Anesthesia and parathyroid diseases
Introduction
The parathyroid glands are located behind the thyroid gland. Although the number
and position can vary, there are usually four parathyroid glands.Parathyroid hormone
consists of 84 amino acids derived from a prohormone. The effects of parathyroid
hormone on serum calcium are mediated by increasing renal tubular resorption of
calcium, increasing calcium absorption from the intestines (via vitamin D) and
increasing release of calcium from bone. A negative feedback mechanism normally
decreases production of parathyroid hormone as the ionized serum calcium level
increases. Disease states with altered protein binding require a correction factor to
determine the ionized calcium level from the total calcium level. A low measured
calcium with low albumin may be corrected by adding 0.8 mg per dL (0.2 mmol per
L) of calcium for each gram per dL that the albumin is below 4 g per dL (1 mmol per
L). Alternatively, the serum ionized calcium level can be measured directly.
Hyperparathyroidism
Hyperparathyroidism is a metabolic disorder characterized by increased production of
parathormone (PTH). It is the most common cause of hypercalcemia in
nonhospitalized patients; however, patients with hyperparathyroidism may have low,
normal, or high serum calcium levels, mostly depending on renal function. It occurs in
1 of 1,200 adults, more commonly in women. The most common cause is a
parathyroid adenoma .It accounts for approximately 85% of cases. It is a benign,
encapsulated neoplasm involving only one parathyroid gland. The tumor is composed
of closely packed cells, predominantly chief cells. The diagnosis is safely confirmed
when normal or suppressed parathyroid tissue is seen in a second gland or in a
remnant of normal tissue in the diseased gland.
Primary parathyroid hyperplasia is the cause of hyperparathyroidism in approximately
12% of patients. It consists of proliferation of parathyroid cells in the absence of a
known stimulus for PTH hypersecretion. Of particular interest is the association of
chief cell hyperplasia and multiple endocrine neoplasia (MEN) syndromes. The
different components of the MEN syndrome and subtypes are noted in Table 1.
Rarely, a parathyroid carcinoma is responsible for hyperparathyroidism.
Characteristically, patients have higher calcium levels than patients with adenoma or
hyperplasia, and most patients have metabolic alterations. In patients with chronic
renal failure or malabsorption syndromes there is an increase in secretion of PTH as a
consequence of chronically low serum calcium levels. This is called secondary
hyperparathyroidism. Patients develop bone pain or pathologic fractures that are
secondary to bone resorption, decalcification, cysts, and brown tumor formation. In
renal failure patients this is complicated by hyperphosphatemia and the inability to
hydroxylate vitamin D2.
Table 1: Multiple endocrine neoplasia
Effects of Hyperparathyroidism
on Body Systems
(MEN)
syndromes
Central Nervous System
Mental
disorders,
especially
depression, and central nervous
system dysfunction are commonly
associated with hypercalcemia and
hyperparathyroidism.
Several
suicides have been attributed to
hyperparathyroidism. Patients (even
those originally believed to be asymptomatic) often feel better after removal of a
dysfunctional parathyroid gland.
Renal and Genitourinary Systems
Nocturia and polyuria result from the effects of calcium on the renal tubule.
Approximately 20 percent of patients with hyperparathyroidism have kidney stones.
Conversely, only 2 to 3 percent of patients with kidney stones have
hyperparathyroidism. Nephrolithiasis is more common in patients with the slow,
insidious form of hyperparathyroidism.
Cardiovascular System
A Swedish study following patients with hyperparathyroidism for over 10 years
showed that mortality from cardiovascular disease was higher in the study subjects
with hyperparathyroidism than in the control population. Hypertrophic
cardiomyopathy and a decrease in function of the muscles of respiration may account
for some of this effect. Patients with hyperparathyroidism are more likely than control
subjects to have hypertension and congestive heart failure, and are more likely to
exhibit changes on electrocardiogram. If the induced hypertension is treated with a
thiazide diuretic, the calcium level may elevate further and, thus, confound the
diagnosis.
Musculoskeletal System
At least in relatively mild cases, the bone loss associated with hyperparathyroidism
involves the peripheral skeleton more than the vertebral bodies and affects cortical
bone more than cancellous bone. Nonspecific myalgias are the most common
musculoskeletal symptoms. The lesions of osteitis fibrosa cystica, previously referred
to as brown tumors, mimic malignant lesions and occur in patients with advanced
disease.
