Congenital goiter, or athyreosis, with an incidence of 1:4000 live births, must be diagnosed at birth and treated immediately by thyroid hormones, as severe mental retardation develops quickly, treatable only by fetal precursor cell transplantation, but not by hormonal substitution. When in doubt, x-ray determination of bone age confirms the validity of TSH testing. Fetal precursor cell transplants of thyroid, frontal lobe of brain, temporal lobe of brain, thalamus, hypothalamus, must be implanted every 3 to 4 months.
Our own study involved two children with congenital hypothyreosis treated by transplantation of human fetal cells at the Endocrinology Research Center of Russian Academy of Medical Sciences in Moscow.
A 18 months old girl was admitted in the state of decompensation, clinically and in terms of laboratory findings, length 76.1 cm, weight 11.3. kg, and extremely high level of TSH. After the 1st fetal cell transplantation of thyroid, hypothalamus, frontal lobe of brain, and with a continuous substitution therapy of 100 mg of L-thyroxin daily, the patient’s length increased 5.9.cm within 4 months, and the weight 0.7 kgm, the physical development advanced, and 2 months after cell transplantation the patient began to walk without assistance, speak 4 – 5 words, and understand what is spoken to her. Three new teeth appeared. Patient was clinically compensated. After the 2nd cell transplantation, carried out 4 months after the 1st one, the clinical improvement continued.
A 4 1/2 years old boy was admitted with inadequately treated congenital struma and hypothyreosis, and perinatal CNS damage, with marked psychosomatic delay, slight left hemiparesis, strabismus of the left eye, height 94.9 cm, weight 14.9 kgm, high TSH, normal T3 and T4. After the cell transplantation of thyroid, hypothalamus, frontal lobe of brain, brain cortex, medulla alba of brain, the patient showed remarkable improvement of physical, mental and psychic development.
Although hypothyroidism is as common as diabetes mellitus, the statistics of its incidence are not too accurate, because hypothyroidism is the cause of death or seriously disabling complications only rarely, and its socio-economic significance is low. Diseases with low function of endocrine glands respond to the hormone replacement therapy not as well as expected today, even in hands of the best endocrinologist. At the same time physicians notice that majority of patients diagnosed with hypothyroidism, Addison disease, etc., developed such endocrine illnesses because of autoimmunity, and that explains a lower success rate of a classical hormone replacement therapy in such patients: the relentless progress of an autoimmune damage of hormone producing cells ultimately leaves patient with a very low quantity of functioning endocrine cells, so that even a high dosage of hormones cannot provide a patient with an adequate substitution of missing hormone, but the competitive inhibition whereby the oral hormone therapy suppresses the function of patient’s own same hormone producing cells plays a part. In such instances it is prudent to consider fetal precursor cell transplantation of thyroid, hypothalamus, anterior lobe of pituitary, thalamus, frontal lobe of brain, medulla alba of brain.
The goal of fetal precursor cell transplantation in the treatment of such autoimmune diseases is mostly immunomodulation, e.g. normalization of immune system function, and thereby suppression of the autoimmune process, and to some degree a substitution of non-functioning hormone producing cells. It is not a purpose of fetal precursor cell therapy to eliminate the need for hormone replacement therapy.
Fetal precursor cell transplantation should aim at balancing regulations of the 'axis hypothalamus – pituitary - peripheral endocrine gland, i.e. thyroid in hypothyroidism', disturbed by years of disharmony and demands for over-compensation.
Level of hormones must be measured much more frequently after fetal precursor cell transplantation, and the dosage of oral hormones lowered accordingly, but as a rule their intake cannot be discontinued.
If we disregard diabetes mellitus, among hormone deficiency disorders the most common indication for fetal precursor cell transplantation in clinical practice has been a pronounced hypothyroidism, that is practically always a result of Hashimoto’s (autoimmune) thyroiditis. Overall the numbers of patients with hypothyroidism so treated have not been high , and clinical reports have been but a few.
Physiology of thyroid hormones:
Hormones thyroxine (T4) and triiodothyronine (T3) are produced in the epithelial cells of follicles of thyroid gland. Their synthesis consist of multiple steps, each fraught with possibility of disorder. Iodine from food is mandatory for the synthesis. It is removed from the blood by a Na+-carrier, taken to the follicular cells, and eventually expelled from the cell into the lumen of follicle by exocytosis.
In the epithelial cells of follicles, thyreoglobulin, rich in thyrosin, is created, and secreted into the lumen of follicles. There thyrosyl remnants of globulin are iodinated into diiodinethyrosyl and monoiodinethyrosyl. Two such remnants merge, and attach to thyreoglobulin, which now contains remnants of tetraiodinetyronyl nd triiodinetyronyl. This thyreoglobulin colloid in the follicular lumen is the storage form of thyroid hormones. By stimulation of thyroid-stimulating hormone the thyreoglobulin is taken back into the thyreocytes, and there splits off thyroxin and triiodinethyronine. In the peripheral tissue thyroxine splits off iodine to become more effective triiodinethyronine.
