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GI > 4- Liver pathophysiology and cirrhosis > Flashcards

4- Liver pathophysiology and cirrhosis Flashcards

1
Q

what is important aspects of livers role?

A

= important metabolic role:

  • detoxifies metabolites in gut
  • synthesis of digestive enzymes
  • production of variety of proteins
  • storing nutrients
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2
Q

what is structure of liver?

A

8 segments - each with portal triad and then central vein which all drain to after cleaning

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3
Q

what is importance of zones in liver?

A

there are 3 zones (zone 1 all of outer area with portal triads and then zone 3 circle in middle with central vein) = important as function changes in zones

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4
Q

what is hepatic sinusoid and describe where it fits into structure of liver?

A

specialised capillaires = tubules that allow movement of blood

in liver:

  • in one end (zone 1) there is portal triad. hepatic artery & portal venule both move into same blood vessel (the sinusoid) that leads to central vein to be drained away. bile duct also in portal triad but remains separate in between hepatocytes and flow in opposite direction
  • the sinusoid (containing blood from portal venule and hepatic artery) has a space on either side of it before hepatocytes called “space of disse”
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5
Q

what is function of space of disse in liver?

A

reminder = it’s the space on either side of sinusoid between hepatocytes

small particles leave small pores in sinusoid into the space of disse - space of disse then facilitates exchange into hepatocytes

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6
Q

what is exchanged between space of disse in liver?

A
  • nutrients like glucose, amino acids, fatty acids, vitamins, minerals etc = essential for metabolic processes within liver, like energy production, protein synthesis, and detoxification
  • normal things like oxygen & CO2
  • some hormones like insulin, glucagon and growth factors = to regulate metabolic processes within the liver, including glucose metabolism, glycogen storage, and protein synthesis
  • toxic substances so hepatocytes can detoxify & eliminate
  • plasma proteins like albumin, clotting factors, transport proteins (albumin made in liver and delivered to rest of body)
  • immune cells like kupffer cells (allows immune surveillance in liver)
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7
Q

what are stellate cells?

A

cells located within space of disse to interact with hepatocytes and other cells to regulate extracellular matrix production, fibrogenesis, blood flow, immune regulation and more = lots of jobs

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8
Q

what are examples of things metabolised in liver?

A
  • glucose
  • lipid
  • protein
  • hormones
  • drugs!
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9
Q

what happens with glucose metabolism in liver when fasting?

A

fasting = lack of glucose →decreased insulin production & increased glucagon →promotes glycogen breakdown in periportal hepatocytes (to get glucose)

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10
Q

what is Gluconeogenesis?

A

= metabolic pathway in liver where glucose made from non-carb precursors like Lactate, pyruvate, amino acids and glycerol

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11
Q

what happens with glucose metabolism in liver when feeding?

A

lots of glucose →increased insulin + decreased glucagon →hepatic glucose uptake by converting to glycogen (glycogenesis) and depositing in hepatocytes

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12
Q

what are the 3 different lipid metabolism processes occurring in liver?

A
  1. endogenous pathway (LDL)
  2. reverse transport pathway (HDL)
  3. exogenous pathway (chylomicrons)
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13
Q

what is the endogenous pathway (LDL) of lipid metabolism in liver?

A

very low density lipoprotein synthesised in liver (made to carry triglyceride & some cholesterol - fat)→fatty acids cleaved (remove triglyceride) which changes its properties →this makes LDL (carrying cholesterol) that then reuptake into liver via LDL receptor or builds up in plaques making foam cells & plaques

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14
Q

what is the exogenous pathway (chylomicrons) in liver?

A

when you eat fats - triglycerides, phospholipids & cholesterol absorbed into enterocytes of small bowel→in the enterocytes, the absorbed lipids reassemble into larger molecules,chylomicrons→chylomicrons first go in lymphatics then into bloodstream and gradually release triglycerides etc to tissues →once just remnants of chylomicrons left, they’re reuptaken by liver via remnant or LDL receptors

(Chylomicrons = large lipoprotein particles composed primarily of triglycerides, phospholipids, cholesterol, and proteins called apolipoproteins)

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15
Q

what is reverse transport pathway (HDL) in liver metabolism of lipids?

