Laboratory Investigation of Liver & GI Tract Disease Flashcards
Describe structure of liver
Comprised of large right lobe and smaller left lobe
Has dual blood supply – 2/3 comes from the gut via the portal vein (nutrient rich) and 1/3 from the hepatic artery (oxygen rich)
Blood leaves the liver through the hepatic veins
Substances for excretion from the liver are secreted from hepatocytes into canaliculi.
The bile canaliculi merge and form bile ductules, which subsequently merge to become a bile duct and eventually become the common hepatic duct.
Major functions of the liver
Carbohydrate metabolism
Fat metabolism
Protein metabolism
Synthesis of plasma proteins
Hormone metabolism
Metabolism and excretion of drugs and foreign compounds
Storage – glycogen, vitamin A and B12, plus iron and copper
Metabolism and excretion of bilirubin
Types of Liver Disease
Hepatitis
Cholestasis
Cirrhosis
Tumours
Hepatitis characteristics
Damage to hepatocytes
Cholestasis characteristics
Blockage
Intra or extra-hepatic
Cirrhosis characteristics
Increased fibrosis
Liver shrinkage
Decreased hepatocellular function
Obstruction of bile flow
Tumours characteristics
Primary cancer
Frequently secondary: colon, stomach, bronchus
Liver Function Test (LFT) - list profile
Liver Function Test (LFT) Standard LFT profile: Bilirubin Albumin Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST) Alkaline phosphatase Gamma glutamyltransferase
LFTs are not diagnostic but can be used for
Differential diagnosis: predominantly hepatic or cholestatic
Screening for the presence of liver disease
Assessing prognosis
Monitoring disease progression
Measuring the efficacy of treatments for liver disease
Assessing severity, especially in patients with cirrhosis
Describe LFT for an inflammatory pattern
Inflammatory pattern (hepatocellular damage)
Bilirubin
N to ↑
ALT
↑↑↑
ALP
N to ↑
Albumin
N
Describe LFT for an cholestatic pattern
Bilirubin
↑ to ↑↑↑
ALT
N to ↑
ALP
↑ to ↑↑↑
Albumin
N
Albumin conc link to liver disease
Albumin concentrations only tend to decrease in chronic liver disease
What is bilirubin
Yellow-orange pigment derived from haem
Bilirubin occurs in 2 forms - list
Conjugated (direct-reacting bilirubin)
Unconjugated (indirect-reacting bilirubin)
Describe conjugation of bilirubin
Binds tightly but reversibly to albumin
Conjugation occurs in the liver → excreted in bile
Jaundice define
Jaundice describes the yellow discolouration of tissue due to bilirubin deposition.
Clinical jaundice may not be evident until when
Clinical jaundice may not be evident until the serum/plasma bilirubin concentration is 2x the upper reference of normal, >50 μmol/L.
↑ serum/plasma concentrations of bilirubin occur when
↑ serum/plasma concentrations of bilirubin occur in imbalance between production & excretion
Describe importance to determine if ↑bilirubin is conjugated or unconjugated
Unconjugated elevation - production is increased which is beyond capacity of liver conjugation
Conjugated bilirubin elevation – obstruction of bilirubin flow
Causes of Jaundice - prehepatic
Excessive RBC breakdown:
Haemolysis
Haemolytic anaemia
Crigler-Najjar, Gilbert’s
Causes of Jaundice - cholestatic = intrahepatic
Dysfunction of hepatic cells:
Viral hepatitis Drugs Alcoholic hepatitis Cirrhosis Pregnancy Infiltration Congenital disorder
Causes of Jaundice - cholestatic = extrahepatic
Obstruction of biliary drainage:
Common duct stone Carcinoma Biliary stricture Sclerosing cholangitis Pancreatitis
Neonatal Jaundice - define
Immaturity of bilirubin conjugation enzymes
Effect of high levels of unconjugated bilirubin to newborn
High levels of unconjugated bilirubin - toxic to the newborn
→ due to its hydrophobicity , can cross the blood-brain-barrier & cause kernicterus
Phototherapy for neonatal jaundice
Phototherapy with UV light – converts bilirubin to water soluble, non-toxic form
Effect of high levels of conjugated bilirubin to newborn
Pathological jaundice if high levels of conjugated bilirubin
E.g. Pale stools in babies with biliary atresia. Urgent surgical treatment is essential.
