Liver pt 2 + SG

what are the causes of hepatocellular disease (6)

• alcohol and dietary excesses

• drugs and toxins

• infections → especially viral

• autoimmune disorders

• genetic metabolic defects

• impairment of hepatic circulation and/or oxygenation

what are abnormal liver functions seen in hepatocellular disease (6)

decreased:

• synthesis

• detoxification

• excretion

• extraction

• storage

• removal

what liver function tests reflect hepatocellular disease

• elevated AST and ALT levels → damaged hepatocytes

• elevated alkaline phosphatase → damaged cholangiocytes

what antibody can be seen in ACUTE viral hepatitis

IgM

what antibody can be seen in CHRONIC viral hepatitis

IgG: will be present if pt has cleared the infection OR if they currently have the chronic infection and they cannot clear it

what antigens are present in viral hepatitis

viral RNA/DNA and/or viral antigen/active

what is ALD

• alcohol associated liver disease

• triggered by toxic effects of alcohol and its oxidative metabolites-acetaldehyde and acetate

what is MetALD

• someone who is taking in too many calories and too much alcohol

• is a combo of metabolic risk factors: obesity and excessive alcohol intake

what is Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD)

• metabolic syndrome → obesity, dyslipidemia, hypertension, prediabetes or diabetes

• basically- the liver has an excess amount of fat in it

what is Metabolic Associated Steatohepatitis (MASH)

• liver inflammation due to excess amount of fat in the liver → from MASLD

• will have hepatocyte death w or w/o fibrosis of liver

  • can lead to cirrhosis/liver cancer

etiology of ALD

alcohol is converted to acetaldehyde → acetate → building block for LFAC → buildup in storage w excess intake → trigger the release of TNF-alpha from Kupffer cells → TNF-alpha start immune cascade

etiology of MASLD

inc calories → convert to TG → there is always a balance between TG and LCFA, so as TG inc → LCFA will inc → kpuffer cells release TNF-alpha → immune cascade

what is the immune cascade caused by the release of TNF-alpha

• progressive fibrosis

• insulin resistance

• immune inflammatory damage

what is the common factor/etiology of ALD vs MASLD

excess long chain fatty acids

what do stellate cells make in the presence of TNF-alpha

will lay down collagen → fibrose liver

what are the leading liver diseases in the US in 2024

• ALD

• MASLD

• hepatitis C

what are the two type of Drug Induced Liver Injuries (DILI)

• reproducible

• idiosyncratic

what is reproducible DILI

• hepatic metabolism of parent compound to toxic metabolite

• is a dose-related injury

what is idiosyncratic DILI

uncommon and unpredictable; such a rare thing it isn’t even spotted in drug trials bc there aren’t that many participants

what do you give for an acetaminophen overdose, why

acetylcysteine → can limit formation of protein and DNA adducts adn generally improve survival

in a person w longer standing alcohol use disorder, is the toxic dose of acetaminophen smaller/the same as/larger compared to a person who does not drink at all

a smaller dose would be toxic for the alcoholic disorder person

what are the 3 patterns of idiosyncratic drug rxns

• hepatocellular

• cholestatic

• mixed

what do the hepatocellular and cholestatic idiosyncratic drug rxn have in common

• delayed onset

• disproportionate elevation of alkaline phosphatase

unique features of hepatocellular idiosyncratic drug rxn

• presents like acute viral hepatitis

• can be asymptomatic

• high mortality rate

• rapid recovery

• risk w re-challenge

unique features of cholestatic idiosyncratic drug rxn

• slow recovery

• low mortality

• drugs interfere w bile salt excretory protein

why can nutritional supplements cause and idiosyncratic drug rxn

these are unregulated, there are various herbs blended together, and the potency is not standardized → DILI

what injuries are associated w zone 1

viral inflammation → Hep B/C, autoimmune

what injuries are associated w zone 3

• vascular → congestive hepatopathy

• toxins→ acetaminophen, alcohol

• metabolic → bile canaliculi, hepatocytes

what are hepatic responses to injuries

• necrosis, apoptosis

• steatosis

• cholestasis

• ballooning degeneration w Mallory inclusions

what is steatosis

abnormal accumulation of fat (TG) within the cytoplasm of parenchymal cells in the liver

what is cholestasis

reduced or obstructed bile flow leading to accumulation of bile components in the liver and the bloodstream

what causes chronic passive congestion of the liver

right sided heart failure: back pressure from IVC leads to retrograde sinusoidal congestion

what zone is most affected by chronic passive congestion of the liver

zone 3- due to location by central vien

what is the website: Livertox.gov.

you can put in a name of a drug and it will give you effects and management of the drug

what are the various classes of substances that are toxic to the liver

• meds

• herbal products

• dietary supplements

• poisonous plants and fungi

• household and industrial products

  • ointments, perfumes, shampoo, cleaning solvents, pesticides

in the US, what is the most common cause of liver failure necessitating transplant

acetaminophen toxicity

how can ALD lead to cancer

steatosis → hepatitis → cirrhosis → hepatocellular carcinoma

___% of adults in the US are affected by ALD

18%

ALD is resonsible for >__% of chronic liver disease and ~___% of deaths from alcohol-associated cirrhosis

