week 2- stomach, duodenum, cancer

describe the anterolateral boundary of the abdominal wall

Anterior and lateral walls are musculofascial.

•Above umbilicus: Subcutaneous tissue is single sheet of connective tissue

•Below umbilicus: Two layers of connective tissue; Camper’s fascia (fatty layer) & Scarpa’s fascia (membranous deep layer)

Five muscles in the anterolateral group of muscles

outline the anterior muscles of the abdominal wall

outline the lateral muscles of the abdominal wall

•External Oblique:

•Superficial

•Inferomedial direction

•Creates inguinal ligament

•Free edge posteriorly

•Internal Oblique:

•Intermediate

• Superomedial direction

•Transverse Abdominis

•Deep

•Transverse (horizontal) direction

•All aponeurotic anteriorly

•Form midline raphe - Linea alba

what structure is used to draw the inferior horizontal line in 9 regions?

the iliac tubercle

describe the vasculature of the anterolateral abdominal wall

Main vessels:

•Descending

Superior epigastric and musculophrenic arteries

(from internal thoracic)

•Ascending

Superficial epigastric and superficial deep circumflex iliac arteries (from femoral)

•Inferior epigastric and deep circumflex iliac arteries (from ext. iliac)

Laterally

•Intercostal and subcostal arteries

(from thoracic aorta)

•Lumbar arteries (from abdominal aorta)

outline the innervation of the anterolateral abdominal wall

Anterior rami of:

•T7 to T11 (intercostal nerves)

•T12 (subcostal nerve)

•L1 (iliohypogastric nerve and ilio–inguinal nerve)

what is found in the posterior abdominal wall?

•Lumbar vertebrae, pelvic girdle, ribs XI & XII

•Posterior abdominal muscles and fascia

what are the posterior muscles of the abdominal wall?

Quadratus Lumborium

•Thick muscular sheet

Psoas Major

(Psoas Minor) - Anatomical variation – not always present!

Iliacus (lines the iliac fossa)

•Combines with psoas major muscle - known as iliopsoas

outline the peritoneum and its 3 parts

Continuous serous membrane that lines abdominopelvic cavity

•Parietal peritoneum - Lines abdominal walls

 

•Visceral peritoneum - Covers viscera

•Peritoneal cavity - Potential space, Peritoneal fluid 

what are 2 things viscera can be in the peritoneum, and where does it come from embryologically?

Intraperitoneal:

•Suspended within the cavity, forms from the gut tube

•Eg stomach & spleen

Retroperitoneal:

•Outside cavity posteriorly, only anterior surface covered with parietal peritoneum, form from intermediate mesoderm

•Eg kidneys

describe the peritoneal folds - greater and lesser Omenta

Omenta are peritoneal folds connecting abdominal organs

Greater omentum:

•Apron-like peritoneal fold that drapes over the intestines

•From greater curvature of stomach & duodenum to the transverse colon

Lesser omentum:

•Peritoneal fold from lesser curvature of stomach & duodenum to inferior surface of liver

•Peritoneal ligaments: Hepatogastric ligament & Hepatoduodenal ligament

•Posterior to the free edge of the lesser omentum is the omental foramen; an opening between the greater and lesser sacs

what is the peritoneal fold - mesenteries?

•Double layers of peritoneum that attaches viscera to the posterior abdominal wall

•It allows neurovascular structures to reach the viscera from the body wall

•Location determines name of mesentery

explain the Mesentery in development

In development, there is a ventral mesentery and a dorsal mesentery

•Ventral mesentery attached to proximal parts of the gut and dorsal mesentery attaches the entire length of the system

•Growth of the liver separates the ventral into the falciform ligament and the lesser omentum

Derivatives of the dorsal mesentery are:

•Mesogastrum-greater omentum in adults

•Mesoduodenum- disappears in adults

•Mesentery proper

•Mesocolon

explain the colic compartments

•The transverse mesocolon divides abdomen into supracolic and infracolic compartments

