K

Secondary and Tertiary Hyperparathyroidism

Overview and Definitions

  • Two main adaptive/paradigm forms are covered in this paper in contrast with primary hyperparathyroidism (PHPT):
    • Secondary hyperparathyroidism (SHPT)
    • Appropriate, physiological rise in parathyroid hormone (PTH) driven by an external stimulus, most often hypocalcaemia.
    • Biochemical signature:
      • \text{Serum Ca}^{2+} = \text{normal}
      • \text{Serum PTH} \uparrow
    • Tertiary hyperparathyroidism (THPT)
    • Long-standing SHPT evolves into semi-autonomous PTH oversecretion; the parathyroid glands behave almost like an adenoma but in a recognisable secondary setting (e.g., chronic kidney disease (CKD)).
    • Biochemical signature:
      • \text{Serum Ca}^{2+} \uparrow (always elevated)
      • \text{Serum PTH} \uparrow (persistently high)
  • Key clinical context: THPT classically emerges in CKD patients after kidney transplantation once the original stimulus is partially corrected yet gland hyperplasia remains.
  • Distinguishing PHPT vs THPT:
    • PHPT = no obvious chronic stimulus; autonomous adenoma/hyperplasia; calcium high.
    • THPT = identifiable chronic stimulus (renal failure, malabsorption, phosphate therapy, etc.); calcium high after a period of SHPT.

Secondary Hyperparathyroidism – Main Triggers

  • Hypocalcaemia (direct PTH stimulus via CASR).
  • Vitamin D deficiency
    • Cut-points debated:
      • <20\,\text{ng·mL}^{-1} \;(50\,\text{nmol·L}^{-1}) vs
      • <30\,\text{ng·mL}^{-1} \;(75\,\text{nmol·L}^{-1}).
    • For defining SHPT, authors recommend clearly sufficient 25-OHD >30\,\text{ng·mL}^{-1} when ruling out deficiency.
  • Renal insufficiency: \text{Creatinine clearance}<60\,\text{mL·min}^{-1}.
  • Malabsorption syndromes (reduced Ca absorption).
  • Medications: lithium, thiazide diuretics, calcitriol in CKD, etc.

Transition to Tertiary Hyperparathyroidism

  • Persistent SHPT → cellular/nodular hyperplasia → altered set-point of calcium-sensing receptor (CASR) → quasi-autonomy.
  • Conceptually similar to an adenoma but still linked to a known stimulus history.

Pathophysiology in Chronic Kidney Disease (Fig. 1 Explained)

  • Reduced nephron mass
    • ↓ 1-α-hydroxylase → ↓ calcitriol (1,25\text{-(OH)}2\text{D}3) → ↓ intestinal Ca absorption → hypocalcaemia → ↑ PTH.
  • Hyperphosphataemia
    • Direct gland stimulation → nodular hyperplasia, ↑ PTH.
    • Indirect loop: ↑ PTH & ↑ FGF-23 promote phosphaturia to restore serum phosphate at the cost of chronically high PTH/FGF-23.
    • In CKD: reduced Klotho/FGF-23 receptor expression blunts inhibitory feedback on PTH.
  • Parathyroid receptor down-regulation
    • ↓ Vitamin D receptors (VDR) & ↓ CASR in hyperplastic/nodular tissue → resistance to calcitriol & Ca feedback.
  • Structural change
    • Gland volume enlarges (diffuse hyperplasia + monoclonal nodules). Nodular tissue = fewer VDR/CASR, more autonomy.

Rare Non-CKD Causes of THPT

  • X-linked hypophosphataemic rickets (XLH).
  • Autosomal dominant (adult-onset) hypophosphataemic rickets.
  • Oncogenic osteomalacia.
    • All treated with high-dose oral phosphate → transient ↓ ionised Ca, ↓ 1,25-(OH)₂D, ↑ FGF-23 → chronic PTH drive → possible autonomy.

Clinical Presentation After Renal Transplantation

  • Most frequent scenario: persistent PTH elevation ± hypercalcaemia beyond 12 months post-transplant.
  • Largest dataset (n = 607):
    • 1 yr post-Tx → 52 % had ↑ PTH; 8 % had ↑ PTH + hypercalcaemia.
  • Typical symptoms/signs (mirroring PHPT severity):
    • Bone pain, low BMD, fractures.
    • Pruritus, nephrolithiasis, pancreatitis, peptic ulcer disease.
    • Soft-tissue & vascular calcifications, muscle weakness.
    • Neuro-cognitive changes; impaired graft function.

