Sandbox:Cherry

Pathophysiology prev

https://https://www.youtube.com/watch?v=5szNmKtyBW4%7C350}}

Cirrhosis Microchapters
Home
Patient Information
Overview
Historical Perspective
Classification
Pathophysiology
Causes
Differentiating Cirrhosis from other Diseases
Epidemiology and Demographics
Risk Factors
Screening
Natural History, Complications and Prognosis
Diagnosis
Diagnostic Study of Choice
History and Symptoms
Physical Examination
Laboratory Findings
Electrocardiogram
Chest X Ray
CT
MRI
Echocardiography or Ultrasound
Other Imaging Findings
Other Diagnostic Studies
Treatment
Medical Therapy
Surgery
Primary Prevention
Secondary Prevention
Tertiary Prevention
Cost-Effectiveness of Therapy
Future or Investigational Therapies
Case studies
Case #1
Sandbox:Cherry On the Web
Most recent articles
cited articles
Review articles
CME Programs
Powerpoint slides
Images
American Roentgen Ray Society Images of Sandbox:Cherry All Images X-rays Echo & Ultrasound CT Images MRI
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
NICE Guidance
FDA on Sandbox:Cherry
CDC on Sandbox:Cherry
Sandbox:Cherry in the news
Blogs on Sandbox:Cherry
Directions to Hospitals Treating Cirrhosis
Risk calculators and risk factors for Sandbox:Cherry

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief:

Overview

Cirrhosis occurs due to long term liver injury which causes an imbalance between matrix production and degradation. Early disruption of the normal hepatic matrix results in its replacement by scar tissue, which in turn has deleterious effects on cell function.

Pathophysiology

Pathophysiology

• When an injured issue is replaced by a collagenous scar, it is termed as fibrosis. The development of fibrosis requires several months, or even years, of ongoing injury.
• When fibrosis of the liver reaches an advanced stage where distortion of the hepatic vasculature also occurs, it is termed as cirrhosis of the liver. If the damage progresses, panlobular cirrhosis may result.
• The cellular mechanisms responsible for cirrhosis are similar regardless of the type of initial insult and site of injury within the liver lobule.
• Viral hepatitis involves the periportal region, whereas involvement in alcoholic liver disease is largely pericentral.
• Cirrhosis involves the following steps:
  • Inflammation
  • Hepatic stellate cell activation
  • Angiogenesis
  • Fibrogenesis
• Kupffer cells are hepatic macrophages responsible for Hepatic Stellate cell activation during injury.
• The stellate cell, a cell type that normally stores vitamin A, plays a pivotal role in the development of cirrhosis.
• Damage to the hepatic parenchyma leads to activation of the stellate cell, which becomes contractile (called myofibroblast) and obstructs blood flow in the circulation.
• The hepatic stellate cell (also known as the perisinusoidal cell or Ito cell) plays a key role in the pathogenesis of liver fibrosis/cirrhosis.
• Hepatic stellate cells(HSC) are usually located in the subendothelial space of Disse and become activated to a myofibroblast-like phenotype in areas of liver injury.
• The stellate cell secretes TGF-β₁, which leads to a fibrotic response and proliferation of connective tissue.
• Connective tissue proliferation leads to the formation of extracellular matrix around hepatocytes and is composed of collagens (especially type I, III, IV), glycoprotein and proteoglycans.
• Collagen and non collagenous matrix proteins responsible for fibrosis are produced by the activated Hepatic Stellate Cells(HSC).
• Hepatocyte damage causes the release of lipid peroxidases from injured cell membranes leading to necrosis of parenchymal cells.
• Activated HSC produce numerous cytokines and their receptors, such as PDGF and TGF-f31 which are responsible for fibrogenesis.
• The matrix formed due to HSC activation is deposited in the space of Disse and leads to loss of fenestrations of endothelial cells, which is a process called capillarization.
• Stellate cell activation leads to disturbance of the balance between matrix metalloproteinases and the naturally occurring inhibitors (TIMP 1 and 2). This is followed by matrix breakdown and replacement by connective tissue-secreted matrix.
• Matrix metalloproteinase (MMP) are calcium dependent enzymes that specifically degrade collagen and non collagenous substrate.
• MMP-2 and stromyelysin-1 are produced by stellate cells.
• MMP-2 degrades collagen and stromelysin-1 degrades proteoglycan and glycoprotein.
• Cirrhosis leads to hepatic microvascular changes characterised by
  •  formation of intra hepatic shunts (due to angiogenesis and loss of parenchymal cells) 
  • hepatic endothelial dysfunction
• Sinusoidal endothelial cells are also important contributors of early fibrosis. Endothelial cells from a normal liver produces collagen, laminin and fibronectin.
• The endothelial dysfunction is characterised by
  • insufficient release of vasodilators, such as nitric oxide due to oxidative stress
  • increased production of vasoconstrictors (mainly adrenergic stimulation and activation of endothelins and RAAS)
• The liver responds to injury with new blood vessel formation. Mediators involved in angiogenesis include:
  • Platelet derived growth factor (PDGF)
  • Vascular endothelial growth factor (VEGF)
  • Nitric oxide
  • Carbon monoxide
• Angiogenesis in cirrhosis results in the production of immature and permeable VEGF induced neo-vessels that further exacerbate liver injury.
• Fibrosis eventually leads to formation of septae that grossly distort the liver architecture which includes both the liver parenchyma and the vasculature. A cirrhotic liver compromises hepatic sinusoidal exchange by shunting arterial and portal blood directly into the central veins (hepatic outflow). Vascularized fibrous septa connect central veins with portal tracts leading to islands of hepatocytes surrounded by fibrous bands without central veins.
• These mechanisms simultaneously occurring in the liver lead to fibrous tissue band (septa) and regenerative hepatocyte nodule formation, which eventually replace the entire liver architecture, leading to decreased blood flow throughout.
• The formation of fibrotic bands is accompanied by regenerative nodule formation in the hepatic parenchyma.
• Advancement of cirrhosis may lead to parenchymal dysfunction and development of portal hypertension.
• The pathological hallmark of cirrhosis is the development of scar tissue that replaces normal parenchyma, leading to blockade of portal blood flow and disturbance of normal liver function.
• Due to portal hypertension, the spleen becomes congested, which leads to hypersplenism and increased platelet sequestration.
• Pathogenesis of cirrhosis based upon its individual cause is as follows:
  • Alcoholic liver disease: Alcohol seems to injure the liver by blocking the normal metabolism of protein, fats, and carbohydrates. Patients may also have concurrent alcoholic hepatitis with fever, hepatomegaly, jaundice, and anorexia. Liver damage due to alcoholic hepatitis may progress to cirrhosis.
  • Chronic hepatitis C: Infection with the hepatitis C virus causes inflammation of and low grade damage to the liver that over several decades can lead to cirrhosis.
  • Non-alcoholic steatohepatitis (NASH): In NASH, fat builds up in the liver and eventually causes scar tissue. This type of hepatitis appears to be associated with diabetes, protein malnutrition, obesity, coronary artery disease, and treatment with corticosteroid medications.
  • Primary sclerosing cholangitis: PSC is a progressive cholestatic disorder presenting with pruritus, steatorrhea, fat soluble vitamin deficiencies, and metabolic bone disease.
    • There is a strong association with inflammatory bowel disease (IBD), especially ulcerative colitis.
  • Autoimmune hepatitis: Immunologic damage to the liver leads to inflammation, scarring and cirrhosis.

