¹ 5.
Digestive system. Liver.
Basic
Functional Anatomy of the Digestive System
The
digestive system is composed of the digestive or alimentary tube and accessory
digestive organs. The basic terminology used to describe parts of the digestive
system is shown below and more detailed description of each is presented in
later sections.
The
digestive system depicted above - a carnivore - is the simplist among mammals.
Other species, even humans, have a more or very much more extensive large
intestine, and ruminants like cattle and sheep have a large set of forestomachs
through which food passes before it reaches the stomach.
Each
of the organs shown above contributes to the digestive process in several
unique ways. If you were to describe their most important or predominant
function, and summarize shamelessly, the list would look something like this:
Mouth:
Foodstuffs are broken down mechanically by chewing and saliva is added as a
lubricant. In some species, saliva contains amylase, an enzyme that digests
starch.
Esophagus:
A simple conduit between the mouth and stomach - clearly important but only
marginally interesting compared to other regions of the tube.
Stomach:
Where the real action begins - enzymatic digestion of proteins initiated and
foodstuffs reduced to liquid form.
Liver:
The center of metabolic activity in the body - its major role in the digestive
process is to provide bile salts to the small intestine, which are critical for
digestion and absorption of fats.
Pancreas:
Important roles as both an endocrine and exocrine organ - provides a potent
mixture of digestive enzymes to the small intestine which are critical for
digestion of fats, carbohydrates and protein.
Small
Intestine: The most exciting place to be in the entire digestive system - this
is where the final stages of chemical enzymatic digestion occur and where
almost almost all nutrients are absorbed.
Large
Intestine: Major differences among species in extent and importance - in all
animals water is absorbed, bacterial fermentation takes place and feces are
formed. In carnivores, that's about the extent of it, but in herbivores like
the horse, the large intestine is huge and of critical importance for
utilization of cellulose.
LIVER
Liver
Liver
of a sheep: (1) right lobe, (2) left lobe, (3) caudate lobe, (4) quadrate lobe,
(5) hepatic artery and portal vein, (6) hepatic lymph nodes, (7) gall bladder.
|
Gray's |
subject
#250 1188 |
|
Artery |
hepatic
artery |
|
Vein |
hepatic
vein, portal vein |
|
Nerve |
celiac
ganglia, vagus |
|
Precursor |
foregut |
|
MeSH |
Liver |
The
liver is an organ in some animals, including vertebrates (and therefore
humans). It plays a major role in metabolism and has a number of functions in the
body including glycogen storage, plasma protein synthesis, and drug
detoxification. This organ also is the largest gland in the human body and lies
beneath the diaphragm in the upper right portion of the abdomen. It produces
bile, which is important in digestion. It performs and regulates a wide variety
of high-volume biochemical reactions requiring specialized tissues. Medical
terms related to the liver often start in hepato- or hepatic from the Greek
word for liver, hepar.
Anatomy
The
adult human liver normally weighs between 1.7 -
It
is located on the right side of the upper abdomen body diaphragm. The liver
lies on the right of the stomach and makes a kind of bed for the gallbladder
(which stores bile).
Flow
of blood
The
splenic vein, joins with the Inferior mesenteric vein, which then together join
with the Superior Mesenteric Vein to form the portal vein, bringing venous
blood from the spleen, pancreas, small intestine, and large intestine, so that
the liver can process the nutrients and byproducts of food digestion.
The
hepatic veins drain directly into the inferior vena cava.
The
hepatic artery is generally a branch from the celiac trunk, although
occasionally some or all of the blood can be from other branches such as the
superior mesenteric artery.
Approximately
3/4 of the blood flow to the liver is from the portal venous system, and 1/4 is
from the hepatic artery.
Flow
of bile
The bile produced in the liver is
collected in bile canaliculi, which merge to form bile ducts.
These
eventually drain into the right and left hepatic ducts, which in turn merge to
form the common hepatic duct. The cystic duct (from the gallbladder) joins with
thecommon hepatic duct to form the common bile duct.
Bile
can either drain directly into the duodenum via the common bile duct or be temporarily
stored in the gallbladder via the cystic duct. The common bile duct and
thepancreatic duct enter the duodenum together at the ampulla of Vater.
The
branchings of the bile ducts resemble those of a tree, and indeed the term
"biliary tree" is commonly used in this setting.
Regeneration
The
liver is among the few internal human organs capable of natural regeneration of
lost tissue; as little as 25% of remaining liver can regenerate into a whole
liver again.
This
is predominantly due to the hepatocytes acting as unipotential stem cells (i.e.
a single hepatocyte can divide into two hepatocyte daughter cells). There is
also some evidence of bipotential stem cells, called oval cells, which can
differentiate into either hepatocytes or cholangiocytes (cells that line the
bile ducts).
Traditional
(Surface) anatomy
Peritoneal
ligaments
Apart
from a patch where it connects to the diaphragm, the liver is covered entirely
by visceral peritoneum, a thin, double-layered membrane that reduces
frictionagainst other organs. The peritoneum folds back on itself to form the
falciform ligament and the right and left triangular ligaments.
These
"ligaments" are in no way related to the true anatomic ligaments in
joints, and have essentially no functional importance, but they are easily
recognizable surface landmarks.
Lobes
Traditional
gross anatomy divided the liver into four lobes based on surface features.
The
falciform ligament is visible on the front (anterior side) of the liver. This
divides the liver into a left anatomical lobe, and a right anatomical lobe.
If
the liver is flipped over, to look at it from behind (the visceral surface),
there are two additional lobes between the right and left. These are the
caudate lobe (the moresuperior), and below this the quadrate lobe.
From
behind, the lobes are divided up by the ligamentum venosum and ligamentum teres
(anything left of these is the left lobe), the transverse fissure (or porta
hepatis) divides the caudate from the quadrate lobe, and the right sagittal fossa,
which the inferior vena cava runs over, separates these two lobes from the
right lobe.
Modern
(Functional) anatomy
The
central area where the common bile duct, portal vein, and hepatic artery enter
the liver is the hilum or "porta hepatis". The duct, vein, and artery
divide into left and right branches, and the portions of the liver supplied by
these branches constitute the functional left and right lobes.
The
functional lobes are separated by a plane joining the gallbladder fossa to the
inferior vena cava. This separates the liver into the true right and left
lobes. The middle hepatic vein also demarcates the true right and left lobes.
The right lobe is further divided into an anterior and posterior segment by the
right hepatic vein. The left lobe is divided into the medial and lateral
segments by the left hepatic vein. The fissure for the ligamentum teres (the
ligamentum teres becomes the falciform ligament) also separates the medial and
lateral segmants. The medial segment is what used to be called the quadrate
lobe. In the widely used Couinaud or "French" system, the functional
lobes are further divided into a total of eight subsegments based on a
transverse plane through the bifurcation of the main portal vein. The caudate
lobe is a separate structure which receives blood flow from both the right- and
left-sided vascular branches. The subsegments corresponding to the anatomical
lobes are as follows:
|
Segment* |
Couinaud
segments |
|
Caudate |
1 |
|
Lateral |
2, 3 |
|
Medial |
4a, 4b |
|
Right |
5, 6, 7, 8 |
Physiology
The
various functions of the liver are carried out by the liver cells or
hepatocytes.
The
liver produces and excretes bile required for emulsifying fats. Some of the
bile drains directly into the duodenum, and some is stored in the gallbladder.
The
liver performs several roles in carbohydrate metabolism:
·
Gluconeogenesis (the synthesis of
glucose from certain amino acids, lactate or glycerol)
·
Glycogenolysis (the breakdown of
glycogen into glucose) (muscle tissues can also do this)
·
Glycogenesis (the formation of
glycogen from glucose)
·
The breakdown of insulin and other
hormones
·
The liver is responsible for the
mainstay of protein metabolism.
·
The liver also performs several roles
in lipid metabolism:
·
Cholesterol synthesis
·
The production of triglycerides
(fats).
·
The liver produces coagulation
factors I (fibrinogen), II (prothrombin), V, VII, IX, X and XI, as well as
protein C, protein S and antithrombin.
·
The liver breaks down haemoglobin,
creating metabolites that are added to bile as pigment (bilirubin and
biliverdin).
·
The liver breaks down toxic
substances and most medicinal products in a process called drug metabolism.
This sometimes results in toxication, when the metabolite is more toxic than
its precursor.
·
The liver converts ammonia to urea.
·
The liver stores a multitude of
substances, including glucose in the form of glycogen, vitamin B12, iron, and
copper.
·
In the first trimester fetus, the
liver is the main site of red blood cell production. By the 32nd week of
gestation, the bone marrow has almost completely taken over that task.
·
The liver is responsible for
immunological effects- the reticuloendothelial system of the liver contains
many immunologically active cells, acting as a 'sieve' for antigens carried to
it via the portal system.
Currently,
there is no artificial organ or device capable of emulating all the functions
of the liver. Some functions can be emulated by liver dialysis, an experimental
treatment for liver failure.
Diseases
of the liver
Many
diseases of the liver are accompanied by jaundice caused by increased levels of
bilirubin in the system. The bilirubin results from the breakup of the
hemoglobinof dead red blood cells; normally, the liver removes bilirubin from
the blood and excretes it through bile.
Hepatitis,
inflammation of the liver, caused mainly by various viruses but also by some
poisons, autoimmunity or hereditary conditions.
Cirrhosis
is the formation of fibrous tissue in the liver, replacing dead liver cells.
The death of the liver cells can for example be caused by viral
hepatitis,alcoholism or contact with other liver-toxic chemicals.
Hemochromatosis,
a hereditary disease causing the accumulation of iron in the body, eventually
leading to liver damage.
Cancer
of the liver (primary hepatocellular carcinoma or cholangiocarcinoma and
metastatic cancers, usually from other parts of the gastrointestinal tract).
Wilson's
disease, a hereditary disease which causes the body to retain copper.
Primary
sclerosing cholangitis, an inflammatory disease of the bile duct, autoimmune in
nature.
Primary
biliary cirrhosis, autoimmune disease of small bile ducts
Budd-Chiari
syndrome, obstruction of the hepatic vein.
Gilbert's
syndrome, a genetic disorder of bilirubin metabolism, found in about 5% of the
population.
Glycogen
storage disease type II,The build-up of glycogen causes progressive muscle
weakness (myopathy) throughout the body and affects various body tissues,
particularly in the heart, skeletal muscles, liver and nervous system.
There
are also many pediatric liver disease, including biliary atresia, alpha-1
antitrypsin deficiency, alagille syndrome, and progressive familial
intrahepatic cholestasis, to name but a few.
A
number of liver function tests are available to test the proper function of the
liver. These test for the presence of enzymes in blood that are normally most
abundant in liver tissue, metabolites or products.
Liver
transplantation
Human
liver transplant was first performed by Thomas Starzl in
Liver
allografts for transplant usually come from non-living donors who have died
from fatal brain injury. Living donor liver transplantation is a technique in
which a portion of a living person's liver is removed and used to replace the
entire liver of the recipient. This was first performed in 1989 for pediatric
liver transplantation. Only 20% of an adult's liver (Couinaud segments 2 and 3)
is needed to serve as a liver allograft for an infant or small child.
More
recently, adult-to-adult liver transplantation has been done using the donor's
right hepatic lobe which amounts to 60% of the liver. Due to the ability of the
liver toregenerate, both the donor and recipient end up with normal liver
function if all goes well. This procedure is more controversial as it entails
performing a much larger operation on the donor, and indeed there have been at
least 2 donor deaths out of the first several hundred cases. A recent
publication has addressed the problem of donor mortality, and at least 14 cases
have been found. The risk of postoperative complications (and death) is far
greater in right sided hepatectomy than left sided operations
Development
The
liver develops as an endodermal outpocketing of the foregut called the hepatic
diverticulum. Its initial blood supply is primarily from the vitelline veins
that drain blood from the yolk sac. The superior part of the hepatic
diverticulum gives rise to the hepatocytes and bile ducts, while the inferior
part becomes the gallbladder and its associated cystic duct.
Fetal
blood supply
In
the growing fetus, a major source of blood to the liver is the umbilical vein
which supplies nutrients to the growing fetus. The umbilical vein enters the
abdomen at the umbilicus, and passes upward along the free margin of the
falciform ligament of the liver to the inferior surface of the liver. There it
joins with the left branch of the portal vein. The ductus venosus carries blood
from the left portal vein to the left hepatic vein and then to the inferior
vena cava, allowing placental blood to bypass the liver.
In
the fetus, the liver is developing throughout normal gestation, and does not
perform the normal filtration of the infant liver. The liver does not perform
digestive processes because the fetus does not consume meals directly, but
receives nourishment from the mother via the placenta. The fetal liver releases
some blood stem cells that migrate to the fetal thymus, so initially the
lymphocytes, called T-cells, are created from fetal liver stem cells. Once the
fetus is delivered, the formation of blood stem cells in infants shifts to the
red bone marrow.
After
birth, the umbilical vein and ductus venosus are completely obliterated two to
five days postpartum; the former becomes the ligamentum teres and the latter
becomes the ligamentum venosum. In the disease state of cirrhosis and portal
hypertension, the umbilical vein can open up again.
Digestion
is the mechanical and chemical breakdown of food into smaller components that
are more easily absorbed into a blood stream, for instance. Digestion is a form
of catabolism: a breakdown of large food molecules to smaller ones.
When
food enters the mouth, its digestion starts by the action of mastication, a
form of mechanical digestion, and the contact of saliva. Saliva, which is
secreted by the salivary glands, contains salivary amylase, an enzyme which
starts the digestion of starch in the food. After undergoing mastication and
starch digestion, the food will be in the form of a small, round slurry mass
called a bolus. It will then travel down the esophagus and into the stomach by
the action of peristalsis. Gastric juice in the stomach starts protein
digestion. Gastric juice mainly contains hydrochloric acid and pepsin. As these
two chemicals may damage the stomach wall, mucus is secreted by the stomach,
providing a slimy layer that acts as a shield against the damaging effects of
the chemicals. At the same time protein digestion is occurring, mechanical
mixing occurs by peristalsis, which are waves of muscular contractions that
move along the stomach wall. This allows the mass of food to further mix with
the digestive enzymes. After some time (typically an hour or two in humans, 4–6
hours in dogs, somewhat shorter duration in house cats), the resulting thick
liquid is called chyme. When the pyloric sphincter valve opens, chyme enters
the duodenum where it mixes with digestive enzymes from the pancreas, and then
passes through the small intestine, in which digestion continues. When the
chyme is fully digested, it is absorbed into the blood. 95% of absorption of
nutrients occurs in the small intestine. Water and minerals are reabsorbed back
into the blood in the colon (large intestine) where the pH is slightly acidic
about 5.6 ~ 6.9. Some vitamins, such as biotin and vitamin K (K2MK7) produced
by bacteria in the colon are also absorbed into the blood in the colon. Waste
material is eliminated from the rectum during defecation.
