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1
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• 9/2009

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3
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• ?????? ??????
• Normiten 50 MG X 2/d
• Disothiazide 25 MG X 1/d
• Enalapril 5 MG X 2/d
• Bondormin 0.25 MG X 1/d
• Flutine 20 MG X 1/d
• Vaben 10 MG X 2/d
• Detrusitol 4 MG X1/d

4
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5
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6
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• ????
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• ?"? 144/70, ???? 80, ??? 36.1, ??????? 95-RA
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• ??? ?????, 88 ????, ??? ????? ??????? ?????
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7
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• ????
• ?????
• ?????
• Cr- 0.96, Urea 50
• Na 137, K 4.1 , Ca 11.9
• Glu 89
• CRP 19 / ESR - 70
• ????? ??
• WBC 8450, ??? ????? ?????
• HB- 13.0, MCV 81
• PLT 295,000
• ?????? ?????
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8
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???? ?????

• ????
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• 1000cc of 0.45 NaCl

9
Calcium Metabolism

• 12 kg of calcium
• Over 99 - in skeleton
• In blood
• 8.510.5 mg/dL
• 50 is ionized/ free (the physiologically
  important)
• bound to negatively charged proteins
• predominantly albumin and immunoglobulins
• loosely complexed with phosphate, citrate,
  sulfate, or other anions
• Corrected Ca Serum Ca 0.8 X (Normal Alb
  Patients Alb)
• Normal Albumin 4.1
• Low Alb ? Total Ca normal / Free Ca high
• High Alb ? Total Ca high / Free Ca normal
• Pseudohypercalcemia
• Direct measurement of ionized Ca

10
Calcium Metabolism Intestine

Normal Dietary
Duodenum Proximal Jejunum
Passive 5
Active 20-70 Vitamin D-1,25
Gastric acid Pancreatic Biliary
Relatively constant daily calcium absorption
(200-400mg/d)
Obligatory 100-200mg/d
11
Calcium Metabolism Kidney

• 810 g/d of calcium are filtered by the
  glomeruli
• only 23 appears in the urine
• proximal tubules 20
• passive, paracellular
• cTAL (cortical thick asc. limb of Henles loop)
  65
• passive, paracellular
• paracellin-1
• inhibited by increased Ca or Mg
• DCT (Distal convoluted tubules) 10
• transcellular
• stimulated by
• PTH
• Thiazide
• reduced by
• dietary Na load
• loop diuretics (distal Na delivery)

12
Calcium Metabolism Bone

• PTH
• Vitamin D-1,25
• osteoclastic bone resorption

13
Vitamin D

• Hormone rather than vitamin
• ultraviolet radiation of the skin
• formation of vitamin D from 7-dehydrocholesterol
  
• dietary sources
• fortified cereals, dairy products, fish oils and
  egg yolks
• 25-hydroxylated in the liver
• not tightly regulated
• major circulating and storage form of vitamin D
• kidney
• 25-hydroxyvitamin D-1?-hydroxylase
• tightly regulated
• PTH, low Phosphate
• Ca, D-1,25, FGF23
• macrophages
• 1?-hydroxylase
• granulomata and lymphomas
• Inactivation by 24-hydroxylase
• most tissues
• D-1,25

14
Vitamin D

Suppresses the transcription of the PTH gene
Increases calcium release from the bones via
osteoclastic activity
Increases calcium absorption in the intestine
15
PTH

• The four parathyroid glands produce PTH
• Calcium sensor
• ionized fraction of blood calcium is the
  important determinant
• High Ca levels, Vitamin D-1,25
• suppresses PTH secretion
• Low Ca
• increases secretion of PTH
• Bone
• osteoclastic
• Ca release
• Kidney
• reduces renal clearance of Ca
• increases production of vit D-1,25
• Intestine
• Ca absorption
• indirectly (vit D-1,25)

16
Calcitonin

• The thyroid - the major source
• hypocalcemic peptide
• several mammalian species - antagonist to PTH
• limited physiologic significance in humans
• tumor marker in medullary carcinoma
• adjunctive treatment in severe hypercalcemia and
  in Paget's disease of bone.

