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innate immunity

This is the pre-existing immunity (naturally present).
It does not amplify with repeated attacks by the same pathogen.
It has no memory.
It is non-specific


cells of the innate immune system

Mast Cells
3.Dendritic Cells
Natural Killer cells


four elements of the innate immune system

1.Physical barriers
2.Antimicrobial factors
3.Phagocytes and natural killer cells
4.Inflammation and fever


physical barriers of the innate immune system

skin: barrier, sweat, sebum
Respiratory tract: mucus, cilia.
Gi tract: stomach acid
Eyes: tears


antimicrobial factors of the innate immune system-complement

complement system-can either cause opsonization, inflamation or lysis requiring C3. Classical, lectin and alternative pathways. good revision link.


antimicrobial factors of the innate immune system-cytokines

e.g. interferons – released by activated macrophages and lymphocytes and virally affected cells. Interferon act internally in these cells and they also bind to receptor on normal cells, causing them to
produce antiviral proteins.
These proteins don’t interfere with the entry of the virus
but they interfere with viral replication inside the cell.


antimicrobial factors of the innate immune system-iron binding proteins

lactoferrin – bind to iron, and in doing so remove essential substrate required for bacterial growth


antimicrobial factors of the innate immune system-antimicrobial peptides AMPs

defensins, found in phagocytes



pathogen enters wound, platelets release blood clotting proteins. mast cells secrete histamine and heparin - vasodilation and vascular constriction factors to inc delivery of blood plasma and cells to injured area. Neutrophils secrete factors that kill and degrade pathogens and with macrophages remove pathogens by phagocytosis. Macrophages secrete cytokines that attract immune cells to site and involved in tissue repair.


adaotive immunity

the early innate usually isnt enough,
3.Discrimination between “self” (host cells) and “non-self” (foreign cells)
Lymphocytes are the cellular vectors of adaptive immune response


3 types of lymphocyte

T Lymphocytes
2.B lymphocytes: Humoral immunity involves resistance against extracellular pathogens
and the production of specific antibodies to combat these pathogens.
3.Natural killer cytotoxic cells
Both are made initially in the
bone marrow.
B-lymphocytes are educated
and matured in the bone marrow.
T-lymphocytes are educated
and matured in the thymus gland.


stages of adaptive immunity

Neutrophils: leading to
B-lymphocyte activation.
Macrophages: leading to
T-helper cell (CD4) activation.
Dendritic Cells: leading to
T-lymphocyte (CD4) activation.
3.T-helper cell activation and
clonal expansion
4.B-lymphocyte activation, clonal expansion and clonal differentiation into plasma cells
(antibody production).


MHC class I

Present in the membranes of
all nucleated cells.
Via the endogenous pathway,
these proteins pick up intracellular peptides and
present them on its surface.
If the cell is healthy and the
peptides are normal, the T cells will ignore the cell.
If the cytoplasm contains abnormal (non-self) peptides
or viral proteins, these will be
presented instead by the
MHC-I proteins.
These activate CD8 cells.


MHC class II

Present only in the membranes of macrophages and dendritic cells (antigen presenting cells (A.P.C)).
Via the exogenous pathway,
these proteins pick up extracellular protein (e.g. antigens from engulfed bacteria) and present them on
its surface.
This is known as antigen processing followed by
antigen presentation.
The A.P.C will now travel to the lymph nodes, where they will activate CD4 cells.
These are T helper cells, Th1 produces IFN gamma which activates macrophages from monocyte. Th2 stimulates t cytoxic cells and IL4 and 5 which stimulates B cells.


functions of the liver

Metabolism of carbohydrates,
proteins, fats, hormones,
foreign chemicals (xenobiotics),
2)Filtration (kupffer cells) of blood
3)Formation of bile and coagulation factors
4)Synthesis of plasma proteins,
glucose, ketone bodies, cholesterol, fatty acids, amino acids
5)Storage of vitamins, iron, glycogen and blood


physiological anatomy of the liver

The basic functional unit of the liver is the liver lobule, which is a cylindrical structure several
millimeters in length and 0.8 to 2 millimeters in diameter.
The human liver contains 50,000 to 100,000 individual lobules.
The liver lobule is constructed around a central veinthat empties into the hepatic veinsand then into the
vena cava.
The liver lobuleitself is composed principally of many liver cellular plates that radiate from the central vein like spokes in a wheel.
Each hepatic plateis usually
two cells thick, and between the adjacent cells lie small bile
canaliculi that empty into bile ducts in the fibrous septa separating the adjacent liver lobules.
In the septa are small portal venules that receive their blood mainly from the venous out flow of the gastrointestinal tract by way of the hepatic portal vein.
From these venules blood flows into flat, branching hepatic sinusoids that lie between the hepatic plates and then into the central vein.
Thus, the hepatic cells are exposed continuously to portal venous blood.
Hepatic arterioles are also present in the interlobular septa. These arterioles supply arterial blood to the septal tissues between the adjacent lobules, and many of the small arterioles also empty directly into the hepatic sinusoids, most frequently emptying into those located about one third the distance from the interlobular septa


In addition to hepatocytes what are the venous sinusoids lined by

1)Typical endothelial cells
2)Large Kupffer cells, which are resident macrophages that line the sinusoids and are
capable of phagocytizing bacteria and other foreign matter in the hepatic sinus blood.


The endothelial lining of the sinusoids has extremely large pores. Beneath this lining, lying between the endothelial
cells and the hepatic cells, are narrow tissue spaces:

spaces of Disse, also known as the perisinusoidal spaces.
The millions of spaces of Disse connect with lymphatic vessels in the interlobular septa.
Therefore, excess fluid in these spaces is removed
through the lymphatics.
Because of the large pores in the endothelium, substances in the plasma move freely
into the spaces of Disse.
Even large portions of the plasma proteins diffuse
freely into these spaces


zones of liver

zone 1 nearest portal vein does amino acid catabolism, gluconeogenesis, chol synthesis. Zone 2 is an intermediate zone between zones 1 and 3.
Zone 3 is the main zone for detoxification of drugs etc. lipid synthesis, ketogenesis, glutamine synth.
Bile production takes place in all zones


blood flow through the liver

The liver has high blood flow and low vascular resistance. About 1050ml of blood flows from the portal veininto the liver sinusoids each minute, and an additional 300ml flows into the sinusoids from the hepatic artery, the total averaging about 1350 ml/min. The pressure in the portal veinleading into the liver averages about 9 mm Hg.The pressure in the hepatic veinleading from the liver into the vena cava normally averages almost exactly 0 mm Hg. This small pressure difference, only 9 mm Hg, shows that the resistance to blood flow through the hepatic sinusoids is normally very low, especially when one considers that about 1350 milliliters of blood flows by this route each minute


cirrhosis of the liver

greatly increases resistance of blood flow. liver parenchymal cells (functional cells) are destroyed, they are replaced with fibrous tissue that eventually contracts around the blood vessels, thereby greatly impeding the flow of portal blood through the liver. causes-alcoholism, poisons, viral like hepatitis, obstruction of bile duct, infection of bile duct. can cause portal hypertension.


liver function as a blood resevoir

expandable organ, blood can be stored, normal volume is 450ml, When high pressure in the right atrium causes backpressure in the liver, the liver expands, and 0.5 to 1 litre of extra blood is occasionally stored in the hepatic veins and sinuses. This occurs especially in cardiac failure with peripheral congestion.



