Donath-Landsteiner Antibodies

The history of the DL antibody goes back to the 1900’s. It was one of the first recognized forms of immune mediated hemolysis and responsible for inducing Paroxysmal Cold Hemoglobinuria (PCH). PCH is a transient condition, meaning that it comes on when immunoglobulins (Antibodies) are formed in response to a viral, bacterial, or spirochete infection. Its history will suggest that there is an association between PCH and syphilis. In over 90% of the cases of PCH in early history, the patient was co-diagnosed with syphilis. Throughout the 1900’s the condition began to evolve and is now seen most commonly in children following some sort of infection. Although it should be noted that PCH is not limited to those of adolescent age. So what really is the Donath-Landsteiner antibody and how does it contribute to PCH?

Clinical Presentation

Paroxysmal Cold Hemoglobinuria (PCH) is an autoimmune hemolytic anemia (AIHA). Autoimmune meaning that they are antibodies that have cross-reacted to attack the individuals own cells. Hemoglobinuria means that there will be hemoglobin present in the blood, which suggests intravascular hemolysis. PCH is one of the more common intravascular hemolytic anemias. Typical patients present with fever, chills, abdominal and back pain, and pronounced hemoglobinuria. PCH typically presents in children following and upper respiratory infection or immunization. These patients often have a rapidly progressing anemia with hemoglobins that can fall as low as 2.5 g/dL. Peripheral blood smears show significant red blood cell agglutination and anisocytosis and poikilocytosis. Anisocytosis indicating variance in size of the red blood cells and poikilocytosis indicating variance in structure to the red blood cells. Schistocytes, spherocytes, and polychromasia are common findings. The spherocytes and polychromasia are indicative of the bone marrow trying to replenish the red cell population as best it can so it forces out immature erythrocytes into the peripheral blood. Its an effort to sustain the hemoglobin as best it can. One distinguishing peripheral blood smear finding in patients with PCH is erythrophagocytosis. Lets break this word down. Erythro- short for erythrocyte meaning red blood cells. Phagocytosis is mediated by neutrophils and monocytes as a way to kill foreign pathogens. In the case of erythrophagocytosis in PCH, neutrophils are characteristically seen engulfing red blood cells, which is diagnostic for AIHA.

The Donath-Landsteiner Antibody

The DL antibody, although being recognized as an cold autoantibody, is an IgG antibody that has developed P antigen specificity and it is a biphasic hemolysin. What that means is that when someone has the DL antibody and is exposed to cold temperatures, it will bind to the individuals red blood cells through the P antigen, but does not cause hemolysis until the coated red blood cells are heated to 37 degrees Celsius as they (RBC:antibody complex) travel from the peripheral fingertips and toes to the core of the human body.   At cold temperatures, the IgG molecule is able to recruit complement (C3), and at the higher temperatures, activates the membrane attack complex (C5-C9) and lyses the red blood cells. One very interesting piece of information regarding the difference between Cold Agglutinin Syndrome (CAS), another autoimmune hemolytic anemia caused by Anti-I, is that the hemolysis from PCH is stronger and more severe because of the DL antibodies ability to detach from lysed red blood cells and reattaching to other cells. 

Laboratory Diagnosis

There are a few different ways to pinpoint PCH in the blood bank. One is by use of a Direct Coombs test (DAT). This test provides information regarding the type of hemolysis, whether it be acquired or inherited. It also tests for antibodies that have are bound in vivo. The most common DAT result in PCH is red blood cells coated with C3d causing a positive reaction. This is sensitive in 94-99% of cases. The other way to diagnosis DLAIHA (Donath-Landsteiner Autoimmune Hemolytic Anemia) is by the indirect DL test. This process involves collection of a fresh serum specimen that is strictly maintained at 37 degrees Celsius from collection all the way through to testing. If the sample is allowed to cool or is refrigerated, there could potentially be autoadsorption of the DL anti-P antibodies onto the patients autologous red blood cells. This could cause a false negative result. Upon testing, the patients serum is mixed with P antigen positive, group O red blood cells, and fresh donor serum. The fresh donor serum is added because the complement level within the patients may be low due to consumption. The patient and donor serum mixture is incubated in a melting ice bath (O degrees Celsius) for 30 minutes, then warmed to 37 degrees Celsius for one hour. The specimen is then centrifuged and examined for hemolysis. If hemolysis is present then this constitutes a positive result for DL antibody.


