We optometrists hear the word ‘diabetes’ on a daily basis but how many times do we get to see patients with diabetes insipidus? Diabetes mellitus is fairly common condition with three million UK sufferers of type 2 diabetes.
Diabetes insipidus is rare, occurring in just 1 in 25,000 patients per year, so 3,000 UK insipidus sufferers as opposed to three million diabetes mellitus sufferers. Diabetes is derived from the Greek word ‘diabainain’ meaning standing with legs apart like a drawing compass, relating to the adopted stance associated with excessive urination.
Diabetes insipidus relates to the production of urine that is insipid, with no smell or taste. Diabetes mellitus, on the other hand, describes excessive sugar in the urine. Both conditions lead to drinking excessive fluid (polydipsia) and passing of excessive urine (polyuria), but the volume of urine produced in diabetes insipidus is much more excessive than in diabetes mellitus.
The simple way to differentiate diabetes mellitus from insipidus is a urine test, which will reveal a high concentration of glucose in the diabetes mellitus patient. This article will describe the presentation of each of these conditions in patients with differing underlying pituitary gland problems.
Case 1
A 47-year-old female patient complained to her general practitioner that she was very, very thirsty and drinking lots of fluid throughout the day (four litres or more), She also reported that she was having to empty her bladder very frequently.
Furthermore, she was losing weight and noticed she had a poor appetite. Blood tests were undertaken and proved negative for diabetes mellitus. The patient was referred to an endocrinologist who undertook a battery of blood tests as well an MRI scan. The results were as follows:
- Pituitary gland appeared normal – there was no enlargement of the pituitary gland and no mass within the pituitary gland.
- Pituitary stalk appeared thickened (figure 1) – diffuse thickening was found, with the superior portion at the level of the optic chasm thickened to 6.2mm (normal thickness is no more than 4.4mm) while the inferior portion as it enters the pituitary gland was 3.6mm thick (normal no more than 2.7mm).
- Sodium, potassium, chloride, bicarbonate, urea and creatinine levels were all normal.
- Somatomedin-C (IGF-1) level was low, at 2.6nmol/l ( normal levels are 12.6 to 35.5 nmol/l). This implies that the pituitary is not producing a normal amount of insulin-like growth factor (IGF-1). The test is usually undertaken for malnourished patients or those with stunted development or short stature (reduced IGF-1) or gigantism (raised IGF-1).
- Low urine osmolarity of 76 mOsmol/Kg was found. This could indicate diabetes insipidus or water diuresis (excretion of urine after drinking water).
- Endocrinology tests – normal levels of follicle stimulating hormone, luteinising hormone, prolactin and cortisol were found. Thyroid stimulating hormone (TSH) level was high at 5.87 mIU/L (normal range 0.27 to 4.2 mIU/L). Elevated TSH levels indicate an underactive thyroid gland (hypothyroidism) and could be due to a pituitary tumour or Hosimoto thyroiditis. Low TSH levels (hyperthyroidism) indicate an overactive thyroid with Graves disease a common cause.
Diagnosis
Low IGF-1, low urine osmolarity and elevated TSH would point towards a pituitary gland problem and in particular diabetes insipidus.
A thickened pituitary stalk seen on MRI scan in a patient with diabetes insipidus would commonly be caused by an autoimmune inflammation, lymphocytic hypophysitis, the rare malignant stalk tumour known as a stalk germinoma, granulomatosis or neurosarcoidosis.
Further blood tests were planned to rule out autoimmune disease, along with chest X-rays (screening for granulomatous disease such as sarcoidosis). Alpha-fetoprotein (AFP) and beta human chorionic gonadotropin (Beta-HCG) marker levels in the serum and cerebrospinal fluid were assessed to rule out a germinoma.
A fluorodeoxy-glucose tracer and a positron emission topography (PET) scan was used to look for increased tracer uptake by the pituitary stalk as would be found in patients with a pituitary germinoma.
Fortunately, no tumour, inflammatory disease or granulomatosis was detected after the various tests.