high hepatic vascular pressures cause fluid transudation into the abdominal cavity from the liver and portal capillaries. fluid begin to transude into the lymph and leak through the outer surface of the liver capsule directly into the abdominal cavity. This fluid is pure plasma. It lacks plasma proteins (usually there is a decrease in the levels of albumin too, which encourages more fluid out of the vessels and into the abdomen)


liver regeneration

Partial hepatectomy, in which up to 70% of the liver is removed, causes the remaining lobes to enlarge and restore the liver to its original size.Hepatocyte Growth Factor (HGF)Promotes cell growthof hepatic progenitor cells into hepatocytes.Producd by mesenchymal cells in the liver, but not by hepatocytes. Levels of HGF rise more than 20-fold after a partial hepatectomy. Epidermal Growth Factor (EGF) and Cytokines (e.g. TNF and IL-6)


transforming growth factor beta

a cytokine secreted by hepatic cells, is a potent inhibitor of liver cell proliferation and is the main terminator of liver regeneration.


hepatic macrophage system

blood in portal veins grows colon bacilli when cultured but its very rare in circulation, kupffer cells that line hepatic sinuses are hepatic macrophages, less than 1% bacteria entering portal blood enters liver.


the liver and carbohydrate metabolism

Storage of large amounts of glycogen (glucose buffer function) 2.Conversion of galactose and fructose to glucose 3.Gluconeogenesis 4.formation of chemical compounds from intermediate products of carbohydrate metabolism


fat metabolism in the liver

Oxidation of fatty acids to supply energy for other body functions 2.Synthesis of large quantities of cholesterol, phospholipids, and lipoproteins (HDL/VDL) 3.Synthesis of fatfrom proteins and carbohydrates


energy derived from neutral fats

The fat is split into glycerol and fatty acids. Then the fatty acids are split by ‘beta-oxidation’into two-carbon acetyl radicals that form acetyl coenzyme A (acetyl-CoA).Acetyl-CoA can enter the citric acid cycle and be oxidized to liberate tremendous amounts of energy.two molecules of acetyl-CoA into acetoacetic acid, a highly soluble acid that passes from the hepatic cells into the extracellular fluid and is then transported throughout the body to be absorbed by other tissues.These tissues reconvert the acetoacetic acid into acetyl-CoA and then oxidize it in the usual manner.


liver synthesis of cholesterol and phospholipids

About 80%of the cholesterol synthesized in the liver is converted into bile salts, which are secreted into the bile.The remainder is transported in the lipoproteins and carried by the blood to the tissue cells everywhere in the body. Phospholipids are also transported principally in the lipoproteins. Both cholesterol and phospholipids are used by the cells to form membranes, intracellular structures, and multiple chemical substances that are important to cellular function.


protein metabolism in the liver

The body cannot dispense with the liver’s contribution to protein metabolism for more than a few days without death.Deamination of amino acids 2.Formation of urea for removal of ammoniafrom the body fluids 3.Formation of plasma proteins 4.Transamination to form non-essentialamino acids



Large amounts of ammonia are formed by the deamination process, and additional amounts are continually formed in the gut by bacteria and then absorbed into the blood.If the liver doesn’t produce urea, the plasma ammonia concentration rises rapidly and results in hepatic comaand death. Even greatly decreased blood flow through the liver - as occurs occasionally when a shunt develops between the portal vein and the vena cava - can cause excessive ammonia in the blood, an extremely toxic condition.


liver as a storage site for vitamins

vitamin A, but large quantities of vitamin Dand vitamin B12are normally stored as well. Sufficient vitamin A can be stored to prevent vitamin A deficiencyfor as long as 10 months. Sufficient vitamin D can be stored to prevent deficiency for 3 to 4 months.Sufficient vitamin B12 can be stored to last for at least 1 year and maybe several years.


liver as a store for iron (ferritin)

xcept for the iron in the haemoglobin of the blood, by far the greatest proportion of iron in the body is stored in the liver in the form of ferritin.The hepatic cellscontain large amounts of a protein called apoferritin, which is capable of combining reversibly with iron.Therefore, when iron is available in the body fluids in extra quantities, it combines with apoferritin to form ferritin and is stored in this form in the hepatic cells until needed elsewhere. When the iron in the circulating body fluids reaches a low level, the ferritinreleases the iron. The apoferritin-ferritin systemof the liver acts as a blood iron buffer, as well as an iron storage medium


coagulation factors produced by the liver

FibrinogenProthrombinAccelerator globulinFactor VIIVitamin Kis required by the metabolic processes of the liver for the formation of several of these coagulation factors, especially prothrombin and Factors VII, IX, and X. In the absence of vitamin K, the concentrations of all these decrease markedly and this almost prevents blood coagulation.


which cell is activated if hepatocyte proliferation is impaired

oval cells


which cell is phagocytic



which cell is produced by the liver in a foetus



which cell converts haem to bilirubin



which cells are exogenous stem cells for liver regeneration

bone marrow cells


which cells are fetal precursers of hepatocytes



which cell is the major type involved in liver fibrosis

hepatic stellate cells Ito cells


which cell represents 70% of liver mass



bilirubin in the bile-red blood cells

Many substances are excreted in the bile and then e
liminated in the faeces.
One of these is the greenish yellow pigment bilirubin. This is a major end product of haemoglobin degradation.
1)When the red blood cells have lived out their life span (on average, 120 days) and have become too fragile to exist in the circulatory system, their cell membranes rupture, and the released haemoglobin is phagocytized by tissue macrophages (also called the reticuloendothelial system) throughout the body. The
haemoglobin is first split into
globin and heme, and the heme ring is opened to give: Free iron, which is transported in the blood by transferrin
A straight chain of four pyrrole nuclei, which is the substrate from which bilirubin will eventually be formed.



The first substance formed is biliverdin, but this is rapidly reduced to free bilirubin, which is gradually released from the macrophages into the plasma.
The free bilirubin immediately
combines strongly with plasma albumin and is transported in this combination throughout the blood and interstitial fluids. 
Even when bound with plasma protein, this bilirubin is still called “free bilirubin” to distinguish it from “conjugated bilirubin”.


storage of bilirubin in the liver

free bilirubin is absorbed through the hepatic cell membrane. In passing to the inside of the liver cells, it is
released from the plasma albumin and soon thereafter
conjugated about:
80% with glucuronic acid to form bilirubin glucuronide
10% with sulfate to form bilirubin sulfate
10% with a multitude of other substances.
In these forms, the bilirubin is excreted from the hepatocytes by an active transport process
into the bile canaliculi and then into the intestines.


formation and fate or urobilinogen

in the intestine, about half of the conjugated bilirubin is
converted by bacterial action
into the substance urobilinogen, which is highly soluble.
90% of this urobilinogen is broken down further into stercobilinogen and stercobilin
and excreted in faeces.
10% of this urobilinogen is absorbed through the intestinal mucosa back into the blood.
Most of this absorbed urobilinogen is re-excreted by the liver back into the gut.
About 5% of this absorbed urobilinogen is excreted by the kidneys into the urine.
After exposure to air in the urine, the urobilinogen becomes oxidized to urobilin


functions of bile

Excretion of waste products (those that are not easily excreted by the kidney) 
Excretion of hormones
Excretion of drugs and other xenobiotics
Secretion of bile acids/salts to aid intestinal lipid digestion and absorption
Secretion of electrolytes and water as a vehicle


electrolyte secretion into bile canaliculi

There is polarised distribution of ‘housekeeping’ transporters e.g. Na,K-ATPase, Ca-ATPase, NHE, NBC, AE, etc.
This means that the normal charges and ion concentrations are maintained in the hepatocytes.
Consequently there is some net fluid & electrolyte secretion:
Secondary active transport of Cl- and HCO3 –Paracellular Na+ transport
Isosmotic water flow
Many other solute transporters for metabolic substrates/products e.g. GLUT2, amino acid transporters etc.


