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Primary Hyperparathyroidism

Dr. Furrat Amen

Primary hyperparathyroidism (PHPT) may be caused by a parathyroid adenoma, a hyperplastic gland, or carcinoma. The diagnosis is made using a radioimmunoassay for PTH and the finding of an increased serum calcium level. Also found is hyperuricaemia and a decreased serum phosphate. In most patients the cause in not known. There are theories that irradiation in the region of 300-1200cGy may be causative and the effect may last for as long as four decades after exposure.

There appears to be an increased incidence in post menopausal women, and so decreased oestrogen has been touted as a possible culprit. In a small proportion of cases the disease is familial and is part of the Multiple Endocrine Neoplasia (MEN) syndrome. It occurs in 85-95% of MEN I patients and they require subtotal parathyroidectomy (1) . The cause of MEN I is thought to be a mutation in chromosome 11 in a tumour suppressor gene. In MEN I multiglandular disease is the rule, and in MEN II the HPT tends to be less severe (3).

MEN IIa consists of medullary carcinoma of the thyroid, phaeochromocytoma, and hyperparathyroidism. In these patients the mutation is found in the centromere part of chromosome 10.

Multiglandular disease means two or more enlarged glands each in excess of 50mg. The frequency is 20-25%. There is no evidence of sex or age difference between this and one gland disease. There is no differentiation that can be made on biochemical grounds, but MEN raises the suspicion of multiglandular disease.

In mild renal failure it is possible to have secondary HPT and calcium stays in the normal range or drops. In advanced renal failure, hyperparathyroidism occurs with an increase in calcium. PTH is increased when nephrons are lost. If one of the hyperplastic glands becomes autonomous then the PTH may remain high even after renal transplantation. This is known as tertiary HPT.

Genetics of HPT

The gene which is likely to cause HPT is PRAD1 on chromosome 11. There is rearrangement of the PRAD1 protooncogene next to the gene responsible for PTH production. The PRAD1 oncogene is present in 10-20% of breast cancers, 30-40% of squamous cell carcinomas of the head and neck, and 30% of oesophageal cancer. There is some suspicion that when the tumour suppressor gene RB is inactivated then this causes parathyroid carcinoma.

The incidence of hypercalcaemia is 1 in 2000. Fifty percent of these are due to PHPT, ie an incidence of 1 in 4000. Few cases occur in children. The sex ratio is 3 to 1 (female:male). The peak incidence is found in the age bracket 51 - 60.

Signs and symptoms

The symptoms are weakness, fatigue, headache, depression, bone pain, polydipsia, polyuria, pruritis, anorexia, nausea, vomiting, and constipation. These symptoms are relieved after the operation. This is possible that even without symptoms progressive osteopenia, and irreversible renal damage are possible. These symptoms seem unrelated to differences in serum calcium, age, PTH levels, and the weight of an adenoma.

Renal colic

This was a feature in 80% of patients with HPT prior to the invention of serum multichannel autoanalysers. Now, the figure has dropped to just 4%. The stones are caused when there is an increase in calcium oxalate. Hyperchloraemic acidosis results when there is decreased resorption of HCO3-. 15% of those presenting with renal calculi develop recurrent stones after parathyroidectomy. Renal failure ensues.

PTH acts on the 1-hydroxylase enzyme in kidney to produce 1,25OH vitamin D. The level increases and causes increased absorption of calcium and hypercalciuria.

Bone signs

These consist of severe osteoporosis, bone cysts, brown tumours, fractures, resorption of the distal phalanges, an increase in pseudogout, chondrocalcinosis, and gout.

Neuromuscular results

There is neuronal degeneration causing weakness, but this reverses following operative intervention.

Neurological manifestations

The patient is quick to fatigue, and is emotionally labile. Psychotic episodes may also occur. Memory decreases, and there is a triad of decreased hearing levels, dysphagia, and anosmia. Reflexes increase.

Gastrointestinal system

There is an increased incidence of peptic ulceration and pancreatitis.

Hypertension

Hypertension is not reversed by surgery. There is also a decrease of the QT interval on the ECG and left ventricular hypertrophy.