• The pathological hallmark of cirrhosis is the development of scar tissue that replaces normal parenchyma, leading to blockade of portal blood flow and disturbance of normal liver function.
• The development of fibrosis requires several months, or even years, of ongoing injury.

• The stellate cell, a cell type that normally stores vitamin A, plays a pivotal role in the development of cirrhosis.
• Damage to the hepatic parenchyma leads to activation of the stellate cell, which becomes contractile (called myofibroblast) and obstructs blood flow in the circulation.
• The stellate cell secretes TGF-β₁, which leads to a fibrotic response and proliferation of connective tissue.
• Connective tissue proliferation leads to the formation of extracellular matrix around hepatocytes and is composed of collagens (especially type I, III, IV), glycoprotein and proteoglycans.

• Sinusoidal endothelial cells are also important contributors of early fibrosis. Endothelial cells from a normal liver produces collagen, laminin and fibronectin.

• The liver responds to injury with new blood vessel formation. Mediators involved in angiogenesis include:
  • Platelet derived growth factor (PDGF)
  • Vascular endothelial growth factor (VEGF)
  • Nitric oxide
  • Carbon monoxide
• Angiogenesis in cirrhosis results in the production of immature and permeable VEGF induced neo-vessels that further exacerbate liver injury.

• Stellate cell activation leads to disturbance of the balance between matrix metalloproteinases and the naturally occurring inhibitors (TIMP 1 and 2). This is followed by matrix breakdown and replacement by connective tissue-secreted matrix.
• Matrix metalloproteinase (MMP) are calcium dependent enzymes that specifically degrade collagen and non collagenous substrate.
• MMP-2 and stromyelysin-1 are produced by stellate cells.
• MMP-2 degrades collagen and stromelysin-1 degrades proteoglycan and glycoprotein.

• These mechanisms simultaneously occurring in the liver lead to fibrous tissue band (septa) and regenerative hepatocyte nodule formation, which eventually replace the entire liver architecture, leading to decreased blood flow throughout.
• Portal hypertension may develop as a consequence of cirrhosis.
• Due to portal hypertension, the spleen becomes congested, which leads to hypersplenism and increased platelet sequestration.
• Portal hypertension is responsible for the most severe complications of cirrhosis.

• Pathogenesis of cirrhosis based upon its individual cause is as follows:
  • Alcoholic liver disease: Alcohol seems to injure the liver by blocking the normal metabolism of protein, fats, and carbohydrates. Patients may also have concurrent alcoholic hepatitis with fever, hepatomegaly, jaundice, and anorexia.
  • Chronic hepatitis C: Infection with the hepatitis C virus causes inflammation of and low grade damage to the liver that over several decades can lead to cirrhosis.
  • Non-alcoholic steatohepatitis (NASH): In NASH, fat builds up in the liver and eventually causes scar tissue. This type of hepatitis appears to be associated with diabetes, protein malnutrition, obesity, coronary artery disease, and treatment with corticosteroid medications.
  • Primary sclerosing cholangitis: PSC is a progressive cholestatic disorder presenting with pruritus, steatorrhea, fat soluble vitamin deficiencies, and metabolic bone disease. There is a strong association with inflammatory bowel disease (IBD), especially ulcerative colitis.
  • Autoimmune hepatitis: This disease is caused by the immunologic damage to the liver causing inflammation and eventually scarring and cirrhosis.

