אנדו Flashcards
(150 cards)
1
Q
2019 NENs NEW Classification?
A
G1- cell monomorphism, Ki67≤3%
G2- cell monomorphism, 3% < Ki67 ≤ 20%
G3- cell monomorphism, 20% < Ki67 (≤ 55%)
10% G4-small cell & large cell NE carcinomas
cell pleyomorphism, necrosis, invasion,
(20%) 55% < Ki67 ≤ 100%
MIB1 stains nucleolus of cells differentiating- city named ‘kill’
2
Q
carcinoid nomenclature?
A
“Carcinoid Syndrome“ - serotonin secreting neoplasm
neuroendocrine tumors of the lung-
typical - G1
atypical - G2
3
Q
NETs classification?
A
NF-NETs 75%
```
F-NETs 25%
Insulinoma
Gastrinoma)
Glucagonoma
VIPoma
Carcinoid Sdr.
Cushing Sdr.
Hypercalcemia
Acromegaly
~~~
4
Q
NETs LAB?
A
Non-specific:
Chromogranin A (CgA) 65% of all NEN
PPI, H2RAs: feedbeck CgA ↑, stop PPI 3w before unless gastrinoma
Neuron Specific Enolase (NSE)- aggressive tumours
PP- pancreatic tumors in MEN-1
(pro) Calcitonin - Medullary carcinoma, PNETs
Alk.Phos, PLT
Specific:
5-HIAA, a serotonin metabolite (carcinoid)
Insulin & C-Peptide & hypoglycemia (insulinomas)
Fasting serum gastrin & PH<2 (gastrinomas, ZES)
Glucagon (glucagonoma)
VIP (VIPoma)
Not for screening!!!!
5
Q
Molecular Imaging of NETs?
A
DOTA-TATE PET-
inject TATE (ss analogue), bound to DOTA (chimeric molecule) 🡪 detect all SSTR2 cells
(+optional therapy of SS analogue)
will be shown in liver (homogenic grey), spleen (vascular, endothel), kidney (excretion)
all else is pathological
FDG- most common PET CT
glucose-radio-active- Fluorine uptake, high metabolic demands
-Low sensitivity in G1&G2
-complementary to Ga-DOTA-PET
6
Q
Current Therapies for GEP NETS?
A
Surgical resection: Curative or Palliative (Debulking)
Intestinal NET- Somatostatin Analogues 1st line (85%) Everolimus- mTORi PRRT Interferon alpha
Pancreatic NET- Somatostatin Analogues 1st line (85%) Everolimus, Sunitinib (TKI) PRRT Chemotherapy (G3)
7
Q
Somatostatin?
A
1st line inhibitory functions: endocrine/exocrine secretions neurotransmission motor and cognitive functions intestinal motility endocrine cell proliferation
Long acting- Octreotide LAR (IM) or Somatuline Autogel (SC) every 4w
Pan-receptor ligand (1-5 at same time) - Pasireotide or SOM230, daily or weekly
> 90% of NENs express SSTR
SSTR2, SSTR5, and SSTR1 are most frequently
Effective Symptom Relief (secretory)
REDUCTION in Diarrhoea Frequency
REDUCTION in Flushing Frequency
Most side effects are transient
8
Q
PRRT Peptide Receptor Radionuclide Therapy - Eligibility Criteria?
A
Coupling a radioisotope to a molecule which would specifically bind to tumor cells & deliver an effective radiation dose to the tumor- TATE (SS analogue)
2nd line
Metastatic/locally advanced/inoperable NETs
20% diseases regression
65% stop advancement
more adverse effects: Acute and subacute-Usually self-limiting. Long term Renal failure - rare MDS or leukemia (2%)
9
Q
insulin lvls at hypoglycemia measurement?
A
C-peptide
low if exogenic insulinemia
high if endogenous insulinemia
10
Q
Insulinoma diagnosis?
A
fast glucose 72h gold standart (in all endocrine do imaging after initial suspicion and DD)
high index of suspicion
blood glucose ≤ 2.2mmol/l (≤40 mg/dl)
insulin ≥6µU/l (≥36pmol/l ) & C-peptide ≥200 pmol/l;
מדידים או גבוהים
HRCT/MRI; EUS/IOUS; 68Ga-DOTATATE, 68Ga-exendin-4
11
Q
Insulinoma treatment?
A
surgery - treatment of choice (laparoscopic, IOUS)
ablation (RFA)
medical therapy (unable/ unwilling for surgery, or for metastatic disease):
self monitoring of glucose
glucose infusion
diazoxide - usually a 1st line drug
glucocorticoids - effective in refractory cases
somatostatin analogues (SSAs) - inhibit insulin secretion (!!paradoxical effect via action on GH & glucagon - worsening hypoglycemia in some patients) 50% check before administration!
malignant insulinoma: SSAs; chemotherapy , PRRT, TKI (sunitinib) or mTOR inhibitors (everolimus);
12
Q
Insulinoma characteristics?
A
the most common F-PNETs
“Rule of 10” (multiple, malignant, MEN1, ectopic [not in pancreas]).
Clinically Whipple’s triad-
Symptoms of hypoglycemia
Low glucose level ≤2.2mmol/l (≤40mg/dl)
Relief of symptoms with glucose administration
13
Q
Gastrinomas & Zollinger-Ellison Syndrome (ZES) characteristics?
A
Gastrinoma triangle (70% duodenum; 20% pancreas; 10% LN)
Sporadic (80%), hereditary (20%, MEN1)
Malignant 60-90%
Clinically, symptoms d/t gastrin-related high gastric acid output (ZES) ± tumor mass
diagnosis:
elevated fasting gastrin (~90-98% patients, after stopping anti-acid drugs, if possible); pH<2.
localization: HRCT/MRI, EUS, SRI
14
Q
Gastrinomas & Zollinger-Ellison Syndrome (ZES) Treatment?
A
surgical excision in localized disease
systemic therapy:
PPI always
SSAs, 1st line; then
advanced :
PRRT, or
Targeted therapy: TKI (sunitinib) or mTOR inhibitor (everolimus), or
capecitabine-temozolomide (CAP-TEM), or
liver metastates:
TACE; RFA
15
Q
Glucagonoma characteristics?
A
7% of F-pNETs usually large (>5 cm) and metastatic (~80% liver) at presentation
clinical Glucagonoma Syndrome: necrolytic migratory erythema (NME) new/uncontrolled DM (75-95%) abdominal pain, anorexia, diarrhea thromboembolism (~30%) neurologic: ataxia, dementia, optic atrophy
16
Q
Glucagonoma diagnosis?
A
fasting plasma glucagon >500pg/ml (50-150)
localization: HRCT/MI; EUS; SRI
17
Q
Glucagonoma treatment?
A
surgical excision in localized disease
systemic therapy:
PPI always
SSAs, 1st line; then
advanced :
PRRT, or
Targeted therapy: TKI (sunitinib) or mTOR inhibitor (everolimus), or
capecitabine-temozolomide (CAP-TEM), or
liver metastates:
TACE; RFA
18
Q
u5HIAA sampling?