A diagnosis of atypical thickened pituitary stalk and diabetes insipidus was made. Treatment was with desmopressin nasal spray and thyroxine for the underactive thyroid. The patient was reminded to drink to thirst and avoid excessive or binge drinking to avoid hyponatraemia (abnormally low levels of sodium in the blood) and its associated health problems.
Diabetes insipidus
The posterior pituitary releases two hormones, oxytocin and antidiuretic hormone (ADH). Oxytocin acts on the smooth muscles of the uterus leading to contract during and after birth. ADH controls urine production as explained in figure 2.
Figure 2: Exercise and water loss through sweating, urination or dehydration through other mechanisms leads to an increase in plasma osmolarity which is detected by the hypothalamus. An anti-diuretic hormone (ADH) is produced by the hypothalamus and stored in the posterior pituitary gland (upper figure). It is released into the bloodstream in response to the osmolarity increase. ADH binding sites on the kidneys are shown in lower figure
Increased plasma ADH levels has the following effects;
- Thirst and subsequent water intake.
- Action on sweat glands leading to reduced sweating and increased plasma volume.
- Action on blood vessels causing vasoconstriction and subsequent increased blood pressure and blood plasma volume.
- Binding to receptors on distal convoluted tubules of the kidneys. Aquaporin-2 channels are activated, leading to aquaporin insertion into the nephron-collecting duct cells and opening the ‘floodgates’ to let water flow into the blood, so increasing blood volume and decreasing osmolarity. Retained water results in a decrease in urine volume and an increase in the concentration of the urine excreted.
- Reduced blood serum osmolarity is detected by the hypothalamus resulting in decreased ADH release.
- This cycle continues to maintain homeostasis.
In normal individuals, maintenance of homeostasis relies on the intake of one to two litres of water daily through drinking, and another 1.2 litres through food and metabolic production. Output of water is via the urine, stools, sweat and exhalation.
Diabetes insipidus is characterised by the excessive production of dilute, hypotonic urine (osmolarity less than 300 mOsmol /kg), of a volume typically greater than three litres a day. Urine excretion can be frequent, every half an hour, and to compensate there is excessive thirst and the urge to drink.
Urine output may range from two litres per day with mild diabetes insipidus to over 15 litres per day in patients with severe diabetes insipidus. In some patients, volume of urine excreted may be as high as 20 litres over 24 hours, leading to severe dehydration and, if untreated, hypernatraemia (serum sodium levels over 145mmOl/litre) may develop and prove fatal without medical intervention.
Figure 3: In cranial diabetes insipidus, damage to the pituitary gland results in reduced ADH output (upper image). In nephrogenic diabetes insipidus, the kidneys fail to respond to ADH (lower image) resulting in reduced urine production regulation. In both cases, there is excessive production of dilute urine at an increased frequency, and increased thirst in an attempt to compensate for the increased water loss
Diabetes insipidus pathophysiology is explained by figure 3 and can be divided into two types:
- Cranial – the most common type whereby there is damage to the hypothalamus or pituitary gland so that not enough ADH is produced to regulate urine production.
- Nephrogenic – there is enough ADH produced by the posterior pituitary but the kidneys, either through damage or inherited disorders, fail to respond to the hormone.
Symptoms of diabetes insipidus include:
- Excessive thirst, with a desire for ice cold water.
- Excessive urination.
- Nocturia – waking up multiple times in the night to urinate.
- Dehydration symptoms of dizziness, blurred vision, headaches, fainting and dry mouth.
Signs include:
- Low blood pressure.
- Dilute urine.
- Reduced capillary fill time.
Neurogenic diabetes insipidus has a number of possible causes:
- Tumours – pituitary adenomas (20%), craniopharyngiomas and metastatic tumours.
- Trauma – head trauma (17%).
- Neurosurgery – 9% of cases.
- Infections – such as meningitis.
- Vascular – Sheehan’s syndrome is a complication of pregnancy in which the pituitary blood supply is reduced causing necrosis of the pituitary gland.
- Sarcoidosis – this results in granuloma formation within the pituitary.
- Haemochromatosis – deposition of iron in pituitary and hypothalamus causing impaired function.
