Deepak Chandrajay MRCP,FRCPath

Consultant- Chemical Pathology and Metabolic Medicine

“Themed” Biochemistry Cases

Unexpected findings

Examples of Assay Interference Addition of further tests by the Duty Biochemist Linking abnormal laboratory findings together

Case 1: Hyperkalaemia

81yr old man with Chronic Lymphocytic Leukaemia

Sodium = 137 mmol/L (133-146) Potassium = 7.5 mmol/L (3.5-5.3) Urea = 6.5 mmol/L (2.5-7.5) Creatinine =138 umol/L (<120)

Patient was admitted to A+E and had a 12 lead ECG – no changes Potassium on a repeat sample was 9.8 mmol/L!

Any Idea’s?

No ECG changes or symptoms suggests spurious cause WBC count was 76 x10^9/L (NR = 4-11 x10^9/L) Shearing of “fragile” white blood cells during clotting can cause K+ release “Pseudohyperkalaemia” Check K+ level on a plasma sample (light green top) – in this patient K+ = 4.1

38 yr old male - back ache, BMI 26.8, BP 125/70 FBC Normal UEs Normal ALT- 36 iu/L Cholesterol -9.0 mmol/L, HDL- 1.6 mmol/L, HbA1C- 39 mmol/mol

Case 2: Hypercholesterolaemia

Continued…..

• Cholesterol -9.2 mmol/L,

• LDL -5.2 mmol/L,

• HDL- 1.6 mmol/L,

• Triglycerides- 2.6 mmol/L

• CK- 1240 iu/L

• FBC Normal

• UEs Normal

• ALT- 36 iu/L

• AST- 60 iu/L

• TSH- 74mIU/L

• Free T4- 3.1pmol/L

• Total T3- 0.7nmol/L

High cholesterol-approach

• Repeat fasting TC, TGL, LDL, HDL

• Urine dipstick

• UEs,

• LFT

• TSH

• Family h/o premature CVD

Case 3: Hypokalaemia and Hypocalcaemia

55 yr old lady - On a long term loop diuretic for heart failure

Recently started on a PPI for acid reflux

Complaining of “slightly tingling” sensations

Sodium = 147 mmol/L (133-146)

Potassium = 2.8 mmol/L (3.5-5.3)

Urea = 10.5 mmol/L (2.5-7.5)

Creatinine =169 umol/L (<120)

eGFR = 29 ml/min/1.73m2

Adjusted Calcium = 1.8 mmol/L (2.2-2.6)

PTH = 3.5 pmol/L (1.3-6.8)

Does anybody know the connection between low Ca2+ and low K+?

Further test was added in the lab;

Magnesium = 0.25 mmol/L (0.7-1.0)

Magnesium required for PTH release and for K+ reabsorbtion in Kidney

Case 4 - Hyponatraemia

• GP request • Clinical details- 34 year old weight loss, loss of

appetite Na- 121 mmol/L Creatinine- 104 umol/L Wbc- 9 x10^9/L CRP,ALT,ALP, Urea, calcium- NT- sample lipaemic • Lab analysed lipids- Chol 24.7 mmol/L Trig + 79.7 mmol/L

Continued……

• Admitted with abdominal pain next day

• Chol- 25.6 mmol/L

• Trigs- 81.5mmol/L

• Na- 123 mmol/L

• Amylase 450

• Treated as pancreatitis

Case 4: Continued…..

Date TC TGL Na

5/6/18 25.6 81.6 125

6/6/18 17.3 31.8 128

27/7/18 4.5 2.0 139

10/10/18 4.4 7.2

30/10/18 6.9 17.2 140

Alcohol >80 units per wk Apo E2/E2 negative

Pseudohyponatremia

Electrolyte exclusion phenomenon

Low Na- approach

• Drugs

• Alcohol

• D+V

• Pseudohyponatremia

Case 5: A difficult case of hypercholesterolaemia

• 56 y old referred from Cardiology.

