Medicine 2 Flashcards
Thrombophilia
= inherited / acquired coagulopathy predisposing to thrombosis (usually venous).
Causes of Inherited vs Acquired thrombophilia
INHERITED
- APC resistance / Factor V Leiden mutation
- Antithrombin III deficiency
- Prothrombin gene mutation
ACQUIRED:
APL syndrome
Indications for screening a patient for thrombophilia
- Arterial thrombosis <50
- Venous thrombosis <40 with no RFs
- Familial VTE
- Recurrent unexplained VTE
- Unusual site of thrombosis (e.g. mesenteric or portal vein thrombosis)
- Recurrent miscarriage (>3)
Thrombophilia- Ix
- FBC
- Clotting
- Fibrinogen concentration +/- APC resistance test
- Lupus anticoagulant / anti cardio-lipin antibodies
- Anti-thrombin and Protein C/S assays for deficiency
- Factor V Leiden mutation PCR (if APC resistance test positive)
- PCR for prothrombin gene mutation
Definition of anaemia
What can cause it ?
= decreased haemoglobin in the blood, such that there is inadequate oxygen delivery to tissues.
=> Hb <135 g/L in men; Hb <115 g/L in women.
Patients become anaemia when they are:
1. Not making enough RBCs
=> Reduced erythropoiesis (or haematopoiesis)
- Losing or breaking down RBCs too quickly.
=> Bleeding
=> Haemolysis
Anaemia - symptoms
Often asymptomatic => a slowly falling Hb allows for haemodynamic compensation.
Non-specific = Fatigue, weakness, headaches
CV = dyspnoea, intermittent claudication, palpitations
Anaemia - signs
GENERAL:
Pallor
Tachycardia
Systolic flow murmur
Cardiac Failure
SPECIFIC:
Koilonychia – IDA
Jaundice – haemolytic anaemia
Leg ulcers – often seen in sickle cell disease
Bone marrow expansion, leading to abnormal facial structure or pathological #s in thalassaemia
Transfusions in anaemia
Transfusion is generally not indicated if there is no acute bleed, and the patient is not symptomatic.
If the anaemia is severe and requires transfusion, beware of associated heart failure:
=> Transfusion should be given very slowly, alongside furosemide.
RBC Lifecycle
Erythropoiesis occurs in the bone marrow.
=> Stimulated by erythropoietin (EPO) produced by the kidneys.
Average RBC lifespan is 120 days.
The ageing RBC are removed from the circulation.
This process normally occurs at the same rate of production by erythropoiesis, balancing the total circulating red blood cell count hence patients have a stable Hb.
Microcytic anaemia - causes
Low Hb, Low MCV
Iron deficiency anaemia (IDA)
Thalassaemia
Lead poisoning
Sideroblastic anaemia (rare)
Normocytic anaemia - causes
Low Hb, normal MCV
Acute blood loss
Anaemia of chronic disease
Renal anaemia
Haemolytic anaemias (or macrocytic)
Marrow failure
Pregnancy
CTDs
Macrocytic anaemia - causes
Low Hb, High MCV
B12 deficiency
Folate deficiency
Alcohol Excess (or severe liver disease)
Myelodysplastic Syndromes
Severe hypothyroidism
Iron deficiency anaemia - causes
BLOOD LOSS UNTIL PROVEN OTHERWISE
Hookworm
Heavy menstruation
GI bleeds
DECREASED ABSORPTION
Coeliac disease
Patients on antacids (less ferric to ferrous iron conversion)
Post-gastrectomy
INCREASED DEMAND
Growth
Pregnancy
INADEQUATE INTAKE
Iron Deficiency Anaemia - Ix
- Clinical examination for signs of iron deficiency
- Koilonychia
- Angular stomatitis
- Brittle nails/hair - Blood Tests:
- Iron studies
- Blood film:
=> Microcytic anaemia is generally also hypochromic (pale on the blood film, representing MCH)
=> Film may show signs of sideroblasts/signs of thalassaemia
- Further tests:
=> If there is a good history of menorrhagia, start oral iron and only further Ix is coeliac serology.
=> In all other patients, without an obvious cause of bleeding:
- Check coeliac serology
- Refer for OGD and colonoscopy
- Stool microscopy is advised if recent foreign travel
What is measured in iron studies?
- Serum iron
- Serum ferritin
- Total Iron binding capacity
- Serum soluble transferrin receptors
Iron Deficiency Anaemia - Mx
Address the underlying cause as appropriate – e.g. menorrhagia, GI bleed, etc.
Lifestyle:
=> Advise increased dietary intake of dark green vegetables, fortified bread/cereals, lead red meat, prunes/raisins
Commence oral ferrous sulphate 200 mg t.d.s and before awaiting investigation results
=> Can start with b.d. as may be better tolerated
If ferrous sulphate is not tolerated, consider switching to ferrous gluconate.
Monitor for improvement in Sx and blood parameters after 1 month of Tx
SEs of ferrous sulphate
cramping, bloating, nausea, vomiting, constipation, black stools.
Adverse effects can be decreased if taken with meals
Can offer laxatives for constipation or dose reduction
How long should Tx with iron be continued in IDA?
Tx should be continued for 3 months after blood parameters return to normal, to replenish supplies.
Rule of 10 for anaemia
The maximum rise in Hb concentration is one week is 10 g/L
If more than 10 g/L decline is seen over a week, then blood is being lost.
When transfusing, one bag will raise the Hb concentration by 10 g/L
Anaemia of chronic disease
Can be microcytic or normocytic, therefore can be a differential for IDA.
Ix:
- Serum iron will be decreased
- TIBC will also be decreased
- STR – normal
- Ferritin will be raised
Plummer-Vinson Syndrome
A rare disease characterised by dysphagia, odynophagia, IDA, glossitis, chelitis and oesophageal webs.
Generally occurs in post-menopausal women
Tx:
=> Iron supplementation and mechanical widening of the oesophagus provides a good outcome.
What is thalassaemia?
= Genetic disorders of Hb synthesis
Common in the middle/far East
Caused by deficient alpha or beta chain synthesis, thus resulting in alpha- or beta- thalassaemia.
Beta-Thalassaemia
MINOR (“trait”)
- Carrier state
- Usually asymptomatic
- Gives a mild microcytic anaemia that may worsen in pregnancy
- HbA2 is raised, with slightly raised HbF also
MAJOR (“Cooley’s anaemia”)
- Abnormality in both globin genes
- Presenting within the first year with severe anaemia, hepatosplenomegaly and failure to thrive.
- Extramedullary haematopoiesis results in facial deformities.
- Survival is possible due to HbF
- Blood film – hypochromic microcytic cells, also target cells and nucleated RBCs
- Mx = lifelong blood transfusions
Alpha-thalassaemia
Bart’s hydrops:
- Deletion of all 4 alpha-globin genes
- This form of Hb is physiologically useless and leads to death in utero
Deletion of 3 genes:
- Moderate microcytic anaemia
- Features of haemolysis
Deletion of 2 genes:
- Asymptomatic carrier state, with reduced MCV
Deletion of 1 gene:
- Clinically normal
Anaemia screening before surgery
Anaemia is the most common abnormality seen in pre-op patients:
<60 g/L will require transfusion
<100 g/L may require transfusion depending on cardiac risk and anticipated blood loss.
What is myeloma?
= a malignant clonal proliferation of plasma cells (derived from B-lymphocytes).
Normally, many different plasma cells produce a range of immunoglobulins – i.e. they are polyclonal.
In myeloma, a single clone of plasma cells produces a single immunoglobulin.
=> When you measure the immunoglobulins in a patient with myeloma, one of the type of antibody will be significantly abundant
Myeloma - RFs
Older age (average age of presentation is 70)
Black African ethnicity
FHx
Obesity
Myeloma - presentation
“CRAB” – calcium, renal, anaemia, bone:
Osteolytic bone lesions (due to osteoclast activation)
=> Backache, pathological fractures, hypercalcaemia (bones, stones, moans and groans)
Bone marrow failure
=> Infection, symptoms of anaemia, bleeding
Renal impairment
=> Seen in 20% at diagnosis, due to light chain deposition
Myeloma - complications
Hypercalcaemia,
Spinal cord compression,
Hyper-viscosity,
Acute renal failure.
Myeloma - Ix
FBC – normochromic normocytic anaemia; leucopaenia
Blood film – rouleaux formation
ESR – raised
U&Es – often deranged
Calcium – raised
ALP – normal
Serum/urine electrophoresis
=> Paraprotein monoclonal band seen
Urine Bence-Jones protein – positive
Skeletal XR
=> Punched out lytic lesions
Bone marrow biopsy
=> Increased clonal plasma cells >10%
=> If under 10%, may be termed “monoclonal gammopathy of uncertain significance” (MGUS)
Myeloma - Mx
- Supportive therapy
- Chemotherapy
- Radiotherapy
- Bone marrow stem cell transplants used if <70
Myeloma - prognosis
The original myeloma cell is very resistant, so often returns.
Median survival is 3-4 years.
Death is usually from renal failure/infection.
What is lymphoma?
= malignant proliferation of lymphocytes.
Most commonly accumulate in peripheral lymph nodes, but can accumulate in the peripheral blood or infiltrate organs.
Most are derived from B cells.
Classified as Hodgkin’s or Non-Hodgkin’s
What is Hodgkin’s Lymphoma?
