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268
Fig. 18.2 Total
thyroidectomy for
medullary thyroid
carcinoma and parathyroid
adenoma
S. Mayilvaganan and P. R. K. Bhargav
18.3.1 PHPT inMEN 2A
PHPT is associated with 15–20% of MEN 2A and is diagnosed more frequently
with mutations in exon II, codon 634, and the RET gene [11]. The genotypephenotype correlation is more characteristic of these mutations. The peak age for
clinical manifestations is the 3rd decade, with symptoms usually mild. The PHPT
is mostly detected on laboratory evaluations, and the treatment is surgical. The
surgical treatment again is an occasion for the enlarged parathyroid gland (adenoma) only. The Intensity of the screening should be higher in those carrying the
ret gene mutation, especially with exon 11 (Algorithm, Box 18.2 and
Fig.18.2) [12].
18.4 Conclusion
Subtotal parathyroidectomy, either three glands or 31/2 gland excision, has the
edge over total parathyroidectomy since a similar recurrence rate is found.
Persistent or prolonged hypoparathyroidism is more frequent with total parathyroidectomy. Clinically evident PHPT is rare associated with MEN 2A. Most
index cases presenting with PHPT as the rst manifestation have synchronous
MTC and are often node-positive, and excision of the enlarged gland is the treatment of choice.
18 Management ofPHPT inMEN 1 andMEN 2 Syndrome
Box 18.1 Salient Features of PHPT in MEN 1
PHPT in MEN I
– Most common endocrinopathy
– 100% penetrance by 50 years of age
– Hypercalcemia is mild
– Hyperparathyroidism induced hypercalcemic crisis rare
– Earlier onset
– Equal male: female ratio
– Total parathyroidectomy + AT Vs subtotal Parathyroidectomy
Box 18.2 Salient Features of PHPT in MEN 2A
PHPT in MEN 2A
– PHPT is generally diagnosed at or after thyroidectomy
– Milder, asymptomatic and caused by single enlarged gland
– Germline mutation at codon 634—highest association
Box 18.3 Take Home Message
MEN Patients
– Risk for multiple conditions
– Complex management
– Lifelong follow up
– Genotype-Phenotype correlation
– New Paradigm in Prophylactic Surgery
– Risk of disease in relatives and counseling
269
References
1. Giusti F, Tonelli F, Brandi ML.Primary hyperparathyroidism in multiple endocrine neoplasia
type 1: when to perform surgery? Clinics. 2012;67:141–4.
2. Lourenço DM Jr, Coutinho FL, Toledo RA, Gonçalves TD, Montenegro FL, Toledo
S. Biochemical, bone and renal patterns in hyperparathyroidism associated with multiple
endocrine neoplasia type 1. Clinics. 2012;67:99–108.
3. Tonelli F, Giudici F, Cavalli T, Brandi ML.Surgical approach in patients with hyperparathyroidism in multiple endocrine neoplasia type 1: total versus partial parathyroidectomy. Clinics.
2012;67:155–60.
4. Nilubol N, Weinstein LS, Simonds WF, Jensen RT, Marx SJ, Kebebew E.Limited parathyroidectomy in multiple endocrine neoplasia type 1-associated primary hyperparathyroidism: a
setup for failure. Ann Surg Oncol. 2016;23(2):416–23.
5. Coutinho FL, Lourenco DM Jr, Toledo RA, Montenegro FL, Toledo S.Post-surgical follow-up
of primary hyperparathyroidism associated with multiple endocrine neoplasia type 1. Clinics.
2012;67:169–72.
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6. Fyrsten E, Norlén O, Hessman O, Stålberg P, Hellman P.Long-term surveillance of treated
hyperparathyroidism for multiple endocrine neoplasia type 1: recurrence or hypoparathyroidism? World J Surg. 2016;40(3):615–21.
7. Montenegro FL, Lourenço Junior DM, Tavares MR, Arap SS, Nascimento Junior CP,
MassoniNeto LM, D’Alessandro A, Toledo RA, Coutinho FL, Brandao LG, Cordeiro
AC.Total parathyroidectomy in a large cohort of cases with hyperparathyroidism associated
with multiple endocrine neoplasia type 1: experience from a single academic center. Clinics.
