CR EOYS8 Flashcards
What are the two products of the alpha globin gene? [2]
What are the products of beta globin genes? [4]
How do the above interact? [1]
What are the two products of the alpha globin gene? [2]
Alpha globin chain
Zeta globin chain
What are the products of beta globin genes? [4]
Epsilon (e) globin
Gamma globin
Delta globin
Beta globin
To form Hb: need interaction of one component of alpha globin chain and beta chain (could be alpha and delta etc)
What are the 3 functional genes found on a-Globin gene? [3]
When are each expressed? [1]
Embryonic: zeta [1] HbZ gene
Fetal / Adult: Alpha 1 / 2 [2] HbA1 and HbA2
α-globin gene expression begins in early fetal life and is predominant throughout fetal and adult life
What are the 5 functional genes found on beta-Globin gene? [3]
When are each expressed? [1]
Embryonic: HBE gene / e-globin gene
Fetal: HBG2 and HBG1 genes Gy and Ay globin gene (The γ-globin genes (Gγ and Aγ) are the major β-like genes expressed in most of fetal life)
Adult: HBD and HBB genes delta and B- globin
Name the different places that haematopoiesis occurs in from embryo to neotate [4]
Embryo (3 weeks): Yolk sac
Fetus (6 weeks): Liver
Fetus (8 weeks): Spleen =
Neonate: Bone marrow
Label the type of Hb that are dominant in each stage of life [3]
Yolk Sac / A: Z2, E2
Fetal liver / B: A2, γ2
Bone marrow / C: A2, B2
What are the normal variants of Hb? [3]
What is the inheritance patten of thalassaemias? [1]
What is the cause of thalassaemias [1]
What are the two types and how do they arise? [2]
Autosomal recessive
Abnormal production of globins:
the red blood cells are more fragile and break down more easily.
Alpha thalassaemia: deletion of HBA1 & HBA2 genes ( alpha-globin chains) (two copies on each chromosome - so have 4 genes. can have deletion of 1-4 of those genes)
Beta thalassaemia: mutations in HBB (beta-globin chains) genes (normally B genes)
Explain the 4 different types of alpha thalassaemias
o1 defective alpha subunit: alpha thalassemia minima
· Minimal effect on Hb synthesis
· The other alpha globin genes produce enough subunits
· No clinical symptoms
· Slightly reduced MCV
· ‘silent carriers’
o2 alpha subunits missing or defective: alpha thalassemia minor
· Mild microcytotic hypochromic anaemia
· The remaining 2 alpha genes produce nearly normal levels of RBCs
· Can be mistaken for iron deficiency anaemia.
o3 alpha subunits missing or defective: Haemoglobin H disease (HbH)
Deletion of three alpha genes
Haemoglobin H (B4)
Moderate microcytic hypochromic anaemia
Excess beta chains cause damage by:
i) damage the red blood cell membrane, resulting in intramedullary hemolysis
ii) HbH has very high affinity for oxygen, and doesn’t release oxygen to the tissues. And a consequence of hypoxia is that it signals the bone marrow, as well as extramedullary tissues like the liver and spleen, to increase production of red blood cells.
o4 alpha subunits missing or defective:
· Foetus cannot live outside of uterus
· May not survive gestation
· Hydrops fetalis: Haemoglobin Barts (γ4) - super high affinity to O2.
Incompatible with life
Why does Hb Bart’s hydrops foetalis syndrome arise? [1]
Describe the structure of Hb in Hb Bart’s hydrops foetalis syndrome in fetus [1]
Describe the structure of Hb in Hb Bart’s hydrops foetalis syndrome in embryo [1]
Hemoglobin Bart’s results from deletion of all four α-globin genes, with the subsequent inability to produce any α-globin chains, leading to failure of synthesis ofHb A, F, or A2. In the fetus, an excess number of γ-globin chains join together to form unstabletetramersknown as Hb Bart’s (γ4)
Haemoglobin in in erythrocytes contain
non-functional homotetramers γ4 (Hb γ4)
, or if in embryo: embryonic Hb Portland (ζ2γ2)
Die in utero (23-38 weeks or shortly after birth)
Describe how Beta-thalassemias occur [2] (be specific)
Explain why Beta-thalassemias are pathological [2]
Beta-thalassemias: occur from mutations within the B-gene [1]
Characterised by a reduced or absent production of haemoglobin A (which contains a2,B2)
As a result: excess α-chains precipitate in red cell precursors (as theres no beta chains) causing ineffective erythropoiesis as well as in mature red cells causing hemolysis.
