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					                                                                                                                                                          28/05/2010




                                                                                       • Hyponatremia
                Water and electrolyte
                   disturbances
                                  Prof. Peter Vollenweider                             • Hypercalcemia
                               Service de de Médecine Interne

                                   Prof. François Pralong
                                  Service d’Endocrinologie

                                      CHUV Lausanne

                    78ème   Assemblée annuelle de la SSMI, 21 Mai 2010
                                                                                   1                                                                            2




                         Case presentation                                                                  Case presentation
• 74 year old presents to the emergency room with 1 day of nausea and
  vomiting                                                                             • Patient was thin and anxious looking, oriented only to person

• Several hours before presentation she developed confusion and slurred                • Temperature: 36.9C
  speech
                                                                                       • Blood pressure 199/96 mm Hg, pulse 95 beats per minute
• Tonic-clonic seizure un the ER
                                                                                       • Respiratory rate 22 per minute
• Past-medical history: left sided stroke, hypertension, diet controlled
  diabetes mellitus, hyperthyroidism, and anxiety disorder                             • Skin turgor was normal; oral mucosae was moist. No edema

• Medications: Olanzapine                                                              • No meningismus
               Propylthiouracil
               warfarin                                                                • Reflexes were normal bilaterally. She was moving her upper and lower
               enalapril/hydrochlorothiazide                                             extremities spontaneously.
               estrogen
                                                                                   3                                                                            4




                         Case presentation                                                                  Case presentation
 • Computed tomography of the brain without contrast did not reveal any
   bleed                                                                               What is the cause of her hyponatremia ?
 • CSF analysis after lumber puncture was normal

 •   Na+:          112 mmol/l
                                                                                           1.   Diabetes mellitus
 •   K+:           3.7 mmol/l
 •   Urea:         12.5 mmol/l                                                             2.   Syndrome of inappropriate Antidiuresis
 •   Creatinine: 92 mol/l                                                                  3.   Thiazide diuretic
 •   Glucose:      13.6 mmol/l
 •   Osmolality (calculated):             239 mOsm/kg ([2xNa+ + glucose + urea])
                                                                                           4.   Polydypsia
 •   Osmolality (measured):               245 mOsm/kg                                      5.   Adrenal insufficiency

 • Urinary osmolality:                    378 mOsm/kg
 • Urinary Sodium:                        51 mmol/l
 • Urinary potassium:                     52 mmol/l                                5                                                                            6




                                                                                                                                                                    1
                                                                                                                                                           28/05/2010




      Hyponatremia approach: some basics                                                 Hyponatremia: Diagnostic approach


 1. Think osmolality first, then salt!
                                                                                                    What is the plasma osmolality?
 2. Think body water rather than salt!                                                              (calculated et and measured)
                                                                                   Plasma osmolality (calculated) = 2x [Na+] + [Glucose] + [Urea]
                                                                                                     (No: 285-290 mOsm/kg)
 3. You have to know what the kidney is
    handling salt and water
     -    UNa+                                                                            If osmolar gap = [osmo measured – osmo calculated] > 10 mOsm/l
                                                                                               Think accumulation of non-calculated osmotic substance
     -    Uosmo                                                                                         mannitol, glycine, (ethanol, methanol)

                                                                           7                                                                                     8




      Diagnostic approach: think osmolality                                      Diagnostic approach: hypovolemic hyponatremia
                        Hyponatremia                                                                              Salt losses > Water losses


    Iso-osmolar           Hypo-osmolar            Hyper-osmolar
                                                                                              Renal losses                                     Extra-renal losses
     (270-295)                (< 270)                    (> 295)

      Pseudo-                  True              « Translocation »
                                                                                        Diuretics (chronic)
                                                                                     Salt loosing nephropathy
                                                                                                                                                    Diarrhea
    hyponatremia           Hyponatremia           hyponatremia                    ( obstructive nephropathy, medullary kystic                       Vomiting
                                                                                     kidney disease, analgetic nephropathy)
                                                                                         Hypoaldosteronism
                                                                                                                                                Perspiration +++
                                                                                                                                               Strenuous exercise
   Hyperproteinemia                              1.Osmo gap < 10
  (multiple myeloma)                              Hyperglycemia                         Una+ > 20 mmol/l
    Hyperlipidemia                                  2. Osmo gap > 10
                                                                                         Uosm variable                                         UNa < 20 mmol/l
      (extreme)                                     Mannitol,glycine
                                                                                                                                                  Uosm
                                                                           9                                                                                    10




