Familial Hypocalciuric Hypercalcemia

Familial Hypocalciuric Hypercalcemia (FHH) is a rare, inherited condition that affects the body’s ability to regulate calcium levels. It leads to high calcium levels in the blood, with low calcium excretion in the urine. FHH is usually a benign condition, meaning it often does not cause significant health issues, but it can sometimes be confused with more serious conditions like primary hyperparathyroidism.

Pathophysiology of Familial Hypocalciuric Hypercalcemia

FHH is primarily caused by mutations in a gene called the calcium-sensing receptor (CaSR) gene, which plays a crucial role in regulating calcium levels. This receptor is found in various tissues, including the parathyroid glands, kidneys, and bone. Here’s how it works:

• Structure & Function:
  • The calcium-sensing receptor is a protein that detects changes in blood calcium levels.
  • In FHH, mutations in the CaSR gene cause this receptor to malfunction.
  • As a result, the body mistakenly perceives calcium levels as low, even when they are actually high, leading to increased calcium reabsorption in the kidneys and reduced calcium excretion in the urine.
• Blood & Nerve Supply:
  • High blood calcium levels in FHH can affect various parts of the body, including nerves and muscles.
  • Despite the high blood calcium levels, the body’s organs, particularly the kidneys and bones, may not excrete or absorb calcium efficiently.

Types of Familial Hypocalciuric Hypercalcemia

FHH is categorized into three types based on genetic mutations:

1. FHH Type 1:
   • Caused by mutations in the CaSR gene.
   • Most common type, accounting for about 65% of cases.
2. FHH Type 2:
   • Caused by mutations in the GNA11 gene.
   • Less common and associated with more severe hypercalcemia.
3. FHH Type 3:
   • Caused by mutations in the AP2S1 gene.
   • Rare and may present with more noticeable symptoms.

Causes of FHH

1. Genetic mutations in the CaSR gene.
2. Inherited in an autosomal dominant pattern.
3. Family history of hypercalcemia.
4. Mutations in the GNA11 gene.
5. Mutations in the AP2S1 gene.
6. Abnormal calcium sensing in the parathyroid glands.
7. Abnormal calcium reabsorption in the kidneys.
8. Dysfunctional calcium metabolism in the bones.
9. Hormonal imbalances affecting calcium regulation.
10. Resistance of kidney cells to parathyroid hormone (PTH).
11. Low sensitivity of the kidneys to calcium levels.
12. Reduced urinary calcium excretion.
13. Increased intestinal calcium absorption.
14. Abnormal calcium handling by the bones.
15. Imbalance in parathyroid hormone secretion.
16. Genetic mutations affecting renal calcium channels.
17. Altered sensitivity of calcium receptors in the intestine.
18. Epigenetic changes affecting the CaSR gene.
19. Variable gene expression in FHH carriers.
20. Overactive reabsorption of calcium in kidney tubules.

Symptoms of FHH

1. High calcium levels in the blood (hypercalcemia).
2. Low calcium levels in the urine (hypocalciuria).
3. Mild fatigue or tiredness.
4. Muscle weakness.
5. Joint pain or stiffness.
6. Abdominal pain or discomfort.
7. Mild constipation.
8. Increased thirst (polydipsia).
9. Frequent urination (polyuria).
10. Decreased appetite.
11. Nausea or mild vomiting.
12. Headache or dizziness.
13. Confusion or memory issues (rare).
14. Depression or mood swings.
15. Heart palpitations (occasionally).
16. Mild hypertension (rare).
17. Kidney stones (in some cases).
18. Bone pain or tenderness.
19. Changes in urinary patterns.
20. No symptoms at all (in many cases).

Diagnostic Tests for FHH

1. Blood Calcium Test: Measures total blood calcium levels.
2. Ionized Calcium Test: Measures active (ionized) calcium levels in the blood.
3. Serum Parathyroid Hormone (PTH) Test: Assesses PTH levels.
4. 24-hour Urine Calcium Test: Measures calcium excretion in urine over 24 hours.
5. Genetic Testing: Detects mutations in the CaSR, GNA11, or AP2S1 genes.
6. Serum Magnesium Test: Checks for abnormal magnesium levels.
7. Kidney Function Test: Assesses how well the kidneys are filtering blood.
8. Bone Density Scan (DEXA): Checks bone density.
9. Thyroid Function Test: Rules out thyroid disorders.
10. Phosphate Test: Evaluates phosphate levels in the blood.
11. Vitamin D Test: Measures vitamin D levels to rule out deficiency.
12. Renal Ultrasound: Looks for kidney stones or calcification.
13. Urine Creatinine Test: Measures creatinine to check kidney function.
14. Serum Albumin Test: Evaluates albumin levels affecting calcium readings.
15. Urinary Calcium-to-Creatinine Ratio: Helps differentiate FHH from other conditions.
16. Calcium Load Test: Determines how the body processes extra calcium.
17. Thyroid Ultrasound: Identifies thyroid nodules affecting calcium levels.
18. Serum Alkaline Phosphatase Test: Assesses bone metabolism.
19. ECG (Electrocardiogram): Checks for heart-related issues due to hypercalcemia.
20. CT Scan of Abdomen: Detects calcifications or abnormalities in the abdomen.

