TI2 Flashcards
Define anemia (2)
Condition in which number of RBCs (+ consequentially their oxygen-carrying capacity) is insufficient to meet they body’s physiological needs
Insufficient oxygen-carrying capacity due to reduced Hb conc. as seen with insufficient RBC
What is haemoglobin and what is seen in anaemia? (2)
An iron-containing oxygen-transport metalloprotein within RBCs
Reduction in haemoglobin = anaemia (reduction in O2 carrying capacity)
What are the cellular components of blood and where are they produced? (2)
RBCs, WBCs + platelets
Produced in bone marrow in long bones
How do Hb levels vary in different people? (7)
Value changes throughout life Vary b/w M + F ~12-14yrs old values = adult values Male > female > pregnant female Pregnant women have increased in physiological volume Lower Hb vol. = more severe anaemia Measured in g/L (used to be g/dL)
What do RBCs require to mature in normal erythropoiesis? (5)
Vit. B12 + folic acid (DNA synthesis) Iron (Hb synthesis) Vitamins Cytokines (erythropoietin) Healthy bone marrow environment
What are the mechanisms of action of anaemia? (3)
Failure of production - hypoproliferation, reticulocytopenic
Ineffective erythropoiesis
Decreased survival - blood loss, haemolysis, reticulocytosis
Mean corpuscular volume (MCV) and type of anaemia? (3)
Microcytic e.g. iron deficiency, thalassaemia etc
Normocytic e.g. sickle cell disease etc
Macrocytic e.g. B12 or folate deficiency, myelodysplasia
What is a nutritional anaemia? (2)
Anaemia caused by lack of essential ingredients that body acquires from food sources
E.g. iron deficiency, vit. B12 deficiency, folate deficiency
What it iron’s role? (3)
Essential for O2 transport
Most abundant trace element in body
Daily iron requirement for erythropoiesis varies depending on gender + physiological needs
How do we use Hb levels to diagnose anaemia? (4)
Measured in g/L
Values changes throughout life + varies b/w male + female
Pregnant women have increased physiological vol.
Lower Hb vol. = more severe anaemia
What is required for normal erythropoiesis? (3)
Vit B12 + folic acid (for DNA synthesis)
Iron (Hb synthesis)
Vitamins, cytokines, healthy bone marrow environment
What’s the MOA of anaemia? ()
Failure of production - hypoproliferation - reticulocytopenic Ineffective erythropoiesis Decreased survival: - blood loss - haemolysis - reticulocytosis
Examples of microcytic anaemia (3)
Iron deficiency
Thalassaemia (globin def)
Anaemia of chronic disease
Examples of normocytic anaemia (5)
Anaemia chronic disease Aplastic anaemia Chronic renal failure Bone marrow infiltration SCD
Examples of macrocytic anaemia (7)
B12 def Folate def Myelodysplasia Alcohol induced Drug induced Liver disease Myxoedema
What is a nutritional anaemia? (4)
Anaemia caused by lack of essential ingredients that body acquires from food sources
Iron def
Vit. B12 def
Folate def
Daily iron requirement (3)
7 months - 14yrs -> M=F (~9mg)
14yrs to menopause -> men + pregnant women require mere
@ menopause M = F (~8mg)
Haem and non-haem source of iron (3)
Recommended intake assumes 75% if from haem iron sources
Veg diet iron requirement is ~2-fold higher
Haem iron is more easily absorbed than non-haem
How is iron distributed in an adult? (4)
Maj. or iron in RBCs
~300g in bone marrow
Dietary iron absorbed predominantly to duodenum
Fe3+ ions circulate bound to plasma transferrin + accumulate within cells in form of ferritin
Average blood loss of men + non-menstruating women (1)
~1mg per day
Why do premenopausal women have lower iron stores? (1)
Due to recurrent blood loss through menstruation
Describe iron metabolism (4)
Ferric (3+) + ferrous (2+) forms Maj. of iron circulates in Hb Remainder as storage + transport proteins: - ferritin + haemosiderin - found in liver cells
How is iron absorption regulated? (3)
By GI mucosal cells
Max. absorption in duodenum + proximal jejunum via ferroportin receptor (hepcidin hormone)
What factors affect absorption of iron? (5)
Source of iron: - haem, ferrous > non-haem, ferric As well as: - iron storage levels - other foods - GI acidity - bone marrow absorption
What is hepcidin? (4)
Iron-regulatory hormone
Causes ferroportin internalisation + degradation
Feedback reg. by [iron] in plasma + liver
+ by erythropoietic demand for iron
What effects does hepcidin have? (4)
Decrease in iron transfer into blood plasma from:
- duodenum
- macrophages (involved in recycling senescent RBCs)
- iron-storing hepatocytes
How is iron transported + stored? (3)
Transported from enterocytes + then either into plasma or stored as ferritin
Once attached to ferritin, binds to transferrin receptors on RBC precursors
IDA -> decreased ferritin stores, increased transferrin
What iron studies can you do when investigating IDA? (4)
Serum Fe - v variable throughout so not v useful overall
Ferritin = primary storage protein, reliable for IDA tests
Transferring saturation = serum Fe:TIBC
- % iron transferrin binding site occupied by iron
Where is transferrin produced? (2)
In liver
Production is inversely proportional to Fe stores
What is TIBC?
