gp educational event 21st november 2019pathology.imperial.nhs.uk/uploads/images/2020/gp educational...
TRANSCRIPT
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GP Educational Event 21st November 2019
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Welcome
Panos Pantelidis
Divisional Manager, Infection & Immunity
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The Hillingdon Hospitals
Imperial College Healthcare NHS Trust
Chelsea and Westminster NHS Foundation Trust
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The NWLP Model
4
Hub &
spoke
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Transformation update
The formal transformation programme governance has 6 programme work streams:
1. Pathology Services Transition
2. IT
3. Workforce
4. Logistics
5. Estates
6. Communications
• Intensive operational planning has taken place and is still underway to develop detailed plans as service transfers across our network to achieve the end state for the hub and spoke model.
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6
Transformation update
Changes for 2018 • successfully changed blood collection
devices for The Hillingdon Hospitals trust and GP’s (Hillingdon and Ealing)
• installation of a new Alifax an
automated platform for ESR (erythrocyte sedimentation rate)
• move of Microbiology testing from Hillingdon Hospital to Charing Cross Hospital
The progress made to date that impacted the GP practices:
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7
Transformation update
Changes for 2019 • completion of phase one of
the new Cellular Pathology laboratory on the 3rd floor at Charing Cross hospital.
• opening of the interim Clinical biochemistry laboratory (ground floor) at Charing
Cross.
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8
Transformation update
Changes for 2019 • 4 November - pathology transport
provider changed for our Ealing GP practices from the Hillingdon hospital trust to DHL to align with our other sites.
• New DHL contract has introduced
temperature monitoring of the samples collected from GP practices
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9
Transformation update
Changes for 2020 • A creation of a multi-disciplinary laboratory (MDAL) will be ready next year
on 1st floor of Charing Cross hospital • Redesign of central specimen reception at Charing Cross hospital which will
include the introduction paperless requests.
• The Hillingdon Hospitals will have both the Laboratory Information Management System and the equipment changes during 2020
• The CCG as our main channel to communication these changes to GPs – via
their newsletters or bulletins and emails.
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10
Influenza Season NWLP Update
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NWLP GP Educational Event Agenda 1.50pm - 2.30pm Matthew Whitlock 2.30pm – 3.15pm Dr Julia Kenkre 3.15pm - 3.30pm Coffee Break 3.30pm – 4.15pm Dr Frances Davies 4.30pm Close
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GP Educational Event 21st November 2019
Female Infertility Matthew Whitlock
Principal Clinical Scientist
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Learning Objectives
• Causes of female infertility
• Ovulatory disorders
• Biochemical investigations and interpretation
• Analytical methods for hormone analysis
• Referral pathways to Endocrinology/Gynaecology
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Infertility
• Clinical assessment and investigation should be offered: – Women of reproductive age (along with partner).
– Not conceived after 1 year of unprotected sexual intercourse
– No known cause of infertility,
• Earlier referral for specialist consultation: – Woman is > 36 yr
– Known clinical cause of infertility
– History of predisposing factors
NICE Clinical guideline [CG156] Fertility problems: assessment and treatment
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Causes of Infertility
• The main causes of infertility in the UK: – ovulatory disorders (25%)
– tubal damage (20%)
– factors in the male causing infertility (30%)
– uterine or peritoneal disorders (10%).
• Unexplained infertility (25%)
• Disorders found in both man and woman (40%)
Fertility: assessment and treatment for people with fertility problems (2013) RCOG
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Ovulatory disorders - confirming ovulation
• Triggered by the LH surge – luteinisation of the mature follicle
– release of the oocyte.
