Chronic inflammation and wound healing1 Cellular components

1
Chronic inflammation and wound healing1Cellular
components

• WWAMI lecture
• Nicole Meissner-Pearson

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Outcome of acute inflammation

• Complete resolution
• due to elimination of the offending agent and
  regeneration of injured tissue with normal
  function
• Healing by connective tissue replacement
  (fibrosis/scar formation)
• Occurs after large tissue destruction,
• fibrinous exudation into serous cavities
• tissue without regeneration capabilities
• Progression to chronic inflammation
• Resulting in granuloma formation to wall off
  injurious agent and tissue fibrosis (scar
  formation)

3
Definition of chronic inflammation an
inflammatory response of prolonged duration
(weeks months - years) provoked by the
persistence of the causative stimulussimultaneou
s presence of acute inflammation, tissue
destruction and repair
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Causes of chronic inflammation

• Infectious organisms that resist clearance and
  form a persistent infection in tissue or
  undrained abscess cavities
• e.g mycobacterium tuberculosis, actinomycetes,
  treponema palidum and Staph aureus (in bone and
  pleural cavities)
• Exposure to irritant non-living foreign material
  that can not be removed
• implanted materials into wounds (wood splinters),
  inhaled materials (silica, asbestos),
  deliberately introduced material (surgical suture
  material or prosthesis)
• Potentially normal tissue components as seen in
  auto-immune diseases
• Beta islet cell in diabetes mellitus type I,
  Acetyl cholin receptor in Myastenia gravis

5
Characteristics of chronic inflammation

• Infiltration of mononuclear cells
• Tissue destruction
• Healing with scar formation and fibrosis

6
The dominant cellular player in chronic
inflammation is the tissue macrophage
Blood monocyte
Tissue macrophage (RES)
migrate into tissue within 48 hours after injury
Kupffer cell (liver) Microglia (CNS) Histiocytes
(spleen) Alveolar macs (lung)
and differentiate
It is joined by lymphocytes and plasma cells,
however mast cells and eosinophils are as well
involved in chronic allergic diseases
Plasma cell
Lymphocyte
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In chronic inflammation macrophage accumulation
persists by different mechanisms

• Continued recruitment of monocytes from the
  circulation
• Local proliferation
• Prolonged survival and immobilization

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During chronic inflammation macrophages serve to
eliminate injurious agents and initiate repair-
however, they are as well responsible for much of
the tissue injury that occurs
Tissue macrophage
Activated T cell or NK cell
IFN-g
Non Immune activation Endotoxins, fibronectin,
chemical mediators
Activated macrophage
Fibrosis (Scaring) Growth factors involved in
fibroblast proliferation (PDGF,TGFb,FGF) Angiogene
sis factors (FGF,VEGF) Collagen deposition
(IL-13 and TGFb)
Tissue injury Toxic oxygen metabolites Metallo-pro
teases Coagulation factors AA metabolites and NO
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Outcome of chronic inflammation

• Ulcers
• Fistulas
• Granulomatous diseases
• Fibrotic diseases (Scaring)
• and combinations of the above

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Examples of severe chronic inflammatory diseases

• Tuberculosis
• Sarcoidosis
• Rheumatoid arthritis and other connective tissue
  diseases
• Inflammatory bowl diseases (Crohns disease,
  ulcerative colitis)
• Silicosis and other pneumoconioses
• Peptic ulcer of the duodenum and stomach
• Liver cirrhosis
• Bronchial asthma

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Mechanisms of regeneration, wound healing and
repair
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Repair of tissue damage can be broadly separated
into two processes

• Regeneration
• Restitution of lost tissue
• Tissue with high proliferative capacity labile
  tissue
• (e.g hematopoietic cells, epithelial cells of
  skin and gastrointestinal tract regenerate from
  stem cells)
• Quiescent tissues stable tissue
• which normally have low levels of
  replication, however can undergo rapid cell
  division when stimulated
• (e.g parenchymal cells of liver, kidney,
  pancreas mesenchymal cells as lymphocytes,
  fibroblasts, smooth muscle cells, endothelial
  cells)
• Healing
• may restore original structures but results in
  collagen deposition and scar formation
• in tissue where scaffold is disrupted
• or damage occurs in non dividing permanent
  tissue (e.g central nervous system, skeletal and
  cardiac muscle)

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Regeneration requires

• Presence of stem cells for renewal
• or tissue cells that are capable to divide in
  response to growth factors
• Intact tissue scaffold

