Undifferentiated Fatigue — DCE Clinical Case

Long case

Patient scenario

Mrs MA is a 62-year-old woman who presents to the general medicine clinic with a 3-month history of progressive fatigue. The fatigue is present throughout the day, worse in the evening, and limits her part-time administrative work and her self-care. She wakes unrefreshed despite 7 to 8 hours in bed. She has gained 4 kg over the 3 months. She describes low mood, reduced interest in her usual activities, and early-morning waking at 4 am. She has no suicidal ideation on direct questioning. [1]

Her past history: type 2 diabetes (diagnosed 12 years ago), hypothyroidism (Hashimoto), hypertension, obesity (BMI 36), and obstructive sleep apnoea (diagnosed 3 years ago, prescribed the CPAP which she uses intermittently). Her medications: metformin 1 g twice daily, gliclazide 80 mg daily, levothyroxine 100 micrograms daily, bisoprolol 5 mg daily, atorvastatin 40 mg daily, ramipril 10 mg daily, aspirin 100 mg daily. She takes the levothyroxine with her breakfast calcium and her morning iron tablet. [1]

She is a former smoker (stopped 10 years ago), drinks alcohol rarely, and lives with her husband. Her mother had type 2 diabetes and her father had ischaemic heart disease. There is no family history of autoimmune disease or malignancy. [1]

Examination findings

The patient is obese (BMI 36), pale, and tired-appearing. The blood pressure is 142/88 lying and 132/82 standing (no significant postural drop). The heart rate is 64 (the beta-blockade). The oxygen saturation is 96 per cent on room air. The hands show pallor of the palmar creases and koilonychia of the nails. There is no clubbing. The thyroid is not palpable and there are no eye signs. The cardiovascular examination reveals no raised JVP, a normal apex, no gallop, and no murmurs. The respiratory examination is clear. The abdominal examination is unremarkable apart from the central obesity. There is no hepatosplenomegaly and no masses. The lymph node examination is normal. There is no hyperpigmentation of the palmar creases or the buccal mucosa. The proximal muscle strength is normal. [1]

Candidate's opening statement (SASPOP)

"Doctor, my patient is Mrs MA, a 62-year-old woman who presents with a 3-month history of progressive fatigue, weight gain, unrefreshing sleep, low mood and early-morning waking, who works part-time as an administrative officer, and who has type 2 diabetes, hypothyroidism, obesity and obstructive sleep apnoea. Her problems are: the multifactorial fatigue with the physical and the psychological contributors; the uncontrolled type 2 diabetes (HbA1c 74); the iron deficiency (ferritin 18); the possibly under-treated hypothyroidism; the poorly-controlled obstructive sleep apnoea; the likely comorbid depression (PHQ-2 of 5); and the polypharmacy with the contributory drugs and the suboptimal levothyroxine administration." [1]

Problem list

1. Multifactorial fatigue — the physiological, the physical and the psychological contributors.
2. Uncontrolled type 2 diabetes (HbA1c 74 mmol per mol).
3. Iron deficiency (ferritin 18 micrograms per litre) — the underlying cause to be investigated.
4. Possibly under-treated hypothyroidism — the TSH to be confirmed; the levothyroxine taken with the calcium and the iron (reducing the absorption).
5. Poorly-controlled obstructive sleep apnoea — the intermittent CPAP adherence.
6. Likely comorbid major depressive disorder (PHQ-2 of 5, the early-morning waking, the anhedonia, the low mood, the weight gain).
7. Polypharmacy — the beta-blocker and the statin as the contributory drugs. [1]

Integrated management plan

The principle: treat each contributor, validate the symptom, and avoid the single-cause anchoring. This patient has the contributors in all three categories — the physical (the diabetes, the iron, the thyroid, the sleep apnoea), the psychological (the depression), and the physiological (the obesity, the deconditioning, the polypharmacy). The integrated management addresses each in turn. [1]

Investigations — the targeted Tier 2. Confirm the TSH and the free T4 (the levothyroxine may be under-dosed or the absorption reduced by the co-administration with the calcium and the iron). Confirm the HbA1c and the renal function. Perform the coeliac screen (the tissue transglutaminase IgA with the total IgA) given the iron deficiency and the autoimmune background. Arrange the faecal immunochemical test (FIT) and the gastrointestinal referral for the gastroscopy and the colonoscopy given the age and the iron deficiency (the occult gastrointestinal malignancy must be excluded). Review the iron studies and commence the oral iron. Perform the full PHQ-9 and the suicide risk assessment. Assess the CPAP adherence and the data download. [1]

