Hepatobiliary 1 Flashcards
Are introns transcribed?
They are not translated during protein synthesis, but they are not transcribed by RNAP II during RNA production.
What is the purpose of the 3’ poly-A tail? Is it transcribed?
It protects the mRNA from degradation within the cytoplasm after it exits the nucleus, but it is not transcribed from DNA - it is added by post-transcriptional modification
Why do women with hemochromatosis present later than men?
Physiologic iron loss through menstruation and pregnancy slows the progression of hemochromatosis in women.
What is defective in hemochromatosis?
There is a defect in the intestinal absorption of dietary iron that results in excess absorption and storage of 0.5-1g of iron each year.
How do ethanol and vitamin C affect iron stores?
increase reabsorption of iron
What type of liver malignancy can be associated with hemochromatosis?
hepatocellular carcinoma
What is the most common benign liver tumor and how does it present?
Cavernous hemangiomas - consist of cavernous, blood-filled vascular spaces of variable sizes lined by a single epithelial layer
What are the 5 enzymes required by pyruvate dehydrogenase?
CoA, FAD, lipoic acid, NAD, and thiamine pyrophosphate
What is the result of decreased pyruvate dehydrogenase activity?
pyruvate will be converted to lactate instead of acetyl CoA in order to regenerate NAD+ which will lead to lactic acidosis
Other than pyruvate dehydrogenase, what else does lipoic acid serve as a cofactor for?
alpha-ketoglutarate dehydrogenase adn branched-chain ketoacid dehydrogenase
What is a urea cycle disorder resulting from a deficiency of argininosuccinate synthetase?
Citrullinemia
What are the two pathways that dispose homocyteine from the body?
- conversion of homocysteine to cysteine by the actions of two vitamin B6 enzymes: cystathionine synthase and cystathionase
- conversion of homocystine to methionine by folate and vitamine B12-dependent process
What occurs d/t defective pyrimidine synthesis resulting from a deficiency of the enzyme orotate phosphoribosyl transferase and requires glutathionine as a coenzyme?
orotic aciduria
What should be suspected in all pts with premature onset (
alpha-1 antitrypsin deficiency
-neonatal hepatitis with cholestasis should increase suspicion
What are the most severe consequences of liver involvement in alpha-1 antitrypsin deficiency?
cirrhosis and hepatocellular carcinoma
What does a northern blot detect and what type of probe is used?
RNA via ssDNA or RNA (hybridization) probe
What does a southern blot detect and what type of probe is used?
DNA via ssDNA or RNA (hybridization) probes
What does a western blot detect and what type of probe is used?
protein via antibody probe
What does a southwestern blot detect and what type of probe is used?
DNA-binding protein via dsDNA probe
What does Ras activate?
MAP kinase
What are homodimeric calcium-binding proteins that serve as markers for cells of neural crest derivation (melanocytes and Schwann cells), as well as Langerhans cells and other dendritic cells?
S-100 proteins
What are nuclear transcription factors that directly bind DNA via leucine zipper motif?
c-Jun and c-Fos
How is the liver involved in the metabolism of TGs?
TGs stored in adipose tissue is metabolized into FFAs and glycerol by lipase. Glycerol is transported into the liver and phosphorylated to glycerol-3-phosphate by liver-specific glycerol kinase which is then converted to DHAP by glycerol-3-phosphate dehydrogenase. DHAP is used to produce ATP through glyoclolysis or glucose through glyconeognesis. Glycerol in the liver can be utilized for TG synthesis
What reaction catalyzes FA activation to acyl-CoA form in urder to undergo B-oxidiation in the mitochondria?
acyl-CoA synthetase
What must fatty acyl-CoA conbine with in order to be transported into the mitochondrion?
carnitine
What is the first enzyme used in the HMP shunt and whoulat does it produce?
- glucose-6-phosphate dehydrogenase
- produces NADPH and pentose sugars for nucleotide synthesis
Where do fatty acid oxidation and synthesis occur respectively?
oxidation: mitochondria
synthesis: cytosol
What catalyzes the first committed step in fatty acid synthesis, and what is this step?
acetyl CoA carboxylase (ACC) converts acetyl CoA to malonyl CoA
What organis can utilize ketone bodies for energy?
skeletal muscle, cardiac muscle, renal cortex, and brain (during starvation)
Why is continuous energy supply via ketone bodies important during prolonged starvation?
The brain has no glycogen or triglyceride stores
Why can’t erythrocytes utilize ketone bodies?
they lack mitochondria
Why can’t the liver utilize ketone bodies for energy?
the liver lacks the enzyme succinyl CoA-acetoacetate CoA transferase (thiophorase), which is required to convert acetoacetate to acetoacetyl CoA
Which to organs cannot utilize ketone bodies for energy?