Gastrointestinal System
Anorexia, constipation and nausea can occur as a result of hyperparathyroidism.
Peptic ulcer disease occurs in 15 percent of patients. If patients take antacids
(particularly those containing calcium) for ulcer symptoms, they risk aggravating
hypercalcemia by adding milk-alkali syndrome (an increased serum calcium level in
the face of calcium intake and an alkaline gastric environment) to the malady. The
anorexia and nausea added to the dehydrating renal effect of polyuria can deteriorate
into a "parathyroid storm" (also referred to as parathyroid poisoning or parathyroid
crisis). Pancreatitis is sometimes an additional manifestation of primary
hyperparathyroidism. Pancreatitis, often accompanied by hypocalcemia, can be a
confusing symptom when considered with an inappropriately high or normal calcium
level.
Pregnancy
Maternal hyperparathyroidism can lead to profound hypocalcemia and tetany in the
newborn. This may be the first manifestation of maternal hyperparathyroidism.
Asymptomatic Effects
A Finnish study found that in 65 percent of "asymptomatic" patients, previously
unrecognized symptoms were relieved after parathyroid surgery. This is about the
same percentage of symptomatic patients who have resolution of symptoms
postoperatively.
Findings of primary hyperparathyroidism
1.
Increased concentration of intact parathyroid hormone.
2.
High total and ionized serum calcium (Normal Ca++ = 8.4-10.5mg/dL).
3.
Hypophosphatemia, phosphaturia.
4.
Hyperchloremia and increabsed chloride: phosphate ratio.
5.
Hypercalciuria (>10mmol/day). Loss of <2mmol of calcium/day suggests a
diagnosis of familial hypercalcemic hypocalciuria.
6.
Increased serum alkaline phosphatase and increased urinary excretion of
cAMP (as markers of bone involvement).
Medical Treatment of Primary Hyperparathyroidism
1.
Biphosphanate: reduces serum calcium concentration & reduces bone
resorption.
First generation: Etidronate (Didronel).
Second generation: Clodronate-Pamidronate (Aredia) 60mg IV over 3 hours.
Third generation: Alendronate-Risedronate-Tiludronate-Zolendronic acid
(4mg IV over >15 minutes).
2. Ca sensing receptor agonist, calcimimetics.
Aim: Serum Ca levels should reach <12mg/dL before any surgical intervention
3. Calcitonin: 4-8 IU/kg SC or IM every 12 h.
4. Glucocorticoids: 3-4 mg/kg/day of hydrocortisone IV or orally.
5. Mithramycin (Plicamycin): 25 pg/kg IV.
Side effects: thrombocytopenia-decreased level of clotting factorshepatotoxicity-renal toxicity- Ca- phosphate- K.
Secondary Hyperparathyroidism
Secondary hyperparathyroidism is the condition in which PTH secretion is increased
to com-pensate chronically existing hypocalcemia with no intrinsic parathyroid
abnormality.This is accompanied by hyperphosphatemia and increased alkaline
phospha-tase demonstrating the severity of bone disease.
Possible causes of secondary hyperparathyroidism:
•
Chronic renal failure.
•
Vitamin D deficiency.
•
Vitamin D resistance syndrome.
•
Renal tubular phosphate wasting disorders.
•
Osteomalacia.
•
Malabsorption
•
Pseudohypoparathyroidism.
•
Complication of high dose phosphate therapy.
Clinical Presentation of secondary hyperparathyroidism
1.
Most of the patients are on dialysis.
2.
Osteitis fibrosa cystica or osteomalacia which may lead to skeletal deformities
or fractures.
3.
Soft tissue calcification (vascular and soft tissues including kidneys i.e.
nephrocalcinosis, lungs, heart and skin.
4.
Calciphylaxis: severe calf pain and tenderness with extensive non ulcerating,
large, hard and tender subcutaneous plaques ® skin & subcutaneous necrosis ® deep
non healing ulcers and gangrene ® threaten patients life.
5.
Pruritis
Medical Treatment of Secondary Hyperparathyroidism
1.
Dietary phosphate restriction (calcium carbonate ® ¯ phosphate intestinal
absorption).
2.
Daily calcium intake ³ 1500 mg (calcium may be added to dialysis fluid).
3.