A
דיאטה 3 ימים לפני ותוך כדי האיסוך ללא דברים שדומים לסרוטונין.
אבוקדו, בננות, וניל, בטונים, קפה שוקו וכו
19
Q
Carcinoid Syndrome initial treatment?
A
(HD) SSA & zolendronic acid
CRF:
diuretics, low salt diet
20
Q
Carcinoid Syndrome characteristics?
A
19% F-NETs originating in SI, lung, pancreas, ovary…
Associated with high serotonin (5HIAA)
Diarrhoea, flushing, bronchospasm
30-60% CHD - increased mortality
Carcinoid crisis - life-threatening
21
Q
Risk Factors for CHD Development & Progression in Carcinoid Syndrome?
A
High circulating serotonin
High u5HIAA (>300 µmol/24h or >30mg/24h)
Prolonged exposure
≥3 diarrhea /day
Overexpression & activation of 5HTRs (mainly 5HT2BR) in cells (fibroblasts, smooth muscle cells, etc.)
22
Q
Approach to a Patient with CS & CHD - Principles of Therapy?
A
1st - Decrease Hormonal Levels
1st line- Somatostatin Analogues (SSA, also high dose)
+-Serotonin synthesis (TH) inhibitor - Telotristat Ethyl
Considered Individually: (PRRT), OR mTOR inhibitor - Everolimus), OR NF-α (rarely used), OR Locoregional (TACE/SIRT), surgical debulking), OR
2nd - Identify & Treat Right HF
3rd - Decide on Valve Replacement (NET MDT)
23
Q
Medullary Thyroid Carcinoma (MTC) characteristics?
A
parafollicular C-cells of the thyroid, neural crest origin
F-NET:
Calcitonin (most common);
Carcinoembryonic antigen (CEA)
ACTH, Substance P, Gastrin
Two types:
Sporadic 25% 50-60y
Familial [AD]: Multifocal and bilateral MEN IIA/IIB Familial MTC >95% germline RET (Tyrosine kinase receptor coder) 20-30y 🡪 found early 🡪 better prog.
24
Q
Medullary Thyroid Carcinoma (MTC) clinical presentation?
A
50-60% nodal involvement when detected
Compressive symptoms (dyspnea, dysphagia)
Hoarseness (RLN)
Paraneoplastic syndromes (Cushing’s)
Diarrhea-Calcitonin causes increased secretion of electrolytes into the intestine
25
Medullary Thyroid Carcinoma (MTC) treatment?
1. Locoregional:
Surgical resection ± EBRT
Or
Vandetanib for unresectable symptomatic or progressive
2. Symptomatic, distant metastases:
Consider palliative resection
Ablation (RFA, TACE) or Vandetanib
```
3. Asymptomatic, distant metastases:
Observe
or
Consider resection (if possible)
Ablation (RFA, TACE) or Vandetanib if PD
```
4. Disseminated Symptomatic Disease
Clinical Trial (preferred) Or EBRT for Focal Symptoms
or
Vandetanib Or Consider other TKIs
or
Dacarbazine (DTIC)-based chemotherapy (RET mute)
Bisphosphonate or Denosumab for bone metastases
26
Diagnostic Pathway in NET?
Clinical Symptoms/ Incidental Finding 🡪 Lab
tests 🡪 Imaging anatomic/ functional 🡪 Histo-pathology 🡪 Prognostic stratification 🡪 Therapeutic
Decision
27
Acromegaly - Signs and Symptoms?
```
GH Excess:
Frontal Bossing
Chin Protrusion
Enlargement of hands and feet
Thick skin
Skin tags
Sweating
Sleep Apnea
Carpal Tunnel Syndrome
Glucose intolerance
Osteoarthritis
Colonic Polyps
macroglossia
```
```
Tumor-related:
Headache
Visual field defect
Loss of pituitary function-
Gonadotrophins
TRH - hypothyroid
ACTH - Addison’s
Diabetes insipidus (very rare unless apoplexy)
```
28
Regulation of GH Secretion?
```
SS is the main inhibitor, regulated by:
sleep🡪 acetylcholine↑ 🡪 ↓
arginine 🡪 ↓
dopamine (more then GH)🡪 ↓
alpha androgenics, opiates, GABA🡪 ↓
glucose 🡪 ↑
GH 🡪 ↑
IGF-1 🡪 ↑
```
```
GH direct regulators:
GRH 🡪 ↑
TRH 🡪 ↑
T3 🡪 ↑
dopamin 🡪 ↓
glucose 🡪 ↑ (BUT SS ↑↑↑)
IGF 🡪↓
stress 🡪 ↑
```
29
Diagnose Acromegaly?
1st-
IGF-1 (Insulin-like Growth Factor 1)
IGF-BP3 (IGF binding protein 3)
1-2hr postprandial GH
2nd. Normal- Acromegaly Excluded
2nd. abnormal:
Oral Glucose Tolerance Test (OGTT)
normal- GH will go down in a blink, Acromegaly Excluded
abnormal 🡪 GH normal or even rise 🡪 Acromegaly diagnosis
↓
3rd. pituitary MRI
Normal🡪 Somatostatin receptor Scan 🡪 Site-specific CT/MRI 🡪 TREATMENT
Abnormal 🡪 treatment
30
Growth-Hormone Excess Etiology?
98%: GH-producing pituitary tumor
```
2%: Ectopic GHRH secretion
Small cell lung cancer
Bronchial or intestinal carcinoid tumors
Pancreatic islet cell tumor
Pheochromocytoma
```
0%: Ectopic GH secretion exceedingly rare
31
Acromegaly with large pituitary tumor "collateral damage”?
1. Pituitary-Adrenal axis:
cortisol insufficiency
Fasting morning cortisol > 350 nmol/l 🡪 deficiency is highly unlikely
2. hypothyroidism
TSH may be low, normal or slightly elevated
(if high 🡪 probably non functional 🡪 no TRH 🡪 No processing 🡪 no functionality
FT4 is low
3. Pituitary gonadal axis
LH, FSH, Sex hormones
4. Diabetes Insipidus- rare if no apoplexy
5. Visual field defect
32
Acromegaly: Treatment options?
surgery
micro 82% , Recurrence 5-10%
macro 47%, Recurrence 100%
Dopaminergics- Cabergoline, 10-20%
Effect minimal and may be transient
Radiotherapy 75% (20 years)
Neuro deficits- allmost none
```
Somatostatin analogs- 50-65%
Gallstones
Monthly injections
80+% reduce IGF1 levels
30-50% normalize IGF1
```
GH receptor antagonist- Pegvisomant
Normalization of GH 90%
Normalization of IGF1 80-90%
33
Acromegaly: Treatment Algorithm?
Pituitary Adenoma
↓
< 1cm 🡪 Transphenoidal surgery
> 1cm:
🡪 non invasive 🡪 Consider preoperative somatostatin analog + Transphenoidal surgery
↓
Post prand GH >1 mcg/l And/or IGF-1 elevated?