Mid-luteal progesterone (nmol/L)
Inadequate Adequate Equivocal
<18 >30 18-30
LH/FSH (Day1-5) Oestradiol
TFT Prolactin
Repeat Investigate other causes
(not ovulatory)
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Hypothalamic-pituitary-gonadal axis
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WHO Classification Ovulation Disorders
Term Definition
Group I Hypogonadotropic hypogonadal anovulation Hypothalamic Pituitary Failure
Group II Normogonadotropic normoestrogenic anovulation Hypothalamic Pituitary Dysfunction
Group III Hypergonadotropic hypoestrogenic anovulation Ovarian Failure
HyperPRL Hyperprolactinemic anovulation Raised prolactin
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WHO Group I: Hypogonadotrophic hypogonadal anovulation
• 10% of ovulation disorders
• Causes: – Functional hypothalamic amenorrhea
– Hypogonadotrophic hypogonadism
• Clinical features – Amenorrhea (1°/2°)
• Diagnosis – History
– Pituitary profile
– Pituitary imaging
↓
↓
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• 85% of ovulation disorders
• Causes: – Polycystic ovary syndrome
– Hyperprolactinaemic anovulation
WHO Group II: Normogonadotrophic normogonadal anovulation
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Polycystic Ovary Syndrome
• Heterogeneous endocrine disorder – ↑ GnRH pulse frequency
– ↑ LH:FSH
– ↑ ovarian androgen production
• Clinical features – Hyperandrogenism
– Infertility
– Obesity
– Depression and anxiety
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Polycystic Ovary Syndrome
• Diagnosis – Rotterdam criteria – At least two of:
• Hyperandrogenism
• Oligo/amenorrhea
• PCO – >12 or more follicles in each ovary
– +/or increased ovarian volume (>10ml)
• Investigations – LH/FSH/E2
– Testosterone/SHBG (FAI)
– Prolactin
– TFT
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Hyperprolactinaemic anovulation
• Causes – Physiological
• Pregnancy
• Stress
– Pathological • Hypothalamic/pituitary disease (prolactinoma)
• Hypothyroidism (enhanced TRH synthesis)
– Drug Induced
– Macroprolactin
• Clinical features – Galactorrhoea
– Decreased libido
– Infertility
– Oligo/amenorrhea
↓
↓
PRL
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WHO Group III: Hypergonadotrophic hypoestrogenic anovulation
• 4-5% of ovulation disorders
• Causes – Premature ovarian insufficiency
– Gonadal dygenesis
• Clinical features – Oligo/amenorrhea
– Symptoms oestrogen deficiency
• Diagnosis – <40 years and FSH > 40 U/L – “Results suggestive of premature ovarian failure. Diagnosis
probable if 2 FSH > 40 U/L a minimum of one month apart and persistent amenorrhea. Suggest repeat at appropriate time interval.”
↑
↓
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WHO Classification Ovulation Disorders
Term Definition Results
Group I Hypogonadotropic hypogonadal anovulation Hypothalamic Pituitary Failure
LH/FSH = ↓/N E2 = ↓/N PRL = N
Group II Normogonadotropic normoestrogenic anovulation Hypothalamic pituitary dysfunction
LH/FSH = ↑/N E2 = N
Group III Hypergonadotropic hypoestrogenic anovulation Ovarian Failure
LH/FSH = ↑ E2 = ↓
HyperPRL Hyperprolactinemic anovulation Raised prolactin
LH/FSH = ↓/N PRL = ↑
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• 25 yr old female
• Reported diagnosis of PCOS abroad
• COC since 16 yrs for hirsutism – amenorrhea 4m during last spell off COC
• Normal pelvic USS
• ‘Monitoring off pill due to patient anxiety’
• Oestradiol 146 pmol/L
• LH 5.9 U/L
• FSH 3.7 U/L
‘?PCOS’
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What other investigations would you request?
a) TSH
b) Cortisol
c) Testosterone
d) Prolactin
e) GH
‘?PCOS’
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• Oestradiol 146 pmol/L
• LH 5.9 U/L
• FSH 3.7 U/L
• Prolactin 748 mIU/L
‘?PCOS’
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Macroprolactin
Re-measure PRL after PEG removal of macroPRL
Macroprolactin
Big-prolactin
Monomeric Prolactin
Total Serum
Prolactin
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e.g. The hyperprolactinaemia is due to raised monomeric prolactin and the cause should be sought. Exclude causes of hyperprolactinaemia such as pregnancy and drugs which alter dopamine metabolism (e.g. many antidepressants) then consider referral for further investigation of a prolactinoma.
