ILO WEEK 2

Question 1

Describe the general principles of pharmacokinetics using the ADME mnemonic.

Answer 1

ADME
A - Absorption
D- Distribution
M- Metabolism
E- Excretion

A- The drug enters the body and reaches the systemic circulation

D- The drug moves from the systemic circulation to reach the target (and possibly non-target) tissues

M- The drug is chemically altered by the body. Usually this alters the drug characteristics to facilitate excretion.

E- The drug is removed from the body, most commonly via concentration in bile or urine

Question 2

Aetiology and clinical features of Coeliac disease

Answer 2

common, chronic , immune-mediated enteropathy that is triggered and maintained by ingestion of gluten in genetically predisposed individuals

various degrees of intestinal inflammation, ranging from intraepithelial lymphocytosis to severe infiltration and total villous atrophy coupled with crypt hyperplasia

clinical presentation ranges from completely asymptomatic to severe malabsorption and malnutrition.

up to 2% in the UK
in general population is 1%
genetic predisposition

Question 3

Pathophysiology of Coeliac Disease and sequelae of malabsorption

Answer 3

• High proline content
• resistant to intestinal protease
• TTG( tissue trans glutamase) which deamidates it to glutamate
• more avidly bound by APCs (antigen presenting cells)
• HLA DQ2/8
• gluten specific T cell receptors
  NEED TO BE EXPOSED
  Proteases cant properly digest gluten
• anti-gluten
  ADD ON

Question 4

Diagnosis of coeliac disease

Answer 4

Test of Coeliac disease:
Patient MUST be on a gluten-containing diet
Bayesian probability/prevalence- how likely is it?
Serology
IgA Deficiency ( more common in coeliac disease)
Duodenal biopsy (endoscopy)
Histology
Immunohistochemistry
sometimes not obvious; less villi; cracks; flatted; less prominent folds
Human Leucocyte Antigen (to clarify diagnosis)
Small bowel imaging NOT FIRST LINE (classical findings: small bowel dilatation, reversal of fold pattern and increased small bowel fluid)
Response to gluten free diet

Serology
Antibody test + IgA Anti-glidin

TTG ( usually given as a number) +ve Biopsy –ve
Patchy disease
Inadequate biopsy
Latent Coeliac

TTG +ve Biopsy +ve
Is the patient on a GFD already?
All the other causes of villous atrophy*
True antibody –ve CD [rare +++]
If HLA DQ2/8 negative -> NO Coeliac disease

Recovery rate of antibodies and recovery of the mucosa do not run in the same pace!!!

Question 5

management of coeliac disease

Answer 5

Gluten free diet
Dietician review
Coeliac UK
GFD = <20ppm or 20mg/kg
GP FP10 prescription
Nutritional assessment; community based, check weight, nutrients
Bone health [DEXA]
Vaccination ( assosiate with hyposplenism; risk of sepsis)
Villous apreophy
Pneumococcus
Meningococcus 
Follow-up
Dietician/pharmacist

Question 6

Describe in detail the biochemistry of bile pigments, especially Bilirubin

Answer 6

-

Question 7

Explain how distinct chemical properties of bile salts are important for their function in lipid digestion

Answer 7

-

Question 8

mechanisms by which bile secretion from the gall bladder is controlled

Answer 8

Between meals (the interdigestive period), the sphincter of Oddi is contracted, meaning the bile cannot enter the duodenum. Pressure increases in the common bile duct and bile flows into the gallbladder. Epithelial cells reabsorb water and electrolytes, thus concentrating the bile.
• Once fatty acids & amino acids enter the duodenum, they stimulate endocrine cells to release cholecystokinin (CCK). This stimulates (via vagus nerve) contraction of the gallbladder smooth muscle and relaxes the sphincter of Oddi, ultimately resulting in bile release.

Question 9

basis for the classification of jaundice into three groups (pre-hepatic, hepatic and post- hepatic) and uses of the distinct effects on Bilirubin metabolism


Answer 9

PREHEPATIC
If jaundice is prehepatic -> most bilirubin is unconjugated and is visible in the skin and eye; elevated heamolysis; liver unable to cope
can be caused by tropical diseases (malaria, yellow fever or sickle cell anaemia)

HEPATIC
result of liver damage causing cholestasis due to swelling and oedema from inflammation:
- impaired uptake of UCB
- impaired conjugation of bilirubin e.g. Glibert’s syndrome
- impaired transport of CB into bile canaliculi e.g. primary biliary cholangitis

Liver damage caused by: cirrhosis, hepatotoxic drugs, viral hepatitis

Increase in both CB( more) & UCB
Bad excretion; seen in urine and bile

POST-HEPATIC
obstruction of cystic or common bile
Caused by:
• Choledocholithiasis - gall stones obstructing the cystic duct.
• Pancreatic Cancer - tumour growth in the head of the pancreas can block bile flow into duodenum. • Pancreatitis - inflammation and swelling of the head of pancreas can also block bile flow.

