The Forgotten History of Parathyroid Tetany

With A Case Study of Overlooked Post-Thyroidectomy Hypoparathyroidism and its Empirical Treatment

By Thomas Pereira - February 2023

Dedicated to Dr. Ray Peat
1936-2022

“Still, no one has reverted to consider Koch’s explanation.” - Ray Peat

“We choose to direct our research along the ‘farmer’ hypothesis.” - William F. Koch

Summary

1. Historical research showed various now-forgotten therapies for parathyroid tetany and the broader consequences of hypoparathyroidism beyond calcium regulation.

2. The gut, liver, blood pH, sex hormones, phosphate, and oxidative metabolism are affected by hypoparathyroidism and are involved in the pathogenesis of tetany.

3. Calcium and vitamin D treatments do not make up for all the necessary functions of parathyroid hormone in hypoparathyroid patients and are not sufficient to robustly prevent symptoms.

4. Diagnosis of hypoparathyroidism should be based on symptoms and parathyroid hormone level and should not be dissuaded by normal total calcium.

5. A case study is presented where post-surgical, symptomatic hypoparathyroidism was overlooked by doctors for seven years due to normal total calcium levels. Empirical interventions that improved symptoms mimicked the early treatments for parathyroid tetany and led to a proper diagnosis.
   
   

Table of Contents

Introduction
Section 1: The History of Parathyroid Tetany
The Early Debate: Toxin vs. Calcium Theory
Ammonia and Guanidine as Toxic Causes of Tetany
Acid Treatments
The Intestines as the Source of Toxins
Criticisms of the Guanidine Theory
Sex Hormones
Phosphate
The Discovery of Parathyroid Hormone
Modern Treatments and Failures
Ray Peat, William F. Koch, and Oxidative Metabolism
Implications
Section 2: Case Study of Overlooked Hypoparathyroidism
Conclusion

Introduction

Hypoparathyroidism occurs most often as a result of thyroidectomy and more rarely from genetic and autoimmune diseases. Excision of the thyroid gland can lead to accidental damage to the parathyroid glands or damage to their blood supply. After thyroidectomy, decreased function of the parathyroid glands (parathyroid hormone <15pg/ml) occurred transiently in 13.28% of patients and permanently in 2.39% when patients were followed for 28 months after surgery[1]. Untreated hypoparathyroidism results in a condition known as tetany, which presents as muscle cramps, spasms, numbness, tingling, and in severe cases, seizures. Parathyroid hormone (PTH) is known to regulate mineral balance by stimulating calcium absorption from the intestines, reabsorption from the kidneys, and resorption from the bones while decreasing renal phosphate reabsorption. Parathyroid tetany is thought to be directly caused by the lower blood calcium, resulting from deficient PTH, causing increased neuromuscular excitability.
After thyroidectomy, patients are typically advised to take calcium supplements until they can be cleared for normalization of their calcium and PTH levels. If after six months their calcium or PTH remain low, they are diagnosed as permanently hypoparathyroid and continued on the standard treatment of calcium and calcitriol (activated vitamin D) to raise their blood calcium. When calcium levels are refractory to these treatments, thiazide diuretics and injectable PTH replacement may be prescribed. If the calcium and PTH appear normal at the early follow-up appointments after surgery, patients will be cleared for healthy parathyroids and no further monitoring of PTH is typically done. However, it is evident that parathyroid dysfunction can progress over many years after surgery, leaving some patients undiagnosed due to the lack of further monitoring[2, 3, 4].
There is great dissonance in the field over the proper diagnostic criteria for hypoparathyrodism[5]. The international standard definition of hypoparathyroidism is “low calcium in the context of low or inappropriately normal PTH”[6]. The prophylactic use of calcium supplements after surgery is seen to decrease the diagnosis frequency of hypoparathyroidism, meaning that doctors are often focusing more on the calcium levels than PTH[5]. When calcium is normal, it is typically assumed that the patient is well. However, many patients with diagnosed hypoparathyroidism present with normal calcium and yet continue to show symptoms, causing some doctors to realize that vitamin D and calcium do not make up for the broader actions of PTH.
The large body of historical research on parathyroid tetany shows that calcium, as critical as it is to properly manage, is but one part of the pathophysiology of tetany and that the loss of sufficient PTH has a broader negative impact on the physiology. Many empirical treatments that did not necessarily impact calcium levels were found in the early 20th century to improve the condition of patients and study animals suffering from hypoparathyroid tetany. These early studies suggested that disruptions of the intestines, liver, pH balance, sex hormones, phosphate, and oxidative metabolism contributed, in addition to the calcium dysregulation, to producing the symptoms of hypoparathyroidism. In order to address the broader consequences, the historical treatments should again be considered as adjuncts to today’s standard therapies, and PTH replacement should be more emphasized, especially in cases of greater symptomatology or serious PTH deficiency.
This article argues that total calcium should not be relied on as a key diagnostic marker of hypoparathyroidism. Albumin-corrected calcium and ionized calcium offer a more accurate assessment of calcium status, but they still do not capture the more complex effects of hypoparathyroidism. With many people becoming more health conscious in the modern day, those who were already eating a high-calcium diet and supplementing vitamin D prior to thyroidectomy may more easily maintain normal calcium levels and distract from a proper diagnosis of low PTH. Symptomatic presentation and PTH are sufficient and better diagnostic markers.
The presented case study of a young woman, renamed here as “Haley”, follows her life for seven years after her thyroidectomy. Haley began showing a variety of symptoms after her surgery, including chronic muscle tension, headaches, and anxiety, all known symptoms of hypoparathyroidism. At a two-month follow-up appointment with an endocrinologist, her PTH was tested to be slightly under the range, but since her total calcium was normal, she was cleared for normal parathyroid function. Various endocrinologists and doctors over the next seven years overlooked her symptoms due to normal total calcium levels until she insisted to have her PTH checked again, finding it to be significantly lower than the initial test after her surgery and well under the range. During multiple doctors visits, Haley’s albumin-corrected calcium (calculated in retrospect) was under the range and her anion gap was elevated (suggestive of lactic acidosis), but these issues were never acknowledged by her doctors.
     I describe the process of empirically addressing Haley’s symptoms before an awareness and confirmation of hypoparathyroidism was made and how those successful empirical methods, with guidance from Dr. Ray Peat, led to the realization that Haley had suffered damage to her parathyroids during her surgery. The research conducted for the writing of this article revealed a remarkable closeness between the methods we discovered to help Haley’s symptoms and the treatments developed by the early parathyroid researchers. Also, it has inspired new concepts for how to progress with Haley’s condition.