A

HDL synthesised by liver →HDL picks up excess cholesterol in tissues and delivers to liver

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16
Q

what protein metabolism occurs in liver?

A

proteins →broken down to amino acids →absorbed in small intestine into blood stream →reach liver and undergo metabolism in hepatocytes via various pathways:

  • Krebs or citric acid cycle where amino acids broken down to useful substances like→Hormones, neurotransmitters, plasma proteins, nucleotides (Purine and Pyrimidine)→also by product of Ammonia
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17
Q

what is significance of ammonia?

A

ammonia is absorbed from gut but also synthesised in liver as by product of amino acid metabolism

  • it needs to be detoxified by: conversion to urea by the Krebs cycle or by combining with glutamate to make glutamine catalysed by glutamine synthetase
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18
Q

what hormones are catabolised in liver?

A
  • Insulin
  • Glucagon
  • Corticosteroids
  • Growth hormone
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19
Q

what happens to vitamin D in liver?

A
  • Vitamin D (also called Cholecalciferol) converted to 25-hydroxy-cholecalciferol which is the form vitamin D circulates in blood stream
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20
Q

what are the 3 different phases of drug metabolism in liver?

A

phase I = oxidation, reduction & hydrolysis →activation/inactivation
phase II = conjugation in cytoplasm of hepatocytes →solubilisation
phase III = secretion into bile, mediated by ATP→excretion

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21
Q

what happens in phase II drug metabolism?

A

= it’s conjugation in cytoplasm of hepatocytes - attachment of ionised groups to drug to increase water solubility

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22
Q

what are some examples of phase II reaction of drug metabolism?

A

glucuronidation, sulphation, acetylation and methylation amongst others

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23
Q

what are important proteins in phase I reactions of drug metabolism?

A

CYP450 = family of proteins in ER of hepatocytes

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24
Q

what proteins are synthesised in liver and so what?

A

= means you can measure these proteins for liver function and also to investigate disease processes themselves

  • albumin
  • transport proteins
  • ferritin (stores iron)
  • ɑ1 antitrypsin
  • CRP
  • AFP = secreted if growth of tumour
  • Complement
  • Fibrinogen
  • Vitamin K dependent coagulation factors = II, V, VII, IX and X
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25
Q

what is function of albumin?

A

= it’s a major protein found in blood plasma making 50-60% of plasma protein, produced in liver and carries insoluble bilirubin, hormones & fatty acids

*amongst other functions

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26
Q

what is role of bile?

A

allow digestion of dietary fats through emulsification

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27
Q

what are primary bile acids?

A
  • made in liver
  • made up of cholesterol & amino acids (from cholesterol through enzymatic reactions - these are then conjugated with amino acids in liver)
  • form conjugated water-soluble bile acids = to prevent precipitation (precipitates like gallstones) and allow reabsorption in the terminal ileum
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28
Q

what are secondary bile acids?

A

= primary bile acids further metabolised by gut bacteria in colon

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29
Q

what are some components of bile?

A
  • Phospholipids = made in liver and secreted into bile to help emulsify dietary fats
  • Cholesterol = major component but excess cholesterol →cholesterol gallstones
  • Bilirubin = conjugated bilirubin in bile and eliminated from body in faeces
  • Conjugated drugs
  • Electrolytes: Na+, Cl-, HCO3- and copper
30
Q

what is bilirubin?

A

= breakdown product of RBC

31
Q

what is the whole bilirubin transport/conversion type process?

A

in spleen heme breakdown product = bilirubin which is converted to unconjugated bilirubin, RBC containing unconjugated bilirubin and albumin is delivered to liver

unconjugated bilirubin →conjugated bilirubin where enters bile and then deconjugated in small bowel → urobilinogen then →stercobilin which gives brown poo

  • some urobilinogen →urobilin then excreted in urine
32
Q

what is immunological role in liver?

