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Metabolic and endocrine disorders
Dynamic tests for cortisol excess
Overnight dexamethasone suppression test—Dexamethasone (1 mg) is taken orally at midnight; plasma cortisol level is measured at 9 a.m. the next morning. In normal
patients, ACTH and cortisol production will be suppressed
by negative feedback.
In all cases of Cushing syndrome there is absence of
suppression of cortisol. In Cushing disease the feedback
mechanism is less sensitive than normal (see High-dose
dexamethasone suppression test). Ectopic ACTH production has no negative feedback mechanism. In adrenocortical tumours, ACTH will already be suppressed and cortisol
level will remain high.
High-dose dexamethasone suppression test—This
is used after positive results from tests to differentiate
between Cushing disease and ectopic ACTH production.
Plasma cortisol level is measured; 2 mg of dexamethasone
is taken orally every 6 hours for 2days. After 48 hours from
the first dose, plasma cortisol level is measured again. In
normal individuals, the plasma cortisol should be almost
undetectable. In Cushing disease the less sensitive feedback
mechanism should be overcome by the high dose, and the
cortisol level should fall by at least half. Suppression should
not be seen in ectopic ACTH production.
Corticotrophin-releasing hormone test—Plasma cortisol and ACTH are measured at several intervals shortly
following administration of CRH. Ectopic ACTH production should not increase, whereas a pituitary adenoma will
respond to the CRH, leading to a rise in ACTH and cortisol
levels. This can be used with the high-dose dexamethasone
test to increase diagnostic accuracy.
Tests for cortisol deficiency
Dynamic tests to demonstrate cortisol deficiency, e.g.
Addison’s disease, include:
Short Synacthen test—Plasma cortisol level is measured
and 0.25 mg of Synacthen (which has the same biological
action as ACTH) is given IM or IV. Plasma cortisol level is
remeasured after 60 minutes. In normal patients, cortisol level
will rise by a minimum of 200 nmol/L to at least 500 nmol/L.
The response will be poor in hypoadrenalism of any cause.
Long Synacthen test—In this test, 1 mg of Synacthen
is given by IM injection daily for 3days. Hypoadrenalism
due to adrenal gland atrophy because of long-term steroid
treatment or secondary hypoadrenalism shows a response
to this level of stimulation. No response will be seen in adrenal hypofunction.
Corticotrophin-releasing hormone test—This can be
used to look for secondary hypopituitarism. There will be a
poor response to CRH administration.
Pituitary function tests
If suspecting hypopituitarism or pituitary failure, initial
blood tests should include measurement of TSH, T4, T3, prolactin, GH, IGF-1, LH, FSH, testosterone and cortisol levels.
Pituitary fossa imaging is then undertaken (e.g. CT/MRI or
lateral skull X-ray). Dynamic tests are sometimes needed:
• Insulin tolerance test: this is used to assess ACTH or
GH deficiency. A bolus of insulin is given to cause
hypoglycaemia and stimulate ACTH and GH release. A
baseline blood sample for measurement of GH, cortisol
and glucose levels is taken. A fast-acting insulin is then
given, and further blood samples are taken at intervals.
Glucose level below 2.2 mmol/L must be achieved.
Cortisol and GH levels should rise.
HINTS AND TIPS
The insulin tolerance test needs test needs
to be conducted in a very controlled fashion
in a safe environment because of the risk of
severe hypoglycaemia requiring correction with
intravenously administration of glucose. Consult
local guidelines and always follow these.
MISCELLANEOUS ENDOCRINE CONDITIONS
Multiple endocrine neoplasia
There are two main syndromes, both autosomal dominant
and both rare. Tumours originate from two or more endocrine glands that produce peptide hormones.
‘MEN type 1’ refers to a predisposition to benign parathyroid adenomas, pancreatic islet cell/gastrointestinal adenomas and pituitary adenomas. Individuals with MEN type
1 are also at higher risk of developing other tumours such as
thymus, carcinoid and adrenal.
‘MEN type 2a’ refers to the association of phaeochromocytoma, medullary carcinoma of the thyroid and parathyroid adenoma or hyperplasia.
In MEN type 2b there is phaeochromocytoma and medullary carcinoma of the thyroid, but no parathyroid adenoma
or hyperplasia. There are developmental abnormalities with a
Marfanoid habitus and intestinal and visceral ganglioneuromas.
