lecture 17 Flashcards
liver disease 2
1
Q
What do you need to have fibrosis?
A
necrosis and inflammation which stimulates fatty stellate cells to start laying down collagen
2
Q
What is alcoholic hepatitis?
A
Characterised histologically by:
- steatosis
- zone 3 ballooning (hydropic swelling) of hepatocytes and presence of Mallory bodies
- zone 3 spotty necrosis and inflammation (clusters of neutrophils and mononuclear cells)
- zone 3 activation of HSC with perisinusoidal collagen deposition and central perivenous fibrosis with or without obliteration of central veins
- fibrosis progressing to micronodular cirrhosis
pathway to cirrhosis in alcoholic liver disease
3
Q
What do you see in alcoholic hepatitis?
A
- ballooned hepatocytes
- mallory bodies
- spotty necrosis/necro-inflammation with clusters of neutrophils
4
Q
Why are the cells enlarged in alcoholic hepatitis?
A
- acetaldehyde leads to cytoskeletal and mitochondrial damage
- in the liver the intermediate filaments are cytokeratin 8 and 18: give shape to the liver cell and control where the various organelles sit within the cytoplasm
- also contractile actins that give contractility to the faces of plasma membrane facing the sinusoids (helps create pits where they can take in stuff?), also around the biliary canaliculus they help propel bile into the groove
- microtubules help transport proteins/fats/vesicles etc around the cell
- acetaldehyde causes the cytoskeleton to collapse and aggregates to form mallory bodies
- acquire certain other proteins e.g. ubiquitin, Hsp62, CK8/18
- can’t transport proteins out either so intracellular osmotic pressure raised - cell swells up to several times its normal size, becomes rounded and eventually dies
5
Q
Why is the central vein lost?
A
- structure of the central vein dependent on the cells around it
- don’t have an independent wall
- if the hepatocytes disappear the framework for the central vein and the sinusoids collapses
- central vein obliterated
- you get complete disorganisation of the vasculature
- -> bridging portal tracts and central zones surrounding and isolating nodules of regenerating liver cells (fibrosis)
6
Q
What is liver disease associated with the metabolic syndrome?
A
- non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH)
- alcoholic-like liver injury in a non-drinker
- mostly middle-aged women (80%)
- asymptomatic with other medical problems (obesity, diabetes, hypertension)
- enzyme elevations/hepatomegaly
- underlying cause – metabolic syndrome and insulin resistance
7
Q
How do we diagnose metabolic syndrome?
A
- central obesity - waist circumference Europid men ≥ 94cm and women ≥ 80cm; asian men ≥ 90cm and women ≥ 80cm
- plus any two of the following 4 factors:
- raised serum TG level: ≥ 1.7mmol/L
- reduced serum HDL cholesterol <1.29mmol/L in females
- raised BP: systolic ≥130 or diastolic ≥85mmHG
- raised fasting blood glucose (FBG) ≥ 5.6mmol/L
8
Q
How does central obesity lead to a metabolic and inflammatory cascade?
A
- complex dyslipidemia: high TG, SD-LDL, low HDL
- systemic inflammation
- endothelial dysfunction
- hypertension
- disordered fibrinolysis
- obstructive sleep apnoea
- atherosclerosis
- polycystic ovary syndrome
- NAFLD/NASH
- Type-2 DM
- insulin resistance
9
Q
What is the histological spectrum of NAFLD in the metabolic syndrome?
A
similar to alcoholic liver disease but proportion of patients in the categories of increasing severity differs:
- 70% of patients have steatosis alone or steatosis with non-specific inflammation
- 25% develop non-alcoholic steatohepatitis (NASH)
- 3-5% get cirrhosis (less often than with alcohol)
- < 0.5% develop cirrhosis with HCC (less often than with alcohol)
10
Q
What are hereditary/genetically determined disorders?
A
- storage diseases
- hereditary iron overload (genetic haemochromatosis) (common in Australia) (tends to manifest in adolescence, adulthood)
- wilson’s disease (copper)
- alpha-1-antitrypsin deficiency (protease inhibitor, PI) (big cause in children)
- other (tyrosinaemia, glycogen storage disease, galactosaemia, etc)
- CF of the pancrease (childhood)
11
Q
What are types of liver injury?
A
- toxic
- metabolic
a) acquired
b) hereditary (storage diseases) - hepatitic
a) infectious (viral hepatitis)
b) immunological (autoimmune hepatitis) - cholestatic (bile not getting out)
- circulatory (cardiac failure)
- neoplastic (cancer)
12
Q
What is the hepatitic pattern?
A
- the hepatitic histological pattern is defined as diffuse inflammation of the liver accompanied by features of hepatocellular injury and regeneration of hepatocytes
- hepatic pattern is seen in:
1) viral hepatitis
2) idiosyncratic reactions to therapeutic drugs
3) autoimmune
13
Q
What is the morphology of the hepatitic pattern?