•Communication between them via the paracolic gutters

•Supracolic:

•Contains liver, spleen, stomach

•Infracolic compartments

•Contains small intestine, ascending and descending colon

•Divided left and right by mesentery of small intestine

explain the innervation of the peritoneum and its localisation of pain

•The innervation of the visceral and parietal peritoneum differs:

Parietal:

•Same spinal nerve that supplies the region of the abdominal wall that it lines

•Pain is well-localised

•Visceral:

•General visceral afferents of the autonomic nervous system

•Activation causes referred and poorly localised pain

where does the peritoneal folds attach on the stomach?

attach to the stomach via its greater and lesser curvatures. The lesser omentum (or hepatogastric ligament) attaches to the stomach's lesser curvature and extends to the liver. The greater omentum (or gastrocolic ligament) hangs from the greater curvature and attaches to the transverse colon

name the regions, sphincters and curvatures of the stomach

Regions of the stomach:

•Cardia

•Fundus

•Body

•Pyloric Part

Sphincters:

•Cardia

Pyloric

Curvatures of the stomach:

•Greater curvature

Lesser curvature

explain the blood supply of the stomach

•The left and right gastric arteries (lesser curvature)

•Left from celiac trunk

•Right from hepatic artery proper

•The left and right gastro-omental arteries (greater curvature)

•Left from splenic artery

•Right from gastroduodenal artery

•Fundus supplied by short gastric arteries

•Branching from splenic artery

how do cancer-associated fibroblasts promote progression of cancer?

by regulating many hallmarks of cancer by secreting multiple cytokines and growth factors:

how do cancer-associated fibroblasts interact with tumour cells?

CAFs directly interact with tumour cells to pull them towards the vasculature and aid metastasis

what cells are part of the immune infiltrate in the innate immune response and in the adaptive response?

INNATE: NK cells, dendritic cells, neutrophils, macrophages

ADAPTIVE: CD3+ T-lymphocytes

what are the initial stages of immune infiltrate response?

what are the 2 things immune cells can be?

Immune cells can be both anti-tumorigenic and pro-tumorigenic depending on the factors secreted by the tumour cells

what is the role of immune cells regulated by?

by cancer-associated fibroblasts (CAFs)

what has been introduced in the last years to combat cancer?

Immunotherapy, it aims to enhance the patients own immune system to attack the tumour cells. Expensive. used for children with Leukaemia, not much else.

which type of immunotherapy commonly prescribed to cancer patients is the most successful to date, and what do they target?

checkpoint inhibitors such as ipilimumab and nivolumab

•These drugs target immune checkpoint proteins CTLA4 and PD-1/PD-L1

what is the main driver of vascular recruitment (angiogenesis) in the tumour microenvironment?

Hypoxia with some help from CAFs

what does tumour vasculature influence?

the tumour microenvironment and immune infiltrate

how does having an inflammatory disease increase cancer risk?

alternating relapses of inflammation and periods of remission. damage and healing continuously. The release of proinflammatory mediators during IBD relapses leads to cancer development by promoting oxidative stress that favours DNA mutagenesis, antiapoptotic pathways and migration, angiogenesis and invasion

what sequence does tumorigenesis in patients with IBD follow?

the inflammation–dysplasia carcinoma sequence (B) instead of Vogelstein Model (A) described for sporadic CRC (colonrectal cancer). Most sporadic CRC develops from the benign precursor then to an early adenoma, and eventually progresses to invasive carcinoma

Colitis-associated CRC (CAC) develops in a chronically inflamed mucosa and follows the sequence of indefinite dysplasia to low-grade dysplasia to high-grade dysplasia to carcinoma

what is the role of liver in the systemic inflammatory response?

The liver, in particular hepatocytes are central to the elaboration of the systemic inflammatory response as they synthesize and release into the circulation a variety of acute phase proteins, such as C-reactive protein (CRP), which sustain the systemic inflammatory response

what measurements are seen to measure the systemic inflammatory response?

