Endocrinology: CAH; DMT1 Flashcards
Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders characterised by enzyme deficiencies in the steroidogenesis pathway of the adrenal cortex.
The most common form involves [1] , which impairs [2] synthesis
Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders characterised by enzyme deficiencies in the steroidogenesis pathway of the adrenal cortex.
The most common form involves 21-hydroxylase deficiency, which impairs cortisol and aldosterone synthesis.
- this results in increased ACTH secretion and and overproduction of steroid precursors.
- Accumulation of 17-hydroxyprogesterone occurs due to blocked conversion to 11-deoxycortisol.
- Excess 17-hydroxyprogesterone is diverted towards androgen synthesis, resulting in elevated levels of androstenedione and testosterone.
- This androgen excess causes virilisation in females and early virilisation or precocious puberty in males.
Chronic ACTH release also causes adrenal hyperplasia
Describe the presentation of mild [2] and severe CAH [2]
Milder:
- may remain undiagnosed until later in life when symptoms such as premature pubarche, hirsutism, oligomenorrhoea, or infertility become apparent due to high androgen levels
Severe:
- ambiguous genitalia in females and salt-wasting crises in both sexes - presenting with hyponatraemia, hyperkalaemia and hypoglycaemia
- This leads to: poor feeding, D&V and arrhythmias
TOM TIP: A textbook and exam clue that a patient has CAH is skin hyperpigmentation.
- Hyperpigmentation occurs because the anterior pituitary gland responds to the low levels of cortisol by producing increasing amounts of ACTH. A byproduct of the production of ACTH is melanocyte simulating hormone. This hormone stimulates the production of melanin (pigment) within skin cells.
Describe how CAH is managed
Management will be coordinated by specialist paediatric endocrinologists. They will be followed up closely for their growth and development. Treatment involves:
Cortisol replacement, usually with hydrocortisone, similar to treatment for adrenal insufficiency
Aldosterone replacement, usually with fludrocortisone
Female patients with “virilised” genitals may require corrective surgery
CAH:
Genetic Testing: Genetic testing can provide definitive confirmation of the diagnosis by identifying mutations in the [] gene that are responsible for more than 90% of CAH cases.
Biochemical Evaluation: This involves assessing the levels of [], which is typically elevated in CAH due to 21-hydroxylase deficiency.
- A baseline early morning level of [] greater than [] nmol/L is suggestive of CAH. In cases where the result is borderline, an ACTH stimulation test may be necessary to confirm the diagnosis.
Genetic Testing:
Genetic testing can provide definitive confirmation of the diagnosis by identifying mutations in the CYP21A2 gene that are responsible for more than 90% of CAH cases.
Biochemical Evaluation:
- This involves assessing the levels of 17-hydroxyprogesterone (17-OHP), which is typically elevated in CAH due to 21-hydroxylase deficiency.
- A baseline early morning level of 17-OHP greater than 30 nmol/L is suggestive of CAH. In cases where the result is borderline, an ACTH stimulation test may be necessary to confirm the diagnosis.
What are key ddx for CAH? [3]
Androgen Insensitivity Syndrome (AIS)
Turner Syndrome
Pituitary Adenoma
How do you differentiate CAH from Androgen Insensitivity Syndrome (AIS)?
- Clinical presentation
- Hormonal proflife
Clinical Presentation:
- Patients with complete AIS typically present with female external genitalia despite having a 46,XY karyotype. Individuals may have undescended testes and lack Müllerian structures such as the uterus and fallopian tubes. Partial AIS can result in ambiguous genitalia.
Hormonal Profile:
- Elevated levels of luteinising hormone (LH) and testosterone are common due to impaired androgen action. Unlike CAH, there is no elevation in 17-hydroxyprogesterone.
How do you differentiate CAH from Turner’ syndrome?
- Clinical presentation
- Hormonal proflife
Clinical Presentation:
- Phenotypically female individuals often exhibit short stature, webbed neck, low-set ears, and primary amenorrhoea due to ovarian dysgenesis.
