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Suzie Rayner

Alimentary System 6.1 – Jaundice Understand the production and excretion of bilirubin Why do we produce bile? Cholesterol homeostasais Dietary lipid and vitamin absorption Removal of drugs/pollutant/endogenous waste products

Bile production: • 5-600ml produced/secreted daily • Golden-yellow colour – glucoronides of bile pigments • 60% of bile secreted by hepatocytes (liver cells) • >40% secreted by cholangiocytes (biliary epithelial cells) • Liver → bile ducts → GI tract • Other substances excreted into bile: adrenocortical and other steroid hormones, drugs, cholesterol, ALP – therefore cholesterol and ALP are increased in obstruction [Note: cholangiocytes also contribute IgA by exocytosis] Role of biliary tree: • 40% of bile secreted by cholangiocytes (biliary epithelium) • Alterations in pH, fluidity and modifies bile as bile flows through biliary tree • H2O drawn into bile (osmosis through paracellular junctions) • HCO3- and Cl- actively secreted into bile by CFTR mechanism (Cystic fibrosis transmembrane regulator)

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Suzie Rayner

Regulation of bile flow and secretion: • Between meals, duodenal orifice closed therefore bile → gall bladder for storage • Gastric contents enters duodenum causing release of CCK – GI mucosal hormone • CCK causes gall bladder contraction and sphincter of Oddi (hepatopancreatic sphincter) relaxation Enterohepatic circulation of bile: • 95% bile is reabsorbed from terminal ileum Mechanisms of reabsorption: o Na+/bile salt co-transporter using Na+/K+ ATPase system o 5% converted to secondary bile acids in colon – deoxycholate absorbed, lithocholate 99% excreted in stool • Absorbed bile salts return to liver via portal vein, re-excreted in bile • Faecal loss 10-20% per day (multiple cycle occurring) Circulation: • Uptake by hepatocyte • Excretion into canaliculus • Bile into GI tract • Reabsorption in terminal Ileum • Transported out of enterocytes • Retuned by portal blood to liver [Some drugs may be conjugated in bile, thus recirculated, prolonging action] Recirculation of bile salt: 3.5g bile salt pool re-cycles If Terminal ileal resection/disease: Decrease in bile salt reabsorption Increase in stool fat Enterohepatic circulation interrupted, liver cannot adequately compensate If bile is stopped from entering GIT: Up to 50% ingested fat appears in faeces – steatorrhoea

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Suzie Rayner malabsorption of fat soluble vitamins. Functions of GALL BLADDER: Store bile (up to 50ml) – release after meal to digest fat Acidify bile (relative) Concentrated bile, H2O diffusion following net absorption of Na+, Cl-, Ca2+, HCO3Gall bladder can reduce volume of stored bile by 80-90% [Gallbladder bile has more bile salts and lower pH than hepatic duct bile] If gall bladder is removed (Cholecystectomy): Periodic discharge of bile aids digestion but is not essential Normal health and nutrition exists with continuous slow bile discharge into duodenum. Avoid high fat content foods Describe the features of pre-hepatic, hepatic and post-hepatic jaundice Give two examples of each of these types of jaundice Describe the pathogenesis of the symptoms and signs associated with jaundice Bilirubin: • Insoluble in water • Yellow pigment • 75% from mature red cell breakdown • 22% from catabolism of other haem proteins • 3% from ineffective bone marrow erythropoiesis Unconjugated bilirubin is transported to the liver bound to albumin. Bilirubin (BR) reaches hepatic cell bound to albumin Conjugated BR dissociates in liver Free BR enters hepatocyte Binds to cytoplasmic proteins Conjugated Conjugated BR is water soluble therefore moves into bile → GIT [Total BR = Free BR + Conjugated BR]

Urobilinogens: Water soluble Colourless Derivatives of BR formed by action of GIT bacteria GIT mucosa is relatively impermeable to conjugated BR, but is permeable to unconjugated BR and urobilinogens.

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Suzie Rayner Therefore some unconjugated BR enter enterohepatic circulation, and some form urobilinogens. • 20% urobilinogens reabsorbed in portal vein, excreted in urine • Some urobilinogens passed into stool (as stercobilinogen) It is the oxidation of Stercobilinogen that gives faeces it’s brown colour. Jaundice: Excess bilirubin in blood (34-50μM/L) Yellow tinge to sclera, skin, mucous membranes Makes skin itch Gall stones: Prevalence increases with age 3 types: Cholesterol (80%) – White Calcium bilirubinate (15%) – Black Brown pigment stones (<5%) – can be within bile ducts of gall bladder, caused by stasis and infection of biliary system (e.g. E. coli, soluble conjugated BR converted → insoluble unconjugated) Aetiology of gall stones • Bile stasis – stones form in bile sequestered in gall bladder > bile flowing in ducts • Supersaturation of bile with cholesterol > capacity of bile salts and lecithin • Other ‘nucleation factors’ o Out of body, bile from gallstone patients form stones in 2 days o Bile from normals form stones in 2 weeks Liver function tests: Hepatocellular: AST ALT (alanine transaminase)

also present in heart/muscle/brain more specific to liver

Cholestatic ALP (alkaline phosphatase)

GGT (γ-glutamyl transferase)

canalicular and sinusoidal membranes Also in bone, intestine and placenta Microsomal enzyme Not exclusive to the liver

Liver synthetic function: • Albumin • Bilirubin • Clotting -INR 4


Suzie Rayner

Bilirubin level Alanine transaminase (ALT) Alkaline phosphatase (ALP) GGP Causes: Pre-hepatic

Pre-hepatic

Hepatic

High Normal

High Very High

Post-hepatic (Cholestatic) High Normal/High

Normal

Normal/High

High

Normal

Normal/High

Very High

Hepatic

Inherited disorders of bilirubin metabolism: Crigler-Najjar

Hepatitis due to:

Gilbert’s

Autoimmune

Rotor

Drugs

Dubin-Johnson

Alcohol

Haemolysis

Metabolic liver disease

Viral

Post-hepatic (Cholestatic) Intrahep cholestasis secondary to drugs or virus Primary sclerosing cholangitis (inflammation of bile ducts Primary biliary cirrhosis Gallstones in common biliary duct Cholangiocarcinoma Carcinome in head of pancreas Carcinoma ampulla (union of pancreatic duct and common bile duct)

Summary: Pre-hepatic: Haemolyic jaundice/anaemia (inherited, immune, drugs, infections) Congenital hyperbilirubinaemia: • Gilbert’s – reduced glucuronosyltransferase action • Crigler-Najjar o Type II, decreased UDP glucuronyl transferase o Type I, absent UDP GT • Dubin-Johnson and Rotor – defects in bilirubin handling in the liver Clinical History of Jaundice: Question

Cause related: 5


Suzie Rayner Weightloss (in older patient) Country of Origin? Outbreak? Intravenous drug use Alcohol consumption Fevers/rigor Drugs – prescribed, over the counter, illicit Travel Occupation Family history

Malignancy Hepatitis B Hepatitis A Hepatitis B/C Cholangitis/liver abscess Prevalent Hepatitis A Sewage workers-leptospirosis Gilbert’s disease

Investigations: Blood tests: • Full blood count, liver function test, urea and electrolytes, International normalized ratio • Viral hepatitis serology • Ferritin/Iron studies/Copper/Caeruloplasmin • Liver antibodies/ α1 – antitrypsin (elastase inhibitor) • α fetoprotein Imaging: • Ultrasound • CT/MRI/MRCP _______________________________________________________________________ _

