Endocrine and metabolic disorders

Osteoporosis

Osteoporosis is a bit of an orphan disease in environments where its management is not driven by some form of high-tech bone densitometer (either radiological or, more recently, ultrasound-based). This is unfortunate, as it is a fairly common disease about which something can be done. The low annual event rate of fracture in women at a time when interventions should be occurring, as opposed to the higher rate in the elderly means that the disease is largely silent until very late. Some studies suggest that osteoporosis is present in about 15% of women under 60 years, and in this 15% fractures occur at a rate of about 1 per 1000 per year, versus 1 in 10-20 per year in those over 75 years of age^[27].

While screening programmes using densitometry might be nice, they are often unaffordable^[28]. It is thus worth thinking about who might be at increased risk, and targeting them. Examples would be:

• any patient chronically on corticosteroids,
• patients with malabsorption,
• patients with back pain and a history of a mother with late stature loss,
• patients with premature menopause (<45 years),
• patients with rheumatoid arthritis or other chronic stable conditions impairing mobility.

In individuals with established severe osteoporosis it is worth thinking about secondary causes: TSH (thyrotoxicosis), alkaline phosphatase (Paget’s, osteomalacia), protein electrophoresis (myeloma) and PTH (hyperparathyroidism). Making the diagnosis early without bone densitometry is not easy, but the demonstration of otherwise unexplained severe osteopenia (normal calcium, phosphate, alkaline phosphatase, and ESR) makes the probability of late disease fairly high. See the perspective section for more tips on clinical diagnosis

Therapy:

General: concentrate on the basics by increasing mobility and reducing or stopping predisposing factors (e.g. steroids) insofar as is possible.

It is probably never too late to consider starting treatment. The clinical impact of vertebral fractures is unclear; the evidence for hip fractures is more obvious. Data on the impact of any therapy on hard endpoints such as mortality and total morbidity and quality of life is still scanty.

Supplemental calcium may reduce the rate of bone loss but probably does not reverse bone loss that has already occurred. A meta-analysis^[29] of 17 trials identified a modest reduction in the risk of fractures of all types (risk ratio 0.88, 95% CI 0.83 – 0.95). You need to give at least 1 gram of elemental calcium per day. Calcium carbonate is inexpensive and reasonably tolerated – giving 2 – 2.5 grams per day in divided doses will provide about 1 gram of elemental calcium. A preliminary caveat is a report from New Zealand^[30] of increased vascular events in women given calcium supplementation.

Vitamin D (800 IU per day) may be of value when given with the calcium, particularly in high risk groups such as patients on long term steroid therapy. The cost of calcitriol and alphacalcidol is similar to vitamin D, but the evidence for their efficacy in reducing long bone fracture rates is unconvincing. A case can be made for giving Vitamin D and calcium to patients on long-term steroids, although an excessive number of pills may reduces compliance…

Oestrogens (HRT) are probably of benefit in hysterectomised women but have an unfavourable breast cancer and cardiovascular risk profile. They are probably best avoided. Ten years of oestrogen-progestagen use has been estimated to result in an extra 19 (95% CI 15-23) breast cancers per 1000 users^[31].

Biphosphonates such as alendronate 10 mg/day do reduce fracture rates^[32]. The problem is that much of this reduction is in vertebral fractures – hip fractures were reduced from 2.2% to 1.1% which is a relatively small absolute risk, and gives an NNT of 90 for 2 years to prevent one hip fracture. Once generic products become available the cost-effectiveness profile may become more favourable. Do not use for more than 5 years.

Fluoride and calcitonin are of unproven value in preventing hip fractures.

Perspective – clinical diagnosis of osteoporosis

Clinical features that effectively exclude osteoporosis are not available, but there are some features that should raise clinical suspicion^[33]. Features with low sensitivity but high specificity are weight less than 51 kg (sens 22%, spec 97%, LR+ 7.3, LR- 0.8), less than 20 teeth (sens 27%, spec 92%, LR+ 0.92, LR- 0.8), and a self-reported hump (sens 21%, spec 97%, LR+ 3.0, LR- 0.85.) More sensitive are the rib-pelvis test (sens 88%, spec 46%, LR+ 3.8, LR- 0.60), and a wall-occiput distance of more than 0 cm (sens 60%, spec 87%, LR+ 4.6, LR- 0.50.)

It is still unclear if the rib-pelvis distance and wall-occiput distance perform independently; if they do, then the combination of both being negative would have a LR- of 0.3, which would be reasonably useful; this needs to be tested. (Rib-pelvis test is positive if you can’t place two fingers between the lower ends of the rib cage and the pelvis in a standing patient; the wall-occiput test measures the distance between the wall and the back of the head in a person standing upright with both feet and her back against the wall, and looking forward horizontally.)