The diabetes. Optimise the glycaemic control — the individualised HbA1c target (53 to 64 mmol per mol, balanced against the hypoglycaemia risk and the comorbidity), the addition of the SGLT2 inhibitor (the cardiovascular and the heart failure benefit, the weight loss, the renal protection) or the GLP-1 receptor agonist (the weight loss), the metformin continuation, the gliclazide review, the lifestyle intervention. The osmotic fatigue and the weight will improve as the glycaemic control improves. [1]

The iron deficiency. Commence the oral ferrous sulfate (65 to 100 mg elemental iron daily or on alternate days, with the vitamin C, separated from the levothyroxine and the calcium by at least 2 hours). Reassess the haemoglobin and the ferritin at 4 weeks. Investigate the cause with the gastrointestinal work-up (the FIT, the gastroscopy and the colonoscopy) and the coeliac screen. [1]

The hypothyroidism. Confirm the TSH; the likely under-replacement (the levothyroxine absorption reduced by the co-administration with the calcium and the iron). Counsel the patient on the empty-stomach dosing, the separation from the calcium and the iron by at least 2 hours, and the 6-week reassessment of the TSH after the dose adjustment. [1]

The sleep apnoea. Address the CPAP adherence — the mask refit, the pressure adjustment, the humidification, the behavioural support, the weight loss. The untreated sleep apnoea is the major contributor to the unrefreshing sleep, the daytime fatigue, the cardiovascular risk (the hypertension, the arrhythmia, the heart failure), and the road safety. [1]

The depression. Perform the full PHQ-9 and the suicide risk assessment. The evidence-based treatment: the CBT (the access via the mental health plan), the SSRI (the sertraline as the first-line, with the 4 to 6 week onset of action and the awareness of the side-effect profile — the nausea, the insomnia, the sexual dysfunction), the addressing of the psychosocial stressors. The regular review for the safety. [1]

The medication review. Consider the beta-blocker dose reduction or the switch (the bisoprolol may contribute to the fatigue — the switch to the ACE inhibitor or the ARB as the primary antihypertensive, or the dose reduction if the indication allows). Consider the statin review (the atorvastatin-associated muscle symptoms — the creatine kinase, the statin holiday if the myalgia is prominent, the rechallenge at the lower dose or the switch to the rosuvastatin or the pravastatin). [1]

The communication and the shared decision-making. Explain the multifactorial nature of the fatigue to the patient in plain language: "Your fatigue has several contributors — the high blood sugar, the low iron, the under-active thyroid, the poorly-controlled sleep apnoea, the low mood, and some of your medications. The good news is that each one is treatable, and the addressing of each in turn will improve your energy over the coming weeks to months. I would like to prioritise the diabetes, the iron, the thyroid and the sleep apnoea first, and to assess your mood more fully at the next visit." Set the realistic expectation, the red flags to report, and the planned review. [1]

Discussion questions

Examiner: "How do you prioritise the management of this complex patient?" I prioritise by the safety and the treatability. The suicide risk assessment is the first safety step. The diabetes optimisation and the CPAP adherence are the cardiovascular safety steps. The iron replacement and the thyroid optimisation are the quick wins. The depression assessment and treatment are the medium-term gains. The medication review is the continuous process. The communication and the shared decision-making run throughout. The registrar who tries to fix everything at once overwhelms the patient and achieves nothing; the registrar who prioritises and sequences achieves the most. [1]

Examiner: "What is the role of the PHQ-2 score of 5, and what is the next step?" The PHQ-2 is a screen, not a diagnosis. The score of 5 is above the threshold of 3 and indicates that the major depressive disorder is likely. The next step is the full diagnostic assessment — the PHQ-9, the DSM-5 criteria, the suicide risk assessment, the bipolar exclusion. The SSRI and the CBT are the evidence-based treatment if the diagnosis is confirmed. The registrar who prescribes the antidepressant on the PHQ-2 alone has not performed the proper assessment. [1]

Examiner: "Why is the timing of the levothyroxine important in this patient?" The levothyroxine absorption is reduced by the co-administration with the calcium and the iron, both of which bind the levothyroxine in the gut. The patient should take the levothyroxine on the empty stomach, at least 30 to 60 minutes before the breakfast, and separated from the calcium and the iron by at least 2 hours. The correcting of the timing alone may normalise the TSH and improve the fatigue, without any dose change. [1]

