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4 pathology > Lab Investigation of Liver and Gastro Intestinal Tract Disease > Flashcards

Lab Investigation of Liver and Gastro Intestinal Tract Disease Flashcards

1
Q

what is the largest organ in the body and where is it located?

A

the liver, located in the upper right quadrant of the abdomen

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2
Q

what is the liver made up of?

A

a large right lobe and smaller left lobe

  • lobes consist of lobules - sheets of hepatocytes
  • the sheets are radiating out from a central vessel which is the blood supply
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3
Q

blood supply to the liver?

A

dual blood supply to the liver

  • portal vein, bringing in nutrient rich blood from the GI tract (2/3)
  • oxygen rich blood from the hepatic artery (1/3)
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4
Q

blood supply from the liver?

A

Blood drains from the liver via the hepatic veins

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5
Q

substances for excretion from the liver go where?

A

they are secreted from hepatocytes into canaliculi (canals)

these canals lead to the bile for the excretion of substances. The canals form ducts, and they drain out to form a common hepatic duct, which joins in with the bile from the gall bladder via the common bile duct.

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6
Q

Major functions of the liver

A

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

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7
Q

Types of Liver Disease

A

Hepatitis

Cholestasis

Cirrhosis

Tumours

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8
Q

Hepatitis

A

inflammation of the liver, leading to damage to hepatocytes

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9
Q

Cholestasis

A

reduction or stoppage of bile flow - blockage

inflammation can cause scarring, making the liver fibrose leading to canaliculi blockage
– this can be within the liver (intra hepatic) or outside of the liver (extra-hepatic)

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10
Q

Cirrhosis

A

Increased fibrosis
Liver shrinkage
Decreased hepatocellular function
Obstruction of bile flow

increased fibrosis leads to scarring, meaning the classical function of the liver is being lost.

The liver itself has a big reserve capacity, so you don’t notice the drop in function unless the situation is extreme.

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11
Q

Biochemical assessment of liver function?

A

Liver Function Test (LFT)

Standard LFT profile:

Total bilirubin
Albumin (tends to only decrease with chronic liver disease)
Alanine and aspartate aminotransferase (ALT/AST)
Alkaline phosphatase
Gamma glutamyltransferase

Insensitive indicators of liver ‘function’, so look for pattern of results - a single result rarely provides a diagnosis on its own.

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12
Q

LFTs are not diagnostic but what can they be used for?

A
  • Screening for presence of liver disease
  • Assessing prognosis, monitoring disease progression
  • Measuring efficacy of liver disease treatments
  • Differential diagnosis: predominantly hepatic or cholestatic
  • Assessing severity, especially in patients with cirrhosis
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13
Q

when do we see an large increase in ALT?

A

inflammatory diseases

-this is because this means damage to hepatocytes, which release ALT

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14
Q

what is bilirubin?

A

a yellow-orange pigment derived from haem

-a product of Hb breakdown

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15
Q

what 2 forms does bilirubin occur in?

A

Conjugated (direct-reacting bilirubin)

Unconjugated (indirect-reacting bilirubin)

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16
Q

why does bilirubin have to be conjugated, and where is it conjugated and excreted?

A
  • because unconjugated bilirubin is very hydrophobic
  • it has to be conjugated in the liver to become more water soluble for excretion
  • excreted in the bile
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17
Q

where does bilirubin bind?

A

binds tightly but reversibly to albumin

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18
Q

delta bilirubin?

A

sometimes chronic liver disease where you get high amounts of bilirubin you may see bilirubin covalently bound to albumin – this is delta bilirubin

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19
Q

summarise bilirubin metabolism

A
  • old RBC’s get taken to the spleen, where they are broken down by reticuloendothelial cells
  • the iron get reutilised, but the Hb part get converted to bilirubin
  • bilirubin binds to albumin and gets transferred to the liver
  • in the liver bilirubin gets conjugated to glucuronide via an enzyme UGT1A1, forming water-soluble bilirubin mono and di glucorinide
  • these products can enter the small intestine via the bile duct where they are converted to urobilinogen
  • urobilinogen enters the liver via the extra-hepatic circulation, and some also enters systemic circulation, where it is excreted via the kidneys
  • the majority of urobilinogen enters the large intestine, where bacteria in the colon convert it into stercobilin – brown pigment associated with stools.
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20
Q

define jaundice?

A

yellow discolouration of tissue due to bilirubin deposition

-Imbalance between bilurubin production and excretion - increase in serum/plasma concentrations of bilirubin

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21
Q

where do you see jaundice?

A

skin

-also in sclera of eyes

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22
Q

its important to determine what about bilirubin?

A

whether it’s conjugated or unconjugated

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23
Q

what do increased conjugated or unconjugated bilirubin levels mean?