Family members should be screened.
HINTS AND TIPS
Multiple endocrine neoplasia (MEN) features
commonly in examination questions.
• MEN type 1 is three P’s ( pituitary, parathyroid
and pancreas),
• MEN type 2 is two C’s ( catecholamines (i.e.
phaeochromocytoma) and medullary carcinoma
of the thyroid) and parathyroid (for MEN 2a) or
mucocutaneous neuromas (for MEN 2b).
328
Metabolic bone disease
↑
↑
↑
3333
Autoimmune polyendocrine syndrome
Autoimmune polyendocrine syndrome (APS) type 1 is an
autosomal recessively inherited disorder characterized by
hypoparathyroidism, adrenal insufficiency and candidiasis.
It usually becomes clinically apparent in the second decade.
Hypogonadism and gastrointestinal malabsorption also occur frequently.
APS type 2 is more common. Around half of cases are
inherited, but this may be in a dominant, recessive or polygenic manner. Adrenal insufficiency is the most common
feature, often with thyroid disease and diabetes, and there
may be a predisposition to nonendocrine autoimmune
disease.
Skin
Provitamin D
(7-dehydrocholesterol)
3
Previtamin D
Congenital adrenal hyperplasia
These inherited deficiencies of enzymes involved in glucocorticoid synthesis lead to deficiency of cortisol and aldosterone, increased ACTH production and increased synthesis
of sex hormones. In children, this may present as failure to
thrive, ambiguous genitalia in females and early virilization
in males. It may present later with precocious puberty, or in
early adulthood with hirsutism and oligomenorrhoea.
METABOLIC BONE DISEASE
Vitamin D metabolism is shown in Fig.33.9.
Diet
3
Vitamin D
(cholecalciferol)
3
25-hydroxy
vitamin D
Ca2+ absorption
Gut
1,25-dihydroxy
vitamin D
vitamin D
3
Kidney
3
Calcification
Resorption
Bone
Kidney
Parathyroid
gland
Fig.33.9 Metabolism of vitamin D.
24,25-dihydroxy
3
Liver
Relative conversion
mediated by Ca2+,
PO
4
thyroid hormone
+
and para-
329
Metabolic and endocrine disorders
Osteoporosis
Bone normally consists of 60% mineral and 40% matrix or
organic matter. In osteoporosis the deposition of calcium
salts occurs normally, but there is a loss of bone matrix and
a reduction in bone mass per unit volume of anatomical
bone. The WHO has defined osteoporosis as a bone mineral density (BMD) of 2.5 standard deviations or more below the mean value for a young adult (T score). Osteopenia
is defined as a T score between −1.0 and −2.5.
The prevalence of osteoporosis in white women aged
50–59 years is 4%, and the prevalence in those aged
80years or older is around 25%. Osteoporosis predisposes
patients to fractures, commonly of the hip, vertebrae or
wrist. It is estimated that almost 200,000 osteoporosisrelated fractures occur in the United Kingdom each year.
These are associated with considerable morbidity and
mortality.
Aetiology
Primary osteoporosis
Involutional bone loss commences at age 35–45years in
both sexes but is accelerated in women following the loss
of sex steroids at menopause, explaining the higher incidence in postmenopausal women. Age-related bone loss
is increased by smoking, alcohol consumption, inactivity,
low BMI and impaired vitamin D production. Family history is also relevant; ask about a parental history of hip
fracture.
Secondary osteoporosis
Causes include steroid therapy, hypogonadism, alcohol
abuse, hyperthyroidism, hyperparathyroidism, anticonvulsants and some chronic diseases such as inflammatory
bowel disease and cystic fibrosis.
Clinical features
Osteoporosis does not cause pain (or other symptoms) until
a fracture occurs. The risk of fracture is related to the BMD
but also to conditions predisposing to falls (e.g. stroke, parkinsonism, dementia, visual impairment). These must also
be assessed.
Investigations
• Blood tests: these results are normal with osteoporosis
but look to identify treatable causes or rule out
differential diagnosis (myeloma/osteomalacia),
including a bone profile (calcium, phosphate,
alkaline phosphatase), vitamin D level, PTH level,
thyroid function tests, coeliac screen and serum
electrophoresis. The results are normal with
osteoporosis.