Long term calcium a ketoglutarate (≈4.5g/d).
4.
Routine vitamin D supp-lementation.
5.
Charcoal hemoperfusion for pruritis.
6.
Dialysis (CAPD removes more PTH than hemodialysis).
7.
Ca++ receptor agonist (Calcimimetic).
8.
Medical therapy fails in 5-10% of patients on long term dialysis and surgery
becomes necessary.
Tertiary Hyperparathyroidism
Either before or more often, after renal transplantation secondary hyperparathyroidism
can develop into a disorder of over secretion of PTH with hypercalcemia.
Ectopic Hyperparathyroidism
It is caused by malignant neoplasms that demonstrate ectopic secretion of PTH
or a PTH related protein (PTHrP).
Hypercalcemia is mainly produced by tumors of the lung, breast, kidney,
ovary and by hematological tumors as well (e.g. Hodgkin lymphoma, multiple
myeloma).
PTHrP binds the receptors of native PTH thus causing the same picture of
hyperpara-thyroidism.
Findings of Ectopic Hyper-parathyroidism
•
Hypercalcemia with absence of detectable PTH by radioimmunoassay.
•
The presence of high urinary cAMP supports the diagnosis of humoral
hypercalcemia of malignancy.
•
Detection pf PTHrP doesn’t rule out parathyroid adenoma as it ha has been
suggested that PTHrP is produced by oxyphill cells of parathyroid gland.
•
Low serum levels of calcitriol.
Surgical treatment of Hyperparathyroidism
Operative management is clearly indicated for all patients with classic
symptoms or complications of hyperpara-thyroidism.
The recommendations of surgical treatment for seemingly asymptomatic
patients are:
A corrected serum Ca++ concentration of >12 mg%.
Marked hypercalciuria-urinary calcium excretion >400mg/day.
Markedly reduced cortical bone density.
Unexplained reduction in creatinine clearance by 30%.
Age <50 years.
Surgical Methods of Treating Hyperparathyroidism
I.
Traditional open surgery.
II.
Minimally invasive techniques:
•
Unilateral approach.
•
Endoscopic and video assisted techniques.
•
Radio-guided technique.
•
Ultrasound guided fine needle aspiration.
•
Ethanol sclerotherapy.
•
Radiofrequency ablation.
Parathyroid Crisis
•
It usually occurs in a symptomatic hyperparathyroid patient who might be
subjected to stress.
•
Severe hypercalcemia occurs in 1-2% of patients with PHPT and has been
referred to as acute hyperparathy-roidism, parathyroid crisis, parathyroid storm and
parathyrotoxicosis.
•
Parathyroid crisis occurs when serum calcium level rises acutely above 14
mg%.
Symptoms and Clinical manifestations:
Renal: Polyuria, poldypsia, dehydration.
GIT: Anorexia, nausea, vomiting, constipation.
Musculoskeletal: Weakness, lethargy and immobility.
CNS: Profound mental changes, cognitive diffi-culties, apathy or even coma.
CVS: Palpitation, hyper-tension, shortened QT interval and enhanced
sensitivity to digitalis.
Differential diagnosis of hypercalcemia
Primary hyperparathyroidism
Malignancy
Hematogenous malignancy: multiple myeloma, Burkit lymphoma, Hodgkin
lymphoma
Solid malignancy with bone metastasis :breast, lung
Solid malignancy without bone metastasis : hypernephroma, squamous
carcinoma.
Granulomatous disease : Sarcoidosis, tuberculosis
Iatrogenic :thiazide diuretics, lithium, Vitamin D intoxication
Familial hypocalciuric hypercalcemia
Milk alkali syndrome.
Prolonged immobilization.
Treatment of hypercalcemic crisis
1.
Rehydration: 4-6 L/day (150-300ml/h) of normal saline.
2.
Forced saline diuresis: using loop diuretics (frusemide 40mg/4h).
3.
Biphosphonates
4.
Calcitonin
5.
Dialysis: is reserved for patients with renal failure (with a low or zero calcium
dialysate) Peritoneal dialysis can remove 100-500mEq of calcium in 24 hours
whereas hemodialysis approximately 70mEq / hour.
