Clinical aspects of common mineral disorders

hypocalcemia

Neuropsychiatric Symptoms

Seizures (all types)

Dementia (in adults), mental retardation (in children)

Emotional problems (anxiety, depression)

Extrapyramidal symptoms (parkinsonism is most common)

Calcif ications of basal ganglia (in longstanding disease)

Papilledema

Increased Neuromuscular Irritability

Chvostek's sign

Trousseau's sign

Paresthesias in circumoral and acral areas (f ingers, toes)

Muscle stiffness, myalgias, and spasms

Cardiovascular Symptoms

Prolongation of QT interval

Congestive heart failure

Hypotension

Autonomic Symptoms

Biliary colic

Bronchospasm

Diaphoresis

Other Symptoms

Cataracts

Dry coarse skin, dermatitis, hyperpigmentation, and eczema

Steatorrhea

Gastric achlorhydria

Normal [Ca2+]total = 8.5-10.5 mg/dl (2.12-2.62 mmol/L)

Normal [Ca2+]ion = 4.65-5.25 mg/dL (1.16-1.31 mmol/L)

hypercalcemiaNormal [Ca2+]total = 8.5-10.5 mg/dl (2.12-2.62 mmol/L)

Normal [Ca2+]ion = 4.65-5.25 mg/dL (1.16-1.31 mmol/L)

Depression Organic brain syndromes

Anxiety

Cognitive dysfunction

Headache

Fatigue

Polyuria Nephrolithiasis

Polydipsia Nephrogenic diabetes insipidus

Nocturia Renal insuff iciency

Renal tubular acidosis

Short QT interval Hypertension

Cardiovascular calcif ications

Constipation Peptic ulcer disease

Anorexia Acute pancreatitis

Abdominal pain

Muscle w eakness Osteopenia, osteoporosis

Aches, pains Gout, pseudogout

Fractures Chondrocalcinosis

Osteitis f ibrosa cystica

Calciphylaxis

Brow n tumors

Hypercalcemic crisis

Musculoskeletal

Other

Neuropsychiatric

Symptoms and Signs

Renal

Cardiovascular

Gastrointestinal

hypophosphatemiaNormal [P] = 2.5-4.5 mg/dl (0.75-1.45 mmol/L)

hypercalciuria

bone resorption

osteomalacia

rickets

2,3-DPG depletion

proximal myopathy

dysphagia

ileus

rhabdomyolysis

delirium, coma

skeletal and smooth muscle

Bone and mineral metabolism

CNS

encephalopathy - irritability, paresthesias,

Blood cells

recued chemotaxis and phagocytosis

hemolysis (rigidity)

defective clot retraction and thrombocytopienia

Symptoms and Signs

Cardiolumonary systems

impaired myocardial contractility

respiratory failure

hyperphosphatemiaNormal [P] = 2.5-4.5 mg/dl (0.75-1.45 mmol/L) • ?

• acute phosphate nephropathy

• increased cardiovascular calcifications and associated morbidity and mortality

Calcium Homeostasis

• [CaICF]~100nM

• [CaECF]~1.2mM

• total serum Ca 2.2-2.6 mM (8.5-10.5 mg%)

• 5% passive absorption

• 20-70% (OH)2D– extremes?

• Causes of hypercalcemia– 1° hyperparathyroidism– malignancy-related– vitamin D-related: intoxication, sarcoid, etc.– high bone turnover: hyperthyroid, immobility– associated with renal failure:

• tertiary hyperparathyroidism• aluminum and adynamic bone disease• milk-alkali syndrome

90%

• Primary hyperparathyroidism– solitary adenoma– parathyroid hyperplasia– multiple endocrine neoplasia (MEN)

• MEN1; MENIN tumor suppressor• MEN2A, MEN2B; RET proto-oncogene

• FHH – CaSR mutations

• Hypercalcemia of malignancy– humoral; tumor secretes PTHrP

• squamous cell carcinoma• renal tumors• many others

– direct bone marrow invasion – bone resorption and local destruction by cytokines

– 1,25(OH)2D

• Clinical features of hypercalcemia– fatigue– depression– confusion– anorexia, nausea, vomiting, constipation– polyuria– calcifications, renal failure– coma– cardiac arrest

• Stones refers to kidney stones, nephrocalcinosis, and DI insipidus

• Bones refers to bone-related complications. The classic bone disease

• Abdominal groans refers to gastrointestinal symptoms of constipation, anorexia, nausea and vomiting. Hypercalcemia can lead to peptic ulcers and acute pancreatitis.

