Valvular Heart Disease


Valvular Heart Disease
•     Left sided valve lesions:
–      Aortic: stenosis / regurgitation
–      Mitral: stenosis / regurgitation

•     Right sided valve lesions:
–      Tricuspid: stenosis / regurgitation
–      Pulmonary: stenosis / regurgitation

•    Prosthetic heart valves





Aortic stenosis
Aetiology

•       Aortic stenosis may be congenital or acquired.

•       Congenital malformations may be tricuspid, bicuspid or more rarely unicuspid / quadricuspid

•       Acquired causes include the following:
      -     Degenerative disease
      -     Rheumatic disease
      -     Calcific e.g. end-stage renal failure, Paget’s disease
      -     Miscellaneous e.g. rheumatoid involvement


Pathophysiology

          

Symptoms
•       Exertional dyspnoea or fatigue
•       Angina
•       Syncope
Physical findings
•       Slow rising pulse
•       Reduced systolic and pulse pressure
•       Systolic thrill over the aortic area
•       Ejection systolic, crescendo-decrescendo murmur
•       Soft or inaudible second heart sound
•       ECG:  LVH, AV node conduction defects



Echocardiography

•       Thickened valves with reduced motion, sometimes calcified
•       Grading of stenosis severity is as follows:
      -     Normal valve area = 3-4cm2
      -     Mild stenosis = 1.5-3cm2
      -     Moderate stenosis = 1.0-1.5cm2
      -     Severe stenosis ≤ 1.0cm2
•       When stenosis is severe, the peak gradient across the aortic valve is usually > 60mmHg.



Medical therapy

•      Conservative treatment should be offered for mild to moderate aortic stenosis and to asymptomatic patients with severe aortic stenosis as follows:

     -    Advise to report symptoms
     -    Avoid vigorous exercise
     -    Antibiotic prophylaxis for endocarditis
     -    Regular follow-up ± echocardiography



Surgical/ Interventional therapy

•       Aortic valve replacement should be offered to the following:
      -     Symptomatic pts with severe AS
      -     Pts with severe AS undergoing CABG surgery
      -     Pts with moderate AS undergoing CABG surgery
      -     Asymptomatic pts with severe AS and LV dysfunction

•       Balloon valvuloplasty: bridge to surgery in haemodynamically unstable patients, or palliation for patients with serious comorbid conditions

•       Transcatheter aortic valve replacement



Aortic valve replacement

•      In the absence of LV dysfunction, operative risk is
     2-5%.

•      Indicators of higher mortality are NYHA class, LV dysfunction, age, concomitant coronary artery disease, and aortic regurgitation.

•      Valve replacement usually results in reduced LV volumes, improved LV performance and regression of LV hypertrophy.


Transcatheter Aortic Valve (TAVI)
•       Novel alternative therapy
•       Performed via femoral, subclavian or transapical approaches
•       Currently reserved for high risk, symptomatic severe degenerative aortic stenosis


Aortic regurgitation
Aetiology

•       Either due to primary disease of the aortic valve or wall of the aortic root or both.

•       Causes of primary aortic valve disease include:
      -     Congenital eg. bicuspid aortic valve
      -     Acquired:  rheumatic valve disease, infective       endocarditis, trauma,   connective tissue disease.

•       Causes of primary aortic root disease include:
      -     Degenerative, cystic medial necrosis (eg. Marfan’s), aortic dissection, syphilis, connective tissue disease,      hypertension.




Clinical history

•       Chronic severe AR
         Dyspnoea is the principal symptom
         Syncope is rare and angina is less frequent than in
         aortic stenosis.

•       Acute severe AR
          LV decompensation occurs readily with fatigue,
          severe dyspnoea and hypotension.


Pathophysiology of aortic regurgitation
                               


Physical findings

•       Collapsing pulse

•       Wide pulse pressure

•       Peripheral signs- De Musset’s, Corrigan’s, Quinke’s, Muller’s, Duroziez’s

•       Hyperdynamic apex beat

•       Early blowing diastolic murmur




•       ECG:  Left axis deviation, LV hypertrophy.

•       CXR:  Cardiomegaly, aortic calcification, aortic root dilatation

Echocardiography
•       Colour flow
      - width of the jet at its origin
      - extent into the LV
•       Doppler
      - Rate of decline of aortic reguritant flow
      - Diastolic flow reversal into the descending aorta




Management

•       Medical treatment
      -     Diuretics, digoxin, salt restriction
      -     Vasodilators
      -     Endocarditis prophylaxis

•       Without surgery, death usually occurs within 4 years of developing angina and within 2 years after onset of heart failure.