Male >350 mIU/L
Female >600 mIU/L
Macroprolactin analysis NWLP
= Macroprolactin screen
PRL recovery % after PEG
Positive
Negative
Equivocal
<40%
>50%
40-50%
e.g. Approximately 45% of the prolactin immunoreactivity is due to the presence of macroprolactin, Monomeric prolactin is therefore elevated. Exclude causes of hyperprolactinaemia such as pregnancy, stress or drugs which alter dopamine metabolism (eg many antidepressants) then consider referral for further investigation of a prolactinoma.
e.g. Approximately 30% of the prolactin immunoreactivity in this sample is due to the presence of macroprolactin. Macroprolactin is not biologically active but cross reacts in the immunoassay used to determine serum prolactin concentration. Its presence in this case makes a prolactinoma unlikely.
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• Oestradiol 146 pmol/L
• LH 5.9 U/L
• FSH 3.7 U/L
• Prolactin 748 mIU/L
• Macroprolactin NEGATIVE
‘?PCOS’
The hyperprolactinaemia is due to raised monomeric prolactin and the cause should be sought. Exclude causes of hyperprolactinaemia such as pregnancy and drugs which alter dopamine metabolism (e.g. many antidepressants) then consider referral for further investigation of a prolactinoma.
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• Oestradiol 146 pmol/L
• LH 5.9 U/L
• FSH 3.7 U/L
• Prolactin 748 mIU/L
• Macroprolactin NEGATIVE
• SHBG 85 nmol/L
• Testosterone Pending confirmatory result
‘?PCOS’
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Immunoassay
Testosterone analysis NWLP
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Testosterone analysis NWLP
“androgens should preferably be measured using tandem mass spectrometry”
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Immunoassay
Testosterone analysis NWLP
Solid Phase Extraction +
LC-MS/MS
Female Testosterone > 2.0 nmol/L
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Testosterone analysis NWLP
Extracted Testosterone 4.1 nmol/L Androstenedione 25.4 nmol/L 17-hydroxyprogesterone 234.3 nmol/L
T
A4
17OHP
Note elevated 17-Hydroxyprogesterone (17-OHP) on LC-MS/MS trace. If you wish to add this test on to this request, please contact the Endocrine Duty Biochemist on 020 331 35910
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• Oestradiol 146 pmol/L
• LH 5.9 U/L
• FSH 3.7 U/L
• Prolactin 748 mIU/L
• Macroprolactin NEGATIVE
• SHBG 85 nmol/L
• Testosterone Pending confirmatory result
• Extracted Testosterone 4.1 nmol/L
• FAI 5.0
• Androstenedione 25.4 nmol/L
• 17-hydroxyprogesterone 234.3 nmol/L
‘?PCOS’
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a) PCOS
b) Androgen secreting tumour
c) Non-classical Congenital Adrenal Hyperplasia
d) Prolactinoma
‘?PCOS’
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NCCAH
• Referred to Endocrinology
• Diagnosis of NCCAH confirmed
• Started on treatment – 3mg prednisolone
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Polycystic Ovary Syndrome
Polycystic Ovary syndrome (2005) N Engl J Med
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Referral
Adapted from Amenorheoa - Clinical Knowledge Summary (2018) NICE
Primary Care
Amenorrheoa
Gynaecology Endocrinology
• PCOS
• Pregnancy
• Hypothyroidism
• Menopause
• Persistent ↑ FSH (<40yr)
• Hx uterine/cervical surgery
• Pelvic infection
• Infertility
• Hyperprolactinaemia
• >1000 mIU/L
• 500-1000 mIU/L (x2)
• LH/FSH ↓
• ↑Testosterone (not PCOS)
• Androgen-secreting tumour
• NCCAH
• Cushing’s syndrome
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Resources
• Contacts: – Clinical Biochemistry
• Endocrine Duty Biochemist 020 331 35910 (Mon-Fri: 09.00 – 17.30)
• Duty Biochemist 020 331 30348 (Mon-Fri: 09.00 – 17.30)
• http://pathology.imperial.nhs.uk/
– Clinical Endocrinology
• Hammersmith 020 331 33380
• Charing Cross 020 331 11065
• St Marys 020 331 23793
Any questions, feedback or comments?