The History of Parathyroid Tetany

The Early Debate: Toxin vs. Calcium Theory

In the early part of the 20th century, there was a rich debate about the pathophysiology of parathyroid tetany, where the removal of the parathyroid glands produces a severe hyper-excitability of the nervous system and tonic spasms of the muscles, called tetany. The first prominent theory, proposed by Vassale and Generally in 1897, was that the parathyroids were involved in the detoxification of some toxin[7, 8]. Supporting the toxin theory was the discovery by Maccallum and Voegtlin in 1909 that replacing a third of a tetanic dog’s blood with saline solution, effectively diluting a possible toxin, would suppress the tetany[9]. Additionally, in 1912, MacCallum showed that routing the blood of a dog in tetany to the leg of a normal dog would produce tetany symptoms in the receiving leg[10]. Inducing diuresis with either normal Ringer’s solution, calcium-free Ringer’s solution[11], or a hypertonic sodium chloride solution[12] all were seen to relieve tetany. Carlson (1911) found that a hypertonic sugar solution had the same effect[13]. Proponents of the toxin theory suggested that the parathyroid glands, or a hormone secreted from them, were involved in neutralizing a toxin or stimulating some other organ to do so. Dilution or diuresis was thought to reduce the toxic burden.
     Concurrently, Maccallum and Voegtlin reported an increased excretion of calcium and a reduction of blood and tissue calcium after parathyroidectomy, and they observed a resolution of tetany symptoms after the injection of calcium salts [9, 14]. This built upon the earlier findings that, even outside of parathyroidectomy, reducing blood calcium would produce tetany symptoms and replacing the calcium would relieve the tetany[15]. These findings led to the development of the calcium deficiency theory of parathyroid tetany and the idea that the main role of the parathyroids is to regulate calcium. In support of this theory, scientists showed the improvements made by various types of calcium salts, the prevention of tetany by the removal of the colon, where calcium is mainly excreted, and the benefits of a milk diet in contrast to the harm of a low-calcium meat diet[15].
     The calcium deficiency theory of parathyroid tetany and the belief that the parathyroids work only to maintain calcium levels both predominate to this day, but they were contended for decades after their origin. The early contentions were the findings that calcium was not always depleted[16], the observation by Voegtlin in 1917 that calcium treatment was only temporarily effective[17], and the discovery of the various beneficial diuretic therapies. Strontium, magnesium, and barium salts worked as well as calcium[18, 19]. Maccallum suggested in 1912 that “the mere fact that it is possible to abolish the symptoms of tetany by injecting calcium into the blood proves nothing, since calcium, like strontium and magnesium, depress the excitability of even normal nerves to a very low point, and doubtless it is through this property that it masks the symptoms of tetany”[10].

Ammonia and Guanidine as Toxic Causes of Tetany

Despite originally formulating the calcium hypothesis, Maccallum and Voegtlin continued to provide evidence to advance the toxin theory. In 1909, they showed increased ammonia and nitrogen in the urine and blood of parathyroidectomized animals[9], which was corroborated by multiple other studies[17]. It was known already that carnivorous animals suffered from more severe tetany, causing some to hypothesize that a toxin from a meat diet could produce the symptoms[20]. Berkeley and Beebe (1909) saw that a meat diet worsened tetany even when mixed with calcium-rich bone meal[18]. Both ammonia[21], a byproduct of protein metabolism, and a related compound, guanidine[22], had already been seen to produce tetany when administered to animals.
     Maccallum and Voegtlin suggested that the alkaline ammonia may be building up to neutralize acidosis in the blood, as other studies had found high lactic acid in the urine, pointing to a possible underlying acidosis in tetany[9]. However, attempts to treat animals through alkalization with sodium bicarbonate failed and worsened their tetany[9, 23], suggesting instead that rising alkalinity could underlie tetany. McCann (1918) found that after parathyroidectomy there is a marked increase in carbon dioxide-combining power that coincides with the development of tetany, indicating a state of alkalosis[24].
Carlson (1910) showed that depressed liver function accounted at least for some part of the ammonia increase[25]. Besides the liver’s known role in converting ammonia to urea for kidney excretion, another avenue for ammonia detoxification is through the bile[26]. It is now known that hypoparathyroidism causes a defective cholecystokinin stimulation of bile secretion[27].
Later, in 1987, Hara showed higher than normal amounts of ammonia after exercise in hypoparathyroid patients[28].
    In 1912-13, W. F. Koch reported on finding high levels of guanidine and methyl-guanidine in the urine of parathyroidectomized dogs[29, 30]. Paton and Findlay (1917) observed similar increases of guanidine in the urine (100-500%) and blood (400-1,200%), and they reported that the symptoms of parathyroid tetany were identical to those produced by the administration of guanidine and methyl-guanidine[31]. Later, Findlay and Sharpe (1920)[32], and Nattras and Sharpe (1921)[33] found increased levels of guanidine in the urine of human patients with parathyroid tetany.
    Koch suggested that calcium decreases the permeability of cells, suppressing tetany by blocking the absorption of guanidine into cells[34]. To explain Voegtlin’s report on the temporary success with calcium therapy, Koch argued that as guanidine accumulates, such excessive amounts of calcium are required to suppress the tetany that the organism will die from calcium toxicity[34]. Other authors also found an antagonism between the actions of guanidine and calcium, such that guanidine interferes with the functions of calcium and vice versa[35].
    Koch initially proposed that body cells produce cyanamide when deficient in the “parathyroid secretion” and that cyanamide was the “mother substance to the guanidins”[34]. Koch detected methyl-cyanamide in the urine of 47 parathyroidectomized dogs[36]. Ammonia usually combines with carbon dioxide to form urea, but with rising levels of cyanamide after parathyroidectomy, Koch suggested that the ammonia more readily combines with cyanamide to form the alkaline guanidines[34]. Once the guanidine raises to a certain threshold, muscle convulsions develop, whereby the muscles produce lactic acid, acidifying the blood so that ammonia can join the acid radicals instead of reacting with cyanamide[34].
     Koch found that guanidine blocks cellular metabolic oxidation by interfering with the functional carbonyl groups associated with mitochondrial ATP synthesis[37], even before they were widely known about[38]. He saw that this inhibition of energy production also produces an interference with oxygen delivery in the blood. The block of oxidation leads to lactic acid production through a shift to the alternative metabolic pathway of glycolysis. Koch asserted, “should a farmer or even a pharmacist observe an animal in the tetany of parathyroidectomy, he would certainly say the animal was poisoned. And after a careful checkup of the calcium theory we choose to direct our research along the ‘farmer’ hypothesis”[39].

Acid Treatments

Wilson (1915) reported that the administration of alkalies to parathyroidectomized dogs worsens their tetany, while injection or oral administration of hydrochloric acid resolves it, supporting Koch’s model[23]. Wilson also reported a lower excretion of ammonia before the onset of tetany and a higher excretion of ammonia and lactic acid after a tetany episode[23]. Koch proposed that this represented the detoxifying effect of the tetany, where the convulsions develop purposefully to acidify the blood with lactic acid to remove the alkaline ammonia[34]. Wilson also witnessed an increase in ammonia excretion after hydrochloric acid injection and, therefore, believed that the beneficial effect of the acid treatment was mediated through its detoxification of ammonia[40].
     Various other acids proved beneficial in dogs and human patients and calcium chloride appeared to work better than calcium lactate due to its more acidifying effect[41, 42, 43]. Inspired by these successes, Swingle (1928) attempted to acidify the blood by placing parathyroidectomized dogs in a CO2 chamber. CO2 reacts with water in the blood to form carbonic acid. Swingle reported that “within 2 minutes following entrance of the gas into the chamber manifest tetany disappears”[44]. Swingle believed the therapy to work through acidification increasing the ionized calcium. While alkalosis causes calcium to bind to albumin and precipitate with phosphate, acidification reverses this and increases the amount of ionized calcium. However, in addition to this effect, the CO2 itself may have been functioning as an anticonvulsant as it was later discovered to directly inhibit neuroexcitation[45, 46].
     Acid treatments were seen to increase urinary phosphate excretion in healthy animals[47], and hydrochloric acid was seen to prevent tetany in children while increasing phosphate excretion in their urine[48, 49]. Acidification would thus increase the ionized calcium by decreasing total phosphate in addition to decreasing the tendency for calcium to bind to phosphate and albumin. Like Swingle, Gamble and Ross (1923) believed that the therapeutic effects of hydrochloric acid in a child with tetany were due to an increase in ionized calcium[49].
     Dragstedt (1923) was able to prevent tetany in dogs with a lactose-rich diet, which was seen to acidify their intestines[50]. Indeed, acids from intestinal microbes are absorbed into the body.
    Later, after the isolation of parathyroid hormone in 1959, studies showed that injection of parathyroid hormone causes a decreased excretion of acid, an increased excretion of bicarbonate, and a drop in serum pH[51, 52]. It was determined that a deficiency of parathyroid hormone both decreases citric acid formation in the body and decreases renal tubular reabsorption of hydrogen ions[51]. Barzel (1969) showed a tendency for elevated blood pH in all seven of his patients with hypoparathyroidism, varying between 7.43-7.54 (normal: 7.37-7.43)[51]. Although alkalosis interferes with calcium regulation, causing a tendency for calcium to bind to albumin or phosphate, acid-base regulation is an independent action of parathyroid hormone unrelated directly to mineral regulation. Even if ionized calcium were maintained at an optimal range, alkalosis presents other complications.

