COMBINACIÓN DE NEGOCIOS

History

An 82-year-old woman is transferred to A&E in a confused state and unable to cope at home. She lives at home with her husband, aged 86 years, who reports that his wife has been increasingly unwell over the previous 10 days. Her symptoms are non-specific.

She has not been eating well because of nausea, has been relatively immobile and now seems unaware of her circumstances and is unable to dress herself.

She appeared dehydrated but was apyrexial. Her pulse was 65 beats per minute, blood pressure (BP) 145/75 mmHg, no ankle oedema and jugular venous pressure (JVP) nor-mal; a few crepitations are found at both bases. No abdominal tenderness is found and there are no focal neurological signs. Previous history from the GP indicates that she has been on thyroxine replacement for many years and that her atrial fibrillation has been well controlled on digoxin and a thiazide diuretic. In addition, she had been treat-ed for breast cancer seven years previously.

Investigations

Admission blood tests showed:

Reference range

Haemoglobin 12.2 g/dL 11.5–16.5 g/dL

White cell count 10.6 × 10⁹/L 4.0–11.0 × 10⁹/L

Neutrophils 5.5 × 10⁹/L 2.0–7.5 × 10⁹/L

Platelets 244 × 10⁹/L 150–450 × 10⁹/L

Sodium 138 mmol/L 135–146 mmol/L

Potassium 3.2 mmol/L 3.2–5.1 mmol/L

Urea 12.1 mmol/L 1.7–8.3 mmol/L

Creatinine 148 μmol/L 44-80 μmol/L

e-GFR 31 mL/min/1.73m² >60 mL/min/1.73m²

Total protein 80 g/L 66–87 g/L

Albumin 45 g/L 34–48 g/L

Bilirubin 17 μmol/L <21 μmol/L

Alanine aminotransferase (ALT) 55 U/L <41 U/L

Alkaline phosphatase (ALP) 195 U/L 35–104 U/L

fT4 (free thyroxine) 12.3 pmol/L 12–22 pmol/L

Tyroid-stimulating hormone (TSH) 19.4 mU/L 0.3–4.2 mU/L

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Checking on the laboratory computer, the only previous electrolyes were undertaken by her GP five years previously and showed:

Sodium 140 mmol/L 135–146 mmol/L

Potassium 3.3 mmol/L 3.2–5.1 mmol/L

Urea 6.5 mmol/L 1.7–8.2 mmol/L

Creatinine 79 μmol/L 44–80 μmol/L

e-GFR 64 mL/min/1.73m² >60 mL/min/1.73m²

Rehydration is started initially with dextrose saline. Repeat blood tests the following day revealed:

Sodium 136 mmol/L 135–145 mmol/L

Potassium 3.2 mmol/L 3.2–5.1 mmol/L

Urea 12.6 mmol/L 1.7–8.2 mmol/L

Creatinine 138 μmol/L 44–80 μmol/L

e-GFR 34 mL/min/1.73m² >60 mL/min/1.73m²

Total protein 75 g/L 66–87 g/L

Albumin 40 g/L 34–48 g/l

Bilirubin 16 μmol/L <21 μmol/L

ALT 53 U/L <41 U/L

AST 55 U/L <32 U/L

Alkaline phosphatase 202 U/L 35–104 U/L

Gamma-glutamyl transferase (GGT) 38 U/L 6–42 U/L

Calcium 2.32 mmol/L 2.15–2.55 mmol/L

Adjusted calcium 2.32 mmol/L 2.15–2.55 mmol/L

Phosphate 1.51 mmol/L 0.87–1.45 mmol/L

Digoxin (time after dose not stated) 3.2 μg/L 1–2 μg/L 8–12 h after dose

A section of her electrocardiogram (ECG) rhythm strip is shown in Figure 21.1.

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96 Section 1: Clinical Chemistry

Figure 21.1

V4

In view of her blood results and confusional state, she was treated with Digibind^®. Repeat digoxin assay showed little change in her digoxin levels.

QUESTIONS

1. What abnormality is highlighted in the ECG trace and what is its significance?

2. Why is relationship to dose important when interpreting the results of digoxin measurements?

3. What metabolic conditions enhance digoxin toxicity?

4. What is the mechanism for digoxin metabolism and excretion? Why is this pertinent to this case?

5. Why did her serum digoxin concentration not fall when treated with Digibind?

6. What conditions may account for her elevated alkaline phosphatase concentration?

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98 Section 1: Clinical Chemistry

ANSwERS

1. The ECG demonstrates the ‘reversed tick’ phenomenon with ST segment depression – this is a feature of digoxin therapy, not a sign of toxicity. Any arrhythmia can occur with digoxin toxicity, including paroxysmal atrial tachycardia with atrioven-tricular block, venatrioven-tricular ectopics and bigeminy and severe bradycardia.