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GP Educational Event 21st November 2019
Parathyroid Hormone Dr Julia Kenkre, Metabolic Medicine Spr and Clinical Research Fellow
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Points of Discussion
Why measure PTH? What does PTH do? Understand what regulates PTH and the causes secondary hyperparathyroidism Identify primary hyperparathyroidism and understand how it is investigated and treated
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Calcium and phosphate homeostasis
Calcium
Phosphate
2+
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Calcium and phosphate homeostasis
Calcium
Phosphate
Vitamin D
PTH
FGF23
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Calcium and phosphate homeostasis
PTH
Vitamin D
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Parathyroid physiology
Ca2+/CaSR : Inhibits PTH transcription, PTH release and is anti-proliferative
Ca2+
PTH
PO43-
Mg2+
PKC
CaSR
Gi
Gq11
PLC
Ca2+
ERK
MAPK
FGF23
Klotho FGFR1
1,25(OH)2D3
Slide courtesy of Duncan Bassett
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Copyrights apply
Under normal circumstances the CaSR is exquisitely
sensitive to changes in calcium
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Parathyroid physiology
Ca2+/CaSR : Inhibits PTH transcription, PTH release and is anti-proliferative
1,25(OH)2D3/VDR: Inhibits PTH transcription, increases CaSR and anti-proliferative
FGF23/FGFR1/Klotho: Inhibits PTH expression and release and increases Klotho
Mg2+ depletion: Inhibits PTH release
Hyperphosphataemia: Stimulates PTH release and parathyroid hyperplasia
Ca2+
PTH
PO43-
Mg2+
PKC
CaSR
Gi
Gq11
PLC
Ca2+
ERK
MAPK
FGF23
Klotho FGFR1
1,25(OH)2D3
Slide courtesy of Duncan Bassett
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Why measure?
Calcium
Phosphate
Renal disease (Do not routinely measure calcium, Phosphate, parathyroid
hormone (PTH) and vitamin D levels in people with a GFR of 30 ml/min/1.73 m2 or more (GFR category G1, G2 or G3).
Post bariatric surgery
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Case 1
• 50 year old female cleaner
• Referred after routine blood tests showed
persistently raised calcium ~2.70 mmol/L
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Further history
• Relatively asymptomatic
• PMH: Lupus, interstitial lung disease (MTX), congenital hearing
loss, PFO – dilated RV and atrium
• DH: Pred 10mg, Hydroxychloroquine 100mg OD, OTC:
magnesium, omega oils and Vitamin C
• Ex smoker (10 year), no ETOH
• No FH
• O/E – mildly cushoingoid, nil else
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Blood tests
• On referral:
– Adjusted Ca 2.72 (2.15 – 2.60 mmol/L)
– Phosphate 0.98 (0.8 – 1.5 mmol/L)
– Mg 0.61 (0.7-1.0 mmol/L)
– Vit D 55.5 (70 -150 nmol/L)
• Normal thyroid function
• Normal renal function
• PTH 5.3 (1.1 – 6.8 pmol/L)
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Mentimeter
Most likely diagnosis?
