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L11, The liver, gall bladder and Pancreas (annex of L9 [GIT]).

(Week 24th-28th December 2017)

The liver is an important organ in the human and is located in the upper right
quadrant of the abdomen, below the diaphragm. The liver is a large, meaty organ
and the heaviest internal organ and the largest gland in the human body too which
weighs up about 3 pounds (1.4-1.600 Kg). It has a reddish-browny color and feels
rubbery to the touch. It often starts in hepat- from the Greek word for liver. The
liver has a wide range of functions, which a most important is detoxification of
various metabolites, protein synthesis, and the production of biochemicals
necessary for digestion. It also plays a role in regulation of glycogen storage,
decomposition of RBC and hormone production. The liver is an accessory
digestive gland and produces bile, an alkaline compound which aids in
digestion via the emulsification of lipids. The gallbladder, a small pouch that sits
just under the liver, stores bile produced by the liver. The liver's highly specialized
tissue consisting of mostly hepatocytes (liver cells) regulates a wide variety of
high-volume biochemical reactions, including the synthesis and breakdown of
small and complex molecules, many of which are necessary for normal vital
functions. The organ's total number of functions vary, but textbooks generally cite
it is being around 500.
The liver is connected to two large blood vessels: the hepatic artery and the portal
vein. The hepatic artery carries oxygen-rich blood from the aorta, whereas the
portal vein carries blood rich in digested nutrients from the entire gastrointestinal
tract and also from the spleen and pancreas (Fig. 1). These blood vessels subdivide
into small capillaries known as liver sinusoids, which then lead to a lobule.

(Fig.1): The internal anatomy of human liver demonstrates the relevant blood vessels
and the location of gallbladder.
Because it's protected by the rib cage, it cannot be felt by hand. The liver has two
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large sections, called the right and the left lobes. There is currently no way to
compensate for the absence of liver function in the long term, although liver
dialysis techniques can be used in the short term. Artificial livers are yet to be
developed to promote long term replacement in the absence of the liver. As of
now, liver transplantation is the only option for complete liver failure.
The pancreas produces enzymes that help digest proteins, fats, and
carbohydrates. It also makes a substance that neutralizes stomach acid. These
enzymes and bile travel through special channels called (ducts) directly into the
small intestine, where they help to break down food. The liver also plays a major
role in the handling and processing of nutrients, which are carried to the liver in
the blood from the small intestine via portal vein.

(Fig. 2): Hepatic microarchitecture demonstrates the main components of its cells.

Architecture of Hepatic Tissue

The liver is covered with a connective tissue capsule that branches and extends
throughout the substance of the liver as septae. This connective tissue tree
provides a scaffolding of support and the highway which along with afferent blood
vessels, lymphatic vessels and bile ducts traverse the liver. Additionally, the sheets
of connective tissue divide the parenchyma of the liver into very small units called
lobules.

Lobules are the functional units of the liver. Each lobule is made up of millions of
hepatic cells (hepatocytes) which are the basic metabolic cells. The lobules are
held together by a fine dense irregular fibro-elastic connective tissue layer
which extends into the structure of the liver, by accompanying the vessels (veins
and arteries) ducts and nerves through the hepatic portal, as a fibrous capsule
called Glisson's capsule. The whole surface of the liver is covered in a serous coat
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derived from peritoneum and this has an inner fibrous coat (Glisson's capsule) to
which it is firmly adhered. The fibrous coat is of areolar tissue and follows the
vessels and ducts to support them (Fig. 2).
Sheets of connective tissue divide the liver into thousands of small units called
lobules. A lobule is roughly hexagonal in shape, with portal triads at the vertices
and a central vein in the middle. The lobule is the structural unit of the liver and
rather easy to observe. In contrast, the hepatic acinus is more difficult to
visualize, but represents a unit that is of more relevance to hepatic function
because it is oriented around the afferent vascular system (Fig. 3).

The parenchymal cells of the liver are hepatocytes. These polygonal cells are
joined to one another in anastomosing plates, with borders that face either the
sinusoids or adjacent hepatocytes. The ultrastructure appearance of hepatocytes
reflects their function as metabolic superstars, with abundant rough and smooth
endoplasmic reticulum, and Golgi membranes. Glycogen granules and vesicles
containing very low density lipoproteins are readily observed.

(Fig. 3): A 3D picture of a lobule shows the hexagonal lobules and the vessels
entering and leaving off.

