28th November 2023

Endocrinology

Disorders of thyroid function

The thyroid gland sits anterior to the trachea and is responsible for helping to manage and maintain the body’s metabolism. The neuropsychiatric symptoms of untreated thyroid dysfunction could be easily misdiagnosed as depression, anxiety or mania, hence why thyroid function tests are performed as first line investigation with patients who are reporting a disturbance in mood.

Thyroid axis

The thyroid is coordinated by the hypothalamus, which releases thyrotropin-releasing hormone (TRH). This causes the anterior pituitary to release thyroid stimulating hormone (TSH). TSH causes the thyroid gland to release triiodothyronine (T3) and thyroxine (T4). The thyroid axis works on a negative feedback loop, meaning that the hypothalamus and anterior pituitary can detect the levels of T3 and T4 and suppress the release of TRH and TSH to ensure that levels of T3 and T4 are kept within acceptable limits. When there is dysfunction in this feedback loop, we get problems with hyper- and hypothyroidism.

Hyperthyroidism

Hyperthyroidism can be split into:

1. Primary hyperthyroidism: where the thyroid itself is the issue, producing too much T3 and T4. Causes include (Leo, Lee and Braverman, 2016):
   • Grave’s disease (the most common cause of hyperthyroidism – Wémeau et al., 2018).
   • Toxic nodular goitre (the second most common cause).
   • Thyroiditis.
   • Thyroid carcinoma.
   • Medications (e.g. Lithium).
2. Secondary hyperthyroidism: The problem here is further up in the feedback loop, with either the hypothalamus producing too much TRH or the anterior pituitary producing too much TSH. Causes include:
   • TSH secreting adenoma.
   • Thyroid hormone resistance.

Hypothyroidism

Hypothyroidism can also be split into primary and secondary causes (Chaker et al., 2017):

Primary:

• Autoimmune – Hashimoto’s thyroiditis is the most common cause (in populations with sufficient iodine intake).
• Iodine deficiency.
• Medications (e.g. Lithium and amiodarone).
• Secondary to treating hyperthyroidism (medications, radioactive iodine or thyroid surgery).

Secondary:

• TSH deficiency.
• Hypopituitarism (e.g. hemochromatosis, amyloidosis).
• Hypothalamic issues (e.g. neoplasms).

On examination – Mental state examination

Appearance and behaviour

Pay attention to what your patient is wearing. Is there any incongruity with the current climate and what their clothes are? The thyroid gland plays a role in thermogenesis (Iwen, Oelkrug and Brabant, 2018); those with hyperthyroidism are intolerant to heat and may be wearing lighter clothing than expected for the weather. Patients with hypothyroidism tend to feel the cold more easily and may be wrapped up in many layers.

A patient’s body habitus may reflect underlying pathology (Biondi, 2015). Those with an underactive thyroid can be overweight secondary to reduced metabolism, and thyroid overactivity is associated with weight loss.

A goitre may be noticed – This can be palpated, but further detail of this is not necessary for the purposes of Paper A.

Mood

A heightened, anxious state is associated with hyperthyroidism. This can be accompanied with symptoms including irritability and lability. Low mood, anergia and psychomotor slowing may be secondary to hypothyroidism (Hage and Azar, 2012).

On examination – Physical examination

Hands

The following nail changes are associated with hyperthyroidism (Malan et al. 2019):

• Thyroid acropachy (similar in appearance to clubbing).
• Onycholysis – Separation of the nail from the nail bed.
• Palmar erythema.

A patient with hyperthyroidism may also have peripheral tremors secondary to sympathetic overactivity.

Whilst looking at the hands, palpate the radial pulse. Hypothyroidism may lead to bradycardia, hyperthyroidism, tachycardia or even atrial fibrillation (an irregularly irregular pulse).

Face

Eye issues are almost synonymous with thyrotoxicosis. These include (Muralidhar, Das and Tiple, 2020):

• Lid retraction – Secondary to excessive contraction of the superior tarsal and levator palpebrae superioris muscles.
• Exophthalmos – Bilateral bulging of the eyes is seen in Graves’ due to oedema and lymphatic infiltration of the muscles of the eyes.
• Ophthalmoplegia – Eye movement pain and restriction seen in Grave’s.
• Lid lag.