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Blood tests
• On referral:
– Adjusted Ca 2.72 mmol/L (2.15 – 2.60 mmol/L)
– Phosphate 0.98 mmol/L (0.8 – 1.5 mmol/L)
– Mg 0.61 mmol/L (0.7-1.0 mmol/L)
– Vit D 55.5 (µmol/L)
• PTH 5.3 (1.1 – 6.8 pmol/L)
Inappropriately normal PTH
Differential is FHH
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Primary hyperparathyroidism
80% Solitary parathyroid adenoma 10-15% 4 gland hyperplasia (familial/sporadic) 2-5% Multiple adenomas (familial/sporadic) <0.5% Carcinoma (familial/sporadic)
Adenomas (loss of sensitivity to Ca2+) Hyperplasia No change in set point Increase in parathyroid cell number
“Impaired negative regulation of PTH secretion resulting in increased PTH, hypercalcaemia and hypercalciuria”
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Familial hypocalciuric hypercalcaemia (FHH)
• Prevalence: Unknown in general population
• Autosomal dominant (100% penetrance by 30 years of age)
• Genes – FHH type 1(~65%) – inactivating
mutations of CASR – FHH2 GNA11 (>10% CASR neg and
AP2S1 neg) – FHH3 AP2S1 (>20% CASR neg)
• (% are gene negative)
Fadil M Hannan et al. J Mol Endocrinol 2016;57:R127-R142
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Further history
• Relatively asymptomatic
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Usually associated with Ca2+ >3.0mmol/l Hypercalciuria (40%) Polyuria and polydipsia Overt skeletal disease (1%) Bone pain, osteitis fibrosa cystica Renal (17%) Nephrolithiasis Neuropsychological Depression, neuromuscular weakness
(Silverberg SJ 2006 Nat Clin Pract Endo Metab 2:494-501)
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Ca2+ is only mildly elevated <2.85mmol/l
Skeletal Reduced cortical bone thickness but increased diameter Reduced BMD; lumbar spine 5%, hip 10%, radius 25%
Renal Hypercalciuria and nephrocalcinosis
Neuropsychological Depression, fatigue, weakness, exhaustion, intellectual weariness
Gastrointestinal Constipation, nausea and dyspepsia
In this case:
(Bilezikian JP 2004 NEJM 350:1746-1751)
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Historic investigations Previous Ca2+ measurements
Biochemical diagnosis Ca2+ elevated in almost all cases PO4
3- reduced in 30% ALP may be elevated PTH elevated or inappropriately normal 25(OH)D3 independent risk factor for fragility # in 10HPT Urinary Ca2+ elevated in 40% Creatinine GFR
Exclusion of FHH is essential Ratio of calcium/creatinine clearance = CaU x CrS / CrU x CaS >0.01
Assessment of end organ damage DXA bone densitometry (lumbar spine, hip and distal radius) Renal ultrasound (nephrocalcinosis and nephrolithiasis)
Investigation and diagnosis of 10HPT
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Our case
• Ca:creat 0.0141
• DEXA no osteoporosis
• Renal US no nephrocalcinosis
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Localisation Tc99 MIBI with SPECT
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Outcome
• Parathyroidectomy
• Histology left hypercellular adenoma
• Biochemical cure
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High PTH Hyperparathyroidism,
FHH
Low PTH Malignancy, non-PTH
mediated
Normal PTH (mid-upper)
Hyperparathyroidism, FHH
Summary - hypercalcaemia
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NICE guidance – primary hyperparathyroidism
Hyperparathyroidism (primary): diagnosis, assessment and initial management(2019) NICE guideline NG132 68
Measure adjusted Ca:
Sx
Osteoporosis
Renal stone
Incidental finding
Chronic non-differentiated sx
REPEAT IF:
•2.6 mmol/litre or above or
•2.5 mmol/litre or above and features of primary hyperparathyroidism are
present.
Parathyroid hormone measurement
• 2.6 mmol/litre or above on at least 2 separate occasions or
• 2.5 mmol/litre or above on at least 2 separate occasions and primary hyperparathyroidism is suspected.
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What about patients who don’t have surgery?
• Watch and wait? When to re-refer • Symptoms of hypercalcaemia develop.
• The adjusted serum calcium concentration increases to 0.25 mmol/L or more above the normal range. Adjusted serum calcium level of 2.85 mmol/L or above.
• The eGFR is less than 60 mL/min/1.73 m2. There are renal stones or increased risk of renal stones (for example following urinary biochemical stone risk analysis).
• There is osteoporosis confirmed on DEXA, or if a vertebral or other fragility fracture occurs.
NWL Pathology 69
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Case 2 • 36 y.o. male
• 6 months of poor energy, tingling in fingers and weight loss with a change in bowel habit.
• Hb 87 g/l, MCV 64.7 fl with low iron.
• Corr calcium 1.30 mmol/l,
• Parathyroid hormone 46.7
• Vitamin D <12.5 nmol/l;
• INR 2.7
NWL Pathology 70 Bairbre Aine McNicholas, and Marcia Bell BMJ Case
Reports 2010;2010:bcr.09.2009.2262
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Thoracic kyphosis.