A
Parenchymal degeneration and cell death
- ballooning degeneration of hepatocytes
- apoptosis – programmed cell death
- necrosis – various types depending on severity
Inflammatory and mesenchymal reaction
- mononuclear inflammatory reaction in lobules and portal tracts
- hardly ever neutrophils
- Hyperplasia of Kupffer cells
- collections of macrophages containing ceroid and iron pigment at sites of necrosis
Regeneration of hepatocytes
- hypertrophy and mitotic replication of hepatocytes
14
Q
What can be viewed histologically in acute viral hepatitis?
A
- lobular disarray and inflammation
- liver cell plates are disordered
- mononuclear cells
- hard to see central vein
- ballooning degeneration and apoptosis of hepatocytes
- collections of pigmented macrophages filled with ceroid demarcating foci of liver cell necrosis (diastase stain)
15
Q
What kills the cells?
A
- often the immune reaction to the cell carrying the virus as opposed to the virus itself
16
Q
What happens after around 6 weeks?
A
- fast resolving
- liver cells start to go back to their regular arrays
- central vein visible
- sinusoids visible
- residual inflammation remains in the portal tract
- still might be some pigmented macrophages in zone 3
17
Q
What is the evolution of acute viral hepatitis?
A
- early stage
- fully developed stage
- later stage
- residual changes
- early stage to resolved stage usually about 6 weeks
- residual changes of inflammatory cells will remain for about 3 months
- peak of parenchymal damage and necrosis in fully developed stage
- soon after that peak of inflammatory and mesenchymal reaction
- also peak of pigmented macrophages slightly later
- all normally subside
- in some individuals you get persistent high levels of inflammatory cells because virus persists –> chronic inflammation
- if it lasts more than 3 months
- people with severe disease progress faster to cirrhosis
18
Q
What is the morphology of acute viral hepatitis?
A
presence of lesions constant (seen in all cases)
lobular lesions:
- lobular disarray with anisocytosis (cell varies in size and shape) and anisonucleosis (nucleus varies in size and shape) of liver cells
- liver cell necrosis - single cell and focal
- inflammatory cell infiltration (mononuclear) and proliferation of Kupffer cells
- accumulation of ceroid and iron in macrophages
- evidence of regeneration of liver cells
portal and periportal lesions
- accumulation of lymphocytes, plasma cells and other cells
- accumulation of ceroid and iron in macrophages
Inconstant (seen only in severe cases)
lobular lesions
- confluent bridging and multilobular necrosis and formation of passive septa
- cholestasis (bile plugs)
portal and periportal lesions
- piecemeal necrosis
- periportal
- periseptal
- fibroblastic activity – fribinogenesis and formation of active septa
- bile duct damage and ductular proliferation
19
Q
What are types of necrosis in the liver?
A
Spotty (focal) necrosis:
- groups of 2-10 hepatocytes undergoing cell death marked by collections of lymphocytes and pigmented macrophages
Confluent necrosis:
- large tracts of contiguous hepatocytes die en masse
- three grades of increasing severity: zonal, BHN (bridging hepatic necrosis), MLN (multilobular necrosis)
Piecemeal necrosis:
- immune-mediated death of hepatocytes at interface of connective tissue and liver parenchyma (periportal and periseptal)
- recognised by dense accumulations of lymphocytes and plasma cells and infiltration by fibroblasts
20
Q
What is the gross appearance of the liver during subacute viral hepatitis?
A
- wrinkled
- balloon-like in that it is empty and soft
- areas that have survived try to regenerate and form nodules fo different size and shape
- usually die in about 8 weaks unless transplanted
21
Q
What is the difference between chronic hepatitis and acute hepatitis?
A
- bridging necrosis and fibrosis is shown for chronic hepatitis but not shown for acute hepatitis (which may also occur?)
22
Q
What happens if you have bridging hepatic necrosis (BHN)?
A
- seen in severe hepatitis
- may be followed by scarring
- BHN
- passive septum
- active septum
- bridging fibrosis
- cirrhosis (if spotty and piecemeal necrosis, inflammation, fibrosis and hepatocyte regeneration continues)
23
Q
What causes viral hepatitis?
A
- Hep A, B, C, D, E
- A, C and E are RNA viruses
- Hep B is partially dsDNA so can integrate into genome –> can’t get rid of it
- Hep C now more treatable
- A and E transmitted feval-oral
- B, C intravenous transmission, sexual (less for C)
- no vaccine for C
- B ~42% of infections
- A ~ 32%
- C ~20%
- B and A becoming less because of vaccine
24
Q
What is the recovery rate for patients with Hep A and E?