Surgical therapy

•       Severe acute AR requires prompt surgical intervention.

•       Chronic severe AR
      -     Symptomatic patients with normal LV function
      -     Symptomatic patients with LV dysfunction or dilatation
      -     Asymptomatic patients with LV dysfunction or dilatation   (EF<50% or end-systolic diameter > 55mm)

•       Aortic valve and root replacement- if aortic root diameter is ≥ 50mm.


Mitral stenosis
Aetiology

•       Rheumatic

•       Congenital

•       Carcinoid, SLE, rheumatoid arthritis,  mucopolysaccharidoses.

•       Left atrial myxoma, ball-valve thrombus, infective endocarditis with large vegetation and cor triatriatum.




Rheumatic mitral stenosis
•       Fusion of the valves, commisures and chordae

•       Symptoms usuually occur in the 3rd or 4th decade, but mild MS in the aged is becoming more common.

•       25% of patients have pure mitral stenosis and two-thirds are female.

•       Lutembacher’s syndrome- associated with an atrial septal defect



Pathophysiology

•       Normal mitral valve area = 4-6cm2.

•       A mitral valve area ≤ 1cm2 equates to severe mitral stenosis.

•       Symptoms usually develop when  mitral valve area ≤ 2.5cm2

•       Symptoms in mild mitral stenosis usually precipitated by exercise, emotional stress, infection, pregnancy or fast atrial fibrillation.



Natural history

•       Long latent period of 20 to 40 years

•       Once significant limiting symptoms occur, 10-year survival rate is 5-15%.

•       With severe pulmonary hypertension, mean survival falls to
     < 3 years.

•       Mortality from untreated mitral stenosis is due to progressive heart failure (60-70%), systemic embolism (20-30%) and pulmonary embolism (10%).



Clinical features

•       Dyspnoea
•       Haemoptysis may also occur
•       Angina
•       Embolic events



Physical findings

•       Mitral facies
•       Tapping apex beat
•       Right ventricular heave, loud P2
•       Loud first heart sound.
•       Opening snap.
•       Rumbling, mid-diastolic murmur with presystolic accentuation in sinus rhythm.






Echo evaluation

•       Assessment of valve morphology: degree of leaflet thickness, mobility and calcification and extent of subvalvular fusion.
•       Estimation of left atrial size.
•       Doppler echo: estimation of mitral valve area, transvalvular gradient and PA pressure.



Medical treatment

•       The asymptomatic patient with mild mitral stenosis should be managed medically. Medical therapy includes:
      -  Avoidance of unusual physical stress.
      -  Salt restriction.
      -  Diuretics if needed.
      -  Control of heart rate – β-blocker or digoxin.
      -  Anticoagulation for AF or prior embolic event.
      -  Annual follow-up.
      -  Echocardiography if deterioration in clinical condition.



Management of symptomatic mitral stenosis

•       Patients with symptoms should undergo clinical re-evaluation with echocardiography.

•       NYHA class II symptoms and mild mitral stenosis may be managed medically.

•       NYHA class II symptoms and at least moderate stenosis (MVA≤1.5cm2 or mean gradient ≥5mmHg) may be considered for balloon valvuloplasty.

•       NYHA class III or IV symptoms and severe mitral stenosis should be considered for balloon valvuloplasty or surgery.




Mitral valve replacement

•       Severe mitral stenosis and contraindications to surgical commisurotomy or balloon valvuloplasty:

      -  Restenosis following surgical commisurotomy or balloon        valvuloplasty

      -  Significant mitral regurgitation

      -  Extensive calcification of the subvalvular apparatus.

•       Operative mortality ranges from 3-8% in most centres.


Mitral Regurgitation
Chronic MR

Acute MR

Mitral valve prolapse



Aetiology

Mitral regurgitation may be caused by abnormalities of the valve leaflets, chordae tendinae, papillary muscles or mitral annulus:

•         Valve leaflets
   - myxomatous degeneration
   - rheumatic heart disease
   - infective endocarditis
•         Chordae tendinae
   - congenital, infective endocarditis, trauma, rheumatic fever, myxomatous
•         Papillary muscles
   - myocardial ischaemia, congenital abnormalities, infiltrative disease
•         Mitral annulus
   - dilatation eg. ischaemic or dilated cardiomyopathy
   - calcification due to degeneration, hypertension, diabetes,                   
     chronic renal failure





Clinical features

•       Symptoms usually occur with LV decompensation: dyspnoea and fatigue.
•       Physical findings include:
     - Pulse: sharp upstroke
     - Apex: displaced, hyperdynamic
     - Pansystolic murmur



Natural history

•       The natural history of chronic MR depends on the volume of regurgitation, the state of the myocardium and the underlying cause.
•       Preoperative LV end-systolic diameter is a useful predictor of postoperative survival in chronic MR.
•       The preoperative LV end-systolic diameter should be < 45mm to ensure normal postoperative LV function.






