Iatrogenic hypoparathyroidism:
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1 Iatrogenic hypoparathyroidism: The 3 syndromes of post-thyroidectomy parathyroid failure Antonio Sitges-Serra, FRCS (Ed) Endocrine Surgery Unit Hospital del Mar, Barcelona No disclosures Publications: BJS 2010, 2015
2 F Chvostek Sr. ( ) WG McCallum ( ) Some historical milestones F. Chvostek (1876): taping the facial nerve N. Weis N (1881): post-thyroidectomy tetany in humans G. Vasale and F. Generali (1896): post-ptx tetany (cats) W.G. McCallum and C. Voegtlin (1908): tetany, Ca and the PGs
3 The 80 s: Total thyroidectomy for everybody! TS Reeve MN Goiter OH Clark Cancer NW Thompson Graves disease
4 The 80 s: Total thyroidectomy for everybody! Total TX for PTC>1 cm in USA Bilimoria KY et al., SURGERY 2007
5 The 90 s: Hypoparathyroidism associations Hadker N et al., Endocr Pract 2014
6 Hypoparathyroidism before 2000 Pattou F et al., World J Surg 1998
7 Hypoparathyroidism before 2000 Methodological issues Lack of precise definitions Mixture of surgical procedures Small series Short/incomplete follow-up Euphoria for total thyroidectomy Conflicts of interest Sitges-Serra A et al., BJS 2010 Wu J & Harrison B, WJS 2010
8 Hypoparathyroidism today The multicentre & registries era Permanent hypoparathyroidism after total thyroidectomy BAETS Audit 12.1% SWEDISH Reg 6.4% GERMAN MC ACS CoC 9.0 % 10 %
9 Definitions: the 3 syndromes 1. Postoperative hypocalcemia Acute parathyroid failure (s-ca<8 mg/dl or 2 mmol/l & PTH< 10 pg/ml) Requiring calcium/vit D supplements at discharge 2. Protracted hypoparathyroidism (1 mo.) Low or undetectable PTH at 1 month Need to keep Ca + Vit D treatment 3. Permanent hypoparathyroidism (1 yr.) Aparathyroidism (undetectable PTH) Hypoparathyroidism (3<PTH<13 pg/ml) Relative parathyroid insufficiency (blunted response)
10 Hospital del Mar Pevalence and prognosis of hypocalcemia after total TX (Initial surgery for cancer or goiter 1:4) Lorente L et al., BJS 2015 Hypocalcemia 278 (42.3%) Total Thyroidectomy 669 Total Thyroidectomy 657 sca 24h <2 mmol/l Normocalcemia 379 (57.7%) Insufficient data 12 No L/U ipth 1mo Yes Yes L/U ipth 1mo No Normocalcemia 172 (62%) Protracted Hypoparathyrodism 106 (38%) Protracted Hypoparathyroidism 15 (4%) Normocalcemia 364 (96%) Protracted Hypoparathyroidism 121 (18.4% of total) Permanent Hypoparathyroidism 30 (25%) (4.5% of total) Yes L/U ipth 1yr No Normocalcemia 91 (75%)