Non-Pharmacological Treatments for FHH

1. Monitoring calcium levels regularly.
2. Adequate hydration to reduce risk of kidney stones.
3. Eating a balanced diet.
4. Consuming low-calcium foods.
5. Limiting dairy intake.
6. Regular physical exercise.
7. Weight management.
8. Avoiding smoking.
9. Reducing alcohol consumption.
10. Managing stress levels.
11. Keeping blood pressure in check.
12. Reducing high-sodium foods.
13. Using oral hydration salts for better fluid balance.
14. Maintaining regular kidney checkups.
15. Using supportive devices for joint pain.
16. Regular bone density checks.
17. Consuming magnesium-rich foods.
18. Limiting vitamin D supplements.
19. Avoiding prolonged sun exposure.
20. Monitoring parathyroid function regularly.
21. Mindfulness techniques for stress.
22. Acupuncture for muscle pain.
23. Yoga or stretching exercises.
24. Physical therapy for muscle weakness.
25. Consuming citrus fruits in moderation.
26. Keeping a symptom diary.
27. Regular cardiovascular health checks.
28. Following a low-fat diet.
29. Consulting with a dietitian.
30. Engaging in social support groups.

Drugs Used for FHH

1. Cinacalcet: Reduces calcium levels by increasing CaSR sensitivity.
2. Bisphosphonates: Lowers calcium levels.
3. Loop Diuretics (e.g., Furosemide): Increases calcium excretion.
4. Calcitonin: Lowers blood calcium levels.
5. Glucocorticoids: Reduces calcium absorption from intestines.
6. Hydrochlorothiazide: Decreases calcium excretion in urine.
7. Vitamin D Supplements: If vitamin D is deficient.
8. Magnesium Supplements: If magnesium levels are low.
9. Parathyroid Hormone Inhibitors: Reduces PTH production.
10. Phosphate Supplements: Lowers calcium absorption.
11. Sodium Bicarbonate: Reduces hypercalcemia symptoms.
12. Calcium Chelators: Bind to excess calcium.
13. Thyroid Hormone Therapy: Manages calcium metabolism.
14. NSAIDs (e.g., Ibuprofen): Relieves pain and inflammation.
15. Antidepressants: Manages mood-related symptoms.
16. Anti-anxiety Medications: Alleviates anxiety symptoms.
17. ACE Inhibitors: Controls blood pressure.
18. Beta-blockers: Manages heart palpitations.
19. Potassium Supplements: Balances electrolytes.
20. Calcimimetics: Lowers PTH secretion.

Surgeries for FHH

1. Parathyroidectomy: Removal of part or all of the parathyroid glands.
2. Kidney Stone Removal Surgery: Removes stones caused by high calcium levels.
3. Minimally Invasive Parathyroid Surgery: Targets affected parathyroid glands.
4. Laparoscopic Parathyroid Surgery: Less invasive option for gland removal.
5. Thyroid Surgery: If thyroid nodules affect calcium levels.
6. Percutaneous Nephrolithotomy: Removes large kidney stones.
7. Laser Lithotripsy: Breaks down smaller kidney stones.
8. Robotic Parathyroid Surgery: Precision removal of parathyroid glands.
9. Bone Biopsy Surgery: To assess bone health.
10. Endoscopic Parathyroid Surgery: Uses endoscope for gland surgery.

Prevention Tips for FHH

1. Genetic counseling for family members.
2. Regular blood calcium checkups.
3. Staying well-hydrated.
4. Consuming a balanced diet.
5. Limiting high-calcium foods.
6. Managing stress effectively.
7. Keeping blood pressure under control.
8. Regular kidney and bone screenings.
9. Avoiding unnecessary calcium supplements.
10. Educating family members about FHH.

When to See a Doctor

• If you experience consistent symptoms of high calcium (e.g., fatigue, muscle weakness, frequent urination).
• If there is a family history of hypercalcemia or related genetic disorders.
• If diagnosed with high calcium levels but no symptoms, regular follow-ups are recommended.

FAQs about Familial Hypocalciuric Hypercalcemia

1. What is FHH?
   • A genetic condition causing high blood calcium and low urine calcium.
2. Is FHH serious?
   • It’s usually mild and doesn’t cause serious health issues.
3. How is FHH diagnosed?
   • Through blood tests, urine tests, and genetic testing.
4. Is FHH inherited?
   • Yes, it’s passed down in families.
5. Can FHH cause kidney stones?
   • In some cases, it may lead to kidney stones.
6. Can FHH be cured?
   • There’s no cure, but symptoms can be managed.
7. What foods should be avoided?
   • High-calcium foods, like dairy products, should be limited.
8. Is medication necessary for FHH?
   • Usually not, but medication can be used if symptoms are severe.
9. Can children have FHH?
   • Yes, it can be present from birth.
10. Can FHH lead to other health problems?
    • Rarely, but monitoring is important to prevent complications.
11. Can FHH affect pregnancy?
    • It’s generally safe, but calcium levels should be monitored.
12. How is FHH different from primary hyperparathyroidism?
    • FHH is genetic and usually benign, while primary hyperparathyroidism may require surgery.
13. Is surgery needed for FHH?
    • Rarely, only if there are complications like kidney stones.
14. Can lifestyle changes help with FHH?
    • Yes, diet and hydration can help manage symptoms.
15. Should I get tested for FHH if my parent has it?
    • Yes, genetic counseling is recommended for family members.

This comprehensive overview provides a simple explanation of Familial Hypocalciuric Hypercalcemia, covering its causes, symptoms, diagnostics, treatments, and more. For personalized guidance, always consult with a healthcare provider.

 

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