• BMD is estimated by dual-energy X-ray
absorptiometry (DXA) scan. There is no evidence to
suggest any benefit of population-based screening. It
is performed if there are risk factors and therapy is
being considered (e.g. premature menopause, steroid
therapy). It may also be done following a fragility (low
trauma) fracture, an X-ray demonstrating osteopenia
or for monitoring the effect of therapy. As well as the
T score (see earlier), a Z score is calculated, which is
an age-matched BMD score. The BMD of the vertebral
body and femoral head is assessed.
• Thyroid function and LH, FSH and testosterone
levels should be measured to exclude secondary
causes. Fifty percent of males with hip fractures are
hypogonadal.
Management
General principles
A holistic approach to the reduction of fracture risk is
important. Fall risk should be assessed and interventions
should be implemented. Alcohol excess, excess caffeine and
smoking should be discouraged, and a good diet with regular weight-bearing activity should be encouraged. A diet
adequate in calcium and vitamin D is essential, with a low
threshold for supplementation.
Drug therapy use is guided by the FRAX or QFracture
scoring systems. In general, for primary prevention treatment with a bisphosphonate will be commenced in postmenopausal women older than 65years with confirmed
osteoporosis. For secondary prevention (i.e. following an
osteoporotic fracture), bisphosphonate therapy will be
commenced in the postmenopausal woman regardless of
age.
CLINICAL NOTES
The risk of fracture can be predicted with FRAX
and the QFracture calculator. The latter can be
used to calculate risk without the need for a bone
mineral density level (i.e. prior to a dual-energy
X-ray absorptiometry scan; see later), and is based
on a UK population.
330
Drugs
Treatment options include bisphosphonates, strontium
ranelate, denosumab, raloxifene (a selective oestrogen
receptor modulator), calcitonin and intermittent PTH.
Bisphosphonates are the first-choice therapy in most cases
and are generally well tolerated. In patients who are unable
to take them, strontium ranelate or denosumab is considered second-line therapy. Raloxifene may be considered for
secondary prevention. Supplementation of calcium and vitamin D should be considered in all patients.
Patients taking steroids long-term are particularly at
risk, and a low threshold is needed for therapy.
Metabolic bone disease
Deafness
— Sensorineural due to
8th nerve compression
— Conductive due to
sclerosis of ossicles
and high-output failure
3333
PATIENT SAFETY
Be aware of side effects of bisphosphonates:
severe dyspepsia, oesophageal erosion and the
rare, but serious, complication of osteonecrosis of
the jaw. Consider renal function in the choice of
bisphosphonate.
Paget disease
In Paget disease there is uncontrolled bone turnover
with areas of increased localized osteoclastic resorption. This is followed by disordered osteoblastic activity, leading to new bone formation that is structurally
abnormal and weak (Fig 33.10). The cause is unknown,
although viruses have been implicated and genetic
factors probably play a role. The highest prevalence is in
the United Kingdom, United States, Australia and New
Zealand, and is estimated to occur in 1%–3% people
older than 55years.
Clinical features
The axial skeleton and femur are most commonly affected.
The condition is most commonly asymptomatic, and is
detected biochemically with a raised alkaline phosphatase
level or by abnormal X-ray. Patients with symptoms complain of bone pain, tenderness and deformity such as an enlarged skull and bowed (sabre) tibia. Complications include:
• pathological fractures of long bones;
• osteogenic sarcoma (patients need lifelong monitoring
to screen them for this);
• conductive deafness due to involvement of the
ossicles.
Skull enlargement
Optic atrophy
(compression of optic
nerve at skull foramen)
Cardiac hypertrophy
Sabre tibia
Fig.33.10 General features of Paget disease of the bone.
331
Metabolic and endocrine disorders
• progressive occlusion of the foramina of the skull,
which can cause deafness due to eighth cranial nerve
compression and visual impairment due to second
nerve compression.
• osteoarthritis of related joints.
• rarely, high-output cardiac failure (with more than 20%
skeletal involvement).
Investigations
Paget disease is generally diagnosed from raised serum alkaline phosphatase level (with normal calcium, phosphate
and PTH levels) and X-ray abnormalities. There may be
mild hypercalcaemia in immobile patients due to unopposed bone resorption.