Indirect DL test: As you can see in tubes 1 and 4, the presence of hemolysis indicates a positive test result for the DL antibody.


There is unfortunately no cure for PCH, and very little reliable treatment options for those with the DL antibody. It is recommended to avoid cold climates as much as possible and when inside to have the temperature at 30 degrees Celsius to keep the hemoglobinuria low. This doesn’t treat the PCH, but it will minimize the recurrence and induced anemia. Steroids have been through extensive trials for treatment of PCH and there are mixed results. Theory is that steroids are better at clearing red blood cells coated with IgG, and less effective at clearing red blood cells that are coated with complement. More aggressive treatment such as splenectomy and Rituximab, which is an monoclonal antibody that targets the transmembrane protein CD20 present on B cells has been found effective for those patients with refractory PCH.


Adrenal 101

The adrenal glands also known as the suprarenal glands. Supra meaning above, and renal meaning kidneys. So these glands are situated on top of the kidneys. These are endocrine glands that produce a variety of hormones, but most notable adrenaline, and the steroids aldosterone and cortisol. Each gland has an outer cortex which is divided into three different zones and an inner medulla. The three zones of the cortex are the zone glomerulosa, zone fasciculate, and zone reticularis.

This article will go briefly touch on the structure of the adrenal gland, including each zone of the cortex. Then it will dive into the function of the adrenal gland and the hormones it produces along with their specific cellular target. Finally the article will conclude with an overview of adrenal insufficiency and cortisol overproduction and diseases that illustrate those two conditions.


adrenal gland sections

As mentioned earlier, the gland is composed of an outer cortex, and an inner medulla. The outer cortex can be further divided into three zones that each have a specific function.

Zona Fasciculata

The zona fasciculata sits between the other two zones (zona glomerulosa, and zona reticularis) and consists of cells responsible for producing glucocorticoids such as cortisol. Its the largest of the three zones consisting of about 80% of the space in the cortex.

Zona Glomerulosa

The zona glomerulosa is the outermost zone of the adrenal cortex. The cells that are situated in this zone are responsible for the production of mineralocorticoids such as aldosterone. Aldosterone is an important regulator of blood pressure. Review the article covering the Renin-Aldosterone system.

Zona Reticularis

The zona reticular is the innermost cortical layer which is primarily responsible for producing androgens. Its main component synthesized is dehydroepiandrosterone (DHEA), and androstenedione, which is the precursor to testosterone.


The medulla is in the centre of each adrenal gland with the cortex around the entire periphery. The chromatin cells within the medulla are the bodies main source of catecholamines. Catecholamines produced in the medulla are adrenaline (epinephrine), and noradrenaline (norepinephrine). Regulation of the synthesis of these catecholamines is driven by the sympathetic nervous system via the preganglionic nerve fibers stemming from the thoracic spinal cord (T5-T11) to the adrenal glands. When the medulla gets stimulated to produce these hormones it secretes them directly into the cardiovascular circulation system, which is unusual of sympathetic innervation as they usually have distinct synapses on specialized cells.


Mineralocorticoids such as aldosterone are named according to its function. They regulate minerals, such as salt and regulate blood volume (blood pressure). Aldosterone, the most prominent mineralocorticoid acts on the distal convoluted tubules and the collecting ducts by increasing the reabsorption of sodium and the excretion of both potassium and hydrogen ions. The amount of salt present in the body affects the extracellular volume, which influences the blood pressure.


Glucocorticoids are also named due to its function. Cortisol is a prominent glucocorticoid that regulates the metabolism of proteins, fats and sugars (glucose). Cortisol increases the circulating level of glucose. They cause protein catabolism into amino acids and the synthesis of glucose from the amino acids in the liver. They also increase the concentration of fatty acids by increasing lipolysis (fat breakdown) which cells can use as an alternative energy source in situations of glucose absence. Glucocorticoids also play a role in suppression of the immune system. They induce a potent anti-inflammatory effect.


Cortisol is the prominent glucocorticoid produced by the adrenal gland. The adrenal gland secretes a basal level of cortisol depending on the time of day it is. Cortisol concentrations in the blood are highest in the early morning and lowest in the evening as part of the circadian rhythm of adrenalcorticotropic hormone (ACTH) secretion. The article on general endocrinology explains what ACTH is and how it affects the adrenal gland. Basically what happens is the hypothalamus secretes corticotropin releasing hormone that acts on the pituitary to produce ACTH that acts on the adrenal gland cortex to produce cortisol.

