Pathophysiology of Liver Disease Flashcards
Describe the structure and role of sinusoids in the liver:
Sinusoids are hepatic capillaries
- Have larger lumens than other types of capillaries
- Have fenestrations (pores) that are larger than usual and large intracellular clefts –> allows unimpeded blood flow to bathe the hepatocytes
- Gaps allow the products of the liver to leave the liver and enter the circulation by first entering the Space of Disse
What are Kupffer cells?
Resident macrophages in the lumen of the liver
- Phagocytose bacteria
- Activate other cell types (stellate cells)
What do stellate cells do?
Located the sinusoids
Usual function is to store Vitamin A
When activated, play a key role in liver scarring and fibrosis
What is the Space of Disse?
The space between the sinusoidal endothelium and hepatocytes
The plasma that collects here flows back toward portal triads, and collects in lymphatic ducts, forming a large portion of the body’s lymph
What role do microvilli of hepatocytes have in the Space of Disse?
Microvilli of hepatocytes extend into the Space of Disse, allowing proteins and other plasma components from the sinusoids to be absorbed by the hepatocytes
Describe the steps of the synthesis, metabolism, and excretion of bilirubin
- Old RBCs are broken down by macrophages. The heme portion of the RBC is converted first to biliverdin and then to bilirubin. This is unconjugated, “indirect” bilirubin.
- Bilirubin tightly binds to albumin; needs a carrier protein in plasma.
- Albumin-bound bilirubin is delivered to the liver.
- In the liver, bilirubin has glucuronides attached to it. This is conjugated, “direct” bilirubin. It is water-soluble, but usually travels in plasma loosely bound to albumin.
- Conjugated bilirubin is excreted into the bile, and works its way through the gut. Bacteria in the gut deconjugate the bilirubin and degrade it to urobilinogen and then stercobilin. Stercobilin is excreted in the feces. A small amount of urobilinogen is recirculated and then excreted in the urine.
Unconjugated vs. Conjugated Bilirubin:
Unconjugated bilirubin: hydrophobic, tightly-bound to albumin, toxic, indirect lab results
Conjugated: hydrophilic, loosely bound to albumin, has glucuronides, not toxic, direct lab results
Conjugation INCREASES water-solubility of bilirubin
What is jaundice? What is it a result of?
Jaundice is green-yellow staining of tissues
Caused by an excess of bilirubin
Common in liver disease (sign by which we quickly know something has gone wrong)
G6PD Deficiency is a _____ cause of jaundice
Prehaptic
Physiologic Jaundice of the Newborn is a _____ cause of jaundice
Hepatic
Cholestasis is a ______ cause of jaundice
Posthepatic
Describe the liver’s regeneration abilities
After damage or disease, the liver recovers, and hepatocytes regenerate via hyperplasia
This ability is not limitless, however
What is acute viral hepatitis?
Inflammation of the liver. Can be caused by many viruses
Hep A (HAV)
Hep B (HBV)
Hep C (HCV)
S/Sx if Hep A, B, and C:
Fever
Fatigue and malaise
A/N/V
Abdominal pain / RUQ pain
Dark urine
Jaundice
What kind of virus is Hep A? How is it spread?
RNA virus
Spread via fecal-oral route, mainly from contaminated food or water
Does Hep A have a vaccine available?
Yes
Can Hep A become chronic?
No
What kind of virus causes Hep B? How is it spread?
DNA virus
Spread primarily by parenteral contact with infected blood, semen, or other body fluids (mucous membranes, non-intact skin)
Who is at the highest risk of developing chronic HBV infection?
Infants and very young children
Is there a vaccine available for Hep B?
Yes
What causes the most damage in Hep B?
Cytotoxic T cells attacking infected cells
What kind of virus causes Hep C? How is it spread?
RNA virus
Spread primarily through IV drug use or other blood exposure
Is an acute HCV infection asymptomatic or symptomatic?
Often asymptomatic
Can HCV become chronic?
Yes
Is there a vaccine available for HCV?
No
Describe fibrosis that occurs in HCV. What can it lead to?
The inflammatory response to viral infection activates the process of fibrosis
Fibrosis may progress slowly or rapidly to compensated cirrhosis and ultimately decompensated cirrhosis or liver cancer
When are babies screened for HCV when born to an HCV-positive mother, why?
After 18 months
False positive can occur prior due to the maternal antibodies
Patient teaching for patients with liver disease:
- Avoid alcohol
- Avoid acetaminophen
- Avoid potentially hepatotoxic drugs
- Avoid aspirin, and NSAIDs due to increased bleeding risk, as well as risk of kidney damage
- Get vaccinated against Hep A and Hep B
What is NAFLD?
Chronic Liver Disease // Nonalcoholic Fatty Liver Disease
Fat droplets accumulate in liver cells –> Enlarged fatty liver -> swelling and damage to the liver
How does NAFLD progress? What causes this progression?
