Hepatic inflammation and fibrosis Flashcards
Inflammation is reversible, fibrosis is irreversible
Histological scorting system: Metavir
Inflammation 0-4 grades (0- none, 4-severe)
Fibrosis 0-4 stages (0- none, 1- portal fibrosis, 2- Periportal fibrosis, 3- Septal fibrosis, 4- cirrhosis)
Kupfer cells produce cytokines (TNFa) that attract all the inflammatory cells
Stellate cells produce collagen in the space of disse causing fibrosis
hepatic Necrosis (Not the same thing as fibrosis)
acute cell death: fibrosis in most cases takes years
Hepatic necrosis can lead to acute liver failure- fulminant liver failure= acute liver failure complicated by coagulopathy and encephalopathy
The most common cause of acute and fulminant liver ailure include meds (tylenol) and viral hepatitis
alcohol drinking patterns
Binge drinking- women 4 drinks in one occasion, men 5
Heavy drinking- more than 1/day, men 2/day
Excessive drinking heavy and binge
Ethanol metabolism aka MEOS (Microsomal, ethanol, oxidizing systeme)
Ethanol–> Acetalaldehyde via Alcohol dehydrogenase (Co factors NAD and NADP to NADPH and NADH)
Alcohol dehodrogenase in Cyp2E1 (acetaminophen)
Acetal aldehyde –> acetic acid via Aldehyde dehydrogenase (co factor- NAd)
Asians sometimes are deficient in aldehyde dehydrase- cant handle their liquo, flushing
alcohol metabolism consequences
Increased NADH–> inhibition of TCA cycle and reduced gluconeogenesis, reduced fatty acid oxidation
Increased acetalaldehyde–> activates stellate cells to form collagen, microfilaments that maintain intracellular skeleton are sheared, Kupffer cells produce TNFa
Alcoholic liver disease (ALD) spectrum of disease
Normal liver will become Fatty Liver (steatosis) which can either become Alcoholic hepatitis (inflammation fat and inflammatory cells) or Cirrhosis (fat and fibrosis)
Alcoholic hepatitis can eventually become cirrhosis
Risk factors for developing ALD- quantity of alcohol (>30 g/day for M, 20 for F), Outside of meals, binge drinking
Gets absorbed in stomach
Hep C infection
Liver panal in ALD
AST:ALT ratio > 2:3 ALT under 300 Normal ALK PHOS Low albumin Bilirubin higher and higher
Prolonged INR (less production)
Macrocytosis/anemia
Thrombocytopenia
Alcoholic hepatitis treatment
Abstinence and lifestyle modification, nutritional support
Antiinflammatory drugs- Prednisone
Who gets prednisone?- Pro thrombin, total bili
Discriminant function: 4.6 (PT- PT control) + T bili
Patients with values> 32 have a 1 month mortality from 30-50%
Contraindication for steroids- a major active infection
non-alcoholic fatty liver disease (NAFLD)- more common than ALD
most common cause of elevated transaminases in the US
Female, obese with DM
2 categories of NAFLD-
NAFLD, simple steatosis: presence of hepatic steatosis without inflammation or hepatocellular injury (ballooning of hepatocytes)
NASH, non alcoholic steatohepatitis- presence of hepatic steatosis and inflammation with hepatocellular injury (ballooning of hepatocytes with/without fibrosis)
Stages in the progression of non-alcoholic fatty liver disease (NAFLD)
Fatty liver (Hepatosteatosis) 10% of the time will progress to Steatohepatits (NASH)–> Steatohepatitis with fibrosis–> Cirrhosis
NAFLD association with metabolic syndrome
Obesity- 30-100% get NAFLD
Diabetes- 15-50
Hyper TGs- 15-80
Pravalence increases with age, severity increases wiht age, M>F, Latino>Caucasions>Af aM
Most common in kids
Causes of Steatosis and Steatohepatitis
Insulin Resistance, Alcohol, Meds (Steroids), Nutritional
Development and progression of NAFLD
You eat too much with genetic factors, obesity, HTN and hyperlipidemia–> insulin resistance–> steatosis
Steatosis with Oxidative stress–. NASH and cirrhosis
Use the spleen as a refrence the liver and spleen should look the same
Treating NAFLD (NASH)
Wt loss of 10% of body wt, oral hypoglycemic agents, Vit E (anti oxidant)
Hereditary hemochromatosis
bone marrow in blood, some iron is stored in liver as ferritin, some iron is in circulation in transferrin
HFE gene –> hereditary hemochromatosis
C282y/C282y- 90% of cases
C282y/H63D- compound
HFE Gene
HFE gene regulates the absorption of iron from the small intestine, when needed iron is absorbed and mobilized in the plasma as transferrin, HFE down regulates Hepcidin when iron supplies are filled
