Thyroid Damage Due to Collagen/Connective Tissue Damage


I wrote this website to describe how fluoroquinolone antibiotics destroyed my thyroid hormone and iodine metabolism.   For this reason, this website takes quite a “thyrocentric” view of things, meaning I explore and describe my symptoms all through the lens of “TH/Iodine” metabolism problems.   But what kind of Fluoroquinolone Toxicity website would this be if I didn’t at least mention the obvious:   the Collagen and Connective Tissue damage that the FQ’s cause?   And Collagen and Connective Tissue Damage could be a very viable mechanism for “thyroid damage” as well.   So here’s my addition from this point of view.


Thyroid Damage Due to Collagen/Connective Tissue Damage

Connective tissue, which includes tendons, are made up of collagens.   “Connective Tissue”, as the name implies, also does just that:   it “connects” everything to each other and holds tissues and cells together.   Connective tissue and collagens are located throughout every organ, tissue, and cell in our body, not just in “tendons”.   This includes the thyroid gland, helping to form the structure of the gland.   However, when it comes to “Connective Tissue and Collagen Damage” from FQT, the most obvious manifestation of this occurs with the severe tendon pain and ruptures that can occur with FQT.   In other words, even though connective tissue and collagen damage may be occurring throughout all of our cells and tissues to some extent for those of us suffering from FQT, we see that effect most obviously in the form of ruptured tendons, such as the Achilles or other tendons.   Yet, this doesn’t mean that connective tissues in other parts of our bodies aren’t falling apart or disintegrating (and if you ask any severely floxed person, they will tell you it feels like their entire body is falling apart or disintegrating).   It just may not be as obvious to the casual observer.   And the thyroid gland may be one example of that.

The thyroid gland is kind of a unique organ in that it is made up of ‘balloon-like’ or ‘sac-like’ structures called follicles.   This is why the thyroid gland always looks “lumpy” in pictures; these lumps are the ‘balloon-like’ follicles.   These follicles store the thyroid hormone, and the precursors to thyroid hormone, in a form called “colloid”.   I sometimes think of the thyroid gland like a bunch of little water balloons, all held together by connective tissue, and surrounded by an outer layer of fibrous connective tissue which gives it its shape.   Each little water balloon is a follicle, which contains the water (colloid) inside.  The rubber “skin” of each balloon keeps the round shape of the balloon, and of course keeps the water inside the balloon.   The “skin” of the balloon is tough, yet, delicate:   you can slowly squish the balloon to some extent without popping it on the one hand, yet on the other hand, all it would take is a pin prick of the balloon to rupture it.   The thyroid gland is kind of similar:  physically tough, yet vulnerable at the same time.   Each follicle (balloon) of the thyroid gland contains the colloid, which in this case is made up of things like thyroglobulin (TG), thyroid peroxidase enzyme (TPO) and Iodine in addition to all the thyroid hormones.  The connective tissue surrounding each follicle is like the “skin” of the balloon, and holds this colloid mixture of Thyroid Hormone (TH), TG, TPO, and Iodine inside it.  The connective tissue also holds the cells that make the colloid, called follicular cells, together, and it’s these cells that help make the colloid and thyroid hormone.   Do a search on “Images for thyroid gland anatomy” and “Images for thyroid follicles” to see lots of different pictures available on the internet.   Here are a couple of pictures of what thyroid follicles look like under a microscope.  They are colored purple because of the type of stain used to help see the follicles, the surrounding follicular cells, and the colloid that these cells produce:


thyroid12 - Copy


thyroid16 - Copy


The thing to note about these pictures is how big the follicles are in relation to the thin layer of connective tissue holding the follicular cells together and giving the follicles their shape.   This thin, delicate, almost gossamer-like connective tissue is all that’s holding these big blobs of colloid follicles intact.   It’s the only thing that keeps all the follicular contents inside the follicles.   The follicles are kind of like large water balloons.   It makes the thyroid gland seem like a very delicate organ indeed.   Under normal circumstances, thyroid hormone is produced inside these follicles, and is only released into the bloodstream in a very, very controlled fashion, on an as-needed basis.    Thyroid hormone (TH), TG, TPO and Iodine should only stay in the colloid inside the follicles until TH is ready to be released in a very careful and controlled manner into the bloodstream.

