Transcript Clinical-Biochmeistry-of-Metabolic-Disorders

Clinical Biochemistry of
Metabolic Disorders - I
Dr Vivion Crowley FRCPath FRCPI
Consultant Chemical Pathologist
St James’s Hospital
Dublin
Definition of Diabetes Mellitus (DM)
DM occurs because of
1. Lack of insulin and/or
2. Factors opposing insulin action
 It results in a state of increased blood glucose
(hyperglycaemia)
Epidemiology of DM
3% of UK population affected (90% T2DM)
300 million people affected globally by 2025
Classification of DM
Pathogenesis of Diabetes
T1DM
-Immune mediated destruction of pancreatic β-cells
-HLA- associated
-? Viral antigen/molecular mimicry
-Some genetic predisposition now recognised
T2DM
-Genetic predisposition, often family hx
-Insulin resistance in liver, muscle, adipose tissue
-Pancreatic β-cell dysfunction
Obesity is a major risk factor for T2DM
Criteria for diagnosis of Metabolic Syndrome
Component
Defining value
Abdominal obesity
WC >88cm in females
>102cm in males
> 1.65mmol/L
Elevated fasting Triglyceride
Reduced HDL cholesterol
Elevated BP
Elevated fasting glucose
< 1/3mmol/L in females
<1.0mmol/L in males
SBP ≥ 130mmHg OR
SBP ≥ 85mmHg
6.0mmol/L
Waist circumference is a clinically useful measure of
central adiposity
Presenting Features of DM
T1DM – abrupt onset, younger age group, Wt loss vs. T2DM (obese)
•Osmotic symptoms – thirst, polyuria, nocturia, blurred vision
•Fatigue, lassitude
•Recurrent infections e.g. fungal infections, UTI
•Macrovascular complications e.g. angina, MI, TIA
•Microvascular complications e.g. visual impairment, proteinuria, neuropathy
•Associated conditions e.g. cataracts
Diagnosis of DM - background
1980 - WHO criteria based on OGTT
(fasting plasma Glucose ≥7.8mmol/L)
1997 ADA – new criteria – fasting plasma Glucose ≥7.0mmol/L
Increased risk of microvascular and macrovascular
complications above this level
1998 WHO adopted ADA level but maintained OGTT
Fasting and 2h post-glucose load - samples
WHO Criteria for the diagnosis of DM
Management of DM
Healthy lifestyle
•Diet
•Exercise
•Avoid CVD risk factors e.g smoking
Medications (T2DM)
•Biguanides – metformin
•Sulphonylurea
•Thiazolidinediones (TZDs)
Insulin regimens
Treating comorbidities
•Hyperlipidaemia, hypertension etc
What lab tests are used to monitor
glycaemic control?
Plasma Glucose – Fluoride oxalate sample
Glucometer
-Point of Care Testing devices (POCT)
-finger prick blood spot
-Patient keeps a diary
-Record reviewed in clinic
-Glucometer cannot be used to diagnose hypoglycaemia
-Glucose > 30mmol/L must be checked in lab
What other lab tests are used to monitor
glycaemic control?
DCCT and UKPDS trials demonstrated that tight glycaemic
control reduced chronic microvascular complications of DM
HbA1c
-results expressed as % of total Hb (Range <5.4%)
-indicates glycaemic control over preceding 6-8weeks
-variant Hb e.g. HbF, HbS can give misleading results
-Increased RBC turnover e.g. haemolytic anaemia can
affect result
Fructosamine
-Indicates Glycaemic control over 3-4 week
-Useful in monitoring “brittle” diabetic e.g. pregnancy
-Much less commonly used than HbA1c
Acute complications of DM
Diabetic Ketoacidosis (DKA)
Primarily seen in T1DM but increasingly recognised in T2DM
Pathogenesis
•Relative insulin deficiency
•Relative excess effects of catabolic hormones
e.g. glucagon, catecholamines
•Increased gluconeogensis and glycogenoloysis
•Decreased glucose uptake in muscle
•Increased lipolysis results in ketone body formation
•Ketone bodies can be metabolised by brain
Precipitating factors
•Conditions that result in an excess of catabolic hoemones
e.g. infections, trauma, MI
•omission of insulin due to illness
•40% of cases no obvious precipitating factors
Clinical Features of DKA
Hx of
