The lysosomes
The lysosomes, first recognized in the liver, are membranebound vesicles that are involved in the digestion and catabolism of various exogenous and endogenous substances, a function that is reflected in their heterogeneous content – autophagic vacuoles, storage products, lipofuscin, hemosiderin and copper complexes.
They are rich in acid hydrolase, for example acid phosphatase, which can be used for their histochemical identification; they are involved in a number of storage disorders.
The peroxisomes (microbodies) are membrane-bound ovoid bodies that contain oxidases and use molecular oxygen for the production of H2O2. This is in turn hydrolyzed by peroxisomal catalase, an enzyme that can be used for the ultrastructural identification of these organelles. Peroxisomes are involved in the metabolism of fatty acid and alcohol; they proliferate following administration of hypolipidemic drugs, such as clofibrate.
The cytoskeleton comprises:
• The microfilaments (6 nm) are composed of filaments of actin and myosin which, associated in bundles, form a three - dimensional meshwork throughout the cytoplasm; they are attached to the plasma membrane, extend into the microvilli, and are particularly abundant in the pericanalicular ectoplasm, being attached to the junctional complex on either side of the canaliculus; they play a major role in bile secretion and flow regulation, as exemplified by intrahepatic cholestasis produced by drugs that cause depolymerization of the pericanalicular actin belt, in particular cytochalasin B and norethandrolone.
• The intermediate filaments (8–10 nm) are a family of selfassembling protein fibers that act as an intracellular scaffold with a role in integrating cytoplasmic space and organellemovement; like in other epithelial cells in the body they react as cytokeratins, more specifically hepatocyte cytokeratins 8 and 18, in contrast to cytokeratins 7 and 19 which characterize biliary epithelium; intermediate filaments contribute to the formation of Mallory bodies as a result of their depolymerization in alcoholic and other liver diseases.
• The microtubules (20 nm) are hollow, unbranched structures that play a role in cell division (formation of mitotic spindle), in the movement of transport vesicles, and in the transport and export of proteins and lipoproteins. Glycogen is abundant, reflecting a principal role of the liver in the synthesis of glycogen from glucose, or lactic and pyruvic acid, and its breakdown and release as glucose into the circulation.
When depletion occurs, glycogen starts disappearing from the perivenular region. In electron microscopy it appears as dense β-particles, 15–30 nm in diameter, and α-particles, aggregates of the smaller particles arranged in rosettes.
The lysosomes, first recognized in the liver, are membranebound vesicles that are involved in the digestion and catabolism of various exogenous and endogenous substances, a function that is reflected in their heterogeneous content – autophagic vacuoles, storage products, lipofuscin, hemosiderin and copper complexes.
They are rich in acid hydrolase, for example acid phosphatase, which can be used for their histochemical identification; they are involved in a number of storage disorders.
The peroxisomes (microbodies) are membrane-bound ovoid bodies that contain oxidases and use molecular oxygen for the production of H2O2. This is in turn hydrolyzed by peroxisomal catalase, an enzyme that can be used for the ultrastructural identification of these organelles. Peroxisomes are involved in the metabolism of fatty acid and alcohol; they proliferate following administration of hypolipidemic drugs, such as clofibrate.
The cytoskeleton comprises:
• The microfilaments (6 nm) are composed of filaments of actin and myosin which, associated in bundles, form a three - dimensional meshwork throughout the cytoplasm; they are attached to the plasma membrane, extend into the microvilli, and are particularly abundant in the pericanalicular ectoplasm, being attached to the junctional complex on either side of the canaliculus; they play a major role in bile secretion and flow regulation, as exemplified by intrahepatic cholestasis produced by drugs that cause depolymerization of the pericanalicular actin belt, in particular cytochalasin B and norethandrolone.
• The intermediate filaments (8–10 nm) are a family of selfassembling protein fibers that act as an intracellular scaffold with a role in integrating cytoplasmic space and organellemovement; like in other epithelial cells in the body they react as cytokeratins, more specifically hepatocyte cytokeratins 8 and 18, in contrast to cytokeratins 7 and 19 which characterize biliary epithelium; intermediate filaments contribute to the formation of Mallory bodies as a result of their depolymerization in alcoholic and other liver diseases.