But what happens if this connective tissue is partially or fully destroyed?   The follicles “rupture”, spewing their contents of TH, TG, TPO, and Iodine into the surrounding tissue and bloodstream.   Think of a pin rupturing a water balloon, in which case the water leaks out or the balloon may even burst.   Or what if the rubber balloon “skin” itself started somehow “melting” or disintegrating, in which case eventually the water inside will all leak out as the rubber, or entire “follicle”, is destroyed.   When it comes to thyroid follicular ruptures, the more sudden, acute, and traumatic the insult, the more sudden, acute, and traumatic the symptoms will be.  Thyroid hormones and iodine are spewed out, ending up in the bloodstream and causing “hyperthyroid” symptoms.   The TG, TPO, and Iodine are not supposed to be spilled outside of the follicles and all over the surrounding tissue, so the immune system sends in cells to clean up this highly antigenic mess – and starts the creation or up regulation of the anti-thyroid antibodies called TgAb and TPO antibodies.   This is one potential mechanism of the start of Autoimmune Thyroiditis, and may be the start of permanent Autoimmune Thyroid Disease.  This could also be a potential mechanism to explain the FQ-Induced Thyrotoxicosis and “Iodine Toxicosis” I talked about here.

Can the thyroid gland recover from such an insult?    Yes, it’s certainly possible, and it probably happens more often during our lives than we realize.   There are probably any number of reasons there can be a “follicular break” here and there throughout our lifetime, and, just like wound healing in our skin, our bodies take care of it.   We get cuts and scrapes and wounds on our skin (which is also made up of connective tissue), which heal over quite nicely if no infection or additional trauma exists.    And the thyroid gland is no different.   If the wound is small enough, and the insult is temporary or transient, and we’re in good general health, then the connective tissue will heal and reconstruct the follicle and all will go back to normal, and we’ll probably never feel that we temporarily lost a follicle or two in the first place.   We’ll also probably never feel the slight increase in TH and Iodine that may occur as well, because numerous homeostasis mechanisms are in place to handle slight fluctuations of TH and Iodine in our system.

But what if a large number of follicles are suddenly damaged?    What if a larger amount of the connective tissue holding these follicles together suddenly becomes damaged?   Here, too, healing can occur, depending on how healthy the thyroid gland and individual were before the destruction occurred.   But the person might have a transient “thyrotoxicosis” in the meantime, or experience a transient hyperthyroidism while TH is spilling out of these follicles.   Eventually, this could lead to a transient or temporary hypothyroidism, because once the spilled TH is used up, if too many follicles are still damaged, then the person can go hypo for a while.   The follicles are like the “factory” where TH production takes place, and it will take a while to get “the factory” up and running again.   It takes time to repair the connective tissue damage, re-form the follicles, and get the machinery working again to produce TH the way it’s supposed to.   Additionally, if the damage is too great, scar tissue – abnormal collagen formation – might occur in some areas instead of normal follicle formation, leaving the tissue there permanently non-functional, and lessening the number of working follicles overall.   However, this may be why sometimes people diagnosed with some forms of hyperthyroidism, if it’s not too bad symptomatically, there is no eye involvement, and no or few TSI antibodies, there will be a recommendation to “wait it out” a bit and monitor, and see what the progression is.   The “blowup” may be a one-time thing, and everything will settle back down to normal.   Or, the person might find themselves hypo after many months, as it now progresses into hypothyroidism.    Here, too, if symptoms aren’t too bad, mainstream physicians may recommend “waiting out this phase” as well.   These swings can be pretty hard to wait out though for many people, depending on the severity of the thyroid pathology and other general health considerations.    And with this particular mechanism in mind, there’s a greater chance that TG/TPO autoimmunity could develop, because of the larger amount of antigenic material acutely flooding the surrounding tissues and area during the initial “blowup”.   But sometimes temporary use of medications or supplements can help a person get through it while the thyroid gland heals.

Using an analogy, think of the BP Gulf Coast oil spill in 2010:    a “ruptured” pipe caused a sudden, large amount of oil spewing out into the surrounding environment, damaging it extensively.   And they didn’t cap that thing in a day; it took 87 days before they were finally able to stop that oil from gushing out into the ocean.   In the meantime, not only the surrounding environment was damaged, but the effects to the environment and wildlife by then were widespread and long distance, as the oil slowly made its way throughout the ocean and even on to shores.   Once the spill was finally capped and stopped, the problems didn’t end there.   The clean up took years after, and according to one headline, “Effects Linger, and Recovery is Slow” years later.    Such could be the case with a severe, acute damage of the thyroid gland as well.   It can take time to “stop all the leaks” and seal up the follicles, clean up the colloid, repair the damage, and start normal production again, as well as repair and readjust the “collateral damage” (everything throughout the body that TH affects).   But in this case, the person would feel all the different effects that hyper and hypo thryoidism would contribute to during the process.

