Efficacy of Percutaneous Ethanol Injection Therapy (PEIT) into Parathyroid Glands in Haemodialysis Patients with Secondary Hyperparathyroidism

Efficacy of Percutaneous Ethanol Injection Therapy (PEIT)into Parathyroid Glands in Haemodialysis Patients with

Secondary Hyperparathyroidism

Mohamed Fouad, Amira Shoukry, Walid M Afifi, Einas M Elsherbiny, Mabrouk I Ismail

Nephrology unit. Internal Medicine Department. Zagazig University Hospital.AbstractBackground: Secondary hyperparathyroidism (SHPT) is a common complication observed in long-term dialysis patients. Its pathophysiology is mainly due to hyperphosphatemia and active vitamin D deficiency and/or resistance. This condition has a high impact on the mortality and morbidity of dialysis patients .Despite recent advances in medical therapy, surgical parathyroidectomy (PTx) is required in a considerable number of uraemic patients. Recently, othermodalities of therapy, such as ultrasound-guided percutaneous parathyroid injection of ethanol has been used to treat refractory SHPT. Objective: To evaluate the efficacy of percutaneous parathyroid injection of ethanol and its impact on parathyroid function.Methods: This study had been carried out at Zagazig University Hospital. In the period from May 2007 to Dec 2008. Fifteen haemodialysis patients with severe SHPT were studied. Whom means SD serum intact PTH (i-PTH) (pg/mL), corrected serum calcium Ca (mg/dL), serum phosphate P (mg/dL) and Ca x P product (mg2/dL2) were 1294.20351.14, 10.700.22, 6.700.45, 71.33 4.68 respectively. PEITguided by ultrasonography was performed and all glands > 0.5 cm3 were destroyed. Follow-up of the serum levels of i-PTH, corrected Ca, P andCa x P product at one month, six month and one year was done.Results: Serum intact PTH, corrected serum Ca, serum P and Ca x P product were significantly reduced following PEIT at one month to 745.93250.96, 10.33 0.23, 5.86 0.43 and 60.65 4.43 respectively P<0.001. At the six month the serum intact PTH, corrected serum Ca, serum P and Ca x P product achieved the Kidney Disease Outcomes Quality Initiative (K/DOQI) target desired levels 310.4051.86, 10.080.11, 4.470.58, 44.8 5.7 respectively and was maintained for one year without relapse with levels 306.3349.91, 9.940.22, 4.460.59, 44.34 6.2 respectively.Conclusion: PEIT is a safe and effective treatment; it was possible tomaintain one year parathyroid function within accepted levels and achieve the" K/DOQI" target desired levels of serum intact PTH,

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calcium , phosphorus and Ca x p product, without relapse. PEIT might decrease Ca x P product and therefore prevent calcification of the arteries in dialysis patients, and decreases cardiovascular complications in patients with severe secondary hyperparathyroidism. PEIT is to be a valid treatment choice for SHPT.Keywords: Secondary hyperparathyroidism; Ultrasonography; Percutaneousethanol injection therapy; Nodular hyperplasia

INTRODUCTIONSecondary hyperparathyroidismis a common complication seenin long-term dialysis patients. In addition to fractures and bone pain caused by osteitis fibrosa, this condition causes ectopic calcification associated with elevated calcium and phosphate products [1] .Over the past decade, a number of large observational studies have evaluated whether markers of chronic kidney disease–mineral and bone disorder (CKD–MBD) determine long-termmortality in haemodialysis (HD)

patients [2]. These studies, generally found higher levelsof intact parathyroid hormone, calcium and/or phosphate to be associated with an increased risk of mortality [3].Based on these findings and supplemented by an expert opinion, the US National Kidney Foundation Kidney Disease Outcomes Quality

Initiative (NKF-KDOQI) published clinical practice guidelines provided recommended target ranges for various markers of MBD, such

as iPTH, total serum calcium and serum phosphate [4].

