N 5

№ 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.

 

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 – 3.0 kilograms, and it is a soft, pinkish-brown “boomerang shaped” organ. It is the second largest organ (the largest organ being the skin) and the largest gland within the human body.

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 io 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:

 

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 USA and Roy Calne in England in 1963 and 1965 respectively. Liver transplantation is the only option for those with irreversible liver failure. Most transplants are done for chronic liver diseases leading to cirrhosis, such as chronic hepatitis C, alcoholism, autoimmune hepatitis, and many others. Less commonly, liver transplantation is done for fulminant hepatic failure, in which liver failure occurs over days to weeks.

 

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

Crystal structure of trac

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 Harvard Medical School (Boston, USA) in two bacterial pathogens, Vibrio cholerae and Pseudomonas aeruginosa. Since then, Type VI secretion systems have been found in most genomes of proteobacteria, including animal, plant, human pathogens, as well as soil, environmental or marine bacteria. While most of the early studies of Type VI secretion focused on its role in the pathogenesis of higher organisms, more recent studies suggested a broader physiological role in defense against simple eukaryotic predators and its role in inter-bacteria interactions. The Type VI secretion system gene clusters contain from 15 to more than 20 genes, two of which, Hcp and VgrG, have been shown to be nearly universally secreted substrates of the system. Structural analysis of these and other proteins in this system bear a striking resemblance to the tail spike of the T4 phage. Vibrio cholerae T6SS sheath (composed of VipA and VipB proteins) was visualized by whole-cell electron cryotomography and dynamics of the T6SS sheath was monitored using fluorescence microscopy. These findings are summarized in a narrated video here. Using live-cell fluorescence microscopy it was further shown that ATPase ClpV binds contracted sheath and disassembles it in seconds.

 

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 obtaiutrients 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 Florence. It is also fried and eaten with onions as part of the Korean dish Makchang gui.

 

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 Latiame 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 Latiames 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: Superior margin of pancreas

 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.

 

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 0.2 mm in diameter.:914 Each is separated from the surrounding pancreatic tissue by a thin fibrous connective tissue capsule which is continuous with the fibrous connective tissue that is interwoven throughout the rest of the pancreas.:914 The combined mass of the islets is 1 to 1.5 grams.

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 ionhuman 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:

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 6.9 m (22 feet 6 inches), and in the adult female 7.1 m (23 feet 4 inches). It can vary greatly, from as short as 4.6 m (15 feet) to as long as 9.8 m (32 feet). It is approximately 2.5–3 cm in diameter.

 

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:

 

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

·        Gardner Syndrome

·        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 Superior Mesenteric Artery or the Superior Mesenteric Vein

·        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 4.9 feet (1.5 m) long, which is about one-fifth of the whole length of the intestinal canal.

 

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 4.9 ft long. On the surface, bands of longitudinal muscle fibers called taeniae coli, each about 1/5 in wide, can be identified. There are three bands, and they start at the base of the appendix and extend from the cecum to the rectum. Along the sides of the taeniae, tags of peritoneum filled with fat, called epiploic appendages (or appendices epiploicae) are found. The sacculations, called haustra, are characteristic features of the large intestine, and distinguish it from the small intestine.

 

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.[citatioeeded] 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

 

Hepatitis C

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 iodules 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[citatioeeded]. 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.[citatioeeded] Thus alternative health care practitioners routinely recommend natural antioxidant supplements like milk thistle[citatioeeded]. 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 1 in 3–4,000 people; the sex ratio is at least 9:1 (female to male).

 

 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 2009 a Canadian led group of investigators reported in the New England Journal of Medicine results from the first PBC genome-wide association study. This research revealed parts of the IL12 signaling cascade, particularly IL12A and IL12RB2 polymorphisms, to be important in the etiology of the disease in addition to the HLA region. In 2012, two independent PBC association studies increased the total number of genomic regions associated to 26, implicating many genes involved in cytokine regulation such as TYK2, SH2B3 and TNFSF11.

 

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 1 in 4000. This is much more common than in South America or Africa, which may be due to better recognition in the US and UK. First-degree relatives may have as much as a 500 times increase in prevalence, but there is debate if this risk is greater in the same generation relatives or the one that follows.

 

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

 

Liver

 

 

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.

        

Reading and Translating

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 7 meters long.

10. The large intestine is about 1.5 meters long.

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.

 

REFERENCES:

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.