Alimentary System 6.2 – Liver Failure •

Define Liver Failure and its main types

Liver failure: Insufficient hepatocyte function to maintain homeostasis. Characterised by: • Rate of onset • Cause • Clinical features Summary of liver functions (mentioned previously): • Excretion: bilirubin, cholesterol, hormones, drugs • Enzyme activation • Storage: glycogen, vitamins, regulation of glucose levels • Synthesis: bile,plasma proteins (e.g. albumin, clotting factors) • Detoxification • Immune regulation •

Understand the important underlying pathophysiology

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Suzie Rayner

Pathophysiology of liver failure: • Centrilobular necrosis of hepatocytes • Activation of macrophages • Release of cytokines – TNF, Il-1, Il-6 •

Name important causes of acute and chronic liver failure

Causes: • Acute vs Chronic • Chronic liver failure – can complicate virtually all forms of chronic liver disease Acute liver failure: Classification: • Develops in previously normal liver • Subdivided according to interval between the onset of jaundice and encephalopathy Type Interval between onsets Hyperacute <7 days between Acute 1-4 weeks Subacute 5-12 weeks Causes of acute liver failure: • Infection: Herpes simplex virus, Epstein-Barr virus, varicella • Durgs: Isoniazid, Ecstasy, Halothane • Metabolic: Wilson’s, Reye’s • Vascular: Budd-Chiari, ischaemic • Other: fatty liver of pregnancy, lymphoma, amanita phalloides •

Know the clinical features and complications of liver failure

Clinical features of acute liver failure: • Hepatic encephalopathy • Cerebral oedema • Coagulopathy • Metabolic o Decrease glucose o Decrease potassium o Decrease sodium o Metabolic acidosis • Infection Hepatic encephalopathy: • Reversible neuropsychiatric state from o Hepatocellular dysfunction

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Suzie Rayner

o Portal-systemic shunting (block in portal veins, blood shunts into systemic) Brain is exposed to increased levels of ammonia and neurotransmitters

Clinical grading of hepatic encephalopathy: Grade 1 2 3 4

Appearance Confused Drowsy Sleeping but can be roused Coma, unrouseable

Test for hepatic encephalopathy using number connection test. Cerebral oedema: • Cause of death in 30-50% of patients with acute liver failure • Present in 80% of people with grade 4 hepatic encephalopathy • Blood supply to brain is balanced by carotid artery pressure vs intracerebral pressure • Disruption to blood brain barrier and increased osmosis into the brain Coagulopathy: • Liver synthesises all coagulation factors (except factor 8) • Platelet count falls and platelets become dysfunctional • Bleeding in mucous membranes, GI tract, brain • Measure prothrombin time to test clotting speed, therefore find lack of clotting factors Metabolic factors: • Hypoglycaemia – high insulin, low liver uptake • Decrease in gluconeogenesis • Decrease potassium, increase urinary loss of potassium • Decrease sodium • Metabolic acidosis [normally, liver has capacity to metabolise many organic acid anions, regenerating bicarbonate in liver. Therefore, less bicarbonate to counter act H+] Infection: • Common in both acute and chronic liver failure • Poor host defence due to: o Kupffer cell and polymorph dysfunction o Reduced conscious state • Increased access for infection o Endotracheal tubes o Lines o Catheters o Ascites (peritoneal fluid) • Bacterial and fungal 8


Suzie Rayner

Budd Chiari syndrome: • Obstruction of hepatic veins at any site from lobule to entry of IVC to right atrium • Presents with abdominal pain, hepatomegaly, ascites • Histology – sinusoidal distension • Causes are o Thrombophillia o Webs o Veno-occlusive disease Wilson’s disease: • Autosomal recessive – 1:30000 • Copper accumulation in liver, basal ganglia, cornea • Presents with acute or chronic liver disease • Treatment is penicillamine – copper chelator • Kayser-Fleischer ring: Copper coloured ring in periphery of cornea.

Acute fatty liver of pregnancy: • 1:1000 incidence in UK • Some: inherited defects of fatty acid oxidation 9


Suzie Rayner • • •

Presents in 3rd trimester – right upper quadrant pain, vomiting Later: Jaundice, encephalopathy, ascites, bleeding Treatment: urgent delivery, supportive

Chronic liver disease: Causes: • Alcoholic liver disease • Chronic viral hepatitis (C, B) • Autoimmune chronic active hepatitis • Primary biliary cirrhosis • Primary sclerosing cholangitis • Haemochromatosis • Non alcoholic fatty liver disease

Features of chronic liver failure: Portal hypertension: • Portal venous system o Blood from abdominal alimentary tract to liver o Normal pressure 7mmHg • Portal hypertension o Collaterals develop o Portal systemic shunting – encephalopathy, septicaemia, impaired liver regeneration [Portal vein made up from superior mesenteric vein, inferior mesenteric vein, splenic vein, left gastric vein]

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Suzie Rayner Oesophageal varices: • Supplied by L gastric vein, drain into azygos system • Deviation of blood into these channels lead to varicosities in lower end of oesophagus • Bleeding → hematemesis, melaena, encephalopathy Ascites: • Extracellular fluid within the peritoneal cavity o Sodium retention o Portal hypertension o Hypoalbuminaemia • Complications: o Spontaneous bacterial peritonitis o Renal failure o Encephalopathy Renal failure: • Acute tubular necrosis – acute liver failure • Hepatorenal syndrome (‘functional renal failure’) – chronic liver failure o Renal vasoconstriction o Decrease in renal prostaglandins o Sepsis o Bleeding, hypotension •

Be aware of possible treatments for liver failure

Treatments for liver failure: • Underlying cause • Supportive o Prevent/control bleeding o Prevent/control infection o Nutrition o Early renal support o Recognise/manage raised intracranial pressure • Transplantation o Done for grades 3/4 encephalopathy, chronic liver failure (Child-Pugh grade C) o 12 month survival (60% acute, 90% chronic) • Artificial liver support o Attractive option due to scarcity of organ, delay in transplantation o Potential for full recovery For artificial liver support system must: • Replace necessary functions – synthetic, eliminatory, metabolic

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Suzie Rayner •

Counter adverse effects of necrotic liver

2 artificial liver support systems: Biological: • Live hepatocytes from human or animal • Immortal cell lines Non-biological: • Blood purification – adsorption and dialysis techniques Or auxillary liver transplant – placed adjacent to native liver. _______________________________________________________________________ _

Alimentary system 7.1 – Introduction to nutrition – malnutrition •

To demonstrate a basic understanding of the role of nutrition in health and disease.

Main function of gut to act as a barrier that allows the movement of nutrients across it Highly adapted for this function Most nutrients are efficiently absorbed in the small bowel States of malabsorption have disastrous effects on function

• • •

Malnutrition: Undernutrition (27% prevalence) – inadequate consumption, poor absorption, excessive loss of nutrients Overnutrition (27% prevalence) – overeating, excessive intake of specific nutrients Epidemiology: • 1/3 global population love below recommended nutritional needs (1200kcal) • Half of western society is overweight, 20% are obese o T2DM o 30-40% CVD o Large risk factor for cancers • Many common chronic western diseases are related to nutrition Causes of undernutrition: Developing world Politics Climate Poor water

Developed world Age Change in social circumstance (isolation, death of partner, poor housing) Illness

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Suzie Rayner Poor agricultural policy Demands of developed world Signs of undernutrition: • Weightloss • Loss of subcutaneous • Muscle wasting • Peripheral oedema • Glossitis, cracking edges of mouth • Hair loss • Chronic infections • Poor wound healing, chronic wounds, pressure sores • Listless, apathetic • Recurrent pulmonary infections Starvation: • Ketones begin to supply brain as free amino acids decline • Body begins energy conservation measures • Little gluconeogenesis occurs from protein catabolism [Note RMR = resting metabolic rate, FFM = fat free mass]