↓
somatostatin analog or dopaminergic
```
🡪 invasive 🡪 somatostatin analog or dopaminergic
↓
GHR, antagonist or dopaminergic
↓
Combination therapy
↓
Radiation Therapy
```
Post-prand GH <1 mcg/l and IGF-1 normal
↓
Annual Follow-up
34
Differential Diagnosis of Hyperprolactinemia?
macroprolactinoma 🡪usually Prolactin levels > 5,000
Stalk compression, medications, hypothyroidism and stress 🡪 usually prolactin levels < 2,000 and virtually always less than 5,000 mIU/l.
Microprolactinomas and mass lesions compressing the pituitary stalk frequently present with similar prolactin levels.
35
Hyperprolactinemia: Clinical Presentation?
```
Women:
Amenorhea 57-90 %
Galactorrhea 30-80 %
Headache 40 %
Visual field defect<25 %
Hirsutism 19 %
```
```
Men:
Decreased libido 75-100 %
Impotence 68-100 %
Headache 70 %
Visual field defect 36-70 %
Galactorrhea 10-30 %
Gynecomastia 4-50 %
```
36
Prolactinoma: Results of Treatment?
Surgery:
Microprolactinoma 60-80% -Recurrence 50%
Macroprolactinoma 10-30% -Recurrence 100%
Radiotherapy -Normalization of PRL after ~10 years
Medical Therapy
Microprolactinoma >90%
Macroprolactinoma 50-80%
37
Clinical Evaluation of Hyperprolactinemia?
Increased fasting, resting prolactin levels
< 5,000 mIU/l:
"Non-functioning" macroadenoma-
Surgery and/or Radiation
Cortisol, thyroid and testosterone replacement
> 5,000 mIU/l:
Dopaminergic Therapy
Dopamine agonist therapy will normalize prolactin and lead to tumor regression in most patients with macro- and micro-prolactinomas
38
Hormone Replacement Therapy in Panhypopituitary Patient?
Adrenal Cortex:
Emergency (Stress)
Hydrocortisone 50-100 mg IV every 8 h.
Maintenance - cortisone in various ways
Thyroid:
Levothyroxin 100-200 mcg/d
Maintain T4 level in upper normal range
Gonadal Steroids:
Estrogen/Progesterone or Testosterone
ADH: Desmopressin (DDAVP)
Growth Hormone
39
Non-Functioning Macroadenoma of Pituitary Treatment?
1. Hormonal Replacement
2. Surgical
Most cases
Dopaminergic for prolactinoma
3. Radiation
Small effect
High probability of pituitary dysfunction
Low probability of secondary tumor
May have long-term subtle neurologic effects
4.Medical
Steroids for hypophysitis
Specific treatment for granulomatous disease
40
Thyrotoxicosis etiology?
primary hyperthyroidism, Endogenous overproduction of thyroid hormone :
grave's disease
toxic multinodular goiter
toxic adenoma
without hyperthyroidism, Release of pre-formed hormone from damage to the gland:
subacute thyroiditis
silent thyroiditis
amiodaron, radiation, infraction of adenoma
```
secondary hyperthyroidism:
TSH secreting pituitary adenoma
Thyroid hormone resistance syndrome
HCG-mediated hyperthyroidism – β-HCG shares α subunit with TSH
Gestational thyrotoxicosis
```
Excess levothyroxine administration
41
Features Unique to Graves’ Disease?
1. אוושה בבלוטה – האזנה לבלוטה > ניתן לשמוע אוושה, עקב זרימת דם מוגברת בתוך הבלוטה.
2. אופתלמופתיה
3. דרמופתיה – עיבוי של העור באזור הטיביה, מאוד נדיר (זה היה נראה בעיקר לפני שהיו לנו דרכים למדוד יתר פעילת של הבלוטה ולטפל)
4. שינוי ציפורניים – מאוד מאוד נדיר.
42
thyroid hormones characteristics?
>99% of Thyroid Hormone is Bound
Bound hormones are inactive, only the free portion is biologically available to tissues
T4- T0.5= 7d 100% production by thyroid
T3- T0.5= 12-18h 20% production by thyroin, 80% in periphery by conversion of T4
TBP- 80% of bound thyroid hormone
Increase: Estrogen, Acute Hepatitis, Drugs
Decrease: Androgens, Glucocorticoids, NS, Cirrhosis
43
Graves’ Disease LAB?
```
LOW TSH (negative feedback)
HIGH T3, T4
```
no further testing needed (book says) but:
Radioactive Iodine Uptake and Scan- increased diffuse uptake (normal around 30%)
Thyroid Ultrasound- elevated blood flow
44
Tests of thyroid autoimmunity?
TPO Ab – Thyroid Peroxidase Ab
very sensitive- graves 50% and hashimoto 80%
Thyroglobulin Ab 30%
TRAb – TSH receptor Ab
specific for graves
TSI – Thyroid Stimulating Ig
specific for graves- 90%
45
graves treatment?
Symptomatic relief -
book- Beta blockers (propranolol at high doses decreases peripheral conversion of T4 to T3)
(short T0.5 so...)
```
1. Antithyroids: methimazole first line
PTU: in thyroid storm and 1st trimester
-[inhibits T4→T3 (high dose)]
relapse 60%
adverse:
Agranulocytosis- discontinue ATDs in case of fever or sore throat
acute hepatitis
```
2. surgery
adverse:
Hypoparathyroidism
RLN paralysis
Intraop thyroid storm, bleeding
Lifelong L-T4
```
3. Radioiodine
adverse:
Pregnancy/breastfeeding
Radiation protection issues
Ophthalmopathy
Lifelong L-T4
```
46
Graves’ Ophthalmopathy?
CASC – score >=3 points, max 7
Activation of TSH-R and IGF-1R leads to inflammatory environment, fibroblast proliferation and increased cytokines/chemokines 🡪 prostaglandin and GAG infiltration/inflammation within the orbit 🡪 ophthalmopathy
can happen without thyroid problem
```
risk factors:
Age
Sex
Genetics/Ancestry: Highest in Caucasians; lowest in Asians
Smoking: Increases GO progression and decreases therapy efficacy
TSH receptor
Thyroid dysfunction
Radioactive iodine therapy (RAI)
```
47
Graves’ Ophthalmopathy - Treatment?
Treat underlying thyroid hormonal imbalance:
Radioactive iodine should be avoided
mild- glucocorticoid therapy should follow RAIodine administration
Smoking cessation
Selenium supplementation
Immunosuppressive therapy-
Glucocorticoids: IV methylprednisolone pulse therapy with 500 mg x 6w followed by 250 mg/week X 6w
Teprotumumab (anti-IGF-1)
second line agents: CellCept, anti-IL-6, anti-B cell mAb, orbital radiation
Decompressive surgery
48
DD of Thyroiditis?
acute (more rare):
bacterial , fungal
I131 treatment
amiodarone (has iodine in it)
```
subacute:
viral
silent (including postpartum)
mycobacterial infection
drugs- interferon, amiodaron
```
chronic:
autoimmunity- hashimoto, atrophic, Riedel's
parasitic
traumatic
49
Thyroiditis LAB/imaging?
```
TSH LOW (negative feedback)
T4 +3 elevated
Thyroglobulin ↑
ESR ↑ (מוגבר בדלקת)
TPO Ab negative
```
Nuclear Medicine Imaging-
no uptake- RAIU< 5%
50
Thyroiditis treatment?
no antithyroids! inhibits production of new hormone; they do not interfere with pre-formed hormone release.
