Spinal cord

From Wikipedia, the free encyclopedia

Spinal cord
The spinal cord (in yellow) connects the brain to nerves throughout the body.
Details
Part of	Central nervous system
Artery	spinal artery
Identifiers
Latin	medulla spinalis
MeSH	D013116
NeuroNames	22
TA	A14.1.02.001
FMA	7647

The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column. It encloses the central canal of the spinal cord, which contains cerebrospinal fluid. The brain and spinal cord together make up the central nervous system (CNS). In humans, the spinal cord begins at the occipital bone, passing through the foramen magnum and entering the spinal canal at the beginning of the cervical vertebrae. The spinal cord extends down to between the first and second lumbar vertebrae, where it ends. The enclosing bony vertebral column protects the relatively shorter spinal cord. It is around 45 cm (18 in) in men and around 43 cm (17 in) long in women. The diameter of the spinal cord ranges from 13 mm (¹⁄₂ in) in the cervical and lumbar regions to 6.4 mm (¹⁄₄ in) in the thoracic area.

The spinal cord functions primarily in the transmission of nerve signals from the motor cortex to the body, and from the afferent fibers of the sensory neurons to the sensory cortex. It is also a center for coordinating many reflexes and contains reflex arcs that can independently control reflexes. It is also the location of groups of spinal interneurons that make up the neural circuits known as central pattern generators. These circuits are responsible for controlling motor instructions for rhythmic movements such as walking.

Structure

Diagram of the spinal cord showing segments

 

The spinal cord is the main pathway for information connecting the brain and peripheral nervous system. Much shorter than its protecting spinal column, the human spinal cord originates in the brainstem, passes through the foramen magnum, and continues through to the conus medullaris near the second lumbar vertebra before terminating in a fibrous extension known as the filum terminale.

It is about 45 cm (18 in) long in men and around 43 cm (17 in) in women, ovoid-shaped, and is enlarged in the cervical and lumbar regions. The cervical enlargement, stretching from the C5 to T1 vertebrae, is where sensory input comes from and motor output goes to the arms and trunk. The lumbar enlargement, located between L1 and S3, handles sensory input and motor output coming from and going to the legs.

The spinal cord is continuous with the caudal portion of the medulla, running from the base of the skull to the body of the first lumbar vertebra. It does not run the full length of the vertebral column in adults. It is made of 31 segments from which branch one pair of sensory nerve roots and one pair of motor nerve roots. The nerve roots then merge into bilaterally symmetrical pairs of spinal nerves. The peripheral nervous system is made up of these spinal roots, nerves, and ganglia.

The dorsal roots are afferent fascicles, receiving sensory information from the skin, muscles, and visceral organs to be relayed to the brain. The roots terminate in dorsal root ganglia, which are composed of the cell bodies of the corresponding neurons. Ventral roots consist of efferent fibers that arise from motor neurons whose cell bodies are found in the ventral (or anterior) gray horns of the spinal cord. 

The spinal cord (and brain) are protected by three layers of tissue or membranes called meninges, that surround the canal . The dura mater is the outermost layer, and it forms a tough protective coating. Between the dura mater and the surrounding bone of the vertebrae is a space called the epidural space. The epidural space is filled with adipose tissue, and it contains a network of blood vessels. The arachnoid mater, the middle protective layer, is named for its open, spiderweb-like appearance. The space between the arachnoid and the underlying pia mater is called the subarachnoid space. The subarachnoid space contains cerebrospinal fluid (CSF), which can be sampled with a lumbar puncture, or "spinal tap" procedure. The delicate pia mater, the innermost protective layer, is tightly associated with the surface of the spinal cord. The cord is stabilized within the dura mater by the connecting denticulate ligaments, which extend from the enveloping pia mater laterally between the dorsal and ventral roots. The dural sac ends at the vertebral level of the second sacral vertebra.

In cross-section, the peripheral region of the cord contains neuronal white matter tracts containing sensory and motor axons. Internal to this peripheral region is the grey matter, which contains the nerve cell bodies arranged in the three grey columns that give the region its butterfly-shape. This central region surrounds the central canal, which is an extension of the fourth ventricle and contains cerebrospinal fluid. 

The spinal cord is elliptical in cross section, being compressed dorsolaterally. Two prominent grooves, or sulci, run along its length. The posterior median sulcus is the groove in the dorsal side, and the anterior median fissure is the groove in the ventral side.