Weight (% losses with fasting):

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Suzie Rayner Organ Brain Liver Gut Muscle Rest Fat Fat free mass â&#x20AC;&#x201C; 55kg Body â&#x20AC;&#x201C; 70kg

Short fast No change 33% loss 33% loss 5% loss No change 5% loss 52.1 66.4

Long fast No change 33% loss 33% loss 50% loss No change 50% loss 39.5 47.0

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Suzie Rayner Maslow’s hierarchy of needs: To human potential is to be fulfilled there are a number of basic needs to be met: • Biological/Physiological • Security/Safety • Social needs • Ego • Self fulfillment Basic needs are oxygen, food, water and shelter. Dietary reference values: • Reflect the nutritional needs of a population and way of assessing nutritional adequacy • Need to know the amount of each nutrient required • These vary between individuals and life stages Estimated average requirement is: • Intake need to maintain circulating level or tissue concentration • Intake associated to absence of disease • Intake needed to maintain balance • Intake needed to cure sign of deficiency • Intake associated with n appropriate biochemical marker of adequacy [Reference nutrient intake: 2.5 standard deviation above estimated average requirement] [Lower reference nutrient intake: 2.5 standard deviation below EAR] Reference nutrition intake Estimated average requirements Lower reference nutrient intake

Body composition will dictate: • Energy expenditure • Response to disease • Risk to many chronic diseases • Sporting ability Growth: • From baby to adult, increase weight x 20 • Weight gain enters body as food and drink • Grossly abnormal diets cause change in body weight, configuration and composition

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Suzie Rayner

Ageing affects on the body: • Decrease in body size • Increase in body fat • Decrease in liver mass, kidney mass, muscle mass • Decrease in total body water • Effects drug dosage and toxicity These effects of ageing are made worse by the effects of illness and institutionalization. • Muscle and fat mass drop → downwards spiral to malnutrition •

To demonstrate a basic understanding of the role of the gastrointestinal track in maintaining nutritional status

Regulation of feeding: Leptin, Ghrelin, PYY3-36 → hypothalamus Region Stomach Pancreas Duodenum Jejunum, Ileum Ascending colon [More detail in 8.1] •

Hormone Ghrelin, Gastrin Pancreatic polypeptide CCK, secretin GIP, Motilin, GLP1, GLP2, oxyntomodulin, neurotensin, PYY GLP1, Oxyntomodulin, PYY

To have a basic understanding of the role of the macro-nutrients in health and disease

Macro-nutrient balance: Intake – expenditure = store [Alcohol, Carbohydrate, Protein, Fat] The auto-regulation of alcohol, carbohydrate and protein adjusts the oxidation of intake. HOWEVER, oxidation hierarchy leads to fat sparing. _______________________________________________________________________

Alimentary system 7.2 – Introduction to nutrition – Obesity •

To describe principles of energy balance

Energy: If nutrients are to be used effectively, the bodies demand for energy must be met.

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Suzie Rayner

Energy expenditure: • Heat produced and work on environment • Adaptive thermogenesis • Physical activity • Resting energy expenditure (energy used for life processes)

Laws of thermodynamics in humans: energy in = energy out + energy stored Weight gain – energy in > energy out • Increased intake • Decreased expenditure • Decreased metabolic rate Typical western diet contains too much fat. Summary of energy metabolism:

Fates of acetyl CoA:

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Suzie Rayner • • • • •

TCA (Kreb’s cycle) Fatty acid production Ketone bodies Amino acid Pyruvate

To describe methods of assessment of energy stores and risks

Stored as: Glycogen – liver, muscle Adipose tissue – main store Muscle – only after prolonged starvation To assess body mass, can be done multiple ways: • BMI = weight (kg) /height2 (m) o Clinically relevant way of measuring adipose tissue <20 Underweight 20-25 Desirable weight 26-30 Overweight 31-40 Obese >40 Morbidly obese •

Waist to hip ratio (android, gynoid)

[Obesity can be defined by weight, in terms of mortality and morbidity, BMI] Metabolic syndrome is characterised by a group of characteristic metabolic factors in one person: • Waist circumference (Men >102, women >88) • Microalbuminuria • Insulin resistance • Hypertension – BP >135/80 • HDL (Men<1, Women<1.3)

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Suzie Rayner •

Fasting glucose >6.0mmol/l

To understand mechanisms of obesity

• • • •

Multifactorial Genes Environment Society

Causes: • Energy intake o Diet composition, little ability to store protein and CHO. o Auto regulation following fat ingestion is poor. • Energy usage o Sedentary lifestyle • Genes o Most not monogenic o Amount and site of weight gain is in part genetic o Genome wide search for T2DM – identified common variant in FTO gene • Brain • Endocrinology o Important physiological role in postprandial satiety and represent therapeutic targets • Behaviour • Culture o Individual behaviour and societal changes have contributed to obesity

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Suzie Rayner •

To describe complication of obesity

• •

Morbidity Mortality

• • •

To understand the basics of obesity management Follow evidence base Lifestyle diet and exercise o Conventional weight management tends to fail over long term due to people stopping intervention. o Diet and exercise combined have overall largest affect Pharmacological o Treatment and prevention suboptimal o Weight loss is most successful when lifestyle measures combined with pharmacotherapy Surgical

Area acted on Gut

Action of drug Reduce fat absorption

Hypothalamus

Central satiety

Adipose and Hypothalamus

Central fat loss and Central satiety

Muscle

Β 3 thermogenesis

Drug Orlistat GI lipase inhibitor Sibutramine Re-uptake NA Rimonabant CB1 antagonist Sibutramine Re-uptake NA

Loss of weight causes: • 20% reduction in mortality • 40% reduced risk of DM 20


Suzie Rayner • • • •

Decrease in LDL Increase in HDL Decrease BP Decreased HbA1c

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Alimentary system 8.1 – Regulation of function: enteric nervous system and gut hormones •

Describe the major features of the enteric nervous system

Summary: Nervous stimulation: neurotransmitters released from neurones innervate target cells Paracrine: hormones released by cells within the vicinity of target cell, reach target cell by diffusion Endocrine: hormones produced by endocrine cells, released into the blood where they reach target cells via circulation Sensory neuron: Respond to mechanical, thermal, osmotic and chemical stimuli Motor neuron: Axons terminate on smooth muscle cells of circular or longitudinal layers, secretory cells of GI tract or GI blood vessels Interneurons: Neurons between neuron (in CNS), integrate sensory input and effector output Alimentary system is regulated by: • Nervous system: o Intrinsic (enteric) o Extrinsic (autonomic) • Paracrine • Endocrine Enteric nervous system: • Wall of GI tract contains many neurons (2nd only to CNS) • Rich plexus of ganglia (nerve and glial cells) interconnected by tracts of fine, unmyelinated nerve fibres. • Integrates motor and sensory activity • Can function independently of central control [if symp. and parasymp. nerves are cut to gut, many activities still continue as controlled by enteric] Enteric NS regulates: • Motility • Blood flow

