liver msc clinical biochemistry dr sarah mapplebeck consultant clinical biochemist
TRANSCRIPT
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LiverMSc Clinical Biochemistry
Dr Sarah Mapplebeck
Consultant Clinical Biochemist
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Lecture structure
Session 1Liver structure and functionLiver investigations
Session 2Liver cases
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Session 1
STRUCTURE AND FUNCTION
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Structure of liver
Largest internal organ Situated in right hypochnodrium Divided into right and left lobes by middle
hepatic vein Subdivided into eight segments by
divisions of the right, middle and left hepatic vein
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Blood supply
Blood supply to liver constitutes 25% of resting cardiac output via two main vessels
Hepatic artery Branch of coeliac axis Supplies 25% of total blood flow Autoregulation of blood flow by hepatic artery ensure a
constant total liver blood flow
Portal vein Drains most of the GI tract and spleen Supplies 75% of blood flow
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Functions of the liver
MetabolicProtein metabolismCarbohydrate metabolismLipid metabolism
Formation of bile Metabolism and excretion of bilirubin Hormone and drug inactivation
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Protein metabolism Synthesis
Principal site of synthesis of most circulating proteins Receives amino acids from intestine and muscle and regulates
plasma levels Plasma contains approx 60-80 g/L (albumin, globulin, fibrinogen) Transport proteins e.g transferrin, caeruloplasmin produced in
liver Coagulation factors and complement components
Degradation (nitrogen excretion) Amino acids degraded by transamination and oxidative
deamination to ammonia Ammonia converted to urea and is renally excreted Failure of excretion occurs in severe liver disease
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Carbohydrate metabolism Glucose homeostasis and maintenance of blood sugar
major function of liver Stores approx 80g glycogen Immediate fasting state
Blood glucose maintained by glucose released from glycogen breakdown (glycogenolysis) or by newly synthesized glucose (gluconeogensis)
Sources for gluconeogensis are lactate, pyruvate, amino acids from muscle (alanine and glutamine)
Prolonged starvation Ketone bodies and fatty acids are used as alternative sources of
fuel Body adapts to lower glucose requirement
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Lipid metabolism
Fats transported in plasma as lipoproteins (protein-lipid complexes)
Liver has major role in metabolism of lipoproteins
VLDL and HDL synthesised by liver Triglycerides (come from diet) also synthesised
in liver from circulating free fatty acids and glycerol
Cholesterol comes from diet but mainly synthesised in liver from acetyl CoA
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Formation of bile
Bile secretion Bile acid metabolism Bilirubin metabolism
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Bile secretion Bile consists of water, electrolytes, bile acids,
cholesterol, phospholipids and conjugated bilirubin Two processed involved in bile acid secretion
Bile salt dependent Bile salt independent
Bile salt dependent Uptake of bile acids (and other organic/inorganic ions) across
the basolateral (sinusoidal) by transport proteins – driven by Na-K-ATPase in basolateral membrane
Sodium and water follow passage of bile acids Bile salt independent
Water flow is due to other osmotically active solutes e.g glutathione, bicarbonate
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Bile acid metabolism Bile acids are synthesised in hepatocytes from
cholesterol Excreted into the bile and pass into duodenum Primary bile acids
Cholic acid and chenodeoxycholic acid are conjugated with glycine or taurine which increases their solubility
Secondary bile acids Primary bile acids converted by intestinal bacteria into
deoxycholic and lithocholic acid Bile acids act as detergents – main function lipid
solubilisation Have both hydrophobic and hydrophilic end and in
aq solution aggregate forming micelles
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Bile acid metabolism
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Hormone and drug inactivation
Major site for metabolism of drugs and alcohol Fat soluble drugs are converted to water soluble
substances facilitating excretion in bile or urine Liver catabolises hormones e.g insulin,
glycogen, oestrogens, growth hormone, glucocorticoids, parathyroid hormone
Prime target organ for hormones e.g insulin
