Pre-hepatic jaundice Flashcards
What are 3 groups into which pre-hepatic causes of jaundice can be classed?
- Conjugation disorders: Gilbert’s disease and Crigler-Najjar
- Haemolysis: malaria or haemolytic anaemia
- Drugs e.g. contrast or rifampicin
What characterises a pre-hepatic cause of jaundice on the LFTs?
isolated raised bilirubin level
How can haemolysis cause jaundice?
destruction of red blood cells or their marrow precursors causes increased bilirubin production
What type of jaundice is casedu by haemolysis?
unconjugated jaundice
What is the commonest form of non-haemolytic hyperbilirubinaemia?
Gilbert syndrome
What are the 2 types of congenital non-haeomlytic uncongjugated hyperbilirubinaemias?
- Gilberts syndrome
- Crigler-Najjar type I and II
What are 2 examples of conjugated non-haemolytic congenital hyperbilirubinaemias?
- Dubin-Johnson syndrome
- Rotor’s syndrome
How is Gilberts syndrome inherited?
Autosomal recessive (can also be autosomal dominant)
What is the pathophysiology of Gilbert’s syndrome?
defective bilirubin conjugation due to deficiency of UDP glucoronosyl transferase, causing reduced bilirubin uptake by liver
due to mutation in the UGT1A1 gene
What is the prevalence of Gilbert’s syndrome in the general population?
1-2%
What are the clinical features of Gilbert’s syndrome?
- unconjugated hyperbilirubinaemia
- jaundice may only be seen during an intercurrent illness, exercise or fasting
What are 4 examples of triggers for jaundice in Gilberts syndrome?
- Stress
- Fasting
- Infection/ intercurrent illness
- Exercise
Wat is the maangement of Gilbert’s syndrome?
none necessary
What are the two types of Crigler-Najjar syndrome and how does the pathophysiology of each differ?
- Gilbert’s syndrome: absent glucuronyl transferase
- Crigler-Najjar: reduced glucuronyl transferase
What is the clinical presentation of Crigler-Najjar syndrome Type I vs Type II?
- Type I: rapid death in neonate - kernicterus
- Type II: presents in neonate
What is the maangement of Crigler-Najjar type II? 3 aspects
- Phenobarbital
- Phototherapy
- Liver transplant
How is Dubin-Johnson syndrome inherited?
autosomal recessive
How is Crigler-Najjar syndrome inherited?
autosomal recessive
What is the pathophysioloy of Dubin-Johnson syndrome?
reduced canalicular excretion of organic anions, including bilirubin. pigentation of liver biopsy tissue
What is the clinical presentation of Dubin-Johnson syndrome?
mild jaundice
What is the management of Dubin-Johnson syndrome?
none necessary
How is Rotor’s syndrome inherited?
autosomal recessive
What is the mechanism of action of Rotor’s syndrome?
reduced bilirubin uptake leading to reduced intrahepatic binding
What is the clinical presentation of Rotor’s syndrome?
mild jaundice
What is the management of Rotor’s syndrome?
none necessary
What are 2 haemolytic causes of pre-hepatic jaundice?
- Malaria
- Haemolytic anaemia
What are 3 types of distinctions that can be made to classify the different types of haemolytic anaemias?
- Hereditary vs acquired
- Intravascular vs extravascular
- Autoimmune (Coombs positive) and non-autoimmune (Coombs negative)
What are 5 general biocheical features of haemolytic anaemias?
- Low haemoglobin
- High bilirubin (unconjugated)
- Reticulocytosis
- Raised LDH
- Raised urinary urobilinogen
What are 5 examples of causes of intravascular haemolytic anaemia?
- Intrinsic cellular injury (e.g. glucose-6-phosphate-deficiency G6PD)
- Intravascular complement mediated lysis - some autoimmune haemolytic anaemias
- Paroxysmal nocturnal haemoglobinuria and acute transfusion reactions
- Mechanical injury - microangiopathic haeomlytic anaemia and cardiac valves
- Autoimmune haemolytic anaemia
What are 3 types of hereditary causes of haemolytic anaemias?
- Metabolism: G6PD deficiency
- Membrane: Hereditary spherocytosis/elliptocytosis
- Haemoglobinopathies: Sickle cell, thalassaemia
What are the 2 groups into which acquired haemolytic anaemia can be split?
immune and non-immune causes
What are 3 acquired immune causes of haemolytic anaemia?
- Autoimmune: warm/cold antibody ype
- Alloimmune: transfusion reaction, haemolytic disease of newborn
- Drug: methyldopa, penicillin
What are 5 acquired non-imune causes of haemolytic anaemia?
- Microangiopathic haemolytic anaemia (MAHA): TTP/HUS, DIC, malignancy, pre-eclampsia
- Prosthetic cardiac valves
- Paroxysmal nocturnal haemoglobinuria
- Infections: malaria
- Drug: dapsone
What is meant by intravascular haemolysis?
occurs in the blood stream, resulting in release of cellular contents (in particular haemoglobin) into the circulation
excess Hb dealt with in many ways:
- combiens with haptoglobin
- combines with albumin (methaemalbuminaemia)
- loss in urine (haemoglobinuria)
- stored in tubular epithelial cells as haemosiderin and sehd into urine (haemosiderinuria)
What are the 4 ways in which excess Hb caused by intravascular haemolytic anaemia can be dealt with by the body?
- combines with haptoglobin
- combines with albumin (methaemalbuminaemia)
- loss in urine (haemoglobinuria)
- stored in tubular epithelial cells as haemosiderin and sehd into urine (haemosiderinuria)
What is the inheritance of G6PD deficiency?