Digestive
systems
Digestive
systems take many forms. There is a fundamental distinction between internal
and external digestion. External digestion is more primitive, and most fungi
still rely on it. In this process, enzymes are secreted into the environment
surrounding the organism, where they break down an organic material, and some
of the products diffuse back to the organism. Later, animals form a tube in
which internal digestion occurs, which is more efficient because more of the
broken down products can be captured, and the internal chemical environment can
be more efficiently controlled.
Some
organisms, including nearly all spiders, simply secrete biotoxins and digestive
chemicals (e.g., enzymes) into the extracellular environment prior to ingestion
of the consequent "soup". In others, once potential nutrients or food
is inside the organism, digestion can be conducted to a vesicle or a sac-like
structure, through a tube, or through several specialized organs aimed at
making the absorption of nutrients more efficient.
Secretion
systems
Secretion
is the process of elaborating, releasing, and oozing chemicals, or a secreted
chemical substance from a cell or gland. In contrast to excretion, the
substance may have a certain function, rather than being a waste product. The
classical mechanism of cell secretion is via secretory portals at the cell
plasma membrane called porosomes. Porosomes are permanent cup-shaped
lipoprotein structure at the cell plasma membrane, where secretory vesicles
transiently dock and fuse to release intra-vesicular contents from the cell.
Secretion
in bacterial species means the transport or translocation of effector molecules
for example: proteins, enzymes or toxins (such as cholera toxin in pathogenic
bacteria for example Vibrio cholerae) from across the interior (cytoplasm or
cytosol) of a bacterial cell to its exterior. Secretion is a very important
mechanism in bacterial functioning and operation in their natural surrounding
environment for adaptation and survival.
Secretion
in eukaryotic cells
Mechanism
Eukaryotic
cells, including human cells, have a highly evolved process of secretion.
Proteins targeted for the outside are synthesized by ribosomes docked to the
rough endoplasmic reticulum (ER). As they are synthesized, these proteins
translocate into the ER lumen, where they are glycosylated and where molecular
chaperones aid protein folding. Misfolded proteins are usually identified here
and retrotranslocated by ER-associated degradation to the cytosol, where they
are degraded by a proteasome. The vesicles containing the properly-folded
proteins then enter the Golgi apparatus.
In
the Golgi apparatus, the glycosylation of the proteins is modified and further
posttranslational modifications, including cleavage and functionalization, may
occur. The proteins are then moved into secretory vesicles which travel along
the cytoskeleton to the edge of the cell. More modification can occur in the
secretory vesicles (for example insulin is cleaved from proinsulin in the
secretory vesicles).
Eventually,
there is vesicle fusion with the cell membrane at a structure called the
porosome, in a process called exocytosis, dumping its contents out of the
cell's environment.
Strict
biochemical control is maintained over this sequence by usage of a pH gradient:
the pH of the cytosol is 7.4, the ER's pH is 7.0, and the cis-golgi has a pH of
6.5. Secretory vesicles have pHs ranging between 5.0 and 6.0; some secretory vesicles
evolve into lysosomes, which have a pH of 4.8.
Nonclassical
secretion
There
are many proteins like FGF1 (aFGF), FGF2 (bFGF), interleukin-1 (IL1) etc. which
do not have a signal sequence. They do not use the classical ER-golgi pathway.
These are secreted through various nonclassical pathways.
At
least four nonclassical (unconventional) protein secretion pathways have been
described. They include 1) direct translocation of proteins across the plasma
membrane likely through membrane transporters, 2) blebbing, 3) lysosomal
secretion, and 4) release via exosomes derived from multivesicular bodies. In
addition, proteins can be released from cells by mechanical or physiological
wounding and through nonlethal, transient oncotic pores in the plasma membrane
induced by washing cells with serum-free media or buffers.
Secretion
in human tissues
Many
human cell types have the ability to be secretory cells. They have a
well-developed endoplasmic reticulum and Golgi apparatus to fulfill their
function. Tissues in humans that produce secretions include the
gastrointestinal tract which secretes digestive enzymes and gastric acid, the
lung which secretes surfactants, and sebaceous glands which secrete sebum to
lubricate the skin and hair. Meibomian glands in the eyelid secrete sebum to
lubricate and protect the eye.
Secretion
in Gram negative bacteria
Secretion
is not unique to eukaryotes alone, it is present in bacteria and archaea as
well. ATP binding cassette (ABC) type transporters are common to all the three domains
of life. The Sec system constituting the Sec Y-E-G complex (see Type II
secretion system (T2SS), below) is another conserved secretion system,
homologous to the translocon in the eukaryotic endoplasmic reticulum and the
Sec 61 translocon complex of yeast. Some secreted proteins are translocated
across the cytoplasmic membrane by the Sec translocon, which requires the
presence of an N-terminal signal peptide on the secreted protein. Others are
translocated across the cytoplasmic membrane by the twin-arginine translocation
pathway (Tat). Gram negative bacteria have two membranes, thus making secretion
topologically more complex. There are at least six specialized secretion
systems in Gram negative bacteria. Many secreted proteins are particularly important
in bacterial pathogenesis.
Type
I secretion system (T1SS or TOSS)
It
is similar to the ABC transporter, however it has additional proteins that,
together with the ABC protein, form a contiguous channel traversing the inner
and outer membranes of Gram-negative bacteria. It is a simple system, which
consists of only three protein subunits: the ABC protein, membrane fusion
protein (MFP), and outer membrane protein (OMP). Type I secretion system
transports various molecules, from ions, drugs, to proteins of various sizes
(20 - 900 kDa). The molecules secreted vary in size from the small Escherichia
coli peptide colicin V, (10 kDa) to the Pseudomonas fluorescens cell adhesion
protein LapA of 900 kDa. The best characterized are the RTX toxins and the lipases.
Type I secretion is also involved in export of non-proteinaceous substrates
like cyclic β-glucans and polysaccharides.
Type
II secretion system (T2SS)
Proteins
secreted through the type II system, or main terminal branch of the general
secretory pathway, depend on the Sec or Tat system for initial transport into
the periplasm. Once there, they pass through the outer membrane via a
multimeric (12-14 subunits) complex of pore forming secretin proteins. In
addition to the secretin protein, 10-15 other inner and outer membrane proteins
compose the full secretion apparatus, many with as yet unknown function.
Gram-negative type IV pili use a modified version of the type II system for
their biogenesis, and in some cases certain proteins are shared between a pilus
complex and type II system within a single bacterial species.
Type
III secretion system (T3SS or TTSS)
It
is homologous to bacterial flagellar basal body. It is like a molecular syringe
through which a bacterium (e.g. certain types of Salmonella, Shigella,
Yersinia, Vibrio) can inject proteins into eukaryotic cells. The low Ca2+
concentration in the cytosol opens the gate that regulates T3SS. One such
mechanism to detect low calcium concentration has been illustrated by the lcrV
(Low Calcium Response) antigen utilized by Yersinia pestis, which is used to
detect low calcium concentrations and elicits T3SS attachment. The Hrp system
in plant pathogens inject harpins through similar mechanisms into plants. This
secretion system was first discovered in Yersinia pestis and showed that toxins
could be injected directly from the bacterial cytoplasm into the cytoplasm of
its host's cells rather than simply be secreted into the extracellular medium.
Type
IV secretion system (T4SS or TFSS)
It
is homologous to conjugation machinery of bacteria (and archaeal flagella). It
is capable of transporting both DNA and proteins. It was discovered in
Agrobacterium tumefaciens, which uses this system to introduce the T-DNA
portion of the Ti plasmid into the plant host, which in turn causes the
affected area to develop into a crown gall (tumor). Helicobacter pylori uses a
type IV secretion system to deliver CagA into gastric epithelial cells, which
is associated with gastric carcinogenesis. Bordetella pertussis, the causative
agent of whooping cough, secretes the pertussis toxin partly through the type
IV system. Legionella pneumophila, the causing agent of legionellosis
(Legionnaires' disease) utilizes a type IVB secretion system, known as the
icm/dot (intracellular multiplication / deffect in organelle trafficking genes)
system, to translocate numerous effector proteins into its eukaryotic host. The
prototypic Type IVA secretion system is the VirB complex of Agrobacterium
tumefaciens.T4SS
Identifiers
Symbol T4SS
Pfam PF07996
InterPro IPR012991
SCOP
- 1gl7
SUPERFAMILY 1gl7
TCDB 3.A.7
Available
protein structures:
Pfam structures
PDB RCSB PDB; PDBe
PDBsum structure summary
Protein
members of this family are components of the type IV secretion system. They
mediate intracellular transfer of macromolecules via a mechanism ancestrally
related to that of bacterial conjugation machineries.
Function
In
short, Type IV secretion system (T4SS), is the general mechanism by which
bacterial cells secrete or take up macromolecules. Their precise mechanism
remains unknown. T4SS is encoded on Gram-negative conjugative elements in
bacteria.T4SS are cell envelope-spanning complexes or in other words 11-13 core
proteins that form a channel through which DNA and proteins can travel from the
cytoplasm of the donor cell to the cytoplasm of the recipient cell.
Additionally, T4SS also secrete virulence factor proteins directly into host
cells as well as taking up DNA from the medium during natural transformation,
which shows the versatility of this macromolecular secretion apparatus.
Structure
As
shown in the above figure, TraC, in particular consists of a three helix bundle
and a loose globular appendage.
Interactions
T4SS
has two effector proteins: firstly, ATS-1, which stands for Anaplasma
translocated substrate 1, and secondly AnkA, which stands for ankyrin repeat
domain-containing protein A. Additionally, T4SS coupling proteins are VirD4,
which bind to VirE2.
Type
V secretion system (T5SS)
Also
called the autotransporter system, type V secretion involves use of the Sec
system for crossing the inner membrane. Proteins which use this pathway have
the capability to form a beta-barrel with their C-terminus which inserts into
the outer membrane, allowing the rest of the peptide (the passenger domain) to
reach the outside of the cell. Often, autotransporters are cleaved, leaving the
beta-barrel domain in the outer membrane and freeing the passenger domain. Some
people believe remnants of the autotransporters gave rise to the porins which
form similar beta-barrel structures. A common example of an autotransporter
that uses this secretion system is the Trimeric Autotransporter Adhesins.
Type
VI secretion system (T6SS)
Type
VI secretion systems have been identified in 2006 by the group of John
Mekalanos at the
Release
of outer membrane vesicles
In
addition to the use of the multiprotein complexes listed above, Gram-negative bacteria
possess another method for release of material: the formation of outer membrane
vesicles. Portions of the outer membrane pinch off, forming spherical
structures made of a lipid bilayer enclosing periplasmic materials. Vesicles
from a number of bacterial species have been found to contain virulence
factors, some have immunomodulatory effects, and some can directly adhere to
and intoxicate host cells. While release of vesicles has been demonstrated as a
general response to stress conditions, the process of loading cargo proteins
seems to be selective.
Secretion
in Gram positive bacteria
Proteins
with appropriate N-terminal targeting signals are synthesized in the cytoplasm
and then directed to a specific protein transport pathway. During, or shortly after
its translocation across the cytoplasmic membrane, the protein is processed and
folded into its active form. Then the translocated protein is either retained
at the extracytoplasmic side of the cell or released into the environment.
Since the signal peptides that target proteins to the membrane are key
determinants for transport pathway specificity, these signal peptides are
classified according to the transport pathway to which they direct proteins.
Signal peptide classification is based on the type of signal peptidase (SPase)
that is responsible for the removal of the signal peptide. The majority of
exported proteins are exported from the cytoplasm via the general Secretory
(Sec) pathway. Most well known virulence factors (e.g. exotoxins of Staphylococcus
aureus, protective antigen of Bacillus anthracis, listeriolysin O of Listeria
monocytogenes) that are secreted by Gram-positive pathogens have a typical
N-terminal signal peptide that would lead them to the Sec-pathway. Proteins
that are secreted via this pathway are translocated across the cytoplasmic
membrane in an unfolded state. Subsequent processing and folding of these
proteins takes place in the cell wall environment on the trans-side of the
membrane. In some Staphylococcus and Streptococcus species, the accessory
secretory system handles the export of highly repetitive adhesion
glycoproteins. In addition to the Sec and accessory-Sec systems, some
Gram-positive bacteria contain the Tat-system that is able to translocate
folded proteins across the membrane. This is especially appropriate for
proteins that need co-factors, such as iron-sulfur clusters and molybdopterin,
which are incorporated in the cytoplasm. Pathogenic bacteria may contain
certain special purpose export systems that are specifically involved in the
transport of only a few proteins. For example, several gene clusters have been
identified in mycobacteria that encode proteins that are secreted into the
environment via specific pathways (ESAT-6) and are important for mycobacterial
pathogenesis. Specific ATP-binding cassette (ABC) transporters direct the
export and processing of small antibacterial peptides called bacteriocins.
Genes for endolysins that are responsible for the onset of bacterial lysis are
often located near genes that encode for holin-like proteins, suggesting that
these holins are responsible for endolysin export to the cell wall.
Specialised
organs and behaviours
To
aid in the digestion of their food animals evolved organs such as beaks,
tongues, teeth, a crop, gizzard, and others.
Beaks
Birds
have beaks that are specialised according to the bird's ecological niche. For
example, macaws primarily eat seeds, nuts, and fruit, using their impressive
beaks to open even the toughest seed. First they scratch a thin line with the
sharp point of the beak, then they shear the seed open with the sides of the
beak.
The
mouth of the squid is equipped with a sharp horny beak mainly made of
cross-linked proteins. It is used to kill and tear prey into manageable pieces.
The beak is very robust, but does not contain any minerals, unlike the teeth
and jaws of many other organisms, including marine species. The beak is the
only indigestible part of the squid.
Tongue
The
tongue is skeletal muscle on the floor of the mouth that manipulates food for
chewing (mastication) and swallowing (deglutition). It is sensitive and kept
moist by saliva. The underside of the tongue is covered with a smooth mucous
membrane. The tongue also has a touch sense for locating and positioning food
particles that require further chewing. The tongue is utilized to roll food
particles into a bolus before being transported down the esophagus through
peristalsis.
The
sublingual region underneath the front of the tongue is a location where the
oral mucosa is very thin, and underlain by a plexus of veins. This is an ideal
location for introducing certain medications to the body. The sublingual route
takes advantage of the highly vascular quality of the oral cavity, and allows
for the speedy application of medication into the cardiovascular system,
bypassing the gastrointestinal tract.