RBCs and liver
What is a middle-aged Caucasian female with long history of pruritis and fatigue who now develops pale stoles and xanthelasma suggest?
primary biliary sclerosis
xanthelesma and pale stool suggest cholestasis
What is primary biliary cirrhosis (PBC) and what is found on histology?
PBC is a chronic liver disease characterized by autoimmune destruction of the intrahepatic bile duct and cholestasis. Histo findings include destruction of interlobular bile ducts by granulomatous inflammation (florid duct lesion) and a heavy portal tract infiltrate of macrophages, lymphocytes, plasma cells, and eosinophils.
What is suggested by a middle-aged obse female with fever and a prolonged episode of severe RUQ pain after fatty meal ingestion?
acute cholecystitis (rather than biliary colic, which is typically briefer and without fever)
What is suggested by a male with a long history of ulcerative colitis presenting with fatigue and high alkaline phosphatase?
primary sclerosing cholangitis
What is suggested by n older female with weight loss, abdominal discomfort, jaundice, and an epigastric mass?
pancreatic cancer
What is suggested by a homeless man with fever, abdominal pain, and jaundice?
acute cholangitis
What is the most common cause of galactosemia and what is excess galactose converted to?
deficiency of galactose-1-phosphate uridyl transferase
-galactose is converted to galactitol
What are the clinical features of galactosemia?
vomiting, lethargy, jaundice, and failure to thrive soon after breastfeeding
What are the 3 stages of alcoholic liver injury?
alcoholic steatosis, alcoholic hepatitis, and cirrhosis
What does hepatocyte injury lead to ?
release of intracellular enzymes and an increase in serum transaminases and serum bilirubin
What are indicators of the liver’s synthetic function?
serum albumin level and elevated prothrombin time
-hypoalbuminemia and prolonged PT (=decreased coag factor synthesis) indicate poor prognosis
What is the role of serum GGT when alkaline phosphatase is elevated?
serum GGT can differentiate whether the cause is biliary disease or alternative cause of elevated alkaline phosphatase like bone disease
*GGT are specific for biliary injury
What causes prolonged bleeding time in alcoholic liver disease?
thrombocytopenia d/t direct toxic effects of alcohol on bone marrow and hypersplenism and splenic sequesteration of palteets
What are indicators of hepatocellular damage?
AST and ALT
What markers have the greatest prognostic significance?
serum albumin level and PT
Where do all the reactions of the pentose phosphate pathway occur?
in the cytosol
What is transketolase involved in and what does it use as a cofactor?
involved in PPP and uses thiamine
What is the importance of the 16S rRNA strand in prokaryotes?
It is essential for intiation of protein synthesis in prokaryotes and expresses a complementary sequence to the Shine-Dalgarno sequence in mRNA which allow mRNA and 30s subunit to bind in preparation for protein translation
Deficiency of what leads to incomplete glycogen degradation?
Debranching enzymes deficiency (Cori disease)
-alpha-1,6-glucosidic branch points cannot be degraded, so small chain dextrin-like material accumulates within the cytosol of the hepatocytes
What are the Sx of Cori dz?
hypoglycemia, hypertriglyceridemia, ketoacidosis, and hepatomegaly
What causes confusion, ophthalmoplegia, and ataxia in an alcoholic pt?
Wernicke encephalopathy
What does a-ketoglutarate dehydrogenase requires thiamine as a cofactor?
thiamine
Why does administration of glucose to a thiamine-deficient pt result in Wernicke encephalopathy?
d/t increased thiamine demand
What is the MOA of Zidovudine (AZT)?
It is a nucleoside RT inhibitor for HIV and it competitively binds to RT and is incorporated into the viral genome as a thymidine analog. AZT does not have a 3’-OH group, making 3’-5’ phosphodiester bond formation impossible
What infection can cause hepatic abscess through hematogenous seeding of the liver?
S. aureus
What are the clinical manifestations of Reye syndrome?
-hepatic encephalopathy: increased AST, ALT, NH3, PT, and PTT
-encephalopathy d/t hyperammonemia in CNS leading to cerebral edema
-
What are the histologic manifestations of Reye syndrome?
microvesicular steatosis of hepatocytes without inflammation and cerebral edema
What is charcterized by autoimmune destruction of the interaheptic bile ducts and cholestasis by anti-mitochondrial antibodies?
primary biliary cirrhosis (PBC)
How do primary biliary cirrhosis and graft vs. host disease have similar presentations?
they both demonstrate granulomatous bile duct destruction and a heavy lymphocyte-predominant portal tract infiltrate
What are the Sx of low-grade fever, anorexia, nausea, dark colored urine, and RUQ tenderness classic for?
acute hepatitis
What are histologic findings of all acute viral hepatitis?