2012;67:131–9.
8. Versnick M, Popadich A, Sidhu S, Sywak M, Robinson B, Delbridge L.Minimally invasive
parathyroidectomy provides a conservative surgical option for multiple endocrine neoplasia
type 1–primary hyperparathyroidism. Surgery. 2013;154(1):101–5.
9. Alevizaki M, Saltiki K. Primary hyperparathyroidism in MEN2 syndromes. In: Medullary
thyroid carcinoma. Cham: Springer; 2015. p.179–86.
10. Magalhães PK, Antonini SR, de Paula FJ, de Freitas LC, Maciel LM.Primary hyperparathyroidism as the rst clinical manifestation of multiple endocrine neoplasia type 2A in a 5-yearold child. Thyroid. 2011;21(5):547–50.
11. Alevizaki M.Management of hyperparathyroidism (PHP) in MEN2 syndromes in Europe.
Thyroid Res. 2013;6(S1):S10.
12. Machens A, Lorenz K, Dralle H.Peak incidence of pheochromocytoma and primary hyperparathyroidism in multiple endocrine neoplasia 2: need for age-adjusted biochemical screening. J Clin Endocrinol Metab. 2013;98(2):E336–45.
S. Mayilvaganan and P. R. K. Bhargav
Hyperparathyroidism ofRenal Origin
19
A.Vimala, RanjaniRavi, andJinsiNBabu
Hyperparathyroidism is dened as increased production of parathormone by parathyroid glands and based on pathophysiology is classied as: primary hyperparathyroidism, secondary hyperparathyroidism, tertiary hyperparathyroidism, and
refractory hyperparathyroidism. This chapter essentially deals with secondary, tertiary, and refractory hyperparathyroidism related to renal dysfunction.
19.1 Secondary Hyperparathyroidism (SHPT)
Deteriorating renal function causes phosphate retention and hypocalcemia.
Parathyroid hyperactivity is a secondary phenomenon to maintain calcium/phosphate metabolism. This is achieved by several feedback loops between the kidney,
the parathyroid glands, bone, and intestine as shown in Fig.19.1.
The normal homeostasis of calcium is based on an interplay among kidneys,
bones, and intestines and is closely linked to phosphate metabolism and vitamin
D.Serum calcium levels may be disturbed by changes in any of the homeostatic
mechanisms and may result in changes in any of the following abnormalities singly
or in combination.
Hyperphosphatemia, hypocalcemia, high serum broblast growth factor 23 (FGF
23), and decreased 1,25OH vitamin D stimulate parathyroid cells to synthesis parathyroid hormone. Common causes of secondary hyperparathyroidism are noted in
Table19.1 [1].
A. Vimala (*) · R. Ravi · J. N. Babu
Cosmopolitan Hospitals, Thiruvananthapuram, Kerala, India
© The Author(s), under exclusive license to Springer Nature Singapore Pte
Ltd. 2024
C. G. Nair, S. J. Abraham (eds.), Surgical Management of Thyroid and
Parathyroid Diseases, https://doi.org/10.1007/978-981-97-3774-1_19
271
272
Increased
calcium and
phosphorous
absorption
A. Vimala et al.
Stimulates
PO
3–
4
Ca
2+
Parathyroid
Inhibits
+
Vit D
PTH
+
Intestine
PTH effect
calcium reabsorption
phosphorous
reabsorption
1,25 Vit D
Increase serum Calcium
Decrease serum phosphorous
Fig. 19.1 Feedback loops involving PTH parathyroid hormone; FGF-23 broblasts growth fac-
tor 23 [1]
+
Kidney
+
+
FGF23
FGF23 effect
phosphorous
reabsorption
↓1,25 Vit D
Bone
Increase
osteoclasts
activity
Table 19.1 Causes of secondary hyperparathyroidism
Causes Remarks
Chronic kidney disease Abnormalities are seen earlier in tubulointerstitial disease
Vit D insufciency 25(OH) vitamin D<20mcg/L
Drugs Bisphosphonates, anticonvulsants, frusemide
Gastrointestinal cause
Hypercalciuria due to renal leak Patients may be normocalcemic
Celiac disease, cystic brosis
19.2 Secondary Hyperparathyroidism ofRenal Origin (SHPT)
Chronic kidney disease (CKD) is commonly associated with disorders of mineral
and bone metabolism and is grouped as Chronic Kidney Disease-Mineral Bone
Disorder (CKD-MBD). Secondary hyperparathyroidism is one of the manifestations of CKD- MBD and is the commonest cause of secondary
hyperparathyroidism.