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Suzie Rayner • • •

Waterand electrolyte transport Secretion Absorption

Enteric neural dysfunction/degeneration: • Inflammation (Crohn’s disease, ulcerative colitis) • Post-operative injury • Irritable bowel syndrome • Ageing (constipation) Summary of nerves in GI: • Submucosal plexus: o In submucosal layer o Sensing environment within lumen o Gut secretions, gut epithelial and endocrine cell function, blood flow • Myenteric plexus (Auerbach’s plexus) : o Between circular and longitudinal muscle layers in muscularis o Controls activity of muscularis externa o Mainly controls gut motor function (peristalsis during feeding and migrating myoelectric complex during fasting) • Minor plexuses: o Including deep musclular plexus (inside circular muscle) and ganglia supplying biliary system and pancreas Intrinsic nervous system (Autonomic): [Repeated from neuro] • Regulates smooth muscle, cardiac muscle and glands • Not accessible to voluntary control • Sympathetic and parasympathetic Sympathetic: • Nerves from T1 – L2/L3 • Cell bodies of pre-ganglionic neurones in the thoracic and lumbar spinal cord • Cell bodies of post-ganglionic neurons in the pre-vertebral and para-vertebral ganglia (paravertebral chains) • Splanchnic nerves carry postganglionic fibres to viscera • Noradrenaline • Inhibit motor and sensory of GI tract • Majority of sympathetic fibres do not directly innervate structures in the GI tract – terminate on neurons in intramural plexuses • HOWEVER, vasoconstrictor sympathetic fibres directly innervate the blood vessels of the GI tract – celiac, superior and inferior mesenteric. • Long post ganglionic fibred to inhibit gut motility and secretion, cause constriction of blood vessels and sphincters. Parasympathetic: 22


Suzie Rayner • • • • • • • • • • • •

Cranio-sacral origin (Cranial nerves 3,7,9,10, and S2-4) Cell bodies of pre-ganglionic neurons in the brainstem and sacral spinal cord Cell bodies of postganglionic neurons close to target organs Preganglionic neurons synapse on ganglia close to gut wall or directly with enteric plexi Acetylcholine Most of GI tract innervated by branches of vagus nerve (down to transverse colon) Rest of colon, rectum and anus stimulates by parasympathetic fibres from pelvic nerves Parasympathetic fibres are preganglionic and predominantly cholinergic Terminate predominately on ganglion cells in the intramural plexuses Excitation usually stimulates the motor and secretory activities of GI tract Short postganglionic neurones to promotes gut motility, secretion, digestion Explain how the autonomic nervous system and the enteric nervous system interact

Summary of nervous systems affecting GI tract:

GI tract innervation - complexity allows fine control of the GI tract: Intrinsic: • Neurons of the enteric NS Extrinsic: • Afferents (pain, nausea, fullness) • Efferents (co-ordination – symp and parasymp NS)

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Suzie Rayner

Describe how gut hormones control GI function

Produced by endocrine cells in mucosa or submucosa of stomach, intestine and pancreas Hormones act on secretory cells located in the wall of the GI tract, pancreas and liver – alter rate or composition their secretions Other hormones act on smooth muscle cells in particular segments of the GI tract and GI sphincters or on musculature of gall bladder. Can act as Paracrine or neurocrine factors.

• • •

Function of GI endocrine system: • Regulated mechanical processes of digestion • Regulation of chemical and enzymatic processes of digestion • Control of post absorptive processes involved in the absorbing digested food and CNS feedback regulated intake • Effects on growth and development of GI tract Paracrine example: • Histamine released from stomach cell wall, stimulated parietal cells to secrete HCl • Secretin can inhibit acid secretion, stimulate pancreatic bicarbonate secretion Endocrine examples: [Mentioned in previous lecture in less detail] Region Hormone Stomach • Ghrelin • Gastrin • Histamine • Somatostatin Pancreas • Pancreatic polypeptide • Insulin • Glucagon • Somatostatin Duodenum • CCK • Secretin • Somatostatin Jejunum, Ileum • GIP (gastric inhibitory peptide) • Motilin • GLP1 • GLP2 • Oxyntomodulin

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Suzie Rayner • • • • • • • •

Ascending colon

Hormones in more detail: Hormone Synthesised/ Secreted from Gastrin Synthesised in gastric antrum and upper small intestine

Somatostatin

Secretin

CCK

Synthesised in endocrine D cells of gastric and duodenal mucosa, pancreas (and hypothalamus)

Secreted by S cells of upper duodenum and jejunum

Secreted by cells most densely located in small intestine

Neurotensin PYY Somatostatin GLP1 Oxyntomodulin PYY Neurotensin Somatostatin

Stimulated by

Action

Stimulates release of HCl from gastric parietal cells

Amino acid and proteins in stomach • Gastric distension • Vagus nerve Inhibited when pH<3 Released in response to mixed meal

Presence of acid in duodenum (pH<4.5)

Fat and peptides in upper small intestine

Universal inhibitor: • Gastric secretion • Motility • Intestinal and pancreatic secretions • Release of gut hormones • Intestinal nutrient • Electrolyte transport • Growth and proliferation Analogues used to treat neuroendocrine tumours Stimulates pancreatic bicarbonate secretion High conc. causes inhibition of gastric acid and gastric emptying Stimulates pancreatic enzyme release, gallbladder contraction

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Suzie Rayner

Independent of vagus GIP

Secreted by mucosal K cells – predominantly in duodenum and jejunum

Following a mixed meal Fat more potent stimulus than CHO

Neurotensin

Released from N cells Fat is most potent in ileal mucosa (smaller amounts in duodenum and jejunum)

PYY

Cells found through mucosa of ileum, colon, rectum

Fat, meal

Released from L cells post meal

Delays gastric emptying Decreases food intake and meal size Stimulates insulin secretion GIP receptor antagonists reduce post meal insulin release • Reduces gastric emptying after fat ingestion • Vasodilation • Increased histamine release • Inhibition of gastric acid secretion Reduces: • Intestinal motility • Gallbladder contraction • Pancreatic exocrine secretion

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Alimentary 8.2 – Immunological mechanisms and infections of the alimentary tract •

List the innate functions of the alimentary system which are part of our defence systems

Immune system of the GI tract protects against: • Absorption of toxins and antigenic material • Entry of microbes Mechanisms: • Non-immunological • Immunological

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Suzie Rayner

Non-immunological factors: • Gastric acid o Acid bath kills micro-organisms o [Acid deficiency – hypochlorhydria] – more at risk of salmonella • Normal oral flora o Upset with antibiotics • Hepatic filtration • Proteases • Digestive enzyme activity • Mucus o From goblet cells • Epithelium (tight junctions) • Bile acids • Peristalsis • Indigenous microbial flora o Most abundant in mouth and colon o Rapid increase from jejunum → ileum Bacteria in distal alimentary tract: Anaerobes Bacteriodes Clostridia Bifidobacteria Eubacteria Streptococci Intestinal host defence: Lumen Dimeric IgA Polymeric IgM [Secretory antibody]

Facultative anaerobes Coliforms Lactobacilli Streptococci Diptheroids

Epithelium IgE IgM IgG IgA Mast cell [Systemic antibody]

Cellular immune system Macrophage Eosinophil B lymphocyte T lymphocyte Plasma cells

Mast cell degranulation causes: [Inflammation, therefore:] • Oedema • Increased vascular permeability (redness) • Increased mucosal permeability • Smooth muscle contraction • Chemotaxis Potential intestinal complications of immune deficiency: 27


Suzie Rayner • • •

Local microbial proliferation (bacteria, virus, parasite) Increased antigen uptake (dietary, bacterial) Both of these lead to chronic enteropathy

Define MALT and GALT

GALT – Gut associated lymphoid tissue Action: • Generates lymphoid cells and antibodies (IgA secretory and interstitial, IgG, IgM, cell mediated immunity) What it is: • Lymphoid follicles • Tonsils • Peyer’s patch in distal ileum • Scattered lymphoid follicles in colon • APC • Intraepithelial lymphocytes (mainly CD8 – killers) • Mesenteric lymph nodes Lymph flows from intestinal trunk and 2 lumbar lymphatic trunks into cisterna chili, a dilated sac at lower end of thoracic duct, then returned to systemic circulation. MALT – mucosa associated lymphoid tissue Intestinal contribution to common mucosal immunity: Lymphatics drain → mesenteric node → thoracic duct → circulation Common mucosal immunity affects: • Eye, oral cavity • Genito-urinary • Lactating mammary gland • Lung • Liver •

