Liver injury Flashcards
What are some causes of acute hepatitis?
Viral (HepA/B/E) Drug induced liver injury Natural remedies Autoimmune hepatitis Idiopathic (seronegative, acute non A non B hep)
When are liver biopsies taken?
Biopsies are not usually done unless the disease is severe, the cause is uncertain, or there is concern for chronic liver disease
What is the clinical definition of acute hepatitis?
Elevation of serum transaminase enzymes for a period of less than 6 months duration, in a patient with no history of chronic liver disease
What do pathologist mean by acute hepatitis?
A process with the same pathological changes in the liver as acute viral hepatitis.
Acute hepatitis is a non-specific pattern of liver injury shared by many different causes.
What are the hallmark features of acute hepatitis histologically?
Death of hepatocytes
Regeneration of hepatocytes to repopulate the areas of death
ABSENCE of fibrosis
What is the acinar model of the liver?
based on terminal portal tract with blood passing through successively less oxygenated zones to reach efferent venule -> useful concept for understanding tissue injury
Which is the vulnerable zone of the acinar?
Zone 3 around the central vein = less oxygenated than hepatocytes in zone 1; therefore more vulnerable to liver injury (toxic or metabolic or ischaemic)
Liver injury therefore most severe in this region
What is cholestasis?
Any condition in which the flow of bile from the liver is blocked
What are the catabolic functions of the liver?
Removal of harmful compound (particularly toxins absorbed in the gut); major contributors to hepatic encephalopathy)
What is synthesised in the liver?
Serum proteins (albumin, clotting factors)
What happens if the synthetic function of the liver ceases?
Hypoalbuminaemia (oedema, ascites = accumulation of fluid in peritoneal cavity)
Coagulopathy (bleeding)
What is the difference between necrosis and apoptosis of liver cells?
Single cell death is by apoptosis (look for the apoptotic bodies).
Death of groups of adjacent hepatocytes is by necrosis
What are 4 types of regional necrosis in the liver?
Single cell
Zonal necrosis
Bridging necrosis
Multi-acinar necrosis
What is zonal necrosis?
Necrosis which is observed in the area surrounding a single central vein
What is bridging necrosis?
Cell death from central veins to portal tracts
What is multi-acinar necrosis?
Cell death involving multiple lobules/acinars etc it is very severe
What is generally seen if the hepatocytes undergo necrosis?
In most cases of necrosis in the liver, the hepatocytes undergo severe osmotic failure and burst (lysis); you will not see the necrotic cells themselves, but the aftermath (collapse of liver reticulin framework and the presence of scavenger macrophages in the liver tissue)
When looking a gross specimen of a liver what do reddish brown areas represent?
Necrosis
When looking a gross specimen of a liver what do yellow nodules represent?
Regenerating group of hepatocytes
What are is seen in acute viral hepatitis?
Pan-lobular disarray Swollen liver cells, Apoptosis. Necrosis of variable extent depending on severity. Aggregates of enlarged macrophages. Cholestasis.
What are the sequelae of acute hepatitis?
Resolution with restoration of normal structure and function.
Massive hepatic necrosis – death or liver transplantation.
Chronic hepatitis – HBV, autoimmune hepatitis and some drugs
What happens in paracetamol induces liver necrosis?
Intrinsic liver toxin (causes hepatocellular injury in a predictable and dose dependent fashion)
Liver injury caused by a toxic metabolite (NAPQ1) which
→ Injures hepatocytes
→ Causes depletion of glutathione ( a natural anti-oxidant)
→ Coagulative necrosis
Where does necrosis typically occur in paracetamol induced liver necrosis?
Necrosis occurs preferentially in zone 3 (this is where the enzyme CPY2E1 is located) but can be pan-acinar, multiacinar, or massive
Is inflammation present in acute hepatitis?
Inflammation present, variable severity, portal and lobular, mixed composition (lymphocytes, plasma cells, macrophages > neutrophils and eosinophils)
Is inflammation present in Paracetemol induced liver necrosis?
Inflammation minimla
What type of necrosis occurs in acute hepatitis?
Necrosis is “lytic” i.e. hepatocytes rupture
Is lobular disarray seen in Paracetemol induced liver necrosis?
Necrosis of hepatocytes involving zone 3; lobular disarray not seen.