2. As with most drugs there is a rise in serum concentration following ingestion fol-lowed by an uptake by tissues to create a steady-state equilibrium. For digoxin, it takes about 6 hours to reach a steady state. In practice, pre-dose sampling is often more convenient. Routine measurement is unnecessary.

3. Digoxin toxicity is enhanced by hypokalaemia, hypercalcaemia, diuretics (e.g.

furosemide), hypomagnesaemia and hypothyroidism. The clinical manifestations of digoxin toxicity include anorexia, nausea/vomiting, visual disturbance (blurred vision – xanthopsia), diarrhoea and arrhythmias.

The effects of digoxin appear to be due to inhibition of the sodium and potassium ATPase mechanism. The net effect is to increase intracellular calcium concentration and decrease intracellular potassium concentration. Hence hypokalaemia and hyper-calcaemia will enhance the actions of digoxin and hence there is an increased risk of toxicity. In hypothyroidism, it is thought the volume of distribution of digoxin is decreased and hence there is a risk of toxicity. Her thyroid function tests show compensated hypothyroidism and this may be a reflection of variable compliance over the preceding months or may be due to a too low dose of thyroxine, causing a compensatory rise in TSH. These should be checked again in two months. Digoxin reduces conductivity at the atrioventricular node and is used commonly to reduce the ventricular rate in atrial fibrillation; it is also a positive inotrope.

4. While up to 20 per cent of digoxin is metabolized in the liver and stomach, the main route for elimination is the kidney. Any reduction in glomerular filtration rate (GFR) is likely to lead to increased circulating concentrations of digoxin. In this case, the significant reduction in renal function was almost certainly the cause for the accumulation of digoxin and the toxicity was enhanced by her borderline hypokalaemia associated with thiazide diuretic treatment. For this reason, monitor-ing of renal function is essential in patients takmonitor-ing digoxin – especially the elderly.

5. Hypokalaemia and hypomagnesaemia contribute to digoxin toxicity.

Bradyarrhythmias are treated with atropine, ventricular arrhythmias are treated by magnesium infusion (8–10 mmol bolus) even in the presence of a normal serum magnesium. Bradyarrhythmias not responding to atropine, or life-threatening ventricular arrhythmias, can be treated with digoxin-specific antibody fragments (Digibind). Temporary pacing may be needed in some cases.

Treatment with Digibind® captures digoxin in the circulation making it unavailable for uptake by tissues. In addition, it removes digoxin from tissues as it changes the concentration of free digoxin in the blood and hence the dynamic equilibrium between tissues and serum. However, digoxin bound to Digibind® may still be

Case 21: Elderly confused woman 99

measured in some immunosassays for digoxin. Hence serum digoxin measurements following Digibind® treatment cannot be relied on as an assessment of the efficacy of treatment. The effect is very assay dependent.

6. Alkaline phosphatase is prevalent in bone, liver and placenta with some also found in the intestine. Some tumours are associated with the production of a placenta-like alkaline phosphatase. There are physiological increases in alkaline phosphatase in blood associated with bone growth in children and adolescents and increases from the placenta in pregnancy. In this particular case, the possibility of secondary neoplasia associated with her previous breast cancer is possible, while at her age Paget’s disease is also a possibility.

The different tissue-specific isoenzymes of alkaline phosphatase may be separated by electrophoresis and quantified by staining and densitometry.

In primary biliary cirrhosis and gall stone obstruction, there would be a significant elevation of GGT in addition to alkaline phosphatase – there is induction of both enzymes linked to biliary obstruction.

In alcoholic cirrhosis, the AST is usually elevated more than the ALT and in addi-tion the GGT would usually be elevated.

The elevation of alkaline phosphatase without GGT indicates the possible sources as bone, placenta or intestine. In this case, either Paget’s disease of bone or secondar-ies from her breast cancer are possible causes. Paget’s disease causes an isolated raised ALP and is a common cause of an isolated raised ALP in the elderly and is often asymptomatic in such patients.

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CASE 22: MIDDLE-AGED wOMAN FEELING