Online X-rays of affected bones show a mosaic of osteolytic and sclerotic lesions, thickening of trabeculae and thick
cortices with an enlarged irregular outline. Isotope bone scans
will demonstrate the extent of skeletal involvement. A bone
biopsy should be performed if malignant change is suspected.
Management
The objectives of treatment are control of pain and to treat active disease at a site where complications might occur. In addition to standard analgesia, the following treatments are given.
Bisphosphonates
Bisphosphonates are the mainstay of treatment (either
orally, e.g. risedronate, or IV, e.g. zoledronic acid). They
reduce bone turnover, reduce bone pain, promote healing
of osteolytic lesions and restore normal bone histological
features. Calcium deficiency and vitamin D deficiency need
to be corrected before bisphosphonate therapy is started to
avoid hypocalcaemia.
Calcitonin
Calcitonin is used as second-line therapy and is used only
when bisphosphonates are not tolerated. It opposes many of
the effects of PTH, and together with PTH regulates bone
turnover and calcium balance. It has a risk of malignancy
with long-term use.
Osteomalacia
This disease occurs because of severe vitamin D deficiency.
It results in inadequate mineralization of the bone matrix.
If this occurs in adults (i.e. after fusion of the epiphyses has
occurred), it is called ‘osteomalacia’. If it occurs in children
(i.e. during the period of bone growth before epiphyseal fusion), it gives rise to rickets.
Aetiology
The causes include factors that cause a low vitamin D level
or cause low calcium/phosphate level. Vitamin D deficiency
is most frequently caused by insufficient sunlight exposure
and nutritional deficiency, but may be secondary to a wide
range of other causes, for example:
• Intestinal malabsorption (e.g. gluten-sensitive
enteropathy and postgastrectomy states) leading to
reduced calcium and phosphate reabsorption.
• Vitamin D resistance: commonly this is due to
ineffective conversion of 25-hydroxyvitamin D3 to
1,25-dihydroxyvitamin D3 in chronic renal disease.
Inherited deficiency of renal 1α -hydroxylase and endorgan receptor abnormality are other causes.
• Drug induced: long-term anticonvulsant therapy may
induce liver enzymes, leading to the breakdown of
25-hydroxyvitamin D3.
Clinical features
Vitamin D deficiency is most commonly asymptomatic, so
be suspicious. With osteomalacia, bone pain and tenderness
are common. Fractures may occur, especially of the femoral
neck. There is often a proximal myopathy, which may cause
a waddling gait and difficulty in rising from a chair.
In rickets there are deformities of the legs (bow legs
and knock knees), the chest (rachitic rosary) and the skull.
There may also be features of hypocalcaemia (e.g. tetany);
see Chapter31.
Investigations
Surgery
Pathological fractures, bone deformity or nerve compression may require surgery. Bisphosphonates should be used
preoperatively to try to reduce disease activity and reduce
the risk of bleeding. Bone healing is often prolonged, and
long rehabilitation is required.
CLINICAL NOTES
Osteosarcoma classically presents with bone pain
that is poorly responsive to medical treatment,
local swelling and possibly a pathological fracture.
Be on guard for this in your patient with Paget
disease.
332
Biochemistry
Serum calcium, phosphate and magnesium levels: tend to
be decreased but may be normal.
• Serum alkaline phosphatase activity: increased.
• Urinary calcium excretion: low.
• Vitamin D level (serum 25-hydroxyvitamin D) is most
routinely measured; this will be low except in resistant
cases (e.g. in the context of renal failure).
• PTH level is generally high because of secondary
hyperparathyroidism due to hypocalcaemia.
Imaging
Online X-rays of bone in rickets show cupped, ragged metaphyseal surfaces. In osteomalacia there is cortical bone loss
and pseudofractures (Looser zones), which are small translucent bands perpendicular to the bone and extending inwards
Metabolic bone disease
3333
from the cortex. They are best seen on the lateral border of
the scapula, on the femoral neck and in the pubic rami.
Isotope bone scans show a generalized diffuse increase
in uptake of isotope.