Spinal cord segments

The human spinal cord is divided into segments where pairs of spinal nerves (mixed; sensory and motor) form. Six to eight motor nerve rootlets branch out of right and left ventro lateral sulci in a very orderly manner. Nerve rootlets combine to form nerve roots. Likewise, sensory nerve rootlets form off right and left dorsal lateral sulci and form sensory nerve roots. The ventral (motor) and dorsal (sensory) roots combine to form spinal nerves (mixed; motor and sensory), one on each side of the spinal cord. Spinal nerves, with the exception of C1 and C2, form inside the intervertebral foramen (IVF). These rootlets form the demarcation between the central and peripheral nervous systems.

A model of segments of the human spine and spinal cord, nerve roots can be seen extending laterally from the (not visible) spinal cord.

 

The grey column, (as three regions of grey columns) in the center of the cord, is shaped like a butterfly and consists of cell bodies of interneurons, motor neurons, neuroglia cells and unmyelinated axons. The anterior and posterior grey column present as projections of the grey matter and are also known as the horns of the spinal cord. Together, the grey columns and the gray commissure form the "grey H." 

The white matter is located outside of the grey matter and consists almost totally of myelinated motor and sensory axons. "Columns" of white matter carry information either up or down the spinal cord.

The spinal cord proper terminates in a region called the conus medullaris, while the pia mater continues as an extension called the filum terminale, which anchors the spinal cord to the coccyx. The cauda equina ("horse's tail") is a collection of nerves inferior to the conus medullaris that continue to travel through the vertebral column to the coccyx. The cauda equina forms because the spinal cord stops growing in length at about age four, even though the vertebral column continues to lengthen until adulthood. This results in sacral spinal nerves originating in the upper lumbar region. 

Within the CNS, nerve cell bodies are generally organized into functional clusters, called nuclei. Axons within the CNS are grouped into tracts. 

There are 31 spinal cord nerve segments in a human spinal cord:

• 8 cervical segments forming 8 pairs of cervical nerves (C1 spinal nerves exit the spinal column between the foramen magnum and the C1 vertebra; C2 nerves exit between the posterior arch of the C1 vertebra and the lamina of C2; C3–C8 spinal nerves pass through the IVF above their corresponding cervical vertebrae, with the exception of the C8 pair which exit between the C7 and T1 vertebrae)
• 12 thoracic segments forming 12 pairs of thoracic nerves
• 5 lumbar segments forming 5 pairs of lumbar nerves
• 5 sacral segments forming 5 pairs of sacral nerves
• 1 coccygeal segment

Spinal cord segments in some common species 

Species	Cervical	Thoracic	Lumbar	Sacral	Caudal/Coccygeal	Total
Dog	8	13	7	3	5	36
Cat	8	13	7	3	5	36
Cow	8	13	6	5	5	37
Horse	8	18	6	5	5	42
Pig	8	15/14	6/7	4	5	38
Human	8	12	5	5	1	31
Mouse	8	13	6	4	3	35

In the fetus, vertebral segments correspond with spinal cord segments. However, because the vertebral column grows longer than the spinal cord, spinal cord segments do not correspond to vertebral segments in the adult, particularly in the lower spinal cord. For example, lumbar and sacral spinal cord segments are found between vertebral levels T9 and L2, and the spinal cord ends around the L1/L2 vertebral level, forming a structure known as the conus medullaris.

Although the spinal cord cell bodies end around the L1/L2 vertebral level, the spinal nerves for each segment exit at the level of the corresponding vertebra. For the nerves of the lower spinal cord, this means that they exit the vertebral column much lower (more caudally) than their roots. As these nerves travel from their respective roots to their point of exit from the vertebral column, the nerves of the lower spinal segments form a bundle called the cauda equina. 

There are two regions where the spinal cord enlarges:

• Cervical enlargement – corresponds roughly to the brachial plexus nerves, which innervate the upper limb. It includes spinal cord segments from about C4 to T1. The vertebral levels of the enlargement are roughly the same (C4 to T1).
• Lumbar enlargement – corresponds to the lumbosacral plexus nerves, which innervate the lower limb. It comprises the spinal cord segments from L2 to S3 and is found about the vertebral levels of T9 to T12.

