Examination Medicine: A Guide to Physician Training, 7th Edition

CHAPTER 10. The endocrine long case

I would like to see the day when somebody would be appointed surgeon somewhere who had no hands, for the operative part is the least part of the work.

Harvey Cushing (1869–1939)

Osteoporosis (and osteomalacia)

Osteoporosis is increasingly encountered in the long-case examination. The patient is often a postmenopausal woman or is taking corticosteroids for an acute or chronic inflammatory illness. Osteoporosis will commonly form part of another medical problem. Osteoporotic fractures can affect 30% of postmenopausal women over their lifetime. Many older women have undergone screening bone densitometry and may be aware that they have asymptomatic osteoporosis. Patients who have had a hip fracture or who have evidence of an endocrine disorder, malabsorption, liver disease, Crohn’s disease or bone marrow disease, or who are taking certain medications, should have the possibility of osteoporosis considered while they are being evaluated (see Table 10.1).

Table 10.1

Major secondary causes of osteoporosis


The history

1. Ask about a history of fractures, particularly fractures of the wrist (risk increases from age 55), hip (risk increases from age 70), humerus and ribs, and vertebral compression fractures (especially T12), which may have occurred with minimal stress (risk increases from age 55). Acute back pain that subsides over weeks or months and then recurs may be caused by compression fractures.

2. If the patient has had a hip fracture, ask about any secondary complications, including pulmonary thromboembolism and nosocomial infections.

3. Ask about symptoms of bone pain, which may be diffuse, and proximal muscle weakness. These features may occur with osteomalacia (characterised by defective bone mineralisation in adults).

4. Ask about risk factors for osteoporosis (Table 10.1). Determine the menstrual history and age of onset of menopause. Enquire about symptoms of thyroid excess or thyroid hormone replacement (thyroxine). Determine whether there are symptoms or a history of anaemia (e.g. coeliac disease).

5. Ask about bone pain and proximal weakness (osteomalacia, usually due to vitamin D deficiency – then you must exclude malabsorption) (Table 10.3).

Table 10.3

Causes of osteomalacia


6. Ask whether the patient has had skeletal X-ray examinations. Note that X-rays are insensitive for bone loss, because a substantial reduction of bone mass must occur before changes will be visible on the X-rays.

7. Take a careful drug history. Medications that cause osteoporosis include steroids, alcohol, heparin, thyroxine over-replacement, anticonvulsants (by affecting vitamin D metabolism), and cyclosporin.

8. Enquire about a poor diet (a low-fat diet often limits calcium intake) or inadequate sunlight exposure if the patient is a nursing home resident, or has a history of renal disease or phenytoin use (all risk factors for osteomalacia) (Tables 10.2 and 10.3). Ask about the patient’s exercise history, as physical activity throughout life preserves bone mass. Cigarette smoking reduces skeletal mass.

Table 10.2

Sun exposure and maintenance of normal Vitamin D levels in moderately fair-skinned people requires:


9. Determine any risk factors for falls: a greater risk of falls increases the risk of fracture at any level of osteoporosis.

10. Determine the social effect of the disease (e.g. immobility, pain, fear of falling).

11. Have vitamin D levels been measured? Were they reduced?

12. Ask about sun exposure (Table 10.2).

The examination

There are usually no signs of osteoporosis unless a recent fracture has occurred.

1. Examine for bone tenderness and proximal weakness (osteomalacia). Look for bowing of the legs (rickets).

2. Look for signs of thyroid disease and Cushing’s syndrome.

3. Thoracic kyphosis is an important sign of vertebral fractures. The occiput to wall distance can be used to follow the condition.

4. Assess weight and general nutritional status.


Vitamin D deficiency is increasingly commonly diagnosed in people of all ages.

Consider this in all patients with reduced bone density and especially in those with bone pain or muscle weakness. Risk factors include lack of exposure to sunlight (nursing home residents), fear of sunburn, dark skin and modest dress.


1. Bone densitometry using dual-energy X-ray absorptiometry (DEXA) of the lumbar spine and/or proximal femur remains the test of choice for evaluation of bone mineral density (BMD; see Table 10.4). Osteopeniais used to refer to a bone mineral density between 1 and 2.5 standard deviations below peak bone mass; osteoporosis refers to a bone mineral density of more than 2.5 standard deviations below peak bone mass. The measurement is often given as a T score. This is the number of standard deviations by which the measured bone density falls below the average for a young normal person of the same sex. Thus, a T score of less than −2.5 defines osteoporosis.

Table 10.4

Indications for bone mineral density (BMD) assay


2. Review the serum calcium and alkaline phosphatase results. In osteoporosis, serum calcium and alkaline phosphatase levels should be normal. Alkaline phosphatase is usually elevated in all forms of osteomalacia. Check 25-OH vitamin D levels (not 1,25-OH vitamin D) if there are any risk factors for osteomalacia. If there is vitamin D deficiency, then serum 25-OH vitamin D levels are usually low (e.g. vitamin D malabsorption, chronic liver disease, lack of exposure to sunlight – especially common in nursing home patients).

  Assessment of calcium, parathyroid hormone and vitamin D levels will usually distinguish the most important causes of osteomalacia and allow specific diagnostic tests to be appropriately directed (Table 10.5). A sustained elevation of alkaline phosphatase should lead to consideration of osteomalacia, as well as Paget’s disease and metastatic malignancy to bone.

Table 10.5

Tests in bone disease


3. A full blood count and ESR estimation should be ordered to look for evidence of myeloproliferative disease, and renal and liver function tests should be ordered to exclude renal or hepatic disease.

4. Thyroid-stimulating hormone should be measured to rule out thyrotoxicosis.

5. If osteoporosis is unexpectedly severe, then an EPG should be considered to rule out multiple myeloma. In men, a serum testosterone level is worthwhile.

6. Ask to review any skeletal X-rays.

• In osteoporosis of the spine, there is characteristic loss of trabecular bone in the vertebral body, including accentuation of the vertebral endplates. The vertebral trabeculae become more prominent with the loss of horizontal trabeculae. Also look for collapse, anterior wedging and the codfish deformity (from expansion of the intervertebral disc; see Fig 10.1).


FIGURE 10.1 X-ray of the lumbar spine showing loss of bone density (1), codfish deformity (2) and anterior wedging (3). Figure reproduced courtesy of The Canberra Hospital.

• In osteomalacia, X-rays may show some decrease in bone density with coarsening of trabeculae and blurring of the margins. A specific abnormality is Looser’s zones (pseudo fractures) in the long bone shafts; these are ribbon-like zones of rarefaction. Other characteristic abnormalities may include a triangular (trefoil) pelvis and biconcave collapsed vertebrae. If there is secondary hyperparathyroidism present with osteomalacia, then bone cysts, erosion of the distal ends of the clavicles and subperiosteal resorption in the phalanges may be seen.

7. In difficult cases, an iliac crest bone biopsy with double tetracycline labelling can help distinguish osteoporosis from osteomalacia.

8. Consider undertaking tests for secondary causes of osteoporosis if the clinical picture suggests this may be helpful.


Established osteoporosis is currently not reversible with medical therapy. Early intervention can prevent progression of osteoporosis and is of value. Secondary causes of osteoporosis should be identified and corrected if present.

