CASE 4 Flashcards
what are short chain fatty acids produced by in the colon?
bacterial fermentation
SCFAs enter the colonocyte via what?
SMCT1 = Na+ coupled transporter
SCFAs are sued by colonocyte for what?
intracellular metabolism
what creates an osmotic gradient for water?
electrolyte absorption
how many litres of water is absorbed a day?
8.5 L
what does the colon secrete?
K+ and HCO3-
what is reabsorbed by the colon?
Na+ and Cl-
the movement of Na+ into plasma produces an electrochemical gradient for what?
Cl- absorption
what is Cl- exchanged for?
HCO3-
Na+ channel is regulated by a steroid hormone called _______ to increase Na+ absorption in the colon
aldosterone
K+ in ileum vs LI
paracellular diffusion in ileum and mainly secretion in LI
what are the functions of the colon?
- absorption of water and electrolytes from the chyme to form solid faeces
- storage of faeces matter until it can be expelled
proximal vs distal colon function
proximal colon = mostly absorption
distal colon = mostly storage
describe the ileogastric reflex
distention of the ileum leads to decreased gastric motility
functions to open the ileocecal valve and increase movement patterns in the small intestine to make room for digested food to move out of the stomach - urge to defacate
describe the gastro-ileal reflex
increased gastric distention leads to increased ileal motility and ileocaecal valve reflexes
what is released at nerves to increase or decrease contraction?
- ACh, substance P, GRP —> depolarisation = increases contractions
- NO, VIP, opioids —> hyperpolarisation = decreases contractions
- NA —> hyperpolarisation = decreases contractions
what hormones are released to increase or decrease contractions?
- motilin —> depolarisation = increases contractions
- secretin, GIP —> hyperpolarisation = decreases contractions
- adrenaline —> hyperpolarisation = decreases contractions
what is important in inter digestive motility? what does it do?
GLP-1 — stimulates the migrating motor complex. clears the SI of any debris into the colon. has episodic release 2/3 x a day
what is the LI lined by?
- mucosa with Crytps of Lieberkuhn which contain glands and the goblet cells - these protect the intestinal wall from the plethora of anaerobic bacteria in the colon and from the pressure exerted on the walls by the concentrated chyme (soon to become faeces)
- the walls also contain GI lymphoid tissue (GALT) that contributes to the body’s immune defences
as the chyme is very concentrated by the time it reaches the colon, it must work against a __________________ than in the rest of the GIT
larger osmotic pressure gradient
what do aldosterone do?
increases the net absoprtion of water and electrolytes by stimulating the basolateral NaK ATPase, this increases the electrochemical gradient and driving force for Na+ absorption. it also increases transcription of epithelial sodium channels
what do glucocorticpids and somatostatin do?
act to increase water and electrolyte absorption by increasing the action of the basolateral NaK ATPase
what do parasympathetic and sympathetic innervation by the ENS promote?
PS - promotes net SECRETION from the intestines
S - promotes net ABSORPTION from the intestines
what is the effect of a subtotal colectomy on absorption?
—> absorption of nutrients in general is not impaired by colectomy
—> the large intestine salvages energy from malabsorbed organic matter through absorption of the short-chain fatty acids produced in bacterial fermentation
—> after a colectomy, the ability of the colon to absorb water is diminished for a period of time. eventually the remaining colon will learn to absorb the water you need
—> more sodium absorption in the jejunum — therefore also more glucose absorption as they are coupled
describe the TNM staging of colon cancer
describe Dukes’ staging for colorectal cancer
provides a 5 year prognosis
• Dukes’ A = 90% chance of survival over next 5 years
• Dukes’ B = 66% chance of survival over next 5 years
• Dukes’ C = 33% chance of survival over next 5 years
• Dukes’ D = <5% chance of survival over next 5 years
describe the number staging for colorectal cancer
- stage 0 = cancer is at its earliest stage and is only in the mucosa (Tis N0 M0)
- stage 1 = cancer has grown into the submucosa or muscle but has not spread to the lymph nodes or elsewhere (T1 N0 M0 or T2 N0 M0
- stage 2 = cancer has grown through the muscle wall or throguh the outer laeyr of the bowel, and many be growing into tissues nearby, the cancer has not spread to the lymph nodes or elsewhere (T3 N0 M0 or T4 N0 M0)
- stage 3 = tumour is any size and has spread to lymph nodes nearby. but has not spread to other parts of the body (any T N1 or N2 M0)
- stage 4 = tumour is any size. it may have spread to nearby lymph nodes, the cancer has spread to other parts of the body such as the liver or lungs (any T any N M1)
grade I vs II vs III
grade I = tumour cells resemble normal (well differentiated) and aren’t growing rapidly
grade II = tumour cells don’t look normal and are growing faster than normal cells
grade III = tumour cells look abnormal (poorly differentiated) and are proliferating rapidly
• cells that resemble ‘tissue’ tend to be well differentiated
• cells that resemble ‘stem cells’ tend to be poorly differentiated
• cancer cells are poorly differentiated which allows them to be more independent in their own growth
familial vs sporadic cancer
what are the general cancer types
- adenoma = cancer of the glands (glandular cells)
- carcinoma = epithelial cells (more than 90% of all cancers)
- lymphoma = lymphocytes or lymphatic system
- sarcoma = connective tissue
- blastoma = immature/pre-cursor cells (dendrites - wbcs)
- papilloma = surface epithelia (skin)
neoplasia means ______ and is described as ________
- new growth (tumour)
- malignant
benign vs malignant tumours
genetic abnormalities found in cancer affect what 2 general classes of genes?