Perspective – bone densitometry

Unbiased (and unsponsored!) commentaries on the role of bone densitometry are difficult to find. The BMJ addressed this with a ‘for and against’ debate, which yielded some interesting numbers^[34]:

The ‘anti’ camp provided evidence to suggest that 85% of the risk of fracture is independent of bone mineral density. From another study, they suggest that doing scans on 8000 women would identify 2000 with low BMD, but would only identify 34 of the 65 who would suffer a fracture. Treatment of the 2000 would only prevent 17 fractures (half of 34). NNT to prevent one fracture is thus 118, and the number needed to screen to be able to prevent one fracture with treatment is 471.

The ‘pro’ camp’s arguments were less numeric and more emotive, but they did make the point that the 85% figure was from a cross-sectional study with some design issues, however they also felt that there was undue reliance on instrumentation rather than ‘clinical skills and reasoning’.

Perspective – Vitamin D

Vitamin D supplementation is unnecessary in normal people with adequate exposure to sunlight. A New Zealand study suggested that calcitriol was better than calcium at preventing vertebral fractures over three years^[35]. Subsequent studies seem to have been done mostly on elderly individuals in Europe. A study looking at intermittent use (Vitamin D3, or cholecalciferol, 100 000 IU given as a single dose orally every 4 months for five years) found a statistically significant risk reduction in composite fracture scores (2.3%, NNT 44) but not in risk of hip or vertebral fracture^[36].

Perspective – Hormone replacement therapy.

Advice on the use of HRT usually concludes with some statement to the effect that the risk and benefits should be discussed with each patient. The problem is accessing the absolute values. The key points are:

1. HRT is of undoubted benefit in reducing perimenopausal symptoms in the short term.
2. It is of benefit in reducing the risk of osteoporosis when given early post menopause.
3. It appears to increase the risk of cardiovascular disease^[37] and breast cancer^[38]
4. The effect on endometrial cancer ^[39] is related to the preparation – cyclic combination therapy had no effect, whereas oestrogen only preparations increased the risk and continuous (non cyclic) combined preparations reduced the risk.

Much of the increased risk information comes from observational studies such as the Million Women Study, which albeit very large suffer from the biases inherent in this design; the WHI trial^[40] was randomised and controlled, included more than 8000 women in each arm, and gives some idea of the absolute figures (five year follow up.)There was no difference in mortality, but the hazard ratio for all fracture reduction was 0.76 (95% CI 0.63 to 0.92). The HR for all CVS events was increased at 1.22 (95% CI 1.00 to 1.49) and for DVT was 2.07 (1.14 to 3.74.)

Hence for 1000 women treated for 10 years in the WHI trial, there would be 44 fewer fractures but 25 more CVS events and 13 more DVTs. WHI didn’t clearly demonstrate increased risk of breast or endometrial cancer, but the Million Women Study did – 19 extra breast cancers for each 1000 women using combination HRT for 10 years, and 5 extra for those using progestin only preparations.

Perspective – bisphosphonates

These agents also are of benefit in patients with confirmed osteoporosis (either identified because of a previous osteoporotic fracture, or because of a bone mineral density measurement) In such patients there is a clearly measurable, although modest benefit from bisphosphonates, with 100 patients being needed to be treated for one year to prevent one non-vertebral fracture, of 200 for 2 years to prevent one hip fracture.¹ There is probably little difference between the various agents in terms of either efficacy or safety.

Hyperlipidaemia.

There are three broad groups to rconsider:

familial hypercholesterolaemia, characterised by tendon xanthomata, a cholesterol of more than 9 mmol/l (usually) and relatively normal triglycerides.

hypertriglyceridaemia, which may be familial but is often associated with diabetes and high fat diets, is associated with eruptive xanthomata, and responds to diet modification but poorly to medication.

as part of global risk factor modification in individuals with other cardiovascular risk factors.

Management.

Check the cholesterol on 2 occasions before instituting drug therapy.

Ask personally about the diet, give dietary advice, a diet sheet, and refer to a dietician. Record the patient’s weight. Emphasize the value of stopping smoking.

Check the TSH.

