Goid

1. THE LIVER & BILE DUCTS
Dr. Tayyaba Ashiq
MBBS, FCPS Chemical Pathology
Senior Registrar at
Hamdard University Hospital

2. LEARNING OUTCOMES
Students should be able to
Appreciate the histological structure of liver.
Enlist the function of liver
Name the tests to asses the liver functions
Understand mode of injury and tissue response
Repair mechanism of liver
Role of liver in immunity

3. The Liver
• The normal adult liver weighs
1400 to 1600 gm.
• It has a dual blood supply, with
oThe Portal vein providing 60% to
70% of hepatic blood flow
oThe Hepatic artery supplying the
remaining 30% to 40%.

4. Liver functions
Liver plays important role in
• Digestion process- Bile production, 1st pass effect
• Storage function (vit A, D, E, K, B12 & minerals-Fe, Cu, Zn-, glycogen )
• Detoxification (toxins, NH3 and drugs)
• Excretory function (cholesterol, bile)
• Synthetic functions (proteins, clotting factors)
• Metabolism (carbohydrate, lipid, proteins, Hb)
• Immunity

7. Histological structure of liver
• The most common terminology
of the hepatic microarchitecture
is based on the lobular model

8. • Division of the parenchyma into
zones is a useful concept since
certain types of hepatic injury tend
to preferentially affect particular
zones.
• Hepatocytes are organized into
anastomosing sheets or “plates”
extending from portal tracts to the
terminal hepatic veins
• Between the trabecular plates of
hepatocytes are vascular sinusoids.

9. • The sinusoids are lined by fenestrated endothelial cells. Scattered
Kupffer cells of the mononuclear phagocyte system are attached to
the luminal face of endothelial cells
• Beneath the endothelial cells lies the space of Disse, into which
protrude abundant hepatocyte microvilli.
• fat-containing myofibroblastic hepatic stellate cells are found in the
space of Disse.

11. • Bile canaliculi are channels 1 to 2 µm in diameter, formed by grooves
in the plasma membranes of facing hepatocytes and separated from
the vascular space by tight junctions.
• These channels drain into the canals of Hering that, in turn, connect
to bile ductules in the periportal region.
• The ductules empty into the terminal bile ducts within the portal
tracts.

13. • Large numbers of lymphocytes are also present in normal liver,
comprising as much as 22% of cells other than hepatocytes

14. General Features of Liver Disease
• The liver is vulnerable to a wide variety of metabolic, toxic, microbial,
circulatory, and neoplastic insults
• primary diseases of the liver are
• viral hepatitis,
• nonalcoholic fatty liver disease (NAFLD),
• alcoholic liver disease, and
• hepatocellular carcinoma (HCC).
• secondary to some of the most common diseases in humans
• such as heart failure,
• disseminated cancer, and
• extrahepatic infections.

15. • The enormous functional reserve
• With the exception of acute liver failure failure, liver disease is an
insidious process in which clinical detection and symptoms of hepatic
decompensation may occur weeks, months, or many years after the
onset of injury.
• liver injury and healing may also occur without clinical detection. The
patient may be asymptomatic and liver injury is detectable only by
abnormal laboratory tests. Hence, individuals with hepatic
abnormalities who are referred to hepatologists most frequently have
chronic liver disease

16. Mechanisms of Injury and Repair
• Depends upon the Hepatocyte and Parenchymal Responses
• Mild injury causes potentially reversible changes, such a
• accumulation of fat (steatosis) and
• bilirubin (cholestasis)
• When injury is not reversible, hepatocytes die principally by two
mechanisms:
• necrosis or
• apoptosis

17. Hepatocyte necrosis
• the cell swells
• and ruptures. Even before
rupture, membrane blebs form,
carrying off cytoplasmic contents
(without organelles) into the
extracellular compartment.
• Macrophages cluster at such
sites of injury and mark the sites
of hepatocyte necrosis
Its predominant mode of death in
ischemic/hypoxic injury and a
significant part of the response to
oxidative stress