11 Hospital del Mar Pevalence and prognosis of hypocalcemia after total TX (Initial surgery for cancer or goiter 1:3) Sitges-Serra A et al. BJS 2010 Lorente L et al., BJS 2014 Hypocalcaemia 278 (42.3%) Total Thyroidectomy 669 Total Thyroidectomy 657 sca 24 Normocalcaemia 379 (57.7%) Insufficient data 12 ipth 1mo ipth 1mo Normocalcaemia 172 (62%) Protracted Hypoparathyrodism 106 (38%) Protracted Hypoparathyroidism 15 (4%) Normocalcaemia 364 (96%) Protracted Hypoparathyroidism 121 (18.4% of total) Permanent Hypoparathyroidism 30 (25%) (4.5% of total) ipth 1yr Normocalcaemia 91 (75%)
12 Postoperative hypocalcemia (s-ca <2 mmol/l at 24h) No standard definition s-ca vs. ipth determinations? Corrected s-ca? Ionized s-ca? Preventive treatment? s-ca <8 mg/dl or 2 mmol/l 24h postop (simple, most commonly used, fast, cheap, corrects for fluid load and recumbency) Negative Predictive Value (669 TTXs): 96%
13 Pathogenesis of acute parathyroid insufficiency Parathyroid autotx Accidental parathyroidectomy Parathyroid devascularization Obstruction of venous outflow Reduction of functioning parathyroid tissue PTH <10-15 pg/ml (parathyroid failure)
14 Parathyroid failure The principal cause of postoperative hypocalcemia ipth <10 pg/ml at 4 h after TTX (n=200) had the best precision to predict a s-ca <8 mg/dl at 24h Sensitivity: 95% Specificity: 99% Positive predictive value: 90% Negative predictive value: 99% Precision: 98% Barczynski M et al., Langenbeck s Arch Surg 2007 Toniato A et al., Am J Surg 2008 Grodski S et al., World J Surg 2008 Cayo AK et al., Surgery 2012
15 Pathogenesis of acute parathyroid insufficiency Accidental PTX PG AutoTX Extensive surgery
16 Pathogenesis of acute parathyroid insufficiency Accidental PTX PG AutoTX Parathyroid glands remaining in situ (PGRIS)= 4-(accidentally resected + AutoTX)
17 Postoperative hypocalcemia (s-ca <2 mmol/l at 24h) Total n:657 Normocalcaemia n:379 (%) (sca 24h 8.0 mg/dl) Hypocalcaemia n:278 (%) (sca 24h <8.0 mg/dl) P* Age (years) > (48) 294 (61) 89 (52) 189 (39) Gender (M:F) 112/545 73:306 39: Extent of surgery TT (60) 217 (40) TT + CCND (51) 31 (49) TT + CCND + LCND (44) 30 (56) Autotransplantation < Yes No (42) 319 (62) 83 (58) 195 (38) Parathyroid glands preserved in situ (PGRIS) < or (26) 91 (49) 277 (64.5) 32 (74) 95 (51) 151 (35.5) Sitges-Serra et al., BJS 2010
18 Postoperative hypocalcemia (s-ca <2 mmol/l at 24h) Total n:657 Normocalcaemia n:379 (%) (sca 24h 8.0 mg/dl) Hypocalcaemia n:278 (%) (sca 24h <8.0 mg/dl) P* Age (years) > (48) 294 (61) 89 (52) 189 (39) Gender (M:F) 112/545 73:306 39: Extent of surgery TT (60) 217 (40) TT + CCND (51) 31 (49) TT + CCND + LCND (44) 30 (56) Autotransplantation < Yes No (42) 319 (62) 83 (58) 195 (38) Parathyroid glands preserved in situ (PGRIS) < or (26) 91 (49) 277 (64.5) 32 (74) 95 (51) 151 (35.5)
