Endgames Picture Quiz

Pathological finger fracture

BMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.f1024 (Published 20 February 2013) Cite this as: BMJ 2013;346:f1024
  1. Tom Rider, core medical trainee,
  2. Irfan Baig, specialty registrar,
  3. Charlie Sayer, specialty registrar,
  4. Anna Crown, consultant endocrinologist
  1. 1Royal Sussex County Hospital, Brighton BN2 5BE, UK
  1. Correspondence to: T Rider bsms345{at}doctors.org.uk

A 75 year old white woman presented to our hospital with pain in her left hand after hearing a crack when pushing herself up from sitting. She immediately felt pain in her little finger and was unable to use her hand.

Over the preceding two years she had become increasingly tired and weak. This had necessitated a stair lift to be installed into her home and she had become unable to lift a plate down from her kitchen shelves. She had developed bone pain in her spine, knees, ankles, and shoulders. She also reported polyuria but no polydipsia. In the five months before admission she had lost two stone (12.6 kg) in weight.

Clinical examination showed no lymphadenopathy, goitre, breast lumps, or organomegaly.

Initial blood tests showed urea of 13 mmol/L (reference range 1.7-8.3; 1 mmol/L=2.8 mg/dL), creatinine 101 µmol/L (44-80; 1 µmol/L=0.01 mg/dL), corrected calcium concentration 3.19 mmol/L (2.15-2.61; 1 mmol/L=4 mg/dL), phosphate 0.79 mmol/L (0.81-1.45; 1 mmol/L=3.1 mg/dL), albumin 41 g/L (37-49), adjusted magnesium 0.54 mmol/L (0.66-0.99; 1 mmol/L=2 mEq/L), total bilirubin 7 µmol/L (0-21; 1 µmol/L=0.06 mg/dL), alkaline phosphatase 931 IU/L (<55; 1 IU/L=0.02 µkat/L), alanine aminotransferase 8 IU/L (0-33; 1 IU/L=0.02 µkat/L), haemoglobin 118 g/L (115-165), and erythrocyte sedimentation rate of 14 mm in the first hour (0-15). What does the radiograph of her hand (fig 1) show?

Questions

  • 1 What does the radiograph show?

  • 2 What is the unifying diagnosis based on the history and investigations?

  • 3 How would you confirm the diagnosis?

  • 4 How should this condition be managed?

  • 5 What are the complications of treatment?

Answers

1 What does the radiograph show?

Short answer

The radiograph shows well defined osteolytic lesions in the fourth metacarpal. The other obvious area of abnormality is the proximal phalanx of the fifth finger, where changes in trabecular pattern, cyst formation, and cortical erosions can be seen.

Long answer

The fourth metacarpal contains well defined focal reactive osteolytic lesions (fig 2). These are typical of the appearance of brown tumours caused by primary hyperparathyroidism. The proximal phalanx of the fifth finger has pronounced changes in trabecular pattern, along with cyst formation and cortical erosions (fig 2). No obvious fracture is seen. Figure 2 also shows generalised osteopenia and chondrocalcinosis of the third and fourth metacarpophalangeal joints.

Figure2

Fig 2 Anteroposterior radiograph of the left hand showing well defined focal reactive osteolytic lesions typical of the appearance of brown tumours (white arrowheads), pronounced changes in trabecular pattern, cyst formation, cortical erosions (black arrow), and chondrocalcinosis of the metacarpophalangeal joint (white arrow)

Brown tumours are a late feature of osteitis fibrosa cystica, the classic skeletal manifestation of advanced hyperparathyroidism, which is caused by disturbance of the balance between bone formation and bone breakdown secondary to high parathyroid hormone (PTH) concentrations. Osteitis fibrosa cystica is characterised by generalised demineralisation, subperiosteal bone resorption, and the development of brown tumours.1 The term brown tumour reflects the grossly brownish colour seen on biopsy. Brown tumours result from microfractures that cause an influx of multinucleated macrophages and haemosiderin deposition.2 Brown tumours are benign, with features including a well defined and narrow transition zone, no cortical breach, no periosteal reaction, and no soft tissue swelling. Brown tumours are rare and their incidence is decreasing as hyperparathyroidism is being detected and treated earlier. Our patient also had multiple brown tumours in her right lower leg (fig 3).