Renal dysfunction is classied based on estimated glomerular ltration rate
(eGFR) and the KDIGO grading system of the renal functional stage is noted in
Table19.2.
19 Hyperparathyroidism ofRenal Origin
Table 19.2 KDIGO CKD staging according to eGFR (mL/min) [2]
CKD stage GFR categories mL/min/1.73m
G1 Normal or high
G2 Mildly decreased 60–89
G3a Mild to moderately decreased 45–59
G3b Moderately to severely decreased 30–44
G4 Severely decreased 15–29
G5 Kidney failure <15
These stages can be further classied into A1, A2, A3 based on albumin excretion
≥90
273
2
eGFR (EPI) = 141 * min (Scr/κ, 1)α * max(Scr/κ, 1)
−1.209
* 0.993
Age
* 1.018 [if
female] * 1.159 [if black] (Scr is serum creatinine (mg/dL), κ is 0.7 for females and
0.9 for males, α is −0.329 for females and −0.411 for males, min indicates the minimum of Scr/κ or 1, and max indicates the maximum of Scr/κ or 1).
Subclinical abnormalities such as loss of klotho, increased FGF23 secretion,
decreased bone formation rates, and vascular calcication occur from stage G2
onwards. But clinical manifestations and biochemically detectable abnormalities in
serum phosphorus, calcium, PTH, and vitamin D become evident only when the
glomerular ltration rate (GFR) falls below 40 mL/min, In CKD stage 5
(eGFR<15 mL/min/1.73 m2), almost all patients have evidence of bone disease.
Approximately 80% of incident dialysis patients have evidence of coronary artery
calcication. Hence, guidelines for CKD-MBD advise monitoring for the same for
patients from CKD stage III onwards. According to KDIGO (Kidney Disease
Improving Global Outcomes) 2012 guidelines, CKD is staged based on eGFR
(eGFR is estimated Glomerular Filtration Rate) calculated by the CKD-EPI
equation.
19.3 Prevalence ofSecondary Hyperparathyroidism
In 1982, Memmos D et al. reported hyperparathyroidism in 90% of patients on
dialysis [3]. Chiranjee Lal Dayma etal. from Rajasthan reported a 72% prevalence
in CKD patients [4]. In our center, 90% prevalence of secondary hyperparathyroidism is seen in dialysis-dependent patients (unpublished).
Pathophysiology. The balance of serum calcium and serum phosphorous is
grossly altered in CKD. Secondary hyperparathyroidism is adaptive parathyroid
gland hyperplasia which maintains calcium phosphate balance. Increased production of PTH is secondary to stimuli such as hyperphosphatemia, hypocalcemia, and
increased FGF23.
The serum PTH production in these patients is increased by three mechanisms
and is shown in Fig.19.2.
1. Hyperphosphatemia: Phosphate homeostasis is maintained by glomerular ltra-
tion and tubular secretion. With the decline in GFR in CKD, ltration and hence
excretion of phosphate is decreased resulting in phosphate retention. During early
274
A. Vimala et al.
CKD ----- Reduced GFR
Phosphorous clearance
leading to
Phosphorous levels
Fig. 19.2 Showing mechanisms of hyperparathyroidism in chronic kidney disease
Serum
Secondary Hyperparathyroidism
FGF 23 levels
Reduced 1, 25 (OH) Vit D
1 alpha hydroxylase
Calcium levels
phases of renal dysfunction, phosphate reabsorption is decreased in remaining
normal nephrons as an attempt to lower mounting serum phosphate levels. This
effect is mediated by both FGF23 and PTH.In advanced stages 4 and 5 of CKD,
phosphate homeostasis cannot be maintained by the above mechanism and
patients develop hyperphosphatemia. Hyperphosphatemia suppresses the renal
hydroxylation of inactive 25-hydroxy vitamin D to 1, 25-hydroxy vitamin D
(calcitriol).