Androgens and Catecholamines

The primary androgen produced by the adrenal gland is DHEA, which is converted to more potent androgens such as testosterone, DHT, and estrogen in the gonads. DHEA acts as a precursor. Androgens drive sexual maturation.

Catecholamines are produced by the chromaffin cells from tyrosine. The enzyme tyrosine hydroxyls converts tyrosine to L-DOPA. L-DOPA is then converted to dopamine before it can be turned into norepinephrine. Norepinephrine is then converted to epinephrine by the enzyme phenylethanolamine N-methyltransferase (PNMT). Epinephrine and norepinephrine act as adrenoreceptors throughout the body, whose primary effect is to increase the blood pressure and cardiac output by way of vasoconstriction. Catecholamines play a huge role in the fight-or-flight response.

Corticosteroid Overproduction


The normal function of the adrenal gland can be impaired from infections, tumors, autoimmune diseases, or from previous medical therapy such as radiation and chemotherapy. Cushing’s syndrome is the manifestation of glucocorticoid excess. Symptoms and sign are a direct result of chronic exposure to glucocorticoids. Diagnosis is difficult because the symptoms are often nonspecific and pathognomonic of the syndrome in isolation. Symptoms include proximal (distant) muscle weakness, wasting of the extremities, increased fat in the abdomen and face often leading to a moon face, bruising without trauma, and a buffalo hump. A buffalo hump is fat on the back of the neck and supraclavicular pads. In women, menstrual irregularities are common such as oligomenorrhea (infrequent menstrual periods), amenorrhea (absence of menstrual periods), and variable menses. Hyperpigmentation can occur by increased secretion of cortisol. Cortisol acts on the melanocyte-stimulating hormone receptors.

Glucose intolerance is common in Cushing’s syndrome. Primarily due to stimulation of gluconeogenesis by cortisol and insulin resistance caused by the obesity. This leads to hyperglycemia, which can exacerbate any diabetic patient.

Bone loss and osteoporosis is common in patients with Cushing’s syndrome because there is less intestinal calcium absorption. Calcium is vital to bone health and growth. The decrease in bone formation is coupled with an increased rate of bone reabsorption which can lead to more pathological fractures.

Adrenal Insufficiency

Addison’s disease is considered primary hypoadrenalism. There is an inherent deficiency of glucocorticoids and mineralocorticoids. Most commonly caused by an autoimmune condition. Autoimmune means that the body is attacking itself by production of antibodies against cells of the adrenal cortex. In cases of adrenal crisis due to autoimmune primary adrenal insufficiency clinical presentation is usually the patient presenting in a state of shock. Abdominal tenderness upon deep palpation is common. Patients present with hyperpigmentation due to chronic ACTH release by the pituitary. Proopiomelanocortin is overproduced which is a pro hormone that is cleaved into its biologically active hormones corticotropin and melanocyte-stimulating hormone (MSH). This causes increased melanin synthesis, causing the hyperpigmentation. Other non-specific symptoms such as lethargy, fatigue, weakness, confusion, anorexia, nausea, vomiting, or even coma can occur. One of the most commonly presented symptoms is fever and infection, which can be exaggerated by the hypocortisolemia.

Its important to take this article slowly. There a lot of different parts, but the aim was to look at the hormones themselves and how they physiologically act on the body, then take what was learned about those and apply them to two scenarios, hypo/hyperadrenalism and how it affects the body. Cushing’s syndrome is where there is hyperproduction of cortisol primarily leading to many disastrous effects on the body. Addisons disease is an autoimmune disease where the body produces antibodies against the cells of the adrenal cortex, causing destruction of the gland itself, again leading to detrimental effects on the body.

Aspirin as a blood thinner?