Neurological

The main neurological finding you could expect is a change in reflexes. In hyperthyroidism, there is a briskness to the tendon reflexes, whereas in hypothyroidism, there is delayed relaxation of the reflexes (Shahid, Ashraf and Sharma, 2022).

Investigations

The first port of call for investigating potential thyroid issues is a blood test, which is done routinely as part of all psychiatric admissions. TSH can be used as a screening test; if raised or reduced, free T3 and T4 can be tested, with free T4 being more important in diagnosis.

Adapted from The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry.

Subclinical variations of hyper- and hypothyroidism exist in clinical practice. In subclinical hyperthyroidism, the TSH is low, but free T3 and T4 are normal- without treatment, there is an increased risk of atrial fibrillation, decreased bone mass density and reduction in quality of life (Hoogendoorn et al., 2004). In subclinical hypothyroidism, TSH is raised, but T3 and T4 are normal.

A third variant which appears in exams is sick euthyroid disease, which is where there is an isolated drop in T3 and can be seen in conditions such as critical illness and anorexia (Ganesan, Anastasopoulou and Wadud, 2022).

Further investigations include:

• FBCs, U+Es, CK and lipid profile.
• Antithyroid peroxidase (anti-TPO) and antithyroglobulin antibodies – +ve in Grave’s and Hashimoto’s (Choi et al., 2019).
• TSH receptor antibodies – Found in Grave’s.
• Imaging – Including USS of the thyroid gland and CT / MRI of the pituitary.

Treatment

Treatment depends on the underlying cause of the thyroid dysfunction (Vasileiou et al., 2020):

• Hyperthyroidism – Carbimazole, propylthiouracil, radioactive iodine and surgery (beta-blockers such as propranolol can be used to control symptoms such as the associated tremor or tachycardia).
• Hypothyroidism – Levothyroxine.

Disorders of sodium imbalance

Disorders of sodium imbalance are another exam favourite, which is no surprise, really, given this can be a side effect of many of the psychotropic medications we use. It is, therefore, necessary that we understand the basic pathophysiology behind this. In this section, we’ll cover the syndrome of inappropriate antidiuretic hormone (SIADH), psychogenic polydipsia and diabetes insipidus.

Syndrome of inappropriate antidiuretic hormone (SIADH)

ADH (antidiuretic hormone), also known as vasopressin, is synthesised by the hypothalamus. It is then stored and released by the posterior pituitary. Its release is triggered by a rise in the plasma osmolality, and it acts on the renal collecting ducts to cause an increase in reabsorption of water, thus reducing plasma osmolality and maintaining homeostasis.

In SIADH, there is an inappropriate increase in the amount of ADH released – Either by the posterior pituitary or from elsewhere in the body. This results in an increased and excessive amount of water reabsorption in the kidneys. This acts to cause a further reduction in plasma osmolality whereby there is essentially dilution of the blood – hence the reason why you get hyponatremia.

Causes

There are many causes of SIADH. However, the most common ones you’ll come across in clinical practice are (Hannon and Thompson, 2010):

• Medications – Including SSRIs, TCAs, antipsychotics (including haloperidol), NSAIDs, and carbamazepine.
• Malignancy – Most commonly with small cell lung cancer.
• Infections – Atypical pneumonia, lung abscesses, meningitis, encephalitis and HIV.

Presentation

A majority of the patients with SIADH will be asymptomatic and will only come to your attention following a finding of hyponatremia when reviewing bloods. Patients with hyponatremia may present with the following non-specific symptoms (Yates, Singer and Morton, 2004):

• Headache.
• Lethargy.
• Dizziness.
• Confusion.
• Muscle weakness/cramps.
• Seizures and reduced GCS (in severe cases only).

As with any finding of sodium imbalance on blood investigations, your physical examination will be predominantly focused on assessing fluid status. In SIADH, the patient will be euvolemic. In a euvolemic state, blood pressure will be normal (with no orthostatic hypotension), mucous membranes will be moist, and there will be no peripheral oedema.

Investigations

• Serum U&Es – Sodium is low.
• Paired serum and urinary osmolality – Plasma osmolality low and urine osmolality high (essentially, the plasma is too dilute, and the urine too concentrated).
• Urinary sodium – High.

It is also recommended that adrenal insufficiency is ruled out. The cause of the hyponatraemia may be obvious, especially if any medication changes have been made. Always be mindful of the possibility of underlying malignancy, and perform any further investigations as necessary.