The
tongue is a muscular hydrostat on the floors of the mouths of most vertebrates
which manipulates food for mastication. It is the primary organ of taste
(gustation), as much of the upper surface of the tongue is covered in papillae
and taste buds. It is sensitive and kept moist by saliva, and is richly
supplied with nerves and blood vessels. In humans a secondary function of the
tongue is phonetic articulation. The tongue also serves as a natural means of
cleaning one's teeth. The ability to perceive different tastes is not localised
in different parts of the tongue, as is widely believed. This error arose
because of misinterpretation of some 19th-century research (see tongue map).
The human tongue
Etymology
The
word tongue derives from the Old English tunge, which comes from Proto-Germanic
*tungōn. It has cognates in other Germanic languages — for example tonge
in West Frisian, tong in Dutch/Afrikaans, tunge in Danish/Norwegian and tunga
in Icelandic/Faroese/Swedish. The ue ending of the word seems to be a
fourteenth-century attempt to show "proper pronunciation", but it is
"neither etymological nor phonetic". Some used the spelling tunge and
tonge as late as the sixteenth century.
It
can be used as a metonym for language, as in the phrase mother tongue. Many
languages have the same word for "tongue" and "language".
Figures
of speech
A
common temporary failure in word retrieval from memory is referred to as the tip-of-the-tongue
phenomenon. The expression tongue in cheek refers to a statement that is not to
be taken entirely seriously; something said or done with subtle ironic or
sarcastic humour. A tongue twister is a phrase made specifically to be very
difficult to pronounce. Aside from being a medical condition,
"tongue-tied" means being unable to say what you want to due to
confusion or restriction. The phrase "cat got your tongue" refers to
when a person is speechless. To "bite one's tongue" is a phrase which
describes holding back an opinion to avoid causing offence. A "slip of the
tongue" refers to an unintentional utterance, such as a Freudian slip.
Speaking in tongues is a common phrase used to describe glossolalia, which is
to make smooth, language-resembling sounds that is no true spoken language
itself. A deceptive person is said to have a forked tongue, and a
smooth-talking person said to have a silver tongue.
Teeth
Teeth
(singular tooth) are small whitish structures found in the jaws (or mouths) of
many vertebrates that are used to tear, scrape, milk and chew food. Teeth are
not made of bone, but rather of tissues of varying density and hardness. The
shape of an animal's teeth is related to its diet. For example, plant matter is
hard to digest, so herbivores have many molars for chewing.
The
teeth of carnivores are shaped to kill and tear meat, using specially shaped
canine teeth. Herbivores' teeth are made for grinding food materials, in this
case, plant parts.
A
tooth (plural teeth) is a small, calcified, whitish structure found in the jaws
(or mouths) of many vertebrates and used to break down food. Some animals,
particularly carnivores, also use teeth for hunting or for defensive purposes.
The roots of teeth are covered by gums. Teeth are not made of bone, but rather
of multiple tissues of varying density and hardness.
The
general structure of teeth is similar across the vertebrates, although there is
considerable variation in their form and position. The teeth of mammals have
deep roots, and this pattern is also found in some fish, and in crocodilians.
In most teleost fish, however, the teeth are attached to the outer surface of
the bone, while in lizards they are attached to the inner surface of the jaw by
one side. In cartilaginous fish, such as sharks, the teeth are attached by
tough ligaments to the hoops of cartilage that form the jaw.
Teeth
are among the most distinctive (and long-lasting) features of mammal species.
Paleontologists use teeth to identify fossil species and determine their relationships.
The shape of the animal's teeth are related to its diet. For example, plant
matter is hard to digest, so herbivores have many molars for chewing and
grinding. Carnivores, on the other hand, need canines to kill prey and to tear
meat.
Mammals
are diphyodont, meaning that they develop two sets of teeth. In humans, the
first set (the "baby," "milk," "primary" or
"deciduous" set) normally starts to appear at about six months of
age, although some babies are born with one or more visible teeth, known as
neonatal teeth. Normal tooth eruption at about six months is known as teething
and can be painful.
Some
animals develop only one set of teeth (monophyodont) while others develop many
sets (polyphyodont). Sharks, for example, grow a new set of teeth every two
weeks to replace worn teeth. Rodent incisors grow and wear away continually
through gnawing, which helps maintain relatively constant length. The industry
of the beaver is due in part to this qualification. Many rodents such as voles
(but not mice) and guinea pigs, as well as leporidae like rabbits, have
continuously growing molars in addition to incisors.
Teeth
are not always attached to the jaw, as they are in mammals. In many reptiles
and fish, teeth are attached to the palate or to the floor of the mouth,
forming additional rows inside those on the jaws proper. Some teleosts even
have teeth in the pharynx. While not true teeth in the usual sense, the
denticles of sharks are almost identical in structure, and are likely to have
the same evolutionary origin. Indeed, teeth appear to have first evolved in
sharks, and are not found in the more primitive jawless fish - while lampreys
do have tooth-like structures on the tongue, these are in fact, composed of
keratin, not of dentine or enamel, and bear no relationship to true teeth.
Living
amphibians typically have small teeth, or none at all, since they commonly feed
only on soft foods. In reptiles, teeth are generally simple and conical in
shape, although there is some variation between species, most notably the
venom-injecting fangs of snakes. The pattern of incisors, canines, premolars
and molars is found only in mammals, and to varying extents, in their
evolutionary ancestors. The numbers of these types of teeth varies greatly
between species; zoologists use a standardised dental formula to describe the
precise pattern in any given group.
Crop
A
crop, or croup, is a thin-walled expanded portion of the alimentary tract used
for the storage of food prior to digestion. In some birds it is an expanded, muscular
pouch near the gullet or throat. In adult doves and pigeons, the crop can
produce crop milk to feed newly hatched birds.
Certain
insects may have a crop or enlarged esophagus.
Abomasum
Herbivores
have evolved cecums (or an abomasum in the case of ruminants). Ruminants have a
fore-stomach with four chambers. These are the rumen, reticulum, omasum, and
abomasum. In the first two chambers, the rumen and the reticulum, the food is
mixed with saliva and separates into layers of solid and liquid material.
Solids clump together to form the cud (or bolus). The cud is then regurgitated,
chewed slowly to completely mix it with saliva and to break down the particle
size.
Fibre,
especially cellulose and hemi-cellulose, is primarily broken down into the volatile
fatty acids, acetic acid, propionic acid and butyric acid in these chambers
(the reticulo-rumen) by microbes: (bacteria, protozoa, and fungi). In the
omasum water and many of the inorganic mineral elements are absorbed into the
blood stream.
The
abomasum is the fourth and final stomach compartment in ruminants. It is a
close equivalent of a monogastric stomach (e.g., those in humans or pigs), and
digesta is processed here in much the same way. It serves primarily as a site
for acid hydrolysis of microbial and dietary protein, preparing these protein
sources for further digestion and absorption in the small intestine. Digesta is
finally moved into the small intestine, where the digestion and absorption of
nutrients occurs. Microbes produced in the reticulo-rumen are also digested in
the small intestine.
Bacteria
use several systems to obtain nutrients from other organisms in the
environments.
The
abomasum, also known as the maw, rennet-bag, or reed tripe, is the fourth and
final stomach compartment in ruminants. It secretes rennin - the artificial
form of which is called rennet, and is used in cheese creation.
The
word abomasum is from New Latin and it was first used in English in 1706. It
comes from Latin ab- + omasum "intestine of an ox," and it is
possibly from the Gaulish language.
The
abomasum's normal anatomical location is along ventral midline. It is a
secretory stomach similar in anatomy and function as the monogastric stomach.
It serves primarily in the acid hydrolysis of microbial and dietary protein,
preparing these protein sources for further digestion and absorption in the
small intestine.
Dairy
cattle on high production diets are susceptible to a number of pathologies,
most commonly after calving. A gas filled abomasum can move into an abnormal
location resulting in left displaced abomasum (LDA) or right displaced abomasum
(RDA). If the abomasum displaces to the right, it is at risk of torsion and
becoming a right torsioned abomasum (RTA). A displaced abomasum will cause cows
to present all or some of the following signs: loss of appetite, decrease rumen
contractions, decrease cud chewing, and drop in milk production. While an LDA
and RDA are not immediately life threatening, veterinary care is required for
surgical correction. Abomasitis is a relatively rare, but serious, disease of
the abomasum whose causes are currently unknown.
The
abomasum is used to make the lampredotto, a typical dish of
Parts
of digestive system:
Mouth.
Esophagus.
he esophagus (oesophagus, commonly known as the gullet) is an organ in
vertebrates which consists of a muscular tube through which food passes from
the pharynx to the stomach. During swallowing, food passes from the mouth
through the pharynx into the esophagus and travels via peristalsis to the
stomach. The word esophagus is derived from the Latin œsophagus, which
derives from the Greek word oisophagos, lit. "entrance for eating."
In humans the esophagus is continuous with the laryngeal part of the pharynx at
the level of the C6 vertebra. The esophagus passes through posterior
mediastinum in thorax and enters abdomen through a hole in the diaphragm at the
level of the tenth thoracic vertebrae (T10). It is usually about 25cm, but
extreme variations have been recorded ranging 10–50 cm long depending on
individual height. It is divided into cervical, thoracic and abdominal parts.
Due to the inferior pharyngeal constrictor muscle, the entry to the esophagus
opens only when swallowing or vomiting.
Head and neck
Digestive
organs. (Esophagus is #1)
Latin Oesophagus
Gray's subject #245 1144
System Part of the digestive System
Artery Esophageal arteries
Vein Esophageal veins
Nerve Celiac ganglia, vagus
Precursor Foregut
MeSH Oesophagus
Dorlands/Elsevier Esophagus
Histology
Course of the esophagus
(anterior view), showing it passing posteriorly to the trachea and the heart.
The
layers of the oesophagus are as follows:
1.
mucosa. he mucous membranes (or
mucosae; singular mucosa) are linings of mostly endodermal origin, covered in
epithelium, which are involved in absorption and secretion. They line cavities
that are exposed to the external environment and internal organs. They are at
several places contiguous with skin: at the nostrils, the mouth, the lips, the
eyelids, the ears, the genital area, and the anus. The sticky, thick fluid
secreted by the mucous membranes and glands is termed mucus. The term mucous
membrane refers to where they are found in the body and not every mucous
membrane secretes mucus.The glans clitoridis, glans penis (head of the penis),
along with the inside of the foreskin and the clitoral hood, are mucous
membranes. The urethra is also a mucous membrane. The secreted mucus traps the
pathogens in the body, preventing any further activities of diseases.
·
nonkeratinized stratified squamous
epithelium: is rapidly turned over, and serves a protective effect due to the
high volume transit of food, saliva and mucus.
·
lamina propria: sparse.
The
lamina propria is a constituent of the moist linings known as mucous membranes
or mucosa, which line various tubes in the body (such as the respiratory tract,
the gastrointestinal tract, and the urogenital tract).
The
lamina propria (more correctly lamina propria mucosæ) is a thin layer of
loose connective tissue which lies beneath the epithelium and together with the
epithelium constitutes the mucosa. As its Latin name indicates it is a
characteristic component of the mucosa, "the mucosa's own special layer".
Thus the term mucosa or mucous membrane always refers to the combination of the
epithelium plus the lamina propria.
The
lamina propria contains capillaries and a central lacteal (lymph vessel) in the
small intestine, as well as lymphoid tissue. Lamina propria also contains
glands with the ducts opening on to the mucosal epithelium, that secrete mucus
and serous secretions. The lamina propria is also rich in immune cells known as
lymphocytes. A majority of these cells are IgA-secreting B cells.
Layers of Stomach Wall:
1. Serosa
2. Tela subserosa
3. Muscularis
4. Oblique fibers of muscle wall
5. Circular muscle layer
6. Longitudinal muscle layer
7. Submucosa
8. Lamina muscularis mucosae
9. Mucosa
10. Lamina propria
11. Epithelium
12. Gastric glands
13. Gastric pits
14. Villous folds
15. Gastric areas (gastric surface)
·
muscularis mucosae: smooth muscle
The
lamina muscularis mucosae (or muscularis mucosae) is the thin layer of smooth
muscle found in most parts of the gastrointestinal tract, located outside the
lamina propria mucosae and separating it from the submucosa.
In
the gastrointestinal tract, the term mucosa or "mucous membrane"
refers to the combination of epithelium, lamina propria, and (where it occurs)
muscularis mucosae. The etymology suggests this, since the Latin names
translate to "the mucosa's own special layer" (lamina propria
mucosae) and "muscular layer of the mucosa" (lamina muscularis
mucosae).
The
muscularis mucosae is composed of several thin layers of smooth muscle fibers
oriented in different ways which keep the mucosal surface and underlying glands
in a constant state of gentle agitation to expel contents of glandular crypts
and enhance contact between epithelium and the contents of the lumen.
Section of
duodenum of cat. X
60. (Muscularis mucosae labeled at right, third from the top.)
General
structure of the gut wall showing the Muscularis mucosa.
2.
submucosa: Contains the mucous
secreting glands (esophageal glands), and connective structures termed
papillae.
In
the gastrointestinal tract, the submucosa is the layer of dense irregular
connective tissue or loose connective tissue that supports the mucosa, as well
as joins the mucosa to the bulk of underlying smooth muscle (fibers running
circularly within layer of longitudinal muscle).
Contents
Blood
vessels, lymphatic vessels, and nerves (all supplying the mucosa) will run
through here.
Tiny
parasympathetic ganglia are scattered around forming the submucosal plexus (or
"Meissner's plexus") where preganglionic parasympathetic neurons
synapse with postganglionic nerve fibers that supply the muscularis mucosae.
The
submucosa in endoscopy
Identification
of the submucosa plays an important role in diagnostic and therapeutic
endoscopy, where special fibre-optic cameras are used to perform procedures on
the gastrointestinal tract. Abnormalities of the submucosa, such as
gastrointestinal stromal tumors, usually show integrity of the mucosal surface.
The
submucosa is also identified in endoscopic ultrasound to identify the depth of
tumours and to identify other abnormalities. An injection of dye, saline, or
epinephrine into the submucosa is imperative in the safe removal of certain
polyps.
Endoscopic
mucosal resection involves removal of the mucosal layer, and in order to be
done safely, a submucosal injection of dye is performed to ensure integrity at
the beginning of the procedure.
Bladder.
Stomach.
3.
muscularis externa (or
"muscularis propria"): composition varies in different parts of the
esophagus, to correspond with the conscious control over swallowing in the
upper portions and the autonomic control in the lower portions:
·
upper third, or superior part:
striated muscle
·
middle third, smooth muscle and
striated muscle
·
inferior third: predominantly smooth
muscles
The
muscular coat (muscular layer, muscular fibers, muscularis propria, muscularis
externa) is a region of muscle in many organs in the vertebrate body, adjacent
to the submucosa membrane. It is responsible for gut movement such as peristalsis.
