Hepatic inflammation and fibrosis

Question 1

Inflammation is reversible, fibrosis is irreversible

Histological scorting system: Metavir

Answer 1

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

Question 2

hepatic Necrosis (Not the same thing as fibrosis)

Answer 2

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

Question 3

alcohol drinking patterns

Answer 3

Binge drinking- women 4 drinks in one occasion, men 5
Heavy drinking- more than 1/day, men 2/day
Excessive drinking heavy and binge

Question 4

Ethanol metabolism aka MEOS (Microsomal, ethanol, oxidizing systeme)

Answer 4

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

Question 5

alcohol metabolism consequences

Answer 5

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

Question 6

Alcoholic liver disease (ALD) spectrum of disease

Answer 6

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

Question 7

Liver panal in ALD

Answer 7

AST:ALT ratio > 2:3
ALT under 300
Normal ALK PHOS
Low albumin
Bilirubin higher and higher

Prolonged INR (less production)
Macrocytosis/anemia
Thrombocytopenia

Question 8

Alcoholic hepatitis treatment

Answer 8

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

Question 9

non-alcoholic fatty liver disease (NAFLD)- more common than ALD

Answer 9

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)

Question 10

Stages in the progression of non-alcoholic fatty liver disease (NAFLD)

Answer 10

Fatty liver (Hepatosteatosis) 10% of the time will progress to Steatohepatits (NASH)–> Steatohepatitis with fibrosis–> Cirrhosis

Question 11

NAFLD association with metabolic syndrome

Answer 11

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

Question 12

Causes of Steatosis and Steatohepatitis

Answer 12

Insulin Resistance, Alcohol, Meds (Steroids), Nutritional

Question 13

Development and progression of NAFLD

Answer 13

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

Question 14

Treating NAFLD (NASH)

Answer 14

Wt loss of 10% of body wt, oral hypoglycemic agents, Vit E (anti oxidant)

Question 15

Hereditary hemochromatosis

Answer 15

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

Question 16

HFE Gene

Answer 16

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

Question 17

who gets hemochromatosis

Answer 17

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)

Question 18

Wilson disease/ progressive Lenticular degeneration

Answer 18

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)

Question 19

Diagnosis of wilson disease

Answer 19

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

Question 20

wilson disease therapy

Answer 20

penicillamine- increases the amount of cu urinated out, lots of SEs
trientine- like penicilamine but less SEs
zn- prevents further absorption of CU

Question 21

alpha 1 anti trypsin (A1AT)

Answer 21

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

Question 22

pathogenesis of lung and liver disease in Alpha 1 Antitrypsin deficiency

Answer 22

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

Question 23

A1AT deficiency diagnosis

Answer 23

Serum A1AT levels, A1AT phenotypes, Liver biopsy

PF positive stains

Question 24

Autoimmune hepatitis

Answer 24

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)

Question 25

Subclassification of Auto immune hepatitis and treatment

Answer 25

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,

Question 26

Primary biliary cirrhosis/cholangitis (PBC)

Answer 26

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

Question 27

Primary biliary cirrhosis/cholangitis (PBC) presentation

Answer 27

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)

Question 28

Primary biliary cirrhosis and fat soluble vitamin deficiency

Answer 28

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)