In patients with cancer as CRP [c-reactive protein] (and systemic inflammation) increases, albumin falls (nutritional marker) and this relationship is similar across many different tumour types including multiple GI cancers (gastroesophageal, colorectal, liver)

what does each score in the CRP (c- reactive protein) results mean?

Biochemical Measures	Score	Meaning
CRP <10mg/ml and Albumin >35mg/ml	0	Normal
CRP >10mg/ml and Albumin >35mg/ml	1	Systemically inflamed
CRP >10mg/ml and Albumin <35 mg/ml	2	Systemically inflamed with nutritional deficit

what can widely influence a cancer patient’s prognosis and survival in GI cancers?

The make up of the TME (tumour microenvironment) and amount and impact of systemic inflammation

what type of prognostic factor is vasculature?

•Increased vasculature is a poor prognostic factor as it promotes tumour progression and metastasis

what type of prognostic factor is increasing numbers of CAFs (Cancer-associated Fibroblasts)?

•In many cancers, increasing numbers of CAFs is a poor prognostic factor as measured by the tumour to stroma percentage

what type of prognostic factor is high levels of T-cells, what about macrophages and neutrophils specifically?

High levels of T-cells are a good prognostic factor.

However, the prognostic value of macrophages is dependent on their subtype and location within the microenvironment. Similarly, the prognostic value of neutrophils is dependent on their location within the microenvironment

what is Modified Glasgow Prognostic Score (mGPS)?

•mGPS predicts prognosis and survival in a variety of GI cancers

describe the arterial blood supply from the celiac trunk

•Celiac trunk is a large branch from anterior surface of the aorta, immediately below the aortic hiatus of the diaphragm

•It immediately divides into the left gastric, splenic, and common hepatic arteries

•It supplies foregut structures, which includes stomach, spleen, liver, gallbladder and part of duodenum

describe the venous drainage of the stomach

•The left and right gastric veins

•The left and right gastro-omental veins

•Short gastric veins

•A prepyloric vein ascends over pylorus and is used to identify this region of the stomach in a living patient

what causes upper GI inflammation?

Imbalance in mucosal protection

• environmental ( smoking, chemicals, drugs, viruses, bacteria)

• Hormonal secretion

• Genetic

• Host Immunity

outline what happens in upper GI inflammation on the cellular level

•Cell damage and turn over

•Inflammation and irritation

list symptoms of upper GI inflammation manifestation

• abdominal pain

• weight loss

• diarrhoea

• dysphagia

• fatigue

• vomiting blood

• anaemia

• vomiting

• nausea

• funny taste

• ulceration

describe and differentiate the epithelium of the stomach and of the oesophagus

name the secretory glands of the stomach and their secretory products

Cells of Gastric Glands	Secretory products
Surface Mucus cells	Mucin in an alkaline fluid
Mucus neck cells	Mucin in an acidic fluid
Parietal cells	HCL and Intrinsic factor
Chief cells	Pepsinogen and lipase
G Cells (enteroendocrine)	Gastrin
D Cells (pyloric region)	Somatostatin

explain the stimulatory pathway

•Gastrin stimulates Enterochromaffin like cell (ECL) to produce histamine

•Gastrin stimulates parietal cell to produce acid

• Ach stimulates G cell to produce Gastrin

• Ach stimulates parietal cell to produce acid

• Somatostatin inhibits ECL cell histamine secretion

• Histamine stimulates acid secretion by acting on parietal cells via H2 receptor