Obesity-related liver disease progression is the fastest-growing reason for NAFLD
Diet changes can reverse NAFLD
It can become NASH (non-alcoholic steatohepatitis) + inflammation
Fibrosis progressing to cirrhosis
Can lead to hepatocellular carcinoma
What is cirrhosis? What does it result in? Describe the state of the liver in cirrhosis
Progressive, irreversible end stage of many different hepatic injuries – not a disease itself
The liver is fibrotic, scarred, and nodular
Results in permanent alteration in hepatic blood and bile flow and liver function
Compensated vs. Uncompensated Cirrhosis
Compensated:
- Liver is scarred/fibrotic, but can still perform many important functions
- Few to no symptoms
Uncompensated:
- Liver is extensively scarred/fibrotic and can no longer perform important functions
- Jaundice, portal hypertension, ascites, edema, varices
Describe the role of Kupffer cells, Stellate cells, and collagen in the path of cirrhosis
Chronic inflammatory process due to Kupffer cells, generating cytokines and other inflammatory mediators
Activation of Stellate cells by Kupffer cells increases the rate of deposition of extracellular matrix, including collagen in the Space of Disse –> FIBROSIS
Subendothelial collagen disrupts blood flow and impairs the movement of solutes between hepatocytes and plasma (ex. proteins)
What happens to the hepatic microvilli and fenestrations in endothelial cells in cirrhosis?
Hepatic microvilli are lost/flattened
Fenestrations between endothelial cells are narrowed or closed
What happens when blood flow is disrupted in cirrhosis?
Disruption of hepatic blood flow can cause:
- Increased vascular resistance
- Portal hypertension
- Ascites
- Hepatic encephalopathy
- A large number of body system dysfunctions
What are the general manifestations of chronic liver disease?
Abnormal storage and release of glucose
Inadequate protein metabolism
Impaired processing of endogenous steroid hormone: estrogen
Impaired clearance of exogenous drugs and toxins (conversion of ammonia to urea is impaired)
Portal hypertension
Hepatic encephalopathy
What is portal hypertension? What causes it?
Increased pressure in the portal circulation
- Due in large part to scarring, fibrosis
The portal vein normally has low pressure and lacks the valves we see in other veins
The pressure will continue back up and engorge other veins
What is hepatic encephalopathy? What causes it?
Complex neuropsychiatric syndrome [occurs in late-stage chronic liver disease]
Blood no longer passes through the liver for the removal of toxic substances. Results in more toxic substances and bacteria in the systemic circulation
Ex. The liver is unable to get rid of ammonia, which can cross the BBB and is toxic
What can portal hypertension result in?
Alternate pathways of blood flow back to the vena cava –> esophageal, GI varices (engorged blood vessels)
Caput meduase (engorged superficial abdominal veins)
Splenomegaly (blood backs up into the spleen)
Hepatic encephalopathy
Ascites
Why does ascites occur in chronic liver disease?
A shift in the Starling forces (movement out of the capillaries into the extravascular/interstitial space)
Increase in hepatic sinusoid/capillary hydrostatic pressure –> lymph fluid formation –> overwhelms the ability of thoracic duct to carry away the lymph –> increased hydrostatic pressure –> fluid moves out of the capillaries
Capillary oncotic pressure decreases –> fluid moves out of the capillaries
Extravascular/tissue oncotic pressure increases –? fluid moves out of the capillaries
How does portal hypertension contribute to ascites?
Causes hemodynamic changes –> hypovolemia signal
Compensatory mechanisms activated –> RAAS
Increased vasopressin/ADH and aldosterone release
Lead to increased sodium retention –. increased water retention and eventually an increase in plasma volume that worsens the ascites
How is ammonia converted to urea?
Liver forms urea by combining
Ammonia + CO2 = Urea + water
Hepatic Encephalopathy S/Sx
Confusion, impaired cognition
Insomnia or hypersomnia
Psychotic symptoms
Asterixis (liver flap // spastic jerking of the hand)
Coma in severe cases
How is serum ammonia level used to test the severity of hepatic encephalopathy?
It does not correlate well with the severity of encephalopathy
Is NOT used to determine encephalopathy severity or prognosis
How does chronic alcohol abuse affect the liver?
Acetaldehyde (a breakdown product of alcohol) can directly injure hepatocytes and increase levels of ROS
Glutathione can be bound to it and unable to exert its effects
Endotoxins from the gut can be released and activate Kupffer cells –> cytokine release –> inflammation –> stellate cell activation –> liver fibrosis
What is Hereditary Hemochromatosis (HH)?
Common autosomal recessive disorder that allows excessive and uncontrolled iron absorption
Iron deposits in numerous organs (liver, pancreas, heart)
Can progress to hepatocellular carcinoma
Hereditary Hemochromatosis (HH) Clinical Manifestations:
Hepatomegaly
Elevated liver enzymes
DM, hyperpigmentation (bronzing) , polyarthritis, hypogonadism
Heart failure
What is the treatment mainstay for Hereditary Hemochromatosis (HH)?
Routine phlebotomy
Avoid iron supplementation, minimize iron-rich foods
How are AST and ALT used in liver function tests?
They are intracellular liver enzymes
Elevated serum levels of these enzymes indicate necrosis –> current liver injury
If acute, they will return to baseline approx. 2 weeks after an injury. Longer = chronic injury
How is alkaline phosphatase or ALP used in liver function tests?
Elevated ALP points to cholestasis
Found in the bile duct epithelium
Bile salts can’t leave the liver –> release of AP into the bloodstream
How is serum albumin used in LFTs?
Elevated urinary bilirubin may be a sign of liver dysfunction
Measured on a urine dipstick