Medical treatment

•       Symptomatic patients may benefit from the following drug therapy whilst awaiting surgery:
•       Vasodilator therapy
•       Diuretics
•       Digoxin / Beta-blockers in presence of atrial fibrillation.
•       Endocarditis prophylaxis




Surgical treatment

•       Symptoms or left ventricular end systolic diameter ≥45mm.

•       Mitral valve repair or replacement.

•       Mitral valve repair better preserves LV function and avoids the need for chronic anticoagulation.



Acute mitral regurgitation
Aetiology

Important causes of acute mitral regurgitation include:
•             Infective endocarditis
•             Ischaemic dysfunction or rupture of papillary       muscle.
•             Malfunction of prosthetic valve.




Chronic versus Acute MR
Finding                       Chronic MR                  Acute MR

Symptoms                 subtle onset                         obvious
Appearance             normal/mildly                        severely ill
                                 dyspnoeic
Tachycardia              not striking                         always present
Apex beat                  displaced                         not displaced
Systolic thrill                   common                      a bsent
Murmur                         harsh pansystolic         soft or absent early     systolic component
ECG-LVH               usually present                      absent
CXR                            severe cardiomegaly     normal heart size




Acute mitral regurgitation
Medical therapy
The following therapies may be beneficial in reducing the severity of MR
- Vasodilator therapy
- Inotropic therapy
- Intra-aortic balloon counterpulsation

Surgical therapy
•        Indicated in patients with acute severe MR and heart  
  failure.
•        Higher mortality rates than for elective chronic MR



Mitral valve prolapse

General features 

•         2-6% of the general population
•         Twice as common in women. 
•         Due to myxomatous proliferation of the mitral valve.
•         Primary condition, or secondary finding in connective tissue
   diseases e.g. Marfan’s syndrome.
•         Vast majority asymptomatic.
•        Palpitations, dizziness, syncope, or chest discomfort.
•        Mid-systolic click, late systolic murmur



Echocardiographic criteria

•         M-mode criterion: ³ 2mm posterior displacement of one or both
   leaflets.

•         2-D echo findings: Systolic displacement of one or both leaflets
   within the left atrium in the parasternal long-axis view; leaflet
   thickening, redundancy, chordal elongation and annular dilatation.




Natural history

•         Benign prognosis in most patients

•         Complications may occur in patients with a systolic murmur,
   thickened leaflets, an increased LV or LA size, especially in men
   > 45 years old

•         Complications include progressive mitral regurgitation, infective
   endocarditis, cerebral emboli, arrhythmias and rarely sudden death.




Management

•       Asymptomatic patients without MR or arrhythmias have an excellent prognosis – follow-up every 3-5 years.

•       Patients with a long systolic murmur may show progression of MR and should be reviewed annually.

•       Severe MR requires surgery, often mitral valve repair.


Tricuspid stenosis
•       Almost always rheumatic

•       The low cardiac output state causes fatigue; abdominal discomfort may occur due to hepatomegaly and ascites.

•       The diastolic murmur of tricuspid stenosis is augmented by inspiration.

•       Medical management includes salt restriction and diuretics.

•       Surgical treatment in patients with a valve area <2.0cm2 and a mean pressure gradient >5mmHg.


Tricuspid regurgitation
•       Most common cause is annular dilatation due to RV failure of any cause

•       Symptoms and signs result from a reduced cardiac output, ascites, painful congestive hepatomegaly and oedema.

•       The pansystolic murmur of TR is usually loudest at the left sternal edge and augmented by deep inspiration.

•       Severe functional TR may be treated by annuloplasty or valve replacement. Severe TR due to intrinsic tricuspid valve disease requires valve replacement.


Pulmonary stenosis
•       Most commonly due to congenital malformation

•       Survival into adulthood is the rule, infective endocarditis is a risk and right ventricular failure is the most common cause of death.

•       Carcinoid plaques may lead to constriction of the pulmonary valve ring.



Pulmonary regurgitation
•       Most common cause is ring dilatation due to pulmonary hypertension, or dilatation of the pulmonary artery secondary to a connective tissue disorder.

•       May be present and well-tolerated for many years

•       The clinical manifestations of the primary disease tend to overshadow the pulmonary regurgitation.