It
usually has two distinct layers of smooth muscle:
·
inner and "circular"
·
outer and "longitudinal"
However,
there are some exceptions to this pattern.
In
the stomach and colon, there are three layers to the muscularis externa.
In
the upper esophagus, part of the externa is skeletal muscle, rather than smooth
muscle.
The
inner layer of the muscularis externa forms a sphincter at two locations of the
alimentary canal:
in
the pyloric stomach, it forms the pyloric sphincter
in
the anal canal, it forms the anal sphincter
Transverse section of ureter
Wall of the
ureter.
4.
adventitia
Adventitia
is the outermost connective tissue covering of any organ, vessel, or other
structure. It is also called the tunica adventitia or the tunica externa.
For
example, the connective tissue that surrounds an artery is called the tunica
externa because it is considered extraneous to the artery.
To
some degree, its role is complementary to that of the serosa, which also
provides a layer of tissue surrounding an organ. In the abdomen, whether an
organ is covered in adventitia or serosa depends upon whether it is peritoneal
or retroperitoneal:
peritoneal
organs are covered in serosa (a layer of mesothelium, the visceral peritoneum)
retroperitoneal
organs are covered in adventitia (loose connective tissue)
In
the gastrointestinal tract, the muscularis externa is bounded in most cases by
serosa. However, at the oral cavity, thoracic esophagus, ascending colon,
descending colon and the rectum, the muscularis externa is instead bounded by
adventitia. (The muscularis externa of the duodenum is bounded by both tissue
types.) Generally, if it is a part of the digestive tract that is free to move,
it is covered by serosa, and if it is relatively rigidly fixed, it is covered
by adventitia.
The
connective tissue of the gallbladder is covered by adventitia where the
gallbladder bounds the liver, but by serosa for the rest of its surface.
Layers of Esophageal Wall:
1. Mucosa
2. Submucosa
3. Muscularis
4. Adventitia
5. Striated muscle
6. Striated and smooth
7. Smooth muscle
8. Lamina muscularis mucosae
9. Esophageal glands
Pancreas.
The pancreas /ˈpæŋkriəs/
is a glandular organ in the digestive system and endocrine system of
vertebrates. It is both an endocrine gland producing several important
hormones, including insulin, glucagon, somatostatin, and pancreatic
polypeptide, and a digestive organ, secreting pancreatic juice containing
digestive enzymes that assist the absorption of nutrients and the digestion in
the small intestine. These enzymes help to further break down the
carbohydrates, proteins, and lipids in the chyme.
1:
Head of pancreas
2: Uncinate process of pancreas
3: Pancreatic notch
4: Body of pancreas
5: Anterior surface of pancreas
6: Inferior surface of pancreas
7:
8: Anterior margin of pancreas
9: Inferior margin of pancreas
10: Omental tuber
11: Tail of pancreas
12: Duodenum
Histology
Under
a microscope, stained sections of the pancreas reveal two different types of
parenchymal tissue. Lightly staining clusters of cells are called islets of
Langerhans, which produce hormones that underlie the endocrine functions of the
pancreas. Darker-staining cells form acini connected to ducts. Acinar cells
belong to the exocrine pancreas and secrete digestive enzymes into the gut via
a system of ducts.
|
Structure |
Appearance |
Function |
|
Islets
of Langerhans |
Lightly
staining, large, spherical clusters |
Hormone
production and secretion (endocrine pancreas) |
|
Pancreatic
acini |
Darker-staining,
small, berry-like clusters |
Digestive
enzyme production and secretion (exocrine pancreas |
Function
The
pancreas is a dual-function gland, having features of both endocrine and
exocrine glands.
The
part of the pancreas with endocrine function is made up of approximately a
million cell clusters called islets of Langerhans. Four main cell types exist
in the islets. They are relatively difficult to distinguish using standard
staining techniques, but they can be classified by their secretion: α
cells secrete glucagon (increase glucose in blood), β cells secrete
insulin (decrease glucose in blood), delta cells secrete somatostatin
(regulates/stops α and β cells), and PP cells or 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. According to the
volume The Body, by Alan E. Nourse, the islets are "busily manufacturing
their hormone and generally disregarding the pancreatic cells all around them,
as though they were located in some completely different part of the
body." The islet of Langerhans plays an imperative role in glucose
metabolism and regulation of blood glucose concentration.
The
pancreas as an exocrine gland helps out 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 islets of Langerhans and indirectly
through the effect of the autonomic nervous system on the blood flow.
Sympathetic
(adrenergic)
α2:
decreases secretion from beta cells, increases secretion from alpha cells,
β2: increases secretion from beta cells
Parasympathetic
(muscarinic)
M3:
increases stimulation of alpha cells and beta cells
Endocrine
pancreas
Islet of
Langerhans (mouse) in its typical proximity to a blood vessel; insulin in red,
nuclei in blue.
Islets of
Langerhans, hemalum-eosin stain.
Anatomy
and histology
There
are about one million islets distributed throughout the pancreas of a healthy
adult human,:914 each of which measures about
The
islets of Langerhans are the regions of the pancreas that contain its endocrine
(i.e., hormone-producing) cells. Discovered in 1869 by German pathological
anatomist Paul Langerhans at the age of 22, the islets of Langerhans constitute
approximately 1 to 2% of the mass of the pancreas.
Cell
types
Hormones
produced in the islets of Langerhans are secreted directly into the blood flow
by (at least) five different types of cells. In rat islets, endocrine cell
subsets are distributed as follows:
Alpha
cells producing glucagon (15–20% of total islet cells)
Beta
cells producing insulin and amylin (65–80%)
Delta
cells producing somatostatin (3–10%)
PP
cells (gamma cells) producing pancreatic polypeptide (3–5%)
Epsilon
cells producing ghrelin (<1%)
It
has been recognized that the cytoarchitecture of pancreatic islets differs
between species. In particular, while rodent islets are characterized by a
predominant proportion of insulin-producing beta cells in the core of the
cluster and by scarce alpha, delta and PP cells in the periphery, human islets
display alpha and beta cells in close relationship with each other throughout
the cluster.
Islets
can influence each other through paracrine and autocrine communication, and
beta cells are coupled electrically to other beta cells (but not to other cell
types).
This photograph shows a mouse
pancreatic islet, an often spherical group of hormone-producing cells. Insulin
is labelled here in green, glucagon in red, and the nuclei in blue
Paracrine
feedback
The
paracrine feedback system of the islets of Langerhans has the following
structure:
Insulin:
activates beta cells and inhibits alpha cells
Glucagon:
activates alpha cells which activates beta cells and delta cells
Somatostatin:
inhibits alpha cells and beta cells
Electrical
activity
Electrical
activity of pancreatic islets has been studied using patch clamp techniques,
and it has turned out that the behavior of cells in intact islets differs
significantly from the behavior of dispersed cells.
Islet
transplantation as a treatment for type 1 diabetes
Islet
cell transplantation has the possibility of restoring beta cell function from
diabetes, offering an alternative to a complete pancreas transplantation or an
artificial pancreas.
Because
the beta cells in the islets of Langerhans are selectively destroyed by an
autoimmune process in type 1 diabetes, clinicians and researchers are actively
pursuing islet transplantation as a means of restoring physiological beta cell
function in patients with type 1 diabetes.
Recent
clinical trials have shown that insulin independence and improved metabolic
control can be reproducibly obtained after transplantation of cadaveric donor
islets into patients with unstable type 1 diabetes.
Islet
transplantation for type 1 diabetes currently requires potent immunosuppression
to prevent host rejection of donor islets.
An
alternative source of beta cells, such insulin-producing cells derived from
adult stem cells or progenitor cells would contribute to overcoming the current
shortage of donor organs for transplantation. The field of regenerative
medicine is rapidly evolving and offers great hope for the nearest future.
However, type 1 diabetes is the result of the autoimmune destruction of beta
cells in the pancreas. Therefore, an effective cure will require a sequential,
integrated approach that combines adequate and safe immune interventions with
beta cell regenerative approaches.
Another
potential source of beta cells may be xenotransplantation. The most likely
source for xenogeneic islets for transplantation into human currently under
evaluation is the pig pancreas. Interestingly, human and porcine insulin differ
only for one aminoacid, and insulin extracted from porcine pancreata has been
used for the treatment of patients with diabetes before the development of recombinant
human insulin technology. Several studies in small and large animals models
have shown that transplantation of islet cells across species is possible.
However, several problems need to be overcome for porcine islet transplantation
to become a viable clinical option. The immunogenicity of xenogeneic tissues
may be different from and even stronger than allogeneic tissues. For instance,
Galalpha1-3Galbeta1-4GlcNAc (alpha galactosidase, alpha-Gal) expressed on
porcine cells represents a major barrier to xenotransplantation being the
target of preformed antibodies present in human blood. Remarkable progress has
been recorded in the development of genetically modified pigs lacking or
overexpressing molecules that may improve acceptance of transplanted tissues
across into humans. Pigs lacking alpha-Gal or overexpressing human Decay
Accelerating Factor (hDAF), amongst others, have been generated to study the
impact on transplanted outcome in nonhuman primate models. Another possible
antigenic target is the Hanganutziu-Deichter antigen, a sialic acid found in
pigs and not humans, which may contribute to immunogenicity of porcine islets.
Another limitation is the risk for transmission of zoonotic infections from
pigs to humans, particularly from Porcine Endogenous Retro-Viruses (PERV).
Amongst the approaches proposed to overcome islet xenorejection is
immunoisolation of the clusters using encapsulation techniques that may shield
them from immune attack. Studies in rodents and large animals have shown great
promise that justify cautious optimism for the near future. Nonrandomized,
uncontrolled pilot clinical trials are current ongoing in subject with
insulin-requiring diabetes to test the efficacy of encapsulation techniques to
protect xenogeneic islets in the absence of chronic anti-rejection drugs.
The diagram shows the structural
differences between rat islets (top) and humans islets
(bottom) as well as the ventral part (left) and the dorsal part (right) of the
pancreas. Different cell types are colour coded. Rodent islets, unlike the
human ones, show the characteristic insulin core.
A porcine
islet of Langerhans.
The left image is a brightfield image created using hematoxylin stain; nuclei
are dark circles and the acinar pancreatic tissue is darker than the islet
tissue. The right image is the same section stained by immunofluorescence
against insulin, indicating beta cells.
Mouse islet immunostained for
pancreatic polypeptide
Mouse islet immunostained for insulin
Mouse islet immunostained for
glucagon
Illustration
of dog pancreas. 250x.
Exocrine
pancreas
The
exocrine pancreas has ducts that are arranged in clusters called acini
(singular acinus). Pancreatic secretions are secreted into the lumen of the
acinus, and then accumulate in intralobular 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 and secretin, which are hormones secreted by cells in the
stomach and duodenum, in response to distension and/or food and which cause
secretion of pancreatic juices.
There
are two main classes of exocrine pancreatic secretions:
|
Secretion |
Cell
producing it |
Primary
signal |
|
bicarbonate
ions |
Centroacinar
cells |
Secretin |
|
digestive
enzymes |
Basophilic
cells |
CCK |
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.)
The
cells are filled with secretory granules containing the precursor digestive
enzymes. The major proteases which the pancreas secretes are trypsinogen and
chymotrypsinogen. Secreted to a lesser degree are pancreatic lipase and
pancreatic amylase. The pancreas also secretes phospholipase A2,
lysophospholipase, and cholesterol esterase.
The
precursor enzymes (termed zymogens or proenzymes) are inactive variants of the
enzymes; thus autodegradation, which can lead to pancreatitis, is avoided. Once
released in the intestine, the enzyme enteropeptidase (formerly, and
incorrectly, called enterokinase) present in the intestinal mucosa activates
trypsinogen by cleaving it to form trypsin. The free trypsin then cleaves the
rest of the trypsinogen, as well as chymotrypsinogen to its active form
chymotrypsin.
Anatomy
Surface projections of the organs of
the trunk, showing pancreas at the transpyloric plane
1.
Bile ducts: 2. Intrahepatic bile ducts, 3. Left and right hepatic ducts, 4.
Common hepatic duct, 5. Cystic duct, 6. Common bile duct, 7. Ampulla of Vater,
8. Major duodenal papilla 9. Gallbladder, 10-11. Right and left lobes of liver.
12. Spleen.
13.
Esophagus. 14. Stomach. Small intestine: 15. Duodenum, 16. Jejunum
17.
Pancreas: 18: Accessory pancreatic duct, 19: Pancreatic duct.
20-21:
Right and left kidneys (silhouette).
The anterior border of the liver is lifted
upwards (brown arrow). Gallbladder with Longitudinal section, pancreas and
duodenum with frontal one. Intrahepatic ducts and stomach in transparency.
Embryological
development
Schematic
illustrating the development of the pancreas from a dorsal and a ventral bud.
During
maturation, the ventral bud flips to the other side of the gut tube (arrow)
where it typically fuses with the dorsal lobe. An additional ventral lobe that
usually regresses during development is omitted.
The
pancreas forms from the embryonic foregut and is therefore of endodermal
origin. Pancreatic development begins [with] the formation of a ventral and
dorsal anlage (or buds). Each structure communicates with the foregut through a
duct. The ventral pancreatic bud becomes the head and uncinate process, and
comes from the hepatic diverticulum.
Differential
rotation and fusion of the ventral and dorsal pancreatic buds results in the
formation of the definitive pancreas. As the duodenum rotates to the right, it
carries with it the ventral pancreatic bud and common bile duct. Upon reaching
its final destination, the ventral pancreatic bud fuses with the much larger
dorsal pancreatic bud. At this point of fusion, the main ducts of the ventral
and dorsal pancreatic buds fuse, forming the duct of Wirsung, the main
pancreatic duct.
Differentiation
of cells of the pancreas proceeds through two different pathways, corresponding
to the dual endocrine and exocrine functions of the pancreas. In progenitor
cells of the exocrine pancreas, important molecules that induce differentiation
include follistatin, fibroblast growth factors, and activation of the Notch
receptor system. Development of the exocrine acini progresses through three
successive stages. These include the predifferentiated, protodifferentiated,
and differentiated stages, which correspond to undetectable, low, and high
levels of digestive enzyme activity, respectively.
Progenitor
cells of the endocrine pancreas arise from cells of the protodifferentiated
stage of the exocrine pancreas. Under the influence of neurogenin-3 and Isl-1,
but in the absence of notch receptor signaling, these cells differentiate to
form two lines of committed endocrine precursor cells. The first line, under
the direction of Pax-0, forms α- and γ- cells, which produce glucagon
and pancreatic polypeptides, respectively. The second line, influenced by
Pax-6, produces β- and δ-cells, which secrete insulin and
somatostatin, respectively.
Insulin
and glucagon can be detected in the human fetal circulation by the fourth or
fifth month of fetal development.
