6. GIT Hum Phys Lec6dw 2003 Format

8/2/2019 6. GIT Hum Phys Lec6dw 2003 Format

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HUMAN PHYSIOLOGY 1

BM1010M

Dr Diana WOOD

[email protected]

Lectures: Nutrition & Gastrointestinal Tract

Lecture 6

LIVER - Structure & Functions


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LIVER - Structure & Functions

After reviewing this topic through lecture and

reading, you should be able to

Describe the structure of a liver lobule and a sinusoid. Explain the dual blood supply to the liver.

Give an account of the functions of the liver, includingthose concerned with processing of nutrients.

Appreciate the key role of the liver in metabolism. Explain the importance of the liver as a buffer of blood

glucose levels.

Outline the common causes of liver disease.

Explain the major features of liver disease.


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LIVER

Liver is the largest organ in the body, weighing

approx 1.5 kg (2% body weight). 2 lobes, right 6x

left. Connects to gall bladder via hepatic ducts.

During digestion and absorption, the liver receives

approx 1.5 litres of blood/min.

80% is portal venous blood, under low pressure and

having low pO2.

20% via hepatic artery, normal arterial blood

supplying O2 and nutritional requirements.


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Fig 1: from Smith & Morton


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LIVER

Blood flow to liver depends on level of activity ingastrointestinal tract, blood will contain variableproportions of nutrients, bacteria, toxins and drugs.

Liver performs many vital metabolic functions:understanding important for appreciation ofconsequences of liver and biliary disease anddamage.

Liver is key organ in metabolism of virtually all drugsand foreign compounds taken in to the body. If thesesubstances or their metabolites are potentially toxicthey can damage the liver. Drugs account for 20-30%of all cases of severe liver failure.


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LIVERSTRUCTURE

Figure 2. 3-dimensional

representation of a liver lobule,

showing its blood supply and the

plate-like arrangement

of the hepatocytes (arrowsindicate direction of blood flow).


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LIVERSTRUCTURE

Figure 3. Enlarged view of aportion of a lobule,

to show the components of a

portal triad, the sinusoids and

the position of the bile canaliculi

and the Kupffer cells. (arrows

show direction of blood & bile

flow)


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LIVER

Blood transported from intestine to liver viahepatic portal vein.

Liver organised into lobules, seed-sized

structural and functional units (50-60,000 perliver), roughly hexagonal arrangements ofcells grouped around a central vein (figure2).

At edges of each lobule, sets of 3 vessels(portal triads), being a branch of the hepaticportal vein, a branch of the hepatic arteryand a bile duct.


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LIVER

Portal venule breaks up into capillary network(hepatic sinusoid), brings venous blood intocontact with liver cells, principally hepatocytesand phagocytic (reticuloendothelial) Kupffer cells

(figure 3).

Arterial blood mixes with venous blood withinsinusoid and mixed blood flows into central veinand ultimately to hepatic vein and vena cava.

Thin fenestrated lining of sinusoid composed ofloose arrangement of endothelial cells and Kupffer(reticuloendothelial) cells and is relatively leaky.


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LIVER

Mixture of venous and arterial blood runningthrough the sinusoid free to move intospaces around the hepatocytes.

Hepatocytes arranged in plates 2 cells thickso that each cell in contact with a sinusoid.

A bile canaliculus runs between the cellswithin each plate and bile formed byhepatocytes collects into canaliculus andhence to bile duct at edge of lobule.


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LIVER

Hepatocytes have microvilli on exposedsurfaces so large surface area for absorptiveand secretory processes.

Hepatocytes responsible for carrying out themany metabolic and secretory functions ofthe liver: arrangement of sinusoid helps

bring blood-borne substances to surface ofthese cells and the draining blood and bileprovide routes for removal of metabolites.


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LIVER FUNCTIONS

1. FILTRATION

Reticuloendothelial (Kupffer) cells are phagocytic,responsible for removal from blood of bacteria &cellular debris entering from gut, and of aged red

blood cells and antibody-antigen complexes.

2. STORAGE

Glycogen (5-8% liver weight), fats, iron, copperand many fat-soluble vitamins including vitamin A.

Also a large amount of blood is present in thevessels of the liver and this can be released to thegeneral circulation in emergency by vascularconstriction.