18. Hepatocyte apoptosis
• its “programmed” cell death
resulting in
• hepatocyte shrinkage,
• nuclear chromatin condensation
(pyknosis),
• fragmentation (karyorrhexis),
and
• cellular fragmentation into
acidophilic apoptotic bodies

19. Severity of injury and tissue response
• In acute toxic or ischemic injuries or in severe viral or autoimmune
hepatitis confluent necrosis occurs.
• Confluent necrosis may begin as a zone of hepatocyte dropout
around the central vein. The resulting space is filled by cellular debris,
macrophages, and remnants of the reticulin meshwork.
• In bridging necrosis this zone may link central veins to portal tracts or
bridge adjacent portal tracts (often with an inapparent central vein
within the zone of injury).

21. • when there is extensive hepatocyte loss & collapse of the supporting
framework the cirrhosis results. In some cases there is scar regression
as depicted in the figure.
• Regeneration of lost hepatocytes occurs primarily by mitotic
replication of hepatocytes adjacent to those that have died,
• In the most severe forms of acute liver failure, there is activation of
the primary intrahepatic stem cell niche, namely the canal of Hering.
• Interestingly, in biliary diseases, the “ductular” progeny of stem cells
can give rise to cholangiocytes

22. Scar Formation and Regression
• The principal cell type involved in scar deposition is the hepatic
stellate cell.
• In its quiescent form, it is a lipid (vitamin A) storing cell.
• However, in several forms of acute and chronic injury, the stellate
cells can become activated and are converted into highly fibrogenic
myofibroblasts.

24. stimuli for stellate cell activation may originate from several sources
(Fig. 18-5):
1. chronic inflammation, with production of inflammatory cytokines such as
TNF, lymphotoxin, and IL1β, and lipid peroxidation products;
2. cytokine and chemokine production by Kupffer cells, endothelial cells,
hepatocytes, and bile duct epithelial cells;
3. in response to disruption of the extracellular matrix (ECM); and
4. direct stimulation of stellate cells by toxins.

25. • These stimuli causes increase in the expression of platelet-derived
growth factor receptor β (PDGFR-β) in the stellate cells
• At the same time, Kupffer cells and lymphocytes release cytokines
and chemokines that modulate the expression of genes in stellate
cells that are involved in fibrogenesis. These, include transforming
growth factor β (TGF-β) and its receptors, MMP-2, and TIMP-1 and -2.

27. • If injury persists, scar deposition begins, often in the space of Disse.
• If the chronic injury is interrupted (e.g. clearance of hepatitis virus
infection, cessation of alcohol use), then stellate cell activation
ceases, scars condense, becoming more dense and thin, and
then, begin to break apart ( by the action of metalloprotease
produced by hepatocytes). In this way, scar formation can be
reversed.

28. • It should be kept in mind that in any chronic liver disease there are
probably areas of both fibrotic progression and regression, but the
balance in active disease favors the former and with remission of
disease the latter is favored
• Eventually, these fibrous septa encircle surviving, regenerating
hepatocytes in the late stages of chronic liver diseases that give rise
to diffuse scarring described as cirrhosis

29. Inflammation and Immunity

30. Inflammation and Immunity
• The liver is a key, frontline immune tissue-ideally positioned to detect
pathogens entering the body via the gut. Containing the largest
collection of phagocytic cells in the body, this organ is an important
barrier between us and the outside world.
• the liver appears designed to detect, capture, and clear bacteria,
viruses, and macromolecules.
• Dynamic interactions between the numerous populations of immune
cells in the liver are key to maintaining this balance and overall tissue
health.

31. Inflammation and Immunity
• KC, dendritic cells & NKC provide innate immunity.
• Antigens in the liver are taken up by antigen presenting cells,
including, Kupffer cells and blood-derived dendritic cells, and
presented to lymphocytes
• Adaptive immunity plays an even more critical role in viral hepatitis.
Antigen-specific and CD8+ T cells are involved in eradication of
hepatitis B and C, largely through elimination of infected hepatocytes.
• Lymphocytes, however, not only play a destructive role, but also help
induce local hepatocyte replication through secretion of cytokines.