2nd Hepatobiliary Disorders - Lyons

short term ingestion of 80g of ethanol (6 beers) over one to several days leads to

reversible steatosis

freq cause of acute and chronic liver disease in us

ethanol

findings in alcoholic liver disease

steatosis

hepatitis

cirrhosis (only 10%)

ast and alt in alcoholic liver disease

AST>ALT (toxic to mitochondria)

steatosis in alcoholic liver disease

predominantly macrovesicular: fat deposition displaces nucleus

usually reversible, eventual fibrosis around central vein

toxic ethanol metabolite

acetaldehyde

fatty liver

macrovesicular steatosis in fatty liver

mallory bodies, “alcoholic hyaline”

what are mallory bodies?

aggregates of cytokeratin intermediate filaments in the cytoplasm resulting from hepatocyte injury

most common cause of chronic liver disease in US

assoc with insulin resistance/obesity

metabolic dysfunction associated steatotic liver disease (MASLD)

previously known as Nonalcoholic fatty liver disease (NAFLD)

steatosis, predominantly macrovesicular

greasy yellow liver

in those who consume little to no alcohol

steatohepetitis

cirrhosis (minority)

MASLD

liver enzymes in MASLD

ALT>AST

MASLD vs ALD

they look very similar but in ALD AST>ALT like 2:1 and in MASLD its ALT>AST

asymptomatic or fatigue, malaise, RUQ discomfort

steatosis clinical picture

diffuse nodule formation in liver due to fibrous bands subdividing liver into regenerative nodules

previously thought to be irreversible but increasing evidence it cane improve/regress with control of disease

50% of cases are alcoholic liver disease

cirrhosis

what mediates fibrosis in cirrhosis

TGF-B produced by stellate/ito cells

cell death, regeneration, and fibrosis in cirrhosis

<3 mm

micronodular cirrhosis

>3mm

macronodular cirrhosis

multiplie regenerative nodules in cirrhosis

trichrome stain

fibrous bands dividing liver into nodules

microscopically

regenerative noduiles surrounded by fibrous connective tissue that bridges between portal tracts

within collagenous tissue, scattered lymphocytes and proliferation of bile ducts

posthepatic cause of portal HTN

budd chiari → congenital malformation and thrombosis of IVC

hepatic causes of portal HTN

liver cirrhosis (most common cause in US of portal HTN)

schistosomiasis

idiopathic

prehepatic causes of portal HTN

splenic/mesenteric vein thrombosis

AV fistula

congenital stenosis of PV

extrinsic compression of portosplenic venous axis

increase in pressure in portal HTN can lead to

ascites

splenomegaly

esophageal/gastric varices

hemorrhoids

caput medusae

hepatic encephalopathy

spider angiomas

testicular atrophy/amenorrhea

hepatorenal syndrome

caput medusae

trematodes/flukes cause this

schistosomiasis

symptoms of schistosomiasis are caused by

body’s reaction to the eggs, not the worms themselves

s mansoni and s japonicum predominantly affect

liver and gut

s haematobium affects the

bladder

systemic hypersensitivity reaction that may occur weeks after the initial infection, esp s mansonia and s japonicum.

fever, cough, ab pain, diarrhea, hepatosplenomegaly, eosinophilia

acute schistosomiais/Katayama fever

how do chronic cases of schistosomiasis lead to portal htn

inflamm. response → activates host stellate cells → fibrosis → portal HTN

pathogenesis of reye syndrome

injury to mitochondria in hepatocytes → impaired FA metabolism

• microvesicular steatosis (fat does not displace nucleus)

• elevated ammonia → cerebral edema, intracranial pressure/coma

  • hypoglycemia (decreased hepatic gluconeogenesis, no resp to glucagon)

reye syndrome

liver failure and encephalopathy in young kids, can be fatal

kids with viral illness get treated with aspirin

most common primary tumor of the liver

hemangioma

benign vascular neoplasm, ASX incidental

hemangioma

in women of childbearing age

assoc with oral contraceptive use, regresses w/d/c of hormones

hepatic adenoma

hepatic adenoma can be mistaken for

carcinoma

hepatic adenomas are at risk for

rupture when they are subcapsular, esp during preg when hormones are high → life threatending hemorrhage

most common primary malignant tumor of liver

HCC hepatocellular carcinom

RF for HCC

chronic hepatitis

• HBC and HCV strongly assoc. HBV carriers 200x increased risk

chronic liver disease

cirrhosis

Aflatoxin from aspergillus flavus present on peanuts and grains

• induces p53 mutations

clinical picture for HCC

patients often already has cirrhosis

elevated serum AFP

hematogenous spread

hep vein obstruction/thrombosis (budd chiari) can lead to infarct

may secrete EPO

most die within 2 yrs diagnosis

large bulky greenish cast

smaller satellite nodules

hepatocelluar carcinoma

irreg thickend cords of pleomorphic atypical cells with frequent prominent nuclei

