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Liver and intrahepatic bile ducts-nontumor

General concepts

Cirrhosis - general


Reviewers: Komal Arora, M.D. (see Reviewers page)
Revised: 6 February 2013, last major update April 2012
Copyright: (c) 2004-2013, PathologyOutlines.com, Inc.

General
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● Diffuse nodulation of liver due to fibrous bands subdividing liver into regenerative nodules
Fibrous bands: the key feature of cirrhosis is not bland fibrosis, but rather vascular septa
● Blood vessels no longer reach outflow via highly expansile sinusoids, but rather through resistant collagen significantly contributing to the portal hypertension
● Blood bypasses hepatocytes via vascularity within the septa which also contributes to the impaired anabolic/catabolic capacity of the liver
● All three features (diffuse nodulation, regenerative nodules, fibrous bands) must be present: congenital hepatic fibrosis lacks regenerative nodules, focal nodular hyperplasia lacks diffuse nodulation, nodular regenerative hyperplasia lacks fibrous bands
● Macroregenerative nodules (MRNs) are 1 cm or more in diameter
● Cirrhosis is usually considered irreversible (regression rare in schistosomiasis, hemochromatosis); fibrosis alters patterns of blood flow and hepatocyte perfusion; initially around portal tracts, central vein or within space of Disse; later subdivides liver into nodules of regenerating hepatocytes surrounded by scar tissue (cirrhosis)
● The fibrosis is reversible; the vascular septa will not go away but fibrosis will (Arch Pathol Lab Med 2000;124:1599)
● Nodules tend to increase in size over time
● Represents the final common pathway of causes listed below; difficult to determine cause once present

Causes
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● Alcoholic liver disease (60%), viral hepatitis (10%), biliary disease (5%), primary hemochromatosis (5%), idiopathic (5%), rare causes are Wilson’s disease, alpha-1-antitrypsin deficiency, galactosemia or tyrosinosis in children, cancer, drugs, syphilis, severe cardiac disease (cardiac cirrhosis), jejunoileal bypass, extensive small bowel resection
● Idiopathic cases are often nonalcoholic steatohepatitis (33%), autoimmune liver disease (22%), alcoholic liver disease (14%, Hum Pathol 2002;33:1098)

Pathogenesis
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● Normally, interstitial collagen types I and III is present in portal tracts, around central veins and occasionally in space of Disse
● Reticulin along hepatocytes is composed of type IV collagen
● In cirrhosis, type I and III collagen are deposited in lobule, creating septal tracts
● New vascular channels form, but blood is shunted around the parenchyma
● Fenestrations in sinusoidal endothelial cells are lost, so sinusoidal space resembles a capillary more than a channel for exchange of solutes between hepatocytes and plasma
● Ito cells (hepatic stellate cells with myofibroblastic features) produce excess collagen in cirrhosis; normally they store vitamin A, but are activated during development of cirrhosis, lose their retinyl ester stores and transform into myofibroblast-like cells
● Collagen synthesis and deposition are due to chronic inflammation (TNF-alpha, TGF-beta, IL-1), cCytokines from Kupffer cells, endothelial cells, bile duct cells and hepatocytes; also disruption of extracellular matrix and toxins
● Ito cells also constrict sinusoidal vascular channels
● Bile channels are obliterated due to disruption of interface between parenchyma and portal tracts, causing jaundice

Clinical features
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Symptoms: none; also anorexia, weight loss, weakness, osteoporosis
Late - frank debilitation, portal hypertension, hepatic failure (with new stress)
Hepatopulmonary syndrome: due to imbalances of pulmonary blood flow, causes further stress
● Death due to progressive liver failure, portal hypertension complications, hepatocellular carcinoma

Regression: controversial; proponents argue that it may occur if therapy halts progression
● Suggested by delicate perforated septa (incomplete fibrous septa whose residual components form linear, usually curved structure), isolated thick collagen fibers (not visibly attached to portal structure, hepatic vein or septum), delicate periportal fibrous spikes (collagenous extensions from portal tracts without visible connection to other portal tracts or hepatic veins), portal tract remnants (artery/duct pairs, unaccompanied arteries, or unaccompanied ducts, usually with absent portal vein, usually have less portal tract collagen than normal)
● Also hepatic vein remnants with prolapsed hepatocytes within the lumen, hepatocytes within portal tracts or splitting septa (clusters/cords of hepatocytes 2 or more cells in thickness within portal tracts or wedged between layers of fibrous septa), minute regenerative nodules (small clusters of hepatocytes less than 10 cells in diameter mixed with ductules), aberrant parenchymal veins (veins within 5 hepatocyte diameters of portal tracts, Arch Pathol Lab Med 2000;124:1599, Best Pract Res Clin Gastroenterol. 2011;25:281)

