Pathophysiology of liver

Department of Pathophysiology,
YSMU, 2020
Memory check: structure of the liver

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 Memory check: the portal circulation 3

Blood from the gastrointestinal tract, spleen, and pancreas travels to the
liver by way of the portal vein before moving into the vena cava for
return to the heart.
 Memory check: the lobular organization

A section of liver
lobule showing the
location of the hepatic
veins, hepatic cells,
liver sinusoids, and
branches of the portal
vein and hepatic artery.

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 Role of liver in homeostasis

Metabolic functions Other specific functions

Proteins Bile formation

Detoxication
Albumins

Inactivation of hormones
Globulins

Carbohydrates Immunological

Bile acids Regulation of hemostasis

Lipids, lipoproteins Hematopoiesis in fetus

Microelements: Fe2+, Cu2+ … Regulation of blood circulation

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Vitamins: A, B, D, E, K, PP…
 Definition LIVER FAILURE
Liver failure or hepatic insufficiency is the inability of liver to
perform its normal function (functions) resulting in the
impairment of body functioning.

Classification
I. 1. Primary 2. Secondary
II. 1. Hepatocellular
2. Shunt
3. Mixed
III. 1. Acute 2. Chronic

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 Etiology of liver disorders
Primary (hepatic) Extrahepatic causes
(secondary)
 Viral hepatitis (A, B, C, D, E, F,
G) •Shock
 Alcoholic liver disease •Heart failure
 Toxic (various drugs, poisons, •Hypoxia
toxins: acetaminophen,
chlorpromasine, isoniazid) •Kidney dysfunction
 Cirrhosis •Hypovitaminosis
 Cholestasis •Metastasis
 Hereditary disorders of liver •Endocrine disorders
 Parasitic infections •…
 Disorders of liver blood
circulation
 Liver tumors
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N-acetylcysteine

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The main nonspecific pathogenetic mechanisms
of liver failure

Hepatocytes
Immune mechanisms Inflammation
membrane damage

Increased ROS production Energetic deficiency

Massive damage of hepatocytes

Progression of inflammation, immune and oxidative reactions

and development of vicious cycles

Liver failure 10
 Manifestations of liver failure -
impaired metabolism of:

Proteins Lipids

Impaired Decreased Impaired synthesis Hyper-

synthesis rate of of LDL, VLDL, cholester
HDL olemia

Albumins Deamination of
amino acids Hepatic
Enzymes lypodystrophy
Urea synthesis in
Procoagulants and ornithine cycle Increased
anticoagulants atherogenesis
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 Manifestations of liver failure -
impaired metabolism of:
Carbohydrates Vitamins Metals

Inhibition of A, D, E, K
glycogenesis Fe2+, Cu2+
Impaired co-enzyme
Impairment of formation from
gluconeogenesis Liver cyrrhosis
vitamins
Hemochromatosis

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 Manifestations of liver failure -
impaired :
Detoxication Antimicrobial Formation and
function secretion of bile

Impaired
Impaired Jaundice
transportation of
detoxication of
IgA to the bile
exogenous and
endogenous toxins Impaired digestion

Decreased phagocytic
activity of Kupffer
cells

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 Laboratory findings in liver failure

Markers of depressed synthetic

activity of hepatocytes Markers of cytolysis
 prolonged PT  ↑ level of AST and ALT
 decreased level of albumins

Markers of cholestasis
Increase in bilirubin
 ↑ level of alkaline
concentration phosphatase and γ-
glutamyl transpeptidase

Indirect Direct
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 Hepatic encephalopathy
Definition:
Hepatic encephalopathy is defined as a spectrum of neuropsychiatric
abnormalities in patients with liver dysfunction, after exclusion of other
known brain disease. Hepatic encephalopathy is characterized by
personality changes, intellectual impairment, and a depressed level of
consciousness. An important prerequisite for the syndrome is bypass of
portal blood into the systemic circulation through portosystemic
collateral vessels.

Manifestations: Classification:
Changes in cerebral function 1. Shunt
Confusion 2. Hepatocellular
Tremor of hands (asterixis) 3. Mixed
Convulsions
Stupor
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Coma
Classification of hepatic encephalopathy

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Pathogenesis of bypass hepatic encephalopathy

Brain

Portal-systemic
bypass

Liver

Toxic metabolites
from gut
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 Pathogenesis of hepatic encephalopathy:
Ammonia as a neurotoxin
Norm hyperammonemia
Astrocyte
Astrocyte

Synapse
Synapse

Receptor
Receptor
Gln-glutamine, Glu-glutamate 20
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(1) - glutaminase, (2) - glutamine synthetase
 Glutаmine as a Trojan horse

astrocyte
O*
Glu
NH4+
2 1
Gln Gln

NH4+
Glu

Glutamine (Gln) enters mitochondria via a histidine-sensitive glutamine carrier, which as noted
is a process potentiated by ammonia. Glutamine is then hydrolyzed by phosphate-activated
glutaminase (PAG), an enzyme located in the inner mitochondrial membrane yielding glutamate
(Glu) and ammonia.
(1) - glutaminase, (2) – glutaminsynthetase, = glutamine transporter 21
 Astrocyte
Aromatic amino
acids entrance Glutamate ↓