Figure3

Fig 3 Anteroposterior right lower leg radiograph showing multiple well defined focal reactive osteolytic lesions (white arrows) typical of brown tumours

2 What is the unifying diagnosis based on the history and investigations?

Short answer

The most likely cause of the radiological features in the context of the patient’s chronic symptoms, renal function, and hypercalcaemia is primary hyperparathyroidism. The site of bone changes would be unusual for multiple myeloma, metastases, or other causes of multiple bone lesions.

Long answer

Causes of multiple bone lesions in adults include osteolytic metastases, multiple myeloma, Langerhans’ cell histocystosis, leukaemia, and multiple bone cysts.2 Brown tumours are usually multiple cystic or mixed lesions within a single bone. However, brown tumours can also be solitary, and in this context radiological diagnosis is more challenging. Correlation with the clinical picture is essential, and whole body skeletal surveys, bone scanning, or bone biopsy may also be needed if the diagnosis is unclear.

Bone disease is found in two thirds of patients with multiple myeloma at diagnosis and almost all patients during the course of their disease. The most common sites of bone disease detectable by radiography in patients with multiple myeloma are the vertebrae (65%), ribs (45%), skull (40%), shoulders (40%), pelvis (30%), and long bones (25%). Bone disease is rarely seen on radiography distal to the knee or elbow in this disease.3 Bone lesions in multiple myeloma tend to have ragged borders and a moth eaten appearance, which is ill defined with multiple holes and a wide transition zone.

Breast, prostate, and lung cancers are the most common sources of bone metastases, followed by kidney and thyroid cancers. Patients typically have increasing and persistent pain when bone metastases are present. Loss of at least a third of bone density must occur before a bone metastasis can be seen on radiography.4 Metastases can have a lytic (reduced density), blastic (increased density), or mixed appearance. Although metastatic lesions can present with any of these appearances, certain primary tumours cause a characteristic appearance. Lytic lesions are usually more aggressive and are associated with lung, kidney, and thyroid cancer. Prostate and breast cancers tend to produce blastic lesions, and mixed lesions are most commonly associated with breast cancer.4 Lung cancer is the most common source of metastases in distal sites of peripheral bones.4

3 How would you confirm the diagnosis?

Short answer

The next most useful investigation would be to measure the serum parathyroid hormone (PTH) concentration. A high or inappropriately normal PTH concentration with hypercalcaemia and normal renal function is diagnostic of primary hyperparathyroidism.

Long answer

Cancer and primary hyperparathyroidism together account for 90% of hypercalcaemia. An indolent presentation of hypercalcaemia, as was seen in our patient, is more likely to be caused by primary hyperparathyroidism. Hypercalcaemia related to cancer usually occurs in the context of known metastatic cancer. The box lists the most common causes of hypercalcaemia.

Causes of hypercalcaemia

Common causes
  • Primary hyperparathyroidism

  • Cancer: paraneoplastic parathyroid hormone (PTH) related peptide

  • Multiple myeloma

Less common causes
  • Tertiary hyperparathyroidism in chronic kidney disease

  • Ectopic PTH production by a tumour—for example, an ovarian tumour

  • Drug induced—for example, the thiazides or lithium

  • Hyperthyroidism

  • Intake of calcium supplements

  • Granulomatous disorders such as sarcoidosis, tuberculosis, and Wegener’s granulomatosis

  • Addison’s disease

  • Milk alkali syndrome

  • Familial hypocalciuric hypercalcaemia

  • Multiple endocrine neoplasia syndromes with primary hyperparathyroidism

  • Vitamin D toxicity

  • Prolonged immobility

A high PTH concentration with hypercalcaemia and normal renal function confirms the diagnosis of primary hyperparathyroidism. Our patient’s serum PTH concentration was extremely high (2072 ng/L; reference range 15-65). The normal physiological response to hypercalcaemia is to suppress endogenous production of PTH, so a low PTH level with hypercalcaemia indicates a different pathology and not primary hyperparathyroidism. Cancer related hypercalcaemia is usually caused by paraneoplastic production of PTH related peptide, which has 70% homology with PTH over the first 13 amino acids at the N terminus but differs considerably after this point. PTH related peptide does not crossreact with standard laboratory PTH assays, so PTH values are suppressed in patients with hypercalcaemia of cancer.

PTH has several effects that increase serum calcium concentrations. These include stimulation of osteoclastic bone resorption, stimulation of calcium reabsorption from renal tubules, and increased intestinal absorption of calcium through activated vitamin D. Primary hyperparathyroidism has a prevalence of 1-4 per 1000 in the general population.1 Women are twice as likely to be affected as men, and the disease is more common in the fifth and sixth decades of life. Eighty per cent of primary hyperparathyroidism is caused by solitary PTH secreting adenomas of parathyroid chief cells. Multiglandular parathyroid hyperplasia is the second most common cause of primary hyperparathyroidism. Parathyroid carcinoma is very rare.