• Psychiatric moans refers to effects on the central nervous system; lethargy, fatigue, depression, memory loss, psychosis, ataxia, delirium, coma

phosphate?

• Indications for surgery in 1° HPTH:– serum Ca > 2.9 mmol/l– urine Ca > 400 mg/d– creatinine clearance reduced 30%– age < 50– osteoporosis

Calcium Homeostasis

• [CaICF]~100nM

• [CaECF]~1.2mM

• total serum Ca 2.2-2.6 mM (8.5-10.5 mg%)

• 5% passive absorption

• 20-70% (OH)2D– extremes?

• Mechanisms of hypocalcemia:– PTH absent: hereditary, acquired, ↓Mg– PTH ineffective: CRF, vit. D deficiency or

resistance, pseudohypoparathyroidism– PTH overwhelmed: severe acute

hyperphosphatemia, hungry bone (osteitis fibrosa after parathyroidectomy)

Phosphorus Homeostasis

• 600 g phosphorus• 85% in bone

• [PICF]~[PECF]

• [PECF] = 0.75-1.45 mM (2.5-4.5 mg/dl)

• Diet: 0.5-1 g/d• Absorption 65% ->

90% with 1,25(OH)2D

Torres et al. KI 2011

HYPERPHOSPHATEMIA

• Phosphate intake above 4 g/day causes only small elevations in serum phosphate concentrations as long as the intake is distributed over the course of the day.

• An acute phosphate load given over several hours causes transient hyperphosphatemia.

• Thus, the diagnostic approach to hyperphos-phatemia involves identification of the reason that phosphate entry into the extracellular fluid exceeds the rate at which it can be excreted.

• There are three general circumstances in which this occurs:– massive acute phosphate load– primary increase in proximal phosphate

reabsorption– renal failure (decreased filtration)

• Phosphate load:– tumor lysis syndrome– rhabdomyolysis– crush injury– hyperthermia– fulminant hepatitis– hemolysis– acidosis– exogenous administration

• Increased phosphate reabsorption– hypoparathyroidism– parathyroid suppression

• hypercalcemia– vitamin D or vitamin A intoxication– sarcoidosis, granulomatous diseases– immobilization, osteolytic metastases

• hypomagnesemia and hypermagnesemia

– pseudohypoparathyroidism– acromegaly– tumoral calcinosis– heparin therapy

• Clinical findings in acute ↑ P:– calcium phosphate precipitates– hypocalcemia

• Treatment of acute ↑ P:– volume expansion– aluminum hydroxide, sevelamer– hemodialysis

HYPOPHOSPHATEMIA

• 600 g phosphorus• 85% in bone

• [PECF]~[PICF]

• [PECF] = 0.75-1.45 mmol/l (2.5-4.5 mg/dl)

• Diet: 0.5-1 g/d• Absorption 65% ->

90% with 1,25(OH)2D

Torres et al. KI 2011

• Mechanisms of hypophosphatemia:– Impaired intestinal absorption– Reduced renal phosphate reabsorption

• PTH/PTHrP-dependent• PTH/PTHrP-independent

– Shifts into cells– Accelerated bone formation

• Decreased intestinal absorption– Inadequate intake– Antacids containing aluminum or magnesium– Steatorrhea and chronic diarrhea– Vitamin D deficiency or resistance

• Increased urinary excretion– Primary hyperparathyroidism and FHH– 2° HPTH incl. vit D deficiency or resistance– Hereditary hypophosphatemic rickets– PTHrP-dependent hypercalcemia– Oncogenic osteomalacia– Fanconi syndrome– Other - osmotic diuresis, acetazolamide,

acute volume expansion

• Internal redistribution– Increased insulin secretion, particularly during

refeeding– Acute respiratory alkalosis– Hungry bone syndrome

• following parathyroidectomy• osteoblastic metastases

• Clinical findings of hypophosphatemia– neuromuscular

• weakness• confusion• hallucinations• oculomotor palsies• ataxia• paralysis• seizures• coma• rhabdomylysis

– respiratory failure, cardiac dysfunction– hemolysis, defective leukocyte and platelet function

• Treatment of acute hypophosphatemia– correct hypocalcemia first– intravenous phosphate over 6 hours

• avoid high Ca×P products

– oral phosphate

• Management of chronic hypophosphatemia– vit D with calcium for vit D deficiency

– oral phosphate and 1,25(OH)2D for blocks

– resection of tumor in TIO