Development

Spinal cord seen in a midsection of a five-week-old embryo

 

Spinal cord seen in a midsection of a 3 month old fetus

 

The spinal cord is made from part of the neural tube during development. There are four stages of the spinal cord that arises from the neural tube: The neural plate, neural fold, neural tube, and the spinal cord. Neural differentiation occurs within the spinal cord portion of the tube. As the neural tube begins to develop, the notochord begins to secrete a factor known as Sonic hedgehog or SHH. As a result, the floor plate then also begins to secrete SHH, and this will induce the basal plate to develop motor neurons. During the maturation of the neural tube, its lateral walls thicken and form a longtitudinal groove called the sulcus limitans. This extends the length of the spinal cord into dorsal and ventral portions as well. Meanwhile, the overlying ectoderm secretes bone morphogenetic protein (BMP). This induces the roof plate to begin to secrete BMP, which will induce the alar plate to develop sensory neurons. Opposing gradients of such morphogens as BMP and SHH form different domains of dividing cells along the dorsal ventral axis. Dorsal root ganglion neurons differentiate from neural crest progenitors. As the dorsal and ventral column cells proliferate, the lumen of the neural tube narrows to form the small central canal of the spinal cord. The alar plate and the basal plate are separated by the sulcus limitans. Additionally, the floor plate also secretes netrins. The netrins act as chemoattractants to decussation of pain and temperature sensory neurons in the alar plate across the anterior white commissure, where they then ascend towards the thalamus. Following the closure of the caudal neuropore and formation of the brain's ventricles that contain the choroid plexus tissue, the central canal of the caudal spinal cord is filled with cerebrospinal fluid. 

Earlier findings by Viktor Hamburger and Rita Levi-Montalcini in the chick embryo have been confirmed by more recent studies which have demonstrated that the elimination of neuronal cells by programmed cell death (PCD) is necessary for the correct assembly of the nervous system.

Overall, spontaneous embryonic activity has been shown to play a role in neuron and muscle development but is probably not involved in the initial formation of connections between spinal neurons.

Blood supply

The spinal cord is supplied with blood by three arteries that run along its length starting in the brain, and many arteries that approach it through the sides of the spinal column. The three longitudinal arteries are the anterior spinal artery, and the right and left posterior spinal arteries. These travel in the subarachnoid space and send branches into the spinal cord. They form anastamoses (connections) via the anterior and posterior segmental medullary arteries, which enter the spinal cord at various points along its length. The actual blood flow caudally through these arteries, derived from the posterior cerebral circulation, is inadequate to maintain the spinal cord beyond the cervical segments.

The major contribution to the arterial blood supply of the spinal cord below the cervical region comes from the radially arranged posterior and anterior radicular arteries, which run into the spinal cord alongside the dorsal and ventral nerve roots, but with one exception do not connect directly with any of the three longitudinal arteries. These intercostal and lumbar radicular arteries arise from the aorta, provide major anastomoses and supplement the blood flow to the spinal cord. In humans the largest of the anterior radicular arteries is known as the artery of Adamkiewicz, or anterior radicularis magna (ARM) artery, which usually arises between L1 and L2, but can arise anywhere from T9 to L5. Impaired blood flow through these critical radicular arteries, especially during surgical procedures that involve abrupt disruption of blood flow through the aorta for example during aortic aneursym repair, can result in spinal cord infarction and paraplegia.

Function

Somatosensory organization

Spinal cord tracts.

 

Somatosensory organization is divided into the dorsal column-medial lemniscus tract (the touch/proprioception/vibration sensory pathway) and the anterolateral system, or ALS (the pain/temperature sensory pathway). Both sensory pathways use three different neurons to get information from sensory receptors at the periphery to the cerebral cortex. These neurons are designated primary, secondary and tertiary sensory neurons. In both pathways, primary sensory neuron cell bodies are found in the dorsal root ganglia, and their central axons project into the spinal cord. 

In the dorsal column-medial leminiscus tract, a primary neuron's axon enters the spinal cord and then enters the dorsal column. If the primary axon enters below spinal level T6, the axon travels in the fasciculus gracilis, the medial part of the column. If the axon enters above level T6, then it travels in the fasciculus cuneatus, which is lateral to the fasciculus gracilis. Either way, the primary axon ascends to the lower medulla, where it leaves its fasciculus and synapses with a secondary neuron in one of the dorsal column nuclei: either the nucleus gracilis or the nucleus cuneatus, depending on the pathway it took. At this point, the secondary axon leaves its nucleus and passes anteriorly and medially. The collection of secondary axons that do this are known as internal arcuate fibers. The internal arcuate fibers decussate and continue ascending as the contralateral medial lemniscus. Secondary axons from the medial lemniscus finally terminate in the ventral posterolateral nucleus (VPLN) of the thalamus, where they synapse with tertiary neurons. From there, tertiary neurons ascend via the posterior limb of the internal capsule and end in the primary sensory cortex.