A
  • firewall → filtering all blood from gut
  • Kupffer cells (sitting in middle of sinusoids) phagocytose pathogens from gut
  • Supply of important chemokines →Interleukins & Tumour necrosis factor
  • Priming T cell responses
33
Q

what is liver cirrhosis?

A

= result of chronic inflammation and damage to liver cells. The functional liver cells are replaced with scar tissue (fibrosis).

  • regenerative nodules of scar tissue form within the liver surrounded by fibrous bands
34
Q

what are causes of cirrhosis? (biglist)

A

= chronic inflammation

  • viral infection
  • hepatitis B&C
  • alcohol
  • metabolic dysfunction associated steatotic liver disease (MASLD)
  • autoimmune disorders →Autoimmune Hepatitis, Primary Biliary Cholangitis, Primary Sclerosing Cholangitis
  • wilson’s disease
  • alpha 1 antitrypsin
  • budd-chiari
  • hemocromatosis
35
Q

what is the pathology of cirrhosis?

A

chronic injury = inflammatory damage, matrix deposition, parenchymal cell death, angiogenesis
→early fibrosis = disrupted architecture, loss of function, natural hepatocytes regeneration
→cirrhosis = liver failure, portal hypertension

36
Q

what are 2 options of what can occur after cirrhosis?

A
  1. transplant
  2. hepatocellular carcinoma
37
Q

at what point can you resolve liver damage?

A

you can resolve early fibrosis as still some regeneration but can’t resolve cirrhosis
= can’t resolve once damaged structure

38
Q

describe the pathophysiology of cell death from liver injury?

A

liver injury →necrosis & apoptosis

  • by release of cell contents & ROS which activated stellate cells→they release chemoattractant proteins and macrophages attracted
  • stellate cells transformed into myofibroblast like cells which produce extracellular matrix proteins like collagen which contributes to fibrosis
39
Q

what happens once of cause of injury of liver removed?

A

reversion and quiescent stellate cells

40
Q

describe the transformation of stellate cells?

A

quiescent cells + injury →activate myofibroblast →increase collagen synthesis + accumulation of collagen→organ failure

41
Q

what is found in normal liver space of disse?

A
  • Type IV collagen
  • Glycoproteins
  • Proteoglycans
42
Q

what is found in normal liver extracellular matrix?

A
  • Collagen type I, III & IV
  • Proteoglycans
  • Glycosaminoglycans
  • Fibronectin
  • Hyaluronic acid
43
Q

what is differences of components found in fibrotic liver? (e.g. collagen types, effect on sinusoids and pressure)

A
  • 10x ↑ type I & III fibrillar collagen
  • ↓metabolite and O2 exchange across space of Disse → hepatocyte dysfunction
  • ↑ angiogenesis, sinusoidal remodeling and ↑ HSCs
  • ↑sinusoidal resistance and portal hypertension
44
Q

what are some consequences of sinusoidal resistance?

A
  • liver failure
  • increased portal pressure
  • hepatopulmonary syndrome
  • portopulmonary hypertension
  • ascites
  • portal-systemic encephalopathy
  • variceal bleeding
45
Q

what are general signs of liver failure?

A

jaundice, fever, loss of body hair

46
Q

what are signs of compensated liver failure?

A

xanthelasmas, parotid enlargement, spider naevi, gynaecomastia, splenomegaly, on hands (liver palms, clubbing, duputren’s contracture, xanthomas), scratch marks, testicular atrophy, purpura, pigmented ulcers

47
Q

what are signs of decompensated liver failure?

A
  • neurological like disorientation, drowsiness
  • ascites
  • dilated veins in abdomen
  • oedema
48
Q

what are 3 options for approaches of liver disease diagnosis?

A
  1. liver biopsy
  2. serum marker
  3. elastography
49
Q

what are +ve and -ve of liver biopsy?