•      Physical examination
–       right ventricular heave
–       high-pitched, blowing, early diastolic decrescendo murmur
•         left sternal edge
•         augmented by deep inspiration.

•      Pulmonary regurgitation is seldom severe enough to require specific treatment. Surgery may be required because of intractable RV failure.



Prosthetic valves
Prosthetic valves may be divided into 2 broad categories:

Mechanical valves
•        Very good durability.
•        Require long-term anticoagulation.
•        May cause mild haemolysis.

Bioprosthetic (tissue) valves
•        Porcine variety most commonly used.
•        Limited durability.
•        Anticoagulation for first 3 months only.



Mechanical versus tissue valves

•       No difference in survival, haemodynamics or in probability of
    developing endocarditis, valve thrombosis or systemic embolism.

•       Valve-related failure is much more common with tissue valves.

•       Anticoagulant-related bleeding occurs with mechanical valves.

•       Elderly patients tend to receive tissue valves.


DOWNLOAD THIS LECTURE


Satheesh Nair

Manchester Heart Centre

Hodgkin’s Lymphoma



Overview of the lymphoid immune system
l   A. Lymphocytes evolve from pluripotent stem cells located in the bone marrow, and differentiate into two major functional cell types:
l   1. B lymphocytes, comprising the humoral immune system, whose ultimate function is the production of antibodies
l   2. T lymphocytes, comprising the cellular immune system, whose functions include
–       a. Direct killing of foreign or intracellularly infected cells, cytotoxic T cells
–       b. Fine control of the immune response through the secretion of cytokines, helper and suppressor T cells.





The anatomical organization of the lymphoid immune system
l     The anatomical organization of the lymphoid immune system can also be divided into two major functional groups: 


l     1. The primary immune organs, which are the sites of initial maturation from immature precursors into immune competent cells:
–        a. B cells- bone marrow
–        b. T cells- thymus
l     2. The secondary immune organs, which are the sites of antigen driven replication and differentiation into committed effector cells
–        a. Lymph nodes
–        b. Spleen
–        c. Mucosal Associated Lymphoid System (MALT)-lymphoid cells lining the respiratory and gastrointestinal tracts
–        d. Everywhere else
l     C. The lymph nodes, in their totality, are the largest of the secondary immune organs, and the site of the majority of lymphoid pathology.




Sub divisions
l   A. The lymph node has 7 major subdivisions.
l   1. The lymph node capsule, which surrounds the lymph node 

l   2. The subcapsular sinus- the initial entryway of lymphatic fluid into the node via afferent lymphatics 

l   3. The lymph node cortex- beneath the subcortical sinus-the location of primary and secondary lymphoid follicles

l   a. In the absence of immune stimulation, the cortical lymphoid follicles are primary follices, composed of small B lymphocytes which may be virgin B lymphocytes or recirculating memory B cells. There is also a fine meshwork or dendritic reticulin cell cytoplasm, which is invisible without special immunolabelling techniques
l   b. With antigenic stimulation, antigen recognizing B cells are stimulated to replication and differentiation. This converts the primary follicle into a secondary follicle or germinal center, surrounded by a mantle zone of transient small lymphocytes, and a central area containing replicating "follicular center cells" and their differentiating progeny- see below.



l  4. The paracortex- the region surrounding and beneath the germinal centers
l  5. The medulla- deep to the cortex/paracortex, and composed of medullary cords and medullary sinuses
l  6. Medullary vessels- artery and vein
l  7. Afferent and efferent lymphatic vessels


lymphoma
l  The term lymphoma describes any neoplastic disorder of lymphoid tissue. Malignant lymphomas fall into two groups:
l  Hodgkin's disease or Hodgkin's lymphoma
l  non-Hodgkin's lymphoma



Major differences exist between the two:
l   age - bimodal distribution in Hodgkin's, many are young; median age of 50 in non-Hodgkin's, increasing with age
l   mode of spread - predictable in Hodgkin's, spread is step-by-step to contiguous lymph nodes, usually starting in the neck; spread is random in Non-Hodgkin's
l   histology - polymorphic in Hodgkin's, with diagnostic Reed-Sternberg cells often outnumbered by reactive cells, especially eosinophils; Non-Hodgkin's is monomorphic, with malignant cells most numerous
l   prognosis - up to 80% of Hodgkin's lymphomas are potentially curable; this proportion is much less for Non-Hodgkin's patients taken as a whole