Most of the processes that are referred to as
regeneration in mammalian organs are actually
compensatory growth processes that involve cell
hypertrophy and hyperplasia (e.g liver
regeneration)
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Stem cells

• They are undifferentiated cells that do not yet
  have a specific function.
• They can replicate for a long period of time and
  give rise to differentiated cells.
• In every cell division one cell retains its self
  renewing capacity while the other cell can
  undergo differentiation (asymmetric replication)

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Two types of stem cells

• embryonic stem cells
• derived from the inner cell mass of a blastocyst
  from in vitro fertilized eggs
• are pluripotent and can generate all tissues

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• adult (somatic) stem cells
• they are present in small numbers in various
  tissues of the adult body
• are typically programmed to form different cell
  types of their own tissue and are therefore
  multipotent
• in tissues with high turn over (hematopoietc
  system, epithelial lining of the gut and skin)
  they are instrumental in renewal
• although present in a variety of permanent
  non-dividing tissues they are not very active

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Bone marrow contains two different types of adult
stem cells the hematopoietic stem cell and the
bone marrow stromal cell
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Potential plasticity of hematopoietic stem cells
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Hematopoietic stem cell transplantationan
established treatment option for hematological
disorders and cancers

• Hematopoietic stem cells can be retrieved from
  the peripheral blood or the bone marrow and
  identified by the expression of the CD34 marker
• 2X106 HSC/KG body weight of recipient are needed
  for a successful autologous HSC transplantation
• Under steady state conditions the number of CD34
  cells in peripheral blood is 1-5/mm3
• Mobilization procedures of CD34 stem cells into
  the peripheral blood can be accomplished by
  administration of G-CSF or GM-CSF to the donor
  and can increase the HSC count in the peripheral
  blood 50 fold

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Repair by Healing(Scarring)

• Healing is a fibro-proliferative responses that
  patches rather than restores tissue and
  involves the following processes
• Induction of an inflammatory response to remove
  dead and damaged tissue
• Proliferation of parenchymal and connective
  tissue cells
• Angiogenesis (blood vessel formation) and
  formation of granulation tissue
• Synthesis of ECM proteins and collagen deposition
• Tissue remodeling
• Wound contraction
• Acquisition of wound strength
• It usually leads to scar formation and does not
  lead to complete restitution of the injured
  tissue

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Angiogenesis growth of new blood vessels

• Angiogenesis occurs in the healthy body for
  healing wounds and for restoring blood flow after
  tissue injury
• Healthy angiogenesis is tightly controlled by a
  serious of on and off switches (Angiogenic
  growth factors versus angiogenesis inhibitors)
• In many serious diseases the body loses control
  over angiogenesis and angiogenesis-related
  diseases occur when new blood vessels grow
  excessively or insufficiently

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Cancer
Rheumatoid arthritis
AIDS complications
Excessive
Psoriasis
Blindness
Angiogenesis
Insufficient
Infertility
Stroke
Scleroderma
Heart disease
Ulcers
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Angiogenesis / Neovascularization is critical to
chronic inflammation and fibrosis, tumor growth
and vascularization of ischemic tissue
Sprouting
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VEGF and Angiopoietins are the most important
angiogenic factors
25
Anti-VEGF Fab-fragment treatment is used in tumor
therapy as well as wet macular degeneration
Macular degeneration is a group of diseases
characterized by the breakdown of the macular
leading to the loss of central vision. It is the
leading cause of vision loss in patients over the
age of 55 years Wet macular degeneration is
rapidly progressive and accounts for 10 of cases
with age related AMD. Is the result of abnormal
vessel growth beneath the macula resulting in
bleeding. The first currently approved anti-VEGF
drug for vitrial injection is MACUGEN R
(pegaptanib)
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Role of extracellular matrix in wound healing
and scar formation

• Extracellular matrix (ECM) is formed by specific
  secreted macromolecules that form a network on
  which cells grow and migrate along
• ECM is secreted locally and forms a significant
  proportion of the tissue volume
• ECM sequesters
• water that provides turgor to soft tissues
• and minerals that provides rigidity to skeletal
  muscles
• Forms a reservoir for growth factors
• ECM proteins assemble into two general
  organizations
• Interstitial matrix (present between cells)
• Basement membrane BM (produced by epithelial
  and mesenchymal cells and is closely associated
  with the cell surface)

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Three groups of macromolecules constitute the ECM

