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Clinical Biochemistry and Metabolic disease II. Dr Vivion Crowley Consultant Chemical Pathologist St James’s Hospital Dublin. Biochemical Investigation of a Patient with Suspected Hypocalcaemia?. What are the causes of Hypocalcaemia. Low albumin Artefact Chronic renal failure

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Clinical Biochemistry and Metabolic disease II

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Clinical Biochemistry and Metabolic disease II

Dr Vivion Crowley

Consultant Chemical Pathologist

St James’s Hospital

Dublin


Biochemical Investigation of a Patient

with Suspected Hypocalcaemia?


What are the causes of Hypocalcaemia

  • Low albumin

  • Artefact

  • Chronic renal failure

  • Hypoparathyroidism

  • PTH resistance

  • Pseudohypoparathyroidism

  • Hypomagneaemia

  • Vitamin D deficiency

  • Vitamin D resistance states

  • Medications

  • Miscellaneous

  • Pacreatitis

  • Sepsis

  • Tumour lysis syndrome


What are the clinical features of Hypocalcaemia

  • PNS: numbness, tingling, muscle cramps

  • CNS: Psychiatric symptoms e.g irritability, rarely tetany and seizures

  • Basal ganglia calcification

  • Chvostek’s sign

  • Trousseau’s sign


Does the patient have “True HypoCa”

  • What is the corrected Ca?

  • Evidence of artefact? - K EDTA contamination

  • What is the local reference range?


What is the Plasma PO4 level?

  • High PO4

  • Hypoparathyroidism

  • Renal failure

  • Low/Normal PO4

  • Vitamin D

  • Renal failure – post dialysis/treatment

  • Other causes

  • NB: PO4 levels are affected by many factors and cannot be relied upon alone

  • Does the patient have Hypomagnesaemia?

  • Causes PTH resistance

  • Must correct Mg deficit before improvement in Ca levels


Is there a clinically apparent cause of Hypocalcaemia?

  • Chronic Renal Failure – high PO4, low 1, 25 (OH) Vit D

  • Pancreatitis – precipitation of Ca and Mg in necrotic adipose tissue

  • Sepsis – low albumin

  • Post thyroid or parathyroid surgery – “Hungry bone syndrome”

  • Tumour lysis syndrome – high PO4 precipitates Ca

  • Rhabdomyolysis – as for TLS, marked increase in CK

  • Osteoblastic metastases


What about Calcium-reducing medications

  • Bisphosphonates

  • Calcitonin

  • Phosphate

  • Foscarnet

  • Pentamidine


What is the plasma PTH Level?

  • Low PTH

  • Hypoparathyroidism

  • Idiopathic – Di George syndrome

  • Autoimmune

  • Post-surgical

  • Hypomagnesaemia

  • High PTH

  • Vitamin D deficiency or resistance (secondary Hyperparathyroidism)

  • Psuedohypoparathyroidism

  • Severe liver disease

  • Chronic renal failure

  • NB: Check Vit D levels in secondary hyperparathyroidism


43 yr old male with renal failure due to analgeisc nephropathy

Na 134

K 5.8

Urea 42.2

Creat 650

Ca 1.82

PO4 2.53

Alb 37

ALP 200

PTH 425

What is the cause of his HypoCa?

Explain the abnormal findings?


70 yr old male presented with the Hx of

Bone pain and malaise

Ca 3.4

PO4 1.5

Alb 30

TP 110

ALP 100

What is the corrected Ca level?

What further investigations would you consider?

The PTH is 10 (9-65), is the HyperCa PTH dependent or independent?

What is the likely diagnosis?

What is MGUS?


Case 2

  • GM 73 old female

  • Admitted April and July 2008 with

    • Left sided weakness, slurred speech, confusion

    • Mild seizures on 2nd admission

    • Poor oral intake, weight loss (57.5 kg on 1/5/08 –48.5 kg on 22/07/08)

  • PMH: HTN, Hypercholesterolaemia, OA

  • Medication: Aspirin, Doxazocin, Perindopril

    Amlodipine, Omeprazole

    Pravastatin


Case 2 cont.