Laboratory findings

Calcium greater than three standard deviations above the mean warrants further investigation. In normal subjects high calcium shuts off PTH secretion. Therefore an increase in PTH secretion is diagnostic. Post op PTH levels remain elevated for a long time.

There is also an increase in 24 hour urinary calcium levels. Low calcium excretion may be indicative of familial hypocalciuric hypercalciaemia. Hyperchloraemia is common in PHPT.

Imaging

CT, oesophagography, MRI, ultrasound, radioactive subtraction thallium-technetium scanning, and technetium-sestamibi nuclear scanning may all be used. In a study of 325 patients use of three tests had a 92% pickup rate, two tests had an 88% pickup rate, and one test used alone had a 79% rate.

Scintigraphy with sestamibi was originally used for evaluation of cardiac perfusion. At that time, it was recognized that it was selectively taken up by the parathyroid glands. 123-I may be used for subtraction of thyroid activity, as sestamibi is found in both thyroid and parathyroid tissue, whereas iodine is only found in thyroid tissue. The computer subtracts the two images and an enlarged parathyroid gland is noted as an area of persistent uptake on the subtraction image.

Alternatively, sestamibi scans are taken two hours after isotope is administered. The isotope is retained for a longer period in the parathyroid than the thyroid. Localisation scans cut operating time by 50%. Invasive tests are rarely indicated. Rarely is it possible to palpate a parathyroid tumour.

Figure 1 shows a sestamibi scan of a patient with a parathyroid adenoma.

In a retrospective study (2) the scan has a positive predictive value of 89% amongst 24 patients - i.e. a match between operative findings and imaging. No false positives were found. Another advantage is that it reduces operation time by an average of 30 minutes. A disadvantage is that it is not possible to predict depth.

In 90% of patients accurate biochemical diagnosis can be made, but in a low number of patients it is not possible to find the gland, or hypercalcaemia persists. In this situation it is generally agreed that before another operation localization studies should be carried out. Definite indications for localization scans are an asymptomatic patient with mild hypercalcaemia, obese, short-necked individuals, high risk patients with poor cardiac risk.

However, there is a train of thought that says that in untreated PHPT the only localization required is that of an good parathyroid surgeon. The cost of the sestamibi scan is $600-800. MRI costs about $1200. False positives may arise from thyroid adenoma and hurthle cell tumours. Hurthle cell tumours contain oxyphilic cells with a high uptake of sestamibi.

Thompson et al found that sensitivity of the technique increases with an increased dose of sestamibi.

Figure 2 shows a parathyroid adenoma localised by ultrasound.

The indications for surgery, as laid down by the National Institutes of Health in 1990, are:

Serum calcium 1mg above the upper limit.
Hypercalciuria.
Decreased creatinine clearance.
Decreased bone mineral density.
Hypertension.
Age over 50.

Complications of long term hypercalcaemia include increased morbidity, osteopaenia, and renal failure. During medical treatment of hypercalcaemia it is possible that renal colic and hypercalcaemic coma may occur.

Medical management is indicated if:

Patient refuses the operation.
Contraindication to operation resulting from past medical history.
Several operations but recurrent hypercalcaemia persists.
Patients with calcium which is usually normal except in situation with increased bone resorption eg. Prolonged immobilization or diuretic therapy when calcium excretion is reduced.
Inoperable parathyroid carcinoma.

In the past, a rather dangerous procedure of injecting alcohol under ultrasound guidance has been employed. This results in recurrent nerve paralysis.