17
HypercalcemiaClassification

90
18
Primary Hyperparathyroidism

• elevated levels of PTH
• mild and intermittent hypercalcemia
• hypophosphatemia

• Etiology
• Solitary adenomas
• 80
• Hereditary syndromes and multiple parathyroid
  tumors
• MEN 1
• MEN 2A
• Clinical Manifestations
• 80 asymptomatic
• may have a benign course for many years or a
  lifetime
• recurrent nephrolithiasis
• bone resorption

19
Primary Hyperparathyroidism

• Treatment
• most patients - does not require urgent surgical
  or medical treatment
• asymptomatic patients should be monitored
  regularly
• surgical correction - when indicated

20
Lithium Therapy

• hypercalcemia in 10
• shift the PTH secretion curve to the right
• higher calcium levels are required to lower PTH
  secretion
• Treatment
• switch to alternative medications
• usually, but not always, subsides when lithium
  is stopped (adenomas)

21
Genetic Disorders

• Familial Hypocalciuric Hypercalcemia
• autosomal dominant
• the majority are asymptomatic hypercalcemia
• mutation in the calcium sensor receptor
• abnormal sensing of the blood calcium
• parathyroid gland - inappropriate secretion of
  PTH
• renal tubule - excessive renal reabsorption of
  calcium
• the majority require no treatment

• Jansens Disease
• autosomal dominant
• excessive biologic activity of the PTH receptor
  in target tissues
• short-limbed dwarfism
• low PTH, hypercalcemia

22
Malignancy Related Hypercalcemia

• common 20 of cancer patients
• hypercalcemia
• usually more severe than in primary
  hyperparathyroidism
• ? low PTH
• solid tumors (breast)
• bone metastases
• solid tumors (renal, lung-SquamousCC)
• bone metastases are absent, minimal, or not
  detectable clinically
• humoral mediators
• PTHrP
• PTH and PTHrP
• distinctive products of different genes
• considerable functional and structural homology
• Hematologic malignancies (multiple myeloma,
  lymphoma, leukemia)
• bone marrow invasion
• lymphokines and cytokines (including PTHrP)
  promote resorption of bone
• In some lymphomas Vit D-1,25

23
Malignancy Related Hypercalcemia

• Treatment
• first directed to control of the tumor
• treatment of the hypercalcemia should be
  vigorous while awaiting the results of definitive
  therapy

24
Vitamin D intoxication

• Chronic ingestion
• 40100 times the normal physiologic requirement
  of vitamin D
• Vitamin D-25
• rather than Vitamin D-1,25
• low, biologic activity
• production is less tightly regulated
• Treatment
• discontinuation of vitamin D
• usually lead to resolution of hypercalcemia
• vitamin D stores in fat may be substantial
• may persist for weeks
• responsive to glucocorticoids

25
Sarcoidosis and Other Granulomatous Diseases

• sarcoidosis, tuberculosis and fungal infections
• excess vitamin D-1,25
• is synthesized in macrophages or other cells in
  the granulomas
• Treatment
• avoiding excessive sunlight exposure
• limiting vitamin D and calcium intake
• glucocorticoids
• blocking
• excessive production of Vitamin D-1,25
• the response to it in target organs

26
Hyperthyroidism

• as many as 20 of hypothyroid patients
• mild hypercalcemia
• increased bone turnover

27
Immobilization

• rare
• bone turnover - disproportion between bone
  formation and bone resorption

28
Thiazides

• Distal convoluted tubules
• Chronic thiazide administration
• leads to reduction in urinary calcium
• administration to normal individuals causes a
  transient increase in blood calcium
• hypercalcemia
• in hyperparathyroidism or increased bone
  turnover from another cause
• Treatment
• hypercalcemia disappear within days of cessation
  of the drug

29
Vitamin A intoxication

• rare
• prolonged ingestion
• increase bone resorption
• treatment
• withdrawal of the vitamin
• glucocorticoids

30
Secondary and Tertiary Hyperparathyroidism

• Chronic Kidney Disease ? Low GFR
• reduced excretion of phosphate ? phosphate
  retention
• diminished vitamin D-1,25 production
• decreased Ca

increased PTH parathyroid hyperplasia
Autonomous growth of the parathyroid glands
Hypercalcemia
Tertiary hyperparathyroidism
31
Milk Alkali Syndrome

• high intake of milk
• high intake of calcium carbonate
• supplementation to treat osteoporosis
• less frequently, treating dyspepsia antacid
• hypercalcemia, alkalosis, renal failure

• Renal function usually returns to baseline after
  cessation
• irreversible injury can occur in patients who
  have prolonged hypercalcemia