• The microtubules (20 nm) are hollow, unbranched structures that play a role in cell division (formation of mitotic spindle), in the movement of transport vesicles, and in the transport and export of proteins and lipoproteins. Glycogen is abundant, reflecting a principal role of the liver in the synthesis of glycogen from glucose, or lactic and pyruvic acid, and its breakdown and release as glucose into the circulation.
When depletion occurs, glycogen starts disappearing from the perivenular region. In electron microscopy it appears as dense β-particles, 15–30 nm in diameter, and α-particles, aggregates of the smaller particles arranged in rosettes.
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The hepatocyte
Hepatocytes occupy some 80–88% of the total liver volume in humans. The individual hepatocyte is a polyhedral and highly polarized epithelial cell approximately 30–40 μm in diameter. The cells are arranged in plates, which appear as ‘cords’ when seen in two dimensions under the microscope (Fig. 1.9).
Figure 1.9 Light microscopy of liver cell plates cut longitudinally. Note the centrally placed nuclei, well demarcated sinusoidal membranes with intimately associated sinusoidal lining cells (SLC), intervening sinusoids (S), and the intercellular membranes with canalicular regions (CR) outlined by basophilic cytoplasmic condensation.
The basolateral or sinus surface area is considerably increased due to the presence of numerous microvilli which project into the perisinusoidal space of Disse, where they are in direct contact with cell-free blood; this intimate relationship is essential to secure the high absorption and secretory activity of the hepatocyte (Fig. 1.10).
Figure 1.10 Relationship between sinusoid, sinusoid lining cells and hepatocyte. The sketch illustrates the various hepatocyte organelles. Note Kupffer cells, the cytoplasmic processes of which are anchored in endothelial fenestrae.
The bile canaliculus is an intercellular space formed by apposition of the margins of a groove half way along the lateral membrane with that of the neighboring cell, the lines of apposition being held together by junctional complexes (Fig. 1.11). The lateral domain is the flat region of the lateral membrane extending from the canaliculus to the sinusoidal surface, an area specialized in cell attachment and communication.
Figure 1.11 Electron micrograph of bile canaliculi (bc), intercellular membranes and junctional complex. Note appearances of various organelles within the two adjacent hepatocytes (H). Open arrows, tight junctions; G, golgi apparatus; g, glycogen; ser, smooth endoplasmic reticulum; rer, rough endoplasmic reticulum; M, mitochondrion; L, lysosome (× 18 000). Courtesy of Professor P Bioulac-Sage.
The canaliculiare not seen in conventional histology, but they can beoutlined by histochemical ATPase staining (Fig. 1.12a), or byimmunostaining using polyclonal carcinoembryonic antigen or antibodies raised against enzymes localized to the canalicular membrane; accumulation of lipofuscin or hemosiderin at the biliary pole of the hepatocyte also outlines negatively stained canaliculi (Fig. 1.12b).
Figure 1.12 Bile canaliculi in light microscopy. (a) Histochemical demonstration of ATPase in pericanalicular cytoplasm. (b) Canalicular network outlined in iron overload due to pericanalicular accumulation of hemosiderin (Perls’ stain).
The nucleus is large, occupying 5–10% of the cell volume, surrounded with one or more prominent nucleoli. About 25% of hepatocytes are binucleated. Hepatocyte nuclei show a variation in size that reflects polyploidy with corresponding increased DNA content.
This increases with age and in pathologic situations. The marked functional diversity is matched by a great variety of cytoplasmic organelles as listed below and illustrated in Figures 1.10 and 1.13. The endoplasmic reticulum – a complex network of parallel membranes and cisternae – comprises:
• the rough endoplasmic reticulum (RER), which is more developed in periportal areas, has attached polyribosomes, which are sites of protein synthesis including both cell constituent proteins and secretory plasma proteins;
• the smooth endoplasmic reticulum (SER) of which cisternae are in continuity with those of the RER; here proteins are collected and transported to the Golgi complex, where they are packaged in vesicles prior to their export from the cell; the SER is the site of the metabolism and detoxification of xenobiotics, the SER harboring the cytochrome P450 oxidation system whose induction is expressed by a proliferation of SER membranes
Figure 1.13 Electron micrograph of a sinusoid with its lining cells (a), and hepatocytes with organelles (b). H, hepatocyte; bc, bile canaliculus; m, mitochondrion; L, lysosome; G, golgi apparatus; g, glycogen; rer, rough endoplasmic reticulum; S, sinusoidal lumen; E, endothelial cell; K, Kupffer cell; Sc, hepatic stellate cell; Co, collagen in Disse space. (a) (× 2600). (b) (× 6400). Courtesy of Professor P Bioulac-Sage..