Gilbert’s Syndrome - define
Benign liver disorder
Frequency : 10% of population
Gilbert’s Syndrome - characteristics
Characterized by mild, fluctuating increases in unconjugated bilirubin
→ caused by ↓ ability of the liver to conjugate bilirubin
Males more frequently affected than females
Liver transaminases ALT and AST - used for
Most commonly measured markers of hepatocyte injury
Catalyse transfer of amino group
α -amino acid → α-oxo acid
ALT Alanine Aminotransferase (ALT) - localisation
predominantly localised to liver
AST Aspartate Aminotransferase (AST) distribution:
AST Aspartate Aminotransferase (AST) has wide tissue distribution:
heart, skeletal muscle, kidney, brain, erythrocytes, lung & liver
ALT/AST - distribution in cell
Both are cytosolic but AST is also present in mitochondria
ALT use
ALT is used to identify liver damage arising from hepatocyte inflammation or necrosis.
Diagnosis if AST/ALN 5 * ULN
Modest elevation (5 x ULN): Fatty liver Chronic viral hepatitis Prolonged Cholestatic liver disease Cirrhosis - In compensated cirrhosis values may be normal
Diagnosis if AST/ALN 10-20 * ULN
Highest elevation (10-20x ULN):
Acute viral hepatitis
Hepatic necrosis induced by drugs or toxins
Ischaemic hepatitis induced by circulatory shock
Alkaline Phosphatase (ALP) - define
Enzyme isoforms mainly produced in liver and bone but also placental and intestinal forms
Bile duct obstruction - effect and cause
Bile duct obstruction - increased ALP synthesis and thus increase in measured activity
Obstruction may be due to:
extrahepatic (stones, tumour or stricture)
intrahepatic (infiltration or space occupying lesion)
ALP values >3 x ULN found in
ALP values >3 x ULN found in intra- & extrahepatic cholestasis
ALP values <3 x ULN found in
ALP values <3 x ULN found in hepatocellular disease
↑↑ in osteoblastic activity effect
↑↑ in osteoblastic activity:
Healing fractures
Vitamin D deficiency
Paget’s disease
The source of an elevated ALP can be determined by
The source of an elevated ALP can be determined by gel electrophoresis. It is possible to separate ALP isoenzymes into liver, bone, and intestinal fractions.
Why can the placental ALP be identified
The placental isoenzyme of ALP can be identified as it is heat stable at 65oC for 10 minutes, unlike the other isoenzymes.
Gamma Glutamyl Transferase (GGT) - define
GGT is a membrane bound enzyme that transfers the gamma glutamyl group from peptides such as glutathione to other peptides and to L-amino acids.
Gamma Glutamyl Transferase (GGT) - distribution
Wide tissue distribution, but liver isoenzyme activity predominates in serum
Gamma Glutamyl Transferase (GGT) - used in combination with
Used in combination with ALP, ↑ value confirms ALP of hepatic origin
Increased GGT due to
↑ levels may be due to enzyme induction by alcohol or drugs e.g. anticonvulsants.