Management
Dietary vitamin D deficiency can be prevented by taking
an oral supplement of ergocalciferol daily. Vitamin D deficiency caused by intestinal malabsorption or chronic liver
disease usually requires vitamin D in pharmacological
doses, such as calciferol tablets daily. Calcium supplements
may also be required, as may phosphate supplements in hypophosphataemic disease.
Hydroxylated vitamin D derivatives (alfacalcidol and
calcitriol) should be used in patients with chronic renal impairment, as they are unable to hydroxylate vitamin D3 to
its active form.
CLINICAL NOTES
Ensure pregnant women and other high-risk
groups (e.g. the elderly) are screened for vitamin
D deficiency. Vitamin D deficiency has been
associated with an increased risk of developing
certain malignancies, diabetes and cardiovascular
disease.
Renal osteodystrophy
The term ‘renal osteodystrophy’ is used to cover the various
forms of bone disease that develop in chronic renal failure.
These include:
• delayed epiphyseal closure in children and young
adults;
• rickets or osteomalacia;
• osteitis fibrosa cystica (brown tumours) due to
secondary or tertiary hyperparathyroidism;
• generalized or localized osteosclerosis.
The kidney does not excrete phosphate effectively as its function drops. This hyperphosphataemia stimulates PTH secretion. The impaired hydroxylation of 25- hydroxyvitamin
D causes osteomalacia and hypocalcaemia, further stimulating the release of PTH (secondary hyperparathyroidism)
and increasing osteoclast activity.
Management
Dietary phosphate intake is reduced, and oral phosphate
binders are used to help control the hyperphosphataemia.
Hydroxylated vitamin D supplements (e.g. alfacalcidol) are
given to help normalize the calcium level and reduce the level
of PTH further. If PTH is not suppressed, autonomous PTH
production can result, causing tertiary hyperparathyroidism,
which tends to require surgery (i.e. parathyroidectomy).
CLINICAL NOTES
In health, there is a balance between bone
formation and reabsorption. If this natural turnover
is underactive or overactive, the fracture rate
increases. Parathyroid hormone level is used as
a surrogate of bone turnover. The aim in renal
osteodystrophy is to achieve a balance. See
Chapter30.
Chapter Summary
• The prevalence of type 2 diabetes is dramatically increasing. Obesity is a major factor for
this worldwide public health issue, which itself causes increased morbidity and mortality.
• Diabetes causes multiple organ dysfunction through microvascular and macrovascular
changes. Type 2 diabetes may be controlled through diet and weight loss; generally
hypoglycaemic agents and insulin therapy are required. Hypoglycaemic agents have
multiple side effects, such as hypoglycaemia and weight gain.
• Type 1 diabetes is less common, is associated with other autoimmune diseases and
typically presents earlier in life. These patients always require insulin. Insufficient insulin
can result in ketone formation and lead to diabetic ketoacidosis, a medical emergency.
• Diabetic ketoacidosis is a triad of a raised glucose level, the presence of ketones and
metabolic acidosis. Treatment involves aggressive fluid resuscitation and, following this,
a fixed rate intravenous insulin infusion. Attention needs to be paid to avoid
hypokalaemia, and to identify and address the underlying precipitant.
333
Metabolic and endocrine disorders
• Hypoglycaemia (blood glucose level below 4 mmol/L) is another medical emergency. This
is treated with orally administered carbohydrate, in the alert, conscious patient, otherwise
with intravenously administered glucose or intramuscularly administered glucagon if
there is no intravenous access.
• Bone is an active organ. Disorders of bone turnover can result in osteoporosis with loss of
bone mass, osteomalacia with defective calcification or Paget disease with uncontrolled
bone turnover. There is a close relationship between the parathyroid gland, vitamin D,
calcium, phosphate and bone.
• Cortisol is produced from the adrenal gland. High levels of cortisol can lead to a Cushing
syndrome. This is most commonly from exogenous glucocorticoid administration, and
can lead to a Cushingoid appearance, with central adiposity, moon facies, proximal
muscle wasting, easy bruising and skin thinning and can predispose to diabetes,
hypertension and osteoporosis.
• Addison disease results in cortisol deficiency through primary adrenal failure. This
condition can present as an Addisonian crisis. This can have nonspecific vague
symptoms such as vomiting, nausea and abdominal pain. Signs include hypotension,
hypothermia and increased pigmentation of skin and biochemically hypoglycaemia,
hyponatraemia and hyperkalaemia may be present. Treatment is with hydrocortisone,
with intravenous fluid resuscitation and by treating the underlying precipitant.