Other cell functions associated with SER include metabolism of fatty acids, phospholipids and triglycerides, and synthesis of cholesterol and possibly of bile acid.
The mitochondria are particularly numerous in the hepatocytes, their inner membranes and cristae being concerned with the oxidative phosphorylation and fatty acid oxidation whereas their matrix contains the enzymes involved in the citric acid and urea cycles.
Although not yet fully characterized, a monoclonal antibody referred to as hepatocyte specific antigen or hepatocyte paraffin- 1 (HepPar-1) appears to identify an antigen unique to hepatocellular mitochondria. This commercialized antibody is widely used when there is a need to identify hepatocytes or hepatocellular neoplasms (Fig. 1.14).
Figure 1.14 Normal hepatocyte cytoplasm shows distinctive brown
granules after immunostaining for hepatocyte specific antigen, which
appears to detect antigenic material unique to hepatocellular
mitochondria. PV, portal venule; HA = hepatic arteriole; BD, bile duct
(HepPar-1, immunoperoxidase).
Hepatocytes occupy some 80–88% of the total liver volume in humans. The individual hepatocyte is a polyhedral and highly polarized epithelial cell approximately 30–40 μm in diameter. The cells are arranged in plates, which appear as ‘cords’ when seen in two dimensions under the microscope (Fig. 1.9).
Figure 1.9 Light microscopy of liver cell plates cut longitudinally. Note the centrally placed nuclei, well demarcated sinusoidal membranes with intimately associated sinusoidal lining cells (SLC), intervening sinusoids (S), and the intercellular membranes with canalicular regions (CR) outlined by basophilic cytoplasmic condensation.
The basolateral or sinus surface area is considerably increased due to the presence of numerous microvilli which project into the perisinusoidal space of Disse, where they are in direct contact with cell-free blood; this intimate relationship is essential to secure the high absorption and secretory activity of the hepatocyte (Fig. 1.10).
Figure 1.10 Relationship between sinusoid, sinusoid lining cells and hepatocyte. The sketch illustrates the various hepatocyte organelles. Note Kupffer cells, the cytoplasmic processes of which are anchored in endothelial fenestrae.
The bile canaliculus is an intercellular space formed by apposition of the margins of a groove half way along the lateral membrane with that of the neighboring cell, the lines of apposition being held together by junctional complexes (Fig. 1.11). The lateral domain is the flat region of the lateral membrane extending from the canaliculus to the sinusoidal surface, an area specialized in cell attachment and communication.
Figure 1.11 Electron micrograph of bile canaliculi (bc), intercellular membranes and junctional complex. Note appearances of various organelles within the two adjacent hepatocytes (H). Open arrows, tight junctions; G, golgi apparatus; g, glycogen; ser, smooth endoplasmic reticulum; rer, rough endoplasmic reticulum; M, mitochondrion; L, lysosome (× 18 000). Courtesy of Professor P Bioulac-Sage.
The canaliculiare not seen in conventional histology, but they can beoutlined by histochemical ATPase staining (Fig. 1.12a), or byimmunostaining using polyclonal carcinoembryonic antigen or antibodies raised against enzymes localized to the canalicular membrane; accumulation of lipofuscin or hemosiderin at the biliary pole of the hepatocyte also outlines negatively stained canaliculi (Fig. 1.12b).
Figure 1.12 Bile canaliculi in light microscopy. (a) Histochemical demonstration of ATPase in pericanalicular cytoplasm. (b) Canalicular network outlined in iron overload due to pericanalicular accumulation of hemosiderin (Perls’ stain).