The pancreas lies in the epigastrium and left
hypochondrium areas of the abdomen
It
is composed of the following parts:
·
The head lies within the concavity of
the duodenum.
·
The uncinate process emerges from the
lower part of head, and lies deep to superior mesenteric vessels.
·
The neck is the constricted part
between the head and the body.
·
The body lies behind the stomach.
·
The tail is the left end of the
pancreas. It lies in contact with the spleen and runs in the lienorenal
ligament.
The
superior pancreaticoduodenal artery from gastroduodenal artery and the inferior
pancreaticoduodenal artery from superior mesenteric artery run in the groove between
the pancreas and the duodenum and supply the head of pancreas. The pancreatic
branches of splenic artery also supply the neck, body and tail of the pancreas.
The largest of those branches is called the arteria pancreatica magna; its
occlusion, although rare, is fatal.
The
body and neck of the pancreas drain into splenic vein; the head drains into the
superior mesenteric and portal veins.
Lymph
is drained via the splenic, celiac and superior mesenteric lymph nodes.
Accessory digestive system
The celiac artery and its branches;
the stomach has been raised and the peritoneum removed.
Lymphatics of
stomach, etc., the stomach has been turned upward.
The duodenum
and pancreas.
The
pancreatic duct.
Pancreas of a
human embryo of five weeks.
Pancreas of a
human embryo at end of sixth week.
Front of abdomen, showing surface
markings for duodenum, pancreas, and kidneys.
Dog pancreas magnified 100 times
Pancreas
Small
intestine
The
small intestine (or small bowel) is the part of the gastrointestinal tract
following the stomach and followed by the large intestine, and is where much of
the digestion and absorption of food takes place. In invertebrates such as
worms, the terms "gastrointestinal tract" and "large
intestine" are often used to describe the entire intestine. This article
is primarily about the human gut, though the information about its processes is
directly applicable to most placental mammals. The primary function of the small
intestine is the absorption of nutrients and minerals found in food. (A major
exception to this is cows; for information about digestion in cows and other
similar mammals, see ruminants.)
Diagram
showing the small intestine.
Size
and divisions
The
average length of the small intestine in an adult human male is
The
small intestine is divided into three structural parts:
·
Duodenum
·
Jejunum
·
Ileum
Histology
Micrograph of
the small intestine mucosa showing the intestinal villi and crypts of
Lieberkühn.
The
three sections of the small intestine look similar to each other at a
microscopic level, but there are some important differences. The parts of the
intestine are as follows:
|
Layer |
Duodenum |
Jejunum |
Ileum |
|
serosa |
1st
part serosa,
2nd - 4th adventitia |
normal |
normal |
|
muscularis
externa |
longitudinal
and circular layers, with Auerbach's (myenteric) plexus in between |
same
as duodenum |
same
as duodenum |
|
Submucosa |
Brunner's glands and Meissner's
(submucosal) plexus |
no
BG |
no
BG |
|
mucosa:
muscularis mucosae |
|
normal |
normal |
|
mucosa:
lamina propria |
no
PP |
no
PP |
Peyer's
patches |
|
mucosa:
intestinal epithelium |
simple
columnar. Contains goblet cells, Paneth cells |
Similar
to duodenum. Villi very long. |
Similar
to duodenum. Villi very short. |
Digestion
and absorption
Food
from the stomach is allowed into the duodenum by a muscle called the pylorus,
or pyloricistalsis.
Digestion
The
small intestine is where most chemical digestion takes place. Most of the
digestive enzymes that act in the small intestine are secreted by the pancreas
and enter the small intestine via the pancreatic duct. Enzymes enter the small
intestine in response to the hormone cholecystokinin, which is produced in the
small intestine in response to the presence of nutrients. The hormone secretin
also causes bicarbonate to be released into the small intestine from the
pancreas in order to neutralize the potentially harmful acid coming from the
stomach.
The
three major classes of nutrients that undergo digestion are proteins, lipids
(fats) and carbohydrates:
Proteins
are degraded into small peptides and amino acids before absorption. Chemical
breakdown begins in the stomach and continues in the large intestine.
Proteolytic enzymes, including trypsin and chymotrypsin, are secreted by the
pancreas and cleave proteins into smaller peptides. Carboxypeptidase, which is
a pancreatic brush border enzyme, splits one amino acid at a time.
Aminopeptidase and dipeptidase free the end amino acid products.
Lipids
(fats) are degraded into fatty acids and glycerol. Pancreatic lipase breaks
down triglycerides into free fatty acids and monoglycerides. Pancreatic lipase
works with the help of the salts from the bile secreted by the liver and the
gall bladder. Bile salts attach to triglycerides to help emulsify them, which
aids access by pancreatic lipase. This occurs because the lipase is
water-soluble but the fatty triglycerides are hydrophobic and tend to orient
towards each other and away from the watery intestinal surroundings. The bile
salts emulsify the triglycerides in the watery surroundings until the lipase
can break them into the smaller components that are able to enter the villi for
absorption.
Some
carbohydrates are degraded into simple sugars, or monosaccharides (e.g.,
glucose). Pancreatic amylase breaks down some carbohydrates (notably starch)
into oligosaccharides. Other carbohydrates pass undigested into the large
intestine and further handling by intestinal bacteria. Brush border enzymes
take over from there. The most important brush border enzymes are dextrinase
and glucoamylase which further break down oligosaccharides. Other brush border
enzymes are maltase, sucrase and lactase. Lactase is absent in most adult
humans and for them lactose, like most poly-saccharides, are not digested in
the small intestine. Some carbohydrates, such as cellulose, are not digested at
all, despite being made of multiple glucose units. This is because the
cellulose is made out of beta-glucose, making the inter-monosaccharidal
bindings different from the ones present in starch, which consists of
alpha-glucose. Humans lack the enzyme for splitting the beta-glucose-bonds,
something reserved for herbivores and bacteria from the large intestine.
Absorption
Digested
food is now able to pass into the blood vessels in the wall of the intestine
through the process of diffusion. The small intestine is the site where most of
the nutrients from ingested food are absorbed. The inner wall, or mucosa, of
the small intestine is lined with simple columnar epithelial tissue.
Structurally, the mucosa is covered in wrinkles or folds called plicae
circulares, which are considered permanent features in the wall of the organ.
They are distinct from rugae which are considered non-permanent or temporary
allowing for distention and contraction. From the plicae circulares project
microscopic finger-like pieces of tissue called villi (Latin for "shaggy
hair"). The individual epithelial cells also have finger-like projections
known as microvilli. The function of the plicae circulares, the villi and the
microvilli is to increase the amount of surface area available for the
absorption of nutrients.
Each
villus has a network of capillaries and fine lymphatic vessels called lacteals
close to its surface. The epithelial cells of the villi transport nutrients
from the lumen of the intestine into these capillaries (amino acids and
carbohydrates) and lacteals (lipids). The absorbed substances are transported
via the blood vessels to different organs of the body where they are used to
build complex substances such as the proteins required by our body. The food
that remains undigested and unabsorbed passes into the large intestine.
Absorption
of the majority of nutrients takes place in the jejunum, with the following
notable exceptions:
Iron
is absorbed in the duodenum.
Vitamin
B12 and bile salts are absorbed in the terminal ileum.
Water
and lipids are absorbed by passive diffusion throughout the small intestine.
Sodium
bicarbonate is absorbed by active transport and glucose and amino acid
co-transport.
Fructose
is absorbed by facilitated diffusion.
Conditions
affecting the small intestine
The
small intestine is a complex organ, and as such, there are a very large number
of possible conditions that may affect the function of the small bowel. A few
of them are listed below, some of which are common, with up to 10% of people
being affected at some time in their lives, while others are vanishingly rare.
Small
intestine obstruction or obstructive disorders
·
Paralytic ileus
·
Volvulus
·
Hernia
·
Adhesions
·
Obstruction from external pressure
·
Obstruction by masses in the lumen
(foreign bodies, bezoar, gallstones)
·
Infectious diseases
·
Giardiasis
·
Ascariasis
·
Tropical sprue
·
Tape worm (Diphyllobothrium latum,
Taenia Solium, Taenia solium, Hymenolepsis nana)
·
Hookworm (e.g. Necator americanus,
Ancylostoma duodenale)
·
Nematodes (e.g. Ascaris lumbricoides)
·
Other Protozoa (e.g. Cryptosporidium
parvum, Isopora belli, Cyclospora, Microsporidia, Entamoeba histolytica)
·
Bacterial Infections
·
Enterotoxigenic E. coli
·
Salmonella enterica
·
Campylobacter
·
Shigella
·
Yersinia
·
Clostridium difficile
(antibiotic-associated colitis, Pseudomembranous Colitis
·
Mycobacterium (disseminated
Mycobacterium tuberculosis)
·
Whipple's Disease
·
Vibrio (Cholera
·
Enteric (Typhoid) Fever (Salmonella
enterica var. typhii) and Paratyphoid fever
·
Bacillus cereus
·
Clostridium perfringens (Gas
Gangrene)
·
Viral Infections
·
Rotavirus
·
Norovirus
·
Astrovirus
·
Adenovirus
·
Calicivirus
·
Small bowel bacterial overgrowth
syndrome
·
Neoplasms (Cancers)
·
Adenocarcinoma
·
Carcinoid
·
Gastrointestinal Stromal Tumor (GIST)
·
Lymphoma
·
Sarcoma
·
Leiomyoma
·
metastatic tumors, especially SCLC or
Melanoma
·
Developmental, Congenital or Genetic
Conditions
·
Duodenal (Intestinal) Atresia
·
Hirschsprung's Disease
·
Meckel's Diverticulum
·
Pyloric Stenosis
·
Pancreas Divisum
·
Ectopic Pancreas
·
Enteric duplication cyst
·
Situs Inversus
·
Cystic Fibrosis
·
Malrotation
·
Persistent Urachus
·
Omphalocele
·
Gastroschisis
·
Disachharidase (lactase) deficiencies
·
Primary Bile Acid Malsorption
·
·
Familial Adenomatous Polyposis
Syndrome (FAP)
·
Other Conditions
·
Crohn's disease, and the more general
Inflammatory Bowel Disease
·
Typhlitis (neutropenic colitis in the
immunosuppressed
·
Coeliac disease (Sprue or Non-Tropical
Sprue)
·
Mesenteric ischemia
·
Embolus or Thrombus of the
·
Arteriovenous malformation
·
Gastric dumping syndrome
·
Irritable Bowel Syndrome
·
Duodenal (Peptic) Ulcers
·
Gastrointestinal perforation
·
Lymphatic Obstruction due to various
causes
·
Hyperthyroidism
·
Diabetic Neuropathy
·
Diverticula
·
Radiation Enterocolitis
·
Drug Induced Injury
·
Diversion Colitis
·
Mesenteric cysts
·
Peritoneal Infection
·
Sclerosing Retroperitonitis
Large
intestine
The
large intestine (or large bowel) is the last part of the digestive system in
vertebrate animals. Its function is to absorb water from the remaining
indigestible food matter, and then to pass useless waste material from the
body. This article is primarily about the human gut, though the information
about its processes are directly applicable to most mammals.
The
large intestine consists of the cecum, colon, rectum and anal canal It starts
in the right iliac region of the pelvis, just at or below the right waist,
where it is joined to the bottom end of the small intestine. From here it
continues up the abdomen, then across the width of the abdominal cavity, and
then it turns down, continuing to its endpoint at the anus.
The
large intestine is about
In
Terminologia Anatomica the large intestine includes the cecum, colon, rectum,
and anal canal. However, some sources exclude the anal canal.
Front of abdomen, showing the large
intestine, with the stomach and small intestine in gray outline.
Front of abdomen, showing surface
markings for liver (red), and the stomach and large intestine
The
large intestine takes about 16 hours to finish the digestion of the food. It
removes water and any remaining absorbable nutrients from the food before
sending the indigestible matter to the Rectum. The colon absorbs vitamins which
are created by the colonic bacteria - such as vitamin K (especially important
as the daily ingestion of vitamin K is not normally enough to maintain adequate
blood coagulation), vitamin B12, thiamine and riboflavin. It also compacts
feces, and stores fecal matter in the rectum until it can be discharged via the
anus in defecation.
The
large intestine differs in physical form from the small intestine in being much
wider and in showing the longitudinal layer of the muscularis have been reduced
to 3 strap-like structures known as the taeniae coli. The wall of the large
intestine is lined with simple columnar epithelium. Instead of having the
evaginations of the small intestine (villi), the large intestine has
invaginations (the intestinal glands). While both the small intestine and the
large intestine have goblet cells, they are abundant in the large intestine.
The
appendix is attached to its inferior surface of the cecum. It contains the
least of lymphoid tissue. It is a part of mucosa-associated lymphoid tissue,
which gives the appendix an important role in immunity. Appendicitis is the
result of a blockage that traps infectious material in the lumen. The appendix
can be removed with no apparent damage or consequence to the patient. The large
intestine extends from the ileocecal junction to the anus and is about
Parts
and location
Parts
of the large intestine are:
·
Cecum – the first part of the large
intestine
·
Taeniae coli – three bands of smooth
muscle
·
Haustra – bulges caused by
contraction of taeniae coli
·
Epiploic appendages – small fat
accumulations on the viscera
Locations
along the colon are:
·
The ascending colon
·
The right colic flexure (hepatic)
·
The transverse colon
·
The transverse mesocolon
·
The left colic flexure (splenic)
·
The descending colon
·
The sigmoid colon – the v-shaped
region of the large intestine
Bacterial
flora
The
large intestine houses over 700 species of bacteria that perform a variety of
functions.
The
large intestine absorbs some of the products formed by the bacteria inhabiting
this region. Undigested polysaccharides (fiber) are metabolized to short-chain
fatty acids by bacteria in the large intestine and absorbed by passive
diffusion. The bicarbonate that the large intestine secretes helps to
neutralize the increased acidity resulting from the formation of these fatty
acids.
These
bacteria also produce large amounts of vitamins, especially vitamin K and
biotin (a B vitamin), for absorption into the blood. Although this source of
vitamins, in general, provides only a small part of the daily requirement, it
makes a significant contribution when dietary vitamin intake is low. An
individual that depends on absorption of vitamins formed by bacteria in the
large intestine may become vitamin-deficient if treated with antibiotics that
inhibit other species of bacteria as well as the disease-causing bacteria.
Other
bacterial products include gas (flatus), which is a mixture of nitrogen and
carbon dioxide, with small amounts of the gases hydrogen, methane, and hydrogen
sulphide. Bacterial fermentation of undigested polysaccharides produces these.
The normal flora is also essential in the development of certain tissues,
including the cecum and lymphatics.