32
Clinical Manifestations

• depend upon both the degree of hypercalcemia and
  the rate of onset
• mild hypercalcemia
• lt12 mg/dL
• often asymptomatic
• moderate hypercalcemia
• 12 to 14 mg/dL
• less symptomatic if the elevation in serum
  calcium is chronic
• polyuria, polydipsia
• anorexia, nausea, and constipation
• severe hypercalcemia
• symptoms can become more severe
• weakness, difficulty concentrating, confusion,
  stupor, and coma

33
Clinical Manifestations

Defect in concentating ability
Longstanding
Ca-induced gastrin secretion MEN1-zollinger-elliso
n syndrome
Deposition of calcium in heart valves, coronary
arteries, and myocardial fibers
34
Diagnostic Approach

• Hypercalcemia Ca gt 10.5
• Pseudohypercalcemia?
• Corrected Ca Serum Ca 0.8 X (Normal Alb
  Patients Alb)
• should be repeated to confirm the diagnosis
• previous values for serum calcium rate?
• subtle/ chronic/ gt 1 year primary
  hyperparathyroidism?
• more abrupt malignancy related?
• degree?
• mild lt 11 - primary hyperparathyroidism?
• gt 13 - malignancy related?
• symptoms?
• diet and medications?
• family history?

35
Diagnostic Approach

Vitamin D metabolites should be measured if no
obvious malignancy and neither PTH nor PTHrP are
elevated
36
Diagnostic Approach

• Serum Phosphate
• Hypophosphatemia
• hyperparathyroidism
• humoral hypercalcemia of malignancy
• Normal or Elevated
• granulomatous diseases
• vitamin D intoxication
• immobilization
• thyrotoxicosis
• milk-alkali syndrome
• metastatic bone disease

37
Diagnostic Approach

• Urinary Calcium Excretion
• relative hypocalciuria (less than 100 mg/day)
• milk-alkali syndrome
• metabolic alkalosis enhances calcium
  reabsorption
• Thiazides
• calcium reabsorption in the distal tubule
• Familial hypocalciuric hypercalcemia
• fractional excretion of calcium is less than 1

• Calcium/Creatinine Clearance Ratio
• (UCa/PCa) / (UCr/PCr)
• lt0.01 ? Familial hypocalciuric hypercalcemia

38
Treatment Saline Hydration / Diuresis

• Many hypercalcemic patients are dehydrated
• hypercalcemia-induced defects in urinary
  concentrating ability
• vomiting
• Hypovolemia exacerbates hypercalcemia by
  impairing the renal clearance of calcium
• The first principle of treatment is to restore
  normal hydration

39
Treatment Saline Hydration / Diuresis

• isotonic saline
• initial rate of 200 to 300 mL/h
• adjusted to maintain the urine output at 100 to
  150 mL/h
• rarely normalizes serum Ca in more than mild
  hypercalcemia
• careful monitoring fluid overload
• impaired renal function
• heart failure
• loop diuretic may be used as necessary

40
Treatment Saline Hydration / Diuresis

• isotonic saline
• Saline therapy beyond that necessary to restore
  euvolemia has fallen out
• availability of bisphosphonates and calcitonin
• inhibit bone resorption (responsible for the
  hypercalcemia)
• careful monitoring
• fluid overload
• electrolyte imbalance (combined with a loop
  diuretic)
• hypokalemia, hypomagnesemia
• volume depletion (if diuretic induced losses are
  not replaced)

41
Treatment Saline Hydration / Diuresis

• life-threatening
• more aggressively forced diuresis
• 6 L of isotonic saline daily
• plus Furosamide in doses up to 100mg every 1-2 h
• serum Ca may decrease by 4 mg/dL/24h
• careful monitoring
• CVP
• electrolytes
• urinary catheterization
• supplemented with agents to block bone resorption

42
Treatment Bisphosphonates

• powerful inhibitors of bone resorption - inhibit
  osteoclast action
• hypercalcemia
• established
• prevent hypercalcemia and adverse skeletal
  events (metastatic breast cancer)
• osteoporosis
• relatively nontoxic
• more potent than calcitonin and saline
• Onset of action within 1-2 days / Maximum effect
  within 2-4 days
• in conjunction with saline and/or calcitonin
• duration of action
• 10 days - gt3 weeks (depends on generation 3
  generations)

43
Treatment Bisphosphonates

• Pamidronate Aredia
• 2nd generation
• treatment of hypercalcemia due to excessive bone
  resorption, including
• malignancy
• acute primary hyperparathyroidism
• immobilization
• hypervitaminosis D
• sarcoidosis
• 30 - 90 mg given as a single IV dose over a few
  hours
• 60 mg if the serum calcium concentration is up
  to 13.5 mg/dL
• 90 mg for higher levels
• onset within 1-2 days
• duration 10-14 days to weeks
• doses should not be repeated sooner than a
  minimum of 7 days