Hepatocytes make contact with blood in sinusoids, which are distensible vascular
channels lined with highly fenestrated endothelial cells and populated with
phagocytic Kupffer cells (Fig.4a). The space between endothelium and
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hepatocytes is called the Space of Disse which collects lymph for delivery
to lymphatic capillaries.

(Fig. 4a): Location of Kupffer cells amongst the hepatocytes

The hepatic duct is continuous with the common bile duct, which delivers bile
into the duodenum. In most species, bile is diverted through the cystic duct into
the gall bladder. The simple columnar epithelium of the gall bladder is devoted
largely to absorption of water and electrolytes.

(Fig. 4b): The arrangements of sinusoids against the hepatocytes inside the liver.
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Understanding function and dysfunction of the liver, more than most other organs,
depends on understanding its structure. The major aspects of hepatic structure that
require detailed attention include:

 The hepatic vascular system, which has several unique characteristics relative
to other organs (Fig. 4b).
 The biliary tree, which is a system of ducts that transports bile out of the liver
into the small intestine
 The three dimensional arrangements of the liver cells, or hepatocytes and
their association with the vascular and biliary systems.

The Hepatic Vascular System

The circulatory system of the liver is unlike that seen in any other organ. Of great
importance is the fact that a majority of the liver's blood supply is venous blood. The
pattern of blood flow in the liver can be summarized as follows:
Roughly 75% of the blood entering the liver is venous blood from the portal
vein. Importantly, all of the venous blood returning from the small intestine, stomach,
pancreas and spleen converges into the portal vein. One consequence of this is that the
liver gets "first pickings" of everything absorbed in the small intestine, which, as we
will see, is where virtually all nutrients are absorbed.

The remaining 25% of the blood supply to the liver is arterial blood from the
hepatic artery (Fig. 5 and 6 a & b).

(Fig. 5): A 3D diagram of blood supply to liver and relevant sinusoids display the
direction of mixed blood inside it passing against the cords of hepatocytes to
empty inside the CV. Central veins coalesce into hepatic veins, which leave the
liver and empty into the vena cava.
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(Fig.6): A 3D and a schematic diagram to demonstrate the directions of

oxygenated and nutrition rich bloods entering and leaving the lobules

Terminal branches of the hepatic portal vein and hepatic artery empty together
and mix as they enter sinusoids in the liver. Sinusoids are distensible vascular
channels lined with highly fenestrated or "holey" endothelial cells and bounded
circumferentially by hepatocytes. As blood flows through the sinusoids, a
considerable amount of plasma is filtered into the space between endothelium and
hepatocytes (the "space of Disse"), providing a major fraction of the body's lymph.
Blood flows through the sinusoids and empties into the central vein of each
lobule (Fig.4).
The Biliary System:
The biliary system is a series of channels and ducts that conveys bile - a secretory and
excretory product of hepatocytes - from the liver into the lumen of the small intestine.
Hepatocytes are arranged in "plates" with their apical surfaces facing and surrounding
the sinusoids. The basal faces of adjoining hepatocytes are welded together by
junctional complexes to form canaliculi, the first channel in the biliary system. A bile
canaliculus is not a duct, but rather, the dilated intercellular space between adjacent
hepatocytes (Fig. 7)..

Hepatocytes secrete bile into the canaliculi, and those secretions flow parallel to the
sinusoids, but in the opposite direction that blood flows. At the ends of the canaliculi,
bile flows into bile ducts, which are true ducts lined with epithelial cells. Bile ducts
thus begin in very close proximity to the terminal branches of the portal vein and
hepatic artery, and this group of structures is an easily recognized and important
landmark seen in histologic sections of liver - the grouping of bile duct, hepatic
arteriole and portal venule is called a portal triad.
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(Fig. 7): A schematic diagram shows arrangement of hepatocytes in a cord like, a bile
canaliculus and bile duct.

Small bile ducts, or ductules, anastomose into larger and larger ducts, eventually
forming the common bile duct, which dumps bile into the duodenum. A sphincter
known as the sphinter of Oddi is present around the common bile duct as it enters the
intestine.

The gall bladder is another important structure in the biliary system of many species.
This is a sac-like structure adhering to the liver which has a duct (cystic duct) that
leads directly into the common bile duct. During periods of time when bile is not
flowing into the intestine, it is diverted into the gall bladder, where it is dehydrated
and stored until needed.

Main functions of the liver:

1). Synthesize of bile. This is a yellow-green liquid that goes into the small
intestines to help digest the food we eat. It has an alkaline pH.

