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UG Biochemistry > 3. Liver > Flashcards

3. Liver Flashcards

1
Q

What makes the liver a notable organ?

A

Largest solid organ w/ large reserve capacity

Capable of regeneration

Receives 25% of cardiac output

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2
Q

How is blood supplied to the liver?

A

Nutrient rich blood from PORTAL VEIN
- drains intestinal tract (sup. mesenteric + splenic veins)

O2 rich blood from HEPATIC ARTERY

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3
Q

Describe the microanatomy of the liver

A

Histological structural unit = liver lobule
- hexagonal prism of tissue

Filled with rows of hepatocytes;

  • radiate from central vein
  • separated by vascular sinusoids

Sinusoids lined sporadically with kuppfer cells;

  • hepatic macrophages - phagocytic
  • part of RES, remove gut bacteria in venous circ

Portal tracts at corners;

  • branches of hepatic artery
  • portal vein
  • bile duct
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4
Q

Describe blood + nutrient flow through the liver lobule

A

Blood flow: portal tracts > central hepatic vein

  • toxins not requiring metabolism damage portal tract periphery 1st
  • toxin + hypoxia metabolites damage central vein area first

Nutrients from GI (except fat micelles): sinusoidal spaces > systemic circulation

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5
Q

What happens to the microanatomy of the liver during damage e.g. cirrhosis?

A

Damage leads to distortion of lobule architecture

  • blood skips directly to central hepatic portal vein then hepatic vein
  • this bypasses hepatocytes = significantly decreased detox
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6
Q

What are the broad functions of the liver?

A

~500 functions

Categories;
- synthetic e.g. circulating proteins, bile + bile acids, storage

  • metabolic e.g. hormone, protein, carbohydrate, lipid
  • detox e.g. drug, immunological
  • excretion of metabolic end products e.g. bilirubin
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7
Q

Describe the synthetic functions of the liver

A

Primary site for synthesis of all circulating proteins -hepatocytes synthesise;

Plasma proteins:

  • albumin (oncotic pressure/TP of water insoluble substances e.g. iron)
  • Igs
  • complement

Binding proteins for hormones

Lipoproteins:

  • VLDL
  • HDL

Most coag factors:

  • fibrinogen
  • prothrombin, FVII, IX, X (synth reqs vit K)
  • FV, XI, XII, XIII

Also the site of bile + bile acid formation;

  • water, electrolytes, bile acids, cholesterol, phospholipids, bilirubin
  • bile acid metabolites synthesised in liver cells from cholesterol
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8
Q

Describe the general metabolic functions of the liver

A

When there is high glucose conc in the portal vein it is converted to;

  • glycogen
  • carbon skeletons of fatty acids (stored in adipose tissues as VLDL)

When fasting, systemic plasma glucose is maintained by; glycogenolysis + GNG

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9
Q

What is GNG?

A

Gluconeogenesis

The synthesis of glucose from substrates - glycerol, lactate, amino acids

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10
Q

Describe the excretory + detox functions of the liver

A

Excretes;

  • bilirubin
  • amino acids: deaminated in liver
  • cholesterol: excreted in bile
  • steroid hormones: metabolised + inactivated by conjugation with gluconate + sulphate
  • many drugs: metabolised + inactivated by ER enzymes
  • toxins: kuppfer cells extract toxins absorbed at GI tract
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11
Q

What are the markers of the livers synthetic function + how are they tested?

A

Albumin;

  • major product of liver
  • may be normal in acute liver injury (long t1/2)
  • decreased albumin = chronic liver disease > oedema

Prothrombin;

  • clotting factor (req vit K)
  • increased prothrombin = liver injury (sensitive)
  • failure to absorb vit K or hepatocellular damage? retest after vit K supplementation
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12
Q

What is the problem with liver tests involving metabolic markers for liver disease?

