Transcript clinical-biochmeistry-and-metabolic-disease

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
K
Urea
Creat
Ca
PO4
Alb
ALP
PTH
134
5.8
42.2
650
1.82
2.53
37
200
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)
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
32
VitaminD
35
41
79
Albumin
28
32
40
42
PTH
148
19
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
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 – 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
1. Exogenous steroids
2. ACTH secreting pituitary tumour
3. Ectopic production of ACTH
4. 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
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
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
Na
K
Urea
Crea
POsmo
UOsmo
Gluc
* fasting
5/5
165
3.6
14.2
167
6/5
410
13.6
12/5
162
3.0
6.9
133
352
222
9.7*
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