The LDL-C lowering benefit of statins does increase with increasing dose, but the incremental benefit in terms of CVS event reduction is less impressive. The new AHA recommendations^[41] have simplified treatment by dropping the ‘treat to target’ concept and focusing instead on risk stratification:

Established CVS disease

LDL-C > 4.9 mmol/l

Diabetics between the ages of 40 and 75

Individuals with 10 yr CVS risk of > 7.5%

The AHA recommendation divides treatment into moderate or high intensity:

Moderate intensity	Moderate to high intensity	High intensity
Established CVS disease, but > 75 yrs Diabetic with 10 yr risk of CVS disease < 7.5%	Non-diabetic but with 10 yr CVS disease risk >7.5%	Established CVS disease and < 75 years LDL-C>4.9 mmol/l Diabetic with 10yr CVS disease risk > 7.5%

Moderate intensity statin therapy amounts to simvastatin 20 to 40 mg; the AHA recommendation for high intensity therapy is atorvastatin 40 to 80 mg or rosuvastatin 20mg. In fact, there is little evidence that these higher doses really have a major impact on CVS outcomes, and a blanket recommendation of simvastatin 20 mg for moderate intensity and 40 mg for high intensity may be reasonable until atorvastatin prices fall further. In patients unable to tolerate these doses, consider simvastatin 10 mg. It is also worth noting that these new recommendations have generated some controversy, and a ‘fire and forget’ strategy of 20mg simvastatin daily is still a quite acceptable option.

The very thin patient

Important causes are:

• AIDS
• Addison’s
• Malabsorption syndromes
• Neglected insulin dependent diabetes
• Malignancy (especially oesophageal, bronchial and pancreatic cancers)
• Neglected tuberculosis.
• Thyrotoxicosis.
• COPD – the ‘pink puffer’ – related to hypoxaemic TNF release?

The patients have all been ill for considerable time and need to be handled with care and forethought. They are chronically anaemic, hypotensive, hypovitaminotic, often have bedsores, and may be septicaemic. They are physiologically brittle and sudden medical interventions can tip them into metabolic chaos. In particular, transfusions of both blood and crystalloid are poorly tolerated. Thus, apart from the specifics directed at the particular underlying condition, consider the following:

Is the low blood pressure medically significant (septicaemia, dehydration) or is it compatible with the patient’s general debility? In the absence of other good evidence of hypovolaemia, be wary of infusing intravenous fluids rapidly, or even at all.

Is the anaemia due to acute blood loss? If not, do not give blood!

Is the patient septicaemic? In the absence of fever, tachycardia or any obvious precipitant such as pneumonia, it is often difficult to tell. One clue is a sudden acute deterioration on top of the chronic process. If in doubt, blood culture the patient and start on ampicillin 1 g 6 hourly I.V. and gentamicin 5 mg/kg/day. (240 mg daily is a reasonable guess for such thin patients.) Remember that gentamicin is partially active against tuberculosis, so if there is no clear improvement, or evidence in support of septicaemia, stop it after a few days.

Always consider hypo-adrenalism, and if in doubt take a plain tube of blood for cortisol (send this to the laboratory in the morning – there is no urgency) then give 100 mg of hydrocortisone intravenously. The decision about whether to continue maintenance steroids while awaiting the cortisol is based on the extent to which is it considered that low dose steroids (not immunosuppressive doses – e.g. prednisone 5 mg daily or 2x/d) will compromise the management of an out of control infection.

Clinically significant hypoglycaemia is quite common and should preferably be treated with regular oral nutrition rather than ongoing dextrose drips.

Hypokalaemia and hypomagnesaemia should be looked for and corrected if found – again, don’t neglect the oral route unless the patient is vomiting or has profuse diarrhoea.

Oral or nasogastric feeding should be introduced on admission. Remember that most severely malnourished patients, regardless of the aetiology, have a degree of enterocyte dysfunction and lactose intolerance may occur. Enteral feeds containing milk products should be started slowly – e.g. 500 ml per day, and not relentlessly increased in the face of ongoing diarrhoea.

Suspected Cushing’s disease

When investigating for this condition, first establish whether it is present before trying to ascertain the cause – in general, if a screening test is positive, patients warrant referral to an endocrine unit for further investigation. High dose dexamethasone suppression test and plasma ACTH are both tests that help decide on the type rather than helping to decide if there is anything there.

A spot morning urinary free cortisol/creatinine ratio has been proposed to avoid the need for an accurate 24 hour collection; a compromise is to try an 8 pm to 8 am urine collection and look at the free cortisol/creatinine ratio on that: at a cut-off of 15-20 nmol/millimol this has a sensitivity of nearly 100% and specificity of 97%^[78]. (Remember serum creatinine is measured in micromol and urinary creatinine in millimol.)

A low-dose dexamethasone test is conventionally considered the ‘next’ test in terms of specificity, although false positives occur in patients on liver enzyme inducers (phenytoin, rifampicin). A serum cortisol of less than 50 nmol/l the morning after giving 1 mg of dexamethasone at midnight means that Cushing’s is excluded.