A

Liver has large functional reserve;
- extensive disease required for detectable deficiencies

= consider non hepatic factors first

Tests for metabolic (synth + secretory) function relatively insensitive for liver disease

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13
Q

Describe liver bilirubin metabolism

A

Bilirubin = yellow compound produced during catabolism of heme from RBCs

  • RBC lifespan ~ 120 days
  • aged/damaged RBCs removed from circ in spleen
  • degraded by splenic macrophages (part of RES)

Degradation of hemoglobin > heme + globin;

  • globin broken into a acids for reuse
  • heme > biliverdin by heme oxygenase (iron released as Fe2+)
  • biliverdin > bilirubin by bilverdin reductase

Bilirubin TPed to liver by fac diffusion bound to serum albumin protein
- taken up by ligandin at sinusoidal membrane

Conjugated with glucuronic acid x2 in liver = water soluble
- catalysed by UDP-glucuronosyl transferase

Conjugated bilirubin excreted from liver in bile;
- excretion of bilirubin from liver > bile canaliculi = active energy dependent + rate limiting process

Intestinal bacteria deconjugate bilirubin-diglucuronide > urobilinogens

  • some absorbed by intestinal cells + TPed to kidneys = excreted as urobilin in urine (yellow)
  • some taken up via enterohepatic circulation + reexcreted as bile
  • most travels down digestive tract + converted to stercobilinogen = oxidised to stercobilin + excreted in faeces (brown)
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14
Q

What is jaundice and how is it characterised?

A

Jaundice aka icterus is raised bilirubin concentration in plasma causing yellow discoloration of skin + eyes;

  • normal = <1.0mg/dL
  • jaundice = >2-3mg/dL
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15
Q

What are the signs + symptoms of jaundice?

A

Yellowish discolouration of skin + conjunctival membranes of eyes;

  • presence = @ least 3mg/dL serum bilirubin
  • eyes one of first tissues to change colour

Dark urine
Commonly assoc with itchiness (pruritis)
May be pale faeces
Kernicterus - newborns

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16
Q

What are the types of bilirubin + causes of their excess in plasma?

A

Unconjugated/indirect bilirubin;

  • excess RBC breakdown
  • large bruises
  • genetic conditions e.g. Gilbert’s syndrome
  • prolonged fasting
  • newborn jaundice
  • thyroid problems

Conjugated/direct bilirubin;

  • liver disease, e.g. cirrhosis/hepatitis
  • infections common in developing world (viral hep, leptospirosis, schistosomiasis, malaria)
  • medications (common in developed)
  • blockage of bile duct (common in developed): gallstones, cancer, pancreatitis
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17
Q

What are the 3 types of jaundice causes (broadly)?

A

Pre-hepatic - excess RBC breakdown

Hepatic - failure of conj system in liver (liver disease)

Post-hepatic - obstruction in flow of bile

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18
Q

How is jaundice classified?

A

Based on part of physiological mechanism affected;

  1. PREHEPATIC/HEMOLYTIC;
    - pathology prior to liver
    - upstream of conjugation
    - intrinsic defects in RBCs/extrinsic causes external to RBCs
  2. HEPATIC/HEPATOCELLULAR;
    - pathology within liver
    - failure of conjugation
    - disease of parenchymal cells of liver
  3. POSTHEPATIC/CHOLESTEROL;
    - pathology after conjugation in liver
    - obstruction of biliary passage
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19
Q

Describe pre-hepatic jaundice

A

Anything causing increased hemolysis

Increased unconjugated bilirubin in blood: deposition = blood

Increased bilirubin production = increased urobilinogen in urine
- no bilirubin in urine: unconjugated not water soluble

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20
Q

Describe causes of pre-hepatic jaundice

A

Tropical: severe malaria

Genetic;

  • sickle cell
  • spherocytosis
  • thalassemia
  • pyruvate kinase deficiency
  • G6PD deficiency

Diseases of kidney;
- hemolytic uremic syndrome

21
Q

What are the lab findings in pre-hepatic jaundice?

A

Urine:

  • no bili (unconj insoluble
  • increased bili = increased urobilinogen >2 units

Serum:
- increased unconj bili

Kernicterus:

  • increased unconj not albumin bound + lipid soluble
  • newborns increased permeability of BBB = neurotoxic
22
Q

Describe hepatic jaundice

A

Due to failure of conj system;

Liver disease/hepatocellular jaundice;

  • cell necrosis = decreased metabolic/excretory function
  • buildup of unconj bili in blood
23
Q

Describe primary biliary cirrhosis (a type of hepatic jaundice)

A

Primary biliary cirrhosis;

  • increased plasma conj bili (impairment of excretion into bile)
  • increased bile salts in blood excreted in urine (dark)

Usually interference at all steps of bili metabolism;
- UPTAKE: TP across hepatocyte impaired = no uptake into cell or TP into biliary canaliculi

  • CONJUGATION: decreased metabolic function
  • EXCRETION: swelling/edema of cells (inflamm) = obstruction of intrahepatic biliary tree but unconj still enters = rupture/backflow via lymph = increased unconj + conj bili in blood

Excretion is the rate limiting step = greatest impaired = conj hyperbilirubinemia predominates;

  • conj bili doesn’t enter intestine
  • not converted to urobilinogen = excreted as conj bili = dark urine
24
Q

What are the causes of hepatic jaundice?