synthesis of bile acids/salts

Liver synthesises cholesterol. Bile acids and salts are derived from cholesterol.
In the liver, cholesterol is converted into primary bile acids. 
Primary bile acids are weakly ionised, hence ‘bile acids’. 
Primary bile acids are released by the liver into bile and are carried to the intestine. 
In the intestine, the bacteria convert these into secondary bile acids.
Conjugation of primary and secondary bile acids with taurine, glycine, sulphate, glucuronate makes them more
water soluble and charged, hence ‘bile salts’.


apical secretion of bile acids/salts

Unconjugated (BA− ) and conjugated bile salts(BA-Z − & BA-Y − ) secreted via:
Bile salt export pump (BSEP) Multidrug resistance associated protein 2 (MRP2)
Both these are ABC transporters with wide substrate specificities (LEARN THIS!) Z: taurine, glycine Y: sulphate, glucuronate


ABC transporters

stands for ‘ATP Binding Cassette’ Transporters.
Huge family of ‘pumps’ using
ATP hydrolysis to import or
export a wide range of substrates.
Common structure:
2 transmembrane domains (TMDs)
2 nucleotide-binding domains (NBDs)
Alternating access mechanism powered by ATP


enterohepatic circulation of bile acids

Some unconjugated bile acids
are passively reabsorbed across the proximal intestinal wall.
This is because they are lipid soluble and so can pass through the lipid cell membranes of the intestinal cells.
Active uptake of conjugated bile salts occurs in the terminal ileum via Na+ -bile salt (co)transporter [ASBT] and organic solute transporter [OST].


Biliary tree

R and L hepatic duct, common hepatic duct, -cystic duct, common bile duct, panreatic duct, sphincter of Oddi-major duodenal papilla. The biliary tree/duct is lined with epithelial cells called cholangiocytes. 
30-50% of hepatic bile is secreted by cholangiocytes.
The bile secreted is a HCO3- -rich, isosmotic fluid.
Mechanism of secretion:
Secondary active transport of Cl- and HCO3 –
Paracellular Na+ transport
Isosmotic water flow
Stimulated by CCK, secretin, VIP, glucagon.
Inhibited by somatostatin.
ACh causes contraction of the gall bladder and the relaxation of the sphincter of Oddi, therefore promoting
the entry of bile into duodenum


plasma proteins

Albumin - major function of albumin is to provide colloid osmotic pressure in the plasma, which prevents plasma loss from the capillaries.
Globulin - perform a number of enzymatic functions in the plasma, but equally important, they are principally responsible for the body’s both natural and acquired
immunity against invading organisms (immunoglobulins – antibodies).
Fibrinogen - polymerizes into long fibrin threads during
blood coagulation, thereby formingblood clots that help repair leaks in the circulatory system.


formation of plasma proteins

All of albumin, fibrogen, and 50-80% of globulin is produced in the liver. 
20-50% of the globulin is produced in lymphoid tissues.
In liver conditions, such as in cirrhosis, the ability of the liver to produce plasma proteins
decreases greatly.
This leads to decreased colloid osmoic pressure, which causes generalised oedema


plasma proteins as a source of amino acids

When tissues become depleted of proteins, the plasma proteins can act as a
source of rapid replacement.
These proteins are taken up by macrophages by pinocytosis; once these plasma proteins enter these cells, they split into amino acids that are transported back into the blood and used
throughout the body to build cellular proteins wherever needed.
In this way, the plasma proteins
function as a protein storage medum and represent a readily available source of amino acids wherever a particular tissue requires them.


amino acid metabolism

Unlike carbohydrates and fatty acids, amino acids have no storage form (except plasma
All must be taken up with the diet or recycled via regular turnover of body proteins (about 400g/ day).
Excess amino acids follow one of three paths: 1)Degraded, and the generated nitrogen excreted largely as urea (Ornithine cycle)
2)Most are used for gluconeogenesis (“glucogenic”).
3)Some are used for ketogenesis – making acetyl-CoA or acetoacetate - (“partially/fully ketogenic”).


catabolising amino acids 'transamination reaction'

The catabolism of most amino acids is carried out via a transaminase reaction.
This reaction depends mainly on the formation of appropriate α-keto acids, which are precursors of the respective amino acids.
Then the process of transamination takes place as follows: 1.An amino radical is transferred to the a-keto acid
2.The keto oxygen is transferred to the donor of the amino radical. This reaction is promoted by transaminase enzymes


example of a transamination reaction

Pryuvic acid, which is formed in large quantitites during the
glycolytic breakdown of glucose, is the α-keto acid
precursor to alanine.
Transamination process:
Amino radical group is transferred from glutamine (amino acid) to pyruvic acid, forming alanine (amino acid)
Keto oxygen is transferred from pyruvic acid to glutamine, forming α-ketoglutamic acid
This reaction is reversible:
Alanine and α-ketoglutamic acid swap the amino radical and keto oxygengroups to form pyruvate and glutamine


transamination of products

Glutamate and Pyruvate can be transaminated into alanine. Glutamine and Pyruvic acid can be transaminated into alanine. Glutamate is converted to α-ketoglutarate acid Glutamine is converted to α-ketoglutamic acid Pyruvic acid and Pyruvate are both converted to alanine


transaminase enzymes

Most transaminases are cytoplasmic enzymes that are quite specific for one or few amino acids.
Alanine transaminase (ALT) is a typical enzyme in that is fully reversible and does not strongly favour one direction:
Aspartate transaminase (AST)
is an exception because the product of this reaction enters the ornitihine cycle.
The α-amino group of glutamate that has come from many other amino acids is transferred to oxaloacetate to form aspartate and from there is fed into the urea cycle (ornitihine cycle).
Therefore, the forward reaction (producing asparate)is favoured in the attempt to remove excess NH2 from the body via the ornithine cycle.
This is why this reaction isn’t fully reversible. Glutamate and Pyruvate can be transaminated into alanine.
Glutamine and Pyruvic acid can be transaminated into alanine.
Glutamate is converted to
α-ketoglutarate acid Glutamine is converted to α-ketoglutamic acid Pyruvic acid and Pyruvate are both converted toalanine.
Increased levels of these enzymes in blood plasma, especially of ALT and AST, are diagnostic of cell/ tissue damage.
ALT is more specifically indicative of liver damage, but serum AST is more sensitive because the liver contains larger amounts of AST than ALT.