Most people who have had previous cardiac issues, those who have even had a minor heart attack or survived a major infarction have often been prescribed to take an aspirin daily. To tackle this issue, its important to understand what a heart attack or an infarction actually is. Usually blood travels to the lungs, it gets oxygenated, and then travels through the coronary arteries to oxygenate the heart muscle itself. People over time can develop plagues that thin the artery lumen, or opening, eventually to the point where only a small amount of oxygenated blood can actually pass through. As a result, the heart can’t keep itself oxygenated. Without oxygen, tissues become hypoxic and die. When they die they release toxic cytokines and chemicals that damage tissue further, which coincidently we can objectively measure to determine whether an individual has experienced a heart attack. Heart attacks can come from a deep vein thrombosis, or an emboli as well. In that scenario, the clot actually happens somewhere else in the body and a piece of it breaks off and circulates until it gets to the heart and blocks the blood flow in the heart, causing an infarct.

Aspirin works as a blood thinner. It impairs the bodies ability to form a clot. What is a clot formed out of? Platelets. So aspirin directly targets a precursor to thromboxane A2, which activates downstream signaling to aggregate platelets and form a clot in primary hemostasis.

Synthesis of TXA2


The synthesis of thromboxane A2 is through the Arachidonic Acid, Cyclooxygenase (COX) pathway. Phospholipids are converted to Arachidonic Acid catalyzed by phospholipase C or phospholipase A2. Arachidonic acid can at that point go to two pathways; the Lipooxygenase pathway, or the Cyclooxygenase pathway. There are two Cyclooxygenase peroxidase; COX-1 and COX-2. COX-1 mediates the pathway through which thromboxane A2 is going to be synthesized, and COX-2 mediates another pathway that works to synthesize prostaglandins which directly counteract the function of thromboxane A2. Its the bodies way of keeping homeostasis. For every action, there has to be an equal reaction. In the next step in the pathway, Arachidonic Acid is converted to Prostaglandin H2 (PGH2) by PGH2 synthase and COX-1/COX-2 working synergistically. Prostaglandin H2 is then converted to thromboxane A2 (TXA2) by thromboxane synthase. TXA2 is a vasoconstrictor and potent hypertensive agent.

So, how does aspirin come into play at all? Good thing you asked. Aspirin as it turns out irreversibly binds to COX-1. This antagonist effect stops the pathway and does not allow for the synthesis of thromboxane A2. Without TXA2, there will be no platelet aggregation, and no clot. Without primary hemostasis being established, coagulation, or secondary hemostasis, can’t take over to stabilize the clot with fibrin.


Ketosis and Ketoacidosis

Ketosis is a metabolic state in which the bodies energy supply comes from ketone bodies in the blood in contrast to a state of glycolysis in which there is adequate glucose breakdown. In most cases, ketosis results from a high metabolism of fatty acids which are converted to ketone bodies. Ketone bodies are formed from ketogenesis when liver glycogen stores are depleted. Most cells in the body utilize both ketone bodies and glucose for energy, and while in ketosis the body works to maintain normal metobolism so it ramps up gluconeogenesis. Gluconeogenesis is glucose synthesis used to go through glycolysis.

Most of the time ketosis is a short interval of time, although long-term ketosis may be a result of fasting or a dietary insufficiency of carbohydrates. In glycolysis, high levels of insulin are released which promotes storage of fat and delayed release of fat from adipose tissue. In ketosis, fat reserves are readily available and are consumed. For this reason, ketosis has become one of the more recent diet fads as a way to burn fat quickly and lose weight.


Although similar, ketosis is not ketoacidosis. Ketoacidosis is a physiological life-threatening situation due to insulin deficiency. Ketone bodies are acidic, and acid-base homeostasis in the blood is normally maintained through bicarbonate buffering, respiratory compensation, and renal compensation. Prolonged excess of ketone bodies can overwhelm the normal compensatory mechanisms and cause a state of acidosis when the blood pH falls below 7.35.

There are multiple precipitating factors that leads to ketoacidosis, which is most prevalent in patients with type 1 diabetes. Ketoacidosis in the case of a patient with type 1 diabetes is deemed diabetic ketoacidosis (DKA). In established type 1 diabetes, patients often forget to take insulin, with non-compliance being the bigger issue. This does not rule out other causes of ketoacidosis, as those are still prevalent. Acute major illnesses such as a myocardial infarction, cerebrovascular accident, sepsis, or pancreatitis. Certain drugs that affect carbohydrate metabolism such as glucocorticoids, diuretics, or anti-psychotic agents can cause ketoacidosis. General malnutrition associated with physiological problems can also lead to ketoacidosis. Such disorders lead to psychological starvation, which leads to ketone production and if prolonged ketoacidosis.