Capacity of transferrin to bind iron
Indirect measurement of transferrin
Easier to measure TIBC than transferrin levels
In IDA, TIBC = high
- increased transferrin produced aiming to transport more iron to tissues in need
Can use combo of trans. sat. + TIBX
Causes of iron deficiency (7)
Not enough in e.g. poor diet, malabsorption, increased physiological need
Losing too much e.g. blood loss, menstruation, GI tract loss, parasite
What investigations are there for IDA? (4)
FBC e.g. MCV, [Hb], MCH, reticulocyte count
Iron studies e.g. ferritin, transferrin sat, TIBC
Blood film
BMAT (bone marrow aspirate + trephine) + iron stores
Development of IDA (5)
Initially normocytic + normochromic
Serum ferritin = most sensitive indicator of mild IDA
% transferrin sat. + free erythrocyte protoporphyrin values do not become abnormal until tissue stores are depleted of iron
Decrease in [Hb] occurs when iron is unavailable for haem synthesis
MCV + MCH are not abnormal until several months after tissue stores are depleted of iron
Lab results in IDA (4)
Decreased ferritin
Decreased transferrin sat.
Decreased/norm serum iron
Increased TIBC
What would be your expected IDA findings? (3)
Low [Hb]
Microcytic (use neutrophils for comparison)
Hypochromic (enlarged area of central pallor) indicating decreased MCHC
How prevalent is IDA? (5)
Most comon nutritional def.
More common in women + over70s
19% Af-Am women
Premenopausal most common cause = excessive menstrual losses
Men/postmenopausal most common cause = blood loss from GI tract
What are the symptoms + signs of IDA? (8)
Symptoms = lethargy, fatigue, dizziness Signs = pallor of mucous membrane, bounding pulse, systolic flow murmers, smooth tongue, koilonychia (nail disease)
What are the findings of B12 + folate def? (6)
Similar findings + clin. symptoms Can be found together or as isolated pathologies Macrocytic anaemia Low [Hb] High MCV Normal MCHC
What are causes of megaloblastic macrocytic anaemia? (3)
Vit. B12/folate def
Interference with B12/folate met
Drug-related
How is megaloblastic macrocytic anaemia characterised on a peripheral smear? (2)
Macrovalocytes (enlarged, oval RBCs)
Hypersegmented neutrophils
What are causes of non-megaloblastic macrocytic anaemia? (4)
Alcoholism (affects BM) Hypothyroidism Liver disease Myelodysplastic syndrome (production of RBCs by BM is disrupted) Reticulocytes (haemolysis)
Vitamin B12 nutritional info (4)
Animal + dairy product source (difficult if vegan) Cooking = 10-30% loss 1-2mcg daily requirement Absorbed at ileum via intrinsic factor Cobalamin
Folate nutritional info (4)
Veg + liver
Cooking = 60-90% loss
100-150mcg daily requirement
Absorbed at duodenum + jejunum
What are B12 + folate important for? (4)
Final maturation of RBC
Synthesis of DNA
Thymidine triphosphate synthese
(Folate also necessary for adenosine, guanine + thymidine synthesis)
Causes of folate def. (3)
Decreased intake e.g. poor diet, elderly, chronic alcohol intake
Decreased absorption e.g. medication (folate antagonists), jejunal resection, tropical sprue (causes malabsorption)
Increased demand e.g. pregnancy/breastfeeding, infancy, growth spurts, disseminated cancer, haemolysis + rapid cell turnover (e.g. in SCD), urinary losses (e.g. heart failure)
Vitamin B12 (5)
Essential cofactor for methylation in DNA + cell metabolism
Intracellular conversion to 2 active co-enzymes necessary for homeostasis of methylmalonic acid (MMA) + homocysteine
Huge variation in recommended daily dietary intake
Require healthy terminal ileum + presence of intrinsic factor
Transcobalamin I+II transport vit B12 to tissues
Where is intrinsic factor produced? (1)
Parietal cells of stomach
Causes of B12 def (5)
Decreased intake e.g. malnutrition, vegan diet
Medication e.g. alcohol, NO, PPI/H2 antagonists, metformin
Increased requirements e.g. haemolysis, HIV, preg, growth spurts
Congenital causes e.g. intrinsic factor receptor def., cobalamin mutn C-G-1 gene
Impaired absorption e.g. pernicious anaemia, gastorectomy/ileal resection, Zollinger-Ellison syndromes, parasites