The proprioception of the lower limbs differs from the upper limbs and upper trunk. There is a four-neuron pathway for lower limb proprioception. This pathway initially follows the dorsal spino-cerebellar pathway. It is arranged as follows: proprioceptive receptors of lower limb → peripheral process → dorsal root ganglion → central process → Clarke's column → 2nd order neuron → medulla oblogata (Caudate nucleus) → 3rd order neuron → VPLN of thalamus → 4th order neuron → posterior limb of internal capsule → corona radiata → sensory area of cerebrum.

The anterolateral system works somewhat differently. Its primary neurons axons enter the spinal cord and then ascend one to two levels before synapsing in the substantia gelatinosa. The tract that ascends before synapsing is known as Lissauer's tract. After synapsing, secondary axons decussate and ascend in the anterior lateral portion of the spinal cord as the spinothalamic tract. This tract ascends all the way to the VPLN, where it synapses on tertiary neurons. Tertiary neuronal axons then travel to the primary sensory cortex via the posterior limb of the internal capsule. 

Some of the "pain fibers" in the ALS deviate from their pathway towards the VPLN. In one such deviation, axons travel towards the reticular formation in the midbrain. The reticular formation then projects to a number of places including the hippocampus (to create memories about the pain), the centromedian nucleus (to cause diffuse, non-specific pain) and various parts of the cortex. Additionally, some ALS axons project to the periaqueductal gray in the pons, and the axons forming the periaqueductal gray then project to the nucleus raphes magnus, which projects back down to where the pain signal is coming from and inhibits it. This helps control the sensation of pain to some degree.

Motor organization

Actions of the spinal nerves

Level	Motor function
C1–C6	Neck flexors
C1–T1	Neck extensors
C3, C4, C5	Supply diaphragm (mostly C4)
C5, C6	Move shoulder, raise arm (deltoid); flex elbow (biceps)
C6	externally rotate (supinate) the arm
C6, C7	Extend elbow and wrist (triceps and wrist extensors); pronate wrist
C7, C8	Flex wrist; supply small muscles of the hand
T1–T6	Intercostals and trunk above the waist
T7–L1	Abdominal muscles
L1–L4	Flex hip joint
L2, L3, L4	Adduct thigh; Extend leg at the knee (quadriceps femoris)
L4, L5, S1	abduct thigh; Flex leg at the knee (hamstrings); Dorsiflex foot (tibialis anterior); Extend toes
L5, S1, S2	Extend leg at the hip (gluteus maximus); flex foot and flex toes

The corticospinal tract serves as the motor pathway for upper motor neuronal signals coming from the cerebral cortex and from primitive brainstem motor nuclei. 

Cortical upper motor neurons originate from Brodmann areas 1, 2, 3, 4, and 6 and then descend in the posterior limb of the internal capsule, through the crus cerebri, down through the pons, and to the medullary pyramids, where about 90% of the axons cross to the contralateral side at the decussation of the pyramids. They then descend as the lateral corticospinal tract. These axons synapse with lower motor neurons in the ventral horns of all levels of the spinal cord. The remaining 10% of axons descend on the ipsilateral side as the ventral corticospinal tract. These axons also synapse with lower motor neurons in the ventral horns. Most of them will cross to the contralateral side of the cord (via the anterior white commissure) right before synapsing. 

The midbrain nuclei include four motor tracts that send upper motor neuronal axons down the spinal cord to lower motor neurons. These are the rubrospinal tract, the vestibulospinal tract, the tectospinal tract and the reticulospinal tract. The rubrospinal tract descends with the lateral corticospinal tract, and the remaining three descend with the anterior corticospinal tract. 

The function of lower motor neurons can be divided into two different groups: the lateral corticospinal tract and the anterior cortical spinal tract. The lateral tract contains upper motor neuronal axons which synapse on dorsal lateral (DL) lower motor neurons. The DL neurons are involved in distal limb control. Therefore, these DL neurons are found specifically only in the cervical and lumbosacral enlargements within the spinal cord. There is no decussation in the lateral corticospinal tract after the decussation at the medullary pyramids.

The anterior corticospinal tract descends ipsilaterally in the anterior column, where the axons emerge and either synapse on lower ventromedial (VM) motor neurons in the ventral horn ipsilaterally or descussate at the anterior white commissure where they synapse on VM lower motor neurons contralaterally . The tectospinal, vestibulospinal and reticulospinal descend ipsilaterally in the anterior column but do not synapse across the anterior white commissure. Rather, they only synapse on VM lower motor neurons ipsilaterally. The VM lower motor neurons control the large, postural muscles of the axial skeleton. These lower motor neurons, unlike those of the DL, are located in the ventral horn all the way throughout the spinal cord.