If surgery is postponed:

Hydrate the patient.
Be cautious with diuretics.
Avoid thiazides.
Frusemide increases urinary calcium excretions and increases the state of negative calcium balance.
Restrict dietary calcium.
Oral phosphate. This increases deposition into bone, and inhibits 1,25OH-vit D production. Decreased absorption of calcium through the GI tract results. It should only be used if the kidney function is good and phosphate levels in the serum are low. Side effects include diarrhoea, renal calculi, muscle cramps, and soft tissue calcification.
Calcitonin has slight success in this situation. It inhibits osteoclastic bone resorption, suppresses renal tubular absorption of calcium. When give i.v. its effect is transient and its cost limits use. It is possible to add corticosteroids. It is useful in recurrent parathyroid carcinoma.
Bisphosphonates inhibit osteoclastic bone resorption. Etidronate was the earliest drug used - but may cause osteomalacia and may decrease bone mineralisation. Aminohydroxypropilidine is a new drug which inhibits osteoclastic bone resorption.
Plicamycin inhibits DNA dependant RNA synthesis. A single iv infusion results in normocalcaemia in 48 hourrs which lasts for hours to weeks. Unfortunately it can cause liver damages, impaired renal function and thrombocytopenia.

Acute severe increases in calcium may cause coma, uraemia, and impending death. This warrants emergency surgery, or iv fluids, frusemide, or plicamycin before surgery. An estimated 90% of sufferers remain undetected. PHPT is associated with increased mortality due to cardiovascular diseases. The operation reduces or eliminates the risk. Symptoms may be mild and the disease is often coincidentally detected during health screening or medical examinations.

Operative intervention

The operation is thought to be safe, with few complications. This is no great chance of post-operative mortality. Hypocalcaemia and recurrent laryngeal nerve damage occur in 1-2%. The time in hospital is one or two days. Follow up is carried out every year to check calcium levels in hyperplasia, and every five years in the case of a single adenoma.

Following the operation 95% achieve a normal calcium after the removal of a single adenoma. The structural abnormalities and X-ray changes from osteitis fibrosa are cured after surgery. There is an increase in bone density in the first few years. Then it remains at 75% of normal as cortical bone loss is difficult to recover.

Renal stone production stops in 90%, and impaired renal function stops progressing. The concentrating power increases. Hypertension remains a feature, but left ventricular hypertrophy resolves to some extent. The weakness, fatigue, and malaise disappear in 80% of patients. Constipation decreases in 60-70% of patients. Musculoskeletal pains reduce in 50%, as is depression and anxiety.

Increased mortality from cardiovascular disease lasts for five to ten years after the operation. This returns to normal (3).

The parathyroid glands are identified. If one gland is large, and three are normal. The large gland is resected and sent for frozen sections, and the others are left alone. If all four glands are large then primary parathyroid hyperplasia is likely. A subtotal parathyroidectomy is performed leaving 50mg of the smallest gland.

Some surgeons remove all four glands and autotransplant. The glands may be also found in the thymus or superior mediastinum.

The incision employed is a short, low collar incision. The strap muscles are retracted. The superior gland is behind the recurrent laryngeal nerve in the upper thyroid lobe. The inferior gland is anterior, lateral or posterior to the lower pole of the thyroid in front of the nerve. A normal gland is pale tan, soft and flat. Adenomas are round, or oval and are dark brown or red and vary from 70mg to a few grams in weight.

Operating time may be reduced by intraoperative monitoring of PTH, to ensure excision of all hyperfunctioning tissue. A quick PTH assay works by immunochemluminescence. The role of surgery in mildly symptomatic patients is yet to be determined.

There are two subpopulations (3):

Benign - mild hypercalcaemia at a later age, stable clinical course, and unspecific symptoms.
Accelerated (10%) - progressive, severe morbidity, impaired renal function.

Cytokines

In PHPT there is an increased bone turnover. IL6, IL1beta, and TNFalpha result in an increase in bone resorption. IL6 stimulates osteoclast production. It is associated with oestrogen deficient bone loss and is produced by osteoblasts in response to PTH. TNFalpha is an agonist for IL6. In a study of 56 patients those with PHPT had an IL6 level 16 times higher than in normal subjects (1). The value returned back to normal after operation. It was thought that the bone derived cytokines are local effectors of bone resorption induced by systemic calcitropic hormones such as PTH. PTH increases production of gp130, part of the interleukin 6 signalling pathway.

There is also an increase in IL6 soluble receptor in PHPT which increases the bone resorbing effects of IL6. Rarely multiple myeloma and PHPT coexist. In multiple myeloma the proliferation of myeloma cells is stimulated by IL6 in a paracrine way.