• Fibrous structural proteins
• Collagen
• Fibrillins
• Adhesive glycoproteins
• Cadherin
• Integrins
• Immunoglobulin family
• Selectins
• Proteoglycans and Hyaluronic Acid

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• Fibrous structural proteins
• Collagens
• Collagens are the most abundant proteins
• 27 different types
• Type I,II, III, V and XI are the most abundant
  (interstitial or fibrillar collagens)
• Provide tensile strength of tissue
• Fibrillar collagen requires hydroxylation of
  proline and lysine in procollagen which is
  dependent on Vitamin C
• Type IV is the main component of Basemant
  membrane and forms sheets)
• Elastins and Fibrillins
• Provide tissue with the ability to recoil
• Elastins are found in large vessels, uterus, skin
  and ligaments
• Fibrillins form a scaffolding for the deposition
  of elastins
• Marfan syndrome is an inherited autosomal
  dominant defect in fibrillin synthesis. Without
  the structural support provided by fibrillin,
  many tissues are weakened, which can have severe
  consequences, for example, ruptures in the walls
  of major arteries.

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• Proteoglycans and hyaluronic acid
• Proteoglycans (mucoproteins) are formed of
  glucosaminoglycans (GAGs) covalently attached to
  core proteins and are highly negatively charged
• Biophysical functions due to ability to fill
  space, bind and organize water molecules and
  repel negatively charges molecules
• They are ideal lubricating fluids in the joint
  due to high viscosity and low compressibility
• Biochemical functions are mediated by specific
  binding of GAGs to other macromolecules
• e.g Antithrombin III (AT III) binds tightly to
  heparin and heparan sulfates and inactivates
  factor II, IXa and XIa thus controlling blood
  coagulation
• Proteoglycans (such as Syndecan) act as
  reservoirs for growth factors secreted into the
  ECM by binding the latter.

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Chronic inflammation 2Cutaneous wound
healingGranulomatous inflammation

• Nicole Meissner-Pearson

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Cutaneous wound healing

• is generally divided into three overlapping
  phases
• Inflammation
• Granulation tissue formation and
  re-epithelialization
• Wound contraction, extracellular matrix
  deposition and remodeling

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The phases of cutaneous wound healing
Injury leads to accumulation of platelets and
coagulation factors. Coagulation results in
fibrin formation and release of PDGF and TGF-b
and other inflammatory mediators by activated
platelets. This leads to more Neutrophil
recruitment which signals the beginning of
inflammation (24 h). After 48 h macrophages
replace neutrophils. Neutrophils and macrophages
are responsible for removal of cellular debris
and release growth factors to reorganize the
cellular matrix. At 72 hours the proliferation
phase begins as recruited fibroblasts stimulated
by FGF and TFG-b begin to synthesize collagen.
Previously formed fibrin forms initial matrix for
fibroblasts Collagen cross-linking and
reorganization occurs following months after
injury in the remodeling phase of repair. Wound
contraction follows in large surface wounds and
is facilitated by actin-containing fibroblasts
(myofibroblasts)
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TGF-b functions as a central regulator of tissue
repair and negatively regulates both acquired and
adaptive immunity
Lack of the TGFb1 gene in mice results in
excessive tissue inflammation and autoimmunity
resulting in death of the animals, however
increased activity leads to excessive scar
formation and loss of organ function
34
Skin wounds are classically described to heal by
eitherprimary or secondary intention and the
distinction is made by the nature and extent of
the wound

• Healing by first intention
• wounds with clean opposing edges (surgical
  incision, should form a narrow scar due to small
  amount of granulation tissue required to fill the
  gap)
• Healing by second intention
• wounds with separated edges (trauma that requires
  abundance of granulation tissue for wound
  closure)
• Granulation tissue consists of newly formed blood
  vessels, macrophages, fibroblasts and loose ECM
  framework
• As collagen accumulation increases, the
  granulation tissue scaffolding is converted into
  a mature scar composed of mature spindle-shaped
  fibroblasts, dense collagen and elastic fibers.
• The mature scar does not contain vessels

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Complications of wound healing

• Deficient scar formation
• Wound dehiscence
• Ulceration
• Excessive formation of scar tissue
• Keloid (excessive collagen deposition)
• Exuberant granulation (proliferation of
  fibroblasts that inhibits re-epithelialization)
• Desmoid (aggressive fibromatosis, semi-malignant)
• Contraction