A
- 99%
- pregnant women can get fulminant hepatitis and die
25
What are risk factors for hepatitis B?
- Heterosexual activity 40%
- homosexual activity 10%
- injecting drug use 20%
- 3% health care workers, non-sexual household contact, other
- 27% unknown
26
What is the strucutre of the hepatitis virus?
- fairly small
- partially dsDNA virus
- viral core surrounded by surface envelope
- soluble component inside the core that circulates around the blood stream called an e antigen
- can be transmitted across the placenta from the mother to the child (noninfectious)
27
What is the e antigen?
- soluble component inside the core that circulates around the blood stream called an e antigen
- can be transmitted across the placenta from the mother to the child (noninfectious)
- tolerises the child to the virus
- child infected when born
- because tolerant, 98% develop chronic hepatitis
- getting it as an adult usually 5% become chronic infections
28
What is the prevalence of HBsAg carrier state worldwide?
- australia: 1-4.9%
| - large populations in Africa and south east asia
29
What is the recovery rate for Hep B?
- 95%
30
What are the potential outcomes of HBV infection in adults?
- acute infection leads to acute hepatitis
a) 70%: subclinical disease
b) 30% icteric disease
of both:
- >90% recovery
- carrier state
- 12-20% cirrhosis
then: 6-15% of cirrhotic patients develop hepatocellular carcinoma
31
What does the fact that there are healthy carriers indicate?
- the virus itself is not what is killing the cell
32
What sometimes happens to children infected at birth as they grow up?
- maybe around the age of 25 get acute infection
- multifocal necrosis and lobular inflammation in a person with perinatally acquired hepatitis B at the time of loss of tolerance
- multiple foci of necrosis and numerous ground glass hepatocytes
- occurs because an antigen is presented on the surface of the HBV-infected hepatocyte
- interact with CD8 cytotoxic T cells that kill the infected cell - apoptosis
33
What are the modes of transmission of hepatitis C?
- mainly injecting drug use
- blood transfusion
- household and sexual contact
- health care exposure, maternal-neonatal
- unknown
34
What is the worldwide prevalence of Hep C?
- high levels in countries like Egypt, other parts of africa, south america, asia
- australia has a very low rate
- very promising in terms of research into curing the disease
35
What is the natural history of hep C virus?
- acute HCV infection
- 25% symptomatic (fulminant hepatic failure rare), 75% asymptomatic
- 15-20% recovery
- other 80-85% chronic infection
- - 60-70% chronic hepatitis (10 years)
- - 30% cirrhosis (20 years)
- - 15% HCC (30 years)
36
What do you see in chronic Hep C?
- chronic portal inflammation and mild steatosis
- some with mild periportal piecemeal necrosis, severe lobular inflammation, portal-central bridging necrosis (arc) and mild steatosis
37
What is the METAVIR fibrosis scoring system for chronic hepatitis?
```
F0 = no fibrosis
F1 = stellate enlargement of portal tracts without septa
F2 = enlargement of portal tracts with rare septa
F3 = numerous septa without cirrhosis
F4 = cirrhosis
```
38
Do all individuals have the same rate of progression?
- no
| - different rates of progression in different individuals with the same virus
39
Can drugs reverse the progression of the disease?
- yes
- sustained virological response by interferon therapy induces gradual regression of liver fibrosis and may eventually lead to resolution of early cirrhosis
- previously there was nothing you could do to treat cirrhosis
40
What is autoimmune hepatitis?
- female preponderance among cases
- HLAA1 B8 DR3 or DR4
- hypergammaglobulinaemia
- circulating autoantibodies
- - anti-smooth muscle antibody (F-actin)
- - anti-nuclear antibody
- arthritis
- rapid response to corticosteroids
- piecemeal necrosis with a lymphoplasmacytic infiltrate
41
What are the acuired aeitologies of Cirrhosis?
- alcoholic and metabolic syndrome associated NAFLD/NASH
- viral hepatitis – HBV; HCV
- autoimmune hepatitis
- cryptogenic
- primary biliary cirrhosis (PBC)
- primary sclerosing cholangitis )PSC)
- secondary biliary cirrhosis (secondary to obstruction of major extra – and/or intra-hepatic bile ducts)
- drug-induced (e.g. Aldomet, Nitrofurantoin, Isonazid, Methotrexate)
- toxins – fungal (aflatoxin), pyrrolizidine alkaloids
- venous outflow obstruction – severe right heart valve disease, constrictive pericarditis, Budd-Chiari syndrome, veno-occlusive disease
- others
42
What is the number of HCC deaths attributable to HCV per age class?
(between 1979 and 95)
- peaks about age 60-69
- common in men
- we think this has peaked now and will start falling due to change in intravenous drug use and other factors etc
