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1
Q

describe the liver

A
  • Large lobulated exocrine and blood processing gland, with vessels and ducts entering and leaving at the porta
  • Enclosed by a thin layer of collagen tissue capsule, mostly covered by mesothelium
  • Collagen tissue of the branching vascular system provides gross support
  • Parenchymal cells are supported by fine reticular fibres
2
Q

describe the vessels of the liver

A
•	Portal vein 
      o	Brings food rich blood from the gut
      o	75% of blood supply	
•	Hepatic artery
      o	Bringing arterial blood
      o	25% of blood supply
•	Hepatic veins 
      o	Bringing away processed blood into the vena 
                cava
•	Lymphatics
•	Hepatic ducts
      o	Bringing away bile to the gallbladder and gut

There is a nerve supply – parasympathetic and sympathetic supply of perivascular structures but this has very little to do with control of sinusoids

3
Q

describe the cell structure in the liver

A

Cells are arranged in perforated plates, one cell wide.
Between the plates are sinusoidal blood channels 9-12um wide, lined by endothelial cells
Scattered in the glandular mass are blood vessels, alone or accompanied by other vessels
These mark out the classic hepatic lobules

4
Q

describe the liver blood vessels

A

• Central vein/ terminal hepatic venule
o Very thin wall
o Lies in the centre of lobule
o Sinusoids converge and open into it

• Sublobular/intercalated vein
o Thicker wall
o Lies alone at the periphery of the lobule

• Branch of portal vein
o Again at periphery
o Accompanied by one or more hepatic arteries
and one or more bile ducts
o These three together make the portal triad
o A portal triad lies in a portal area

5
Q

how does blood flow through the sinusoids

A

Mixed blood (oxygenated from hepatic artery and not from portal vein) starts from the portal triad and moves along toward the central vein. Flow is very slow and exchange takes place with the cells lining the sinusoids

6
Q

describe rappaports liver acinus

A

functional unit comprising of three or so lobules to try and describe the differences in exposure to the blood supply along the various parts of the lobules.
Such differences are reflected in the varied functional activities and susceptibility to toxic agents.
The portal triads are places into the middle instead of peripheral.
There are three zones, each getting closer to the central vein
• Periportal (zone 1) – deals with sampling of components of blood - can detect low blood sugar and send signals to cells downstream (closer to the central vein) to break down glycogen to glucose to enrich the blood. The opposite can be true
• Intermediate (zone 2)
• Perivenous (zone 3)

7
Q

what can you see in the periportal area in evidence of liver damage?

A

undifferentiated cells

8
Q

describe sinusoids

A

• Lined by fenestrated endothelial cells
o These are loosely attached and rest on microvilli without a basal lamina intervening
o Plasma can therefore pass through the sieve plate, formed by the lining cells, out into the perisinusoidal space of Disse to interact with the hepatocytes
o Disse’s space contains ECM but not a visible basal lamina
• Hold phagocytic Kupffer cells (larger, stellate with a pale oval nucleus)
• Scarce, fat-storing, Stellate cells lie outside of the endothelial cells
o Store vitamin A
o Respond to a variety of insults by making collagen and causing cirrhosis (fibrosis)

9
Q

describe the sinusoidal wall

A

• Cleanses the blood (of gut bacterial toxics etc)
• Haemopoiesis in the embryo
• Bringing plasma into intimate contact with the hepatic cell for its many metabolic functions of
o Storage
o Transformations
o Syntheses
o Regulation of plasma concentrations
o Detoxification
o Production of bile
o And assisting defence by production of acute
phase proteins

10
Q

describe hepatocytes

A

• Main functional cells of the liver
• 80% of the mass of the liver
• Arranged in plates which anastomose with each other
• The cells are in a polygonal shape and their sides are in contact with sinusoids (sinusoidal face) or another cell (lateral face)
• A portion of lateral faces are modified to form bile canaliculi
• Microvilli are present abundantly on sinusoidal faces and project sparsely into bile canaliculi
• Hepatocyte nuclei are distinctly round with one or two distinct nucleoli
o Most have one nucleus but binucleate cells are common