Characterised by Reed-Sternberg cells
=> Binucleate “mirror cells” on biopsy.
Largest peak of incidence is young adults (20-35 years)
Second peak in 50-70-year olds.
Disease is slow growing, usually localised and rarely fatal.
RFs for Hodgkin’s Lymphoma
- Affected sibling
- HIV, EBV
- Autoimmune conditions – e.g. SLE, RA
- FHx
Hodgkin’s Lymphoma - Presentation
Enlarged, non-tender, “rubbery” lymph nodes (typically cervical)
Fatigue, itching
25% will have B-symptoms, with profuse night sweats.
For some patients, alcohol can induce lymph node pain
Mediastinal lymph nodes can have mass effects (SVC/bronchial obstruction)
O/E:
- Lymphadenopathy
- Hepatosplenomegaly in 50%
- Potentially signs of cachexia/anaemia
What is Non-Hodgkin’s Lymphoma?
Includes all lymphomas without the presence of Reed-Sternberg cells.
Peak incidence = 70 years
Can be further classes into high/low grade
=> HIGH grade – divide rapidly, typically present with rapid onset lymphadenopathy; more aggressive but better prognosis if identified and treated.
=> LOW grade – divide slowly, typically present more insidiously and thus tend to be widely disseminated at diagnosis, often incurable.
Non-Hodgkin’s Lymphoma - Presentation
Nodal disease – 75% have superficial lymphadenopathy
Extra-nodal disease – oropharynx, skin, CNS, gut, lung
B-symptoms – weight loss indicates disseminated disease.
Bone marrow failure
Presentation is similar to Hodgkin’s lymphoma and often they can only be differentiated when the lymph node is biopsied.
Lymphoma - Ix
FBC, U&E, LFT, ESR, blood film, Ca2+
LDH
=> Often raised in Hodgkin’s lymphoma but is not specific and can be raised in other cancers and many non-cancerous diseases.
Lymph node biopsy is the key diagnostic test.
=> Reed-Sternberg cells in Hodgkin’s Lymphoma
Staging CT/MRI/PET
Ann Arbor Staging
The staging system used for both Hodgkins and non-Hodgkins lymphoma.
The system puts importance on whether the affected nodes are above or below the diaphragm.
Stage 1: Confined to one region of lymph nodes.
Stage 2: In more than one region but on the same side of the diaphragm (either above or below).
Stage 3: Affects lymph nodes both above and below the diaphragm.
Stage 4: Widespread involvement including non-lymphatic organs such as the lungs or liver.
Lymphoma - Mx
HODGKIN’S
- Chemotherapy
- Radiotherapy
- Chemo-radiotherapy
NON-HODGKIN’S
Involves a combination of treatments depending on the type and staging of the lymphoma:
- Watchful waiting
- Chemotherapy
- Monoclonal antibodies such as rituximab
- Radiotherapy
- Stem cell transplantation
Macrocytic anaemia - Ix
Blood film
=> Hyper segmented neutrophils in B12/folate deficiency
LFTs / TFTs
=> ?Thyroid / hepatic cause
=> Raised bilirubin in B12/folate deficiency
Serum B12 and folate levels
If B12 low:
- Anti-parietal cell antibodies
- Anti-intrinsic factor antibodies
- Schilling test
Bone marrow biopsy:
Megaloblasts suggest B12/folate deficiency (also seen in myelodysplasia)
Deoxyuridine suppression test – can be used to differentiate B12/folate deficiency in vitro after bone marrow biopsy.
What can be a problem with measuring serum folate levels?
Serum folate reflects recent intake, so many labs do red cell folate.
Schilling test
distinguishes between pernicious anaemia and small bowel disease
Radiolabelled B12 given with and without IF
The amount of labelled B12 excreted in the urine then detected.
How does B12/folate deficiency lead to macrocytic anaemia?
B12 acts as a co-enzyme for the conversion of folate (B9) to activated folate.
Activated folate is required for DNA synthesis, and thus if there is a deficiency in either B12 or folate, DNA synthesis malfunctions.
In this case, the DNA fails to stop erythrocyte development, leading to very large cells, which are eventually trapped and destroyed in the reticulo-endothelial system.
B12 absorption
Intrinsic factor is secreted by gastric parietal cells, and binds free B12.
Receptors for the IF-B12 complex are present on the brush border of the terminal ileum, where B12 is absorbed.
IF is generally necessary for B12 ingestion, but even in its complete absence, around 2% of B12 can still be absorbed.
Sources of B12
Humans rely on animal sources of B12 – e.g. meat, fish, eggs and milk.
The liver contains very large stores of B12
=> It is secreted in bile but most of this is normally reabsorbed.
Pernicious Anaemia - Mx
high dose PO B12 supplementation can be enough to treat pernicious anaemia (as ~2% can still be absorbed in the abscence of IF)
Initially patients are often treated with IM B12 on alternate days before switching to PO for maintenance
Causes of B12 deficiency
Chronic low dietary intake – vegans
Impaired binding in the stomach – pernicious anaemia, congenital absence of IF, gastrectomy.
Small bowel disease – resection, Crohn’s/backwash ileitis in UC, bacterial overgrowth.
(Pancreatitis, coeliac disease and metformin can all cause mild impairment of B12 absorption, but not enough to cause significant B12 deficiency. )
Pernicious anaemia
= Autoimmune disease, resulting in severe B12 deficiency
There are 3 autoantibodies that may contribute towards disease:
- Autoantibodies against parietal cells
- Blocking antibodies
- Prevent IF-B12 binding
- Most common abnormality - Binding antibodies:
- Prevent IF binding to ileal receptors
Subacute degeneration of the spinal cord
Simultaneous dorsal column and corticospinal tract loss due to B12 deficiency
=> Gives a combination of UMN and LMN signs.
Initial presentation is with peripheral neuropathy
O/E there is classical triad of extensor plantars, brisk knee jerk reflex but absent ankle jerk reflex
=> Tone and power usually normal
=> Gait may be ataxic
Sources of folate
Folate (folic acid monoglutamate) is not itself present in nature, but occurs as polyglutamates dihydrofolate (DHF) or tetrahydrofolate (THF)
These are found in green vegetables and offal (however cooking causes a loss of up to 90% of the folate).
DHF and THF are converted to folate in the upper GI tract, and folate is absorbed in the jejunum
Causes of folate deficiency
Poor nutritional intake – poor diet, alcohol excess, anorexia.
Malabsorption – coeliac disease
Anti-folate drugs – trimethoprim, methotrexate, anti-convulsants
Excess physiological use – pregnancy, lactation, prematurity.
Excess pathological use – excess erythrocyte production, malignancy, inflammatory diseases
Folate deficiency - Mx
Folic acid 5 mg/day PO for 4 months
Always combined with B12, unless the patient is known to have normal B12 levels.
Approach to normocytic anaemia
Is there acute blood loss?
Is there underlying chronic disease?
Is it haemolytic?
Are other cell lines affected (i.e. bone marrow failure)?
Anaemia of chronic disease
Normochromic or hypochromic, rarely severe.
Seen in chronic infection, malignancy, CKD, rheumatoid disorders.
Pathology involves predominant WBC production in the bone marrow.
Low serum iron, raised ferritin, low TIBC, normal STR.
Bone marrow failure
- investigations
- causes
Hb, reticulocytes, WBC and platelets all equally low.
There will be alterations on the blood film
These patients require bone marrow biopsy.
No abnormal blasts in pancytopaenic marrow = aplastic anaemia (idiopathic or due to drugs).
Other causes will be apparent on marrow examination
=> E.g. haematological malignancies, metastatic disease, myelofibrosis, myelodysplasia.
Parvovirus infection can also cause cessation of marrow erythropoiesis.
Myeloproliferative Disorders
A group of disorders including – myelofibrosis, polycythaemia rubra vera, and essential thrombocytosis.
Clones of haematopoietic stem cells proliferate in the marrow, yet retain the ability to differentiate.
Considered PRE-LEUKAEMIC.
Essential Thrombocytosis
Clonal proliferation of megakaryocytes, leading to persistently raised platelets
=> This is often asymptomatic
=> The platelets have abnormal function
Symptoms:
=> The most common presentation is microvascular occlusion.
=> Other symptoms may be related to bleeding or arterial/venous thrombosis.
Polycythaemia Rubra Vera (PCV)
= Malignant proliferation of a clone derived from one pluripotent marrow cell.
Excess production of RBCs, WBCs and platelets lead to serum hyper-viscosity and thrombotic complications.
Presentation:
- Often asymptomatic
- Arterial/venous thrombosis
- Rarer – vague hyperviscosity symptoms (headache, dizziness, tinnitus, facial swelling, burning sensation in fingers/toes; splenomegaly; gout.
Polycythaemia Rubra Vera - Ix and Mx
Diagnosis:
- Increased red cell mass
- Ix for JAK2 mutation (PCV cells often carry activating mutation in the tyrosine kinase (JAK2) gene)
Key differentials to r/o = hypoxia and renal disease (in these secondary PCV’s only the RBCs are raised).
Treatment:
- Repeated venesection
- Low dose aspirin
Primary Myelofibrosis
= Hyperplasia of megakaryocytes, which produce excess platelet-derived growth factor, leading to marrow fibrosis and metaplasia.
There is secondary haematopoiesis in the liver/spleen, leading to massive hepatosplenomegaly (= most common presentation).
