Perioperative management - Total Parathyroidectomy with Autotransplantation

Secondary renal hyperparathyroidism (sHPT)

Pathophysiology of sHPT

Hyperparathyroidism (HPT) is based on a chronically elevated parathyroid hormone (PTH) secretion. A distinction is made between pHPT (primary hyperparathyroidism) with autonomous secretion from one or more parathyroid glands (PTG) and sHPT with chronically elevated PTH secretion as a result of a permanently disturbed calcium/phosphate balance in chronic renal insufficiency or disturbed intestinal resorption.

renal hyperparathyroidism

The two most important hormonal control elements of the calcium and phosphate balance are PTH and the steroid hormone calcitriol (activated vitamin D). PTH is secreted by the parathyroid gland and promotes the provision of calcium. To this end, it mobilizes calcium from bone tissue, enhances renal and enteral calcium resorption, and simultaneously lowers the phosphate level by inhibiting renal phosphate reabsorption. Calcitriol, on the other hand, which is formed in the kidney, stimulates both calcium and phosphate resorption in the kidney and intestine. It thereby promotes bone mineralization.

Vitamin D deficiency and hyperphosphatemia in advanced kidney disease lead to an upregulation of PTH, particularly to increase renal phosphate elimination. All four parathyroid glands are affected.

The first-line therapy consists of conservative measures:

• Drug therapy: Vitamin D analogs, phosphate binders (calcium salts), calcimimetics (cinacalcet). Calcimimetics are modulators of the calcium-sensing receptor and can presumably permanently lower calcium and PTH levels
• Low-phosphate diet
• Increased dialysis duration and frequency

The operation cannot achieve a cure, but can reduce the total mass of active parathyroid tissue so that an adequate PTH value is achieved. This may be a definitive measure or a bridging measure until kidney transplantation.

Indication for surgery exists in:

• Symptomatic renal HPT refractory to conservative measures in connection with high PTH values (> 800 pg/ml)
  Note: The ESES (European Society of Endocrine Surgeons) recommends using this laboratory chemical reference point for indication. 
• Before kidney transplantation: Patients on the waiting list for kidney transplantation should be operated on if PTH values > 800 pg/ml or symptoms are present
• Hypercalcemic crisis (Ca > 3.5 mmol/l): as soon as possible after intensive care stabilization and ability to undergo anesthesia
• Calciphylaxis (calcifying uremic arteriolopathy) with severe ulcerating skin necroses
• Rapidly progressive atherosclerosis with uncontrolled PTH level
• Tertiary HPT after kidney transplantation: Long-lasting stimulation of the parathyroid glands can lead to their autonomy, so that the HPT persists even after successful kidney transplantation. This situation is referred to as tertiary HPT

Primary hyperparathyroidism (pHPT) in multi-gland disease, especially in the context of hereditary syndromes

• In familial diseases, pHPT should always be considered in the overall context of the syndrome disease
• About 2 - 5 % of all pHPT cases occur in the context of multiple endocrine neoplasia type 1 (MEN 1) with equal frequency in women and men at an early age (younger than 40 years). The entire organ system, i.e., all 4 parathyroid glands, are affected
• pHPT is the leading diagnosis in MEN 1 and is almost always observed. The operation presented is almost always indicated
• In MEN 2a, pHPT is observed in 15 - 20 % of cases, but here the medullary thyroid carcinoma represents the leading tumor. Often not all four parathyroid glands are hyperplastic or adenomatously altered. Therefore, resection should only be performed on the parathyroid gland(s) enlarged at the time of surgery to reduce the risk of postoperative hypoparathyroidism

Surgical technique

The total parathyroidectomy with thymectomy and synchronous parathyroid autotransplantation presented here is recommended by the Surgical Working Group Endocrinology (CAEK) and in the S2k guideline in the above indications as a recognized surgical technique. The autotransplantation should preferably be performed into the forearm musculature. In the event of a recurrence, evidence can be provided by exsanguination of the transplant-bearing arm for 5 - 10 min as to whether the recurrence is caused by the transplanted tissue or a remaining parathyroid gland cervical or ectopic mediastinal. Blood sampling is performed on the contralateral arm.

The professional societies AAES (American Association of Endocrine Surgeons) and ESES (European Society of Endocrine Surgery) recommend routine cervical thymectomy (especially in tertiary HPT) to reduce the postoperative persistence/recurrence rate while preserving parathyroid tissue through autotransplantation to keep the risk of permanent hypoparathyroidism low.

Alternative to the surgery shown here is subtotal parathyroidectomy with thymectomy.In subtotal resection, parathyroid tissue is left cervical at well-accessible defined sites. A lower parathyroid gland on the thyroid capsule is more suitable than an upper one dorsal to the thyroid near the entry of the recurrent laryngeal nerve into the larynx. In this case, the parathyroid remnant should be marked with a non-resorbable suture plus metal clip.

In planned kidney transplantation, a procedure with preservation of functionally active parathyroid tissue should be aimed for, so that autoregulation of the calcium balance after transplantation is not already initially excluded.

Parathyroidectomy without autotransplantation and without thymectomy may be a treatment option for older patients without planned kidney transplantation.

• cardiopulmonary risk assessment 
   
• General anesthesia incapacity 
   
• Coagulation disorder or intake of anticoagulants
  Guidelines recommend before elective operations an individual benefit-risk analysis: If the operative bleeding risk clearly outweighs the potential cardiovascular benefit, the ASA therapy should be discontinued.
  In cases of higher-grade anticoagulation such as P2Y₁₂-ADP receptor antagonists (e.g. Clopidogrel), NOACs (e.g. Xarelto) or vitamin K antagonists (e.g. Falithrom or Marcumar), a therapy concept should be developed in an interdisciplinary council regarding the indication of anticoagulation, possibility of bridging with heparin and operative bleeding risk.
   
