Liver and Nutrition Flashcards
Function of hepatic portal vein
Carries blood from GI tract, gallbladder, pancreas and spleen TO THE LIVER
Where does drug metabolism occur
Liver- can occur in lung or gut
What enzyme is central to drug metabolism and where is it found
Cytochrome P450 in liver
What are drugs metabolised into?
Water soluble chemicals that can be excreted by kidney in urine
First pass metabolism
Concentration of a drug administered orally is greatly reduced before it reaches the systemic circulation because of its metabolism by the liver
eg. take drug orally -> gut -> hepatic portal vein -> liver (before it reaches arterial circulation and can be distributed to relevant target organ) may be metabolised by liver like morphine
much less reaches target organ vs if given via IV
Majority of drugs follow ___ order kinetics
First order kinetics - where elimination is proportional to concentration
-> higher concentration of drug in blood = more quickly eliminated from body
Some drugs follow ____ order kinetics
Zero order kinetics - where a constant amount of drug is eliminated
-> enzyme for metabolism saturated so constant amount can only be metabolised at a time and then excreted
eg. aspirin or alcohol
due to enzyme saturation
Half life
Time required for concentration of drug in blood to be halved
Cmax
Maximum concentration of drug in blood
Phase 1 of drug metabolism
Make drug more hydrophilic
- oxidation
- hydrolysis
- reduction
Phase 2 of drug metabolism
Follows phase 1, makes drug even more hydrophilic by adding polar (charged) group
- glutathione conjugation
- acetylation
- sulfation
- glucuronidation
What drugs induce Cytochrome P450 (increase its presence) ?
Phenytoin Carbamazepine Rifampin Alcohol (chronic) Barbiturates St. John's Wort
Co-prescription of these with inhibitors may cause drug interactions
What drugs inhibit Cytochrome P450?
Grapefruit Protease inhibitors Azole antifungals Cimetidine Macrolides (except azithromycin) Amiodarone Non-DHP CCBs
Co-prescription of these with inducers may cause drug interactions
Where are drugs primarily excreted?
Kidneys
How does kidney excrete drugs?
Drugs are filtered into nephron of kidney, then into collecting duct, and out of body in the urine
Define Clearance
Volume of plasma cleared of the drug over a certain time, affected by:
Reabsorption - how much of drug is absorbed in kidney
Active excretion - how much is pumped into nephrons and excreted
Concentration in plasma
CLEARANCE = Conc of drug in urine X Vol of urine produced / Conc of drug in plasma
How are drugs that are more difficult to dissolve in water eliminated?
Hepatobiliary system (eg. rifampicin) and faeces
Excreted in bile or faeces
What are the cells of the liver?
Hepatocytes (60%) – perform most metabolic functions
Kupffer cells (30% of NPC) – type of tissue macrophage
(also liver sinusoidal endothelial cells and Stellate cells)
Hepatocyte function vs Kupffer cell function
Hepatocytes – perform most metabolic functions of the liver
Endothelial Kupffer cells (aka reticuloendothelial cells – type of macrophage) - phagocytic activity by removing aged/damaged red blood cells, bacteria, viruses and immune complexes.
Hepatic lobule
functional unit
hexagonal plates of hepatocytes around central hepatic vein –
at each of 6 corners is triad of branches of portal vein, hepatic artery and bile duct
How does liver’s microstructure support its roles?
Massive surface area for exchange of molecules
Liver has dual blood supply:
- 75% from portal vein to liver
- 25% from hepatic artery to liver
Sophisticated separation of blood from bile.
Specific positioning of pumps to achieve its functions (at a cellular level).
e.g. conjugated substances from biotransformation are eliminated into blood or bile using ATPase pumps.
What is bile?
Complex fluid = water, electrolytes + mix of organic molecules
Organic molecules = bile acids, cholesterol, bilirubin and phospholipids
Greenish yellow
What are the 2 stages of bile secretion?
- By hepatocytes
(bile salts, cholesterol & other organic constituents) - By epithelial cells lining bile ducts
(large quantity of watery solution of Na+ & HCO3-)
» this is stimulated by hormone SECRETIN in response to acid in duodenum.
Initially the hepatocytes secrete bile into the canaliculi, which flows into the bile ducts and contains large amounts of bile salts, cholesterol and other organic constituents. It is then modified by water and bicarbonate-rich secretion from epithelial ductal cells.
What is bile synthesised from?
Cholesterol
Describe process of bile synthesis
In liver:
Cholesterol -> cholic acid or chenodeoxycholic acid via enzyme 7 alpha hydrolase, requires O2 + CP450 + NADH
Before primary bile acid is secreted into bile canaliculi, must be conjugated with 2 amino acids (glycine or taurine) to form either:
Glycocholic acid
Taurocholic acid
To form bile salt then -> into bile canaliculi -> small intestine
Then metabolised by intestinal bacteria , deconjugated into cholic acid (primary bile acid again) then can also be converted to secondary bile acid by intestinal bacteria like Deoxycholic acid or Lithocholic acid
What happens to bile if not needed for digestion of fat?
Stored in gallbladder
What happens to most of the bile secreted into small intestine?
ENTEROHEPATIC CIRCULATION (95% of bile)
Reabsorbed back into circulation and goes into liver
leads to negative feedback because level of bile acid in circulation increases, so liver stops using cholesterol to synthesise bile
Journey of bile
Bile secreted by hepatocytes ↓ Canaliculi (series of channels between cells) ↓ hepatic ducts ↓ common bile duct ↓ duodenum OR diverted via cystic duct ↓ GALL BLADDER ↓ concentrated & stored (30-50ml) ↓ Released by cholecystokinin in response to presence of fat in duodenum
Summarise the diagram
- Liver synthesises bile acids from cholesterol to primary bile acids, a) Cholic acid; 3-OH groups, b) Chenodeoxycholic acid; 2-OH groups
- Synthesis regulated by the enzyme 7 α- hydroxylase which requires O2, NADH and cytochrome P-450
- Presence of -COOH and -OH groups makes bile acids water soluble than cholesterol
- Primary acids conjugate with glycine or taurine, prior to secretion into bile canalicular. (ratio of glycine to taurine 3:1)
- Conjugated bile salts in sinusoidal blood actively taken up and transported against conc gradient into bile canaliculi by ATP-dependent carrier hBSEP also referred to as cBAT (canalicular bile acid transporter).
hBSEP – human bile sale export pump.
What controls entry into the duodenum?
Entry into the doudenum is controlled by opening of the Sphincter of Odii. Bile can also be diverted into the gall bladder via the cystic duct where it is stored and concentrated 5-fold.
Why is bile important?
Essential for fat digestion & absorption via emulsification
Bile + pancreatic juice neutralises gastric juice as it enters the small intestine aids digestive enzymes
Eliminates waste products from blood in particular bilirubin & cholesterol - 500mg of cholesterol converted to bile acids per day
What is gallstones?
Abnormal conditions caused by an imbalance in the chemical make-up of bile inside the gallbladder
2 types of stones:
Cholesterol (80%) & Pigment (20%)
Cholesterol is virtually insoluble in aqueous solution but is made soluble in bile. In abnormal conditions the cholesterol precipitates out of solution forming gall stones. Initially get formation of small crystals of cholesterol precipitating and then progress to larger gall stones.