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Wound ulceration
Wound dehiscence
Contracture
Keloid
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Factors that influence wound healing

• Systemic factors
• Malnutrition
• Protein deficiency
• Vitamin C deficiency (inhibition of collagen
  synthesis)
• Metabolic status
• e.g Diabetes mellitus
• Consequence of microangiopathy
• Cortison treatment
• inhibits inflammation and collagen synthesis
• Circulatory status
• Inadequate blood supply due to ateriosclerosis
• Varicose veins (retarded venous drainage)

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Factors that influence wound healing (continue)

• Local Factors
• Infection (single most important reason for
  delayed wound healing)
• Foreign bodies
• suture material, bone and wood splinters .
• Mechanical factors
• Early movement
• Pressure

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Granulomatous inflammation
Granulomas are millimeter size nodules of chronic
inflammatory cells that can be isolated or
confluent. Granuloma formation is the result of
dealing with indigestible substances or pathogens
and walls them off The essential component are
modified macrophages named epithelioid cell
(because of shape). Epithelioid cells can form
multinucleated giant cells. Epithelioid cells are
surrounded by a collar of lymphocytes and
occasionally plasma cells. Fibrous connective
tissue often surrounds granulomas (remodeling of
tissue) Areas within the granuloma can undergo
necrosis (prototype caseous necrosis in
tuberculosis). Necrosis can lead to calcification
or liquefaction and formation of a cavern if
drained.
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Examples of granulomatous inflammation

• Specific infections (immune granuloma)
  Mycobacteria (tuberculosis, lepprosy) syphilis,
  brucellosis,
• Foreign bodies
• endogenous
• ( keratin, necrotic bone or adipose tissue uric
  acid crystals)
• Exogenous
• (wood, silica, asbestos, silicone)
• Specific chemicals
• Beryllium
• Drugs
• Allupurinol, phenylbutazone, sulphonamides (in
  liver)
• Unknown origin
• Sarcoidosis
• (although granuloma typically form to defend the
  host against known injurious agents, they can
  develop for unknown reasons and become injurious
  themselves)
• Hypersensitivity pneumonitis

Tuberculosis
Foreign body aspiration
Berrylliosis
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Granuloma a hallmark of tuberulosis

• Infectious bacilli are inhaled by droplets
• Infectious dose is estimated by a single
  bacterium
• Bacteria are phagocytosed by alveolar macrophages
• A localized inflammatory response recruits more
  mononuclear cells
• The granuloma consists of a kernel of infected
  macrophages surrounded by foamy macrophages and a
  ring of lymphocytes and a fibrous cuff
  (containment phase)
• Containment usually fails when the immune status
  of the patient changes the granuloma caseates,
  ruptures and spills into the airway

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Microscopic and macroscopic appearance of
tuberculosis
Cavity formation due to liquefaction and
drainage of TBC lesion
Characteristic tubercle with caseating necrosis
in center
Macroscopic lesion in TBC
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Pulmonary Granulomatous inflammationTuberculosis
, Sarcoidosis, hypersensitivity Pneumonitits
Normal lung
Characteristic sarcoid noncaseating granuloma of
the lung with many giant cells
Characteristic tubercle with caseating necrosis
in center
Hypersensitivity Pneumonitits with loosely formed
interstitial granuloma
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Sarcoidosis versus Hypersensitivity Pneumonitits

• Sarcoidosis
• is a systemic disease of unknown origin
  characterized by non-caesating granulomas in many
  tissues
• 90 of cases have primarily pulmonary
  manifestations
• Histological diagnosis is made by exclusion
• Prevalence is higher in women
• Is 10 X higher in American blacks versus whites
• Histologically the lesions are distributed
  primarily along lymphatics, around blood vessels
  and
• The process is driven by CD4-T cells
• Intra-aveolar and interstitial accumulation of
  CD4-T cells results in CD4CD8 ratios of 51 and
  151

• Hypersensitivity Pneumonitis (HP)
• also called extrinsic allergic alveolits
• HP is caused by sensitization to repeated
  inhalation of dusts containing organic antigens
• The dust can be derived from a variety of sources
  such as dairy and grain products, animal dander
  and others
• The most common antigen are thermophilic
  actinomycetes (farmers lung) and avian proteins
  (bird fanciers disease)
• The disease is immunologically mediated
• The immune pathogenesis involves macrophages, CD4
  T-cells and particularly CD8 T-cells

