1
Q
What is the immunological function of the liver (2)
A
- Secrete IgA into bile and upper GIT
2. Destruction of bacteria in blood via Kupffer and Nk cells
2
Q
Which vitamins are stored in the liver (3)
A
- A
- D
- B12
3
Q
Outline the metabolic functions of the liver
A
see Michelle Ramsay PBL notes for diagrams
4
Q
Which acute phase proteins are synthesised by the liver? (5)
A
C-reactive protein (CRP) Caeruloplasmin α1-antitrypsin α1-acid glycoprotein α2-macroglobulin
5
Q
Which glyoprotein and lipoprotein transport proteins are synthesised by the liver? (5)
A
- Transcortin (corticosteroid-binding globulin)
- Thyroid-binding globulin
- Sex hormone-binding globulin (testosterone,
oestradiol) - Transferrin (Fe)
- Lipoproteins (lipids)
6
Q
Which clotting factor is used to measure liver function?
A
Factor vii since it has the shortest 1/2 life (5 hours)
7
Q
What are the different classsifications of cirrhosis (3)
A
Macroscopic:
• micronodular - uniform nodules <3 mm
• macronodular - nodular variation >3 mm
• mixed
8
Q
What are the microscopic features of cirrhosis (3)
A
- Diffuse involvement of liver
- Fibrous septa
- Inflammation affecting border of nodules or within the nodules themselves
See picture in notes of cirrhosis
9
Q
What are the vascular and architectural changes seen in cirrhosis (4)
A
• Activated myofibroblasts (derived from hepatic stellate cells) and portal or central vein
fibroblasts, proliferate and produce excess extracellular matrix (ECM) resulting in:
- fibrous portal tract expansion
- capillarization of the sinusoids, with loss of endothelial fenestrations
- congestion of the space of Disse with ECM
- central vein fibrosis
10
Q
Explain the mechanisms by which alcohol causes liver damage and how it may alter the metabolism of other drugs. (PBL1+2)
A
in anki under IODs
11
Q
Explain the mechanisms by which paracetamol causes liver damage. (PBL 2 + CPT session)
A
see michelle ramsay notes
12
Q
Describe how to treat paracetamol overdose, and which clinical findings can be used to predict a patient with a poor prognosis who should be referred for liver transplantation. (PBL 2 + liver damage session)
A
see michelle ramsay notes
13
Q
Explain the role of the liver in drug metabolism and the effect of liver disease. (CPT session)
A
see michelle ramsay notes
14
Q
Which aspect of the liver do the hepatic veins arise form?
A
posterior aspect
15
Q
What is the organisation o the structures at the porta hepatis
A
from anterior to posterior:
- Heptic ducts
- Hepatic artery
- Portal vein
16
Q
Which ligaments attach the liver to the abdomen?
A
- Falicform
2. Left and right triangular ligaments
17
Q
Where does the IVC lie in respect to the liver
A
lies in a deep groove on the posterior aspect
18
Q
What is the hepatopancreatic ampulla surrounded by?
A
Sphincter of Oddi
19
Q
What is the landmark location of the spleen
A
between 9, 10 and 11 ribs
20
Q
What is the spleen covered by?