Risk factors for cholesterol stones
High fat diet
increased synthesis of cholesterol
More common in women than men
Risk factors = obesity, excess oestrogen (e.g. during pregnancy), HRT
In gallstones what changes in the gallbladder?
Inflammation of GB epithelium changes absorptive characteristic of mucosa
→ excessive absorption of H2O & bile salts cholesterol concentrates
Where can gallstones form?
Anywhere along biliary tract
What is bilirubin
Yellow pigment formed from breakdown of haemoglobin (gibes bile its colour)
useless & toxic but made in large quantities (~6g/day) must be eliminated
Haem converted into biliverdin and then into free bilirubin
Bilirubin released into plasma – carried around bound to albumin
Albumin-bound bilirubin is stripped of albumin and absorbed into hepatocytes as free bilirubin → conjugated with glucoronic acid
Conjugated bilirubin secreted into bile → metabolised by bacteria intestinal lumen & eliminated into faeces/urine
Part of the bilirubin is broken down to colourless substances, hepatocytes produce urobilinogen, and colonic bacteria convert this to stercobilinogen. Both substances can be oxidised to yellow urinary urobilin and brown faecal stercobilin.
Stercobilin and urobilin/urobilinogen
Major metabolite in faeces is Stercobilin – brown colour
In urine – Yellow urobilin & urobilinogen
What cells act as a protective barrier in sinusoids and how?
Kupffer cells-found in sinusoids;
- Represent approx 80% of all fixed tissue macrophages
- And function as mononuclear phagocyte system (MPS)
- Exposed to blood from gut that contain pathogenic substances.
- Clear gut-derived endotoxin from portal blood
Kupffer cells efficiently cleanse the blood as it passes through the sinus. When a bacterium comes in contact with Kupffer cell the bacterium passes inward through the wall of the Kupffer cells to become permanently lodged there till digested.
Carbohydrate metabolism in liver
Fill in the missing products, enzymes, hormones and processes
Glucose, the monosaccharides are transported across the wall of the small intestine and into the circulatory system, which transports them to the liver.
In the liver, hepatocytes either pass the glucose on through the circulatory system or store excess glucose as glycogen.
Cells in the body take up the circulating glucose in response to insulin and thru glycolysis, transfer some of the energy in glucose to ADP to form ATP.
The last step in glycolysis produces the productpyruvate.
Glycolysis begins with the phosphorylation of glucose by hexokinase (found in other tissues) to form glucose-6-phosphate.
What are the different processes of fat metabolism
- Triglycerides oxidized in hepatocytes to produce energy
- Lipoproteins synthesised in liver
- Excess carbohydrates & proteins converted into FA & TGs – stored in adipose
- Synthesis of large quantities of cholesterol & phospholipids – some packaged as lipoproteins
Triglycerides hydrolysed to fatty acids and glycerol and then fatty acid is oxidised by hepatocyte to produce energy -> oxidised to acetyl coA -> goes into citric acid cycle for release of energy as ATP. and acetyl CoA can also be converted into ketone bodies
Liver also able to synthesise lipoproteins (LDL, HDL) Lipids insoluble in water & are assembled into lipoproteins (complexes of lipid & protein) in liver for transport in blood
Excess carbohydrates and proteins converted to fatty acids and triglycerides to be stored as adipose tissue.
5 classes of lipoproteins
Going from lowest to highest density: Chylomicrons very low density (VLDL) intermediate density (IDL) LDL HDL
How are amino acids regulated based on need?
by deamination & transamination of amino acids conversion of non-nitrogenous part to glucose & lipids
The catabolism of glucogenic amino acids produces either pyruvate or one of the intermediates in the Krebs Cycle. The catabolism of ketogenic amino acids produces acetyl CoA or acetoacetyl CoA
Enzymes used in these pathways e.g. alanine & aspartate aminotransferases are routinely assayed in serum to assess liver damage
What proteins does the liver synthesise?
Synthesis of nearly all plasma proteins (90%)
Major proteins (albumin, acute-phase proteins, C-reactive proteins)
Carriage proteins (Transferrin, TBG, Haptoglobin, GHB protein)
Factors involved in haemostasis /fibrinolysis
What haemostasis/fibrinolysis proteins does the liver synthesise?
Coagulation: (Fibrinogen and all others except factor VIII)
Inhibitors of coagulation (protein S, protein C, antithrombin III
Fibrinolysis: (plasminogen)
What removes ammonia from the body
Urea
What happens if there is no urea formation?
Ammonia is very dangerous and can depress cerebral blood flow & cerebral oxygen consumption. Large amounts of ammonia formed by deamination & in gut by bacteria.
If there is no urea formation then plasma [ammonia] increases & is extremely toxic especially to brain → hepatic encephalopathy
Vitamin B12 deficiency may occur when what happens in liver?
Vit B12 deficiency may occur when there is malabsorption of fat due to liver dysfunction
Liver dysfunction leading to fat malabsorption causes what?
Liver dysfunction ⇒fat malabsorption ⇒vitamin deficiency
Liver dysfunction leading to fat malabsorption causes what?
Liver dysfunction ⇒fat malabsorption ⇒vitamin deficiency
What is stored in hepatocytes and stellate cells?
Hepatocytes and stellate cells in particular are important depots for storage of fat-soluble, vits A, D, E and K.
What 3 things related to anaemia are stored in the liver?
Stores Vit B12, enough to last 2-3 years
Vit B12 deficiency ⇒ pernicious anaemia
Stores folate, which is required in early pregnancy.
Iron is stored as ferritin (blood-Fe buffer)
Pernicious anaemia
Vit B12 Deficiency eventually leads to pernicious anaemia
Pernicious anaemiacauses your immune system to attack the cells in your stomach that produce the intrinsic factor, which means your body is unable to absorb vitamin B12..
Dietary deficiency of folate is more common in alcoholics than vit B12 deficiency.
How does iron act as a blood-Fe buffer?
Hepatic cells contain large amounts of apoferritin protein, which combines reversibly with Fe (when in excess) to form ferritin, until needed. When Fe in circulating body fluids reaches low level, the ferritin releases Fe. Hence acts as a blood iron buffer as well as storage system.
Steroid hormones in liver
All steroid hormones (oestrogen, androgens, cortisol & aldosterone) & thyroxine are inactivated & catabolised in liver
Most steroids excreted as glucuronide/sulphate conjugates
Hence impairment in liver function can lead to overactivity of hormonal system E.g. steroid hormone metabolism → gonadal dysfunction in men and spider angioma in women
(Spider Angioma in women due to excess oestrogen – more than five is indicative of liver damage)
Liver metabolization of drugs and hormones
Phase 1 – primarily oxidation or reduction
– occurs in smooth ER, catalysed primarily by family of cytochrome P450 enzymes → mainly to make substrate into polar compound
Phase 2 - conjugation in order to make the drug water soluble to be eliminated. Usually conjugated with glucuronyl (most important), sulphate.
Phase 3 – elimination - the conjugate substance is eliminated into blood or bile using ATPase pumps.
Paracetamol therapeutic index
Paracetamol aka acetaminophen
Narrow therapeutic index
Accidental/deliberate overdose common
Paracetamol o/d has 2 phase effects
Maximum dose 4g/day or 1g/dose
Not to be taken after alcohol consumption
Paracetamol overdose and treatment
Paracetamol has a narrow therapeutic index and accidental/deliberate overdose is common. The liver has limited capacity of these enzymes and stores of glutathione.
