced antifungal-resistance towards most antifungals tested, under high iron."
https://www.tandfonline.com/doi/full/10.1080/20002297.2022.2044110#abstract

CrumblingCookie

This study has an interesting hint: we need small and hydrophilic molecules for an anti-fungal effects that isn't reduced by bile.

"In contrast, small and hydrophilic molecules, such as cycloheximide, flucytosine, or sodium azide kept their antifungal properties. "

It's difficult to not despair in the face of things continueingly worsening since the stop of fluconazole 300mg pd in spite of having commenced flucytosin treatment (100mg/kg BW /day) already 5 days ago.
Flucytosine's mechanism of action is a slow, gradual, delayed intracellular conversion and poisoning in contrast to the rather immediate mechanism of action of fluconazole.
Whilst Flu especially accumulates in mucosal tissues, it principally seems true that FCy doesn't even start to work within a couple of days but requires about 2 weeks to get going:
Fluconazole vs. flucytosine in the treatment of esophageal candidiasis in AIDS patients: a double-blind, placebo-controlled study, 1995
On the other hand, the FCy (5-FC) has been making me feel weak and woozy in the head since day one. It's also been exerting a weak cardiovascular burden.

I've read in some paper that the fear of developing resistancy to FCy monotherapy is much exaggerated as there have been very few reported cases of it happening in-vivo.
The urgent recommendation of pairing FCy with i.v. AmB for at the very least 2 weeks of treatment induction must be, to a great extent, down to bridging the temporal gap until onset of FCy efficacy.

Serologically, my C. albicans antibodies are nil and serum CAGTA antigen is also nil (that's the Candida spp. hyphal protein).
Thus, unless there's a specific humoral defect, C. albicans has no involvement at all in my case. C. glabrata, however, generally doesn't do hyphae but is able to be sufficiently nasty and virulent in its yeast form.
Circulating serum 1,3-beta-D-Glucan levels (as a systemic marker for most fungal species) also aren't elevated but at half of the lab's threshold.
There are therefore really no lab markers at all to support any physician in joining speculations on a hepatic/biliary fungal infection. It's difficult to not despair.

Have stopped the borax drinking water.
Have started 500-1000mg of UDCA per day to enhance bile solubility and hydrophilicity.
Also trialled alpha-GPC for two days in this context. However, that turned super awful. Choline and in particular alpha-GPC is a superfood to fungi which they gobble up for its choline and phosphate.
Kind of disadvantageous when you know that the liver needs substantial amounts of choline for itself.
Have pinned 100mg Thiamin-HCl i.m.

@mossy I wouldn't know! I dislike and distrust liver so have gone for the isolated substances and followed them up with testing of serum (free) copper, ceruloplasmin and retinol. IIRC there was one guy writing on the old RPF that he had eaten lots of liver regularly and his lack of copper was surprisingly unaffected until he started supplements.

sunsunsun

any opinion on pH and yeasts?

Mauritio

@CrumblingCookie I hear you. It's frustrating.

Molybdenum might be good addition to help die off and metabolize acetaldehyde.

Ive recently noticed that eating radish seems to help me . I think it is downstream from improved liver and gallbladder health. Raddish can increase phase 2 detox in the liver and help with bile flow.
It's metabolites (sulforophane) also activate Nrf2.

I've also ordered TUDCA and some homeopathic remedies, to help with bile flow.

CrumblingCookie

@Mauritio
Radish is an excellent idea. Both Horseradish and Tropaeolum majus / Nasturtium have significant selective antibiotic properties due to their isothiocyanate (ITC) content.
I've looked up the few (mostly in vitro) studies on it and Candida spp. are among the listed susceptible pathogens. C. albicans significantly more so than C. glabrata or C. krusei or C. tropicalis yet all are highly susceptible.
Allyl-ITC is the very volatile compound of fresh horseradish or also wasabi. It gives the pungent nasal effect.
Benzyl-ITC is the much less volatile liquid component. Whilst I cannot find any aetherial oil extract of horseradish, nasturtium or papaya seed (96% benzyl-ITC) it's actually available and even affordable as a pure substance: Even Sigma-Aldrich sells it for c. USD120 per 25g. Don't know how much and in what concentration to take it but benzyl-ITC looks well worth looking into.
It's reported to work by conjugating and thereby depleting cysteine and glutathione of yeasts and that provision of exogenous GSH (or NAC, I reckon) cancels out the antifungal effect.

I've ordered capsules with a powdered horseradish + nasturtium blend for now and hope they will arrive soon.
In Eastern Europe there are traditional "Kren" tinctures (btw said to be great topically for hair roots and microcirculation).

CrumblingCookie

Hepatic fungal infections do occur in patients up to >8years after liver transplantation.

Can't see whether those are due to preexisting chronic infection of the donor organ (and remaining relatively dormant until idiosyncratic exacerbation or building up at a steady, gradual pace) or whether it's acquired by translocation during the life-long requirement of post-transplant immunosuppression.

