Diagnosis of disorders of the gut and liver using blood tests Flashcards
What enzymes catalyse these reactions?
Transaminase enzymes – ALT and AST
Where are these enzymes found?
What is the LFT?
Serum activities of ALT and AST are based on which three factors?
- The extent of the damage to the tissue releasing transaminases
- The amount of each transaminase in that tissue
- The rate of clearance of the enzyme from the circulation
The published half-life for ALT is ____h and for AST only ___h
The published half-life for ALT is 47h and for AST only 17h
What are the 2 types of AST in hepatocytes?
Complicating factor – Hepatocytes have two forms of AST – cytosol and mitochondrial.
Does BMI cause ALT to increase or decrease?
Increase
What can change transaminases results?
- Biological variables
- Diurnal variation
- Dietary factors eg coffee
- Race - values higher if African or Hispanic
- Weight - Reference range selection
- Population exclusion criteria - the more rigorous the lower the reference range
- Skewed distribution curve
3.Drugs - both prescribed and over-the-counter
What is ALP?
Alkaline phosphatase (ALP)
catalyzes the hydrolysis of phosphate monoesters.
membrane-bound and mainly found in the liver and bone.
In liver its found in cells which are next to the canaliculi
Upregulated (rather than released due to damage) in response to bile duct obstruction and infiltrative or space-occupying lesions within the liver.
What is GGT?
GGT
mainly found in hepatobillary system
Increase in blood concentration due to induction/increase synthesis:
by alcohol or drugs (anticonvulsants)
biliary obstruction
liver tumours
smaller increase seen in hepatitis
Which tissues contain these enzymes?
Both ____ and ____ may be induced by drugs or alcohol
Also some tumours contain ______
________ sometimes required
NB – Both ALP and GGT may be induced by drugs or alcohol
Also some tumours contain placental ALP
ALP isoenzyme pattern sometimes required
What are Protein Synthesis routine tests and what do they test?
Protein Synthesis routine tests are:
- Serum albumin concentration
- Prothrombin time – INR
- Removal of potentially toxic substances:
- Drugs eg alcohol, paracetamol
- Bilirubin – end product of haem (from Hb) degradation
How is bilirubin produced from haem?
80% of bilirubin is from red cells taken up by the reticuloendothelial system for degradation.
Haem oxygenase releases the iron from the haem molecule to form biliverdin.
Biliverdin is then converted to bilirubin by biliverdin reductase.
Bilirubin released is tightly bound to albumin
What does total bilirubin measure?
Total bilirubin = conjugated + unconjugated
What is the difference between conjugated and unconjuagetd bilirubin?
•Conjugated
oApprox 40% of total
oWater soluble
oExcreted in bile
oIf elevated it appears in the urine giving a dark colour
•Unconjugated
oNot water soluble
oBound to albumin and does not therefore appear in the urine
What are the presenting features of liver disease?
- Jaundice with or without itching
- Pain - constant or colicky
- Non-specific - nausea, fatigue, weight loss
- Incidental laboratory finding
When is jaundice clinically identifiable?
Jaundice is clinically detectable at a serum bilirubin concentration of about 50 mmol/l and obvious to the individual at 100 mmol/l
How is liver disease diagnosed?
- The clinical presentation
- The pattern of routine liver tests
- How these point to more specific tests including diagnostic radiology
Female 49y colicky abdominal pain, RUQ tenderness, later jaundice, pale stools
- Presentation related to her pain
- Early elevation of ALP and GGT – before jaundice
- Then elevated bilirubin – recognising her jaundice
- ALT remaining relatively normal
- Pattern of dark urine and pale stools
The rise in ALP and GGT is due to enzyme induction secondary to obstruction of the biliary tree.
What pattern of LFTs do not occur in the presence of protein synthesis inhibitors?
The rise in ALP and GGT is due to enzyme induction secondary to obstruction of the biliary tree.
Animal studies show this rise in serum ALP and GGT activities does not occur in the presence of inhibitors of protein synthesis.
What are the extrahepatic and intrahepatic causes of obstructive jaundice?
Extrahepatic
- Gallstones – by far the commonest cause
- Malignancy – bile duct, pancreas
- Pancreatitis
Intrahepatic
- Hepatocellular disease (eg, resolving viral hepatitis)
- Drug-induced cholestasis
- Cholangitis
- Cirrhosis
- Clinically generally unwell and no significant pain
- Very raised ALT with raised bilirubin
- Some elevation of ALP and GGT due to swelling of liver tissue causing mild obstruction within the liver.
However these results just show severe hepatocyte damage and not the cause of that damage – that requires additional tests – in this case virology tests showed hepatitis B as the cause.
What does alcoholism do to AST and ALT?
In alcoholic hepatitis the serum activities of these transaminases are much less marked.
However the ratio of AST:ALT is frequently >2
Studies have indicated that in chronic alcohol excess mitochondrial AST is also elevated – NB its much longer half-life
Clinically - Presence of itching - due to the accumulation of bile salts
Laboratory
- Raised serum bilirubin concentration
- Obstructive pattern of liver enzymes
- Raised serum IgM concentration
- Raised serum cholesterol concentration
- Prolonged INR
- Anti-mitochondrial antibody positive
What is a FIB 4 test?
<1.45 strong predictive value for absence of fibrosis;
>3.25 strong predictive value for advanced fibrosis
Whats the diagnosis?