• IHD- MI twice in last 5 years

• PCI and stents

• Intolerance to statins- muscle aches

• Strong family history of premature CVD

• TC- 7.7, LDL-5.7, Trigs- 1.6, HDL-1.3

(on ezetimibe)

Statin intolerance- approach

• Check TSH, vit D

• Retrial- Rosuvastatin 5 mg weekly- titrate

• Ezetimibe

• Cholestagel

• PCSK9 inhibitors- refer

Referral

• https://www.valeofyorkccg.nhs.uk/rss/data/uploads/cardiology/car06-lipid-referral-published.pdf

• https://www.valeofyorkccg.nhs.uk/rss/data/uploads/cardiology/car05-v1.1-management-of-cardiovascular-risk-using-statins-published.pdf

PCSK9

• Proprotein convertase subtilisin/kexin type 9

• produced in the liver.

• PCSK9 binds to the LDL-R on the surface of hepatocytes, leading to the degradation of the LDL-R

• PCSK9 inhbitors interfere with its binding of the LDL-R leading to higher hepatic LDL-R expression and lower plasma LDL-C levels.

PCSK 9 inhibitors

Without CVD With CVD

High risk of CVD1 Very high risk of CVD2

Primary non-familial

hypercholesterolaemia or mixed

dyslipidaemia

Not recommended at

any LDL-C concentration

Recommended only if LDL-C

concentration is persistently

above 4.0 mmol/litre

Recommended only if LDL-C

concentration is persistently

above 3.5 mmol/litre

Primary heterozygous-familial

hypercholesterolaemia

Recommended only if

LDL-C concentration is

persistently above 5.0

mmol/litre

Recommended only if LDL-C concentration is persistently

above 3.5 mmol/litre

1 High risk of CVD is defined as a history of any of the following: acute coronary syndrome (such as myocardial infarction

or unstable angina needing hospitalisation); coronary or other arterial revascularisation procedures; chronic heart

disease; ischaemic stroke; peripheral arterial disease. 2 Very high risk of CVD is defined as recurrent cardiovascular events or cardiovascular events in more than 1 vascular bed

(that is, polyvascular disease).

Abbreviations: CVD, cardiovascular disease; LDL-C, low-density lipoprotein cholesterol.

NICE Technology appraisal guidance [TA393 and TA394] Published date: 22 June 2016

Case 6: Unexpected high FT4….

• 35 year old lady with flushing

• Ft4 23 pmol/L (11-22 pmol/L) and

• TSH 1.5 mU/L (0.27-4.20) mU/L

Is the flushing due to raised FT4?

Case 7: Unexpected findings – Tired

Mrs MC 72yo: SOB, Tires easily GP requested “usual panel” – including ferritin

Ferritin = 318ug/L (20 – 291), Lab added iron studies – Transferrin Saturation = 75%

Elevated ferritin and iron sat >50% - lab added comment: “Consider sending fasting sample for iron saturation and 2 x EDTA samples for haemochromatosis gene analysis which will be processed if indicated. Consider requirement for patient consent for genetic testing.”

• GP referred to gastro noting TATT (normally fit and well) and joint aches, with mildly raised ferritin and ALP.

• Gastro arranged liver screen due to raised ALP (prior to genotype results) – all NAD.

• Genetic testing confirmed C282Y homozygosity • Commence venesection. • Advise siblings to be screened.

Discrepancy between lab results and clinical picture

Case 1

• Elderly lady with persistent elevated serum amylase

(500-700)

• CT shows no evidence of acute of chronic pancreatitis

• Faecal elastase normal

• Duty Biochemist contacted by junior doctor for advice

• Suggested checking lipase and urinary amylase.

• Lipase added to current bloods – result was normal

• No urine received.

• Case 2

• 26y lady; ?PCOS

• GP requested testosterone / FAI and prolactin

• Prolactin = 1050 (<500) – advice given on report about common causes of raised prolactin.