In paracetamol o/d the liver enzymes are saturated and glutathione stores rapidly depleted – get liver necrosis and damage to kidney by toxic metabolites.
Treatment involves giving N-acetylcysteine, the precursor to glutathione which increases it’s levels. Paracetamol o/d has this 2 phase effect – i.e. damage is not immediate and patients can wake up feeling fine and do not seek help till it’s too late for effective treatment
Paracetamol overdose: Pathogenesis
Narrow therapeutic index so easy to accidentally overdose, has phase 2 effects
Majority of drug goes down glucuronidation or sulfonation pathways
5% of drug goes down CP450 (CYP2E1) pathway to be metabolised into NAPQ1 or N-acetyl-p-benzoquinoneimine (toxic metabolite)
So normally quickly converted to non-toxic metabolite by glutathione into mercapturic acid (water soluble)
But if overdose - main pathways saturated and more of the drug goes down CYP2E1 pathway - > more NAPQ1 -> glutathione depleted
So more toxic NAPQ1 in blood = toxicity, nausea, vomiting and anorexia
NAPQ1 also binds to hepatic proteins increasing its concentration = hepatic necrosis = right upper quadrant pain, can also lead to extensive hepatic necrosis = fulminant hepatic failure = jaundice, hepatic encephalopathy, coma, death
uncoupling of oxidative phosphorylation, which results in a failure of ATP synthesis, lactic acidosis, and the release of ionised calcium from mitochondrial stores
The consequence of this is hepatocellular apoptosis and necrosis.
Clinical features of paracetamol overdose
(1) pallor, malaise, vomiting
(2) tachycardia, hypotension
(3) jaundice, bleeding; encephalopathy
Management of paracetamol overdose
Alcohol flush reaction
Alcohol flush reaction is a condition in which the face and/or body experiences flushes or blotches, due to an accumulation of acetaldehyde. The acetaldehyde accumulation can be caused by a missense polymorphism that encodes the enzyme, acetaldehyde dehydrogenase (ALDH2).
50% of Asians have one normal copy of the ALDH2 gene and one mutant copy that encodes an inactive mitochondrial isoenzyme. A remarkably higher frequency of acute alcohol intoxication among Asians than among Caucasians who have been repeatedly shown to be related to the very much reduced activity of the mutant ALDH2-2 isoenzyme.
Why must alcohol be oxidised in the liver?
Alcohol is readily absorbed from the gastrointestinal tract; however, alcohol cannot be stored and therefore, the body must oxidize it to get rid of it. Alcohol can only be oxidized in the liver, where enzymes are found to initiate the process and then it enters into normal metabolic pathways and metabolised as if it were fat.
Ethanol metabolism
- OXIDATION OF ETHANOL
catalysed by alcohol dehydrogenase w NAD+ (converted to NADH + H+ in reaction) into acetaldehyde TOXIC
Acetaldehyde converted to acetate via acetaldehyde dehydrogenase enzyme (NAD+ converted to NADH + H+ in reaction)
Acetate goes into circulation
Adverse effects of excess alcohol
Once alcohol metabolised to acetaldehyde, NADH is produced - normally NADH needed to convert pyruvate into lactic acid
If too much is produced, it converts pyruvate to lactic acid so pyruvate can no longer be used to produce glucose via gluconeogenesis for body -> hypoglycaemia
Lactic acid build up can also lead to acidosis
Excess NADH can also cause lipogenesis -> overweight
NADH also in ETC -> direct effect of INHIBITING the acetyl CoA from going into citric acid cycle so Fats or acetyl CoA may accumulate producing ketone bodies (ketosis) . Accumulation of fat in the liver can be alleviated by secreting lipids into the blood stream. The higher lipid levels in the blood may be responsible for heart attacks.
The excess acetaldehyde itself it toxic to the liver leading to hepatitis and cirrhosis.
Fatty liver
Alcohol abuse can lead to the accumulation of fat within the liver cells.
High level of alcohol related acetyl CoA lead to increased synthesis of neutral fats and CHO. But export of this form of VLDL is reduced due to alcohol so storage occurs (fatty liver). Up to 50% dry weight of fat is initially reversible, but chronic alcoholism permanent damages parenchyma.
Alcoholic hepatitis
Excessive use of alcohol can cause acute and chronic hepatitis (inflammation of the liver).
Alcoholic cirrhosis
Anything which results in severe liver injury can cause cirrhosis. Common causes include excessive alcohol intake, chronic hepatitis B and C infection, intake of certain chemicals and poisons, too much iron or copper, severe reaction to drugs and obstruction of the bile duct.
Cirrhosis of the liver is a degenerative disease where liver cells are damaged and replaced by scar formation.
Gynaecomastia
Gynecomastiais an enlargement or swelling of breast tissue in males, most commonly caused by male oestrogen levels that are too high or are out of balance with testosterone levels.
Liver disease orcirrhosis. In liver disease there is an increased production of androstenedione by the adrenal glands, increased aromatisation of androstenedione to oestrogen, loss of clearance of adrenal androgens by the liver and a rise in Sex Hormone Binding Globin, resulting in gynaecomastia.
Partial hepatectomy
The removal of specific lobes of the liver, generally by ligation of the blood supply and resection. The procedure normally does not involve a specific incision in a liver lobe.
Portal tracts
Portal tracts contain the ‘triad’ of hepatic artery, portal vein and bile duct branches, lymphatics, nerves etc
Liver regeneration
Adult hepatocytes are long lived and normally do not undergo cell division i.e. they are in G0 phase of cell cycle.
–> after partial hepatectomy (removal of 70% of liver) or in response to toxic injury, they rapidly re-enter cell cycle and proliferate
The regeneration is rapid and proliferation stops once the original mass of the liver is established
–> allows for use of partial livers from living donors for transplantation
Does NOT involve liver stem cells or progenitor cells, but replication of mature functioning liver cells.
Still not understood fully but 2 pathways may be involved:
- Growth-factor mediated pathway → most important HGF (hepatocyte growth factor) and TGFα (transforming growth factor alpha)
- Cytokine signalling pathway using IL-6 via TNFα binding to its receptor on Kuppfer cells
Prolonged alcohol misuse can reduce regenerative ability of liver.
Mechanism of liver regeneration
After partial hepatectomy or liver injury, several signals are initiated simultaneously in the liver. Gut-derived factors, such as lipopolysaccharide (LPS), are upregulated after liver injury or hepatectomy and reach the liver through the portal blood supply.
They activate hepatic non-parenchymal cells (including Kupffer cells and stellate cells) and increase the production of tumour necrosis factor (TNF) and interleukin (IL)-6.
Other factors are released from the pancreas (insulin), duodenum or salivary gland (epidermal growth factor; EGF), adrenal gland (norepinepherine), thyroid gland (triodothronine; T3) and stellate cells (hepatocyte growth factor; HGF).
Cooperative signals from these factors allow the hepatocytes to overcome cell-cycle checkpoint controls and move from G0, through G1, to the S phase of the cell cycle. This leads to DNA synthesis and hepatocyte proliferation.