Haemotological consequences of B12/folate def. (7)
Normal/raised MCV
Normal/low Hb
Low reticulocyte count
Increased LDH
Macrocytes, ovalocytes, hypersegmented neutrophils
BMAT -> hypercellular megaloblastic, giant metamyelocytes
Methylmalonic acid increased
What are the clinical consequences of B12/folate def? (6)
Cognitive, depressive, psychotic effects
Neurology -> myelopathy, sensory changes, ataxia, spasticity (SACDC)
Infertility
Cardiac cardiomyopathy
Tongue -> glossitis, taste impairment
Pancytopenia (def of RBCs, WBCs + platelets)
What is pernicious anaemia? (5)
Autoimmune disease Gastric parietal cell Abs IF Abs Lack of IF Lack of B12 absorption
How do we treat anaemias? (1)
Treat underlying causes e.g. treat heavy menstrual bleeding that causes excessive blood loss
How do we treat IDA? (3)
Diet
Oral/parenteral supplementation
Stop the bleeding
How doe we treat folic acid def? (1)
Oral supplements
How do we treat vit. B12? (1)
Oral vs. IM treatment
Why do we need blood glucose haemostasis? ()
To avoid hyper- + hypoglycaemia
How are blood glucose levels maintained? (2)
Dietary carb
Glycogenolysis, gluconeogenesis (from lactate/glycerol/a.a.s) etc
What is the liver’s role in blood glucose haemostasis? (2)
After meals -> stores glucose as glycogen
During fasting -> makes glucose available through glycogenolysis + gluconeogenesis
Why do we need to avoid hypoglycaemia? (1)
Brain + RBCs require continuous supply - don’t produce glucose themselves
Why doe we need to avoid hyperglcaemia? (2)
Increased glucose/metabolites cause micro- + macrovascular pathological changes to tissues
Can lead to diabetes + complications arising from diabetes
Describe insulin (6)
Main reg. of glucose levels
Peptide hormone (51a.a.s)
Synthesised in beta-cells of islets of Langerhans as pro-insulin:
- amino terminal B-chain connected to carboxyl A-chain by C-chain
- ER peptidases cleave proinsulin to insulin + C-chain
Secretion stimulated by rise in blood glucose
What are the metabolic actions of insulin in the liver? (6)
Decreased ketogenesis Decreased gluconeogenesis Decreased glycogenolysis Increased amino acid uptake Increased glycogen synthesis Increased fatty acid synthesis
What are the metabolic actions of insulin in adipose tissue? (2)
Increased lipogenesis
Decreased lipolysis
What are the metabolic actions of insulin in muscle? (3)
Decreased protein breakdown
Increased a.a. uptake
Increased glycogen synthesis
What are the generalised tissue effects of insulin? (1)
Increased glucose uptake
Glucose counter-regulatory hormones (4)
Glucagon
- secreted by alpha cells in response to hypoglycaemia
- stims. gluconeogenesis + glycogenolysis
Adrenaline
- increased glycogenolysis + lipolysis
Cortisol
- increased glycogenolysis + lipolysis
GH
- increased gluconeogenesis + glycogen synthesis
What is diabetes mellitus? (5)
Met disorder characterised by chronic hyperglycaemia, glycosuria + associated lipid/protein met abnormalities
Hyperglycaemia due to increased hepatic glucose production + decreased cellular uptake
Blood glucose >10mmol/L exceeds renal threshold
LT complications can lead to micro/macrovascular disease
Kideny can only absorb so much glucose + high conc. in renal tubules causes osmotic effects (polyuria, polydipsia) as a result of volume depletion./dehydration
What is the prevalence of DM? (3)
4/5million globally
UK 2013 = 3.2mil (more than doubled since 1996)
Increased diagnosis due to - increased awareness, poor diet, low physical activity
Why is weight loss a symptom of DM? (2)
Insulin is important in protein catabolism so if insulin is ineffective/not present than protein is broken down
How is DM diagnosed? (4)
Presence of symptoms - random plasma glucose ≥ 11.1mmol/L - fasting plasma glucose ≥ 7.0mmol/L - 2hr plasma glucose ≥11.1mmol/L (2hrs after 75mg oral glucose tolerance test) Absence of symptoms - test blood samples on 2 separate days
What is impaired glucose tolerance? (2)
Fasting plasma glucose = 6.1-6.9mmol/L
OGTT value of
What is impaired fasting glucose? (2)
Fasting plasma glucose