Spinocerebellar tracts

Proprioceptive information in the body travels up the spinal cord via three tracks. Below L2, the proprioceptive information travels up the spinal cord in the ventral spinocerebellar tract. Also known as the anterior spinocerebellar tract, sensory receptors take in the information and travel into the spinal cord. The cell bodies of these primary neurons are located in the dorsal root ganglia. In the spinal cord, the axons synapse and the secondary neuronal axons decussates and then travel up to the superior cerebellar peduncle where they decussate again. From here, the information is brought to deep nuclei of the cerebellum including the fastigial and interposed nuclei. 

From the levels of L2 to T1, proprioceptive information enters the spinal cord and ascends ipsilaterally, where it synapses in Clarke's nucleus. The secondary neuronal axons continue to ascend ipsilaterally and then pass into the cerebellum via the inferior cerebellar peduncle. This tract is known as the dorsal spinocerebellar tract. 

From above T1, proprioceptive primary axons enter the spinal cord and ascend ipsilaterally until reaching the accessory cuneate nucleus, where they synapse. The secondary axons pass into the cerebellum via the inferior cerebellar peduncle where again, these axons synapse on cerebellar deep nuclei. This tract is known as the cuneocerebellar tract. 

Motor information travels from the brain down the spinal cord via descending spinal cord tracts. Descending tracts involve two neurons: the upper motor neuron (UMN) and lower motor neuron (LMN). A nerve signal travels down the upper motor neuron until it synapses with the lower motor neuron in the spinal cord. Then, the lower motor neuron conducts the nerve signal to the spinal root where efferent nerve fibers carry the motor signal toward the target muscle. The descending tracts are composed of white matter. There are several descending tracts serving different functions. The corticospinal tracts (lateral and anterior) are responsible for coordinated limb movements.

Clinical significance

A congenital disorder is diastematomyelia in which part of the spinal cord is split usually at the level of the upper lumbar vertebrae. Sometimes the split can be along the length of the spinal cord.

Injury

Spinal cord injuries can be caused by trauma to the spinal column (stretching, bruising, applying pressure, severing, laceration, etc.). The vertebral bones or intervertebral disks can shatter, causing the spinal cord to be punctured by a sharp fragment of bone. Usually, victims of spinal cord injuries will suffer loss of feeling in certain parts of their body. In milder cases, a victim might only suffer loss of hand or foot function. More severe injuries may result in paraplegia, tetraplegia (also known as quadriplegia), or full body paralysis below the site of injury to the spinal cord. 

Damage to upper motor neuron axons in the spinal cord results in a characteristic pattern of ipsilateral deficits. These include hyperreflexia, hypertonia and muscle weakness. Lower motor neuronal damage results in its own characteristic pattern of deficits. Rather than an entire side of deficits, there is a pattern relating to the myotome affected by the damage. Additionally, lower motor neurons are characterized by muscle weakness, hypotonia, hyporeflexia and muscle atrophy. 

Spinal shock and neurogenic shock can occur from a spinal injury. Spinal shock is usually temporary, lasting only for 24–48 hours, and is a temporary absence of sensory and motor functions. Neurogenic shock lasts for weeks and can lead to a loss of muscle tone due to disuse of the muscles below the injured site. 

The two areas of the spinal cord most commonly injured are the cervical spine (C1–C7) and the lumbar spine (L1–L5). (The notation C1, C7, L1, L5 refer to the location of a specific vertebra in either the cervical, thoracic, or lumbar region of the spine.) Spinal cord injury can also be non-traumatic and caused by disease (transverse myelitis, polio, spina bifida, Friedreich's ataxia, spinal cord tumor, spinal stenosis etc.)

In the U.S., 10,000–12,000 people become paralyzed annually as a result of various injuries to the spinal cord.

Treatment

Real or suspected spinal cord injuries need immediate immobilisation including that of the head. Scans will be needed to assess the injury. A steroid, methylprednisolone, can be of help as can physical therapy and possibly antioxidants. Treatments need to focus on limiting post-injury cell death, promoting cell regeneration, and replacing lost cells. Regeneration is facilitated by maintaining electric transmission in neural elements.

Lumbar puncture

The spinal cord ends at the level of vertebrae L1–L2, while the subarachnoid space —the compartment that contains cerebrospinal fluid— extends down to the lower border of S2. Lumbar punctures in adults are usually performed between L3–L5 (cauda equina level) in order to avoid damage to the spinal cord. In the fetus, the spinal cord extends the full length of the spine and regresses as the body grows.