Symptoms:
- B symptoms
- Abdominal discomfort
- Sx of bone marrow failure
Essential thrombocytopaenia and PCV both may progress to myelofibrosis or AML, yet the risk is relatively rare.
Aplastic Anaemia
= A rare stem cell disorder leading to pancytopenia and hypoplastic bone marrow.
Most commonly autoimmune
Triggered by drugs, viruses or irradiation.
Can be inherited (Fanconi anaemia)
Symptoms are of bone marrow failure
Diagnosis is with bone marrow biopsy.
Aplastic Anaemia - Mx
Blood product transfusion
Immunosuppression in autoimmune conditions
In younger patients, allogenic bone marrow transplant may be curative.
What is haemolysis?
Where can it occur?
How does it present?
= the breakdown of RBCs before the end of their normal lifespan (120 days).
Can be:
1. Intravascular
2. Extravascular (reticuloendothelial system of the liver, spleen and bone marrow).
This may be asymptomatic, but haemolytic anaemia develops if the bone marrow does not sufficiently compensate.
Causes of haemolysis
INTRINSIC
Haemoglobinopathies – e.g. sickle cell/thalassaemias
Membranopathies – spherocytosis/elliptocytosis
Enzymeopathies – G6PD/PK deficiency
EXTRINSIC
Autoimmune disease
Alloimmune disease – transfusion/transplant reaction, rhesus disease
Drug-induced – e.g. penicillins
Infection – malaria and some other parasites
Microangiopathic haemolytic anaemias – e.g. DIC
Haemolysis - Ix
Signs suggestive of increased RBC breakdown:
- Anaemia with raised MCV
- Raised bilirubin – unconjugated, pre-hepatic jaundice
- Raised serum LDH (gets released from RBCs)
Signs suggestive of increased RBC production:
- Raised reticulocyte count
BLOOD FILM can give clues as to the cause
Further tests:
- Coomb’s test (DAT) = Identifies RBCs coated with antibodies or complement, indicating an immune cause of haemolysis.
- Hb electrophoresis = Can identify different haemoglobinopathies
- Enzyme assays = If other causes have been excluded
What aspects of a blood film can show the cause of haemolysis?
Hypochromic, microcytic cells – thalassaemia
Sickle cells – SCA
Spherocytes – hereditary spherocytosis or autoimmune haemolytic anaemia
Elliptocytes – hereditary elliptocytosis
Heinz bodies / “bite” cells – G6PD deficiency
Schistocytes – microangiopathic haemolytic anaemia
Glucose-6-phosphate dehydrogenase (G6PD) deficiency - Inheritance and Presentation
X-linked inheritance
=> More common in African and Mediterranean males (females will have mild symptoms).
Presentation:
- Mostly asymptomatic, but susceptible to oxidative crises due to reduced glutathione production.
- These attacks cause rapid anaemia and jaundice with “bite cells” and “blister cells” seen on the blood film.
Attacks may be precipitated by drugs (aspirin, primaquine, sulphonamides), broad bean consumption or illness.
G6PD - Ix and Mx
Diagnosis is with enzyme assay 3 months after initial crisis
BITE CELLS on blood film
Tx:
- Precipitant avoidance (e.g. broad beans)
- Transfusion if severe
- Splenectomy may help with chronic haemolysis
Pyruvate Kinase (PK) Deficiency - Inheritance and presentation
Autosomal recessive condition
Reduced ATP production, shortening the lifespan of RBCs
Homozygotes usually present with neonatal jaundice and later chronic jaundice with hepatosplenomegaly.
Pyruvate Kinase (PK) Deficiency - Ix and Management
Dx = enzyme assay
Tx = Often well tolerated and no specific therapy is needed, although splenectomy may help.
Hereditary Spherocytosis
Autosomal dominant membrane defect => Leading to spherical RBCs
These are less deformable, thus can become trapped in the spleen => leads to haemolysis, splenomegaly and jaundice.
Hereditary Elliptocytosis
Autosomal dominant defect => “elliptocytes”
Mostly asymptomatic
Mx of membranopathies (spherocytosis/elliptocytosis)
Both are treated with folate.
Splenectomy is curative, but reserved for severe disease.
What causes Sickle cell disease?
= Autosomal recessive disorder
Causes abnormal production of beta-globulin chains, due to a single amino acid substitution (glu6val)
This results in the production of HbS rather than HbA
Much more common in patients of African origin
There are two genotypes:
- HbSS – sickle cell anaemia phenotype
- HbAS – sickle cell trait
What causes Sickle cell disease?
= Autosomal recessive disorder
Causes abnormal production of beta-globulin chains, due to a single amino acid substitution (glu6val)
This results in the production of HbS rather than HbA
Much more common in patients of African origin
There are two genotypes:
- HbSS – sickle cell anaemia phenotype
- HbAS – sickle cell trait
HbS polymerises when deoxygenated, causing RBCs to form “sickle cells” which are fragile and haemolyse, and can also block small vessels
HbAS – sickle cell trait
HbAS confers protection from falciparum malaria
rarely symptomatic
=> BUT vaso-occlusive events may occur in hypoxia – e.g. when flying or under anaesthesia
Sickle cell disease - Ix
Usually on the newborn bloodspot screening
Sickle cells can be seen on blood film
Hb electrophoresis can confirm diagnosis and also distinguish variants.
Sickle Cell disease - Presentation
Often presents in the first few months of life, with anaemia developing as HbF levels fall.
Acute haemolytic crises occur, causing bone infarcts and painful dactylitis
Untreated, there is:
- Splenic infarction, leading to hyposplenism
- Renal infarction, causing CKD
- Cerebrovascular accidents
In adulthood, there is normally a chronic haemolytic anaemia (60-90 g/L) but this is well tolerated unless there is a crisis.
Complications of sickle cell disease
Hyposplenism,
CKD,
Bone necrosis,
Chronic leg ulcers,
Iron overload (if multiple transfusions)
Long-term pulmonary damage
Sickle cell disease - Long-term Tx
Lifelong folate supplementation
Pneumococcal vaccination and prophylactic penicillin (due to hyposplenism)
Hydroxycarbamide (hydroxyurea) can help by increasing HbF production and is advised if there are frequent crises.
Regular life-long transfusions (2-4 weekly), with iron chelators to prevent overload.
Bone marrow transplantation is curative – but limited by availability of matched donors.
Sickle-cell - Vaso-occlusive Crises
PAINFUL CRISES
Occur due to micro-vascular occlusion, often affecting the bone marrow, causing severe pain.
Can be precipitated by cold, infection, dehydration or hypoxia.
Other presentations are mesenteric ischaemia (mimicking acute abdomen), cerebral infarctions or priapism
Sickle cell - aplastic crises
Due to parvovirus B19
Causes a sudden reduction in marrow production (particularly RBCs)
Usually self-limiting, but transfusion may be required.
Sickle cell - sequestration crises
Mainly affects children as spleen has not yet undergone atrophy.
Pooling of blood in the spleen +/- liver, with organomegaly, severe anaemia and shock
Urgent transfusions are required.
Sickle cell - haemolytic crises
Rarer
Hb falls due to haemolysis
Mx of sickle cell crises
A-E resuscitation – high flow oxygen and IV fluids
Strong analgesia within 30 minutes
FBC, reticulocytes, XM blood
Screen for signs of infection (culture, MSU, CXR) & treat early.
Prophylactic enoxaparin should be given
Fully cross-matched blood transfusion if Hb/reticulocytes fall sharply.
Exchange transfusion if rapidly deteriorating.
Autoimmune Haemolytic Anaemia
Autoantibodies lead to extravascular haemolysis and spherocytosis
Most commonly idiopathic, but can be secondary to lymphoproliferative diseases or other autoimmune diseases.
Classified according to the optimal temperature at which antibodies bind to RBCs in vitro:
- Warm AHA – IgG mediated; optimal binding 37 degrees
=> Treated with steroids or immunosuppresants +/- splenectomy - Cold AHA – IgM mediated; optimal binding below 4 degrees
=> Often associated with raynaud’s
=> Treated with cold-avoidance +/- chlorambucil
Drug-induced Haemolysis
Penicillin-based drugs can cause formation of RBC antibodies
Drugs such as quinine cause production of immune complexes
Microangiopathic Anaemia
= Mechanical haemolysis caused by physical trauma in the circulation, due to:
- Malignant HTN / pre-eclampsia
- Haemolytic Uraemic syndrome
- Thrombotic thrombocytopaenic purpura
- Vasculitis (e.g. SLE)
- DIC
- Mechanical heart valves
The blood film will show schistocytes irregular, asymmetrical cells).
Alloimmune Reactions/Haemolysis
Transplant/transfusion/rhesus reactions
Immune-mediated, yet Coomb’s negative.
Types of WBC and their purpose
NEUTROPHILS – ingest and kill bacteria, fungi & cellular debris
LYMPHOCYTES – produce antibodies for cell-mediated immunity.
EOSINOPHILS – play a role in allergic reactions and defence against parasitic infection.
MONOCYTES – precursor of tissue macrophages
BASOPHILS – release histamine in inflammatory reactions
Neutrophilia - causes
Bacterial infection
Inflammatory reactions
Disseminated malignancy
Stress – e.g. surgery, burns
Myeloproliferative conditions
Corticosteroid therapy.