Another possibility is that if the damage is not repaired 100%, this could result in chronic, smaller leakage of colloid contents out of the follicles.  This would contribute to ongoing immune cells in the area trying to constantly clean up the spilled colloid and seal these leaks.   These autoimmune antibodies can get quite aggressive, and all it takes is entry into another follicle to go after the TG and TPO with a vengeance, which it now sees as “foreign”, thereby destroying the follicle completely.   The solution (antibodies) now becomes the problem (autoimmune disease), as the “thyroid gland” becomes the target of these antibodies.    Everything gets chewed up in an attempt to contain TG and/or TPO, and a vicious cycle ensues:   the more TG/TPO/Iodine spills out, the more antibodies come in to try and clean it up, causing even more destruction in the process.   Depending on the nature of the “leaks”, the complete destruction of the thyroid gland can take months or it can take years and years, and people often suffer terribly during the process due to the flaring and other reasons as the thyroid gland attempts to compensate  (See “T3/T4 Flares” and “TSH and T4: Useful or Useless?” and  “Thyrotoxicosis and “Iodine Toxicosis” ).   This is what often happens with Hashimoto’s disease.    Many mainstream physicians often recommend waiting until “the thyroid gland is destroyed enough that you go hypo” before treating – which for some people, can result in a long, slow, miserable decline with years of misery due to compensatory flaring while “waiting for their thyroid gland to konk out” before their doctor will consider taking action.   Many alternative physicians will recommend diet changes and supplements in an effort to decrease or stop the autoimmune attack, with varying rates of success.   There is also always a portion of the population who are asymptomatic for any form of thyroid disease, but are antibody positive.   This may represent a well-compensated slower process going on, perhaps indefinitely for the person’s lifetime.    Or, there is always the possibility these antibodies aren’t pathologic at all, but more “natural”, serving other functions is some genetically pre-disposed individuals. (See Natural Autoantibodies, here, here, here, here, and here).   I don’t know what my antibody status was pre-flox because it was never tested for.   But there’s always the possibility that I was in this category, which I suspect may have contributed to my flox reaction.

Lastly, another possibility is that proper collagen/connective tissue can’t be formed properly in the first place, making the follicles more susceptible to rupture, or complete repair impossible.   Instead of functional follicular connective tissue, partially functional, or even non-functional fibrous scar tissue formation or other collagen formation may occur.   Such may be the case for people with clinical or subclinical collagen/connective tissue disorders.   Or, it could occur if something comes along that destroys the ability of normal collagen formation to occur – such as what may occur with the fluoroquinolone antibiotics.


Who is at Risk for Thyroid Problems and Fluoroquinolone Toxicity of the Thyroid?

With this model of thyroid damage in mind, who would be more susceptible to thyroid problems, especially autoimmune ones?    Well, for starters, people with known connective tissue or collagen disorders as described here.    This turns out to be the case, as it’s well known and accepted that those diagnosed with rheumatic and connective tissue disorders are often diagnosed with thyroid disorders sooner or later, and vice versa, especially AITD.   Anything that destroys connective tissue or collagen, or prevents its proper formation in the first place, would probably increase the risk of thyroid damage and AITD (Autoimmune Thyroid Disease).   But it’s not just people with existing or known collagen or connective tissue disorders who are at risk.   There are probably genetic and/or epigenetic predispositions within people that remain “silent” or subclinical without symptoms until a stressor or trigger comes along.    Environmental stressors exist.   And with the fluoroquinolone antibiotics propensity for targeting collagen and connective tissue as an adverse effect, they would be at the top of the list.    So from a “Connective Tissue” point of view, Thyroid Damage/Disease secondary to Collagen and Connective Tissue destruction due to FQ’s could be a very viable mechanism.

A legitimate question to ask about the process I have described above is why is the thyroid gland in particular so susceptible to collagen/connective tissue destruction, and therefore, FQ-Induced damage?   After all, virtually all organs, tissues, and cells contain some form of collagen or connective tissue.   Why doesn’t all connective tissue disintegrate or malform equally for a person who takes an FQ antibiotic?   I think there are several possibilities:

  • For starters, there are a variety of collagens, and FQ damage may be targeting only some of them.   This may include the connective tissue and collagens that make up the thyroid gland.   Genetic and epigenetic pre-dispositions for different collagen and thyroid disorders in different individuals could make a difference.   Not everyone who takes an FQ antibiotic develops thyroid disease, and not even everyone who experiences an FQ ADR develops thyroid disease (although I believe the long term risk for developing thyroid disease is increased substantially in FQT/FQAD victims).
  • Those with subclinical, or unknown but existing thyroid problems, in particular Autoimmune Thyroid Disease (AITD) who are already experiencing some destruction and antibody production, may be more susceptible to FQ’s.    I suspect I was in this category before I was floxed, but I didn’t know it, because my thyroid was compensating adequately and I didn’t have any obvious symptoms.
  • In my opinion, one of the biggest reasons why the thyroid gland may be susceptible to these insults is simply due to the architecture, or structure, of the gland itself.   The ratio of the follicle size to the surrounding connective tissue containing the follicle is large; a thin amount of connective tissue is containing a relatively large amount of colloid.   Once that thin “balloon” wall is popped, or breached, a large amount of colloid can spill out.   If you look at pictures of salivary glands, lacrimal glands, sweat glands, or other secretory glands, which are also made up of cells surrounding a small “storage sac” (acini), there is nowhere near this huge size difference.    The “sacs” or lumens of these other glands are small in comparison to the thyroid follicles.    Having said that, many flox victims do report a temporary or permanent loss of tears (dry eyes), saliva (dry mouth), and ability to sweat, so perhaps this mechanism of collagen destruction is contributing to that as well.    Viruses and bacteria can secrete or affect enzymes which destroy collagen (collagenase, MMP’s), which may also contribute to connective tissue destruction and thyroid damage.    Studies reveal FQ’s not only increase destruction of connective tissue through various mechanisms, but also prevent formation of new healthy collagen/connective tissue as well.    This may contribute to or account for the long term or permanent damage that some flox victims experience.   The thyroid gland, with its thin, lacy, delicate layer of connective tissue throughout holding these large follicles with their highly antigenic colloid together, may be more susceptible than other tissues to a variety of stressors simply because of this architecture.   This may be one contributing factor as to why “thyroid disorders”, especially autoimmune ones, are reaching epidemic proportions overall.


Is Hashimoto’s Disease a Connective Tissue Disorder?

Hashi’s is usually described as a “thyroid disorder” due to the obvious destruction of the thyroid gland, the anti-thyroid antibodies, and the disturbances in thyroid function tests (serum levels of TSH, T4, T3, etc).

However, it could also be described as an “Immune System Disorder”, due to the autoimmune anti-thyroid antibodies that usually help to confirm diagnosis. As I questioned in “Were My Problems With TH/Iodine a Primary or Secondary Problem?”:

So even within this one diagnosis, the question can be asked:   is it a “thyroid problem” first – with an “immune system” problem that develops secondarily?   Or is it an immune system problem first, with “immune cells” going haywire, and attacking the thyroid gland proteins, thereby creating “thyroid problems” secondarily?    (No one knows the answer to that yet).

Here, I present yet a third way to consider Hashi’s:   Is it possible that Hashi’s could be a Collagen/Connective Tissue Disorder first, with secondary antibody formation, immune destruction of the thyroid gland, and thyroid function test disturbances?   I think it’s a legitimate hypothesis worthy of exploration, based on the reasoning I’ve presented here.   Given that genetic and epigenetic pre-disposition, viruses, bacteria, and environmental stressors such as the fluoroquinolone antibiotics can all affect collagen/connective tissue, it seems a viable mechanism to consider.   The additional connection of collagen forming enzymes (prolyl 4 -hydroxylases) to cellular thyroid hormone binding protein, as well as other steroid hormones (see  “Research” below), may be yet another approach to consider.

Others have asked similar questions because of the clear associations of thyroid disease with other Collagen and Connective Tissue Disorders (here, here, here, here, and review PubMed to see numerous other studies).    Arguing against follicular destruction as a mechanism, are these two studies, which reveal intact basement membranes and normal collagen and fibril formation in Hashi’s from an electron microscopic visual perspective (1, 2).    On the other hand, fibrosis, which is abnormal collagen formation due to connective tissue disruption, is sometimes a prominent feature of those with Hashis (see “Pathology” and “Pathogenesis”, here).    It would be interesting to repeat the electron microscope studies on follicular status during the acute phases of FQT, or acute phase of thyroiditis due to viruses known to secrete or affect collagenases and MMP’s.    Epithelial cell destruction also appears to occur in Hashi’s; with the FQ’s, perhaps this could occur from direct damage of epithelial cells by FQ’s, or via destruction of basement membranes or collagen/fibrils in the surrounding stroma (which would also likely affect blood supply to these cells).    As I’ve suggested before, as an additional mechanism to consider, I suspect FQ’s may be damaging or affecting secretory cells in general, which would include endocrine and exocrine epithelial cells, and cells with well developed ER/Golgi apparatus (ER Stress).   FQ’s target rapidly proliferating cells — or possibly rapidly proliferating cellular products (ie, secretory products) via higher rates of topoisomerase activity for those products.    From a patient perspective, anecdotally, reviewing the numerous thyroid and rheumatic forums, there appears to be a connection between Collagen and Connective Tissue Disorders and Thyroid Disorders.   On a personal level, as an FQ victim, this entire website was built on the fact that both TH and Iodine alone have profound effects on my tendons.   There is a definite relationship between TH and Iodine on my tendon pain (as well as with all my other symptoms).   How this relates to my antibody status and diagnosis of AITD, I can’t say definitively.  I just know that TH and Iodine have affected, and continue to affect my tendons greatly.