•	Functions
o	Extensive granular ER
	Protein synthesis
o	Smooth ER
	Steroid hormone and cholesterol metabolism
	Lipid processing
o	Very rich in mitochondria
o	Actin and other microfilaments
o	Golgi bodies (bile production)
o	Lysosomes (bile production)
o	Peroxisomes
o	 Glycogen granules
o	Fat droplets (appear after meals)
o	Lipofuscin – pigment from aging
11
Q

what happens in liver fibrosis

A
  • Fenestrations close up
  • This leads to increase in sinusoidal pressure – portal hypertension
  • As this gets worse, hepatocytes die and others are surrounded by fibrous tissue
12
Q

describe bile ducts

A
  • Bile flows in opposite direction – TOWARDS PORTAL TRIAD
  • Bile duct formed by many bile canaliculi
  • These flow to the canals of herring which have hepatocytes, bile ducts and stem cells
  • Common bile duct drains to the ampulla at the sphincter of Oddi and finally to the duodenal outlet
13
Q

describe lymphatics

A
  • Lymph formed by filtration of plasma into the spaces of Disse as blood flows through sinusoids
  • Then lymph percolates between the space of Disse and portal tracts then lymphatics are formed and run along portal vessels and biliary ducts
  • The exact correlation between lymphatics and the rest of liver microanatomy is not clear
14
Q

how many bacteria per gram of colon contents in health

A

10^12

15
Q

what factors in the GI tract prevent infection

A
•	pH
       o	high in stomach which kills 
•	flow rate
       o	high at mouth and lower in gut
•	mucus
       o	between gut cells and contents
•	competition between bacteria: colonization resistance
•	presence of bile and digestive enzymes
•	redox potential/oxygen tension
      o	top of gut is aerobic and bottom tends to be 
                anaerobic
16
Q

what are some pathogenic mechanisms of pathogens

A

• adherence mechanisms
o stick to gut wall

• toxin production
o often enzymes which cause harm

• motility
o burrow through mucous layer

  • site of pathogenicity
  • resistance to bile and digestive enzymes

• avoidance of immune mechanisms
o secretory antibody (IgA)
o capsules and lipopolysaccharides

• immunopathological mechanisms
o often what cause the most damage

17
Q

describe H. pylori

A
  • curved/spiral
  • gram-negative
  • microaerophiles
  • highly motile
  • causes gastritis
  • gastric and duodenal ulcers – gastric carcinoma
  • produces urease (urea  ammonia – high pH)
  • very common well adapted pathogen
  • present in up to 50% in western adults and 100% in developing world
  • several putative virulence factors but with no simple correlations with pathogenicity
  • developing antibiotic resistance
18
Q

describe vibrio cholerae

A
•	gram-negative
•	comma shaped
•	motile with polar flagellum
•	water borne pathogen
•	causes cholera
•	cholera toxin (CT) and toxin co-regulated pilus – both produced by same trigger
•	encoded by CT-bacteriophage
•	watery diarrhoea – rice water stools
•	severe dehydration
•	Cholera toxin
       o	Bipartite toxin
       o	ADP ribosylating
       o	5 B subunits – B BINDS to GM1 ganglioside 
                on enterocytes
       o	1 A subunit – A is ACTIVE part

Cholera toxin sits on the surface of the cell and codes for a product which affects adenyl cyclase – products of adenyl cyclase is cAMP. This builds up in the cell and reverses sodium pump – water tends to go out of the cell

In villus cells – net reduction of absorption of Na and Cl ions and hence water moves out
In crypt cells – increase in secretion of water and Cl

Rehydration therapy – oral/IV

19
Q

describe shigella sp.