Neutropaenia - causes
Viral infections
Severe sepsis
Neutrophil antibodies – e.g. SLE
Bone marrow failure
Hypersplenism – e.g. Felty’s
Cytotoxic drugs
Agranulocytosis
= A complete absence of circulating neutrophils
Can be caused by drugs such as carbimazole/clozapine/etc.
Lymphocytosis - causes
Viral infections
Chronic infections (TB, hepatitis)
Myeloproliferative conditions
Lymphopaenia - causes
Bone marrow failure
Corticosteroid therapy
SLE
Uraemia
HIV Infection
Cytotoxic drugs
What is Disseminated Intravascular Coagulation (DIC)?
Systemic activation of the coagulation pathways, leading to extensive intravascular coagulation and fibrin clot development.
There is thrombotic occlusion of the arterial microvasculature
The simultaneous depletion of clotting factors and consumption of platelets leads to haemorrhage.
Eventually organ failure develops.
Causes of DIC
Infection
Trauma
Malignancy
Obstetric complications (amniotic fluid emboli, pre-eclampsia)
Severe liver failure
Tissue destruction (pancreatitis/ burns)
Toxic / immunogenic stimuli
DIC - clinical features
Bruising
Excessive bleeding from any sites
Renal failure
DIC - Ix
Low platelets, low fibrinogen
Raised PT & APTT
Raised D-dimer
Blood-film – broken RBCs (schistocytes)
DIC - Tx
Treat the cause
Aggressive resuscitation, replacing platelets, coagulation factors (FFP) and fibrinogen (cryoprecipitate).
Protein C – reduces mortality in multi-organ failure / severe sepsis.
Haematopoiesis
The haematopoietic stem cell first divides into the common myeloid or lymphoid progenitor cell.
COMMON MYELOID PROGENITOR cell then subdivides to form
- Erythrocytes
- Mast cell
- Megakaryocytes (go on to form platelets)
- Myeloblasts (go on to form monocytes, basophils, neutrophils, and eosinophils)
COMMON LYMPHOID PROGENITOR cell subdivides to form:
- NK cells
- T and B lymphocytes
Acute Lymphoblastic Leukaemia (ALL)
= Malignancy of lymphoid cells (of either B or T cell lineages), leading to uncontrolled proliferation of immature blast cells.
Leads to eventual bone marrow failure and tissue infiltration
Most common malignancy of childhood; it is rare in adults (“L for little”)
More common in certain genetic syndromes – e.g. Down’s
Prognosis of ALL
Prognosis is good in children under 10
Poor prognosis suggested by:
- older age of presentation,
- male sex,
- B-cell disease,
- presence of Philadelphia chromosome (9:22 translocation).
Acute Myeloid Leukaemia (AML)
= Malignancy of blast cells from the marrow myeloid elements.
It can arise de novo, or on a background of myeloproliferative conditions/ previous chemotherapy/ ionising radiation/ genetic syndromes.
Can occur at any age (median age of presentation = 65 years) – “M for mature”
AML - prognosis
Rapidly progressive
=> Only 20% 3-year survival after chemotherapy.
Acute leukaemias - presentation
Regardless of subtype, acute leukaemias generally present with:
B-symptoms
=> Fatigue, weight loss, night sweats, fevers, pruritis
Bone pain from marrow infiltration
Symptoms related to bone marrow failure
=> Anaemia (SoB on exertion, weakness)
=> Leucopaenia** (recurrent infections)
=> Thrombocytopaenia – bleeding/bruising (more common in AML)
Hepatomegaly/ splenomegaly.
** Although presenting with leucocytosis, the cells are immature and non-functioning blast cells, thus symptoms of leucopaenia are seen.
Acute leukaemias - Ix
FBC
Blood film
=> Blasts are diagnostic
=> Lineage identified morphologically and confirmed with immunophenotyping
CXR – T-cell ALL classically shows mediastinal widening
Bone marrow aspiration – to confirm diagnosis and confirm lineage.
PET scanning – to check for metastatic disease
U&Es, LFTs and cardiac function testing (ECG/ echo) are essential for planning therapy.
Acute leukaemias - general Mx
Supportive care:
- Barrier nursing
- Hickman line for venous access
- High-calorie diet
- Frequent blood and platelet transfusions
- Allopurinol to prevent tumour lysis syndrome due to chemotherapy.
- Check frequent bloods and observations for sign of infection
Antibiotics
=> If temperature is >38oC on 2 occasions greater than an hour apart, assume sepsis and start broad spectrum ABX until afebrile for 72 hours.
ALL - Management
High-dose chemotherapy to induce remission
=> Then 2 years of maintenance therapy
Consider marrow transplant if poor prognosis or relapse.
Transplant is necessary to cure those with the Philadelphia chromosome
AML - Management
Intensive chemotherapy
In disease with poor prognosis – allogenic marrow transplant from HLA-matched siblings is indicated after the first round of chemotherapy.
=> This then allows further high-dose chemotherapy
In intermediate prognosis disease, autologous marrow transplants may be used (cells grown from own bone marrow)
=> Further chemotherapy must be at lower doses.
Chronic Myeloid Leukaemia (CML) - presentation
Rare in childhood, most common in people age 40-60
Philadelphia chromosome is present in 95% with CML
Symptoms:
- 30% are detected by chance
- Insidious B symptoms are the most common presentation
- Gout, due to purine breakdown
- Abdominal discomfort due to splenic enlargement
O/E:
- Massive splenomegaly / hepatomegaly
- Signs of anaemia/thrombocytopaenia.
CML - Ix
FBC
=> WCC very high (raised across whole spectrum of myeloid cells)
Blood film – spectrum of myeloid cells
Bone marrow biopsy – hypercellular
CT/PET
Cytogenic analysis of blood/marrow for Philadelphia chromosome.
CML - Mx
Imatinib chemotherapy is 1st line
Stem cell transplant is the only treatment that may achieve remission, but carries significant mortality/morbidity.
CML - prognosis
Median survival 6 years.
There are 3 phases:
1. Chronic phase – few symptoms, lasts for years
2. Accelerated phase – increasing symptoms, difficulty controlling counts
3. Blast transformation – features of acute leukaemia, eventual death.
Chronic Lymphocytic Leukaemia (CLL) - pathophysiology and presentation
= Most common leukaemia
Median age at presentation = 70 years.
Accumulation of mature B-cells that have escaped apoptosis, and this increasing mass of immune-incompetent cells leads to bone marrow failure.
Presentation:
- Often asymptomatic, found on routine FBC
- May be anaemia or infection-prone
- If severe, there can be B-symptoms
O/E:
- Enlarged non-tender lymph nodes
- Hepatosplenomegaly
CLL - Ix
FBC
- Markedly raised lymphocytes
- May be signs of bone marrow failure
- Autoimmune haemolysis develops later
Blood film – predominant SMUDGE cells (small mature lymphocytes).
CLL - Mx
Without treatment:
- 1/3rd never progress
- 1/3rd will eventually progress
- 1/3rd actively progress from diagnosis.
Treatment is thus only indicated if symptomatic, or there are cytogenic markers of poor prognosis.
Treatment can be with chemotherapy or radiotherapy.
CLL - prognosis
prognosis depends on Rai stage (stage 0 - 4)
Death is usually due to infection, or transformation to an aggressive lymphoma (Richter’s syndrome).
Phaeochromocytoma
= catecholamine secreting tumours, arising from sympathetic paraganglionic cells (known as chromaffin cells).
PCC - location
usually located in adrenal medulla
10% are extra-adrenal
10% are bilateral
10% are familial
=> MEN 2a/2b
=> Neurofibromatosis
=> Von Hippel-Lindau Syndrome
PCC - presentation
Usually severe/episodic HTN, unresponsive to medical treatment.
Also often vague episodic symptoms:
- General – sweating, heat intolerance, pallor or flushing
- Neurological – headaches, visual disturbances, seizures
- CV – palpitations, chest tightness, dyspnoea, postural hypertension
- GI – abdominal pain, nausea, constipation
Symptoms may be worsened by stress, exercise or drugs.
PCC - diagnosis
3x 24-hour urine collections for raised free metadrenaline and nor-metadrenaline.
MRI/CT/functional imaging to locate the tumour
PCC - Mx
Alpha blockade with phenoxybenzamine.
Beta-blockers AFTER alpha blockade is established
=> Used if significant tachycardia remains after alpha blockade.
Surgical excision
What is important to remember with using beta-blockers in phaeochromocytoma?
Should only be initiated after alpha-blockade.
=> can induce life-threatening hypertensive episodes in patients without adequate alpha blockade.
What is Addison’s disease?
= Primary Adrenal Insufficiency
Destruction of the entire adrenal cortex, leading to deficiencies in:
1. Glucocorticoid (cortisol)
2. Mineralocorticoid (aldosterone)
3. Sex steroids
How does Addison’s differ from hypothalamic-pituitary-adrenal disease?
HPA disease generally spares mineralocorticoid production, which is stimulated by ATII.
Causes of Addison’s disease
- Autoimmune (most common in UK)
- TB (most common worldwide)
- Overwhelming sepsis
- Metastatic cancer – lung/breast
- Lymphoma
- Adrenal Haemorrhage (Waterhouse-Friedrichsen syndrome)
Addison’s disease - presentation
Symptoms:
- Often vague and non-specific
- Weight loss, malaise, weakness, myalgia
- Syncope
- Depression
Signs:
- Pigmentation, especially of new scars and palmar creases.