1. Calcium. Because calcium absorption decreases with age, calcium therapy has a modest benefit in both early and late postmenopausal women. Consumption of 1200–1500 mg of calcium daily in adults over the age of 65 is advisable.

2. Vitamin D supplementation. Encourage sun exposure if that is possible. Moderate or severe vitamin D deficiency (serum 25-OH D <25 nmol/L) should be treated with high-dose supplements of vitamin D of 3000–5000 IU/day for 6–12 weeks, and then 1000 IU/day from then on. Elderly women in nursing homes who have inadequate intake should receive supplementation of vitamin D 800 IU/day and calcium 1200 mg/day. This has been shown to reduce non-vertebral fracture risk.

3. Generally recommend ceasing smoking, avoiding excess alcohol consumption. Institute fall prevention measures and prescribe regular weight-bearing exercise. Consider a hip protector.

4. Bisphosphonates (risendronate and alendronate). These drugs increase bone mineral density in postmenopausal women and have been shown to reduce the risk of fracture for postmenopausal women with osteoporosis by 50%. Patients unable to tolerate oral bisphosphonates can be given the drug as an infusion once every 3 months or, with some of the newer agents, once a year. The oral drugs can cause oesophageal ulceration that presents with odynophagia, usually within 1 to 2 months of commencing therapy. Osteonecrosis of the jaw is another serious possible side-effect, which is more likely to occur with intravenous formulations in the presence of previous dental infections. These drugs are now indicated for patients older than 70 who have a BMD T score of −3 or less and for those who have had a fracture after minimal trauma.

  Strontium ranelate is an alternative drug for people who are unable to take bisphosphonates. Its effectiveness for preventing hip fractures has not been established, but there is evidence for its use in protecting against vertebral and rib fractures. It should be taken at bedtime at least 2 hours after eating.

5. Oestrogen. Hormone replacement therapy will prevent loss of cortical and trabecular bone in postmenopausal women. Therapy is probably more effective if started earlier in menopause as bone loss is most rapid then. Because oestrogen increases the risk of endometrial carcinoma, combination with progesterone is important unless a hysterectomy has been performed. A past history of endometrial cancer is a contraindication. There is an increased risk of breast cancer, as well as DVT and pulmonary embolism. Cardiovascular risk is also increased and hence its use in postmenopausal women has declined.

6. Selective oestrogen receptor modulators. Raloxifene, closely related to tamoxifen, reduces the risk of spine fractures. It increases the risk of DVT, but lowers the risk of breast cancer (and is not associated with an increased risk of endometrial cancer). Tamoxifen is a mixed oestrogen receptor antagonist and agonist that prevents bone loss. It increases the risk of endometrial cancer.

7. Parathyroid hormone peptide. This drug is very effective for osteoporosis but very expensive.

8. Calcitonin. There have been inconsistent results with calcitonin and any effect is smaller than with other therapies. The drug can be given subcutaneously or intranasally. Administration can cause nausea, flushing and inflammation.

9. Denosumab, a humanised monoclonal antibody that reduces osteoclastogenesis by binding RANKL (receptor activator of nuclear factor kappa-B ligand), may have a role when other therapies fail.

10. Men with osteoporosis. In men who have osteoporosis and androgen deficiency, androgen replacement should be given unless there is a history of prostatic carcinoma. If there is secondary hypogonadism, human chorionic gonadotrophin or pulsatile gonadotrophin-releasing hormone may be worthwhile. Bisphosphonates and teriparatide (PTH) are efficacious in men; the role of raloxifene is not clear.

11. Steroid-induced osteoporosis. This is very important because, if prednisone is considered likely to be needed for a number of months or longer, then measures to prevent bone loss are important from the time steroids are begun, particularly in postmenopausal women or when high doses are needed. Co-administration of bisphosphonates is of value here. Calcium and 25-OH vitamin D in combination have also been shown to be effective. These are the only drugs that have been shown to reduce fracture risk for patients on steroids. Other general measures, such as cessation of smoking and a regular exercise regimen, are probably important and should be recommended to the patient.

12. Surgical treatment of fractures. This is often required. Frail elderly patients with other medical problems require careful assessment of anaesthetic risk.

Vertebral fractures may cause severe pain that requires potent analgesics. Bed rest should be as brief as possible. Injection of bone cement into the vertebral body (vertebroplasty) is a new treatment that may relieve pain and possibly has other benefits.


Hypercalcaemia is a common medical problem and therefore can appear in a long case. It is most likely to be a diagnostic problem. Most patients (90%) have hyperparathyroidism or malignancy (Table 10.6). The asymptomatic patient usually has hyperparathyroidism. A malignant condition that is advanced enough to cause hypercalcaemia is likely to have caused other symptoms.

Table 10.6

Causes of hypercalcaemia


CKD = chronic kidney disease.

The history

1. If the patient tells you that he or she has high calcium levels, enquire about the non-specific symptomatic manifestations. These include tiredness, weakness and episodes of confusion. Enquire about anorexia and constipation, as well as nausea and vomiting; acute abdominal pain from acute pancreatitis may have occurred. Enquire about polyuria and polydipsia. Ask about a history of hypertension or a slow heart rate.

2. Enquire about a history of peptic ulcer or renal colic (‘stones, moans, bones and abdominal groans’ from primary hyperparathyroidism). Ask about joint pain from pseudogout (chondrocalcinosis in primary hyperparathyroidism). Enquire about a past history of hypertension (hyperparathyroidism).

3. Ask the patient whether he or she was known to have a neck mass in the past or has had an operation to remove the parathyroid gland. In most cases a single adenomatous gland is found but they can be multiple. Surgical parathyroidectomy is the definitive treatment for primary hyperparathyroidism. Most neck masses will be coincidental thyroid nodules rather than a benign or malignant parathyroid tumour.

4. Ask whether the patient has had an eye examination and whether calcium was seen (band keratopathy). Also ask whether X-rays of the bones have been taken. In hyperparathyroidism, X-rays of the hand may show subperiosteal reabsorption with a moth-eaten appearance on the radial sides of the phalanges and in the distal phalangeal tufts (osteitis fibrosa cystica), as well as in the distal clavicles.

5. Determine whether there is any past history of malignant disease, including diseases that metastasise to bone (e.g. carcinoma or myeloma) or haematological disease such as lymphoma (ectopic vitamin D production).

6. Ask about drugs, including thiazide diuretics, lithium and ingestion of calcium or vitamin D.

7. Enquire about known chronic kidney disease, a cause of secondary hyperparathyroidism because of resistance to parathyroid hormone and growth of the size of the glands. These enlarged glands then produce partly non-suppressible parathyroid hormone and hypercalcaemia.