Cirrhosis

Pathophysiology

• When an injured issue is replaced by a collagenous scar, it is termed as fibrosis.
• When fibrosis of the liver reaches an advanced stage where distortion of the hepatic vasculature also occurs, it is termed as cirrhosis of the liver.
• The cellular mechanisms responsible for cirrhosis are similar regardless of the type of initial insult and site of injury within the liver lobule.
• Viral hepatitis involves the periportal region, whereas involvement in alcoholic liver disease is largely pericentral.
• If the damage progresses, panlobular cirrhosis may result.
• Cirrhosis involves the following steps:
  • Inflammation
  • Hepatic stellate cell activation
  • Angiogenesis
  • Fibrogenesis
• Kupffer cells are hepatic macrophages responsible for Hepatic Stellate cell activation during injury.
• The hepatic stellate cell (also known as the perisinusoidal cell or Ito cell) plays a key role in the pathogenesis of liver fibrosis/cirrhosis.
• Hepatic stellate cells(HSC) are usually located in the subendothelial space of Disse and become activated to a myofibroblast-like phenotype in areas of liver injury.
• Collagen and non collagenous matrix proteins responsible for fibrosis are produced by the activated Hepatic Stellate Cells(HSC).
• Hepatocyte damage causes the release of lipid peroxidases from injured cell membranes leading to necrosis of parenchymal cells.
• Activated HSC produce numerous cytokines and their receptors, such as PDGF and TGF-f31 which are responsible for fibrogenesis.
• The matrix formed due to HSC activation is deposited in the space of Disse and leads to loss of fenestrations of endothelial cells, which is a process called capillarization.
• Cirrhosis leads to hepatic microvascular changes characterised by
  •  formation of intra hepatic shunts (due to angiogenesis and loss of parenchymal cells) 
  • hepatic endothelial dysfunction
• The endothelial dysfunction is characterised by
  • insufficient release of vasodilators, such as nitric oxide due to oxidative stress
  • increased production of vasoconstrictors (mainly adrenergic stimulation and activation of endothelins and RAAS)
• Fibrosis eventually leads to formation of septae that grossly distort the liver architecture which includes both the liver parenchyma and the vasculature. A cirrhotic liver compromises hepatic sinusoidal exchange by shunting arterial and portal blood directly into the central veins (hepatic outflow). Vascularized fibrous septa connect central veins with portal tracts leading to islands of hepatocytes surrounded by fibrous bands without central veins.
• The formation of fibrotic bands is accompanied by regenerative nodule formation in the hepatic parenchyma.
• Advancement of cirrhosis may lead to parenchymal dysfunction and development of portal hypertension.
• Portal HTN results from the combination of the following:
  • Structural disturbances associated with advanced liver disease account for 70% of total hepatic vascular resistance.
  •  Functional abnormalities such as endothelial dysfunction and increased hepatic vascular tone account for 30% of total hepatic vascular resistance.

Pathogenesis of Cirrhosis due to Alcohol:

• More than 66 percent of all American adults consume alcohol.
• Cirrhosis due to alcohol accounts for approximately forty percent of mortality rates due to cirrhosis.
• Mechanisms of alcohol-induced damage include:
  • Impaired protein synthesis, secretion, glycosylation
• Ethanol intake leads to elevated accumulation of intracellular triglycerides by:
  • Lipoprotein secretion
  • Decreased fatty acid oxidation
  • Increased fatty acid uptake
• Alcohol is converted by Alcohol dehydrogenase to acetaldehyde.
• Due to the high reactivity of acetaldehyde, it forms acetaldehyde-protein adducts which cause damage to cells by:
  • Trafficking of hepatic proteins
  • Interrupting microtubule formation
  • Interfering with enzyme activities
• Damage of hepatocytes leads to the formation of reactive oxygen species that activate Kupffer cells.
• Kupffer cell activation leads to the production of profibrogenic cytokines that stimulates stellate cells.
• Stellate cell activation leads to the production of extracellular matrix and collagen.
• Portal triads develop connections with central veins due to connective tissue formation in pericentral and periportal zones, leading to the formation of regenerative nodules.
• Shrinkage of the liver occurs over years due to repeated insults that lead to:
  • Loss of hepatocytes
  • Increased production and deposition of collagen

Pathology

• There are four stages of Cirrhosis as it progresses:
  • Chronic nonsuppurative destructive cholangitis - inflammation and necrosis of portal tracts with lymphocyte infiltration leading to the destruction of the bile ducts.
  • Development of biliary stasis and fibrosis
• Periportal fibrosis progresses to bridging fibrosis
• Increased proliferation of smaller bile ductules leading to regenerative nodule formation.