This is the removal of amino groups from the amino
acids. The greatest amount of deamination occurs by the following schema:
The amino acid (which contains an amine group [-NH2) reacts with water and NAD+. This forms NADH, H+ and NH3. NH3 can now travel to the liver. NH3 cannot frrely travel in the blood and so is converted to glutamine (in peripheral tissue) or alanine (in muscles), which can then travel to the liver for the removal of NH3 in the ornithine cycle.


delivery of Ammonia to the liver for removal as urea

In peripheral tissues excess ammonia is converted - glutamine and sent liver. there two NH3 are released from glutamine by glutaminase and then glutamate dehydrogenase. Amm can also be transferred to oxaloacetate by aspartate transaminase. feeds into urea cycle. Can also go to liver by alanine glucose shuttle, alanine from muscle deliver NH3 via ALT-pyruvate goes into gluconeogenesis.
In liver mitochondria AM and CO2 joined by carbamoyl phosphate synthetase I, 2ATP used. In urea cycle 2 AM and 1 BiC are converted urea. total 4ATP. Urea-kidney for excretion.


urea formation

The ammonia released during deamination of amino acids is removed form the blood almost entirely by conversion to urea. The urea is synthesised in the liver (ornitihine cycle).  In liver pathology, ammonia accumulates in the blood, which is extremely toxic, especially to the brain, often leading to a state called hepatic enencephalopathy/ coma


gluconeogenesis and ketogenesis

Certain deaminated amino acids can be used to synthesize glucose or fatty acids in hepatocytes. e.g, deaminated alanine and pyruvic acid can be converted into Either glucose or glycogen Acetyl-CoA, which can then be: Polymerized into fatty acids, Condensed to form acetoacetic acid which is one of the ketone bodies. The conversion of amino acids into glucose or glycogenis called gluconeogenesis.The conversion of amino acids into keto acids or fatty acids is called ketogenesis.Of the 20 deaminated amino acids, 18 have chemical structures that allow them to be converted into glucose, and 19 of them can be converted into fatty acids.


growth hormone

Yafaa Chaudhary: Semester 4 – Case 5 Notes: Jay Jones 20 Urea Formation The ammonia released during deamination of amino acids is removed form the blood almost entirely by conversion to urea. The urea is synthesised in the liver (ornitihine cycle).  In liver pathology, ammonia accumulates in the blood, which is extremely toxic, especially to the brain, often leading to a state called hepatic enencephalopathy/ coma. Protein Use for Energy Gluconeogenesis and Ketogenesis Certain deaminated amino acids can be used to synthesize glucose or fatty acids in hepatocytes. For example, deaminated alanine and pyruvic acid can be converted into: Either glucose or glycogenAcetyl-CoA, which can then be: Polymerized into fatty acidsCondensed to form acetoacetic acidwhich is one of the ketone bodies. The conversion of amino acids into glucose or glycogenis called gluconeogenesis.The conversion of amino acids into keto acidsor fatty acidsis called ketogenesis.Of the 20 deaminated amino acids, 18 have chemical structures that allow them to be converted into glucose, and 19 of them can be converted into fatty acids. Hormonal Regulation of Protein Metabolism Growth Hormone Growth Hormone increases the synthesis of cellular proteins. Growth hormonecauses the tissue proteins to increase. This results from: Increased transport of amino acids through the cell membranes.Acceleration of the DNA and RNA transcription and translation processes for protein synthesis



Insulin is necessary for protein synthesis and storage.Total lack of insulin reduces protein synthesis to almost zero. Insulin:Accelerates the transport of some amino acids into cells, which acts as a stimulus for protein synthesis. Increases the availability of glucose to the cells (gluconeogenesis), so that the need for amino acids for energy is correspondingly reduced.



Yafaa Chaudhary: Semester 4 – Case 5 Notes: Jay Jones 20 Urea Formation The ammonia released during deamination of amino acids is removed form the blood almost entirely by conversion to urea. The urea is synthesised in the liver (ornitihine cycle).  In liver pathology, ammonia accumulates in the blood, which is extremely toxic, especially to the brain, often leading to a state called hepatic enencephalopathy/ coma. Protein Use for Energy Gluconeogenesis and Ketogenesis Certain deaminated amino acids can be used to synthesize glucose or fatty acids in hepatocytes. For example, deaminated alanine and pyruvic acid can be converted into: Either glucose or glycogenAcetyl-CoA, which can then be: Polymerized into fatty acidsCondensed to form acetoacetic acidwhich is one of the ketone bodies. The conversion of amino acids into glucose or glycogenis called gluconeogenesis.The conversion of amino acids into keto acidsor fatty acidsis called ketogenesis.Of the 20 deaminated amino acids, 18 have chemical structures that allow them to be converted into glucose, and 19 of them can be converted into fatty acids. Hormonal Regulation of Protein Metabolism Growth Hormone Growth Hormone increases the synthesis of cellular proteins. Growth hormonecauses the tissue proteins to increase. This results from: Increased transport of amino acids through the cell membranes.Acceleration of the DNA and RNA transcription and translation processes for protein synthesis. Insulin Insulin is necessary for protein synthesis and storage.Total lack of insulin reduces protein synthesis to almost zero. Insulin:Accelerates the transport of some amino acids into cells, which acts as a stimulus for protein synthesis. Increases the availability of glucose to the cells (gluconeogenesis), so that the need for amino acids for energy is correspondingly reduced. Glucocorticoids Glucocorticoids increase breakdown of most tissue proteins. The glucocorticoidssecreted by the adrenal cortex:Decreasethe quantity of protein in mosttissues while increasing the amino acid concentration in the plasma.Increaseboth liver proteins and plasma proteins. Glucocorticoids act by increasing the rate of breakdown of extrahepatic proteins, thereby making increased quantities of amino acids available in the body fluids.This allows the liver to synthesize increased quantities of hepatic cellular proteins and plasma proteins



Testosterone increases protein deposition in tissues. Testosterone, the male sex hormone, causes increased deposition of protein in tissuesthroughout the body, especially the contractile proteins of the muscles (30-50% increase).The mechanism of testosterone is different from the effect of growth hormone, in the following way: Growth hormonecauses tissues tocontinue growing almost indefinitely, whereas testosterone causes the muscles and, to a much lesser extent, some other protein tissues to enlarge for only several months. Once the muscles and other protein tissues have reached a maximum, despite continued administration of testosterone, further protein deposition ceases



Oestrogen, the principal female sex hormone, also causes some deposition of protein, but its effect is relatively insignificant in comparison with that of testosterone



Thyroxineincreases the rate of metabolism of all cells and, as a result, indirectly affects protein metabolism. If insufficient carbohydrates and fats are available for energy, thyroxine causes rapid degradation of proteins and uses them for energy. Conversely, if adequate quantities of carbohydrates and fats are available and excess amino acids are also available in the extracellular fluid, thyroxine can actually increase the rate of protein synthesis. In growing animals or human beings, deficiency of thyroxine causes growth to be greatly inhibited because of lack of protein synthesis


drug disposition

absorption, metabolism and excretion of a drug


pharmacokinetics and dynamics respectivly

body does to drug (metabolism)
Drug does to body (effect of drug)


absorption of drugs

in stomach and small intestine. dministered orally, it must first undergo dissolution (disolving of the solid tablet); then it undergoes absorption (stomach/ small intestine) into the bloodstream (hepatic portal vein). Travels to liver. undergoes first pass metabolism then to systemic circulation. Greater conc of drug greater bio availability. there are portal/systemic anaastomoses which allow bypassing presystemic metab. Lipid sol drugs pass cell mem. Water sol cant. distribution of drug dependant lipid sol.


factors effecting distribution

Lipid solubility of the drugLipid-soluble can diffuse across cell membrane 2.Blood flow to the tissue/organ 3.Protein Bindingof the drug to proteins Free drug can bind to carrier proteins in the plasma, e.g. albumin Only free or unbound drug can diffuse across membranes and have an affect Decrease in the levels of albumin will lead to more free drug(increased volume of distribution [Vd]) in the blood, thus a greater affect caused by the drug – this is problematic with drugs with a narrow therapeutic window. An increase in bilirubin can cause displacement of drugs from albumin.
vol=dose/plasma conc