Describe a Peyer’s patch

Peyer’s patches and scattered lymphoid follicles: Specialised epithelium - Dome epithelium: • Controlled uptake of antigens • Smaller epithelial cells and brush border • Less goblet cells • Less mucus • No sIgA 28


Suzie Rayner •

M cells – take up antigen

M cells: • Membranous or microfold • Portal entry for antigens • Transported to lymphocytes, macrophages and dendritic cells Mucosal lymphocytes: • Stimulated by antigens and cytokines • Migrate to mesenteric lymph nodes • Then into thoracic duct • Return to mucosal surfaces Local immunization in peyer’s patch: Lymphocytes enter Peyer’s patch → B lymphoblast or T lymphoblast

Describe the importance of colonic flora

Infection of GI tract: Oral and GI flora: • Upset with antibiotics • Immunodeficiency • Candida infection (thrush) Peristalsis: • Stagnation due to: • Surgery • Drugs • Electrolyte imbalance Gastroenteritis – differential diagnosis: • Incubation period • Foodstuffs • Risk factors • Travel

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Describe the circulation of lymphocytes within the alimentary system and how this relates to the immune system elsewhere

Summary of some immunoglobulin roles: • Specific maternal antibodies passed from mother to baby via breast feeding (IgG) • IgA secreted from biliary duct Potential responses to local immunization: • Allergy • Local antibody • Systemic tolerance Local immunity and systemic tolerance: • Dimeric IgA and IgM class antibodies produced in lamina propria, function to prevent antigen absorption and entry of microbes • Systemic tolerance prevents induction of IgG complement fixing antibody which would result in an ‘Arthus reaction’ in gut wall (hypersensitivity reaction) • •

List three mechanisms of infectious diarrhoea Describe the global importance of childhood diarrhoea

Traveller’s diarrhoea – main causes: • E coli • Shigella • Salmonella • Cholera E. coli strains: • Enterotoxigenic o Non-inflammatory o Watery diarrhoea o Travellers diarrhoea • Enterohaemorrhagic o Haemolytic uraemic syndrome • Enteropathogenic o Childhood diarrhoea • Enteroinvasive o Bloody diarrhoea E. coli can be caught from school trips to farms, unpasteurised milk, burgers Avoid travellers diarrhoea by: Safe food and water 30


Suzie Rayner • • • •

Handwashing Bottle water No ice Salads

Cholera (Vibrio cholarae): Range of mild → full blown • Liquid stool → coma in 4012 hours • Peristalsis → gurgling • Rice water stools • Salt and water loss • Hypovolaemic shock Treatment: Fluid replacement – salt, water, sugar, IV fluids •

Define the role of IgA in the GI tract

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Alimentary system 9.1 – Lifestyle! Alcohol and you •

To understand the biochemistry and metabolism of ethanol

Biochemistry: • Ethanol is practically insoluble in fats and oils • Concentration in tissue depends on relative water content of the tissue • Rapidly reaches equilibrium with the concentration of ethanol in the plasma • No plasma protein binding for ethanol It is metabolized by 2 different pathways: Rate of metabolism is affected by: • Diet • Gender • Body-habitus • Race • Genetics

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Suzie Rayner

First pass metabolism: • Up to 75% of absorbed alcohol can be broken down by liver before it reaches the systemic circulation • Small bowel is up to 20x more efficient at absorbing alcohol than the stomach • Food within the stomach, especially fat, delays gastric emptying. •

To understand the physiological effects and disease processes that alcohol can bring about in the various organ systems, with particular reference to liver disease and cirrhosis.

Direct and indirectly alcohol affects hepatocytes: • Directly through • Or breakdown products of ethanol pass through hepatocytes • Cause cell death

Alcohol-related liver injury: 70% Steatosis 6% Alcoholic hepatitis 10-20% Alcoholic cirrhosis Fatty liver: • Occurs in up to 60% heavy drinkers • Fat droplets deposited in liver

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Suzie Rayner • •

Leads to steatohepatitis(inflammation) and abnormal live function tests Reversible if alcohol intake reduced

Alcoholic hepatitis: • Secondary immune reaction directed against the liver • Jaundice • Fever • Neutrophil leucocytosis • Cholestatic liver function tests (bile cannot flow from liver → duodenum) Immune changes in alcoholics with liver disease: Increase Decrease IgA, IgG, IgM B and T lymphocyte in the blood T lymphocytes (persistently activated) Response to tuberculin skin tests (delayedtype hypersensitivity) IL1, TNFα, IL6, IL8 Neutrophils and monocytes Cirrhosis: • Irreversible scarring of liver with fibrous bands and regenerative nodules • Eventually develops in 20% after 15 years Morbidity common, associated with: • Jaundice • Ascites • Bleeding • Cachexia • Infections • Encephalopathy • 3-5% per annum risk of developing liver cancer • Death in most within 10 years Oesophagus: • Cancer • Reflux • Oesophagitis Stomach: • Gastritis • Ulcers • Cancer Chronic pancreatitis: • Up to 45% due to alcohol • Exocrine insufficiency o Steatorrhoea 33


Suzie Rayner

• • •

o Vitamin deficiencies o Hypocalcaemia Endocrine insufficiency o Diabetes Chronic pain Weight loss

Hypertension – caused by heavy alcohol consumption (increased both systolic and diastolic) Alcoholic Cardiomyopathy Stroke: • Heavy alcohol consumption increases risk of haemorrhagic stroke • >5 drinks per day increases risk by 250-450% Effects on the CNS (neurological): • Wernicke’s encephalopathy • Korsakoff’s psychosis • Optic toxicity • Autonomic dysfunction • Peripheral neuropathy Immune system: • Immunosuppressant o Increased incidence of infectious disease [Bacterial pneumonia, septicemia, TB, hepatitis C, meningitis, lung abscess, diphtheria, cellulitis] • Increased autoimmunity o Contributes to liver disease and renal dysfunction [alcoholic hepatitis, liver cirrhosis, renal disease associated with IgA deposition] Cancer: • Increased oral cavity and larynx • Oesophagus and stomach • Liver • Pancreas Moderate association with breast and colon. Musculoskeletal: • Gout • Fractures • Myopathies • Dupuytren’s contracture

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Suzie Rayner Fetal alcohol syndrome: • One of most common causes of mental retardation • Major public health problem • Gives specific pattern of facial features • Pre and/or post natal growth deficiency • Evidence of CNS dysfunction Effect on male reproductive system: • Strong leydig cell toxin • Adverse effect on synthesis and secretion of testosterone • One of commonest causes of male impotence • Direct testiculat toxin – atrophy of seminiferous tubules, decrease sperm concentration, output, motility and morphology Symptoms of acute alcohol withdrawal: Moderate Hyperthermia Tachycardia. Tachypnoea Hypertension Nausea and vomiting Tremor and sweating Anxiety and agitation

Severe Disorientation Tactile hallucinations Visual hallucinations Auditory hallucinations Convulsions

Acute alcohol poisoning: • Ataxia and anaesthesia • Dysarthria and nystagmus • Drowsiness → coma • Inhalation of vomit • Hypoglycaemia Hangover: • Headache – cerebral dehydration • Nausea and vertigo – altered osmolarity of endolymph, hypoglycaemia • Wretching and vomiting – gastritis [Treatment – fluid, sugar, analgesia, sleep] •

To appreciate the psychological and material impact of alcohol on both the individual and society as a whole

Alcohol abuse: • Failure to carry out major obligations (work, home, school) because of repeated alcohol use • Using alcohol even when dangerous to do so • Legal problems • Continued use of alcohol despite it has caused social/interpersonal problems 35


Suzie Rayner

Alcohol dependence: • Tolerance • Withdrawal • Amount or duration of use often greater than intended • Trying without success to control/reduce alcohol use • Abandoning normal activities Alcoholism markers: • Use alcohol to avoid withdrawal • Overtakes everything else • Large quantities due to tolerance • Relapse • Know they cannot control it

Medical cost: • 20-60% of hospital admission in US due to alcohol • 4th cause of death in US NHS cost: • 60% of assault and head injury patients to A and E are intoxicated • 19% of accidents in the home have positive blood alcohol • Alcohol causes more severe injuries • 27% of admittance to general medical ward in London had alcohol related illness Unit of alcohol = 8g Grams of alcohol = % x volume/100 % alcohol is number of grams of alcohol in 100ml.