Glutamine ↑

Glutamine ↑

Glutamatergic
neuron Expression of key genes
5H ↓

blood
T
DA
NM

5-HT1 receptors
affinity ↑

NH3
Glutamate GABA ↑

Mercaptans, butirate

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 Formation of “pseudo” neurotransmitters in
hyperammonemia

- tyrosine-3
monoxygenase

Phenylalanin Tyrosine X DOPA

X

Dopamine
X

β-phenylethanolamine Octopamine Catecholamines

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 Bilirubin NH3 Hypoglycemia

Acidosis Bile acids

Disturbances of systemic
Hypoxia Astrocyte blood circulation

Glutamine ↑ Glutamate ↓
Mitochondrial damage
«False»
Swelling and damage neuromediators
of astrocytes
Indole, phenol,
skatole, cresol Impairment of neurotransmission

Stimulation of GABA effects

(theory of increased GABA-ergic
transmission)

Hepatic encephalopathy
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 Liver cirrhosis

Liver cirrhosis is a chronic disease of liver, characterized by:

 decrease in number of functionally normal hepatocytes
 diffuse overgrowth of connective tissue
 decrease in overall diameter of sinusoids
 pathological regeneration of parenchyma, formation of pseudonodules
 reconstruction of parenchyma and vasculature

PUBMED definition: Liver disease in which the normal microcirculation, the gross
vascular anatomy, and the hepatic architecture have been variably destroyed and altered
with fibrous septa surrounding regenerated or regenerating parenchymal nodules.

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 Types and causes of cirrhosis
Type Etiology
1. Alcohol (portal or Ethanol and it’s degradation products (acetaldehyde) influence
fatty, Laennec's cirrhosis) on hepatocyte
2. Biliary cirrhosis Develops due to impaired bile flow
 Primary biliary cirrhosis is believed to be autoimmune
(antimitochondrial antibodies are usually found)
 Secondary biliary cirrhosis – due to obstruction by
concrement or a tumor

3. Nonalcoholic It is a consequence of obesity usually.

steatohepatitis

4. Postnecrotic  Viral hepatitis

 Various toxins, chemicals
 Autoimmune destruction of hepatocytes

5. Metabolic Glycogen storage diseases, α1-antitripsin deficiency,

6. Cardiac cirrhosis
7. Cryptogenic cirrhosis
hemochromatosis, Wilson disease, etc.
Due to right-sided heart failure.
Cause is not found.
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 Regeneration or repair by
scarring?

HSC-hepatic stellate cells 27

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Matrix and cellular alterations in hepatic fibrosis. Changes in the subendothelial space of Disse and
sinusoid as fibrosis develops in response to liver injury include alterations in both cellular responses and
extracellular matrix composition. Stellate cell activation leads to accumulation of scar (fibril-forming)
matrix. This in turn contributes to the loss of hepatocyte microvilli and sinusoidal endothelial fenestrae,
which result in deterioration of hepatic function. Kupffer cell (macrophage) activation accompanies liver
injury and contributes to paracrine activation of stellate cells.
Schematic of stellate cell activation and liver fibrosis in comparison to the normal liver. Kupffer cell activation leads to
secretion of multiple cytokines; cytokines also may be released by endothelial cells, hepatocytes, and inflammatory cells
entering the liver (not shown). These cytokines "activate" stellate cells, whereby they loose their lipid droplets (which are
present in the quiescent state) and acquire a myofibroblastic state.
Stellate cell proliferation is stimulated in particular by platelet-derived growth factor (PDGF); tumor necrosis factor
(TNF) is a potent stimulant of the change to a myofibroblastic phenotype. Contraction of the activated stellate cells is
stimulated by endothelin-1 (ET-1). Deposition of extracellular matrix (fibrogenesis) is stimulated especially by
transforming growth factor b (TGF-b). Chemotaxis of activated stellate cells to areas of injury, such as where
hepatocytes have undergone apoptosis, is promoted by PDGF and monocyte chemotactic protein-1 (MCP-1). Kupffer
cells also are a major source of TNF released into the system circulation. (Schematic based on concepts presented in
Friedman250 SL: Molecular regulation of hepatic fibrosis: an integrated cellular response to tissue injury. J Biol Chem
275:2247–2, 2000; and Crawford JM: Cellular and molecular biology of the liver. Curr Op Gastroenterol 13:175–185,
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Liver cirrhosis:
clinical signs and symptoms

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 Portal hypertension is a frequent syndrome – most often caused by
chronic liver diseases – which is characterized by an increased
portal pressure gradient (PPG; the difference in pressure between
the portal vein and the inferior vena cava, which represents the
perfusion pressure of the liver with portal blood).
Normal – PPG 1-5 mm Hg
Clinically significant portal hypertension PPG >10mm Hg