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Pathogenesis of immune Granuloma formation a
result of delayed type hypersensitivity reaction
Alveolar macrophages appear first to come in
contact with the offending agent (e.g are
infected by mycobacteria) Activated macrophages
produce IL-1, TNF-a, IL-12, IL-6 TGF-b and IL-10
and process the antigen Dendritic cells migrate
to the regional lymphnode and activate antigen
specific T-cells, which under the influence of
IL-12 produce IFN-g and further activate
recruited macrophages Release of TNF-a and IL-8
leads to recruitment of neutrophils and monocytes
from the circulation, IL-15 and RANTES leads to
recruitment of T cells. This is followed by the
organization of cells into a tight granuloma and
development of epithelioid cells. Chronic
granulomatous inflammation can result into
connective tissue deposition and fibrosis (tissue
remodeling)
46
Severe pulmonary changes with honey comb like
structures suggesting fibrosis
Bi-hiliar lymphadenopathy and pulmonary
infiltrate in sarcoidosis
47
Mechanisms of fibrosis

• Nicole Meissner-Pearson

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Mechanisms of Fibrosisa result of chronic
inflammation and repair

• Fibrosis
• excessive accumulation of extracellular-matrix
  components such as collagen that is produced by
  local fibroblasts leading to a permanent fibrotic
  scar
• Macrophages and fibroblasts are the main effector
  cells involved in the pathogenesis of fibrosis
• Pro-fibrotic mediators such as TGF-b and IL-13
  amplify this process
• The degradation of collagen is controlled by
  Matrix-Metallo-proteinases (MMPs) and are
  activated by IFN-g
• Therefore the net increase of collagen within a
  wound is controlled by the balance of these
  opposing mechanisms
• Although severe acute injuries can cause marked
  tissue remodeling. Fibrosis that is associated
  with chronic injury (repetitive) is unique in
  that the adaptive immune response is thought to
  have an important role

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TH-2 cytokines IL-4 and IL-13 lead to
alternative activation of macrophages

• Macrophages differentiate into at least two
  functionally distinct populations depending on
  whether they are exposed to TH-1 or TH-2
  cytokines
• TH-1 cytokine activate NOS2 in classically
  activated macrophages whereas TH-2 cytokines IL-4
  and IL-13 preferentially stimulate Arginase-1
  (ARG1) leading to an alternative activation
  pathway
• ARG1 promotes the generation of polyamines and
  L-proline via metabolism of L-arginine to
  L-ornithine and activation of ODC and OAT
• Polyamines are crucial for cell growth and
  L-proline is a substrate for collagen synthesis

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A balance between TH-2 and TH-1 cytokines is
necessary to promote healing but inhibit
excessive fibrotic tissue remodeling
Therapeutics that modulate this balance may be
beneficial in patients suffering from fibrotic
diseases. Drugs that directly inhibit TGF-b1 and
IL-13 might prove the safest and most effective
approach
51
Fibrotic tissue remodeling can result in loss of
organ function

• Fibrotic changes can occur in various vascular
  diseases including
• Cardiac diseases
• Peripheral vascular diseases
• They affect as well main organ systems like
• Skin
• Lung
• Liver
• Kidney

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Tight skin and skin necrosis due to Sclerodermia
Lung fibrosis due to sarcoidosis
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Liver cirrhosis
Liver cirrhosis macroscopic and microscopic
normal liver histology
54
Liver cirrhosis

• Cirrhosis represents the common histological
  pathway for a wide variety of liver diseases
• It is defined histologically as a diffuse hepatic
  process characterized by the presence nodular
  proliferation of hepatocytes surrounded by bands
  of fibrosis

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Most common causes of liver cirrhosis in the USA
(updated Nov. 2005 Davis C. Wolf, New York
Medical College)

• Hepatitis C (26)
• Alcoholic liver disease (21)
• Hepatitis C plus alcoholic liver disease (15)
• Cryptogenic causes (18)
• Hepatitis B (with or without Hepatitis D, 15)
• Miscellaneous(5)

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Clinical consequences and signs of liver disease

• Characteristic signs
• Jaundice and cholestasis
• Hypoalbuminemia
• Hyperammonemia
• Hypoglycemia
• Palmar erythema
• Spider angiomas
• Hypogonadism
• Gynecomastia
• Muscle wasting

• Portal hypertension due to fibrosis
• Ascites
• Splenomegaly
• Hemorrhoids
• Caput medusa