Transforming growth factor (TGF) signalling, which inhibits hepatocyte DNA synthesis, is blocked during the proliferative phase but is restored at the end of the process of regeneration by helping to return hepatocytes to the quiescent state.
Function of hepatic artery
Hepatic artery branches run close beside the bile ducts in the portal tracts, sending off a capillary network to nourish the ducts, then branching out to supply blood to the terminal hepatic venules and the sinusoids.
Function of hepatic vein
Hepatic artery branches run close beside the bile ducts in the portal tracts, sending off a capillary network to nourish the ducts, then branching out to supply blood to the terminal hepatic venules and the sinusoids.
Function of portal vein branches
Portal vein branches bring in the blood loaded with nutrients absorbed from the capillary bed in the gut . (Kupffer cells in the sinusoids phagocytose any debris or bacteria which have inadvertantly entered via the gut.)
Function of bile ducts
Bile ducts carry bile (containing cholesterol, bile salts) out of the liver, into the gut via the Ampulla of Vater in the duodenum. Bile emulsifies fat, enabling it to be absorbed, along with fat-soluble vitamins. Many bile salts are reabsorbed in the ileum (enterohepatic circulation).
Function of connective issue sleeve
A sleeve of connective tissue surrounds and supports these structures as they ramify through the liver; they are enclosed by the limiting plate, which separates them from the liver parenchyma.
Liver parenchyma and susceptibility to damage
The liver parenchyma is the functional tissue of the organ made up of around 80% of the liver volume as hepatocytes.
Inflammatory damage in response to infectious agents such as viral hepatitis or toxic damage, eg alcohol or non-infective conditions eg autoimmune hepatitis.
Can be harmed by accumulation of fat (in alcoholics or obesity +/- metabolic syndrome)
What damage is portal vein susceptible to?
sepsis at the liver hilum can cause thrombosis; cirrhosis can obstruct blood flow.
What damage is hepatic artery suceptible to?
vasculitis or thrombosis can impair nutrition of vital liver structures, eg bile ducts.
What damage is sinusoids susceptible to?
obstruction due to cirrhosis, swelling of endothelium and liver cells (eg chemotherapy-related), sickling of RBCs
What damage are hepatic veins susceptible to?
cardiac failure causes backflow with severe pressure effects.
What damage are bile ducts susceptible to?
easily obstructed, eg by gallstones, liable to secondary infection (ascending cholangitis). Liver flukes may ascend from gut (SE Asia).
Classical lobule vs acinar concept
The ‘classical lobule’ depicts a terminal hepatic venule in the middle of a liver lobule which drains several portal tracts. This echoes how the liver looks down the microscope.
The ‘acinar concept’ considers the liver in terms of its blood flow. Though more abstract, this ‘functional’ view of the way the liver works is a logical way of considering liver histology.
Classical liver lobule: blood flow
Portal tracts in group of 6 hexagon shape
As blood comes in from hepatic artery on one portal tract -> flows down towards terminal hepatic venule -> then joins up to lobular venules -> vena cava
As blood flows down, blood in sinusoids very close to liver cells -> LCs can secrete proteins, clotting factors etc into blood and metabolise drugs
Liver cells lined up between sinusoids, are back to back with other liver cells and a tube between, called…
Bile canaliculi
Bile does NOT go from portal tract to terminal hepatic venule, instead…
It goes OTHER WAY- through sinusoids, into portal tract, into bile duct, into gallbladder
Call that RETROGRADE (mans gonna make a question about this)
Acinar concept: What are the zones?
The acinar concept considers the liver as collections of acini, related to the branches of the portal vein and hepatic artery:
zone 1 is the region nearest to the portal vessels
zone 3 is nearest to the terminal hepatic venule and is the least well-oxygenated part of the liver, most likely to get damaged by drug toxicity or back-pressure from the liver, and the part in which fatty change occurs first.
image- foreshortening from portal tract
Terminal hepatic venules
Terminal hepatic venules collect pooled blood from sinusoids and return it via hepatic veins to the IVC
Summary of normal liver microscopical structures
Vascular compartment:
Blood comes in via portal vein and hepatic artery.
The hepatic artery functions to nourish the liver, but there is some mixing of blood in the sinusoids.
Sinusoidal endothelium is fenestrated to facilitate transfer of substances from blood to liver and vice versa.
Blood exits via the hepatic veins.
Parenchymal compartment:
Liver cells have microvilli on borders facing the sinusoids to increase interactions (to and from the blood)
Space of Disse:
Ito (stellate) cells store vitamin A and can generate collagen.
Bile ducts:
Fed by canaliculi which start as grooves between hepatocytes.
Kupffer cells (tissue macrophages): Patrol sinusoids, engulf gut bacteria and foreign material entering via portal vein.
Nerves, lymphatics present in portal tracts.
How can damage to liver be detected clinically?
Jaundice
Malaise
Bruising
Features of portal hypertension
LFT looking at bilirubin
Bilirubin: isolated rise suggests familial syndromes (Gilbert, Dubin-Johnson, Rotor) or haemolysis; raised in many types of liver disease – establish whether conjugated or unconjugated to distinguish obstruction of bile ducts from hepatitis or pre-hepatic causes.
LFT looking at ALT
‘Transaminases’: Alanine aminotransferase (ALT) is most liver-specific
Catalyse the reversible transformation of alpha-keto-acids into amino acids.
Raised levels indicate recent hepatocellular damage and death.
Values >10x the upper limit of normal are seen in hypoxia and acute biliary obstruction
High levels in acute hepatitis, toxin-induced necrosis.
Serial values are used to follow patients’ progress during an acute episode, but because of short half life only reflect recent events, and may be normal in compensated cirrhosis.
LFT looking at ALP
Alkaline phosphatase (ALP): Found in hepatocytes, bile duct epithelium and non-liver tissue (bone, kidney, lung, intestine, placenta).
Isolated ↑ ALP normal in 3rd trimester of pregnancy or after ingesting a fatty meal
ALP high in cholestasis, eg PBC, and very high in extrahepatic biliary tract obstruction
LFT looking at GGT
Gammaglutaryltransferase (GGT): not liver-specific but taken in conjunction with other LFTs is useful.
Increased in damage to liver cell membranes, if hepatocyte regeneration occurs or if liver enzymes are induced, as in alcoholic liver disease or with drugs such as phenytoin or carbamazepine.
Cholestasis can also induce GGT synthesis.
LFT looking at serum albumin
Serum albumin: a liver-specific protein. Half-life 22days, hence normal values may be found in acute liver failure.
Low levels often reflect liver disease but albumin can also be lost via intestines, kidneys, increased vascular permeability, increased catabolism and in haemodilution (by over-hydration).
Coagulation tests
Liver is main site of coagulation protein manufacture. Factor VII has a very short half life (2-5 hours), so after administering vit K, use prothrombin time to estimate liver synthetic function.
LFT interpretation: Liver parenchyma
Damage to the liver causes ↑ transaminases (eg ALT)
Impaired bile conjugation or secretion may cause Bilirubin ↑
Increased drug metabolism, eg alcohol, may cause GGT ↑
Interference with liver synthetic mechanisms: albumin ↓ and clotting problems: INR↑
LFT interpretation: Bile ducts
Obstruction to, or loss of bile ducts causes Alkaline phosphatase ↑ and often GGT↑ , which is synthesised by liver near the portal tracts. Bilirubin ↑ or ↔, depending on sites affected.