• Hypothyroid crisis (i.e. myxoedema coma) is another endocrine emergency. This can
present with hypothermia, hypotension and reduced mental status. Treatment is with
intravenous administration of thyroxine, intravenous fluid resuscitation, rewarming and
identifying and treating the underlying precipitant. It is crucial to ensure that the patient
has sufficient cortisol levels.
• Correcting thyroid function in the absence of sufficient cortisol levels can precipitate an
Addisonian crisis.
FURTHER READING
Endobible. Advice on endocrine symptoms, diagnosis, treatment:
a free online diagnostic and management tool and educational
resource authored by a consultant endocrinologist. Available
online at: http://www.endobible.com.
Finlayson, A., 2007. Crash Course: Endocrine and Reproductive
Systems, third ed. Mosby, Edinburgh.
National Institute for Health and Clinical Excellence, 2015. Type 1
diabetes in adults, diagnosis and management. Available online
at https://www.nice.org.uk/guidance/ng17.
334
National Institute for Health and Clinical Excellence, 2006. Obesity.
Clinical guideline CG43. Available online at: http://www.nice.
org.uk/CG43.
National Institute for Health and Clinical Excellence, 2008. Type
2 diabetes in adults: management. Clinical guideline NG28.
Available online at: https://www.nice.org.uk/guidance/ng28
World Health Organization, 2006. Definition and diagnosis of di-
abetes mellitus and intermediate hyperglycaemia. World Health
Organization, Geneva. Available online at: http://apps.who.
int/iris/bitstream/handle/10665/43588/9241594934_eng.pdf;jsessionid=24F18E23CB16F78F3E7A1A821D6E2DB0?seque
nce=1.
Musculoskeletal system
OSTEOARTHRITIS
Osteoarthritis (OA) is one of the most common joint
conditions and is characterized by a syndrome of joint pain
with various degrees of physical limitation. It is a degenerative disorder affecting mainly the weight-bearing joints and
the hand (the overall prevalence of hip arthritis is 11% and
that of knee arthritis is 24%). Risk factors include increasing
age, family history, obesity, trauma, occupational and recreational stress on joints and female sex.
Pathology
OA is a degenerative disease of cartilage, which becomes
eroded and progressively thinned as the condition proceeds.
At the onset of disease the collagen matrix of the cartilage
becomes disorganized and there is marked decrease in proteoglycan content. This results in loss of water and makes
cartilage susceptible to degeneration. Joint inflammation
even though usually mild can also contribute to decay.
OA can affect other structures within the joint, including
menisci. These can wear away and tear, ligaments become
fibrotic and subchondral bone becomes hypomineralized.
New bone can form and produce osteophytes usually scattered around the joint edge. Radiologically this presents as
loss of joint space, subchondral sclerosis, subchondral cysts
and marginal osteophytes (Fig.34.1).
34
Fig.34.1 Knee X-ray showing severe osteoarthritis with
joint space narrowing and osteophyte formation on the
medial site. (Reprinted from Li K-J. and Hsieh S-C. Clinical
application of musculoskeletal ultrasound in rheumatic
diseases. Journal of Medical Ultrasound. 2011 19(3):73–80,
with permission from Elsevier.)
Clinical features
The clinical signs and symptoms of OA are described in
Chapter24. Diagnosis of the condition can be made clin-
ically if all of the following are present:
• The patient is 45years or older.
• There is activity-related joint pain.
• Lack of morning joint stiffness or stiffness lasts less
than 30 minutes.
The joints commonly affected include the hips, knees, distal interphalangeal (DIP) joints, the first metacarpophalangeal (MCP) and metatarsophalangeal (MTP) joints and the
lumbar and cervical spine. Pain in joints is exacerbated by
movement and relieved by rest. In knees, it is often bilateral.
If OA affects the hip, it can present as pain in the groin,
the anterior and lateral parts of the thigh or the testicles in
males. It can also be referred to the ipsilateral knee. Signs include pain and reduced range of movement in all directions,
stiffness, joint swelling and synovitis. The joint deformity is
often seen, and in the hands can be described as Herberden
(at DIP joint) and Bouchard (at proximal interphalangeal
(PIP) joint) nodes.