Short case — focused bedside examination

Instruction

"Examine this fatigued patient. Focus on the bedside signs that discriminate the systemic causes of fatigue." [1]

Systematic examination routine

1. General inspection. Confirm the patient is comfortable; assess for the cachexia, the obesity, the pallor, the pigmentation, the signs of the distress.
2. Vital signs. The heart rate, the blood pressure (lying and standing for the postural drop), the respiratory rate, the oxygen saturation, the temperature, the body mass index.
3. The hands. The pallor of the palmar creases, the koilonychia, the clubbing, the palmar erythema, the Dupuytren contracture, the tremor.
4. The thyroid. The goitre, the bruit, the eye signs (the exophthalmos, the lid lag).
5. The cardiovascular. The JVP, the apex, the gallop, the murmurs, the pericardial knock.
6. The respiratory. The crackles, the wheeze, the hyperinflation, the pleural effusion, the cyanosis.
7. The abdominal. The hepatomegaly, the splenomegaly, the masses, the ascites, the palpable bladder.
8. The lymph nodes. The cervical, the supraclavicular, the axillary, the epitrochlear, the inguinal.
9. The skin. The hyperpigmentation (the palmar creases, the buccal mucosa, the recent scars), the pallor, the bruising, the spider naevi. [1]

Key signs this patient demonstrates

• Pallor of the palmar creases — consistent with the anaemia (the iron deficiency).
• Koilonychia — the spoon-shaped, thin, brittle nails of the iron deficiency.
• Obesity (BMI 36) — the contributor to the sleep apnoea and the deconditioning.
• The bradycardia of the beta-blockade.
• No hyperpigmentation, no postural drop — the Addison disease is not suggested in this patient. [1]

Presentation template

"On general inspection the patient is obese and pale. The vital signs: heart rate 64, blood pressure 142 over 88 lying and 132 over 82 standing, no significant postural drop, oxygen saturation 96 per cent on room air, BMI 36. The hands show pallor of the palmar creases and koilonychia of the nails, consistent with the iron deficiency. There is no clubbing. The thyroid is not palpable and there are no eye signs. The cardiovascular, the respiratory and the abdominal examinations are unremarkable. There is no lymphadenopathy. There is no hyperpigmentation of the palmar creases or the buccal mucosa. The findings are consistent with the iron deficiency, and the multifactorial fatigue with the contributors as described. I would confirm the iron studies, investigate the underlying cause of the iron deficiency, and address the diabetes, the thyroid, the sleep apnoea, the mood and the medications." [1]

Discussion — the Addison disease and the ME/CFS discriminators

Examiner: "How would your differential change if the patient had the postural drop, the hyperpigmentation and the hyponatraemia?" Then the diagnosis is the primary adrenal insufficiency (Addison disease) until proven otherwise. The fatigue, the weight loss (rather than the weight gain), the postural hypotension, the hyperpigmentation (from the elevated pro-opiomelanocortin), the salt craving, and the hyponatraemia with the hyperkalaemia are the classic presentation. The diagnostic test is the 250 microgram short Synacthen test (the peak cortisol below 500 nmol per litre confirms), per the 2016 Endocrine Society guideline. The treatment is the hydrocortisone and the fludrocortisone, and the critical patient education is the sick-day rules and the adrenal crisis prevention. [1]

Examiner: "How would your management change if the patient had the post-exertional malaise?" Then the diagnosis is the ME/CFS or the post-COVID condition, and the management is the energy management and the pacing, NOT the graded exercise therapy. The 2021 NICE NG206 guideline withdrew the GET for the ME/CFS because of the risk of the harm from the post-exertional malaise. The registrar who prescribes the graded exercise to the ME/CFS patient has misread the guideline and may worsen the patient. The management is the pacing, the energy management, the symptom control, the supportive CBT, and the multidisciplinary care. [1]

Examiner: "What is the single most important communication principle with the chronically fatigued patient?" The validation of the symptom. The patient who feels heard, who understands the findings, and who has a clear plan is far less likely to re-present or to seek the alternative-medicine pathway. The dismissive "there is nothing wrong" is the communication trap that drives the chronic disability. The validation, the explanation, the plan and the planned review are the treatment. [1]