HCC

malignant neoplasm of vascular endothelial cells

rarely originates in liver

assoc with exposure to Thorotrast, arsenic, vinyl chloride

lethal, widespread mets

angiosarcoma

pleomorphic malignant cells with poorly formed vascular spaces

angiosarcoma

multicentric hemorrhagic nodules

angiosarcoma

most common cancer in liver

usually results in heptomegaly and mult nodules on exam

metastatic carcinoma

adults; colon breast lung panc

kids: neuroblastoma, wilms, rhabodomyosarcoma

some central necrosis in larger mass lesions

obstruction from masses elevates alkaline phosphatase but not all bile ducts obstructed so usually no hyperbilirubinemia

transaminases usually not greatly elevated

metastatic carcinoma

prehepatic jaundice causes

anything that increases hemoglobin breakdown

congenital and acquired hemolysis

hepatic jaundice causes

congenital abnormalities of hemoglobin

• gilbert disease (metabolism)

posthepatic jaundice causes

mechanical obstruction to bile flow

processes involved in conjugation

issues with bilirubing conjugation

neonatal jaundice

toxic jaundice

crigler najar syndrome

gilbert syndrome

problems with secretion of conjugated bilirubin

dubin johnson syndrome

impaired uptake of unconjugated bilirubin

drugs

damage

injury

what turns conjugated bilirubin to urobilinogen

converted by bacteria in the gut

RBC hemolysis → increased unconjugated bilirubin in blood

liver tries to compensate → more conjugated bilirubin in the bile

hemolytic anemia bilirubin effects

increased risk of this with hemolytic anemia

pigmented gallstones

dark urine

what leads to physiologica jaundice of newborn

fetal red cells have short life span → breakdown increased unconjugated bilirubin in the blood

Low UGT (UDP glucuronyl transferase enzyme) → decreased conjugation of bilirubin

decreased gut bacteria → increased deconjugation of bilirubin by intestinal beta glucuronidase and increase reabsorption of unconjugated bilirubin

→ buildup of unconjugated bilirubin

complications of neonatal physiologic jaundice

kernicterus

unconjugated bilirubin is not water soluble but it is fat soluble, can get into brain/basal ganglia

→ neuro damage/death

kernicterus

tx for newborn jaundice

phototherapy. transforms unconjugated into water soluble isomers (NOT CONJUGATING IT)

autosomal recessive UGT1A1

decrease in UGT activity in liver → decreased conjugation

buildup and mild increase in unconjugated bilirubin

gilbert syndrome

autosomal recessive UGT1A1 gene

two types:

1. absence of UGT, no response to phenobarbital

2. greatly decreased UGT, responds to phenobarbital

marked decreased conjugation, marked increase in unconjugated bilirubin

crigler najar syndrome

crigler najar syndrome, esp type I, may results in

fatal kernicterus

definitive tx for crigler najar type I

liver transplant

good to look at

rare autosomal recessive disease ABCC2 (MRP2) gene mutation

defect in bilirubin canalicular transport protein, decreased bilirubin excretion → buildup of conjugated bilirubin, leaks into blood → dark pigment , liver appears black,

ASx and not clinical significant

coproporphyrin excretion is normal

dubin johnson syndrome

dark pigment in dubin johnson accumulates in ______ and contains ______

hepatocye lysosomes

epinephrine metabolites

dubin johnson syndrome

rare autosomal recessive disease SLCO1B1/B3 gene mutations

• affects organix anion transporting polypeptides OATP1B1/B3

results in defect in reuptake/storage of conjugated hyperbilirubinemia → decreased bili excretion

INCREASED urinary copropoyphyrin (comp with DJS)

rotor syndrome

less severe than DJS

liver not black/discolored

biopsy appears normal

rotor syndrome

increased serum unconjugated bilirubin (hepatocyte destruction) and increased serum conjugated bilirubin (biliary duct destruction)

dark urine → increased conj bilirubin in urine

normal to decreased urine bilinogen → nor to dec urobilinogen prod in gut

viral hep and jaundice