The Intestines as the Source of Toxins

Carlson (1912) and Keeton (1914) reported on the depression of motor and secretory digestive processes in tetanic dogs and cats, which would favor the absorption of toxins formed in the gut[53, 54]. Dragstedt (1922) believed that the intestines were the source of guanidine and other toxic amine bases (methyl-guanidine, histamine, trimethylamine) in parathyroid tetany[55]. He noted that tetany could be produced after various experimental obstructions in the intestines of healthy dogs, that feeding large quantities of meat to dogs with liver injury or Eck’s fistula would produce tetany, that starvation could allay tetany in parathyroidectomized dogs, and that tetany was often seen in people with gastrointestinal disorders. It was known that the toxic bases are produced by proteolytic bacteria in the intestines and that a high-protein diet would increase the amount of these species. Alternatively, a high carbohydrate diet had been seen to protect against parathyroid tetany, and the ingestion of carbohydrates, in the form of lactose or glucose, had been seen to change the microbiome to be more carbohydrate fermentative/aciduric[56, 57]. This was seen to spare dietary proteins from being metabolized by microbes into the toxic amines. Portis and Albus (1931) showed that Lactobacillus acidophilus could also change the microbiome to be more carbohydrate fermentative and reduce proteolytic bacteria and their toxins, but this was not tested in parathyroid tetany[59].
     Dragstedt tested the hypothesis that shifting the gut microbiome away from proteolysis through dietary changes would treat tetany. Typically, dogs die within five days after parathyroidectomy. In Dragstedt and Peacock’s 1923 study, parathyroidectomized dogs in one group were given 50 grams of lactose and a low-calcium diet of rice and beef heart, and the other group was given 50-125 grams of lactose and a calcium-containing diet of skimmed milk and bread[50]. In the first group, 45% of the dogs survived the acute recovery stage and were still alive a year after the surgery. In the milk and bread group, 60% survived the acute stage and the majority of them were continuing to live after many months at the time of publication. After a week of the dietary treatments, the stools of the animals became odorless and more acidic, with almost exclusively aciduric (acid-tolerant), gram-positive bacteria present. The effect was more prominent with the lactose, milk and bread diet. After six weeks of treatment, the dogs were able to return to their normal meat and vegetable diet without recurrence of tetany.
     Salvasen (1923) argued that the beneficial effects of lactose were due to lactose’s known ability to enhance calcium absorption[61]. Mccullagh (1932), however, showed no increase in calcium absorption after lactose administration[62] and the influence of lactose on calcium absorption was later disproven[63].
     Koch, in 1926, changed his earlier perspective on the endogenous source of guanidine and, instead, agreed with Dragstedt that the source of guanidine was the intestinal anaerobic bacteria[64]:

“The reactions possible for any chemical substance are determined by the characteristics of the medium, the influence of other chemical bodies. Thus the conversion of the cyanamides to urea in the anaerobic medium of the colon does not take place, but the cyanamides in the colon take up ammonia radicals and become the guanidines, or they may polymerize with increase in entropy, becoming the melamines.

These are toxic substances of anaerobic germ origin and are continually absorbed from the colon by the blood and circulated throughout the body. So the situation requires a protective mechanism to permit a normal physiology.

In the presence of parathyroid function, these melamines and guanidines are again reverted to cyanamides and then to ureas and made harmless, and the body is thus protected. When the parathyroids are removed from the body, the guanidine toxins increase with production of tissue degenerations, convulsions and, death.

So the parathyroid glands are a physiological immunity mechanism, perfected and established in the animal body. They protect against poisoning by a product of anaerobic germ activity in the colon, as we observed in 1912. This research has been later confirmed at Glasgow and other European universities.”

Last year, Zhou (2022) showed that intermittent PTH administration to rats improves their microbiotal beta-diversity, increasing strains of carbohydrate-fermenting, butyrate-producing organisms and strains associated with decreased gut permeability, while also decreasing pathogenic bacteria[65].

Criticisms of the Guanidine Theory

The guanidine theory was subject to much criticism. Carlson and Jacobson (1911) used an alternative method for determining ammonia and found no increase in its excretion[13]. Greenwald (1924) criticized the techniques used by Koch and Paton for isolating the guanidine and used different methods to show that no guanidine was present in the urine of parathyroidectomized animals[66]. Paton (1926) responded to Greenwald with a double-blind study showing increased guanidine in the blood and urine and argued that the methods for detection were reliable[67]. In 1926, Collip provided evidence that the nature of guanidine tetany and parathyroid tetany were different based on their different urea and non-protein nitrogen curves[68]. Dolev, in a 1987 review of the history of parathyroid studies, claimed that Collip was decisively against the guanidine theory when Collip stated, “It is our opinion that these results show quite conclusively that guanidine tetany (i.e., tetany produced by the guanidine compounds which have been used in these experiments) is of a different order from parathyroid tetany”[68, 69]. However, a few sentences later, Collip elaborated: “It is evident that the above results are not in accord with the guanidine intoxication theory of parathyroid tetany. They do not constitute final proof against the validity of the theory, however, since certain guanidine derivatives might have a much greater toxicity than the compounds used, and it may be argued that cumulative action might cause a different response in the blood chemistry”[68]. Koch never doubted the efficacy of his techniques and continued writing on the relationship of guanidine to parathyroid tetany for decades after.

Sex Hormones

As of 2020, women account for 79% of thyroidectomies and are 1.5 times more likely than men to experience hypocalcemia after surgery (36.4% vs. 23.7%) and 5 times more likely to experience permanent hypoparathyroidism (5% vs 0.9%)[70]. In 1931, the Mayo Clinic reported on 13,300 cases of thyroidectomy, with a ratio of 3:1 women to men. 1.5% of patients (200) developed tetany afterward but not one case in men was reported[71].
     Attacks of tetany are seen most frequently during or before the onset of menstruation[72]. Multiple doctors have reported that their patients with tetany were free from tetany or much improved during pregnancies and after menopause[72, 73]. These observations suggest an involvement of the female sex hormones.
    McCullah (1935) tested a variety of hormones on his parathyroid tetany patients and found no relief from the estrogenic treatments, Amniotin and Menformon, nor from the HCG in Follutein[72]. He did, however, see significant benefit from Antuitrin-S, another HCG-containing drug. Holtz and Rossman (1938) found that estradiol benzoate causes a small drop in calcium and acted as an antagonist to the beneficial effects of dihydrotachysterol (a vitamin D analog)[74]. Maranon (1939) found that administration of estrogen to a female patient caused latent tetany to become active, while the “corpus luteum substance”, later discovered to contain progesterone, had the opposite effect[75]. Kaplan (1942) tested estrogen, progesterone, or a combination of both in his tetany patients and found that progesterone was the beneficial part of the treatment[76].
    In parallel to the hormone treatment studies, the observed exacerbation of tetany around menstruation indicates a role of estrogen in promoting neuromuscular excitability, while the cessation of tetany at pregnancy suggests a protective role of progesterone and HCG in calming excitation. More recently, it was discovered that the placenta and breasts during pregnancy and lactation secrete PTH-related peptide that, while suppressing PTH further, fulfills many of the same functions and also explains some degree of the relief from tetany around pregnancy[77].