A normal parathyroid glands (PTG) measures; 6x5x2 mm and should be well within the detection limit of the latest ultrasonographic apparatus. The size estimated by ultrasonography is reproducible and correlates with the actual gland weight [5].

A large parathyroid gland representsnodular hyperplasia composed of proliferating monoclonal cells [6], with a low density of calcitriol receptors [7] and Ca-sensing receptors [8] .Such glands are thus resistant to medical therapy, such as intravenous calcitriol or maxacalcitol therapy. When one or more parathyroid glands progress to the stage of nodular hyperplasia, itis usually difficult to control parathyroid hormone secretion, even by vitamin D3 therapy. In such patients with severe secondary hyperparathyroidism, surgical parathyroidectomy is indicated [9]. However, PTx is considered

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unsuitable for patients with severe heart failure and/or old age, also low parathyroidhormone (PTH) levels after PTx was reported as a problematic complication [10].

Then, in the 1980s, an epoch-making new technique, percutaneous ethanol injection therapy, was introduced in Europe [11]. The concept of selective PEITis to destroy the glands withnodular hyperplasia and then to manage the remaining glands with diffuse hyperplasia [12].Then, post-PEIT management is the key for maintaining optimal parathyroid function [13].

Percutaneous ethanol injection therapy has been widely applied as an alternative treatment for SHPT in Japan [14].Many otherreports showed the effectiveness of PEIT for secondary hyperparathyroidism[15], [16], [17].

Japanese Society for Parathyroid Intervention issued the new clinical guidelines for selective direct injection therapy of

the parathyroid glands in chronic dialysis patients. [18].

Percutaneous ethanol injection therapy

Indication

Therapy is indicated for those who meet all of the following three criteria:

(i) Difficult cases for continuous treatment, despite of medical treatments, showing *intact PTH ≥ 400 pg/ml or hyperphosphataemia and / or hypercalcaemia induced by Treatment

(ii) Enlarged parathyroid glands with suspected nodular hyperplasiaon ultrasonography**

(iii) Patients who have given informed consent to undergo PEIT.

Exclusion criteria

(i) Enlarged parathyroid gland located where ultrasonographic-guided puncture is impossible

(ii) Paralysis of the recurrent laryngeal nerve on the opposite side.

(iii) Operation in the neck region for thyroid carcinoma.

ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ* Intact PTH = 1–84 PTH × 1.7 **Estimated volume (calculated by length× width × depth × π/6) >0.5 cm3 or abundant blood flow inside the gland suggests nodular hyperplasia.

Aim of the work

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In this study, we evaluated the usefulness of PEIT for severe secondary hyperparathyroidism, based onthe clinical course of 15 patients treated with PEIT for one year post injection in Zagazig University Hospital.

PATIENTS AND METHODS

This study had been carried out in Nephrology unit. Internal Medicine Department.Zagazig. University Hospital. In the period from May 2007to Dec 2008.

The study included 15 patients, 10 were male and 5 females. There age ranged from 37 to 65 years (53.067.6 years).

They were undergoing maintenance haemodialysis therapy for 5 to 10 years (7.731.62). Dialysis was performed three times weekly using 3.5 mEq/l dialysate Calcium. Duration of each dialysis was 4 hours; protocols were not changed during the study.

The main cause of end-stage renal failure was chronic glomerulonephritis.

All of them with refractory secondary hyperparathyroidism. "Resistance to medical treatment is defined as PTH level above the target range despite administration of vitamin D or analogues, and uncontrollable serum Ca and P levels".

At time of commencement the serum intact PTH, corrected serum Ca, serum P and Ca x P product were measured. And we followed up our patients via these parameters for 1 year. Ultrasonographic results showed that 12 patients had only oneenlarged parathyroid gland. 3 patients had two enlarged parathyroid glands. Patients had three or more glands >0.5 cm3 in sizewere considered unsuitable for PEIT.