Hypoparathyroidism
Describes a condition in which there are low circulating levels of parathyroid
hormone (PTH) or insensitivity to its action. The causes of hypoparathyroidism vary;
however, they all share a common feature of hypocalcemia. The presentation of
hypoparathyroidism also varies depending on the chronicity of the resultant
hypocalcemia. Muscle spasms/tetany, paresthesias, and seizures may occur in an
acute onset, whereas chronic hypoparathyroidism may only be evidenced by visual
impairment due to cataract formation.
Pathophysiology
Many underlying pathologic etiologies of hypoparathyroidism exist.
* The most common causes are neck surgery and autoimmune processes.
Hypoparathyroidism resulting from thyroid or parathyroid surgery can become
clinically apparent 1-2 days after the procedure or follow the operation by many
years. The incidence of permanent hypoparathyroidism varies with the extent of the
procedure, the surgeon’s experience, and the underlying disease process being treated.
Rarely, hypoparathyroidism can be a complication of radioactive iodine treatment of
external localized radiotherapy.
* Autoimmune insult to the parathyroid gland can be isolated or associated with a
variety of polyglandular syndromes. Antibodies to the parathyroids have been
detected in up to 30% of patients with isolated hypoparathyroidism and 40% of
patients with polyglandular disease. The calcium sensor-receptor is another target of
autoantibodies in hypoparathyroidism. In patients with polyglandular autoimmune
syndrome type 1, more than 50% will have this antibody.
* Maternal hyperparathyroidism can result in transient neonatal
hypoparathyroidism. Maternal PTH suppresses neonatal parathyroid activity;
however, this resolves rapidly after birth and removal from excessive maternal PTH.
* Both hypermagnesemia and hypomagnesemia can result in decreased PTH
secretion. In the case of hypermagnesemia, elevated magnesium levels result in
stimulation of a calcium-sensing receptor on the pituitary. This, in turn, attenuates
PTH secretion. In the case of chronic alcoholics with hypomagnesemia, there is
diminution of PTH secretion levels and a resistance to hormone activity.
* This condition is characterized by thymus and parathyroid dysgenesis, cardiac
malformation, and facial dysmorphogenesis. Other complex syndromes associated
with hypoparathyroidism have been described and include Sanjat-Sakati syndrome,
HDR syndrome, Kenny-Caffey syndrome, Kearns-Sayre syndrome, and Pearson
marrow-pancreas syndrome..
* Infiltration of the parathyroid gland can lead to clinically significant
hypoparathyroidism. Causes include metastatic carcinoma, hemochromatosis,
transfusion-related iron overload, Wilson disease and sarcoidosis
Insufficient production of PTH is known as true hypoparathyroidism, while decreased
action on target tissues is called pseudohypoparathyroidism.
Effects of Hypoparathyroidism on Body Systems
The clinical manifestation of hypoparathyroidism is due to hypocalcemia.
* Head, ears, eyes, nose, and throat signs
o Surgical/traumatic scars
o Mucocutaneous candidiasis
* Neurologic signs
o Hyperreflexia
o Tetany
o Chvostek sign - Chvostek sign has low sensitivity and specificity. Twentyfive percent of healthy persons will have a positive result; 29% of hypocalcemic
patients will have a negative result.
o Trousseau sign (carpal spasm caused by occluding the brachial artery) Trousseau sign is more reliable. Only 1-4% of healthy persons will have a positive
sign; 94% of hypocalcemic persons will have a positive sign.
o Seizures
o Altered mental status
* Cardiovascular signs
o Heart failure
o Bradycardia
o Hypotension not responsive to fluids or pressors
* Ophthalmologic signs - Cataracts
* Signs in infants
o Vomiting
o Abdominal distention
o Apneic spells
o Intermittent cyanosis
o Twitching, tremors, and seizures
Management of hypoparathyroidism
Acute, symptomatic hypocalcemia is a medical emergency. The main goal of
treatment is to restore serum calcium levels to alleviate symptoms of acute
hypocalcemia. In the setting of severe symptoms, calcium therapy should be given
even if serum levels are only mildly reduced. Care to prevent long-term complications
from hypocalcemia or hypercalcemia should be coordinated with an endocrinologist.
