Hypothyroidism: Symptoms And Treatment
In the lower front part of your neck, there’s a butterfly-shaped gland called the thyroid. You might not know it, but this little gland helps keep your body running optimally in several ways, from your heart rate and weight to your digestion and moods.
However, when the thyroid gland isn’t functioning properly, the rest of the body can be affected. Read on to learn more about what happens when your thyroid becomes underactive, what hypothyroidism symptoms look like and how to treat it.
Home Thyroid Test
LetsGetChecked offers two options: the generic thyroid test and the thyroid antibody test. These at-home tests are easy to use and understand.
What Is Hypothyroidism?
Hypothyroidism is a condition that occurs when you don’t have enough thyroid hormones in your body, stemming from an underactive thyroid gland (or removal of part of or all of the thyroid gland). Subclinical hypothyroidism is the term used to describe mild hypothyroidism which is indicated by elevated thyroid stimulating hormone (TSH), but does not result in thyroid hormone abnormalities on blood work.
About 4.6% of the population 12 years of age and older in the U.S. has hypothyroidism, according to the National Health and Nutrition Examination Survey (NHANES III). The condition is more common in women and in people over the age of 60. Certain pre-existing conditions can also lead to higher risk of hypothyroidism, such as Turner syndrome (a genetic disorder), type 1 diabetes, rheumatoid arthritis and lupus (a chronic autoimmune disease). Family history of autoimmune hypothyroidism can make someone more susceptible to developing autoimmune hypothyroidism as well.
What Causes Hypothyroidism?
A person can develop hypothyroidism in a few ways.
Hashimoto’s disease is a common cause of hypothyroidism. This autoimmune disease sends antibodies—part of the immune system that neutralizes foreign viruses and bacteria—to the thyroid gland, which damages the gland and, over time, can prevent it from producing thyroid hormones.
Surgical removal of a part of or all of the thyroid gland may be necessary in someone with thyroid nodules (abnormal growths that form lumps on the thyroid gland), Grave’s disease (a cause of hyperthyroidism, or overactive thyroid) or thyroid cancer. This removal may leave a person with insufficient thyroid tissue (or no tissue at all), therefore causing hypothyroidism.
Radioactive treatment, such as radioactive iodine treatment for hyperthyroidism or radiation for Hodgkin’s disease, certain cancers or lymphoma can harm thyroid function.
Thyroiditis, or inflammation of the thyroid gland, may make the thyroid release its entire backup store of hormones into the body at one time. In painless, subacute and postpartum thyroiditis there is the initial hyperthyroidism phase, meaning the thyroid becomes overactive. Once that store of hormones is used up, the thyroid becomes underactive, triggering hypothyroidism. In this case, thyroid function is typically recovered. Thyroiditis can be caused by a range of factors, including viral or bacterial infections, use of medications that interfere with or damage thyroid cells and post-partum.
Congenital hypothyroidism occurs when a baby is born with hypothyroidism due to a partly formed thyroid, the lack of one or a misplaced thyroid.
Additional causes may also include iodine deficiency or excess iodine in the body, medicines that may impact thyroid function, pituitary gland dysfunction, which controls thyroid hormone production, and other rare diseases.
Symptoms of Hypothyroidism
Since thyroid hormones are used in every part of the body, a deficiency can lead to the slowing of certain bodily functions.
Therapeutic Cannabis and Endocannabinoid Signaling System Modulator Use in Otolaryngology Patients
1) review benefits and risks of cannabis use, with emphasis on otolaryngic disease processes; 2) define and review the endocannabinoid signaling system (ESS); and 3) review state and federal regulations for the use and research of cannabis and ESS modulators.
This manuscript is a review of the current literature relevant to the stated objectives.
Cannabis (marijuana) use is increasing. It is the most widely used illicit substance in the world. There is increasing interest in its therapeutic potential due to changing perceptions, new research, and legislation changes controlling its use. The legal classification of cannabis is complicated due to varied and conflicting state and federal laws. There are currently two synthetic cannabinoid drugs that are FDA approved. Current indications for use include chemotherapy‐related nausea and vomiting, cachexia, and appetite loss. Research has demonstrated potential benefit for use in many other pathologies including pain, inflammatory states, and malignancy. Data exists demonstrating potential antineoplastic benefit in oral, thyroid, and skin cancers.