   Diagnostic approach: euvolemic hyponatremia                                 Diagnostic approach: Syndrome of inappropriate antidiuresis

              EC volume « normal » = Excess free water
                                                                                • Causes: CNS and pulmonary disease, neoplasia, post-
                                                                                   operative, pain, nausea, drugs (Neuroleptics, cyclophosphamide,
 ↓Excretion H2O             ↑ Na excretion            ↑Intake H2O
                            ↑ADH secretion
                                                                                   vincristin, carbamazpin, chlorpropamide, tricyclics, NSAID…)
                           Thirst stimulation
                             K+ depletion
     SIADH                                                                      • Diagnosis:
                                                         Polydipsia
 Hypothyroidism                                           Beer potomania
                                                                                    –   Hypo-osmolar hyponatremia
                          Diuretics (acute)                                         –   EC volume “normal”
↓ Glucocorticoïds
                             (thiazides)                                            –   UNa+ > 40 mmol/l with normal salt intake
                                                                                    –   Uosm ↑ (> 100 mOsom/kg water)
                                                   UNa > 20 mmol/l                  –   Normal thyroid and adrenal function
UNa+ > 40 mmol/l          UNa > 20 mmol/l                Uosm                       –   No recent diuretic use
   Uosm ↑
                                                    (< 100 mosm/l)
                                                                       11                                                                                       12




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                          Case presentation                                          Diagnostic approach: euvolemic hyponatremia

  •    Na+:          112 mmol/l                                                                    EC volume « normal » = Excess free water
  •    Glucose:      13.6 mmol/l
  •    Osmolality (calculated):    239 mOsm/kg ([2xNa+ + glucose + urea])
  •    Osmolality:                 245 mOsm/kg (270-295 mOsm/kg)                   ↓Excretion H2O                        ↑ Na excretion                      ↑Intake H2O
                                                                                                                         ↑ADH secretion
                                                                                                                        Thirst stimulation
  • Urinary osmolality:            378 mOsm/kg                                                                            K+ depletion
  • Urinary Sodium:                51 mmol/l                                            SIADH                                                                  Polydipsia
                                                                                   Hypothyroidism                     Diuretics (acute)                        Beer potomania
  •    Our patient has a true hypo- osmolar hyponatremia.                         ↓ Glucocorticoïds                      (thiazides)
  •    The osmolar gap is normal ( 245-239= 6)
  •    She is euvolemic from the clinical presentation                                                                                                      UNa > 20 mmol/l
                                                                                  UNa+ > 40 mmol/l                    UNa > 20 mmol/l
  •    Urinary osmolality is > 100 mOsm/kg                                                                                                                        Uosm
                                                                                     Uosm ↑
  •    The daughter tells us that she was started on anti-                                                                                                   (< 100 mosm/l)
       hypertensive medication two weeks before                             13                                                                                              14




                          Case presentation                                                 Treatment: General considerations
Which of the following is true about the therapy for this
patient ?                                                                        • If chronic hyponatremia ( > 48 hours) correct slowly
                                                                                   because of increased risk of osmotic demyelination.


      1. Rapid correction with hypertonic saline is indicated                    • Plasma Na+ should not increase by more than 10-12 mmol
      2. Slow correction with isotonic saline is indicated                         over the first 24 hours! (unless CNS symptoms are present)
                                                                                   and more than 18 mmol in the first 48 hours
      3. Water restriction only is the appropriate therapeutic
         strategy
      4. Aggressive therapy should be continued until                            • Premenaupausal women, patients with hypokalemia,
         sodium reaches normal range                                               hypoxia, malnutrition, chronic alcohol abuse and liver
                                                                                   disease are at increased risk of osmotic demyelination

                                                                            15                                                                                              16




                               Treatment                                                          Treatment: “Na+ substitution”
Administer     Na+

      a) If severe symptomatic hyponatremia

        Correct plasma Na at a rate of 1-3 mmol/hour with NaCl 3%
        until resolution of clinical symptoms , then slow down!