2. Hypocalcemia: Hypocalcemia results secondary to phosphate accumulation
and decreased production of calcitriol by kidneys and is evident in stage 5 of
CKD.Hypocalcemia has a negative feedback effect on calcium-sensing receptors (CaSR) on parathyroid cells leading to cellular hyperplasia excessive synthesis and secretion of PTH.
3. FGF 23: Reduction in GFR results in an increase in FGF 23 from the bones
which directly acts on parathyroid cells as well as indirectly by suppressing calcitriol synthesis.
19.3.1 Bricker’s Trade-off Hypothesis
Bricker proposed the following sequence. There is increased reabsorption of phosphate from the GI tract. An increase in phosphate leads to a reduction in calcium as
it forms complexes with calcium. This is sensed by parathyroid which increases
19 Hyperparathyroidism ofRenal Origin
275
PTH response. Increased PTH restores calcium balance and decreases phosphate
reabsorption. A trade-off thus occurs in which SHPT is the price paid for normal
calcium and phosphorous.
Low calcitriol stimulates parathormone production. So, in end-stage renal diseases, parathyroid glands are stimulated by various factors which include hyperphosphatemia, hypocalcemia, low serum calcitriol, and elevated FGF 23. SHPT is a
reversible condition and overactive glands revert to the normal state when the stimuli are removed.
Monitoring in CKD for secondary hyperparathyroidism (Table19.3):
• Serum calcium and phosphorous should be monitored every 6–12 months in
CKD stage III, every 3–6 months in stage CKD stage 4, and every 1–3 months
on CKD stage V including G 5 D (dialysis).
• Serum PTH should be monitored every 6–12 months in CKD stage IV and every
3–6 months in CKD stage V.The value of PTH in CKD VD should be maintained
between two to nine times the upper limit of PTH assay.
• Serum alkaline phosphatase (ALP) is an indirect indicator of CKD MBD; how-
ever, its use as an indicator and to monitor the same has not been validated or
recommended. Serum ALP is an enzyme that removes phosphate from protein
and nucleotides. Other than bone it is present in the liver, intestine, and placenta.
Although ALP levels reect bone turnover and are usually raised in secondary
hyperparathyroidism of renal origin, ALP is not a specic indicator for the same.
Bone-specic ALP may be a better marker however further studies are required
to validate the same.
The swing of PTH, serum calcium, and phosphorous with a decrease in eGFR is
shown in Fig.19.3.
Table 19.3 Showing appropriate monitoring of parameters in various CKD stages
CKD stage
Monitoring of
Calcium and
phosphorous
Parathyroid
hormone
levels
Alkaline
phosphatase
CKD stage III
(eGFR- 30–59mL/
min)
Every 6–12
months
Serum alkaline phosphatase is an indirect indicator of CKD MBD; however,
its use as an indicator and to monitor the same has not been validated or
recommended
IV (eGFR15–29mL/
min)
3–6 months 1–3 months Phosphorous should
6–12 months 3–6 months In CKD V, iPTH
CKD stage V/V D
(eGFR<15mL/
min)
Remarks
be maintained in the
normal range and
calcium in the low
normal range
should be
maintained 2–9
times the upper
limit of normal
276
Fig. 19.3 Showing
change in various
laboratory parameters with
the decline in GFR
A. Vimala et al.
19.3.2 Consequences ofSecondary Hyperparathyroidism
Apart from bone loss secondary hyperparathyroidism can lead to soft tissue and
vascular calcications in patients with chronic kidney disease. The presence of
CKD MBD is a strong predictor of increased cardiovascular morbidity and mortality. Hence, the treatment of secondary hyperparathyroidism should be initiated in
the early stages itself.