ESS modulators may play both a causal and therapeutic role in several disorders seen in otolaryngology patients. The use of cannabis and cannabinoids is not without risk. There is a need for further research to better understand both the adverse and therapeutic effects of cannabis use. With increasing rates of consumption, elevated public awareness, and rapidly changing legislation, it is helpful for the otolaryngologist to be aware of both the adverse manifestations of use and the potential therapeutic benefits when talking with patients.
The purpose of this review is to provide the practicing otolaryngologist with a foundational knowledge of current therapeutic uses of cannabinoids and effectors of the endocannabinoid signaling system (ECS). It includes a brief overview of the biochemical principles guiding the physiologic effects of the ECS, addresses the risks and adverse effects of cannabis use, and finally reviews current state and federal legislation.
Cannabis (marijuana) use is increasing and is currently the most widely used illicit substance both worldwide and within the United States. 1 Cannabis has been used for centuries as a treatment for myriad medical ailments. It has shown potential to be of therapeutic use in several pathologies including nausea, pain, weight/appetite loss, inflammation, anxiety, multiple sclerosis‐related muscle spasticity, neuropathy, seizure, and even cancer. 2 , 3 , 4 , 5 , 6 , 7 , 8 There has been a recent resurgence of interest in its therapeutic potential, which is likely due to a combination of changing societal perceptions, new scientific discoveries, and recent legislation measures relating to its regulation. The legal classification of cannabis is complicated due to conflicting legislation of the state and federal governments. At present, the federal government still classifies marijuana as a schedule I controlled substance and does not approve it for any medical uses. At the state level, 29 states and the District of Columbia have legalized comprehensive medical marijuana and cannabis programs, while an additional 17 states have highly regulated medical marijuana programs legalizing its use in more limited medical situations. This means that for patients in a majority of states, medical marijuana is increasingly becoming an accessible and entirely novel option for management of their ailments. The current increase in use for medical purposes appears to be commensurate with recent changes in state and federal legislative policies as well as international studies demonstrating a biochemical basis for the therapeutic effects seen with cannabis use. As the use of marijuana and other complementary medicine therapies continues to rise, patients may expect their physicians to explain both the potential merits and harms they may experience with its use.
Unlike many other bioceutical therapies which may be used by the otolaryngology patient, marijuana poses additional challenges due it its current federal classification as a schedule I substance. As scientific evidence of its therapeutic benefit advances, it is vital that physicians are well informed in order to confidently provide sound guidance when questioned by patients. Additionally, the physician must be kept abreast of the current regulatory status in order to ensure they keep their practice within the rapidly changing legal boundaries of both state and federal legislation.
CANNABIS CLASSIFICATION AND BIOLOGY
Marijuana is derived from plants in the Cannabis family. There are two main species: Cannabis sativa and Cannabis indica. Hemp is a nonpsychoactive cannabis plant product that is used in beauty creams, rope, clothing and other domestic goods. There are hundreds of marijuana “chemotypes” derived from the foundational sativa and indica strains. Each strain is designed with a goal of modulating the relative concentrations of certain biologically active molecules, called phytocannabinoids. Customized variations in phytocannabinoid levels subsequently provide the user with a customized sensory experience (in the case of recreational use) or therapeutic effect (medicinal use).
Although there are many biologically active phytocannabinoids in cannabis, two predominate in the current literature. In 1964, Gaoni and Mechoulam described the psychoactive cannabinoids found in Cannabis sativa: Δ8‐tetrahydrocannabinol (Δ8‐THC) and Δ9‐tetrahydrocannabinol (Δ9‐THC). 9 Δ9‐THC is more potent and found in higher concentrations within the plant. It is the primary cannabinoid referred to when “THC” is referenced in this paper. THC is metabolized within the lungs and liver into 11‐hydroxy‐Δ9‐THC which is active within the CNS and elsewhere. 10 Jean‐Baptiste Lamarck described Cannabis indica as a second strain of cannabis in 1785. Cannabis indica is clinically distinct from Cannabis sativa due to the higher relative concentration of cannabidiol (CBD), another phytocannabinoid.
THC is most commonly associated with the euphoric feelings users experience due to its psychoactive effects. In addition to a sense of euphoria, it also appears to possess anti‐emetic, anti‐inflammatory, analgesic, and antioxidant properties. 11 In contrast to THC, CBD has traditionally been viewed as a nonpsychoactive cannabinoid. CBD is credited for offering users analgesic, anticonvulsant, anxiolytic, antipsychotic, and sedative effects. 11 , 12 , 13 , 14 The anxiolytic and antipsychotic effects have been purported to participate in decreasing these adverse effects seen with THC use. This observation is one reason some proponents argue for extracts instead of synthetic cannabinoids which could ultimately cause more adverse effects through loss of this natural synergistic relationship between phytocannabinoids. When derived from hemp, and absent of THC, CBD containing products are not under federal regulation.