- Postural hypotension
- Signs of dehydration
- Loss of body hair (particularly axillary/pubic)
Addison’s disease - Investigations
Bloods:
- U&Es – low sodium, high potassium (due to mineralocorticoid insufficiency).
- Calcium – raised
- Glucose – low, due to lack of cortisol
Short ACTH stimulation test / Synacthen Test
- Measure plasma cortisol before, and 30 mins after.
- A 2nd value >550nmol/L excludes Addison’s
9am ACTH/cortisol
=> Raised ACTH and low/normal cortisol confirms Addison’s
Investigations for cause:
- 21-hydroxylase adrenal autoantibodies – autoimmune
- CXR – TB
- Adrenal CT – to look for TB/metastatic disease
How is a Short ACTH stimulation test / Synacthen Test performed?
- Give tetracosactide IM (ACTH analogue).
- Measure plasma cortisol before, and 30 mins after.
- A 2nd value >550nmol/L excludes Addison’s
Addison’s Disease - Mx
Long-term glucocorticoid cover:
=> 15-25mg HYDROCORTISONE daily, in 3 divided doses (mimic diurnal variation)
=> Avoid giving late in the day, as can cause insomnia.
Long-term mineralocorticoid cover:
=> Required if postural hypotension
=> FLUDROCORTISONE 50-200 micrograms daily.
Patient education:
- Steroids should never be abruptly stopped
- Extra doses of steroid are needed for strenuous exercise, surgery, febrile illness, or trauma.
- Patient should have a steroid card/bracelet and should carry IM hydrocortisone in case of Addisonian Crisis.
Addisonian Crisis
Severely inadequate levels of cortisol, occurring either as a first presentation of adrenal disease or triggered by physiological stress.
Presents with:
- Fever, N&V
- Shock
- Hypoglycaemia
- Hyponatraemia and hyperkalaemia
Treat with IV fluids and IV hydrocortisone as part of resuscitation.
What is Congenital Adrenal Hyperplasia?
Due to congenital deficiency in 21-alpha-hydroxylase
=> This enzyme is necessary for the production of mineralocorticoids and glucocorticoids (but not sex hormones)
Autosomal recessive.
Aldosterone and cortisol levels decrease, and thus ACTH rises.
=> Precursors such as progesterone build-up and go down the alternative pathway to form sex hormones => testosterone levels raised
CAH - presentation
Virilisation of the external genitalia in females
=> Clitoral hypertrophy (resembling a penis) and variable fusion of the labia (resembling a scrotum).
Enlarged penis and pigmented scrotum is seen in males (but rarely noticed).
Presents with salt-losing crisis in 80% of males at 1-3 weeks of age (failure to thrive, and potentially fatal hypovolemia and shock)
In the non-salt-losing males, presents as hyper-virilisation (early pubarche, adult body odour, muscular build).
CAH - Investigations
17-alpha-hydroxyprogesterone levels = markedly raised => this is diagnostic
Other features may be:
- Low sodium
- High potassium
- Metabolic acidosis
CAH - Mx
Steroid cover, as per Addison’s disease.
Also at risk of Addisonian crisis.
What is Conn’s Syndrome?
Adrenal adenoma, leading to primary hyperaldosteronism
Most common in young females.
Hyperaldosteronism leads to sodium and water retention.
Conn’s syndrome - presentation
Mostly asymptomatic
HTN (resistant to Tx)
Features of hypokalaemia (Cramps, weakness, tetany, polyuria)
Conn’s syndrome - Investigations
Biochemical features:
=> Hypernatraemia, Hypokalaemia
=> Elevated plasma aldosterone:renin ratio
=> Plasma aldosterone levels will not be suppressed by fludrocortisone administration.
Further Investigations:
=> Once primary hyperaldosteronism is confirmed, adrenal CT is indicated
=> Adrenal scintography is alternative method (Unilateral uptake of the isotope in Conn’s)
Conn’s - Mx
Laparoscopic adrenalectomy to remove adenoma
Spironolactone pre-op to control HTN/hypokalaemia.
RFs for DVT
= anything causing blood stasis or hypercoagulability
- Age/immobility
- Pregnancy/OCP
- Malignancy
- Obesity
- Surgery (typically occur 2 weeks post-surgery)
- Previous DVT
DVT - presentation
Most DVTs are silent
Classical Clinical features:
- Calf tenderness & firmness
- Oedema
- Erythema & calor
- Distension of superficial veins
- Superficial thrombophlebitis
Atypical Presentation:
- Ilio-femoral thrombosis can present with severe pain, but few physical signs.
- Complete occlusion of a large vein can lead to cyanotic discolouration.
DVT - Ix
Calculate Well’s Score – by risk stratifying to low risk (Wells’ Score <2) and a negative d-dimer the clinician can exclude the need for ultrasound (US) to rule out DVT.
D-dimer
= Highly sensitive, not specific for DVT (also increased in infection, pregnancy, malignancy, post-op etc.)
=> If pre-test probability is low and D-dimer is negative – can r/o DVT
=> If D-Dimer is positive or high/intermediate pre-test probability, do compression USS.
Compression USS:
=> Non-collapsing veins indicate presence of DVTs
Thrombophilia screen
=> Ensure this is done prior to commencing anticoagulant therapy if there are no pre-disposing factors.
Preventing post-surgical DVT
Stop COCP 4 weeks pre-op
Mobilise as early as possible
Immobile patients should be heparinised
At risk patients should have TEDs/intermittent pneumatic pressure until 16 hours post-op.
Treating proven DVT
LMWH to prevent propagation of the clot
Warfarin started simultaneously
=> LMWH can be stopped when INR = 2-3
Length of warfarin treatment:
- 3 months for post-op DVT
- 6 months if there was no precipitating cause
- Lifelong if known thrombophilia/recurrent DVT
PE - presentation
Classically present with:
- Sudden-onset breathlessness
- Pleuritic pain
- Haemoptysis
However, PE should be included in almost any respiratory differential as they are so common and variable in presentation.
Possible Signs:
- Evidence of a DVT
- Raised JVP
- Cyanosis if embolus is large
Massive PE
~5% of PEs
> 60% of the pulmonary circulation is blocked
Leads to rapid cardiovascular collapse
Major PE
~10% of PEs
Middle-sized pulmonary arteries are blocked
Leads to breathlessness, pleuritic chest pain and haemoptysis
Minor PE
~85% of PEs
Small peripheral vessels are blocked
Patients may be asymptomatic or classical presentation.
Massive PE may ensue following minor PE (known as premonitory embolus)
PE - Investigations
FBC, U&E, clotting, D-dimer
ABG – T1RF
CXR
=> Often normal
-> May see dilated pulmonary artery or wedge-shaped opacities
ECG:
=> Tachycardia, RBBB, RV strain
=> Classical SIQIIITIII is rare
Echo:
=> Can confirm right heart strain
CTPA = gold-standard
=> V/Q if this is unavailable, but less accurate
SI QIII TIII ECG pattern
Large S wave in lead I
Q-wave in lead III
T wave inversion in lead III
Rare; but sometimes seen in PE (sign of right-heart strain)
PE - Management
Major/minor PE should be managed as per DVT.
Massive PE:
- Emergency A-E resuscitation
- IV morphine + antiemetic
- Heparin therapy – LMWH/UH
If SBP >90mmHg – commence anticoagulant therapy
If SBP <90mmHg – start vasopressors (noradrenaline) before commencing thrombolytic therapy.
Causes of CKD
- Diabetes mellitus (20-40%)
- HTN
- Chronic glomerulonephritis
- Chronic pyelonephritis
- Obstructive uropathy
- Renovascular disease
- Drugs (e.g. long-term NSAIDs)
- PKD
CKD - symptoms
Often asymptomatic until very advanced – may be some vague fatigue and anorexia.
- Polyuria/nocturia
- Restless leg syndrome
- Sexual dysfunction
- Nausea & Pruritis (early uraemia)
- Yellow pigmentation, encephalopathy and pericarditis (severe uraemia)
- Pedal oedema & pulmonary oedema.
CKD - signs
- Pallor – due to anaemia
- Excoriations – due to pruritis
- Hypertension/fluid overload signs
- Pericardial rub (rare)
- Proteinuria
Diagnosis of CKD
diagnosed when any two tests, 3 months apart show reduced eGFR and can be stages 1-5 depending on the level of reduction.
(in some situations a 24-hour urinary creatinine may be collected to calculate true creatinine clearance)
CKD Stage 1
eGFR >90
Normal eGFR but urine findings/structural abnormalities/ genetic traits suggest CKD.
Asymptomatic
CKD Stage 2
GFR 60-89
Mildly reduced eGFR and other findings (as for stage 1) point to CKD
Asymptomatic
CKD Stage 3A
eGFR 45-59
= Moderate CKD
Usually asymptomatic
CKD Stage 3B
eGFR 30-44
= Moderate – severe CKD
Pts are often anaemic
CKD Stage 4
eGFR 15-29
= Severe CKD
Symptoms often at eGFR <20
Electrolyte disturbances
CKD Stage 5
eGFR <15 / dialysis
= End-stage renal failure (ESRF)
Significant complications and symptoms
Dialysis usually at eGFR <10
CKD - Investigations
Bloods:
=> FBC, U&Es, LFTs, calcium, phosphate, PTH levels, Glucose
Urinalysis:
- Any blood?