Beta-blockers- drugs of choice
symptomatic relief and suppression of tachyarrhythmia
Use NSAIDS (Advil or nexin) or corticosteroids prn for pain management
51
Natural course of thyroiditis?
pathogenesis: destruction of thyroid and hormones spill to blood
↓
thyrotoxic 🡪 hypothyroid (easy) 🡪 recovery
TSH ≥ 10 (mU/L) or symptomatic:
50-100 mcg of L-T4 for 6-8 weeks and TFTs should be reassessed thereafter
52
acute iodine load thyroid response?
normal thyroid-
wolf chaikoff effect (organification of iodine↓, massive emptying)
defective thyroid-
jod-basedow effect (massive deposition)
53
Amiodarone-Induced Thyroid Dysfunction?
39% iodine by weight
Very long half life! (50-100 days)
Acutely inhibits T4 release (Wolf-Chaikoff effect)
Inhibits 5’ deiodinase 🡪 reduces FT3 with normal-elevated T4 and transient TSH elevation
Can cause hypothyroidism (13% )
More common in those with TPO Ab +
No need to discontinue drug, simply treat hypothyroidism
Can cause hyperthyroidism (2%) (AIT) - 2 forms:
Type 1- increased T4/T3 synthesis -underlying thyroid pathology (Jod-Basedow effect)
Type 2- (destructive thyroiditis) resulting in excess release of T4/T3 without increased hormone synthesis
Treat with high dose ATDs or thyroid surgery (type 1) or steroids (type 2)
54
Amiodarone-Induced Thyroid evaluation?
Thyroid Nuclear Medicine Scan- Not helpful
Procore had saturated the thyroid
Ultrasound-
high blood flow, nodes 🡪 Type 1 AIT
55
Amiodarone-Induced Thyroid Treatment?
has type 1 AIT-
Discontinuing amiodarone if possible – remember t½ is long
high dose methimazole (ATD)
Beta blockers for symptom control
type 2 AIT
steroids and BB without methimazole
56
DD of hypothyroidism?
primary-
hashimoto, 131 treatment, drugs (thyroiditis), surgery, infiltration (amyloidosis, sarcoidosis)
transient- thyroiditis
secondary-
hypopituitarism
hypothalamic disease
57
hypothyroidism LAB?
high TSH
low T3+4
TPO Ab positive (HASHIMOTO)
58
Treatment of Hypothyroidism?
Levothyroxine (L-T4) (BETTER T0.5 THAN T3)
Full dose replacement ~ 1.6 mcg/kg
Slow replacement in Elderly (>75Y), CAD
Liothyronine (L-T3)
short half life and fluctuating levels
Follow up TSH 6w
59
Subclinical Hypothyroidism treatment?
When TSH is ≥ 10
When symptomatic
Pregnant women should be treated from the first trimester as it may affect pregnancy outcome
Always repeat the test prior to starting therapy!!
60
Toxic nodule?
ברוב המוחלט של המקרים נודולה פעילה לא ממאירה
רוב הנודולות לא ממאירות
mostly Activating mutation of TSH-R
הטיפול – יוד רדיואקטיבי (ולפעמים מתימזול)
61
Thyroid Risk of malignancy?
```
US:
Hypoechogenic
Irregular margins
Microcalcifications
Intranodular vascular pattern (dopler)
Solid consistency
Taller more than wide shape on transverse view
Suspected cervical lymph nodes
```
```
Age < 20 or > 65
Male gender
Family history - MEN2, familial adenomatous polyposis
Vocal cord paralysis, hoarse voice
Fixation to adjacent tissue
```
62
nodule clinical presentation?
Commonly associated with normal FT4 and TSH (non-functioning, non-toxic)
Usually asymptomatic – but :
-Dysphagia
-Pemberton's sign is used to evaluate venous
obstruction in patients with goiters- Dyspnea with arms raised or lying down, facial plethora
- Hoarseness which does not resolve
- Stridor
Asymptomatic nodules require further evaluation for cancer
63
Thyroid Cancer Classification?
Epithelial-derived thyroid cancers:
differentiated tumors:
Papillary - good prognosis (10-yr survival 98%)
Follicular - good prognosis (10-yr survival 92%)
undifferentiated tumors:
Anaplastic - poor prognosis (10-yr survival 13%)
Medullary thyroid cancer (MTC)
Thyroid lymphoma
Metastases from breast, colon, renal, melanoma
64
Diagnosis and Management of Thyroid Nodules?
TSH is normal or elevated a fine needle aspiration (FNA) should be considered based on ultrasonographic characteristics
65
ARC- TIRADS
```
cytological exam!!!!
score determining which nodule to biopsy:
composition
echogenicity
shape
margin
echogenic FOCI
```
66
Bethesda classification of thyroid cytology?
1. nondiagnostic or unsatisfactory 1-5% RR
2. benign 2-4%
3. atypia or follicular lesion of unknown significance 5-15%
4. follicular neoplasm- 15-30%
5. suspicious for malignancy- 60-75%
6. malignant 97-100%
67
evaluation of thyroid nodule management?
1. THS
1. 1 low 🡪 radionuclide scan 🡪 hyperfunctioning 🡪 evaluate and Rx hyperthyroidism
1.2 low 🡪 radionuclide scan 🡪 nodule not functioning
1. normal or high
↓
US and LN assesment 🡪 FNA based on US (bethesda)
🡪Bethesda 1- repeat US, if non diagnostic follow up or surgery
🡪Bethesda 5-6 🡪 surgery
🡪Bethesda 4 🡪 molecular testing 🡪 surgery if indicated
🡪Bethesda 3 🡪repeat US, FNA 🡪 surgery if indicated
🡪Bethesda 2 🡪 follow up
68
Thyroid Cancer Treatment?
Surgery – Lobectomy vs. total thyroidectomy
Lobectomy:
- Tumor <1 cm without extrathyroidal extension and no lymph nodes
- Tumor 1 to 4 cm without extrathyroidal extension and no lymph nodes (more)
thyroidectomy:
- Tumor 1 to 4 cm without extrathyroidal extension and no lymph nodes
- Tumor ≥4 cm, extrathyroidal extension, or metastases, any tumor size and history of childhood head and neck radiation, multifocal papillary microcarcinoma (more than five foci)
Radioactive iodine
ATA low risk – no
ATA intermediate risk – in some patients
ATA high risk – yes
TSH suppression (growth factor for carcinoma, give exogenous T4)
69
Side effects of RAI?
```
Xerostomia (dry mouth)
Xeropthalmia (dry eyes)
Myelosuppression
High cumulative dose (>600 miCi)-
secondary malignancies
```
70
Complications of TSH suppression?
Atrial fibrillation (especially age > 60)
Accelerated bone loss in postmenopausal women
71
THYROID Tumor marker?
Thyroglobulin (Tg)-
reflects residual thyroid tissue
LVLS determined BY:
thyroid hormone replacement
elevation in response to ↑TSH
how?