Bairbre Aine McNicholas, and Marcia Bell BMJ Case
Reports 2010;2010:bcr.09.2009.2262
©2010 by BMJ Publishing Group Ltd
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Bairbre Aine McNicholas, and Marcia Bell BMJ Case
Reports 2010;2010:bcr.09.2009.2262
©2010 by BMJ Publishing Group Ltd
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Bairbre Aine McNicholas, and Marcia Bell BMJ Case
Reports 2010;2010:bcr.09.2009.2262
©2010 by BMJ Publishing Group Ltd
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Most likely diagnosis?
Mentimeter
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• Coeliac serology positive antitissue transglutaminase and antiendomysial.
• OGD mild atrophic gastritis, loss of granularity in the duodenal bulb, scalloping of mucosa with mosaic appearance, and no villi were seen.
• Histology revealed subtotal villous atrophy, crypt hyperplasia and diffuse increase in intraepithelial lymphocytes, increased inflammatory cells in the lamina propria, mild chronic gastritis
NWL Pathology 75
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• 1. Calcium absorption
• 2. Vitamin D
PTH
PO43-
Mg2+
PKC
Gi
Gq11
PLC
Ca2+
ERK
MAPK
FGF23
Klotho FGFR1
1,25(OH)2D3
CaSR
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PTH and renal disease
Common in those with GFR <60ml/min
Sustained elevated parathyroid hormone (PTH) levels can cause:
– high-turnover bone disease (osteitis fibrosa cystica), fracture, hypercalcemia and hyperphosphatemia, and calciphylaxis.
Sarah Tomasello Diabetes Spectr 2008;21:19-25
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• 1. Dietary
• 2. Vitamin D
• 3. Kidney • 4. Mg
• 5. FGF23
• 6. Lithium
• (7. Normocalcaemic hyperparathyroidism)
PTH
PO43-
Mg2+
PKC
Gi
Gq11
PLC
Ca2+
ERK
MAPK
FGF23
Klotho FGFR1
1,25(OH)2D3
CaSR
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Hypocalcaemia – summary
High PTH
Vit D
PTH resistance
Renal
Calcium loss from circulation
Low PTH
Genetic
Post-op
Infiltration, HIV, Radiation, AI, mg
2+
Normal PTH Mg2+
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Biological variation
(Smit, van Kinschot et al. 2019)
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Any questions,
feedback or comments?
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GP Educational Event 21st November 2019
Frances Davies Consultant Microbiologist
Rise in Carbapenemase Producing Enterobacteriacae (CPE)
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Points of Discussion
• What is a CPE
• National rise in CPE
• How to treat a CPE
• Infection control implications in primary care
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What is a CPE
• Carbapenemase producing enterobacterales
• Enzymes that destroy carbapemens
• Genes carried on plasmids
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What are the different types of CPE
• Class A – KPC, GES, SME
• Class B (Metallo) – VIM, NDM, IMP
• Class D - OXA 48 – like
• Most international spread has been in K. pneumoniae and E. coli
• Clinically and IPC distinct from Pseudomonas and Acinetobacter
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CPE – national increase
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International picture
KPC NDM
OXA48
Lee et al, Frontiers in Microbiology 2016
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Where do our CPE arise
• Healthcare abroad
• Holiday abroad
• Healthcare UK
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How to treat
• Call for specialist advice
• Multidrug regimen may be needed
• Usually IV therapy
• Occasional oral drugs work
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Options – depends on sensitivities
• Oral: Ciprofloxacin, co-trimoxazole, fosfomycin, nitrofurantoin
• IV: Colistin, amikacin, high dose meropenem, tigecycline
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A typical sensitivity pattern (NDM)
• Resistant: Ciprofloxacin, gentamicin, amikacin, tobramycin, amoxycillin, co-
amoxiclav, cefuroxime, cefotaxime, ceftazidime, piperacillin-tazobactam, temocillin, aztreonam, ertapenem and meropenem (MIC 4-32)
• Intermediate: Tigecycline (MIC 2)
• Sensitive: colistin, cotrimoxazole
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How are they acquired
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Community Infection control
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Risk assessment
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Any questions,
feedback or comments?