Tumours

Spinal tumours can occur in the spinal cord and these can be either inside (intradural) or outside (extradural) the dura mater.

Bronchitis

From Wikipedia, the free encyclopedia

Bronchitis
Figure A shows the location of the lungs and bronchial tubes. Figure B is an enlarged view of a normal bronchial tube. Figure C is an enlarged view of a bronchial tube with bronchitis.
Pronunciation	bron-kye-tis
Specialty	Infectious disease, pulmonology
Symptoms	Coughing up mucus, wheezing, shortness of breath, chest discomfort
Types	Acute, chronic
Frequency	Acute: ~5% of people a year Chronic: ~5% of people

Bronchitis is inflammation of the bronchi (large and medium-sized airways) in the lungs that causes coughing. Symptoms include coughing up sputum, wheezing, shortness of breath, and chest pain. Bronchitis can be acute or chronic.

Acute bronchitis usually has a cough that lasts around three weeks, and is also known as a chest cold. In more than 90% of cases the cause is a viral infection. These viruses may be spread through the air when people cough or by direct contact. A small number of cases are caused by a bacterial infection such as Mycoplasma pneumoniae or Bordetella pertussis. Risk factors include exposure to tobacco smoke, dust, and other air pollution. Treatment of acute bronchitis typically involves rest, paracetamol (acetaminophen), and nonsteroidal anti-inflammatory drugs (NSAIDs) to help with the fever.

Chronic bronchitis is defined as a productive cough – one that produces sputum – that lasts for three months or more per year for at least two years. Most people with chronic bronchitis have chronic obstructive pulmonary disease (COPD). Tobacco smoking is the most common cause, with a number of other factors such as air pollution and genetics playing a smaller role. Treatments include quitting smoking, vaccinations, rehabilitation, and often inhaled bronchodilators and steroids. Some people may benefit from long-term oxygen therapy.

Acute bronchitis is one of the most common diseases. About 5% of adults are affected and about 6% of children have at least one episode a year. Acute bronchitis is the most common type of bronchitis. In the United States, in 2016, 8.6 million people were diagnosed with chronic bronchitis.

Acute bronchitis

Bronchitis

Acute bronchitis, also known as a chest cold, is short term inflammation of the bronchi of the lungs. The most common symptom is a cough, that may or may not produce sputum. Other symptoms include coughing up mucus, wheezing, shortness of breath, fever, and chest discomfort. The infection may last from a few to ten days. The cough may persist for several weeks afterwards, with the total duration of symptoms usually around three weeks. Symptoms may last for up to six weeks.

Cause

In more than 90% of cases, the cause is a viral infection. These viruses may spread through the air when people cough or by direct contact. Risk factors include exposure to tobacco smoke, dust, and other air pollutants. A small number of cases are due to high levels of air pollution or to bacteria such as Mycoplasma pneumoniae or Bordetella pertussis.

Diagnosis

Diagnosis is typically based on a person's signs and symptoms. The color of the sputum does not indicate if the infection is viral or bacterial. Determining the underlying organism is usually not required. Other causes of similar symptoms include asthma, pneumonia, bronchiolitis, bronchiectasis, and COPD. A chest X-ray may be useful to detect pneumonia.

Another common sign of bronchitis is a cough which lasts ten days to three weeks. If the cough lasts a month or a year, it may become chronic bronchitis. In addition, a fever may be present. Acute bronchitis is normally caused by a viral infection. Typically, these infections are rhinovirus, parainfluenza, or influenza. No specific testing is normally needed in order to diagnose acute bronchitis.

Treatment

Prevention is by not smoking and avoiding other lung irritants. Frequent hand washing may also be protective. Treatment for acute bronchitis usually involves rest, paracetamol (acetaminophen), and NSAIDs to help with the fever. Cough medicine has little support for its use, and is not recommended in children under the age of six. There is tentative evidence that salbutamol may be useful in treating wheezing; however, it may result in nervousness and tremors. Antibiotics should generally not be used. An exception is when acute bronchitis is due to pertussis. Tentative evidence supports honey and pelargonium to help with symptoms. Getting plenty of rest and drinking enough fluids are often recommended as well.

Epidemiology

Acute bronchitis is one of the most-common diseases. About 5% of adults are affected, and about 6% of children have at least one episode a year. It occurs more often in the winter. More than 10 million people in the US visit a doctor each year for this condition, with about 70% receiving antibiotics which are mostly not needed. There are efforts to decrease the use of antibiotics in acute bronchitis. Acute bronchitis is the most common type of bronchitis.