- Serum bilirubin within the reference interval
- Slightly raised transaminase activities
- Rather greater increase in ALP and GGT activities
- Slightly low albumin and raised globulin concentrations
- Mild anaemia with macrocytosis but no decrease in B12 or folate
- Rather low platelet count
- Slightly raised serum ferritin concentration
- Mild hypocalcaemia with low serum 25-OH Vit D concentration
- Borderline high serum AFP concentration
- High FIB-4 score
Mild hypocalcaemia with low serum 25-OH Vit D concentration – this would trigger a parathyroid hormone response and ALP activation from bone
Borderline high serum AFP concentration – marker for hepatocellular carcinoma
High FIB-4 score indicating probable cirrhosis
What are the markers of liver fibrosis?
- The FIB-4 score is derived from the formula:
- NFS is derived from the formula:
- The Enhanced Liver Function test (ELF) - combines three serum markers measured by immunoassay; hyaluronic acid (HA), procollagen III amino terminal peptide (PIIINP) and tissue inhibitor of metalloproteinase 1 (TIMP-1) using an algorithm developed by the European Liver Fibrosis Group.
What are the causes of hepatocellular disease?
Infections -
Metabolic -
Autoimmune -
Genetic -
Infections
- Viral - Hepatitis A,B,C,D,E, CMV
- Parasitic – malaria
- Bacterial
Metabolic
- Alcohol
- Drugs – paracetamol poisoning
- NAFLD
Autoimmune
- Primary biliary cholangitis
- Primary sclerosing cholangitis
Genetic
- A1AT deficiency
- Haemochromatosis
Wilson’s disease
Label each diagnosis
What investigations would be done for persistently elevated serum ALT activity?
- LFTs inc GGT and AST
- Total protein, albumin, immunoglobulins
- Glucose, lipids – Metabolic syndrome, NAFLD
- Full blood count - MCV
- Autoimmune profile
- Iron, transferrin, saturation, ferritin
- Copper, caeruloplasmin, a1 antitrypsin, coeliac screen
- Viral studies – Hepatitis, CMV, HIV
- Carbohydrate deficient transferrin
- Drug history is also important
Serum bilirubin within its reference interval
Mixed pattern of liver enzymes
Very elevated serum iron concentration with a high saturation of transferrin
Very elevated serum ferritin concentration
Elevated HbA1c
These are the findings in haemochromatosis:
Genetic screening for those of N European ancestry is for C282Y/H63D mutations.
If positive family studies are indicated.
Treatment by venesection
- Very Obese
- Borderline fasting hyperglycaemia
- Serum bilirubin within the reference interval
- Elevated serum ALT and AST activities
- ALT>AST
- Serum ALP activity within the reference interval for a growing child
- Elevated serum triglyceride and cholesterol concentrations
Other metabolic causes of liver disease excluded
Probable diagnosis Non-alcoholic Fatty Liver Disease - NAFLD
What is non-alcoholic fatty liver disease?
NAFLD is present when >5% of hepatocytes are steatotic in patients who do not consume excessive alcohol.
What are the risk factors for NAFLD?
- Age
- Males > Females
- Metabolic syndrome
- Ethnic – high in Hispanic
- Diet – saturated fat, high fructose
- Sleep apnoea
- Genetic
What are the 3 stages of NAFLD?
- 90% simple steatosis – reversible and relatively benign
- Of these 10-30% progress to NASH – non-alcoholic steatohepatitis
- Of these 25-40% develop fibrosis - cirrhosis
When can you find incidentally abnormal LFTs?
- ~ 5% population
- Transient impossible to explain
- Obesity – metabolic syndrome
- Medication
- Non-Alcoholic Fatty Liver Disease (NAFLD) 26%
- Alcohol related liver disease (ARLD) 25%
- Hepatitis B/C, haemochromatosis, autoimmune < 1% each
Whats the diagnosis?
Unconjugated hyperbilirubinaemia
Normal haematology
Serum haptoglobin within its reference interval
Gilbert’s syndrome is relatively common – perhaps 3-7% of the population.
The serum bilirubin concentration is usually 20 - 40 umol/L and rarely reaches 80 umol/L.
What are the causes of unconjugated hyperbilirubinaemia?
•Increased bilirubin production
oHaemolysis
oResolution large haematoma
•Impaired bilirubin uptake
oPoor liver perfusion
oDrugs eg rifampicin
•Impaired bilirubin conjugation
oPhysiological in new-born – due to hepatic immaturity
oHereditary defects of conjugation - UDP-glucuronosyltransferase
Gilbert syndrome (mild but common)
Crigler-Najjar syndrome type I and II (rare and more severe)
oDrugs inhibiting conjugation - chloramphenicol, gentamycin, protease inhibitors
What does this show?
Typical Blood Film – Haemolytic Anaemia
This picture shows red blood cells of varying shape and colour density - the darker red cells have lost their slightly paler centre of the normal biconcave disc and are spherical; others are just very misshapen and there is a large variation in red cell size.
How does a Direct Antiglobulin Test (Coomb’s test) work?
Unconjugated hyperbilirubinaemia
Elevated red cell enzyme activities – LDH>AST>ALT
Very low serum haptoglobin concentration
Very abnormal blood film
Positive anti-globulin test
Whats the diagnosis?
Autoimmune haemolytic anaemia
