LiverMSc Clinical Biochemistry

Dr Sarah Mapplebeck

Consultant Clinical Biochemist

Lecture structure

Session 1Liver structure and functionLiver investigations

Session 2Liver cases

Session 1

STRUCTURE AND FUNCTION

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

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

Functions of the liver

MetabolicProtein metabolismCarbohydrate metabolismLipid metabolism

Formation of bile Metabolism and excretion of bilirubin Hormone and drug inactivation

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

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

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

Formation of bile

Bile secretion Bile acid metabolism Bilirubin metabolism

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

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

Bile acid metabolism

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

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

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)

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

Bilirubin metabolism

LIVER INVESTIGATIONS

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

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

Hypoalbuminaemia

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

Hyperalbuminaemia

Increased albuminDehydration/haemoconcentrationVenous stasisHealthy young adult

Liver biochemistry

Bilirubin Aminotransferases

alanine amino transferase (ALT) and asparate amino transferase (AST)

Alkaline phosphatase (ALP) Gamma glutamly transpeptidase Total protein

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

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

Laboratory investigation of jaundice

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

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

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

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

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

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

Non-hepatic causes of elevated ALT Coeliac disease Muscle disease Strenuous exercise

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

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

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)

Other investigations with elevated ALP Further investigation may include

Calcium and phosphateVitD and PTHLiver enzymesPSAElectrophoresis IsoenzymesRadiology

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

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

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

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

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

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

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

Imaging techniques

Ultrasound (USS) Computed tomography (CT) Magnetic resonance imaging (MRI) Plain X ray of abdomen Endoscopy

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

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

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

Signs of liver disease

Session 2

LIVER CASES

Case 1

AW (1)

Age 48 male Hairdresser Painful joints Exhaustion Low libido

AW (2)

On examinationpigmented

ALT 167, ALP 175, GGT 147 Alb 43, BR 7 USS = hepatosplenomgaly. No varices

AW (3)

Viral studies negative Auto-antibodies negative α1-AT normal TSH 1.05

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

Iron Overload Syndromes

Primary overload Secondary overload Others

Iron loading due to liver disease

Pietrangelo A. N Engl J Med 2004;350:2383-2397

Normal Iron Homeostasis in Humans

Hereditary Haemochromatosis

Type 1 Classical HFE Type 2a Juvenile HH (Hemojuvelin) Type 2b Juvenile HH (Hepcidin) Type 3 TfR2 mutations Type 4 Ferroportin

HFE relatedHaemochromatosis C282Y mutation in HFE gene Autosomal recessive Mechanism complex/unclear Excess duodenal iron absorption leads to

deposition in specific organs

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 ???

Haemochromatosis (3)

Often middle age More males 80% fatigue 56% abdo pain 45% arthralgia (2nd + 3rd metacarpals) 37% loss of libido

Complications of HH

Diabetes Joint symptoms Cardiac disease Skin pigmentation Impotence

Sites of iron deposition

Skin Liver Pancreas Endocrine (ant pit, rarely thyroid, adrenal) Myocardium

Pietrangelo A. N Engl J Med 2004;350:2383-2397

HFE-Related Hereditary Hemochromatosis, a Multistep, Multifactorial Iron-Overload Disorder

How to diagnose?

Detection of HH

Transferrin saturation (>45%) Ferritin (?) HFE genotype

C282Y homozygoteC282Y + H63D (4%)

(Liver biopsy) (MRI)

How to treat?

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

EndoscopyUnit

Who to biopsy?

HH with ferritin >100040% risk of cirrhosis

HH with ferritin <1000cirrhosis very unlikely

Further Management

Rx diabetes Testogel etc Bone density FU for cirrhosis Family screening

Learning Points

HH is common HH is usually easy to diagnose HH is easy to treat Early treatment prevents “disease” Think: iron overload

Case 2

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

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

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

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

Other conditions in patient

Osteoarthritis Osteoarthritis FibromyalgiaFibromyalgia Rheumatoid arthritisRheumatoid arthritis DepressionDepression

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

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

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

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

Patient

Investigations

Liver function tests Total protein Albumin Bilirubin ALT (Aminotransferase) ALP (Alkaline Phosphatase)

Clotting screen INR (International Normalised Ratio)

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

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

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

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.

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

ALT ResultsALT ResultsALT ResultsALT Results

INR ResultsINR ResultsINR ResultsINR Results

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

Finally

She had a lucky escape

Paracetamol poisoning is a very slow and agonizing process of death

Case 3

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

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

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?

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?

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

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

Other results

Reticulocyte count 15.5 % Blood film Direct Coombes test Negative Hep B/ Hep C Negative ANA, ANCA Haemolysed

Blood film

Red cell fragments and polychromasia with occasional nucleolated red cells

Burr cells Acanthocytes Schistocytes Consistent with mechanical haemolysis

from prosthetic heart valves

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

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

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

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

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

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