Whether Hashi’s is primarily a “thyroid disorder”, “autoimmune disorder”, “connective tissue disorder”, or something else entirely, remains to be seen.    In the meantime, there are clear associations between AITD and connective tissue or rheumatic disorders, and clear associations between FQT/FQAD and connective tissue disorders, causing a large amount of significant disability and suffering for those who suffer from them.   The fluoroquinolone antibiotics may be contributing to the AITD and Connective Tissue Disorder epidemics in ways that are currently not recognized.    Only non-biased studies will be able to determine if and how damage to the “thyroid system” in any form may be occurring with FQ’s.   Such studies might help elucidate the links between Collagen and Connective Tissue Disorders and Thyroid Disorders, in particular, AITD.     Whether such studies will ever be done – or published – remains to be seen.


Research:   FQ’s Destroy Existing Collagen/CT and Prevent Formation of New Functional Tissue

Most people reading this are probably already aware of the numerous publications relating FQ’s with tendon and collagen disorders.    However, for those who are not, and are interested, here are a few references to get you started.

Musculoskeletal Complications of Fluoroquinolones   Since tendons are made up of collagen and connective tissue, the tendon problems that the FQ’s can cause could be considered at least one representation, if not a comprehensive one, of FQ-Induced Collagen and Connective Tissue damage in general.    Several basic molecular mechanisms have been proposed to describe the tendon damage that can occur with FQT.    A good overview of these mechanisms, with their references, can be found in this Mayo Clinic 2011 paper.    This paper is an excellent review overall regarding what was known about FQT and tendon disorders up to its publication date in February 2011.   My only comment on it might be that historically and statistically, I think FQT tendon disorders may have been under acknowledged and under reported overall, and that both the incidence and prevalence may be greater than is known and published in papers like these.    Additionally, whatever mechanisms are causing FQT in tendons may very well also be responsible for collagen or connective tissue damage in other organs, tissues, and cells.   Fluoroquinolone-associated Tendinopathy is another 2011 nice summary and review, with a flow chart demonstrating several potential molecular mechanisms to account for Ciprofloxacin induced tendinopathy.

Metal Complexes of Quinolone Antibiotics and Their Applications: An Update. (2013).    One of the more well known proposed hypotheses of FQT, mentioned in the Mayo paper as well, is the “Chelation Hypothesis”, or what I called the “Divalent/Trivalent Cations” Hypothesis (which I mention as an Additional Mechanism to Consider).    Most non-science people know the more common “Divalent/Trivalent Cations” by their more common names such as calcium, magnesium, manganese, copper, iron, nickel, zinc, etc .   Most people have at least some feeling and understanding that these minerals are important to our health overall.     For example, many people have heard that “calcium is needed for our bones and teeth”.    Even tendons have some metals such as copper, manganese, and calcium as part of their composition.   However, trace amounts of minerals are very important for other reasons as well, such as acting as “cofactors” in many enzymatic reactions and cell signaling, and I think this is what is important to keep in mind with FQ’s.    The “Chelation Hypothesis” stems from the fact that it’s well known that FQ’s form metal complexes due to their capacity to bind metal ions such as these.    This means that FQ’s may tend to target the enzymes and receptors that utilize these metal cofactors, and may therefore be unintentional targets of the FQ’s.    The focus of this paper, as most of the historical ones are, is on FQ’s binding with metals.    However, from a “thyroid perspective”, I suggested that Selenium (Se2+) should also be a consideration for binding, as well as Iodine (which can assume positive oxidation states) and even anions such as Phosphorus or Iodide.    I also suspect monovalent metals, such as sodium, potassium, and lithium, should also be considered.   I’m including this paper here because the “Chelation Hypothesis” is so prevalent overall in regards to FQT/FQAD, and provides the basis for the next couple of references on FQ-Induced Collagen and Connective Tissue damage.