A

Unconjugated elevation - production is increased which is beyond capacity of liver conjugation

Conjugated bilirubin elevation – obstruction of bile flow

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24
Q

types of jaundice?

A
  • prehepatic
  • cholestatic (intrahepatic)
  • extrahepatic
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25
Q

whats is pre hepatic jaundice and what are the causes?

A

too much unconjugated bilirubin

caused by excessive RBC breakdown:

  • Haemolysis
  • Haemolytic anaemia
  • Gilbert’s
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26
Q

causes of cholestatic/intrahepatic jaundice

A

Dysfunction of hepatic cells (can lead to scarring, unconjugated and conjugated bilirubin)

  • Viral or alcoholic hepatitis
  • Cirrhosis
  • Pregnancy
  • Drugs
  • Congenital disorder
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27
Q

whats is extra hepatic jaundice and what are the causes?

A

too much conjugated bilirubin
-bilirubin can enter and be conjugated, but cannot leave the bile duct

obstruction of biliary drainage

  • Common duct stone
  • Carcinoma
  • Biliary structure
  • Pancreatitis
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28
Q

is neonatal jaundice common and is it long term?

A

it is common

it is not long term, it’s transient and resolves within the first 10 days

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29
Q

what is neonatal jaundice caused by?

A

Immaturity of bilirubin conjugation enzymes

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30
Q

why are high levels of unconjugated bilirubin toxic to newborns?

A

due to unconjugated bilirubin’s hydrophobicity it can cross the blood-brain-barrier & cause kernicterus

  • toxic to neurones
  • kernicterus causes sleepiness, drowsiness, seizures and floppiness
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31
Q

in neonatal jaundice, how can unconjugated bilirubin levels be treated?

A

treated by phototherapy with UV light

– converts bilirubin to water soluble, non-toxic form

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32
Q

when does this neonatal jaundice become pathological?

A

becomes pathological jaundice if there are high levels of conjugated bilirubin

  • pale stools in babies with biliary atresia
  • urgent surgical treatment is essential
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33
Q

what is biliary atresia?

A

biliary tree not formed properly

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34
Q

what is Gilbert’s Syndrome?

A
  • not very common, 10% of population
  • males more frequently affected then females
  • benign liver disorder
  • genetic mutation in promoter region of UDP gene
  • characterized by mild, fluctuating increases in unconjugated bilirubin
  • caused by decreased ability of the liver to conjugate bilirubin
  • usually increases when people are fasting or under physiological stress
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35
Q

name 2 commonly measured markers of hepatocyte injury

A

ALT and AST
-v good markers of hepatic damage, because damage to liver (due to inflammation or necrosis) will mean hepatocyte damage/death and higher enzyme levels in the blood

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36
Q

ALT?

A

Alanine Aminotransferase

  • predominantly localised to liver
  • cytosolic
37
Q

AST?

A

Aspartate Aminotransferase
-wide tissue distribution:
heart, skeletal muscle, kidney, brain, RBC’s, lung, liver
-cytosolic and present in mitochondria

38
Q

when do levels of ALT and AST increase?

A

Values increased in almost all liver disease

Modest elevation (5 x ULN):
Fatty liver
Chronic viral hepatitis
Prolonged Cholestatic liver disease
Cirrhosis
In compensated cirrhosis values may be normal

Highest elevation (10-20x ULN):
severe liver damage
Acute viral hepatitis
Hepatic necrosis induced by drugs or toxins
Ischaemic hepatitis induced by circulatory shock

39
Q

when might you get a false decrease in ALT and AST?

A

In v severe cirrhosis there is so much liver damage you may get a false decrease in ALT and AST

-doesn’t mean anything has improved, it just means there’s so little liver left there isn’t much ALT and AST to be leaked out anymore

40
Q

what is ALP and where is it synthesised?

A

Alkaline Phosphatase

-enzyme isoforms mainly produced in liver and bone but also placental and intestinal forms

41
Q

what is ALP a good marker for and why?

A

ALP is a good marker for cholestasis

-mainly found in the bile canaliculi membranes, and increased when there is bile canaliculi obstruction (i.e. activity goes up with intra and extra hepatic cholestasis)

-Obstruction may be due to:
extrahepatic (stones, tumour)
intrahepatic (infiltration or space occupying lesion)

42
Q

increase in osteoblastic activity causes?

A

Healing fractures
Vitamin D deficiency
Paget’s disease

43
Q

the source of an elevated ALP can be determined by?

A

gel electrophoresis

-It is possible to separate ALP isoenzymes into liver, bone, and intestinal fractions.