What can be said about the livers reserve?
The liver has a high functional reserve, but when necrosis is extensive acute liver failure may develo
Are alcoholic liver disease, NASH, chronic inflammatory liver disease, classified as “chronic hepatitis”?
No
What is the clinical definition of chronic hepatitis?
Raised serum for more than 6 months
What are the most common causes of chronic hepatitis?
HBV and HCV
Aside from HBV and HCV what are some common causes of chronic liver disease?
Autoimmune hepatitis, drugs also ideopathic hepatitis (very rare)
What are some cases in which patients may have chronically raised liver enzymes and not have chronic hepatitis?
Alcohol
NASH
(Just a definition thing really)
What percentage of HCV infected individuals will develop chronic disease?
80%
What percentage of patients will chronic HCV will develop cirrhosis?
20%
What are some commonalities between chronic and acute hepatitis?
Inflammatory infiltrate is mainly T lymphocytes
What is the difference between chronic and acute hepatitis?
Pattern of injury:
Acute hepatitis: Predominantly pan-lobular hepatocellular injury
Chronic hepatitis: Inflammation of the portal tracts and the periportal liver tissue associated with injury of the periportal hepatocytes
What does periportal mean?
Situated around the portal vein of the liver
What is interface hepatitis?
Death of hepatocytes at the interface between portal tracts and lobular parenchyma
+
Lymphoplasmacytic inflammation
What is the result of lymphoplasmacytic inflammation?
Periportal ‘spill’ of chronic inflammation into periportal parenchyma
Results in irregular portal tract border
Is interface hepatitis specific to chronic hepatitis?
No
How is interface hepatitis measured?
Grade
Determinant of the rate at which fibrosis develops
Are lobular changes seen in chronic hepatitis?
They are commonly present, bnut usually mild
How is the type of hepatitis determined with severe lobular activity?
Pathologist find it difficult to distinguish between acute and chronic.
Clinicians need assist with information about the patient often
When does fibrosis of the liver occur?
Can occur and progress in chronic hepatitis (resulting in cirrhosis)
It is ascent in acute hepatitis
What happens in the earliest form of fibrosis?
Earliest form recognized = portal tract has smooth outline BUT it is bigger than it should be as there is more portal fibrous tissue than there is normally
What happens in the later form of fibrosis?
Later form = progression leads to growth of fibrous septa out from the edge of the portal tract, called septal fibrosis -> characteristic of chronic liver disease
a. Portal tract is irregular with speculated boundary
What happens in the advanced form of fibrosis?
Advanced = lots of fibrous septa surrounding the portal tract extending out into the lobule which end up linking up to form bridging fibrous tissue -> on the way to developing cirrhosis
What cells are responsible for producing the fibrosis of the liver?
Portal fibroblast (only a little bit) Hepatic stellate cell (mostly)
Where is the hepatic stellate cell found?
In the space of disse
What activates the hepatic stellate cell?
Cytokines
What type of cells are hepatic stellate cells?
Myofibroblasts
Where is the fibrosis laid down?
In the space of disse
How is stage of fibrosis defined?
Degree of fibrosis (how far is the liver towards cirrhosis) (0-4)
What is stage 1 fibrosis?
Enlarged portal tracts, no septa
What is stage 2 fibrosis?
Septa but not much linking between portal tracts
What is stage 3 fibrosis?
Portal to portal bridging
What is stage 4 fibrosis?
Cirrhosis
What is alcoholic liver disease?
Very common cause of liver disease induced by overconsumption of alcohol
It may present acutely
What is the pathogenesis of ALD?
- Hepatocellular damage from acetaldehyde
- Oxidative stress
- Impaired carbohydrate and fat metabolism
- Stimulation of collagen synthesis by alcohol
- Genetic susceptibility
What is a fatty change (steatosis)?
Abnormal accumulation of lipid in hepatocytes (reversible and does not cause hepatocellular death or fibrosis)
Occurs after consumption of alcohol
What is alcoholic steatohepatitis ?
A process which leads to heaptocellular death and fibrosis.
Progressive fibrosis eventually leads to cirrhosis
What differentiates steatohepatitis from steatosis?
Steatohepatitis is defined by the presence of fat + hepatocellular injury
Steatosis = just fat
What are the characteristics of hepatocellular injury a seen in Steatohepatitis?