A
peritoneum
21
Q
What are the three medial impression of the spleen
A
- Gastric
- Renal
- Colic
- also has a hilum where the splenic artery enters and splenic vein exits
22
Q
What are the embryological supplies to the abdomen
A
the foregut extends from the lower part of the oesophagus the
second part of the duodenum
the midgut extends to the splenic flexure of the transverse colon
the hindgut extends to the upper part of the anal canal
the liver, spleen and pancreas are supplied by the coeliac artery
23
Q
What are the consequences of an obstruction in portal flow (4)
A
- Shunts will open up between the portal and systemic circulation
- Portal-left gastric wtih
azygos veins in lower
oesophagus:
oesophageal varices
- Retroperitoneal veins enlarged at junction of mesenteric with retroperitoneal veins and also behind liver (‘bare area)
- Portal-epigastric veins newly reopened
in falciform ligament
with paraumbilical veins (‘Caput
Medusae’ around umbilicus) - Portal – splenic – inferior
mesenteric – superior rectal
with inferior rectal veins in
lower rectum (haemorrhoids)
24
Q
What are the mechanisms of hepatic encephalopathy (6)
A
- Porto-systemic shunting
- Impaired NH3 metabolism to urea
- Impaired NH3 metabolism to glutamine
- Intrahepatic shunting
- Muscle breakdown, impaired NH3
metabolism to glutamine - Increased renal NH3 synthesis
also see michelle ramsay notes
25
Treatment of hepatic encephalopathy
```
• Treat sepsis, dehydration and other predisposing
conditions
• Ammonia-lowering therapies:
– Lactulose
• shorter GIT transit time
• acidification of stool
• modification of gut flora
– Non-absorbable antibiotics
• rifaximin
• neomycin, vancomycin
• Dietary protein restriction not necessary (may worsen
encephalopathy)
```
26
What is the natural history of chronic liver disease
see michelle ramsay notes
27
What are the three types of liver failure (3)
– Acute: sudden, no pre-existing liver
disease
– Chronic: gradual, progression of CLD
(cirrhosis) causing decompensation
– Acute on chronic: acute deterioration
of previously well-compensated CLD
28
What is acute on chronic liver failure
```
• Acute deterioration of liver function over
2-4 weeks in patients with previously
well-compensated CLD; high associated
mortality (>50% at 6 weeks)
• Responsible for 30% of decompensation
episodes in cirrhotic patients
```
29
What are the clinical manifestations of acute on chronic liver failure
```
• Clinical manifestations:
– jaundice
– hepatic encephalopathy (HE)
– hepatorenal syndrome (HRS)
– rapidly evolving multiorgan failure
```
• Usually associated with a precipitating
event
30
What are examples of preciptating events in acute on chronic liver failure
• Direct:
– hepatotoxic drugs (NSAIDs, antibiotics)
– alcohol
– viral hepatitis (superinfection, reactivation)
```
• Indirect:
– sepsis
– variceal bleeding
– surgery
– sedative drugs
– electrolyte disturbances
– constipation
– high protein diet
```
31
How does acute (fulminant) liver failure manifest (5)
– jaundice
– coagulopathy (INR ≥1.5, PT >20 sec)
– encephalopathy (any degree)
• Onset of encephalopathy usually within 2 weeks
from the appearance of jaundice
• Can progress to multiorgan failure with a high
associated mortality
32
Classifcation of ALF
SEE MICHELLE RAMSAY NOTES
33
What is the most common cause of acute liver failure
viral hepatitis (A, B and E most common)
- HCV very rare
- HEV more severe
- Prognosis worse in the elderly and those with CLD
34
Classifcation, clinial featues and prognosis of ALF
see michelle ramsay notes
35
What are the clinical features of ALF (3)
```
• Progressive multiorgan failure
• Resembles septic shock (2o bacterial
infections, endotoxaemia)
• Severity of illness depends upon:
– adverse metabolic consequences of loss of
liver function
– systemic effects of circulating toxins
– rate and degree of liver regeneration
```
36
Why are ALF patients more prone to infection? (1) What are they most likely to be infected by? (3)
• ALF patients prone to infection - severe
complement deficiency, impaired neutrophil
and Kupffer cell function
• Bacteraemia and endotoxinaemia (20-80%),
predominantly Gm +ve (S. Aureus) and
Gm -ve bacteria (E. Coli)
• Fungaemia (30%), predominantly Candida
albicans, occurs late in the course of the
disease
• Antibiotic and antifungal prophylaxis (± gut
decontamination) usually given; predisposes
to development of multi-resistant strains
37
Tx of ALF in paracetamol toxicity
• N-acetylcysteine
38
Tx of ALF in mushroom poisoning
Silibilin + penicillin G
39
Tx of ALF in HBV
Nucleoside analogues
40
Tx of ALF in HSV
Aciclovir
41
Tx for ALF in pregnany
delivery
42
Does wilson disease induce ALF respond to chelation therapy
(Wilson’s disease-related ALF does NOT
| respond to chelation therapy)
43
Describe tghe use of n acetylcysteine for Tx of ALF
```
- Paracetamol induced ALF:
can prevent or reduce liver damage even
after large ODs if given within 24 h
– late administration (>24 h) recommended
but not proven
```
• Non-paracetamol ALF:
– well tolerated
– improves non-transplant survival if given
early in patients with low-grade HE
44
What are the two main determining factors oof ALF prognosis (2)
1. Aetiology
| 2. Coma grade on admission
45
What is the only reliable treatment option for ALF?