Increased CB as not excreted in the bile
pale stools; dark urine -> increased CB in the blood

Question 10

Structure and functions of enteric nervous system

Answer 10

• Mediates reflex activity in the absence of CNS input (interprandial period- between meals)

Influenced by extrinsic factors
Vagal Control : excitatory to non-sphincteric muscle (ACh)
Sympathetic control : inhibitory to non-sphincteric muscle. Excitatory to sphincteric muscle
Other neurohormonal influences -
5 hydroxy-tryptamine
Motilin
Opioid receptors

Question 11

Normal movements of GI system

Answer 11

Mouth: skeletal muscle voluntary control

Oesophagus: swallowing (first voluntary then involuntary) primary peristalsis wave (vagus) controlled by swallowing centre in medulla
Secondary peristalsis when food stuck pressure receptors in oesophagus

Stomach: storage through receptive relaxation- BER (Basal electric rhytm) in the body; mixing food with gastric secretions; peristalsis; 3 types of muscles; cannot have too much food in duodenum-> good control from duodenum and stomach

Small intestine: 1. Segmentation mixes chyme and enzymes; oscillating ring ; contractions of circular smooth muscle, control by BER, influenced by gastrin and extrinsic nervous system
2. Migrating Motility Complex: following absorption these between-meal short peristaltic contractions “sweep up” meal remnants a swell as mucosal debris and bacteria, moving towards colon 100-150 minutes to migrate from stomach.

!Regulated by hormone Motilin!

Large intestine: Primarily for storage and drying Haustral contractions initiated by the autonomous rhytmicity

Question 12

Control of GI functions

Answer 12

Controlled by type of food in the GI; Hormones: Secretin, CCK, Gastrin
Nerves: Vagus nerve

Question 13

Common disorders of gut motility and their causes

Answer 13

Achalasia -> failure of LOS to relax and open when required (oesophagus)

Oesophagus in scleroderma -> A chronic hardening and contraction of the skin and connective tissue; distal oesophagus dilated; apparent shortening of length due to fibrosis; weak LOS; gastric reflux; absent peristalsis and severe esophagitis

Nutcracker oesophagus -> Excessive amplitude and duration of muscular contractions of the smooth muscle of the oesophagus
(increased pressures associated with severe pain on swallowing

Diffuse oesophagus -> uncoordinated contractions of the oesophagus resulting in spasms which do not propel food effectively to the stomach; corkscrew appearance (radiography)

Disorders of gastric emptying -> Accelerated gastric emptying, dumping syndrome (too quickly)
Delayed gastric emptying -> ab. pain, vomiting, poorly controlled reflux

Disorders of bowel transit -> signs of mechanical obstruction (without it occurring) neuropathic aetiology
-Acute post-operative ileus; painful obstruction, physiological

• Acute colonic pseudoobstruction (ogilvie’s syndrome) large bowel parasympathetic dysfunction, common after cardiothoracic or spinal surgery

Problems with Anorectal function ->

• Excessive rectal distension (acute or chronic diarrhoeal illness)
• Anal sphincter weakness (sphincter damage, pudendal nerve damage)
• Hirschrung’s disease (congenital megacolon; lack of congenittal development of nerve plexi and ganglia resulting in lack of nervous control of the colon; rectocele; anal fissure (pain on defecation)

Question 14

Metabolism of Bilirubin

explain how it is transformed from a hydrophobic “un-conjugated” form to a hydrophilic “conjugated” form by the liver

Answer 14

Haem breakdown
Unconjugated bilirubin -> transported with albumin to the liver
(hydrophobic)
conjugated by glucoronic acid UDP Glucoronyl Transferase
Conjugated can be transported with bile into small intestine

Goes into urobilinogens (converted by intestinal bacteria); some recirculated in enterohepatic urobilinogen cycle recirculation; rest out with stool and urine

Question 15

Pathophysiology, diagnosis and management of portal hypertension

Answer 15

PATHOPHYSIOLOGY
caused by cirrhosis and scarring of liver (liver damage) blocks blood flow and slows processing functions; may also be caused by thrombosis or blood clots in portal vein; portal vein bypass -> porto systemic shunting

