liver ann parasram 8 th february 2010. liver physiology what are lft’s role of lft’s in...
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Liver Ann Parasram
8th February 2010
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• Liver Physiology • What are LFT’s• Role of LFT’s in investigation of Liver
Disease• Investigation of abnormal LFT • Case studies
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Major functions of liver
•Carbohydrate Metabolism
•Fat Metabolism
•Protein Metabolism
•Hormone Metabolism
•Removal of endogenous and exogenous waste
products
•Storage
•Metabolism and excretion of bilirubin
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Liver Physiology
• 6 segments, each with own branch of hepatic artery, portal vein and
bile duct
• Metabolic activity occurs within parenchymal cells.80% of organ mass
• Remarkable reserve and Ig functional reserve
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Bilirubin Metabolism
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What are LFT’s?
•No standard LFT profile•Basildon use –
-Total protein
- Albumin
- Total Bilirubin
- Alkaline phosphatase (ALP)
- Alanine aminotransferase (ALT)
•Do standard ‘LFT’ assess liver capacity to perform
normal function
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What are LFT’s?
• Other biochemical LFT options
– Total protein – Conjugated bilirubin – Gamma glutamyl transferase (GGT) – Aspartate aminotransferase (AST)
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Normal Ranges
• Total Protein 60 – 80g/l• Total Bilirubin <20µmol/l• ALT 5 – 40IU/l• ALP 30 – 130IU/l• Albumin 35 – 50g/l
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Laboratory Investigations
Diagnosis
Prognosis
Monitoring
Screening
No single lab test currently exists which:
i) Provides answers to the above
ii) Provides a quantitative assessment of functioning liver capacity
Use of combination of standard LFT’s and serial monitoring enhances clinical utility
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Aminotransferase
•ALT and AST
• Intracellular enzymes
• ↑ plasma enzymes activity due to leakage from damaged or necrotic hepatocytes
• Not liver specific – wide tissue distribution, heart, muscle
• Plasma activities of AST and ALT are sensitive indicators of hepatocyte damage due to toxins and viruses but are not specific for liver pathology
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• AST
- 2 genetically distinct isoenzymes exist;
mitochondrial AST (80%) and cystolic AST (20%)
- Mild tissue injury results in predominately cystolic
release
•ALT
- cystolic enzymes
- shows greater liver specificity than AST
- Majority of liver disease ALT elevated to a
greater degree
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Abnormal ALT in asymptomatic patients
• Is it abnormal?• Alcohol abuse (GT useful)• Drugs
– Antibiotics - penicillins, ciprofloxacin etc.– AED’s - phenytoin, carbamazepine– Statins– NSAID’s– Sulphonylureas - glipizide– Herbs, homeopathic Rx - ephedra, senna– Drugs of abuse - steroids, cocaine, MDMA, glues
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Abnormal ALT in asymptomatic patients
• Chronic hepatitis – hepatitis C, B
• Autoimmune hepatitis– raised globulin (80%) on electrophoresis– auto-antibody tests (ANA)
• Haemochromatosis – transferrin saturation (>45%)
• Coeliac disease• Wilson’s disease (<40 yrs)
– caeruloplasmin (85%), Kaiser-Fleischer rings
• Alpha1-antitrypsin deficiency
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Alkaline Phosphatase
• Membrane bound enzyme
• Family of isoenzymes and isoforms
• Present in many tissues
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Alkaline Phosphatase
• Plasma ALP levels are increased further by the solubilisation of membrane bound enzyme due to the detergent action of bile acids
• Plasma ALP is a sensitive indicator of Choleostasis but is non-specific for liver pathology
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Alkaline Phosphatase
• Produced by the biliary tract at all levels from the canalculi to the mucosa of the gall bladder
• Involved in metabolic transport across cell membrane
• Obstruction to bile flow or secretion results in enzyme induction with increased mucosal synthesis of ALP
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Alkaline Phosphatase
• Liver or bone? (pregnancy, adolescence)– GT useful to exclude liver
• Age related changes– increase (particularly women) between 40 and 65
yrs• If persistent raised ALP of liver origin• Primary biliary cirrhosis
– anti-mitochrondrial antibodies• Ultrasonography