Anyway:
The way such hepatic fungal infections are being treated is by flooding systemic antifungals to reign in extra-hepatic dissemination and then replacing the liver a couple of months later.
They discard the infected liver and put in another one. They don't even try to achieve hepatic tissue clearance.
What an astonishingly harsh fact to have sink in.

Mauritio

@CrumblingCookie I meant Raphanus sativus, but horseradish is a good choice too.
I made a thread about it some time ago .

CrumblingCookie

@sunsunsun said:

any opinion on pH and yeasts?

Which pH where are you thinking of?
I'd confidently say that high stomach pH is a very significant risk factor.
Especially over time.
Not only is there a higher quantity of yeasts passing the stomach but also the less acidic chymus will be met by less alkalic bile (or lesser quantities thereof).
Unless there's some metabolic bicarbonate depletion (on top) which puts the less alkalic bile into first place of such chicken-egg interdependencies.
Any way, there'll be more exogenous microorganisms than there ought to be and along with the incomplete digestion and shifts in microbiome more mucosal disturbances and pathogenic colonization and translocation.

I've come across this publications from 1965 on moniliasis (=candidiasis) Moniliasis, Steatorrhea, Diabetes Mellitus, Cirrhosis, Gallstones, and Hypoparathyroidism in a 10-Year-Old Boy and found it interesting how they (unsuccesfully) discussed the very confusing and complex relations.
They had probably stumbled upon the back then still unestablished "Autoimmune Polyglandular Syndrome Type 1 (APS-1) / Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED)".
Yet I don't know whether such a term and associated genetic variance has resolved any underlying mechanisms.
They were really confused as to what's causing what.
What they observed were strongly reduced magnesium uptakes (probably because of fungal infection), which is necessary for parathyroid hormone synthesis, followed by accordingly diminshed calcium uptake. D3 was of no assistance. There was also lots of steatorrhea which preceded many of the other symptoms by years and is somehow reciprocally dependent on calcium. And autoimmunity (intracellular fungal vacuoles? antibody or T-cell cross-reactivity? antigenic mimickry?) against the (para)thyroid gland, as well as hepatic changes. A real mess!

-> I'm suspecting that any mess with having both decreased magnesium yet also decreased/intolerable Mg uptake and a chronically fluctuating/insufficent calcium metabolism should point oneself to consider fungal infections! It surely won't be as extreme as in those genetic cases but how would you ever know whether PTH levels are as high as they need to be?

Disturbances of these essential alkaline electrolytes sort of lead back, over a long stretch, to your general pH question.

Pertinent to the discussion may be work presented by Louria and Brayton in Nature (Jan. 18, 1964, p. 309), who found a substance in blood lethal to Candida albicans in normal persons. A moderate to marked reduction to this substance was found among patients with cirrhosis, hepatitis, diabetic azotemia, and in patients with mucocutaneous and systemic moniliasis.

The percentage of persons possessing the factor is slightly reduced among groups of patients with diabetes (without azotaemia) and with disseminated carcinoma.

This is about transferrin again @sunsunsun .
Specifically, back then they had narrowed it down to a molecule between 10-20kDa - which surprisingly doesn't match up with transferrin but suggests an even more potent polypeptide that has been split off the complete transferrin molecule. Unless their filter meshes back then were somehow wrong. Anyway the results of the other studies suggest that transferrin is a direct source of this active polypeptide.

The substance appears to have impressive specificity. It is active against Candida albicans and Candida stellatoidea but not against other Candida species [glabrata, krusei] or other yeasts such as Cryptococcus neoformans or Saccharomyces cerevisae.

! The iron-chelating property of this likely transferrin peptide does not harm C. glabrata or C. krusei or other non-albicans fungi! This is highly relevant.

Puts the approaches directed at iron-chelation also in a highly species-specific context to consider.
Tannic acids are highly anti-fungal. Among other mechanisms, they inhibit hyphal growth of C. albicans and hinder their adhesion to mucosal cells. In animal experiments, sufficient dietary tannic acids directly increased Candida excretion (i.e. fungi which failed to colonize or invade).

This may be an important mechanism behind the acutely anti-diarrheal and anti-microbial activities of oral tannin-albuminate or tannin-gelatinate.

Sort of shifts the dietary focus away from those merry-go-round prebiotic and soluble or insoluble fiber discusstion and puts weight onto dietary tannic acid content. Which also lead to fruit (berries!) and vegetables and rather more traditional, more natural, tarter or more bitter varieties than today's varieties aimed at maximizing sweetness and yield.

One of the most widespread and available tannins which also offers large mucosal absorption is EGCG.
EGCG of course strongly chelates iron. Surprisingly, though, it provides a more complex mechanism of action.
EGCG is indeed most antifungal against C. glabrata! EGCG sort of also targets liver tissues so this is good news.
Have ordered EGCG (decoffeinated) to augment the FCy/5-FC and horseradish.