May cause oesophageal varices and splenomegaly, ascites, hepatic encelopathy

Decrease blood pressure; prevent further damage; transplant

Question 16

Effects of coeliac disease on iron homeostasis in human body

Answer 16

generally decreased absorption; unregulated
can lead to anemia
surface absorptive area in the duodenum is reduced

Question 17

Bilirubin conjugation

Answer 17

Liver cells -> Glucoronic Acid -> UDP Glucoronic Transferase

Question 18

Reference ranges of bilirubin

Answer 18

total <21 mmol/L
conjugated <7mmol/L

with >30 visible in sclera
>100 visible in skin

Question 19

The role of the Pancreas in the digestion of food in the human gut

Answer 19

Pancreas produces pancreatic enzymes which digest most of the food groups; also increases pH from the gut (bicarbonate)

Produced in inactive form (ZYMOGEN) except for the amylase and lipase
trypsin activated by enterokinase (brush border) later activates all of the rest
- trypsin
- chymotrypsin
- pancreatic lipase
- amylase
-ribonuclease, deoxyribonuclease,
carboxypeptidase gelatinase and elastase.

Also produces bicarbonate and water

ADD MORE

Question 20

Taurocholic acid

Answer 20

chemical is released into the bile by the liver and plays a role in digestion in the small intestine -> in bile

Question 21

At what interval these MMC occurs during the interdigestive phase (between meals)

Answer 21

Every 90-120 minutes

Question 22

Gilbert’s syndrome

Answer 22

symptoms of fever, myalgia, mild neck stiffness and loss of appetite. There was nothing of note both in past medical and family history
ALT; AST; gamma GT decreased
CRP increased

Question 23

Which test should be carried out to confirm the diagnosis of Gilbert’s syndrome?

Answer 23

Unconjugated bilirubin

Question 24

Vasoactive Intestinal polypeptide (VIP)

Answer 24

Gall Bladder relaxation and closure of Sphincter of Oddi

Question 25

Dermatitis Herpetiformis

Answer 25

skin condition is associated with coeliac disease

Question 26

Haemochromatosis

Answer 26

excess dietary iron absorption and excess iron release from macrophage stores leading to

Question 27

List the normal functions of the liver

Answer 27

1. Amino acid, carbohydrate and lipid metabolism.
2. Storage of proteins, glycogen, vitamins and minerals.
3. Plasma protein and enzyme synthesis (Such as coagulation proteins)
4. Detoxification
5. Production of bile
6. Immune functions (Kuppfer Cells)

Question 28

Describe the structure of the liver in terms of broad structure and histology.

Answer 28

Lobular in anatomy: Left and Right Lobes, Caudate (posterior superior) and Quadrate (posterior and inferior) Lobes.

Clearly marked by the Falciform Ligament. The Porta Hepatis allows access to the Liver to the Hepatic Portal Vein, Hepatic Artery and Hepatic Duct.

Parenchymal liver cells and connective tissue matrix organise the histology into sinusoids.

Parenchymal cells:

1. Hepatocytes
2. Endothelial Cells
3. Kupffer Cells
4. Perisinusoidal Cells (Stellate, Ito Cells)
5. Liver Associated Lymphocytes

A counter current flow in the sinusoids allows Bile to flow to and blood to flow from the Portal Field as the “Portal Triad” (vice versa from the Central Vein)

Question 29

Describe the liver’s vasculature, parenchyma and its normal connective tissue.

Answer 29

Served by the:

1. Hepatic Artery
   - 30-40%
2. Portal Vein
   - 60-70%
3. Hepatic Vein

Parenchymal Reticulin is organised to allow passage of portal tracts and is encapsulated in the Liver Capsule.

It is attached to neighbouring tissues by ligaments.

1. Falciform Ligament. Attaches to the abdominal wall. Contains the Round Ligament (Ligamentum Teres).
2. Coronary Ligament. Attaches to the inferior surface of the diaphragm.
3. Triangular Ligaments. Attaches the left and right lobes of the liver to the diaphragm.
4. Lesser Omentum. Attaches the Liver to the lesser curvature of the stomach and the first part of the duodenum.

Question 30

Briefly describe the contents of bile and how it is produced and secreted. Describe how Jaundice may arise.

Answer 30

Recipe for hepatic bile:

97% water, 0.7% bile salts (mainly Cholic Acid and Chenodeoxycholic Acid which is conjugated with Glycine and Taurine), 0.2% billirubin, 0.51% fats, 200meq/L inorganic salts.the pigment is provided by biliverdin and bilirubin.

Jaundice can arise in three major ways. Pre-hepatic, hepatic, post hepatic.

Typically, pre-hepatic jaundice in caused by RBC defects causing haemolysis resulting in an increased volume of bilirubin produced.

