Depression and lethargy: A latent endocrine problem?

Case study introduction

A 14.3-year-old girl presents to her GP with depression, lethargy, not paying attention at school, and being socially withdrawn. Her parents are worried as she was previously a bright, bubbly girl, with lots of friends.

You start by taking a history from the family and ask questions about how the girl is feeling:

  • Lack of energy?
  • Sleep?
  • Dizziness or fainting?
  • Appetite?
  • Nausea, stool frequency and other gastrointestinal symptoms?
  • Urinary symptoms?

Read the patient information and answer the questions below.

  • Achieved menarche aged 12 years
  • She has not had a period for 4 months ago, prior to this her periods were regular
  • Doing well at school until the past 3 months
  • Recently losing interest in school, wants to sleep when comes home
  • Lost appetite and around 3 kg in weight
  • Usually enjoys netball but has stopped going to her club
  • Parents report she has low mood
Previous history
  • Born at 38 weeks’ by planned Caesarean section
  • Birth weight 3.2 kg
  • Up to date with immunisations
  • No problems developmentally
  • Born in UK to an Afro-Caribbean family
  • Has an older sister doing her GCSEs, clinically well
  • Non-consanguineous parents
  • Family history of autoimmune disease – mother has autoimmune hypothyroidism, father has type 1 diabetes

Question 1.

What is the first step?

  • Refer to Child and Adolescent Mental Health Services (CAMHS)
  • Refer to a psychologist
  • Make a meeting with the school
  • Undertake a physical examination
  • Refer to a dietitian

Undertake a physical examination
After taking the history and examination, the first steps must be to do basic general paediatric tests


Question 2.

Which of the following physical examinations are essential at this point?

  • Auxology 
  • Abdominal assessment
  • Thyroid assessment
  • Gynaecological examination
  • Blood pressure
  • Auxology 
  • Abdominal assessment
  • Thyroid assessment
  • Blood pressure

Gynaecological examination in younger girls need to be treated with care, and only undertaken if absolutely necessary by the relevant individual with consent.

On examination, your findings are:


  • Height – 165.0 cm (0.674 SDS)
  • Weight – 42 kg (–1.318 SDS)
  • BMI – 15.4 kg/m2 (–2.16 SDS)

Clinical examination

  • Cardiovascular, respiratory, abdominal and neurological examinations: normal.
  • No cyanosis or clubbing
  • No oral ulcers or candidiasis
  • Clinically euthyroid with no palpable goitre
  • Blood pressure – 102/70 mmHg
  • Possible pigmentation of gums

Question 3.

Which initial biochemical investigations would you want to undertake?

  • Full blood count
  • Erythrocyte sedimentation rate (ESR)
  • Urea and electrolytes (U&E)
  • Blood glucose
  • HbA1c
  • Full blood count
  • ESR
  • U&E
  • Blood glucose
  • HbA1c
Results of these were as follows:
  • Full blood count – normal
  • ESR – 5 mm/hour
  • U&E
    • Sodium 130 mmol/L (normal range [NR] 133–146 mmol/L)
    • Potassium 5.7 mmol/L (NR 3.5–5.3 mmol/L)
    • Chloride 99 mmol/L (NR 95–108 mmol/L)
    • Urea 4.2 mmol/L (NR 2.5–6.5 mmol/L)
    • Creatinine 45 µmol/L (NR 40–68 µmol/L)
  • Blood glucose
    • 6 mmol/L (NR 3.5–11)
  • HbA1c:
    • 25 mmol/L (NR <42 mmol/L)

Low sodium and high potassium with normal creatinine and renal function need further investigation and are suggestive of adrenal insufficiency. Liver function tests are normal. Requires urgent referral to a paediatric endocrinology clinic.

Question 4.

What endocrine tests should be performed?

  • Thyroid function tests
  • Cortisol and adrenocorticotrophic hormone (ACTH)
  • IgA anti-tissue transglutaminase antibodies
  • Luteinising hormone (LH) and follicle-stimulating hormone (FSH)
  • Thyroid function tests
  • ACTH
  • IgA anti-tissue transglutaminase antibodies
  • LH and FSH


    • Thyroid function tests
      • FT4: 20.1 pmol/L (NR 10.5–24.5 pmol/L)
      • TSH: 5.5 mU/L (NR 0.27–4.2 mU/L)
    • Cortisol and ACTH
      • Cortisol 80 nmol/L (NR 140–690 nmol/L)
      • ACTH – 1898 ng/L (NR <50 ng/L)
    • IgA anti-tissue transglutaminase antibodies
      • Negative
    • LH and FSH
      • LH 5.1 IU/L (14–17 years: <0.02–16.7 IU/L)
      • FSH 7.8 IU/L (>10 years–15 years: 0.9–8.9 IU/L)


    Low 09.00 h cortisol is consistent with primary adrenal insufficiency and loss of cortisol circadian rhythm. High ACTH supports this diagnosis. The low sodium and high potassium also indicate a degree of mineralocorticoid deficiency. Thyroid function is normal.