Clinical Presentation

The clinical presentation of DKA is a two headed monster. The earliest symptoms of marked hyperglycemia is polyuria, polydipsia, and unexplained weight loss. As the duration of hyperglycemia continues neurological symptoms, including lethargy, focal signs and obtundation develop. Further progression can lead to a coma. The other head is the extent of the metabolic acidosis due to the excess ketone bodies. As the acidemia worsens accompanied with it is abdominal pain which can sometimes be severe. The electrolyte imbalance and metabolic acidosis causes delayed gastric emptying and an ileus (obstruction of the bowel). Vomiting and nausea are common.

Diagnostic Evaluation

The initial laboratory evaluation of patients with suspected DKA should include a serum glucose to establish whether or not the patient is hyperglycemic or not. Its helpful to measure the serum electrolytes and calculate the anion gap, BUN, plasma creatinine, and a plasma osmolality. This gives a broad picture of the metabolic state of the patient. Urinalysis is commonly performed along with urine ketones measured by dipstick method. Serum ketones are also measured to assess whether or not the patient is undergoing ketogenesis. An arterial or venous blood gas can be helpful to determine whether the serum bicarbonate is substantially reduced, which presumptively leads to metabolic acidosis. This also aids in determining hypoxia if it is present.


Hyperglycemia and hyperosmolality are the two primary laboratory findings in patients with DKA. Patients with DKA have a high anion gap metabolic acidosis. Serum glucose often times exceeds 350-500 mg/dL. Three ketone bodies are produced and accumulate in DKA; acetoacetic acid, beta-hydroxybutyric, and acetone. Acetoacetic acid is the only true ketoacid. A serum ketone measurement gives levels of beta-hydroxybutyric, while a urine dipstick measures the presence of acetoacetic acid using the nitroprusside method.

Other findings that may or may not be present are leukocytosis, and lipidemia. The majority of patients with hyperglycemic emergencies present with leukocytosis, which is proportional to the degree of ketonemia. Patients with DKA also present with marked hyperlipidemia. Lipolysis, primarily caused from insulin deficiency, and to a lesser extent elevated levels of lipolytic hormones including catecholamines, GH, ACTH, and glucagon. Lipolysis releases glycerol and free fatty acids into circulation which causes insulin resistance and serves as the substrate for ketoacid generation in the hepatocyte mitochondria.

To recap, ketosis is a dietary manipulation that if done right can lead to results. Ketoacidosis is a life-threatening metabolic state that requires immediate medical care.

This discussion will be continued with the next article focusing on ketoacid generation.

Thyroid 101

The thyroid gland is one branch of the endocrine system that is located in the neck that has two lobes connected by an isthmus. The hypothalamus secretes Thyrotropin-releasing hormone (TRH) which stimulates the anterior pituitary to secrete Thyroid-stimulating hormone (TSH). TSH acts on the thyroid gland to secrete the hormones triiodothyronine (T3) and thyroxine (T4). Within the circulation T4 is converted to its active metabolite T3. There are two different types of thyroid cells. Follicular cells produce the thyroid hormones T3 and T4. The parafollicular cells produce calcitonin. Calcitonin causes calcium reabsorption and maintains calcium homeostasis.

Synthesis of Thyroid Hormones is from iodine and tyrosine. Triiodothyronine (T3) has three atoms of iodine per molecule and thyroxine (T4) has four atoms of iodine per molecule. The hormones are created from thyroglobulin which is a protein within the follicular space that is originally created within the rough endoplasmic reticulum (RER). Thyroglobulin contains 123 units of tyrosine with reacts with iodine within the follicular space. A sodium-iodide symporter pumps iodide actively into the cell where it enters the follicular lumen from the cytoplasm by the transporter pendrin. In the colloid, iodide is oxidized to iodine by the enzyme called thyroid peroxidase. Iodine is very reactive and iodinates the thyroglobulin at tyrosyl residues in its protein chain. This forms the precursors of the thyroid hormones monoiodotyrosine (MIT), and diiodotyrosine (DIT). The adjacent tyrosyl residues are then paired together and subsequently the entire complex re-enters the follicular cell by endocytosis. Proteolysis liberates triiodothyronine and thyroxine and they enter the blood stream. Of the hormones secreted from the gland, 80-90% is T4, and only about 10-20% is T3. The production of T3, and T4 is primarily regulated by thyroid-stimulating hormone (TSH) which is released by the anterior pituitary gland. The thyroid hormones provide negative feedback to the thyrotropes TSH and TRH; when the thyroid hormones are high, TSH production is suppressed, and when levels are low, TSH secretion is increased.