- Withdrawal of LT4 (TSH > 30) OR
- With use of recombinant TSH
72
Advanced DTC therapy?
Observation (if asymptomatic, slow growing)
External beam radiation (palliative)
Tyrosine kinase inhibitors
Cytotoxic chemotherapy (last resort, in patients who have failed TKI)
73
Burch-Wartofsky Point Scale (BWPS) for Thyrotoxicosis (thyroid storm)?
```
Temperature °F
Central nervous system effects
Gastrointestinal-hepatic dysfunction
tachycardia
congestive heart failure
atrial fibrillation
precipitating event
```
<25 thyroid storm unlikely
25-44 impending storm
<=45 highly suggestive of thyroid storm
74
factors contributing for thyroid storm?
TSH, t4, t3- NOT RELEVANT, SAME LVLS AS HYPERTHYROIDISM
```
TRIGGERS!!
anti thyroids (thionamides) cessation
trauma/ surgery/ infection/ contrast/ delivery
```
75
thyroid storm treatment?
same as in hyperthyroidism buy more agrresive
BB – thcycarida and adrenergic symptoms
anti thyroid –PTU is preferred on methimazole, can be given analy
iodine pulse – block thyroid hormones release
glucocorticoids –
block T4 to T3 transition
adrenal failure+-
bile acid sequestrants- inhibit thyroid hormones reabsorption
76
thyroidal function in non thyroidal illness?
sick 🡪 sicker 🡪 sickest
T4 goes down (absolute lvl higher than T3)
low TBP
T3 goes down before T4
deiodinase ↓ (amiodaron, steroids)
TSH goes down in correlation to T4
steroids, vasopressors, TRH↓ (cytokines storm)
rT3- picks at 'sicker' and stays
low excretion
77
non thyroidal illness (euthyroid sick syndrome)?
T3 isn't checked routinely and might differentiate between NTIS to hyperthyroidism
central hypothyroidism?
check for cortisone lvls of hypophyseal injury inquiry
when NTIS remission 🡪 TSH might be elevated
when:
TSH>20 🡪 suspect "real" hypothyroidism
TSH<0.01 🡪 suspect "real" hyperthyroidism
78
non thyroidal illness treatment?
reevaluate after remission
| thyroid hormones if needed
79
Myxedema coma characteristics?
clinical diagnosis (no score), trigger usually
T4 very low by definition
TSH elevated (can be normal low when central hypothyroidism)
hyponatremia in 50%
hypoglycemia
+- adrenal failure 🡪 hyponatremia, hypoglycemia (?)
immune or central
ECG: QRS widening
pericardial effusion
80
Myxedema coma treatment?
TSH cortisol T4 lvls check before treatment
high suspicion: start treating- correct later if needed
(a scar on neck, previous LABs)
T3 (Levothyroxine)
hydrocortisone for addison's until proven otherwise (Short synacthen test)
palliative:
- ventilation (macroglosia)
- passive warming (direct with fluids 🡪 vasodilation)
- vasopressors
- dextrose fluids (watch for hyponatremia)
- antibiotics if infection suspected
- constant cardiac monitoring
81
Actions of glucocorticoids (cortisone)?
↑ WBC, ↓Eosinophils, anti inflammatory
gluconeogenesis ↑
glucose uptake and utilization ↓
lipolysis ↑
increase protein catabolism ↑
Impaired wound healing (less collagen production, impaired fibroblast function)
Inhibit osteoblasts (osteoporosis),
intestinal and renal calcium absorption↓ 🡪 PTH ↑
Differentiation of organs in the fetus
arousal and cognition
82
Action of mineralocorticoids?
Major regulators of blood pressure and extra-cellular volume
Regulate K+ balance
83
algorithm for evaluation of Cushing syndrome?
1. 24H urinary cortisol X3 UNL- repeat X3 times
2. dexamethasone overnight test ( 1mg dexamethasone at 11pm 🡪 ACTH ↓ 🡪 plasma cortisol >50nmol/l at 8-9am, <50 in normal situation)
3. midnight salivary cortisol >5nmol/l
possitive? (2 of 3)
4. DD- plasma ACTH:
>15 pg/ml- ACTH dependent cushing 90%
cushing disease (ACTH producing pituitary adenoma)
ectopic ACTH syndrome (carcinoid, pheochromo...)
<5 pg/ml- ACTH independent cushing
adrenocortical adenoma/ carcinoma
rare- adrenal hyperplasia, McCune-Albright syndorme
5. ACTH dependent cushing DD evaluation?
-MRI pituitary, sensitivity 50%-60%
-CRH test (CRH IV 🡪 30min ACTH↑ 40% 🡪 45-50min cortisol↑ 20%)
-high dose DEX test (2mg every 6h for 2d 🡪 ACTH↓ 🡪
cortisol ↓ >50%)
CRH test DEX test possitive🡪 cushing sidease 🡪 surgery
CRH test DEX test negative 🡪 ectopic ACTH production 🡪 locate and remove 🡪 if negative than bilateral adrenalectomy
( tumors ectopic ACTH syndrome are completely resistant to feedback inhibition,
pituitary adenomas is only relatively resistant)
5. ACTH independent cushing:
🡪bilateral micro/macronodular adrenal hyperplasia 🡪
bilateral adrenalectomy
🡪 unilateral adrenal hyperplasia 🡪 unilateral adrenalectomy
```
Drugs increasing metabolism of steroid hormones:
Tegretol
Phenitoin
Rifampicin
Lamictal
```
84
Cushing physical exam?
```
blood pressure
easy cruising
abdominal red striae
thin arms and legs
buffalo hump
sweating
gynecomastia
moonface
osteoporosis
supraclavicular fat pas
```
procoagulation: DVT, PE
85
Inferior petrosal sinus sampling (IPSS)?
equivocal results of CRH test and DEX test
Measure cortisol and ACTH simultaneously from:
Right petrosal sinus
Left petrosal sinus
Peripheral vein
Before and after stimulation with CRH (100 ucg).
Central/Peripheral >3 → Pituitary Cushing’s
Central/Peripheral <2 → Ectopic ACTH
86
Pseudo-Cushing’s syndromes?
```
blood pressure
easy cruising
abdominal red striae
thin arms and legs
buffalo hump
sweating
gynecomastia
moonface
osteoporosis
supraclavicular fat pas
```
procoagulation: DVT, PE
87
Pseudo-Cushing’s syndromes?
Some evidence of hypercortisolism.
Alcohol
Depression
Obesity
88
algorithm for management / treatment of Cushing syndrome?
transphenoidal tumor resection
1. biochemical cure 🡪 glucocorticoid replacement if needed (Addison's)
2. persistent hypercortisolism
↓
🡪pasierotide (SS receptor agonist)
🡪glucocorticoid receptor antagonist
🡪steroidogenic inhibitors
🡪pituitary irradiation
↓
repeat 1/2
↓
adrenalectomy (in same results)
↓
irradiation (risk nelson's syndrome- we removed the excess cortisol 🡪 no negative feedback of pituitary ACTH secreting tumor residues🡪 tumor growth)
89
Medical treatment for cushing syndrome?
Bridge to surgery.
High risk for surgery.