- (proto) oncogenes
• gain of function
• dominant (only need 1 mutated allele to be activated) - tumour suppressor genes
• loss of function
• recessive (need 2 mutated alleles to be inactivated)
what is a proto-oncogene?
- a normal gene that may be activated into an oncogene due to mutations or increased expression
- promote cell division, survival and growth
what is an example of a proto-oncogene and what does it do?
Myc — this is a regulator gene that codes for a transcription factor. If translocated, Myc will be continually expressed, causing unregulated expression of many genes, some of which are involved in cell proliferation (eg. cyclin D1) and results in formation of cancer
what is a gene that has the potential to cause cancer called?
oncogene
name 2 oncogenes
B-catenin and KRAS
what happens when one allele of an oncogene is mutated?
there is gain of function in the protein
what do oncogenes usually code for?
- secreted growth factors (eg. EGF/Wnt/Ras)
- cell surface receptors (HER)
- signal transduction system components (ABL)
- nuclear proteins, transcription factors (eg. Myc)
- cyclins/cyclin-dependent kinases (cyclin D1, CDK4)
what are the body’s natural defence mechansim against malignancy?
tumour suppressor genes
what happens when both alleles of a TSG are mutated?
there is loss in protein function
what is the “two hit hypothesis”?
if there is a familial predisposition, then one allele has already been mutated, therefore only a second hit is required for fatal effects
- TSG
what causes inactivation of TSGs?
• mutations
• chromosomal abnormalities
• methylation of promoters
• interaction with viral proteins
is loss of TSG or activation of oncogenes worse?
loss of TSG
what are 5 functions of TSGs?
- inhibit progression through cell cycle (CDKIs = p21)
- promote apoptosis (eg. p53 and APC)
- inhibit cell growth (anti-proliferative)
- DNA repair and genomic stability (mismatch DNA repair genes (replication error genes) and BRCA1 gene)
- cell adhesion to prevent metastasis
what is metastasis?
the development of secondary malignant growths at a distance to the primary site of cancer
marks a tumour as malignant because benign neoplasms do not metastasise
all cancers metastase except what?
- glial cells of the CNS - these usually form benign tumours
- basal cell carcinomas of the skin
cancer spreads by what 3 pathways?
- direct seeding of body cavities or surfaces (local invasion or surrounding tissue)
- lymphatic spread
- hematogenous spread (blood)
colon cancer is usually what type of cancer?
adenocarcinoma
most colon cancers are sporadic, but what severe rare familial diseases are there?
FAP (1%) and HNPCC (lynch syndrome = 2/3%)
epidemiology of colon cancer
• causes 10% of all cancer deaths
• 13% of all cancer cases
• over 40,000 cases a year, over 16,000 deaths
• 3rd most common cancer and 2nd most common cause of Uk cancer deaths
• 56% of presentations are over 70 years old
• more common in white people than asian or black
• most common site is the rectum
what are the locations of colon cancer?
• 15% caecum and ascending colon
• 10% transverse colon
• 5% descending colon
• 25% sigmoid colon
• 45% rectum
what are risk factors for colon cancer?