- They do not display virilisation or ambiguous genitalia typical of CAH.
Hormonal Profile:
- Gonadotrophins (LH and follicle-stimulating hormone [FSH]) are elevated due to gonadal failure. Unlike CAH, there is no evidence of adrenal hyperandrogenism or elevated 17-hydroxyprogesterone levels.
How do you differentiate CAH from Pituitary adenoma
- Clinical presentation
- Hormonal proflife
Clinical Presentation:
- Symptoms vary based on the hormonal activity of the adenoma.
- For example, corticotroph adenomas cause Cushing’s disease characterised by central obesity, moon face, hypertension, and skin changes.
- Gonadotroph adenomas may lead to menstrual irregularities but do not cause virilisation or ambiguous genitalia seen in CAH.
Hormonal Profile:
- Hormone secretion profiles differ based on tumour type but do not show elevated 17-hydroxyprogesterone as seen in CAH. Imaging studies often reveal an enlarged pituitary gland or mass effect symptoms such as headaches and visual disturbances.
The management of CAH depends on the severity experienced through enzyme deficiency.
Describe how you would treat patients? [2]
Adrenal insufficiency
- immediate medical intervention with intravenous hydrocortisone and fluid resuscitation.
Aldosterone replacement, usually with fludrocortisone
T1DM is most commonly a type [] hypersensitivity autoimmune reaction, in which CD4+ T helper cells and CD8+ cytotoxic T cells attack pancreatic beta cells, eventually eliminating any insulin production.
T1DM is most commonly a type IV hypersensitivity autoimmune reaction, in which CD4+ T helper cells and CD8+ cytotoxic T cells attack pancreatic beta cells, eventually eliminating any insulin production.
Describe the typical presentation of DMT1 in children
About 25 – 50% of new type 1 diabetic children present in diabetic ketoacidosis (DKA). This is the result of a situation where the pancreas can no longer produce enough insulin to maintain basic blood glucose regulation:
* Polyuria
* Polydipsia
* Nausea and vomiting
* Weight loss
* Acetone smell to their breath
* Dehydration and subsequent hypotension
* Altered consciousness
* Symptoms of an underlying trigger (i.e. sepsis)
The remaining paediatric patients present with the classic triad of symptoms of hyperglycaemia:
* Polyuria (excessive urine)
* Polydipsia (excessive thirst)
* Weight loss (mostly through dehydration)
Further symptoms include:
* secondary enuresis
* recurrent infections
When a new diagnosis of DMT1 is established the following bloods should be taken to exclude other associated pathology and get a baseline idea of the child’s overall health [6]
Baseline bloods including FBC, renal profile (U&E) and a formal laboratory glucose
Urine testing: Glucosuria and ketonuria
Blood cultures should be performed in patients with suspected infection (i.e. with fever)
HbA1c can be used to get a picture of the blood sugar over the previous 3 months. This gives an idea of how long they have been diabetic prior to presenting.
Thyroid function tests and thyroid peroxidase antibodies (TPO) to test for associated autoimmune thyroid disease
Tissue transglutaminase (anti-TTG) antibodies for associated coeliac disease
Insulin antibodies, anti-GAD antibodies and islet cell antibodies to test for antibodies associated with destruction of the pancreas and the development of type 1 diabetes
What would c-peptide levels be like a child w new DMT1? [1]
C-peptide measurement: C-peptide is co-released with insulin from beta cells in pancreas. Low levels of C-peptide (< 0.6 ng/mL) along with hyperglycaemia suggest type 1 diabetes due to beta-cell destruction.
Although - note image (from NICE)
What are the dx criteria for DTM1? [4]
Random plasma glucose level ≥11.1 mmol/L (≥200 mg/dL) in the presence of symptoms of hyperglycaemia;
OR
Fasting plasma glucose ≥7.0 mmol/L (≥126 mg/dL);
OR
Plasma glucose level ≥11 mmol/L (≥200 mg/dL) 2 hours after a 75 g oral glucose load;
OR
HbA1c ≥48 mmol/mol (≥6.5%) - note that HbA1c can be unreliable if a patient has any concurrent condition affecting red blood cell survival.
