International Medical News

No.523ISSN 0535-1405

INTERNATIONAL MEDICAL NEWSInternational Medical Society of Japan
Since 1925
May 31, 2024

The 463th International Symposium on Therapy
The 463th International Symposium on Therapy was held at the Kioi Forum in Tokyo on March 21, 2024. Dr. Kouichi Ito,Managing Director of the International Medical Society of Japan (IMSJ), presided over the meeting.

Up-to-date management of parathyroid disease■Introductory Message from the Chair
K. Ito, MD, PhD. Managing Director, IMSJ

■LectureⅠ
Surgical Treatment for Renal Hyperparathyroidism
Yatsuka Hibi MD, PhD
Professor, Department of Endocrine Surgery,Fujita Health University School of Medicine■LectureⅡ
Management and surgical treatment of primary hyperparathyroidism
Chisato Tomoda MD, PhD
Medical Director of Surgery, Ito Hospital

Published by International Medical Society of Japan,Chairman, Board of Directors: Kenichi Ishibashi, MD, PhD,
Editors: K. Ito, MD, PhD, T. Kondo, MD, K. Ichihashi, MD, PhD, T. Murakami, PhD,R. Nagai, MD, PhD, T. Sumiyama, MD, PhD, I. Taniguchi, MD, PhD, and T. Yamazaki, MD, PhD.
1-11-9-3F Kamiuma, Setagaya-ku, Tokyo154-0011, Japan.
TEL 03(5486)0601 FAX 03(5486)0599 E-mail: imsj@imsj.or.jp https://www.imsj.or.jp/

International Medical News

Introductory Message from the Chair
K. Ito, MD, PhD
Managing Director, IMSJ

LectureⅠ
Surgical Treatment for Renal Hyperparathyroidism
Yatsuka Hibi MD, PhD
Professor
Department of Endocrine Surgery,Fujita Health University School of Medicine
It has been recognized that the mineral metabolic disorder Chronic Kidney DiseaseMineral and Bone Disorder (CKD-MBD), which occurs in chronic kidney disease, has asignificant impact on life expectancy not only through bone abnormalities but also
through

calcificationofbloodvessels

orcardiacvalve

leaflets.

Secondaryhyperparathyroidism (SHPT) caused by chronic kidney disease has also been
incorporated into the concept of CKD-MBD and treatment strategies need to beconsidered. In other words, it is now important to control serum P and Ca levels to therecommended control targets with the endpoint of improving life expectancy, rather
than simply lowering blood PTH levels to improve bone lesions. The CKD-MBD guidelinesof the Japanese Society for Dialysis Therapy recommend maintaining serum P, serum
corrected Ca, and serum intact PTH levels within the recommended control targets, inthat order of priority.
When blood intact PTH exceeds 500 pg/mL, the parathyroid glands are likely to betransformed into nodular hyperplastic glands, which are more likely to become resistantto vitamin D therapy. Therefore, the CKD-MBD guidelines recommend
parathyroidectomy (PTx) for severe SPHT (intact PTH >500 pg/mL or whole PTH >300
pg/mL) that is resistant to medical therapy. Since SPHT can cause subjective symptoms
such as osteoarthralgia, muscle weakness, and pruritus, the indication for PTx should beconsidered with the aim of improving these symptoms as well. The guidelines also statethat even if a patient's blood PTH level does not reach the above, it is reasonable toconsider PTx when hyperphosphatemia or hypercalcemia exceeding the target values
for management is difficult to correct. The PTx procedures for SPHT include subtotal
parathyroidectomy, total parathyroidectomy (without autograft), and total