• Prolactin repeated 3 weeks later = 1105

• Lab checked for macroprolactin

• Monomeric prolactin = 260

Assay interference

• Case 3

• GP Diabetes review – routine bloods including Vitamin D

• Level measured in lab = >375 nmol/L

• D/w GP – patient not on supplements

• Referred for measurement by an alternative method (mass spec) –

• Vit D = 47.5nmol/L

Chemical Pathology and IT

Dan Turnock

Consultant Clinical Scientist in Biochemistry York Teaching NHS Foundation Trust

What do I hope to cover

Brief background to lab testing and lab errors ICE functionality – current and future possibilities Re-testing intervals Laboratory Medicine website GP “Demand Optimisation” group for pathology

The laboratory: The past

The laboratory now

Lots of Automation!!! 1500 – 2000 samples per day Urgent turnaround 2hrs Non-urgent turnaround 4hrs Specialist tests take longer…..

We depend on our hard working and dedicated BMS staff! We now have to think more about what goes on outside the lab!

Brain to Brain loop in laboratory testing

Comments on reports Hyperlinks to information Telephone advice Additional tests

Make use of ICE functionality

Traditional lab role

A rough idea of the IT process…..

Can a GP see results of investigations done at the hospital and vice versa? ICE is a single repository of ALL results for York and Scarborough Hull is getting ICE so we will be able to see their results (and vice versa) in future Can we see results done in other laboratories via the ICE system? Yes – set up for Leeds and Harrogate, Middlesbrough can see our results…

Screenshot of the ICE order comms system

Sample type and number

Other “pop-up” messages should appear on ICE for: Unusual requests Unstable tests

Simple things that ICE can do….

Name of the test can give you some information! Hyperlinks to advice/guidance documents Tests can be grouped under buttons (see later) Tests that are not usually needed (e.g. PSA in Women) can be greyed out to prevent requesting

Toolbar can give messages

More complex things in ICE…….

“Help” type pop up boxes “Questions” designed to direct to requesting

Lots of potential here!!! Requesting by indication/picklist We have to balance what is useful and what is annoying! This is your chance to tell us….

Condition/disease specific requesting

The idea is to have all the tests you need under one button to speed up requesting Facilitate requesting by non-medical staff?

Name of Profile

Request the tests individually as required or use “select all” Possible to default to “select all” to speed things up

Click the button to see the profile content and request the tests

ICE re-design - March 2019

Summary of main changes: Increase prominence of “Test Profiles” Split “Test Profiles” into “Diagnosis”, “LTC Monitoring” and “Drug monitoring” Condense “Addition Biochemistry” and “Immunology/Allergy” pages

Work ongoing with East Riding GPs to develop the Test Profiles further

We need to: 1. Refine the content of the “Monitoring” profiles 2. Add new “Diagnostic” profiles as required (link to documents on RSS) 3. Add more “Drug Monitoring” profiles (shared care drugs)

Click on the “Test Profiles” tab at the top of the main screen to be able to request by clinical condition or possible diagnosis

Profiles can be split by whether they are for Diagnosis or Monitoring Or we could split by clinical speciality e.g. Gastroenterology, Diabetes/Endocrinology, Elderly Medicine

Click the button to see the profile content

Minimum re-testing intervals

https://www.rcpath.org/discover-pathology/news/national-minimum-retesting-intervals.html

Not a very practical document sadly…. I was asked to produced a simple 2 page summary for Scarborough+Ryedale Hopefully you have seen it or know where to find it!

There are a variety of IT levels we can embed these: 1. At the point of placing the order comms request 2. At the point of receiving the sample in the lab

Would it be valuable to have them in GP systems?