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Bilirubin metabolism Produced mainly from breakdown of mature red cells in
Kupffer cells of liver and reticuloendothelial cells 15% bilirubin comes from catabolism of other haem
containing proteins (myoglobin, cytochromes, catalases) Typically 250-300mg bilirubin produced daily Iron and globulin removed from the haem and reused Biliverdin is formed from the haem and is reduced to
form bilirubin Bilirubin produced is unconjugated
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Bilirubin metabolism Uncongugated bilirubin
Not water solubleTransported to liver bound to albuminDissociates from albumin and taken up by
hepatic cell membrane and transported to ER In ER is conjugated with glucuronic acid by
bilirubin-uridyl diphosphate (UDP)
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Bilirubin metabolism
Conjugated bilirubin Water soluble Secreted into biliary canaliculi reaching small intestine In gut bilirubin converted into urobilinogen (colorless) Most urobilinogen oxidised in colon to brown pigment
stercobilin excreted in stool Some urobilinogen is absorbed from gut into portal
blood and small amount excreted in urine
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Bilirubin metabolism
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LIVER INVESTIGATIONS
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Investigations Blood tests
Liver function tests Serum albumin Prothrombin time
Liver biochemistry ALT/AST – reflecting hepatocellular damage ALP and GGT – reflecting cholestasis Total protein
Viral markers Additional blood investigations; haematological, biochemical,
immunological and genetic Urine tests
For bilirubin and urobilinogen Imaging techniques
To define gross anatomy Liver biopsy
For histology
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Liver function tests Serum albumin
Marker of synthetic function Guide to severity of chronic liver disease Falling serum albumin is poor prognostic sign In acute liver disease albumin may be normal
Prothrombin time (PTT) Marker synthetic function Short half life so sensitive indicator of both acute and chronic
liver disease Vit K def should be excluded as cause of prolonged PTT Vit K def commonly occurs in biliary obstruction as low intestinal
concentration of bile salts results in poor absorption of vit K INR often used as PTT varies in laboratories
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Hypoalbuminaemia
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Causes of hypoalbuminaemia Haemodilution
Pregnancy, iv therapy, cirrhosis, antidiuretics Decreased synthesis
Severe liver disease (chronic hepatitis, cirrhosis) Malabsorption, malnutrition
Altered distribution Liver failure/cirrhosis Malignancy
Loss from the body Skin (burns, exudative lesions) Gut (protein loosing enteropathy)
Increased catabolism Malignancy
Misc Acute/chronic illness, malignancy
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Hyperalbuminaemia
Increased albuminDehydration/haemoconcentrationVenous stasisHealthy young adult
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Liver biochemistry
Bilirubin Aminotransferases
alanine amino transferase (ALT) and asparate amino transferase (AST)
Alkaline phosphatase (ALP) Gamma glutamly transpeptidase Total protein
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Bilirubin and jaundice
Yellow discoloration of tissues due to bilirubin deposition
Clinical jaundice may not be clear until plasma bilirubin >50 umol/L
First observed in sclera of the eye
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Laboratory investigation of Jaundice Classified on basis of other LFTs
Isolated hyperbilirubinaemia High serum bilirubin only abnormality
Unconjugated Conjugated
Hepatobiliary disease High bilirubin accompanies other abnormalities in
LFTs
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Laboratory investigation of jaundice
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Isolated hyperbilirubinaemia Increased production
Haemolytic anaemias, hypersplenism, mechanical heart valves, resorption of haematomas,
Decreased hepatic uptake Gilbert’s syndrome Drugs- Rifampicin, Testosterone, Sulphasalazine
Decreased conjugation Gilbert’s syndrome
Gallstones
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Further investigation Bilirubin fractionation
Conjugated, unconjugated or mixed hyperbilirubinaemia FBC
Haemolytic disease and pernicious anaemia (megaloblastic anaemia)
Associated with mild isolated hyperbilirubinaemia Reticulocytes
Haemolytic disease does not always produce low Hb High retic indicated high red cell production rate seen in
haemolytic disease Lactate dehydrogenase