44
Treatment Bisphosphonates

• Zolendronate - Zomera
• 3rd generation
• treatment of malignancy associated hypercalcemia
  
• more potent and effective than Aredia
• adminestered over a shorter time period (patient
  convenience)
• onset within 1-2 days
• duration gt3 weeks

45
Treatment Bisphosphonates

• Side-effects
• Flu-like symptoms (fever, arthralgia, myalgia,
  fatigue, bone pain)
• Ocular inflammation (uveitis)
• hypocalcemia
• hypomagnesemia
• hypophosphatemia
• impaired renal function
• nephrotic syndrome
• osteonecrosis of jaw (treated with multiple
  doses)

46
Treatment Bisphosphonates

• Dosing in renal impairment
• Crgt4.5 mg/dL
• adequate hydration with saline
• reduced dosage and/or slower infusion rate
• 4 mg ZA over 30 minutes
• 30 to 45 mg pamidronate over 4 hours

47
Treatment Calcitonin

• by decreasing bone reabsorption via interference
  with osteoclast maturation
• increasing renal calcium excretion
• 28 U/kg of body weight IV, SC, or IM every 612
  h
• onset within a few hours
• weak agent in combination with other therapies
• relatively nontoxic
• mild nausea / rare hypersensitivity reaction
• rapid tachyphylaxis (receptor downregulation)
• efficacy is limited to the first 48 hours

48
Treatment Glucocorticoids

• increase urinary calcium excretion
• decrease intestinal calcium absorption
• hypercalcemia due to certain osteolytic
  malignancies
• multiple myeloma, leukemia, Hodgkin's disease,
  other lymphomas
• carcinoma of the breast, at least early in the
  course
• vitamin D intoxication and sarcoidosis
• autoimmune disorders in which inactivating
  antibodies against the receptor imitate FHH
• effect develops over several days
• dosage is 40100 mg prednisone (or its
  equivalent) daily in four divided doses
• side effects of chronic glucocorticoid therapy

49
Treatment Dialysis

• severe hypercalcemia complicated by renal
  failure/ heart failure
• last resort
• onset within hours
• very useful

50
Treatment Phosphate

• Intravenous phosphate
• one of the most dramatically effective
  treatments available for severe hypercalcemia
• toxic and even dangerous (fatal hypocalcemia
• used rarely
• only in severely hypercalcemic patients with
  cardiac or renal failure where dialysis, the
  preferable alternative, is not feasible or is
  unavailable.

51
Treatment Gallium Nitrate

• inhibiting bone resorption
• not used
• superior alternatives

52
Treatment Plicamycin

• inhibits bone resorption
• now seldom used
• toxicity
• the effectiveness of bisphosphonates

53
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• ??????
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• Cr-0.96 / Urea 50
• ?????????? ???? 11.9
• ??????? ???? 4.0
• ???? ???? ??????
• ?????????? ??????
• ???? ????? ??????? Normal Saline
• ????? ??????? ?????
• ????? ???? ????? ????, ??? ??????

54
????? ??????

• CRP 19
• ESR 70
• PTH ????
• Urine Calcium (24h) 127 mg
• calcium/creatinine clearance ratio 0.03
• PTHrP ???? ?? ?? ????
• Vitamin D-25 ???? ??????
• Vitamin D-1,25 ???? ?? ?? ????
• ??? ACE ???? ??????
• TSH ???? ??????
• BENCE JONES ?????

55
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• CT ???, ??? ????
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• ????????????
• ???? ???
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• ?????????????? ??????????
• ???????

56
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• ?????? ?????
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  ??? ?????? ????????
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• ??? ??
• ??? ???? ????

57
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• ??????? ?? ????? ????? ???? ???
• NON-NECROTISING EPITHELIOID GRANULOMAS sarcoid
  like
• Histochemistry for Fungi (PAS, Methanamine
  silver) and mycobacteria (Ziegl-nilsen) is
  negative
• Sarcoidosis
• ???? ????? ???????? 60 ?"? ???? ?????? ????? ?-
  40 ?"? ????
• ???? ???? ???? ??????? ???? ????? ?????????'
• ???? ?????? ????? ???? ????? ?????? (????? ?????
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