Stahlmann, R., et al.    Go to Pubmed and type in “Stahlmann, fluoroquinolones” to see his group’s various studies on FQ ADR’s or click on the link.    Stahlmann also proposed the “Chelation Hypothesis”, in this case, FQ’s binding with Magnesium as one mechanism of FQ-Induced tendon and cartilage damage, examples here, here, here, and here.    These studies are responsible for FQ victims the world over trying magnesium as an antidote to FQT/FQAD.    Although loss of magnesium can certainly be problematic, simple replacement of it does not help all FQ victims, and millions of people who may have low magnesium reserves (such as the “21 million patients in 2009” who took a prescribed magnesium chelator proton pump inhibitor, or even those who take the antibiotic doxycycline, (which also chelates calcium, magnesium, iron and other metals, 1, 2, 3, 4, 5, 6, 7, 8), don’t experience tendon ruptures or the permanent FQAD-like symptoms.    This is one reason why I suspect it’s specific enzymes or receptors that utilize magnesium or other cofactors that are a big factor.   Low Mg could cause the problem, but so could loss of any part of that complex, such as low amounts of a specific enzyme overall, or the biochemical precursors that make up the enzyme, or the genetic/epigenetic predispositions to be low on said enzyme.     As I suggested in “TKI’s: An Existing Example of Chemotherapeutic Drug Induced Acute, Delayed, and Permanent Thyroid Problems. Can FQ’s Act as TKI’s?” this is one reason I felt the “Mg-Tyrosine as a critical residue” (along with ATP utilization) combination, important in so many replication, signaling, and receptor processes, may be one target, and not just the loss of Ca or Mg itself.    On the other hand, another possibility might be deficient or damaged Mg receptors or transporters, making intracellular or mitochondrial Mg availability low.   Having said all that, we all owe a big thank you to Dr. Stahlmann and his group for his numerous and excellent studies on FQT and publishing about the relationships between FQ’s and Magnesium in the first place.    Mineral binding, including Magnesium, does seem to be a significant part of the FQT puzzle, and taking magnesium supplements does appear to help some FQT victims with their symptoms.

Nonantibiotic Effects of Fluoroquinolones in Mammalian Cells   In this most recent Mayo Clinic 2015 study, here again, the “Chelation Hypothesis” is proposed, but this time, the metal of interest is Iron, not magnesium.    FQ’s were shown to inhibit enzymes called “alpha-ketoglutarate dependent dioxygenases” which require iron as a cofactor.   Three of these dioxygenase enzymes were studied and inhibited by FQ’s.   One of them is necessary for appropriate collagen formation, and the other two affect epigenetic changes on DNA.   This was only an in vitro study, but it suggests a mechanism not only for FQ-Induced Tendon and Collagen damage, but may account for the long-term or permanence of these reactions via epigenetic changes (Also see Epigenetic side-effects of common pharmaceuticals: A potential new field in medicine and pharmacology for additional discussion of  FQ’s inducing epigenetic changes).    As with magnesium, iron deficiency can cause a host of symptoms, and many people may run low on iron at some point in time in their life, but tendons don’t rupture as a result.   This suggests there’s more to the story than simple iron deficiency.   For example, perhaps for people low on one of these enzymes to begin with (existing genetic or epigenetic aberrations), or any of their precursors, or alpha-ketoglutarate in this case, in addition to low iron, might increase the risk of FQT substantially if these enzymes are targeted in vivo.    Additionally in this study, the suggestion that FQ’s may abolish a protein called “HIF-1 alpha”, and therefore suggests yet another “anti-cancer” use for the FQ’s, seems to me to be of some concern.    Although blocking this protein may help cancer patients, what does this mean for the rest of us who don’t have and never had cancer when we take an FQ?    Over and over again the FQ’s are “suggested” to be good chemotherapy drugs – which is why it’s quite frightening to think of these drugs being given en masse to people without cancer, including children and babies.   As an aside, note that prolyl 4-hydroxylase, one of the enzymes studied here, has a multifunctional polypeptide beta subunit identical to the enzyme protein disulfide isomerase and a major cellular thyroid hormone binding protein (1, 2, 3, 4) , and shows partial homology with phosphoinositide-specific phospholipase C, thioredoxins, the estrogen-binding domain of the estrogen receptor, and progesterone and glucocorticoid receptors.  The COOH-terminus of this beta subunit has an amino acid sequence which has been suggested to be necessary for the retention of a polypeptide within the lumen of the rough ER.     Additionally, appropriate collagen formation is necessary for AChE function and ACh transmission, and lack of it can result in Myasthenia Gravis like symptoms and neuromuscular symptoms (1, 2, 3, 4, 5), which I’ve discussed in several places in this website( here, here).   Again, this is only one in vitro study, but I think it’s an important and significant one, and I hope follow up studies will be done on some of these findings.    A big thank you to Dr. Maher and his group for publishing this study as well.