Phosphate

In 1898, Ver Ecke detected lower urinary phosphate excretion after parathyroidectomy[78]. This was later reiterated by Greenwald in 1913, who showed both a large increase in blood phosphate and a reduction of phosphate excretion in the urine to 2% of the usual rate[79]. In 1924, after experimenting on 50 dogs, Greenwald stated that “tetany has never appeared when this retention of phosphate was absent”[80]. In 1929, Albright presented evidence that the principal action of PTH is on phosphate excretion in the kidneys[81]. He argued that the impact of parathyroidectomy on depleting calcium levels has only to do with the decreased excretion of phosphate since phosphate retention forces down the calcium concentration[82]. McCullagh, in 1932, showed that raising calcium proved less therapeutic than reducing the phosphate[62]. He stated that, while reducing phosphate could work by increasing the percentage of calcium ionized, 
“it is also possible that the decrease in phosphates independently decreases neuromuscular excitability”.
    McCullagh showed that both orally administered glucose and, more powerfully, lactose, reduced serum phosphate and tetany symptoms in his human patients, echoing the studies of Dragstedt[62]. While 100 grams of glucose reduced phosphate and tetany symptoms for up to four hours, a single dose of 100 grams of lactose improved symptoms and reduced phosphate for up to fourteen hours. The benefits of lactose had previously been argued by others to be due to enhancing calcium absorption, but McCullagh’s patients did not show increased calcium content of the blood, only a lowering of elevated phosphate to the normal range. In one patient, tetany symptoms improved in association with normalizing phosphate, even though there was also a further decrease in blood calcium. Patients who had been dependent on parathyroid extract injections to prevent violent tetany were able to wean off the injections when given 23-31 grams of lactose per day. They remained symptom-free and reported feeling better than they had in years.
    McCullagh did not know how lactose reduces blood phosphate. There was no increase in phosphate excretion in the urine. The effects of lactose were not repeatable by oral glucose or galactose, the hydrolysis products of lactose. Injectable lactose also did not replicate the benefits. It appeared, then, that the effects of lactose on reducing blood phosphate were dependent on some effect of lactose in the gut. McCullagh likened this to Dragsted’s earlier studies. Recently, Ajeeta (2019) showed that the lactose-digesting Lactobacillus and Bifidobacterium species possess phosphate-binding capacity, which is enhanced in the presence of lactosucrose[83]. These probiotics are, therefore, being considered for the treatment of hyperphosphatemia in chronic kidney disease patients. Gut binders can rapidly reduce blood minerals, such as is the case with the binder sodium zirconium cyclosilicate, which significantly reduces blood potassium levels within one hour[84]. Jones (1936) showed that parathyroidectomized animals placed on low-calcium diets could be spared from both hypocalcemia and tetany when given a phosphate binder[85].
    The treatments used by the early supporters of the toxin theory may also have worked by decreasing phosphate. Diuresis, low-meat diets, acids, and lactose all have the capacity to reduce blood phosphate levels. However, there is substantial evidence that bacterial toxins may also play a role in tetany and this should not be discounted. It is possible that these therapies were of most notable benefit due to their ability to target both the bacterial disturbance and the phosphate excess. Of particular interest, is the discovery that supporting the aciduric bacteria of the microbiome protects against both phosphate elevation and the toxic amines of proteolytic bacteria.

The Discovery of Parathyroid Hormone

    In 1925, Collip concentrated a parathyroid extract and saw that when injected, it both cured tetany and raised blood calcium[86]. To this day, this is considered to be the “definitive series of experiments (Collip 1925) [that] resolved the controversy and established the principal physiological role of the parathyroid glands in calcium regulation as we now understand it”[87]. Now that PTH had been effectively concentrated, the field began to lose interest in understanding the true underlying pathophysiology of parathyroid tetany, since there was now a drug that could treat the disease. However, the use of Collip’s parathyroid extract, Parathyrin, to treat chronic hypoparathyroidism was short-lived. Studies by Albright (1929)[81] and Macbryde (1938)[88] showed that tolerance to the drug developed, eventually rendering it useless. Therefore, further developments in treatments that followed the dominant calcium theory would be made, but the lively debate over the origin of tetany would not recover and the many empirical treatments that supported alternative theories would be largely forgotten.

Modern Treatments and Failures

Jones, in 1926, showed that cod liver oil administered before parathyroidectomy prevented tetany and prolonged the lives of animals despite not raising blood calcium compared to untreated dogs[89]. In 1930, Brougher transitioned human hypoparathyroid patients from the vitamin D-containing cod liver oil therapy to an isolated form of vitamin D, viosterol, and achieved similar success[90]. Macbyrde, in 1938, had even better effects in humans with a newer synthetic vitamin D, dihydrotachysterol[88].
    To this day, different forms of calcium and vitamin D are used as the main treatments for hypoparathyroidism. The most commonly used form of “active” vitamin D, calcitriol, more powerfully stimulates intestinal calcium absorption. However, calcitriol also directly suppresses the residual PTH secretion, increases intestinal phosphorus absorption[91], and is associated with renal decline in hypoparathyroid patients[92]. When normocalcemia is achieved through these methods, the therapy is considered satisfactory, since calcium regulation is believed to be the only target of PTH. But this has never adequately protected patients from various complications nor improved their quality of life. A number of authors have clarified this in recent years:

“One study of women with postsurgical hypoparathyroidism treated with calcium and vitamin D supplementation vs healthy controls showed that despite the majority of subjects demonstrating eucalcemia, hypoparathyroid patients had significantly higher global complaint scores in various validated quality of life questionnaires, with predominant increases in the subscale scores for anxiety, phobic anxiety and their physical equivalents.” (Cusano 2013)[93]

“Although this approach can correct the hypocalcemia associated with hypoparathyroidism, it does not replace other functions of PTH and can lead to or worsen hypercalciuria.” (Mannstadt 2019) [94]

"The lower quality of life measures seem to be irrespective of the etiology of the hypoparathyroidism, the duration of disease, or the extent to which biochemical control is achieved with calcium and active vitamin D.” (Brandi 2016) [95]

“Some patients whose serum calcium is in the low-normal range may experience symptoms of hypocalcemia.”… “In addition, conventional therapy with calcium and active vitamin D does not alleviate quality of life (QoL) complaints, nor does it reverse abnormalities in bone remodeling characteristic of the disease. In short, conventional therapy does not provide a physiological replacement remedy for the lack of PTH in hypoparathyroidism." (Bilezikian 2016) [96]

“Despite serum calcium levels being maintained within the normal range, signs and symptoms of hypocalcemia, including paresthesia and muscle twitching, can persist in patients with chronic hypoparathyroidism that contribute toward the burden of illness, suggesting that the disease is not adequately controlled in these patients.” (Gittoes 2021) [97]

From Michael Levine’s live presentation at the ThyCa Conference in 2015, titled “Hypocalcemia/Hypoparathyroidism: Now That You Have It, What Do You Do?”[98]:

"Our definition of hypoparathyroidism [is] a clinical disorder characterized by a low calcium and an elevated phosphorus… This is important because some patients with mild hypoparathyroidism will have only an elevated phosphate and their calcium may be within the normal range, but there might be times during the day when the calcium level goes down and a patient develops symptoms. I think this also draws our attention to the fact that when your doctor, your care provider, is monitoring you and following your biochemical tests, they have to measure the phosphorus as well as the calcium…