>60% chronic liver disease; ~50% of deaths

what are the histological features of ALD

• steatosis→ fat droplets in hepatocytes

  • usually in zone 3

• steatohepatitis → steatosis and inflammation

  • ballooning degradation

  • mallory-denk bodies

    • clumps of cytoskeletal filaments

what are non-hepatitis viruses that affect the liver

• EBV

• CMV

• dengue

• yellow fever

what viruses can lead to chronic hepatitis

• HBV< HDV < HCV

• HEV in immunocompromised pts

• NEVER HAV

what is the route of transmission in Hep A

fecal-oral route, highly contagious

who is commonly affected by Hep A

happens as outbreaks in US, restaurants, institutions

Hep A risk of development

no carrier state so it cannot lead to chronic infection of cirrhosis/cancer

what is the route of transmission of Hep B

mother child, sex/IVDA

who is commonly affected by Hep B

unvaccinated people in the US

adult prognosis of Hep B compared to babies

• adult: will more than likely undergo slow, complete recovery from illness, <1% progress to chronic

• babies: 95% who are infected perinatally become chronic carriers, and 30% of them develop chronic active hepatitis

people w chronic hepatitis are _____________ for the rest of their life

infectious-carriers

many cases of chronic hepatitis will develop cirrhosis, there is a high risk of…

hepatocellular carcinoma

progression of HBV infection

(5-10% of the time) HBV → acute infection → chronic hepatitis → cirrhosis → hepatocellular carcinoma

what is the route of transmission of Hep C

bloodborne

who is commonly affected by Hep C

high incidence in boomers, but new cases are in younger

what hepatitis virus in the #1 cause of cirrhosis in the US

Hep C

Hep C risk of progression

80-90% will result in chronic hepatitis; higher risk for cirrhosis and carcinoma

incubation period of hep A

2-6 week

initial signs of Hep A

abdominal pain, pale stool, dark urine, jaundice, pruritis, RUQ tenderness

incubation period of hep B

1-4 months

incubation period of hep C

2-6 weeks

what is autoimmune hepatitis

chronic, progressive disorder w features that include a genetic predisposition, an association w other autoimmune diseases, and the presence of autoantibodies

what is the predominate cell type in autoimmune hepatitis

plasma cells

what is Hemochromatosis

is an autosomal recessive disorder w a defect in the HFE gene, leading to excessive intestinal absorption of iron

what is the normal role of hepcidin

a peptide hormone that helps iron exit the enterocyte from the intestines

what is happening w hepcidin in hemochromatosis

there is a lot less hepcidin which will result in more iron being secreted into the blood

what organs are affected in hemochromatosis

• liver

• pancreas

• heart

• joints

• endocrine organs

• skin pigmentation: “BRONZE DIABETES”

what is wilson’s disease

autosomal recessive disorder or copper metabolism that results in accumulation of copper in organs

what organs are affected in wilsons disease

• liver

• brain

• eye

what is the function of ceruloplasmin

will regulate body’s copper levels

what is happening w ceruloplasmin in wilson’s disease

there is decreased serum ceruloplasmin so there is not regulation of copper → buildup of copper in certain organs/tissues

what is Kayser-Fleisher ring

• later manifestation of Wilson’s disease

• ring at the periphery of the cornea

what is alpha 1 antitrypsin deficiency

autosomal co-dominant disorder that has a defect in the SERPINA1 gene, characterized by a reduction in serum A1AT levels

what does A1AT normally do

usually protects the lungs from damage

what is happening to A1AT during alpha 1 antitrypsin deficiency

there is a dec in A1AT that will lead to excessive protease activity → will destroy alveolar walls

what organs are affected by alpha 1 antitrypsin deficiency

• liver

• lung

LFT in alcohol vs hepatitis B

• alcohol: very slightly elevated AST > ALT (2:1 ratio)

• Hep B: very elevated ALT > AST

what is Ag testing for in serology

testing for an antigen on the viral surface

if you test positive for an Ag, this means…

you are infectious UNLESS you have anti-ag

what is “anti-X” test for

antibodies against an antigen

if you test positive for “Anti-X” this means…

you are immune

HBsAg +

infectious

anti-HBc IgM +

early immune response so recent infection, and STILL infectious

anti-HAV IgG +

immune to Hep A (+ means they have been exposed)

anti-HCV -

not immune to Hep C → not exposed in the past → does NOT mean they have Hep C now

anti-HEV IgM and IgG -

not exposed to hep E

serology report if pt was immune due to natural infection

• HBsAG: -

• Anti-HBs: +

• Anti-HBc: +

• IgM anti-HBc: -

• HBV DNA: -

serology report if pt was immune due to Hep B vaccine

• HBsAG: -

• Anti-HBs: +

• Anti-HBc: -

• IgM anti-HBc: -

• HBV DNA: -

serology report if pt had an acute infection

• HBsAG: +

• Anti-HBs: -

• Anti-HBc: -

• IgM anti-HBc: +

• HBV DNA: +

serology report if pt had a chronic infection

• HBsAG: +

• Anti-HBs: -

• Anti-HBc: ±

• IgM anti-HBc: -

• HBV DNA: +

what is happening biologically in acute acetaminophen toxicity

glutathione is used to detoxify many chemicals → if it is used up by one substance (alcohol), it cannot detoxify other substances (acetaminophen) → tylenol can get converted to quinone substance and causes liver failure