Pathophysiology of Liver Disease

Question 1

Describe the structure and role of sinusoids in the liver:

Answer 1

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

Question 2

What are Kupffer cells?

Answer 2

Resident macrophages in the lumen of the liver

• Phagocytose bacteria
• Activate other cell types (stellate cells)

Question 3

What do stellate cells do?

Answer 3

Located the sinusoids

Usual function is to store Vitamin A

When activated, play a key role in liver scarring and fibrosis

Question 4

What is the Space of Disse?

Answer 4

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

Question 5

What role do microvilli of hepatocytes have in the Space of Disse?

Answer 5

Microvilli of hepatocytes extend into the Space of Disse, allowing proteins and other plasma components from the sinusoids to be absorbed by the hepatocytes

Question 6

Describe the steps of the synthesis, metabolism, and excretion of bilirubin

Answer 6

1. 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.
2. Bilirubin tightly binds to albumin; needs a carrier protein in plasma.
3. Albumin-bound bilirubin is delivered to the liver.
4. 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.
5. 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.

Question 7

Unconjugated vs. Conjugated Bilirubin:

Answer 7

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

Question 8

What is jaundice? What is it a result of?

Answer 8

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)

Question 9

G6PD Deficiency is a _____ cause of jaundice

Answer 9

Prehaptic

Question 10

Physiologic Jaundice of the Newborn is a _____ cause of jaundice

Answer 10

Hepatic

Question 11

Cholestasis is a ______ cause of jaundice

Answer 11

Posthepatic

Question 12

Describe the liver’s regeneration abilities

Answer 12

After damage or disease, the liver recovers, and hepatocytes regenerate via hyperplasia

This ability is not limitless, however

Question 13

What is acute viral hepatitis?

Answer 13

Inflammation of the liver. Can be caused by many viruses

Hep A (HAV)

Hep B (HBV)

Hep C (HCV)

Question 14

S/Sx if Hep A, B, and C:

Answer 14

Fever

Fatigue and malaise

A/N/V

Abdominal pain / RUQ pain

Dark urine

Jaundice

Question 15

What kind of virus is Hep A? How is it spread?

Answer 15

RNA virus

Spread via fecal-oral route, mainly from contaminated food or water

Question 16

Does Hep A have a vaccine available?

Answer 16

Yes

Question 17

Can Hep A become chronic?

Answer 17

No

Question 18

What kind of virus causes Hep B? How is it spread?

Answer 18

DNA virus

Spread primarily by parenteral contact with infected blood, semen, or other body fluids (mucous membranes, non-intact skin)

Question 19

Who is at the highest risk of developing chronic HBV infection?

Answer 19

Infants and very young children

Question 20

Is there a vaccine available for Hep B?

Answer 20

Yes

Question 21

What causes the most damage in Hep B?

Answer 21

Cytotoxic T cells attacking infected cells

Question 22

What kind of virus causes Hep C? How is it spread?

Answer 22

RNA virus

Spread primarily through IV drug use or other blood exposure

Question 23

Is an acute HCV infection asymptomatic or symptomatic?

Answer 23

Often asymptomatic

Question 24

Can HCV become chronic?

Answer 24

Yes

Question 25

Is there a vaccine available for HCV?

Answer 25

No

Question 26

Describe fibrosis that occurs in HCV. What can it lead to?

Answer 26

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

Question 27

When are babies screened for HCV when born to an HCV-positive mother, why?

Answer 27

After 18 months False positive can occur prior due to the maternal antibodies

Question 28

Patient teaching for patients with liver disease:

Answer 28

- 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

Question 29

What is NAFLD?

Answer 29

Chronic Liver Disease // Nonalcoholic Fatty Liver Disease Fat droplets accumulate in liver cells --> Enlarged fatty liver -> swelling and damage to the liver

Question 30

How does NAFLD progress? What causes this progression?

Answer 30

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

Question 31

What is cirrhosis? What does it result in? Describe the state of the liver in cirrhosis

Answer 31

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

Question 32

Compensated vs. Uncompensated Cirrhosis

Answer 32

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

Question 33

Describe the role of Kupffer cells, Stellate cells, and collagen in the path of cirrhosis

Answer 33

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)

Question 34

What happens to the hepatic microvilli and fenestrations in endothelial cells in cirrhosis?

Answer 34

Hepatic microvilli are lost/flattened Fenestrations between endothelial cells are narrowed or closed

Question 35

What happens when blood flow is disrupted in cirrhosis?

Answer 35

Disruption of hepatic blood flow can cause: - Increased vascular resistance - Portal hypertension - Ascites - Hepatic encephalopathy - A large number of body system dysfunctions

Question 36

What are the general manifestations of chronic liver disease?

Answer 36

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

Question 37

What is portal hypertension? What causes it?

Answer 37

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

Question 38

What is hepatic encephalopathy? What causes it?

Answer 38

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

Question 39

What can portal hypertension result in?

Answer 39

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

Question 40

Why does ascites occur in chronic liver disease?

Answer 40

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

Question 41

How does portal hypertension contribute to ascites?

Answer 41

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

Question 42

How is ammonia converted to urea?

Answer 42

Liver forms urea by combining Ammonia + CO2 = Urea + water

Question 43

Hepatic Encephalopathy S/Sx

Answer 43

Confusion, impaired cognition Insomnia or hypersomnia Psychotic symptoms Asterixis (liver flap // spastic jerking of the hand) Coma in severe cases

Question 44

How is serum ammonia level used to test the severity of hepatic encephalopathy?

Answer 44

It does not correlate well with the severity of encephalopathy Is NOT used to determine encephalopathy severity or prognosis

Question 45

How does chronic alcohol abuse affect the liver?

Answer 45

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

Question 46

What is Hereditary Hemochromatosis (HH)?

Answer 46

Common autosomal recessive disorder that allows excessive and uncontrolled iron absorption Iron deposits in numerous organs (liver, pancreas, heart) Can progress to hepatocellular carcinoma

Question 47

Hereditary Hemochromatosis (HH) Clinical Manifestations:

Answer 47

Hepatomegaly Elevated liver enzymes DM, hyperpigmentation (bronzing) , polyarthritis, hypogonadism Heart failure

Question 48

What is the treatment mainstay for Hereditary Hemochromatosis (HH)?

Answer 48

Routine phlebotomy Avoid iron supplementation, minimize iron-rich foods

Question 49

How are AST and ALT used in liver function tests?

Answer 49

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

Question 50

How is alkaline phosphatase or ALP used in liver function tests?

Answer 50

Elevated ALP points to cholestasis Found in the bile duct epithelium Bile salts can't leave the liver --> release of AP into the bloodstream

Question 51

How is serum albumin used in LFTs?

Answer 51

Elevated urinary bilirubin may be a sign of liver dysfunction Measured on a urine dipstick