Ineffective erythropoiesis and hemolysis cause anaemia
When there’s a β-globin chain deficiency, free α-chains accumulate within red blood cells, and they clump together to form intracellular inclusions, which damage the red blood cell’s cell membrane. This causes hemolysis,
What are the three different types of Beta-thalaseemia and what do they arise from? [3]
Mutations can be either deletion or defective
Thalassaemia minor: Mutation in one HBB gene
( β/βo or β/β+ genotype)
* They have one abnormal and one normal gene.
* mild microcytic anaemia
Thalassaemia intermedia: Mutation in two HBB genes ((β+/βo or β+/β+ genotype)
* This can be either two defective genes or one defective gene and one deletion gene.
* more significant microcytic anaemia
Thalassaemia major: Mutations in both HBB genes (βo/βo genotype)
* major are homozygous for the deletion genes. They have no functioning beta-globin genes at all.
* Severe microcytic anaemia
Explain why Beta Thalassaemia minor & Thalassaemia intermedia & Thalassaemia major have different symptoms [3]
There is one copy of Beta gene on each chromsome (but alpha gene, have 2)
Thalassaemia minor: Mutation in one HBB gene
( β/βo or β/β+ genotype):
causes - reduced or no production of beta chains from one gene, but normal beta globin produced from other gene to form HbA: asymptomatic
Thalassaemia intermedia: Mutation in two HBB genes*
*- significantly reduced levels of beta chains. can form some HbA, but present with microcytic hypochromic anaema
Thalassaemia major: Mutations in both HBB genes (βo/βo genotype)
- No beta chains formed: No HbA formed –> HbF and HbA2 increased instead, get accumulation of a-globin chains: which causes aggregations in rbc
How would you distinguish between anaemia from ID versus thalassemia?
In thalassaemia, although red cells are microcytic, serum iron and ferritin are normal (as iron absorption is normal )
How do you treat a/b thalassemia? [1]
What is an issue with this treatment? [1] & how do you treat this? [1]
Thalassaemia major (a+b) treatment:
Regular blood transfusion
BUT: can get Iron overload from constant blood transfusion: this happens because excess haemolysis can lead to excess free iron in blood (usually bound to ferritin in the spleen), which is oxidising
Undergo iron chelation
what is the mutation the that causes SCA ? [3]
what does is the name of the Hb this mutation leads to? [1]
Single base mutation of Adenine to Thymine. Produces a substitution of valine for glutamic acid at the sixth codon of the beta-globin chain. Hb gene found on chromosome 11
Creates a hydrophobic spot on the outside of the protein that sticks to the hydrophobic region of an adjacent haemoglobin molecule’s beta chain: intracellular hemoglobin polymerization, loss of deformability and changes in cell morphology
Repeated sickling / non sickling causes change in membrane to permenant sickled
What are the clinical features of SCA? [4]
(haemolytic) Anaemia
Jaundice (increased bilirubin due to shorter lifespan)
Increased susceptibility to infection (particularly encapsulated bacteria)
Vaso-occlusive crises (pain due to hypoxia in tissue where capillaries occluded)
Chronic tissue damage (eg stroke, avascular necrosis of hip, retinopathy
Why does hemoglobin H, or HbH, disease lead to splenomagaly or hepatomegaly? [3]
HbH = Hb β4. This form of Hb causes
Damage to the red blood cell membrane, resulting in intramedullary hemolysis, or red blood cell breakdown in the bone marrow; or extravascular hemolysis, when red blood cells are destroyed by macrophages in the spleen.
Second, HbH has very high affinity for oxygen, and doesn’t release oxygen to the tissues. And a consequence of hypoxia is that it signals the bone marrow, as well as extramedullary tissues like the liver and spleen, to increase production of red blood cells. This may cause the bones that contain bone marrow, as well as the liver and spleen, to enlarge.
Why does beta thalassamia minor symptoms only appear after 3-6 months?
Symptoms are produced by alh
During the first 3 to 6 months of life, fetal hemoglobin is still produced, and that process uses up some of the free α-chains
What are the mising alpha globins replaced with in HbH as a fetus and adult? [2]
Hemoglobin H forms when only one normal alpha gene has been inherited. This causes significantly impaired alpha globin production. In the neonatal period, this will cause an excess of gamma, and in adults, this leaves an excess of beta-globin chains
3 symptoms of beta thal. major? [3]
Severe microcytic anaemia
Splenomegaly
Bone deformities
Jaundice: chronic haemolytic anaemia of abnormal red blood cells
What are the 3 different classifications / types of heart failure?
