jaundice (from progressive biliary obstruction)

liver toxicity (from buildup of bilirubin)

eventual progression to secondary biliary cirrhosis

Primary Sclerosing Cholangitis--chronic inflammation of the walls of the bile ducts (cholangitis) that can lead to fibrosis (sclerosing); probably auto-immune

generalized itching, weight loss, fever, changes in stool (pale, chalky) or urine (dark yellow) color

jaundice (if extrahepatic)

abdominal pain (if intrahepatic)

cholangiocarcinoma--cancer of the glandular epithelium of the bile duct

damage to an neonate's brain caused by very high levels of unconjugated bilirubin

it is only seen in jaundiced infants because the blood-brain barrier is immature in infants & can't keep bilirubin out

to prevent kernicterus.

Criggler-Najjar--a very rare syndrome (more common in the Amish) characterized by a lack or deficiency of UGT, an enzyme necessary to conjugate bilirubin

type 1 has no UGT

kernicterus--unconjugated bilirubin moves into the brain of a newborn (who have an incomplete BBB) & causes damage

yes--5-10% of the population has it most common hereditary cause of increased bilirubin

(recall Gilbert's is Gormless--UDPGT is present, but doesn't work well

Crigler-Najjar is Not Copious--not enough UDPGT)

Mutations in promoter region for UDP-Glucuronyltransferase(UDP-GT) lead to reduced transcription of gene, thus decreased amount of enzyme.

UDP-GT is the enzyme that conjugates bilirubin in the liver, so this can lead to high levels of unconjugated bilirubin in the blood.

Coding region of UDPGT is normal.

Benign course; Life expectancy is normal;

Patients should be warned that pregnancy, oral contraceptive use, and intercurrent illness can exacerbate the icterus.

Correct diagnosis important to prevent unnecessary tests and procedures.

Can occasionally progress to liver failure if there is another cause of hepatic compromise.

(Dubin-Johnson--mutation in cMOAT transporter protein means that hepatocytes can't excrete conjugated bilirubin into the bile ducts)

Gilbert’s syndrome (most common; UGT doesn't work properly-->not enough conjugation)

Crigler-Najjar syndrome (not enough UGT-->not enough conjugation)

Dubin-Johnson Syndrome (mutation in cMOAT transporter protein-->hepatocytes can't excrete conjugated bilirubin into bile ducts)

Rotor syndrome (hepatocytes can't excrete conjugated bilirubin into bile ducts; idiopathic)

Alpha 1 antitrypsin deficiency

Cystic fibrosis

Wilson ‘s disease

Primary Hemochromatosis

portal tracts infiltrated by lymphocytes (especially neutrophils), also macrophages, plasma cells, and occasionally eosinophils

 inflammatory destruction of medium-sized intrahepatic bile ducts with portal inflammation

scarring, eventual cirrhosis and liver failure

10-15 years

Primary Biliar Cirrhosis--an autoimmune disease of the liver marked by the slow progressive destruction of the small bile ducts (bile canaliculi) within the liver.  Bile gradually builds up & destroys liver tissue.

advise to quit smoking and alcohol abuse

supportive medical care

Alpha-1-AntiTrypsin (A1AT) is created in the liver & helps protect the lungs from damage.  In Alpha-1-AntiTrypsin Deficiency, A1AT is mutated and can't leave the liver.  Lack of A1AT leads to lung damage (COPD) in people who smoke and/or have severe A1AT deficiency.  A1AT accumulates in the liver and causes liver damage, particularly in people who abuse alcohol 

A mutation in CF transmembrane conductance regulator (CFTR) results in impaired chloride anion (Cl-) transport.

Impaired chloride anion results in impaired Na+ transport, which results water retention by osmotic pressure. This result in thick mucus in mucous membranes. All pathologic consequences attributed to presence of thick mucus.

Inspissated (thickened, dried) mucous secretions in the intrahepatic biliary system

(in cystic fibrosis, dried mucous in the bile ducts obstructs bile flow & secondary biliary cirrhosis develops)

Northern European (0.4% - 1%)

(Think of Santa Clause with his rosy nose & cheeks--he's pretty northern European & obviously has a healthy hematocrit on him)

Clinical history (Joint pain, fatigue, low libido, amenorrhea, pain in RUQ, or asymptomatic)

high saturation of serum transferrin (iron-binding blood plasma glycoproteins that control the level of free iron in biological fluids)

Liver biopsy indicates high iron levels and/or liver damage

visible fat accumulation in the cytoplasm of most hepatocytes

mallory bodies (squiggly pink cytoplasmic hyaline inclusions) within hepatocytes

neutrophilic inflammation

necrosis of hepatocytes (especially inthe central zone; that is, zone 3, the zone nearest the central vein & farthest from the portal triad)

perivenular fibrosis

1. clinical presentation of encephalopathy in a person younger than 18

(earliy signs: vomiting, lethargy, confusion

later signs: seizures, coma, multi-organ failure)

