Liver
Ann Parasram
8th February 2010
• Liver Physiology
• What are LFT’s
• Role of LFT’s in investigation of Liver
Disease
• Investigation of abnormal LFT
• Case studies
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
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
Bilirubin Metabolism
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
What are LFT’s?
• Other biochemical LFT options
–
–
–
–
Total protein
Conjugated bilirubin
Gamma glutamyl transferase (GGT)
Aspartate aminotransferase (AST)
Normal Ranges
•
•
•
•
•
Total Protein
Total Bilirubin
ALT
ALP
Albumin
60 – 80g/l
<20µmol/l
5 – 40IU/l
30 – 130IU/l
35 – 50g/l
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
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
• 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
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
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
Alkaline Phosphatase
• Membrane bound enzyme
• Family of isoenzymes and isoforms
• Present in many tissues
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
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
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
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
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
GT
• 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
Albumin
• Index of hepatic synthetic function
• Low ALB often accompanies chronic liver disease
• May not indicate reduced synthesis
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
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
Bilirubin
• Plasma bilirubin levels >50µmol/l detected clinically as
jaundiced
• Bilirubinuria is always conjugated and is always
pathological
Typical patterns of abnormalities of
simple LFT in various liver diseases.
Condition
Acute
Hepatitis
Chronic
Hepatitis
Cirrhosis
Choleostasis Malignancy
or
Infiltration
N to ↑
↑
N§
N to ↓
↑
N to ↑
N to ↑
N to ↑
N to ↑↑
N to ↓
↑
N to ↑*
↑ to ↑↑↑
N to ↑
↑↑↑
N
N
N to↑†
Test
Bilirubin
Aminotransferase
Alkaline Phosphatase
Albumin
-Globulins
Prothrombin Time
N to ↑↑
↑↑↑
N to ↑↑
N
N
N to ↑*
N = Normal
*Not corrected by parental Vitamin K
§ May be increased if Cirrhosis present
†Corrected by parental Vitamin K
N
N to ↑
↑↑
N to ↓
N
N
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
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
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
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)
Role of LFT’s in the Investigation of Liver
Disease
B) Monitoring – Main role of LFT
Typical Biochemical Changes
during Acute Hepatitis
Plasma bilirubin
Plasma aminotransferase
Plasma alkaline phosphatase
Urinary bilirubin
Urinary urobilogen
Pre – icteric
Icteric
N/↑
↑↑↑
N
↑
↑
↑↑
↑
N/↑
↑
absent
Typical biochemical changes during acute hepatitis
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).
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
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
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
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
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
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
New Generation LFT
• Need cheap, reliable, convenient test:
– ‘accurately diagnose liver pathology’
– ‘provide a quantitative assessment of functional
hepatic mass’
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.
New Generation LFT
• Hepatocellular damage – glutathione-5transferase, 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
Investigation of abnormal LFTs
• Causes of liver disease
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
• Gold Std – Imaging and endoscopy
30 years
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
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
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.
Case History -1
Investigations
on presentation
Serum:
bilirubin
albumin
AST
ALP
GGT
Urine:
bilirubin
urobilinogen
one week later
38µmol/l
40g/l
450U/l
70IU/l
60U/l
230µmol/l
38g/l
365U/l
150IU/l
135U/l
positive
positive
positive
negative
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
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.
Case History - 2
Investigations
Serum:
Albumin
Bilirubin
ALP
AST
GGT
25g/l
260µmol/l
315U/l
134U/l
360U/l
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
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
Case History – 3
• Serum:
Albumin
ALP
Bilirubin, AST and GGT
30g/l
314U/l
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
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
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.
Case Study - 4
Investigations
Serum:
Total Protein
Albumin
Bilirubin
ALP
AST
GGT
85g/l
28g/l
340µmol/l
522U/l
98U/l
242U/l
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
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.
Case Study – 5
Serum
Bilirubin
ALP
AST
Hb
Retics
Urine
bilirubin
60umol/l
74 U/l
35 U/l
16g/dl
1%
Neg
Inherited disorder of bilirubin metabolism
Include;
Crigler-Najjar
Dublin-Johnson
Rotor