• Histamine stimulates acid secretion by acting on D cell via H3 receptor to inhibit somatostatin production

name and explain the roles of the different gastric juices

list some common upper GI inflammatory conditions

• GORD: Gastro-oesophageal reflux disease

• Gastritis

• Ulcers-Oesophageal, Gastric and duodenal

• Eosinophilic Oesophagitis

explain GORD: Gastro-oesophageal reflux disease, and the causing factors

Reflux of acidic acid contents

Incompetent lower oesophageal sphincter

The cells: non-keratinised Squamous epithelial cells    

DO NOT secrete mucus

Less protection against acid

C/o

Burning, radiation behind sternum

Bending, lying, jumping

Waterbrash; regurgitation acid contents to back of throat

Spicy food, carbonated drinks, alcohol, smoking

Obesity, pregnancy, structural abnormality– increased pressure

Dysphagia ( acid related strictures)

explain Eosinophilic Oesophagitis and its risk factors

- Chronic, allergic inflammatory

-Eosinophils

-Inflammation

- Narrowing

- Food bolus obstruction

Risk factors

-Asthma, allergy, environment-dust, dander, pollen

explain Gastritis and duodenitis and the causing factors

•Inflammation lining of stomach or duodenum

“Dyspepsia”

Imbalance in mucosal protection factors

-Stress, alcohol, drugs, H.pylori, bile

describe the basic of drug treatments

Antacids

•Calcium carbonate

“neutralise”

Raise gastric pH

Reduce pepsin activity

• Alignate/antacid

-Raft barrier

-Raise gastric pH

•H2 antagonists

The “tidines”

Cimitidine

Famotidine

• Proton pump inhibitors

-The Prazoles : Omeprazole, Lansoprazole

•Proton pump (H+/K+-ATPase) is the FINAL step in the secretion of acid in the gastric lumen from parietal cells.

-Bind irreversibly to the proton pump (H+/K+ antiporter) in parietal cell to INHIBIT acid secretion
By BLOCKING the secretion of H+ ions from the cell into the lumen

Most effective suppressors of acid secretion

outline the cause of cancer in the upper GI

Hormones and bacteria are involved in the digestive process

Imbalance in mucosal protection

environmental ( smoking, chemicals, drugs, viruses, bacteria)

Hormonal secretion

Genetic

Imbalance in mucosal protection

•Cell damage and turn over

•Inflammation and irritation

=CANCER

explain the metastatic process of cancer

Describe the Gastric and Oesophageal pre-cancerous cascade

Chronic inflammation

- sustained tissue damage

-Damage induced cell proliferation

-Tissue repair

Metaplasia: cell change from one type to another

Dysplasia: cell proliferation leading to atypical cell production

=

Cancer

describe the Oesophageal pre-malignant change in Barret’s Oesophagus and the management pathway

Barret's Oesophagus

Metaplasia

-Abnormal cell change in epithelium

-Stratified  squamous to simple columnar

- Goblet cells

management:

Acid damage (management)

Suppress (medication)

Surveillance (regular)

explain the treatment of gastric cancer

H.Pylori

- eradicate

Intestinal metaplasia “transformation”

- Cellular change- small bowel---goblet cells

- Surveillance

Atrophic gastritis

-Chronic inflammation

-loss of gastric gland cells

-replaced by intestinal type epithelium-----fibrous tissue

- Surveillance

outline the oesophageal cancer cascade, grade and metastasis

name the 3 gastric cancers and their risk factors

Adenocarcinoma

•  Signet ring cell

•  Lymphoma

• - H.pylori ( maltoma)

RISK FACTORS:

• H.Pylori

• Smoking

• Being overweight or obese

• A diet high in smoked, pickled, or salty foods

• Stomach surgery for an ulcer

• Epstein-Barr virus infection

• Genes

• Working in coal, metal, timber, or rubber industries

• Exposure to asbestos

what are the components of gastric juice?

•Hydrochloric acid

•Pepsin

•Mucin

•Intrinsic factor

what is the difference between Oxyntic and Pyloric glands?