Elevated in haemolysis, pernicious anaemia and hepatitis Haptoglobulin
Bind to haemoglobin released in intravascular haemolysis causing low levels
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Gilberts syndrome
Autosomal dominant (7% population) Bilirubin between 20 and 60 μmol/L Decreased conjugation especially during intercurrent
illness or starvation Elevation <100 umol/L Measure Conjugated and unconjugated bilirubin Reflexed in lab on all GP requests when total bilirubin is
over 30 umol/L and no other abnormalities >75 % unconjugated is consistent with Gilberts
Syndrome Become jaundiced when unwell or fasting Reassure that no further tests are required
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Cholestatic jaundice
Extrahepatic cholestasisDue to large duct obstruction of bile flow at
any point in the biliary tract distal to the bile canaliculi
Intrahepatic cholestasisFailure of bile secretion
Pale stools and dark urine with conjugated serum bilirubin
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Transaminases ALT and AST are present in hepatocytes and leak into blood with
liver cell damage Indicate hepatocellular damage AST
Mainly mitochondrial and also present in heart, muscle, kidney and brain High levels seen in hepatic necrosis, MI, muscle injury and CCF
ALT Cytosol enzyme More liver specific rise only in liver disease
Released early in liver damage and remain elevated for weeks In hepatocelluar disease ALT rises before jaundice Cholestatic disease ALT may not rise Many labs only measure ALT as more specific than AST
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Levels of ALT Minor elevations (<100 U/L)
Chronic hepatitis B and C Haemochromatosis Fatty liver
Moderate elevations (100-300 U/L) Alcoholic hepatitis Autoimmune hepatitis Wilson’s disease
Major elevations (>300 U/L) Drug toxins e.g. paracetamol Acute viral hepatitis Ischaemic liver
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Non-hepatic causes of elevated ALT Coeliac disease Muscle disease Strenuous exercise
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Alkaline phosphatase (ALP)
Present in canalicular and sinusoidal membranes of liver
Present in other tissues Bone, intestinal, placenta
Normal situations bone and liver are the major isoenzymes
If required, origin determined by electrophoretic separation of isoenzymes
If elevated GGT, ALP can be presumed to come from liver
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Alkaline phosphatase (ALP)
Raised in cholestasis from any cause (intra or extra hepatic)
Synthesis of ALP is increased and realsed into blood
Cholestatic jaundice levels may be 4XURL Raised levels also in conditions with infiltration
of liver e.g metastases and cirrhosis often in absence of jaundice
Highest levels due to liver disease seen with hepatic metastases and primary bilary cirrhosis
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Isolated mild rise in Alkaline Phosphatase Bone disease
Paget’s disease Osteomalacia Healing fractures Metastases Hyperparathyroidism Vitamin D deficiency
Drugs Anti epileptics
Pregnancy Growth
Children and teenage growth spurt Biliary disease
Primary biliary cirrhosis (AMA positive)
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Other investigations with elevated ALP Further investigation may include
Calcium and phosphateVitD and PTHLiver enzymesPSAElectrophoresis IsoenzymesRadiology
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GGT
Microsomal enzyme present in many tissues as well as liver
Activity can be induced by drugs e.g phenytoin and alcohol
If ALP normal a raised GGT good guide to alcohol intake
Mild elevations in GGT is common even with small alcohol consumption and doesn’t mean liver damage if other liver biochemistry normal
In cholestasis GGT rises in parallel with ALP
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Isolated rise in Gamma GT Only measure to clarify raised alkaline phosphatase or DVLA
fitness to drive Alcohol (although not always) Drugs
Anticonvulsants, NSAIDs, antibiotics, antifungals, cytotoxics, testosterone
Non alcoholic fatty liver Congestive cardiac failure Afro-Caribbeans have higher reference range Main use to identify source of ALP cheaper the ALP isoenzymes
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Other liver function tests
Total proteins Measurement alone is of little value Globulin fraction calculated Elevated globulin fraction is liver disease is usually
polyclonal due to increased circulating immunoglobins (rather than monoclonal in myeloma)
Viral markers Viruses are major cause of liver diease Virology investigations are often key in diagnosis e.g.
