Secondary Hyperparathyroidism in Chronic Kidney Disease
Chronic kidney disease is frequently complicated by secondary hyperparathyroidism, which causes bone disease and vascular calcification, leading to increased risk of morbidity and mortality. In secondary hyperparathyroidism the parathyroid glands have responded to a stimulus that appropriately leads to increased PTH secretion. By definition, in secondary hyperparathyroidism, the serum calcium concentration is normal but the PTH level is elevated. For example, any malabsorption syndrome in which calcium absorption is impaired can be associated with an increase in PTH secretion. Renal insufficiency defined by a creatinine clearance lower than 60 mL/min is often associated with an increase in PTH. Vitamin D deficiency, as defined by a low 25-hydroxyvitamin D level, can be associated with an increase in PTH. Long-standing CKD is associated with several metabolic disturbances that lead to increased secretion of PTH, including hyperphosphatemia, calcitriol deficiency, and hypocalcemia. Hyperphosphatemia has a direct stimulatory effect on the parathyroid gland cell resulting in nodular hyperplasia and increased PTH secretion. The size of the parathyroid glands progressively increases as CKD worsens, and gland size is positively correlated with serum PTH levels. Because the parathyroid glands are autonomously functioning, in some patients, PTH levels remain persistently high despite serum calcium levels that are within normal range.
Secondary Hyperparathyroidism After Gastric Bypass and Weight Reduction (Bariatric) Surgery Procedures
Bariatric surgery is an effective treatment option for obesity. Commonly utilized procedures are either restrictive, malabsorptive, or both. Substantial weight loss can be achieved. Postoperatively, patients experience nutritional, metabolic, and hormonal changes that have important clinical implications. Bone metabolism is greatly affected, in part due to vitamin D deficiency, decreased calcium absorption, and secondary hyperparathyroidism. Secondary Hyperparathyroidism occurs most often after biliopancreatic-diversion with "duodenal switch". The risk of developing Secondary Hyperparathyroidism after biliopancreatic-diversion with "duodenal switch" is 12.5 times higher than after gastric banding and 16.7 times higher than after sleeve-gastrectomy. Secondary Hyperparathyroidism does develop in 40 % gastric bypass patients and in 100 % duodenal switch patients. Supplements of vitamin D and calcium does not associate with a lower prevalence of Secondary Hyperparathyroidism at 5 years follow-up studies.
Uncontrolled secondary hyperparathyroidism is associated with an increased risk of fractures and mortality. Patients with end stage of renal disease (ESRD) experience substantial physical, emotional, mental, and psychosocial impairments that are reflected in decreased quality of life.
Patients are experiencing following symptoms: pain in the bones, feeling tired easily, mood swings, feeling ‘‘blue’’ or depressed, pain in the abdomen, feeling weak, feeling irritable, pain in the joints, being forgetful, difficulty getting out of a chair, headaches, itchy skin (pruritus), being thirsty. Cognitive impairment is common among patients with secondary hyperparathyroidism.
Therapeutic options include medical therapy (phosphate binders, vitamin D analogs, and calcimimetics) and parathyroidectomy
Clinical Practice Guidelines KDOQI: Parathyroidectomy in Patients with Chronic Kidney Disease (Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease):
1) Parathyroidectomy should be recommended in patients with severe hyperparathyroidism (persistent serum levels of intact PTH >800 pg/mL [88.0 pmol/L]), associated with hypercalcemia and/or hyperphosphatemia that are refractory to medical therapy.
2) Indication for surgical parathyroidectomy is the presence of calciphylaxis with PTH levels that are elevated (>500 pg/mL [55.0 pmol/L]), as there are several reports of clinical improvement in patients with calciphylaxis after such therapy.
3) Effective surgical therapy of severe hyperparathyroidism can be accomplished by subtotal parathyroidectomy, or total parathyroidectomy with parathyroid tissue autotransplantation.
Surgical Treatment of Secondary Hyperparathyroidism
Secondary hyperparathyroidsm is a common complication in hemodialysis patients associated with morbidity and sometimes mortality. The majority of patients with secondary hyperparathyroidsm can be managed by medical treatment. However, medical treatment does not always provide control of parathyroid disorder.
The recently introduced NKF-K/DOQI guidelines recommended much more restricted ranges for serum levels of Ca, P and parathyroid hormone (PTH). While medical therapy is often effective for the control of hyperparathyroidism, surgical therapy can provide effective reductions in the serum levels of PTH.
To determine the best surgical approach it is important to have good communication between physicians who are taking care of this complex disease, which usually include endocrine surgeon, nephrologist (renal doctor) and possibly endocrinologist. The standard surgical procedures in patients with secondary hyperparathyroidism include: 1) subtotal, three and 1/2 glands, parathyroidectomy with superficial partial thymectomy; 2) total parathyroidectomy with autotransplantation of one portion of the parathyroid gland into the strenoclaidomastoid muscle in the neck or into to the patient's forearm, with superficial partial thymectomy, and with or without cryopreservation of the portion of one parathyroid gland for a possible future re-implantation; 3) total parathyroidectomy without autotransplantation, and with superficial partial thymectomy.
One and probably the best option for the initial surgical therapy is to perform subtotal, three and 1/2 glands, parathyroidectomy. In case if disease is re-occured, and in case if physicians have collaborative discussion about specific patient issues would suggest different procedure then the second option would be to perform a total parathyroidectomy with or without portion of parathyroid gland autotransplantation into the strenoclaidomastoid muscle in the neck or into to the patient's forearm. Autotransplantation can be performed immediate or can be delayed to use frozen protion of the gland in the future. In most patients, the onset of graft function is documented in about 1 week after autotransplantation. Replantation after cryopreservation is performed in and in up to 50% of patients this graft will survive. Intraoperative PTH monitoring is advocated for routinely use during parathyroidectomy and help to determine co0mpltness of the surgery and influence on surgical strategy in about 40 % of patients.