The nucleus is large, occupying 5–10% of the cell volume, surrounded with one or more prominent nucleoli. About 25% of hepatocytes are binucleated. Hepatocyte nuclei show a variation in size that reflects polyploidy with corresponding increased DNA content.
This increases with age and in pathologic situations. The marked functional diversity is matched by a great variety of cytoplasmic organelles as listed below and illustrated in Figures 1.10 and 1.13. The endoplasmic reticulum – a complex network of parallel membranes and cisternae – comprises:
• the rough endoplasmic reticulum (RER), which is more developed in periportal areas, has attached polyribosomes, which are sites of protein synthesis including both cell constituent proteins and secretory plasma proteins;
• the smooth endoplasmic reticulum (SER) of which cisternae are in continuity with those of the RER; here proteins are collected and transported to the Golgi complex, where they are packaged in vesicles prior to their export from the cell; the SER is the site of the metabolism and detoxification of xenobiotics, the SER harboring the cytochrome P450 oxidation system whose induction is expressed by a proliferation of SER membranes
Figure 1.13 Electron micrograph of a sinusoid with its lining cells (a), and hepatocytes with organelles (b). H, hepatocyte; bc, bile canaliculus; m, mitochondrion; L, lysosome; G, golgi apparatus; g, glycogen; rer, rough endoplasmic reticulum; S, sinusoidal lumen; E, endothelial cell; K, Kupffer cell; Sc, hepatic stellate cell; Co, collagen in Disse space. (a) (× 2600). (b) (× 6400). Courtesy of Professor P Bioulac-Sage..
Other cell functions associated with SER include metabolism of fatty acids, phospholipids and triglycerides, and synthesis of cholesterol and possibly of bile acid.
The mitochondria are particularly numerous in the hepatocytes, their inner membranes and cristae being concerned with the oxidative phosphorylation and fatty acid oxidation whereas their matrix contains the enzymes involved in the citric acid and urea cycles.
Although not yet fully characterized, a monoclonal antibody referred to as hepatocyte specific antigen or hepatocyte paraffin- 1 (HepPar-1) appears to identify an antigen unique to hepatocellular mitochondria. This commercialized antibody is widely used when there is a need to identify hepatocytes or hepatocellular neoplasms (Fig. 1.14).
Figure 1.14 Normal hepatocyte cytoplasm shows distinctive brown
granules after immunostaining for hepatocyte specific antigen, which
appears to detect antigenic material unique to hepatocellular
mitochondria. PV, portal venule; HA = hepatic arteriole; BD, bile duct
(HepPar-1, immunoperoxidase).
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Basically there are two different concepts regarding the threedimensional organization and functional unit of the liver:
• 1. The Kiernan or classic lobule is organized around a central venule, a terminal tributary of the hepatic vein, and is traditionally represented as hexagonal in outline, the boundaries of which are well defined by thin interlobular septa of connective tissue in a few species only (Fig.1.1).
In humans, such lobules are delineated by an imaginary line with the portal tracts lying in between the ‘corners’ of adjacent lobules. This lobular concept is the basis for describing as centrilobular or perilobular (peripheral) the structural alterations occurring around the hepatic venules or portal tracts, respectively.
The term mid-zonal is used for changes affecting the intermediate parenchyma. This concept is convenient for descriptive purposes and is still largely used even though it is simplistic to regard the liver lobule as a microcirculatory unit. In reality, each lobule is supplied by several terminal hepatic arterioles and portal venules, which also feed portions of adjacent lobules.
• 2. The liver acinus is arranged around the terminal branches of the afferent vessels as a pear-shaped cuff of parenchyma lying between and draining into terminal hepatic venules, which in this model become peripheral.
The diagrammatic representation of the liver simple acinus, the arbitrary zonation of the liver parenchyma within its boundaries, and the relationships with the classic lobule are illustrated in Figure. 1.2.