Drug elimination= metabolism + excretion. Most drugs are lipophilic. Therefore, it is hard for the body to excrete them. In order for the body to excrete the drug, it must convert it into a water-soluble substance.


drug metabolism

This is the enzyme-mediated conversion of a lipid-soluble drug intoa more water-soluble one, so that it may be excreted. Sites of metabolism: liver(SER), kidney, lung, GI tract, Brain, plasma.


liver metabolism-detoxification: functionalisation

Addition/uncovering of functional (chemically reactive) groups, e.g. C-H to C-OH.This prepares the molecule for the next phase by making it slightly polar (slightly more water-soluble)


liver metabolism-detoxification: oxidation

This occurs via enzymes such as alcohol dehydrogenase, MAO, and mainly by CYP450 and CYP3A4 (cytochrome family of enzymes)


liver metabolism-detoxification: pharmacological activation

The inactive compound has now become chemicallyactive. Usually this would reduce the activity of the drug.But, for some drugs, their activity is increased – PRODRUGS


liver metabolism phase 2

Conjugation with charged species. Active compounds become less active because now the molecule is bigger and more water soluble and so can no longer bind to its receptor (decreased receptor affinity) in tissues, but instead can be excreted in urine (enhanced excretion) – PHARMACOLOGICAL INACTIVATION


drug metabolizing enzymes

Enzymes can be induced: decrease the duration of drug action (e.g. alcohol can cause this/ smoking induces CYP1A2)Enzymes can be inhibited: increase the duration of drug action (e.g. grapefruit juice can cause this by inhibiting CYP3A4 – this enzyme metabolises 30% of all drugs)These effects occur due to drug interactions with certain substances


outcomes of drug metabolism

Pharmacological Activation, e.g. pro-drugs – the drug has increased effect.2.Pharmacological Inactivation, e.g. paracetamol – the drug has a reduced effect.3.Change in Type of Pharmacological Response, e.g. diazepam → oxazepam 4.No Change in Pharmacological Activity, e.g. lidocaine → monoethylglycylxylidide 5.Change in Drug Distribution


factors effecting metabolism of drugs

Age – reduced; drug inactivation is slower; reduced first-pass metabolism GenderPregnancy – increased hepatic metabolism Genetic Disease – this damages the metabolic enzymes, therefore reducing metabolism


external factors effecting metabolism of drugs

Lifestyle- cigarette smoking induces metabolism of by inducing CYP1A2: theophylline, caffeine, tacrine, imipramine, haloperidol, pentazocine, propranolol, flecainide, estradiol Environment (pollutants) Diet (BBQed meat, brussel sprouts ↑, grapefruit juice ↓by inhibiting CYP3A4) These factors can be inducers or inhibitors


liver disease outcomes on metabolism

Serum albumin used as marker of liver pathology.Reduced hepatocyte function CYP450 reduced in severe diseaseReduced blood flow through the liverReduced first-pass metabolism- this causes increased plasma concentration of metoprolol, labetalol and clomethiazoleIncreased half-life of the drugReduced clearance (e.g. diazepam, tolbutamide, rifampicin)



This is the removal of a drug (drug metabolites (phase 1 and phase 2 products) and water-soluble drugs) from the body. Sites of excretion: urine, bile, faeces, lungs and skin. To increase drug excretion: 1.Increase blood flow to the kidneys. 2.Decrease plasma protein binding.


prescribing for patients with liver disease

Risk/benefit analysis Select alternative drugs eliminated by routes other than liver. Monitoring of drugs with narrow therapeutic windows, e.g. warfarin. Drugs with known hepatotoxicity (e.g. cytotoxic drug) should only be used for strongest of indications


adverse drug reactions

Aim - desired effect with minimum toxicity. People exhibit variable responses:This is due to a genetic or heritable component.The genetic variability can have an effect on:Transport – uptake and efflux (e.g. P-gp)Cellular targets and signalling pathways (e.g. B2-adrenorecptors and salbutamol)Metabolism (changes in enzymes) Polymorphisms (due to mutations) have been identified in every pathway of drug metabolism



P-gp- protects cells from toxic substances or metabolites by preventing their absorption in the duodenum, e.g. anticancer drugs and digoxin. Expressed in liver, kidney, GI tract & BBB. A mutation (SNP in C3435T) can lead to decreased amounts of P-gp in the intestine. This means that more toxic substances can be absorbed, leading to side effects


genetic variability and effect on clearance

The more severe the mutation, the longer it takes to clear the drug after metabolism. However, this genetic variablility can lead to a variety of proteins which cause metabolisation at different rates E.g. Ultrarapid Metabolisers These increase metabolism and decrease the concentration of plasma drug concentration. These ultrarapid metabolisers form because there are extra copies of genes that encode these proteins.


causes of hepatitis

Viral infection - e.g. hepatitis A, hepatitis BImmunological - e.g. autoimmune, graft v host disease Toxins - e.g. carbon tetrachloride, alcoholDrugs - e.g. paracetamol, rifampicin Bacterial infection - e.g. leptospirosis Parasite infection - e.g. hydatid, clonorchiasis Vascular congestion - e.g. portal vein thrombosis


symptoms of hepatitis

non-specific and include fatigue, lethargy, itching. It may also lead to some specific symptoms, for example: jaundice, right upper quadrant pain.


diagnostic markers of the liver

AST and ALT will be elevated in a hepatitis infection. If AST > ALT = alcoholic hepatitis. If ALT > AST = other causes (mainly viral)


causes of viral hepatitis

Common Causes: Hepatitis A Virus (HAV) Hepatitis B Virus (HBV) Hepatitis C Virus (HCV) Hepatitis D Virus (HDV) – hepatitis delta Hepatitis E Virus (HEV) Less Common Causes: Cytomegalovirus (congenital and perinatal infection)Epstein-Barr virus (adolescence
Rare Causes: Herpes simplex (congenital and perinatal infection)Yellow fever


course of viral hepatitis

Acute infection = this can be resolved by the body and the symptoms aren’t severe. An acute infection can develop into a chronic infection. Chronic infection = symptoms are more severe than an acute infection and can develop into cirrhosis/ hepatocellular carcinoma. Fulminant infection


transmission of hepatitis

Hep A and E are Enteral (faecal/oral involves GI)
Hep B,C,D are Parenteral (IVDU blood sex vertical doesnt involve GI)


nucleic acid in Hepatitis

Hep A and E are RNA no envolope.
Hep C and D are RNA with envolope. Hep B is DNA with envolope.


type of infection with hepatitis

they are all acute, Hep D must have Hep B. Hep A and E are self limited so can resolve itself. Only Hep B-D are chronic and can develop into cirrhosis and hepatocellular carcinoma.