  • Routine bloods:

    • GluR 5.5 mmol/L

    • U/Es: urea 20.9…5.4 mmol/L, creatinine 202…66 umol/L (after rehydration), Na 140 mmol/L, K 2.9 mmol/L

    • Ca 1.24 mmol/L Albumin 28 g/L, PO4 1.16 mmol/L (ref. 0.8-1.4)

    • LFTs NAD


Case 2 cont.

  • Laboratory tests cont.

    • FBC- Hb 10.3, MCV 77.7, tTG 1.6, iron 2 (ref 14-3) umol/L, transferin sat. 7 (ref 30-40) %, ferritin and folate NAD

    • TFTs TSH 0.71 mU/L, fT4 23 pmol/L


  • 25OH Vit D 32 nmol/L (>80)

  • PTH 148.5 pg/mL (ref 15-65)


Case 2 cont

  • Mg 0.15( 0.7-1.0) mmol/L,


Case 2 cont.

  • Other investigations:

    • CXR/PFA NAD

    • OGD/Colonoscopy NAD

    • AUS: loss of normal cortical medullary differentiation

    • MRI brain NAD


Case 2 cont.

  • Treatment:

    • iv Magnesium 7 g in total

    • Vit D2 50 000 iu im

    • Magnesium Verla 5 g bd ( 5g equiiv. 5 mmol or 121.5 mg magnesium)

    • One-Alpha 0.5 mcg (alfacalcidol) for 1/52

    • Calcichew D3Forte ii od (one tablet= 400 IU Vit D3, 500 mg Ca++carbonate)

    • Kay-Cee-L (75 mg KCl per 1 mL)


Biochemical test play an essential role in

the management of endocrine disease

Screening – TSH in neonatal hypothyrroidism

Case finding – e.g. Pentagastrin test in medullary thyroid ca

Diagnosis – over or under production of hormones

Monitoring response to Rx or recurrence


Disorders of Endocrine Glands

  • Underactivity with under production of normal hormone

  • Overactivity with over production of normal hormone

  • Inappropriate production of hormone not normally produced

  • Ectopic production of hormone by a non-endocrine gland


Disorders involving the Pituitary Gland


Hypopituitarism

  • Partial or complete deficiency of anterior and/or posterior

  • pituitary hormones

  • Causes

  • Pituitary tumours

  • Parapituitary tumours e.g. craniopharingioma, metasases

  • Radiotherapy

  • Apoplexy (infarction)

  • Infiltration – sarcoidosis, histiocytosis x, haemochromatosis

  • Infections – TB, abscess

  • Trauma- post head injury

  • Genetic syndromes e.g. Kallmann’s syndrome, Laron dwarfism


Hypopituitarism- Clinical Manifestations


Hypopituitarism – Biochemical investigation

  • Basal hormone levels

  • LH, FSH, Testo / E2

  • TSH and T4

  • 9am cortisol

  • Prolactin (PRL)

  • IGF-1 (marker of GH action)

  • Dynamic function tests

  • Insulin tolerance test (ITT) – for Cortisol and GH response

  • GnRH test for LH, FSH reserve

  • TRH test for TSH reserve (rarely used now)

  • Also need to consider imaging pituitary gland – MRI, CT


Acromegaly - Excess GH secretion

  • Causes

  • Pituitary tumour

  • Macroadeneoma >10mm

  • Microadenoma <10mm

  • Clinical presentaion

  • Pituitary gigantism in childhood

  • Acromegalic symptoms

  • Increased sweating

  • Headaches

  • Fatigue/tiredness, joint pains

  • Change in shoe size, ring size


Acromegaly – clinical signs

  • Facial appearances - characteristic

  • Deep voice

  • Macroglossia

  • Enalarged hands/feet

  • Carpal tunnel syndrome


Biochemical Investigation of Suspected GH Excess

  • Oral glucose tolerance test (75g load)