International Medical News

parathyroidectomy followed by autograft. Overseas reports have shown that there isno clear superiority between subtotal parathyroidectomy and total parathyroidectomy
followed by autograft. However, in patients with SPHT in Japan, where opportunities forrenal transplantation are rare and patients are often required to undergo long-term
dialysis even after PTx, total parathyroidectomy followed by autograft is often chosen,
accounting for approximately 80% of all cases.
On the other hand, the Ca-receptor agonist, cinacalcet, was approved in Japan in2008 for the treatment of SHPT in patients on maintenance hemodialysis. Therefore, it canbe expected to suppress calcification of the cardiovascular system as well as PTx. Since
the number of cases in which SHPT can be controlled by administration of cinacalcet has
been increasing in cases where PTx was previously indicated, PTx is now limited to cases
in which the patient is unable to continue treatment due to gastrointestinal symptoms orother side effects, or when the patient is refractory to treatment with cinacalcet.
According to the PTx Study Group for Secondary Hyperparathyroidism, the annual
number of PTx cases in Japan has decreased from a peak of 1771 cases in 2007 to 123
cases in 2018. Cinacalcet is an oral formulation, so there are some cases patients may
not actually be taking it, but the introduction of intravenous Ca-receptor agonists suchas etelcalcetide in 2017 has allowed for more stable dosing in dialysis patients. Moreover,with the approval in 2018 of evocalcet for secondary hyperparathyroidism under
maintenance dialysis with less frequent gastrointestinal symptoms and other indications,the number of cases requiring PTx is expected to be even more limited in the future.
However, it has been reported that PTx in post-cinacalcet use cases poses a risk ofdifficulty in identifying and of damaging the recurrent laryngeal nerve due to adhesions
to surrounding tissues caused by changes such as hemorrhagic infarction and fibrosis of
the parathyroid gland, and that PTx is a cost-effective option from a medical economicperspective.
After kidney transplantation, the curative treatment for end-stage chronic kidneydisease, SHPT is expected to improve, and after about one year, fluctuations in serum Ca
and P levels are expected to decrease. However, Egbuna et al. reported that 24% ofpatients with intact PTH remained above 130 pg/mL one year after kidneytransplantation, and patients with a corrected Ca level above 10.5 mg/dL had asignificantly higher risk of graft loss. Based on this, the CKD-MBD guidelines recommendthat the indication for persistent hyperparathyroidism after kidney transplantation(tertiary hyperparathyroidism;THPT), is persistently hypercalcemia (corrected Ca ≥ 10.5mg/dL) and high PTH levels (above the upper reference limit) even one year after kidneytransplantation, in which case PTx should be considered. Regarding when PTx for THPT
should be performed after kidney transplantation, some argue that early PTx after kidney

International Medical Newstransplantation should be avoided because of the concern that PTx may cause a sudden
decrease in eGFR, which was apparently elevated due to hypercalcemia, while othersargue that this eGFR decrease is transient and does not affect the long-term graft survival,
and that it is better to remove the harmful effects of hypercalcemia and other factors on
the transplanted kidney at an early stage. As for the technique, it is reasonable to perform
total parathyroidectomy followed by autograft, considering the risk of recurrence andreoperation, since there are few opportunities for re-transplantation after graft function
is abolished and cinacalcet is not approved for THPT in Japan. Even if SPHPT is wellcontrolled by Ca-receptor agonists prior to kidney transplantation, there is concern thatit may be discontinued after kidney transplantation, because it is not approved for THPT
in Japan, resulting in worsening of THPT. Therefore, we believe that PTx should be
performed in advance when a large gland that appears to be a nodular hyperplastic
gland is found prior to kidney transplantation.

LectureⅡManagement and surgical treatment of primary
hyperparathyroidism
Chisato Tomoda MD, PhD
Medical Director of Surgery
Ito Hospital

1．Background
In Japan, primary hyperparathyroidism is reported to affect approximately 1 in 2,000
to 3,000 people, and it is more common in middle-aged and older women. In the1970s, it was a rare disease, but it is now often detected asymptomatically during
health checkups and other tests.
2．Subjective symptoms
The main symptoms are those caused by hypercalcemia, urinary stones, and bonelesions.
① Symptoms due to hypercalcemia
As a result of impaired urine concentration, polyuria, dry mouth, and polydipsia
appear. Gastrin secretion is also increased, resulting in gastrointestinal symptoms