The pressure in portal system is calculated based on the

equation: P = Q x R
Normally much important is the increase in HEPATIC VASCULAR RESISTANCE (R),
because PORTAL VENOUS INFLOW (Q) is more stable factor. But in liver cirrhosis
Q also increases because of increase in cardiac output (so called hyperdynamic
circulation).
Types of portal hypertension:
1. Prehepatic – causes are portal vein thrombosis, compression by tumor or
enlarged lymphatic node, severe splenomegaly.
2. Intrahepatic- liver cirrhosis, liver parasitic diseases (Schistosoma), etc.
3. Posthepatic – thrombosis of inferior vena cava, occlusion of the hepatic veins
(Budd-Chiari syndrome), pericarditis, severe right-sided heart failure. 32
 Portal hypertension

Increased pressure in Portosystemic Spelnomegaly

abdominal cavity shunt formation
capillaries Anemia Leucopenia

Thrombocytopenia
Ascites Development of Entrance of ammonia
collaterals and other toxins from
intestines into the blood
circulation
Esophageal varices Caput
medusae
Bleeding

hemorrhoids Liver encephalopathy

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 Fig. 1

Functional aspects on the pathophysiology of portal hypertension in cirrhosis

Juan-Carlos García-Pagán, Jorge Gracia-Sancho, Jaume Bosch

Journal of Hepatology
Volume 57, Issue 2, Pages 458-461 (August 2012)

Journal of Hepatology 2012 57, 458-461DOI: (10.1016/j.jhep.2012.03.007)

Copyright © 2012 European Association for the Study of the Liver Terms and Conditions
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The intrahepatic component of portal hypertension pathophysiology
Caput medusae Ascites

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Pathogenesis of
ascites Cirrhosis

Sinusoidal Portal Hepatocyte

hypertension hypertension failure

Increased lymph Increased Altered

hypoalbuminemia
production and its capillary filtration steroid
percolation into the pressure and hormone
peritoneal cavity intestinal fluid metabolism
(crying liver) leakage Low capillary
colloid-osmotic
pressure RAAS
activation
Bacterial
peritonitis ↓Effective
plasma volume Na+ and H20
retention
↑ capillary
permeability
ASCITES 36
Serum-Ascites Albumin Gradient (SAAG)

SAAG = albumin in serum – albumin in ascitic fluid

SAAG ≥ 1.1 g/dL portal hypertension

present 37
 Hypervolemic hyponatremia is common in cirrhosis

Splanchnic vasodilation
(e.g. NO release in
portal system)

RAAS ↑ hypotension

Hypervolemic (dilutional)
hyponatremia ADH ↑↑
Correlation of hyponatremia with hepatic encephalopathy and severity of liver disease. 38
Causes and classification of jaundice

Indirect bilirubin ↑

Direct bilirubin ↑

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 Hepatocellular failure is characterized with:

Signs and Pathogenetic unit Manifestations

symptoms
1. Impairment Impairment of metabolic Fatigue, anorexia, indigestion, weight loss
of nutrition processes

2. fever  Necrosis of hepatocytes,,. Left shift leukocytosis

(380 - 400C)  Leakage of toxins to blood
 Bacteremia

3. Jaundice Massive hepatocytes Yellow color of skin and mucosal

necrosis membranes

4. Endocrine Impaired hormonal  Decreased libido, testicular atrophy,

impairments metabolism gynecomastia etc.
Diabetes mellitus and secondary
aldosteronism

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5. Hemodynamic Increased production of  Diffuse vasodilatation
disorders vasoactive substances  Compensatory increase of cardiac
(histamine, NO) output
6. Edema, ascites Hypoproteinemia, Ascites
elevated aldosterone
level
7. Fetor hepaticus Is caused by dimethyl Unpleasant smell from mouth
sulfide and to a lower
extent by ketones in
alveolar air
8. «Liver signs»  Endocrinopathies Ttelangiectasias (spider veins)
 Impairment of blood  Palmar erythema (red skin on the
circulation palmar aspects of the hands)
9. Hemorrhagic  Impairment of  Bleedings
diathesis inactivation of active  DIC syndrome
procoagulants
 Impaired synthesis of
components of
hemostasis

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Liver biopsy of 45-year-old female revealed dilated bile
canaliculi with green-brown plugs and pigmented
hepatic parenchyma. Which of the following is the most
likely associated condition in this patient?
(A) lung emphysema
(B) right sided heart failure
(C) osteoporosis
(D) atrophic gastritis
(E) hypochromic anemia
A 65-year-old man with a history of alcohol abuse has had
hematemesis for the past day. Physical examination reveals mild
jaundice, spider angiomas, and gynecomastia. He has mild pedal
edema, normal jugular venous pulsation, and a massively
distended abdomen. Paracentesis is performed and the fluid
obtained shows accumulation of protein-poor fluid that is free of
inflammatory cells. Which of the following factors is most likely
to be responsible for the collection of abdominal fluid in this man?
A Congestive heart failure
B Hepatopulmonary syndrome
C Hyperbilirubinemia
D Portosystemic shunts
E Splanchnic arterial vasodilation