All patients fulfilled the aforementioned criteria of Japanese Society for Parathyroid Intervention, and also obeyed the exclusion criteria of Japanese Society for Parathyroid Intervention. [18]. PEIT equipment andtechniques: Neck ultrasound examinationwas performed using a colour Doppler

ultrasonogram with a 7.5-10MHz Scanner.

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Glandular volumes were estimated by measurement of three dimensions of the glands, and glands with a volume of > 0.5 cm3 were treated.

We chose the largest gland for the first ethanol injection in 12 patients and the remaining 3 patients needother injection to the secondlargest gland Ethanol 98% injection was performed using a 22-gauge needle, and the tip of the needle was guided to the centre of the gland. The amount of absoluteethanol injected wascalculated according to glandvolume. If gland volume wasbetween 0.5 and 1 cm3, theethanol injected was 80% ofgland volume, but if thegland volume was >1 cm3 theethanol injected was 50% ofgland volume [18]. Destruction of the glandular tissue confirmed byincrease echogenecity, decrease in size and disappearance of the blood supply [18].

Complications: All patients complaint pain at site of injection, only two patients develop small hematoma treated conservatively and one

patient suffer from horsiness of voice managed conservatively.

Post-PEIT management

After PEIT, all patients weretreated with oral active vitamin Dsterols and calcitriol pulse therapy(4 mcg twice per week).

PEIT repeated only in onepatient 2 weeks after PEIT as PTHconcentration did not decrease significantly. Imaging for ectopic glandsshould not be carried as the PTHconcentration is decreased inall patients post PEIT.

All patients were followed up by serum intact PTH, corrected serumCa, serum P and Ca x P product at1month, 6month and 1year post injection.

Characteristics of participating patients:Age (years) 53.067.64Sex (male : female)

10 : 5

Period of hemodialysis (years)

7.731.62

Intact-PTH (pg/mL) 1294.20351.14Serum Ca (mg/dL) 10.700.22Serum P (mg/dL) 6.700.45Ca x P (mg2/dL2) 71.33 4.68Values are expressed as mean±standard deviation.

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Statistical analysis

All results are expressed as means ± standard deviation (SD). Multivariate analysis (Wald’s test) was used for multiple comparisons, the standard deviation, Analysis of variance (ANOVA or F-test), Least significance difference (LSD), used for analysis of results of the study [19].

*P values of <0.05 were considered significant

…………………………………………………………………………

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Parathyroid gland after

Enlarged parathyroid gland before PEIT

RESULTS:

Effectiveness of PEIT

The means value SD of serumiPTH (pg/mL),) serum Ca(mg/dL), serum P (mg/dL) andCa x P (mg2/dL2) product attime of commencement were1294.20351.14, 10.70 0.22, 6.70 0.45 and 71.334.68 respectively.

One month later the meansvalue SD significantlydecreased to 745.93 250.96,10.33 0.23 , 5.860.43 and60.65 4.43respectively.

Six months later the meansvalue SD significantlydecreased to 310.4051.86,10.080.11, 4.470.58 and44.8 5.7 respectively.

Finally at one year the meansvalue SD non significantlydecreased to 306.3349.91,9.940.22, 4.460.59 and44.34 6.2respectively."Table 2"

Table (2): Showed the mean value SD, of intact-PTH (pg/mL),serum Ca (mg/dL), serum P (mg/dL) and Ca x P (mg2/dL2) product preinjection and

1month, 6 month and 1 year post injection. (One way anova test).

Preinjection level

1 monthlater

6 monthslater

1yearlater

F P

Intact-PTH (pg/mL)

1294.20351.14

745.93250.96

310.4051.86

306.3349.91

65.614

<0.001

Serum Ca (mg/dL)

10.70 0.22

10.33 0.23

10.080.11

9.940.22

40.009

<0.01

Serum P(mg/dL)

6.70 0.45

5.860.43

4.470.58

4.460.59

66.93 <0.001

Ca x P mg2/dL2

71.334.68

60.654.43

44.85.7

44.346.2

62.45 <0.001

Intact-PTH Comparing the mean valueSD of serum intact-PTH, at time of commencement versus different times of the study we found the following.