Question 5.

What other adrenal function investigations would you now undertake?

  • 17-hydroxyprogesterone (17-OHP) 
  • Synacthen test
  • Low-dose dexamethasone suppression test
  • Urine steroid profile
  • 24-hour urine collection
  • Plasma-renin activity 
  • Aldosterone
  • Adrenal cortex antibodies
  • Adrenals ultrasound
  • Further physical examination
  • 17-OHP
  • Synacthen test
  • Plasma-renin activity 
  • Aldosterone
  • Adrenal cortex antibodies
  • Further physical examination

Results of investigations

  • – 17-OHP – 2.0 nmol/L (NR <10 nmol/L)

    Synacthen test

    Time (min)




    Cortisol (nmol/L)




    Normal response will be a peak serum cortisol level of ⩾ 500 nmol/L

    ACTH – 1898 ng/L (NR <50 ng/L)
    – Na – 131 mmol/L
    – K – 5.5 mmol/L

    – Plasma-renin activity –  7 nmol/L per hour (NR 0.5–3.5 nmol/l/hr)     

    – Aldosterone – 100 pmol/L (NR Supine 150–550 pmol/L, Upright 250–950 pmol/L)

    – Adrenal cortex antibodies

                – Positive adrenal cortex antibody (anti-21-hydroxylase and anti-17-alpha hydroxylase antibodies)

    Further physical examination finds pigmented palmar creases and pigmented gums.

Question 6.

What is the definitive diagnosis?
-Addison’s disease

The most common type of primary adrenal insufficiency in childhood is 21-hydroxylase deficiency congenital adrenal hyperplasia. However, the normal 17-OHP level and the positive adrenal cortex antibodies lead to the diagnosis of Addison’s disease. Mineralocorticoid deficiency is confirmed with the high renin and low aldosterone level. Synacthen test also confirms primary adrenal insufficiency.

Question 7.

What is the immediate management plan for this girl?

  • Commence hydrocortisone tablets: 8–12 mg/m2 per day
  • Commence fludrocortisone tablets 100 µg/day (Bornstein, Allolio et al. 2016)
  • Intensive sick day management from the Clinical Nurse Specialist, including doubling up of hydrocortisone and emergency hydrocortisone injections (100 mg)
  • Close liaison with the school to initiate emergency management care plans
  • Educate the family on Addison’s disease with written information
  • Plan for Medic-Alert bracelet
  • Introduce family to the Addison’s Disease Self-Help Group


The most common type of Addison’s disease is autoimmune, and can affect one in every 5000 people (Carsote and Nistor 2023). Clinical presentation can vary, with an association of other autoimmune polyendocrinopathies (Elsayed, Negm et al. 2023), such as Type 1 diabetes or Coeliac disease. However, other signs can be an indication of an Addison’s disease diagnosis, such as depression or insomnia (Momayez Sanat and Mohajeri-Tehrani 2022), so healthcare professionals need to be aware of such non-clinical manifestations, particularly in the absence of a family history.

Further history taking is always beneficial in order to reach the final diagnosis. In general, hyperpigmentation can involve sun-exposed areas, such as elbows and knees, or any scars that had formed after the disease onset. Closer inspection for hyperpigmentation in the palmar creases, gums and nail beds is needed in patients with a darker skin tone (Tong and Ooi 2021).

Intensive management for supportive education is needed for the young person, family and school. Regular follow-up is needed to ensure full understanding and adherence to medication regimes, and referral to transition clinics and adult services will need to be considered in the near future.


Bornstein, S. R., B. Allolio, W. Arlt, A. Barthel, A. Don-Wauchope, G. D. Hammer, E. S. Husebye, D. P. Merke, M. H. Murad, C. A. Stratakis and D. J. Torpy (2016). “Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline.” J Clin Endocrinol Metab 101(2): 364-389.

Carsote, M. and C. Nistor (2023). “Addison’s Disease: Diagnosis and Management Strategies.” International Journal of General Medicine 16: 2187 – 2209.

Elsayed, M., E. Negm, M. Gahr and C. Schonfeldt-Lecuona (2023). “Autoimmune polyglandular syndrome type 2 and recurrent depression.” Ann Med Surg (Lond) 85(3): 494-496.

Momayez Sanat, Z. and M. R. Mohajeri-Tehrani (2022). “Psychotic Disorder as the First Manifestation of Addison Disease: A Case Report.” Int J Endocrinol Metab 20(1): e121011.

Tong, C. V. and X. Y. Ooi (2021). “Addison’s disease presenting with hyperpigmentation.” BMJ Case Rep 14(8).

Meet the author

Kate Davies, Li Chan

Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK

Martin Savage
Programme Director
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