•T1DM with poor control (younger female patients)
•May be first presentation of T1DM
•Polyuria
•Polydipsia
•Wt loss, fatigue
•Nausea, Vomiting
•Abdominal pain (can have raised plasma amylase)
O/E
•Drowsiness
•Dehydrated
•Hypotensive
•Tachypnoea (air hunger or Kaussmaul breathing)
•Acteone breath
HyperOsmolar Non-Ketotic (HONK) coma
Associated with T2DM
Pathogenesis
•Relative insulin deficiency
•Excess glucose production
•Decreased glucose uptake
•Hyperosmolar plasma as a result of severe hyperglycaemia
•However ketone body production is not a feature ? Reason why
Precipitating factors
•Similar to DKA
•Also may be first presentation of T2DM
Clinical Features of HONK
2-3 week hx of
•polyuria
•polydipsia
•increasing confusion
O/E
•Obtunded
•Dehydrated
•Hypotensive
•Focal neurological signs
Biochemistry features of DKA and HONK
Lactic Acidosis (LA)
Characterised by
•pH < 7.35
•plasma lactate > 5mmol/L
LA associated with biguanides – associated with renal impairment
Chronic Complications of DM
Microvascular - Retinopathy
Pre-proliferative
Maculopathy
Microvascular - Neuropathy
Diffuse polyneuropathy
Autonomic neuropathy
-Erectile dysfunction
-Gastroparesis
Symmetrical sensory neuropathy
- Can lead to neuropathic ulcers etc
Mononeuropathies
Proximal motor (femoral) neuropathy
Radiculopathies
Cranial nerve palsies
Acute painful neuroapthies
Microvascular - Nephropathy
Early stage – hyperfiltration with increased GFR
Incipient stage – microalbuminuria
Persistent – detectable proteinuria
Progressive renal failure – decreasing GFR leading to ESRD
Detection of microalbuminuria
•Key indicator of diabetic renal disease
•Also an indicator of increased CVD risk in T2DM
•Screening test : Albumin-Creatinine ratio
2.5mg/mmol/L (Men) and >3.5 (women)
•Urinary albumin excretion rate
Pathogenesis of microvascular complications
Chronic hyperglycaemia may cause
Accumulation of sorbitol via polyol pathway
Myoinositol depletion
Protein glycosylation forming AGE
(AGE = Advanced Glycosylation End-Products)
AGE can lead to
-Basement membrane damage
-Intracellular protein and DNA damage
-Stimulation of ROS through AGE receptors
Macrovascular Complications
Coronary heart disease (CHD)
Peripheral vascular disease (PVD)
Cerebrovascular disease
In CVD risk assessment charts DM is considered CVD risk
Equivalent i.e. must treat risk factors
•Dyslipidaemia
•Hypertension
•Obesity
Hypoglycaemia
Definition
•plasma glucose < 2.8mmol/l (blood glucose < 2.2mmol/l)
Clinical presentation
•Adrenergic features,
•Neuroglycopaenia
“Whipple’s triad”
•Symptoms & signs of hypoglycaemia
•Plasma glucose < 2.8mmol/l
•Relief of symptoms by glucose intake (infusion/oral)
Hypoglycaemia -Aetoiology
Fasting Hypoglycaemia
Causes:
Drug therapy - Insulin, Sulphonylurea, -blockers, Quinine
Factitious - Insulin, sulphonylureas (healthcare workers)
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 - Aetiology
Reactive (post-prandial) Hypoglycaemia
Hypoglycaemia – up to 4 hrs after food intake
Idiopathic
Early diabetes
Post-gastric surgery
Non-Insulinoma Pancreatogenous Hypoglycaemia
(adult-onset Nesidioblastosis)
Hypoglycaemia – Biochemical Investigations
Ensure that
1. hypoglycaemia is documented by laboratory plasma glucose
2. sample collected into a fluoride tube
5hour OGTT
-Hypoglycaemia may occur between 2-5 hours after glucose load
-This may occur in normal individuals (? Significance)
Definitive investigation for fasting Hypoglycaemia:
•Supervised - 72 hour prolonged fast
•If pt develops neuroglycopaenic symptoms then measure
Plasma Glucose, Insulin, C-pepetide
Other routine investigations
U/E, LFTs, ? Endocrine (R/O Hypopit, Addison’s disease)
Clinical Biochemistry and Calcium metabolism
What are the main factors influencing
plasma calcium levels?