  • in acromegaly there is a failure to suppress GH to < 2 mU/L

  • IGF-1 – usually elevated

  • Check other pituitary hormones ( see in Hypopit section)

  • Imaging of pituitary


Cushings’ syndrome - Excess circulating cortisol

  • Causes

  • Exogenous steroids

  • ACTH secreting pituitary tumour

  • Ectopic production of ACTH

  • Adrenal tumour

  • Clinical Features

  • Facial appearance – moon facies, plethoric complexion, acne

  • Weigt gain – central obesity, “buffalo hump”

  • Thin skin, easy bruising,

  • Proximal muscle weakness

  • Mood disturbance

  • Menstrual disturbance, hirsutism

  • Hypertension


Cushing’s Syndrome


Investigation of suspected Cushing’s syndrome

Does the patient have Cushing’ syndrome?

What is causing the patient’s Cushing’ syndrome?


Does the Patient have Cushing’s syndrome?

Out-patient tests

Overnight dexamethasone suppression (1mg at midnight)

Normal = 9am cortisol < 50nmol/l

24 hour urinary free cortisol

In-patient tests

Midnight cortisol – looking for loss of cicardian rhythm

Low dose dexamethasone suppression test (0.5mg qds for 48hour)

Normal = 48hr cortsiol < 50 nmol/l


What is the underlying cause of Cushing’s syndrome?

  • Plasma ACTH level

  • ACTH-dependent if non-suppressed or elevated

  • - Pituitary

  • Ectopic

  • ACTH independent if suppressed

  • Adrenal

  • To differentiate Pitutary ad ectopic causes

  • High dose dexamethasosne suppression (2mg qds x 48hr)

  • Pituitary suppresses to < 50% basal value

  • CRH test

  • exagerated cortisol and ACTH response in pituiray Cushing’s

  • Inferior petrosal sinus sampling + pituitary imaging


Hyperprolactinaemia


Hyperprolactinaemia – clinical presentation

  • Females

  • Oligo/amenorrhoea

  • Galatorrhoea

  • Infertility

  • Reduced libido

  • Symptoms relating to pituitary tumour

  • Males

  • Symptoms relating to pituitary tumour e.g. headache, visual disturbance#

  • Less frequently, reduced libido, infertility, galatorrhoea


Biochemical investigation of Hyperprolactinaemia

  • Plasma Prolactin

  • -At least two confirmed elvations in plasma prolactin

  • -Must screen for Macroprolactinaemia ( a high

  • mol wt form of circulating prolactin)

  • -Macroprolactinaemia is not clinicall significant

  • -Prolactin levels > 5000mU/L are indicative of a pituitary adenoma

  • Check routine bloods

  • -renal and liver function

  • -TFTs

  • -Pregnancy test (hCG)

  • -FSH/LH, E2

  • Imaging of pituitary gland if indicated


What are the commonly measured TFTs?

  • Total T4 – includes protein bound and Free Thyroxine

  • Free Thyroxine is the active hormone

  • TBG is the main protein binding Thyrxoine

  • Increased TBG s seen in pregnancy

  • Free T4 (FT4)

  • TSH – reflects the pituitary response to FT4 level

  • Total T3

    – useful in the diagnosis of T3 toxicosis

    - Normal T4 and suppressed TSH


Patterns of Thyroid Function Tests


Hypoglycaemia

  • Definition: plasma glucose < 2.8mmol/l (blood glucose < 2.2mmol/l)

  • Clinically presents with - adrenergic features, neuroglycopaenia

  • “Whipple’s triad” -

  • Symptoms & signs of hypoglycaemia

  • Plasma glucose < 2.8mmol/l

  • Relief of symptoms by glucose intake (infusion/oral)


Hypoglycaemia

  • Causes:

  • Drug therapy - Insulin, Sulphonylurea, -blockers, Quinine

  • Factitious - Insulin, sulphonylureas (healthcare workers)

  • Fasting Hypoglycaemia

  • Insulinoma

  • Hepatic failure - gluconeogenesis

  • Sepsis, Cardiac failure

  • Hypopituitarism, Addison’s disease

  • Tumour-related hypoglycaemia

  • - mesenchymal tumours e.g. fibrosarcoma etc.