There was statistically highly significant decrease in the mean value SD of intact-PTH from time of commencement to 1month, 6months and 1year post injection.

There was statistically highly significant decrease in the mean value SD of intact-PTH from 1month post injection to 6months and 1year post injection.

There was statistically non significant decrease in the mean value SD of intact-PTH from 6 months to 1year."Table 3"

Table (3): Comparison between mean values ±SD of intact-PTH (pg/mL) at different times of the study."LSD"

Preinjection level

1 monthlater

6 monthslater

1yearlater

1 month later

<0.001 ----- <0.001 <0.001

6 month later

<0.001 <0.001 ----- NS

1year later

<0.001 <0.001 NS -----

Serum Ca Comparing the mean value SDof serum Ca at time of commencement versus differenttimes of the study we found the following.

There was statistically highly significant decrease in the mean value SD of serum Ca from time of commencement to 1month, 6months and 1year post injection.

There was statistically highly significant decrease in the mean value SD of serum Ca from 1month post injection to 6months and1year post injection.

There was statistically nonsignificant decrease in themean value SD of serum Cafrom 6 months to 1year "Table4"

Table (4): Comparison between mean values ±SD of serum Ca(mg/dL) at different times of the study."LSD"

Preinjection level

1 month later

6 months later

1year later

1 month later

<0.001 ----- <0.005 <0.001

6 month later

<0.001 <0.005

----- NS

1year later

<0.001 <0.001

NS -----

Serum P Comparing the mean valueSD of serum P at time of commencement versus differenttimes of the study we found the following.

There was statistically highly significant decrease in the mean value SD of serum P from time of commencement to 1month, 6 months and 1year post injection.

There was statistically highly significant decrease in the mean value SD of serum P from 1month post injection to 6months and 1year post injection. There was statistically non significant decrease in the mean value SD of serum P from 6months to 1year "Table 5"

Table (5): Comparison between mean values ±SD of serum P (mg/dL) at different times of the study. "LSD"

Preinjection level

1 month later

6 months later

1year later

1 month later

<0.001 ----- <0.001 <0.001

6 month later

<0.001 <0.001 ----- NS

1year later

<0.001 <0.001 NS -----

Ca x P product Comparing the mean valueSDof Ca x P product at time ofcommencement versus differenttimes of the study we foundthe following.

There was statisticallyhighly significant decreasein the mean value SD of Cax P product from time ofcommencement to 1month,6months and 1year postinjection.

There was statisticallyhighly significant decreasein the mean value SD of Cax P product from 1month postinjection to 6months and1year post injection.

There was statistically nonsignificant decrease in themean value SD of Ca x Pproduct from 6 months to1year "Table.6"

Table (6): Comparison between mean values ±SD of Ca x P product at different times of the study."LSD"

Preinjection level

1 month later

6 months later

1year later

1 month later

<0.001 ----- <0.001 <0.001

6 month later

<0.001 <0.001 ----- NS

1year later

<0.001 <0.001 NS -----

P<0.0

0

2

4

6

8

10

12

Calcium

1 m onth 6 m onth 1year

Beforeinjection

After injection

P =NS

Intact

-PTH (

pg/m

L)

P =NS

P<0.00

P

P

0

1

2

3

4

5

6

7

Phosph

orus

1 m onth 6 m onth 1year

Beforeinjection

After injection

P =NS

P<0.00

P =NS

P<0.0

P<0.0

P<0.00

DISCUSSION

SHPT is a common complicationobserved in long-term dialysis patients. Despite improvements in clinical treatment for SHPT, a considerable number of patients do not respond to calcitriol therapy. Consequently, surgery is indicated for these patients [20]. This non-response is related to enlarged parathyroid glands whose histopathology generally shows nodular hyperplasia [21]. However, PTx is considered unsuitable for patient with severe heart failure and/or old age, also low PTH levels after PTx was reported as a problematic complication [10].