METHODS OF CONSUMPTION
There are several methods commonly used in cannabis consumption. The most traditional method of cannabis consumption is unfiltered smoking. This results in the user inhaling the combustion products in cannabis smoke. Smoking cannabis allows for rapid onset of effects (2–10 minutes), short duration of action, and ease of titratability. 8 , 15 It is important to note that smoking is the primary delivery method used in nearly all studies assessing the risks of cannabis use. Cannabis is typically smoked in an unfiltered manner and the smoke itself may reach temperatures as high as 700°C. The combustion process results in partial breakdown of cannabinoids with simultaneous production of undesirable carcinogens. 16 , 17 Marijuana smoke has a similar carcinogen profile as tobacco smoke, but may have higher relative concentrations of certain carcinogens. 18 , 19
Another method of cannabis use is enteral consumption. Although this method avoids the carcinogen exposure of smoked cannabis, it has several downfalls. The onset of action and maximum effect is significantly more delayed (1–6 hrs) than smoking, therapeutic effects are less easily titratable secondary to inconsistent bioavailability (6–20%), and the duration of action is prolonged (20–30 hours). 8
Recently, vaporization has gained popularity as a method of cannabis consumption. Vaporization is a process by which a material is heated to temperatures that allow for vaporization of phytocannabinoids (170–300°C). Vaporization retains the desirable pharmacokinetic profile of smoked marijuana while preventing the creation of harmful carcinogens by avoiding combustion. 15 , 20 , 21 , 22 Although vaporization appears to be a promising delivery method, it is not well studied and vaporization units are not FDA regulated, subjecting users to potential untoward exposure to heat mediated degradation products of plastics or heavy metals within the vaporizer unit. 23 , 24
ENCANNABINOID SIGNALING SYSTEM
The endocannabinoid signaling system (ESS) is complex and promiscuous. In vivo, it acts as a short‐range, short‐term response system to acute physiologic events. 25 The ESS can be thought of as an “on demand” system, where endocannabinoids are synthesized locally in response to acute local stimuli. It is composed of ligands (cannabinoids), cell surface receptors, and several intracellular signaling pathways that induce enzymatic reactions. These enzymatic reactions may either agonize or attenuate cellular function. 25 Stimulation of the ESS can induce myriad effects, which are discussed elsewhere in this paper. Ligands of the ESS can be autogenous molecules (endocannabinoids), plant derivatives (phytocannabinoids), or synthetic cannabinoids. Phytocannabinoids, synthetic cannabinoids, and ESS modulating drugs exert their effects within the body through manipulation of normal ESS physiology. 10
Endocannabinoids are biologic molecules made within the body that act on known cannabinoid receptors. In 1992, the first endocannabinoid, anandamide (AEA), was described. 25 , 26 Since then, several other arachidonic acid‐derived endocannabinoids have been described, including 2‐arachidonylglycerylether (2‐AG), O‐arachidonoyl‐ethanolamine (virohdamine), and N‐arachydonoyl dopamine (NADA). In general, endocannabinoids act in a paracrine fashion by binding to appropriate cell surface receptors that express appropriate cannabinoid‐sensitive receptors. 27 , 28 , 29 After internalization, endocannabinoids are metabolized by various degradatory enzymes including FAAH, DAGL, and MAGL (fatty acid amine hydrolase, diacyl glycerol lipase, monoacyl glycerol lipase) (Table (Table1 1 ). 30 , 31
Select Endocannabinoids by Common and Chemical Name.
