E P Pest, G McQuaker*, J A Hunter#, D Moffat+, A J Stanley Departments of Gastroenterology, Haematology*, Rheumatology# and Pathology+, Glasgow Royal Infirmary.
Correspondence to: Dr Adrian J. Stanley, Glasgow Royal Infirmary, Department of Gastroenterology, 4th Floor Medical Block, 84 Castle Street Glasgow G4 0SF
E-mail: Adrian.Stanley@northglasgow.scot.nhs.uk
(Dr Pests current position: Medical Intern, Hospital Nacional Alejadro Posadas, Buenos Aires, Argentina)
SMJ 2005 50(1): 32-34
Abstract
We report the case of a 76 year-old woman with a diagnosis of Primary Hyperparathyroidsm and Systemic Amyloidosis, in whom subsequent investigations revealed the presence of Multiple Myeloma. We discuss the relationship between these conditions and the implications for management.
Introduction
Primary hyperparathyroidsm (PHPT) and multiple myeloma (MM) are conditions with an incidence in the general population of eight per 100,000 persons and four per 100,000 persons respectively.1,2 It has been reported that PHPT accounts for 20% of cases of hypercalcaemia, with the vast majority of the others due to a variety of malignancies including Multiple myeloma.3 We describe a patient with hypercalcaemia in association with PHPT, Multiple myeloma and systemic amyloidosis, and discuss the relationships between these conditions.
Case report
A 76 year old lady was transferred to our hospital with a history of one stone weight loss, diarrhoea, abdominal cramps, a dry mouth, polyuria and polydipsia. She had a past medical history of asthma, ischemic heart disease, hypertension, epilepsy, and previous surgery for carpal tunnel syndrome. Her medications were aspirin, bendrofluazide, felodipine, atenolol and isosorbide mononitrate. She had been admitted to another hospital several weeks earlier with similar symptoms, and investigations revealed a diagnosis of hypercalcemia and Primary Hyperparathyroidsm. A sestamibi scan there had suggested a probable parathyroid adenoma inferior to the right thyroid lobe. At subsequent neck exploration, a parathyroid adenoma was not identified on either side. The thymus was removed and a right hemithyroidectomy was performed with no histological evidence of parathyroid tissue or an adenoma. However the thymus and the thyroid tissue demonstrated amyloid deposition within the blood vessel walls. A CT scan of her abdomen and pelvis showed a thickened appearance to the bowel in the right iliac fossa, suggestive of a colonic tumor. However subsequent colonoscopy revealed exaggerated mucosal vascularity and numerous diverticula in the left colon, but normal right colon and caecum. Random biopsies of the colon also revealed the presence of amyloid.
On admission to our hospital she was apyrexial, with a degree of macroglossia and the signs of her previous neck surgery. Results revealed: adjusted serum calcium 3.04 mmol/l (normal range 2.20-2.60 mmol/l), alkaline phosphatase 343 U/L (normal 60-300 U/L), Gamma GT 77 U/l ( normal ranges 5-50 U/L), with normal renal function. Parathyroid Hormone (PTH) level was raised at 13pmol/l (normal 1-6pmol/l). The Full Blood Count was within normal limits with ESR 20mm/hr. Serum protein electrophoresis revealed IgA levels at 16.10 g/l (normal range: 0.80-4.50g/l) with IgM 0.30 g/l (normal range:0.40-2.20 g/l) and IgG 5.7 g/l (normal range 5.30-19.0 g/l). There was an IgA paraprotein of 10.7g/l and the 24-hour urinary protein was <0.1 g/l. Upper gastrointestinal endoscopy was macroscopically normal, but biopsies revealed submucosal amyloid infiltration in the stomach and duodenum.
The electrocardiogram was unremarkable and an echocardiogram revealed mild left ventricular hypertrophy with good function and no definite evidence of cardiac amyloid. Radiology of the chest, pelvis, skull, both femora, cervical, thoracic and lumbar spine revealed osteoporotic and degenerative changes only. A bone marrow aspiration and trephine were subsequently performed with histology showing a significant clonal plasma cell population consistent with myeloma with amyloid deposition (Fig 1). A diagnosis of Multiple Myeloma with associated Systemic (AL) Amyloidosis was made in addition to her known PHPT.
