Causes of Chronic Liver Disease Flashcards
What defines chronic liver disease?
Duration greater than 6 months
- can present after the 6 months
What is the pathology of chronic liver disease?
recurrent inflammation and repair with fibrosis and regeneration
What cells initiate the inflammatory response in the liver in response to damage?
Hepatic Stellate Cells
What do Hepatic Stellate Cells turn into before turning into fibrosis?
Hepatic Myofibroblast
What is the progression of Hepatic Stellate Cells producing fibrosis?
QUIESCENT HSC
ACTIVATED HSC
APOPTOTIC HSC
What are the causes of chronic liver disease?
Alcohol NAFLD Hepatitis C Primary Biliary Cholangitis Autoimmune Hepatitis Hepatitis B Haemochromatosis Primary Sclerosing Cholangitis Wilsons Disease alpha 1anti-trypsin Budd-Chiari Methotrexate
What is Non Alcoholic Fatty Liver Disease (NAFLD)?
Fatty Liver or steato-hepatitis in absence of other cause
In obese = 60% have it
What is the pathogenesis of NAFLD?
“2 Hit” Paradigm
“First hit” – Excess fat accumulation
“Second hit” – Intrahepatic oxidative stress
Lipid peroxidation
TNF-alpha, cytokine cascade
Ischeamia reperfusion injury
What can generate TNFa?
Hepatocytes
What is the treatment for simple steatosis?
weight loss and exercise
increased CVS risk
What is the diagnosis and treatment for NASH?
Diagnosis = liver biopsy
Weight loss & exercise
Other treatments experimental
What is a risk of NASH?
progression to cirrhosis
Name some Autoimmune liver diseases?
Primary Biliary Cholangitis (Cirrhosis) Auto-immune Hepatitis Primary Sclerosing Cholangitis Alcohol related liver disease Drug Reactions
What causes Primary Biliary Cirrhosis (PBC)?
Autoimmune component 1960s,1970s-1980s AMAs M1-M9
1980s target M2-E2 E3 subunits of PDC-E2 n inner leaflet of mitochondrial membrane
T-cell mediated, CD4 cells reactive to M2 target, why loss of tolerance
What are the symptoms of PBC?
Fatigue
Itch without rash
Xanthesalma and xanthomas - hypercholesterolemia
Normally middle aged women
How is PBC diagnosed?
2 of 3:
Positive AMA
Cholestatic LFTs
Liver Biopsy
How is PBC treated?
Urseo deoxycholic acid
What are the consequences of PBC?
Most will not develop symptoms in their life time
The majority with PBC symptoms do not develop liver failure
- Itch can be particularly problematic.
Many developing liver failure will be unfit for transplant
Describe auto-immune hepatitis?
Affects women more than men (3.6:1)
If untreated approximately 40% die within 6 months
40% develop cirrhosis
Describe type 2 auto-immune hepatitis?
Children & young adults
LKM-1
Exclusive
AMA
Describe type 1 auto-immune hepatitis?
Adult (teenagers + above)
ANA
ASMA - anti smooth muscle antibody
SLA severity
IgG –positive
AMA –positive
pANCA –positive
What extrahepatic manifestations are associated with Type 2 auto-immune hepatitis?
Autoimmune thyroiditis, graves disease, chronic UC
Less commonly with RA, pernicious anemia, systemic sclerosis, ITP, SLE
What is the clinical presentation of auto-immune hepatitis?
Hepatomegaly Jaundice Stigmata of chronic liver disease Splenomegaly Elevated AST and ALT Elevated PT Non-specific symptoms: malaise, fatigue, lethargy, nausea, abdominal pain, anorexia
How is auto-immune hepatitis?
Elevated AST and ALT
Elevated IgG
Presence of autoimmune antibodies
Liver biopsy – confirms diagnosis
What is the pathology of auto-immune hepatitis?
Chronic hepatitis with marked piecemeal necrosis and lobular involvement
Numerous plasma cells
Interface hepatitis: hallmark finding
What are the genetic predisposing factors of auto-immune hepatitis?
HLA-DR3: early onset, severe form
HLA-DR4: caucasian, late onset, better response to steroids, higher incidence of extrahepatic manifestations
IgG: part of the IgG molecule (mainly the heavy chain)
T-Cell receptors
What drugs can cause auto-immune hepatitis?
Oxyphenisatin Methyldopa Nitrofurantoin Diclofenac Minocycline statins
What is the treatment of auto-immune hepatitis?
Corticosteroids Azathioprine Children: azathioprine or 6MP Combination Therapy Prednisone + Azathioprine Prednisone: start at 30mg daily and taper down to 15mg at week 4, then maintain on 10mg daily until therapy endpoint Azathioprine 50-100mg daily MUST GIVE STEROIDS OR THEY WILL DIE
What are the typical consequences of auto-immune hepatitis?
40% of all pts with AIH develop cirrhosis
54% develop esophageal varices within 2 years
Poor prognosis if has presence of ascites or hepatic encephalopathy
13-20% of patients can have spontaneous resolution
Of patients who survive the most early and active stage of disease, approximately 41% of them develop inactive cirrhosis.
Describe Primary Sclerosing Cholangitis?
Autoimmune destructive disease of large and medium sized bile ducts.
M:F 4:1, 40% also have Colitis (mainly UC)
Commonest liver disease in Scandinavia.
Clinical: recurrent cholangitis
Diagnosis: imaging of biliary tree
Treatment: maintain bile flow, monitor for cholangiocarcinoma and colo-rectal cancer
What are the three features of the “bronzed diabetic”?
Cirrhosis
cardiomyopathy
Pancreatic failure
Describe Haemochromotosis?
Genetic Iron overload syndrome
Mono-genetic autosomal recessive disease of Iron over load, C282Y or H63D, mutations in HFE gene.
Gene carrier frequency 10%, genetic haemochromatosis 1 in 200 but partial penetrance.
Cirrhosis, cardiomyopathy, Pancreatic failure
Treatment: Venesection
Describe Wilsons Disease?
Lenticulo-hepatic degenerationMono-genetic autosomal recessive disease.
loss of function or loss of protein mutations in caeruloplasmin
Causes massive brain and liver damage
What is the clinical presentation of Wilsons Disease?
Neurological- chorea-atheitoid movements
Hepatic – cirrhosis or sub-fulminant liver failure
Kaiser Fleisher rings
What is the treatment of Wilsons Disease?
copper chelation drugs
Describe Alpha 1 anti-trypsin deficiency?
Genetic, Mutations in the A1AT genes, multiple sites, causes variable phenotype
Protein Function lost meaning excess tryptic activity
Trypsin destroys lung membrane and causes liver damage
What are the clinical features and treatment of Alpha 1 anti-trypsin deficiency?
Lung emphyesma
Liver deposition of mutant protein, cell damage
Treatment is supportive
Describe Budd-Chiari?
Thrombosis of the hepatic veins Congenital webs Thrombotic tendency, protein C or S deficiency Clinical: - Acute- Jaundice, tender hepatomegaly - Chronic- Ascites Diagnosis: U/S visualisation of hepatic veins Treatment: recanalization or TIPS
What can the drug Methotrexate do to the liver?
cause progressive fibrosis
Describe cardiac cirrhosis?
Secondary to High right heart pressures Incompetent tricuspid valve Congenital malformation Rheumatic fever Constrictive pericarditis Clinical: CCF, with too much ascites and or liver impairment Treatment: Treat the cardiac condition