Pathophysiology of Alcoholic liver disease

• Ethanol metabolism in the liver is carried out mainly by two enzymes:
  • Alcohol dehydrogenase
  • Aldehyde dehydrogenase
• Both of these enzymes use NAD+ as a cofactor. Alcohol is converted to acetaldehyde and acetaldehyde is then further oxidized to acetate. Acetaldehyde is the toxic metabolite in this process.
• The metabolism of alcohol in the liver ends up producing an excess of reduced nicotinamide adenine dinucleotide (NADH). This changes the reduction-oxidation potential in the liver and inhibits key metabolic processes in the liver such as, the tricarboxylic acid cycle and the oxidation of fatty acids and thereby ends up promoting lipogenesis.
• Since acetaldehyde has an electrophilic nature it can form covalent chemical bonds with proteins, lipids and DNA. These covalent bonds that are formed are extremely pathogenic, as they have the ability to alter cell environments, protein structures and they can enable DNA damage and mutation.

• The cytochrome P450 enzymes (CYP) are a part of the microsomal ethanol oxidizing system. These are a large group of enzymes involved in numerous oxidizing reactions on different substrates. They catalyze many different reactions in order to make them in to more polar metabolites that are easier to excrete.

• There is an ethanol inducible form of CYP enzymes that is working in a small amount under normal physiological conditions. This enzyme CYP2E1 is converting ethanol to acetaldehyde and then to acetate. When there is chronic alcohol abuse, there is induction of the microsomal system and there is an increase in the expression of CYP2E1. This increase in CYP2E1 expression under chronic ethanol consumption can be hazardous, as this oxidation reaction can produces many different ROS; O₂^-, H₂O₂, OH^- and hydroxyethyl radical (HER).

• Ethanol metabolism additionally promotes lipogenesis through the inhibition of peroxisome proliferator activated receptor α (PPAR-α) and AMP kinase, as well as the stimulation of sterol regulatory element binding protein 1, which is a membrane bound transcription factor. The sequence of all these events results in a fat storing metabolic remodeling of the liver.

• Two key factors that play an important role in the inflammatory process that leads to the alcohol mediated liver injury are:
  • Endotoxin
  • Gut permeability
• Endotoxin is associated to the lipopolysaccharide (LPS) component of the outer wall of gram-negative bacteria and is thought to be the key trigger in this inflammatory process.
• Gut permeability is the factor that is either enabling or preventing the transfer of the LPS-endotoxin from the intestinal lumen into the portal circulation.
• The fact that long term exposure to alcohol increases gut permeability has been observed in humans as LPS-endotoxin levels have been found to be elevated in patients with alcoholic liver injury.

• After the entry of LPS-endotoxin in to the portal circulation it binds to the LPS-binding protein, this is a key step in the inflammatory and histopathological response to alcohol ingestion.
• The LPS-LPS binding protein complex binds to the CD14 receptor on the cell surface membrane of the Kupffer cells in the liver.
• Activation of these Kupffer cells requires 3 main cellular proteins:
  • CD14 (monocyte differentiation antigen)
  • Toll-like receptor 4 (TLR4)
  • MD2, a protein, binds TLR4 with LPS-LPS binding protein
• The TLR4 then signals activation of early growth response 1 (EGR1), which is an early gene-zinc-finger transcription factor.
• The nuclear factor-kB (NF-kB) and the TLR4 adapter also play an important role in the activation of the kupffer cells.
• EGR1 plays the pivotal role in lipopolysaccharide-stimulated TNF-α production.
• In mice the absence of EGR1 prevents alcohol induced liver injury.

• Ethanol administration stimulates the release of mitochondrial cytochrome c and the expression of the Fas ligand, this leads to hepatic cell apoptosis mediated by the cascade-3 activation pathway.
• The cumulative effect of TNF-α and Fas-mediated apoptotic signals make the hepatocytes more susceptible to injury by stimulating an increase in natural killer T cells in the liver.

Pathophysiology of Portal Hypertension

Increased resistance

• Portal hypertension is related to elevation of portal vasculature resistance.
• Increased resistance in portal system can be due to both intra-hepatic and also portosystemic collaterals resistances.
  • Intra-hepatic resistance
    • The main factor in intra-hepatic resistance is hepatic vascular compliance, which is greatly decreased in various liver diseases, such as liver fibrosis or cirrhosis.
    • Portal hypertension occurs when compliance is decreased and blood flow is increased in liver.
    • Pre-hepatic and post-hepatic portal hypertension are due to some secondary obstruction before or after liver vasculature, respectively.
    • Schistosomiasis causes both pre-sinusoidal and sinusoidal pathologies. The granulomas compress the pre-sinusoidal veins. In late stages sinusoidal resistance is also increased.
    • Alcoholic hepatitis causes both sinusoidal and post-sinusoidal pathologies.
    • Hepatic vascular endothelium synthesizes and secretes both vasodilator (e.g., nitric oxide, prostacyclins) and vasoconstrictor (e.g., endothelin and prostanoids) chemicals.
    • Increased resistance due to the elevation of vascular tone may be caused by excess of vasoconstrictors or lack of vasodilators.
    • It is postulated that in cirrhotic liver the nitric oxide level is lower and the response to endothelin response in myofibrils is higher than normal liver.
  • Portosystemic collateral resistance
    • Collateral formation is the consequence of portal hypertension which is also the main contributor to esophageal varices.
    • The main purpose of the collaterals is to decompress and bypass the portal blood flow.
    • However, the resistance in collaterals is less than the normal liver.
    • Thus, portosystemic collaterals can not lead to a complete decompression.
    • Portosystemic collateraling occurs between the short gastric, coronary veins, and the esophageal azygos and the intercostal veins; the superior, the middle, and the inferior hemorrhoidal veins; the paraumbilical venous plexus and the venous system of abdominal organs juxtaposed with the retroperitoneum and abdominal wall; the left renal vein, the splanchnic, the adrenal, and the spermatic veins.