  • ? Ectopic IGF II by tumour cells

  • Autoantibodies - Insulin, Insulin receptor


Hypoglycaemia

Reactive Hypoglycaemia

Idipopathic

Early diabetes

Post-gastric surgery

Investigations:

Ensure that hypoglycaemia is documanted by laboratory blood/plasma glucose

Determination on a sample collected into a fluoride tube

5hour OGTT - hypoglycaemia may occur between 2-5 hours after glucose load

Definitive investigation for fasting Hypoglycaemia:

Supervised - 72 hour prolonged fast

If pt develops neuroglycopaenic symptoms then measure

Plasma Glucose, Insulin, C-pepetide

Other routine invsetigations: U/E, LFTs, ? Endocrine


Polyuria

Urine output > 3 litres/day

(explain the difference between polyuria and urinary frequency)

Confirm polyuria - 24hr urine collection

Causes of polyuria

Drugs - diuretics, lithium

Diabetes mellitus - fasting ± random glucose, OGTT

Chronic renal failure - plasma urea & creatinine, Creatinine clearance

Hypokalaemia

Hypercalcaemia


Polyuria

  • In clinical practice the most common reason for doing a

  • water deprivation test is to differetiate between

  • Psychogenic polydipsia

  • Diabetes Insipidus - central AVP (ADH) deficiency

  • - nephrogenic AVP action on renal tubule

  • Water Deprivation test ± vasopressin administration


Addison’s Disease

  • Primary adrenal insufficiency

  • - differentiate from secondary i.e. ACTH deficiency

  • - tertiary :CRH suppression by exogenous steroids

  • Clinically

  • Weakness, fatigue, anorexia, wt loss, postural hypotension, Coma

  • Hyperpigmentation

    - elbows, knees, buccal mucosa, recent scars (ACTH levels)

  • Causes

  • Autoimmune - ? Polyglandular autoimune syndromes

  • Infections - TB, fungal infections, HIV

  • Metastatic disease - lung, Breast, colon (bilateral disease)

  • Medications - ketoconazole

  • Waterhouse Freidrickson - bilateral adreanl haemorrahage (sepsis e.g menigococcus)


Biochemical abnormalities in Addison’s Disease

  • Hyponatraemia

  • Hyperkalaemia

  • Pre-renal failure plasma urea & creatinine

  • ? Hypercalcaemia

  • Abnormal TFTs - TSH, T4 (hypothyroid picture)

  • - May be a transient picture

  • NB: treat hypoadrenalism before giving L-T4

Acute presentation:

Take blood sample for plasma Cortisol and ACTH levels before

steroid administration

Plasma Cortisol Plasma ACTH

NB: Dexamethasone does not interfere with cortisol assay


Biochemical Diagnosis of Addison’s disease

  • Chronic Presentation

  • Short synacthen test

  • does not differentiate between primary and secondary

  • -Synacthen 250 μg IM

  • 0, 30 and 60 min plasma cortisol

  • 30 min Plamsa Cortisol > 550 nmol/L

  • Long synacthen test

  • Adrenal antibodies


Biochemical paraneoplastic syndromes

  • Tumours of specific endocine glands e.g. insulinoma, pituitary etc.