The pattern of joint involvement tends to be asymmetrical. The most commonly affected joints in the hands are the
DIP joints, the PIP joints and first carpometacarpal joint,
giving an appearance of ‘square hands’. Unlike rheumatoid
arthritis (RA), there are no extraarticular manifestations of
the disease.
Management
A holistic approach should be used when you are considering OA management. The impact on daily life, the support
network available and appropriate pain assessment should
be determined.
Nonsurgical and surgical treatments can be considered.
The former concentrate on combinations of drugs paired
with physical treatments (e.g. weight reduction and heat application), electrotherapy (transcutaneous electrical nerve
stimulation), supporting exercises and mobility aids (e.g.
walking sticks, special footwear, joint supports). Initially,
simple analgesia (e.g. paracetamol) and topical nonsteroidal antiinflammatories (NSAIDs) should be trialled. Oral
NSAIDs, cyclooxygenase 2 (COX-2) inhibitors and opioids
335
Musculoskeletal system
are the next line. Intraarticular corticosteroids can be used
as adjuncts. Glucosamine and chondroitin plus their combinations, and hyaluronan are not recommended as OA
treatments. Surgical review can be considered if nonsurgical
treatments have not shown desired benefits. Surgical referral should be prompt to prevent over-degeneration of the
joint. The available surgical options include joint lavage, debridement, osteotomy, arthroplasty and joint replacement.
RHEUMATOID ARTHRITIS
RA is an autoimmune, systemic disease producing symmetrical inflammatory deforming polyarthropathy with
extraarticular involvement of many organs. In the United
Kingdom it affects around 1% of the population, and is two
to four times more common in women than in men. The
peak age of onset is in the 40s, although it can start at almost
any age. Both environmental and genetic factors play a part
in disease development. Smoking, silica exposure and diabetes mellitus are risk factors for RA. There is often a family
history of the condition and, in particular, certain HLA serotypes (HLA-DR4 and HLA-DR1) have been shown to be
present in severe disease.
Pathology
RA starts with persistent cellular activation that results in
autoimmunity and inflammation. This primarily occurs
within the synovial membrane, where swelling and congestion lead to infiltration of immune cells and cartilage, bone
and tendon erosion.
Three distinct disease stages can be identified:
• infiltration phase (nonspecific inflammatory features)
• amplification phase (T cell-mediated disease
progression)
• chronic inflammation phase (tissue injury due to
cytokines interleukins (IL)-1, IL-6 and TNF-α)
Once immune response has been established, B cell- mediated
production of autoantibodies, including rheumatoid factor
and antibodies to citrullinated peptides, contributes to an
integral part of the condition. This includes disease progression where soft tissue inflammation surrounding the joint
gives rise to granulation tissue with extensive angiogenesis
and enzyme formation that damages the joint. Rheumatoid
nodules (present in about 20% of cases) appear in consequence. These are usually subcutaneous nodules most commonly affecting extensor surfaces but that can also occur in
other tissues (e.g. lungs, heart and sclera).
to involve larger joints. This is symmetrical and usually
associated with nonspecific systemic symptoms. Joint inflammation produces swelling, heat and redness. Persistent
inflammation leads to joint and tendon destruction, muscle
wasting and therefore deformity and loss of function.
In the hands the MCP joints, PIP joints and wrists are
most commonly affected (Fig.34.2). Shoulders, hips and elbows are less affected by the disease (for more detailed joint
signs and symptoms, see Chapter19). Extraarticular mani-
festations are summarized in Table34.1.
The diagnosis of RA is made on a combination of clinical
and laboratory findings. Investigations should include:
Clinical features
RA usually presents with an insidious onset of pain and
stiffness (especially in the morning and after inactivity)
in the small joints of the hands and feet that may progress
336
Fig.34.2 Finger and hand abnormalities in
rheumatoid arthritis. DIP, Distal interphalangeal; MCP,
metacarpophalangeal; PIP, proximal interphalangeal.