- diffuse ballooning degeneration (hepatocyte swelling)
- mononuclear cell infiltrates
- Councilman bodies (eosinophilic apoptotic hepatocytes)
What leads to the formation of brown pigment stones?
They arise secondary to infection of the biliary tract, which results in the release of B-glucoronidase by injured hepatocytes and bacteria
What is the function of B-glucuronidase by injured hepatocytes and bacteria?
contributes to hydrolysis of bilirubin glucuronides and increases the amount of UCB in the bile
What is the MOA of hepatocyte injury by HBV?
the presence of HBsAg and HBcAg on the cell surface stimulate the host’s cytotoxic CD8+ T lymphocytes to destroy infected hepatocytes
What is usually the first Sx of primary biliary cirrhosis?
pruritis
How is PBC diagnosis confirmed?
anti-mitochondiral Abs in the serum
What are physical findings in PBC?
hepatosplenomegaly and xanthomatous lesions in the eyelids or skin and tendons
what are associated conditions with PBC?
Sjogren, Raynaud, scleroderma, autoimune thyroid disease, hypothyroidism, and celiac
What is the pathogenesis of alcohol-induced hepatic steatosis?
it is related primarily to a decrease in free fatty acid oxidation secondary to excess NADH production by the 2 major alcohol metabolism enzymes, alcohol dehydrogenase and aldehyde dehydrogenase
What is the molecular mechanism of hemochromatosis?
The hemochromatosis gene (HLA-H) is on the short arm of chromosome 6 and encodes for a molecule that appears to affect iron absorption from the GI tract
How is hepatocellular carcinoma associated with HBV infection?
integration of viral DNA into the genome of host hepatocytes triggers neoplastic changes
What are properties of drugs that have high intrinsic hepatic clearance?
high lipophilicity and a high volume of distribution via bile breakdown into the feces
-high lipophilicity allow drugs to cross cell barriers more easily and enter hepatocytes
What is is impaired with carnitine deficiency?
It reduces the ability of fatty acids to enter the mitochondria for B-oxidation
What does B-oxidation of fatty acids produce?
acetyl CoA, a precursor of acetoacetate (one of the three primary ketone bodies)
What should a moderately elevated alkaline phosphatase of unclear etiology be followed up with?
GGTP
What are the normal levels for total and direct bilirubin, respectively?
total: 0.2-1 mg/dL
direct: <0.2 mg/dL
What is Gilbert syndrome?
A familial disorder of bilirubin glucuronidation in which the produciton of UDP glucuronyl transferases is reduced
What are lab findings for acute viral hepatitis?
ALT > AST, followed by rises in bilirubin and alkaline phosphatase
What is the MOA of statins?
inhibit RLS of HMG-CoA reductase in cholesterol biosynthesis
What are the SE of statins?
hepatotoxicity and muscle toxicity
What is the MOA of fibrates?
increased LPL activity, decreased hepatic VLDL secretion, increased HDL synthesis
What are the SE of fibrates?
muscle toxicity, especially when combined with statins and gallstones
What is the MOA of bile acid sequestrants?
binds bile acids in the intestine, decreases reabsorption, and increases de novo synthesis from cholesterol
What are the side effects of bile acid sequestrants?
nausea, bloating, cramping, decreased absorption of digoxin, warfarin, and fat-soluble vitamins
What is the MOA of niacin?
decreased lipolysis in adipose tissue causing decreased VLDL synthesis in liver; increased HDL by reducing clearance
What are the SE of niacin?
flushing, warmth, and pruritis
hepatotoxicity
What is the MOA of Ezetimibe?
decreased cholesterol absorption at the brush border of the intestine
What are the SE of ezetimibe?
increased hepatotoxicity when coadministered with statins
What is the inheritance pattern of classical galactosemia?
autosomal recessive
What is HBV associated with in the prodromal period?
serum-sickness like syndrome
How does hyperestrinism in alcoholic cirrhosis occur and what are Sx?
- decreased catabolism of estrogens and increased sex hormone-binding globulin (decreases T:E ratio)
- Sx: gynecomastia, testicular atrophy, decreased body hair, and spider angiomata
What is a rare autosomal recessive disorder characterized by an asymptomatic conjugated hyperbilirubinemia that results from numerous defects in the hepatic uptake and excretion of bilirubin pigments?
Rotor syndrome
How does hepatocyte injury with viral hepatitis present?
diffuse swelling termed “ballooning degeneration” which causes the cytoplasm to appear empty with only an occasional eosinophilic organelle remnant remaining
How does viral-induced hepatocyte death present?
lobular architectural disruption, cytolysis, apoptosis, and confulent hepatocyte necrosis
What is the genetic mechanism behind high levels of dietary aflatoxin exposure?
It is associated with a G:C –> T:A transversion in codon 249 of the p53 gene that increases the risk of hepatocellular carcinoma