2). Converts glucose to glycogen and stores following absorption by intestine, then
breaks the glycogen down into glucose and back into the blood when our blood
glucose level goes down. This may happen when we have not eaten for a while.

3). Takes protein and fat and turns it into glucose. This is important during fasting or
starvation. We can use the fat we have saved as energy and convert it into glucose to
use.

4). The liver also makes some fats and cholesterol.

5). The liver metabolizes (breaks down) many things in the blood e.g. hemoglobin;
proteins like enzymes; insulin and serum amyloid, ammonia and toxins (substances
that are poisons or [detoxification]) and waste from the body.

6). Stores vitamins and minerals.

7). Synthesize many proteins e.g. proteins that make the blood clot called
coagulation proteins; proteins like albumin
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8). In fetuses when they are very small, the liver makes red blood cells.

9). There are many different liver diseases that can make someone very sick because
of all the important work the liver does. People who have bad liver disease usually die
unless they can get a liver transplant. This is when the liver from someone who has
just died is put in another person by surgery. Such surgeries are usually technically
challenging but can be life-saving.
Liver Conditions
1. Hepatitis: Inflammation of the liver, usually caused by viruses like hepatitis A, B,
and C. Hepatitis can have non-infectious causes too, including heavy drinking,
drugs, allergic reactions, or obesity.
2. Cirrhosis: Long-term damage to the liver from any cause can lead to permanent
scarring, called cirrhosis. The liver then becomes unable to function well.
3. Liver cancer: The most common type of liver cancer, hepatocellular carcinoma,
almost always occurs after cirrhosis is present.
4. Liver failure: Liver failure has many causes including infection, genetic diseases,
and excessive alcohol.
5. Gallstones: If a gallstone becomes stuck in the bile duct draining the liver,
hepatitis and bile duct infection (cholangitis) can result.
6. Hemochromatosis: Hemochromatosis allows iron to deposit in the liver,
damaging it. The iron also deposits throughout the body, causing multiple other
health problems.
7. Primary sclerosing cholangitis: A rare disease with unknown causes, primary
sclerosing cholangitis causes inflammation and scarring in the bile ducts in the
liver.
8. Primary biliary cirrhosis: In this rare disorder, an unclear process slowly destroys
the bile ducts in the liver. Permanent liver scarring (cirrhosis) eventually
develops.
(4). Pancreas
The pancreas is a compound, finely nodular gland that is grossly similar to but less
compact than the salivary glands. It is surrounded by fine connective tissue but does
not have a fibrous tissue capsule. The lobules are visible on gross examination and
are connected by connective tissue septa that contain the blood vessels, nerves,
lymphatics, and excretory ducts (constituting about 18% of this organ). The gland
is a mixed exocrine (about 80%) and endocrine (about 2%) organ. The pancreas is a
soft, elongated, flattened gland 12 to 20 cm in length. The adult gland weighs between
70 and 110 gm. The head lies behind the peritoneum of the posterior abdominal wall
and has a lobular structure. The pancreas is covered with a fine connective tissue but
does not have a true capsule. The head of the pancreas is on the right side and lies
within the curvature of the duodenum. The neck, body, and tail of the pancreas lie
obliquely in the posterior abdomen, with the tail extending as far as the gastric surface
of the spleen. The pancreas is a secretory structure with an internal hormonal
role (endocrine) and an external digestive role (exocrine). It has two main ducts,
the main pancreatic duct, and the accessory pancreatic duct. These drain enzymes
through the ampulla of Vater into the duodenum. The pancreas is also a digestive
organ, secreting pancreatic juice containing digestive enzymes that assist digestion
and absorption of nutrients in the small intestine. These enzymes help to further break
down the carbohydrates, proteins, and lipids in the chyme.
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Histology of Pancreas:
The pancreas contains tissue with an endocrine and exocrine role, and this division is
also visible when the pancreas is viewed under a microscope. The tissues with
an endocrine role can be seen under staining as lightly-stained clusters of cells,
called pancreatic islets (islets of Langerhans). Darker-staining cells form clusters
called acini, which are arranged in lobes separated by a thin fibrous barrier. The
secretory cells of each acinus surround a small intercalated duct. Because of their
secretory function, these cells have many small granules of zymogens that are visible.
The intercalated ducts drains into larger ducts within the lobule, and
finally interlobular ducts. The ducts are lined by a single layer of columnar cells.
With increasing diameter, several layers of columnar cells may be seen making them
striated cuboidal or columnar epithelium. The pancreas forms from the
embryonic foregut and is therefore of endodermal origin.
1). Endocrine:
The part of the pancreas with endocrine function is made up of approximately 3
million cell clusters called pancreatic islets. These small micro organs are arranged
along the pancreas in the form of density routes. Four main cell types exist in the
islets. They are relatively difficult to distinguish using standard staining techniques
(H&E), but they can be classified by their secretion: α alpha cells secrete glucagon
(increase glucose in blood), β beta cells secrete insulin (decrease glucose in blood),
δ delta cells secrete somatostatin (regulates/stops α and β cells) and PP cells, or γ
(gamma) cells, secrete pancreatic polypeptide.
The islets are a compact collection of endocrine cells arranged in clusters and cords
and are crisscrossed by a dense network of capillaries. The capillaries of the islets are
lined by layers of endocrine cells in direct contact with vessels, and most endocrine
cells are in direct contact with blood vessels, either by cytoplasmic processes or by
direct apposition. The pancreatic islets play an imperative role in glucose metabolism
and regulation of blood glucose concentration.