Production and release of thyroxine and triiodinethyronine is stimulated by thyroid-stimulating hormone(TSH) of anterior lobe of pituitary, and its secretion is regulated by thyrotropin-releasing hormone(TRH) from hypothalamus.
Thyroid hormones increase anabolic processes in many tissues, activity of Na+/K+-ATP-ase, as well oxygen utilization, and thereby increase the basal metabolic rate and body temperature. They stimulate glycogenolysis and gluconeogenesis, lipolysis, breakdown of VLDL and LDL, and excretion of bile acids via bile. They stimulate secretion of erythropoietin, sensitize adrenoreceptors and thereby increase the contractility of myocardium and heart rate, stimulate intestinal motility, glomerular filtration rate, and tubular transport, and neuromuscular reaction treshhold. They support intellectual development, and growth of body length, and catabolic process in bones.
Majority of causes of lowered secretion of thyroid hormones lie in the thyroid gland. Disturbance of synthesis and effectiveness of thyroid hormones can happen in any of the several known steps of thyroid hormone synthesis. The most common cause are inflammations of thyroid gland, or thyroidectomy because of cancer.
Lack of thyroid hormones causes increased levels of TSH, and thereby hyperprolactinemia, that in turn causes disturbance of gonadotropin release and infertility.
Lack of thyroid hormones in fetus and newborn causes irreversible brain damage. Without thyroid hormines there is no growth of dendrites, axons, and synapses, no glia development, and no myelinization. Already in utero the brain development is retarded, and if the condition is not recognized at birth, and thyroid hormone substitution started immediately, the ensuing brain damage cannot be repaired later on. There is nanism and deafness.
The most common cause of hyperthyreoidism is LATS (long acting thyroid stimulator), or TSI (Thyreoid stimulating immunoglobulin), that easily bounds onto the TSH receptors, as is the case in Graves disease, known also as Basedow disease, as well as thyroid tumors, thyreoditis, increased TSH secretion. Fetal precursor cell transplantation must be used with utmost care, if at all, usually focusing on the autoimmune pathogenesis.
The exophthalmos, typical of Graves disease, is due to immune reactions against retrobulbar antigens, that are apparently very similar to the TSH receptors. As a result there is retrobulbar inflammation with edema of extraocular muscles, lymphocytic infiltration, accumulation of acid mucopolysaccharides and of retrobulbar connectiuve tissue.
Clinical protocol for fetal precursor cell transplantation treatment of hypo-endocrinopathies (for Hashimoto’s thyroiditis, Graves disease, Addison’s diseases see also the protocol for autoimmune disorders).
Parameters to be followed in patients before and after fetal precursor cell xenotransplantation, and the frequency:
General: once a month or as necessary:
i/ growth chart, i.e. height and weight over time
ii/ measurement of body proportions once every 3 months
iii/ observation of symptoms & signs of puberty
iv/ x-rays of sella turcica
v/ CT scan or MRI of sella turcica and surrounding parts of brain
vi/ bone age by hand x-rays
vii/ chromosomal evaluation, if necessary
viii/ clinical status of female or male hypogonadotropism
ix/ clinical status of primary & secondary hypothyroidism
x/ clinical status of primary & secondary hypoadrenalism
xi/ clinical status of primary & secondary hyperthyroidism
xii/ clinical status of hypoparathyroidism:
Immunological: once a month for 3 months, then every 3 months
i/ total lymphocytes
ii/ T-lymphocytes (CD3+)
iii/ T-helpers (CD4+)
iv/ T-suppressors (CD8+) and CD4/CD8
v/ NK (CD16)
vi/ B-lymphocytes (CD22 and CD19)
vii/ serum IGG, IGA, IGM
viii/ serum complement
Special: once every 3 months as clinically necessary for the disease(s) under treatment:
i/ T3, T4, TSH by radioimmunoassay
ii/ thyrotropin releasing hormone stimulation test
iii/ growth hormone level
iv/ somatomedin C (IGF-1) level
v/ insulin tolerance test
vi/ 24-hour urine for free cortisol, 17 OH-cortisol and ketogenic steroids
vii/ ACTH stimulation test or Metyrapone test
viii/ corticotropin releasing hormone stimulation test
ix/ prolactine level
x/ FSH and LH levels
xi/ gonadotropin-releasing hormone stimulation test
xii/ simultaneous testing of pituitary secretory reserve, i.e. of insulin, growth
hormone, thyrotropin releasing hormone + gonadotropin releasing hormone
xiii/ thyroid hormone binding ratio (T3 resin uptake) if necessary
xiv/ radioactive iodine uptake if necessary
xv/ serum electrolytes: Na, K, Cl
xvi/ blood urea nitrogen
xvii/ blood glucose
xviii/ serum calcium and phosphorus .
xix/ 24 hour urine for calcium
xx/ serum parathyroid hormone level by radioimmunoassay
Frequency of office visits: 4 weeks and 48 hours before fetal precursor cell xeno-transplantation, 24 hours after, and then once a week for the first month after fetal precursorcell xeno-transplantation, once a month thereafter.