Figure 1.2 Liver simple acinus. Diagrammatic representation with the
zonal arrangement of the hepatocytes and two neighboring classic lobules
outlined by a discontinuous line. Blood becomes progressively poorer in
oxygen and nutrients from zone 1 to zone 3, which thus represents the
microcirculatory periphery. The most peripheral portions of zone 3 from
adjacent acini form the perivenular area, the so-called centrilobular zone
of the ‘classic lobule’. PT, portal tract; ThV, terminal hepatic venule
(central venule of ‘classic lobule’); 1, 2, 3: microcirculatory zones; 1′, 2′,
3′: microcirculatory zones of a neighboring acinus
Acinar zones 1, 2 and 3 are roughly equivalent to periportal, mid-zonal and centrilobular areas of the lobular concept. Three or more simple acini form a complex acinus, a sleeve of parenchyma surrounding the preterminal portal vein and hepatic
arterial branches.
Several complex acini in turn form part of larger units or acinar agglomerates.
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• 1. The Kiernan or classic lobule is organized around a central venule, a terminal tributary of the hepatic vein, and is traditionally represented as hexagonal in outline, the boundaries of which are well defined by thin interlobular septa of connective tissue in a few species only (Fig.1.1).
Figure 1.1 Light microscopy of a pig liver showing the traditional hexagonal lobule (Kiernan) outlined by thin fibrous septa. CV, ‘central’ venule; PT, portal tracts. (Silver stain for reticulin)
In humans, such lobules are delineated by an imaginary line with the portal tracts lying in between the ‘corners’ of adjacent lobules. This lobular concept is the basis for describing as centrilobular or perilobular (peripheral) the structural alterations occurring around the hepatic venules or portal tracts, respectively.
The term mid-zonal is used for changes affecting the intermediate parenchyma. This concept is convenient for descriptive purposes and is still largely used even though it is simplistic to regard the liver lobule as a microcirculatory unit. In reality, each lobule is supplied by several terminal hepatic arterioles and portal venules, which also feed portions of adjacent lobules.
• 2. The liver acinus is arranged around the terminal branches of the afferent vessels as a pear-shaped cuff of parenchyma lying between and draining into terminal hepatic venules, which in this model become peripheral.
The diagrammatic representation of the liver simple acinus, the arbitrary zonation of the liver parenchyma within its boundaries, and the relationships with the classic lobule are illustrated in Figure. 1.2.
Figure 1.2 Liver simple acinus. Diagrammatic representation with the
zonal arrangement of the hepatocytes and two neighboring classic lobules
outlined by a discontinuous line. Blood becomes progressively poorer in
oxygen and nutrients from zone 1 to zone 3, which thus represents the
microcirculatory periphery. The most peripheral portions of zone 3 from
adjacent acini form the perivenular area, the so-called centrilobular zone
of the ‘classic lobule’. PT, portal tract; ThV, terminal hepatic venule
(central venule of ‘classic lobule’); 1, 2, 3: microcirculatory zones; 1′, 2′,
3′: microcirculatory zones of a neighboring acinus
Acinar zones 1, 2 and 3 are roughly equivalent to periportal, mid-zonal and centrilobular areas of the lobular concept. Three or more simple acini form a complex acinus, a sleeve of parenchyma surrounding the preterminal portal vein and hepatic
arterial branches.
Several complex acini in turn form part of larger units or acinar agglomerates.
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People usually complain about sinus headache. The question is: what does ‘sinus headache’ mean? The common symptoms of sinus headache include headache, sinus and nasal congestion, and facial pressure and pain. Various over-the-counter medications are available to relieve these symptoms. However, the way these products are treated in the market led to the belief that sinus headache is a common condition, when it is not as what other people might think.
Sinus headache is a migraine that has sinus symptoms. A study of about 3,000 patients revealed the importance of assessing frequent complaint of sinus headache. The participants had experienced a minimum of six sinus headaches for the past six months prior the study. The participants had not been diagnosed to have migraine.
Hence, they had not been treated with any migraine-specific medication. The results of the study revealed that 80% of the participants were diagnosed to have migraine headache, and not sinus headache.
Some research studies revealed how the common sinus symptoms associate migraine. A study particularly shows 45% of patients with migraine had one symptom of either watery eyes or nasal congestion. Significantly, if congestion is a part of migraine, the congestion would be expected to be resolved by a migraine-specific treatment.