Write us an article. Ask us any questions about the websites, or give us suggestions.	Primary Hyperparathyroidism Dr. Furrat Amen Primary hyperparathyroidism (PHPT) may be caused by a parathyroid adenoma, a hyperplastic gland, or carcinoma. The diagnosis is made using a radioimmunoassay for PTH and the finding of an increased serum calcium level. Also found is hyperuricaemia and a decreased serum phosphate. In most patients the cause in not known. There are theories that irradiation in the region of 300-1200cGy may be causative and the effect may last for as long as four decades after exposure. There appears to be an increased incidence in post menopausal women, and so decreased oestrogen has been touted as a possible culprit. In a small proportion of cases the disease is familial and is part of the Multiple Endocrine Neoplasia (MEN) syndrome. It occurs in 85-95% of MEN I patients and they require subtotal parathyroidectomy (1) . The cause of MEN I is thought to be a mutation in chromosome 11 in a tumour suppressor gene. In MEN I multiglandular disease is the rule, and in MEN II the HPT tends to be less severe (3). MEN IIa consists of medullary carcinoma of the thyroid, phaeochromocytoma, and hyperparathyroidism. In these patients the mutation is found in the centromere part of chromosome 10. Multiglandular disease means two or more enlarged glands each in excess of 50mg. The frequency is 20-25%. There is no evidence of sex or age difference between this and one gland disease. There is no differentiation that can be made on biochemical grounds, but MEN raises the suspicion of multiglandular disease. In mild renal failure it is possible to have secondary HPT and calcium stays in the normal range or drops. In advanced renal failure, hyperparathyroidism occurs with an increase in calcium. PTH is increased when nephrons are lost. If one of the hyperplastic glands becomes autonomous then the PTH may remain high even after renal transplantation. This is known as tertiary HPT. Genetics of HPT The gene which is likely to cause HPT is PRAD1 on chromosome 11. There is rearrangement of the PRAD1 protooncogene next to the gene responsible for PTH production. The PRAD1 oncogene is present in 10-20% of breast cancers, 30-40% of squamous cell carcinomas of the head and neck, and 30% of oesophageal cancer. There is some suspicion that when the tumour suppressor gene RB is inactivated then this causes parathyroid carcinoma. The incidence of hypercalcaemia is 1 in 2000. Fifty percent of these are due to PHPT, ie an incidence of 1 in 4000. Few cases occur in children. The sex ratio is 3 to 1 (female:male). The peak incidence is found in the age bracket 51 - 60. Signs and symptoms The symptoms are weakness, fatigue, headache, depression, bone pain, polydipsia, polyuria, pruritis, anorexia, nausea, vomiting, and constipation. These symptoms are relieved after the operation. This is possible that even without symptoms progressive osteopenia, and irreversible renal damage are possible. These symptoms seem unrelated to differences in serum calcium, age, PTH levels, and the weight of an adenoma. Renal colic This was a feature in 80% of patients with HPT prior to the invention of serum multichannel autoanalysers. Now, the figure has dropped to just 4%. The stones are caused when there is an increase in calcium oxalate. Hyperchloraemic acidosis results when there is decreased resorption of HCO3-. 15% of those presenting with renal calculi develop recurrent stones after parathyroidectomy. Renal failure ensues. PTH acts on the 1-hydroxylase enzyme in kidney to produce 1,25OH vitamin D. The level increases and causes increased absorption of calcium and hypercalciuria. Bone signs These consist of severe osteoporosis, bone cysts, brown tumours, fractures, resorption of the distal phalanges, an increase in pseudogout, chondrocalcinosis, and gout. Neuromuscular results There is neuronal degeneration causing weakness, but this reverses following operative intervention. Neurological manifestations The patient is quick to fatigue, and is emotionally labile. Psychotic episodes may also occur. Memory decreases, and there is a triad of decreased hearing levels, dysphagia, and anosmia. Reflexes increase. Gastrointestinal system There is an increased incidence of peptic ulceration and pancreatitis. Hypertension Hypertension is not reversed by surgery. There is also a decrease of the QT interval on the ECG and left ventricular hypertrophy. Laboratory findings Calcium greater than three standard deviations