Management

• Stop any medications which could be contributing to hyponatremia.
• SLOW correction of sodium levels in the blood – The aim is for the sodium level in the blood not to increase more than 10 mmol / L in 24 hours (Gross, 2012).
• Discuss with endocrinology – They may suggest a fluid restriction (of around 500mls – 1000mls) or medications such as tolvaptan or demeclocycline. Please note that an infusion of normal saline would not correct the hyponatremia.
• Depending on the severity of the hyponatremia, the patient may require hospitalisation to allow for monitored correction.

Diabetes insipidus

Diabetes insipidus is essentially the opposite of SIADH, where you get a reduction in the available amount of ADH in the body. This may be due to reduced production or due to the kidneys not responding to the ADH. In either case, the renal collecting ducts do not absorb water, leading to a reduction in their ability to concentrate the urine. The patient, therefore, presents with concentrated blood (hypernatremia) and dilute urine (leading to polyuria). In an attempt to correct this, the body increases thirst levels (polydipsia).

Causes

The causes of diabetes insipidus are:

1. Due to issues with the kidneys – Nephrogenic diabetes insipidus.
2. Issues with the brain – Cranial diabetes insipidus.

Nephrogenic diabetes insipidus

The collecting ducts lose the ability to respond to ADH. Causes of this include:

• Medications – Lithium.
• Congenital (Moeller, Rittig and Fenton, 2013) – Mutations to the gene coding for the ADH receptor (AVPR2) – X linked. There can also be a mutation to the AQP2 gene, which is autosomal recessive. This normally encodes for the aquaporin-2 channel, which normally facilitates rapid water transport.
• Renal disease.
• Electrolyte disturbances – Namely hypokalaemia and hypercalcaemia.

Cranial diabetes insipidus

Here, the hypothalamus is the issue – It does not synthesise ADH. Causes include:

• Acquired – Head injuries, cerebral infections (e.g. meningitis) or following brain surgery.
• Tumours – These could be in the brain (e.g. hypothalamic tumours) or elsewhere in the body following metastatic spread.
• Idiopathic.

Presentation

As above, the patient presents with polyuria (including nocturia), polydipsia and hypernatremia.

Depending on the extent of the disease, the patient will either be euvolemic on examination or may show signs consistent with hypovolaemia. These signs include tachycardia, hypotension, dry mucous membranes, and poor capillary refill.

Investigations

The investigations that will be required are (Moeller, Rittig and Fenton, 2013):

• Serum U&Es – Sodium is high.
• Paired serum and urinary osmolality – Plasma osmolality high and urine osmolality low (the plasma is too concentrated, and the urine too dilute – Essentially the opposite of SIADH).
• Other first line tests – FBC, bone profile, plasma glucose and HBa1c (due to the similarity in presentation of diabetes mellitus).

A water deprivation test is also undertaken, where exogenous ADH is administered after a period of absolute fluid restriction. The osmolality of the urine is measured after the fluid restriction and again after the administration of the synthetic ADH. The following is seen (Gubbi et al., 2022):

Nephrogenic diabetes insipidus

• Baseline – Low urine osmolality.
• Post-water restriction – Low urine osmolality
• Post-ADH administration – Low urine osmolality is low – This is because the kidneys are unable to respond to the ADH.

Cranial diabetes insipidus

• Baseline – Low urine osmolality.
• Post-water restriction – Low urine osmolality.
• Post-ADH administration – High urine osmolality – As the kidneys are functioning normally and so can respond to the exogenous ADH – Can act to concentrate the urine.

Here, it is worth mentioning psychogenic polydipsia, also known as primary polydipsia (Kotagiri and Sridharan, 2022). There is normal production of ADH by the hypothalamus and a normal response by the renal system, but there is an excess consumption of fluid (which can be fatal). In psychogenic polydipsia, nocturia is rare. During the water deprivation test, you will see:

• Baseline – Low urine osmolality.
• Post-water restriction – High urine osmolality (therefore, no need to progress with the test).

Management

As always, treat the underlying cause. In most mild cases, no further treatment is needed. Sometimes, desmopressin (Kapić , Becić, and Todić, 2002) can be used for both cranial and nephrogenic (at high doses) causes. Primary polydipsia is managed with fluid restriction.