As you'll see during my talk about management, the true management of hypocalcemia in a patient with hypoparathyroidism is really managing the phosphate… If you and your clinical provider don't pay attention to the phosphate, you'll never get the calcium just right. So phosphorus is important and whenever you get a blood test, not only should you be looking at the calcium level, but you also must be looking at the serum phosphorus…

Other manifestations of low PTH people talk about is brain fog. I'm sure you've all heard the term. Some people think this might be a manifestation of low PTH rather than a manifestation of low calcium. The jury is still out on this and we're looking, I think with extreme interest, in what features of hypoparathyroidism might be due to the absence of PTH rather than a low serum calcium level. So stay tuned. I think we'll have more information about that in the coming years”

Therefore, with the growing awareness of the shortcomings of the conventional treatments, there is an increased interest in using PTH replacement. In 2015 in the USA, the FDA approved recombinant PTH(1-84), which was sold under the brand name Natpara. Despite the lack of long-term success seen in the 1920s and '30s with Collip’s parathyroid extract, the new recombinant PTH showed promising long-term efficacy[99, 100] and improved quality of life[101]. However, in 2019, the FDA halted its production, resulting in its removal from the market. An earlier drug, a shorter fragment of the hormone, PTH (1-34), continues to be utilized off-label with comparable effectiveness, despite requiring more frequent injection[102].

Ray Peat, William F. Koch, and Oxidative Metabolism

In a radio interview with Politics and Science from 2001 about “Suppressed Cancer Treatments", Ray Peat described Koch’s studies on tetany[103]:

“[Koch’s] early publications had to do with the muscle spasms that typically follow removal of the thyroid gland. The parathyroids tend to be removed along with the thyroid if the surgeon doesn’t make a special effort. Even though that was usually the explanation for why thyroid surgery causes these muscle spasms, the most careful surgeon who takes out the thyroid, even when he leaves the parathyroids, it’s typical for the patient to suffer these spasms. Koch experimented with the removal of just the parathyroid glands and found that if you give any salt electrolyte such as potassium, sodium, magnesium or calcium, if you give it generously, you prevent the spasms. He was arguing that the parathyroid glands were involved in detoxifying compounds that derive from ammonia - guanidine and methyl-guanidine - and that these chemicals are poisonous and known to cause seizures and muscle spasms. He could demonstrate that he was causing those to be passed off in the urine by increasing the salt intake. That was published 1917.

But then, A. J. Carlson, a very powerful professor at the University of Chicago, and his group decided that one hormone has only one action. They basically proclaimed that the parathyroid hormone has the action of mobilizing calcium and that in a calcium deficiency you get the spasms. But there are just terrible problems with that, the whole setup, because their description of what’s happening to calcium turned out to be without foundation. It was all a hypothetical theory that attempted to describe this hormone in terms of one singular action on calcium, and that one turns out not to be the way they thought it was. And still, no one has reverted to consider Koch’s explanation.”

Peat went on in this interview to explain how Koch’s study of guanidine and ammonia led to the development of Koch’s cancer treatment that made him maligned in the scientific community. This probably did not help the case for the guanidine theory of parathyroid tetany which was associated with Koch’s name.
    Koch defended and built upon the guanidine theory for the rest of his life. In 1967, the year of his death and 55 years after his initial discovery of guanidine in the urine of parathyroidectomized dogs, he wrote this[104]:

“It was back in 1912, when this writer was given a position of opportunity at the University of Michigan’s Laboratory, by providing the facilities to investigate the function of the parathyroid glands. This subject, previously investigated by the eminent physiologist Carlson of the University of Chicago, as well as by others, had reported that the parathyroid glands controlled the calcium metabolism of the body. They based their conclusion on the finding that the fatal convulsions, which followed removal of these glands could be ameliorated by injections of calcium solutions, and because excessive amounts of calcium were eliminated in the urine during parathyroid deficiency.

However, it was evident to me that other solutions of salts, as sodium chloride and even distilled water also ameliorated the convulsions, but only so long as the kidneys could eliminate and the same fact held for the calcium injections, as well. So it was evident that the benefit came from washing a toxic convulsion producing substance from the blood, until other changes took place, which blocked the liver and kidney functions. I therefore set out to isolate the toxic substances from the urine that caused the convulsions and the other fatal changes observed at autopsy. These were primarily a loss of the colloidal dispersion of the blood contents, so that they separated as striated clots in the large veins and capillaries before death took place.

Analysis of the urine after the parathyroidectomies yielded two toxic bases, Methyl-guanidine and guanidine; both were present in fatal amounts causing the fatal convulsions along with the other pathological changes. The results were published in the Journal of Biological Chemistry of 1912 and 1913, and were fully confirmed three years later by the Department of Physiology of the University of Glasgow, and for the excellency of their work in this confirmation they were awarded the Triennial Prize in Medicine from Harvard University. My work was thereby confirmed, and I set about learning how guanidine did its mischief.

One significant finding was that the urine carried large amounts of lactic acid, which meant that the oxidation mechanism was too badly handicapped to provide the energy for the tissue activities, including the convulsions. So, too, the autopsy findings of striated blood clots meant that the tissue colloids were not sufficiently charged to give them good dispersion, especially in the blood, which let the elements settle out and also reduced their fluidity and carrying power of oxygen, calcium, and other elements. So the sum-total meant that the guanidine bases blocked the oxidation mechanism.”

    Koch’s discovery that guanidine and similar toxins block cellular oxidative metabolism (oxidative-phosphorylation), causing nerve excitation and tetany, led him to search for ways to reverse this blockade and restore proper oxidation. He developed a variety of pro-oxidative substances to treat various diseases, including cancers. The treatment successes impressed upon him the central importance of oxidative metabolism as the key driver of human health.
    Ray Peat often referenced Koch as one of his great influences and endeavored to build upon his work, broadening the scope of understanding of the centrality of oxidative metabolism in health and disease and the various things that influence it. It was through his 2001 interview on Politics and Science that parathyroid damage became suspected in Haley’s case described below, and it was through his public education efforts that important practices were implemented to improve her health. Peat taught that supporting cellular oxidative metabolism has an anti-excitatory effect, calming the nerves and muscles. Increasing metabolic oxidation, therefore, works fundamentally against anything that would induce tetany.
     If tetany is, in fact, a syndrome of inhibited metabolic oxidation, then the successful empirical treatments for tetany should also be protective of proper cellular oxidation. Indeed, they are congruent with many of the important concepts that Ray Peat emphasized. Perhaps the most central factor in Peat’s metabolic model is the role of thyroid hormone, the body’s principal stimulator of mitochondrial oxidation. Those with hypoparathyrodism after thyroidectomy certainly require special attention to swiftly normalize their thyroid status. Aub (1932) saw that normalization of the metabolic rate with thyroxine in hypothyroid-hypoparathyroid patients led to a rise in blood calcium, an increase in phosphate excretion, and an improvement in tetany symptoms[43]. Working alongside thyroid, Peat emphasized the important metabolic boosting effects of calcium, sodium, 25(OH) vitamin D, lactose, magnesium, low protein and low phosphorus diets, gut-cleansing, progesterone, and carbon dioxide, which is produced from the oxidation of carbohydrates. All these things have historically been seen to protect against tetany.
     Ray Peat developed a philosophy of biology and health practices that, at their root, are protective against tetany. The whole movement of bioenergetic medicine has its origin in the early studies on parathyroid tetany and people who suffer from hypoparathyroidism deserve to know the rich history and benefit from the many lessons therein.