Oxyntic glands, located in the stomach's fundus and body, secrete hydrochloric acid (HCl) and intrinsic factor from parietal cells, while pyloric glands are in the antrum and secrete the hormone gastrin from G cells to stimulate acid production. The main difference is that oxyntic glands are the primary site of gastric acid secretion, whereas pyloric glands regulate this process by producing gastrin

explain the 3 gastric stimulants and 1 gastric inhibitor of gastric secretion

•Acetylcholine (neuronal – parasympathetic) [acts on muscarinic receptors, on parietal cells]

CEPHALIC PHASE

•Histamine (ECL cell – paracrine) [paracrine messenger in the gastric mucosa, stimulates parietal cells to secrete acid]

•Gastrin (G cell – endocrine) [in the pyloric antrum, stimulates both parietal cells and ECL cells, promoting acid secretion and gastric mucosal proliferation]

IN RESPONSE TO HIGH pH – GASTRIC PHASE

•Somatostatin (D cell – endocrine)

Inhibits gastric acid secretion by acting on somatostatin receptors on parietal cells and inhibiting the release of other stimulatory molecules like gastrin. 

IN RESPONSE TO LOW pH – INTESTINAL PHASE

explain the process of gastric secretion

•Gastrin stimulates ECL cell to produce histamine

•Gastrin stimulates parietal cell to produce acid

•ACh stimulates G cell to produce gastrin

•ACh stimulates parietal cell to produce acid

•Somatostatin inhibits parietal cell acid secretion

•Somatostatin inhibits ECL cell histamine secretion

•Histamine stimulates acid secretion by acting on parietal cell via H2 receptor

•Histamine stimulates acid secretion by acting on D cell via H3 receptor to inhibit somatostatin production

Describe Hydrochloric acid concentration and pH, and its functions

Hydrochloric acid  :  160 mmol/l   pH 0.8

• Digestion (converts pepsinogen to pepsin)

• Absorption of iron, Vitamin B12, calcium

• Antimicrobial

outline the gastric cascade, stage and metastasis

what is Melena?

rapid transit of partly digested blood

why do peptic ulcers occur?

when the protective mucus lining of the stomach or small intestine is damaged, allowing stomach acid to eat away at the underlying tissue. This imbalance between damaging factors (like stomach acid and digestive enzymes) and protective mechanisms is most often caused by H. pylori bacteria or long-term use of NSAIDs.  

what’s the Stomach’s Defence Against Gastric Acid?

prostaglandin rich mucus layer

which diseases cause Peptic ulcers?

•Too much attack:

-Zollinger Ellison Syndrome= Gastrin producing tumour

-Helicobacter pylori antral gastritis

•Weakened defence:

- Non steroidal anti-inflammatory drugs

- “Stress” ulceration

- Helicobacter pylori corpus/pan gastritis

what are complications of Peptic ulcer Disease?

air in the diaphragm

anaemia (pale conjuctiva)

what type of bacteria is Helicobacter Pylori?

gram negative bacillus

what is the risk for having an ulcer in different parts of the stomach?

how can H. pylori survive in the stomach’s acidic environment?

H. pylori neutralizes its immediate acidic environment in the stomach by producing the enzyme urease, which converts urea into ammonia and carbon dioxide.

How is Helicobacter pylori detected?

•Blood test : serology for antibody

•Stool test for Helicobacter antigen in faeces

•Tests of urease activity

    Urea breath test

  Rapid Urease Test from endoscopic biopsy

•Histological biopsy

how do we reduce gastric acid secretion? (to treat H. Pylori)

H2 Receptor antagonists:

•Cimetidine (Tagamet)

•Ranitidine (Zantac)

•Famotidine (Pepcid)

Competitively and reversibly inhibit H2 receptor on parietal cell

Proton Pump Inhibitors:

•Omeprazole  (and Esomeprazole)

•Lansoprazole

•Pantoprazole

•Rabeprazole

what are the surgical procedures that are rarely used and performed only in select cases of severe, persistent peptic ulcer disease?

Vagotomy with Antrectomy: surgical procedure involving cutting the vagus nerve (vagotomy) and removing the stomach's antrum (antrectomy)

what is Proton Pump Inhibitors (PPI) mechanism of action?