With this being said, how will a person know if the headache is a migraine instead of a sinus? The person should be asking some questions to yourself.
For the last three months, are your headaches interfering with your functional ability? Are they disabling you? (Do you miss family, school, or work activities because of your headaches?) Have you ever experienced nausea with your headaches? Have you ever experienced sensitivity to sound and/ or light with your headaches?
These criteria are based on the ID Migraine Questionnaire that Dr. Richard Lipton of Albert Einstein College of Medicine has developed. If the person experiences two out of the three criteria, diagnosis of migraine is 93% probable. If the person experiences all the criteria occur, diagnosis of migraine is 98% probable.
Further, the International Classification of Headache Disorders provided criteria to classify headache types. Aside from the common symptoms of migraine headache such as sinus and nasal congestion, and facial pressure and pain, sufferers often have experienced other symptoms associated with migraine. These include headache worsened by movement, throbbing pain, moderate up to severe headache, sensitivity to noise and/or light, and nausea.
If the person feels that the sinus headache being experienced could be a migraine, there might a need to ask your provider if any migraine-specific medication could be used to treat the condition. If so, that individual should try migraine-specific medication for the next three sinus headaches you will experience.
Look for medications that will improve your headache symptoms or headache associated symptoms better than all other previous treatments taken. In several cases, work-up might be done, for example, a CT scan of the sinuses. This will rule out secondary causes like sinus disease. This might simply reassure that it is a migraine diagnosis, not a sinus issue.
Most sinus headaches are migraine headaches having sinus symptoms. This basic knowledge might help to get the correct diagnosis as well as treatment. This might eventually free a sufferer from the recurring headache.
Neti pots have become common objects in several households for reasons other than making tea. Neti pots are small teapots that have long spouts. These are used in rinsing nasal channels with salt-based or saline solution. These have become a popular treatment for moistening nasal channels exposed to dry air (indoor air), colds, and sinuses.
Nasal rinsing procedure might have slight differences with the device used. These are the steps involved in the procedure. First, lean over the sink, tilt your head to the side with the chin and forehead roughly level. This avoids liquid flowing into the mouth. Second, breathe through an open mouth and insert the spout of the container filled with saline solution in the upper nostril.
This allows the liquid to drain through the lower nostril. Lastly, clear the nostrils. Repeat the steps, but this time, tilt your head on the other side.
Nasal rinsing can remove pollen, dust, dirt, and similar debris and helps in loosening thick mucus. This might also be helpful in relieving nasal symptoms of certain conditions such as flu, colds, and allergies.
Similar to air filters used in homes or car filters, the nose traps the debris present in the air. Using saline solution in rinsing your nose is like using saline eye drops in rinsing out pollen.
However, the FDA or Food and Drug administration has concerns regarding risk of having infection that comes with improper usage of neti pots, as well as other devices used in nasal rinsing. The agency informs health care professionals, manufacturers, and consumers with regards to safe practices in using all kinds of devices in nasal rinsing. This includes the use of pulsed water devices that are battery-operated, squeeze bottles, and bulb syringes.
Devices used to rinse nasal channels are useful and safe. They should be used as well as cleaned properly. Nevertheless, the source of water, which will be used with these devices, is very important. Processed, treated, or filtered tap water will not be safe to be used in nasal rinsing.
Certain tap water has low levels of some organisms like protozoa which include amoebas and bacteria. These might be safe to be swallowed since the stomach acid can kill them. These microorganisms are able to stay alive in the nasal channels. These might cause potential serious infections.
In 2011, two deaths due to a rare brain infection occurred in Louisiana. This might be caused by improper usage of neti pots.
The state health department linked the deaths to tap water that is contaminated with a type of amoeba, Naegleriafowleri.
A device used for nasal rinsing should include information that gives more detailed instructions regarding its usage and care. FDA discovered that the instructions of certain manufacturers provide contradictory or misleading information. Some products even lack guidelines.
For instance, certain manufacturers recommended the use of plain tap water. Other manufacturers warned against the use of tap water in the printed directions while their videos or images are showing its use.
The nasal rinsing device might not have instructions with it. If a person ordered a custom-made neti pot, for instance, the artist might assume you already know how it is used.
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