Fatty Liver, Cirrhosis and Dysfunction

Question 1

Label this

Answer 1

Question 2

What are stellate cells?

Answer 2

Stellate cell
Reside in perisinusoidal space/space of Disse (space between endothelial cells and hepatocytes)
Major cell type involved in liver fibrosis
Major store of vitamin A and retinol in intracellular lipid droplets

Question 3

What are Kupffer cells?

Answer 3

Kupffer cells
Line sinusoids, adhere to endothelium
Largest population of tissue-resident macrophages in the body
First line of defence against gut bacteria, endotoxins etc transported from the GI tract in the portal vein

Question 4

What is the mechanism of liver fibrosis?

Answer 4

Chronic hepatocyte injury releases damage-associated patterns (DAMPs) and apoptotic bodies that activate HSCs and recruit immune cells. HSCs proliferate
Complex multidirectional signalling between activated HSCs and Kupffer cells (HSCs), as well as innate immune cells promote trans-differentiation into myofibroblasts.
Myofibrobalsts synthesise and deposit extracellular matrix (ECM) and hyaluronic acid

Question 5

Myofibrobalsts synthesise and deposit extracellular matrix (ECM). What is the significance of this?

Answer 5

The accumulation of ECM proteins distorts the hepatic architecture by forming a fibrous scar, and the subsequent development of nodules of regenerating hepatocytes which defines cirrhosis.
Cirrhosis produces hepatocellular dysfunction and increased intrahepatic resistance to blood flow, which result in hepatic insufficiency and portal hypertension

Question 6

Why is too much fibrogenesis a problem?

Answer 6

Fibrogenesis is a healing process that preserves tissue integrity. However, sustained fibrosis can become pathogenic.
Most causes of chronic liver injury result in liver fibrogenesis, which takes many years and is often asymptomatic.
Therefore, patients have end-stage liver disease when they develop symptoms e.g. liver cirrhosis, decompensated liver disease or even hepatocellular carcinoma.

Question 7

What does this show?

Answer 7

This shows liver biopsy at different stages

Stage four shows the development of nodules due to scar tissue

Question 8

Fatty liver is a common pathology. What is it?

Answer 8

It is associated with diabetes, cardiovascular mortality and liver mortality, through the development of NASH (nonalcoholic steatohepatitis), fibrosis and cirrhosis

Question 9

What is NASH and NAFL?

Answer 9

Excess fat infiltration can lead to the highest degree of fatty liver damage, causing cirrhosis

Question 10

Describe the The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD)

Answer 10

Obesity, raised Fatty As, adipocyte proliferation and overload causes adipose tissue damage, insulin resistance and leaky gut which induces inflammation.

IR leads to lipolysis w increased FFA, adipokine and proinflammatory cytokine release

FFAs normally undergo B-oxidation but mitochondria are overwhelmed leading to lipotoxicity: oxidative stress, ROS, ER stress, NASH

Question 11

How does the gut microbiome contribute to pathogenesis of NAFLD?

Answer 11

Alterations of the intestinal microbiome increase gut permeability, via reduced concs of Short Chain FA and altered T-reg

LPS from bacterial cell walls triggers TLR-4 on Kupffer cells leading to inflammation and fibrosis

Primary bile acids are converted to secondary bile acids by gut microbiota. Bile acid receptor-mediated signaling affect liver metabolism with steatosis and inflammation

Gut microbiota converts choline–> methylamines. Elevated choline metabolism may cause choline deficiency and subsequently to liver injury and fibrosis

Question 12

What does this liver biopsy show?

Answer 12

Question 13

Liver biopsies can have massive variation between samples. What are alternative tests?

Answer 13

Scores based on standard laboratory blood tests e.g. FIB4
Measurement of molecules in serum related to fibrosis e.g. ELF
Measurement of physical properties of liver e.g. vibration controlled transient elastography = FibroScan
Imaging – Ultrasound, CT, MRI - pick up cirrhosis well but not earlier stages of fibrosis

Fibroscan:
Measures liver elasticity
Stiffness’ score correlates to fibrosis score
Useful tool in managing NAFLD

Question 14

How is there portal hypertension in cirrhosis?

Answer 14

There is increased portal pressure due to: increased Portal venous outflow resistance x increased Portal venous flow

Question 15

What is the reasoning behind the portal increased venous outflow resistance in cirrhosis?

Answer 15

Increased portal venous outflow resistance:
Structural (70%): fibrosis, nodules, sinusoidal capillarisation
Vascular tone (30%)
Activation of hepatic stellate cells causes increased constrictors (endothelin, thromboxane A2, angiotensin II). Also causes decreased sinusoidal vasodilators (NO)

Question 16

What is the reasoning behind the portal increased venous flow in cirrhosis?

Answer 16

Splanchnic vasodilation causes increased production of intestinal VEGF, NO and eNO.
Effective reduction in blood volume
Activation of baro and volume receptors
This causes Na and water retention, increasing plasma volume and therefore contributes to portal hypertension

Question 17

How can ascites arise from cirrhosis?
What is refractory ascites?

Answer 17

Cirrhotic ascites develops in portal vein (carries blood from the digestive organs to the liver) hypertension. As the pressure rises, kidney function worsens and fluid builds up in the abdomen.

As the liver struggles to manage this fluid, it is forced into the abdominal cavity, resulting in ascites.

Ascites that cannot be mobilised or the recurrence of which after paracentesis (drainage) can not be prevented by diuretics is called refractory ascites

Question 18

What is hepatorenal failure?

Answer 18

Acute renal failure in a patient who usually has advanced liver disease, usually due to cirrhosis
Type 1: Rapidly progressive, oligoanuric
Type 2: Less rapidly progressive, diuretic resistant ascites