hepatitis
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Additional blood investigations - Biochemical Alpha1 antitrypsin
Deficiency can produce cirrhosis
Alpha fetoprotein Normally produced by fetal liver Reappearance in high conc indicates hepatocellular
carcinoma
Serum and urine copper Wilsons disease
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Additional blood investigations - Immunoglobulins Increased serum immunoglobulins
Due to reduced phagocytosis by sinusoidal and Kupffer cells of antigen from the gut
Antigens then stimulate antibody production
Immunoglobulins (not produced by liver) Polyclonal elevations in chronic liver disease IgM elevated in primary biliary cirrhosis (PBC) IgA elevated in alcoholic liver disease IgG increased in autoimmune liver disease
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Additional blood investigations - Autoantibodies Anti mitochondrial Antibodies (AMA)
Found in serum in >95% patients primary biliary cirrhosis
Nucleic, smooth muscle, liver/kidney microsomal antibodiesHigh titre in autoimmune hepatitisAlso in other autoimmune conditions e.g. SLE
and liver disease
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Other tests
Genetic analysis HFE in haemochromatosis Copper transporting ATPast in Wilsons disease
Urine tests Bilirubin not found in urine in health Bilirubinuria is due to presence of conjugated (soluble) bilirubin
Found in jaundiced patient with hepatobilary disease Absence implies that jaundice is due to increased unconjuated
bilirubin Urobilinogen
Little value but suggests haemolysis or hepatic dysfunction of any cause
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Imaging techniques
Ultrasound (USS) Computed tomography (CT) Magnetic resonance imaging (MRI) Plain X ray of abdomen Endoscopy
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Liver biopsy
Histological examination of liver used in the differential diagnosis of diffuse or localised parenchymal disease
Can be done day case Mortality rate <0.02% in good hands Guided by US or CT when specific lesions need to be
biopsied Minor complications
Usually in first 2hrs Abdominal or shoulder pain Minor bleeding
Major complications Major bleeding Sepsis
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Symptoms of liver disease Acute liver disease
May be asymptomatic Symptomatic (usually viral) produces generalised symptoms of
malaise, anorexia ad fever Jaundice as illness progresses
Chronic liver disease May be asymptomatic or complain of non specific symptoms esp
fatigue Specific symptoms include
Right hypochondrial pain due to liver distension Abdominal distension due to ascites Ankle swelling due to fluid retention Haematemesis and melaenia due to GI haemorrhage Ithcing due to cholestasis Gynaecomastia, loss libido and amenorrhoea due to endocrine
dysfunction
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Signs of liver disease Acute liver disease
Few signs apart from jaundice and enlarged liver Cholestatic phase
Pale stools and dark urine Spider naevi and liver palms may occur
Chronic liver disease May be normal in advanced disease Skin
Chest and upper body may show spider naevi Hands show palmar erythema Xanthomas
Abdomen Hepatomegaly will be followed by small liver in well-established cirrhosis Splenomegaly seen in portal hypertension
Endocrine system Gynaecomastia and testicular atrophy
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Signs of liver disease
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Session 2
LIVER CASES
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Case 1
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AW (1)
Age 48 male Hairdresser Painful joints Exhaustion Low libido
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AW (2)
On examinationpigmented
ALT 167, ALP 175, GGT 147 Alb 43, BR 7 USS = hepatosplenomgaly. No varices
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AW (3)
Viral studies negative Auto-antibodies negative α1-AT normal TSH 1.05
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AW (4)
Ferritin 5740 (rpt 6540) Testosterone 1.1 (n>10) Fasting Glu 9.7 Cortisol 612; prolactin 144; LH 3; FSH 3 IGF1 53 (n94-252); GH 0.12 Homozygous for C282Y Rx venesection, testogel liver biopsy (Jan 2009) = cirrhosis
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Iron Overload Syndromes
Primary overload Secondary overload Others
Iron loading due to liver disease
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Pietrangelo A. N Engl J Med 2004;350:2383-2397
Normal Iron Homeostasis in Humans
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Hereditary Haemochromatosis
Type 1 Classical HFE Type 2a Juvenile HH (Hemojuvelin) Type 2b Juvenile HH (Hepcidin) Type 3 TfR2 mutations Type 4 Ferroportin
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HFE relatedHaemochromatosis C282Y mutation in HFE gene Autosomal recessive Mechanism complex/unclear Excess duodenal iron absorption leads to
deposition in specific organs
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Frequency of HH 1 in 5000 ‘bronze diabetes” 1 in 200 N Europeans homozygous
C282Y 1 in 9 carriers for C282Y Commonest autosomal genetic disorder
in caucasians ???