Oral glucose tolerance test (4)
OGTT used in individuals with fasting glucose
Why carry out OGTT? (4)
Patients with impaired fasting glycaemia
Unexplained glycosuria
Clincical features of diabetes with normal plasma glucose values
Diagnosis of acromegaly (excess GH)
- normally GH levels will fall over 2hrs
- in acromegaly the levels will stay high
Classification of DM (4)
Type 1 - def insulin due to autoimmune destruction of beta-cells in pancreas by T-cells
Type 2 - insulin secretion is maintained but target organ resistance to its actions
Gestational (occurs for 1st time during preg)
Secondary - due to chronic pancreatisis, pancreatic surger, secretion of antagonists
What are the features of type I DM? (6)
Mainly kids + YAs
Sudden onset
Symptoms may be preceded by pre-diabetic period
Autoimmune destruction of beta-cells is most common cause
Interaction b/w genes + environment
Strong link to HLA genes on chr 6
What is the pathogenesis of type I DM (6)
Circulating autoAbs to various T-cell Ags
- glutamic acid decarboxylase
- tyrosin-phosphate-like molecule
- islet auto-Ag (most commonly detected0
90% of DM type I patients have one of these Abs
Destruction of pancreatic B-cells cause hyperglycaemia due to absolute deficiency of insulin + amylin
What is amylin? (2)
Glucoreg peptide hormone, co-secreted with insulin
Lowers blood sugar by slowing gastric emptying + suppressing glucagon output from pancreatic cells
What are the metabolic complications of type I DM? (6)
POLYPHAGIA (excessive eating/appetite)
Too much sugar in circ -> kidney cannot absorb all in renal tubule -> glucose passes out in urine (GLYCOSURIA)
Increased glucose levels in kidney –> osmotic effects -> increase in volume passed (POLYURIA)
Leads to VOL. DEPLETION/dehydration -> POLYDIPSIA
Increased lipolysis in absence of insulin -> increase in FFAs -> increased beta-oxidation of FFAs to produce ketone bodies -> KETOACIDOSIS
VOL. DEPLETION + KETOACIDOSIS can lead to DIABETIC COMA
What are the features of type II DM? (7)
Produce insulin but insulin resistance
Slow onset
Middle aged/elderly
Strong familial incidence
Uncertain pathogenesis (insulin resistance, beta-cell dysfunction)
May be due to lifestyle factors
Emergency presentation as HONK (hyper-osmolar non-ketotic state)
HONK coma (9)
Met. complication of type II DM Ketone bodies not produced As only produced when you don't have insulin due to increased lipolysis Dev. of severe hyperglycaemia Extreme dehydration Increased plasma osmolality No ketosis, minimal acidosis Impaired consciousness Death (if untreated)
Biochemical monitoring of type II DM (5)
Immediate = blood glucose finger prick test
Few hours = urinary dipstick
3-4 months = blood HbA1c (glycated Hb, covalent linkage of glucose residue in Hb)
Others = urinary albumin (index of risk of progression of nephropathy, albumin in urine indicates kidney damage) + abnormalities of serum lipids common in DM (increased risk of MI + stroke)
What are the aims of monitoring type II DM? (5)
Prevent complications through tight control
Avoid hypoglycemia (avoid over control)
Self monitoring through:
- capillary blood measurement
- urine analysis -> glycosuria indicates blood glucose conc. is above renal threshold
Aim at
Stepwise treatment of type II DM (4)
- Look at changing lifestyle
- If ineffective, patient is given monotherapy e.g. METFORMIN
- Then combine another anti-diabetic drug with diff. MOA
- Insulin + oral agents prescribed if prev. treatment is ineffective
Long term DM complications (3)
Microvascular diease (retinopathy, neuropathy, nephropathy) Macrovascular disease (rel. to atherosclerosis heart attack/stroke) Unclear mechanism
How to reduce CV risk in diabetes? (7)
Eat food low in fat + salt Exercise Stop smoking Attain normal weight + waist circumference HbA1c
What is hypoglycaemia? (3)
Plasma glucose
Causes of hypoglycaemia (4)
Insulinoma
Drugs e.g. sulphonyureas, insulin, alcohol abuse
Endocrine disorder e.g. of cortisol
Inherited met. disorders e.g. glycogen-storage disease, galactosaemia, hereditary fructose intolerance