        Regularly and closely check plasma Na+ values! (every 2 hours
        at the beginning)

                                                                                  Examples are to correct serum sodium of 110mmol/l to a desired level of 120 mmol/l
      b) If hypovolemic hyponatremia                                              in a man with body weight of 70 kg and total body water of 42 liters using a 513 mmol/l
                                                                                  infusion ( NaCl 3%). Time of 10 hours , urinary volume of 1 liter, and UNa+ of 80 mmol/l

      Favor isotonic NaCl in the absence of severe symptoms
                                                                            17                                                                                              18
                                                                                                              Ellison DH and Berl T, 2007; NEJM:356; 2064




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           Treatment: “Na+ substitution”                                                   Case presentation: Treatment

           The pragmatic approach                                            1.    Neurological symptoms→ NaCl 3% infusion at 1-2 ml/kg*hour
                                                                                   until normalization of neurological state
• To increase plasma Na+ by
                                                                             1.    Check plasma Na+ every two hours


  – 1-2 mmol/l per hour → Use NaCl 3% 1-2 ml/kg weight* hour                 2.    Slow infusion when neurological symptoms subside and stop when 8-10
                                                                                   mmol/l increase of plasma Na+ in the first 24 hours

  – 0.5-1 mmol/l per hour→ Use NaCl 3% 0.5 ml/kg weight* hour                3.    Stop diuretic


  – (2-4 ml/kg* hour of NaCl 3% can be used for a limited time               4.    Be very careful for over correction (due to auto-correction) in thiazide
                                                                                   induced hyponatremia (water diuresis with discontinuation of diuretic)
    period in subjects with seizures)
                                                                                   → follow closely urinary output!

                                                                             5.    High rate of recurrence: do not rechallenge with thiazide diuretic
                                                                        19                                                                                    20
                  Verbalis JG et al. Am J med, 2007; 120 (11A) S1-S21




      Treatment for chronic hyponatremia                                          Vaptans: selective vasopressin antagonists
   Water Restriction (<800-1000ml/j)                                                Non-peptidic
                                                                                    Can be administered orally


      – If euvolemic hyponatremia

      – If hypervolemic hyponatremia




                                                                        21                                                                                    22
                     Ellison DH and Berl T, 2007; NEJM:356; 2064                                      Ellison DH and Berl T, 2007; NEJM:356; 2064




                                                                                                   Patient presentation
                A history of fatigue
                                                                                    •   Woman, 23 yo
                                                                                    •   Turquish origin
                                                                                    •   Good general health, idiopathic hirsutism
                       François Pralong                                             •   Main complaints, april 2003:
                                                                                        1) Asthenia-tendency to fall asleep
  Service of Endocrinology, Diabetology and Metabolism
                                                                                        2) Polyuria-polydipsia

                                                                                    • What work up ? What diagnosis ?




                                                                                                                                                                   4
                                                                                                  28/05/2010




          Patient presentation                                Patient presentation

• GP:                                               • GP:
  - Corrected calcium at 3,2 mmol/l, PTH elevated     - Corrected calcium at 3,2 mmol/l, PTH elevated

• CHUV 4.3.2003:                                    • CHUV 4.3.2003:
  - Total Ca   2,56 mmol/l     (2,15-2,55)            - Total Ca   2,56 mmol/l   (2,15-2,55)
  - Corr Ca    2,50 mmol/l     (2,1-2,5)              - Corr Ca    2,50 mmol/l   (2,1-2,5)
  - PO4        0,72 mmol/l     (0,8-1,4)              - PO4        0,72 mmol/l   (0,8-1,4)
  - PTH        581 ng/l         (10-70)               - PTH        581 ng/l       (10-70)


Diagnosis ?   Additional work up?                     - 25(OH)-vitamine D3: 3,2 ug/l (8,4-52,3)




      Primary hyperparathyroidism
                                                                    Diagnosis:

                                                           Primary hyperparathyroidism

                                                               with hypovitaminosis D


                                                              (with osteomalacia component)
                  2.0    2.5      3     mmol/l




                                                       Primary hyperparathyroidism


                                                      Clinical presentation of primary
                                                      hyperparathyroidism has profoundly
                                                      changed these last few years, going
                                                      from rare and symptomatic disease to a
                                                      relatively frequent and pauci-symptomatic
                                                      affection.