After secretion, there is a very small percentage of the thyroid hormones that travel freely in the blood and that are metabolically active. Most are bound to thyroxine-binding globulin (TBG), transthyretin, and albumin. They act upon their respective tissues by crossing the cell membrane and binding to intracellular nuclear thyroid hormone receptors, which bind with hormone response elements and transcription factors to modulate DNA transcription. This modulation is what drives protein synthesis within the target tissue to actively project its physiological function within on the tissue and body.

Calcitonin is secreted by the parafollicular cells which helps maintain calcium homeostasis. Calcitonin is produced in response to high blood calcium. This causes inhibition of the release of calcium from the bone by decreasing the activity of osteoclasts. Osteoclasts are cells which break down bone. Bone is constantly reabsorbed by osteoclasts and created by osteoblasts, so calcitonin is effectively stimulates movement of calcium into bone. The effects of calcitonin are opposite of those of the parathyroid hormone (PTH) produced by the parathyroid gland.


The primary function of the thyroid gland is the production of the thyroid hormones that have downstream metabolic, cardiovascular, and developmental effects. The basal metabolic rate is increased which effects all tissues. Gut adsorption and motility is increased. The generation, uptake by cells and breakdown of glucose is increased. The thyroid hormones also increase the breakdown of fats which increases free fatty acids, but contrary to believe, thyroid hormones decrease cholesterol levels.

There is an increase in cardiac output, as well as rate of breathing, intake and consumption of oxygen and increase in oxidative respiration within the mitochondria. These factors combine increase vascular pressure and elevate the bodies temperature.

The thyroid hormones are important for normal development. The cells of the developing brain are a major target for the thyroid hormones. They play a crucial role in brain maturation during fetal development. The thyroid hormones also play a role in maintaining normal sexual function, circadian sleep rhythm, and thought patterns.

The overarching effect is an augmented flight-or-fight response. It increases the release of the catecholamines which drives sympathetic innervation.

Clinical Significance

Hyperthyroidism is an excessive production of the thyroid hormones, most commonly a result of Graves Disease. Graves disease, also known as toxic diffuse goiter is an autoimmune disease that results in an enlarged thyroid. The exact cause is unknown, however it appears to be a combination of both genetic and environmental factors. An antibody, called the thyroid-stimulating immunoglobulin (TSI) which mimics the effect of TSH. This causes an increased T3 and T4, and an increased radio iodine uptake. Laboratory tests will show a decreased level of TSH, because there is negative feedback on the pituitary, but because of the antibody, production of the thyroid hormones continuous. One of the classic findings of Graves disease is exophthalmos, which is bulging of the eyes. This is often accompanied by irritability, muscle weakness, sleeping problems, increased heart rate and blood pressure and unintentional weight loss. Patients may complain of being “hot” all the time, illustrating a poor tolerance of heat.

Hypothyroidism is an underactive thyroid gland which results in decreased secretion of thyroid hormones. One of the most common causes is an autoimmune disorder called Hashimotos thyroiditis or chronic lymphocytic thyroiditis. The disease is characterized by gradual destruction of the thyroid gland. There are various antibodies that have been identified targeting against thyroid peroxidase, thyroglobulin, and TSH receptors. There is activation of cytotoxic T-cells in response to a cell mediated immune response affected by helper T-cells that drives thymocyte destruction. Cytokine release recruits macrophages within the gland to further drive destruction. Early on in the disease there may be no clinical evidence or symptoms of Hashimotos, but as the disease progresses, so does the clinical presentation. The most common symptoms are fatigue, weight gain, feeling cold, joint and muscle pain, depression, and bradycardia. This disease is about seven times more common in women than in men. Diagnosis is from TSH and T4 levels, imaging, along with other clinical symptoms. The thyroid gland may become firm, large and lobulated. There is lymphocytic infiltration and fibrosis that is seen.

These are not all the causes of hyper/hypothyroidism, but these are the most common, and in most cases, the most severe.