Liver transplantation
46
Indications for liver transplantation
see notes
47
Contraindications for liver transplantation (4)
Contraindications: severe multi-organ failure and
comorbidity, alcohol and substance abuse, social and
psychiatric problems
48
What is the survival following liver transplantation
• Emergency OLT outcomes worse than those of elective OLT; high early
post-op mortality due to sepsis and multiorgan failure
• Surgical outcomes show progressive improvement; currently 1-year
survival ca. 80%
• Outcome affected by: age of recipient, severity of pre-transplant illness
and the quality of the donor liver
49
What are the liver support systems in ALF (2)
• Principle: extracorporeal devices to replace
liver function, either to stabilise the patient
as a bridge to OLT or until spontaneous
liver regeneration occurs
• 2 types:
– biological with live hepatocytes
– non-biological blood detoxification using
adsorption and dialysis techniques
• Systems experimental - no conclusive
evidence of clinical benefit
50
Indications for nutrition support in hospital and the community (NICE, 2006) (5)
Nutritional support should be considered in people who are malnourished, defined by any of the following:
1. BMI < 18.5 kg/m2
2. Unintentional weight loss > 10% within the last 3-6 months
3. BMI < 20 kg/m2 and unintentional weight loss > 5% within the last 3-6 months
4. Have eaten little of nothing for more than 5 days and/or are likely to eat little or nothing for the next 5 days or longer
5. Have a poor absorptive capacity, and/or have high nutrient losses and/or have increased nutritional needs from causes such as catabolism
51
WHich anthropometric measurements are most commonly used? (4)
Most commonly used:
Body weight
Height
Adiposity (waist, BMI, skinfold)
Muscle mass (MAMC, grip strength)
Estimates of body water, body composition
52
Use of albumin to evaluate nutrition
Serum proteins – indicate visceral protein status and hence clinical outcome
Serum albumin:
Normal range: 3.5 to 5.5 g/dL or 35-55 g/l
Long half-life (14-20 days)
Not a very sensitive indicator to short-term changes in protein status
Affected by age, infection, zinc depletion and dehydration
Low levels correlate poorly with nutritional status
But albumin concentration <35 g/l, indicates body’s impaired ability to cope with major illness and can be used in nutritional ax.
53
Use of prealbumin (transthyretin) to evaluate nutritional status
Prealbumin (transthyretin):
Normal range: 19-38 mg/dl or 190-380 mg/l
Sensitive index of early response to nutritional support
Short half life <2 days
Also affected by hydration and acute changes in liver and renal function, but less than albumin
Concentration may be depressed in inflammatory states independently of nutritional status
Consider C-reactive protein concentration
54
Use of nitrogen in nutritional evaluation
Measurement of nitrogen excretion over a period of time will reflect nitrogen balance and changes in total body protein mass
Urinary urea nitrogen is measured using 24-hour urine collection
24-hour nitrogen intake is calculated as: 24-hour protein intake/6.25
Nitrogen output is calculated taking into account renal losses, skin & faecal losses
Positive nitrogen balance = patient excretes less nitrogen than they consumed, thus incorporating nitrogen into newly formed protein (i.e. muscle).
N balance (g/day) = Protein intake/6.25* – UUN** + faecal losses + obligatory losses (faecal and obligatory losses= 2-4 g/day)
* conversion coefficient might be different for specialized enteral or parenteral formulations
** urinary urea nitrogen
55
What is the mini nutritional assessment used for?
Mini Nutritional Assessment for screening people over 65 years for malnutrition
Available also as a mobile application
56
Wht is total energy expenditure
Hoe does this differ in stressed indivduals
In healthy individuals:
TEE = BMR + DIT + PAL
BMR = most dominant part of TEE (45-70%)
= metabolic activity for life e.g. respiration, heat etc.