Oral ingestion

Absorbed via small intestine

Uptake only when ATPase making acid

Short plasma t ½ (30-60 minutes)

MOST effective on an empty stomach

what are potential mechanism of PPI (protein pump inhibitors) adverse effects?

(1) Reduction in Gastric Acid Output

  - Reduced nutrient absorption (vitamin B12, iron, calcium)

  - Reduced gastric antimicrobial function (Community Acquired Pneumonia, Enteric infections=illness that enters the body through the GI)

(2) Increase in serum gastrin Levels (Neoplasia, Osteoporosis-Risk higher with shorter duration of therapy, Rebound acid hypersecretion-return or worsening of acid-related symptoms after stopping PPIs)

(3) Idiosyncratic (rare, unpredictable reaction in an individual that isn't a typical side effect) (Lymphocytic colitis- too high lymphocytes level in colon, Interstitial Nephritis- kidney inflammation in the spaces between kidney tubules, Hypomagnesaemia- abnormally low levels of magnesium in the blood)

(4) Interaction with metabolism of other drugs

describe peptic ulcer disease: including what they are, symptoms, the 2 main causes, treatment for the drug induced cause (drug group, drug name, length of treatment, route)

Peptic ulcer disease 

Peptic ulcer disease includes gastric or duodenal ulceration, which is a breach in the epithelium of the gastric or duodenal mucosa. 

Symptoms: The main symptom of peptic ulcer disease is upper abdominal pain but other less common symptoms include nausea, indigestion, heartburn, loss of appetite, weight loss and a bloated feeling. 

Causes: The most common causes of peptic ulcer disease are Non-steroidal anti-inflammatory (NSAIDs) drug use and Helicobacter pylori (H. pylori) infection. Smoking, alcohol consumption, and stress may also contribute to the development of peptic ulcer disease.

Treatment:

• NSAID drug use peptic ulcer disease

  1. Proton pump inhibitor OR histamine H₂ antagonists

describe Helicobacter pylori infection, including description, associated diseases, symptoms, cause and treatment (drugs groups, drug name, length of treatment, route)

Helicobacter pylori infection

Helicobacter pylori (H. pylori) infection is one of the most common causes of peptic ulcer disease, with 95% of duodenal and 70–80% of gastric ulcers associated with it. The use of NSAIDs may have an additive effect if there is co-existent H. pylori infection, further increasing the risk of peptic ulceration and bleeding. H. pylori is also associated with acute and chronic gastritis, gastric cancer, and gastric mucosa associated lymphoid tissue (MALT) lymphoma.

Symptoms: Severe indigestion that does not respond to over the counter or other medications, as well as nausea, bloating. Rare symptoms include stomach and duodenal ulcers, unintentional weight loss, vomiting blood, melaena (black, sticky poo).

Causes: many people have it, but it does not cause any problems and therefore, do not require any treatment. Coming into contact with the bodily fluids/faeces of a person that has it will however cause effects on the other people.

describe Gastro-oesophageal reflux disease (GORD), the 2 classifications, causes, symptoms and treatment (drug group, drug name, length of treatment, route)

Gastro-oesophageal reflux disease (GORD) is usually a chronic condition where there is reflux of gastric contents (particularly acid, bile, and pepsin) back into the oesophagus. GORD can be classified as:

• non-erosive when a person has symptoms of GORD but the endoscopy is normal 

• erosive oesophagitis when oesophageal inflammation and mucosal erosions are seen at endoscopy.

Symptoms: GORD causes symptoms of heartburn and acid regurgitation. Less common symptoms such as chest pain, hoarseness, cough, wheezing, asthma and dental erosions can also occur if acid reflux reaches the oropharynx and/or respiratory tract.

Causes: Consumption of trigger and fatty foods, pregnancy, hiatus hernia, family history of GORD, increased intra-gastric pressure from straining and coughing, stress, anxiety, obesity, drug side-effects, smoking and alcohol consumption.

Treatment: Proton pump inhibitor or H₂ antagonist