Suspected phaeochromocytoma

Clinical suspicion – episodic hypertension, flushing, sweating. Ask about these symptoms. In the absence of hypertension, or heart failure, phaeochromocytoma is very unusual – most patients with just episodic flushing or sweating do not have it.

A reasonable screening test is a 24 hour urine for NMA. A special diet is not necessary, and only send a single specimen if the index of suspicion is low. Most patients with phaeochromocytomas have results at least two or three times the upper end of the normal range for the laboratory. The very rare patient in whom the NMA has not given a satisfactory answer should be referred to an endocrine service for further testing.

Management of hypertension with suspected pheochromocytoma:

Therapeutic options that are locally available are quite limited One option is the alpha-blocker is doxazosin (usually reserved for prostatic hyperplasia patients) starting at 2 mg/d and increasing slowly to 16 mg/d. Labetalol and carvedilol probably lack sufficient alpha blocking effect to be used on their own, but can be used synergistically with doxazosin^[79]. Plain beta-blockers (atenolol) should NOT be used until there is adequate alpha blockade on board. (Never start with them as the unopposed alpha activity may cause worsening hypertension.).) Volume replacement may assist in securing cardiovascular stability. Amlodipine may be of additional benefit, but try to avoid ACE inhibitors or diuretics.

Perspective – testing for pheochromocytoma

As usual, the utility of a test is dependent on the pre-test probability. Remember that the diagnosis is rare, so the pre-test probability will be very low unless significantly helped by history or examination. A review^[80] found that urinary metanephrines (sens 97%, spec 93%, LR+ 13.9, LR- 0.0) were as sensitive as plasma metanephrines (99%, spec 89%, LR+ 9.0), but urinary VMA was marginally more specific (95%) but relatively insensitive (64%, LR+ 12.8, LR- 0.4.) Urinary catecholamines had the lowest specificity (88%), but were relatively sensitive (86%, LR+ 7.2, LR- 0.2.) For practical purposes, a urinary VMA less than 2x normal is unlikely to be pathological.

Hypoglycaemia

Test for this in ANY individual with a behavioural disturbance, altered consciousness, or autonomic features (sweating, tachycardia, nausea). Diabetics who have been poorly controlled may have symptoms of hypoglycaemia with sugars of 4 mM. Treatment is with sufficient intravenous dextrose to either get the patient to wake fully or to have a repeat finger prick glucose reading well within the normal range, and preferably both.

Give 20 to 50 ml of 50% dextrose IV. The solution is very viscous, so you need a decent size of venous access. If you have immediate access to the tubes (don’t let this delay treatment!) it is worthwhile taking blood in a fluoride tube to get laboratory confirmation of the exact extent of hypoglycaemia, and if in doubt about the cause (non-diabetic), pull a tube that can later be used for insulin/C-peptide determination.

Once the glucose is up, find out why it went down and make a management plan:

Inadvertent insulin dose error of judgment – when questioned the patient knows exactly what went wrong (usually injected without eating) Get the patient something to eat and do an adequate amount of counselling to avoid recurrence.

On oral hypoglycaemic agents and then ill so that not eating although taking pills. Normal renal function. Usually a chest or urinary tract infection. Treat this and reduce or stop the oral agents in the short term.

No obvious infection, but on oral hypoglycaemic agents – check the renal function. If this is impaired the patient must be admitted so that the blood glucose can be monitored for long enough to demonstrate that it remains normal for at least 12 hours without IV dextrose. Oral agents should be stopped and not used again unless the renal dysfunction proves to be reversible.

Other causes of hypoglycaemia in non-diabetics include Addison’s, hepatitis, septicaemia, soft tissue or hepatic tumours, injections as part of a Munchausen presentation. (Normal C peptide, but it is cheaper and quicker to just take a decent history) and very rarely insulinomas or ACTH deficiency.

Pituitary disorders.

The investigation of suspected pituitary diseases generally falls into three groups:

Suspected excess production of one hormone

Suspected underproduction of one or more hormones

Post-neurosurgical assessment of pituitary reserve.

For excess production, see testing under the individual diseases, for post-neurosurgical (pituitary surgery) assessment, investigate as for suspected underproduction of the individual hormones. In practice this boils down to an ACTH stimulation test, a TSH/T4, and a FSH/LH and an oestrogen or testosterone level.

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1. Deardorff WJ, Cenzer I, Nguyen B, Lee SJ. Time to Benefit of Bisphosphonate Therapy for the Prevention of Fractures Among Postmenopausal Women With Osteoporosis: A Meta-analysis of Randomized Clinical Trials. JAMA Intern Med. 2022;182(1):33–41. doi:10.1001/jamainternmed.2021.6745 ↩

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