Implications

The diagnostic criteria for hypoparathyroidism has been “low calcium in the context of low or inappropriately normal PTH”. Besides at the initial follow-up visit post-thyroidectomy with an endocrinologist, PTH is rarely tested unless calcium is low. It has been known for over 100 years that patients with hypoparathyroidism can still experience tetany and various other symptoms even with normal calcium levels. Currently, endocrinologists like Michael Levine are arguing for the use of PTH replacement since calcium and vitamin D do not make up for the other physiological roles of PTH. Due to the over-reliance on calcium for diagnosis, it is likely that many people with damaged parathyroids are being overlooked due to their normal calcium levels. Their symptoms are being regarded as unrelated since hypocalcemia is widely believed to be the only cause of symptoms in hypoparathyroidism.
     It has been known for a century that elevated phosphate is more important in producing tetany than decreased calcium and yet serum phosphate is typically only checked after a diagnosis has been made. Additionally, disruption of the gut microbiome, liver, ph-balance, female hormones, and oxidative metabolism are drivers of symptoms in hypoparathyroid patients, and yet they are never considered in the present day. These consequences of hypoparathyroidism are not visible in a calcium test and they produce symptoms independent of calcium regulation. For the many patients that remain symptomatic after normalization of calcium levels, these are obvious alternative avenues to explore.
     With many people becoming more health conscious, especially after a cancer or Graves disease diagnosis, patients may already be taking vitamin D, getting sunlight, and eating or supplementing plenty of calcium prior to their thyroidectomy. This may help normalize their calcium levels and obscure a proper diagnosis of hypoparathyroidism by doctors who give more weight to calcium than PTH levels. Patients should be thoroughly questioned about their diet and supplements, and the diagnosis of hypoparathyroidism should draw from an expanded perspective that places primacy of the evidence on low PTH levels and symptoms. Additionally, loss of parathyroid function can progress over years after thyroidectomy[2, 3, 4]. Patients are typically cleared for good parathyroid function within weeks to months post-thyroidectomy. Patients should, instead, be monitored for the onset of hypoparathyroidism, with the expanded diagnostic lens, for years after their surgery.
    In the context of a mild disease, it is less likely that patients and doctors will wish to use PTH injections. However, with the failure of calcium and vitamin D to raise quality of life satisfactorily, additional measures must be taken. The various therapies used a century ago to prevent tetany, before the discovery of PTH and vitamin D, should be considered for the treatment of mild hypoparathyroidism and as supportive adjuncts to PTH injections in patients with severe disease. These empirical treatments found a century ago still have merit and should be considered in addition to vitamin D and calcium:

Sodium and Water
Diuretics
Low Protein Diet
High Carbohydrate Diet
Lactose
Low Phosphate Diet and Phosphate Binders
Liver Support
Probiotics and Gut Support
Hydrochloric Acid
CO2
Progesterone
Thyroid
Magnesium

Case Study of Overlooked Hypoparathyroidism

In February of 2016, a woman 22 years of age, Haley, underwent a full thyroidectomy after a diagnosis of Hashimoto’s Thyroiditis and Partially Unencapsulated, Follicular Variant of Papillary Thyroid Carcinoma. After the procedure, she was given levothyroxine and told to take calcium supplements.
     Blood work was taken at a two-month checkup. The blood showed a low level of PTH at 14.1pg/ml (range: 15.1-85.7pg/ml) and a normal calcium of 9.5mg/dl (range: 8.8-10.3mg/dl). Albumin was not tested, which would have allowed a calculation of albumin-adjusted calcium. Vitamin D was 56ng/ml (range: 30-100ng/ml]. BMI was underweight at 17.1 (range: 18.5-25). TSH was 24.46 mIU/L (range: 0.5-5mIU/L; target <0.5 after thyroid cancer surgery). She showed a high anion gap of 19mEq/L (range: 8-12mEq/L). According to the doctor’s notes, Haley complained of headache, weakness, fatigue, anxiety, depression, sleep disturbance, polyuria, irritability, and mood swings. The doctor reviewed the pathology report of the excised thyroid tissue and added in her notes that parathyroid tissue was present in the sample, but this was not communicated to Haley. Despite the low blood PTH and parathyroid tissue in the sample, the doctor concluded in the notes, “no parathyroid disease”, evidently because of the normal calcium level. The high anion gap indicated a state of acidosis, which I now presume to have been lactic acidosis related to the muscle contraction of tetany, which Koch, Wilson, and McCann all reported on. Acidosis, however, was not mentioned in the doctor’s notes.
    At the six-month follow-up with the same endocrinologist, only thyroid labs were drawn, showing normalization of TSH at 0.25 mIU/L (range: 0.5-5mIU/L; target <0.5). Haley made the same symptom complaints without improvement. Even though her symptoms began after the surgery, she was told by the doctor that they were unrelated to the procedure. BMI was even lower at 16.5 (range: 18.5-25).
    Haley contacted me at this point looking for advice on her health. We developed an informal but close conversation about her health that has persisted to the present day.
    In addition to the symptoms described in the doctor’s notes, she told me about nausea, vomiting, painful muscle tension, shooting pains in fingers, bruising, perioral dermatitis, debilitating daily headaches, and hot flashes. At the time, I was engrossed in studying Ray Peat’s work on philosophy, physiology, and nutrition. I encouraged Haley to raise her caloric intake to increase her body weight while paying special attention to a high micronutrient intake in line with Peat’s nutritional teachings. Haley, who had been previously pesco-vegetarian, added other meats and dairy (cheeses and lactose-free milk) to her diet and emphasized carbohydrates. She began supplementing with B vitamins, fat-soluble vitamins, collagen, and magnesium glycinate. Additionally, since Haley’s symptoms mostly began after the thyroidectomy, and were not resolved with T4 monotherapy, I encouraged her to ask her doctor about trying T3 in addition to the T4. The first endocrinologist denied her request. Within a few months of the nutritional changes, Haley reported feeling somewhat improved. She regained her menstrual period after years without it. The vomiting and nausea gradually diminished. With consistent use of cholecalciferol (vitamin D) at 5,000 IU/day, her bruising went away. She was sleeping well. She began regaining weight.
    It became obvious that Haley's symptoms were exacerbated in the premenstrual and menstrual phases. I encouraged her to try cycling bio-identical progesterone during her luteal phase. This resulted in the first notable degree of relief of her headaches, tension, hot flashes, and mood swings.
    In late 2017, Haley began 5mcg t.i.d. of T3 on top of her T4. Haley reported improved energy. She eventually discovered that T3 helped her menstrual cramping. At this point, she had raised her BMI to 19 (range: 18.5-25).
     In the summer of 2018, Haley moved from New York to California. The move exacerbated her anxiety, caused it to develop a phobic nature, and initiated renewed weight loss. I contacted Ray Peat to ask him about Haley’s post-thyroidectomy symptoms, especially regarding her anxiety, weight loss, and skin issues. This was his response:

“I think it’s important to keep phosphate low. Aspirin, coffee, and antihistamines might help; has she had any signs of histamine-like reactions?
Does she eat seafood, eggs, and liver occasionally, and lots of milk or cheese? Does she get enough salt? Is she getting full midday sunlight exposure? Has she recently had blood tests, including TSH, vitamin D, calcium, and prolactin? Blood level of D3 should be in the range of 50 to 80 ng/ml.
Calcium and vitamin D have very powerful anti-anxiety effects. I think two or three quarts of milk is a good way to assure enough calcium, and that amount will displace some of the high phosphate/low calcium foods.”