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Suzie Rayner •

To develop the knowledge and skills to advise on how to enjoy alcohol responsibly and to identify and deal with problem drinking.

• • • • •

Keep alcohol diary Atleast 2 alcohol free days each week Drink for a reason Read the label Avoid rounds

_______________________________________________________________________ _

Alimentary system 9.2 – Diarrhoea in Children _______________________________________________________________________ _

Alimentary system 10.1 – Specific issues in alimentary absorption • • • •

Water and ions Calcium Iron Vitamins (B12)

Briefly describe the processes of diffusion and osmosis.

Diffusion: the process whereby atoms or molecules intermingle because of their random thermal motion • Occurs rapidly over microscopic distances, slowly over macroscopic distances • Multicellular organs evolve circulatory systems to bring individual cells within diffusion range • Cell membrane acts as diffusion barrier, maintains different cytoplasmic and extracellular concentration of substrates • Lipid soluble can cross membrane more easily than water soluble (polar) Osmosis: flow of water across a semi-permeable membrane from solution of lower conc. to higher conc. Water flows: Hypotonic (low solute) → Isotonic → Hypertonic (high solute) •

Describe the different protein-mediated transport systems that move substances across membranes.

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Suzie Rayner

Membrane transport: • Active transport requires energy (ATP) • Primary active transport – process directly linked to cellular metabolism (ATP) • Secondary active transport – process derives energy from the concentration gradient of another substance that is actively transported (co-transport) • Facilitated transport - enhances the rate a substance can flow down its concentration gradient. Tends to equilibrate the substance across the membrane and does not require energy. • Paracellular transport – movement through tight junctions and lateral intercellular spaces • Transcellular transport – passage through epithelial cell [Tight junctions between epithelial cells are leaky (permeable to water and ions)] Standing gradient osmosis: • Driven by Na • Transport of Na from lumen → enterocytes. • This transport is complex, varies between species. More efficient as more down intestine o Proximal Bowel – counter transport in exchange for H+ o Jejunum – Co-transport with amino acids, monosaccharides o Ileum – co-transport with Clo Colon – restricted movement through ion channels • Active transport of Na+ into lateral intercellular spaces by Na+K+ATPase transport in lateral plasma membrane •

Cl- and HCO3- transported into the intercellular spaces due to electrical potential created by the Na+ transport. • High concentrations of ions in the intercellular spaces causes the fluid to be hypertonic. Water movement: • Osmotic flow of water from gut lumen via adjacent cells and tight junctions into the intercellular space • Water distends the intercellular channels, increasing hydrostatic pressure • Ions and water move across the basement membrane of the epithelium and are carried away by the capillaries. Absorption of CHO: Absorption of: Glucose, galactose Fructose • •

Mechanism: Secondary active transport Facilitated diffusion

Carrier protein SGLT-1, apical membrane GLUT-5, apical membrane

GLUT-2 facilitates exit at the basolateral membrane Human small intestine can absorb 10kg of simple sugars per day.

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Suzie Rayner •

Explain the mechanisms involved in absorbing water, Na+ K+ Ca++ Cl- HCO3-, Iron and vitamins in the alimentary tract.

Water and electrolytes: • 99% of H2O presented to GI tract is reabsorbed • Absorption of water is powered by absorption of ions • Most water absorbed in small intestine, mainly jejunum • Many ions are slowly absorbed by passive diffusion [Calcium and iron are incompletely absorbed, regulated absorption] Region of GI tract/Secretion Saliva (Mouth) Ingested Gastric secretions Bile Pancreas Intestinal Small intestine Colon

Secretion (input) volume

Absorption (output) volume

1.2L 2L 2L 0.7L 1.2L 2.4L 8L 1.4L

Absorption of other ions: • Cl- co-transported with Na+ (ileum) • Exchanged with HCO3- (colon) into enterocytes • Both of these are secondary active transport • •

K+ diffuses in via paracellular pathways in small intestine, leaks out of cells in colon. This is passive transport.

Diarrhoea: • In secretory diarrhoea, secretion of Cl-, Na+ and H2O into intestinal lumen by cells in the crypts of Lieberkuhn is elevated. • Cholera toxin permanently activates adenylyl cyclase, elevating cAMP in the crypt cells and thus enhances the secretion of Cl- (Na+ and H2O) • Cholera patients may produce up to 20L/day watery stool • Patients that are loosing excessive water through diarrhoea are likely to die unless promptly and adequately rehydrated. Calcium: • • • •

Duodenum and Ileum absorb Ca2+ Ca2+ deficient diet increases guts ability to absorb Vit D and parathyroid hormones (PTH) stimulate absorption. Diet: 1-6g/day 39


Suzie Rayner • •

Secretion: 0.6g Absorb: 0.7g

Ca2+ carried across apical membrane by intestinal calcium-binding protein (IMcal) – facilitated diffusion Ca2+ pump across basolateral membrane by Ca2+ ATPase and Na+/Ca2+ exchanger Binds to calbindin in cytosol

• •

Vitamin D: • Essential for normal Ca2+ absorption • Deficiency causes rickets, osteoporosis • 1,25-dihydroxycholecalciferol taken up by enterocytes: o Increases transport of Ca2+ across the brush border o Enhances the transport of Ca2+ through the cytosol o Increases levels of calbindin o Increases rate of extrusion across basolateral membrane by increasing Ca2+ ATPase in membrane Iron: • • • •

Diet ingests: 15-20mg/day Absorbs: 0.5-1.5mg/day Iron forms insoluble salts with hydroxide, phosphate, HCO3Vitamin C increases iron absorption (Fe3+ → Fe2+, prevents formation of insoluble complexes) Iron presents in diet as: • Inorganic iron • As part of Haem group (smaller part of diet but more readily absorbed) Haem: • Absorbed intact via facilitated diffusion • Fe2+ liberated by haem oxidase Fe2+:

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Suzie Rayner • • • • • •

Binds to transferrin, secreted by duodenum and jejunum Complex binds to transferrin receptor on brush border Fe2+ released into cytosol by endocytosis and divalent metal transporter (H+ coupled cotransporter) Fe2+ binds to mobilferrin, moves via ferroportin ion channel into blood (through basolateral membrane) OR binds to apoferrin, to form ferritin micelle Ferritin – globular protein complex, Fe2+ → Fe3+ which crystallizes within protein shell

