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]