Hodgkin's disease
l     aetiology

l     Hodgkin's disease is of unknown aetiology.
l     Because of the origin of the tumour from immune cells there has been put forward the theory that Hodgkin's disease may be immunologically mediated.
l     The mechanism for development of the tumour may be the result of a continuous antigen challenge mechanism or by failure of the innate immunological surveillance system.
l     However, at present this theory remains unproven.
l     It seems likely that there is a multifactorial mechanism for the development of Hodgkin's lymphoma.


epidemiology
l   In adults aged 15+ years in England and Wales in 1992 - there were 1,188 new cases of Hodgkin's lymphoma; the number per annum per 2000 population was 0.05 (1).
l   The disease has a bi-modal age incidence. The first peak occurs between 15 and 34 years and the second peak occurs after 50 years.
l   Ninety-five per cent of patients present with lymph gland involvement


histology
l     Hodgkin's disease is divided by the Rye classification into four types:
l     lymphocyte predominant:
–        thought to be a clinically distinct B cell lymphoma
–        often only affects a single lymph node
l     nodular sclerosis:
–        accounts for 70-80% of Hodgkin's disease
–        classically a disease of young women
–        presents with cervical and mediastinal lymphadenopathy
l     mixed cellularity:
–        commonly found in elderly people
–        often widespread at presentation
l     lymphocyte depleted:
–        a rare disease
l     The classical cell seen on histological examination is the Reed-Sternberg cell, which is a necessary, but not sufficient element, for a diagnosis of Hodgkin's disease. Other cells seen in diseased tissue include histiocytes, lymphocytes, plasma cells, eosinophils and fibroblasts.


clinical features
l   The majority of patients present with lymphadenopathy.Other features include:
l   generalised pruritus

l   anaemia
l   immune dysfunction
l   B symptoms:
–       fever
–       night sweats
–       weight loss
l   In advanced disease there may be infiltration of any organ often presenting with hepatosplenomegaly. Other sites for tumour localisation include bone, bone marrow, lung, kidneys.The Ann Arbor system is used to stage Hodgkin's


differential diagnosis
l      In a young patient the differential includes:
l      infection:
–        EBV
–        CMV

–         
–        HIV
–        toxoplasmosis
–        brucellosis
l      ongoing regional sepsis:
–        cat scratch disease
–        tuberculosis
l      sarcoidosis
l      lymphadenopathy associated with collagen vascular diseases
l      chronic lymphocytic leukemia
l      non-Hodgkin's lymphoma
l      In older patients, secondary carcinoma must be included in the differential diagnosis of any localised lymphadenopathy.


investigations
l   Investigative procedures include:
l   lymph node biopsy
l   FBC
l   ESR
l   liver function tests
l   renal function tests e.g. renal clearance
l   chest radiography
l   CT scan and ultrasound - to demonstrate abnormalities of the upper Para-aortic and mesenteric nodes
l   lymphography - rarely used
l   Splenectomy has been used in the past as a diagnostic and therapeutic procedure. Althought the spleen is involved in 30% of cases of Hodgkin's disease there is no prognostic advantage for patients who undergo splenectomy.
l    


prognosis
l   In localised disease treated with irradiation there is a 5-year survival rate of at least 80%.In disseminated disease treated with cytotoxic chemotherapy ---

the 5-year survival falls to 50%.Overall, a 5 year survival of >70% should be achieved.
l   Prognostic indicators include:
l   age - better prognosis in younger patients
l   histology - lymphocytic predominant > nodular sclerosis > mixed cellularity > lymphocytic depletion
l   stage - lower has better prognosis
l   symptoms - generalised symptomatic disease has worst prognosis



Dr Mohamed Iqbal Musani

Hemolytic anemias


OBJECTIVES
By the end of this lecture you will be able to know the followings:
-Definition and Etiology of Thalassemia, Sickle cell anemia, G6PD, and congenital spherocytosis.
-Diagnosis, and investigations of these types of anemias.
-Prevention and management of these diseases




Hemolytic Anemias


In hemolytic anemia there is shortened life span of RBCs (normal= 120 days).

1.Increased breakdown of Hemoglobin leading to :
A. Increased serum bilirubin (mainly indirect).
B. Increased urobilinogen in urine and stercobilinogen in faeces.
C. Increased serum iron and decrease in iron binding capacity.
2.Bone marrow compensatory reaction which lead to:
A. Accelerated erythropoiesis (reticulocytosis more than 2%), reversed M/E ratio.
B. Expansion of bone configuration seen clinically and in X-ray especially in the skull (hair on end appearance).