Describe the long term management of DMT1
Insulin
- usually prescribed as a combination of a background, long acting insulin given once a day, and a short acting insulin injected 30 minutes before the intake of carbohydrates (i.e. at meals). This is termed basal (long acting - Lantus), bolus - typically given in evening and shorting acting (Actrapid) usually 3xday
- insulin pump: continuously infuse insulin at different rates to control blood sugar levels.
Encourage young people with type 1 diabetes to attend clinic 4 times a year, and explain that regular contact with the diabetes team will help them maintain optimal blood glucose levels.
Explain to children and young people with type 1 diabetes and their families or carers that, like people without diabetes, they should have:
- regular dental examinations
- an eye examination by an optician at least every 2 years
Encourage children and young people with type 1 diabetes to wear or carry something that tells people they have type 1 diabetes (for example, a bracelet)
Immunisations:
* annual immunisation against influenza, starting when they are 6 months old
* immunisation against pneumococcal infection if they are taking insulin or oral hypoglycaemic medicines
What are glucose monitoring target ranges? [3]
fasting plasma glucose level of 4 mmol/litre to 7 mmol/litre on waking
a plasma glucose level of 4 mmol/litre to 7 mmol/litre BEFORE meals at other times of the day
a plasma glucose level of 5 mmol/litre to 9 mmol/litre AFTER meals
What are typical features of hypoglycaemia?
hunger
tremor
sweating
irritability
dizziness
pallor
More severe hypoglycaemia will lead to reduced consciousness, coma and death unless treated.
The child w DMT1 is be sweaty overnight. What is the most likely cause? [1]
Nocturnal hypoglycaemia
- Morning blood glucose levels may be raised.
1 unit of novorapid reduces their sugar level by around [?] mmol/l
1 unit of novorapid reduces their sugar level by around 4 mmol/l
Describe what is meant by Kartagner’s syndrome [1]
an autosomal recessive condition affecting the cilia of various cells in the body.
- Dynein arm defect results in immotile cilia
Kartagner’s triad describes the three key features of PCD. Not all patients will have all three features. These are: [3]
Paranasal sinusitis
Bronchiectasis
Situs Inversus
Describe the clinical significance of sinitus invertus [1]
Situs inversus on its own does not cause any problems, and patients can expect to live a normal life. A small number have associated congenital heart disease, such as transposition of the great arteries.
NB: Dextrocardia is when only the heart is reversed.
Describe the dx of PCD [3]
Patients typically present with recurrent respiratory tract infections. Take a careful family history and a history of consanguinity in the parents.
Examination and imaging (e.g. chest xray) can be used to diagnose situs inversus. Semen analysis can be used to investigate for male infertility.
The key investigation for establishing the diagnosis is to take a sample of the ciliated epithelium of the upper airway and examine the action of the cilia. A sample can be obtained through nasal brushing or bronchoscopy. Often several samples are required.
What questions do you need to ask about the parents of a patient with PCD ? [1]
It is more common in populations where there is consanguinity, meaning the parents are related to each-other. Consanguinity increases the risk of a child having two copies of the same recessive genetic mutation.
Describe the management of Kartagener’s syndrome
Chest physiotherapy:
- Regular chest physiotherapy is essential to promote clearance of bronchial secretions. Techniques such as postural drainage and percussive techniques may be beneficial.
Bronchodilators:
- These medications can help to widen the airways and make it easier for patients to breathe. Short-acting beta2-agonists (SABAs) or long-acting beta2-agonists (LABAs) can be used depending on the severity of symptoms.
Antibiotics:
- Prophylactic antibiotics may be considered in patients with frequent exacerbations. When infections do occur, they should be treated promptly with appropriate antibiotics targeting potential organisms such as Pseudomonas aeruginosa and H. influenzae.