1. Left ventricular systolic dysfunction (LVSD, known as HFrEF): where EF is less than 40%
The EF is low enough to not require further signs or symptoms for diagnosis
2. Heart failure with mildly reduced LV function (HFmrEF): Where EF is 40-49%
Also requires:
Elevated naturietic peptides
One of: structural heart disease OR diastolic dysfunction
3. Heart failure with mildly reduced LV function (HFmrEF): Where EF is >50%
Also requires:
Elevated naturietic peptides
One of: structural heart disease OR diastolic dysfunction
.
What are 4 causes of heart failure? [4]
Coronary artery disease: myocardial ischaemia or MI (as that part of the heart wont be working)
Hypertension: get left ventricular hypertrophy (LV stiffened and can’t relax)
Cardiomyopathy: dilated cardiomyopathy: reduces EF, hypertrophic cardiomyopathy leads to LV thickening, inflammatory disorders of LV, tachyarythmias (e.g. chronic afib will lead to heart failure)
Valvular heart disease: aortic and mitral regurgitation lead to LV dilatation and LV failure.
Why might a patient develop acute decompensation heart failure and therefore present with significant symptoms? [4]
Cardiac arrhythmias (e.g., AF):
Hypertension
Anaemia
Infections
What symptoms would someone with heart failure present with? [3]
What else do you need to do if suspect heart failure and why? [1]
Shortness of breath
Ankle oedema
Fatigue
Also need to conduct an ECHO as the above are very non-specific
Which investigations may you undertake to ID heart failure?
Detailed history and exam
If previous MI: Echo: Ventricles should appear the same size, if not suggests heart failure (systolic or diastolic). If appear ok, heart failure unlikely.
If no previous MI: Check BNP levels.
If raised: have an Echo and repeat above.
If not raised, heart failure unlikely
CXR: Look for pulmonary oedema pulmonary congestion (upper lobe blood diversion)
ECG
How does targeting sympatho-adrenal activation and RAAS systems cause an increase in contractile function?
What are features of dilated cardiomyopathy? [1]
What are the physiological consequences of dilated cardiomyopathy? [3]
Left or biventricular dilation & systolic dysfunction in absence of CAD, hypertension valvular disease or congenital heart disease. Dilated left ventricle which contracts poorly/has thin muscle
Causes:
- Reduced stroke volume and therefore CO
- Disordered myocytes: impaired ventricular filling
- Increase in preload / end diastolic pressure
Describe the pathology behind hypertrophic cardiomyopathy (HCM)
The hypertrophic, non-compliant ventricles impair diastolic filling resulting in reduced stroke volume and thus cardiac output
Septum can also be affected: causes left ventricular outflow tract obstruction or mitral valve dysfunction. Significant thickening of septum causes tightening of aortic valve – reduced ejection fraction
Causes a disarray of cardiac myocytes so conduction is affected
Describe the aetiology of IPF xx
Describe the pathophysiology of IPF
Occurs due to:Unknown cause [1]
Environmental factors, chronic viral infections, smoking, Fx causes scarring and honeycombing of the lungs: airway remodelling. Causes impaired oxygen transfer.
Airway remodelling cccurs due to:
- fibroblast remodelling and activation: causes fibroblast plaques occurring & collagen deposition. Causes Traction bronchiectasis: where there is irreversible dilatation of bronchi and bronchioles within areas of pulmonary fibrosis
- ↓ Epithelial cell integrity
- Accelerated ageing-associated changes
- Exaggerated fibroblast expansion
What is the key diagnostic test for identificaiton of IPF?
How do you calculate this?
DLCO (Diffusing capacity of the lungs for CO): measures the quantity of carbon monoxide (CO) transferred per minute from alveolar gas to red blood cells (mL/min/mm Hg)
DLCO = Lung surface area available for gas exchange (Va) X rate of capillary blood CO uptake (Kco)
(Kco is particularly affected by IPF)
Describe the diagnostic pathway for IPF xx
- Suspected ILD
- ID the cause? If yes - not IPF
- If no, conduct Chest High Resolution CT Scan. If you see usual interstitial pneumonia (honeycombing lungs) then v likely to have IPF.
Still unsure? - Lung biopsy
- MDT Diagnosis
- IPF / Not IPF
Treatment pathway for IPF?
Define sarcoidosis
Caused by multi system granulomas (is a tiny cluster of white blood cells and other tissue that can be found in the lungs). Inflammation causes multi-system granulomas
Most cases are acute, self-limiting (needs no medicinal treatment)
About 90% of diagnosed cases are deemed to be pulmonary sarcoidosis.
How do you diagnose sarcoidosis? (probably dont need to know)
Clinicoradiographic data / CXR:
- Bilateral hilar adenopathy on the chest radiograph
- Lofgren syndrome (erythema nodosum skin rash + bilateral hilar adenopathy on chest radiograph +/- fever and arthritis)