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Haemochromatosis (3)
Often middle age More males 80% fatigue 56% abdo pain 45% arthralgia (2nd + 3rd metacarpals) 37% loss of libido
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Complications of HH
Diabetes Joint symptoms Cardiac disease Skin pigmentation Impotence
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Sites of iron deposition
Skin Liver Pancreas Endocrine (ant pit, rarely thyroid, adrenal) Myocardium
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Pietrangelo A. N Engl J Med 2004;350:2383-2397
HFE-Related Hereditary Hemochromatosis, a Multistep, Multifactorial Iron-Overload Disorder
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How to diagnose?
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Detection of HH
Transferrin saturation (>45%) Ferritin (?) HFE genotype
C282Y homozygoteC282Y + H63D (4%)
(Liver biopsy) (MRI)
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How to treat?
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Therapeutic Venesection
Aim for ferritin 50-100 (satn<30%) Weekly to fortnightly Improves
fatigueLFTsdiabetic controlarthropathy
If fit can go to blood donation once ferritin down
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EndoscopyUnit
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Who to biopsy?
HH with ferritin >100040% risk of cirrhosis
HH with ferritin <1000cirrhosis very unlikely
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Further Management
Rx diabetes Testogel etc Bone density FU for cirrhosis Family screening
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Learning Points
HH is common HH is usually easy to diagnose HH is easy to treat Early treatment prevents “disease” Think: iron overload
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Case 2
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3rd July
47 year old female47 year old female Called ambulance 26 hours after Called ambulance 26 hours after
taking a paracetamol overdosetaking a paracetamol overdose Seen at 22:00Seen at 22:00
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The patient (1)
Suffers from depression due to physical pain and death of mum in 2008
Took overdose of approx. 50g paracetamol (100 tablets) at approx. 20:00 on 2nd July 08
Taken on empty stomach
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The patient (2)
Started vomiting at 23:00 which made her regret her actions
Started feeling cold and sweaty at 18:00 on 3rd July 08
Impulsive O/D following an argument with son
No further suicidal thoughts or plans
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Initial assessment, 3rd July
No suspicion of alcohol or illicit drugsNo suspicion of alcohol or illicit drugs Airway clear and respiratory rate 20/minAirway clear and respiratory rate 20/min
(normal: <8-25/min)Temperature of 36.7(normal: <8-25/min)Temperature of 36.7ooCC Bp: 154/112 (normal: 127/85)Bp: 154/112 (normal: 127/85) Heart rate: 116 (normal: 54-83)Heart rate: 116 (normal: 54-83) Glasgow coma score (15/15)Glasgow coma score (15/15) AlertAlert Quite nervous Quite nervous
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Other conditions in patient
Osteoarthritis Osteoarthritis FibromyalgiaFibromyalgia Rheumatoid arthritisRheumatoid arthritis DepressionDepression
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Past drug history Pain killers
Fentanyl Transdermal Patches Naproxen E/c Tramadol m/r Paracetamol 500mgs (8 per day)
Antidepressants Amitriptyline Sertraline
Arthritis drugs Alendronic Acid Calcichew-D3 Folic Acid Hydroxylchloroquine Sulphate Prednisolone E/c
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Paracetamol poisoning <24h
Anorexia, nausea and vomiting
24 – 48h Abdominal pain, hepatic tenderness, prolonged PT,
elevated plasma aminotransferases and bilirubin
>48h Jaundice, encephalopathy, renal and hepatic failure
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Paracetamol poisoning
No immediate effect after O/D The PT is the best marker of severity The likelihood of a liver damage can be
predicted from the plasma concentration of paracetamol, which also helps with the determination of appropriate decisions for antidotal therapy
ALT indicates severity of overdose
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Treatment options
Antidote of choice is N-acetylcysteine Antidote of choice is N-acetylcysteine (intravenous) (intravenous)