A 
Acute/chronic hepatitis
Hepatotoxicity
Cirrhosis
Drug induced hep
Alcoholic LD
Primary biliary cirrhosis
Newborns: immature hepatic mechanisms
Leptospirosis
Defects in bili metabolism: Gilbert's (5% pop) or Crigler-Najjar
25
Q

What are the lab findings in hepatic jaundice?

A

Depends on cause

Urine:

  • conj bili present
  • urobilinogen = dark (>2 units, variable)

No associated kernicterus

Plasma protein characteristic changes;

  • decreased plasma albumin
  • increased plasma globulins (increased Ab formation)

Serum;
- increased conj + unconj bili

26
Q

Describe post-hepatic jaundice

A

Due to obstruction of bilirubin from liver (cholestatic obstructive jaundice)

Mainly increased conj bilirubin (backflow)

Complete obstruction = no no access to intestine for conversion to uro/stercobilinogen+ partial reabsorption/urine excretion;

  • pale stools
  • dark urine (conj bili but no urobilin)
27
Q

Describe the causes of post-hepatic jaundice

A 
Gallstones in common bile duct
Pancreatic cancer (head)
Drugs
Parasites (liver fluke) in common bile duct
Strictures of duct
Biliary atresia (absence/narrowing)
Cholangiocarcinoma
Pancreatitis
Cholestasis of pregnancy
Pancreatic pseudocysts
Mirizzi's syndrome
28
Q

What are the common lab findings in post-hepatic jaundice?

A

Serum;

  • increased conj bili
  • increased cholesterol

Urine;

  • no urobilin
  • conj bili = dark
  • characteristic but not distinguishing as present in other illnesses

Pale stool: no uro/stercobilinogen

Severe itching: deposition of bile salts in skin

29
Q

List the common causes of liver injury

A

Infection - viral hep
Drugs - paracetamol
Toxins - alcohol
Tumours
Metabolic disease - hemochromatosis, Wilson’s
Autoimmune disease
Vascular disorders - clots (thrombosis), heart failure

30
Q

How is liver disease classified?

A

May be classified by site of damage;

  • hepatocellular damage
  • cholestatic obstructive disease
31
Q

Describe hepatocellular disease + its causes

A

Direct damage to liver cells

Causes;

  • alcohol
  • hepatitis (many forms: most common = viral)
  • toxins
  • drugs
32
Q

Describe cholestatic (obstructive) liver disease + its causes

A

Obstruction: bile cannot flow liver> duodenum

Causes;

  1. Within liver = intrahepatic
    - secretion: hepatocytes > canaliculi impaired
    - or impairment of bile formation
    - e.g. viral hep, drugs (chlorpromazapine), autoimmune, e.g. primary biliary cirrhosis, toxins (alcohol), cystic fibrosis
  2. Outside liver = extrahepatic
    - obstruction of bile through biliary tract/bile duct
    - gallstones, strictures, tumours (pancreas head), inflammation of biliary tract
33
Q

What is liver cirrhosis?

A

Replacement of normal liver tissue with fibrous scar tissue

  • loss of functional hepatocytes
  • due to long term damage (chronic)
  • typically slow development: months > years
34
Q

Describe the signs + symptoms of liver disease

A 
Tired/weak
Itchy
Lower leg swelling
Yellow skin
Easy bruising
Ascites with spontaneous infection
Spider like blood vessels
35
Q

What are the possible complications of liver cirrhosis?

A

Hepatic encephalopathy = confusion + unconsciousness

Bleeding from dilated veins (oesophagus/stomach)

Liver cancer

36
Q

What are the causes of liver cirrhosis?

A

Alcohol abuse (most common)
Hep B + C
NAFLD (obesity, diabetes, high blood fats, high BP)

Uncommon causes;
Hep autoimmune
PBC (primary biliary cholangitis)
Hemochromatosis
Medications
Gallstones
37
Q

What is the treatment for cirrhosis?