A defective HFE gene fails to down regulate hepcidin and iron continues to be absorbed from the small intestine, the iron then deposits in organs and leads to the development of free radicals which can cause organ damage
who gets hemochromatosis
Most common genetic diseases in populations of European ancestry- Heterozygous (10% in caucasians), Homozygous state in .5%-1% C282Y/C282Y)
Bronze diabetes, Get genetic test, give phlebotomy (ferritin<50)
Wilson disease/ progressive Lenticular degeneration
Human Copper metabolism
Copper is absorbed (some is just ecreted), what is absorbed is sent to the liver,
Then eliminated thru bile, or bound to ceruloplasmin
Wilsons disease- cant transport copper into the bile, ceruloplasmin is also low. So most copper is in nonceruloplasmin form, so the only way out is urine, and lots accumulate in extrahepatic deposition (kidney, brain, cornea)
Diagnosis of wilson disease
any pt 3-40, need multiple tests, usually unexplained liver disease, Acute liver failure, cirrhosis, neurologic symptoms and psychiatric symptoms
Ceruloplasmin will 95% of the time be low, high CP levels occur in inflammation and may lead to false negatives
Urinary copper is nonceruloplasmin copper, rate of excretion in symtomatic patients may be high
kayser fleischer rings, liver biopsy has a high amount of copper
wilson disease therapy
penicillamine- increases the amount of cu urinated out, lots of SEs
trientine- like penicilamine but less SEs
zn- prevents further absorption of CU
alpha 1 anti trypsin (A1AT)
inhibitor of proteolytic enzyme ELASTASE (damages tissues), part of unique protease inhibitors SERPINS, predominantly made in the liver,
A1AT made in the liver, 100 alleles with different letter codes
most common cause of genetic liver disease in Kids, nees liver transplant, and most common cause of genetic emphysema in adults
Main form is M, (M, Z), ZZ- A1AT mutation
pathogenesis of lung and liver disease in Alpha 1 Antitrypsin deficiency
Lungs- loss of fucntion mechanism (uninhibited PMN medicated proteolytic damage to connective lung tissue)
Liver- gain of function- (Retention of inefficiently secreted A1AT Z molecule in ER triggers a series of hepatotoxic events)- can excrete the A1AT and cant get excreted
Null- Null- Causes just lung
ZZ- liver and lung
A1AT deficiency diagnosis
Serum A1AT levels, A1AT phenotypes, Liver biopsy
PF positive stains
Autoimmune hepatitis
hepatocyte inflammation, autoantibodies in serum, insidious/ acute onset F>M, 50% have other AI disorders
Really high > 1000 ALTs and ASTs, elevated IgG, Auto antibodies, Interface hepatitis, portal plasma cell infiltration
Autosmooth muscle antibody or ANA (anti nuclear)
Subclassification of Auto immune hepatitis and treatment
Type 1 (Classic 80-90%) organelle- nucleus (ANA and ASMA)
Type 2 in the microsome
Prednisone with/and Azathioprine
treatment endpoints: Normal ALT, AST, IgG, gamma globulin, resolution of inflammation
treated pts65% within 18 mo,
Primary biliary cirrhosis/cholangitis (PBC)
chronic, progressive, cholestatic liver disease
Destruction of intrahepatic bile ducts, probable Autoimmune pathogenesis
predminantly caucasian women mig age
Autoimmune pathogenesis: High prevalence of serum autoantibodies (antimitochondrial Abs, AMA)- present in 95%, elevated IgM, association with other Autoimmune diseases, increased familial incidence of disease (6% family history of PBC)
AMA Abs target the multi enzyme complex PDC (pyruvate dehydrogenase complex)- PDC-E2 predominantly, located on the membrane of the biliary epithelial cells
Primary biliary cirrhosis/cholangitis (PBC) presentation
raised AlkPhos, AMA +, and usually other AI diseases (usually rheum pts)
can be asymptomatic, Fatigue, pruritus, bile salts deposit in the skin (itching=PRURITIS= Cholangitis)
Lipid disease- tuberous Xanthomata, Xanthelasma (dont get heart disease)
Primary biliary cirrhosis and fat soluble vitamin deficiency
You need bile to absorb fat soluble vitamins (A D E K)
Vit d- osteomalacia, fractures, and regular bone densitometry
Vit K- prolonged PT
Treatment- ursodeoxycholic acid (synthetic bile acid)