Causes of Chronic Hemolytic Anemia:

A. Corpuscular causes :

1. Membrane defect :
A. Hereditary spherocytosis.
B. Hereditary elliptocytosis.

2. Enzyme defect :
A. G6PD. deficiency.
B. Pyruvate kinase deficiency.

3. Hemoglobinopathies :
A. Thalassaemia (quantitative β-chain defect).
B. Sickle cell anaemia (qualitative β-chain defect).

B- Extracorpuscular causes:
1- Immune:-Iso-immune: Rh and ABO incompatibility. Auto-immune: (e.g SLE).
2- Non- immune:-
-Paroxysmal nocturnal hemoglobinuria
-Infections (Malaria, toxoplasmosis, septicemia).
-Toxic: snake venom.




Hereditary Spherocytosis

 It is a chronic haemolytic anaemia transmitted as autosomal dominant trait due to dysfunction of a cell membrane protein “spectrin” making the cell more permeable to Na+ influx result in increase intracellular water → swelling & spherocytosis.

 The spherocyte is relatively rigid and passes with difficulty through the minute apertures between splenic cords and sinuses and thus becomes easily destroyed.

 After splenectomy the haemolysis improves, although the biochemical and morphological abnormalities are not corrected.



Clinical Picture:
-Onset in infancy and may be a cause of neonatal jaundice.
-General feature of anemia, jaundice, splenomegaly, aplastic crisis and gall stone formation.
-Folate deficiency, and hemosiderosis.

Laboratory Finding:
-Anemia: normocytic normochromic.
-Reticulocytosis (count from 5 up to 20%).
-Unconjugated hyperbilirubinemia.
-Spherocytes in peripheral film.
-Increase osmotic fragility: spherocytes are destroyed in higher concentration of saline than normal RBCs.
-Bone marrow: erythroid hyperplasia .




Differential diagnosis:-
-From other congenital hemolytic anemias.
-ABO incompatibility.
-Autoimmune hemolytic anemia: comb's test is positive.

Treatment:
1- Supportive: packed red cell transfusion for severe anemia. Folic acid supplementation.
2- Splenectomy invariably produces a clinical cure.
Splenectomy in early childhood may causes increased susceptibity to infection, the operation should be delayed if possible, until 5-6 years old.
3- Splenectomized children should receive:
 pneumococcal and hemophilus influenzae b vaccines.
 Prophylactic long acting penicillin.




Glucose-6-phosphate dehydrogenase deficiency
(Favism, Drug induced Hemolytic Anemia)

Etiology:-
-Hereditary :
X-linked recessive disorder. Males more than females.
Age : may present in the neonatal period.
-More than 200 variant of the enzyme could be recognized in different localities in the world.
A. G6PD.(A):- Common among American, enzyme activity in 5-15% of normal.
B. G6PD.(B):- Common in Mediterranean area, where enzyme activity is less than 5% and lead to haemolytic attack.
C. G6PD. (C):- Common in Chineese.


Pathogenesis:
-G6PD is Responsible for Production of NADPH and renewal of reduced glutathione (GSH) in the red cell membrane.
-GSH protects red cells from oxidants by reducing them.
-G6PD deficiency → ↓NADPH →↓ GSH →↓ protection of RBCs from oxidants.
-Exposure of G6PD deficient RBC to an oxidant → impaired elimination of oxidant → oxidation of Hb → oxidized Hb is denaturated and deposited as Heinz inclusion bodies in RBCs lead to ↓ red cell integrity → hemolysis.




Examples of oxidant agents :
-Fava beans (Contains L-Dopa)
-Infections: Due to release of oxidants from active phagocytes . -Viruses; Respiratory, hepatitis, infectious mononucleosis -Bacterial pneumonias.
-Metabolic: Diabetic Ketoacidosis.
-Drugs:- -Antipyretics: Aspirin, phenacetin
-Sulfonamides. – Antimalarials. -Nitrofurans
-Antibiotics: chloramphenicol – Para-aminosalicylic acid, -synthetic vitamin k, Naphthalene - Methylene blue.

Clinical picture:
 Favism: ingestion of fava beans → acute hemolytic anemia
 Neonatal hyperbilirubinemia of unconjugated type: there is hemolysis plus immaturity of hepatic enzymes.


Signs and symptoms:
 Acute anemia (Marked pallor, irritability, etc.)
 Nausea vomiting and epigastric pain
 Hemoglobinuria (if hemolysis is severe) –Mild splenomegaly.
 Jaundice with dark orange colored urine (urobilin) and dark stools
 Death → may occur in cases of severe hemolysis
 Course: spontaneous recovery from the attack is the rule.

Laboratory: Normochromic normocytic anaemia, Heinz bodies in blood smear. Diagnosis is confirmed by estimation of G.6.P.D activity in RBC, better around few weeks after the attack.