Some of the limits we have in our lab IT system (York/Scarborough)

TFTs - block repeats within 1 month Ferritin, B12, Folate - block repeats within 1 month Vitamin D -block repeats within 3 months All checked prior to rejection by Duty Biochemist

42

Laboratory Handbooks – a useful source of info

• York Handbook– available onthe internet

https://www.yorkhospitals.nhs.uk/our-services/a-z-of-services/laboratory-medicine1/

General information (address for samples, opening hours etc) Test specific information (sample types etc) Guides to interpretation

Searchable test directory for more information on a particular test (e.g. sample requirements)

“Add-on” requests

E-mail system for add-on tests - Would you find this useful? Does anybody want to pilot it for us?

https://www.yorkhospitals.nhs.uk/our-services/a-z-of-services/lab-med/general-information/information-for-health-care-professionals1/

Click the link

If there is a topic you want us to add then please let us know!

Troponin testing in Primary Care

Troponin is a cardiac structural protein released during myocyte injury. Two of its subunits can be measured to indicate myocardial damage: Troponin I and Troponin T. The labs at York and Scarborough provide Troponin T

DO NOT request troponin in Primary Care / Community: • If the patient has suspected acute coronary syndrome (ACS) with chest pain >15

minutes duration – dial 999 • If the patient has had symptoms suggestive of ACS within the past 72h – urgent

assessment in ED required • If the chest pain is non-cardiac

The Universal Definition of MI requires: Rise or fall in cardiac troponin with

1 value above the 99th centile AND relevant ECG changes OR symptoms of ischaemia

• To diagnose angina

• If hs Troponin T <5ng/L ACS is excluded if >3hr post chest pain • If hs Troponin T 5-14ng/L ACS is unlikely if >3hr post chest pain • If hs Troponin T 14-51ng/L Discuss with cardiology/ambulatory care • If hs Troponin T >51ng/L Further assessment in ED usually required

The laboratory will phone primary care Troponin T results >14ng/L to either GP

surgery or GP out of hours service.

The 99th centile for Troponin T is 14ng/L. This means that 99% of healthy individuals will have a Troponin T <14ng/L.

Troponin T results must be interpreted in light of the clinical presentation.

Directorate of Laboratory Medicine Department of Clinical Biochemistry Filename: CB-INF-GPTPT Version: 1.0 Date of Issue: November 2017

Some Non-Cardiac causes of elevated hs TroponinT in the absence of an MI: Pulmonary Embolism, Renal Failure, COPD, Diabetes, Acute neurological event, Drugs/Toxins Non-acute elevations in hs Troponin T >14ng/L - seek Cardiology advice

Some useful contact numbers……

Clinical Advice from Duty Biochemist 01904 72 6366 9am to 6pm, Monday to Friday Duty Biochemist email - yhs-tr.Biochemist@nhs.net Lead Clinician Alison Jones 01904 72 5786 Consultant Clinical Biochemist alison.jones@york.nhs.uk Operational Issues Mrs Joanna Andrew Head Biomedical Scientist 01904 72 5872 joanna.andrew@york.nhs.uk Mr Carl Burkinshaw Operational Manager 01723 342028 carl.burkinshaw@york.nhs.uk

Learning points

• Diagnostic approach for FH and when to refer patients

• Suspected assay interference or strange result – please contact the Duty Biochemist for advice

• Laboratory Medicine website contains useful information to support test requesting/interpretation

“Demand Optimisation” group

Other parts of the country (including Hull and Leeds) – have a Pathology GP “user group” to discuss areas of mutual interest! This potentially covers all the area’s that I’ve talked about plus potentially others 1. Error reduction 2. Demand optimisation (reduce over-testing and under-testing) 3. Profile/condition based requesting 4. Information to support test interpretation

We are hoping to form a group to cover York and Scarborough CCG with the first meeting later this month or in October. So far, we have 3 GPs from York area interested but only 1 GP from Scarborough If you are interested then please speak to me at the end or send me an e-mail!

daniel.turnock@york.nhs.uk - 01904 721847