8. Ask about symptoms of thyrotoxicosis or phaeochromocytoma. Ask about recent immobilisation.

9. Check whether there is a family history of high serum calcium levels, such as familial hypocalciuric hypercalcaemia (autosomal dominant). Classically a patient with this condition has had hypercalcaemia since a relatively young age, with only a slight elevation in the serum parathyroid hormone level at most, and with a personal or family history of unsuccessful neck exploration; it does not require any therapy. A family history of hypercalcaemia may also occur with the multiple endocrine neoplasia syndromes, MEN1 and MEN2A. These are both autosomal dominant conditions. These patients may have symptoms related to the other features of their MEN syndrome (e.g. peptic ulceration from the Zollinger-Ellison syndrome owing to excess gastrin secretion).

10. Many patients are asymptomatic and had hypercalcaemia detected on a routine set of biochemical tests. Hyperparathyroidism has been recognised much more commonly since automated biochemical analyses have become routine.

The examination

1. Look for any evidence of a neck scar from parathyroid surgery, as well as forearm scars from re-implantation of the parathyroid gland from the neck.

2. Evaluate the patient for evidence of malignancy, including lymphadenopathy or organomegaly.

3. Look for evidence of renal failure.

4. Carefully evaluate the respiratory system for any evidence of sarcoidosis, as well as tuberculosis or histoplasmosis.

5. Take the pulse for bradycardia, a result of a high serum calcium level. Measure the blood pressure for evidence of phaeochromocytoma.

6. Examine for signs of thyrotoxicosis.

7. Look for pigmentation from Addison’s disease.

8. Examine for proximal weakness and signs of pseudogout in the joints.

9. Examine the cornea for band keratopathy (calcification horizontally across the centre of the cornea).


1. Look at the total serum calcium level. Remember that apparently high calcium levels can be the result of haemoconcentration while the blood is being collected. Correct for hypoalbuminaemia: add 0.02 mmol/L to the serum calcium concentration for every 1 g/L by which the serum albumin level is less than 40 g/L. The calcium level at which symptoms occur varies, but most patients have symptoms when the corrected calcium level reaches 3 mmol/L. Higher levels are associated with tissue calcification and the risk of renal failure, especially if the phosphate level is normal or increased by renal impairment. Once the calcium level approaches 4 mmol/L, unconsciousness and cardiac arrest can occur.

2. Measure the parathyroid hormone (PTH) level. If elevated, primary hyperparathyroidism is the most likely diagnosis (the PTH can be inappropriately in the high normal range in 10%; the phosphorous should be low). If the patient is taking lithium or thiazide, the test should be repeated after discontinuing drug treatment, because these drugs may influence both calcium and parathyroid hormone secretion.

3. In a young otherwise asymptomatic person with a marginal elevation of parathyroid hormone, a 24-hour urine calcium examination should be asked for to exclude familial hypocalciuric hypercalcaemia (FHH). Alternatively, collect a fasting morning spot urine and measure the urine calcium/creatinine clearance ratio (<0.01 in FHH). This autosomal dominant condition is caused by faulty calcium sensing by the parathyroid glands and renal tubules.

4. If there is a low or undetectable parathyroid hormone level, consider the possibility of granulomatous disease, including sarcoidosis, tuberculosis, berylliosis, leprosy and lymphoma. An increased level of 25-OH vitamin D supports this possibility.

5. Ask to review the chest X-ray. Investigations to look for malignancy if suspected may then be required (e.g. protein electrophoresis, CT scan etc.).


There is evidence that asymptomatic patients with hyperparathyroidism who are not treated have increased bone loss compared with controls. Significant increases in fracture risk (especially of the wrist and spine) have been demonstrated.

1. If the diagnosis is hyperparathyroidism and the patient is symptomatic, has renal stones or has a reduced bone density, surgical parathyroidectomy is usually indicated. If the patient is asymptomatic, then treatment is more controversial, but younger patients (<50 years) with higher serum or 24-hour urine calcium levels will usually be offered surgery. Preoperative localisation is not required for the skilled surgeon, but if there is a need for a repeat procedure this can be evaluated using ultrasonography, CT or technetium-99m sestamibi scanning.

2. Note whether there has been hypocalcaemia after surgery. If there is no residual parathyroid tissue left, lifelong vitamin D therapy is necessary or, alternatively, autotransplantation of parathyroid tissue into the forearm may be offered.

3. Primary hyperparathyroidism is associated with vitamin D deficiency. Treatment is controversial if the patient is unfit for surgery, but cautious calcium and vitamin D replacement is probably safe and desirable.

4. In malignant hypercalcaemia the underlying tumour should be treated. Steroids are often effective in lowering the serum calcium level. With granulomatous disease, steroids are also effective in lowering the calcium level (but avoid if infection is the cause); chloroquine may be useful in patients who cannot tolerate steroids. Lithium treatment may need to be stopped. Hypercalcaemia does not necessarily mean lithium toxicity.

5. Familial hypocalciuric hypercalcaemia rarely causes symptoms and should not be treated with parathyroidectomy. Consider screening all first-degree relatives.

6. In an emergency, rehydration with intravenous saline and frusemide is indicated for hypercalcaemia. Parenteral calcitonin lowers calcium levels only transiently. The use of intravenous bisphosphonates is very effective.

Paget’s disease of the bone (osteitis deformans)

This is usually a disease of the elderly, but it may occur in younger patients. In populations from western or southern Europe up to 10% of people over the age of 85 are affected. The condition is characterised by excessive resorption of bone and increased formation of new bone in an irregular ‘mosaic’ pattern. Bone turnover may be increased 20 times early on in the course of the disease. The aetiology is unknown but may be caused by a persistent paramyxovirus infection of osteoclasts. There are reports of familial occurrence (15% have a family history) and of autosomal dominant inheritance. The condition is rare in Asian populations. It presents as a management problem.

The history

1. Ask about symptoms that led to the diagnosis:

a. isolated elevation of alkaline phosphatase on routine blood testing

b. an incidental finding on an X-ray

c. bone pain

d. secondary osteoarthritis

e. change in height or hat size

f. progressive bone deformity or pathological fracture; gait abnormalities associated with change in length of a long bone

g. neurological symptoms – hearing loss, neurological gait disturbance (suggestive of basilar invagination with long tract signs, or cerebellar involvement or spinal cord compression), cranial nerve symptoms, headache

h. symptoms of congestive cardiac failure

i. symptoms of renal colic (as there is an increased incidence of calcium nephrolithiasis in this disease, especially during the resorptive phase)

j. gout, secondary to increased bone turnover

k. sarcoma of bone (very rare – less than 1% of cases, occasionally multicentric)

l. symptoms of hypercalcaemia – thirst, polyuria, nausea, coma (a rare occurrence even in immobilised patients, or alternatively caused by coexisting primary hyperparathyroidism, which is common)

m. pathological fractures, especially of the convex side of weight-bearing bones; can be multiple.

2. Enquire about articular pain, which may be caused by secondary osteoarthritis in joints adjacent to sites of Pagetic involvement, and true bone pain. Secondary osteoarthritis is characterised by pain and stiffness, which improves with joint movement; alternatively it may initially be exacerbated by weight-bearing and relieved by rest. True bone pain is more often constant or gnawing and is worse at night. A sudden exacerbation of bone pain may indicate a pathological fracture or the development of an osteosarcoma.