They
are also involved in the production of cross-reactive antibodies. These are
antibodies produced by the immune system against the normal flora, that are
also effective against related pathogens, thereby preventing infection or
invasion.
The
most prevalent bacteria are the bacteroides, which have been implicated in the
initiation of colitis and colon cancer. Bifidobacteria are also abundant, and
are often described as 'friendly bacteria'.
A
mucus layer protects the large intestine from attacks from colonic commensal
bacteria.
Liver
diseases
Liver
disease (also called hepatic disease) is a type of damage to or disease of the
liver.
Micrograph of
non-alcoholic fatty liver disease, demonstrating marked macrovesicular
steatosis. Trichrome stain.
Signs
and symptoms
The
symptoms related to liver dysfunction include both physical signs and a variety
of symptoms related to digestive problems, blood sugar problems, immune disorders,
abnormal absorption of fats, and metabolism problems.
The
malabsorption of fats may lead to symptoms that include indigestion, reflux,
deficit of fatsoluble vitamins, hemorrhoids, gall stones, intolerance to fatty
foods, intolerance to alcohol, nausea and vomiting attacks, abdominal bloating,
and constipation.
Nervous
system disorders include depression, mood changes, especially anger and
irritability, poor concentration and "foggy brain", overheating of
the body, especially the face and torso, and recurrent headaches (including
migraine) associated with nausea.
The
blood sugar problems include hypoglycaemia.
Abnormalities
in the level of fats in the blood stream, whether too high or too low levels of
lipids in the organism. Hypercholesterolemia: elevated LDL cholesterol, reduced
HDL cholesterol, elevated triglycerides, clogged arteries leading to high blood
pressure, heart attacks and strokes, build up of fat in other body organs
(fatty degeneration of organs), lumps of fat in the skin (lipomas and other
fatty tumors), excessive weight gain (which may lead to obesity), inability to
lose weight even while dieting, sluggish metabolism, protuberant abdomen (pot
belly), cellulite, fatty liver, and a roll of fat around the upper abdomen
(liver roll) etc.[citation needed] Or too low levels of lipids:
hypocholesterolemia: low total cholesterol, low LDL and VLDL cholesterol, low
triglyderides.
Types
·
Hepatitis, inflammation of the liver,
is caused mainly by various viruses (viral hepatitis) but also by some liver
toxins (e.g. alcoholic hepatitis), autoimmunity (autoimmune hepatitis) or
hereditary conditions.
Hepatitis
(plural hepatitides) is a medical condition defined by the inflammation of the
liver and characterized by the presence of inflammatory cells in the tissue of
the organ. The name is from the Greek hepar (ἧπαρ), the root being hepat- (ἡπατ-), meaning liver,
and suffix -itis, meaning "inflammation" (c. 1727). The condition can
be self-limiting (healing on its own) or can progress to fibrosis (scarring)
and cirrhosis.
Hepatitis
may occur with limited or no symptoms, but often leads to jaundice, anorexia
(poor appetite) and malaise. Hepatitis is acute when it lasts less than six
months and chronic when it persists longer. A group of viruses known as the
hepatitis viruses cause most cases of hepatitis worldwide, but hepatitis can
also be caused by toxins (notably alcohol, certain medications, some industrial
organic solvents and plants), other infections and autoimmune diseases.
Alcoholic hepatitis evident by fatty
change, cell necrosis, Mallory bodies
Signs
and symptoms
Acute
Initial
features are of nonspecific flu-like symptoms, common to almost all acute viral
infections and may include malaise, muscle and joint aches, fever, nausea or
vomiting, diarrhea, and headache. More specific symptoms, which can be present
in acute hepatitis from any cause, are: profound loss of appetite, aversion to
smoking among smokers, dark urine, yellowing of the eyes and skin (i.e.,
jaundice) and abdominal discomfort. Physical findings are usually minimal,
apart from jaundice in a third and tender hepatomegaly (swelling of the liver)
in about 10%. Some exhibit lymphadenopathy (enlarged lymph nodes, in 5%) or
splenomegaly (enlargement of the spleen, in 5%).
Acute
viral hepatitis is more likely to be asymptomatic in younger people.
Symptomatic individuals may present after convalescent stage of 7 to 10 days,
with the total illness lasting 2 to 6 weeks.
A
small proportion of people with acute hepatitis progress to acute liver
failure, in which the liver is unable to clear harmful substances from the
circulation (leading to confusion and coma due to hepatic encephalopathy) and
produce blood proteins (leading to peripheral oedema and bleeding). This may
become life-threatening and occasionally requires a liver transplant.
Chronic
Chronic
hepatitis often leads to nonspecific symptoms such as malaise, tiredness and
weakness, and often leads to no symptoms at all. It is commonly identified on
blood tests performed either for screening or to evaluate nonspecific symptoms.
The occurrence of jaundice indicates advanced liver damage. On physical
examination there may be enlargement of the liver.
Extensive
damage and scarring of liver (i.e. cirrhosis) leads to weight loss, easy
bruising and bleeding tendencies, peripheral edema (swelling of the legs) and
accumulation of ascites (fluid in the abdominal cavity). Eventually, cirrhosis
may lead to various complications: esophageal varices (enlarged veins in the
wall of the esophagus that can cause life-threatening bleeding) hepatic
encephalopathy (confusion and coma) and hepatorenal syndrome (kidney
dysfunction).
Acne,
abnormal menstruation, lung scarring, inflammation of the thyroid gland and
kidneys may be present in women with autoimmune hepatitis.
Diagnosis
Diagnosis
can be made using various Hepatitis biochemical markers in conjunction with the
history and physical.
The
following are biochemical markers used in the diagnosis of hepatitis:
Hepatitis
A
|
Marker |
Detection
Time |
Description - |
Significance |
Note |
|
HAV-specific
IgM |
------------ |
--------------- |
Recent
infection of virus - |
----------- |
|
Total
HAV antibody (IgG & IgM) |
-------------- |
Enzyme
Immunoassay for antibodies |
Positive
test demonstrates previous exposure to HAV |
---------- |
Hepatitis
C
|
Marker |
Detection
Time |
Description |
Significance |
Note |
|
HCV-RNA |
1–3
weeks |
PCR |
Demonstrates
presence or absence of virus |
Results
may be intermittent during course of infection. Negative result is not
indicative of absence. |
|
anti-HCV |
5–6
weeks |
Enzyme
Immunoassay for antibodies |
Demonstrates
past or present infection |
High
false positive in those with autoimmune disorders and populations with low
virus prevalence. liver
disease. |
|
ALT |
5–6
weeks |
---------- |
Peak
in ALT coincides with peak in anti-HCV |
Fluctuating
ALT levels is an indication of active |
Data taken from the WHO website on Hepatitis C.
Pathology
The
liver, like all organs, responds to injury in a limited number of ways and a
number of patterns have been identified. Liver biopsies are rarely performed
for acute hepatitis and because of this the histology of chronic hepatitis is
better known than that of acute hepatitis.
Acute
In
acute hepatitis the lesions (areas of abnormal tissue) predominantly contain
diffuse sinusoidal and portal mononuclear infiltrates (lymphocytes, plasma
cells, Kupffer cells) and swollen hepatocytes. Acidophilic cells (Councilman
bodies) are nor prominent. The normal architecture is preserved. There is no
evidence of fibrosis or cirrhosis (fibrosis plus regenerative nodules). In
severe cases prominent common. Hepatocyte regeneration and cholestasis
(canalicular bile plugs) typically are present. Bridging hepatic necrosis
(areas of necrosis connecting two or more portal tracts) may also occur. There
may be some lobular disarray. Although aggregates of lymphocytes in portal
zones may occur these are usually neither common hepatocellular necrosis around
the central vein (zone 3) may be seen.
In
submassive necrosis – a rare presentation of acute hepatitis – there is
widespread hepatocellular necrosis beginning in the istribution and
progresscentrizonal ding towards portal tracts. The degree of parenchymal
inflammation is variable and is proportional to duration of disease. Two
distinct patterns of necrosis have been recognised: (1) zonal coagulative
necrosis or (2) panlobular (nonzonal) necrosis.[10] Numerous macrophages and
lymphocytes are present. Necrosis and inflammation of the biliary tree occurs.
Hyperplasia of the surviving biliary tract cells may be present. Stromal
haemorrhage is common.
The
histology may show some correlation with the cause:
Zone
1 (periportal) occurs in phosphorus poisoning or eclampsia.
Zone
2 (midzonal) – rare – is seen in yellow fever.
Zone
3 (centrilobular) occurs with ischemic injury, toxic effects, carbon
tetrachloride exposure or chloroform ingestion. Drugs such as acetaminophen may
be metabolized in zone 1 to toxic compounds that cause necrosis in zone 3.
Where
patients have recovered from this condition, biopsies commonly show multiacinar
regenerative nodules (previously known as adenomatous hyperplasia).
Massive
hepatic necrosis is also known and is usually rapidly fatal. The pathology
resembles that of submassive necrosis but is more markered in both degree and
extent.
Chronic
Chronic
hepatitis has been better studied and several conditions have been described.
Chronic
hepatitis with piecemeal (periportal) necrosis (or interface hepatitis) with or
without fibrosis. (formerly chronic active hepatitis) is any case of hepatitis
occurring for more than 6 months with portal based inflammation, fibrosis,
disruption of the terminal plate, and piecemeal necrosis. This term has now
been replaced by the diagnosis of 'chronic hepatitis
Chronic
hepatitis without piecemeal necrosis (or interface hepatitis) (formerly called
chronic persistent hepatitis) is chronic hepatitis with no significant
periportal necrosis or regeneration with a fairly dense mononuclear portal
infiltrate. Councilman bodies are frequently seen within the lobule.
Chronic
hepatitis without piecemeal necrosis (or interface hepatitis) (formerly called
chronic lobular hepatitis) is chronic hepatitis with persistent parenchymal
focal hepatocyte necrosis (apoptosis) with mononuclear sinusoidal infiltrates.
The
older terms have been deprecated because the conditions are now understood as
being able to alter over time so that what might have been regarded as a
relatively benign lesion could still progress to cirrhosis. The simpler term
chronic hepatitis is now preferred in association with the causative agent
(when known) and a grade based on the degree of inflammation, piecemeal or
bridging necrosis (interface hepatitis) and the stage of fibrosis. Several
grading systems have been proposed but none have been adopted universally.
Cirrhosis
is a diffuse process characterized by regenerative nodules that are separated
from one another by bands of fibrosis. It is the end stage for many chronic
liver diseases. The pathophysiological process that results in cirrhosis is as
follows: hepatocytes are lost through a gradual process of hepatocellular
injury and inflammation. This injury stimulates a regenerative response in the
remaining hepatocytes. The fibrotic scars limit the extent to which the normal
architecture can be reestablished as the scars isolate groups of hepatocytes.
This results in nodules formation. Angiogenisis (new vessel formation)
accompanies scar production which results in the formation of abnormal channels
between the central hepatic veins and the portal vessels. This in turn causes
shunting of blood around the regenerating parenchyma. Normal vascular
structures including the sinusoidal channels may be obliterated by fibrotic
tissue leading to portal hypertension. The overall reduction in hepatocyte
mass, in conjunction with the portal blood shunting, prevents the liver from
accomplishing its usual functions – the filtering of blood from the
gastrointestinal tract and serum protein production. These changes give rise to
the clinical manifestations of cirrhosis.
Specific
cases
Most
of the causes of hepatitis cannot be distinguished on the basis of the
pathology but some do have particular features that are suggestive of a
particular diagnosis.
The
presence of micronodular cirrhosis, Mallory bodies and fatty change within a
single biopsy are highly suggestive of alcoholic injury. Perivenular,
pericellular fibrosis (known as 'chicken wire fibrosis' because of its
appearance on trichrome or van Gieson stains) with partial or complete
obliteration of the central vein is also very suggestive of alcohol abuse.
Cardiac,
ischemic and venous outflow obstruction all cause similar patterns. The
sinusoids are often dilated and filled with erythrocytes. The liver cell plates
may be compressed. Coagulative necrosis of the hepatocytes can occur around the
central vein. Hemosiderin and lipochrome laden macrophages and inflammatory
cells may be found. At the edge of the fibrotic zone cholestasis may be
present. The portal tracts are rarely significantly involved until late in the
course.
Biliary
tract disease including primary biliary cirrhosis, sclerosing cholangitis,
inflammatory changes associated with idiopathic inflammatory bowel disease and
duct obstruction have similar histology in their early stages. Although these
diseases tend to primarily involve the biliary tract they may also be
associated with chronic inflammation within the liver and difficult to
distinguish on histological grounds alone. The fibrotic changes associated with
these disease principally involve the portal tracts with cholangiole
proliferation, portal tract inflammation with neutrophils surrounding the
cholangioles, disruption of the terminal plate by mononuclear inflammatory
cells and occasional hepatocyte necrosis. The central veins are either not
involved in the fibrotic process or become involved only late in the course of
the disease. Consequently the central–portal relationships are minimally
distorted. Where cirrhosis is present it tends to be in the form of a
portal–portal bridging fibrosis.
Hepatitis
E causes different histological patterns that depend on the host's background.
In immunocompetent patients the typical pattern is of severe intralobular
necrosis and acute cholangitis in the portal tract with numerous neutrophils.
This normally resolves without sequelae. Disease is more severe in those with
preexisting liver disease such as cirrhosis. In the immunocompromised patients
chronic infection may result with rapid progression to cirrhosis. The histology
is similar to that found in hepatitis C virus with dense lymphocytic portal
infiltrate, constant peacemeal necrosis and fibrosis.
·
Alcoholic liver disease is any
hepatic manifestation of alcohol overconsumption, including fatty liver
disease, alcoholic hepatitis, and cirrhosis. Analogous terms such as
"drug-induced" or "toxic" liver disease are also used to
refer to the range of disorders caused by various drugs and environmental
chemicals.
Alcoholic
liver disease is a term that encompasses the hepatic manifestations of alcohol
over consumption, including fatty liver, alcoholic hepatitis, and chronic
hepatitis with hepatic fibrosis or cirrhosis. It is the major cause of liver
disease in Western countries. Although steatosis (fatty liver) will develop in
any individual who consumes a large quantity of alcoholic beverages over a long
period of time, this process is transient and reversible. Of all chronic heavy
drinkers, only 15–20% develop hepatitis or cirrhosis, which can occur
concomitantly or in succession.
How
alcohol damages the liver is not completely understood. 80% of alcohol passes
through the liver to be detoxified. Chronic consumption of alcohol results in
the secretion of pro-inflammatory cytokines (TNF-alpha, IL6 and IL8), oxidative
stress, lipid peroxidation, and acetaldehyde toxicity. These factors cause
inflammation, apoptosis and eventually fibrosis of liver cells. Why this occurs
in only a few individuals is still unclear. Additionally, the liver has
tremendous capacity to regenerate and even when 75% of hepatocytes are dead, it
continues to function as normal.