2. exclusion of other etiologies of encephalopathy

3. three-fold or greater increase in serum aminotransferases (AST & ALT) and/or ammonia

prehepatic (obstruction before portal vein enters liver)

intrahepatic (obstruction within liver parenchyma)  posthepatic (obstruction in hepatic veins beyond liver lobules)

portal vein thrombosis

congenital atresia of the pre-hepatic portal vein

abdominal pain ascites hepatomegaly

Budd–Chiari syndrome is the clinical picture caused by occlusion of the hepatic veins

I have a big liver and tummy pain

From that damned old clot in my hepatic vein

I once was as pretty as Mata Hari

But now I’m fat ‘cause of Budd Chiari

1. GI tract

2. breast

3. lung

(cancer in the liver is most often due to metasteses from elsewhere, not due to liver cancer)

Dubin-Johnson Syndrome (a rare, fairly benign inherited disorder in which a transporter mutation makes it difficult for hepatocytes to secrete conjugated bilirubin into bile ducts; conjugated bilirubin builds up in liver, leading to hyperpigmentatin & spills over into blood)

Rotor Syndrome (inherited in which hepatocytes can't secrete conjugated bilirubin into bile ducts; we don't know why; liver is not hyperpigmented)

(isolated meaning that ALT and AST are not elevated)

bilirubin that has been conjugated with an acid by the liver to make it water-soluble

(so called because its water-solubility means that it can be DIRECTLY dyed)

bilirubin as it is released from the RBC (unconjugated)

(so called because its lack of water-solubility means that it can be canNOT be directly dyed)

chronic liver disease/cirrhosis

acute liver failure

(synthetic function doesn't go until something is seriously wrong with the liver)

(ALT & AST are markers of hepatocellular injury) chronic hepatitis B

chronic hepatitis C

fatty liver/NASH

alcoholic liver disease

drugs

no; it's also in the heart, muscle, kidney, brain, pancreas, and lungs

(but mostly inthe liver)

kids(kids have high alkaline phosphatase because it's also found in bone & they're growing bone)

pregnant women (the highest concentration of alkaline phosphatase in the body is in the placenta)

from the GI tract & spleen

to the liver

N-acetyl glutamate is a positive regulator of the rate-limiting step of the urea cycle (that is, turns it on)

The urea cycle is a cycle of biochemical reactions that produces urea ((NH₂)₂CO) from ammonia (NH₃). The urea cycle takes place primarily in the liver, and to a lesser extent in the kidney.

orotic acid (orotate)

As part of the urea cycle,

carbamoyl phosphate + ornithine --(ornithine transcarbamoylase)-->citrulline + phosphate

if there's no ornithing transcarbamoylase, then

carbamoyl phosphate + ornithine --> pyrimidines + orotic acid

fed state:  glucose from food

fasting state:  first, glucose from glycogen breakdown

second, glucose from gluconeogenesis 

starved state:  glucose primarily from gluconeogenesis

lactate dehydrogenase

it converts pyruvate (the final product of glycolysis) to lactate in muscles and RBCs when oxygen is in short supply

it converts lactate to pyruvate in the liver, which is fed into glyconeogenesis.  The resultant glucose is sent back to muslces and RBCs to complete the Cori cycle

they're fed into the TCA cycle:

fatty acid-->acetyl co-A-->ATP

Hepatic artery brings oxygenated blood to liver from heart

Portal vein brings partly deoxygenated, nutrient rich, toxic (sometimes) blood to liver from GI tract & spleen

Hepatic veins drain venous blood from liver into Inferior Vena Cava

• fair-skinned (Heredity)—northern Europeans (even more common in Mexican Americans and Native Americans, though)

• fat (Diet, Obesity)—obesity is a risk factor

• flatulent (Slow intestinal transit)—constipation is a risk factor (even for non-obese women)

• females

• fertile:  a history of several pregnancies. Excess estrogen stimulates the production of gallstones.

• forty (Age) Gallbladder disease often strikes people over forty years of age (middle-aged)

anti-viral drug

Blocks inosine monophosphate dehydrogenase-->blocks GTP synthesis-->blocks nucleic acid synthesis

appears to prevent GTP-dependent 5’capping of viral mRNA by blocking GTP synthesis, and inhibiting RNA-dependent RNA polymerases (and activity of other GTP-dependent enzymes)

steatorrhea is greasy diarrhea due to fat malapsorption

an inflammaed pancreas doesn't secrete lipase, which leads to steatorrhea

uncoated

Enteric-coated won’t be released by the time you get to the duodenum; only uncoated can relieve pain & malabsorption

CholeCystoKinin (CCK)

lots of CCK stimulates lots of ductal pressure, which causes pain

sexual

blood

(B is spread by Blood and the Birds & the Bees)

Explain the following mnemonic with relation to hepatitis viruses:

All Eliminated

hep B

hep C

hep D (hep D only occurs as a super-infection on top of hep B; hep D & B combined infection is very dangerous)

From inside to out, the HBV (Hep B) virus consists of: DNA

a capsid

a protein layer (core) of _____________

an outer layer of _______________

HBcAg (Hepatitis B core antigen)

HBsAg (hepatitis B Surface antigen)

Hepatitis B core antigen--the protein that makes up the hepatitis core (inside the outer layer and outside of the capsid)

HBsAg is hepatitis B Surface antigen