Treatment: -Avoid offending agents e.g infection.
-In severe cases, emergency packed RBC transfusion.
-Vitamin E (400-800 U/day) protect against hemolysis and antioxidant.
-In severe neonatal jaundice: exchange transfusion.



Hemoglobinopathies

 Hemoglobin is a tetramer formed of 4 polypeptide chain with a heme group attached to each chain.
 Each chain is controlled by a special sequence gene which is activated and inactivated in a special sequence.

Types of Globin Chain (α. β. γ. δ): Each chain is controlled by 2 sets of gene

Types of Hb.:
HbF, (2α +2 γ).
HbA1 (2α + 2 β).
HbA2 (2α +2δ).

At birth After 6 months
 HbF : 65%. HbF: 2%.
 HbA1 : 34%. HbA1:95%.
 HbA2: <1% HbA2: 3%



Sickle Cell Disease

It is transmitted as an incomplete autosomal dominant trait.


-Homozygotes (both parents are affected) →sickle cell anemia 85-95% HbS+ 5-15% HbF+ 2% HbA2.
-Heterozygotes (only one parent is affected) →sickle cell trait 55-60% HbA+ 25-45% HbS + 2-3% HbA2 .


This is a benign condition usually there is no anemia sickling does not occur except if patient is exposed to hypoxia.

-HbS is similar in structure to HbA except that at position 6 of the β-polypeptide chain, glutamic acid is replaced by Valine.


Clinical picture: Onset after 6 months and is expected only when patient is homozygous for sickle cell gene.


1- vaso-occlusive (thrombotic or painful) crisis:
 Vaso-occlusive is due to occlusion of small blood vessels → distal ischemia and infarction ,this is usually preceded by infection or spontaneously.
-Hand-foot syndrome (sickle dactylitis). -Bone crisis.
-Severe abdominal pain.
-Acute painful hepatomegaly + direct hyperbilirubinemia.
-Repeated painful splenic infarcts → autosplenectomy.
-Cerebral occlusion → strokes, acute hemiplegia.
-Acute episodes of painless hematuria.
-Acute chest syndrome.
-Acute episodes of painful priapism.

2. Aplastic Crisis :
-Aplasia of the bone marrow during or following parvovirus 19 infection.
-Decrease in reticulocytic count.
-Severe anemia
-Lasts about 10-14 days and usually recovers spontaneously.



3-Sequestration crisis:
 Pooling of the blood become, for no obvious reasons sequestrated in spleen, leads to massive splenomegaly.
 Shock collapse and may be dehydration.
 In late childhood this splenomegaly diminish in size as result of the multiple infarcts this leads to hyposplenism considered as functional asplenia with liability of overwhelming infection caused by pneumococcal, H. influenza infection and salmonella osteomyelitis.


4-Hyperhemolytic crisis:
May be precipitated by bacterial infection and presented by anemia, jaundice and fever.


Laboratory investigation:
-Normocytic normochromic anemia -RBC show sickling under low O2 tension. -Hb electrophoresis studies:
*HbS (80-95%), HbA2 (2-3%) and HbA (5-15%) in sickle cell anemia.
* HbS (25-45%), HbA2 (2-3%) and HbA (55-60%) in sickle cell trait.
-Bone marrow aplasia during an aplastic crisis.


Treatment:
◦ Treatment and prevention of infection by :
 Prophylactice long acting penicillin.
 Polyvalent, pneumococcal, and haemophilus infleunza b vaccine every 2 years.
◦ Blood transfusion correct anemia and prevent crisis.
◦ Vigorous treatment of crisis:
 Painful crisis: give hydration, packed RBC, analgesic,vasodilator, (L carnitine, nitric oxide inhalation).
 Aplastic crisis: give packed RBC.
 Sequestration crisis, plasma expander, blood transfusion.


Thalassemia syndromes

β – Thalassemia major (cooley's anemia):

β - Most common around meditranian sea. In β - thalassemia there is impaired production of β -chain due to mutation of one gene "heterozygous" or both genes homozygous".



According to degree of β – chain deficiency β thalassmia is divided into:
 Βo no β-chain synthesis no HbA only HbF and HbA2.
 β+ little β-chain synthesis, so HbA is scanty and more HbF and HbA2.
 β++ more β chain synthesis → thalassemia intermediate.
 β+++ normal in individual.
Thalassemias are hereditary chronic haemolytic anemias caused by impaired or absent synthesis of α or β globin chain.