A
Shigella sp.
•	Four species
o	S. dysenteriae  (most dangerous)
o	S. boydii
o	S. flexneri
o	S. sonnei (least dangerous)
•	Members of Enterobacteriaceae
•	Lactose negative
•	Non-motile
•	Cause of dysentery
20
Q

describe dysentery

A
  • Invades mucosa and damages cells causing blood in diarrhoea
  • S. dysenteriae only one to produce shiga toxin

Get into the mucosal cells via M-cells
Then ingested by macrophages which are killed by apoptosis which releases cytokines causing inflammation and tissue destruction

21
Q

describe C. diff

A

• Most common cause of nosocomial (healthcare acquired) diarrhoea
• Ranges from asymptomatic carriage to life threatening pseudomembranous colitis
• Highly motile – many flagelli
• Gram positive
• Anaerobic
• Spore former
• Increasingly resistant to antibiotic
• Combination of direct cellular damage and immunopathology
• Necessary stages in pathogenesis
o Colonization resistance compromised by antibiotics
o Gut becomes susceptible to colonization
o Evades immune response
o Produces toxins A and B – causes collapse of cytoskeleton
o Neutrophils and fibrin on the surface of cells cause pseudomembranes – pseudomembranous colitis
o UK type O27s
 Have the same tcdC gene deletion
 Hyper-toxin producers – produce more than other strains
 Resistant to quinolone antibiotics

22
Q

what are some treatments for C. diff

A

• Antibiotics
o Metronidazole or vancomycin - anti-anaerobe
o Fidaxomicin – new frontline treatment – very little collateral damage

23
Q

describe microbial food poisoning

A

acute gastroenteritis due to eating (or drinking) food containing microorganisms or their toxic products – viable organisms or pre-formed toxins

24
Q

how do you diagnose microbial food poisoning

A
•	Type of food implicated
•	Time to develop symptoms (incubation period)
•	Symptoms (all or some)
o	Vomiting
o	 diarrhoea (watery, scant, perhaps blood)
o	Fever
o	Stomach cramps
•	How long the symptoms last
25
Q

describe campylobacter

A
  • Microaerophilic
  • Gram-negative
  • Curved rods
  • Grows well at 42C
  • Commonest cause of diarrhoea in the developed world
  • C. jejuni (90%) and C. coli
  • Associated with poultry (frozen)
  • Incubation 24 -72 hours
  • sporadic
  • Duration 1 week
  • Diarrhoea and severe stomach cramps
  • Rare but significant cause of Guillain Barre syndrome (peripheral neuropathy)
26
Q

describe non-typhi Salmonella sp.

A
  • Associated with poultry and eggs
  • Sporadic and outbreaks
  • Incubation 6-48 hours
  • Duration 1-7 days
  • Often serious: diarrhoea, vomiting, fever
27
Q

describe clostridium perfringens

A
  • Often associated with bulk cooking of meat
  • Often in large outbreaks
  • Incubation 8-22h
  • Duration 1-2 days
  • Severe abdominal cramps and diarrhoea
  • Warm food – contamination by spores which germinate
  • Produce an enterotoxin
28
Q

describe Clostridium botulinum

A
  • Anaerobic
  • Spore forming
  • Types A-G
  • Widely distributed in nature
  • Produces the most powerful toxin
29
Q

describe Staphylococcus aureus

A
  • Common skin organism
  • Contaminates salty food and dairy produce
  • Incubation 2-6 hours
  • Duration 1-24 hours
  • Very acute vomiting followed often by diarrhoea
  • Staph enterotoxins are superantigens
30
Q

what are some examples of intoxications

A
•	Botulism
      o	Neurotoxins
•	Staphylococcus enterotoxins
      o	Classic superantigens
•	Bacillus cereus enterotoxins
•	Mycotoxins
31
Q

describe Bacillus cereus

A
•	Often associated with cooked rice
•	Acute vomiting followed by diarrhoea
•	Incubation 1-5 hours
•	Duration 12-24 hours
•	Spores germinate in warm cooked rice – survives 
        reheating
32
Q

describe norovirus

A
  • Sporadic
  • Small outbreaks
  • Larger outbreaks on cruise ships and hospitals
  • Usually spread directly but some outbreaks associated with shellfish
33
Q

describe EHEC – enterohaemorrhagic E-coli

A

• Food borne (faecal contamination)
• Environmental contamination by domestic animals
• Infectious dose – 10 bacteria or so
• Efface microvilli and form a pedestal of fibrin to sit
on

