Cirrhosis pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sudarshana Datta, MD [2]

Overview

Cirrhosis occurs due to long term liver injury which causes an imbalance between matrix production and degradation. The pathological hallmark of cirrhosis is the development of scar tissue which leads to replacement of normal liver parenchyma, leading to blockade of portal blood flow and disturbance of normal liver function. 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 pathogenesis of cirrhosis involves inflammation, hepatic stellate cell activation, angiogenesis and fibrogenesis. Kupffer cells are hepatic macrophages responsible for hepatic stellate cell activation during injury. Hepatic stellate cells (HSC) which are located in the subendothelial space of Disse, become activated in areas of liver injury and secrete transforming growth factor-beta 1 (TGF-β₁), which leads to a fibrotic response and proliferation of connective tissue. Cirrhosis may also lead to hepatic microvascular changes including the formation of intra-hepatic shunts (due to angiogenesis and loss of parenchymal cells) and endothelial dysfunction. Fibrosis eventually leads to formation of septae that grossly distort the liver architecture which includes both the liver parenchyma and the vasculature, accompanied by regenerative nodule formation.

Pathophysiology

The pathogenesis of cirrhosis is as follows:

• When an injured tissue is replaced by a collagenous scar, it is termed as fibrosis. The development of fibrosis requires several months, or even years of ongoing injury.
• The pathological hallmark of cirrhosis is the development of scar tissue that leads to replacement of normal liver parenchyma, leading to blockade of portal blood flow and disturbance of normal liver function.
• When fibrosis of the liver reaches a point 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

Hepatic stellate cell activation

• Kupffer cells are hepatic macrophages responsible for hepatic stellate cell activation during injury.
• The stellate cell, (also known as the perisinusoidal cell or Ito cell) is a type of cell that normally stores vitamin A and plays a pivotal role in the development of 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. This contractile cell (known as a myofibroblast) 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.
• 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.

Vascular changes

• 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

• Angiogenesis in cirrhosis results in the production of immature and permeable VEGF induced neo-vessels that further exacerbate liver injury.

Fibrosis

• 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 according to cause

• Pathogenesis of cirrhosis based upon the underlying 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.

• Portal hypertension may result from a 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.

Pathophysiology of cirrhosis due to alcohol

• Mechanisms of alcohol-induced liver damage include:
  • Impairment of:
    • 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
• Reactive oxygen species begin to form as a result of hepatocyte damage that activate Kupffer cells.
• Kupffer cell activation leads to the production of profibrogenic cytokines which in turn, stimulates stellate cells.
• Stellate cell activation leads to connective tissue formation due to deposition 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 and regenerative nodule formation in a background of fibrosis

Pathophysiology of Portal Hypertension

Increased resistance

• Portal hypertension is related to elevation of portal vasculature resistance.
• Increased resistance in portal system may be due to both intra-hepatic and also portosystemic collateral resistance.
  • Intra-hepatic resistance
    • The main factor responsible for 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 arise 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 may also be increased.
    • Alcoholic hepatitis causes both sinusoidal and post-sinusoidal pathologies.
    • Hepatic vascular endothelium synthesizes and secretes both vasodilators (e.g., nitric oxide, prostacyclins) and vasoconstrictors (e.g., endothelin and prostanoids).
    • 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 blood circulation develops as a consequence of portal hypertension which is the main contributor to esophageal varices.
    • The main purpose of the collaterals is to decompress and bypass portal blood flow.
    • However, portosystemic collaterals may 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, 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 have 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 involved in the pathogenesis of cirrhosis and 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: 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	-

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.

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

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  Cirrhosis: Gross, external view of micronodular cirrhosis

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

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  Cirrhosis: Gross, close-up image

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  Macronodular cirrhosis and hepatoma

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

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

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  Cirrhosis: Gross, close-up view

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

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  Micronodular cirrhosis: Gross, close-up image

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  Micronodular cirrhosis: Gross (an excellent example)

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

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

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

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  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

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  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)

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

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  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.

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  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

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  Macronodular cirrhosis: Gross, natural color slab of liver

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  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)

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  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.

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

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

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

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

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

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

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

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

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  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

• Microscopic pathology reveals the four stages of cirrhosis as it progresses:
  • Chronic nonsuppurative destructive cholangitis: inflammation and necrosis of portal tracts with lymphocyte infiltration leads 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 leads to regenerative nodule formation
• Microscopically, cirrhosis is characterized by regeneration nodules surrounded by fibrous septa.
• In these nodules, regenerating hepatocytes are present.
• Portal tracts, central veins and the radial pattern of hepatocytes are absent.
• Fibrous septa are present and inflammatory infiltrate composed of lymphocytes and macrophages) are also visible.
• If the underlying cause is secondary biliary cirrhosis, biliary ducts are damaged, proliferated or distended leading to bile stasis.
• 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 and are referred to as "bile lakes".

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

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References