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LIVER FUNCTIONS

3. METABOLISM OF HORMONES & FOREIGNAND ENDOGENOUS COMPOUNDS.

Activation of vitamin D, in association withthe kidneys.

Detoxification or degradation of body waste

substances and hormones (pancreatic,adrenal, thyroid etc) as well as drugs andother foreign compounds.


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LIVER FUNCTIONS

Extensive enzyme systems (including thecytochrome P450 isoenzyme systems) found inthe smooth endoplasmic reticulum (microsomes)of the hepatocytes and may modify molecules,

both structurally and by conjugation with othercompounds (including sulphate, glucuronide,glutathione).

Amount of orally administered drug reaching

general circulation following absorption from thegut may be severely reduced by initial delivery toliver via portal blood and subsequent metabolismby hepatocytes (first pass effect).


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LIVER FUNCTIONS

In liver disease, symptoms may arise due

to build-up of unmetabolised hormones

etc. and dosage of many drugs may need

to be lowered to take into account

lowered metabolic capability of the liver.

British National Formulary (BNF) givesadvice on calculation of drug dosages in

patients with impaired liver function.


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LIVER FUNCTIONS

4. SECRETION OF BILE (BILE SALTS, BILEPIGMENTS, WASTE PRODUCTS)

Bile consists of aqueous alkaline fluid and several

organic constituents including bile salts (65-90%),cholesterol (5-25%), lecithin (2-25%) and bilirubin.

Organic components derived from hepatocyteactivity, each hepatocyte in close contact with a

bile canaliculus which collects bile and delivers itto a bile duct. Aqueous components are added byduct cells.


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LIVER FUNCTIONS

Bile flows from liver to gall bladder forconcentration and storage prior to release ondemand into duodenum. Strongest stimulus

to bile secretion is level of bile saltsthemselves.

Bile salts are conjugated derivatives of

cholesterol, principally sodium andpotassium salts of cholic, deoxycholic andchenodeoxycholic acids coupled to glycineor taurine.


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LIVER FUNCTIONS

They are actively secreted into the bile by thehepatocytes, function to emulsify fats in thesmall intestine and stabilise fat in micelles

(polymolecular aggregates of fat solublematerial).

Bile salts are mostly (90%) reabsorbed from

terminal ileum and thus recycled through theliver and biliary tract (enterohepaticcirculation).


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LIVER FUNCTIONS

Bilirubin is toxic yellow pigment derived from

breakdown of haemoglobin, principally in spleen.

After undergoing modification in liver (conjugation

with glucuronic acid) and intestine, it isresponsible for the yellow colouration of urine and

for the colouration of faeces.

If the formation of bilirubin exceeds its excretionthen the patient shows the characteristic yellowing

of jaundice.


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LIVER FUNCTIONS

Waste products arising from metabolism of drugs andendogenous compounds are delivered from hepatocytesinto bile and hence into intestine, to undergo excretionvia faeces and/or enterohepatic circulation (reabsorptionfrom intestine and recycling through liver, bile tract etc).

Gallstones usually form in the gallbladder from bile(cholelithiasis). Change in composition of bile may permitsubstances with low solubility to precipitate out of bile,usually cholesterol, calcium bilirubinate and calciumcarbonate.

Formation of gallstones usually causes inflammation ofgallbladder (cholecystitis) and movement of a stone maycause pain - biliary colic.


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LIVER FUNCTIONS

5. METABOLISM OF PROTEINS

a)Synthesis of proteins from absorbed amino acids

Plasma proteins, including albumin, blood

coagulation proteins such as prothrombin andtransport proteins for steroid hormones, thyroidhormones and cholesterol. Also structural andenzymatic proteins.

b)Synthesis of non-essential amino acidsFrom keto acids, involving transaminationreactions.


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LIVER FUNCTIONS

Figure 4

Step 1 Step 2


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LIVER FUNCTIONS

c) Breakdown of protein for glucose/energy

production

Individual amino acids are converted to -keto acids

via oxidative deamination reactions which generatetoxic ammonia as a product (figure 4, step 1). This

ammonia is processed through the ornithine cycle

which results in formation of urea, excreted via the

kidneys. (figure 4, step 2). The -keto acid generatedmay be used for production of energy or glucose.