LFT interpretation: Sinusoids and venules
Venous or sinusoidal obstruction is best detected by ultrasound examination and Doppler flow studies.
Major causes of liver disease
Fatty liver disease, alcoholic and non-alcoholic
→ Steatosis vs steatohepatitis (ASH, NASH)
Viral hepatitis
→ acute and chronic hepatotropic viral disease
→ systemic viral disease
Autoimmune hepatitis (AIH)
Metabolic/genetic disorders
→ eg haemochromatosis, Wilsons’s, A1AT deficiency
Bile duct diseases
→ Primary biliary cirrhosis, primary sclerosing cholangitis
Vascular disorders
→ eg Budd-Chiari syndrome
Tumours and tumour-like lesions
→ Malignant eg HCC; Benign eg focal nodular hyperplasia
Drugs and Toxins
→ distinguish predictable from idiosyncratic reactions
Major causes of chronic liver disease
Fatty liver disease, alcoholic and non-alcoholic*
→ Steatosis vs steatohepatitis (ASH, NASH)
Viral hepatitis*
→ acute and chronic hepatotropic viral disease
systemic viral disease
Autoimmune hepatitis (AIH)*
Metabolic/genetic disorders
→ eg haemochromatosis, Wilsons’s, A1AT deficiency
Bile duct diseases
→ Primary biliary cirrhosis, primary sclerosing cholangitis
*Most common in UK
Hepatotropic viruses
HAV (hep A)
HBV +- HDV
HCV
HEV
Systemic viruses that can involve liver
EBV
Systemic infections of various kinds can occasionally cause mild hepatocyte necrosis, eg influenza or non-viral infections.
Other viral involvement, eg CMV, is more usually seen in immunosuppressed patients.
Routes of transmission for viruses
Oral
- HAV
- HEV
Needlestick/fluids
- HBV [ + HDV delta virus]
- HCV
- HGV – rare
Best way of diagnosing Hep B?
HBsAg+ (Hep B surface antigen- if positive) is the best way method of identifying
1) current HBV infection
2) patient may infect others.
HBeAg + (e antigen) indicates HBV infection and a risk of infecting others
–> BUT note that mutant strains may be eAg -ve so the best test is to look for high levels of replicating HBV DNA in the blood.
Vaccination against Hep B
Childhood:
High risk of vertical transmission of HBV can be averted by neonatal vaccination. Transmission generally occurs in the perinatal or childhood period, not across the placenta.
Adulthood:
HBV vaccination for those in exposure prone occupations (protects practitioner and patient).
Recommended for travel to high risk countries
No significant harm if given to people already immunised by having had the infection (they can be distinguished from those vaccinated by the presence of anti-HBc as well as anti-HBs antibodies).
Microscopical features of acute hepatitis
Acute viral hepatitis: inflammation is scattered throughout lobule as well as portal tract.
What has the higher percentage chance of developing chornic disease- Hep B or Hep C?
Hep C (80% in adults vs 10% Hep B)
Microscopical features of chronic hepatitis
Chronic viral hepatitis: inflammation is mainly in portal tracts, with patchy liver parenchymal inflammation.
Cytoplasm appearance in Hep B
‘ground glass cell’: cytoplasm packed with HBsAg has appearance of sanded glass
orcein stain highlights HBsAg in cytoplasm of liver cells
Fatty liver disease: alcoholic vs non-alcoholic
Alcoholic: histological features typical of alcohol are fat, Mallory’s hyaline and neutrophil polymorphs in liver
Non-alcoholic: obesity, diabetes mellitus, malnutrition. Mallory’s hyaline is less common. May be part of ‘metabolic syndrome’: obesity, diabetes and hypertension.
Fatty liver disease: alcoholic vs non-alcoholic
Alcoholic: histological features typical of alcohol are fat, Mallory’s hyaline and neutrophil polymorphs in liver
Non-alcoholic: obesity, diabetes mellitus, malnutrition. Mallory’s hyaline is less common. May be part of ‘metabolic syndrome’: obesity, diabetes and hypertension.
Steatohepatitis microscopic changes
Polymorphs
Mallory’s hyaline
Fat
At what stage are the changes of fatty liver disease irreversible?
Changes are considered irreversible once fibrosis develops.
Fat is thought to secrete adipokines and also generates toxic free radicals. These may stimulate the Ito/Stellate cells in the Space of Disse to lay down collagen.
Progressive fibrosis may lead to cirrhosis.
Clinicopathological diagnosis of autoimmune hepatitis
Clinicopathological diagnosis
Autoantibodies (eg ANA, anti-LKM, anti-SMA)
Microscopy findings at presentation are highly variable - from fulminant acute hepatitis to established cirrhosis.
Key histological feature : plasma cell clusters.
Clinicopathological diagnosis of autoimmune hepatitis
Clinicopathological diagnosis
Autoantibodies (eg ANA, anti-LKM, anti-SMA)
Microscopy findings at presentation are highly variable - from fulminant acute hepatitis to established cirrhosis.
Key histological feature : plasma cell clusters.
Clinicopathological diagnosis of autoimmune hepatitis
Clinicopathological diagnosis
Autoantibodies (eg ANA, anti-LKM, anti-SMA)
Microscopy findings at presentation are highly variable - from fulminant acute hepatitis to established cirrhosis.
Key histological feature : plasma cell clusters.
Clinicopathological diagnosis of autoimmune hepatitis
Clinicopathological diagnosis
Autoantibodies (eg ANA, anti-LKM, anti-SMA)
Microscopy findings at presentation are highly variable - from fulminant acute hepatitis to established cirrhosis.
Key histological feature : plasma cell clusters.
Clinicopathological diagnosis of autoimmune hepatitis
Clinicopathological diagnosis
Autoantibodies (eg ANA, anti-LKM, anti-SMA)
Microscopy findings at presentation are highly variable - from fulminant acute hepatitis to established cirrhosis.
Key histological feature : plasma cell clusters.
Clinicopathological diagnosis of autoimmune hepatitis
Clinicopathological diagnosis
Autoantibodies (eg ANA, anti-LKM, anti-SMA)
Microscopy findings at presentation are highly variable - from fulminant acute hepatitis to established cirrhosis.
Key histological feature : plasma cell clusters.
Clinicopathological diagnosis of autoimmune hepatitis
- Autoantibodies (eg ANA, anti-LKM, anti-SMA)
- Microscopy findings at presentation are highly variable - from fulminant acute hepatitis to established cirrhosis.
- Key histological feature : plasma cell clusters.
Clinicopathological diagnosis of autoimmune hepatitis
Clinicopathological diagnosis
Autoantibodies (eg ANA, anti-LKM, anti-SMA)
Microscopy findings at presentation are highly variable - from fulminant acute hepatitis to established cirrhosis.
Key histological feature : plasma cell clusters.
What are the long term complications for patients with chronic liver disease?
Cirrhosis and chronic liver failure
Portal hypertension
Hepatocellular carcinoma
Which are the most important causes of cirrhosis in the West?