types of antigen

Surface antigens (sAg) = the presence of these indicates the presence of the virusin the body. Core antigens (cAg) = indicates that the body is producing antibodies against the virus.Modified core antigens (eAg) = the presence of these indicates the viral cell is actively replicating. This means the person has higher infectability



mmune response against the antigen. The body can make: IgM – this is the iMMediate response IgG – this is the chronic response


hep B virus

HBsAg = this is the surface antigen found on the envelope of HBV. HBcAg = this is the core antigen found around the nucleus of HBV. HBeAg = this is the modified c antigen that appears when the viral cell is actively replicating. Anti-HBs antibody = the presence of this would give the person immunity against HBVAnti-HBc antibody = this can be HBc IgM (immediate) or HBc IgG (chronic) Anti-HBe antibody = the presence of this would reduce infectability


hep A

The hepatitis A virus (HAV)belongs to the picornavirus group of enteroviruses.HAV is highly infectious and is spread by the faecal-oral route.Hepatitis A infection is usually asymptomatic because the virus remains in the faeces for about 2-3 weeks before the onset of symptoms for a further 2 weeks or so.Infection is common in children, in areas of overcrowding, and areas of poor sanitation/ underdeveloped areas. HEPATITIS A INFECTION IS ALWAYS ACUTE!!! high in africa. found in shelfish.


investigations for hep a

The HAV carries a HAV antigen. Individuals infected by HAV make an antibody against the HAV antigen(anti-HAV). Anti-HAVof the IgM type= indicates a primary immune response (diagnostic of an acute HAV infection). Anti-HAVof the IgG type= this antibody persists for years after infection (no diagnostic value), but it can be used as a marker of previous HAV infections. Its presence indicates immunity to HAV.


course of hep A

ncubation Period – 2-6 weeks Normally:ACUTE, self-limited, mildNEVER CHRONIC Jaundice about 1 week, LFTs up for 3 weeks Often asymptomatic, especially children Cholestatic:


prevention of hep A

Human normal immunoglobulin (immunoglobulin/antibody replacement therapy) After contact with case. Hepatitis A vaccination (e.g. Harvix) After contact Before travel to endemic areas Higher risk groups Occupational (e.g. sewage workers, primate handlers) Drug users, prisoners MSMs Infection is best prevented by improving social conditions, especially overcrowding and poor sanitation.


symptoms of hep b

ncubation Period = 4-20 weeks Many people have no symptoms during the initial infection but some develop a rapid onset of sickness with vomiting, yellow skin, feeling tired, dark urine and abdominal pain. Often these symptoms last a few weeks and rarely does the initial infection result in death. It may take 30 to 180 days for symptoms to begin.


epidemiology of hep b

>2000 million have had infection 367 million carriers (WHO estimate) 177 countries universal vaccination In Europe: 1 million new cases per year 40000 at risk of progression to cirrhosis 20000 at risk of primary liver cancer Universal vaccination - except UK, Scandinavia


prevalence of hep b

A current infection is indicated by the presence of HBsAg (antigens on the Hep B virus) in the blood. A past infection is indicated by the presence of anti-HBsantibodies in the blood.  N.Europe, USA, Australasia HBsAg 0.2-0.5% anti-HBs antibody 4-6% E.Europe, S.Europe, USSR, S.America HBsAg 2-7 % anti-HBs 20-50% China, S.East Asia, sub-Saharan Africa HBsAg 8-20% anti-HBs 70-95%


hep B virus replication

HBV binds to the NTCP bile receptor on hepatocytes. This allows the virus to enter the cell. 2.The HBV DNA is partially double stranded. 3.The viral DNA enters the host cell nucleus and uses the host cell’s DNA to complete its DNA from partially double-stranded to a ‘covalently closed circular DNA’ (cccDNA).4. The viral DNA is now transcribed into viral RNA. 5.This is then translated to produce viral antigens and other viral proteins. 6.The viral RNA undergoes reverse transcription in the viral nucleocapsid to form its partially double stranded DNA once again. 7.This is now packaged within the viral antigens. 8.This is then exocytosed and infects other cells.


screening for hep B

Is the person currently infected with hepatitis B? Hepatitis B surface antigen (HBsAg) POSITIVE – refer these people to secondary care. Vaccinate their contacts.Hepatitis B surface antigen (HBsAg) NEGATIVE – not currently infected but may have been exposed to infection. 2.Has the person ever been exposed to hepatitis B? Total antibody to hepatitis B core antigen (anit-HBc) if HBsAgpositive: Other markers are used to help define: 1.Whether this is an acute infectionoIndicated by IgM antibodyto core antigen (anti-HBc IgM)2.How infectious the patient is to their contacts oPositive for e antigen (HBeAg) and/or high levels of HBV DNA. f HBsAgnegative: Other markers are used to help define: 1.Whether the person has ever been exposed to hepatitis B oIndicated by total antibody to core antigen (anti-HBc) 2.Whether the person is immune to hepatitis B oIndicated by being positive for antibody to HBsAg (anti-HBs). oIf not known, or low levels, complete vaccination course.


antigens and antibodies in hep b

HBsAg = this is the surface antigen found on the envelope of HBV. HBcAg = this is the core antigen found around the nucleus of HBV. HBeAg = this is the modified c antigen that appears whenthe viral cell is actively replicating. Anti-HBs antibody = the presence of this would give the person immunity against HBV Anti-HBc antibody = this can be HBc IgM (immediate) or HBc IgG (chronic) Anti-HBe antibody = the presence of this would reduce infectability. Anti-HBc IgG + HBsAg = the presence of this combination indicates a chronic infection. Anti-HBc IgG + Anti-HBsAg = the presence of this combination indicates complete immunityagainst the infection


4 phases of Hep B life cycle

Immune tolerance: HBeAg+ HBV DNA high +. ALT normal. mild liver inflam.
2-immune clearence- HBeAG+ to - with appearece of anti HBe. HBV DNA high +, ALT raised, liver inflam. fibrosis.
3. Low replication inactive carrier- anti-HBe+, HBV DNA -. ALT normal. Poss HbsAg loss.
4. reactivation phase-HBeAg but mutant virus. HBV DNA and ALT raised. liver inflam.


aims of HBV therapy

o convert HBV from High replication phase to a Low replication phase HBeAg + to anti-HBe ALT normalization Reduced hepatic inflammation Prevent histological progression – Decrease risk of progression to cirrhosis and HCC 20-40% cases seroconvert to anti-HB


antiviral agents active in Hep B

nterferonIf HBeAg+ low HBV DNA more chance of losing HBsAg but side effects Nucleoside analogues (NUCs)- Fall to


prevention of hep B

Vaccination is recommended by the World Health Organization in the first day of life if possible. Two or three more doses are required at a later time for full effect (0 months, 1 month, 6 months). This vaccine works about 95% of the time. Use in UK for people at high risk including: Close family members & sexual partners of carriers Healthcare workers Drug users, prisoners Male homosexuals Babies born to HBV carrier mothers It is also recommended that all blood be tested for hepatitis B before transfusion and condoms be used to prevent infectio


interventions to protect babies in the UK

Antenatal screening - HBsAg positive woman: If HBeAg positive motherActive infection, High HBV viral load Hepatitis B immunoglobulin plus Hepatitis B vaccine oAccelerated schedule (0, 1m, 2m, 12m) If anti-HBe positive motherHepatitis B vaccine only oAccelerated schedule (0, 1m, 2m, 12m)


hep c

Non-A, Non-B (NANB) Hepatitis. Flavivirus RNA virus 1989 Hepacivirus genus Incubation period: Average 6-7 weeks Range 2-26 weeks Acute illness (jaundice) Mild (≤20%) Case fatality rate Low Chronic infection*60%-85. HCV Therapy: Combination therapy 24-48 weeks Pegylated interferon-αweekly RibavirinRNA-dependent RNA polymerase inhibitor Reduces GTP pool RNA mutagen giving defective HCV (“error catastrophe”) Immunomodulator.