Fluoroquinolones and collagen associated severe adverse events: a longitudinal cohort study .  This 2015 study is also starting to recognize that other severe collagen-associated adverse effects, in addition to “tendon ruptures”, may be occurring.   Again, in the past, studies on the adverse effects of FQ’s tended to focus on one “system” at a time, ie, CNS, cardiac, tendons, neuromuscular, etc.  This study and the one above by Maher are starting to investigate multi-system damage, potentially all collagen/connective tissue related, that may occur with FQ usage.

Fluoroquinolone-Induced Serious, Persistent, Multisymptom Adverse Effects.   First published case series describing the severe, disabling multi-symptom “syndrome” developing in previously healthy individuals due to FQ usage.   In this study, mitochondrial toxicity is suggested as the underlying causal mechanism.   I include it here to demonstrate the widespread adverse effects of “FQT/FQAD”.    Additionally, mitochondria are the major organelles required for cellular Fe storage and usage, the TCA cycle (alpha ketoglutarate), most O2 consumption, and ROS production, all of which can influence and modulate intracellular HIF prolyl hydroxylase function as well (1).

MicroRNA‑142‑5p contributes to Hashimoto’s thyroiditis by targeting CLDN1 (2016).  This study is not specific to connective tissue, but to the tight junctions and adherens junctions between the monolayer of epithelial cells that make up the thyroid follicles.  For this reason, I am including this information on this webpage.  Above, I suggested that the thyroid gland may be more susceptible to various insults because of its architecture of a single layer of epithelial cells within a very small amount of connective tissue surrounding the colloid follicles.  Here, in this interesting study, the suggestion is made that the epithelial cell barriers themselves (ie, the tight junctions and adherens junctions) may be compromised by downregulation of a specific protein (claudin) due to increased expression of a specific miRNA, miR-142-5p.  An excerpt from this paper:

“The functional unit of the thyroid is the follicle composed of single-layered epithelium and the follicular lumen, in which Tg is stored and iodothyronines are synthesized. The junctional complex of thyroid follicular cells consists of tight junctions and adherens junctions, which limit paracellular permeability. CLDN1 is a membrane protein that belongs to the claudin family and a component of tight junctions serving as a physical barrier to prevent solutes from passing freely through the paracellular space. Studies have shown that downregulated CLDN1 contributes to autoimmune diseases [17, 45–48] and particularly impairs the epithelial barrier function in primary cultured human thyrocytes [16, 30]. Similarly, we found that artificially raised expression of miR-142-5p in thyrocytes obtained a diminished staining pattern of CLDN1 and increased the permeability of the monolayer thyrocytes. Thyrocytes hold a unique position similar to the blood–brain barrier, making a tight barrier between the extracellular compartments, the lumen, and the extra follicular space. We hypothesized that miR-142-5p can break the paracellular barrier by downregulating CLDN1, which allows the exposure of normally secluded autoantigens, Tg, and TPO to the immune system. Thus it might contribute to the occurrence of HT.”

Micro-RNAs are thought to “fine tune” gene expression and therefore play an important role in “homeostasis”.    As with everything else in the body, having just the right amount of miRNA – not too much, and not too little – is important for overall homeostasis.   I experience many of my symptoms as a “homeostasis” or “regulatory” problem.   This is particularly true of my chronic and disabling CNS symptoms, which can fluctuate due to any exogenous or endogenous metabolic changes due to exertion/exercise, eating various foods, taking various drugs or supplements, or experiencing extreme emotions.   Compromised tight and adherens junctions within the brain, as well as within other critical tissues and organs, could certainly be on the hypothesis list for this.   Many of the symptoms of severe floxings appear similar to numerous “autoimmune” conditions and CFS/ME; in this recent CFS/ME study, miR-142-5p was one of three miRNA’s found to be significantly upregulated as well.   On the other hand, decreased expression of one of the other two miRNA’s, miR-143-3p, was one of several miRNA’s found to be a possible biomarker for Fibromyalgia in this study here, suggesting a potential differentiating biomarker profile between CFS/ME and FM may exist.   When it comes to FQT/FQAD, I would like to see similar miRNA biomarker studies such as these done with the flox population.    Interestingly enough, a number of FQ’s were shown to enhance the effect of miRNAs, creating interest in yet another way to use these drugs as “anti-cancer” chemotherapeutic drugs ( 1, 2, 3, 4, 5, 6, 7 ).    Keep in mind that increasing miRNA’s often results in decreasing or “shutting off” effects for the targeted proteins.   This may be great for unregulated tumor growth in cancer victims.   However, for those of us who never had cancer and as flox victims, chronic overexpression of miRNA’s could potentially mean we may be “losing” or chronically underexpressing critical enzymes and other proteins absolutely necessary for normal function and quality of life.    MicroRNA’s are a hot topic of study for all kinds of conditions; here are a few more references related to AITD ( 1, 2, 3, 4, 5 ) and for tendons/collagen ( 1, 2, 3, 4, 5, 6 ) to get started with for those that are interested.