DIT = energy expended in nutrient digestion/absorption/transport
PAL = physical activity level
In stressed individuals:
TEE = BMR + DIT + PAL + stress factor
e.g. recent surgery/
inflammation/trauma/burns
57
Revise the different types of drug interactions from last year
```
Augmented
Bizarre
Chronic
Dose related
End of reaction
```
58
What is the function of phase 2 metabolism
Phase 1 metabolism
Catabolic
Oxidation, reduction or hydrolysis
Metabolism may
Activate a pro-drug
Inactivate a drug
Create a toxic metabolite
59
What is phase 2 metabolism
Phase 2 metabolism
Anabolic
Produces inactive or readily excretable metabolite by
conjugating with another substance
60
which type of drug reaction is a paracetamol overdose
Type A “Augmented” toxicity
Predictable, dose-related
Will affect everyone if they receive enough of the
drug
61
Why is NAPQI toxic
NAPQI
Highly reactive
Oxidizes key enzymes causing cell death
Also can bind renal cells to cause renal failure
62
What does N acetyl cysteine do
replenishes glutathione - cysteine is an aa - glutathione made of aa's
63
When is the optimal time of Nacetylcysteine admin
8 hours
64
What do you give <1 hour since overdose
activated charcoal - prevents absorption of paracetamol into blood stream
65
What are other examples of type a drug reactions
1. Carbon tetrachloride (dry-cleaner) –
apoptosis/necrosis
2. Alcohol – hepatitis
66
Chlorpromazine is a...?
D2 antagonist
67
Slide 16 in the liver drug Dr Soulla lectures
CHOLESTATIC HEPATITIS
- bizarre reaction
- GGT raised
- Pale stools and dark urine = obstruction - increase CB = blockage makes the buildup of CB to enter blood stream = dark urine
- Due to the fact that amine group have a positive charge and bile acids form a negative charge = precipitate and form salts and block bile ducts = bizarre because you can't predict which patients will experience this
- can occur in low doses since they are bizarre
- usually occurs within four weeks of starting Tx
- May be accompanied by fever and eosinophilia as immune system is activated to get rid of the precipitates
68
Patient 3 of lecture
ACUTE HEPATOCELLULAR NECROSIS
- Allergic to halothane - first exposure to antibodies
- Immune mediated usually classified under bizarre
69
What are the difference in Patient 4's tests
these are functional tests whereas the other tests were structural
70
What blooop pressure hormones is excreted by the liver - what are the clinical imlications
aldosterone = cannot be excreted = retention of water
71
mechanism of palmar erythema
low albumin usually binds estrogen - low albumin = high estrogen which is a vasodilation = palmar erythema
72
Why does the MEOS pathway lead to liver damage
produces reactive oxygen species
73
how does acetate create fatty acids from alcohol
through the production of mannolyl co A
74
Which drugs may cause chronic drug reactions (3)
Methotrexate - fibrosis
Amiodarone - fibrosis and cirrhosis
Methyldopa (not commonly used but used in gestational HTN), isoniazid - chronic hepatitis
75
Which type of drug reaction did patient 5 have
delayed type
May occur even if drug has been stopped
Synthetic androgens, oral contraceptive pill
(OCP)
Benign liver tumours, hepatocellular
carcinoma - risk of either problem very low
Cholestasis more common with OCP
76
Are end of treatment reactions common with the liver
uncommon
Other examples include
Alcohol – seizures (depresses CNS - therefore sudden cessation may cause it to go hyperexcitable state)
Beta blockers – angina (oxygen demand goes up after you remove them)
Steroids – psoriasis recurrence
77
Patient 6
Rifaminpicin is an inducer and isonizid produces toxic metabolites
to prevent what happened to patient you should be monitoring the patient
78
Drugs to avoid in liver failure (5)
Opiates (increase risk of hepatic encephalopathy)
Diuretics (increase risk of hepatic encephalopathy) - decreased blood volume increases concentration of toxins that cause the ecephalopathy
Oral hypoglycemics (loss of glucose homeostasis)
Warfarin (effects enhanced)
79
How do sinsusoids appear and what are they made of
Composed mainly of collagen type III and this
| may be demonsrated with a reticulin stain.
80
How does ballooning degeneration apper on histology
See slide 24
```
Damage
from toxic or immunologic insult cause
hepatocytes to take a swollen
appearance, pycnotic centered nucleus.