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Jaundice (note yellow sclera and skin)
Spider angioma
Palmar erythema
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Laboratory evaluation of liver diseases

• Disruption of Hepatocyte integrity
• Elevated serum aspartate amino transferase (AST
  sGOT)
• Elevated serum alanine amino transferase (ALT
  sGPT)
• Biliary excretory function
• Elevated total bilirubin (unconjugated and
  conjugated)
• direct bilirubin conjugated
• indirect bilirubin unconjugate
• Plasma membrane enzymes
• Elevated serum alkaline phosphatase (ALP)
• Elevated serum g-glutamyl transpetidase (gGT)
• Hepatocyte function
• Decreased serum albumin
• Hypoglycemia
• Decreased clotting time (early decrease of PT due
  to short half live of factor VII, cholestasis
  results in decreased uptake of vitamin K)
• Elevated serum ammonia

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Bilirubin metabolism

• Bilirubin end product of heme degradation
• Majority is derived from the break down of
  senescent erythrocytes
• Heme is oxygenized to biliverdin and reduced to
  bilirubin by phagocytes
• Bilirubin is virtually water insoluble and needs
  to be bound to albumin to be transported to the
  liver
• Upon uptake into the liver bilirubin will be
  conjugated with one or two molecules of
  glucuronic acid by bilirubin UDP-glucuronyl
  transferase in the endoplasmatic reticulum
• Conjugated bilirubin is non toxic, water- soluble
  and is excreted into bile
• Most bilirubin glucuronides are de- conjugated in
  the intestines to urobilinogen and 20 is
  reabsorbed and promptly excreted via bile

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Cholestasis and jaundice

• Hepatic bile formation serves two major
  functions
• Emulsification of dietary fat (bile acids are
  strong detergents)
• Elimination of systemic waste products
  (bilirubin, excess cholesterol and other water
  insoluble products)
• Jaundice is the result of tissue accumulation of
  unconjugated or conjugated bilirubin in tissues.
  It becomes evident when plasma levels exceed
  2mg/dl. Clearance of bilirubin can be disturbed
  by
• Excessive production (e.g. hemolysis)
• Reduced hepatocyte uptake (e.g. drugs,
  hepatocellular disease)
• Impaired conjugation (enzyme defect or
  overwhelmed system)
• Cholestasis
• Clinically, Cholestasis is any condition in which
  substances normally excreted into bile are
  retained
• Increased serum concentrations of conjugated
  bilirubin is the principal sign of cholestasis
• Conjugated bilirubin is water soluble and is
  secreted in urin (dark urine)
• Complete cholestasis leads to decoloration of
  feces
• Cholestasis may present with jaundice and
  pruritus due to deposition of bilirubin and bile
  acids in peripheral tissues

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Histopathologically Cholestasis is defined by the
appearance of bile within the elements of the
liver

• Mechanisms of Cholestasis are broadly classified
  into
• Hepatocellular (impaired bile formation,
  histological appearance of bile within
  hepatocytes feathery degeneration, and
  canalicular spaces leading to hepatocyte injury)
• Obstructive (impairment of bile flow usually due
  to physical obstruction of bile duct
  extraheaptic stone/tumor bile plugging of the
  interlobular bile ducts, portal expansion and
  bile duct proliferation)
• Unrelieved obstruction leads to portal tract
  fibrosis and ultimately end-stage bile stained
  cirrhotic liver disease

62
Role of Kupffer cells and Stellate cells in
induction of cirrhosis
63
Portal hypertension increased resistance to
portal vein blood flow

• Causes
• Pre-Hepatic
• Obstructive thrombosis of portal vein
• Intra-Hepatic
• Fibrosis
• Schistosomiasis
• Granulomatous diseases
• Post-Hepatic
• Sever right heart failure
• Constrictive pericarditis
• Hepatic vein out flow obstruction

64
Portal hypertension in cirrhosis results from
increased flow resistance at the level of
sinusoids and compression of terminal hepatic
veins by perivenular scaring
The four clinical consequences Ascites Formation
of porto-systemic shunts Congestive
splenomegaly Hepatic Encephalopathy
65
Life threatening complications of chronic liver
disease and fibrosis

• Hepatic failure leading to
• Hepatic Encephalopathy (due to ammonemia)
• Coagulopathy
• Multiorgan failure
• Portal hypertension from cirrhosis
• Esophageal varices with bleeding
• Ascites with spontaneous peritonitis
• Hepatocellular carcinoma (very long term)