• In the presence of adynamic bone disease and renal HPT
  Renal osteodystrophy is a general term for bone diseases in patients with terminal renal insufficiency. There are different types of renal osteodystrophy:
  • Osteitis fibrosa is the most common form (> 40 %) with increased bone turnover due to high parathyroid hormone levels.
  • Adynamic (aplastic) bone disease is found in up to 40 % of patients; it is a manifestation of pathologically reduced bone turnover. Low PTH levels (< 100 pg/ml) are predictors for this form. Removal of the parathyroid glands would worsen this disease and is contraindicated. 
     
•  MEN 2a
  • In case of detection of pHPT in MEN 2A syndrome, only the morphologically conspicuous parathyroid tissue should be removed, as the HPT does not represent the disease determining morbidity and lethality. Intraoperative PTH determination can support the resection strategy.

The diagnosis of secondary hyperparathyroidism is made by detecting elevated parathyroid hormone levels in the blood.
In contrast to primary hyperparathyroidism, the calcium level is in the normal range or decreased except in severe forms of sHPT, tertiary autonomy, vitamin D overdose or medication with calcium-containing phosphate binders. Vitamin D (25 and 1-25 (OH) D3) is often decreased and phosphate increased.
Since patients with renal insufficiency almost regularly have hypoalbuminemia, a determination of albumin-corrected calcium is recommended. Preoperatively, a complete thyroid laboratory should be performed.

The systemic nature of the disorders of mineral and bone metabolism in renal insufficiency has been emphasized since 2006 by the acronym CKD-MBD (Chronic Kidney Disease-Mineral Bone Disorder). Renal hyperparathyroidism is one of the main features of CKD-MBD.

In the medical history, the classic symptom picture of sHPT should be inquired: bone and joint pain, pruritus, extraosseous calcifications with movement restrictions, vascular calcifications, severe skin manifestations such as calciphylaxis.

Parathyroid hormone values up to 300 pg/ml are to be evaluated as reactive in dialysis patients and in the value range of 300 - 600 pg/ml there are no reliable associations with the Mineral Bone Disorder, the bone remodeling phenotype in chronic renal insufficiency. A parathyroid hormone value > 800 pg/ml largely excludes an adynamic bone disease, in which parathyroidectomy is contraindicated, possibly taking a bone biopsy/histology.

A localization diagnostics is not necessarily required, since in any case a bilateral cervical exploration is necessary. However, sonography is indicated to rule out a thyroid concomitant disease requiring surgery and to detect an intrathyroidal parathyroid gland. This examination is also recommended for assessing the size of the parathyroid glands and their localization.

Only in re-operations due to persistence/recurrence is imaging required before a renewed cervical exploration corresponding to the diagnostics in pHPT.

In primary hyperparathyroidism (pHPT) in the context of a multiglandular disease also in the context of hereditary syndromes, we refer to the diagnostics presented in contribution 29 (LINK to 29).

In pHPT patients ≤ 30 years with biochemically confirmed pHPT, a mutation analysis of potential candidate genes (e.g. MENIN gene, RET proto-oncogene, CDC73, CDKN1B), based on the family history, should be performed after genetic counseling.

• The day after dialysis is recommended as a suitable time for the operation
   
• The surgical risk is increased in dialysis patients. Cardiovascular comorbidities should be considered perioperatively
   
• Frozen section examination: The intraoperative frozen section can confirm parathyroid tissue, but cannot distinguish between hyperplasia and adenoma
   
• Intraoperative peripheral venous parathyroid hormone determination (IOPTH): IOPTH is considered the best quality indicator for postoperative normocalcemia. 10 - 15 min after adenoma removal, the drop in PTH is measured. For intraoperative PTH measurement, an established interpretation criterion and a standardized protocol should be used. Common are either the “soft” Miami criteria with a drop in PTH level after adenoma removal to < 50 % of the baseline value or the “hard” Halle criteria with a drop in PTH level < 35 pg/ml. With the Miami criteria, there is a risk of overlooking multi-gland disease; with the Halle criteria, the risk is greater of unnecessarily exploring the contralateral side.

        Note:Intraoperative PTH determination can be used in renal HPT, 
        to predict surgical success. However, an exact transfer of the         interpretation criteria as in pHPT is difficult. Due to the divergent literature and the  different experiences, the operation of renal HPT can also be performed without intraoperative PTH determination.

• Pre- and postoperative laryngoscopy
   
• Pre- and post-resection vagus stimulation using neuromonitoring; in intubation anesthesia, intraoperative neuromonitoring is preferably performed using a tube electrode to derive the M. vocalis electromyogram. Verifiable documentation of the stimulation EMG of the ipsilateral N. vagus before and after resection is recommended for forensic reasons.  LINK to IONM
   
• In renal HPT, due to the multimorbidity of the patients, perioperative antibiotic prophylaxis should be performed.

• usual risks of a surgical procedure (bleeding, infection, wound healing disorder, follow-up procedure)
• Inability to locate all parathyroid glands and revision surgery
• In case of intraoperative signal failure, resection of the contralateral side at a later time
• persistent hyperparathyroidism
• postoperative hypoparathyroidism
• recurrent laryngeal nerve palsy, in case of bilaterality possibly tracheotomy
• autotransplantation into neck or forearm musculature
• exploration of the thyroid with possible resection in case of abnormalities
• pneumothorax
• recurrence
• possibly simultaneous thyroid resection