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GT – Gamma Glutamyl Transferase
• Membrane bound, wide tissue distribution; liver, kidney and pancreas
• Elevated plasma activity results from solubilisation of bound enzyme by bile salts, cell necrosis and altered membrane permeability
• Slightly more sensitive than ALP in Obstructive Liver Disease
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GT
• Synthesis induced by drugs such as DPH, BARBS, Tricyclics and ETOH in absence of liver pathology
• Sensitive indicator of liver disease but will differ hepatocellular from choleostatic disease
• An increase GT activity can confirm an increase ALP activity as being liver in origin
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• Very sensitive for hepatobiliary disease
• Poor specificity– pancreatic disease, AMI, renal failure, diabetes,
COPD, alcoholism
• Alcohol abuse – poor marker– Reported sensitivity 52 - 94%
• Best used to evaluate rises in other LFT’s
GT
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Albumin
• Index of hepatic synthetic function
• Low ALB often accompanies chronic liver disease
• May not indicate reduced synthesis
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Albumin
• Plasma ALB also affected by nutritional stasis, leakage into ascites, renal losses and dilation due to fluid retention
• Prothrombin better indicator as shorter ½ life
• Normal ALB is good indicator of adequate synthetic function in chronic liver disease
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Bilirubin
• Specific for liver dysfunction
• Assessment of hepatic anion transport
• Insensitive due to large hepatic functional reserve
• Normally 92% of bili unconjugated
• Raised bili due to increased production, impaired metabolism or reduced excretion
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Bilirubin
• Plasma bilirubin levels >50µmol/l detected clinically as jaundiced
• Bilirubinuria is always conjugated and is always pathological
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Typical patterns of abnormalities of simple LFT in various liver diseases.
Condition Acute Chronic Cirrhosis Choleostasis Malignancy Hepatitis Hepatitis orTest Infiltration
Bilirubin N to ↑↑ N to ↑ N to ↑ ↑ to ↑↑↑ NAminotransferase ↑↑↑ ↑ N to ↑ N to ↑ N to ↑ Alkaline Phosphatase N to ↑↑ N§ N to ↑↑ ↑↑↑ ↑↑ Albumin N N to ↓ N to ↓ N N to ↓ -Globulins N ↑ ↑ N NProthrombin Time N to ↑* N to ↑ N to ↑* N to↑† N
N = Normal*Not corrected by parental Vitamin K§ May be increased if Cirrhosis present†Corrected by parental Vitamin K
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Miscellaneous tests of Liver Disease
• Plasma Bile Acids – highly specific indicator of hepatic anion transport, technically demanding
• Immunoglobulins – Generally increased in chronic disease. IgM greatly increased in Primary biliary cirrhosis. IgG in autoimmune chronic active hepatitis
• α-fetoprotein – Increased in 70% of primary hepatocellular carcinomas
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Role of LFT’s in the Investigation of Liver Disease
A )Diagnosis• Poor diagnostic tool
• Non-specific, cannot quantitate extent of liver damage
• Imaging, Clinical history and histology better
• Cheap, non-invasive, automated, can direct further investigation
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Role of LFT’s in the Investigation of Liver Disease
Surgical v’s non-surgical jaundice
• Raised Bilirubin in range 20 – 100µmol/l with other LFT’s normal
• Haemolytic jaundice or Gilberts rather than extrahepatic biliary dysfunction
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Role of LFT’s in the Investigation of Liver Disease
Hepatocellular v’s Choleostasis
• Raised Bili, ALP and GT with normal or slightly
raised ALT
• Indicates Choleostasis (but cannot distinguish intra from extrahepatic)
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Role of LFT’s in the Investigation of Liver Disease
B) Monitoring – Main role of LFT
Typical Biochemical Changes during Acute Hepatitis
Pre – icteric Icteric
Plasma bilirubin Plasma aminotransferasePlasma alkaline phosphataseUrinary bilirubinUrinary urobilogen
N/↑↑↑↑N↑↑
↑↑↑N/↑↑absent
Typical biochemical changes during acute hepatitis
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Role of LFT’s in the Investigation of Liver Disease
Causes of Acute Viral hepatitis
• Pre icteric – ALT/AST raised; other LFT normal
• Icteric – AST/ALT peak; 6 – 100 ULN
• Normally ALT>AST
• AST>ALT poor prognosis
• ALP normal/slightly raised (unless choleostatic element).