 (Fig. 9): Cells of islet of Langerhans
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2). Exocrine:
The pancreas also functions as an exocrine gland that assists the digestive system.
It secretes pancreatic fluid that contains digestive enzymes that pass to the small
intestine. These enzymes help to further break down the carbohydrates, proteins
and lipids (fats) in the chyme. In humans, the secretory activity of the pancreas is
regulated directly via the effect of hormones in the blood on the pancreatic islets
and indirectly through the effect of the autonomic nervous system on the blood
flow. The exocrine component of the pancreas, often called simply the exocrine
pancreas, is the portion of the pancreas that performs exocrine functions. It has
ducts that are arranged in clusters called acini (singular acinus). Pancreatic
secretions are secreted into the lumen of the acinus, then accumulate in intra-
lobular ducts that drain to the main pancreatic duct, which drains directly into
the duodenum. Control of the exocrine function of the pancreas is via the
hormones: gastrin, cholecystokinin [CCK] secretes (digestive enzymes,
basophilic cells) and secretin (bicarbonate ions, Centro-acinar cells), which are
secreted by cells in the stomach and duodenum, in response to distension and/or
food and which cause secretion of pancreatic juices. Pancreatic secretions from
ductal cells contain bicarbonate ions and are alkaline in order to neutralize the
acidic chyme that the stomach churns out. The pancreas is also the main source of
enzymes for digesting fats (lipids) and proteins. (The enzymes that
digest polysaccharides, by contrast, are primarily produced by the walls of
the intestines).


(Fig. 10): Schematic diagram of pancreatic acini and ducts.

 Goblet cells and occasional Argentaffin cells also are present. The interlobular
ducts anastomose to become the main pancreatic duct. The larger ducts have a
somewhat thick wall consisting of connective tissue and elastic fibers. Acinar,
ductal, and islet cells can be distinguished by monoclonal antibodies
specifically reactive with these cell types. Acinar cells are tall, pyramidal or
columnar epithelial cells, with their broad bases on a basal lamina and their
apices converging on a central lumen. In the resting state, numerous
eosinophilic zymogen granules fill the apical portion of the cell. The basal
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portion of the cells contains one or two centrally located, spherical nuclei and
extremely basophilic cytoplasm.


 (Fig-11): Locations of Islet of Langerhan's and acinar parts of pancreas in CS.

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Although the acinar cell secretes several different digestive enzymes in the
exocrine pancreas, each cell type in the endocrine pancreas appears to secrete a
single hormone. The 4 major types of cells found are B cells, A cells, D cells, and
PP cells. β-cells (beta cells), the most numerous (50% to 80%), secrete insulin. α-
cells or alpha cells (5% to 20%) secrete glucagon. PP-cells (pancreatic
polypeptide) cells (10% to 35%) secrete pancreatic polypeptide. D-cells (5%)
secrete somatostatin. Other rare cell types occur in the islet. In humans, the islets
are subdivided into units, each of which exhibits a central aggregation of β-cells
surrounded by varying numbers of peripherally located cells that secrete the other
hormones.

(Fig 12): Histology of pancreatic islet cells (Langerhan's iset) treated for
immunohistochemistry (IHC). Note the distribution of alpha α-cells containing glucagon
(almost peripherally located cells) on the left while the beta cells containing insulin on
the right are located in the middle and more abundant (The brown color is the Di-
Amino-Benzidine [DAB]).