Gross images
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Micronodular and macronodular cirrhosis

Micro description
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● Disruption in architecture of entire liver (loss of normal central-portal relationships) with bridging fibrous septa (delicate bands, broad scars) and rounded parenchymal nodules of regenerating hepatocytes without central veins; also abnormal vasculature due to parenchymal damage and scarring
Hard to diagnose cases: fragmented specimens with rounded edges containing connective tissue (use Trichrome or reticulin stains to visualize), no normal portal tracts, irregular central veins, two cell thick plates, large cell change is suggestive

Micro images
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Fibrosis (trichrome)

       
Bridging fibrosis types (left to right): portal-portal; central-central; portal-central

                   

                   
Images and diagrams of regression of cirrhosis

Biopsy description
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● Cannot distinguish cirrhosis from bridging fibrosis due to small sample size, although reticulin stain may confirm regenerative nodules based on cell plates 3+ cells thick; if reticulin fibers are on three for four sides of a parenchymal fragment that indicates cirrhosis
● Absence of regenerative activity or presence of normal portal tracts and central veins argues against diagnosis of cirrhosis
● Don’t call definite cirrhosis unless at least one complete regenerative nodule can be identified
● Cirrhotic liver biopsy often has multiple small fragments of hepatocytes with smooth rounded contour due to leaving fibrous tissue behind

Positive stains
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● Reticulin stain and collagen stains may highlight disordered lobular features, cirrhotic fibrosis is strongly positive for vitronectin (Hum Pathol 2001;32:1356)

Differential diagnosis
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● Localized subcapsular or parenchymal scars might be interpreted as the sequel to injury whereas the capsule often "dips" into the parenchyma and can be interpreted as a septum, wedge biopsies (subcapsular connective tissue is more prominent and extends into portal tracts within 1 cm of capsule), normal portal tract containing large artery and large duct with “normal” fibrous tissue, nodular regenerative hyperplasia

Additional references
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Arch Pathol Lab Med 2000;124:1587


Alcoholic cirrhosis

General
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● Larger nodules are associated with periodic alcohol abstinence, causing more regeneration of hepatocytes

Gross images
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Alcoholic cirrhosis

Micro description
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● Micronodular cirrhosis, Mallory bodies, fatty change
● Also perivenular and pericellular fibrosis (highlighted with Trichrome stain) with partial/complete obliteration of central vein (identify as central vein due to lack of arterioles)
● More prominent bridging from central zone to central zone and central zone to portal zone than in other causes of cirrhosis
● Usually few inflammatory cells unless superimposed viral or alcoholic hepatitis

Micro images
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Alcoholic cirrhosis

Differential diagnosis
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● Non-alcoholic steatohepatitis

Additional references
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Gastroenterology 2011;141:1572


Biliary tract disease related

General
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● Caused by primary biliary cirrhosis, primary or secondary sclerosing cholangitis, idiopathic inflammatory bowel disease, duct obstruction

Laboratory
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● Elevated serum alkaline phosphatase

Micro description
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● Jigsaw pattern of cirrhosis due to portal to portal bridging fibrosis
● No rounded cirrhotic nodules
● Minimal distortion of central veins until late
● May have cholangiole proliferation, portal tract inflammation with pericholangiole neutrophils, disruption of terminal plate by mononuclear cells and piecemeal necrosis
● Often has prominent zone 1 cholate stasis (formerly referred to as "feathery degeneration") with deposition of copper-associated protein and sometimes copper (orcein or Victoria blue)

Positive stains
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● Copper (due to chronic cholestasis)

Differential diagnosis
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● Chronic hepatitis

Additional references
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Best Pract Res Clin Gastroenterol 2011;25:701


Hepatitis C

Micro description
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● Rounded nodules; lymphoid aggregates, the key feature is interface hepatitis

Micro images
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Hepatitis C with cirrhosis

Additional references
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Clin Liver Dis 2010;14:555


Incomplete septal cirrhosis

General
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● Portal hypertension with normal liver function
● Hepatic nodules separated by extremely thin bands of collagen difficult to recognize on needle biopsy
● May have disorganized cell plates / zones resembling nodular regenerative hyperplasia
● Associated with various diseases such as regenerative nodular hyperplasia, idiopathic portal hypertension, and partial non-cirrhotic nodular transformation, as well as with progression and regression of cirrhosis of any etiology
● Good prognosis if portal hypertension is controlled

Micro images
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Incomplete septal cirrhosis

Additional references
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Liver Int 2004;24:452, Histopathology 1988;13:593, Arch Pathol Lab Med 2000;124:1599

End of Liver and intrahepatic bile ducts-nontumor > General concepts > Cirrhosis - general


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