above the mean warrants further investigation. In normal subjects high calcium shuts off PTH secretion. Therefore an increase in PTH secretion is diagnostic. Post op PTH levels remain elevated for a long time. There is also an increase in 24 hour urinary calcium levels. Low calcium excretion may be indicative of familial hypocalciuric hypercalciaemia. Hyperchloraemia is common in PHPT. Imaging CT, oesophagography, MRI, ultrasound, radioactive subtraction thallium-technetium scanning, and technetium-sestamibi nuclear scanning may all be used. In a study of 325 patients use of three tests had a 92% pickup rate, two tests had an 88% pickup rate, and one test used alone had a 79% rate. Scintigraphy with sestamibi was originally used for evaluation of cardiac perfusion. At that time, it was recognized that it was selectively taken up by the parathyroid glands. 123-I may be used for subtraction of thyroid activity, as sestamibi is found in both thyroid and parathyroid tissue, whereas iodine is only found in thyroid tissue. The computer subtracts the two images and an enlarged parathyroid gland is noted as an area of persistent uptake on the subtraction image. Alternatively, sestamibi scans are taken two hours after isotope is administered. The isotope is retained for a longer period in the parathyroid than the thyroid. Localisation scans cut operating time by 50%. Invasive tests are rarely indicated. Rarely is it possible to palpate a parathyroid tumour. Figure 1 shows a sestamibi scan of a patient with a parathyroid adenoma. In a retrospective study (2) the scan has a positive predictive value of 89% amongst 24 patients - i.e. a match between operative findings and imaging. No false positives were found. Another advantage is that it reduces operation time by an average of 30 minutes. A disadvantage is that it is not possible to predict depth. In 90% of patients accurate biochemical diagnosis can be made, but in a low number of patients it is not possible to find the gland, or hypercalcaemia persists. In this situation it is generally agreed that before another operation localization studies should be carried out. Definite indications for localization scans are an asymptomatic patient with mild hypercalcaemia, obese, short-necked individuals, high risk patients with poor cardiac risk. However, there is a train of thought that says that in untreated PHPT the only localization required is that of an good parathyroid surgeon. The cost of the sestamibi scan is $600-800. MRI costs about $1200. False positives may arise from thyroid adenoma and hurthle cell tumours. Hurthle cell tumours contain oxyphilic cells with a high uptake of sestamibi. Thompson et al found that sensitivity of the technique increases with an increased dose of sestamibi. Figure 2 shows a parathyroid adenoma localised by ultrasound. The indications for surgery, as laid down by the National Institutes of Health in 1990, are: Serum calcium 1mg above the upper limit. Hypercalciuria. Decreased creatinine clearance. Decreased bone mineral density. Hypertension. Age over 50. Complications of long term hypercalcaemia include increased morbidity, osteopaenia, and renal failure. During medical treatment of hypercalcaemia it is possible that renal colic and hypercalcaemic coma may occur. Medical management is indicated if: Patient refuses the operation. Contraindication to operation resulting from past medical history. Several operations but recurrent hypercalcaemia persists. Patients with calcium which is usually normal except in situation with increased bone resorption eg. Prolonged immobilization or diuretic therapy when calcium excretion is reduced. Inoperable parathyroid carcinoma. In the past, a rather dangerous procedure of injecting alcohol under ultrasound guidance has been employed. This results in recurrent nerve paralysis. If surgery is postponed: Hydrate the patient. Be cautious with diuretics. Avoid thiazides. Frusemide increases urinary calcium excretions and increases the state of negative calcium balance. Restrict dietary calcium. Oral phosphate. This increases deposition into bone, and inhibits 1,25OH-vit D production. Decreased absorption of calcium through the GI tract results. It should only be used if the kidney function is good and phosphate levels in the serum are low. Side effects include diarrhoea, renal calculi, muscle cramps, and soft tissue calcification. Calcitonin has slight success in this situation. It inhibits osteoclastic bone resorption, suppresses renal tubular absorption of