Risk
factors
The
risk factors presently known are:
Quantity
of alcohol taken: consumption of 60–80g per day (about 75–100 ml/day) for 20
years or more in men, or 20g/day (about 25 ml/day) for women significantly
increases the risk of hepatitis and fibrosis by 7 to 47%,
Pattern
of drinking: drinking outside of meal times increases up to 2.7 times the risk
of alcoholic liver disease.
Gender:
females are twice as susceptible to alcohol-related liver disease, and may
develop alcoholic liver disease with shorter durations and doses of chronic
consumption. The lesser amount of alcohol dehydrogenase secreted in the gut,
higher proportion of body fat in women, and changes in fat absorption due to
the with menstrual cycle may explain this phenomenon.
Hepatitis
C infection: a concomitant hepatitis C infection significantly accelerates the
process of liver injury.
Genetic
factors: genetic factors predispose both to alcoholism and to alcoholic liver
disease. Monozygotic twins are more likely to be alcoholics and to develop
liver cirrhosis than dizygotic twins. Polymorphisms in the enzymes involved in
the metabolism of alcohol, such as ADH, ALDH, CYP4502E1, mitochondrial
dysfunction, and cytokine polymorphism may partly explain this genetic
component. However, no specific polymorphisms have currently been firmly linked
to alcoholic liver disease.
Iron
overload (hemochromatosis)
Diet:
malnutrition, particularly vitamin A and E deficiencies, can worsen
alcohol-induced liver damage by preventing regeneration of hepatocytes. This is
particularly a concern as alcoholics are usually malnourished because of a poor
diet, anorexia, and encephalopathy.
Pathophysiology
Pathogenesis of alcohol induced liver
injury.
Fatty
change
Fatty
change, or steatosis is the accumulation of fatty
acids in liver cells. These can be seen as fatty globules under the microscope.
Alcoholism causes development of large fatty globules (macro vesicular
steatosis) throughout the liver and can begin to occur after a few days of
heavy drinking. Alcohol is metabolized by alcohol dehydrogenase (ADH) into
acetaldehyde, then further metabolized by aldehyde dehydrogenase (ALDH) into
acetic acid, which is finally oxidized into carbon dioxide (CO2) and water ( H2O).
This process generates NADH, and increases the NADPH/NADP+ ratio. A higher NADH
concentration induces fatty acid synthesis while a decreased NAD level results
in decreased fatty acid oxidation. Subsequently, the higher levels of fatty
acids signal the liver cells to compound it to glycerol to form triglycerides.
These triglycerides accumulate, resulting in fatty liver.
Alcoholic
hepatitis
Alcoholic
hepatitis is characterized by the inflammation of hepatocytes. Between 10% and
35% of heavy drinkers develop alcoholic hepatitis (NIAAA, 1993). While
development of hepatitis is not directly related to the dose of alcohol, some
people seem more prone to this reaction than others[citation needed]. This is
called alcoholic steato necrosis and the inflammation appears to predispose to
liver fibrosis. Inflammatory cytokines (TNF-alpha, IL6 and IL8) are thought to
be essential in the initiation and perpetuation of liver injury by inducing
apoptosis and necrosis. One possible mechanism for the increased activity of
TNF-α is the increased intestinal permeability due to liver disease. This
facilitates the absorption of the gut-produced endotoxin into the portal
circulation. The Kupffer cells of the liver then phagocytose endotoxin,
stimulating the release of TNF-α. TNF-α then triggers apoptotic
pathways through the activation of caspases, resulting in cell death.
Cirrhosis
Cirrhosis
is a late stage of serious liver disease marked by inflammation (swelling),
fibrosis (cellular hardening) and damaged membranes preventing detoxification
of chemicals in the body, ending in scarring and necrosis (cell death). Between
10% to 20% of heavy drinkers will develop cirrhosis of the liver (NIAAA, 1993).
Acetaldehyde may be responsible for alcohol-induced fibrosis by stimulating
collagen deposition by hepatic stellate cells. The production of oxidants
derived from NADPH oxi- dase and/or cytochrome P-450 2E1 and the formation of
acetaldehyde-protein adducts damage the cell membrane.
Symptoms
include jaundice (yellowing), liver enlargement, and pain and tenderness from
the structural changes in damaged liver architecture. Without total abstinence
from alcohol use, will eventually lead to liver failure. Late complications of
cirrhosis or liver failure include portal hypertension (high blood pressure in
the portal vein due to the increased flow resistance through the damaged
liver), coagulation disorders (due to impaired production of coagulation
factors), ascites (heavy abdominal swelling due to build up of fluids in the
tissues) and other complications, including hepatic encephalopathy and the
hepatorenal syndrome.
Cirrhosis
can also result from other causes than alcohol abuse, such as viral hepatitis
and heavy exposure to toxins other than alcohol. The late stages of cirrhosis
may look similar medically, regardless of cause. This phenomenon is termed the
"final common pathway" for the disease.
Fatty
change and alcoholic hepatitis with abstinence can be reversible. The later
stages of fibrosis and cirrhosis tend to be irreversible, but can usually be
contained with abstinence for long periods of time.
There
are many tests to assess alcoholic liver damage. Besides blood examination,
doctors use ultrasound and a CT scan to assess liver damage. In some cases a
liver biopsy is performed. This minor procedure is done under local anesthesia,
and involves placing a small needle in the liver and obtaining a piece of
tissue. The tissue is then sent to the laboratory to be examined under a microscope.
The differential diagnoses for fatty liver non-alcoholic steatosis,
drug-induced steatosis, include diabetes, obesity and starvation.
The
first treatment of alcohol-induced liver disease is cessation of alcohol
consumption. This is the only way to reverse liver damage or prevent liver
injury from worsening. Without treatment, most patients with alcohol-induced
liver damage will develop liver cirrhosis. Other treatment for alcoholic
hepatitis include:
Nutrition
Doctors
recommend a calorie-rich diet to help the liver in its regeneration process.
Dietary fat must be reduced because fat interferes with alcohol metabolism. The
diet is usually supplemented with vitamins and dietary minerals (including
calcium and iron).
Many
nutritionists recommend a diet high in protein, with frequent small meals eaten
during the day, about 5–6 instead of the usual 3. Nutritionally, supporting the
liver and supplementing with nutrients that enhance liver function is
recommended. These include carnitine, which will help reverse fatty livers, and
vitamin C, which is an antioxidant, aids in collagen synthesis, and increases
the production of neurotransmitters such as norepinephrine and serotonin, as
well as supplementing with the nutrients that have been depleted due to the alcohol
consumption. Eliminating any food that may be manifesting as an intolerance and
alkalizing the body is also important. There are some supplements that are
recommended to help reduce cravings for alcohol, including choline, glutamine,
and vitamin C. As research shows glucose increases the toxicity of
centrilobular hepatotoxicants by inhibiting cell division and repair, it is
suggested fatty acids are used by the liver instead of glucose as a fuel source
to aid in repair; thus, it is recommended the patient consumes a diet high in
protein and essential fatty acids, e.g. omega 3. Cessation of alcohol
consumption and cigarette smoking, and increasing exercise are lifestyle
recommendations to decrease the risk of liver disease caused by alcoholic
stress.
Drugs
Abstinence
from alcohol intake and nutritional modification form the backbone in the
management of ALD. Symptom treatment can include: corticosteroids for severe
cases, anticytokines (infliximab and pentoxifylline), propylthiouracil to
modify metabolism and colchicine to inhibit hepatic fibrosis.
Antioxidants
It
is widely believed that alcohol-induced liver damage occurs via generation of
oxidants.[citation needed] Thus alternative health care practitioners routinely
recommend natural antioxidant supplements like milk thistle[citation needed].
Currently, there exists no substantive clinical evidence to suggest that milk
thistle or other antioxidant supplements are efficacious beyond placebo in
treating liver disease caused by chronic alcohol consumption.
Transplant
When
all else fails and the liver is severely damaged, the only alternative is a
liver transplant. While this is a viable option, liver transplant donors are
scarce and usually there is a long waiting list in any given hospital. One of
the criteria to become eligible for a liver transplant is to discontinue
alcohol consumption for a minimum of six months.
Complications
and prognosis
As
the liver scars, the blood vessels become noncompliant and narrow. This leads
to increased pressure in blood vessels entering the liver. Over time, this
causes a backlog of blood (portal hypertension), and is associated with massive
bleeding. Enlarged veins, also known as varicose veins, also develop to bypass
the blockages in the liver. These veins are very fragile and have a tendency to
rupture and bleed. Variceal bleeding can be life-threatening and needs
emergency treatment. Once the liver is damaged, fluid builds up in the abdomen and
legs. The fluid buildup presses on the diaphragm and can make breathing very
difficult. As liver damage progresses, the liver is unable to get rid of
pigments like bilirubin and both the skin and eyes turn yellow (jaundice). The
dark pigment also causes the urine to appear dark; however, the stools appear
pale. Also with the progression of the disease, the liver can release toxic
substances (including ammonia) which then lead to brain damage. This results in
altered mental state, and may cause behavior and personality changes.
·
Fatty liver disease (hepatic
steatosis) is a reversible condition where large vacuoles of triglyceride fat
accumulate in liver cells. Non-alcoholic fatty liver disease is a spectrum of
disease associated with obesity and metabolic syndrome, among other causes.
Fatty liver may lead to inflammatory disease (i.e. steatohepatitis) and,
eventually, cirrhosis.
·
Cirrhosis is the formation of fibrous
tissue (fibrosis) in the place of liver cells that have died due to a variety
of causes, including viral hepatitis, alcohol overconsumption, and other forms
of liver toxicity. Cirrhosis causes chronic liver failure.
·
Primary liver cancer most commonly
manifests as hepatocellular carcinoma and/or cholangiocarcinoma; rarer forms
include angiosarcoma and hemangiosarcoma of the liver. (Many liver malignancies
are secondary lesions that have metastasized from primary cancers in the
gastrointestinal tract and other organs, such as the kidneys, lungs, breast, or
prostate.)
·
Primary biliary cirrhosis is a serious
autoimmune disease of the bile capillaries.
Primary
biliary cirrhosis, often abbreviated PBC, is an autoimmune disease of the liver
marked by the slow progressive destruction of the small bile ducts of the
liver, with the intralobular ducts (Canals of Hering) affected early in the
disease . When these ducts are damaged, bile builds up in the liver
(cholestasis) and over time damages the tissue. This can lead to scarring,
fibrosis and cirrhosis. It was previously thought to be a rare disease, but more
recent studies have shown that it may affect up to
Signs and symptoms
Individuals
with PBC may present with the following:
·
Fatigue
·
Pruritus (itchy skin)
·
Jaundice (yellowing of the eyes and
skin), due to increased bilirubin in the blood.
·
Xanthoma (local collections of
cholesterol in the skin, especially around the eyes (xanthelasma))
·
Complications of cirrhosis and portal
hypertension:
·
Fluid retention in the abdomen
(ascites)
·
Hypersplenism
·
Esophageal varices
·
Hepatic encephalopathy, including
coma in extreme cases.
·
Association with an extrahepatic
autoimmune disorder such as rheumatoid arthritis or Sjögren's syndrome (in
up to 80% of cases).
Diagnosis
Intermediate magnification micrograph of PBC
showing bile duct inflammation and periductal granulomas. Liver biopsy. H&E
stain.
Immunofluorescence
staining pattern of sp100 antibodies (nuclear dots) and AMA.
To
diagnose PBC, distinctions should be established from other conditions with
similar symptoms, such as autoimmune hepatitis or primary sclerosing
cholangitis (PSC).
Diagnostic
blood tests include:
Deranged
liver function tests (elevated gamma-glutamyl transferase and alkaline
phosphatase)
Presence
of certain antibodies: antimitochondrial antibody (AMA), antinuclear antibody
(ANA)
Abdominal
ultrasound or a CT scan is usually performed to rule out blockage to the bile
ducts. Previously most suspected sufferers underwent a liver biopsy, and — if
uncertainty remained — endoscopic retrograde cholangiopancreatography (ERCP, an
endoscopic investigation of the bile duct). Now most patients are diagnosed
without invasive investigation since the combination of anti-mitochondrial
antibodies (see below) and typical (cholestatic) liver function tests are
considered diagnostic. However, a liver biopsy is necessary to determine the
stage of disease.
Anti-nuclear
antibodies appear to be prognostic agents in PBC. Anti-glycoprotein-210
antibodies, and to a lesser degree anti-p62 antibodies correlate with
progression toward end stage liver failure. Anti-centromere antibodies
correlate with developing portal hypertension. Anti-np62 and anti-sp100 are
also found in association with PBC.
Biopsy
Primary
biliary cirrhosis is characterized by interlobular bile duct destruction.
Histopathologic findings of primary biliary cirrhosis include:
Inflammation
of the bile ducts, characterized by intraepithelial lymphocytes, and
Periductal
epithelioid granulomata.
Summary
of stages
Stage
1 — Portal Stage: Normal sized triads; portal inflammation, subtle bile duct
damage. Granulomas are often detected in this stage.
Stage
2 — Periportal Stage: Enlarged triads; periportal fibrosis and/or inflammation.
Typically characterized by the finding of a proliferation of small bile ducts.
Stage
3 — Septal Stage: Active and/or passive fibrous septa.
Stage
4 — Biliary Cirrhosis: Nodules present; garland
Etiology
The
cause of the disease is unknown at this time, but research indicates that there
is an immunological basis for the disease, making it an autoimmune disorder.
Most of the patients (>90%) seem to have anti-mitochondrial antibodies
(AMAs) against pyruvate dehydrogenase complex (PDC-E2), an enzyme complex that
is found in the mitochondria.
Primary
biliary cirrhosis is considerably more common in those with gluten sensitive
enteropathy than the normal population. In some cases of disease protein
expression may cause an immune tolerance failure, as might be the case with
gp210 and p62, nuclear pore proteins. Gp210 has increased expression in the
bile duct of anti-gp210 positive patients. Both proteins appear to be
prognostic of liver failure relative to anti-mitochondrial antibodies.
A
genetic predisposition to disease has been thought important for some time, as
evident by cases of PBC in family members, concordance in identical twins, and
clustering of autoimmune diseases. In
In
2003 it was reported that an environmental Gram negative alphabacterium —
Novosphingobium aromaticivorans was strongly associated with this disease.
Subsequent reports appear to have confirmed this finding suggesting an
aetiological role for this organism. The mechanism appears to be a cross
reaction between the proteins of the bacterium and the mitochondrial proteins
of the liver cells. The gene encoding CD101 may also play a role in host
susceptibility to this disease.