Hyperdynamic circulation in portal hypertension

• Peripheral vasodilatation is the basis for decreased systemic vascular resistance and mean arterial pressure, plasma volume expansion, elevated splanchnic blood flow, and elevated cardiac index.
• Systemic vasodilation
  • Three main mechanisms which contribute to the peripheral vasodilation are as following:
    • Increased vasodilators production in systemic circulation
    • Increased vasodilators production in local endothelium
    • Decreased vascular response to local vasoconstrictors
• Plasma volume
  • There are several events which contribute to the hyperdynamic circulation such as:
    • Initial vasodilatation, induced by systemic and local endothelial factors
    • Subsequent plasma volume expansion

Genetics

• Certain TERT (Telomerase reverese transcriptase)gene variants resulting in reduced telomerase activity has been found to be a risk factor for sporadic cirrhosis
• An uncharacterized nucleolar protein, NOL11, has a role in the pathogenesis of North American Indian childhood cirrhosis
• Loss of interaction between the C-terminus of Utp4/cirhin and other SSU processome proteins may cause North American Indian childhood cirrhosis
• Genes are involved in the pathogenesis of portal hypertension include the following:

Gene	OMIM number	Chromosome	Function	Gene expression in portal hypertension	Notes
Deoxyguanosine kinase (DGUOK)	601465	2p13.1	DNA replication	Point mutation	Mutation leads to: Liver failure Neurologic abnormalities Hypoglycemia Increased lactate in body fluids Homozygous missense mutation leads to: Non-cirrhotic portal hypertension
Adenosine deaminase (ADA)	608958	20q13.12	Irreversible deamination of adenosine and deoxyadenosine in the purine catabolic pathway	Reduced	Some roles in modulating tissue response to IL-13 The main effects of IL-13 are: Inflammation Chemokine elaboration Fibrosis
Phospholipase A2 (PL2G10)	603603	16p13.12	Catalyzing the release of fatty acids from phospholipids	Reduced	Identifier of PL2G10 expression: Arachidonic acid (AA) Prostaglandins (PG) Leukotrienes (LT)
Cytochrome P450, family 4, subfamily F, polypeptide 3 (CYP4F3)	601270	19p13.12	Catalyzing the omega-hydroxylation of leukotriene B4 (LTB4)	Increased	-
Glutathione peroxidase 3 (GPX3)	138321	5q33.1	Reduction of glutathione which reduce: Hydrogen peroxide Organic hydroperoxide Lipid peroxides	Increased	Protects various organs against oxidative stress: Liver Kidney Breast
Leukotriene B4 (LTB4)	601531	14q12	Include: Increasing intra-cellular calcium Elevation of inositol 3-phosphate (IP3) Inhibition of adenylyl cyclase	Mutated	Increase blood flow to target tissue (esp. heart) about 4 times more.
Prostaglandin E receptor 2 (PTGER2)	176804	14q22.1	Various biological activities in diverse tissues	Reduced	-
Endothelin (EDN1)	131240	6p24.1	Vasoconstriction	Increased	The most powerful vasoconstrictor known
Endothelin receptor type A (EDNRA)	131243	4q31.22-q31.23	Vasoconstriction through binding to endothelin	Reduced	Directly related to hypertension in patients
Natriuretic peptide receptor 3 (NPR3)	108962	5p13.3	Maintenance of: Blood pressure Extracellular fluid volume	Increased	Released from heart muscle in response to increase in wall tension. ANP can modulate blood pressure by binding to NPR3
Cluster of differentiation 44 (CD44)	107269	11p13	Lymphocyte activation Lymph node homing	Reduced	Related to fibroblast growth factor (FGF) Increased expression during collateral arteriogenesis
Transforming growth factor (TGF)-β	190180	19q13.2	Tissue transformation Apoptosis regulation	Reduced	Hyper-expressed in African-American hypertensive patients
Ectonucleoside triphosphate diphosphohydrolase 4 (ENTPD4)	607577	8p21.3	Increasing phosphatase activity in intracellular membrane-bound nucleosides	Reduced	-
ATP-binding cassette, subfamily C, member 1 (ABCC1)	158343	16p13.11	Multi-drug resistance in small cell lung cancer	Reduced	-

Associated Conditions

Gross Pathology

Macroscopically, the liver may initially be enlarged, but with progression of the disease, it becomes smaller. Its surface is irregular, the consistency is firm, and the color is often yellow (if associates steatosis). Depending on the size of the nodules there are three macroscopic types: micronodular, macronodular and mixed cirrhosis.

• In the micronodular form (Laennec's cirrhosis or portal cirrhosis) regenerating nodules are under 3 mm.
• In macronodular cirrhosis (post-necrotic cirrhosis), the nodules are larger than 3 mm.
• The mixed cirrhosis consists of a variety of nodules with different sizes.