International Medical News

such as nausea, anorexia, reflux esophagitis, and peptic ulcers.
② Symptoms due to urolithiasis
Increased calcium excretion in the urine and inhibition of bicarbonate ion
reabsorption make the urine alkaline, which causes nephrolithiasis due to calciumoxalate. Lower back pain, colic, and hematuria appear. Decreased renal
function is also often observed.
③ Symptoms due to bone lesions
A lesion called osteitis fibrosa cystica is observed due to increased bone turnover
and the appearance of excessive osteoclasts. Bone mass, especially corticalbone mass, decreases, leading to osteoporosis.
3．Points to note during diagnosis
The criteria for diagnosis are hypercalcemia, high parathyroid hormone levels, andurinary calcium excretion (FECa) of 1% or more. If urinary calcium excretion (FECa) is
less than 1%, familial or acquired hypocalciuric hypercalcemia is suspected, and notreatment is necessary. On the other hand, care must be taken, because FECa will
be low in cases of worsening renal function or vitamin D deficiency.
4．Points to consider when deciding on surgical treatment
After primary hyperparathyroidism is diagnosed, it is necessary to evaluate whether
surgery is appropriate, where it is localized, and whether it is hereditary.
① Regarding surgical indications
Recently, asymptomatic mild hypercalcemia has often been detected, and theindications for surgery in such cases are being debated from the viewpoint ofprognosis and surgical complications. According to the NIH guidelines, theindications include: serum calcium level +1 mg/dL or higher than the upper
reference limit; bone density T score is -2.5 or higher; vertebral fracture is detected
on imaging; the estimated glomerular filtration rate (eGFR) is <60 cc/min; andurinary calcium excretion is 250 mg/day or higher in women. For men, surgery isrecommended if any one of the following indications is met: urinary calcium
excretion of 350 mg/day or more, kidney stones or calcareous deposits are seenon imaging, or age under 50 years.
② Localization
The basic tests are neck ultrasound and 99mTc-methoxyisobutylisonitrile (MIBI)
scintigraphy. Neck ultrasonography shows that the dorsal side of the thyroid glandInternational Medical Newsis flat, oval, with a clear border, and internally hypoechoic. The accumulation in
the parathyroid glands on the MIBI test depends on the content of mitochondriarich eosinophilic cells, and a large amount is taken up in adenomas with many
eosinophilic cells. Recently, localization has become more accurate bysimultaneously merging single-photon emission CT (SPECT) images. In addition, CTexamination (thin-slice imaging) and MRI are useful for locations anatomicallydifficulttodetectbycervicalultrasoundexamination(suchasthetracheoesophageal groove, mediastinum, and just below the thyroid cartilage).
③ Hereditary
Hereditary hyperparathyroidism is observed in approximately 5-10% of cases ofprimary hyperparathyroidism. In addition to multiple endocrine neoplasia type 1(MEN1), hyperparathyroidism jaw tumor syndrome is also recognized. If it ishereditary, the surgical procedure requires a complete gland search on bothsides, and screening for related diseases is also required.
5．Changes in surgical techniques
The surgical technique has changed over the years. In the 1970s, bilateral (all gland)searches were performed, but the surgery was long and carried the risk of bilateral
recurrent laryngeal nerve paralysis. Currently, minimally invasive parathyroidectomy(focused exploration) has become mainstream. Since the mid-1990s, it has become
possible to accurately diagnose the site using MIBI scintigraphy and by measuring
intraoperative parathyroid hormone levels. As a result, the incision line is small, andthe surgery can be completed in a short time, making it less invasive.
6．Future challenges
The success rate is low when the pathological gland is not obvious, and patients may
hesitate to undergo surgical treatment, especially if they are elderly and have many
underlying diseases. Medical treatment is performed, but it is necessary to compare
its outcomes with those of surgical treatment.