Prognosis after Surgery:
Parathyroidectomy increases long-term survival in dialysis patients, also improves bone mineral density and decreases the risk of fractures. Furthermore, muscle power, anemia, blood pressure, and calciphylaxis may be improved after parathyroidectomy. Most patients experienced a subjective improvement in bone pain, joint pain, pruritus, and malaise, sleep and cognition disturbances. Neuropsychiatric symptoms such as fatigue, mood swings, depression, forgetfulness, and headache are significantly and durably decrease after parathyroidectomy. Also there is a marked improvement in health-related quality of life among patients with secondary hyperparathyroidism after parathyroidectomy. There is significant improvement in all symptoms of the secondary hyperparathyroidism at one year after parathyroidectomy (up to 40% improvement). About 96% of patients claims that they are satisfied or very satisfied with the result of the parathyroidectomy (per study of Cheng )
Secondary Hyperparathyroidism and Cinacalcet (Sensipar)
Cinacalcet hydrochloride, a calcimimetic, is a new modality for the treatment of Secondary Hyperparathyroidism and is able to suppress a high parathyroid hormone level remarkably well. However, for patients with uncontrollable Secondary Hyperparathyroidism while on cinacalcet, those with severe Secondary Hyperparathyroidism symptoms and those with difficulty being treated with cinacalcet because of side-effects, parathyroidectomy may be indicated as usual. Parathyroidectomy can induce a remarkable improvement in Secondary Hyperparathyroidism: postoperative serum phosphorus and calcium levels are easily maintained within their target ranges, quality of life is improved, survival rates are improved and the procedure has high cost-effectiveness, so for the patients with Secondary Hyperparathyroidism refractory to conventional vitamin D or vitamin D analog treatment in whom long-term survival is expected, parathyroidectomy might be a more preferable treatment. On the other hand, cinacalcet is the first choice for patients in whom it is difficult to manage Secondary Hyperparathyroidism with parathyroidectomy. Indications are patients (i) for whom surgery under general anesthesia would be highly invasive; (ii) whose parathyroid glands are located in an area making resection difficult; (iii) in whom the affected parathyroid tissues are difficult to identify; (iv) in whom it is difficult to resect all affected parathyroid tissues; and (v) who have undergone repeated surgery or percutaneous ethanol injection therapy and may develop serious complications such as bilateral recurrent laryngeal nerve paralysis. Cinacalcet may be a rescuer treatment for these patients. Cinacalcet DOES NOT decrease all-cause mortality and cardiovascular mortality compare with parathyroidectomy.
1) Jamal SA, Miller PD.. Secondary and tertiary hyperparathyroidism. J Clin Densitom. 2013 Jan-Mar;16(1):64-8.
2) Riss P, Asari R, Scheuba C, Niederle B. Current trends in surgery for renal hyperparathyroidism (RHPT)--an international survey. Langenbecks Arch Surg. 2013 Jan;398(1):121-30.
3) Toelle P, Peterli R, Zobel I, Noppen C, Christoffel-Courtin C, Peters T. Risk factors for secondary hyperparathyroidism after bariatric surgery: a comparison of 4 different operations and of vitamin D-receptor-polymorphism. Exp Clin Endocrinol Diabetes. 2012 Nov;120(10):629-34.
4) Hewitt S, Søvik TT, Aasheim ET, Kristinsson J, Jahnsen J, Birketvedt GS, Bøhmer T, Eriksen EF, Mala T. Secondary hyperparathyroidism, vitamin D sufficiency, and serum calcium 5 years after gastric bypass and duodenal switch. Obes Surg. 2013 Mar;23(3):384-90.
5) Strohmayer E, Via MA, Yanagisawa R. Metabolic management following bariatric surgery. Mt Sinai J Med. 2010 Sep-Oct;77(5):431-45.
6) Tominaga Y, Matsuoka S, Uno N. Surgical and medical treatment of secondary hyperparathyroidism in patients on continuous dialysis. World J Surg. 2009 Nov;33(11):2335-42.
7) Tominaga Y, Matsuoka S, Sato T. Surgical indications and procedures of parathyroidectomy in patients with chronic kidney disease. Ther Apher Dial. 2005 Feb;9(1):44-7.
8) Mazzaferro S, Pasquali M, Farcomeni A, Vestri AR, Filippini A, Romani AM, Barresi G, Pugliese F. Parathyroidectomy as a therapeutic tool for targeting the recommended NKF-K/DOQI ranges for serum calcium, phosphate and parathyroid hormone in dialysis patients. Nephrol Dial Transplant. 2008 Jul;23(7):2319-23.
9) KDOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease (http://www.kidney.org/professionals/KDOQI/guidelines_bone/Guide14.htm)
10) Noordzij M, Korevaar JC, Boeschoten EW, Dekker FW, Bos WJ, Krediet RT; Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD) Study Group. The Kidney Disease Outcomes Quality Initiative (K/DOQI) Guideline for Bone Metabolism and Disease in CKD: association with mortality in dialysis patients.Am J Kidney Dis. 2005 Nov;46(5):925-32.
11) Parathyroidectomy for secondary hyperparathyroidism in the era of calcimimetics. Tominaga Y, Matsuoka S, Uno N, Sato T. Ther Apher Dial. 2008 Oct;12 Suppl 1:S21-6.
12) Cheng SP, Lee JJ, Liu TP, Yang TL, Chen HH, Wu CJ, Liu CL Parathyroidectomy improves symptomatology and quality of life in patients with secondary hyperparathyroidism. Surgery. 2014 Feb;155(2):320-8.