Gross Pathology

On gross pathology, cirrhotic liver, splenomegaly, and esophageal varices are characteristic findings in portal hypertension.
Cirrhosis On gross pathology there are two types of cirrhosis: Micronodular cirrhosis which is uniform and diffuse, mostly due to alcohol. Macronodular cirrhosis which is irregular, mostly due to viral hepatitis.	Micronodular cirrhosis - By Amadalvarez (Own work), via Wikimedia Commons	Macronodular cirrhosis
Splenomegaly On gross pathology, diffuse enlargement and congestion of the spleen are characteristic findings of splenomegaly.	Splenomegaly - By Amadalvarez (Own work), via Wikimedia Commons
Esophageal Varices On gross pathology, prominent, congested, and tortoise veins in the lower parts of esophagus are characteristic findings of esophageal varices.	Esophageal varices

Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology

• 

  Cirrhosis: Gross, external view of micronodular cirrhosis

• 

  Cirrhosis: Gross, cut section of previous one (an excellent example)

• 

  Cirrhosis: Gross, close-up image

• 

  Macronodular cirrhosis and hepatoma

• 

  Cirrhosis: Gross, close-up, natural color (an excellent example)

• 

  Cirrhosis: Gross, close-up (an excellent example)

• 

  Cirrhosis: Gross, close-up view

• 

  Micronodular cirrhosis: Gross, external view (an excellent example)

• 

  Micronodular cirrhosis: Gross, close-up image

• 

  Micronodular cirrhosis: Gross (an excellent example)

• 

  Macronodular cirrhosis: Gross, natural color (perfect color for cirrhosis), close-up, an excellent example

• 

  Cirrhosis with portocaval shunt: Gross, severe cirrhosis with extensive liver necrosis due to thrombosis of portocaval shunt (well shown)

• 

  Endstage cirrhosis: Gross, natural color, close-up (an excellent example)

• 

  Endstage cirrhosis: Gross, natural color, close-up view is an excellent example for nodules of yellow-orange liver tissue and broad irregular bands of fibrosis

• 

  Endstage cirrhosis: Gross, natural color, close-up cut surface, very well shown nodules of yellow and necrotic opaque liver tissue with broad and irregular bands of fibrosis (an excellent example)

• 

  Macronodular cirrhosis: Gross, natural color, external view of liver and very enlarged spleen (liver has variable size nodules up to about 2 cm)

• 

  Macronodular cirrhosis: Gross, natural color, cut surface, large irregular bands of fibrosis with variable size liver cell nodules up to about 8 mm and all necrotic appears to be an end stage liver disease.

• 

  Macronodular cirrhosis: Gross, natural color view of frontal sections of liver and spleen showing a contracted macronodular liver and an enlarged spleen as large as the liver

• 

  Macronodular cirrhosis: Gross, natural color slab of liver

• 

  Fatty change and early cirrhosis: Gross, natural color, rather close-up image showing typical fatty color, and in lighting at lower right of micrography micronodularity is evident (quite good example)

• 

  Cirrhosis with portal vein thrombosis: Gross, natural color, sectioned liver with portal vein exposed and filled with red thrombus. A good example of end stage cirrhosis.

• 

  Endstage cirrhosis with lobular necrosis: Gross, natural color, very close-up view (an excellent example of alcoholic cirrhosis)

• 

  Micronodular cirrhosis: Gross, natural color view of whole liver through capsule with obvious cirrhosis (note to quite large liver)

• 

  Micronodular cirrhosis: Gross, natural color, view of whole liver showing external surface typical cirrhotic liver (history of alcoholism)

• 

  Lung: Idiopathic Interstitial Fibrosis: Gross, natural color, an excellent photo of lung cirrhosis (close-up view)

• 

  Endstage cirrhosis: Gross, natural color, slice of liver. Portal vein is opened to show size and patency.

• 

  Endstage cirrhosis: Gross, natural color, severe cirrhosis with bile stasis

• 

  Portal Vein Thrombosis with cirrhosis: Gross, close-up, micronodular cirrhosis with portal vein thrombosis

• 

  Lung: Hematite: Gross, natural color, external view of "pulmonary cirrhosis" with typical hematite color

• 

  Gross, natural color of liver and stomach view from external surfaces, micronodular cirrhosis and hemorrhagic gastritis (as the surgeon would see these in natural color)

Microscopic Pathology

Microscopically, cirrhosis is characterized by regeneration nodules surrounded by fibrous septa. In these nodules, regenerating hepatocytes are disorderly disposed. Portal tracts, central veins and the radial pattern of hepatocytes are absent. Fibrous septa are important and may present inflammatory infiltrate (lymphocytes, macrophages). If it is a secondary biliary cirrhosis, biliary ducts are damaged, proliferated or distended - bile stasis. These dilated ducts contain inspissated bile which appears as bile casts or bile thrombi (brown-green, amorphous). Bile retention may be found also in the parenchyma, as the so called "bile lakes".