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LIVER FUNCTIONS

6. METABOLISM OF FATS

a) Synthesis of complex fats from fatty acidsand triglycerides

e.g. cholesterol, phospholipids such aslecithin which are then used in themanufacture of lipoproteins of variousdensities (high, low, very low densities), whichare involved in lipid transport in plasma.

b) Synthesis of triglycerides

From carbohydrates and proteins when inoversupply.


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LIVER FUNCTIONS

c) Breakdown of fats for glucose and energyproduction

via lipolysis (figure 6)

Fig 6

Disruption of fat metabolism as result of liverdamage often seen as fatty liver, wherehepatocytes become filled with droplets of lipid.

Triglycerides

Glycerol

Glucose

Fatty Acids

Energy

Production

Lipolysis


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LIVER FUNCTIONS

7. METABOLISM OF CARBOHYDRATES &REGULATION OF BLOOD GLUCOSE

Importance of

blood glucose control

Rapid and large rise in blood glucose(hyperglycaemia) following feeding not desirable,this would markedly increase osmotic pressure of

blood, increase blood volume and thus increasework of heart. Glucose is thus driven into body cellsand stored as glycogen or used for energyproduction.


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LIVER FUNCTIONS

Low blood glucose level (hypoglycaemia) ininterdigestive period not desirable because somecells, particularly red blood cells and cells ofnervous system, renal medulla and retina rely

totally on glucose for energy production.

Buffer system required which will regulate andmaintain blood glucose in range 4-7.5 mmol/litre

(fasting-fed). Liver has important role in buffersystem because it can store, generate and releaseglucose depending on conditions.


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LIVER FUNCTIONS

a) Storage and release of carbohydrates

Glycogen is an insoluble polysaccharide whichcan be stored without exerting osmotic effects andreadily converted to and from glucose by

hepatocytes.

Figure 7 shows how glycogen is formed(glycogenesis) and stored when glucose is readilyavailable to the hepatocytes (after feeding).

Glucose is readily taken up by liver cells. Thehormone insulin from the pancreas is important inregulating the activity of the enzyme glucokinase.


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LIVER FUNCTIONS

Figure 7


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LIVER FUNCTIONS

Figure 7 shows how glycogen is broken downto glucose (GLYCOGENOLYSIS) when bloodglucose levels fall (in the interdigestiveperiod).

Hormone glucagon from pancreas important inregulating enzymes responsible.

During periods of metabolic stress, hormoneadrenaline (from adrenal medulla) alsoincreases glycogenolysis so that glucose isgenerated by liver and released into thebloodstream.


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LIVER FUNCTIONS

b. Synthesis of carbohydrates

Carbohydrates (glucose and glycogen) canbe synthesised from non-carbohydrate

sources (amino acids, glycerol, lactic acid)by hepatocytes - GLUCONEOGENESIS isliterally the formation of new glucose (figure8). This glucose can then be released intobloodstream for use by other cells.


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LIVER FUNCTIONS

Fig 8 - Gluconeogenesis


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LIVER FUNCTIONS

c. Release of carbohydrates into bloodstream

Most cells which have glycogen stores (such as

skeletal muscle) can break it down to a

phosphorylated form of glucose which can be usedfor internal production of energy by the cells.

The liver is unique in being able to produce glucose

itself (see points a & b above) which can then leave

hepatocytes into bloodstream and be made available

to other cells for production of energy.


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LIVER- PATHOLOGY & PATHOPHYSIOLOGY

Cells of liver under constant threat because theyare directly exposed to blood draining fromstomach and intestines which may containabsorbed micro-organisms and their toxins,

absorbed toxic chemicals and drugs in highconcentrations.

As main site of metabolism, liver cells may beexposed to toxic metabolites and intermediates.

In defence, liver has great reserve capacity (onlyabout 10% in everyday use) and regenerativecapability. This means that disease processes areususally well-advanced before signs andsymptoms become obvious.


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COMMON CAUSES OF LIVER DISEASE &

FAILURE

1. Hepatitis - inflammation of liver which may be acute or

chronic, and usually results in moderate to severe injury

with areas of necrosis (dead cells) and regenerating

hepatic parenchyma. It can be caused by:

Viruses selective for the liver - A (infectious, eg from

contaminated shellfish, 3-6 week incubation period), B &

C (via blood infusions, contaminated needles,

contaminated blood products, longer incubation period,

chronic hepatitis). Also viruses D,E,F.

Parasites such as Schistosoma mansoni, Amoeba

histolytica, Echinococcus.