- Langerhan’s cell histiocytosis – proliferation of Langerhan’s cells forming lesions in many organs including pituitary stalk.
Twenty-five percent of cases are idiopathic. Nephrogenic insipidus results from damage to the kidney causing problems with reabsorption of fluid. Some cases are inherited, with familial insipidus including X-linked recessive disease, where there is a mutation in the ADH receptor gene results in inadequate production. A faulty aquaporin 2 gene may be inherited as a recessive trait.
In some cases, diabetes insipidus is a secondary condition, as with the following:
- Metabolic disorders, including hypercalcaemia, hyperglycaemia and hypokalaemia (high serum potassium)
- Drugs – lithium and demeclocycline may interfere with the binding of ADH.
- Chronic renal disease, such as polycystic kidneys.
- Amyloidosis.
- Gestational diabetes insipidus – is caused by the placenta during pregnancy producing vasopressinase, an enzyme which breaks down vasopressin (an alternative name for ADH).
Treatment is not always necessary, and mild diabetes insipidus may be managed by increasing the amount of water drunk to compensate for the fluid lost through urination. In cranial diabetes insipidus, with marked symptoms, desmopressin (a synthetic ADH) may be taken as oral tablets, nasal spray, or via sub-cutaneous or intravenous routes.
In nephrogenic diabetic insipidus, desmopressin is ineffective so hydrochlorothiazide (a thiazide diuretic) is prescribed and, in diabetes insipidus cases, it leads to urine retention. Amiloride and hydrochlorothiazide (Moduretic) may be used to lower blood pressure and reduce oedema. Amiloride also minimises potassium loss.
Case 2
A 62-year-old female presented with a history of numerous bronchial problems and chest infections from the early 1990s but with no obvious cause for the problems having been established. In 1995, she developed an enlarged thyroid with a number of separate growths within the gland. Multinodular goitre was the diagnosis and she was treated with radioactive iodine. In 2001, aged 49, the patient was under the care of an endocrinologist when she developed the following:
- Elevated blood pressure.
- Huge increase in fat around the waistline and on the face.
- Bruising and thinning of the skin.
- Loss of libido.
The patient was also much smaller in stature than would be normal for her age. After exhaustive tests she was diagnosed with Cushing’s disease. The symptoms were typical of Cushing’s syndrome. An MRI scan showed a left pituitary microadenoma (figure 4) and the cause of the symptoms was increased production of the hormone cortisol.
Figure 4 (a) – Right pituitary microadenoma (red arrow) contained within the sella turcica. Note the black round holes representing the internal carotid arteries either end of the sella turcica. (b) – Right pituitary microadenoma removed. The purple arrow indicates remnants of the pituitary on the left side of the sella turcica. (c) – Note the empty sella turcica seen in sagittal scan following loss of pituitary tissue (red lines)
Concurrent with the increase in waist line was impaired insulin action (type 2 diabetes mellitus), so she was prescribed metformin tablets to treat this.
In September 2001, trans-sphenoidal surgery was undertaken to remove the right pituitary tumour (measured as less than 1cm) contained within sella turcica. The patient subsequently developed pan hypopituitarism. Figure 4b shows no remnant of right pituitary adenoma and an intact infundibulum with no sphenoid or cavernous sinus involvement.
In October 2001 the patient was admitted to hospital as an emergency, complaining of back pain, excessive weakness and confusion. A diagnosis of Addison’s crisis was made and explained by very low cortisol levels. She was immediately given hydrocortisone injections to address the crisis.
Figure 5: Hormones released from the posterior pituitary
In 2004, she underwent lengthy tests to ascertain her eligibility for adult growth hormone treatment and eventually was given somatropin subcutaneous injections in 2005.
By 2015, she had pan-hypopituitarism following removal of the pituitary tumour and impairment of hormone production by the pituitary. Her medication is listed as follows:
- Hydrocortisone – steroid hormone to manage a deficiency of ACTH hormone.
- Metformin – diabetes medication.
- Levothyroxine – for an underactive thyroid resulting from a deficiency of TSH hormone.