Ferritin prevents absorption of too much iron (toxic): • Irreversible binding of iron to ferritin in epithelial cells • Iron/Ferritin cannot be transported into plasma • Iron/Ferritin is lost in the intestinal lumen, excreted in faeces Increased iron in cytosol, increased ferritin synthesis, decreased synthesis of transferrin receptors. Vitamins (B12): • Organic compounds that cannot be manufactured by the body but vital to metabolism • Passive diffusion predominant mechanism • Fat soluble vitamins (A, D, E, K) transported to brush border in micelles. K taken up by active transport • Specific transport mechanisms for vitamin C (ascorbic acid), folic acid, vitamin B1 (thiamine), Vitamin B12 Vitamin B12: • Liver contains a large store (2-5mg) • Most vitamin B12 in food is bound to proteins • Low pH and the digestion of proteins by pepsin releases free vitamin B12 • Vitamin B12 binds to R proteins • R proteins digested in duodenum Intrinsic factor: • Vit B12 binding glycoprotein • Secreted by gastric parietal cells in stomach • Vit B12/IF is resistant to digestion • If no IF, then no absorption of Vit B12 • Vit B12/IF complex binds to cubilin receptor – taken up in distal ileum • Once in cell Vit B12/IF completely broken • B12 binds to TC2 (transcobalamin II), crosses basolateral membrane • B12 bound to TC2 travels to liver • TC2 receptors on cell allow them to uptake complex • Broken down inside cell

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Suzie Rayner

Vitamin B12 deficiency: • Retards the maturation of red blood cells • Pernicious anaemia • Schilling Test _______________________________________________________________________ _

Alimentary system 10.2 – Hunger, thirst and control of intake Comorbidities of obesity: • Stroke • Sleep apnoea • Bowel cancer • Osteroarthritis • Gout • Hypertension • MI • Diabetes • Peripheral vascular disease • Depression Thrifty gene hypothesis: • Evolutionarily sensible to put on weight, thin humans didn’t survive, therefore didn’t pass on genes to modern humans • Today, little exercise and high caloric intake cause humans to easily become obese • Evidence – populations traditionally prone to starvation become obese when exposed to western diet and sedentary lifestyle. Why some fat some thin? 42


Suzie Rayner • • •

Perhaps as societies developed agriculture and starvation less of a threat, obesity began to be selected against Cultures more threatened by starvation selected for ability to put on weight Western society carries ‘genetic legacy’ of both environments

Adaptive drift hypothesis: • Generally, fat eaten by predators, thin starve in hard times. • Humans learnt to defend themselves • Thus obesity not selected against, current inheritors – obese •

Draw a simple diagram explaining how the hypothalamus regulates appetite.

Hypothalamic circuits controlling body weight: Other brain regions involved in food intake: • Signals from higher centres • Signals from amygdale (emotion, memory) • Signals from other parts of the hypothalamus (lateral hypothalamus) • Vagal nerves signal to brain stem, transmitted to hypothalamus Balance between energy intake and energy expenditure [3V = 3rd ventricle]

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Suzie Rayner

Orexigenic hormones (stimulate appetite) γ – amino butyric acid (GABA) Growth hormone releasing hormone (GHRH) Melanin concentrating hormone (MCH) Neuropeptide Y (NPY) Opioid peptides (β endorphin) Agouti-related peptide (AgRP) Galanin

Anorexigenic hormones (inhibit appetite) α- melanocyte stimulating hormone (αMSH) Cocaine and amphetamine regulated transcript (CART) Corticotrophin releasing hormone (CRH) Cholecystokinin (CCK) [duodenum] Glucagon-like peptides 1 and 2 (GLP-1/2) Insulin Leptin Neurotensin Proinflammatory cytokines (IL1-β, TNFα) Serotinin Urocortin Amylin

Describe the main neural populations involved.

Arcuate nucleus (see previous diagram): • Key brain area involved in regulation of food intake • Incomplete blood brain barrier, allows access to peripheral hormones • Integrates peripheral and central feeding signals • Two neuronal populations o Stimulatory (Neuropeptide Y/ Agouti-related peptide neuron) – NPY/Agrp

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Suzie Rayner o Inhibitory (pre-opiomelanocortin/cocaine and amphetamine regulated transport) – POMC/CART Action of hormones from arcuate nucleus: • Circulating factors act on arcuate nucleus • Arcuate nucleus contains centrally projecting neurons containing stimulatory or inhibitory hormone • Signals sent via centrally projecting neurons to paraventricular nucleus to increase or decrease feeding

Explain how mutations disrupting these neural systems can influence energy balance.

Human CNS mutations affecting appetite:

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Suzie Rayner • • • • •

No NPY or Agrp mutations associated with appetite discovered in humans (stimulatory) POMC deficiency and MC4-receptor mutations cause morbid obesity CART mutations causing obesity found Mutations not responsible for the prevalence of obesity – useful to explain signalling Describe the role of leptin in energy homeostasis.

Peripheral signals of body homeostasis: Long term - Leptin: Adipostat mechanism: • Circulating hormone produced by fat • Hypothalamus senses concentration of hormone • Hypothalamus then alters neuropeptides to increase or decrease food intake [Perhaps problem with regulation of adipostat mechanism leads to obesity] Leptin: • 167 AA hormone • Made by adipocytes in white adipose tissue • Circulates in plasma • Acts upon the hypothalamus regulating appetite and thermogenesis. • Increased leptin increases thermogenesis and decreases food intake (therefore should reduce weight) Leptin is low when low body fat, high when high body fat. Ob/ob mouse: Missing in ob/ob mouse – mouse is at least 2x bigger than normal If leptin is replaced, mouse loses weight.

There are 3 ways the leptin regulatory loop could lead to obesity: • Failure to produce leptin • Inappropriately low leptin secretion for a given fat mass • Leptin resistance (in hypothalamus receptors)

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Suzie Rayner Correct mechanism is Leptin resistance – obese humans (and rodents) have high plasma leptin levels. Leptin resistance: • Leptin circulates in plasma in concentrations proportional to fat mass (therefore obese, high concentration) • In leptin resistance hormone is present but doesn’t signal effectively. • Due to leptin resistance, leptin does not decrease body weight in obese humans • Congenital leptin deficiency: Small number of cases, mutation in ob gene, severely hyperphagic (increased appetite) and obese. o In these cases, replacement of leptin is effective. •

Explain why gut hormone systems may be good targets for anti-obesity drugs.

Peripheral signals of body homeostasis: Short term – Ghrelin, PYY: Peptide YY (PYY): • 36AA, tyrosine at both ends • Released from gut into circulation after a meal as PYY3-36 Directly modulates neurons in arcuate nucleus: • Inhibits NPY release • Stimulates POMC neurons • Decreases appetite [Reduces food intake by 36% - study] Ghrelin: • 28AA, octanyl at position 3 • Gastric hormone • High when fasting, falls after eating. Directly modulates neurons in the arcuate nucleus: • Stimulates NPY/Agrp • Inhibits POMC • Increases appetite Future obesity treatments: • Gut hormones may provide treatment • Target only relevant circuits • Released daily without side effects • Exert effects throughout life without escape Summary of effects on hypothalamus: Leptin: Decreases food intake Ghrelin: Increases food intake PYY3-36: Decreases food intake

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Suzie Rayner • •

Briefly describe the role of ADH in water balance. Detail how the hypothalamus regulates water intake.

The control of thirst: Thirst is perceived when: • Blood fluid osmolality is increased – most potent stimulus • Blood volume reduced • Blood pressure reduced [2-3% change in osmolality stimulates same response as 10-15% change in volume or pressure] Vasopressin/ADH: • Acts on kidneys to regulate volume and osmolality of urine • Low plasma ADH = large volume of urine excreted – water diuresis • High plasma ADH = small volume of urine – anti diuresis Osmoreceptors influence ADH release: • Located in hypothalamus and subfornical organ (SFO) • Sense change in body fluid osmolality • Cells shrink or swell in response • Signals sent to ADH producing cells in hypothalamus, altering ADH release To maintain water balance: Increased plasma osmolality Invokes drinking ADH release Increased ADH stimulates kidney to conserve water

Decreased plasma osmolality Suppresses thirst ADH release suppressed Absence of ADH, kidney excretes more water

Thirst sensation: • Thirst is decreased by drinking, even before sufficient water has been absorbed (by GI tract) to correct osmolality. • Receptors in mouth, pharynx, oesophagus • Relief of thirst via these receptors is short lived • Only completely satisfied once plasma osmolality is decreased or blood volume or arterial pressure corrected • Circuits involved? •

Describe the role of angiotensin II in the perception of thirst.