- Quantify proteinuria
- Exclude infection
- May do 24-hour urinary protein / creatinine clearance
- To assess severity / for nephrotic syndrome
CXR – ?pulmonary oedema.
ECG – if hyperkalaemia
Renal USS:
- To exclude obstruction
- Can look for polycystic kidneys
Further Ix:
- Renal biopsy – if cause unclear
- Renal DTPA scan – investigate vascular supply
- Bone imaging – screen for renal bone disease
CKD - Management
Treat reversible causes – e.g. obstruction, nephrotoxic drugs
1st line = BP control/diabetic control
=> BP controlled to <130/80
=> If proteinuric, BP <125/75 (ACEi 1st line)
Primary CV prevention is also important (statin and low-dose aspirin)
2nd line = control of complications
=> Recombinant EPO for anaemia
=> Calcium/vitamin D supplementation for bone disease
=> K+ restriction for hyperkalaemia
Renal replacement therapy is indicated in those with ESRD = dialysis or transplantation
=> Any symptomatic CKD stage 5 patient
Complications of CKD
Renal Anaemia
Renal Bone disease
Secondary HTN
Electrolyte disturbances
Myopathy
Peripheral neuropathy
Increased risk of infection
GI – Anorexia, N&V
Pericarditis
Depression is common – particularly in later stages/dialysis
Renal Anaemia
In CKD, the kidney partly loses its secretory EPO function, leading to anaemia.
=> Correlates with the severity of renal disease
Recombinant EPO can be given to those on dialysis with ESRD as part of renal replacement therapy to combat this anaemia
Target Hb 100-120
Renal Bone Disease
- cause
- investigation results
- treatment
In CKD the kidneys produce less 1-alpha-hydroxylase and excrete less phosphate
=> low VitD, low Calcium, hyperparathyroidism
=> Ultimately osteopaenia and osteoporosis
Tx:
- Restriction of dietary phosphate,
- Phosphate binders (calcichew)
- AdCal (calcium and vitD supplementation).
Indications for Renal Replacement Therapy
ESRF is not a clear cut line, and RRT may be required at different levels in different individuals, but general indications are:
A intractable acidosis
E electrolyte disturbance (hyperkalaemia, hyponatraemia, hypercalcaemia)
I Intoxicants
O intractable fluid overload
U uraemia symptoms
Haemodialysis
Diffusion of solutes between blood and dialysate, which flow in opposite directions with a semi-permeable membrane between.
Vascular access is most commonly achieved by:
1. AVF (at the wrist / cubital fossa)
2. Double lumen arterial lines (vascath / permcath)
Dialysis must occur for 4 hours, three times weekly.
- Normally occurs at hospital
- Home treatment is available, but requires support and training in dialysis unit.
The main issue is haemodynamic instability during dialysis
How is Peritoneal Dialysis performed?
What is the main risk?
Continuous ambulatory peritoneal dialysis patients instil up to 2 litres of isotonic/ hypertonic solution into the peritoneal cavity.
This then equilibrates with the blood in peritoneal capillaries.
The fluid is then drained out after 2 hours.
This is performed 3-4 times daily at home
Main risk is peritonitis
Which is preferable - haemodialysis or peritoneal dialysis?
There is no difference in clinical outcomes between peritoneal and haemodialysis.
Renal Transplantation - process and prognosis
Patient assessment:
- Virology / TB status – active infection is a CI due to risks of immunosuppression
- Blood group / HLA matching
- Full systemic examination – comorbid disease is a CI.
Prognosis is good
=> 1 year graft survival rate of 90-95% depending on extent of HLA match
Complications of kidney transplant
Operative – bleed, thrombosis, infection, urinary leaks.
Rejection – risk highest in 1st 3 months; need lifelong immunosuppression
Ciclosporin / Tacrolimus toxicity
Infection / malignancy due to immunosuppression (typically skin cancer, anal cancer, lymphoma).
Kidney anatomy
Lie in the retroperitoneum of the abdomen.
Typically extend from T12 to L3.
=> The right kidney is generally lower than the left due to the liver.
The kidney parenchyma consists of two main regions, covered with a fibrous capsule:
1. inner medulla
2. outer cortex
Components of nephron and their function
RENAL CORPUSCLE - site of initial filtration
PCT - reabsorption of ions and solutes; regulation of pH by secreting bicarbonate
LOOP OF HENLE - Ascending limb aims to create a strong osmotic gradient for absorption of large amounts of water from the descending limb
DCT - Secretion of ions, acids, drugs and toxins; Variable reabsorption of water/sodium under the control of aldosterone.
COLLECTING DUCT - Variable reabsorption of water under the control of ADH
Renin-Aldosterone-Angiotensin System
The juxtaglomerular cells of the kidneys are stretch receptors:
1. Decrease in blood volume => reduced stretch
2. Leads to the release of renin.
3. Renin is involved in the cleavage of angiotensinogen to form AI
4. AI undergoes conversion by ACE to form AII
Angiotensin II causes:
- Vasoconstriction (of afferent arteriole)
=> BP increases until it returns to normal
- Release of aldosterone from the adrenal cortex
=> Enhances reabsorption of sodium and water (and increases secretion of K+ and H+), thereby increasing blood volume.
Causes of hyperkalaemia
Pseudo-hyperkalaemia (Haemolysis, Incorrect order of blood draw, Sample taken from drip arm)
AKI / CKD
Drugs:
=> Supplements, K+-sparing diuretics, ACEis, NSAIDs
Acidosis (including DKA)
Addison’s disease
Tumour-lysis syndrome
Burns
Symptoms of hyperkalaemia
Often asymptomatic if mild/moderate
Muscle weakness, numbness, tingling,
N&V
Palpitations (=> arrythmias if untreated)
Hyperkalaemia - Ix
Raised K+ on U&Es / blood gas
ECG signs:
- Tall, peaked T waves
- Widened QRS complexes
- Flattened P-waves / prolonged P-R interval
If it goes untreated, ventricular fibrillation / tachycardia can develop.
Hyperkalaemia - aims of Tx
Aims of Tx:
1. Stabilise the Heart – Calcium Gluconate
2. Drive potassium intracellularly – insulin & dextrose / salbutamol
3. Tackle the underlying issue to reduce total body potassium
Hyperkalaemia - Mx
If potassium >6.5 mmol/L or there are ECG changes, initiate emergency management:
- Start continuous ECG monitoring
- 10ml of 10% Calcium gluconate IV to stabilise the heart
=> Repeat at 5 min intervals until a max of 3 doses or ECG normal - 50ml 50% glucose with 10 units Actrapid Insulin into a large vein over 30 minutes to decrease K+ concentration
=> Onset 1-4 hours, consider BM - Consider 10mg Salbutamol neb
- If pH <7.2, consider sodium bicarbonate IV (if advised by renal registrar)
- Recheck K+ after 2 hours
- Consider potassium binders
- Ensure the underlying cause is being treated.
What is AKI?
= a sudden deterioration in kidney function occurring over hours or days, as measured by serum urea and creatinine.
This results in a failure to maintain fluid, electrolyte and acid-base homeostasis.
Can be PRE-RENAL, RENAL or POST-RENAL
Pre-renal AKI
Occurs when renal perfusion is interrupted
Main causes:
1. Shock – hypovolaemic, cardiogenic, distributive.
2. Renovascular obstruction:
- AAA,
- Renal artery stenosis (and ACEis given in bilateral renal artery stenosis),
- Renal vein thrombosis
If interruption in the blood supply is prolonged, there will be acute tubular necrosis (ATN)
Post-Renal AKI
Occurs when there is obstruction of the urinary tract
Blockage is often in the ureters – e.g. stones, strictures, clots, external/internal malignancy.
Can also be due to bladder outlet obstruction – e.g. prostatic enlargement, urethral strictures, paraphimosis.
Intrinsic/ Renal AKI
If there is no pre-renal or post-renal cause of AKI, then intrinsic cause should be suspected
Injury or damage to the renal parenchyma, by 3 mechanisms:
- Acute Tubular Injury (85%)
- Interstitial Nephritis (10%)
- Glomerular Disease (5%)
AKI - acute tubular injury
Renal causes are due to drugs/toxins damaging the tubular cells (rather than ischaemia, which is pre-renal).
Drugs – aminoglycosides, cephalosporins, radiological contrast mediums, NSAIDs.
Toxins – heavy metal poisoning, myoglobinuria, haemolytic uraemic syndrome (HUS).
Myoglobinuria
Follows an episode of rhabdomyolysis (muscle breakdown from trauma, strenuous exercise or medications), releasing myoglobin which is readily filtered by the glomerulus.
Gives the classical dark urine, but in high quantities will precipitate out within the tubules to cause damage.
Causes ACUTE TUBULAR INJURY & thus AKI
haemolytic uraemic syndrome
Occurs in children following diarrhoeal illness caused by verotoxin-producing E. coli O157, or following a URTI in adults.
Thrombocytopaenia, haemolysis and ACUTE TUBULAR INJURY (=> AKI).
Children recover within a few weeks, prognosis for adults is poor.
Treatment is supportive, including dialysis.
AKI - Interstitial Nephritis
Damage is not limited to tubular cells (as in ATN) and bypasses the basement membrane to cause damage to the interstitium.
Most commonly caused by drugs (especially antibiotics, but also diuretics, NSAIDs allopurinol and PPIs).