34
Q

describe viruses

A

Viruses are unable to replicate by themselves and need a host cell and their biochemical machinery
Consist of DNA or RNA in a virus encoded protein coat (nucleocapsid) and sometimes an outermost membrane derived envelope
Attach to host cell via receptor proteins

35
Q

what are the clinical symptoms of hepatitis

A
  • Yellowing of skin and eyes (jaundice)
  • Dark urine
  • Clay-coloured stool
  • Nausea and vomiting
  • Loss of appetite
  • Fever
  • Abdominal pain
  • Weakness
36
Q

what are some tests for hepatitis

A
•	Biochemical
o	Liver enzymes (ALT, AST, ALP, GGT)
o	Other liver proteins (albumin, prothrombin)
o	Bilirubin (direct, indirect)
•	Serological
o	Enzyme immunosorbent assays (EIA)
	Viral antigen
	Anti-viral antibody
o	Molecular assays
	PCR
•	Viral load
	Sequencing 
•	Genomes
•	Antiviral resistance
•	Liver biopsy
37
Q

describe hep A

A
•	Single strand positive RNA Picornavirus
•	Incubation time 10-50 days
•	Faecal oral transmission
•	Primarily infects children and young adults
•	Abrupt onset
•	Very high liver enzymes
•	Treat symptoms but not cause
•	Detection
      o 	Anti HAV IgM
      o	Anti HAV IgG
      o	HAV RNA
38
Q

describe hep B

A

• Enveloped partially dsDNA hepadnavirus
• Parenteral, sexual and vertical
• Incubation 40-180 days
• Primarily in babies and young adults
• Virus remains in hepatocytes for life and can
reactivate in immunosuppression
• Chronic infection develops in 5-10% of patients and
is associated with hepatocellular cancer

• Treatment for chronic infection
o Interferon alpha or antivirals

• Tests
o Hep B surface antigen (HBsAg)
 Found in HBV envelope
 Indicates active infection
 Found in serum in acute or chronic
infection
 Anti-HBsAg indicates past HBV infection
or immune response to HBV vaccine or
passive antibody transfer following
administration of HBV Ig
o Hep core antigen (HBcAg
 Part of HBV nucleocapsid
 Anti-HBcAg IgM
• Recent infection
• Persists 4-6 months after infection
 Anti-HBcAg IgG
• Indicates recent or past infection
• Persists for life
o Hep B E antigen (HBeAg)
 Associated with nucleocapsid
 Indicates active infection

39
Q

describe hep C

A
•	Enveloped ss positive RNA flavivirus
•	15-160 days incubation
•	Primarily adults
•	Parenteral transmission (sexual?)
•	Acute phase very often completely asymptomatic
•	Chronic infection in 70-90% of cases
•	Associated with hepatocellular cancer
•	Interferon alpha with ribavirin or direct acting anti 
        virals
•	Tests
       o	Anti-HCV antibodies
              	Indicates recent or past infection
              	Take up to 3 months to develop
       o	HCV antigen
              	Reflects viraemia
       o	HCV PCR
              	Determines viraemia
40
Q

describe hep D

A
  • Cannot infect without hep B due to not having surface antigen
  • Enveloped circular ss negative RNA
  • HBV vaccine provides indirect protection against this
  • Can get super infection along with hep B
41
Q

describe hep E

A
  • Non-enveloped ss positive RNA hepevirus
  • Incubation time 15-60 days
  • Faecal oral transmission
  • No chronicity identified apart from in immunocompromised patients
  • No vaccine
  • Supportive treatment
42
Q

what are some other causes of hepatitis

A
  • Epstein-Barr virus
  • Cytomegalovirus
  • Herpes simplex virus ½
  • Rubella virus
  • Enteroviruses
  • Yellow fever virus
43
Q

how are hepatitis viruses transmitted

A

A and E transmitted fecal orally

BCD transmitted in blood and sexual contact – often cause chronic disease

44
Q

what are some things to remember about hepatitis viruses

A

Hepatitis viruses are from different families
D can only infect a patient with Hep B – can be a super infection
A and E are non envelope as they need to be hardy to live in stool before transmission and envelopes make you sensitive. BCD are envelope

45
Q

what does failure to clear bilirubin lead to?