Alcoholic and non-alcoholic fatty liver 60% Viral hepatitis 10% Biliary disease 10% Autoimmune disease 5% Other 5%
Microscopical features of cirrhosis
Diffuse involvement of the liver
Architecture disrupted by fibrous septa
Often shows inflammation affecting borders of nodules or within nodules (‘active cirrhosis’)
May show features of predisposing condition, eg fat/Mallory’s hyaline in alcoholic cirrhosis, iron in haemochromatosis
Portal hypertension is a long term complication of cirrhosis- what are its consequences ?
bleeding varices
portal-systemic encephalopathy
ascites
splenomegaly
Hepatocellular carcinoma is a long term complication of what?
Cirrhosis
In a non-cirrhotic liver the majority of tumours are…
metastatic from somewhere else, often the gastrointestinal tract (reflecting the portal drainage)
In a cirrhotic liver the majority of tumours are…
primary hepatocellular carcinoma (HCC). HCC, though a rare tumour in the UK, is more common than metastastic disease in a cirrhotic liver.
HCC rarely occurs in a non-cirrhotic liver, other than childhood-acquired chronic viral hepatitis (HBV or HCV).
Main causes of hepatocellular carcinoma
In the UK and other developed countries:
Alcoholic & Non-alcoholic fatty liver disease
Viral (HBV and HCV)
Autoimmune hepatitis.
Globally :
HBV viral hepatitis
HCV viral hepatitis
Alcoholic liver disease
Micronodular cirrhosis vs Hepatocellular carcinoma
Micronodular cirrhosis:
Small, centrally placed, nuclei (arrow), trabecular arrangement of cells.
Hepatocellular carcinoma:
here is nuclear atypia (arrow) and the trabeculae are thicker.
What is nutrition?
Nutrition is concerned with understanding the effects of food on the human body in health and disease
Macronutrients
Fat
Carbs
Protein
Alcohol
kcal in fat, alcohol, protein and carbs
Fat 9kcal/g
ETOH 7kcal/g
Protein 4kcal/g
CHO 4kcal/g
Micronutrients
Vitamins:
- fat soluble (A D E K)
- water soluble (B and C)
Trace minerals
Role of calcium in body
Helping build strong bones and teeth, regulating muscle contractions, including heartbeat, making sure blood clots normally
Role of iron in body
The major role of iron is as an oxygen carrier in haemoglobin in blood & myoglobin in muscle.
Role of vitamin K in body
Intracellular cation and plays a fundamental role in acid-base regulation, fluid balance, muscle contraction & nerve conduction.
Sources of calcium in diet
Milk, cheese and other dairy foods, fish where you eat the bones – such as sardines and pilchards, bread and anything made with fortified flour, soya beans, soya drinks with added calcium, tofu, nuts, green leafy vegetables – such as broccoli, cabbage and okra, but not spinach
Sources of iron in diet
Haem - well absorbed and not affected by other dietary components. Liver, black pudding, meat
Non-haem- absorption reduced by tannins & phytates, increased by Vit C. beans, nuts, dried fruit, wholegrains – such as brown rice; fortified breakfast cereals, soybean flour, most dark-green leafy vegetables
Sources of vitamin K in diet
Some fruit (i.e. bananas), certain vegetables (i.e. broccoli, parsnips and brussels sprouts), pulses, nuts and seeds, fish, shellfish, beef, chicken and turkey.
What is a key biochemical marker of nutrient status?
Ferritin
How is iron stored in the body and what indicates iron stores are depleted?
Iron stored in the body as ferritin.
Small amounts of ferritin are secreted into the plasma.
The concentration of plasma (serum) ferritin is positively correlated with the size of total body iron stores.
Low serum ferritin = depleted iron stores.
HOWEVER, ferritin is also a positive acute phase protein. Concentrations increase during inflammation and no longer reflect the size of the iron store.
How to calculate total energy expenditure
Total energy expenditure = Basal metabolic rate + diet induced thermogenesis + Activity +/- stress (illness/inflammation/surgery).
TEE = BMR + DIT + Activity (+stress).
Direct or indirect calorimetry
Use predictive equations (based on data from healthy subjects) and adjust to account for the clinical condition. 25-35 kcal/kg Schofield equations Harris-Benedict equation Ireton Jones.
What affects nutrient requirements?
Age
Gender
Body size
Level of physical activity
State of health
Physiological status- pregnancy and lactation
Growth
Dietary reference values (DRVs)
COMA Report (1991).
Estimates of the amount of energy and nutrients needed by different groups of healthy people in the UK population.
Allowances for physiological state (e.g. growth, pregnant, breast feeding).
NOT:
Individuals, illness/injury, outside UK.
COMA superseded by SACN.
Types of DRVs
Estimated Average Requirement (EAR)
Reference Nutrient Intake (RNI)
Lower Reference Nutrient Intake (LRNI)
Safe Intake (SI)
What is EAR?
An estimate of the average requirement for energy, or a nutrient.
Approximately 50% of the population will need less and 50% will need more.
EAR is used for energy.
What is RNI?
The amount of a nutrient that is enough to ensure that the needs of nearly all the population (97.5%) are being met.
Many within the group will need less.
Only 2.5 % of the group will need more.
Often used as a reference amount for population groups.
Used for protein, vitamins and minerals.
What is LRNI?
The amount of a nutrient that is enough for only the small number of people who have low requirements (2.5%). The majority of the population will need more.
Intakes below the LRNI are almost certainly not enough for most people.
Useful measure of nutritional inadequacy.
Why do we estimate nutrient requirements?
Benchmark to evaluate dietary adequacy inhealthygroups.
Plan what to provide (e.g. hospital menus, school meals, war rations).
Example of clinical application of DRVs
Anaemic child.
What is the chance the child’s IDA is due to:
- Low intake
- Illness e.g. blood loss, malabsorption?
Estimating the child’s intake can be helpful.
If their habitual intake is above the RNI, it is unlikely their IDA is due to inadequate intake.
If it is below the LRNI, it is likely that they are not meeting their requirements.
What are the cons of DRVs?
Bioavailability.
Assume that requirements for other nutrients are met.
Differences in DRVs between countries.
Based on best available evidence.
Reflect the needs of healthy people and are not usually appropriate in clinical circumstances.
Why do we develop nutrient deficiencies?
Inadequate intake (reduced appetite, poor availability of food)
Reduced absorption (Coeliac disease)
Increased losses (diarrhoea, vomiting)
Increased demand (growth, pregnancy)
Vitamin A excess vs deficiency
Toxicity in excess
Deficiency: Depleted liver stores Low blood levels Increased risk of infection Xeropthalmia Non blinding Blinding
Nutrient deficiency Case:
40-year-old woman with Crohn’s disease.
3 week history of abdominal pain, 8 watery bowel movements a day, and 8kg weight loss.
Imaging revealed a terminal ileal (TI) stricture.
Prescribed Prednisolone, but develops vomiting, abdominal distension and worsening abdominal pain - thought to be related to a bowel obstruction.
She was taken to the operating room where 30cm of TI was resected. The rest of her bowel looked normal.
After surgery, she develops profuse, watery diarrhoea after eating.
How do you explain the origins of her diarrhoea?
Which vitamins and minerals do you expect her to be deficient in?
From a nutritional perspective, what can be done to help her?
How do you explain to her the origin of her diarrhoea?
Ileal resection leads to malabsorption of bile acids. Unabsorbed bile acids irritate the mucosa of the colon and produce “bile acid diarrhoea”.
Which vitamins and/or minerals could you expect her to be deficient in?