Can be caused by infection, auto-immune mechanism or lymphoma.
Normally responds to withdrawal of the drugs and a short course of oral steroids.
AKI - Glomerular Disease
Glomerulonephritis, thrombosis, HUS, IgA nephropathy
AKI - Presentation
Symptoms:
- Reduced urine output
- Nausea and vomiting
- Dehydration
- Confusion
- Fatigue
Signs - Dependent on the underlying cause – look for:
- Fluid overload
- Hypotension in pre-renal causes, HTN in CKD
- Palpable abdominal mass
- Associated features of vasculitis – petechiae, skin changes, bruising, etc.
Approach to patient with reduced urine output / raised creatinine / decreased GFR
- Is it AKI or CKD?
=> Suspect CKD if history of comorbidities (HTN, DM) and long duration of Sx (confirm with USS showing small kidneys) - If it is AKI, is it pre-renal / renal / post-renal?
=> Pre-renal – look for signs of shock and treat appropriately; listen for renal bruits and take vascular Hx
=> Post-renal – order abdominal or KUB USS; examine prostate in older males.
=> Renal – drug history, Hx of recent infections / joint pains/ rashes; urine dip (?blood / protein); any red cell casts on microscopy
Diagnosis of AKI
NICE recommends using any of the following criteria:
- A rise of serum creatinine >26 micromol/L in 48 hours
- A 50% or greater rise in serum creatinine over the past 7 days
- A fall in urine output to <0.5mL/kg/hour for > 6 hours
AKI Stage 1
SERUM CREATININE
150-200% increase OR >25 micromol/L increase in 48h
URINE OUTPUT
<0.5 mL/kg/hour for 6h
AKI Stage 2
SERUM CREATININE
200-300% increase
URINE OUTPUT
<0.5 mL/kg/hour for 12h
AKI Stage 3
SERUM CREATININE
>300% increase OR >350 micromol/L increase in 48h
URINE OUTPUT
<0.3 mL/kg/h for 24h OR Anuria for 12h
How should oliguria/anuria be confirmed in patients with suspected AKI?
In order to confirm oliguria/anuria, the patient first needs to be volume replaced to ensure they are euvolaemic.
AKI - Investigations
BEDSIDE
Urine dip and MC&S
Observations
Glucose
ECG – ?hyperkalaemia
BLOODS
FBC, U&E, LFTs, clotting, CRP
ABG/VBG – ?acid-base imbalance
Nephritic Screen if cause unclear
Creatine Kinase (if indicated)
IMAGING
Renal USS to rule out obstruction
CXR if pulmonary oedema
CT KUB if obstruction
Nephritic Screen
ANCA & anti-GBM – Rapidly progressive glomerulonephritis (RPGN)
ANA, dsDNA & complement – SLE
Immunoglobulins, serum electrophoresis – myeloma
Rheumatoid Factor – RA-associated GN
Hepatitis B/C screen – Mesangiocapillary glomerulonephritis (MCGN)
ASO – post-streptococcal
AKI - Management
A – E assessment (with correction of any hypoxia)
Hold any potentially damaging drugs
Restrict potassium intake
Then manage cause:
PRE-RENAL
= Treat shock
RENAL
= Assess fluid status
Volume replacement (normal saline) to match losses (fluid balance chart)
If there is urine output after fluid replacement, continue large quantities of fluid +/- diuretics – furosemide stress test
If there is no urine output / there are complications – nephrologist input
POST-RENAL
= Refer to urology
AKI - complications
Hyperkalaemia
Hypernatraemia (unless pre-renal cause)
Metabolic acidosis
Rapidly progressive Uraemia
Volume overload => pulmonary oedema
CKD and End-stage renal disease
What is lymphoedema?
= swelling which results from an increased quantity of fluid in the interstitial space of soft tissues, due to failure of lymphatic drainage.
Can be PRIMARY or SECONDARY
It causes chronic, non-pitting oedema – commonly affecting the legs and progressing with age
Primary lymphoedema
Presents in early life
Due to an inherited deficiency of lymphatic vessels (e.g. Milroy’s disease)
Secondary Lymphoedema
Due to obstruction of lymphatic vessels (e.g. filarial infection, repeated cellulitis, malignancy, post-op).
Lymphoedema - Ix
Lymphoscintography can be used to confirm diagnosis, after other causes of oedema have been excluded (CCF, renal disease, deep venous insufficiency).
Lymphoedema - Mx
Elevation
Compression stockings
Physical massage
Long-term ABX if recurrent cellulitis (each episode further damages lymphatic drainage).
Raynaud’s Phenomenon vs Raunaud’s Syndrome
Phenomenon = general term describing episodic digital vasospasm in the absence of an identifiable associated disorder.
Syndrome = Raynaud’s phenomenon occurring secondary to another condition
Secondary causes of Raynaud’s
Connective Tissue Disease :
- Systemic Sclerosis
- Mixed connective tissue disease
- SLE
- Sjogren’s syndrome
- Polyarteritis Nodosa
Macrovascular Disease:
- Atherosclerosis
- Thoracic Outlet Obstruction
- Buerger’s disease
Occupational Trauma
- Vibration white finger
- Repeated extreme cold or chemical exposure
Drugs
- Beta-blockers
- Cytotoxic drugs
Others
- Malignancy
- AVF
Raynaud’s - presentation
Common triggers = cold exposure or emotional stress.
There are 3 phases:
1. Pallor – due to digital artery spasm
2. Cyanosis – due to accumulation of deoxygenated blood
3. Rubor – erythema due to reactive hyperaemia.
As the fingers return to normal, there may be numbness or a burning sensation and severe pain.
Attacks are usually <45 minutes; but can last for hours.
=> Very severe cases can involve tissue infarction and loss of digits.
Raynaud’s - Investigations
Primary Raynaud’s does not require further investigation.
if any features suggesting secondary cause:
- FBC, U&E, coagulation, glucose
- TFTs
- ANA/RF/APA – autoimmune screen if suspecting secondary cause.
Raynaud’s - Management
Keep extremities warm
Smoking cessation
Stop exacerbating drugs – e.g. beta-blockers, OCP
1st line medical therapy = nifedipine
=> Losartan/prazosin/fluoxetine = 2nd line
Sympathectomy may help those with severe disease, but may be short lived.
Paracetamol overdose - pathophysiology
Paracetamol = intrinsic hepatotoxin
- It is conjugated with glucuronide and sulphate at therapeutic doses.
- A small amount is metabolised by mixed function oxidase systems to form NAPQI
- NAPQI is immediately conjugated with glutathione due to its toxicity.
- In overdose, the normal conjugation pathways become saturated
- Large amounts of NAPQI are created.
- This overwhelms the liver glutathione stores to cause cellular damage.
Severity is dose-related, however those who are malnourished/low weight or with high alcohol intake appear to be more susceptible.
Paracetamol overdose - Presentation
Most remain asymptomatic for 24 hours – or at most develop anorexia, nausea and vomiting.
Symptoms/signs start to develop after 24 hours:
- RUQ pain
- Metabolic acidosis
- Hypotension
- Hypoglycaemia
- Pancreatitis
- Arrythmias
Liver damage is not detectable on blood tests until 18 hours after ingestion.
=> Damage peaks at 72-96 hours post-ingestion (deranged ALT/ALP and INR)
Without Tx, some develop fulminant liver failure.
Renal failure due to acute tubular necrosis can also occur.
Paracetamol overdose - Tx
A-E approach
Lavage if >12g (>150mg/kg) taken within 1 hour.
Give activated charcoal if <1 hour since ingestion.
Take a full set of bloods at 4 hours post ingestion
- Including INR, ABG, LFTs, U&Es, glucose, blood salicylate and paracetamol level
If <8 hours after ingestion – give IV acetylcysteine if blood levels above the treatment line on the hospital protocol.
If >8 hours after ingestion – treat immediately with N-acetylcysteine if >150mg/kg has been ingested.
=> Discontinue if plasma levels return below the treatment line, and the patient is asymptomatic with normal biochemistry.
If the patient continues to deteriorate then discuss with the liver team.
Discharge only after mental health team review.
Why is paracetamol level not measured until 4 hours after overdose ingestion?
Paracetamol level is unreliable before the 4-hour mark due to continuing absorption/distribution
N-acetylcysteine
Replenishes cellular glutathione stores and may repair oxidative damage.
Potential SEs:
- Rash, oedema, hypotension, bronchospasm (rarely serious; treated with IV chlorphenamine).
- Only stop the infusion in true anaphylaxis
Causes of splenomegaly
Infection
=> E.g. IE, bacterial sepsis, EBV, TB, malaria, schistosomiasis.
Inflammation
=> E.g. RA, SLE, sarcoidosis
Portal HTN
Haematological disease
=> Haemolytic anaemia, leukaemia, lymphoma, myeloproliferative disorders
–
MASSIVE splenomegaly (palpable in the RIF) can be seen in myelofibrosis, CML, lymphoma, malaria, leishmaniasis or Gaucher’s disease.
Hypersplenism
Splenomegaly of any cause can lead to hypersplenism, which results in:
- Pancytopaenia
- Increased plasma volume
- Haemolysis
What is the function of the spleen?
= largest lymphoid organ in the body
functions to break down erythrocytes and for immunological defence
Splenic Rupture
Most commonly caused by blunt trauma, occasionally by penetrating injuries.