44
Q

Gamma Glutamyl Transferase (GGT)

A
  • membrane bound enzyme
  • transfers the gamma glutamyl group from peptides (such as glutathione) to other peptides and L-amino acids
  • wide tissue distribution, but liver isoenzyme activity predominates in serum
45
Q

what is GGT used in combination with?

A

used in combination with ALP, value confirms ALP of hepatic origin

46
Q

when may there be increased GGT levels?

A
  • enzyme induction by alcohol or drugs e.g. anticonvulsants
  • cholestasis and hepatocellular disease
  • non-hepatic disorders, e.g. pancreatitis, myocardial infarction and diabetes mellitus
47
Q

Interpretation of ALP and GGT results

A

↑ ALP and ↑ GGT – suggestive of hepatic cause (cholestasis)
↑ ALP and N GGT – suggestive of bone source of ALP
N ALP and ↑ GGT – suggestive of excess alcohol intake

48
Q

what is albumin?

A

a major circulating plasma protein that is synthesised exclusively in the liver (12g produced each day)

49
Q

why is albumin an important plasma protein?

A

v important plasma protein because it helps with plasma oncotic pressure
-binds to hormones, FFA and circulating drugs

50
Q

albumin concentration is an index of?

A

hepatic synthetic function

-note: albumin levels can be normal in early acute hepatitis due to its long half-life (21 days)

51
Q

in what situations is serum albumin decreased?

A
  • acute or chronic destructive liver diseases of moderate severity
  • Haemodilution (in pregnant ladies, albumin concentration drops purely because there’s more volume in the plasma)
  • Impaired synthesis (e.g. malnutrition, people don’t have the building blocks to make albumin)
  • Increased loss e.g. nephrotic syndrome
  • Inflammatory leak
52
Q

common cause of an abnormal LFT?

A

Non-Alcoholic Fatty Liver Disease (NAFLD)

53
Q

which is more prevalent, NAFLD or alcoholic liver disease?

A

NAFLD

20% in general population, up to 70% in type 2 diabetes

54
Q

is NAFLD reversible?

A
  • Benign and reversible at the beginning – changes to lifestyle should be okay (exercise, diet)
  • If it progresses to inflammation and hepatitis, will lead to greater risk of fibrosis, cirrhosis and hepatocellular carcinoma
55
Q

stages of NAFLD?

A
  1. Hepatic steatosis (fat >5% liver volume)

2. Greater risk of progressing to fibrosis, cirrhosis, HCC

56
Q

Major risk factors of NAFLD?

A

Obesity
Diabetes/insulin resistance
Hypertension

57
Q

some typical features of non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease

A

AST
NAFLD: normal
Alcoholic liver disease: increased

Fasting plasma glucose
NAFLD: increased
Alcoholic liver disease: normal

HDL cholesterol
NAFLD: low
Alcoholic liver disease: increased

(when alcohol is involved AST is increased)

58
Q

Non-alcoholic fatty liver fibrosis algorithm?

A

calculate a FIB4 score
– combination of patient age, platelets and AST/ALT together

-second line test called the ELF (enhanced liver fibrosis), involves serum biomarkers of hyloriic acid, pro collagen and TIMP - combined in an algorithm in an ELF score – becoming a more popular test.

59
Q

Overview of the GI Tract

A

7-10 m long, running from mouth to anus
-main function is to absorb food

Oesophagus
Stomach
Duodenum
Jejunum
Ileum
Colon
60
Q

how much of the cardiac output does the GI tract take?

A

30%

61
Q

what are Gastric Ulcers caused by?

A

break in the protective stomach mucosal lining

62
Q

Signs and symptoms of gastric ulcers?

A

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

63
Q

Common causes of gastric ulcers?

A

Helicobacter pylori infection (80% of cases)
Use of aspirin and NSAIDs – non-steroidal anti-inflammatory drugs (20% of cases)

drugs can cause an imbalance in the mucosal lining

64
Q

how does the stomach protect itself from the harsh acid secretions?

A

produces mucus

65
Q

Helicobacter Pylori

A
  • helix-shaped gram-negative bacteria
  • survives in gastric acid by secreting urease
  • Urease breaks down urea, also produces toxins which are released and cause more epithelial damage
  • H. pylori is the cause of most gastric and duodenal ulcers
66
Q

how is Helicobacter Pylori detected?

A

urea breath test

rapid, non-invasive procedure used to identify active infection by H. pylori

  • 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
67
Q

what is Vitamin B12?

A
  • cobalamin, a water soluble vitamin
  • it has essential role in the nervous system and in the formation of RBC’s, and as a co-factor for DNA synthesis
  • converts homocysteine to methionine
68
Q

can vit B12 produced by the body?

A

Vitamin B12 cannot be produced by the human body and so must be obtained from the diet

69
Q

When dietary B12 enters the stomach what is it bound to and where does it travel to?