These are sick hepatocytes undergoing
apoptosis, and the process of ballooning
is irreversible
```
81
How does foamy degeneration appear o histology
Biliary deposits cause a foamy, swollen
appearance of the hepatocytes
see slide 24
82
When do you see alcoholic steatosis
Appear in conditions such as alcoholic
liver disease and acute fatty liver of
pregnancy
83
What are councilman bodies
Formation of Councilman Bodies-
Eosonophilic globule with often fragmented
nucleus. It represents a hepatocyte that is
undergoing apoptosis
see slide 26
84
What is the most common area of necrosis in the lboule
The most common is necrosis of the hepatocytes around the terminal hepatic
vein- centrilobular necrosis.
Midzonal and periportal necrosis is rare.
85
What is the risk of hepatotoxicity following paracetamol posioning
• Risk of severe liver damage and death is
determined by the extent of delay beyond 8 h until
Rx with the antidote N-acetylcysteine (NAC)
commences
NAC Rx within 8 h will prevent all serious hepatic
injury
• Do not treat all patients with NAC as it has frequent
side-effects, is moderately expensive and requires
hospitalisation
86
When are low phosphate levls seen
early in paracetemol poisoning
low phosphate feature of APAP overdose with or without
hepatotoxicity; reflects severity of overdose
87
What is the glucose oxidation rate?
(4-7mg/kgbwt/min/day)
88
What is the aim of estimating accurate carbohydrate requirements?
Avoid excess CO2 production
89
What percentage of total energy do carbohydrates contribute
45-65%
90
How to estimate fluid requirements
30 - 35mls/kgbwt/day *
Consider:
Fever = increased reqs (by 2-2.5 ml increase per 1°C increase above 37°C)
Xs losses due to wound exudate, diarrhoea etc = increased reqs.
Obesity – review total volume
Consider all sources of fluid to prevent over-prescription
e.g. feeds, intravenous feeds and medication.
Estimate fluid requirements by assessing losses:
Fluid input = Urinary losses + 500-750 ml (to allow for insensible
fluid losses)
91
What are the NICE guidelines for suggested total intake
25-35 kcal/kg/day total energy (including that derived
from protein)
0.8-1.5 g protein (0.13-0.24 g nitrogen)/kg/day
30-35 ml fluid/kg (with allowance for extra losses e.g. from
drains and fistulae and extra input from e.g. intravenous
drugs)
92
What are the indications for gastrostomy feeding
Unsafe swallow
CVA
Parkinson’s disease
Motor neurone disease
Chronic inability to meet
oral requirements
Anorexia
dementia
Oesophageal stricture
Pre-head and neck
surgery/DXT
93
What are the complications of gastonomy feeding
Refeeding syndrome
Aspiration
Diarrhoea
Tube blockage
Feed contamination
Infected stoma site
Tube displacement
94
What is refeeding syndrome
- Complication that occurs when a malnourished person begins receiving nutrition again
- During periods of starvation:
1. Secretion of insulin is decreased in response to reduced intake of carbohydrates
2. Fat and protein stores are catabolised for energy
3. Results in intracellular loss of electrolytes - especially phosphate however serum levels remain normal due to compensatory mechanisms
4. When carbohydrates are given again, energy source switches to carbohydrates and insulin is released which results in cellular uptake of phosphate resulting in severe depletion of serum phosphate (within four days of starting to feed again)
5. phsophate needed for phosphorylation reactions and lack of it leads to refeeding syndrome which is:
```
Rhabdomyolysis
Leukocyte dysfunction
Resp failure
Cardiac failure
Hypotension
Arrythmias
Seizures
Coma
Sudden death
```
also see michelle ramsay notes for each electrolyte sequelae
95
What does low magnesium as a result of refeeding syndrome lead to
Decreased PTH secretion leading to hypocalcemia
96
When/how to give nutritional support - what so you need to consider
see michelle ramsay notes
97
Which conditions make a person more at risk of refeeding syndrome?