Rheumatoid arthritis
3434
Table34.1 Extraarticular features of rheumatoid arthritis
Organ system Effects
Eyes Sjögren syndrome occurs in 15% of
Nervous system Carpal tunnel syndrome (most
Lymphoreticular
system
Blood Normochromic normocytic anaemia
Respiratory system Pleural effusions (more common in
Cardiac Pericarditis and pericardial effusions
Skin Vasculitis may produce nail-fold
Kidneys Secondary amyloidosis may affect
CRP, C-reactive protein; ESR, erythrocyte sedimentation rate.
patients
Scleritis causes a painful red
eye and may lead to uveitis and
glaucoma
Scleromalacia perforans is an
uncommon complication where a
rheumatoid nodule in the sclera
perforates
common)
Peripheral neuropathy causing
glove and stocking sensory loss and
occasionally motor weakness
Mononeuritis multiplex due to
vasculitis of vessels supplying
nerves
Atlantoaxial subluxation resulting in
spinal cord compression
Generalized lymphadenopathy and
splenomegaly may be present
Felty syndrome (seropositive
arthritis, neutropenia and
splenomegaly)
or iron-deficiency anaemia
Raised ESR; CRP level may be
modestly raised or normal
Reactive thrombocytosis
men)
Rheumatoid nodules
Diffuse fibrosing alveolitis
Caplan’s syndrome (the presence
of large rheumatoid nodules and
fibrosis in patients with
RA exposed to various industrial
dust)
may occur
infarcts, ulcers and digital gangrene
Peripheral oedema may be present
and is due to increased vascular
permeability
the kidneys, leading to proteinuria,
nephrotic syndrome and renal failure
• full blood count (FBC) (may show anaemia of
chronic disease (Table34.2), thrombocytosis or
thrombocytopenia and leucopoenia).
• erythrocyte sedimentation rate (ESR).
• rheumatoid factor, antinuclear antibodies (ANAs) and
antibodies (anti-cyclic citrullinated peptide).
Table34.2 Causes of anaemia in rheumatoid arthritis
Anaemia of chronic disease
Hypersplenism due to splenomegaly (Felty syndrome if
also neutropenic)
Chronic blood loss from peptic ulceration due to steroid
and nonsteroidal antiinflammatory administration
Bone marrow suppression by disease-modifying drugs
such as gold and penicillamine
Folate deficiency (increased utilization of folate)
• joint X-rays, especially of hands, wrists and feet:
to aid in diagnosis and to monitor the baseline at
presentation.
• aspiration of synovial fluid.
Management
The aims of treatment are to control symptoms and to
modify the underlying disease process. Lifestyle changes,
drug therapy and physiotherapy are the first-line treatment.
Surgery may be used to correct deformities. Once a diagnosis of RA is considered, patients should be treated as soon
as possible to prevent mechanical damage to joints. Refer
them to a rheumatologist. While patients are waiting for
an appointment, they can be treated with simple analgesia
and steroids. Paracetamol, oral nonselective NSAIDs and
COX-2 selective drugs can reduce RA signs and symptoms,
and low-dose oral corticosteroids and intraarticular injections can be used for short-term symptom control.
When the patient has been reviewed by a rheumatologist, treatment with disease-modifying antirheumatic drugs
(DMARDs) can be started so disease progression and joint
destruction can be limited early. Methotrexate and sulphasalazine are the DMARDs of choice. Others include azathioprine, ciclosporin, -penicillamine, hydroxychloroquine,
leflunomide and mycophenolate mofetil. In a new RA diagnosis, treatment with methotrexate and DMARDs of choice
plus short-term glucocorticoid therapy should be started
within 3 months of the onset of persistent symptoms.
Therapy should be sustained and combination, rather than
monotherapy used, in patients with inadequate response.
The aim is to fully suppress the disease, and therefore close
control is needed especially because of potential serious
toxic side effects of DMARDs (Table34.3).
In DMARD-resistant disease, biological therapies can be
useful. Their use is recommended if at least two DMARDs,
including methotrexate, failed to control the disease.
Examples include TNF-α inhibitors (infliximab and etanercept), rituximab and adalimumab. Side effects are serious
and can show immunosuppression and hypersensitivity,
and so close monitoring is needed (Table34.3).
Last resort options include surgical interventions.
Furthermore, urgent surgical review is necessary if septic arthritis or any signs or symptoms suggesting cervical
myelopathy are present.
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