|Noladin ether||2‐arachidonyl glyceryl ether|
There are two primary cannabinoid receptors that have been well described. They were sequentially named cannabinoid receptor 1 and 2 (CB1, CB2) based on timing of discovery. CB1 was discovered and described in the late 1980s and early 1990s using a rat model. CB2 was subsequently described in 1993 in a study using human cell cultures. 26 , 32 , 33 Both CB1 and CB2 are G‐protein coupled receptors (GPCRs), and each of them has been shown to function in unique physiologic pathways, in part due to their distinct sites of expression. 34 , 35 , 36 , 37 , 38 Apart from CB1 and CB2, transient receptor potential vanilloid type 1 (TRPV1), a lipid responsive ion channel, has also demonstrated some cannabinoid binding affinity. 39 Of note, CBD has a relatively weak affinity for both CB1 and CB2, which may explain the apparent antagonistic effect it has been reported to have when used with other CB receptor agonists. 25 , 40
CB1 is predominantly found within the brain and other central nervous system structures but is also expressed in other locations including the spleen, eye, and reproductive organs (Fig. (Fig.1). 1 ). Upon receptor activation, CB1 acts through a variety of intracellular mechanisms. It inhibits adenylate cyclase, resulting in decreased levels of cyclic adenosine monophosphate (cAMP). CB1 also activates mitogen‐activated protein kinase (MAPK), extracellular signal‐related kinase (ERK), and phosphatidylinositol‐3 kinase (PI3K) signaling pathways, among others. 6 , 19 , 34 , 41 , 42 CB1 is able to couple with any class of receptor‐activated G‐proteins, including Gs,Gi, and Gq, each of which initiates its own set of unique signaling mechanisms. CB1‘s diversity in effector mechanisms is further broadened by the receptor’s ability to form heterodimers with other receptors. The distinct combination of g‐protein pairing and heterodimerization of any one CB1 receptor creates a nuanced structural conformation, which influences its affinity for specific ligands. Through structural modulation and diverse binding interactions, CB1 exerts broad and complex downstream effects. 43
CB1 and CB2 are membrane bound GPCRs. CB1 receptors (left) are found predominantly in the brain and in tissues of the central nervous system. It is expressed to a lesser degree in the spleen, eye, and reproductive organs. Upon activation, CB1 activates MAPK, ERK, and PI3K pathways, while inhibiting AC and decreasing cellular cAMP. CB2 receptors (right) are found in immune tissues, predominantly B cells and natural killer cells, with additional expression in T cells and neutrophils. Upon activation, CB2 activates MAPK and PI3K pathways while decreasing the generation of ROS.
Unlike CB1, CB2 appears to predominate peripherally within immune regulatory tissues. CB2 expression appears to be highest in B cells and natural killer (NK) cells but is also found in T cells and polymorphonuclear (PMN, neutrophils). 44 CB2 acts to help regulate inflammatory responses. Similar to CB1, CB2 induces many of its physiologic effects through MAPK and PI‐3K signaling pathways. 45 , 46 Unlike CB1, which may promote a proinflammatory response, CB2 signaling appears to decrease reactive oxygen species (ROS). 47
OTOLARYNGIC AND GENERAL MANIFESTATIONS OF CANNABIS USE
As with other aspects of marijuana, there is conflicting data regarding the risks associated with cannabis and cannabinoid use. In general, adverse effects can be separated into those seen with acute or chronic use, and those seen with extremely high (intoxication) doses. These effects are summarized in Tables Tables2 2 and and3. 3 . Most purported adverse effects of marijuana use appear to present in a dose‐dependent manner, regardless of age. 48
Overview of Adverse Effects of Cannabis Use.