Very little or no food for >5 days (Esp BMI<20)
Unintentional weight loss >5% within the last 3-6
months
98
Who is at HIGH RISK of refeeding syndrome
With any of the following:
BMI<16
Unintentional weight loss >15% in last 3-6 months
Very Little or no nutrition for >10 days
Low levels of potassium, phosphate or magnesium
prior to feeding
__________________
2. With two or more of the following:
BMI<18.5
Unintentional weight loss >10% in last 3-5 months
Very little or no nutrition for >5 days
History of alcohol abuse or drugs –insulin,
chemotherapy, antacids, diuretics
99
What nutrtion should you give to someone at risk of refeeding syndrome
Nutrition support should be cautiously introduced
It should be started at no more than 50% of the
estimated target energy and protein needs
Built-up to meet full needs over the first 24-48
hours according to metabolic and gastrointestinal
tolerance.
Full requirements of fluid, electrolytes, vitamins
and minerals should be provided from the outset
of feeding.
100
Nutrtion support for people at HIGH RISK of refeeding syndrome
Starting nutrition support at a maximum of 10 kcal/kg/day,
increasing levels slowly to meet or exceed full needs by 4-7
days.
Using only 5 kcal/kg/day in extreme cases (e.g. BMI < 14
kg/m2) and monitoring cardiac rhythm continually.
Restoring circulatory volume and monitoring fluid balance and
overall clinical status closely.
Providing immediately before and during the first 10 days of
feeding: oral thiamin 200-300 mg daily, Vitamin B co strong
1-2 tablets 3 times a day, and a balanced multivitamin/trace
element supplement once daily.
Providing oral, enteral or intravenous supplements of
potassium (2-4 mmol/kg/day), phosphate (0.3-0.6
mmol/kg/day) and magnesium (0.2 mmol/kg/day IV, 0.4
mmol/kg/day oral) unless pre-feeding plasma levels are high.
Pre-feeding correction of low plasma levels is unnecessary.
101
Indications for parenteral nutrtion
```
Parenteral nutrition (PN): administration of nutrients by the intravenous
route via a dedicated central or peripheral placed line.
```
Used where there is:
a. failure of gut function (e.g. with obstruction, ileus, dysmotility, fistulae,
surgical resection or severe malabsorption) to a degree that definitely
prevents adequate gastrointestinal absorption of nutrients
and
B. the consequent intestinal failure has either persisted for several days (e.g.
>5 days) or is likely to persist for many days (e.g. 5 days or longer) before
significant improvement.
It may also be needed in patients with reasonable gut function who
cannot eat when ETF is impossible or impractical for reasons of tube
Intestinal obstruction
Intestinal perforation
Short bowel
Anatomical
Functional
High output small bowel fistula
(prolonged ileus)
Multi-organ failure where requirements cannot be
met by the enteral route
Intractable vomiting
Chronic malabsorption
102
What is a NON INDICATION for parenteral nutrition
Post major (GI) surgery
Acute pancreatitis
Absence of bowel sounds
103
Problems with parenteral nutrition?
infection
thrombosis
electrolyte disturbances
hepatic dysfunction
Hyperglycaemia
104
What are the five main responses to hgepatic injury
Degeneration and Intracellular Accumulation
Necrosis and Apoptosis
Inflammation
Regeneration
Fibrosis
105
Which is more common micro or macrovesicular steatosis
Macro
106
In which conditions are fatty livers seen
1. Alcoholic liver disease
| 2. Acute fatty liver of pregnancy
107
What is the term for Injury to the liver which associate with an influx of acute or chronic inflammatory
cells
hepatitis
108
Main difference in appearance between acute and chronic viral hepatitis
Acute viral hepatitis:
inflammation is scattered
throughout lobule as well as
portal tract.
Chronic viral hepatitis:
inflammation is mainly in portal
tracts, with focal interface
hepatitis
see slide 31
109
What is the basis of hepatocellular regeneration
Liver has the ability to regenerate. Hepatocellular proliferation is
signified by mitoses, thickening of the hepatocyte chords and some
disorganization of the liver parenchyma
110
What is cholestasis
condition
| characterized systemic retention of bilirubin and other solutes eliminated in bile.
111
How do regenerative nodules appear on histology
see slide 38 of histology lecture
112
how doe smassive hepatic necrosis appear on histology
a wide spectrum of morphological changes in the parenchyma,
from areas of extensive hepatocyte loss and parenchymal
collapse to areas of hepatocytic regeneration with the
appearance of regenerating nodules.
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