new advances in treatment

Telaprevir, Bocepravir Protease inhibitors >70% response at 12 weeks genotype 1 Cf 40% G1 IFN/ribavirin Simeprevir good response G1 if Q80K negative Polymerase i`nhibitors Sofusbuvir Interferon-free treatments daclatasvir + asunaprevir ombitasvir–ABT-450/r and dasabuvir with ribavirin sofosbuvir + simepravi


hep D

Can only occur in presence of hepatitis B. Transmission by blood, especially IVDU, sexTwo forms of infection: Coinfection with HBV HDV acquired at same time as HBV.Increase in fulminant hepatitis.SuperinfectionHDV acquired by hepatitis B carrier. High risk of progression to cirrhosis - 70% High risk of hepatocellular carcinoma - 16%


hep E

Hepatitis E is caused by an RNA virus which is endemic in India and the Middle East. 20 million infections per year 3 million acute cases 57000 HEV-related deaths – principally due to genotypes 1,2 Incubation period 15-60 days (mean 40d). Symptoms Jaundice Abdominal pain Nausea and vomiting Anorexia Commonly anicteric in children High death rate in pregnant women Overall death rate 1-2 % (cf hepatitis A



Jaundice - refers to a yellowish tint to the body tissues, including a yellowness of the skin as well as the deep tissues. It is caused by large quantities ofbilirubin(freeor conjugated)in the extracellular fluids: I.Pre-hepatic Jaundice II.Intra-hepatic JaundiceIII.Post-hepatic JaundiceThe normal plasma concentration of bilirubin, which is almost entirely the free form, averages 0.5 mg/dl of plasma. In certain abnormal conditions, this can rise to as high as 40 mg/dl, and much of it can become the conjugated type. The skin usually begins to appear jaundiced when the concentration rises to about three times normal—that is, above 1.5 mg/dl


pre hepatic jaundice

This is caused either by haemolysis or by congenital hyperbilirubinaemia, and is characterised by an isolated raised bilirubin level (other liver biochemistry remains normal).Haemolysis:This is the destruction of RBCs or their precursors in the bone marrow. This causes increased bilirubin production.Therefore, the plasma concentration of unconjugated bilirubinrises to above normal levels. Likewise, the rate of formation of urobilinogenin the intestine is greatly increased, and much of this is absorbed into the blood and later excreted in the urine. Jaundice due to haemolysis is usually mild because a healthy liver can excrete a bilirubin load six times greater than normal before unconjugated bilirubin accumulates in the plasma


intra hepatic jaundice/hepaticellular

caused by impaired cellular uptake, defective conjugation or abnormal secretion of bilirubin by hepatocytes, occurring as a consequence of parenchymal liver disease. Bilirubin transportacross the hepatocytes may be impaired at any point between uptake of unconjugated bilirubin into the cells and transport of conjugated bilirubin into the canaliculi. In hepatocellular jaundicethe concentrations of both unconjugated and conjugated bilirubin in the blood increase. Hepatocellular jaundicecan be due to acute or chronic liver injury and clinical features of acute or chronic liver disease may be detected clinically. Characteristically, jaundice due to parenchymal liver disease is associated with increases in transaminases (AST, ALT), but increases in other LFTs, including GGT and ALP may occur, and suggest specific aetiologies. Acute jaundice in the presence of raised AST is highly suggestive of an infectious cause (e.g. hepatitisA, B), drugs (e.g. paracetamol) or hepatic ischaemi


post hepatic jaundice/obstructive(cholestatic)

Failure of hepatocytes to initiate bile flow. Obstruction of bile flow in the bile ducts or portal tracts. Obstruction of bile flow in the extrahepatic bile ducts between the porta hepatis and the papilla of Vater. In obstructive jaundice, caused either by obstruction of the bile ducts (e.g. gallstone/ cancer blocking the common bile duct) or by damage to the hepatic cells (which occurs in hepatitis), the rate of bilirubin formation is normal, but the bilirubin formed cannot pass into the intestines.The unconjugated bilirubinstill enters the liver cells and becomes conjugated in the usual way. This conjugated bilirubinis unable to enter the bile canaliculi and passes back into the blood.Thus, most of the bilirubin in the plasma becomes the conjugated type rather than the unconjugated type.unable to enter the bile canaliculi and passes back into the blood. There is a failure of clearance of unconjugated bilirubin arriving at the liver


obstruction of bile/bilirubin

When there is total obstruction of bile flow, no bilirubin can reach the intestines to be converted into urobilinogen by bacteria. Therefore, no urobilinogen is reabsorbed into the blood, and none can be excreted by the kidneys into the urine (urobilin). Consequently, in total obstructive jaundice, tests for urobilinogen in the urine are completely negative.Also, the stools become clay (pale) coloured owing to a lack of stercobilin.



Hepatic cirrhosisis a common disease characterised by diffuse hepatic fibrosis and nodule formation. It can occur at any age, has significant morbidity and is an important cause of premature death.Worldwide, the most common causes of cirrhosis are: Chronic viral hepatitis (B or C) Prolonged excessive alcohol consumptionChronic use of alcohol raises the mean corpuscular volume (MCV) and the enzyme GGT. Cirrhosis is the most common cause of portal hypertension and its associated complications. Any condition leading to persistent or recurrent hepatocyte death, such as chronic hepatitis C infection, may lead to cirrhosis.


pathophysiology of cirrhosis

increase in fibrous tissueProgressive and widespread death of liver cellsInflammation leading to loss of normal liver architecture Following liver injury, stellate cells in the space of Disse are activated by cytokinesproduced by Kupffer cells and hepatocytes. This transforms the stellate cell into a myofibroblast-like cell, capable of producing collagen, pro-inflammatory cytokines and other mediators which promote hepatocyte damage and cause tissue fibrosis. Destruction of liver architecture causes distortion and loss of normal hepatic vasculature with the development of portosystemic vascular shunts and the formation of nodules. Cirrhosisevolves slowly over years to decades, and normally continues to progress even after the removal of the aetiology agent (e.g. abstinence of alcohol). Cirrhosis is a histological diagnosis characterised by diffuse hepatic fibrosis and nodule formation. These changes usually affect the whole liver. A reduction in liver size is especially common of the cause of cirrhosis is viral hepatitis or autoimmune liver disease


liver function tests-bilirubin



liver function test-albumin

Serum albumin levels are reduced in patients with liver disease. This is due to the change in the volume of distribution of albumin, as well as reduction in synthesis. Since the plasma half-life of albumin is about 2 weeks, serum albumin levels may be normal in acute liver failure but are almost always reduced in chronic liver failure



Alanine aminotransferase (ALT) and Asparate aminotransferase (AST)normally transfer the amino group from an amino acid – alanine in the case of ALT and asparate in the case of AST – to a ketoacid, producing pyruvate and oxaloacetate respectively. Both ALT and ASTare located in the cytoplasm of the hepatocyte. AST is also located in the cytoplasm of the mitochondria. Although both transaminase enzymes are widely distributed, expression of ALT outside the liver is relatively low and therefore this enzyme is considered more specific for hepatocellular damage. Large increases (>300 U/L) of aminotransferase activity favour hepatocellular damage, and this pattern of LFT abnormality is known as ‘hepatitic


Alkaline Phospatase ALP

Alkaline Phosphatase (ALP)is the collective name given to the several different enzymes that are capable of hydrolysing phosphate esters at alkaline pH. These enzymes are widely distributed around the body, but the main sites of production are the liver, GI tract, bone, placenta and kidney. ALP enzymesin the liver are located in cell membranes of hepatic sinusoids and the biliary canaliculi/ducts. ALP rise in plasma concentration is indicative of intrahepatic and extrahepatic biliary obstruction and with sinusoidal obstruction, as occurs in infiltrative liver disease.