X-linked recessive
What is G6PD deficiency?
red-cell enzyme disorder, may present in neonatal period with jaundice, or later in life with episodic intravascular haemolysis following exposure to oxidative stressors
What are 2 ways that G6PD deficieny?
- Neonatal period with jaundice
- Later in life with episodic intravascular haemolysis - following exposure to oxidative stressors
What are 4 examples of triggers for G6PD deficiency?
- Intercurrent illness or infection
- Fava beans (favism)
- Henna
- Medictions: primaquine, sulfa-drugs, nitrofurantoin, dapsone, NSAIDs/ aspirin
What are 5 examples of medications that can trigger G6PD defiency?
- Primaquine
- Sulfa-drugs
- Nitrofurantoin
- Dapsone
- NSAIDs/aspirin
What are 2 investigations to perform in G6PD deficiency and what will they show?
- Blood film: Heinz bodies and bite cells
- G6PD enzyme assay - diagnostic test
What are 2 aspects of management of G6PD deficiency?
- Avoidance of precipitants
- Rarely -transfusions
What is extravascular haemolytic anaemia?
extravascular haemolysis occurs in reitculo-endothelial system (spleen and liver) and therefore not associated with dramatic release of free Hb into circulation. splenomegaly and hepatomegaly are typical
What findings on examination are typical of extravascular haemolytic anaemia?
- splenomegaly and hepatomegaly
What are 2 examples of causes of extravascular haemolytic anaemia?
- Abnormal red blood cells, e.g. sickle cell anaemia and hereditary spherocytosis
- Normal cells marked by antibodies for splenic phagocytosis
What is the inheritance of hereditary spherocytosis?
autosomal dominant
In which patient populations is hereditary spherocytosis seen?
northern European
What is the pathophysiology of hereditary spherocytosis?
caused by mutations in structural red cell membrane proteins. abnormal sections of membrane removed by the spleen, resulting in a reduced surface area to volume ratio and causing spherical distortion of cells (Seen as spherocytes on blood film)
eventually as more membrane removed, cells haemolyse (extravascular haemolysis) are removed from circulation in spleen
How does hereditary spherocytosis typically present?
neonatal or childhood onset jaundice/anaemia, and splenomegaly
What is the management of hereditary spherocytosis? 2 aspects
- Conservatively - folic acid supplementation
- Splenectomy before age of 5 - if severe. = curative
What is the key diagnostic test to identify a haemolytic anaemia?
Direct Coombs test - in AIHA there are antibodies against cell surface markers on the red blood cells. Coombs cell tests for AIHA by using antibodies against autoantibodies, to cross link and agglutinate red cells
What are the 2 key types of Coombs-positive haemolytic anaemia (i.e. autoimmune haemolytic anaemia)?
- Warm autoimmune haemolytic anaemia
- Cold autoimmune haemolytic anaemia
What is the pathophysiology of warm autoimmune haemolytic anaemia?
IgG mediated extravascular haemolytic disease in which the spleen tags cells for splenic phagocytosis
the antibody causes haemolysis best at body temperature and tends to occur in extravascular sites e.g. spleen
What are 4 examples of causes of warm AIHA?
- Idiopathic
- Lymphoproliferative neoplasms (CLL and lymphoma)
- Drugs including methyldopa
- SLE
What are 3 management options for autoimmune haemolytic anaemia?
- Steroids
- Immunosuppression
- Splenectomy
What is the pathophysioloy of cold autoimmune haemolytic anaemia?
the antiobdy is usually IgM and causes haemolysis best at 4oC. haemolysis is mediated by complement and is more commonly intravascular - causes direct intravascular haemolysis (aka cold agglutinins)
What are 4 key differences between warm and cold autoimmune haemolytic anaemia?
- warm mainly extravascular, cold extravascular
- warm haemolysis at body temp, cold at 4 degrees
- warm responds well to steroids while cold does not
- warm IgG mediated, cold IgM
What are 5 examples of Coombs negative haeomlytic anaemias?
- Microangiopathic haemolytic anaemia
- Paroxysmal nocturnal haemoglobinuria
- Physical lysis of red cells e.g. malaria
- Haemolytic uraemic syndrome (E. coli 0157:H7)
- Infectious causes of DIC (such as fulminant meningococcemia)
What is microangiopathic haemolytic anaemia?
intravascular haemolytic disorder caused by physical lysis of red cells by deposited fibrin strands, resulting in the presence of schistocytes (fragments of red blood cells) on the blood film
What will be present on a blood film in microangiopathic haemolytic anaemia?
schistocytes (fragments of red blood cells)
What diseases may microangiopathic haemolytic anaemia occur in association with?
can be isolated or occur with thrombotic microangiopathy syndrome, such as haemolytic uraemic syndrome and thrombotic thrombocytopenia purpura
or in severe cases, disseminated intravascular coagulation
What blood product is used to treat disseminated intravasular coagulation?
cryoprecipitate
What is paroxysmal nocturnal haemoglobinuria?
rare acquired stem cell disorder of unknown aetiology
What is the pathophysiology of paroxysmal nocturnal haemoglobinuria?
abnormal surface glycoprotein expressed on a subclone of red blood cells marks these cells for complement mediated haemolysis - severity depends on the size of this subclone
How do patients with paroxysmal nocturnal haemoglobinuria present?
present in early adulthood with nocturnal episodes of intravascular haemolysis (it is not known why this occurs at night)
What may paroxysmal nocturnal haemoglobinuria be associated with?
other stem cell defects and increased risk of thrombosis (via effect on complement mediated platelet aggregation)
How is a diagnosis of paroxysmal nocturnal haemoglobinuria made?
flow cytometry
What are 3 examples of causes of physical lysis of red cells?
- Malaria
- Babesiosis (parasite grows in red cell cytoplasm)
- Prosthetic heart valves