Her symptoms and serum calcium levels improved with intravenous fluids and intermittent pamidronate infusions, and she was discharged on folic acid, and frusemide in addition to her cardiac medications. A decision was taken not to continue searching for an occult parathyroid adenoma, which would probably require invasive investigations, but to manage the multiple myeloma with chemotherapy in an attempt to have some control of her amyloid and improve her predominantly gastrointestinal symptoms.
She received six months of Melphalan chemotherapy with a repeat bone marrow examination revealing a partial response in her myeloma. She is currently being considered for further chemotherapy with cyclophosphamide and steroids. Her dry mouth has improved with saliva substitutes and she continues on regular pamidronate infusions which controls her hypercalcaemia. She has mild nausea, abdominal bloating and constipation but is otherwise asymptomatic with a steady weight nine months following the initial diagnosis.
Discussion
This patient presented with an unusual association of PHPT, MM and amyloidosis.
The diagnosis of PHPT was based on laboratory tests with a parathyroid adenoma identified in a sestamibi scan (a radionucleide agent which concentrates in parathyroid tissue). Although a subsequent neck exploration did not confirm the presence of an adenoma, this occurs in approximately 2% of cases despite close examination of the thymus, thyroid and carotid sheath. In these cases the gland is usually found in the mediastinum, but direct mediastinal exploration is required, with a morbidity rate up to 30%.4 Her parathyroid hormone (PTH) level was high on three separate occasions using an assay of high specificity excluding parathyroid related peptide (PTH-rP). In view of the risks of further surgical exploration and her improved symptoms and serum calcium levels with chemotherapy, we decided not to continue searching for an occult parathyroid adenoma. Although her prognosis remains guarded, she remains relatively well more than nine months following the diagnosis.
Histological evidence of amyloidosis of the gastrointestinal tract, thyroid and thymus was detected in this patient which initiated a search for MM. She also had clinical evidence of amyloid of the tongue and salivary glands. Systemic Amyloidosis most commonly involves the heart, liver and kidneys. Extracellular proteins are deposited in these and other organs affecting their size and function. Amyloidosis is classified according to the cause of the abnormal protein production,5 with immunoglobulin-lightchain related (AL) the most common cause of Systemic Amyloidosis. This is usually due to secretion of immunoglobulins by a plasma cell dyscrasia such as MM. Familial Transthyretin-associated amyloidosis (ATTR) is a less common cause of amyloidosis in which the liver produces an abnormal protein as a result of a genetic alteration. Secondary(AA) amyloidosis is also less common, and usually associated with rheumatoid arthritis and inflammatory bowel disease or with chronic infections such as tuberculosis or osteomyelitis.
The association between PHPT and MM or monoclonal gammopathy of undetermined significance has been previously reported.6-9 Each report has been in a patient with hypercalcaemia thought to be due to either PHPT or MM which did not normalize or reappeared after appropriate treatment. Whether this association is due to the relatively high frequency of both conditions in the general population or due to a direct link remains unclear. Bertrand et al.6 conducted a prospective study to determinate the prevalence of monoclonal gammopathy of undeterminated significance in patients with surgically proven PHPT. They found monoclonal gammopathy in 10% of the 101 patients with PHPT (including two with MM) compared with 3% of controls. However Rao et al. reported that only 1% of 386 patients with PHPT had evidence of a coexistant monoclonal gammopathy.7
It has been suggest that the possible link between these conditions might be due to the influence of PTH on the liberation of IL-6 , which acts as a growth factor for myeloma cells and prevents spontaneous or dexamethasoneinduced apoptosis.2,10 In addition, Greenfield et al. demonstrated that PTH induces the expression by osteoblasts of IL-6, in a process mediated by cAMP signal transduction.11However this relationship has not been shown in patients with Secondary hyperparathyroidsm, even with similarly high levels of PTH for long periods of time.1 It would be interesting to postulate that high PTH levels may trigger the development of MM in a patient with or without previous monoclonal gammopathy, but this is not proven.
Conclusion
In conclusion, we believe that the co-existence of PHPT and MM should be suspected in patients known to have either condition alone, when appropriate treatment fails to normalise serum calcium levels. Whilst the pathophysiological mechanisms responsible for a relationship between these conditions remain unclear, the recognition of a link may lead to earlier diagnosis and treatment.
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