Increased GGT can occur in
↑ levels occur in cholestasis and hepatocellular disease
Can be ↑ in non-hepatic disorders, e.g. pancreatitis, myocardial infarction and diabetes mellitus
Interpretation of ALP and GGT results
- ↑ ALP and ↑ GGT
↑ ALP and ↑ GGT – suggestive of hepatic cause (cholestasis)
Interpretation of ALP and GGT results -
↑ ALP and N GGT
↑ ALP and N GGT – suggestive of bone source of ALP
Interpretation of ALP and GGT results -
N ALP and ↑ GGT
N ALP and ↑ GGT – suggestive of excess alcohol intake
Albumin - define + synth where
Major circulating plasma protein
Synthesised exclusively in the liver, 12g produced each day
Albumin - importance of the concentration value
Concentration widely regarded as an index of hepatic synthetic function
Can be normal in early acute hepatitis due to its long half-life (21 days)
Values may be normal in well compensated liver disease
Decreased serum albumin in what
Acute or chronic destructive liver diseases of moderate severity show decreased serum albumin
What can decreased albumin be consistent with
Decreases also consistent with: Haemodilution Impaired synthesis e.g. malnutrition Increased loss e.g. nephrotic syndrome Inflammatory leak
Non-Alcoholic Fatty Liver Disease (NAFLD) - stages
Stages:
Hepatic steatosis (fat >5% liver volume) Greater risk of progressing to fibrosis, cirrhosis, HCC
Non-Alcoholic Fatty Liver Disease (NAFLD) - major risk factors
Major risk factors:
Obesity
Diabetes/insulin resistance
Hypertension
Overview of the GI Tract
Oesophagus
=
Ingestion, release enzymes
Stomach = digestion, lower pH + release enzymes
SI =
Duodenum = digestion, Increase pH + add pancreatic enzymes + bile
Jejunum + ileum + colon (LI)
=
Absorption
stabilise pH, signal to brain and body to handle incoming nutrients, modify hunger
Gastric Ulcers - causes
Gastric ulcers are caused by a break in the protective stomach mucosal lining
Helicobacter pylori infection (80% of cases)
Use of aspirin and NSAIDs – non-steroidal anti-inflammatory drugs (20% of cases)
Signs and symptoms of gastric ulcers include:
Signs and symptoms of gastric ulcers include:
Pain in the abdomen that may come and go (may be eased with antacid)
Waking up with a feeling of pain in the abdomen
Bloating, retching and feeling sick
Feeling particularly ‘full’ after a normal size meal
Helicobacter Pylori - define
H. pylori - helix-shaped gram-negative bacteria, survives in gastric acid by secreting urease
Urea breath test - function
The urea breath test is rapid and non-invasive procedure used to identify active infection by H. pylori.
Urea breath test - process + result
Patient drinks a solution containing urea labelled with an uncommon isotope (non-radioactive carbon-13).
The detection of isotope-labelled carbon dioxide in exhaled breath indicates that the urea was split by urease -secreting H. pylori, present in the stomach.
Vitamin B12 - define
Vitamin B12 (cobalamin) is a water soluble vitamin that has an essential role in the nervous system and the formation of red blood cells as a co-factor for DNA synthesis.
Vitamin B12 absorption
When dietary B12 enters the stomach it is bound by intrinsic factor (IF), a 45 kDa glycoprotein by the parietal cells of the stomach
The B12-IF complex enters the intestine where it binds to receptors on the mucosal cells of the ileum and is absorbed into the blood stream.
Effect of pernicious anaemia
Pernicious anaemia, an autoimmune attack on the gastric mucosa, causes severe Vitamin B12 deficiency. This leads to the atrophy of the stomach wall and the IF secretion is absent or severely depleted.
Signs and symptoms of vitamin B12 deficiency include:
Macrocytic anaemia (increased MCV, decreased haemoglobin)
Weakness and tiredness
Pale skin
Glossitis – inflammation of the tongue
Nerve problems such as numbness or tingling (severe deficiency)
Testing for Vitamin B12 deficiency - Serum vitamin B12 level:
Serum vitamin B12 level: <150 pmol/L indicates probably B12 deficiency
Testing for Vitamin B12 deficiency - Methylmalonic acid:
Methylmalonic acid: elevated in tissue B12 deficiency (may also be elevated in renal disease)
Testing for Vitamin B12 deficiency - Homocysteine:
Homocysteine: elevated in B12 deficiency as not converted to methionine. Less specific than MMA as it is also elevated in folate deficiency and hypothyroidism, but test is more readily available
Testing for Vitamin B12 deficiency - Holotranscobalamin (active B12):
Holotranscobalamin (active B12): measurement of B12 bound to transcobalamin and may be the first detectable marker of B12 deficiency
Intrinsic factor and antiparietal cell antibodies in pernicious anaemia
Intrinsic factor and antiparietal cell antibodies are positive in pernicious anaemia
Coeliac Disease - define
Coeliac disease is an autoimmune disorder, primarily affecting the small intestine.
Coeliac Disease - cause
The disease results from immunological hypersensitivity to ingested to gliadin (gluten protein), found in wheat and other grains such as barley and rye.
Upon exposure to gluten in the small intestine there is an inflammatory reaction leading to the shortening of the villi lining and villous atrophy.