Mucolytic agents:
- Medications like N-acetylcysteine can help to thin mucus in the lungs, making it easier for patients to cough up.
Sinus management:
- Regular nasal irrigation with saline solution can help manage sinus symptoms.
- Topical corticosteroids may also be beneficial.
Surgical interventions:
- In severe cases where medical management has failed, surgical interventions such as lobectomy or bronchiectasis may be considered. Sinus surgery might also be needed for chronic sinusitis unresponsive to medical treatment.
Which vaccinations are rec. for Kartagener’s syndrome? [2]
In addition to these specific measures, regular vaccinations against respiratory pathogens including influenza and pneumococcus are recommended
. Nutritional support may also be required due to increased energy demands from chronic lung disease.
Describe the pathophysiology of adrenal insufficiency (in children) [1]
Describe the differences between primary, secondary and tertiary causes of adrenal insuffiencys
Adrenal insufficiency is where the adrenal glands do not produce enough steroid hormones, particularly cortisol and aldosterone. Steroids are essential for life. Therefore, the condition is life threatening unless the hormones are replaced.
Addison’s disease - primary adrenal insufficiency refers a the specific condition where the adrenal glands have been damaged, resulting in reduced secretion of cortisol and aldosterone. The most common cause is autoimmune.
Secondary adrenal insufficiency
- is a caused by inadequate ACTH stimulating the adrenal glands, resulting in low levels of cortisol being released.
- This is the result of loss or damage to the pituitary gland. This can be due to congenital underdevelopment (hypoplasia) of the pituitary gland, surgery, infection, loss of blood flow or radiotherapy.
Tertiary adrenal insufficiency
- is the result of inadequate CRH release by the hypothalamus.
- This is usually the result of patients being on long term oral steroids (for more than 3 weeks) causing suppression of the hypothalamus.
- When the exogenous steroids are suddenly withdrawn the hypothalamus does not “wake up” fast enough and endogenous steroids are not adequately produced.
Desribe the role of aldosterone receptors [1]
Aldosterone causes sodium to be absorbed and potassium to be excreted into the lumen by principal cells
Describe the features of adrenal insufficiency in babies [5] and older children [+]
Features in Babies
* Lethargy
* Vomiting
* Poor feeding
* Hypoglycaemia
* Jaundice
* Failure to thrive
Features in Older Children
* Nausea and vomiting
* Poor weight gain or weight loss
* Reduced appetite (anorexia)
* Abdominal pain
* Muscle weakness or cramps
* Developmental delay or poor academic performance
* Bronze hyperpigmentation to skin in Addison’s caused by high ACTH levels. ACTH stimulates melanocytes
How would U&Es [2] and glucose [1] in adrenal insufficiency present?
All children with suspected adrenal insufficiency should have U&Es (hyponatraemia and hyperkalaemia) and blood glucose (hypoglycaemia) levels checked.
Mx of adrenal insufficiency?
- Medications [2]
- Follow ups [6]
Hydrocortisone is a glucocorticoid hormone used to replace cortisol.
Fludrocortisone is a mineralocorticoid hormone used to replace aldosterone if aldosterone is also insufficient
Patients should be followed up by a specialist paediatric endocrinologist and have an individual care plan. They are monitored closely for:
* Growth and development
* Blood pressure
* U&Es
* Glucose
* Bone profile
* Vitamin D
What might be the first presentation of Addision’s in children? [1]
Describe how this would present [5]
Addisonian crisis:
* Reduced consciousness
* Hypotension
* Hypoglycaemia, hyponatraemia and hyperkalaemia
Triggered by infection / trauma / stress
Management of Addisonian Crisis (in children) [5]
- Intensive monitoring if they are acutely unwell
- Parenteral steroids (i.e. IV hydrocortisone)
- IV fluid resuscitation
- Correct hypoglycaemia
- Careful monitoring of electrolytes and fluid balance