Some flavonoids markedly downregulate Candida CDR1 (which regulates the efflux pumps and resistances against azoles!):
Flavones, Flavonols, and Glycosylated Derivatives-Impact on Candida albicans Growth and Virulence, Expression of CDR1 and ERG11, Cytotoxicity

The reduction of both fungal virulence and expression of antifungal resistance-linked genes was the most pronounced for apigenin and apigetrin; these results indicate flavonoids' indispensable capacity for further development as part of an anticandidal therapy or prevention strategy.

Here, however, kaempferol's antifungal properties beat apigenin, which exhibits some ambiguous and controversial effects (like upregulating ERG11, inhibition of which is the target for azoles) by miles. Kaempferol seems worth noting down.
Inhibition of Candida albicans extracellular enzyme activity by selected natural substances and their application in Candida infection, 2008

Mossy

@LucH said in Bile can serve as a reservoir for funghi, making them harder to treat:

Thank you for the detailed answer.

And Yes, retinol is also required in the immune process (interaction with A D K). I take 2x/wk. 5 000 UI (retinyl palmitate).

So, you obviously don't think the vitamin A from liver is enough or effective in the same manner as supplementing vitamin A? If AI is correct, it states: "A 4-ounce serving of beef liver contains approximately 9,000 to 25,000 IU of vitamin A, while chicken liver has around 13,000 to 16,000 IU."

Mossy

@CrumblingCookie said in Bile can serve as a reservoir for funghi, making them harder to treat:

I wouldn't know! I dislike and distrust liver so have gone for the isolated substances and followed them up with testing of serum (free) copper, ceruloplasmin and retinol. IIRC there was one guy writing on the old RPF that he had eaten lots of liver regularly and his lack of copper was surprisingly unaffected until he started supplements.

Ok, I can appreciate that perspective. I don't like the taste of liver. I take it purely as a medicine. I only eat 2 oz at a time now, because I dislike the taste so much. When I used to eat 4 oz, I could feel the positive effect it had on me. Sometimes with the 2 oz, but not as much.

LucH

@Mossy said in Bile can serve as a reservoir for funghi, making them harder to treat:

you obviously don't think the vitamin A from liver is enough or effective in the same manner as supplementing vitamin A?

No. Whenever I can eat 2 chicken livers (broth) it's fine. Not always available.
No need to supplement if I eat liver.
Apart case: Infection, higher ratio and more D3.

CrumblingCookie

@Mauritio Any new ventures into this? I've seen in your other threads that you've been harbouring fungal suspicions for a very long time.
Your mentioning of molybdenum to potentially counter any initial fungal "die-off" symptoms made me wonder if those dogmatic followers on the LTF are also actually onto chronically persisting fungi with all their EGCG megadosing. Thoughts?
Mo doesn't seem to help me.

EGCG absorption is quite low and it's highest on an empty stomach after fasting.
So I'm moving the complete daily dose to the morning instead of having it split up, so it can reach at least inhibitory concentrations in the body. 1050mg EGCG pd.

Have also started the horseradish and nasturtium powders throughout the day. 3,000mg nasturtium and 1,200mg horseradish pd.
When I open the capsules, however, they don't taste very pungent at all in my mouth. Only very slightly and super-transiently. Gone after 10 seconds. 1.2g of ground, dried horseradish also sounds very little. I probably should be taking four times as much per day, as 1.2g would only be about 8g of fresh horseradish. I didn't get a brand product because of the nasty tablet fillers so there could be further variances in the raw products and drying process.
Perhaps an appropriate amount of benzyl-ITC could indeed be better?

Peak serum levels of FCy (5-FC) at my 95mg/kg dosage are still unknown to me after two weeks of administration - which really isn't ideal. Hopefully they're high enough to be therapeutic.
So far there's not a hint of hematological / bone marrow suppression. CBC is as fine as always.

In summary:
I'll continue now every day with FCy 95mg/kg, EGCG 1050mg, dried nasturtium/horseradish 10g/4g, UDCA 500mg. And the aforementioned probiotics, few B vitamins, colloidal silicium.
And I'm now going to start artichoke leaf extract, equivalent to 4g - 12g of raw artichoke leaf, 3-4x daily. Predominantly for increasing hepatic bile synthesis and output. If it inhibits and decreases hepatic cholesterol synthesis and storage that should theoretically assist.
I had the oregano essential oil and garlic slip. Either my initial garlic bulbs were very weak and the Chinese garlic bulbs I have now are hugely more pungent or I have grown tired of it, or both.

sunsunsun

@Mossy chicken liver is actually scrumptious when prepared via my world-famous bbq baked bean and chicken liver recipe. I dont exactly like eating fried liver and onions plain other than on the rarest occasions, and even then I have to chase it with mashed potatoes, ketchup, and an ice cold Coca Cola, but the chicken liver and bbq baked beans recipe I have is fire af on buttered bread, lmk if u want it, it's easy to make with canned baked beans too. it actually gets better in the fridge a day or two after cooking it too.

alfredoolivas

@sunsunsun let us know