• diet — high in red meats and processed meats —contain high levels of N-nitros compounds (NOCs) which are carcinogenic
• lack of physical activity and obesity
• smoking
• heavy use of alcohol
• age >50
• family history - neoplastic adenomatous polyps, colorectal cancer
• inherited diseases - Familial Adenomatous Polyposis (FAP), Hereditary Non-Polyposis Colon Cancer (HNPCC)
• history of inflammatory bowel disease (IBD) (eg. chron’s disease, ulcerative colitis)
• hormonal factors - late age at first pregnancy, early menopause, nulliparity
• diabetes mellitus
right colon cancer presentation
right = disorder with absorption
weight loss, anaemia, occult bleeding, mass in right iliac fossa, disease more likely to be advanced at presentation.
left colon cancer presentation
left = disorder with storage
often colicky pain, rectal bleeding, bowel obstruction, tenesmus, mass in left iliac fossa, early change in bowel habit, less advanced disease at presentation.
what are the most common presenting symptoms and signs of cancer or large polyps?
rectal bleeding, persisting change in bowel habit and anaemia
what do jaundice and hepatomegaly indicate?
advanced disease with extensive liver metastases
(peritoneal metastases with ascites are often also present)
colon cancer spread to liver symptoms
fatigue, jaundice, swelling in the extremities, nausea or abdominal bloating
colon cancer spread to lungs symptoms
SOB, difficulty breathing, chest pain or a persistent cough
colon cancer spread to brain symptoms
headaches, confusion, memory loss or blurred vision
colon cancer spread to lymph nodes in abdominal area symptoms
abdominal bloating and swelling as well as a reduced appetite
colon cancer spread to peritoneum symptoms
abdominal pain, bloating, a constant feeling of fullness, weight gain or loss or nausea
what would a FBC show in colon cancer?
low serum levels (microcytic anaemia)
why would you check for calcium in cancer?
check for metastatic hypercalcaemia (bone metastasis)
liver function tests in cancer
• bilirubin — colorectal cancer liver metastasis causes severe hyper bilirubin anemia
• alkaline phosphatase ALP — ALP levels elevated with liver metastasis of colorectal cancer
what are creatinine levels like in kidney metastasis of colorectal cancer?
elevated
ferritin levels in iron deficiency anaemia?
low
what is c reactive protein and levels in cancer?
protein made by the liver. CRP levels increase when there is inflammation in the body. higher than normal levels seen in cancer
what is ESR? when are there high levels?
= erythrocyte sedimentation rate - measures how long it takes RBCs to fall to the bottom of a test tube, the quicker they fall the more likely it is there are high levels of INFLAMMATION (cells clump together so are heavier so fall faster)
what does low K+ reflect?
fluid loss in stool
when do you get elevated ferritin?
when in a pro inflammatory state (also get elevated CRP)
can get anaemia with high ferritin - would worry about cancer
describe a FIT test
• faecal-immunochemical-test
• tests for blood in faeces
• can detect very small amounts of blood
• designed to identify possible signs of bowel disease
• patients with a positive FIT result are referred for further investigation by colonoscopy
describe the bristol stool chart
a lower GI endoscopy consists of what 2 types?
- sigmoidoscopy
- colonoscopy
both of these allow the doctor to view the mucosal lining of the lower GIT
indications for lower GI endoscopy
screening, abdominal pain, rectal bleeding, change in bowel habits
what can a lower GI endoscopy detect?
inflammation, infections, ulcerationsl, diverticulosis, intestinal narrowing, colorectal polyps, cancer
what happens before a colonoscopy procedure?
IV pain medication and sedative, blood pressure/pulse/O2 monitored, supplemental oxygen — a sigmoidoscopy doesn’t require this much preparation
why might a biopsy be taken?
distinguish between benign and malignant tissue, identify the cause of bleeding, inflammation, diarrhoea
describe a barium enema
• test used to identify problems in the colon, such as polyps, inflammation (colitis), narrowing of the colon, tumours etc
• a thick liquid (containing barium) is placed in the lower gut via the rectum
• this coats the mucosal lining of the colon, thus highlighting the colon in an x-ray
what sign on barium enema does colon cancer give?
apple core sign
what is a coffee bean sign a classic radio graphic finding of?
sigmoid volvulus
colorectal cancer treatment surgery, radiotherapy, chemotherapy summary
what is fluorouracil (5-FU)?