In developed countries it is rare for patients with primary hyperparathyroidism to present with symptomatic hypercalcaemia. Most primary hyperparathyroidism is diagnosed after routine screening or as an incidental finding. Symptoms and manifestations of late presentations include reduced bone mineral density, fragility fractures, recurrent nephrolithiasis, nephrocalcinosis, polyuria, renal insufficiency, nausea, peptic ulcer disease, constipation, pancreatitis, neuropsychiatric disturbances, left ventricular hypertrophy, cardiac calcification, conduction abnormalities, endothelial dysfunction, a short QT interval, muscle weakness, and involuntary muscle contractions.1 Patients diagnosed as having primary hyperparathyroidism should be referred to an endocrinologist to confirm the diagnosis and help plan further investigations and management.

Hypercalcaemia and a normal or slightly high PTH concentration can also be seen in patients receiving thiazides or lithium, tertiary hyperparathyroidism associated with end stage renal failure, and familial hypocalciuric hypercalcaemia.5 It is especially important to take a detailed family history in younger patients with hyperparathyroid disease to avoid missing an underlying genetic cause. A low urinary calcium to creatinine clearance ratio can help to distinguish between primary hyperparathyroidism and familial hypocalciuric hypercalcaemia if suspected.1 Low 25-hydroxyvitamin D concentrations, thiazide diuretics, and raised serum creatinine may all lead to a spuriously low urinary calcium to creatinine clearance ratio. Familial hypocalciuric hypercalcaemia is an autosomal dominant disorder in which the calcium sensing receptors in the parathyroid gland and kidneys are inactivated. This disorder results in hypercalcaemia with increased calcium reabsorption. Patients typically present before the age of 25 years. Patients with longstanding chronic kidney disease may develop hypercalcaemia as a result of tertiary hyperparathyroidism, so calcium and PTH concentrations must always be interpreted in the context of the estimated glomerular filtration rate.

4 How should this condition be managed?

Short answer

In symptomatic patients with primary hyperparathyroidism caused by a parathyroid adenoma, parathyroidectomy is the definitive treatment of choice. Surgery is also recommended for asymptomatic patients with a serum calcium value 0.25 mmol/L above the normal reference range, reduced bone mineral density with a T score lower than −2.5 at any site, creatinine clearance less than 30% of normal, renal stones, or age less than 50 years.

Long answer

Parathyroidectomy is the treatment of choice in symptomatic patients if the general health of the patient allows. Resection of a parathyroid adenoma leaves the other three parathyroid glands to regulate calcium concentrations. Figures 4 and 5 show the macroscopic and microscopic appearances after our patient’s left parathyroidectomy and hemithyroidectomy.

Figure4

Fig 4 The postoperative specimen. The large multilobulated parathyroid mass was difficult to resect because of adherence to the thyroid and oesophagus

Figure5

Fig 5 Pathology slide showing a band of fibrosis running down the centre of the image. Several cystic areas that contain haemorrhage are also seen

Most patients are diagnosed on routine screening and are therefore asymptomatic. Parathyroidectomy is still a valuable option in these patients because it normalises serum calcium and PTH, while also reducing fracture risk.1 Evidence also suggests that surgery reduces the incidence of renal stones and may slightly improve neurocognitive dysfunction.1 The decision to offer surgery in such patients can be complicated. A National Institutes of Health consensus panel suggests recommending surgery in asymptomatic patients if any of the following are present:

  • Serum calcium concentration more than 0.25 mmol/L above the upper limit of normal

  • Creatinine clearance less than 30% of normal

  • Marked bone density reduction, with a T score lower than −2.5 at any site

  • Renal tract calcification or history of renal stone disease

  • Age less than 50 years (if the problem is left untreated, many younger patients eventually develop complications of primary hyperparathyroidism)

  • A request for surgery from the patient or difficulty in following up the patient.

Imaging of parathyroid glands before surgery helps to localise adenoma and guide the surgical approach. Imaging techniques such as ultrasound, computed tomography, and sestamibi (functional nuclear medicine scan) have variable sensitivity and positive predictive value, with sensitivities of 76.1%, 89.4%, and 78.9%, respectively.1 It is therefore recommended that two imaging modalities are used to localise the adenoma, typically sestamibi with ultrasound or computed tomography. Selective venous sampling can be performed at specialist centres when imaging is negative or non-concordant, and also for recurrent hyperparathyroidism after surgery. This technique has the highest sensitivity for localisation and can be used for ectopic parathyroid adenomas.