3. Ask about treatment, its effectiveness and side-effects.

4. Enquire about disability at home and work. Remember, though, that most patients are asymptomatic.

The examination (see Table 10.7)

Table 10.7

Paget’s disease


1. Inspect generally for short stature and obvious deformity (Fig 10.2).


FIGURE 10.2 Paget’s disease in an adult. M C Hochberg, A J Silman, J S Smolen et al., Rheumatology, 5th edn. Fig 202.7. Elsevier, 2011, with permission.

2. Look at the face. Measure the skull diameter (>55 cm may be abnormal). Look for prominent skull veins, feel for bony warmth (actually caused by vasodilatation in the skin) and auscultate for systolic bruits. Examine the fundi for angioid streaks (Fig 10.3), and for papilloedema or optic atrophy, which are rare. Also assess visual acuity and visual fields.


FIGURE 10.3 Angioid streaks in fundus. S J Ryan. Retina, 5th edn. Fig 69.1 a and b. Elsevier, 2012, with permission.

3. Test to see if hearing is decreased as a result of ossicle involvement or eighth nerve compression. Remember, all the other cranial nerves may rarely be affected owing to overgrowth of foramina or basilar invagination, so examine them carefully.

4. Look at the neck for basilar invagination. These patients have a short neck and low hairline, the head is held in extension and neck movements are decreased.

5. Assess the jugular venous pressure and examine the heart for signs of cardiac failure owing to a hyperdynamic circulation.

6. Examine the back. Note any deformity, especially kyphosis. Tap for tenderness. Feel for warmth. Auscultate for systolic bruits over the vertebral bodies.

7. Look at the legs for anterior bowing of the tibia and lateral bowing of the femur. Feel for warmth. Note any changes of osteoarthritis in the hips and knees. There may be limitation of hip movements – especially abduction, which suggests protrusio acetabulae – and fixed flexion deformity of the knees. Be careful, as the bones may be tender.

8. Sarcomas (a feared, but rare complication) should be looked for, particularly in the femur, humerus and skull; they usually present as tender, localised swellings. They can be multiple.

9. A full neurological examination is necessary for spinal cord compression and basilar invagination, which may even cause quadriparesis. If the patient is mobile, do not forget to assess walking for any disability. Cerebellar signs may also rarely occur with basilar invagination.

10. Check the urine analysis (for blood, as renal stone incidence is increased) and measure the patient’s height (for serial follow-up).


These are indicated in symptomatic patients requiring treatment and in asymptomatic subjects to determine the extent of skeletal involvement. Paget’s disease is occasionally confused with osteoblastic bone secondaries (e.g. from prostate, Hodgkin’s disease) or fibrous dysplasia.

1. Testing for hypercalcaemia may be worthwhile for any patient who is immobilised.

2. The serum alkaline phosphatase level is an indicator of disease activity, as is the urinary hydroxyproline level. Other biochemical markers of bone turnover will also be increased (e.g. osteocalcin, urine or serum cross-links of collagen).

3. Radiologically the bones most often involved are the pelvis, femur, skull and tibia (see Figs 10.4 and 10.5). Look for bony enlargement, increased density, an irregular widened cortex and cortical infractions (incomplete pseudofractures) on the convex side of the bowed long bones. The early lytic phase of the disease, presenting with a flame-shaped osteolytic wedge advancing along the bones, is often overlooked. Secondary arthritic changes may occur (e.g. hips). Bone scanning is more sensitive than an X-ray in assessing the extent of disease. CT scanning or MRI may be useful in the investigation of an atypical lesion, especially if sarcoma is suspected.


FIGURE 10.4 MRI of the lower leg of a patient with Paget’s disease. A large osteosarcoma of the tibia can be seen (arrow). Figure reproduced courtesy of The Canberra Hospital.


FIGURE 10.5 Skull X-ray of a patient with Paget’s disease. Note the bony enlargement of the cranium. Figure reproduced courtesy of The Canberra Hospital.


The indications for treatment are bone pain, progressive deformity or complications such as neural compression or high-output cardiac failure, and as a prelude to orthopaedic surgery. Treatment of patients with Pagetic involvement of weight-bearing bones may be indicated to attempt to prevent deformity and pathological fracture. Proof of benefit is not available, however.

1. Simple analgesics (paracetamol) or NSAIDs, including COX-2 inhibitors, should be used first to control pain. Orthopaedic procedures such as total hip replacement may be indicated.

2. A number of drugs are available that reduce bone resorption.

a. An oral bisphosphonate (e.g. alendronate) is usually the first-line treatment. These drugs are effective at reducing hydroxyproline excretion and often relieve symptoms, but may exacerbate bone pain initially. They also impair bone mineralisation and may cause osteomalacia. However, bone turnover is reduced and new bone is usually more normal in structure. The bisphosphonates should be given in combination with calcium supplements and vitamin D. Ulcerating oesophagitis causing dysphagia is an important side-effect. The bisphosphonates are not generally indicated for asymptomatic patients. Intravenous infusions of the potent bisphosphonate pamidronate may produce prolonged suppression of Pagetic activity and may normalise bone turnover in patients with mild disease without adverse effects on bone mineralisation or bone formation.

b. Calcitonin of salmon or human origin, given subcutaneously, often improves bone pain and may be useful in the treatment of neurological complications. Although side-effects (nausea, flushing and diarrhoea) are common and may limit treatment in up to 20% of patients, it is still regarded as a first-line therapy. Resistance to salmon calcitonin after 1 to 2 years may indicate the development of neutralising antibodies. Serum alkaline phosphatase levels and urinary hydroxyproline levels are useful guides to the effect of treatment; a 50% reduction in either test value indicates a good response to treatment.

c. Mithramycin, given intravenously, can be very effective. It is reserved for occasions when rapid remission is required (e.g. spinal cord compression). There may be significant increases in bone lysis and predisposition to fractures with this drug, as well as bone marrow depression.

3. Surgery, including osteotomy for misshapen femurs, may be useful. It is important for the patient to avoid immobilisation in the postoperative period because of the risk of hypercalcaemia.

4. The appearance of osteosarcoma (see Fig 10.4) is associated with a poor prognosis. Preoperative chemotherapy followed by amputation – the current treatment for spontaneously occurring tumours – is being evaluated.


Although an uncommon condition, three to four new cases per million people a year, acromegaly is a chronic illness and common as a long or a short case.

The history

The patient will probably know the diagnosis, although if the condition has been suspected only recently investigations may still be underway. The patient may be in hospital for these tests because of a complication of the condition or, perhaps more likely, has been brought in for the clinical examinations.

1. Find out when the diagnosis was made and how long ago; in retrospect, the patient may have had symptoms for years. The average time taken to make the diagnosis is more than 10 years.

2. Ask why the diagnosis was suspected. The onset of abnormalities is usually very gradual. The common features of the condition are listed in Table 10.8. Ask what changes the patient has been aware of and whether these have improved with treatment. Bony and acral changes are irreversible and early diagnosis is worthwhile.