calcium. When give i.v. its effect is transient and its cost limits use. It is possible to add corticosteroids. It is useful in recurrent parathyroid carcinoma. Bisphosphonates inhibit osteoclastic bone resorption. Etidronate was the earliest drug used - but may cause osteomalacia and may decrease bone mineralisation. Aminohydroxypropilidine is a new drug which inhibits osteoclastic bone resorption. Plicamycin inhibits DNA dependant RNA synthesis. A single iv infusion results in normocalcaemia in 48 hourrs which lasts for hours to weeks. Unfortunately it can cause liver damages, impaired renal function and thrombocytopenia. Acute severe increases in calcium may cause coma, uraemia, and impending death. This warrants emergency surgery, or iv fluids, frusemide, or plicamycin before surgery. An estimated 90% of sufferers remain undetected. PHPT is associated with increased mortality due to cardiovascular diseases. The operation reduces or eliminates the risk. Symptoms may be mild and the disease is often coincidentally detected during health screening or medical examinations. Operative intervention The operation is thought to be safe, with few complications. This is no great chance of post-operative mortality. Hypocalcaemia and recurrent laryngeal nerve damage occur in 1-2%. The time in hospital is one or two days. Follow up is carried out every year to check calcium levels in hyperplasia, and every five years in the case of a single adenoma. Following the operation 95% achieve a normal calcium after the removal of a single adenoma. The structural abnormalities and X-ray changes from osteitis fibrosa are cured after surgery. There is an increase in bone density in the first few years. Then it remains at 75% of normal as cortical bone loss is difficult to recover. Renal stone production stops in 90%, and impaired renal function stops progressing. The concentrating power increases. Hypertension remains a feature, but left ventricular hypertrophy resolves to some extent. The weakness, fatigue, and malaise disappear in 80% of patients. Constipation decreases in 60-70% of patients. Musculoskeletal pains reduce in 50%, as is depression and anxiety. Increased mortality from cardiovascular disease lasts for five to ten years after the operation. This returns to normal (3). The parathyroid glands are identified. If one gland is large, and three are normal. The large gland is resected and sent for frozen sections, and the others are left alone. If all four glands are large then primary parathyroid hyperplasia is likely. A subtotal parathyroidectomy is performed leaving 50mg of the smallest gland. Some surgeons remove all four glands and autotransplant. The glands may be also found in the thymus or superior mediastinum. The incision employed is a short, low collar incision. The strap muscles are retracted. The superior gland is behind the recurrent laryngeal nerve in the upper thyroid lobe. The inferior gland is anterior, lateral or posterior to the lower pole of the thyroid in front of the nerve. A normal gland is pale tan, soft and flat. Adenomas are round, or oval and are dark brown or red and vary from 70mg to a few grams in weight. Operating time may be reduced by intraoperative monitoring of PTH, to ensure excision of all hyperfunctioning tissue. A quick PTH assay works by immunochemluminescence. The role of surgery in mildly symptomatic patients is yet to be determined. There are two subpopulations (3): Benign - mild hypercalcaemia at a later age, stable clinical course, and unspecific symptoms. Accelerated (10%) - progressive, severe morbidity, impaired renal function. Cytokines In PHPT there is an increased bone turnover. IL6, IL1beta, and TNFalpha result in an increase in bone resorption. IL6 stimulates osteoclast production. It is associated with oestrogen deficient bone loss and is produced by osteoblasts in response to PTH. TNFalpha is an agonist for IL6. In a study of 56 patients those with PHPT had an IL6 level 16 times higher than in normal subjects (1). The value returned back to normal after operation. It was thought that the bone derived cytokines are local effectors of bone resorption induced by systemic calcitropic hormones such as PTH. PTH increases production of gp130, part of the interleukin 6 signalling pathway. There is also an increase in IL6 soluble receptor in PHPT which increases the bone resorbing effects of IL6. Rarely multiple myeloma and PHPT coexist. In multiple myeloma the proliferation of myeloma cells is stimulated by IL6 in a paracrine way.