Microscopic Pathology

The main microscopic histopathological findings in portal hypertension are related to cirrhosis, esophageal varices, hepatic amyloidosis, and congestive hepatopathy due to heart failure or Budd-Chiari syndrome.
Cirrhosis Robbins definition of microscopic histopathological findings in cirrhosis includes (all three is needed for diagnosis): Bridging fibrosis Nodule formation Disruption of the hepatic architecture	Cirrhosis with bridging fibrosis (yellow arrow) and nodule (black arrow) - By Nephron, via Librepathology.org
Esophageal varices The main microscopic histopathological findings in esophageal varices are: Large dilated submucosal veins (key feature) Blood (fresh) Hemosiderin-laden macrophages.	Esophageal varices with submucosal vein (black arrow), via Librepathology.org
Hepatic amyloidosis The main microscopic histopathological findings in hepatic amyloidosis is amorphous extracellular pink stuff on H&E staining.	Hepatic amyloidosis with amorphous amyloids (black arrow) and normal hepatocytes (blue arrow), via Librepathology.org
Congestive hepatopathy The main microscopic histopathological findings in congestive hepatopathy (due to heart failure or Budd-Chiari syndrome) are: Atrophy of zone III Distension of portal venule (central vein) Perisinusoidal fibrosis which may progress to centrilobular fibrosis and then diffuse fibrosis Sinusoidal dilation in all zone III areas (key feature)	Congestive hepatopathy with central vein (yellow arrowhead), inflammatory cells, Councilman body (green arrowhead), and hepatocyte with mitotic figure (red arrowhead), via Librepathology.org

Chronic active hepatitis - Cirrhosis

{{#ev:youtube|CzKGvWZrUpU}}

Micronodular cirrhosis

{{#ev:youtube|CV8OYeIUXko}}

Primary biliary cirrhosis

{{#ev:youtube|Jj8ozr_IttM}}

References

the end

-

Portal HTN results from the combination of the following:

• Structural disturbances associated with advanced liver disease account for 70% of total hepatic vascular resistance.
•  Functional abnormalities such as endothelial dysfunction and increased hepatic vascular tone account for 30% of total hepatic vascular resistance.

Pathogenesis of Cirrhosis due to Alcohol:

• More than 66 percent of all American adults consume alcohol.
• Cirrhosis due to alcohol accounts for approximately forty percent of mortality rates due to cirrhosis.
• Mechanisms of alcohol-induced damage include:
  • Impaired protein synthesis, secretion, glycosylation
• Ethanol intake leads to elevated accumulation of intracellular triglycerides by:
  • Lipoprotein secretion
  • Decreased fatty acid oxidation
  • Increased fatty acid uptake
• Alcohol is converted by Alcohol dehydrogenase to acetaldehyde.
• Due to the high reactivity of acetaldehyde, it forms acetaldehyde-protein adducts which cause damage to cells by:
  • Trafficking of hepatic proteins
  • Interrupting microtubule formation
  • Interfering with enzyme activities
• Damage of hepatocytes leads to the formation of reactive oxygen species that activate Kupffer cells.
• Kupffer cell activation leads to the production of profibrogenic cytokines that stimulates stellate cells.
• Stellate cell activation leads to the production of extracellular matrix and collagen.
• Portal triads develop connections with central veins due to connective tissue formation in pericentral and periportal zones, leading to the formation of regenerative nodules.
• Shrinkage of the liver occurs over years due to repeated insults that lead to:
  • Loss of hepatocytes
  • Increased production and deposition of collagen

Pathology

• There are four stages of Cirrhosis as it progresses:
  • Chronic nonsuppurative destructive cholangitis - inflammation and necrosis of portal tracts with lymphocyte infiltration leading to the destruction of the bile ducts.
  • Development of biliary stasis and fibrosis
• Periportal fibrosis progresses to bridging fibrosis
• Increased proliferation of smaller bile ductules leading to regenerative nodule formation.

Causes

Drugs and Toxins	Infections	Autoimmune	Metabolic	Biliary obstruction(Secondary bilary cirrhosis)	Vascular	Miscellaneous
Alcohol	Hepatitis B	Primary Biliary Cirrhosis	Wilson's disease	Cystic fibrosis	Chronic RHF	Sarcoidosis
Methotrexate	Hepatitis C	Autoimmune hepatitis	Hemochromatosis	Biliary atresia	Budd-Chiari syndrome	Intestinal bypass operations for obesity
Isoniazid	Schistosoma japonicum	Primary Sclerosing Cholangitis	Alpha-1 antitrypsin deficiency	Bile duct strictures	Veno-occlusive disease	Cryptogenic: unknown
Methyldopa			Porphyria	Gallstones
			Glycogen storage diseases (such as Galactosaemia, Abetalipoproteinaemia)