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COMMON CAUSES OF LIVER DISEASE &FAILURE

Drugs & chemicals - directly and predictably toxic

e.g. CCl4, benzene, plant toxins, chloroform,

paracetamol, salicylates, methotrexate,

tetracycline; idiosyncratic (unpredictable toxicity)e.g. other anaesthetics such as halothane,

antidepressants, chlorpromazine, monoamine

oxidase inhibitors, anti-inflammatory drugs,

diuretics, antibiotics, etc, etc.


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2. Cirrhosis - (literally orange-coloured) - diffuse andprogressive chronic inflammation of liver, typicallyresulting from chronic alcoholism or severe chronichepatitis. There is cell death (typically in zones 2 & 3,figure 2), some regeneration and scarring (fibrosis,

degeneration & nodularity), which leads to obstructivedamage to blood vessels. It can be caused by:

infection (hepatitis B & C viruses particularly)

chemical damage (alcohol abuse accounts for 50% ofcirrhotic patients).

obstruction ofbile flow(cholestasis).


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Cirrhosis


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3.Liver tumours:

ususally multiple secondaries from

metastatic tumours in colon, breast, lung.

more rarely, may occur as primariesfollowing hepatitis B & C infections.

strong association between primarymalignancies and cirrhosis (70%).


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MAJOR FEATURES OF LIVER

DISEASE


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MAJOR FEATURES OF LIVER DISEASE

1. Jaundice:

yellow colour develops in skin & sclera(white of eye). Skin becomes itchy (pruritis).

levels of bilirubin in blood rise above normalrange of 0.3-1 mg/dl.

hepatocellular jaundice - failure of liver cellsto take up, process or excrete bilirubin. Mostcommon type seen clinically, usually inassociation with viral or other hepatitis orgenetic cause. Mild form often seen innewborn.


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obstructive jaundice - obstruction of bile ductsystem so bile doesnt drain into duodenumand backs up in canaliculi. May be due toswelling or inflammation of liver or toobstuction of bile ducts by tumours orgallstones.

haemolytic jaundice - excessive breakdown of

red blood cells/haemoglobin, usuallyimmunological in cause eg transfusionincompatibility, rhesus factor.


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2. Malabsorption:

failure to secrete bile (due to obstructionof bile duct system) may result in poor

absorption of fat and fat soluble vitamins.

leads to weight loss, steatorrhoea(passage of fatty faeces), poor bloodcoagulation (due to vitamin K deficiency).


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3.Portal hypertension:

restriction of blood flow through damaged

(especially cirrhotic) liver causes pressureof blood to rise in portal system.

This creates back pressure and shunting

which can result in damage to bloodvessels of the intestine and especiallyoesophagus (oesophageal varices).


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These may rupture and lead to severeblood loss via haematemesis ( vomiting ofblood) in patients who already haveimpaired ability for blood coagulation.

Portal hypertension also gives rise toascites (fluid accumulation in peritonealcavity), splenomegaly (enlargement of

the spleen) and a visible network ofdistended veins around naval (caputmedusae).


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4. Disordered hepatic metabolism may lead to:

Fatigue & weightloss, anorexia, vomiting.

Blood coagulation abnormalities (vit Kdeficiency, lack of prothrombin synthesis).

Lack of albumin synthesis so plasma albuminfalls, giving pitting tissue oedema.

Effects on brain - hepatic encephalopathy( lethargy, disorientation, coma)


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fat accumulation in liver, reversible orirreversible.

failure to metabolise drugs and hormones

normally, hence exaggerated effects(e.g. feminisation in male alcoholics due toaccumulation of adrenal oestrogens, pepticulcer due to accumulation of gastrin).

Kidney failure, possibly due to accumulation of

vasoconstrictors which damage kidney bloodflow.


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DIAGNOSIS OF LIVER FAILURE

1. Blood & urine tests (liver function tests, LFTs)

serum bilirubin urine bilirubin

plasma albumin

plasma alpha fetoprotein

plasma alkaline phosphatase*

plasma gammaglutamyl transaminase*

plasma alanine transaminase*

plasma aspartate transaminase (AST)*

*liver problem indicated by increases to more than twice theupper limit of the reference range.

2. Imaging techniquesCT, Ultrasound

3. Needle biopsy

Taken through abdominal wall under local anaesthetic.

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6. GIT Hum Phys Lec6dw 2003 Format