Gamma Glutamyl Transferase GGT

Gamma-Glutamyl Transferase (GGT) is a microsomal enzymeproduced in high concentrations by hepatocytes and by the epithelium lining of the small bile ducts. The function of GGT is to transfer glutamyl groups from gamma-glutamyl peptides to other peptides and amino acids. The pattern of a modest increase in aminotransferase activity and large increases in ALP and GGT activity favours biliary obstruction and is commonly described as ‘cholestatic’ or ‘obstructive’.


differences in bilirubin in pre, intra and post hepatic jaundice

pre-plasma concentration of unconjugated bilirubin rises
intra-the concentrations of both unconjugated and conjugated bilirubin in the blood increase.
post-conjugated bilirubin is unable to enter the bile canaliculi and passes back into the blood.
There is a failure of clearance of unconjugated bilirubin arriving at the livertests for urobilinogen in the urine are completely negative.


in an absorptive state



in a fasting state

glycogenolysis ketogenesis



Catabolism (breaking down) of
glucose (and most other
carbohydrates via glucose) in all
Generation of intermediates for
other pathways
Generation of energy and (in
aerobic conditions) reducing
End product depends on O2
Pyruvate under aerobic
conditions, Lactate under
anaerobic conditions
A family of glucose transporters (GLUT) facilitates
diffusion of glucose into cells.
Many are tissue-specific: GLUT-4 in adipose tissue;
GLUT-2 in liver
GLUT-2 can facilitate both glucose entry into liver cells and exit


trapping glucose in the liver

Phosphorylation traps glucose in the cell. because the
ionic phosphate cannot cross the membrane
The reaction is catalysed by the enzyme Hexokinase.
Enzyme variants in most tissues (Hexokinase I-III) are
relatively slow but are fully active at very low
concentrations of glucose.
Hexokinase-IV, or Glucokinase, in the liver has a much
higher capacity to trap glucose in the liver, but only
when glucose concentrations are high- eg after a meal


phosphofructokinase 1

acts after isomerisation of Glucose-6-P to
Fructose-6-P and is catalyses the most important
regulated step of glycolysis:
• It is the rate-limiting (slowest) step in glycolysis
• PFK-1 is allosterically activated by AMP
(activation by low energy levels in the cell) and
repressed by ATP and citrate
• PFK-1 is activated by Fructose-2,6-
bisphosphate whose biosynthesis in turn is
regulated by insulin and glucagon


glycolysis after PFK1

the C6 molecule F-1,6-BP is cleaved into two
C3 molecules;
• In the only oxidative step of glycolysis, GA-3P
is converted to 1,3-BPG.
• NADH + H+ generated in this oxidative step can
be regenerated under anaerobic conditions by
reducing pyruvate to lactate.
• This happens in exercising skeletal muscle and
poorly vascularized and/ or mitochondria-free
• The liver can re-oxidise lactate to pyruvate.
1,3-BPG and PEP are high-energy compounds
that can transfer phosphate to ADP (substrate
level phosphorylation). That way, 4 ATP are
generated from each molecule of F-1,6.
• Accounting for the “investment” of 2 ATP per
molecule glucose early on, there is a net
generation of 2ATP per glucose in
• Pyruvate kinase, the last enzyme of glycolysis,
is activated by Fructose-1,6-bisphosphate
(feed forward activation!) and repressed by



Glycogen stores in the liver can
supply glucose-dependent
tissues with most of the fuel
during an overnight fast, but not
much longer. Gluconeogenesis
is a pathway active in the liver
(and after prolonged fasting,
the kidney) that regenerates
glucose from non-carbohydrate
• Lactate from skeletal
muscle is re-oxidised to
Pyruvate. This liver-muscle cycle is called Cori Cycle
Glucagon is the main
regulator of gluconeogenesis.
It acts by repressing ( )
pyruvate kinase, thus
increasing the availability of
PEP for gluconeogenesis.
Glucagon also increases the expression ( ) of PEP
carboxykinase. Finally, glucagon represses
the formation of F-2,6-BP,
which is a repressor of
in gluconeogenesis (while it is
an activator of PFK-1 in



Is a highly branched, all-glucose polysaccharide
with an α-1,4-linked backbone and
α-1,6-linked branches
• Resembles the amylopectin component of plant
starch, but is more highly branched.
• Is the storage form of glucose, mainly in
skeletal muscle (1-2% by weight, total ~400g)
and liver (up to 10% by weight, total ~100g


glucogenesis and glycogenolysis

Glycogen metabolism is controlled hormonally by
glucagon and insulin.
• Glucagon triggers the production of cAMP in cells,
which in turn activates protein kinase A (PKA).
• PKA phosphorylates glycogen synthase directly,
and glycogen phosphorylase via phosphorylase
• Phosphorylation has opposite effects on the two
enzymes: glycogen synthase becomes inactive,
while glycogen phosphorylase is activated by
• As a result, glucagon promotes glycogenolysis
and inhibitis glycogenesis.


pyruvate dehydrogenase complex

Pyruvate is shuttled into
mitochondria with the help of a dedicated transporter.
• The Pyruvate Dehydrogenase
complex (PDH) is a gigantic multi-enzyme complex with dozens of copies each of three enzymes E1, E2 and E3.
• The complex needs no fewer than five cofactors, some derived from vitamins:
Thiamine-PP (B1), lipoic acid, Coenzyme A (from
pantothenate, B5), FAD (from riboflavin, B2) and NAD (from nicotinamide, B3).


tca cycle

The TCA cycle (or Krebs cycle, or citric acid cycle) is a central “metabolic roundabout” with
multiple entry and exit points. Several of the intermediates are involved in gluconeogenesis, amino
acid and heme metabolism.
• The oxidative catabolism of carbohydrates, lipids and amino acids comes together here.
• All TCA cycle reactions happen in mitochondria and require oxygen to recycle the reduced
coenzymes NADH+H+ and FADH2
The TCA cycle provides for full oxidation of acetyl-CoA to 2 CO2 and generation of reducing equivalents, which upon oxidation in the mitochondrial electron
transport chain generate 28 ATP per molecule glucose (6 from
PDH, 22 from cycle) and 2 GTP. Four intermediates of the TCA
cycle are amino acid
metabolites. This allows their conversion to glucose by gluconeogenesis


fatty acid synthesis

Most of the fatty acids needed by the body
are provided with a normal diet. Any
carbohydrates or proteins in excess of the
body’s needs can be converted to fatty
acids by the liver and ultimately stored as
fats (triacylglycerols) in adipocytes.
• The process starts with cytoplasmic acetyl-coA.
• Since most acetyl-Co-A is generated in mitochondria and cannot cross the membrane, a shuttle is needed
The next step, catalysed by AcetylCoA
carboxylase (ACC) is ratelimiting
and regulated:
• It is activated by citrate.
• The enzyme is active as a multisubunit
polymer stabilised by citrate.
• ACC is inactivated directly by fatty
acyl-CoA and by phoshorylation by
• Via regulation of ACC phosphorylation,
insulin indirectly activates ACC; glucagon and AMP inactivate ACC