Cirrhosis

Pathophysiology

• When an injured issue is replaced by a collagenous scar, it is termed as fibrosis.
• When fibrosis of the liver reaches an advanced stage where distortion of the hepatic vasculature also occurs, it is termed as cirrhosis of the liver.
• The cellular mechanisms responsible for cirrhosis are similar regardless of the type of initial insult and site of injury within the liver lobule.
• Viral hepatitis involves the periportal region, whereas involvement in alcoholic liver disease is largely pericentral.
• If the damage progresses, panlobular cirrhosis may result.
• Cirrhosis involves the following steps:
  • Inflammation
  • Hepatic stellate cell activation
  • Angiogenesis
  • Fibrogenesis
• Kupffer cells are hepatic macrophages responsible for Hepatic Stellate cell activation during injury.
• The hepatic stellate cell (also known as the perisinusoidal cell or Ito cell) plays a key role in the pathogenesis of liver fibrosis/cirrhosis.
• Hepatic stellate cells(HSC) are usually located in the subendothelial space of Disse and become activated to a myofibroblast-like phenotype in areas of liver injury.
• Collagen and non collagenous matrix proteins responsible for fibrosis are produced by the activated Hepatic Stellate Cells(HSC).
• Hepatocyte damage causes the release of lipid peroxidases from injured cell membranes leading to necrosis of parenchymal cells.
• Activated HSC produce numerous cytokines and their receptors, such as PDGF and TGF-f31 which are responsible for fibrogenesis.
• The matrix formed due to HSC activation is deposited in the space of Disse and leads to loss of fenestrations of endothelial cells, which is a process called capillarization.
• Cirrhosis leads to hepatic microvascular changes characterised by
  •  formation of intra hepatic shunts (due to angiogenesis and loss of parenchymal cells) 
  • hepatic endothelial dysfunction
• The endothelial dysfunction is characterised by
  • insufficient release of vasodilators, such as nitric oxide due to oxidative stress
  • increased production of vasoconstrictors (mainly adrenergic stimulation and activation of endothelins and RAAS)
• Fibrosis eventually leads to formation of septae that grossly distort the liver architecture which includes both the liver parenchyma and the vasculature. A cirrhotic liver compromises hepatic sinusoidal exchange by shunting arterial and portal blood directly into the central veins (hepatic outflow). Vascularized fibrous septa connect central veins with portal tracts leading to islands of hepatocytes surrounded by fibrous bands without central veins.
• The formation of fibrotic bands is accompanied by regenerative nodule formation in the hepatic parenchyma.
• Advancement of cirrhosis may lead to parenchymal dysfunction and development of portal hypertension.
• Portal HTN results from the combination of the following:
  • Structural disturbances associated with advanced liver disease account for 70% of total hepatic vascular resistance.
  •  Functional abnormalities such as endothelial dysfunction and increased hepatic vascular tone account for 30% of total hepatic vascular resistance.

Pathogenesis of Cirrhosis due to Alcohol:

• More than 66 percent of all American adults consume alcohol.
• Cirrhosis due to alcohol accounts for approximately forty percent of mortality rates due to cirrhosis.
• Mechanisms of alcohol-induced damage include:
  • Impaired protein synthesis, secretion, glycosylation
• Ethanol intake leads to elevated accumulation of intracellular triglycerides by:
  • Lipoprotein secretion
  • Decreased fatty acid oxidation
  • Increased fatty acid uptake
• Alcohol is converted by Alcohol dehydrogenase to acetaldehyde.
• Due to the high reactivity of acetaldehyde, it forms acetaldehyde-protein adducts which cause damage to cells by:
  • Trafficking of hepatic proteins
  • Interrupting microtubule formation
  • Interfering with enzyme activities
• Damage of hepatocytes leads to the formation of reactive oxygen species that activate Kupffer cells.
• Kupffer cell activation leads to the production of profibrogenic cytokines that stimulates stellate cells.
• Stellate cell activation leads to the production of extracellular matrix and collagen.
• Portal triads develop connections with central veins due to connective tissue formation in pericentral and periportal zones, leading to the formation of regenerative nodules.
• Shrinkage of the liver occurs over years due to repeated insults that lead to:
  • Loss of hepatocytes
  • Increased production and deposition of collagen

Pathology

• There are four stages of Cirrhosis as it progresses:
  • Chronic nonsuppurative destructive cholangitis - inflammation and necrosis of portal tracts with lymphocyte infiltration leading to the destruction of the bile ducts.
  • Development of biliary stasis and fibrosis
• Periportal fibrosis progresses to bridging fibrosis
• Increased proliferation of smaller bile ductules leading to regenerative nodule formation.

Video codes

Normal video

{{#ev:youtube|x6e9Pk6inYI}}

Video in table

{{#ev:youtube|5ucSlgqGAno}}

Floating video

Title

https://https://www.youtube.com/watch?v=ypYI_lmLD7g%7C350}}

Redirect

1. REDIRECTEsophageal web

synonym website

https://mq.b2i.sg/snow-owl/#!terminology/snomed/10743008

Image

Normal versus Abnormal Barium study of esophagus with varices

Image to the right

C. burnetii, the Q fever causing agent

Image and text to the right

<figure-inline><figure-inline><figure-inline><figure-inline><figure-inline><figure-inline><figure-inline><figure-inline><figure-inline><figure-inline><figure-inline><figure-inline><figure-inline><figure-inline></figure-inline></figure-inline></figure-inline></figure-inline></figure-inline></figure-inline></figure-inline></figure-inline></figure-inline></figure-inline></figure-inline></figure-inline></figure-inline></figure-inline> Recent out break of leptospirosis is reported in Bronx, New York and found 3 cases in the months January and February, 2017.

Gallery

• 

  Histopathology of a pancreatic endocrine tumor (insulinoma). Source:https://librepathology.org/wiki/Neuroendocrine_tumour_of_the_pancreas

• 

  Histopathology of a pancreatic endocrine tumor (insulinoma). Chromogranin A immunostain. Source:https://librepathology.org/wiki/Neuroendocrine_tumour_of_the_pancreas

• 

  Histopathology of a pancreatic endocrine tumor (insulinoma). Insulin immunostain. Source:https://librepathology.org/wiki/Neuroendocrine_tumour_of_the_pancreas

References

REFERENCES