gp educational event 21st november 2019pathology.imperial.nhs.uk/uploads/images/2020/gp educational...

GP Educational Event 21st November 2019

Welcome

Panos Pantelidis

Divisional Manager, Infection & Immunity

The Hillingdon Hospitals

Imperial College Healthcare NHS Trust

Chelsea and Westminster NHS Foundation Trust

The NWLP Model

Transformation update

The formal transformation programme governance has 6 programme work streams:

1. Pathology Services Transition

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.

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:

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.

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

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.

Influenza Season NWLP Update

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

Female Infertility Matthew Whitlock

Principal Clinical Scientist

Learning Objectives

• Causes of female infertility

• Ovulatory disorders

• Biochemical investigations and interpretation

• Analytical methods for hormone analysis

• Referral pathways to Endocrinology/Gynaecology

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

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

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)

Hypothalamic-pituitary-gonadal axis

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

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

• 85% of ovulation disorders

• Causes: – Polycystic ovary syndrome

– Hyperprolactinaemic anovulation

WHO Group II: Normogonadotrophic normogonadal anovulation

Polycystic Ovary Syndrome

• Heterogeneous endocrine disorder – ↑ GnRH pulse frequency

– ↑ LH:FSH

– ↑ ovarian androgen production

• Clinical features – Hyperandrogenism

– Infertility

– Obesity

– Depression and anxiety

• 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

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

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.”

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 = ↑

• 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’

What other investigations would you request?

a) TSH

b) Cortisol

c) Testosterone

d) Prolactin

‘?PCOS’

• LH 5.9 U/L

• FSH 3.7 U/L

• Prolactin 748 mIU/L

‘?PCOS’

Macroprolactin

Re-measure PRL after PEG removal of macroPRL

Macroprolactin

Big-prolactin

Monomeric Prolactin

Total Serum

Prolactin

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%

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.

• LH 5.9 U/L

• FSH 3.7 U/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.

• LH 5.9 U/L

• FSH 3.7 U/L

• SHBG 85 nmol/L

• Testosterone Pending confirmatory result

‘?PCOS’

Immunoassay

Testosterone analysis NWLP

“androgens should preferably be measured using tandem mass spectrometry”

Immunoassay

Solid Phase Extraction +

LC-MS/MS

Female Testosterone > 2.0 nmol/L

Extracted Testosterone 4.1 nmol/L Androstenedione 25.4 nmol/L 17-hydroxyprogesterone 234.3 nmol/L

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

• LH 5.9 U/L

• FSH 3.7 U/L

• 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’

a) PCOS

b) Androgen secreting tumour

c) Non-classical Congenital Adrenal Hyperplasia

d) Prolactinoma

‘?PCOS’

• Referred to Endocrinology

• Diagnosis of NCCAH confirmed

• Started on treatment – 3mg prednisolone

Polycystic Ovary syndrome (2005) N Engl J Med

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

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)

• ICHC-tr.biochemistryadvice@nhs.net

• 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?

Parathyroid Hormone Dr Julia Kenkre, Metabolic Medicine Spr and Clinical Research Fellow

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

Interactive

• www.menti.com

• Enter code

NWL Pathology 45

Calcium and phosphate homeostasis

Calcium

Phosphate

Calcium

Phosphate

Vitamin D

Parathyroid physiology

Ca2+/CaSR : Inhibits PTH transcription, PTH release and is anti-proliferative

Klotho FGFR1

1,25(OH)2D3

Slide courtesy of Duncan Bassett

Copyrights apply

Under normal circumstances the CaSR is exquisitely

sensitive to changes in calcium

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

Klotho FGFR1

1,25(OH)2D3

Slide courtesy of Duncan Bassett

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

Case 1

• 50 year old female cleaner

• Referred after routine blood tests showed

persistently raised calcium ~2.70 mmol/L

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

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)

Mentimeter

Most likely diagnosis?

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

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”

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

Further history

• Relatively asymptomatic

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)

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)

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

Our case

• Ca:creat 0.0141

• DEXA no osteoporosis

• Renal US no nephrocalcinosis

Localisation Tc99 MIBI with SPECT

Outcome

• Parathyroidectomy

• Histology left hypercellular adenoma

• Biochemical cure

High PTH Hyperparathyroidism,

Low PTH Malignancy, non-PTH

mediated

Normal PTH (mid-upper)

Hyperparathyroidism, FHH

Summary - hypercalcaemia

NICE guidance – primary hyperparathyroidism

Hyperparathyroidism (primary): diagnosis, assessment and initial management(2019) NICE guideline NG132 68

Measure adjusted Ca:

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.

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

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

Thoracic kyphosis.

Bairbre Aine McNicholas, and Marcia Bell BMJ Case

Reports 2010;2010:bcr.09.2009.2262

Most likely diagnosis?

Mentimeter

• 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

• 1. Calcium absorption

• 2. Vitamin D

Klotho FGFR1

1,25(OH)2D3

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

• 1. Dietary

• 2. Vitamin D

• 3. Kidney • 4. Mg

• 5. FGF23

• 6. Lithium

• (7. Normocalcaemic hyperparathyroidism)

Klotho FGFR1

1,25(OH)2D3

Hypocalcaemia – summary

High PTH

PTH resistance

Calcium loss from circulation

Low PTH

Genetic

Post-op

Infiltration, HIV, Radiation, AI, mg

Normal PTH Mg2+

Biological variation

(Smit, van Kinschot et al. 2019)

Any questions,

feedback or comments?

Frances Davies Consultant Microbiologist

Rise in Carbapenemase Producing Enterobacteriacae (CPE)

Points of Discussion

• What is a CPE

• National rise in CPE

• How to treat a CPE

• Infection control implications in primary care

What is a CPE

• Carbapenemase producing enterobacterales

• Enzymes that destroy carbapemens

• Genes carried on plasmids

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

CPE – national increase

International picture

KPC NDM

Lee et al, Frontiers in Microbiology 2016

Where do our CPE arise

• Healthcare abroad

• Holiday abroad

• Healthcare UK

How to treat

• Call for specialist advice

• Multidrug regimen may be needed

• Usually IV therapy

• Occasional oral drugs work

Options – depends on sensitivities

• Oral: Ciprofloxacin, co-trimoxazole, fosfomycin, nitrofurantoin

• IV: Colistin, amikacin, high dose meropenem, tigecycline

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

How are they acquired

Community Infection control

Risk assessment

Any questions,

feedback or comments?

gp educational event 21st november 2019pathology.imperial.nhs.uk/uploads/images/2020/gp educational...

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