A

Jaundice

46
Q

what does failure to clear gut-derived toxins (NH3) lead to?

A

Encephalopathy

47
Q

what does failure to produce clotting factors lead to?

A

Coagulopathy on blood tests

48
Q

what does failure to produce albumin lead to?

A

oedema, impaired binding of drugs

49
Q

what does failure to store glucose or release it lead to?

A

hypoglycaemia

50
Q

what does failure to utilise carbohydrates lead to?

A

muscle breakdown

51
Q

what does failure to produce clotting inhibitors as well as clotting factors lead to?

A

balance in practice?

52
Q

what is the difference between acute and chronic liver failure

A

Acute liver failure <2-3 months
Chronic liver failure >2-3 months
Have different aetiologies and different presentations

53
Q

describe acute liver failure

A
Acute liver failure
•	Rapid onset, no underlying liver disease
•	Acute liver injury – high ALT     
       o	 common
•	Severe acute liver injury -high ALT      
       o	Uncommon
       o	Jaundice and coagulopathy
•	Acute liver failure – high ALT
       o	rare
       o	jaundice and coagulopathy
       o	encephalopathy
•	causes
       o	paracetamol overdose – most common  80- 
                90%
       o	less common	
              	herbal remedies
              	anti – TB drugs
              	ecstasy
              	acute viral infections – hep B most likely 
              	autoimmune hepatitis
o	rare 
              	Budd-Chiari
              	Wilson’s 
              	Acute fatty liver of pregnancy
              	Cancer
              	Ischaemia
              	Amanita phalloides mushroom
              	Carbon tetrachloride
54
Q

why is vitamin K given in preference to fresh frozen plasma (FFP)?

A

Giving vitamin K will not mask the liver’s function like giving FFP (fresh frozen plasma) will so it is a first option.

55
Q

what is the prognosis in paracetamol ALF

A

• Unlikely to recover spontaneously if
o PT > 1000 and
o Anuric / creatine >300 and
o Grade 3/4 encephalopathy (stupor/coma)

56
Q

what is the prognosis in non-paracetamol ALF

A
  • Age (<10 or >40 worse)
  • Aetiology (drug or seronegative worse than viral)
  • PT >50 or INR >3.5
  • Bilirubin >300
  • Time from jaundice to encephalopathy <7d
  • 3/5 unlikely to recover spontaneously
57
Q

what is the difference between paracetamol ALF and non-paracetamol ALF

A

Paracetamol causes hyperacute liver failure
Rapid progression of coagulopathy over hours rather than days
Usually encephalopathy in under a week

Other causes more gradual onset over several weeks

58
Q

describe chronic liver failure

A

• Impaired hepatocyte function causes:
o Low albumin
o Jaundice
o Coagulopathy

• Hepatic encephalopathy
o Failure of hepatocyte function (NH3 clearance)
o Portosystemic shunting (from portal circulation
to systemic)
o Often triggered by other events
 Constipation
 Drugs (opioids, sedatives)
 Dehydration (diurectics)
 Infections
 GI bleeding

• Ascites
o Low albumin
o Portal hypertension
o Renal hypoperfusion

59
Q

what are some causes of CLF

A
  • Alcohol
  • Non-alcoholic fatty liver disease
  • Hepatitis B or C
  • Haemochromatosis
  • Wilson’s disease
  • Primary biliary cholangitis
  • Autoimmune hepatitis
  • Primary sclerosing cholangitis
60
Q

what are the ways of managing CLF

A

• Identify cause
o Abstinence from alcohol
o Antivirals for hep B/C
o Steroids for autoimmune hepatitis
• No treatment for jaundice
• Low salt diet and diuretics for ascites
• Laxatives and antibiotic for encephalopathy
• Liver transplant if appropriate