                                                                                                          5
                                                                                                                                28/05/2010




                                                                                            Primary hyperparathyroidism
              Diagnostic criteria of PHPT

• Persistent hypercalcemia, with high normal                                     Incidence:
  (especially in patients < 40 yrs) or elevated PTH,                                    28 to 358 / 100’000
  as measured by IRMA assay.

                                                                                 Pathology (MGH, Boston, 914 cases):

• Not all patients with PHPT have elevated calcium                                      - adenomas              82.9 %
  levels, calcemia can also be high normal.                                             - hyperplasias          14.6 %
                                                                                        - carcinomas             2.5 %




      Epidemiology - Symptomatology                                         Epidemiology - Symptomatology

  • Symptomatic: rarely typical nowadays                                 • Symptoms linked to:

      - renal lithiasis
      - fibrocystic osteititis (exceptional)                                   - hypercalcemia, dehydration
                                                                               - high PTH
  • Pauci-symptomatic: frequent
                                                                               - hypercalciuria
      - 3rd endocrinopathy after diabetes mellitus and thyroid disease         - hypophosphatemia
            F:H = 2; especially between 40-75 yrs

      - minor symptoms: fatigue, memory loss, dysthymia, sleeping        • Also slightly dependent upon patient’s background:
      troubles, digestive troubles and abdominal pain
                                                                                      psychic / somatic




      Epidemiology - Symptomatology                                             Work up PHPT and surgery
SN:     - adynamia, fatigue, depression..                                • Etiology (adenoma, hyperplasia…)
                                                                         • Role of (surgery criteria):
SCV: - fatigue, EKG abnormalities                                           – Calcemia
                                                                            – Renal function
SD:     -epigastric pain, constipation, weight loss
                                                                            – Calciuria
                                                                            – Lithiasis
SUG: - nephrolithiasis, polyuria
                                                                            – Osteopenia/osteoporosis
SOA: - chondrocalcinosis, osteoporosis (pain)
     - pseudo-arthralgias, myalgias, fatigue




                                                                                                                                        6
                                                                                                                                     28/05/2010




Comparison of recommendations in favor
              of surgery                                                            Blood: What calcium? - PTH?


                                                                               • Ionized calcium = active form of calcium, hence more
                                                                                 representative
                                                                                      NOT-recommended, since often not available

                                                                               • Measure intact PTH (reaction with both amino et
                                                                                 carboxy ends at the same time)




                                   J Clin Endocrinol Metab 94: 335–339, 2009




                                                                                      Imaging studies: US, scintigraphy ?
                       Urines?
                                                                               • Traditional surgery: no prior diagnostic investigations
                                                                                 necessary
 • Measure calciuria over 24h                                                  • Era of minimal invasive surgery :
                                                                                 - Localization step = US
 • Surgery criteria ? Not any more.
                                                                                 - If negative, ad MIBI scintigraphy

                                                                                     + thyroid function tests and thyroid ultrasound




        Bone densitometry: role ?                                                               Surgery
                                                                                    « Large vs minimally invasive? »

                                                                                • Traditional surgery:
 • Surgery criteria if bone density (T-score) < 2.5 SD                            Bilateral cervical exploration under general anesthesia
       (osteopenia in 1/4 patient)
                                                                                • « Minimally invasive » parathyroidectomy :
 • If no surgery, allows follow up of PHPT                                        - Pre-surgery scintigraphy localization
                                                                                  - Anesthesia by cervical block
                                                                                  - Small incision
                                                                                  - PTH measurement during surgery
                                                                                  - Decrease surgical duration by 50%, and
                                                                                  hospitalization duration by 7x




                                                                                                                                             7
                                                                                                                                           28/05/2010




                                                                                      Clinical evolution at 10 yrs of PHPT
      Follow up without surgery                                                                 (S.J.Silverberg, NEJM 21.10.99, vol 341)




                                          J Clin Endocrinol Metab 94: 335–339, 2009




        Patient presentation (part 2)
Evolution of calcium and PTH levels (RxViDé3)
                                                                                          Patient presentation (part 2)
                    3

                   2.5

                    2
          mmol/l




                   1.5                                 calcium


                                                                                      • Tc 99m MIBI scintigraphy :
                    1

                   0.5

                    0                                                                   - Right posterior parathyroid adenoma
                         mars   juillet
                   700
                   600
                   500
                   400
          ng/l




                                                       PTH
                   300
                   200
                   100
                    0
                         mars   juillet




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