* Intravenous calcium: 100-300 mg elemental calcium diluted in 150 mL D5W
over 10 minutes (10-30 mL of 10% calcium gluconate [9.3 mg/mL elemental
calcium])
o This solution raises ionized calcium level by 0.5-1.5 mmol. Calcium chloride may
be used if infused through a central line, as it can be harmful when given in a
peripheral vein.
o Initial rate of infusion is 0.3-2 mg elemental calcium/kg/h. This scale is not
exact; base subsequent adjustments on serial calcium measurements every 2-4 hours.
o Infuse children with 2 mg/kg elemental calcium, or about 0.2 mL of 10%
calcium gluconate/kg, IV.
* Oral therapy: Calcium carbonate, 1-2 grams or more per day, in 3-4 divided
doses. May be appropriate for patients with mildly lowered calcium levels and mild or
no symptoms.
Anesthetic Implications of hyperparathyroidism
Electrolyte imbalance-ECG changes.
Pathological fractures.
Monitoring of: BP-ECG-temperature, peripheral nerve stimulator.
Requirements of anaesthetics in somnolent patients are reduced.
Hydration is necessary.
Aspiration prophylaxis must be done in case of altered mental status.
Intubation may be difficult and extension if needed must be done with care.
Tracheal intubation increases serum PTH level.
Muscle relaxants: their action is unpredictable. There may be increased
sensitivity to suxamethonium and resistance to atracurium, rocuronium &
vecuronium. This suggests that hyperparathyroidism may cause acetylcholine
receptors up regulation.
Intravenous propofol infusion doesn’t alter PTH levels significantly during
parathy-roidectomy.
Hyperventilation with resul-tant respiratory alkalosis should be avoided as it
reduces serum K+ level and leaves the action of Ca++ unopposed.
Postoperative complications include nerve injury, vocal cord palsy, bleeding
and hypocalcemia.
Recovery
Postoperative serum calcium level should be monitored.
Hypocalcemia should not be treated when asymptomatic because it resolves
on the 4th or 5th postoperative day.
Intravenous calcium infusion may be necessary for 1-2 days if serum Ca++ is
< 7.7mg/dL with symptoms of tetany.
Persistent hypocalcemia is due to hungry bone syndrome or organic
hypoparathyroidism that should be treated with vitamin D and calcium.
Anesthetic Implications of hyypoparathyroidism
Management of anesthesia is intended to prevent further decreases in serum
calcium concentrations and to recognize and treat adverse effects of hypocalcemia,
particularly on the heart. During anesthesia and surgery it is important to appreciate
that respiratory or metabolic alkalosis can rapidly decrease serum ionized calcium
concentrations. This can occur during hyperventilation of the lungs or after
intravenous administration of sodium bicarbonate to treat metabolic acidosis.
Responses to nondepolarizing muscle relaxants are not well defined, but the
preoperative existence of skeletal muscle weakness suggests decreased dose
requirements for these drugs,
Further readings
 Hiroshi Takami, Yoshifumi Ikeda .Recent advances in the management of
primary hyperparathyroidism, Endo-crine journal 2003; 50, 369-377.
 Silverberg SJ, Bone HG, Marriott TB Short-term inhibition of parathyroid
hormone secretion by a calcium receptor agonist in primary
hyperparathyroidism. N Eng J Med 1997;337:1506-1510 ,
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Aliya
Khan , John Bilezikian
.Primary hyperparathyroidism :
pathophysiology and impact on bone. Canadian Medical Association Journal
2000; 16:184-7.
Thomas Stefenelli , Claudette Abela , Herbert Frank, Janette Koller Cardiac
Abnormalities in patients with primary hyperparathyroidism: Implication for
follow-up. Journal of Clinical Endocrinology and Metabolism 1997; 8: 10612.
R. Mahai, J R Farndom Parathyroid and calcium metabolism . British Journal
of Anaesthesia 2000; 85: 29-43
William G. Goodman Medical management of secondary hyperparathyroidism
in chronic renal failure. Nephrol Dial Transplant 2003;18:113-114 .
John T Potts Parathyroid hormone (PTH): past and present . Journal of
Endocrinology 2005; 187: 311-325.
R.M. Kiewiet, H.H. Ponssen, E.N Janssens, Ph. Fels Ventricular fibrillation in
hypercalcaemic crisis due to primary hyperparathyroidism. The journal of
medicine 2004; 62: 94-99 .
Thierry Massfelder Jean- Jacques Helwig Parathyroid hormone- related
protein in cardiovascular development and blood pressure regulation. J
Endocrinol 1999; 14: 1507-1509.