Cirrhosis pathophysiology

Revision as of 19:58, 20 December 2017 by Sudarshana Datta (talk | contribs)
Jump to navigation Jump to search
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

Cirrhosis pathophysiology On the Web

Most recent articles

cited articles

Review articles

CME Programs

Powerpoint slides

Images

American Roentgen Ray Society Images of Cirrhosis pathophysiology

All Images
X-rays
Echo & Ultrasound
CT Images
MRI

Ongoing Trials at Clinical Trials.gov

US National Guidelines Clearinghouse

NICE Guidance

FDA on Cirrhosis pathophysiology

CDC on Cirrhosis pathophysiology

Cirrhosis pathophysiology in the news

Blogs on Cirrhosis pathophysiology

Directions to Hospitals Treating Cirrhosis

Risk calculators and risk factors for Cirrhosis pathophysiology

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

The pathogenesis of cirrhosis is as follows: [1][2][3][4][5][6]

  • 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 replaces normal 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. 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: [7]
    • Inflammation
    • Hepatic stellate cell activation
    • Angiogenesis
    • Fibrogenesis
  • 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 cell type 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.[8]
  • 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: [9]
    • 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.[10][11]
  • The endothelial dysfunction is characterised by [12]
    • 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:
  • Angiogenesis in cirrhosis results in the production of immature and permeable VEGF induced neo-vessels that further exacerbate liver injury. [13][14]
  • 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.[15][16][17]
  • 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:

Cirrhosis

  • 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.[6]
  • 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.
  1. Arthur MJ, Iredale JP (1994). "Hepatic lipocytes, TIMP-1 and liver fibrosis". J R Coll Physicians Lond. 28 (3): 200–8. PMID 7932316.
  2. Friedman SL (1993). "Seminars in medicine of the Beth Israel Hospital, Boston. The cellular basis of hepatic fibrosis. Mechanisms and treatment strategies". N. Engl. J. Med. 328 (25): 1828–35. doi:10.1056/NEJM199306243282508. PMID 8502273.
  3. Iredale JP (1996). "Matrix turnover in fibrogenesis". Hepatogastroenterology. 43 (7): 56–71. PMID 8682489.
  4. Gressner AM (1994). "Perisinusoidal lipocytes and fibrogenesis". Gut. 35 (10): 1331–3. PMC 1374996. PMID 7959178.
  5. Iredale JP (2007). "Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ". J. Clin. Invest. 117 (3): 539–48. doi:10.1172/JCI30542. PMC 1804370. PMID 17332881.
  6. 6.0 6.1 Arthur MJ (2002). "Reversibility of liver fibrosis and cirrhosis following treatment for hepatitis C". Gastroenterology. 122 (5): 1525–8. PMID 11984538.
  7. Wanless IR, Wong F, Blendis LM, Greig P, Heathcote EJ, Levy G (1995). "Hepatic and portal vein thrombosis in cirrhosis: possible role in development of parenchymal extinction and portal hypertension". Hepatology. 21 (5): 1238–47. PMID 7737629.
  8. Iredale JP. Cirrhosis: new research provides a basis for rational and targeted treatments. BMJ 2003;327:143-7.Fulltext. PMID 12869458.
  9. Fernández M, Semela D, Bruix J, Colle I, Pinzani M, Bosch J (2009). "Angiogenesis in liver disease". J. Hepatol. 50 (3): 604–20. doi:10.1016/j.jhep.2008.12.011. PMID 19157625.
  10. Maher JJ, McGuire RF (1990). "Extracellular matrix gene expression increases preferentially in rat lipocytes and sinusoidal endothelial cells during hepatic fibrosis in vivo". J. Clin. Invest. 86 (5): 1641–8. doi:10.1172/JCI114886. PMC 296914. PMID 2243137. Unknown parameter |month= ignored (help)
  11. Herbst H, Frey A, Heinrichs O; et al. (1997). "Heterogeneity of liver cells expressing procollagen types I and IV in vivo". Histochem. Cell Biol. 107 (5): 399–409. PMID 9208331. Unknown parameter |month= ignored (help)
  12. García-Pagán JC, Gracia-Sancho J, Bosch J (2012). "Functional aspects on the pathophysiology of portal hypertension in cirrhosis". J. Hepatol. 57 (2): 458–61. doi:10.1016/j.jhep.2012.03.007. PMID 22504334.
  13. Lee JS, Semela D, Iredale J, Shah VH (2007). "Sinusoidal remodeling and angiogenesis: a new function for the liver-specific pericyte?". Hepatology. 45 (3): 817–25. doi:10.1002/hep.21564. PMID 17326208. Unknown parameter |month= ignored (help)
  14. Rosmorduc O, Housset C (2010). "Hypoxia: a link between fibrogenesis, angiogenesis, and carcinogenesis in liver disease". Semin. Liver Dis. 30 (3): 258–70. doi:10.1055/s-0030-1255355. PMID 20665378. Unknown parameter |month= ignored (help)
  15. Schuppan D, Afdhal NH (2008). "Liver cirrhosis". Lancet. 371 (9615): 838–51. doi:10.1016/S0140-6736(08)60383-9. PMC 2271178. PMID 18328931.
  16. Desmet VJ, Roskams T (2004). "Cirrhosis reversal: a duel between dogma and myth". J. Hepatol. 40 (5): 860–7. doi:10.1016/j.jhep.2004.03.007. PMID 15094237.
  17. Wanless IR, Nakashima E, Sherman M (2000). "Regression of human cirrhosis. Morphologic features and the genesis of incomplete septal cirrhosis". Arch. Pathol. Lab. Med. 124 (11): 1599–607. doi:10.1043/0003-9985(2000)124<1599:ROHC>2.0.CO;2. PMID 11079009.