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 - PowerPoint PPT PresentationTRANSCRIPT
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Clinical Biochemistry and Metabolic disease II
Dr Vivion Crowley
Consultant Chemical PathologistSt James’s HospitalDublin
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Biochemical Investigation of a Patient with Suspected Hypocalcaemia?
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What are the causes of HypocalcaemiaLow albumin
Artefact
Chronic renal failure
Hypoparathyroidism
PTH resistance-Pseudohypoparathyroidism-Hypomagneaemia
Vitamin D deficiency
Vitamin D resistance states
Medications
Miscellaneous-Pacreatitis-Sepsis-Tumour lysis syndrome
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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
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Does the patient have “True HypoCa”
What is the corrected Ca?
Evidence of artefact? - K EDTA contamination
What is the local reference range?
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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
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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
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What about Calcium-reducing medications
Bisphosphonates
Calcitonin
Phosphate
Foscarnet
Pentamidine
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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
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43 yr old male with renal failure due to analgeisc nephropathy
Na 134K 5.8Urea 42.2Creat 650Ca 1.82PO4 2.53Alb 37ALP 200PTH 425
What is the cause of his HypoCa?
Explain the abnormal findings?
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70 yr old male presented with the Hx of Bone pain and malaise
Ca 3.4PO4 1.5Alb 30TP 110ALP 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?
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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
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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
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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
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– 25OH Vit D 32 nmol/L (>80)
– PTH 148.5 pg/mL (ref 15-65)
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Case 2 cont
• Mg 0.15( 0.7-1.0) mmol/L,
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Case 2 cont.
• Other investigations:
– CXR/PFA NAD– OGD/Colonoscopy NAD– AUS: loss of normal cortical medullary
differentiation– MRI brain NAD
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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)
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25/4 22/7 28/8 13/11
Ca 1.24 1.72 2.44 2.46
Mg 0.15 0.11 0.89 0.89
K 2.9 2.5 4.4 4.6
25 OH
VitaminD
32 35 41 79
Albumin 28 32 40 42
PTH 148 19
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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
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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
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Disorders involving the Pituitary Gland
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Hypopituitarism
Partial or complete deficiency of anterior and/or posteriorpituitary 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
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GH Children – growth delay
Adults – GHD
FSH/LH Delayed puberty
Oligo/amenorrhoea
Erecile dysfunction + testicular atrophy
Loss of secondary sex characteristics
ACTH hypoadrenalism
TSH hypothyroidism
Prolactin Failure of lactation
AVP (ADH) Diabetes insipidus
Hypopituitarism- Clinical Manifestations
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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
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Acromegaly - Excess GH secretion
CausesPituitary tumour-Macroadeneoma >10mm-Microadenoma <10mm
Clinical presentaionPituitary gigantism in childhood
Acromegalic symptoms-Increased sweating-Headaches-Fatigue/tiredness, joint pains-Change in shoe size, ring size
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Acromegaly – clinical signs
•Facial appearances - characteristic•Deep voice•Macroglossia•Enalarged hands/feet•Carpal tunnel syndrome
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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
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Cushings’ syndrome - Excess circulating cortisol
Causes1. Exogenous steroids2. ACTH secreting pituitary tumour3. Ectopic production of ACTH4. 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
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Cushing’s Syndrome
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Investigation of suspected Cushing’s syndrome
Does the patient have Cushing’ syndrome?
What is causing the patient’s Cushing’ syndrome?
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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
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What is the underlying cause of Cushing’s syndrome?
Plasma ACTH levelACTH-dependent if non-suppressed or elevated- Pituitary- Ectopic
ACTH independent if suppressed-Adrenal
To differentiate Pitutary ad ectopic causesHigh 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
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Hyperprolactinaemia
Condition Example
Physiological Pregnacy, lactation
Idiopathic
Stress venepuncture
Drugs Dopamine agonistse.g
Phenothiazines
Chronic liver/renal disease Cirrhosis, CRF
Hypothalamic/pituitary
disorders
Micro/macroadneoma
Stalk compression syndrome
Primary hypothyroidism
PCOS
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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
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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
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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
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Patterns of Thyroid Function Tests
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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)
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Hypoglycaemia
Causes:Drug therapy - Insulin, Sulphonylurea, -blockers, QuinineFactitious - Insulin, sulphonylureas (healthcare workers)
Fasting Hypoglycaemia
InsulinomaHepatic failure - gluconeogenesisSepsis, Cardiac failureHypopituitarism, Addison’s disease
Tumour-related hypoglycaemia - mesenchymal tumours e.g. fibrosarcoma etc.? Ectopic IGF II by tumour cells
Autoantibodies - Insulin, Insulin receptor
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HypoglycaemiaReactive HypoglycaemiaIdipopathicEarly diabetesPost-gastric surgery
Investigations:
Ensure that hypoglycaemia is documanted by laboratory blood/plasma glucoseDetermination 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 fastIf pt develops neuroglycopaenic symptoms then measurePlasma Glucose, Insulin, C-pepetide
Other routine invsetigations: U/E, LFTs, ? Endocrine
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Polyuria
Urine output > 3 litres/day(explain the difference between polyuria and urinary frequency)
Confirm polyuria - 24hr urine collection
Causes of polyuria
Drugs - diuretics, lithiumDiabetes mellitus - fasting ± random glucose, OGTTChronic renal failure - plasma urea & creatinine, Creatinine clearance
Hypokalaemia
Hypercalcaemia
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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
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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)
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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 pictureNB: 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
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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
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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)
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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
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Case 1: TFTs
TT4= 223 (63-142)
TSH= 4.87
Repeated 2-3 weeks later
TT4 = 171
TSH = 2.89
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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
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Case 1: Differential Dx
TSHoma
Thyroid hormone resistance (RTH) - Refetoff’s syndrome
FDH – rare
Heterophile abs
MRI scan of pituitary – Macroadenoma - TSHoma
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Case 2: HistoryPhone 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
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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
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Case 2: Endocrine assessment
Stimulation testing (ITT)
-Achieved hypoglcaemia
-GH deficient
-ACTH/Cortisol deficient
-Centrally hypothyroid
MRI scan – empty sella ? cause
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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)
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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
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Case 3: Diagnosis
Biochemical Dx:
-Hypothyoid-Hypogonadal-Hypocortisolaemic-Hyperprolactinaemic
Hypopituitarism
MRI scan – Macroadenoma - ? Macroprolactinoma
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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
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Case 4:
5/5 6/5 12/5
Na 165 162
K 3.6 3.0
Urea 14.2 6.9
Crea 167 133
POsmo 352
UOsmo 410 222
Gluc 13.6 9.7** fasting
•Result brought to attention of Consultnat Chem Path•Hypernatraemia ? Cause
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Case 4: Dx?
Results suggestive of
-DI-DM
Paired urine and plasma osmolality are very usefulin directing management of
-hypernatraemia-hyponatraemia
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24 yr old male
Unwell – Hx of admissions with hypoNa
Na 121K 5.5Urea 9.3Crea 118
T4 83TSH 4.97
Cortisol 52ACTH 1122