As usual, I will once again make the case and a plea for research to be done on the adverse effects of these antibiotics.    As I wrote about here, FQT/FQAD appears to mimic a number of conditions.   Millions of patients suffer from the “Connective Tissue Disorders”, and Collagen and Connective Tissue Damage is a well known ADR of FQ’s.    If FQ’s can cause the same or similar symptoms as these other conditions, then it only makes sense that some of the underlying biochemical, genetic, or epigenetic causal mechanisms may be similar as well.    In my opinion, studying FQ adverse effects and the underlying mechanisms could probably teach us a lot about many of these other conditions as well.   This means that millions of people suffering from these conditions could potentially be helped by studying FQ ADR’s.   I think there is a lot to be learned about each of these conditions simply by studying a drug that appears to cause or trigger them.   There are thousands of permanently disabled FQT victims of all ages, both genders, and who considered themselves healthy, with no known co-morbid conditions, available for study as a population.   There are cases of multiple family members who have been affected, and even FQ-affected people with a twin.    Informal polls and anecdotal stories suggest approximately 20% of FQT/FQAD patients are diagnosed with new thyroid disorders post flox as well.   Researchers have a real opportunity here.   Do the in vitro binding studies on FQ’s, as well as basic in vivo lab studies and association studies within the human population who are going to get these drugs either way.    As FQT victims, we must have something in common with each other that we were so affected by the FQ’s.    Study the connections between tendons and the brain, because there is one – a strong one, and every FQ victim knows this and experiences this first hand, and there is much to be learned from this about tendinopathies as well as CNS pathologies.   With the FDA now recognizing these severe adverse effects, coining the phrase “Fluoroquinolone Associated Disability” (FQAD) to describe these syndromes, along with the push for “Personalized / Precision Medicine”, which is supposed to help reduce pharmaceutical ADR’s in general, perhaps more funding will be available to study these adverse effects in an effort to learn causal mechanisms, diagnostic markers, and ultimately, treatment for those adversely affected.   I suspect that in the process, much progress would be made on numerous other fronts for millions more patients as well, not just FQT/FQAD ones.


Collagen and Connective Tissue Damage Can Have Systemic and Widespread Effects

When people experience tendon pain or ruptures from taking an FQ antibiotic, it’s not like the antibiotic will only target one tendon, or even one connective tissue, in the body.    It’s not like the antibiotic zeroes in on the Achilles tendon to rupture it, which seems to be how many people (ie, medical professionals) view FQT.    It’s well known that FQ’s “rarely affect the Achilles tendon”.    But the collagen and connective tissue that make up “tendons” are widely expressed, even if in different types and amounts, throughout the body.    The FQ’s are no doubt affecting many of these in people experiencing FQT, even if symptoms specific to one organ or tissue aren’t exhibited yet.    What would throw a person over the edge, or make a person more susceptible to the FQ’s overall?

Some people believe that there is a “threshold” tolerance for FQ’s, and that sooner or later, everyone will experience the ADR’s of these antibiotics.    Certainly, this could be the case, if for no other reason than every single substance on the planet can be deadly if taken to excess.    However, upping this hypothesis considerably is the extensive existing published research available showing all the ways FQ’s act as chemotherapy agents, affecting fundamental, conserved, and necessary enzymes and proteins, not to mention the direct DNA breaks and damage they cause in nuclear or mitochondrial cells, making them highly mutagenic and clastogenic as well.   People with existing genetic and epigenetic predispositions, which may increase the chances of the drugs binding to human proteins and DNA, would probably feel the effects first, depending on what these predispositions are.   People with existing inability of specific repair mechanisms at a molecular level might also feel these effects first, struggling to recover from the effects of the drugs that most people don’t even know or feel may be occurring while they are on them.   However, giving these drugs that at a fundamental level inhibit cell growth, survival, migration, proliferation, glucose metabolism, energy metabolism, blood vessel formation, oxygen sensing abilities, mitochondrial viability, and more, and that create genetic and epigenetic mutations to boot, to the healthy population with simple or presumed infections, doesn’t seem like a very good idea at all.

Collagen and Connective Tissue Damage can certainly be a very viable mechanism not only for “tendon pain and ruptures”, but for connective tissue damage overall. This would include all the connective tissues in the body.   Look up any FQT/FQAD symptom, and a connection to Collagen/Connective Tissue can be made to symptoms involving tendon, cardiac, ocular, neuromuscular, central, peripheral and autonomic dysfunctions, endocrine, neuroendocrine, immune regulatory functions, and more.    This includes “thyroid damage” as well.



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