  • Hypercalcaemia of malignancy

  • Syndrome of inappropriate antidiuresis (SIAD) - hyponatraemia

  • Cushing’s syndrome

  • Tumour-induced hypoglycamia

  • Tumour-induced osteomalacia - mesenchymal tumours (hemangiopericytoma)

  • Normal Ca, PO4, 1,25 (OH)2 Vit D

  • ??Renal phosphate wasting

  • Carcinoid syndrome - facial flushing, diarrhoea, brochospasm

  • Laboratory diagnosis - urinary 5 hydroxyindole actetic acid (5HIAA)


Case 1: Hx

  • 35 yr old male

  • Hx EBV infection 8 weeks previously

  • No medical or family hx of note otherwise

  • Not on regular medication

  • C/O vague/nonspecific symtoms, fatigue

  • GP performed “routine blood tests” including TFTs


Case 1: TFTs

  • TT4= 223 (63-142)

  • TSH= 4.87

  • Repeated 2-3 weeks later

  • TT4 = 171

  • TSH = 2.89


Case 1: TFTs (cont)

  • FT4 = 51.3 (9-24)

  • T3 = 3.5 (0.8-2.5)

  • Biochemical Hyperthyroidism

  • No clinical features of thyrotoxicosis

  • No biochemical evidence of heterophile ab interference

  • No family hx of thyroid dx


Case 1: Differential Dx

  • TSHoma

  • Thyroid hormone resistance (RTH) - Refetoff’s syndrome

  • FDH – rare

  • Heterophile abs

  • MRI scan of pituitary – Macroadenoma - TSHoma


Case 2: History

  • Phone call from a GP regarding TFTs:

  • 54 yr old male – vague hx fatigue

  • T4 = 40 (69-141)

  • TSH = 1.53

  • Sample recovered and tested for

  • FT4 = 5.7 (9-24)

  • TBG = 25 (13-24)

  • A large clot was noted in serum

  • R/O artefact – repeat investigation with


Case 2: Repeat TFTs

  • TT4 = 44

  • FT4 = 4.9

  • TSH= 1.2

  • Cortisol = 130 (random am)

  • Testo = 10.5 (8.7 –33.0)

  • LH = 2.4

  • FSH = 6.3

  • GH < 1.0

  • IGF-1 < 25

  • PRL = 419 (70-413)

Central Hypothyroidism – Referred to endocrine service SJH


Case 2: Endocrine assessment

  • Stimulation testing (ITT)

  • Achieved hypoglcaemia

  • GH deficient

  • ACTH/Cortisol deficient

  • Centrally hypothyroid

  • MRI scan – empty sella ? cause


Case 3: Background

  • 23 yr old male

  • Hx Migraine and fatigue

  • GP performed TFTs

  • TT4 = 43

  • TSH = 2.89

  • Biochem Registrar signing out - ? Hypothyroid

    - Put on some additional test

  • FT4 = 5.8 (9-24)


Case 3: Endocrine tests

  • More additional tests after discussion with GP

  • Cortisol = 97 (244-727) but NB diurnal variation

  • FSH = 2.7 (1.0-10.5)

  • LH = 2.2 (1.0 –6.0)

  • Testo = 1.3 (8.7-33)

  • Prolactin = 4490 (70-413)

  • Post fractionation Prolactin (PFP) = 3960


Case 3: Diagnosis

  • Biochemical Dx:

  • Hypothyoid

  • Hypogonadal

  • Hypocortisolaemic

  • Hyperprolactinaemic

  • Hypopituitarism

  • MRI scan – Macroadenoma - ? Macroprolactinoma


Case 4: background

  • 43 yr old female

  • Hx Spina Bifida (wheel chair bound)

  • Currently in Cheshire Home

  • 4/52+ hx malaise

  • Admitted to St Elsewhere

  • Atonic Bladder

  • Renal impairement

  • GP to monitor U/Es


Case 4:

  • Result brought to attention of Consultnat Chem Path

  • Hypernatraemia ? Cause

* fasting


Case 4: Dx?

  • Results suggestive of

  • DI

  • DM

Paired urine and plasma osmolality are very useful

in directing management of

-hypernatraemia

-hyponatraemia


24 yr old male

Unwell – Hx of admissions with hypoNa

Na 121

K 5.5

Urea 9.3

Crea 118

T4 83

TSH 4.97

Cortisol 52

ACTH 1122


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