Table 10.8

Symptoms and signs in acromegaly

Acral enlargement*

Muscle weakness

Carpal tunnel syndrome


Diabetes mellitus

Peripheral neuropathy

Enlarged jaw and facial features* (see Fig 10.6)

Skin tags and colon polyps


Soft-tissue enlargement*



Impotence and hypogonadism

Symptoms of sleep apnoea

*In >50% of patients

3. Ask about the associations and complications of the condition. The mortality rate for untreated acromegaly is about twice that of the age-matched population, mostly as a result of an increased risk of cardiovascular disease. There is also an increase in the incidence of colonic polyps and carcinoma of the colon.

4. There is now a recognised association with obstructive sleep apnoea and questions should be asked about snoring, daytime sleepiness and other relevant symptoms. The reason for the association is the enlargement of the tongue and swelling of the upper airway.

5. Ask if the patient knows what investigations have been performed (see investigations below).

6. Ask about current and past treatment and how helpful this has been. Pituitary surgery and radiotherapy have a number of complications.

7. As with any chronic illness, the effect of acromegaly on the patient’s life may be severe. Ask about occupation and ability to work.

The examination

See page 380 and Fig 10.6.


FIGURE 10.6 Acromegalic appearance.


1. The preferred test is measurement of insulin-like growth factor I (IGF-I). Unlike growth hormone (GH) which is affected by exercise and diet, the level of IGF-I does not fluctuate and the absolute level reliably reflects the average GH level. There is physiological elevation of the level in pregnancy and during puberty, but otherwise elevation is very specific for acromegaly. The diagnosis is usually confirmed with a glucose tolerance test, where GH suppression (normal to <0.33μg/L – 1mIU/L) is measured in response to a glucose load. Failure of suppression is characteristic of acromegaly, but the test is non-specific and may be abnormal in renal impairment, thyrotoxicosis and diabetes.

2. In 25% of acromegalic patients, the prolactin level is elevated and this can be associated with galactorrhoea. Other pituitary hormone levels may be low because of interference with normal pituitary function by the large mass of the tumour. Baseline pituitary function should be assessed with measurements of prolactin, cortisol, thyroxine, follicle-stimulating hormone (FSH), luteinising hormone (LH) and free alpha subunit.

3. Imaging is performed once an elevated IGF-I is confirmed. MRI scanning is the modality of choice as it provides excellent anatomical definition of the tumour (see Fig 10.7). If the tumour is close to the optic chiasm visual field assessment should be performed.


FIGURE 10.7 MRI of the brain showing a large pituitary tumour (arrow). Figure reproduced courtesy of The Canberra Hospital.


The aim of treatment is to prevent excess GH production without interfering with normal pituitary function. Early diagnosis makes treatment easier and more effective, and IGF-I testing makes the diagnosis easier.

Acromegaly is cured when the IGF-I level is normal and GH is suppressed to less than 1.2 mIU/L after an oral glucose load. However, symptomatic relief can be obtained without complete cure.

Medical treatment with long-acting somatostatin analogues is increasingly useful, both before surgery and afterwards if removal is incomplete. Overall, surgery remains the treatment of first choice.


1. Long-acting somatostatin analogues, such as octreotide LAR and lanreotide autogel, are available. These drugs mimic the inhibition of GH release by somatostatin. They have the advantage that they are long-acting enough to be effective when given by subcutaneous or intramuscular injection. The usual dose of octreotide LAR is 20 mg by intramuscular injection 4-weekly, but this can be increased or decreased depending on the GH and IGF-1 levels. Lanreotide autogel is given as a starting dose of 60 mg by s.c. injection 4-weekly. Unlike somatostatin, these drugs do not significantly inhibit insulin secretion. Unless surgery or radiotherapy has cured the disease, treatment must be continued indefinitely. Symptoms such as headache, arthralgia and sweating improve after a few weeks. Biochemical remission occurs in up to 70% of patients. The drugs sometimes cause a 50–70% reduction in the size of the tumour, which can make surgery easier. Side-effects of treatment are usually relatively mild and include discomfort at the injection site, diarrhoea, anorexia, abdominal bloating and cholelithiasis.

  Long-acting depot injections are now available but expensive. For this reason, they are usually reserved for patients in whom other treatment has not been completely successful or is contraindicated.

2. Cabergoline is also available for treating acromegaly. It causes a paradoxical suppression of GH release in acromegalics, but at tolerated doses remission is not usually obtained. Side-effects include nausea, anorexia and hypotension. The drug is most often used as adjunctive treatment after radiotherapy or surgery.


1. Trans-sphenoidal pituitary surgery is effective at selectively resecting the benign adenoma and preserving pituitary function in 50–80% of surgically treated cases. If cure is defined as a return of IGF-I to the normal range, then surgical cure is less often obtained. Nevertheless, symptoms are almost always greatly relieved by surgical debulking of the tumour.

2. The perioperative mortality rate should be less than 1%.

3. Uncommon complications include cerebrospinal fluid rhinorrhoea, diabetes insipidus and stroke. Hypopituitarism follows eventually in about 10% of patients.


Radiotherapy is usually considered as a second-line treatment where surgery has not been completely effective.

1. Conventional radiotherapy delivers about 5000 cGy to the pituitary over 5 weeks. It works only slowly. GH levels take a year to fall by 25%. Even after 10 years few patients achieve normal IGF-I levels. Hypopituitarism is common after radiotherapy, but other side-effects are rare.

2. Newer, more promising techniques use computerised MRI to deliver larger doses accurately to the gland (‘stereotactic radiosurgery’).


1. Cardiovascular; echocardiography 5- to 10-yearly (heart failure, valve disease).

2. Gastrointestinal; colonoscopy for polyps – at diagnosis and as required for surveillance.

3. Thyroid; thyroid examination and TFTs regularly.

4. Metabolic; check blood pressure, check lipids annually, fasting BSL annually.

5. Musculoskeletal; ask about symptoms; carpal tunnel, arthropathy.

Types 1 and 2 diabetes mellitus

This is a common subject for the long case since patients with diabetes are always available. A large proportion of long-case patients have type 2 diabetes, often as part of the ‘metabolic syndrome’. Diabetes usually presents a management rather than a diagnostic problem. The examiners like this disease because it tests very practical management skills.


Candidates are often tempted to unleash a set piece diabetes long case formula on the examiners. Don’t do it! Tailor the presentation to the actual patient you have seen.

Juvenile diabetes (immune-mediated diabetes) is called type 1 and maturity-onset diabetes (non-immune-mediated diabetes) is called type 2. Most type 1 diabetes (type 1A) is associated with autoimmune destruction of islet cells, but a small proportion of these diabetics do not have these abnormalities (type 1B). Table 10.9 lists the antibodies known to be associated with Type 1 diabetes. The cause of type 1B diabetes in these patients is not known, but it is more common in Asian populations. Type 2 diabetes is increasingly found in obese adolescents and children. More than 90% of diabetics have type 2 disease.

Table 10.9

Type 1 diabetes – associated antibodies


Don’t forget the criteria for diagnosis of diabetes mellitus – a fasting (overnight) blood sugar level (BSL) of 7.0 mmol/L or higher on at least two separate occasions or, in the absence of fasting hyperglycaemia, a 2-hour postprandial glucose level of 11.1 mmol/L or higher. Fasting blood glucose levels between 6.1 and 7.0 mmol/L are considered to represent impaired fasting glucose levels. In a patient with symptoms of diabetes a random BSL of >11.1mmol/L is diagnostic. There is evidence that complications of diabetes may occur in some populations when the fasting glucose level is over 6.1 mmol/L. An HbA1c level of >48 mmol/mol (>6.5%) is consistent with a diagnosis of diabetes.