Pre-existing illness can markedly increase the risks of splenic injury
Presentation:
- Immediate massive bleeding
- Peritonism from progressive blood loss
- Eventually shock
Rupture can occur hours-days after the initial trauma, due to expanding haematoma beneath the capsule (asymptomatic interval).
3 main routes of bacterial infection of the liver
- Ascending spread from cholangitis
- Portal spread from a focus of sepsis in the abdomen
- Systemic bloodstream spread in septicaemia
Pyogenic Liver Abscess - cause and presentation
Most common organisms:
- E. coli
- Strep. Milleri
- Anaerobes
Presentation:
- Patients are often not acutely unwell, may just have a long history of malaise.
- Can present acutely unwell with abdominal sepsis and a tender enlarged liver.
- May be pleural effusion in the right lower chest.
Pyogenic Liver Abscess - Investigations
USS/CT can detect a liver abscess.
CXR may show elevation of the right hemidiaphragm +/- pleural effusion
Pyogenic Liver Abscess - Management
Aspiration under USS guidance.
IV ABX
Treat underlying cause
Amoebic Liver Abscess - causes and presentation
Consider in patients with a Hx of travel.
Faeco-oral spread of entamoeba histolytica.
Presentation:
- May be asymptomatic
- Can get profuse/bloody diarrhoea
- Swinging high fever, RUQ pain and tenderness
Amoebic Liver Abscess - Investigations
Stool microscopy will show offending organism, blood and pus.
USS/CT to visualise the abscess
Amoebic Liver Abscess - Mx
Metronidazole for 5 days = Tx for amoebic dysentery
USS drainage may also be required.
Liver Hyatid Cyst - cause and presentation
Caused by echinococcus granulosis (dog tapeworm).
Infects humans coming into contact with infected dogs or food/water contaminated with dog faeces.
Thick-walled, slow-growing cyst
Either Asymptomatic or dull ache in RUQ
Liver Hyatid Cyst - Investigations
Positive hyatid complement fixation test/haemagglutination, eosiniphilia.
AXR – may show calcification of cyst wall
USS/CT – shows cyst
Liver Hyatid Cyst - Management
Albendazole and FNA under USS guidance
Deworming of pet dogs.
Liver Mets
90% of liver tumours are secondary metastases.
Primaries commonly in the lung/stomach/colon/breast/uterus.
Management = investigation to find the primary
Hepatocellular Carcinoma - causes
= Malignant tumour of hepatocytes – accounts for the majority of primary liver cancers.
Common in China and Sub-Saharan Africa (rare in the west)
Causes:
- Chronic hepatitis / cirrhosis
- Metabolic liver diseases
- Aspergillus aflatoxin
- Parasites
- Anabolic steroids
Hepatocellular Carcinoma - presentation
Symptoms:
- Non-specific fever, malaise, weight loss.
- RUQ pain
Signs:
- Hepatomegaly (may be smooth or hard/irregular)
- Signs of chronic liver disease / decompensation
- Abdominal mass / bruit over liver
- Jaundice is late presentation
Hepatocellular Carcinoma - Ix
Bloods – FBC, LFTs, clotting, hepatitis serology, AFP (raised in >50% of HCC)
USS/CT to identify lesions and guide biopsy
MRI to distinguish between benign/malignant lesions
ERCP/biopsy if cholangiocarcinoma suspected
Hepatocellular Carcinoma - Mx
Surgery for solitary HCCs <3cm, but high risk of recurrence
Liver transplantation if there are small tumours due to cirrhosis
=> Resection in cirrhosis can lead to decompensation
Benign liver tumours
Most commonly haemangiomas (incidental finding on CT/USS)
If the patient is a young woman on the OCP, it may be more likely to be a liver cell adenoma.
A benign liver tumour should only be treated if large/symptomatic
Jaundice
= yellow discolouration of the sclera, skin and mucous membranes secondary to hyperbilirubinaemia
Generally, the bilirubin needs to be around 2x the upper limit to be clinically visible
Bilirubin Metabolism
- Bilirubin is a product of haemoglobin breakdown. When a red cell is broken down (typically in the spleen), this releases unconjugated bilirubin (UCB).
- UCB is binds to albumin before being transported to the hepatocytes of the liver.
- In the liver it is conjugated by a hepatic enzyme. This conjugated bilirubin (CB) is then stored in the gallbladder as part of bile.
- Bile is released during digestion, where the CB is then broken down in the small intestine into Urobilinogen.
- Urobilinogen then takes 1 of 3 paths:
- Converted to stercobilin in the gut and excreted in the stool
- Absorbed into blood before being excreted by the kidney in the urine.
- Recycled back to the liver to be re-excreted in bile.
Stercobilin and Urobilinogen
Stercobilin gives stools their dark colour
Urobilinogen in the urine is oxidised to urobilin when exposed to air, eventually giving the urine a dark colour (as opposed to immediate dark urine of cholestasis, which is caused by conjugated bilirubin).
What are the 3 sub-types of jaundice?
- Pre-hepatic – Increased RBC breakdown
- Hepatic – Dysfunction of hepatocytes
- Post-hepatic – Cholestasis due to obstruction
Pre-hepatic Jaundice
Occurs due to increased breakdown of RBCs leads to increased UCB – this overwhelms the capacity of the hepatocytes to conjugate it
There will be leftover UCB in the bloodstream and results in jaundice.
Causes = anything causing haemolysis.
Hepatic Jaundice - causes
Hepatitis (Viral, autoimmune, alcoholic)
Cirrhosis
Drug-induced liver injury
Wilson’s Disease
Jaundice occurs due to:
- UCB not conjugated at a sufficient rate, leading to increased circulating UCB.
- A degree of obstruction means that CB not being transported into biliary ducts, CB builds up in the hepatocytes and ends up in the bloodstream (increased circulating CB).
ISOLATED unconjugated hyperbilirubinaemia
= hyperbilirubinaemia with no other blood test abnormalities (i.e. LFTs and reticulocytes)
DUE TO GILBERT’S SYNDROME
Gilbert’s Syndrome
Autosomal recessive inherited condition
Leads to defective gene encoding for the hepatic conjugation enzyme.
Intermittent jaundice in the absence of haemolysis or underlying liver disease.
Will see isolated elevated UCB on investigation
=> Normal LFTs and reticulocytes
Benign and self-limiting condition
Hepatic Jaundice - stool/urine colour
Urinary urobilinogen may be raised (due to inability of the liver to re-excrete what is reabsorbed)
If conjugated bilirubin levels are high enough => dark urine.
Stools could be paler than usual (due to a decrease in the ability to conjugate bilirubin and excrete it into the gut)
Pre-hepatic Jaundice - stool/urine colour
Large amounts of bilirubin excreted into the gut => normal stools
Urinary urobilinogen also raised (but no clinically dark urine as takes time to oxidise).
UCB cannot be excreted in urine
Post-hepatic jaundice - causes
Due to obstruction of bile outflow from the liver – leading to cholestasis.
Obstruction can be INTRA or EXTRA-HEPATIC
=> Pressure backs up bile between hepatocytes back to vasculature and CB is pushed back into the bloodstream (conjugated hyperbilirubinaemia).
Causes of intra-hepatic bile outflow obstruction
Hepatitis
Cirrhosis
Neoplasm
Drugs (chlorpromazine, flucloxacillin, isoniazid, OCP)
Pregnancy
Causes of extra-hepatic bile outflow obstruction
Gallstones
Cholangiocarcinoma
Primary sclerosing cholangitis
Congenital atresia of CBD
Pancreatitis
Tumour of pancreatic head
Post-hepatic jaundice - stool/urine colour
Pale stools – very little/no bilirubin reaching the GI tract.
Dark urine – conjugated bilirubin reaches the kidneys through the blood.
Jaundice - Investigations
Bloods:
=> FBC, reticulocytes, LFTs, U&Es, clotting, glucose, bilirubin levels.
Urinary urobilinogen/bilirubin
Further Investigations:
- Blood films / Coomb’s test – if ?haemolysis
- Viral serology/autoantibodies – if ?hepatitis
- USS - ?dilated duct system
- CT/MRI - intrahepatic / pancreatic lesions
ERCP if ductal system dilated on USS
Acute causes of hepatitis
Viral infections (Hep A-E or non-Hep infections)
Autoimmune
Drug reactions
Alcohol
Chronic causes of hepatitis
Hepatitis B +/- D virus
Hepatitis C virus
Autoimmune hepatitis
Alcohol
Hyperlipidaemia (NAFLD)
Drugs (methyldopa, nitrofurantoin)
Metabolic disorders (Wilson’s, alpha1-antitrypsin deficiency, haemochromatosis)
Liver screen
Done in any patient with suspected hepatitis / liver pathology of unknown origin
Microbiology – viral screen
Clinical chemistry:
- Ferritin / transferrin
- Lipids
- Caeruloplasmin
- AFP
- Alpha-1 antitrypsin
Immunology – autoantibodies
Abdominal USS
Hepatitis A
Transmitted faeco-orally
Notifiable disease
Does not lead to chronic liver disease, thus there are no carriers.
No specific treatment
Hepatitis E
Transmitted faeco-orally
Clinically similar to HepA infection:
- Causing epidemics of acute, self-limiting hepatitis
- No progression to chronic disease
Common in indo-china, so consider if recent travel.
Can cause severe disease in pregnant women