Clinical picture:
 Age of presentation usually start at the age of 6-12 months.
 Clinical evidence of haemolytic anemia, pallor, jaundice hepatosplenomegaly mongoloid facies (enlarged head, prominent malar bone, frontal bossing, depressed nasal bridge protrusion of maxilla ± exposure of upper teeth due to hyperplasia of B.M.)
 Crisis:
◦ Haemolytic crisis precipitated by infection by parvovirus B19.
◦ Megaloblastic crisis due to folic acid deficiency
 Cardiomegally and hemic murmur.
 Growth retardation
 short stature
 delayed puberty due to endocrinal disturbances.



Complication:-
 Increase susceptabilty to infection
 Iron overload (haemochromatosis) due to increase iron absorption from gut and excess iron from repeated transfusion .iron accumulate in vital organ leads to heart failure, hepatomegally .D.M., bronze skin.
 Anemic heart failure. -Hypersplenism. -Pathological fracture.
 Complications of repeated blood transfusion: e.g. hepatitis C.


Diagnosis:
 Hypochromic microcytic anemia with anisocytosis, poikilocytosis, target cell.
 Reticulocytic count: increased nucleated RBCs in peripheral blood.
 Increase serum iron with decrease serum iron binding capacity.
 Hb electrophoresis: (increase HbF).
 B.M. examinations show erythroid hyperplasia.
 X-ray bone of skull → hair on end apearance due to widening of diploid space. -Cardiomegaly may be present.



 Evident diagnosis: Genotyping or P.C.R. (Polymerase Chain Reaction) to detect the mutation on chromosome 11.
 -Weak mutation → thalassemia intermedia
 Strong mutation → thalassemia major

TREATMENT
1- Symptomatic treatment:

1- Packed RBC transfusion 10-15ml/kg/dose every 4-6wks.
 Better to transfuse washed RBCS by saline.
 Better to transfuse (neocyte) rich with hemoglobin
 Better to transfuse from single donor.
Blood transfusion to keep Hb above 12gm/dl in order to:
a- Permit normal activity with comfort.
b- Improve crisis.
c- Minimize cardiac dilatation.
d- Prevent skull bone changes.



.
2- Iron chelation:
Desferroxamine (desferal) given S.C. by small iron infusion pump in dose 30-50mg/kg/dose 5 days/week. Vit C potentiate the action of desferal. -Recently oral chelating agent deferazirox (Exjade) 20-30mg/kg/dose.
3- Folate, 1mg Daily to compensate B.M. over activity.
4- Low iron diet with increase tea drinking (decreasing iron absorption)
5- Indications of splenectomy:
◦ Secondary hypersplenism.
◦ Huge spleen, cause dragging pain
-Splenectomy should be done after the age of 5 yr.
to guard against severe infection.
-Prophylactic pneumococcal and meningococcal vaccination should be given 2wk. before operation.
-long acting penicillin prophylactic 1,200,00 I Monthly.
6- New modalitiy: α chain stimulation by hydroxyurea, β hydroxybuterate to cause increase HbF that decrease ineffective erythropoiesis.




II. Curative therapy
 B.M. transplantation from HLA identical of non affecting sibling
 gene therapy by insertion of normal gene into B.M. stem cell
β Thalassemia minor (Heterozygous ) It may be asymptomatic or symptomatic:
-Mild anemia (Hb 9-11 g/dl) accentuated during infections.
-Anemia is microcytic hypochromic and does not respond to iron therapy.
-No jaundice or other signs of hemolysis.
-Hb electrophoresis: Hb A is predominant, Hb A2 is increase (<4%), Hb F may be slightly increase.


β Thalassemia intermedia :

Affects 2-10 % of homozygous patients and is characterized by:
 Patients have higher ability to produce β –chain and high production of γ-chains.
 Genetic, morphologic and biochemical features: like β-thalassemia major.
 Anemia is milder (Hg level 7-10g/dl).
 Pallor, jaundice, facial bony changes, splenomegaly and hepatomegaly are present.
 No growth retardation and no hypogonadism.


Treatment: -Blood transfusion is usually not needed and given only when required.
-Decrease iron absorption from GIT (e.g. drink a cup of tea after each meal).
-Chelation therapy and folic acid supplementation.

α Thalassemia
 There is decrease synthesis of α chain and Hb A, F, A2 genetic deletion can affect one or more of the gene represent for α chain synthesis.
 1- Deletion of one gene → silent carrier.
 2- Deletion of two gene → α thalassemia trait.
 3- Deletion of three gene → HbH.
 4- Deletion of four gene → hydrops fetalis → miscarriage of non viable fetus,

COURTESY:DR. SHAHENAZ M. HUSSIEN


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