Extensive necrosis and sclerotic changes in parathyroid tissue can be obtained after PEIT, reducingthe parathyroid mass and thusinterfering with one of the main factors sustaining hyperparathyroidism. [12].

So in this study we evaluate the usefulness of PEIT as an alternative to PTx in patients with severe secondary hyperparathyroidismand analyse its effects on

parathyroid functions for oneyear post injection.

All patients in this study were resistant to medical treatment, their intact-PTH (pg/mL) was extremely high 1294.20351.14,with hypercalcaemia "corrected serum Ca" 10.70 0.22 mg/dL, hyperphosphatemia 6.70 0.45 mg/dL and high Ca X Pproduct mg2/dL2 71.33 4.68.

One month after PEIT the intact-PTH, corrected serum Ca, serum phosphorus and lastly Ca x P product were significantly decreased. The K/DOQI guidelines recommendedthat iPTH 150–300 pg/mL, serum P should be < 5.5 mg/dL, Ca<10.2 mg/dl and the Ca x P at <55 mg2/dL2 [4]

Six months after PEIT we achieved the target levels recommended by K/DOQI

guidelines as serumintact-PTH, correctedserum Ca, serum phosphorusand Ca x P product wereapproximately similar. Theseresults supported by resultsobtained by Motoko Tanaka[15].

One year after PEIT the desired levels of intact-PTH,corrected serum Ca, serum phosphorus and the Ca x P product were maintained without relapse.

We have demonstrated in the present study that PEIT is a useful treatment for suppression of intact-PTH, corrected serum Ca, serum phosphorus and the Ca x P product levels to the target desired levels recommended byNational Kidney Foundation. Similar results obtained by Fumihiko Koiwa [16] and ReikaTanaka [17].

The effect of secondary hyperparathyroidism on mortality was thought to be mainly caused by hyperphosphatemia. The last phase of the Dialysis Outcomes and Practice Patterns Study identified hyperphosphatemia P > 6.1

mg/dL, hypercalcaemia Ca > 10mg/dL, and high PTH > 600 pg/mL as three independent risk factors for all-cause and cardiovascular mortality,with hazard ratios of 1.18, 1.16, and 1.21, respectively [3].

Hypercalcaemia has been reported to cause not only ectopic calcification, including in the vasculature [22], but also to be directlyrelated to a reduced life expectancy [23].

High serum P and Ca x P product were reported as important risk factors for death from coronary artery disease and sudden death [24].

Moreover, it is known that a calcium x phosphorus product > 72 mg2/dL2 is associated with a 34% increased risk of mortality and metastatic calcification

These risks further increasesby 11% for every 10 points ofelevation of the calcium-phosphorus product [2].

In this study we found that PEIT effectively lowered serum Ca, P and Ca x P product, to desired levels,

so PEIT may be helpful to reduce the risk of ectopic calcification, including thevasculature and reducing cardiovascular mortality in patients with severe SHPT.

PEIT is considered relativelysafe intervention. The only

encountered complications were pain at the site of injection, small sized hematomas and non serious horsiness of voice, all thesecomplications were managed conservatively. Many authors reported these non serious side effects which were managed conservatively [15] [25].

Conclusion:

Percutaneous ethanol injection therapy is a safe and effective treatment for patients with severe secondary hyperparathyroidism.

It is possible to maintain1 year parathyroid function within the normalrange and achieve the desired "K/DOQI" target without relapse.

PEIT might decrease Ca x Pproduct and therefore may help to prevent calcification of the arteries in dialysis patients and decrease cardiovascular complications in patients with severe secondary hyperparathyroidism.

Early application PEITshould be considered in

patients with severesecondaryhyperparathyroidism forthe prevention ofirreversible bone diseases

Acknowledgement: We thank Prof. Dr.Mohammed Zanaty, for his invaluablesuggestions and support for ourwork .and Prof. Dr. Kaled Lakouz forhis help in the field of ultrasonography

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