Vitamin B12.
From a nutritional perspective, what can be done to help her?
Restrict dietary fat (long-chain triglycerides).
Substitute with medium chain triglyceride (MCT) which can passively diffuse into enterocytes.
Prophylactic treatment with B12 by IM injection.
How are LRNI, EAR and RNI calculated?
Normal distribution
RNI- enough to meet needs of 95% of population
LRNI- only 2% of populations needs met
EAR- in the middle
Malnutrition
Nutritional imbalance
Not just under nutrition but also over-nutrition
The two can co-exist
A person can move from one form of malnutrition to the other.
Overnutrition
A condition of excess nutrient and energy intake over time
Overnutrition may be regarded as a form of malnutrition when it leads to morbid obesity
BMI classification of obesity
People with BMI>25-30 are classed as overweight.
People with BMIs over 30 are obese.
BMI classification of obesity
People with BMI>25-30 are classed as overweight.
People with BMIs over 30 are obese.
Undernutrition
Term malnutrition is usually used instead of undernutriton
Is a state in which a deficiency of nutrients such as energy, protein, vitamins and minerals
Causes measurable adverse effects on body composition, function or clinical outcome
As a result of: Starvation- related Inadequate intake Disease- related Malabsorption of micro/macronutrients Increased requirements
Consequences of malnutrition
Immune system – less able to fight infection
Impaired wound healing
Loss of muscle mass – falls, pressure ulcers, chest infection heart failure
Kidneys – Over hydration or dehydration
Reproduction – reduces fertility
Brain – apathy, depression
Impaired temperature regulation - hypothermia
Micronutrient deficiencies – anaemia, rickets, scurvy, night blindness
Impact of malnutrition on mortality
Increases mortality and hospital stay
Cycle of malnutrition in patients
Malnourished patients often enter a vicious cycle
Approx 1/3 of patients admitted to hospital are malnourished.
Because illness and injury nearly always result in loss of appetite, patients may have increased losses due to diarrhoea and vomiting, and increased requirements due to metabolic stress.
In hospital, malnutrition increases the risk of wound infections, chest infections, pressure ulcers…
Which increases length of hospital stay, and makes their malnutrition even worse.
70% of patients lose weight during their hospital stay
The malnourished patient has an increased risk of falls and CAP.
Making hospital readmissions are more likely.
Unfortunately, each admission may make the situation worse.
Screening for malnutrition
Malnutrition universal screening tool (MUST)
When should a patient in hospital be screened for malnutrition?
Every person admitted to hospital should be screened for malnutrition within 24 hours.
Then re-screened on a weekly basis.
Malnutrition Universal Screening Tool (MUST) Steps
MUST consists of 5 steps.
Step 1: is to calculate BMI.
Step 2: is to calculate recent weight loss.
Step 3: asks “has the patient been unable to eat for 5 days or more due to acute illness”.
Step 4: is simply a case of adding the previous scores together.
MUST scores: what do they mean
A score of 0 means low risk of malnutrition.
So the patient just needs to be rescreened weekly.
A score of 1 indicates medium risk.
So a food record chart should be started and the screening repeated weekly.
A score of 2 or more indicates high risk.
So the patient is referred to the dietitian.
Subjective global assessment (SGA)
SGA is a little more detailed than MUST, but more sensitive. Validated in different disease states Chronic Renal Failure Chronic Liver Disease Cancer Cerebrovascular disease Like MUST, it assesses weight change And changes in dietary intake.
It also takes into account gastro symptoms, especially those that could lead to malabsorption.
And prompts the clinician to look for clinical signs of malnutrition i.e. muscle wasting, loss of fat, and oedema.
There is no scoring system.
The clinician makes their own decision based on the overall picture.
What are nutritional assessments?
Nutritional assessments allow us to determine patient’snutritional status & identify which ones are likely to benefit from nut. support
There is no single way of assessing nutritional status
We usually rely on a combination of:
- Anthropometry
- Blood biochemistry
- Clinical state and physical condition
- Diet (Diet history, Food Frequency Questionnaire, 24 hour recall, Food Record Chart)
Anthropometry
Anthropometry is the external measurement of body composition
Body weight:
-A single measure of body weight is not useful (other than to determine Body mass index)
- A body mass index of <18.5 suggests a risk of malnutrition
-Serial weights – used to calculate percentage weight change
-Weight loss ≥10% over 3-6 month period assoc. 7 fold increase in mortality
-(Powell-Tuck & Hennessy, 2003)
Limitations of anthropometry
Limitations:
- Difficult to obtain weight in acutely ill patients who can not be taken out of bed
- Medical staff aren’t always the best an estimating a patient’s weight.
- 1stdegree relatives can estimate wt. to within 3-5% of measured wt. (Reed & Price, 1998)
- Affected by the presence of fluid retention / oedema / ascites
Estimating dry weight in ascites and oedema
If your patient is fluid overloaded, you can hazard a guess at their dry weight using these estimates.
But there is a lot of room for error.
Hand grip strength
Index of muscle function
Mean value can be compared to reference data (values below 85% of normal may indicate PEM and predispose to serious post operative morbidity)
Serial measure assess change over time
- I.e. is your patient getting better or worse?
Respond more quickly to nutritional support than other anthropometric parameters
Easy, minimally invasive, inexpensive
Limitations of hand grip strength
Limitations:
Affected by motivational status
Ability improves with repeated use
Can not beused in pts with arthritis, confusion, severe illness
Biochemical markers of malnutrition
Albumin (35 – 55 g/L)
- Levels fall if the body is not absorbing enough protein
- And when there is increased demand for acute phase proteins, like CRP.
Urea (6 – 20 mg/dL)
- Formed when protein breaks down
- Low levels may indicate poor protein intake or low body muscle mass.
Creatinine and muscle
Creatinine levels are related to the amount of muscle the person has, low levels may be a consequence of decreased muscle mass (such as in the elderly), but may also be occasionally found in advanced liver disease
Why was David Blaine’s albumin normal after not eating or drinking for 44 days?
Albumin has a long half life (21days) – not sensitive to short-time changes in protein status
It increases in dehydration.
In simple starvation, the synthesis of albumin falls, but blood volume also reduces, therefore its Alb concentration may stay constant.
Albumin decreases when patient is severely stressed as liver produces acute phase proteins of greater physiological significance e.g. CRP.
it is wise to consider albumin levels with CRP valuesto distinguish reduction due to illness versus malnutrition
What do you look for in screening for malnutrition?
Sunken eyes, dry mouth, skin pinch test to look for dehydration
Skin pinch test can be used to look for dehyration
Pressure sores- need additional protein to heal.
Increased losses via diarrhoea / vomiting / pain
Diuretics cause increased losses of potassium
Examples of significant physiological stress?
Complex surgery, Traumatic brain injury Severe burns Severe sepsis. Starvation
Metabolic response to starvation
Adaptive process
Maintain supply of glucose to tissues
Minimise protein losses
↓in mass of metabolically active tissues (liver & GI tract)
In prolonged starvation basal metabolic rate (BMR) falls by 30%
First priority of metabolism in starvation?
To provide glucose to the brain and other tissues that are absolutely dependent on it.
Second priority of metabolism in starvation?
To preserve protein and prevent loss of muscle function.
In starvation, which energy reserve do we go to first?