There
is no known cure, but medication may slow the progression so that a normal
lifespan and quality of life may be attainable for many patients. Specific
treatment for fatigue, which may be debilitating in some patients, is limited
and currently undergoing trials.
Ursodeoxycholic
acid (Ursodiol) is the most frequently used treatment. This helps reduce the
cholestasis and improves blood test results (liver function tests). It has a
minimal effect on symptoms and whether it improves prognosis is controversial.
To
relieve itching caused by bile acids in circulation, which would normally be
removed by the liver, cholestyramine (a bile acid sequestrant) may be
prescribed to absorb bile acids in the gut and be eliminated, rather than
re-enter the blood stream. Alternative agents include naltrexone and
rifampicin.
To
relieve fatigue associated with primary biliary cirrhosis, current studies
indicate that Provigil (modafinil) may be effective without damaging the liver.
Though off-patent, the limiting factor in the use of modafinil in the U.S. is
cost. The manufacturer, Cephalon, has made agreements with manufacturers of
generic modafinil to provide payments in exchange for delaying their sale of
modafinil. The FTC has filed suit against Cephalon alleging anti-competitive
behavior.
Patients
with PBC have poor lipid-dependent absorption of Vitamins A, D, E, K.
Appropriate supplementation is recommended when bilirubin is elevated.
Patients
with PBC are at elevated risk of developing osteoporosis and esophageal varices
as compared to the general population and others with liver disease. Screening
and treatment of these complications is an important part of the management of
PBC.
As
in all liver diseases, excessive consumption of alcohol is contraindicated.
In
advanced cases, a liver transplant, if successful, results in a favorable
prognosis.
Obeticholic
acid is in phase III clinical trials for PBC.
Epidemiology
The
female:male ratio is at least 9:1. In some areas of the US and UK the
prevalence is estimated to be as high as
Prognosis
The
serum bilirubin level is an indicator of the prognosis of primary biliary
cirrhosis, with levels of 2–6 mg/dL having a mean survival time of 4.1 years,
6–10 mg/dL having 2.1 years and those above 10 mg/dL having a mean survival
time of 1.4 years.
After
liver transplant, the recurrence rate may be as high as 18% at 5 years, and up
to 30% at 10 years. There is no consensus on risk factors for recurrence of the
disease.
Patients
with primary biliary cirrhosis have an increased risk of hepatocellular
carcinoma.
History
Addison
and Gull in 1851 described the clinical picture of progressive obstructive
jaundice in the absence of mechanical obstruction of the large bile ducts.
Ahrens et al in 1950 coined the term primary biliary cirrhosis for this
disease. The association with anti mitochondrial antibodies was first reported
in 1986.
Low
magnification micrograph of PBC. H&E stain.
·
Primary sclerosing cholangitis is a
serious chronic inflammatory disease of the bile duct, which is believed to be
autoimmune in origin.
rimary
sclerosing cholangitis (PSC) is a disease of the bile ducts that causes
inflammation and subsequent obstruction of bile ducts both at a intrahepatic
(inside the liver) and extrahepatic (outside the liver) level. The inflammation
impedes the flow of bile to the gut, which can ultimately lead to cirrhosis of
the liver, liver failure and liver cancer. The underlying cause of the
inflammation is believed to be autoimmunity; and more than 80% of those with
PSC have ulcerative colitis. The definitive treatment is liver transplantation.
Cholangiogram
of primary sclerosing cholangitis.
Signs
and symptoms
PSC
is characterized by recurrent episodes of cholangitis (infection of the bile
ducts), with progressive biliary scarring and obstruction.
Chronic
fatigue (a non-specific symptom often present in liver disease)
Severe
jaundice with intense itching
Malabsorption
(especially of fat) and steatorrhea (fatty stool) due to biliary obstruction,
leading to decreased levels of the fat-soluble vitamins, A, D, E and K.
Signs
of cirrhosis
Hepatomegaly
(enlarged liver)
Portal
hypertension
Ascending
cholangitis, or infection of the bile duct.
Dark
urine due to excess conjugated bilirubin, which is water soluble, being
excreted by the kidneys
Hepatic
encephalopathy (confusion caused by liver dysfunction)
Diagnosis
The
diagnosis is by imaging of the bile duct, usually in the setting of endoscopic
retrograde cholangiopancreatography (ERCP, endoscopy of the bile duct and
pancreas), which shows "beading" (both strictures and dilation) of
the intrahepatic and extrahepatic bile ducts. Another option is magnetic
resonance cholangiopancreatography (MRCP), where magnetic resonance imaging is
used to visualise the biliary tract.
Most
patients with PSC have evidence of autoantibodies. Approximately 80% of
patients have perinuclear anti-neutrophil cytoplasmic antibodies, also called
p-ANCA; however, this finding is not specific for PSC. Antinuclear antibodies
and anti-smooth muscle antibody are found in 20%-50% of PSC patients and,
likewise, are not specific for the disease.
Other
tests often done are a full blood count, liver enzymes, bilirubin levels
(usually grossly elevated), renal function, electrolytes. Fecal fat
determination is occasionally ordered when the symptoms of malabsorption are
prominent.
The
differential diagnosis can include primary biliary cirrhosis, drug induced
cholestasis, cholangiocarcinoma, and HIV-associated cholangiopathy.
Etiology
The
cause of PSC is unknown, although it is thought to be an autoimmune disorder.
There is an increased prevalence of HLA alleles A1, B8, and DR3 in primary
sclerosing cholangitis.
Pathophysiology
Inflammation
damages bile ducts both inside and outside of the liver. The resulting scarring
of the bile ducts blocks the flow of bile, causing cholestasis. Bile stasis and
back-pressure induces proliferation of epithelial cells and focal destruction
of the liver parenchyma, forming bile lakes. Chronic biliary obstruction causes
portal tract fibrosis and ultimately biliary cirrhosis and liver failure.
Bile assists in the enteric breakdown and
absorption of fat; the absence of bile leads to fat malabsorption and
deficiencies of fat-soluble vitamins (A, D, E, K).
Epidemiology
There
is a 2:1 male-to-female predilection of primary sclerosing cholangitis. The
disease normally starts from age 20 to 30, though may begin in childhood. PSC
progresses slowly, so the disease can be active for a long time before it is
noticed or diagnosed. There is relatively little data on the prevalence and
incidence of primary sclerosing cholangitis, with studies in different
countries showing annual incidence of 0.068–1.3 per 100,000 people and
prevalence 0.22–8.5 per 100,000; given that PSC is closely linked with
ulcerative colitis, it is likely that the risk is higher in populations where
UC is more common.
Related
diseases
Primary
sclerosing cholangitis is associated with cholangiocarcinoma, a cancer of the
biliary tree, and the lifetime risk for PSC sufferers is 10-15%. Screening for
cholangiocarcinoma in patients with primary sclerosing cholangitis is
encouraged, but there is no general consensus on the modality and interval of
choice.
Colon
cancer is also associated with PSC.
PSC
has a significant association with ulcerative colitis, an inflammatory bowel
disease primarily affecting the large intestine. As many as 5% of patients with
ulcerative colitis may progress to develop primary sclerosing cholangitis and approximately 70% of people with primary
sclerosing cholangitis have ulcerative colitis.
Therapy
Standard
treatment includes ursodiol, a bile acid naturally produced by the liver, which
has been shown to lower elevated liver enzyme numbers in people with PSC, but
has not improved liver- or overall survival. Treatment also includes medication
to relieve itching (antipruritics), bile acid sequestrants (cholestyramine),
antibiotics to treat infections, and vitamin supplements, as people with PSC
are often deficient in vitamin A, vitamin D, vitamin E and vitamin K.
In
some cases, ERCP, which may involve stenting of the common bile duct, may be
necessary in order to open major blockages (dominant strictures).
Liver
transplantation is the only proven long-term treatment of PSC. Indications for
transplantation include recurrent bacterial cholangitis, jaundice refractory to
medical and endoscopic treatment, decompensated cirrhosis and complications of
portal hypertension. In one series, 1, 2, and 5 year survival following liver
transplantation for PSC was 90%, 86% and 85% respectively.
Prognosis
A
German study in 2007 estimated the average survival time from time of diagnosis
to be approximately 25 years, and the median time until either death or liver
transplantation to be approximately 10 years.
·
Budd-Chiari syndrome is the clinical
picture caused by occlusion of the hepatic vein, which in some cases may lead
to cirrhosis.
·
Hereditary diseases that cause damage
to the liver include hemochromatosis, involving accumulation of iron in the
body, and Wilson's disease, which causes the body to retain copper. Liver
damage is also a clinical feature of alpha 1-antitrypsin deficiency and
glycogen storage disease type II.
·
In transthyretin-related hereditary
amyloidosis, the liver produces a mutated transthyretin protein which has
severe neurodegenerative and/or cardiopathic effects. Liver transplantation can
provide a curative treatment option.
·
Gilbert's syndrome, a genetic
disorder of bilirubin metabolism found in about 5% of the population, can cause
mild jaundice.
There
are also many pediatric liver disease, including biliary atresia, alpha-1
antitrypsin deficiency, alagille syndrome, progressive familial intrahepatic
cholestasis to name but a few. The most effective way to treat alcoholic liver
disease and non-alcoholic fatty liver disease is to make lifestyle changes,
such as:
Cutting
out alcohol. Improving your diet. Taking regular exercise. Anti-viral
medications are available to treat infections such as hepatitis B and hepatitis
C. This is an area of active research and drug development and today many
treatments offer improved outcomes, by clearing or controlling the virus to
slow any decline in the condition of your liver.
Other
conditions may be managed by slowing down disease progression:
By
using steroid-based drugs in autoimmune hepatitis. Regularly removing a
quantity of blood from a vein (venesection) in the iron overload condition,
haemochromatosis. Wilson’s disease, a condition where copper builds up in the
body, can be managed with drugs which bind copper allowing it to be passed from
your body in urine. In cholestatic liver disease (where the flow of bile is
affected) a medication called ursodeoxycholic acid (URSO, also referred to as
UDCA) may be given. Made from naturally occurring bile acid, it may offer some
protection for the liver from the harmful chemicals in the bile, slowing
damage.
Diagnostics
A
number of liver function tests are available to test the proper function of the
liver. These test for the presence of enzymes in blood that are normally most
abundant in liver tissue, metabolites or products. LFT's, serum proteins, serum
albumin, serum globulin, A/G Ratio, alanine transaminase, aspartate
transaminase, prothrombin time, partial thromboplastin time, platelet count.
VIDEO
1. Translate and memorize the following words
and phrases pertaining to the text “Digestive System”.
1. Translate and memorize the following words and phrases:
Digestive
system, alimentary canal, accessory organs, to be covered with, serous coat,
visceral layer, parietal layer, contain the organ for taste, to divide and mix
the food, passage of food and air, to convey food, dilated portion, retaining
and mixing reservoir, the glands of the and body, thin-walled muscular tube,
secrete bile, red bone marrow, external secretion, internal secretion.
2. Complete the sentences using one of
the following medical terms. The first one has been done for you as an example.
the
pharynx, colon, muscular, the teeth, the
stomach, the glands, fibrinogen, accessory, the peritoneum, the diaphragm,
digestion
1. The digestive system consists of the
alimentary canal and accessory organs.
2. The organs of the digestive system are
covered with _____________.
3. Important structures of the mouth are
_____ which divide and mix the food.
4. The oral and laryngeal portions of
________ serve as a channel for the passage of food and air.
5. The esophagus conveys food from the
pharynx to __________.
6. The stomach lies under ________.
7. In the stomach the process of ___________ begins.
8. The _________ of the stomach are
important in the secretion of gastric juice.
9. The small intestine is a thin-walled
________ tube.
10. The large intestine includes caecum,
_______ and rectum.
11.
The liver fulfils production of
_________.
Find
substitutes for the following word combinations. Then use them in the sentences
of your own.
|
the
end organ for taste |
retaining
and mixing |
|
organs
which divide and mix food |
liver |
|
dilated
portion of the alimentary canal |
pancreas |
|
accessory
organs which secrete gastric juice |
glands |
|
glands
which consist of three pairs of glands |
peritoneum |
|
organ
of the human body that secrets bile |
teeth |
|
accessory
organ that forms an external and internal secretions |
stomach |
|
substance
concerned with carbohydratic metabolism |
tongue |
|
serous
coat that covers the organs of digestive system |
salivary |
|
kind
of reservoir in which the process of digestion begins |
insulin |
Read
the text carefully to obtain detailed understanding of it.
Comprehension
check
1.
True or false statements. Make true with “T”, false with “F”. Correct the false
statements.
1.
The digestive system consists only of the alimentary canal. _______
2.
The accessory organs are the teeth, tongue, salivary glands, hard and soft
palates, liver, gallbladder and pancreas.
_________
3.
The organs of the digestive system are covered with the periosteum. ______
4.
Important structures of the mouth are the tongue and teeth. ______
5.
Our food passes from the stomach to the esophagus. _________
6.
Diaphragm conveys food from the pharynx to the stomach. ______
7.
The stomach is a narrowed portion of the alimentary canal. _______
8.
The process of digestion begins in the pancreas. ______
9.
The glands of the fundus and body are very important in the secretion of bile.
________
10.
The liver secrets gastric juice. ______
2.
Here the answers to some questions from the text. What are the questions?
1.
The digestive system consists of the alimentary canal and accessory organs.
2.
The organs of the digestive system are covered with the serous coat,
peritoneum.
3.
Peritoneum has the visceral and parietal layers.
4.
Our food passes from the mouth to the esophagus.
5.
The air passes from the nasal pharynx to the stomach.
6.
The esophagus conveys food from the pharynx to the larynx.
7.
The stomach is a dilated portion of the alimentary canal.
8.
The stomach lies in the upper abdomen under the diaphragm.
9.
The small intestine is a thin-walled muscular tube about
10.
The large intestine is about
11.
The large salivary glands consist of three pairs of glands which open in to the
mouth.
12.
The liver secrets bile and fulfils many other functions.
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1.
Chatterjee, SN and J Das.
"Electron microscopic observations on the excretion of cell wall material
by Vibrio cholerae." "J.Gen.Microbiol." "49" : 1-11 (1967) ; Kuehn, MJ and NC Kesty.
"Bacterial outer membrane vesicles and the host-pathogen
interaction." Genes Dev.and then the 19(22):2645-55 (2005)
2.
Kong F, Singh RP (June 2008).
"Disintegration of solid foods in human stomach". J. Food Sci. 73
(5): R67–80.
3.
Viola-Villegas N, Rabideau AE,
Bartholomä M, Zubieta J, Doyle RP (August 2009). "Targeting the
cubilin receptor through the vitamin B(12) uptake
pathway: cytotoxicity and mechanistic insight through fluorescent Re(I)
delivery". J. Med. Chem. 52 (16): 5253–61.