Plasma Ca
•50% free (ionised Ca)
– influenced by pH
•40% bound to protein
– influenced by Albumin and Globulin levels
•10% complexed to PO4, HCO3, Lactate etc
– influenced by levels of these molecules
Parathyroid hormone
•Increases Bone resorption
•Increases Renal Ca reabsorption
•Decreases Renal PO4 reabsorption
•Increases Renal production of 1, 25 (OH)2 VitD
Net effect:
Ca
PO4
Vitamin D - (1,25 (OH)2 Vit D
•Increases bone resorption
•Increases renal reabsorption of Ca and PO4
•Increases GI absorption of Ca and PO4
•Decreases PTH production
•Decreases renal Vit D
Net Effect: Ca
PO4
Calcitonin
•Net effect:
Ca
PO4
•(? Clinically relevant e.g. MTC no hypocalcaemia)
PTH related Peptide (PTHrP)
•Binds to the PTH receptor – similar effects as PTH
•Physiological role - ? Involved in Ca regulation in pregnancy
Biochemical Investigation of a Patient
with Suspected Hypercalcaemia
What are the causes of Hypercalcaemia?
Hyperparathyroidism
Malignancy
“The Rest”
•Dehydration
•Vitamin A or D toxicosis
•Immobilisation
•Thiazides
•Sarcoidosis
•Dialysis fluid
•Milk-alkali syndrome
•Addison’s disease
•Thyrotoxicosis
•Phaeochromocytoma
•Familial Hypocalciuric Hypercalcaemia (FHH)
What are the clinical features of Hypercalcaemia?
Mild HyperCa – asymptomatic
Moderate/Severe HyperCa
•CNS: lethargy, stupor, coma, psychosis
•GItract: anorexia, nausea, PUD, pancreatitis
•Renal: Nephrolithiasis, polyuria
•Mus Skel: arthralgia, bone pain
•CVS: hypertension, ECG changes (shortened Q-T, arrythmias)
“Bones, stones, moans, groans”
Does the patient have “True Hypercalcaemia”?
“What is the local reference range?”
Dehydration
Venepuncture – hamoconcentration
What is the albumin concetration?
Calculate “corrected”plasma Ca
Corrected plasma Ca = Total Ca + [(40 – Albumin g/L) x 0.02]
Example:
Ca 2.60 mmol/L (2.15-2.55)
Alb 50g/L
CorrCa 2.60 + [(40-50) x 0.02]
2.60 – 0.2 = 2.4mmol/L
Further Investigation of a single hypercalcaemic sample
Repeat plasma Ca
Fasting non-tourniquet sample x 2
•If normal monitor – repeat in 6 months
•If still elevated then proceed with further investigations
Is the patient on “Calcium-raising” medications?
Thiazides
Vit D or A
Milk-alkali syndrome
Lithium
Discontinue meds and recheck Plasma Ca
What is the PTH level?
PTH ref range (15 - 65ng/ml) – St James’s Hospital
If normal or elevated this implies HyperCa is PTH-dependent
(Hyperparathyridism)
Primary – adenoma (85%), hyperplasia (14%), malignancy (1%)
Secondary – Vit D deficiency (ESRD)
Tertiary - ESRD
FHH
Hyperparathyroidism is the most common cause of
HyperCa in the community
If PTH suppressed the HyperCa is PTH-independent
Consider other causes
What is FHH?
Familial Hypocalciuric Hypercalcaemia
Charcaterised by
•Mild HyperCa (usually < 3.0mmol/L)
•Normal or mildly elevated PTH
•Rarely have symptoms related to hyperCa
•Caused by a loss of function mutation in CaSR
•Family Hx of “Ca problems” or parathyroidectomy
Need to diagnose to avoid inappropriate parathyroidectomy
Measure FECa in second voided morning urine (Random)
- <1% in the presence of HyperCa suggestive of diagnosis
Does the patient have evidence of neoplastic disease
PTH-independent HyperCa – commonest cause is malignancy
Mechanisms
Humoral HyperCa of Malignancy (HHM) – secretion of PTHrP
-Squamous (head/neck, lung), renal, thyroid, breast,
Localised osteolytic HyperCa (LOH)
- myeloma, leukaemia, breast
Increased Vit D production (rare)
- lymphoma
Malignancy is the most common cause of HyperCa in hospitals
Other investigations: serum/urine protein electrophoresis,
Other Causes
•Sarcoidosis – Serum ACE
•Thyroid disorders – TFTs
•Addison’s disease – Synacthen test
•Vit D toxicity – Vit D levels
•Immobilisation – multiple fractures, Paget’s disease
NB: 90%+ of HyperCa is caused by PHPT or malignancy
Routine GP sample from 62 yr old female
Clinical details: fatigue
Ca 2.75 (2.15-2.55)
PO4 0.73 (0.8-1.35)
ALB 36 (35-40)
ALP 104 (30- 120)
TP 74 (60-80)
Is this “true hypercalcaemia”?
The PTH is 85 (9-65), so what is the working diagnosis?
What other investigations would you consider?
How would you advise this patient?
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?