• it is a pyrimidine analog that is an antineoplastic antimetabolite
• an antimetabolite prevents purine/pyrimidine (eg. thymine) from incorporating into the DNA during the S phase, stopping normal development and division
• it blocks the enzyme that converts cytosine nucleotide into the deoxy derivative
• it inhibits the incorporation of thymidine (a pyrimidine) nucleotide into the DNA strand
side effects of 5-FU
diarrhoea, nausea and vomiting, stomatitis (inflamed or sore mouth)
what is folinic acid?
OxMdG aka leucovorin
• generally administered as calcium or sodium folinate (or leucovorin calcium/sodium)
• it is an adjuvant used in cancer chemotherapy involving the drug methotrexate
• also used uni synergistic combination with chemotherapy agent 5-FU
• can be taken as a pill or injected into a vein or muscle
indications of folinic acid
used to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosages of folic acid antagonists, and to treat megaloblastic anaemias due to folic acid deficiency. also used in combination with 5-FU to prolong survival in the palliative treatment of patients with advanced colorectal cancer. it enhances the effect of 5-FU by inhibiting thymidylate synthase
folinic acid:
a medication used to decrease the toxic effects of methotrexate and pyrimethamine. It is also used in combination with ____________ to treat _________ cancer and ________ cancer, may be used to treat _________ deficiency that results in _________, and methanol poisoning
a medication used to decrease the toxic effects of methotrexate and pyrimethamine.[ It is also used in combination with 5-fluorouracil to treat colorectal cancer and pancreatic cancer, may be used to treat folate deficiency that results in anemia, and methanol poisoning
as ___________ is a derivative of folic acid, it can be used to increase levels of folic acid under conditions favouring folic acid inhibiton (following treatment of folic acid antagonists such as methotrexate)
leucovorin
how does leucovorin enhance the activity of 5-FU?
by stabilising the bond of the active metabolite (5-FdUMP) to the enzyme thymidylate synthetase
this is because 5-FU doesn’t stay long in the system and so folinic acid allows 5-FU to bind to this enzyme
describe oxaliplatin
• platinum-based chemotherapy drug
• typically administer in combination with fluorouracil and leucovorin for treatment of colorectal cancer
• selectively inhibits the synthesis of DNA
• after activation, oxaliplatin binds preferentially to the guanine and cytosine moieties of DNA, leading to cross-linking of DNA, thus inhibiting DNA synthesis and transcription.
what are colonic crypts the site of?
stem cells
> if the mutation occurs in the ___________________, then the development of tissue isn’t so harmful
if mutation occurs in the _______ (the site of colon stem cells), then the development of tissue is very harmful (polyps)
- differentiated villi/epithelial cells
- crypts
all colon cancers have either a mutation in _____ or ______ — 80/90% of CRCs have ____ mutation, 10/20% have _______ mutations
- APC or B-catenin
- APC
- B-catenin
what is an obligate step in becoming a colon cancer?
deregulation of Wnt signalling — get upregulation of cyclin D which drives proliferation even in absence of signals
what is citalopram and how does it affect the heart?
= selective serotonin reuptake inhibitor
effect on heart : can cause dose-dependent QT interval (heart relaxation phase) prolongation, which can cause Torsades de Pointes, ventricular tachycardia, and sudden death
what else can increase the QT phase?
hypokalaemia and antiemetics
what is a polyp?
a projecting growth of tissue from a surface in the body, usually a mucous membrane. can develop in the colon, rectum, ear canal, cervix
—> bowel polyps are small growths on the inner lining of the colon or rectum. they are common, affecting 15-20% of the UK population, and dont usualy cause symptoms
—> some polyps if left untreated will develop into cancer
symptoms of polyps?
rectal bleeding, abdominal pain, diarrhoea or constipation, unexplained iron deficiency anaemia or weight loss, change in bowel movements
what are haemorrhoids?
aka piles
• when veins beneath the mucous membranes lining the lowest part of the rectum and anus become swollen and distended (= swelling and inflammation of the veins in the rectum and anus)
• the most common cause of rectal bleeding — blood will be bright red
• associated with constipation and pregnancy
internal vs external haemorrhoids
internal:
• typically painless as there are no pain receptors in this area
external:
• painful and typically covered with skin
• form at the anal opening
• especially painful if they develop thrombosis
• many thrombus and flare up again. thrombosis usually resolves over a period of weeks and the haemorrhoid will shrink down adn size and then generally be less troublesome
read toxicity bear
ok
2 common chemo symptoms
- immunosuppressive — neutropenic sepsis
- tumour lysis syndrome