|Tachycardia, bronchodilation, conjunctival irritation, decreased intraocular pressure 48||Dependence||Anxiety|
|Impaired judgment||Respiratory tract inflammation (smoked)||Psychosis, paranoia, mania|
|Impaired short‐term memory||Correlation with mental illness incl. depression & schizophrenia a||Hallucinations|
|Increased appetite||Cognitive impairment|
ENT‐Specific Adverse and Therapeutic Effects Associated With Cannabinoid Use. a
|Associated Increased Risk||Associated Decreased Risk|
|Allergic reaction (type I hypersensitivity)||Tongue cancer|
|HPV‐related oropharyngeal cancer||Other oropharyngeal cancers|
|Cough, increased sputum production||Decreased intraocular pressure|
|Fungal sinusitis (Aspergillus)||Potential antineoplastic effects in skin cancer (melanoma, basal cell, squamous cell)|
|Inflammation of respiratory mucosa (rhinitis, stomatitis, uvulitis, pharyngitis, bronchitis)||Potential antineoplastic effects in thyroid cancer (anaplastic)|
|Peridontal disease, dental caries|
Acute physiologic effects of cannabis use include tachycardia, bronchodilation, conjunctival irritation, and decreased intraocular pressure. 49 Although previous data appears to support marijuana use having a negative effect on neural development when used in young people, a recent prospective study conducted in the UK demonstrated this tendency might be negated in moderate users when other factors such as tobacco and alcohol use are accounted for. 48 , 50 , 51 , 52 There is data supporting a correlation with mental illness, including schizophrenia, and heavy use. 50 The association between marijuana use and mental illness has not been shown to be causative. Marijuana may induce earlier or stronger psychotic events in individuals with a preexisting disposition toward mental illness. 3
Driving impairment remains a concern in patients under the influence of marijuana. In contrast to alcohol intoxication, cannabis intoxication levels and risk of driving impairment are not as predictable due to wider levels of tolerance between users. 53 Cannabis intoxication does not appear to impair drivers to the same extent as alcohol, but has been shown to function synergistically when individuals are intoxicated by both. 53 , 54 This association with increased motor vehicle accidents extends to other sources of trauma as well. Gerberich et al. found that cannabis use to increase hospital admission rates for all causes of injury. 55
Chronic effects of marijuana use include respiratory tract inflammation (primarily if smoked), dependence, depressive symptoms, and failure to achieve academically and professionally. Although less addictive than many other illicit substances, marijuana does carry a risk of dependence, with approximately 1 in 10 users demonstrating some level of dependence. 3 , 48 , 56 Marijuana does not appear to increase the rate of birth defects when used during pregnancy, but may be associated with decreased birth weight, preterm labor, and increased rate of admission to a neonatal intensive care unit after birth. 57 Finally, although the mortality risk of marijuana use remains unclear, it has also been associated with an increased risk of cardiac events and stroke. 48 , 58 , 59
Despite the apparently similar carcinogenic profile between marijuana and tobacco smoke, current data does not clearly support marijuana smoking as a clear risk factor for lung cancer. 60 , 61 , 62 , 63 , 64 Studies assessing marijuana use and risk of head and neck cancers are also mixed and data is weakened by confounding factors (namely tobacco), low power, and exposure to recall bias due to their retrospective nature. 61 , 62 , 64 , 65 , 66 , 67 Some data shows marijuana use to be potentially protective against tongue cancers (OR 0.47, 95% CI 0.29–0.75) and other oropharyngeal cancers, while concomitantly serving as an independent risk factor for human papilloma virus (HPV)–positive oral tumors. 68 , 69 Gillison et al reported the possibility that the increased risk of HPV positive cancers seen in marijuana smokers may be due to certain immunomodulatory effects of cannabis. By inducing a shift from Th1 to TH2 immune responses, cannabinoids may decrease resistance to intracellular bacterial and viral infection. Once infected, the host would also suffer from attenuation of normal physiologic clearing of viral infection. This would ultimately result in more virulent HPV infections and increased rates of HPV‐positive cancer. 68 There are no clinical studies assessing cancer risk in users via oral ingestion or vaporization.
Although a correlation between cannabis smoking and lung cancer is non‐definitive, there is data that demonstrates cannabis smoke as a mucosal irritant and source of oxidative stress to respiratory epithelium. 70 There are also reports of increased incidence of fungal sinusitis; possibly due to Aspergillus contaminant of the smoked plant. 71 , 72 Although rare, allergic reactions to marijuana have also been reported. These reactions range from type I hypersensitivity (rhinoconjunctivitis) to anaphylaxis. 73 There is also evidence that marijuana users experience increased rates of periodontal disease and dental carries. 74 Data also correlates marijuana smoking with respiratory mucosa inflammation, stomatitis, uvulitis, cough, and increased sputum production. 19 , 75 Fortunately, these acute respiratory inflammatory responses to smoked marijuana tend to subside soon after cessation of smoking. 76
CURRENT CANNABINOID‐BASED THERAPIES
At the time of this writing, there are no FDA approved uses for cannabis. There are currently two synthetic THC formulations available within the United States, dronabinol (Marinol) and nabilone (Cesamet). Dronabinol is a schedule III cannabinoid and nabilone is a schedule II cannabinoid. Nabiximols (Sativex) is a liquid cannabis extract composed of THC and CBD. It is used as an oral spray and is approved for use in several European countries, but not currently within the United States. Indications for both dronabinol and nabilone include the treatment of recalcitrant nausea and vomiting following chemotherapy in cancer patients. Dronabinol is also approved as an appetite stimulant in diseases such as AIDS which result in severe weight loss. 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 (Table (Table4 4 )