19 Pathogenesis of postoperative hypocalcemia Hypocalcemia and the extension of TTX TT n=551 TT+CND n=64 TT+LND n=54 P Hypocalcemia (sca 24h <8.0 mg/dl) Protracted hypoparathyroidism (ipth 1mo < 13 pg/ml) Permanent hypoparathyroidism (ipth 1y < 13 pg/ml and/or Ca± Vit.D treatment 1y ) 220 (40%) 31 (48%) 31 (57%) (17%) 18 (28%) 12 (22%) (4%) 4 (6%) 4 (7.4%) s-ca at 24h (mg/dl) 8.1 ± ± 1 7.7± ipth 24h (pg/ml) 22.2 ± ± ± ipth 1 mo (pg/ml) 34.3 ± ± ± PGRIS 3/4 93% 94% 89% N.S. Parathyroid ischemia is the most plausible explanation for higher hypocalcemia rates in more extensive total thyroidectomies
20 Pathogenesis of postoperative hypocalcemia Parathyroid glands remaining in situ PGRIS = 4 (autotransplanted + accidentally removed) Hypocalcemia (s-ca 24h <8.0 mg/dl) Protracted hypoparathyroidism (ipth 1mo < 13 pg/ml) Permanent hypoparathyroidism (ipth 1y < 13 pg/ml and/or Ca±Vit.D treatment 1y ) 1-2 PGRIS n=43 (6.4%) 3 PGRIS n=187 (28%) 4 PGRIS n=438 (65.6%) 32 (74 %) 95 (51%) 155 (35%) (44%) 46 (25%) 57 (13%) (16%) 12 (6.4%) 11 (2.5%) P s-ca at 24h (mg/dl) 7.6 ± ± ± ipth at 24h (pg/ml) 7.4 ± ± ± ipth 1 mo (pg/ml) 19.7 ± ± ± Lorente-Poch L et al., BJS 2015
21 Pathogenesis of postoperative hypocalcemia Proportion hypocalcemia/permanent hypopara Hypocalcemia (s-ca 24h <8.0 mg/dl) Permanent hypoparathyroidism (ipth 1y < 13 pg/ml and/or Ca±Vit.D treatment 1y ) 1-2 PGRIS n=43 (6.4%) 3 PGRIS n=187 (28%) 4 PGRIS n=438 (65.6%) 32 (74 %) 95 (51%) 155 (35%) (16%) 12 (6.4%) 11 (2.5%) P Rate hypoca /permhypo 5/1 8/1 14/1 Lorente-Poch L et al., BJS 2015
22 Risk factors for protracted hypoparathyroidism Total n:657 No protracted hypoparathyroidism n: 536 (%) Protracted Hypoparathyroidism n:121 (%) P* (ipth 1mo 13pg/mL) (ipth 1mo <13 pg/ml) Age (years) > (79) 399 (83) 37 (21) 84 (17) Gender (M:F) 112/545 96:440 16: Extent of surgery TT (83) 91 (17) TT + CCND (71) 18 (29) TT + CCND + LCND (78) 12 (22) Autotransplantation < Yes No (68) 439 (85) 46 (32) 75 (15) Parathyroid glands preserved in situ (PGRIS) < or (56) 140 (75) 372 (87) 19 (44) 46 (25) 56 (13)
23 Risk factors for protracted hypoparathyroidism Total n:657 No protracted hypoparathyroidism n: 536 (%) Protracted Hypoparathyroidism n:121 (%) P* (ipth 1mo 13pg/mL) (ipth 1mo <13 pg/ml) Age (years) > (79) 399 (83) 37 (21) 84 (17) Gender (M:F) 112/545 96:440 16: Extent of surgery TT (83) 91 (17) TT + CCND (71) 18 (29) TT + CCND + LCND (78) 12 (22) Autotransplantation < Yes No (68) 439 (85) 46 (32) 75 (15) Parathyroid glands preserved in situ (PGRIS) < or (56) 140 (75) 372 (87) 19 (44) 46 (25) 56 (13)
24 Protracted hypoparathyroidism What s in a definition? No reliable predictors of PH <1 month Need for prolonged replacement therapy Patient s and surgeon s uncertainty Need for prolonged follow-up Tentative prognosis can be made Overall: 75%/25% ipth Dx vs UnDx: 65%/35% Is there something we can do at this satge?