Certainly, Haley’s attempt to follow this advice, much of which was already in practice, continued to prove beneficial. She ate oysters, eggs, plenty of cheese, some milk (lactose-free at the time), drank coffee, occasionally used aspirin for headaches, salted her food to taste, and exposed herself to midday sunlight as often as possible. However, we were not keenly attentive at the time to the importance of lowering phosphate intake. We tried antihistamines for her perioral dermatitis but did not see an improvement. Instead, a week-long course of minocycline cleared the dermatitis and it never returned.
    Haley visited multiple new doctors and endocrinologists over the following years, searching for answers. In November of 2018, Haley had a normal BMI of 19.4 (range: 18.5-25). Her blood work showed a calcium of 9.4mg/dl and an albumin of 4.5g/dl (range: 3.4-5.4g/dl). Using the equation [corrected calcium mg/dL = (0.8 * (4 - Pt's Albumin)) + Total Ca], her albumin-corrected calcium is now calculated in retrospect to have been 9mg/dl (8.8-10.3mg/dl). Her vitamin D was 55ng/ml (range: 30-100ng/ml). TSH was 0.01uIU/ml (range: 0.5-5mIU/L; target <0.5) (Haley reported having taken 5mcg of T3 within two hours prior to the blood test). No anion gap was calculated at the time but is calculated here in retrospect in range at 10mEq/L (range: 8-12mEq/L), using the data from the comprehensive metabolic panel and the equation [AGAP=(Na+) – (Cl- + HCO3-)].
    In December of 2018, another blood test showed her TSH at 0.132uIU/ml (range: 0.5-5mIU/L; target <0.5). This time her calcium was at 9.2mg/dl, but her albumin was tested at 5.2g/dl. Therefore, her albumin-corrected calcium level, calculated in retrospect, was low at 8.32mg/dl (range: 8.8-10.3mg/dl). The doctor did not pick up on this. Vitamin D was 40.2ng/ml (range: 30-100ng/ml). Bicarbonate was low at 21mEq/L (range: 22-29mEq/L). Anion gap was not listed but is calculated in retrospect to be high at 18mEq/L (range: 8-12mEq/L), again indicating acidosis.
    In April of 2019, Haley was in a worsened state after a period of increased life stress. Her BMI had fallen to a low 17.9 (range: 18.5-25). Her calcium was 9.5mg/dl and albumin was 5.1g/dl. A retrospective adjustment to albumin leads to a low corrected-calcium of 8.62mg/dl (range: 8.8-10.3mg/dl). Vitamin D was 51ng/ml (range: 30-100ng/ml). Her TSH was 7.8mIU/L (range: 0.5-5mIU/L; target <0.5), as she had begun struggling with regular dosing of her medication. Her bicarbonate was again low at 21mEq/L (22-29mEq/L) and her anion gap again indicated acidosis at 20mEq/L (8-12mEq/L), which was incorrectly listed as “normal” by the lab company. The doctor diagnosed: underweight, irregular menstrual cycle, migraine, and hypothyroidism. The low albumin-corrected calcium and high anion gap acidosis were not acknowledged. Together the low calcium and acidosis indicate that Haley was in a state of tetany.
    Later that year, Haley reported malaise and headache worsening after fatty foods. We resolved to try a daily dose of 500mg of the bile salt tauroursodeoxycholic acid (TUDCA), for fat digestion, gall bladder, and liver support. This resulted in a whole month without headaches, and a greatly reduced frequency thereafter.
    Some time later, we realized that the headaches and neck tension were worsened by slowed bowel motility and that both cascara sagrada, and more rapidly, Swedish bitters, could stimulate a bowel movement and relieve the symptoms. Although Haley did not suffer from constipation, any mild delay in bowel clearance would produce symptoms, while quickening the transit protected against them.
     In early 2020, Haley expressed a craving for broths and soups. I suspected that she was craving extra sodium and water. I encouraged her to follow the craving. Frequently eating salty soups or drinking salty water resulted in a profound decrease in her headaches and muscle tension. It became especially evident that Haley needed more salt water on hot days and that heat and dehydration were major contributors to symptoms. Although her total daily intake of sodium was difficult to measure, based on my observations, I estimate that Haley often consumed above 10 grams of elemental sodium in order to relieve her symptoms. For a year, she adhered to the TUDCA, bitters, and salty water with great success. During this time she regained a healthy BMI of 20 (range: 18.5-25).
    In late 2020, I chanced upon Ray Peat’s 2001 Politics and Science interview that is quoted in the section above, where he discussed the tendency for parathyroid damage after thyroidectomy and the resulting muscle spasms[103]. Peat’s explanation of Koch’s salt treatment, where generously increasing the salt intake would prevent the muscle spasms, aligned with our observation of sodium’s beneficial effect on Haley’s muscle tension, pain, and headaches.
    With this connection, we began to suspect that Haley had been suffering from parathyroid damage all along. As I later discovered during the research for this article, her successes with TUDCA and laxatives likely relate to the known roles of the gut and liver in parathyroid tetany, described in the early studies. The main gastrointestinal complication of hypoparathyroidism is steatorrhea due to defective cholecystokinin stimulation of bilio-pancreatic exocrine secretion[27]. This may explain the malaise Haley felt after high-fat meals and the improvement of this reaction from taking TUDCA. TUDCA effectively stimulates bile flow in cholestasis, supports proper fat digestion, and supports regeneration from liver damage[105, 106]. The improvements Haley experienced with progesterone are likely connected to the previously discovered involvement of sex hormones in tetany and the benefits of progesterone for treating it. Additionally, the worsening of symptoms in hot weather mimics the findings by Bryan (1933) that guanidine is raised in parathyroidectomized dogs when they are dehydrated in hot weather[107].
    As I began to research the subject more, I saw the similarities between Haley’s presentations and the known symptoms of hypoparathyroidism[97] (+ marked for Haley’s positive symptoms):

Paresthesia      +
Muscle twitching
Muscle cramping
Headache      +

Muscle pain      +
Brain fog      +
Muscle weakness      +

Joint Pain                

Anxiety and Phobic Anxiety[6]       +
Weakness in extremities      +
Pain in extremities      +
Bone pain

Constipation

Nausea      +
Vomiting      +

Back pain    +
Painful Menses      +
Hair loss          +
Dermatitis[109, 110]     +
Steatorrhea  (possible but never tested)
Chvostek’s Sign +