19.3.3 Medical Treatment
The treatment of secondary hyperparathyroidism is aimed at treating the trigger for
PTH secretion.
Treat vitamin D deciency: Correction of vitamin D deciency is recommended
except when associated with severe hyperphosphatemia or hypercalcemia [5].
Control hyperphosphatemia: Serum levels of phosphate should be maintained
between 3.5 and 5.5mg/dL.
Measures to Lower Serum Phosphate:
1. Dietary restriction of phosphate.
2. Dietary regulations alone are not effective in the control of hyperphosphatemia.
Phosphate binders are recommended in patients with persistently elevated serum
phosphate >5.5mg/dL in addition to dietary restriction. Phosphate binders are
calcium-based—calcium acetate, calcium carbonate, non-calcium binders such
as sevelamer carbonate, sevelamer hydrochloride, lanthanum carbonate, nicotinic acid, ferric citrate, and tenapanor.
Correction of hypocalcemia: Maintaining serum calcium levels to a low normal
is done by supplementation when symptomatic hypocalcemia is encountered. The
serum corrected calcium is maintained above 7.5mg/dL.Calcium supplements with
19 Hyperparathyroidism ofRenal Origin
dihydroxy vitamin D are done to treat hypocalcemia. Adverse effects of calcium
supplementation are hypercalcemia or positive calcium balance without hypercalcemia both of which can contribute to cardiovascular mortality.
Treatment of persistent progressive parathormone levels (PTH> 150–200 pg/
mL) if upper limit of normal is 65pg/mL.
Patients with renal dysfunction and elevated PTH are given calcitriol (1-25OHD-
0.25μg) thrice weekly especially in patients with hypovitaminosis but better avoided
when associated with hypercalcemia.
277
19.4 Tertiary Hyperparathyroidism
Secondary hyperparathyroidism is an adaptive phenomenon and resolves to the
normal stage when the precipitating factors are removed. Prolonged stimulation
of parathyroid cells due to increased phosphate, low calcitriol, and hypocalcemia
results in nodular or diffuse hyperplasia. These hyperplastic nodules do not
undergo regular involution. Rarely these nodules can undergo a malignant transformation as well. In patients with tertiary hyperparathyroidism decreased expression of CaSR and VDR result in a lack of suppression of PTH by increased
calcium levels or vitamin D analogs. In contrast to SHPT which is a reversible
condition, tertiary hyperparathyroidism is irreversible. Tertiary hyperparathyroidism is a progression from SHPT.The parathyroid glands are autonomous and are
no longer regulated by calcium levels. This results in hypercalcemia and variable
phosphate levels. At our center, 12.5% of dialysis patients have tertiary hyperparathyroidism. We have taken hypercalcemia as corrected calcium> 9.5 mg/
dL.This is after excluding calcium supplements and vit D as a cause for hypercalcemia. [Corrected calcium = serum calcium + 0.8 * (4 − serum albumin)]
Example: if measured Ca is 7.5 mg/dL and measured Albumin is 3g/L, corrected
Ca = 7.5 + 0.8 × (4−3) =7.5 +0.8 = 8.3mg/dL.
Treatment of Tertiary Hyperparathyroidism:
1. Calcitriol or other vitamin D analog supplementation after correcting hyper-
phosphatemia– Vitamin D supplementation suppresses serum parathyroid levels
by reducing production as well as by increasing serum calcium levels.
2. Calcimimetics: The activation of calcium-sensing receptor (CaSR) decreases PTH
secretion. Calcimimetics like cinacalcet increase the sensitivity of the CASR to
calcium thereby reducing plasma PTH concentration and in turn reducing calcium
and phosphorous levels. However, although they do cause a decrease in PTH levels, they have not been shown to have any cardiovascular mortality benet [6].
19.5 Refractory Hyperparathyroidism
Denition: Severe persistent progressive elevation of PTH that cannot be treated
adequately by medical therapy including VIT D analogs and calcimimetics without
causing signicant hyperphosphatemia or hypocalcemia. PTH levels should be
more than 800 pg/mL.