A

most accurate but can have complications (morbidity) and sampling error

50
Q

what are +ve and -ve of serum marker?

A

widely available but non-specific (good for advanced or no serosis but area in between not good at)

51
Q

what are +ve and -ve of elastography?

A

non invasive done either ultrasound or proprietary, shows how stiff the liver which correlated with biopsy results, they’re expensive

52
Q

what is staging used for liver biopsy?

A

METAVIR staging
F0 = no fibrosis
F4= nodular cirrhosis

53
Q

what are serum biomarkers that can be tested?

A
  • albumin
  • prothrombin time
  • bilirubin
  • platelets
54
Q

what change to albumin in end stage liver disease?

A

decrease - has long half life so useful biomarker

55
Q

what effect does advanced liver disease have on prothrombin time?

A

liver usually makes clotting factors, if damaged then makes less clotting factors so increased prothrombin time (as harder to clot)

56
Q

how does end stage liver disease effect bilirubin levels?

A

Increased in end stage cirrhosis due to decreased clearance

57
Q

what effect on platelets if cirrhosis?

A

low, because:
1. Splenomegaly →↑ consumption (if portal hypertension then back pressure on splenic vein and splenomegaly)
2. Decreased Thrombopoietin production by cirrhotic liver

58
Q

what composite scores examples to measure cirrhosis?

A

FIB-4 (ALT, AST, age, platelets)

and ELF test = enhanced liver fibrosis test (measures extracellular matrix markers)

59
Q

what is hazardous and harmful drinking cause of liver disease?

A

hazardous is between 14 and 35/50 units and harmful is above 35/50 units = instead of term alcoholic

60
Q

what is progression of alcohol →liver disease?

A

chronic alcohol consumption →healthy liver →alcoholic fatty liver →alcoholic steatohepatitis (inflammation) →alcoholic cirrhosis →hepatocellular cancer

61
Q

what us steatotic liver disease?

A

fatty liver disease now called steatotic liver disease = encompasses lots of diseases

62
Q

how is alcohol metabolised?

A

by CYP2E1 alcohol converted to acetaldehyde using ADH (NAD+ to NADH and H+)
- acetaldehyde converted to acetate which can cause fibrogenesis

63
Q

how can alcohol cause fibrogenesis?

A

2 ways
- when metabolised makes acetate that can cause fibrogenesis
- alcohol causes inflammation which leads to release of ROS which causes a number of steps including hepatic stellate cells causing fibrogenesis

64
Q

what is MASLD?

A

metabolic dysfunction associated steatotic liver disease (new nicer term for alcoholic fatty liver)

65
Q

what is MetALD?

A

MetALD = person who consumes moderate high alcohol and has metabolic syndrome →combination contributing to liver disease

66
Q

what are some causes of steatotic liver disease?

A
  • drug induced liver injury
  • monogenic diseases
  • miscalleneous
67
Q

what are some signs to use to diagnose MASLD, MetALD or steatotic liver disease?

A
  • high glucose levels
  • low HDL
  • plasma triglycerides
  • fasting serum
  • low BMI
68
Q

what is steatohepatitis?

A

inflammation of liver →without biopsy we don’t have good way of knowing for sure (you’d think ALT would help but not really good)

69
Q

what is haemochromatosis?

A

type of liver disease that can cause cirrhosis
= Mono-genetic autosomal recessive disease of Iron over load, C282Y or H63D, mutations in HFE gene

70
Q

what is wilson’s disease?

A

rare liver disease that can cause cirrhosis
= Mono-genetic autosomal recessive disease → loss of function or loss of protein mutations in ceruloplasmin
= Loss of copper regulation → deposition of copper in tissues, especially liver and basal ganglia

71
Q

what is alpha 1 antitrypsin deficiency?

A

rare cause of liver cirrhosis
= Genetic, Mutations in the A1AT genes, multiple sites, causes variable phenotype

72
Q

what is budd chiari?

A

rare cause of liver cirrhosis
= Thrombosis of the hepatic veins

GI (56 decks)

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