Methionine (oral)Methionine (oral) 5% dextrose (for hydration)5% dextrose (for hydration) Liver transplantation may be appropriate in Liver transplantation may be appropriate in
the most severe casesthe most severe cases
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Patient
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Investigations
Liver function tests Total protein Albumin Bilirubin ALT (Aminotransferase) ALP (Alkaline Phosphatase)
Clotting screen INR (International Normalised Ratio)
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Patient results 3rd July BLOOD COUNT BLOOD COUNT (normal value)(normal value)
Haemoglobin 15.1 g/dl Haemoglobin 15.1 g/dl 12 – 16 12 – 16 White cell count 13.6 10White cell count 13.6 1099/L /L 3.9 – 11.1 3.9 – 11.1 Platelet count 386 10Platelet count 386 1099/L /L 150 – 450 150 – 450
LFT (liver function test)LFT (liver function test) TP (total protein) 85 g/L TP (total protein) 85 g/L 60 – 80 60 – 80 Albumin 44 g/L Albumin 44 g/L 35 – 5035 – 50 ALP 78 u/L ALP 78 u/L 30 – 13030 – 130 Total bilirubin 29 umol/L Total bilirubin 29 umol/L 0 – 20 0 – 20 ALT 3533 u/L ALT 3533 u/L 5 - 655 - 65
FULL CLOTTING SCREENFULL CLOTTING SCREEN PT 15.1 secs PT 15.1 secs 10.2 – 13.310.2 – 13.3 INR 1.3 INR 1.3 0.8 – 1.20.8 – 1.2 APTT 29.5 secs APTT 29.5 secs 27.8 – 36.327.8 – 36.3
PARACETAMOLPARACETAMOL paracetamol 30 mg/Lparacetamol 30 mg/L
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Treatment
DATE INFUSION FLUID
VOLUME DRUG DOSE DURATION
3/7/08 5% DEXTROSE
200ml N-acetylcysteine 20000mg 15mins
3/7/08 5% DEXTROSE
500ml N-acetylcysteine 6000mg 4hourly
3/7/08 5% DEXTROSE
1000ml N-acetylcysteine 13000mg 16hourly
5/7/08 5% DEXTROSE
1000ml N-acetylcysteine 11g 16hourly
5/7/08 5% DEXTROSE
1L N-acetylcysteine 11g 16hourly
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N-acetylcysteine
Paracetamol is metabolised in the liver, mainly by conjugation with glucuronide and sulphate to form a reactive, potentially toxic, metabolite
In paracetamol overdose, the glucuronide and In paracetamol overdose, the glucuronide and sulphate conjugation pathways are saturated, so sulphate conjugation pathways are saturated, so that more of the toxic metabolite that more of the toxic metabolite N-acetyl-p-benzoquinoneimineN-acetyl-p-benzoquinoneimine (NAPQI)is is formedformed
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N-acetylcysteine
Acetylcysteine protects the liver from damage by restoring depleted hepatic-reduced glutathione levels, or by acting as an alternative substrate for conjugation with, and thus detoxification of, the toxic paracetamol metabolite.
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Results 6th July BLOOD COUNT (normal value)
Haemoglobin 13.4 g/dl 12 – 16 White cell count 9.9 109/L 3.9 – 11.1 Platelet count 386 109/L 150 – 450
LFT (liver function test) TP (total protein) 72 g/L 60 – 80 Albumin 38 g/L 35 – 50 ALP 62 u/L 30 – 130 Total bilirubin 12 umol/L 0 – 20 ALT 1472 u/L 5 - 65
FULL CLOTTING SCREEN PT 14.7 secs 10.2 – 13.3 INR 1.2 0.8 – 1.2 APTT 27.0 secs 27.8 – 36.3
PARACETAMOL paracetamol <10 mg/L
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ALT ResultsALT ResultsALT ResultsALT Results
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INR ResultsINR ResultsINR ResultsINR Results
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Outcome
Reviewed by psychiatrist Medically fit for discharge (after review of
anti-depressant therapy) Referral for bereavement counselling Discharged Thoughts of taking O/D again
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Finally
She had a lucky escape
Paracetamol poisoning is a very slow and agonizing process of death
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Case 3
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SW Female Age 69
Retired secretary November 2009 short of breath for 3-4 weeks
on exertion (step aerobics, dog walking) Hb 10.2 No recent loss of weight, blood loss, melaena
or altered bowel habit Microcytic anaemia
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Results from GP 12/11/09
Hb 8.2 WBC 5.9 Platelets 213 MCV 99.4 Ferritin 95
Na 140 K Haemolysed Urea 11.1 Creat 152 TP 69 Alb 44 Glob 25 Alk phos 47 Bilirubin 67 ALT Haemolysed
Referred by GP to A&E
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A&E results 12/11/09
16:28 hours, jaundiced anaemic dehydrated
Hb 8.0 WBC 5.9 Platelets 213
Na 137 K
Haemolysed Urea 11.4 Creat 165 Bili 68 ALT Haemolysed
What tests would you do now?