Failed surgery.
Prior to adrenalectomy in patients with adrenal cushing- to reduce surgical complications and morbidity.
Adrenal adenoma and carcinoma:
Mitotane- Adrenolytic= =adrenal atrophy and necrosis
metyrapone- CYP11B1 inhibitors
ketoconazole/chemotherapy- CYP11A1+B1inhibitors
for non-resectable or metastatic carcinoma
Ectopic ACTH Syndrome
Chemotherapy, radiotherapy
Drugs ( mitotane, metyrapone, ketoconazloe )
90
Addison's (Adrenal Insufficiency) general characteristics?
Symptoms:
Weakness & fatigue
Anorexia
Gastrointestinal symptoms
Signs:
Weight loss
Hyperpigmentation (primary)-high ACTH activates MC2 receptor
scars- stay darkened permanently
black people- Oral Hyperpigmentation
Hypotension
Salt craving (primary)
Postural hypotension symptoms
91
Addison's Laboratory Findings?
Normocytic normochromic anemia (chronic disease)
Neutropenia and eosinophilia, relative lymphocytosis
Hyponatremia (dilutional SIADH, MC def, 90%)
Hyperkalemia (MC def, 65%)
Hypoglycemia (rare)
Hypercalcemia (rare)
92
algorithm for management of suspected adrenal insufficiency?
1. clinical suspicion
2. screening/ confirmation-
morning cortisol (fast)- very very low is suggestive to adrenal insufficiency and doesn't require cosyntropin test (ACTH stimulation test)
ACTH stimulation test- 250ug cosyntropin IM/IV 🡪 30-60min cortisol < 450-500nmol/l 🡪 NORMAL
CBC, serum sodium, potassium, creatinine, urea, TSH
3. DD- plasma ACTH, plsama Renin, plasma aldosterone
🡪high ACTH, high Renin, low aldosterone
primary adrenal insufficiency==Addison’s Disease
🡪inappropriately normal ACTH, normal Renin, normal aldosterone
secondary adrenal insufficiency (pituitary 🡪 adrenal atrophy 🡪 ACTH resistance)
93
Etiology of Addison’s Disease?
Autoimmune (80%)
Isolated, Autoimmune polyglandular syndrome Type 1&2
```
Infections-TB, AIDS
Infiltration- Amyloidosis, Hemochromatosis
Hemorrhage
Infarction (bilateral – rare)
Bilateral Metastasis, Lymphoma (rare)
Bilateral adrenalectomy
Drugs- ketoconazol, tegretol
Congenital Adrenal Hyperplasia
Familial GC deficiency
```
94
Secondary Hypoadrenalism (↓ACTH)
Iatrogeni- Abrupt withdrawal of Chronic steroid Tx
```
Pituitary-
Tumor (stalk effect)
Radiation, Surgery, Infarct
Hemorrhage
Sheehan syndrome – low BP during birth +/- hemorrhage
```
95
Autoimmune Polyglandular Syndrome Type 1(APECED or Whitaker's syndrome?
```
[AR]
includes AD ( Addison’s disease),
HP (hypoparathyroidism) and
chronic mucocutaneus candidiasis
Vitiligo and alopecia
Pernicious anemia, Gonadal failure
```
96
Autoimmune Polyglandular Syndrome Type 2 Schmidt's syndrome?
```
POLYGENIC- HLA-DQ2, HLA-DQ8 and HLA-DR4
DM type 1
Vitiligo
Graves or Hashimoto
Addison (atrophy of the cortex while the medulla is intact)
Pernicious anemia
```
97
Chronic treatment of Addison’s disease?
Hydrocortisone 15-20 mg in the morning & 5-10 mg at 4-6 PM
or
prednisone 5-7.5 mg orally once a day.
+Fludrocortisone 0.05-2 mg/day (primary).
98
Acute Syndrome (Addisonian Crisis)?
```
Withdrawal:
Acute stress
Infection
trauma
Surgery
Dehydration
```
Acute syndrome:
Hemorrhage
Infarct
Meningococcemia (Waterhouse-Friderichsen syndrome)
Rare in secondary adrenal insufficiency
diagnosis should always be considered in any patient with unexplained shock
99
Acute Syndrome (Addisonian Crisis) Treatment?
Hydrocortisone 100 mg IV, every 6-8 hours for 24 hr not PO !!!
Correct volume depletion, dehydration, hypotension and hypoglycemia with IV saline and glucose
As soon as the patient is eating and drinking and off IV fluids add fludrocortisone.
100
Congenital adrenal hyperplasia, due to 21 hydroxylase deficiency?
Salt wasting – absolute deficiency of the hormone (SEEN AT BIRTH)
Simple virilizing form (normal cortisol and aldosterone)
Non-classic – late onset CAH
HIGH ANDROGENS due to 'spill' effect- (no production of aldosterone, cortisol) 🡪 hirsutism
traetment:
steroids! 🡪 ACTH ↓ 🡪
101
Adrenal incindentaloma definition?
any adrenal focal lesion (>1cm) found unanticipated
| during imaging examinations (US, CT, MRI etc.) performed for unrelated causes
102
Adrenal incindentaloma DD?
80-85% no clinical imortance
adrenocortical adenoma
inactive
10-15% functional tumors
cortisol producing
aldosterone producing
pheochromocytoma
malignancy 2-5%
103
Adrenal incindentaloma Hormone secretion evaluation?
```
clinical assessment
plasma & urinary metanephrines
Aldosterone/Renin ratio
sex hormones and steroid precursors-
night salivary cortisone, 24h cortisol collection, 1mg DEX test
```
104
Adrenal incindentaloma imaging?
CT- always no contrast! (elevates body specific gravity)
bening - low specific gravity < 10HU
adrenal myelolipoma (attenuation as fat) >> lipid rich adenoma (<10HU) >> lipid poor adenoma (>10HU) 🡪 do washout CT/MRI 🡪 AbsoluteWO>60%, RWO>40% 🡪 benign
105
Adrenal incindentaloma unilateral adrenalectomy?
```
over 4cm
every functional edocrine tumor
growing tumor
>10HU
non conclusive MRI results
```
106
Primary Aldosteronism (Conn syndrome) clinical features?
40-65y, 50% of excess mineralocorticoid (other is 50% bilat adrenal hyperplasia)
15% of hypertensive population
30% moderate to severe hypokalemia---70% normokalemia!!!)
107
Familial Hyperaldosteronism (FH) Type I?
fusion of the promoter region of CYP11B1 with the coding regions of the aldosterone synthase gene (CYP11B2
Aldosterone regulated by ACTH and independent of renin
Early onset HTN before age of 21
cerebral aneurysms and intracranial bleeding
Mild hypokalemia
Metabolic alkalosis
Low plasma renin levels
Tx: low dose dexametasone
108
Syndrome of Apparent Mineralocorticoid Excess (AME?
AR inactivating mutation in the HSD11B2 gene.
inactivates 11bHSD2 which converts cortisol to cortisone 🡪 cortisol🡪 can mimic hyperaldosteronism by activation of MR instead of GR due to high [lvls] (Concentration dependent)
no aldosterone or renin higher lvls!!!