The history

1. Ask about the age at which diabetes was diagnosed and its manner of presentation – thirst, polyuria and polydipsia, weight loss, infection, ketoacidosis, asymptomatic glycosuria. Remember, the rare causes of glucose intolerance (Table 10.10).

Table 10.10

Causes of glucose intolerance


2. Ask about the treatment initiated at diagnosis and major changes that have occurred over time (insulin is required for survival in type 1 diabetes, which usually has an onset below age 30 years; in type 2 diabetes, control typically becomes more difficult with time).

3. Ask about the diet prescribed (Table 10.11). The previous strict dietary rules using exchanges and portions have largely been abandoned, but some patients may still use them (one exchange = 15 g of carbohydrate = 60 calories = 250 kilojoules (kJs, but the definition does vary); e.g. for an average-sized male, three exchanges for each main meal and two exchanges for morning and afternoon tea and supper are required to provide an even carbohydrate distribution – 50% of the diet). Ask whether the patient knows about the glycaemic index (GI) factor. What has happened to the patient’s weight since the diagnosis was made?

Table 10.11

Dietary recommendations for type 1 and type 2 diabetes


4. Ask whether oral hypoglycaemic drugs have been used or are being taken.

5. Ask about insulin treatment – how much and when taken. The usual dose is 0.5 units/kg/day, with 40% of the dose comprising a long-acting insulin. Also ask where the insulin is injected and by whom, and find out the type of insulin syringe used (e.g. a pen injector).

6. Ask about the progress of the disease:

a. assessment of control adequacy – does the patient use a home blood glucose monitoring meter? If the patient is blind, is the glucometer a talking version? Which glucose reagent strip is used and which meter? (Remember that different meters require different reagent strips.) Enquire how often the test is done, the usual results, at what time of day the test is performed (pre- or postprandial or both) and whether the dose is adjusted at other times (e.g. gastrointestinal upset). Ask about recent glycosylated haemoglobin (HbA1c) results. Ask about symptoms of poor control:

i. hyperglycaemia – polyuria, thirst, weight loss, intermittent blurring of vision, hospital admissions with ketoacidosis (type 1 diabetes only)

ii. hypoglycaemia/hypoglycaemia awareness – ask the patient to describe the symptoms and how they are managed; ask specifically about morning headaches, morning lethargy and night sweats (symptoms suggestive of nocturnal hypoglycaemia), weight gain and seizures; ask about the time of day in relation to food, alcohol, exercise and insulin injection

b. involvement of other systems:

i. vascular system – ischaemic heart disease, intermittent claudication, cerebrovascular disease

ii. nervous system – peripheral neuropathy, autonomic neuropathy (causing erectile dysfunction, fainting, nocturnal diarrhoea), amyotrophy

iii. eyes – regular visits to an ophthalmologist or retinal photography at the diabetes clinic and treatment received (ask especially about laser treatment)

iv. renal system – dysuria, nocturia, oedema, hypertension; is the patient taking an ACE inhibitor or AR blocker for renal protection; has there been proteinuria?

v. skin – boils, vaginitis and balanitis, Candida, necrobiosis lipoidica.

7. Ask about drug history – steroids, thiazides, oral contraceptives, beta-blockers.

8. Ask about associated other diseases – history of pancreatitis, Cushing’s syndrome, acromegaly.

9. Enquire about social background – type of work, living conditions (living alone or with family), coping with giving insulin (associated blindness etc.), eating habits, financial situation, driving (type of licence held).

10. Ask about variations in weight and a regular exercise program. Have diet and exercise led to a fall in weight since the diabetes was diagnosed?

11. Ask about cardiovascular risk factors, including family history, serum cholesterol level, smoking and hypertension, and drug and non-drug attempts at control of these factors (except family history).

12. Enquire about family history of diabetes and obstetric history (e.g. big babies, stillbirths), and other risk factors for type 2 diabetes (see Table 10.12).

Table 10.12

Risk factors for type 2 diabetes


13. Ask whether the patient has an ‘action plan’ for hypoglycaemic symptoms and what this involves.

Table 10.13

Particular considerations for type 1 diabetes


The examination

Detailed examination is essential, looking specifically for complications of the disease (Figs 10.8 and 10.9). In particular, don’t forget to look at the retina. Inspect the feet and assess for peripheral neuropathy. Test the urine. If the patient is obese, assess BMI and waist circumference.


FIGURE 10.8 Acanthosis nigricans (a) View of the axillar region. (b) View of the neck and anterior chest wall. I Tonguc, S Cenc, D Iscen, K Yildiz. Acanthosis nigricans and an alternative for its surgical therapy. Journal of Plastic, Reconstructive and Aesthetic Surgery, 2008, 62(1):148–150, with permission.


FIGURE 10.9 Partial lipodystrophy, acquired. (a) Face (b) hypertrophy of subcutaneous fat on the lower half of the body. W D James, T Berger, D Elston. Andrews’ diseases of the skin: clinical dermatology. 11th edn. Fig 23-9. Saunders, Elsevier, 2011, with permission.


The general aim is to regulate diet, exercise and insulin so as to allow the patient to lead a normal life while avoiding short- and long-term complications.

In adults with type 1 diabetes, multiple injection regimens are preferred because the improved control prevents or retards the progression of complications.


The major management decision here is whether insulin is required. In some cases this will be obvious (e.g. for the type 1 patient with ketoacidosis), but for many elderly obese diabetics the position is not so clear. If insulin is not indicated at presentation, attempt to gain control first by weight loss and diet, followed by oral hypoglycaemic agents.

1. Weight loss. Weight loss to achieve ideal body weight increases insulin sensitivity. Abdominal obesity (waist–hip ratio >0.9 for women and >0.8 for men) increases the risk of metabolic complications. Realise that there is some disagreement about the ideal diet, but achieving ideal weight is essential.

2. Diet. The recommended diet (see Table 10.11) should be tailored to the patient’s requirements and activities. For example, kilojoule recommendations for a 20-year-old man undertaking normal activities are 175 kJ/kg of body weight and for a 75-year-old man are 140 kJ/kg. Distribution of carbohydrate should be worked out on an individual basis. Fat intake should be kept to ≤30% of kilojoules for patients who are not overweight and considerably less for obese patients. The distribution of kilojoules is more important for insulin-requiring patients, who should usually have about 20% for breakfast, 35% for lunch, 30% for dinner and 15% for supper. Patients who use short-acting insulin before each meal may be able to vary the insulin dose to suit the meal. The diet should include high-fibre foods and monounsaturated fats. Polyunsaturated fats can raise triglyceride levels but monounsaturates tend to reduce them. Patients with nephropathy may be advised to restrict protein intake, usually to about 10% of kilojoule intake.