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Results over next few days
Date 9.12 9.12 10.12 12.12 14.12 15.12 16.12
Hb 8.0 8.0 7.6 7.4 7.2 8.9 9.1
K H H H H H H H
Urea 11.3 11.4 10.0 7.7 8.0 7.7 7.1
Creat 163 165 143 129 123 125 131
Bili 67 68 61 39 50 49 36
ALT H H H H H H H
What do you make of these? What other tests would you do?
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Clinical History Hypothyroidism Hysterectomy Psoriasis Mitral valve replaced 1988 and 1994 Aortic valve replaced 1994 Hypertension Left hip and right knee replaced due to OA Perforated peptic
ulcer Drug therapy
Thyroxine 125 ug Candesartan 8mg OD Warfarin 5mg/ 4mg
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Other results
Conjugated/ unconjugated bilirubin Haemolysed
LDH 5450 IU/L Haptoglobin <0.3 g/l B12 282 Folate Haemolysed Ferritin 277 Serum appearance noted by Biochemistry
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Other results
Reticulocyte count 15.5 % Blood film Direct Coombes test Negative Hep B/ Hep C Negative ANA, ANCA Haemolysed
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Blood film
Red cell fragments and polychromasia with occasional nucleolated red cells
Burr cells Acanthocytes Schistocytes Consistent with mechanical haemolysis
from prosthetic heart valves
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Additional tests Haptoglobin
Protein which binds to free haemoglobin in the blood
Acute phase protein Complex removed by spleen Low result indicates
intravascular haemolysis Methaemalbumin
Haemoglobin is converted to Haematin which is then bound to albumin-brown pigment
•Direct Coombe’s test
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Further course
Another 20 U&Es done with no potassium available due to haemolysis
Transfused ECHO showed para prosthetic mitral regurgitation
from 20% of surface. Referred to Essex CTC for mitral valve replacement then to UCLH
In May vegetation on valve so not operated on RIP May 2010
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Haemolytic anaemia Due to breakdown of red blood cells (normally 1% break down each day,
removed by spleen) Intravacular Extravascular
Inherited or acquired Lab tests required
Haemoglobinopathy screen if indicated Film and direct Coombe’s test, reticulocyte count Conjugated bilirubin, LDH and haptoglobin
Treatment depends on the cause Transfusion Steroids or Rituximab Bone marrow transplant Splenectomy Avoiding triggers
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Inherited causes Defects in Hb production
Thalassaemia Sickle cell Haemoglobinopathies
Defects in red cell membranes Hereditary spherocytosis Hereditary ellipsoidosis
Defects in red cell metabolism G-6-PD deficiency Pyruvate kinase deficiency
Paroxysmal nocturnal haemoglobinuria
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Acquired haemolytic anaemia Immune mediated causes
AIHA or CHAD Hypersplenism Aquired
Burns, infections Toxins
Lead, fava beans Drugs
Penicillin, anaesthetics, antimalarials, Dapsone in succeptible patients,
Transfusion reaction/ rhesus incompatability Physical destruction
mechanical heart valves, heart-lung machines Footstrike haemolysis
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Mechanical heart valves
Mechanical Stented or open surgery Last indefinitely Lifelong treatment with
anticoagulants Damage red cells
Biological Allograph or xenograph (pigs) Only last 15 years No anticoagulation required Do not damage red cells
Mitral valve