25 Prognosis of protracted hypoparathyroidism Factors favoring parathyroid function recovery Pattou F et al., World J Surg 1998
26 Prognosis of protracted hypoparathyroidism The momment of truth Sitges-Serra A et al., BJS 2010
27 Prognosis of protracted hypoparathyroidism The momment of truth Lorente-Poch L et al., BJS 2015; 102:359-67
28 Prognosis of protracted hypoparathyroidism The momment of truth Lorente-Poch L et al., BJS 2015; 102:359-67
29 Recovery from protracted hypoparathyroidism The parathyroid splinting hypothesis The reduced/ischemic parathyroid parenchyma requires rest in a normal-high Ca ++ environment to restart PTH secretion
30 Recovery from protracted hypoparathyroidism 65 yr female. Total TX for endothoracic goiter PGRIS 3 Ca ++ 3g + Calcitriol 0.75 mcg/day
31 Pathogenesis of permanent hypoparathyroidism Parathyroid autotransplantation The end of a wishful thinking? Wells SA et al., NEJM 1976 Hypocalcemia (sca 24h <8.0 mg/dl) Protracted hypoparathyroidism (ipth 1mo < 13 pg/ml) Permanent hypoparathyroidism (ipth 1y < 13 pg/ml and/or Ca±Vit.D treatment 1y ) No ATX n=512 (79%) ATX n=143 (21%) P 194 (38%) 83 (58%) (15%) 46 (32%) (3.1%) 14 (9.8%) s-ca postop 24h (mg/dl) 8.12 ± ± ipth 24h (pg/ml) * 21.1 ± ± ipth 1 mo (pg/ml) 35.4 ± ± * Available in 174 patients.
32 Pathogenesis of permanent hypoparathyroidism PGRIS 3: a new look at autotx Wells SA et al., NEJM 1976 Hypocalcemia (sca 24h <8.0 mg/dl) Protracted hypoparathyroidism (ipth 1mo < 13 pg/ml) Permanent hypoparathyroidism (ipth 1y < 13 pg/ml and/or Ca±Vit.D treatment 1y ) ATX N=110 (59%) Accidental N=76 (41%) P 57 (52%) 38 (50%) N.S. 28 (25.5%) 18 (24%) N.S. 8 (7%) 4 (5%) N.S. s-ca at 24h (mg/dl) 7.9 ± ± 0.8 N.S. ipth 24h (pg/ml) * 4 ± 2 8 ± 9 N.S. ipth 1 mo (pg/ml) 26 ± ± 28 N.S. Glands identified (n) * Available in 174 patients. 3.3 ± ± 0.7 <0.001
33 Relative parathyroid failure The unexpected patient Delayed hypocalcemia with normal ipth Vomiting/diarrhea Mg containg calcium salts Intercurrent disease Medication (HIV) Calcium salts Malabsortion Pancreatic resection Small bowel resection Right colectomy Roux-en-Y gastric bypass Biphosphonates Lactation Severe vit D deficiency Promberger R et al., Thyroid 2012 Lassig AA et al., Head Neck 2011
34 65 yr female. Total TX plus prophylactic CND and MRND for medullary cancer. PGRIS 4 Alendronate Oral Ca 2g/d
35 Relative parathyroid failure Wade JSH et al., BJS 1965 Anastasiou OE et al., J Clin Endocr Metab 2012
36 Conclusions I Factors relevant for postoperative hypocalcemia (s-ca <8 mg/dl) are age, gender, the extension of TTX and PGRIS Protracted hypoparathyroidism is associated with fewer PGRIS Recovery of protracted hypoparathyroidism is associated to a higher s-ca concentrations and detectable ipth at 1 month, and PGRIS.
37 Conclusions II The happy parathyroid gland From a surgical standpoint it appears essential to avoid accidental parathyroidectomy and autotrasplantation Keeping s-ca >9 mg/dl or 2,25 mmol/l during the early postoperative period (parathyroid splinting), may improve the long term prognosis of postoperative hypocalcemia
38 To the memory of J. Attie Ch. Proye P.O. Granberg Signed: The happy parathyroid
39
40 The state of the art in 2015 The law of 30%: a reasonable aim 1st time total thyroidectomy (30% cancer) 30% will develop postop hypocalcemia 30% will develop protracted hypopara 30% will develop permanent hypopara (<4%)
41 Parathyroid splinting: A rational hypothesis to improve the prognosis of postoperative hypocalcemia
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