A

bound by intrinsic factor (IF), a glycoprotein secreted 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.

Stored in the liver

70
Q

does vit B12 deficiency present quickly?

A

no

may take a long period of time for vitamin B12 deficiency to present itself

71
Q

causes of vit B12 deficiency?

A

Pernicious anaemia

  • an autoimmune attack on the gastric mucosa that causes severe Vitamin B12 deficiency
  • auto antibodies made against IF, so no IF production
  • leads to the atrophy of the stomach wall and the IF secretion is absent or severely depleted
72
Q

Signs and symptoms of vitamin B12 deficiency include:

A

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)

73
Q

why does vit b12 deficiency cause nerve problems?

A

Vb12 converts methanionyl coA to succicinyl coA (krebs cycle and energy production)

-too much methanionyl coA impairs myelin sheath production, leads to neuropathy, CNS function impaired, slows response between neurons – numbness and tingling

74
Q

Testing for Vitamin B12 deficiency

A

methylmalonic acid - elevated

homocysteine - elevated as not converted to methionine

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 are positive in pernicious anaemia

75
Q

Coeliac Disease

A
  • autoimmune disorder that primarily affects the small intestine, affects up to 1% of the general population
  • results from immunological hypersensitivity to ingested to gliadin (gluten protein), found in wheat, barley and rye
  • exposure to gluten in small intestine causes inflammatory reaction, leading to shortening of villi lining and villous atrophy
76
Q

classic symptoms of coeliac disease?

A

anaemia, weight loss, and GI problems e.g. diarrhoea, abdominal distention, malabsorption and loss of appetite.

77
Q

Testing for Coeliac disease

A

Tissue Transglutaminase Antibodies

IgG deamidated gliadin peptide (DGP) antibodies

Endomysial antibodies (EMA): become elevated as part of ongoing damage to the intestine

78
Q

what are Tissue Transglutaminase Antibodies?

A
  • an enzyme that deaminates glutamine residues to glutamic acid on the gliadin fragment
  • 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.
  • Anti-TTG antibodies belong to the IgA subclass of immunoglobulins.
79
Q

Inflammatory bowel disease

A

-encompasses two distinct autoimmune conditions of the GI tract: ulcerative colitis and Crohn’s disease.

80
Q

Ulcerative colitis

A

diffuse inflammation affecting the mucosa of the colon only

81
Q

Crohn’s disease

A

Patchy ulceration affecting any part of the GI tract and may extend through the full thickness of the bowel.

Complications include fistulae, abscess formation and stricturing.

82
Q

what is the definitive test for diagnosis of IBD?

A

Colonoscopy

83
Q

IBD - Clinical Presentation

A

Crohn’s disease and Ulcerative colitis have common signs and symptoms:

Abdominal pain
Prolonged diarrhoea with bowel urgency
Blood and/or mucus in stools
Fatigue
Weight loss and malnutrition

Crohn’s disease may also present with:

Perianal lesions
Bowel obstruction i.e. abdominal bloating, distension, vomiting or constipation

84
Q

common signs and symptoms for both IBS and IBD?

A

abdominal pain or discomfort with diarrhoea or constipation

-given they are quite similar, you need biochemical markers to distinguish between the 2

85
Q

Calprotectin

A

~60% of the cytosolic protein content in neutrophils

Any disturbance in the mucosal architecture due to the inflammatory process results in leakage of neutrophils and calprotectin

Calprotectin is excreted in stools

Calprotectin levels will give an indication as to whether there is inflammatory damage in the bowel

86
Q

Faecal Calprotectin

A

Zinc and calcium binding protein released by neutrophils in inflammation

Stable in stool and extracted and measured at St George’s hospital using a fluorescence enzyme immunoassay

Useful for differentiating IBS and IBD in younger age group

87
Q

Faecal calprotectin testing is recommended as what?

A

as an option to support clinicians with the differential diagnosis of inflammatory bowel disease (IBD) or irritable bowel syndrome (IBS) in adults

88
Q

Colorectal cancer

A

third most common malignancy in the Western world.

arises predominantly from adenomatous polyps

often asymptomatic until late-stage disease - poor prognosis

Early detection greatly improves prognosis, and the condition is now routinely screened for in individuals > 60y

Tests must detect the small amounts of blood in faeces that may be present in asymptomatic individuals with bowel lesions. Guaic faecal occult blood (FOB) method widely used in screening.

89
Q

Faecal Immunochemical Test (FIT)

A
  • ‘Dipstick’ test for blood in stool
  • Quantitative measurement of Hb in faeces
  • Guide referral for suspected colorectal cancer patients who do not meet criteria for a suspected cancer pathway referral

-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

4 pathology (14 decks)

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