A

Depends on cause

Goal often to prevent complications/worsening;

  • avoid alcohol in all cases
  • hep B + C = antivirals
  • autoimmune = steroids
  • bile duct blockage = ursodiol
  • severe = liver transplant
38
Q

Describe the pathophysiology of cirrhosis

A

Often preceeded by hepatitis + FLD (steatosis) independent of cause;
- if cause removed at this stage = fully reversible

Pathological hallmark of cirrhosis = scar/fibrous tissue replacing normal parenchyma;

  • blocks portal flow of blood through organ
  • increases BP + disturbs normal function
39
Q

What does recent research say regarding cirrhosis pathophysiology?

A

Shows pivotal role of STELLATE CELL in development of cirrhosis (normally stores vit A)

Inflammation;

  • activates stellate cells
  • increases fibrosis by production of of myofibroblasts = obstruction of hepatic blood flow

Stellate cells secrete;

  • TGF-B = fibrotic response + proliferation of CT
  • TIMP1 + 2 = inhibitors of MMP = can’t breakdown fibrotic material of ECM

Cascade of processes leads to fibrous tissue bands (septa) separating hepatocyte nodules
- replaces entire liver architecture = decreased bloodflow throughout

40
Q

What is the purpose of liver function tests (LFTs)?

A

Measurements of the presence, extent + type of liver disease

Can also be used to monitor treatment

41
Q

What components of the blood can be measured in an LFT?

A

Plasma proteins;

  • Prothrombin time (PT/INR)
  • aPTT
  • albumin (functionality)

Bilirubin (direct/indirect + total)
Ammonia

Liver enzymes;
Liver transaminases:
 - aspartate transaminase (AST)
 - alanine transaminase (ALT)
 - assess cellular integrity

Gammaglutamyltranspeptidase (GGT)
Alkaline phosphatase (ALP)
- both assess biliary tract

42
Q

Describe the use of the bilirubin LFT

A

Total = unconj (indirect) + conj (direct)

Total bili:

  • liver disease >17umol/L
  • deposition + jaundice >40umol/L

Increased unconj bili;

  • overproduction
  • decreased uptake
  • decreased conj

Increased conj;

  • directly proportional to degree of hepatocyte injury
  • backward leakage

NOT a sensitive indicator of hepatic dysfunction due to reserve capacity of liver;
- max daily excretion = >10x greater than average daily production

43
Q

Why are liver enzymes used to test LF?

A

Liver cell damage typified by release of enzymes from damaged liver cells which causes their activity levels to rise in plasma

44
Q

Describe the use of aminotransferases as LFTs

A

AST: aspartate aminotransferase
ALT: alanine aminotransferase

Increased activity = cell damage

  • high levels = hepatocellular disease
  • also rise in cholestatic (obstructive) disease

ALT more specific to liver than AST;

  • ALT = highest conc in liver
  • AST = highest conc in liver but decreasing concentrations in cardiac/ skeletal muscle/ kidneys/ brain/ pancreas/ lungs/ leukocytes /RBCs
45
Q

How have recent studies proposed to increase the specificity of AST as an LFT?

A

Studies have shown 2 isotypes of AST;

  • ~80% AST activity in liver = mitochondrial isotype
  • healthy pop have predominantly cytosolic isotype circulating
  • distinguishable by assay
46
Q

Describe the use of ALP as an LFT

A

ALP: alkaline phosphatase

Liver not only source of ALP activity;
- when associated with increased GGT suggests liver origin

Usually = cholestasis (intra/extra) but also rises in hepatocellular

47
Q

Describe the use of GGT as an LFT

A

GGT: gamma glutamyl transpeptidase

Enzyme produced in bile ducts

Sensitive indicator of liver disease;
- raised in any liver disease (cholestasis/hepatocellular)

NOT SPECIFIC;
- inducible enzyme: may be increased by alcohol intake + drugs

48
Q

Describe the use of ammonia as an LFT

A

Elevated in severe acute or chronic LD

Due to impaired breakdown of nitrogenous waste

Elevated levels cause lethargy + confusion

49
Q

What can LFTs help differentiate between and how?

A

Acute hepatocellular damage

  • greatly increased AST + ALT
  • ALP normal or increased
  • bilirubin normal/greatly increased

Obstruction of biliary tract/cholestatic LD

  • greatly increased ALP + GGT
  • increased AST + ALT
  • bilirubin increased (may be normal if cholestasis v localised, e.g. with liver secondaries)

Reduced functioning tissue mass/chronic LD/cirrhosis;

  • decreased albumin
  • prolonged PT

UG Biochemistry (14 decks)

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