- Ramipril – blood pressure medication.
- Aspirin – as an anti-coagulant.
- Simvastatin – anti-cholesterol.
- Drospirenone with estradiol – birth control and post menopausal therapy, in this case to counter the deficiency of LH hormone.
- Fluoxetine – an antidepressant.
- Somatropin injections daily – for the deficiency of adult growth hormone.
- Protopic ointment 0.03% – to treat severe atopic dermatitis.
- Eflornithine cream 60mg – to treat excess facial hair caused by excess cortisol in the blood stream.
Cushing’s Disease and Cushing’s Syndrome
Cushing’s syndrome and Cushing’s disease are both conditions that occur when the body produces too much cortisol. Cushing’s disease is one cause of Cushing’s syndrome rare, affecting 10 to 15 people per million per year, typically adults between the age of 20 and 50 years.
It is three times more common in women than in men and occurs when a tumour on the pituitary gland causes the gland to produce too much ACTH, the hormone responsible for cortisol production. Too much ACTH in the system makes the adrenal glands produce cortisol in high levels. Cushing’s disease can also occur with excess growth of the pituitary gland.
Cushing’s syndrome is the impact of excess cortisol and often develops as a side effect of treatment with corticosteroids used to treat inflammatory and autoimmune conditions.
A tumour of the pituitary gland affects production of hormones by the anterior and posterior pituitary. Table 1 summarises the hormones produced by the anterior pituitary giving rise to pan hypopituitarism a condition of adequate or absent production.
Table 1: Summary of hormones released from the pituitary gland
Cushing’s syndrome is often associated with obesity and high blood pressure. Weight gain, excess fat around the face and abdomen, thinning of skin that bruises easily, decreased libido and short stature are characteristics of the syndrome. Henry VIII was thought by some historians to have suffered from Cushing’s disease, having a weight estimated to be 300lbs and a waistline of 52 inches.
Cushing’s disease results from pituitary adenomas which arise in the pituitary/sellar region. They are often asymptomatic and are classified as either endocrine-active or endocrine-nonactive adenomas.
Endocrine-nonactive tumours do not cause hypersecretion of hormones but their growth can cause visual loss (typically heteronymous field loss) due to their impact upon the optic nerve or chiasma, headaches and symptoms of hypopituitarism.
Endocrine-active tumours are two times more likely to occur and vary according to the hormones that are hypersecreted, for example ACTH hypersecretion in Cushing’s disease, GH hypersecretion resulting in acromegaly, and TSH resulting in an enlarged thyroid gland (or goitre).
Pathology of Diabetes Mellitus In Cushing’s Disease
In Cushing’s disease, diabetes mellitus may present as a consequence of glucocorticoid excess and an impairment of glucose metabolism in the liver and skeletal muscles. Glucocorticoid describes a corticosteroid, such as cortisol and cortisone, and is secreted by the adrenal glands. They are essential for the metabolism of carbohydrates, proteins and fats by the body. Steroids may lead to excess glucose in the blood leading to steroid-induced diabetes mellitus.
An excess of glucocorticoid indirectly stimulates the expression of several key enzymes with a resultant increase of glucose production. Glucocorticoid excess also stimulates the breakdown of lipids and proteins and this contributes to development of resistance to insulin. Glucocorticoid excess directly impairs insulin secretion through its action on pancreatic beta cells.
Addison’s Crisis
Addison’s crisis is a serious medical emergency caused by low levels of the important stress hormone cortisol normally produced by the adrenal gland. The lack of this ‘fight or flight’ hormone causes back pain, extreme weakness, diarrhoea, confusion, vomiting, dehydration and a significant drop in blood pressure. If left untreated, the crisis can lead to severe shock, seizure or coma. Treatment is an immediate sub-cutaneous injection of hydrocortisone.
Conclusion
I hope through these two distinct cases to have clarified the different nature of diabetes insipidus from mellitus and emphasised the delicate inter-relationship between hormones in the normal working of the human body.
Kirit Patel is an optometrist in independent practice in Radlett, Hertfordshire.