Tx:
MR antagonists
Epithelial Na channel blockers
Thiazides with potassium supplementation
109
Adrenal venous sampling?
Lateralization of aldosterone excess
| Ratio left/right = 15.6/2.4 = 6.5
110
enhanced CT adrenals further investigation?
Adrenal venous sampling (check which adrenal is hyperactive)
Lateralization of aldosterone excess
Ratio left/right = 15.6/2.4 = 6.5
if bilat MR antagonists
if unilat laparascopic ADX or MR antagonists
111
Pheochromocytomas and paragangliomas (PPGL)?
Catecholamine-producing tumors derived from the sympathetic or parasympathetic nervous system.
Mean age ~40 years
“Rule of tens”:
~10% are bilateral
~10% are extra-adrenal
~10% are malignant
headache
high blood pressure
sweating
rapid heartbeat
112
PPGL biochemical diagnosis?
24h urinary test
catecholamines
fractioned metanepherine
total metanepherine
Rare tumor 🡪 Low pre-test probability
false-positive results >> true-positive results
tricyclic antidepressants, phenoxybenzamine monoamine oxidase inhibitors, levodopa ) can cause false-positive
surgery!!!
113
PPGL PRE-OPERATIVE MANAGEMENT?
α-adrenergic blockers !!!
Calcium channel blockers (add on)
Beta blockers can then be added if patient tachycardic (not as first line tx!)
Volume-constriction due to sustained prolonged HTN once BP controlled severe orthostatic hypotension liberal salt intake and hydration.
114
PPGL hereditary syndromes?
60% sporadic tumors
40% germline mutation in genes involved in tumorigenesis
Cluster 1 genes:
VHL, Von Hippel Lindau sy.
SDHx, familial paraganglioma sy.
Cluster 2 genes:
RET, MEN2 (A&B)
NF1, neurofibromatosis type
115
PPGL imaging?
PETCT for SS
116
criteria for diagnosis of diabetes (1+2, no difference)?
1. A1C ≥6.5% X2
OR
2. FPG ≥126 mg/dL (7 mmol/L) X2
Fasting is defined as no caloric intake for at least 8 hours.*
OR
3. 2-hour plasma glucose ≥200 mg/dL (11.1 mmol/L) during an OGTT X2
75 g anhydrous glucose dissolved in water
OR
4. In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis:
a random plasma glucose ≥200 mg/dL (11.1 mmol/L)
no need for X2
117
Auto-antibodies in Type 1 Diabetes?
Islet cell autoantibodies (ICAs)
(against beta cells):
1. Insulin
(not good due to development of antibodies due to exogenous administration of insulin)
2. glutamic acid decarboxylase- More in elderly
3. Insulinoma associated antigens 2 (alpha and beta)- more in children
4. ZnT8 (zinc transporters)
absolute count correlates with prognosis
118
Type 1 diabetes presentation?
Classic signs:
Polyuria, Polydipsia, Polyphagia
Weight loss (2nd most common presentation, elderly and very young patients)
Diabetic ketoacidosis
Nausea, Vomiting, Abdominal pain, Dehydration,
Coma
Death
Neonatal diabetes is commonly caused by one of several genetic defects in pancreatic development or beta cell function!
HLA-DR3/4 strong correlation
119
Diabetic Ketoacidosis etiology?
Presentation of type 1 diabetes
Infection, trauma (stress)
Missed insulin injection
SGLT2i- euglycemic (can be less than 200, rarely 150) DKA
120
Pathophysiology of DKA?
Liver:
Glucose production↑
Ketone bodies formation↑
pancreas:
Insulin secretion↓
Glucagon secretion↑
FAT:
FFA release ↑
low glucose in FAT and MUSCLE
↓
Ketone bodies↑
Blood glucose↑
121
DKA Clinical Presentation?
-Anorexia, polydipsia and polyuria
-Dehydration:
Sings of dehydration ( HR, postural hypotension...)
- Nausea, Vomiting, Abdominal pain & tenderness
- Kussmaul breathing with acetone “fruity ” odor
- Normal or low temperature, unless infection
- Stupor/coma
122
Diagnostic Criteria for DKA?
- Hyperglycemia (usually >250 mg/dl)
- Ketosis (ketonemia or ketonuria +++)
- Acidosis (pH<7.3, HCO3<15mEq/L)
123
Therapy of Diabetic Ketoacidosis?
-Monitoring (ICU)
-Fluids:
Normal saline 1 L/h
If pH <7.0 or bicarbonate <5 give bicarbonate (100 mmol/l)
Glucose < 250 mg/dl, switch to 1/2 N/S with 5% glucose
-Insulin:
“loading” ~ 0.3 U/Kg (IV, periphery is 'closed')
Then ~ 0.15 U/Kg (IV drip)
Adjustment of the dose according to astrup and blood glucose
-Potassium (hyperkalemia):
Loss may be 300-500 meq/l
Avoid hypokalemia !!!
Add KCl to the fluids (10-30 mmeq/L)
124
היפוגליקמיה- טיפול?
20%-10% גלוקוז דרך הוריד 60-120 מל’ בולוס ראשון, אם אין שיפור במצב יש לחזור על הבולוס עד להתעוררות
בהמשך עירוי של 5-10% גלוקוז. יש לשמור את רמת הגלוקוז בערכים של 100-150 מג’/דל’
תמיסות מרוכזות של גלוקוז (10% ויותר) יש לתת לוריד פריפרי גדול
אם אין אפשרות לתת גלוקוז דרך הוריד יש לתת גלוקגון 1.0 מג’/דל’ בזריקה לתוך השריר
125
Classifications of Insulin?
Intermediate acting- NPH
Long-acting- Glargine (lantus, BasaGlar), Detemir (Levemir)
Ultra-long acting- Degludec, Glargine 300
Short-acting- Regular HI
Rapid-acting
Lispro=Humalog
Aspart=Novorapid
Glulisine=Apidera
Ultra-short:
FIA (LISPRO)
126
The Basal/Bolus Insulin Concept- The treatment for Type 1 Diabetes?
Basal Insulin:
Suppresses glucose production between meals and overnight
~50% of daily needs
Bolus Insulin (Mealtime or Prandial):
Limits hyperglycemia after meals
10% to 20% of total daily insulin requirement at each meal
(Glargine + Short Acting Analogs)
127
prediabetes diagnosis criteria?
FPG >=110 mg/dL (>=6.1 mmol/L) and <126 mg/dL (<7.0 mmol/L)
| IGT is defined by 2-hour PG measurements >=140 mg/dL (>=7.8 mmol/L) and <200 mg/dL (<11.1 mmol/L).
128
anti hyperglycemic therapy: glycemic targets?
HbA1c< 7.0%
Individualization is key:
tight target: 6-6.5- younger
loose target: 7.5-8- elder, comorbidities, hypoglycemia prone
avoid hypoglycemia!
129
Pharmacologic Targets of Current Drugs Used in the Treatment of T2DM?