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Role of LFT’s in the Investigation of Liver Disease
• Enzyme levels can be expected to return to normal in about 5 weeks
• Persistently raised levels (3 x ULN) could indicate chronic persistent hepatitis
• Sudden reduction in aminotransferase activity bad sign indicating fulminant liver function
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Role of LFT’s in the Investigation of Liver Disease
Neonatal raised Bilirubin
• Need accurate measure of Bilirubin at critical levels (age, weight and ALB dependant)
• Phototherapy > 200µmol/l
• Exchange transfusion >3
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Role of LFT’s in the Investigation of Liver Disease
Autoimmune Chronic Hepatitis Therapy
- Successful immunosuppressant indicated by reduced AST activity. Relapse indicated by raised ALP activity
Post-op Obstructive Jaundice
- Clearance of obstructive jaundiced followed by serial bilirubin measurement
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Role of LFT’s in the Investigation of Liver Disease
Cirrhosis
- No reliable test for compensated cirrhosis
- Procollagen Type III peptide. Non-invasive marker for fibrosis but it is non-specific
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Role of LFT’s in the Investigation of Liver Disease
Alcoholic Liver Disease
• GT induced by ETOH • If raised as a result ETOH intake may never return to
normal
Liver Transplant
• Std LFT used to monitor rejection • Raised Bilbirubin increased when rejection occurs
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Role of LFT’s in the Investigation of Liver Disease
C) Prognosis • Limited role
• Pre-transplant assessment of end stage liver disease
• Primary Biliary Cirrhosis
- raised bili .....poor sign......<2yr survival bili >120µmol/l
• Fulminant hepatic failure
- bili >300µmol/l, poor prognostic sign
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New Generation LFT
• Need cheap, reliable, convenient test:
– ‘accurately diagnose liver pathology’– ‘provide a quantitative assessment of functional
hepatic mass’
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New Generation LFT
• Quantitative LFT but are complex and limited to specific centres
– Aminopyrine Breath Test, measures Cyto P450 (dependent demethylation of Carbon 14 labelled aminopyrine to Carbon Dioxide)
– Indocyanine green clearance – asses hepatic blood flow and hepatocellular activity.
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New Generation LFT
• Hepatocellular damage – glutathione-5-transferase, molecule sensitive to AST/ALT. Evenly distributed throughout liver, half-life 90 minutes, early marker of liver injury
• Choleostasis – CA19-9, Increased serum level due to biliary clearance
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Investigation of abnormal LFTs
• Causes of liver disease
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Liver Pathology
• Hepatitis – Inflammation and cell damage– Toxins, metabolites, infections, autoantibodies
• Cirrhosis – fibrosis infiltration, shrinkage
• Tumours (Carcinoma)– Primary or Secondary metastases
• Obstruction (Choleostasis)
- failure of secretion of bile
e.g. Chronic hepatitis cirrhosis 30 years
• Gold Std – Imaging and endoscopy
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Hepatitis
• Viral or toxic • Acute or chronic
Viral Agents: Hep A B C (D + E) CMV, EBV
Toxic Agents: Paracetamol, Alcohol
Acute Disease: < 6 months duration
Chronic Disease: > 6 months with non resolution of acute
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Outcome of Hepatitis
• Majority of hepatitis cases result in complete resolution
• Minority will develop fulmanant hepatic failure
• All forms of acute hepatitis may develop into chronic
disease except Hep A
•Chronic hepatitis may be classified by histology - Chronic persistent hepatitis (benign)- Chronic acute hepatitis (histological distinct)
• Chronic disease can progress to Cirrhosis, can progress to
Carcinoma
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Case History 1
• A 20 year old student developed a flu-like illness with a loss of appetite, nausea and pain in the right hypochondrium.