Rarely, patients with primary hyperparathyroidism have four gland hyperplasia rather than a single parathyroid adenoma.

Bilateral neck exploration for all four glands is the traditional approach but is now mainly reserved for four gland parathyroid hyperplasia and recurrent hyperparathyroidism. A unilateral approach is justified because solitary adenomas account for 80% of cases of primary hyperparathyroidism. Minimally invasive parathyroidectomy, a modification of a unilateral approach, is preferred because this reduces the operation time, hospital stay, and postoperative complications, but success depends on localisation of the adenoma.

Patients managed conservatively should have a serum 25-hydroxyvitamin D concentration maintained above 50 nmol/L; dietary restriction of calcium may be detrimental.6 Pre-existing mild hypercalcaemia is not worsened by replacing vitamin D. Renal function and calcium should be monitored yearly.6 Patients should also be advised to avoid dehydration and to seek medical help if they have persistent vomiting or diarrhoea.1

Conservative management is considered in symptomatic patients or those with very high calcium concentrations (approaching 3 mmol/L) who are not fit for surgery. Cinacalcet, a calcimimetic agent, works by increasing the sensitivity of the calcium sensing receptors in the parathyroid gland, thereby inhibiting PTH secretion and lowering calcium concentrations. This treatment has no significant benefit for bone mineral density.1

5 What are the complications of treatment?

Short answer

Complications of surgery include wound infection, haematoma, keloid scar formation, and damage to the recurrent laryngeal nerve resulting in a hoarse voice. Postoperative hypocalcaemia can be mild to severe and may require treatment with calcium and activated vitamin D (calcitriol or alfacalcidol).

Long answer

Surgical wound related complications are rare, and with minimally invasive parathyroidectomy for localised adenomas the incidence is further reduced. Recurrent laryngeal nerve injury is also rare, with an incidence of less than 1%. Mild transient postoperative hypocalcaemia is more common (10-30%). Hypocalcaemia results from transient ischaemia and pre-existing suppression of the remaining parathyroid glands.7 Patients are usually discharged home on oral calcium and vitamin D supplements, with clinic follow-up in two to three weeks. Surgical removal of all parathyroid tissue causes hypocalcaemia secondary to hypoparathyroidism and requires stabilisation before discharge with activated vitamin D (calcitriol or alfacalcidol), because PTH is needed for hydroxylation of vitamin D.

Less often hypocalcaemia can be severe, prolonged, and associated with hypophosphataemia and hypomagnesaemia. Sudden lowering of PTH concentrations in patients with prolonged hyperparathyroidism causes extensive and rapid remineralisation of the skeleton. This was first demonstrated on bone tissue biopsy by Albright in 1948, who named the condition “hungry bone syndrome.” Predictive factors for hungry bone syndrome included older age, relatively large parathyroid tumour size, and raised alkaline phosphatase and urea preoperatively.7 These patients require treatment with calcium, activated vitamin D (calcitriol or alfacalcidol), and magnesium, together with close postoperative monitoring of calcium concentrations. Optimising the vitamin D status preoperatively reduces the risk of postoperative hypocalcaemia.

Our patient had prolonged and severe hyperparathyroidism that caused severe parathyroid bone disease, as shown in the radiographs. She also had all the other predictive factors for hungry bone syndrome. On the third day postoperatively, her serum calcium dropped to 1.88 mmol/L, with serum phosphate at 0.35 mmol/L and serum magnesium at 0.43 mmol/L. The hungry bone phase lasted for four weeks and she needed intravenous calcium and calcitriol during this time. After four weeks her calcium concentration stabilised at more than 2 mmol/L, and she was discharged on high dose (4 µg/day) calcitriol and 1 g calcium (calcium carbonate and calcium lactate gluconate; Sandocal) three times a day.

Patient outcome

Our patient’s calcitriol and calcium requirements gradually lessened over time. Her ankle pain worsened postoperatively during the hungry bone phase and limited her mobility further. However, this pain—along with pain at other sites—improved after discharge. She remains under endocrinology outpatient care with her serum calcium being monitored.

Notes

Cite this as: BMJ 2013;346:f1024

Footnotes

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

  • Patient consent obtained.

References