Hepatic jaundice arises when the liver is unable to conjugate bilirubin, usually due to liver disease.

Post-hepatic jaundice is typically obstructive. This can be caused by gallstones, pancreatitis or neoplasia. Results in a spill over of both conjugated and uncojugated bilirubin.

Question 31

List the so called Liver Functions Tests (LFTs)

Answer 31

Standard Liver Panel:

Total Bilirubin
Alanine Transaminase (ALT)
Aspartame Transaminase (AST)
AST:ALT Ratio
Alkaline Phosphatase (ALP)
Gamma Glutamyl Transpeptidase (GGT)
Albumin

Included in PBL Class: INR

Question 32

Briefly describe what abnormality of any one LFT may mean and outline the pattern of abnormal LFTs in Jaundice of different causes.

Answer 32

Standard Liver Panel:

1. Total Bilirubin - provides information on pre/ post hepatic insult or hepatic injury proper.
2. Alanine Transaminase (ALT) - marker of hepatocellular injury. A cytosolic enzyme, it is more specific to liver disease.
3. Aspartame Transaminase (AST) - marker of hepatocellular injury. Less specific than ALT in indicating liver disease.
4. ALT:AST Ratio
   - a high ratio indicates alcoholic liver disease, a low ratio indicates nonalcoholic fatty liver disease.
5. Alkaline Phosphatase (ALP)
   - raised in Bile Duct obstruction. Probably due to increased synthesis. It’s not really known.
6. Gamma Glutamyl Transpeptidase (GGT)
   - elevated in chronic liver disease. It provides indication for the clinician to enquire about alcohol abuse. It is not specific nor fully understood.
7. Albumin
   - the liver produces plasma proteins, Albumin being one. Particularly in acute injury, levels of these are reduced. Same goes for INR (clotting will be slower).

Follow these LFTs like a flow chart, and with clinical judgement it will guide you to a diagnosis.

EXAMPLE:

If a patient presents with clinical Jaundice, clinicians have to differentiate between hepatocellular causes, pre-hepatic pathology or obstructive Jaundice.

ALT, which is increased in hepatocellular injury indicates hepatocellular injury of the liver. (Liver disease).

ALP synthesis is increased in response to cholestasis, so would indicate obstructive Jaundice.

A raised ALP indicates the need to measure GGT. If this is also raised, Cholestasis is highly likely. ALP alone is not specific to the liver, and can direct investigations towards bone disease such as sarcoma, fracture or Vitamin D deficiency.

If LFTs appear normal with clinical Jaundice, usually a pre-hepatic pathology is responsible, such as increased haemolysis. A full blood count is therefore indicated to direct investigations.

• example from Geeky Medics

Question 33

Define Cirrhosis

Answer 33

“Cirrhosis is the pathological end stage of any chronic liver disease” it is defined as “a diffuse pathological process, characterised by fibrosis and conversion of normal liver architecture to structurally abnormal nodules known as regenerative nodules”

• BMJ Best Practice 2019

Question 34

Describe the pathogenesis of Cirrhosis.

Answer 34

The “central event” that initiates the pathophysiology of Cirrhosis is the activation of stellate cells which deposit Type I/ III collagen in the Space of Disse. This results in the loss of normal sinusoidal architecture and loss of finestrae a process called “.

Activation of stellate cells also cause them to become contractile, producing portal resistance and increasing Cirrhosis.

Pathophysiology is progressive. Increasing capillarisation increases portal hypertension increases hepatic insult termed acute-on-chronic liver failure.

Complications include a Porto-systemic shunt, producing varices, ascites, metabolic diseases (the liver being a central organ in the production of proteins and clearance of waste)

Cirrhosis is usually end stage, terminal, irreversible. It is marked by the formation of regenerative nodules and diffused liver scarring.

Causes of stellate cell activation are any agent causing hepatic damage:

Viral Hepatitis 
Alcoholic-related liver disease
Drugs (methotrexate)
Right sided heart failure
Biliary obstruction

Question 35

List the possible complications of Cirrhosis.

Answer 35

Ascites (the most common complication)
Gastric-oesophageal varices (in about 50% of patients with cirrhosis)
Hepatocellular Carcinoma
Bleeding/ thrombosis
Portopulmonary hypertension

(Amongst others)

Question 36

Describe the effects of liver failure.

Answer 36

Jaundice as the liver is unable to conjugate and clear bilirubin.

Coagulopathy - the Liver is unable to produce clotting factors. The cascade fails.

Hepatic encephalopathy, as the liver is unable to clear metabolic waste, principally ammonia.