GLP-1 analogues (Liraglutide)
Improve pancreatic islet glucose sensing, slow gastric emptying, improve satiety
STOP DDP4 IF GIVEN
```
Biguanides (metformin):
Hepatic glucose production ↓
Intestinal glucose absorption ↓
Insulin action ↑
No hypoglycemia
Lactic acidosis (rare)
Vitamin B12 deficiency
Contraindications: reduced kidney function
30
```
130
Diabetes type 2 risk factors?
```
IGT (is a cardiovascular risk too, abdominal fat correlates strongly with it)
A1C
LDL
HTN
albuminuria
smoking
```
131
Diabetes type 2 risk factors treatment?
aggressive approach (prevent metabolic memory)
```
life style change
consider metformin (family Hx, non conclusive values)
treat CV risk!
```
DKD / albuminuria- require GLP1 a/o SGLT2i (benefit ASCVD, CHF (SGLT2 Only), progression of DKD)
132
Prevention and treatment of Diabetic Nephropathy?
Glycemic control
BP control
Protein restriction
Smoking secession
Treatment of dyslipidemia
RAAS blocker (ACEI/ARB/Aldo/Renin In)
133
Hypocalcemia sings?
Trousseau sign- facial nerve tapping induced spasm
Chvostek’s sign- hypoxia induced arm flexors contraction (extensors too but weaker 🡪 we see flexetion)
pathophysiology-
NA channels open at lower membrane voltage in presence of Ca+2 🡪 Na basal current is higher 🡪 AP threshold is lower
134
Hypocalcemia on ECG?
long QT -> polymorphic VT
135
Treatment of hypocalcemia?
symptomatic or Ca+2 <1.9mmol/L
control immediately 🡪 IV Ca-glucoronate
control over days/weeks: VIT-D
if PTH deficient 🡪 VIT-D analogue (active)
if PTH intact 🡪 Cholecalciferol or ergocalciferol
136
hypocalcemia lab interpertation?
calcium is 50% bound to albumin 50% free
thus
for every 10gr/l reduction in albumin when lower than 40 🡪 add 0.8mg% (0.2mmol/l) to calcium lvl
can order ionized Ca+2 (free calcium)
137
hypoparathyroidism etiology?
thyroid resection 66%
33%:
autoimmune-
Autoimmune polyendocrinopathy candidiasis with ectodermal dystrophy= APECED
genetic (<10%)
hemochromatosis
Wilson's
metastases
138
hypoparathyroidism: genetic?
-DiGeorge syndrome Type 1
no 22q11.2 chromosome 🡪 no T box protein 1 🡪 no thymus and parathyroid
```
-Autoimmune polyendocrine syndrome type 1 (AIRE = autoimmune regulator gene)
diagnosis (2 of 3)-
Mucocutaneous candidadiasis
hypopara
adrenal insufficiency
```
-autosomal dominant hypocalcemia
Gain of function mutations of the CaSR (type 1) or G11alpha (type 2 ) proteins
139
Hypocalcemia and hypoparathyroidism treatment?
symptomatic or Ca+2 <1.9mmol/L:
control immediately 🡪 IV 10% Ca-glucoronate
10-20 ml over a period of 10-15 minutes
(glucoronate because than we can give in peripheral vein)
control over days/weeks:
calcium carbonate =40% elemental calcium (p.o needs low pH, thus in PPI use or elderly: calcium citrate)
or VIT-D
if PTH deficient 🡪 VIT-D analogue (active)
if PTH intact 🡪 Cholecalciferol or ergocalciferol
adverse of VIT-D (active):
hypercalciuria, renal calcifications, hyperphosphatemia
↓
PTH 1-84
140
Hypercalcemia symptoms?
Stones, Bones, Abdominal groans,
| Thrones, and Psychiatric overtones
141
hypercalcemia DD?
90%:
- 1° hyperparathyroidism 🡪 most common
- malignancy-related (PTHrP)
10%:
- 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
Familial Hypocalciuric Hypercalcemia (FHH)
```
142
Etiology and Pathophysiology of Primary Hyperparathyroidism?
Etiology
Solitary parathyroid adenomas (85%)
Hyperplasia of 2 or more glands (15%)
-in MEN 1, 2A syndromes or familial isolated hyperparathyroidism)
Parathyroid carcinoma (1-2%)
Pathophysiology
- Ca+2 is reset at a higher threshold due to increased mass of pathological parathyroid tissue
- Reduction (CaSR) on the surface of parathyroid cells m
143
Familial Hypocalciuric Hypercalcemia (FHH)?
[AD] inactivating mutation of CaSR
located on juxtaglomerular cells too, thus no Ca+2 excretion 🡪 hypercalcemia, hypocalciuria
no treatment needed
144
Treatment of Primary Hyperparathyroidism?
Surgery is the only definitive treatment:
Remove adenoma in the case of solitary adenoma
4-gland hyperplasia, 3 ½ glands are resected
surgery contraindicated?
cinacalcet (Mimpara) 🡪 calcimimetic CaSR agonist 🡪 PTH secretion↓
145
Indications for Surgery in Primary Hyperparathyroidism?
Age <50 years
Symptoms of hypercalcemia
Serum calcium >1mg/dL above upper limit of normal
Skeletal manifestations: Reduced bone mineral density by DXA to a T-score 400 mg/24 hr)
146
Primary Hyperparathyroidism
required only if surgery is planned
Neck ultrasound
```
Nuclear scanning (Sestamibi scan)
Scan can include the mediastinum; useful in ruling out ectopic adenoma or in cases of previously failed surgical exploration
```
147
Hypercalcemia of Granulomatous Diseases?
Caused by unregulated conversion of 25-OH vitamin D to active form of vitamin D by macrophages from the granuloma
can become hypercalcemic after sunlight exposure or oral vitamin D intake
148
Treatment of hypercalcemia?
+ renal failure 🡪 dialysis
hypercalcemia 🡪 dehydration🡪
aggressive IV rehydration 🡪low loop diuretic if evidence of volume overload with IV fluids
osteoclasts inhibition 🡪
(1st) bisphosphonate +- calcitonin
lymphoma / leukemia 🡪 steroids
refractory 🡪 gallium or denosumab
149
FRAX?
```
a clinical tool to assess fracture risk:
age
sex
BMI
prior fragility fracture
smoking
glucocorticoids
rheumatoid arthritis
alcohol- 3 units daily
```
150
treatment for osteoporosis?
פעילות גופנית נושאת משקל : הליכה 30 דקות 3 פעמים בשבוע
הפסקת עישון
שתיית אלכוהול בכמות מתונה
סידן : דיאטה +תוסף סה"כ 1000-1200 מ"ג ליום
ויטמין די: 800-2000 יחידות ליום
טיפול בגורמים משניים ( תרופות, תת משקל)
```
SERM= selective estrogen.r modulator
RALOXIFENE = EVISTA
Reduces vertebral fracture risk
Reduces Breast cancer risk
advers:
Venous thrombo-embolism
Hot flushes
Increases risk of hemorrhagic stroke
```
bisphosphonates- analogues of natural pyropho.
aldronate p.o (once a weak)
zoledronic acid IV (once every month)
denusumab (RANK-L inhibitor)
advers:
Osteonecrosis of the Jaw (both above) very rare
Atypical Femoral fractures very rare