Diagnostic Considerations

  • Always exclude:
    • Pre-existing/unrecognised PHPT.
    • Drug-induced hypercalcaemia (calcitriol, lithium, thiazides).
    • Familial hypocalciuric hypercalcaemia.
  • Observe first 12 mo post-transplant (mild Ca/PTH fluctuations common while homeostasis resets) unless hypercalcaemic crisis.
  • Important laboratory thresholds:
    • Sustained serum Ca >11.0\,\text{mg·dL}^{-1} (≈>2.75\,\text{mmol·L}^{-1}).
    • PTH persistently 2\text{–}9\times the upper reference limit, even if Ca normal.

Treatment & Management Framework

  • Initial approach (months 0–12 post-Tx):
    • Optimise phosphate (replace if post-Tx hypophosphataemic).
    • Replete vitamin D; avoid unnecessary calcitriol over-supplementation.
    • Monitor Ca, P, PTH, renal function.
  • Definitive therapy once THPT established
    1. Parathyroidectomy (PTx) – gold standard
    • Goal: reduce gland mass → normalise Ca.
    • Indications: sustained hypercalcaemia >11.0\,\text{mg·dL}^{-1} OR unacceptable PTH elevation.
    1. Calcimimetics (cinacalcet) – off-label
    • Enhances CASR sensitivity → ↓ PTH secretion, ↓ Ca.
  • Adjunct monitoring: Bone-specific alkaline phosphatase, serial DXA for BMD (changes more informative than single value), vascular imaging if calcification concern.

Surgical Options – Evidence Summary

  • Subtotal PTx (3½ gland removal)
    • Trial (n = 7 subtotal vs 7 total): subtotal avoided postoperative hypocalcaemia; similar op-time & length of stay.
  • **Total PTx with *or* without autotransplantation**
    • Retrospective series (n = 26, follow-up 5–9 yrs) showed sustained normocalcaemia & normal PTH when no autograft placed + postoperative 1-α-calcidiol.
  • No long-term RCTs; choice remains surgeon-dependent.

Medical Therapy – Calcimimetics

  • Small open-label trials (total n = 37; 10–26 wk):
    • ↓ Serum Ca (often to normal range).
    • ↓ PTH in majority.
    • No change in graft function; minimal side-effects.
  • Discontinuation study (n = 10): 3 mo post-cessation → Ca rose but stayed normal in 80 %; PTH unchanged.
  • Implication: trial off-therapy may be reasonable; need larger RCTs.

Monitoring & Follow-up Checklist

  • Quarterly for first year, semi-annual thereafter:
    • \text{Serum Ca}^{2+},\;\text{P},\;\text{PTH}, alkaline phosphatase, 25-OHD.
    • Renal graft function: \text{eGFR},\;\text{Cystatin C},\;\text{Creatinine}.
    • DXA every 1–2 yrs to track BMD trend.
    • Vascular/soft-tissue imaging if calcification suspected.

Key Numerical / Statistical Highlights

  • CKD threshold for SHPT: \text{CrCl}<60\,\text{mL·min}^{-1}.
  • Vitamin D sufficiency cut-off: >30\,\text{ng·mL}^{-1} (≈>75\,\text{nmol·L}^{-1}).
  • Post-Tx prevalence (largest study):
    • 52 % ↑ PTH; 8 % ↑ PTH + ↑ Ca.
  • Calcium intervention threshold: >11.0\,\text{mg·dL}^{-1}.
  • PTH surgical consideration: 2\text{–}9\times ULN on a persistent trend.

Ethical, Practical & Philosophical Points

  • Balancing surgery vs medical therapy requires patient-specific risk assessment (operative risk, graft longevity, access to cinacalcet, cost).
  • Delaying action beyond 12 mo post-Tx avoids unnecessary procedures yet must not ignore ongoing vascular calcification risk from hypercalcaemia.
  • Informed consent for surgery should address possibility of permanent hypocalcaemia (especially with total PTx) and lifelong calcitriol supplementation.
  • Equity: Access to bone densitometry & calcimimetics can be limited; clinicians should advocate for coverage given potential morbidity reduction.

Links to PHPT & Other Disorders

  • Pathophysiological overlap: autonomously functioning nodular tissue in THPT shares traits with adenomas in PHPT (monoclonal expansion, altered CASR set-point).
  • In differential diagnosis always contrast with:
    • PHPT (no chronic stimulus),
    • Familial hypocalciuric hypercalcaemia (low urinary Ca),
    • Drug-induced states.

Real-World Clinical Pearls

  • Mild biochemical THPT early post-Tx is common; treat only if persistent/severe.
  • Always correct vitamin D and phosphorus first; these are inexpensive, low-risk interventions.
  • When interpreting DXA in CKD 5/Tx patients, trend not T-score informs fracture risk.
  • Consider measuring bone-specific alkaline phosphatase as dynamic marker of skeletal turnover during therapy.