Coeliac Disease - symptoms
Classic symptoms of coeliac disease include anaemia, weight loss, and GI problems e.g. diarrhoea, abdominal distention, malabsorption and loss of appetite.
Severe coeliac disease can lead
Severe coeliac disease can lead
to anaemia and osteoporosis
Tissue transglutaminase (TTG) - define
Tissue transglutaminase (TTG) is a enzyme that deaminates glutamine residues to glutamic acid on the gliadin fragment.
Tissue transglutaminase (TTG) - target for what
The enzyme can be a target autoantigen in the immune response, leading to destruction of intestinal epithelial cells and the production of anti-TTG antibodies.
TTG in coeliac disease testing
Anti-TTG antibodies belong to the IgA subclass of immunoglobulins.
A proportion of the healthy population are deficient in IgA
this test would produce a false negative result in IgA deficient patients with coeliac disease.
Endomysial antibodies (EMA) use
Testing for Coeliac disease
Endomysial antibodies (EMA): these become elevated as part of ongoing damage to the intestine
A duodenal biopsy use
Testing for Coeliac disease
A duodenal biopsy is the gold standard diagnosis of coeliac disease.
Gluten challenge use
Testing for Coeliac disease
Gluten challenge: patients already on a gluten-free diet cannot be diagnosed as serology and histology tests will be normal until gluten is ingested.
Inflammatory bowel disease - includes what
Inflammatory bowel disease(IBD) encompasses two distinct autoimmune conditions of the GI tract: ulcerative colitis and Crohn’s disease.
Ulcerative colitis - define
Diffuse inflammation affecting the mucosa of the colon only.
Crohn’s disease - define
Patchy ulceration affecting any part of the GI tract and may extend through the full thickness of the bowel.
Crohn’s disease - complications
Complications include fistulae, abscess formation and stricturing.
IBD test
Colonoscopy is the definitive test for diagnosis of IBD.
Crohn’s disease and Ulcerative colitis have common signs and symptoms: list them
Abdominal pain Prolonged diarrhoea with bowel urgency Blood and/or mucus in stools Fatigue Weight loss and malnutrition
Crohn’s disease may present with:
Perianal lesions
Bowel obstruction i.e. abdominal bloating, distension, vomiting or constipation
IBD vs IBS - define
IBD = inflammation of intestinal system
IBS = not a disease, functional disorder w/vague GI symptoms
IBD vs IBS - features
IBD = extra intestinal manifestations in addition to GI symptoms
IBS = only in intestine area
IBD vs IBS - treatment
IBD = anti-inflammatory meds + might need surgery
IBS = not with A-I meds + don’t need surgery
Common signs and symptoms for IBD and Irritable bowel syndrome (IBS):
Common signs and symptoms for IBD and Irritable bowel syndrome (IBS): abdominal pain or discomfort with diarrhoea or constipation.
IBD vs IBS - what is needed for differential diagnosis
Need biochemical markers for differential diagnosis.
Leakage of neutrophils and calprotectin due to
Any disturbance in the mucosal architecture due to the inflammatory process results in leakage of neutrophils and calprotectin
Calprotectin - define + function
Calprotectin is a protein released by neutrophil
When there is inflammation in GI tract, calprotectin released, resulting in an increased amount released into the stool
What do neutrophils release in inflammation
Zinc and calcium binding protein released by neutrophils in inflammation
Colorectal cancer - from where
It arises predominantly from adenomatous polyps
Colorectal cancer - signs
Colorectal cancer is often asymptomatic until late-stage disease (poor prognosis)
Colorectal cancer - testing
Tests must detect the small amounts of blood in faeces that may be present in asymptomatic individuals with bowel lesions
Guaiac faecal occult blood (FOB) method widely used in screening.
Faecal Immunochemical Test (FIT) - define and compare with FOB
‘Dipstick’ test for blood in stool
Quantitative measurement of Hb in faeces
Higher sensitivity than guaic FOB method
Colorectal testing in symptomatic patients meeting the following criteria
Over 50y with unexplained abdominal pain or weight loss
50 to 60y with changes in bowel habit or iron-deficiency anaemia
60y or over with anaemia without iron deficiency
OC-Sensor FIT kit - use
OC-Sensor FIT kit (made by MAST) -immunoassay test which can be used with an automatic analyser.