We release glycogen stored in liver and skeletal muscle. This is used up within 24 hours.
What is the second step in metabolic response to starvation?
We degrade muscle protein to provide glucose by gluconeogensis,
but long-term this would result in functional problems due to loss of muscle.
So, after 3-4 days, we turn to fat or adipose tissue to provide FFAs to the liver, which makes ketones for energy.
And gluconeogenesis from muscle protein starts to decline.
To utilise this energy, the brain and skeletal muscle must switch from using glucose as a fuel to using ketone bodies.
By utilising fat, we can keep going for 2 months.
In prolonged starvation where does energy get derived from?
In prolonged starvation 95% energy will be derived from fat
The remaining 5% energy will be derived from protein via gluconeogenesis
The metabolic response to injury, trauma or sepsis
Different to starvation
Need to mobilise energy for defence and repair
BMR ↑
Instead of preserving protein, the body mobilises it for defence and repair,
This burning of protein means that the energy expenditure/BMR goes up..
There are three metabolic stages in injury: ebb, flow and anabolic phases.
3 stages: –Ebb phase –Flow phase –Anabolic phase (recovery phase)
Stage 1 of metabolic response to injury/trauma/sepsis
Ebb (shutting down) phase last 24 hours:
Energy reserves including (glycogen and free fatty acids) are mobilised,
but the bodies ability to utilise them is impaired.
Reduction in metabolic activity and a fall in body temperature
Stage 2 of metabolic response to injury/trauma/sepsis
Flow:
Length of flow phase depends on the severity of injury, but usually lasts 2-3 weeks.
the body is still mobilising energy
•Muscle is being broken down and used for gluconeogenesis
•This burning of muscle increases BMR and body temperature increase
• ↑ Counter-regulatory hormones like adrenalin/cortisol/glucagon are released in response to injury
This causes insulin resistance
So, the body can not utilise the glucose.
This causes high blood sugar.
The loss of visceral muscle for protein affects heart and lung function. Losee of skeletal muscle affects muscle function. - will impact on rehabilitation.
Overfeeding in this stage causes fatty liver, pancreatitis, high BMS and delayed weaning from ventilation.
Step 3 of metabolic response to injury/trauma/sepsis
Anabolic:
• Insulin sensitivity return to pre-injury levels
Nutritional therapy aims to restore muscle mass
Resting energy expenditure in starvation vs injury
in prolonged starvation, resting energy expenditure falls by approx 30%
But in major burns it can go up by as much as 100%
Protein in starvation vs injury
In starvation we have energy saving metabolism with reduced protein losses.
In injury, patients use a lot more energy than usual and they lose a lot more protein also.
CASE:
35 yr old female BMI 38kg/m2 Car accident- Traumatic Brain Injury & facial fractures Unconscious Unable to put feeding tube in for 1 week
Would you:
a) Suggest IV fluids for 1 week and feed once tube can be placed
b) Consider other feeding options ASAP
Do you think Anne should be okay to wait for a week till her facial fractures are more stable and she can have an NGT passed for feeding?
Or.. Do you think we must find a way to provide feeding to her asap?
We should really feed Anne from day one as her TBI will mean that her body is using lots and lots of energy and losing protein, therefore, if we don’t provide her nutritional support, she will be more likely to
develop infections,
need to be ventilated for longer,
Increased LOS, complications & mortality.
She will be losing large amounts of muscle in her flow phases with functional consequences. Skeletal and visceral losses inhibit organ function and mobility.
Define acute liver failure
- Rapid onset
- Severe liver injury with hepatocyte necrosis
- Diminished hepatic function
- -> Coagulopathy (INR > 1.5)
- -> Hepatic encephalopathy
- No pre-existing liver disease
Define Hepatic encephalopathy
Brain dysfunction / altered mentation
Caused by liver insufficiency (or portosystemic shunting)
Spectrum of neurological and psychiatric manifestations
Define cirrhosis
Chronic liver injury leading to chronic inflammation
Extensive fibrosis (scar tissue)
Presence of regenerative nodules
Acute failing liver vs Chronic failing liver
West Haven Criteria of severity of hepatic encephalopathy
Risk of jaundice to encephalopathy, cerebral oedema and survival in acute liver failure
King’s College selection criteria for adult super-urgent liver transplantation
Early Indicators of prognosis. Repeated validated – patients meeting the criteria have a greater 85% mortality without emergency transplantation. Bernal data for paracetamol induced liver failure –needs to be validated with other centres - > 3 after volume resuscitation
CASE:
24 year old, from Lithuania; in UK for 3 years
Jaundiced
Started omeprazole recently / one tattoo
LFTs: TBr 152, AST 1328, ALP 254, GGT 175, albumin 40
Normal FBC, INR 2
Diagnosis and next steps?
Diagnosis: Acute hepatitis ? cause
Liver ultrasound with Doppler – normal
Viral hepatitis screen –ve
Auto antibodies -ve
Repeat autoantibodies: weakly +ve anti Sm Ab
24 hour urinary copper 2 µmols / 24 hours
Kayser Fleisher rings –ve
IgG 18.5
Commenced prednisolone 40mg od, improvement in LFTs, fall in INR
Most common liver disorder in the West
NAFLD
Normal liver blood supply
In normal liver The main blood supply to the liver is the portal vein, this being formed from the superior mesenteric and splenic veins, draining the intestinal tract
The liver also receives oxygenated blood from the hepatic artery, these 2 bloods mixing together in the hepatic sinusoids before leaving the liver via the hepatic vien
CASE:
56 year old male
Known history of chronic hepatitis C and alcoholic liver disease
Presents to A+E with large haematemesis
Examination:
confused and agitated, abdo distension & jaundiced
P 110 BP 90/50
Bloods: Hb 74, plts 68, bil 143, alb 22, ALT 76, ALP 210, GGT 643
Diagnosis?
DDx
Cirrhosis with acute on chronic liver failure
Acute variceal haemorrhage
Hepatic encephalopathy
Ascites
5 clinical stages of cirrhosis
Child Pugh score
The Child-Pugh score consists of five clinical features and is used to assess the prognosis of chronic liver disease and cirrhosis
Grade A- compensated, 2 year survival
Grade B
Grade C- survival much less
What hepatic venous pressure gradient is clinically significant for cirrhosis?
10 mmHG
UKELD (MELD plus Na)
UKELD score of 49 indicates a 9% one-year risk of mortality, and is the minimum score required to be added to the liver transplant waiting list in the U.K.[1] A UKELD score of 60 indicates a 50% chance of one-year survival.[
What is this
Oesophageal varices
Sengstaken-Blakemore tube
If can’t get endoscopic control of bleeding this is used to stop bleeding from oesophageal varices
Management of encephalopathy
Treat sepsis, dehydration, constipation
Lactulose
- reduced colonic pH
- increased transit
Antibiotics
- Rifaximin
Dietary protein restriction rarely necessary
*If ALF: renal replacement therapy, reducing cerebral oedema & transplantation
Ascites as a complication of cirrhosis
Most common complication
60% of cirrhotics develop over 10 years
Splanchnic vasodilatation
Reduced effective blood volume
Activation of RAAS system and renal sodium retention
Expansion of extracellular fluid volume leading to ascites and oedema
Cumulative mortality
40% 1 year, 50% 2 years