3. Oral hypoglycaemic agents. The use of oral hypoglycaemic agents is first line treatment for type 2 patients where diet has not been successful. Table 10.14 shows the NHMRC treatment chart for type 2 diabetes.

Table 10.14

Major secondary causes of osteoporosis


a. Metformin is the only available biguanide and is regarded as the agent of choice in the obese patient with type 2 diabetes. They are contra-indicated for patients with an eGFR < 30mL/min/1.73m². Side-effects of biguanides include:

i. diarrhoea, anorexia, nausea and occasionally vomiting

ii. vitamin B12 malabsorption

iii. lactic acidosis (the risk is increased in the elderly and in patients with cardiovascular, liver and kidney disease); the drug is contraindicated in heart failure

iv. interaction with radiocontrast materials; the drug should be stopped on the day of a procedure requiring contrast and for 48 hours afterwards

v. Metformin rarely causes hypoglycaemia and there is a synergistic effect when it is used in combination with sulfonylureas.

b. Sulfonylureas include first-generation drugs (e.g. chlorpropamide and tolbutamide) and second-generation drugs (e.g. gliclazide, used for obese patients; glipizide, used for thin patients; and glibenclamide). Second-generation drugs are as effective as the first-generation ones and are associated with fewer drug interactions. The mechanism of action of sulfonylureas is to increase insulin action peripherally and to increase insulin secretion. Side-effects of sulfonylureas include:

i. possibly an increase in the cardiovascular death rate – this fear seems not to have been well founded, as the UKPDS (see below) did not find any increase in cardiovascular mortality for patients on these drugs

ii. prolonged hypoglycaemia – this is greatest with glibenclamide, which is therefore not recommended for those over the age of 60; gliclazide and glipizide are as effective and are safer

iii. weight gain (owing to increase in appetite and mild hypoglycaemia)

iv. bone marrow depression

v. cholestatic jaundice

vi. skin rash

vii. alcohol intolerance, causing flushing

viii. water retention and hyponatraemia (syndrome of inappropriate antidiuretic hormone).

The effectiveness of the sulfonylureas is variable and rates of secondary failure vary between agents. Primary failure occurs in 40% of cases and secondary failure in 3–30%; only 20–30% of patients continue with satisfactory control. Substitution of one drug for another may be worth trying (Table 10.15).

Table 10.15

Oral hypoglycaemic agents


c. Thiazolidinediones (TZDs) are a newer class of oral hypoglycaemic drugs (Table 10.15). They reduce insulin resistance, blood sugar levels and triglycerides. Pioglitazone and rosiglitazone are available in Australia: their use is restricted to patients whose HbA1c is over 7% during the preceding 3 months and who are on maximum tolerated doses of metformin and a sulfonylurea. Patients on insulin must also be on metformin and have a raised HbA1c. Liver function tests must be performed every 2 months for the first year and the drug stopped if the alanine aminotransferase (ALT) level rises above 2.5 times normal. The drugs are associated with small rises in HDL and LDL cholesterol and with peripheral oedema. Some are associated with an increased risk of ischaemic heart disease. They are contraindicated for patients with class III or IV heart failure.

d. Acarbose inhibits intestinal alpha-glucosidase, slowing polysaccharide degradation and absorption. It is a useful agent taken before meals with other treatment. Side-effects include flatulence, diarrhoea and abdominal pain, but there is no major toxicity.

e. The gliptins (DPP-IV inhibitors) sitaglitin, vidagliptin, saxagliptin and linagliptin increase the levels of incretin peptides (e.g. glucagon-like peptide) by inhibiting their degrading enzyme. Insulin release is increased and glucagon suppressed. They can only be used in combination with metformin or a sulfonylurea except for linagliptin which can be used with both. They are weight neutral and can be used in old patients but chronic kidney disease is a relative contraindication.

f. GLP-1 analogues. The only approved drug currently is exenatide. This glucagon analogue is resistant to DPP IV degradation. It has to be given by injection twice a day. It can be especially useful for overweight patients.


1. Insulin requirements initially are generally between 0.4 and 1.0 U/kg/day. An anorectic agent should be considered when requirements exceed 1.5 U/kg/ day. Insulin therapy is often begun on an outpatient basis and under these circumstances small doses (e.g. 0.25 U/kg/day), sufficient to prevent ketosis, are used with a view to avoiding hypoglycaemia.

  Modern insulins are either recombinant human insulin or analogue insulin (see Table 10.16). Analogue insulins have been genetically altered to maintain their monomeric form when injected subcutaneously. This better mimics physiological insulin release.

Table 10.16

Available insulins









Humilin R




Humulin NPH

Protamine suspension


Protamine suspension

Biphasic mixtures


Humulin 30/70

Protamine suspension +neutral

Mixtard 30/70

Protamine suspension +neutral

Mixtard 50/50

Protamine suspension +neutral











Biphasic analogue insulins


Novomix 30

Aspart +aspart protamine

Humalog mix 25

Lispro + lispro suspension

Humalog mix 50

Lispro +lispro suspension

Long-acting insulins






a. Possible insulin regimens include: the basic bolus regimens, using a short-acting insulin at mealtimes, with an intermediate- or long-acting insulin at suppertime; twice-daily double mix, using a combination of short- and intermediate-acting insulin (premixed ratios – short:intermediate are commercially available (Table 10.16), or the patient may mix insulins in a syringe); and in patients with type 2 diabetes, a combination of oral hypoglycaemic agents at mealtimes with an intermediate- or long-acting insulin at supper is an option.

b. Continuous subcutaneous insulin infusion is a treatment option, but infusion devices remain beyond the means of most patients with diabetes and may be associated with an increased risk of morbidity and mortality related to hypoglycaemia. The administration of intraperitoneal insulin via the dialysate can be useful in the management of patients on continuous ambulatory peritoneal dialysis (CAPD), and continuous intraperitoneal infusion has been attempted in some centres.

c. Human insulin has replaced the highly purified (monocomponent) insulins. Many patients reported altered symptoms of hypoglycaemia and a more rapid onset of symptoms after changing to human insulin. Aim for euglycaemia: ideally the glucose level should be between 3.5 and 7.0 mmol/L throughout the day and night.

2. Insulin resistance is defined as a requirement of more than 200 units per day. Causes of insulin resistance are:

a. obesity (decreased receptor number)

b. insulin antibodies (uncommon, and an indication for a more purified insulin)

c. circulating antagonist hormones – growth hormone (e.g. in puberty), cortisol, thyroxine, glucagon

d. association with acanthosis nigricans (e.g. receptor abnormalities, lipodystrophies). Remember, injecting into a lipoatrophied site may cause poor control because of unpredictable absorption.

3. Insulin allergy has been uncommon since the widespread introduction of human insulins, but they can cause immediate local reactions (e.g. pruritus, local pain) or delayed reactions (e.g. swelling). Urticaria and anaphylaxis can also occur. Treatment in mild cases is with antihistamines and local steroids, but in severe cases desensitisation is important. Insulin allergy is more common in patients who stop and start insulin therapy.

