Hepatology Flashcards
What percentage of cardiac output runs through the liver? What are the sources and proportions of that blood flow?
About 25% of cardiac output will go through the liver; the hepatic artery provides 20-40% of flow, the portal vein provides 60-80%
What are the contents of portal vein delivery?
Pancreatic hormones, nutrients, drugs, toxins, bacteria, and cells (why the liver is a common site of metastasis)
How are the hepatocytes regionally classified into zones?
Hepatocytes near the portal triads are in zone 1; those by the central vein are in zone 3; those in the middle are in zone 2
What are some of the structural distinctions of the sinusoids and how do they affect hepatic blood pressure?
Sinusoidal endothelial cells do not adhere to each other very much; their basement membranes are highly fenestrated. These allow rapid diffusion to the hepatocytes and helps to keep hepatic blood pressures low
What happens to the sinusoids with chronic liver damage? What happens to some hepatocytes with chronic liver damage?
Stellate cells are activated to deposit matrix components into the space of Disse and the endothelial cells start to interact with each other more readily; some hepatocytes will convert to mesenchymal cells
What is the major consequence of sinusoid capillarization?
Resistance of the blood vessels increases and the portal pressures rise (portal hypertension)
What is the definition of cirrhosis?
It is a progressive disease caused by diffuse damage to parenchymal cells with nodular regeneration, fibrosis, and architectural disturbances in the liver (nodular regeneration and fibrosis are required for diagnosis)
What are some etiologies of cirrhosis?
Hepatitis, chronic alcohol intake (zone 3 damage), fatty liver disease
What chemicals change composition in the portal system as structural alterations in disease happen?
Nitric oxide (vasodilator) drops; endothelin (vasoconstrictor) increases
What is the body’s initial response to portal hypertension?
The changes in vascular resistance promote splanchnic vasodilation; which actually makes the problem worse by increasing flow to the liver (Pressure=resistance x flow)
What is a major effect of portal hypertension to the vasculature?
Excess portal blood tries to escape the portal system via anastomoses near the esophagus, umbilicus, and anus. Varices develop that can hemorrhage
What are cardiac responses to portal hypertension?
Increased heart rate and cardiac output, but decreased total peripheral vascular resistance; poorly responsive to vasoconstrictors
What is the kidney’s response to portal hypertension?
The kidney senses vasodilation in the splanchnic system as a loss of blood volume and promotes sodium reabsorption to retain additional water. Ascites starts to develop
Why are ALT and AST good lab tests to perform with liver damage?
Since the liver is the lone site of amino acid transformation and nitrogen elimination, ALT and AST are almost exclusively in the liver; their presence in the blood is indicative of hepatocytolysis
What is the physiological consequence of excess ammonia from hepatic failure?
Hepatic encephalopathy (high ammonia levels cause the brain to shunt ammonia into alpha-ketoglutamate and oxaloacetate; Krebs cycle starts to shut down. Glutamate used to make GABA as well–which is lost)
What classes of serum proteins does the liver produce?
1) Proteins that bind and transport hormones and metals
2) Blood coagulants and inhibitors
3) Protease inhibitors
What is the significance of acute phase reactants?
In acute stressing situations, the liver will significantly upregulate its production of certain proteins; the hallmark is CRP, which rises with any inflammatory process.
What class of enzymes catalyze phase I drug reactions? What three cofactors or substrates are required for them to complete their reactions?
Cytochrome P-450 family (CYP); need O2 as a substrate and heme and NADPH as cofactors
Where do phase I reactions happen in hepatocytes?
Endoplasmic reticulum
How do inducers affect drug metabolism in phase I? What effect do inhibitors have?
Inducers speed up the cytochrome’s reactions, so it weakens the effect of drugs; inhibitors slow their reactions and enhance drugs
What is the goal of phase II drug reactions?
Conjugation of a substrate to a polar compound helps to improve a drug’s solubility for excretion
How is acetaminophen regularly metabolised by the liver?
95% of the ingested compound is metabolized by phase II reactions that add sulfates or glucuronides; residual five percent handled by cytochrome P450s that create a toxic intermediate neutralized by glutathione
What happens to the liver with acetaminophen overdose?
The phase II pathway exhausts its enzyme supply, so there is a shift to phase I reactions. If the liver’s supply of glutathione is depleted, hepatocyte failure occurs and liver death is a possibility
What makes up bile?
Bilirubin, bile acids, amino acids, cholesterol, water, and electrolytes
How does bilirubin come about?
When RBCs die or when cytochromes are recycled, their heme is cleaved to save iron; the porphyrin portion is transformed to bilirubin via biliverdin reductase
How does conjugation of bilirubin occur?
Hepatocytes use UDP glucuronyl transferase to add glucuronide groups to the carboxyl ends of bilirubin to make it more soluble. Most bilirubin in adults is conjugated twice
How is bilirubin secreted?
Bilirubin is transported to hepatocytes by albumin and is conjugated there. It then enters the bile canaliculus via the cMOAT transporter (an ATP binding cassette)
What are the consequences of elevated unconjugated hyperbilirubinemia?
If unconjugated, can cross cell membranes, including the blood brain barrier. When it rises in the brain, the term is kernicterus (unconjugated bilirubin is cytotoxic)
What is the genetic cause and consequence of Gilbert’s syndrome?
Mutations in the promoter region of UDP glucuronyl transferase reduce the amount of enzyme made; mild elevated hyperbilirubinemia occurs
What is the genetic cause and consequence of Crigler-Najar syndrome?
Mutations in the coding region of UDP glucuronyl transferase yield a non-functional enzyme and requires a liver transplant to cure.
What is the genetic cause and consequence of Dubin-Johnson syndrome?
cMOAT mutations inhibit the export of conjugated bilirubin into the bile canaliculus
What is the genetic cause and consequence of Rotor syndrome?
Mutations in the OATP transporter (to get bilirubin into hepatocytes) yields an elevated conjugated bilirubin level
What consequence occurs in patients with OATP mutations?
Hepatocytes are unable to metabolize statins well; high statin levels in the blood are myotoxic and rhabdomyelysis can result
What are the primary bile acids and what type of cell produces them?
Hepatocytes make chenodeoxycholic acid and cholic acid
What are the secondary bile acids and what types of cells produce them?
Most secondary bile acids are products of bacterial metabolism and include lithocholic acid, ursodeoxycholic acid, and deoxycholic acid
How are bile salts added to bile?
They are exported using ATP against their concentrations gradient via the BSEP
What is the genetic cause and consequence of progressive familial intrahepatic cholestasis?
PFIC1 and 3 are mutations in chaperone molecules, so some minor jaundice and intermittent cholestasis occurs; PFIC 2 is more serious as there is a mutation in BSEP and bile salts cannot be excreted–>cirrhosis
Where are most bile salts recycled in the intestines?
Terminal ileum
What is the consequence of high bile acids in the stool?
Diarrhea due to water being drawn into stool
What are the contributing factors of cholelithiasis?
High saturation of cholesterol in bile, low motility, and nucleation of crystals
What risk factors contribute to cholesterol stones?
Increased age, female sex, Native American ancestry, weight changes, medications, diabetes
What are causes of pigmented stones?
Calcium bilirubinate from chronic hemolysis, cirrhosis, and chronic infections