Haley requested that her endocrinologist order a PTH test, but upon receiving the panel results she realized that the PTH test had been forgotten. Haley lost motivation to seek out another test and was content with the successful treatments. However, over time, she felt burdened by the abnormally large requirement for sodium and began lessening the treatment, resulting in some recurrence of symptoms, although milder than before. Haley’s headaches remained infrequent but she began to mention tension in the head, neck, and shoulders more often.
     In September of 2021, Haley’s calcium was 8.9mg/dl with an albumin of 4.4, leading to a retrospective corrected calcium of 8.58 mg/dl (range: 8.8-10.3mg/dl), under the normal range again. Anion gap was listed at a normal 10mEq (range: 8-12mEq/L). TSH was 3.2mIU/L (range: 0.5-5mIU/L; target <0.5).
     By October of 2022, Haley was motivated again to seek out confirmation of her parathyroid damage with a new endocrinologist, demanding that PTH be tested. Her PTH tested low at 9pg/ml, with a given range of (16-77pg/ml). Calcium was 9.6mg/dl (range: 8.8-10.3mg/dl). The albumin was 4.4, leading to a retrospective corrected calcium of 9.3mg/dl. This new endocrinologist said that the PTH was “fine”, likely by again giving more importance to the total calcium level and ignoring the low PTH. TSH was 3.23mIU/L (range: 0.5-5mIU/L; target <0.5). Interestingly, this time, the bicarbonate was above the range at 31mEq/L (range: 22-29mEq/L) and the anion gap is retrospectively calculated to have been 5mEq/L (range: 8-12mEq/L). The higher bicarbonate and lower anion gap suggest a trend toward alkalosis. PTH is known to reduce bicarbonate excretion and alkalosis was historically seen before the onset of tetany, which is then followed by subsequent acidosis. It is possible that this test caught Haley in a state of pre-tetany.
    Before this, no doctor had checked Haley’s PTH since her first post-surgery follow-up. No doctor ever tested her for Chvostek’s sign, or her blood phosphate, or ever considered ordering an ionized calcium test or at least calculating the albumin-corrected calcium. Haley’s doctors were well aware of her symptoms and medical history of thyroidectomy. In her search to find an attentive doctor, she only saw two of the six doctors more than once, for three visits each. It is possible that a diagnosis of hypoparathyroidism may have been made sooner had Haley committed to a single doctor for a longer period of time, but I’m not sure that would have been the case. What her sampling of four endocrinologists, one physician, and one doctor of osteopathic medicine showed was a widespread inattention to the broad symptoms of hypoparathyroidism, its relationship to pH disturbance, and to the importance of adjusting the total calcium to albumin or testing ionized calcium. Since Haley’s condition is milder than the extreme presentation that leads to more blatant calcium depletion and seizures, it was more likely to be overlooked by doctors who are better equipped to diagnose advanced diseases.
I recently checked Haley for Chvostek’s sign, a test used to monitor tetany, by percussing with my finger over the facial nerve by the ear. I found a mild but clear and repeatable spasm of the obicularis oris (upper lip). Though mild compared to the marked sign of a contraction of also the orbicularis oculi and ala nasi, the contraction of only the upper lip is still considered a positive sign[111]. A positive Chvostek sign is a general indication of nerve hyper-excitability[111].
    The confirmation of low PTH in October of 2022 is what motivated me to begin research for this article. Some of the discoveries made while working on this article have already been implemented. For example, Haley is experimenting with consuming less protein and less phosphorus. Haley now takes her milk more seriously and has begun drinking lactose-containing milk, around 4-5 cups per day. So far, she suspects that the introduction of lactose, especially, has been a positive change, reducing her sodium dependence to some extent. She may also add a calcium supplement. Magnesium glycinate is now being replaced with magnesium chloride, which I’ve seen to have much higher absorbability, and Haley has reported reductions in anxiety and muscle tension after taking it. She remains reluctant to frequently consume very large amounts of sodium due to an acquired distaste for it, despite knowing its definite curative effect. She is beginning probiotics containing Lactobacillus and Bifidobacterium species and has already reported an improvement in bowel movements. TUDCA and bitters remain helpful tools when needed, though this is less often than before. Haley is also resuming progesterone after a couple of years without it. Hydrochloric acid is being considered. Carbon dioxide-raising methods, such as bag breathing, will also be tested. Haley is regularly taking her thyroid medication and has implemented a better system to ensure frequent dosing. She is looking for an endocrinologist that will understand her story and offer appropriate support.
    Haley’s mood, energy, and quality of life are very much improved from where she began seven years ago. Her anxiety, headaches, and muscle tension are greatly reduced and are well-controlled by the tools we have discovered. Haley already suspects positive results from the recent changes and is motivated to try the other new methods to improve her condition and reduce her dependence on salt water. Updates will be made on her story when notable changes occur.

Conclusion

Haley’s symptomatic and laboratory presentation after her thyroidectomy were suggestive of hypoparathyrodism. Her condition appears mild, since, although she has suffered significantly, it has not debilitated her to the extent those with more severe hypoparathyroidism experience. Since the symptoms began shortly after the surgery and were not resolved by thyroid treatment with T4 and T3, it became more likely that parathyroid damage, the only other consequence of thyroid surgery aside from hypothyroidism, was the cause of the problems. However, likely due in part to her early supplementation of calcium and vitamin D, and later, the inclusion of dairy, Haley’s total calcium remained normal, and doctors ignored her low PTH level of 14.1pg/ml as a likely cause of the symptoms. Even when her PTH was tested much lower at 9pg/ml years later, she was still dismissed due to having normal total calcium levels.
    When corrected for albumin, Haley had three instances of low calcium tested. It is possible that the rise in her dietary protein made in 2016 increased her albumin production, helping to obscure a diagnosis of hypocalcemia. The findings of a high anion gap on three occasions indicate she was in a state of tetany-induced lactic acidosis. On the latter two instances of acidosis, albumin-adjusted calcium scores were low. On another occasion, her bicarbonate was high and anion gap was low, indicating a state of alkalosis. This pattern of fluctuating pH fits with the studies on pH imbalance in hypoparathyroidism made a century ago, where alkalosis was found to precede the onset of tetany and acidosis to follow it.
    In the years after surgery, attempts to empirically treat Haley’s symptoms yielded multiple successful therapies: large amounts of very salty water, TUDCA, a high-calcium diet, vitamin D, progesterone, T3, and laxatives. More recently, lactose and magnesium chloride have proved helpful. These therapies are congruent with the early studies on parathyroidectomy that showed protective effects of diluting the blood or stimulating diuresis with salt water, maintaining good liver health, balancing female hormones, calming nerve excitation, decreasing phosphate, improving oxidative metabolism and preventing the absorption of bacterial toxins from the gut. Altogether, Haley’s symptoms and treatments, especially the salt water and gut therapies, lend some credence to the toxin theory of parathyroid tetany, a long-forgotten theory championed by W. F. Koch and more recently promoted by Ray Peat.
    It is evident that restoring eucalcemia with vitamin D and calcium is not sufficient to protect against various complications of hypoparathyroidism. Managing phosphate levels, gut and liver health, acid-base balance, female hormones, and metabolism should also be prioritized. Diagnosis of hypoparathyroidism should be made based on symptoms and PTH level and should be considered even many years after thyroidectomy.
    We learn from the work of Koch and Peat that tetany is fundamentally a state of over-excitation due to inhibited cellular oxidation. Therefore, supporting mitochondrial energy metabolism should inspire the general approach to resolving symptoms of hypoparathyroidism. A wealth of information on how to improve energy metabolism is found in the vast work of Ray Peat.

Memorial To Dr. Ray Peat (1936-2022)

    Dr. Ray Peat learned from W. F. Koch that certain chemicals have an excitatory effect on cells through blocking their metabolic oxidation, while others can restore oxidation and produce relaxation. This idea influenced a central concept of Peat’s work, that proper oxidation should be robustly protected to create what he called the “high energy resting state”. Peat viewed living systems as structures that are built and organized by the energy streaming through them. In line with Gilbert Ling’s model of a cell as a sensitive gel, Peat understood life as an implicit principle of the laws of physics. Peat taught that life on Earth was inevitable, that we are not here by mistake, and that we are evolving towards something wonderful. Ray Peat embodied the ideal of a high energy resting state, an always calm and intelligent generator of life-promoting ideas. Now he rests and his energy is everywhere.

References

(1) Qiu, Y.; Xing, Z.; Xiang, Q.; Yang, Q.; Su, A.; Luo, Y. Duration of Parathyroid Function Recovery in Patients With Protracted Hypoparathyroidism After Total Thyroidectomy for Papillary Thyroid Carcinoma. Front. Endocrinol. 2021, 12, 665190. https://doi.org/10.3389/fendo.2021.665190.

(2) Kamath, S. D.; Rao, B. S. Delayed Post-Surgical Hypoparathyroidism: The Forgotten Chameleon! J Clin Diagn Res 2017, 11 (2), OD07–OD09. https://doi.org/10.7860/JCDR/2017/23609.9260.

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