Renin-angiotensin-aldosterone system [Remember zona glomerulosa stimulated by angiotensin II, decreased Na+, increased K+, corticotrophin]

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Suzie Rayner Angiotensin II (AGAIN): • Evokes thirst sensation • AII increased when blood volume and pressure reduced • Activates subfornical organ (SFO) neurons • AII contributes to homeostatic response to restore and maintain body fluids at normal level _______________________________________________________________________ _

Alimentary system 11.1 – Colon and rectum: Intestinal mucosal organisation and function •

Review the anatomical sections and main anatomical relations of the large intestine and related structures.

Basic anatomy of large intestine: • Caecum – blind pouch just distal to ileocaecal valve – larger in herbivores • Appendix – thin, finger-like extension of the caecum – not physiologically relevant • Ascending colon • Transverse colon • Descending colon • Sigmoid colon • Rectum • Anus Colon: • Principle functions: reabsorption of electrolytes and water and elimination of undigested food and waste • 1.5m long • 6cm diameter Ascending colon: • R side of abdomen • Runs from caecum to hepatic flexure Transverse colon: • Hepatic flexure to splenic flexure • Hangs off the stomach attached by a wide band of tissue called the mesocolon (continuous with 2 posterior layers of greater omentum) Descending colon: • Splenic flexue to sigmoid colon Sigmoid colon: • S shaped 49


Suzie Rayner • Descending colon to rectum Rectum: • Dilated distal portion of alimentary canal • Histology similar to colon, distinguished by transverse rectal folds in submucosa and absence of taenia coli in muscularis externa. • Terminal portion is anal canal, surrounded by internal (circular muscle) and external (striated muscle) anal sphincters. Mucosal structure: Summary (from lumen outwards): • Epithelium • Lamina propria • Muscularis mucosae • Submucosa (submucosal plexus) • Inner circular muscle layer • Myenteric plexus • Outer longitudinal muscle layer

• • •

Enterocytes and goblet cells are abundant Abundant crypts Stem cells are found in crypts ( villus ‘escalator’ – replace damaged cells of microvilli)

Mucosal organisation: • Mucosa appears smooth at gross level because it has no villi • Enterocytes have short, irregular microvilli and are primarily concerned with resorption of salts • Water is absorbed as it passively follows electrolytes – therefore more solid gut contents • Crypts dominated by goblet cells • No paneth cells • Enteroendocrine cells are rarer than in small intestine • Glycocalyx does not contain digestive enzymes Goblet cells: • Higher number in large intestine than small • More prevalent in crypts than along surface • Number increase distally towards the rectum 50


Suzie Rayner • •

Mucus facilitates passage of increasingly solid colonic contents, covers bacteria and particulate matter Acetylcholine stimulates goblet cell secretion

Describe the main functions of the large intestine.

Peritoneum carries fatty tags (appendices epiploicae) – unknown function, may protect against intra-abdominal infections

Circular muscles are segmentally thickened

• •

Muscle coat has 3 thick longitudinal bands (taeniae coli) – necessary for motility Bundles of muscle from the taenia coli penetrate the circular layer at irregular intervals.

Gut wall appears pouched in appearance (haustra) o Haustra are ovoid segments o Structual and dynamic elements o Can contract individually o In rectum and anal canal – substantial and continuous o Not always in same place o Still present post mortem

Nodules of lymphoid tissue are common in walls of distal small intestine (Peyer’s patches) and large intestine (solitary nodules)

Reabsorption: • Colon absorbs electrolytes and water • More absorbed in proximal colon • Na+ and Cl- absorbed by exchange mechanisms • Water follows by osmosis • K+ move passively into lumen (excreted) • Usually reabsorbs 1.5L, can absorb up to 4.5L, above this diarrhoea • •

Compare the structure and functions of the small and large intestines. Describe how the motility of the large intestine is regulated.

Movements of large intestine are more complicated than the small intestine. Large intestine motility: • Colonic contractions: kneading process – minimally propulsive • Promotes absorption of electrolytes and water • In proximal colon, ‘antipropulsive’ patterns dominate to retain chyme • In transverse and descending, localised segmental contraction of circular muscle (Haustral contractions) cause back and forth mixing 51


Suzie Rayner • •

Short propulsive movements every 30mins Increase in frequency of propulsive movements following a meal

Mass movement: • 1-3x daily, mass movement resembles peristaltic wave • Can propel contents 1/3 – ¾ of length of large intestine in a few seconds • Food that contains fibre promotes rapid transport through colon. Regulation: • Parasympathetic - ascending colon and most of the transverse colon innervated by vagus nerve. More distal innervated by pelvic nerve • Sympathetic – lower thoracic and upper lumbar spinal cord • External anal sphincter controlled by somatic motor fibres in pudendal nerve (voluntary) • Afferent sensory neurons detect pressure • Enteric nervous system also important – Hirschsprung’s disease (no enteric intramural ganglia) • Myenteric plexus ganglia concentrated below taenia coli • Presence of food in stomach can stimulate mass movement • Hormonal/paracrine control – aldosterone •

Describe the control of defaecation.

Defecation: • Rectum filled with faeces by mass movement in the sigmoid colon • Stores stool until convenient to void • Defecation reflex controlled primarily by sacral spinal cord – both reflex and voluntary actions. •

Reflex to sudden distension of walls of rectum

Pressure receptors signal via myenteric plexus → initiates peristaltic waves in descending sigmoid colon and rectum. Internal and external sphincter inhibited Weak intrinsic signal augmented by autonomic reflex External anal sphincter under voluntary control Urge resisted, the sensation subsides.

• • • •

Rectum: • Last few centimetres – ‘social part’ of rectum • Can distinguish between solid, liquid and gas • Perceptual ability is important in knowing what can be passed in what circumstance Faeces: 52


Suzie Rayner • • • • •

150g/day in adults 2/3 water Solids: cellulose, bacteria, cell debris, bile pigments(bilirubin), salts (K+) Bile pigments give colour (lack of bile due to blockage gives white) Bacterial fermentation gives odour.

Flora: • Symbiotic relationship with gut microbial community – protects • Stomach and small intestine have few bacteria as protected • Large intestine contain many, essential to normal function •

Diverse and highly metabolically active community in large intestine

Microbiome in average adult – 1.5kg of live bacteria

Role of intestinal flora: • Synthesise and excrete vitamins (vitamin K) • Prevent colonisation by pathogens by competing for attachment sites or for essential nutrients • Antagonise other bacteria through production of substances which inhibit or kill foreign species. • Stimulate production of cross-reactive antibodies. Antibodies produced against components of normal flora can cross react with certain related pathogens, thereby preventing infection/invasion • Stimulate development of certain tissue – caecum and lymphatics Types of normal flora: Bacteroides Gram negative Anaerobic Non-sporeforming Implicated in the initiation of colitis and colon cancer.

Bifidobacteria Gram positive Lactic acid bacteria Non-sporeforming ‘Friendly’ bacteria Prevent colonization by potential pathogens

Links between gut bacteria and: • Drug metabolism • Insulin resistance • Bile acid metabolism • Lipid metabolism • Obesity

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Suzie's Part 2 Alimentary  

Suzie's Part 2 Alimentary

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