Ballooning (swelling) and formation of Mallory-Denk bodies
What are Mallory-Denk bodies?
- Collapse of the hepatic cytoskeleton.
- Intermediate filaments (cytokeratin 8 and 18) and other proteins including ubiquitin.
- Attract neutrophils (not seen in this image)
What happens in severe Alcoholic steatohepatitis?
If severe can cause “acute alcoholic hepatitis” which is a syndrome with features of jaundice, fever, hepatomegaly, markedly impaired liver function, and leucocytosis. This disease carries a 50% 30 day mortality.
What is seen histologically in steatohepatitis?
Inflammatory cells (mainly neutraphils)
Densely stained Mallory bodies
Large fat vacuoles
Blue stained collagen surrounds individual hepatocytes: “chicken wire fibrosis”
What are the associations with Non-alcoholic fatty liver disease?
Obesity
Metabolic syndrome
Diabetes
What is seen histologically in NAFLD?
Histological spectrum the same as for alcoholic, although severe steatohepatitis with numerous Mallory bodies is much less common.
How does one distinguish between NAFLD and ALD?
Clinical rather than histological
What is NASH?
Non-alcoholic steatohepatitis
What are the two catagories of NAFLD?
Isolated fatty liver >80%
(Minimal chance of progression to cirrhosis, no increased risk of death as compared to general pop)
NASH Nash cirrhois ↓ Decompensation Noncirrhotic Hepatocellular Carcinoma (can also result directly from NASH without cirrhosis)
How rapid is the onset with autoimmune hepatitis?
It is an aggressive from of chronic hepatitis
How long does autoimmune hepatitis take to progress to cirrhosis if untreated?
85% progress to cirrhosis within 5 years
Who is mostly affected by autoimmune hepatitis?
Women
Those with a genetic predisposition
How is autoimmune hep detected?
Presence of serum auto-antibodies
How is autoimmune hep treated?
Therapeutic response to immune suppression
What are the 2 types of autoimmune hep?
Type 1
Type 2
What is type 1 autoimmune hep?
Occurs in adults women - associated with anti-smooth muscle antibodies
What is type 2 autoimmune hep?
Occurs in children and teenagers, associated with anti-liver kidney microsome
What is a microsome?
Microsomes are vesicle-like artifacts re-formed from pieces of the endoplasmic reticulum (ER) when eukaryotic cells are broken-up in the laboratory; by definition, microsomes are not ordinarily present in living cells
How does autoimmune hep present?
acute hep (both clinically and pathologically)
Define cirrhosis
Describes the anatomical end stage common to many chronic liver diseases
What happens to the liver during cirrhosis
Conversion of the liver into nodules of regenerating hapatocytes surrounded by bands of fibrous scar tissue
This is a diffuse process
What is used to score the Child-Pugh?
Total bilirubin Serum albumin PT INR Ascites Hepatic encephalopathy
What are the classes of Child-Pugh and what is the one year survival?
A 100%
B 81%
C 45%
What does the external surface of the liver look like in cirrhosis?
It has green/black nodes = bile
What do white nodes on the liver mean?
Heptocellular carcinoa
What are the common causes of cirrhosis?
ALD NASH Chronic Viral Hep B/C Autoimmune Hep Chronic biliary disease Wilson's disease Drugs
What is the current thinking with regard to cirrhosis?
It may be regressive
Is it possible to determine the cause of cirrhosis just by looking at the path report?
No - it is a non specific endpoint
What is the new model of cirrhotic development?
Portal vein is occluded leading to an area of hepatocellular extinction (driven perhaps by vascular occlusion)
Scar tissue contracts
Fibrous septa form
Fibrous septa are deformed
Fibrous septa perforate - portal veins have dropped out entirely
What is the definition of portal hypertension?
> 8mm Hg
or
Increase in the pressure gradient between the portal vein and hepatic vein of 5mmHg
What causes portal hypertension?
Obstruction to flow
What are the three causes of portal hypertension
Post
Intra
Pre
(sinusoidal)
What is the post common cause of portal hypertension?
Cirrhosis
What are the clinical signs of portal hypertension?
Ascites
Porto-systemic anastomoses
Congestive splenomegaly
Hepatic encephalopathy