On examination, the liver was just palpable and was tender.
Two weeks later he developed jaundice, his urine became darker in colour and his stool became pale.
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Case History -1 Investigations
on presentation one week later
Serum:
bilirubin 38µmol/l 230µmol/l
albumin 40g/l 38g/l
AST 450U/l 365U/l
ALP 70IU/l 150IU/l
GGT 60U/l 135U/l
Urine:
bilirubin positive positive
urobilinogen positive negative
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Cirrhosis • Aetiology – autoimmune, chronic viral, alcohol Inherited,
metabolic disease or Primary cirrhosis
• Diagnosed by demonstration of fibrous and architectural disruption in biopsy specimen
• Irreversible
• No symptoms whilst compensated due to functional reserve
• Symptoms manifest after decompensation – haematemesis, ascites, portal hypertension, encephalopathy, coma
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Case History 2
A middle aged female was admitted to hospital following a haematemesis. Endscopy revealed the presence of oesophageal varices.
The only biochemical abnormality was an elevated GGT (245IU/L). The patient was told to abstain from alcohol.
She was admitted one year later, jaundiced, drowsy and with clinical signs of liver disease.
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Case History - 2
Investigations
Serum:
Albumin 25g/l
Bilirubin 260µmol/l
ALP 315U/l
AST 134U/l
GGT 360U/l
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Hepatocellular Carcinoma (HCC)
•Only 2% of all Cancers in the UK
•Significant problem worldwide (Hep B, C; Haemachromatosis)
•80% due to Cirrhosis
•5yr Survival rate – 15%
•Imaging used to identify tumour, biopsy
Inappropriate and surgical resection is only treatment
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Case History 3
A elderly woman, weight loss and constipation.
She has lost approx 8kg in weight in 2 months and had lost her appetite .
She had previously opened her bowels daily but had recently had several days between movements and had passed a small amount on each occasion.
On examination she was anaemic and had obviously lost weight .
The liver was enlarged and had an irregular edge, a mass was palpable in the right iliac fossa
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Case History – 3
• Serum:
Albumin 30g/l
ALP 314U/l
Bilirubin, AST and GGT normal
Stool Occult Blood positive
A barium enema revealed a carcinoma of the caecum; an isotopic liver scan showed multiple filing defects characteristic of tumour deposits
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Choleostasis
• Intrahepatic – Bile secretion from the hepatocytes into the canaliculi is impaired
• Extrahepatic - due to obstruction to the flow of performed bile through the biliary tract
• Symptoms; Pruritis, jaundice, pale stools and dark urine
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Case History 4
A 40 yr old women presented with jaundice.
There was no history of contact with hepatitis, recent foreign travel, injections or transfusions.
She did not drink alcohol. She had been well in the past but had suffered pruritus during the past 18months.
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Case Study - 4
Investigations
Serum:
Total Protein 85g/l
Albumin 28g/l
Bilirubin 340µmol/l
ALP 522U/l
AST 98U/l
GGT 242U/l
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Gilbert’s Syndrome – inherited disorder of bilirubin metabolism
• Asymptomatic, episodes of raised bilirubin• Especially if fasting, tired, other illness• Common, up to 5% - male > female• Hyperbilirubinaemia <100 umol/l• All other biochemical LFT’s normal• Unconjugated hyperbilirubinaemia• Prolonged fasting (45hrs): 2-3 fold increase• Nicotinic acid (I.v. 50mg): 2-3 fold increase
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Case History - 5
A medical student recovering from an attack of influenza was noticed to be slightly jaundiced.
Worried that he might have hepatitis, the student had some blood taken for biochemical tests.
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Case Study – 5
Serum Bilirubin 60umol/lALP 74 U/l
AST 35 U/l Hb 16g/dl Retics 1%Urine
bilirubin Neg
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Inherited disorder of bilirubin metabolism
Include;
Crigler-Najjar
Dublin-Johnson
Rotor