4. Fasting hyperglycaemia is a major management problem. The ‘Somogyi effect’ refers to rebound morning hyperglycaemia following nocturnal hypoglycaemia, which is thought to be caused by the release of counter-regulatory hormones. This is now, however, a matter of considerable debate. The treatment is to reduce the evening insulin dose. The ‘dawn’ phenomenon is early morning hyperglycaemia in the absenceof nocturnal hypoglycaemia; the treatment is to increase the insulin coverage without inducing hypoglycaemia.

5. Causes of hypoglycaemia in a previously stable diabetic on insulin therapy are:

a. decreased food intake, increased exercise or weight loss

b. injection errors

c. diabetic renal disease

d. rare causes – high level of insulin antibodies, malabsorption, hypothyroidism, autoimmune adrenal insufficiency, panhypopituitarism or an insulinoma.

6. Haemoglobin A1c gives an indication of control over the preceding three months: aim for a level of 53 mmol/mol (7%) or less, although the numbers may be distorted by one or two high blood sugar levels. Spurious readings may occur in kidney failure, iron deficiency, haemoglobinopathies and pregnancy.


Because diabetes is a lifelong disease, detailed education by the team looking after the patient is important. Regular follow-up is essential.

1. Blood glucose monitoring with a glucose meter is essential for all patients who can manage it – initially, testing several times a day before and 2 hours after meals, and before bed, may be necessary; later, in stable diabetes, twice-daily may be enough.

2. Exercise promotes glucose utilisation; in the well-controlled diabetic it is important to reduce the dose of regular insulin before exercise or supplement with glucose. (Note: Exercise in the poorly controlled diabetic may precipitate ketoacidosis because of increased release of counter-regulatory hormones.)

Management of chronic complications

Complications are probably a result of damage caused by glycosylated proteins. Convincing evidence that tight control prevents or reverses complications is now available. Following the Diabetes Control and Complications Trial published in 1994 and the more recent United Kingdom Prognosis in Diabetes Study (UKPDS), clinicians now agree that rigorous control of blood sugar levels and aggressive control of blood pressure and other cardiovascular risk factors is essential. These measures are probably more effective in the early stages of the disease.

1. The blood pressure can be managed with any antihypertensive but the use of an ACE inhibitor or AR blocker (but not both) is strongly indicated when proteinuria has been detected, and is often used routinely. The goal blood pressure about 130/80 mmHg.

2. Lipid control with the statins is being assessed in a number of trials. The high cardiovascular risk of these patients suggests that aggressive lipid-lowering with one of these drugs will be of value. Remember to control other risk factors, such as smoking (for retinopathy and vascular disease) and alcohol intake (for neuropathy and hypertriglyceridaemia). Aspirin prophylaxis is controversial, but for primary prophylaxis may be considered in older patients with one other risk factor (e.g. hypertension).

3. Ideally, all patients should be assessed every 2 years by an ophthalmologist. Less sophisticated fundoscopy may miss early diabetic retinopathy (see Table 16.43). Retinal cameras can now be used at the clinic to take clear retinal photographs, which can be repeated often and ‘read’ by an ophthalmologist. Retinopathy almost always precedes diabetic nephropathy.

4. Diabetic nephropathy is a common cause of chronic kidney failure and results from arteriolar disease or glomerulosclerosis (classic Kimmelstiel-Wilson lesion or, more commonly, diffuse intercapillary glomerulosclerosis). The evolution of diabetic nephropathy has been well studied and can be divided into the following stages:

a. glomerular hyperfiltration

b. microalbuminuria

c. dipstick proteinuria

d. proteinuria in the nephrotic range

e. end-stage kidney disease.

5. Microalbuminuria is defined as a urinary albumin excretion of 20 to 200 μg/ minute (measured using sensitive immunoassays) on more than two occasions in the absence of urinary tract infection and intercurrent illness. The albumin-to-creatinine ratio may be a more sensitive way of assessing the presence of significant proteinuria. Regular screening for microalbuminuria is now considered an important component of good diabetes management. The microalbuminuria stage is probably reversible with a combination of ACE inhibitor therapy, strict metabolic control and possibly dietary protein restriction.

6. Once proteinuria develops, progression to end-stage kidney disease appears inevitable over a period of about 5–10 years. The rate of progression may be modified by:

a. control of hypertension – ACE inhibitors are the agents of choice, but it is important to be aware of the risk of hyperkalaemia as a result of hyporeninaemic hypoaldosteronism and deteriorating kidney function in patients with renovascular disease

b. treatment of urinary tract infections

c. dietary protein restriction

d. possibly improving glucose control.

  ACE inhibition is indicated as soon as proteinuria is detected. ARBs are an alternative for those intolerant of ACE inhibitors. ACE-I and ARB combination treatment may reduce proteinuria further, but has little additive effect on blood pressure and is associated with an increased risk of acute kidney failure. There is an increased incidence of papillary necrosis with urinary tract infection.

7. The best form of management for end-stage chronic kidney disease in a diabetic is peritoneal dialysis and early kidney transplantation. Remember that diabetics with chronic kidney failure almost invariably also have retinopathy, which may be worsened by haemodialysis.

8. For those with severe systemic complications or end-stage kidney disease, whole-organ pancreas (with or without kidney) transplantation is a promising therapeutic option. A number of successful kidney/pancreas transplants have been performed. Patients are generally euglycaemic without hypoglycaemic treatment. This is the treatment of choice for diabetics with kidney failure.

The pregnant patient with diabetes

Remember that blood sugar levels are normally lower in pregnancy. A woman with no diabetic history should be screened for gestational diabetes in the 24th–28th week. A 50-g glucose load is given and the blood sugar is measured 1 hour later. The normal result is <7.0 mmol/L. Between 7.0 and 7.8 mmol/L is borderline (repeat) and ≥7.8 mmol/L means that a formal 75-g glucose tolerance test is required: a fasting level of ≥5.3 mmol/L and a 2-hour level of ≥8.6 mmol/L indicates gestational diabetes mellitus.

1. Insulin requirements vary during pregnancy owing to the effects of human placental lactogen (HPL). In the first trimester, insulin requirements usually remain unchanged or may decrease, but in the second trimester some increase in insulin requirements occurs owing to rising HPL levels. By the third trimester insulin requirements are usually at least 50% higher than before pregnancy, but after delivery there is a dramatic decrease in insulin requirements.

2. Blood glucose control should be improved as much as possible before conception in a diabetic woman wanting to undertake pregnancy. Haemoglobin A1c should be normalised, as strict metabolic control at the time of conception has been shown to prevent the otherwise increased incidence of congenital malformations in the offspring of diabetic mothers. The complications of poor control seen in the infant are:

a. congenital malformations such as spina bifida (incidence about 6%, double the normal rate)

b. macrosomia

c. intrauterine fetal death in the later stages of pregnancy

d. hypoglycaemia after delivery

e. complications related to immaturity (e.g. respiratory distress syndrome, hypocalcaemia, jaundice).

3. Use of home blood glucose monitoring, with testing of both pre- and postprandial glucose levels, is essential. Strict glucose control must be maintained during labour and delivery. Paediatric services and a neonatal intensive care unit should be available. Remember that statins, ACE inhibitors and ARBs must be ceased in pregnancy.