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
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
Microscopical features of acute hepatitis
Acute viral hepatitis: inflammation is scattered throughout lobule as well as portal tract.
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
Steatohepatitis microscopic changes
Polymorphs
Mallory’s hyaline
Fat
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
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.
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
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.
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.
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.
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
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.
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
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 is this
Oesophageal varices