Chronic bronchitis

When bronchitis, marked by a productive cough, occurs for longer than three months, in two consecutive years, it is classed as chronic bronchitis. When this occurs together with decreased airflow it is known as chronic obstructive pulmonary disease (COPD) or chronic obstructive bronchitis. Most people with chronic bronchitis have COPD however most people with COPD do not have chronic bronchitis. Previously the term "chronic bronchitis" was also used for a type of COPD. Chronic bronchitis is a respiratory tract disease marked by mucus hypersecretion. The cough is often worse soon after awakening, and the sputum produced may have a yellow or green color and may be streaked with specks of blood. The ICD-11 lists chronic bronchitis with emphysema (emphysematous bronchitis) as a "certain specified COPD".

Cause

Most cases of chronic bronchitis are caused by tobacco smoking. Chronic bronchitis in young adults who smoke is associated with a greater chance of developing COPD. In addition, chronic inhalation of air pollution or irritating fumes or dust from hazardous exposures in occupations such as coal mining, grain handling, textile manufacturing, livestock farming, and metal moulding may also be a risk factor for the development of chronic bronchitis. Bronchitis caused in this way is often referred to as industrial bronchitis. Rarely genetic factors also play a role.

Treatment

Decline in lung function in chronic bronchitis may be slowed by stopping smoking. Chronic bronchitis is treated symptomatically and may be treated with or without medications. Nonpharmacologic approaches may include pulmonary rehabilitation, and oxygen therapy.

A distinction has been made between exacerbations (sudden worsenings) of chronic bronchitis, and otherwise stable chronic bronchitis. A Cochrane review found that mucolytics in chronic bronchitis may slightly decrease the chance of the developing an acute exacerbation. The mucolytic guaifenesin is a safe and effective treatment for stable chronic bronchitis. This has an advantage in that it is available as an extended use tablet which lasts for twelve hours. Erdosteine has been found to be effective in promoting the discharge of mucus and improving lung function in the elderly. Another mucolytic Fudosteine works by inhibiting MUC5AC expression, reducing the secretion of mucin.

In those with chronic bronchitis and severe COPD, the phosphodiesterase-4 inhibitor roflumilast may decrease significant exacerbations.

Epidemiology

Chronic bronchitis affects about 3.4% to 22% of the general population. Individuals over age 45 years of age, smokers, those that live or work in areas with high air pollution, and anybody with asthma all have a higher risk of developing chronic bronchitis. This wide range is due to the different definitions of chronic bronchitis that can be diagnosed based on signs and symptoms or the clinical diagnosis of the disorder. Chronic bronchitis tends to affect men more often than women. While the primary risk factor for chronic bronchitis is smoking, there is still a 4%-22% chance that never smokers can get chronic bronchitis. This might suggest other risk factors such as the inhalation of fuels, dusts, fumes and genetic factor. In the United States, in 2016, 8.6 million people were diagnosed with chronic bronchitis, and there were 518 reported deaths. Per 100,000 of population the death rate of chronic bronchitis was 0.2.

Bilirubin

From Wikipedia, the free encyclopedia

Bilirubin

Identifiers
CAS Number	635-65-4
3D model (JSmol)	Interactive image Interactive image
ChEBI	CHEBI:16990
ChEMBL	ChEMBL501680
ChemSpider	4444055
ECHA InfoCard	100.010.218
IUPHAR/BPS	4577
PubChem CID	5280352
UNII	RFM9X3LJ49
CompTox Dashboard (EPA)	DTXSID90239827
InChI[show]
SMILES[show]
Properties
Chemical formula	C33H36N4O6
Molar mass	584.673 g·mol−1
Supplementary data page
Structure and properties	Refractive index (n), Dielectric constant (εr), etc.
Thermodynamic data	Phase behaviour solid–liquid–gas
Spectral data	UV, IR, NMR, MS

Bilirubin is a yellow compound that occurs in the normal catabolic pathway that breaks down heme in vertebrates. This catabolism is a necessary process in the body's clearance of waste products that arise from the destruction of aged or abnormal red blood cells. First the hemoglobin gets stripped of the heme molecule which thereafter passes through various processes of porphyrin catabolism, depending on the part of the body in which the breakdown occurs. For example, the molecules excreted in the urine differ from those in the feces. The production of biliverdin from heme is the first major step in the catabolic pathway, after which the enzyme biliverdin reductase performs the second step, producing bilirubin from biliverdin.

Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases. It is responsible for the yellow color of bruises and the yellow discoloration in jaundice. Its subsequent breakdown products, such as stercobilin, cause the brown color of faeces. A different breakdown product, urobilin, is the main component of the straw-yellow color in urine.

It has also been found in plants.

Structure and function

Bilirubin consists of an open chain tetrapyrrole. It is formed by oxidative cleavage of a porphyrin in heme, which affords biliverdin. Biliverdin is reduced to bilirubin. After conjugatation with glucuronic acid, bilirubin is excreted. 

Bilirubin is structurally similar to the pigment phycobilin used by certain algae to capture light energy, and to the pigment phytochrome used by plants to sense light. All of these contain an open chain of four pyrrolic rings. 

Like these other pigments, some of the double-bonds in bilirubin isomerize when exposed to light. This isomerization is relevant to the phototherapy of jaundiced newborns: the E,Z-isomers of bilirubin formed upon light exposure are more soluble than the unilluminated Z,Z-isomer, as the possibility of intramolecular hydrogen bonding is removed. Increased solubility allows the excretion of unconjugated bilirubin in bile. 

Some textbooks and research articles show the incorrect geometric isomer of bilirubin. The naturally occurring isomer is the Z,Z-isomer.

Function

Bilirubin is created by the activity of biliverdin reductase on biliverdin, a green tetrapyrrolic bile pigment that is also a product of heme catabolism. Bilirubin, when oxidized, reverts to become biliverdin once again. This cycle, in addition to the demonstration of the potent antioxidant activity of bilirubin, has led to the hypothesis that bilirubin's main physiologic role is as a cellular antioxidant.

Metabolism

Heme metabolism

Unconjugated

The measurement of unconjugated bilirubin is underestimated by measurement of indirect bilirubin, as unconjugated bilirubin (without glucuronidation) reacts with diazosulfanilic acid to create azobilirubin which is measured as direct bilirubin.

Conjugated

In the liver, bilirubin is conjugated with glucuronic acid by the enzyme glucuronyltransferase, making it soluble in water: the conjugated version is the main form of bilirubin present in the "direct" bilirubin fraction. Much of it goes into the bile and thus out into the small intestine. Though most bile acid is reabsorbed in the terminal ileum to participate in enterohepatic circulation, conjugated bilirubin is not absorbed and instead passes into the colon.

There, colonic bacteria deconjugate and metabolize the bilirubin into colorless urobilinogen, which can be oxidized to form urobilin and stercobilin. Urobilin is excreted by the kidneys to give urine its yellow color and stercobilin is excreted in the faeces giving stool its characteristic brown color. A trace (~1%) of the urobilinogen is reabsorbed into the enterohepatic circulation to be re-excreted in the bile.

Although the terms direct and indirect bilirubin are used equivalently with conjugated and unconjugated bilirubin, this is not quantitatively correct, because the direct fraction includes both conjugated bilirubin and δ bilirubin (bilirubin covalently bound to albumin, which appears in serum when hepatic excretion of conjugated bilirubin is impaired in patients with hepatobiliary disease). Furthermore, direct bilirubin tends to overestimate conjugated bilirubin levels due to unconjugated bilirubin that has reacted with diazosulfanilic acid, leading to increased azobilirubin levels (and increased direct bilirubin).

Urine

Under normal circumstances, only a very small amount, if any, of urobilinogen, is excreted in the urine. If the liver's function is impaired or when biliary drainage is blocked, some of the conjugated bilirubin leaks out of the hepatocytes and appears in the urine, turning it dark amber. However, in disorders involving hemolytic anemia, an increased number of red blood cells are broken down, causing an increase in the amount of unconjugated bilirubin in the blood. Because the unconjugated bilirubin is not water soluble, one will not see an increase in bilirubin in the urine. Because there is no problem with the liver or bile systems, this excess unconjugated bilirubin will go through all of the normal processing mechanisms that occur (e.g., conjugation, excretion in bile, metabolism to urobilinogen, reabsorption) and will show up as an increase in urine urobilinogen. This difference between increased urine bilirubin and increased urine urobilinogen helps to distinguish between various disorders in those systems.

Toxicity

Unconjugated hyperbilirubinaemia in a newborn can lead to accumulation of bilirubin in certain brain regions (particularly the basal nuclei) with consequent irreversible damage to these areas manifesting as various neurological deficits, seizures, abnormal reflexes and eye movements. This type of neurological injury is known as kernicterus. The spectrum of clinical effect is called bilirubin encephalopathy. The neurotoxicity of neonatal hyperbilirubinemia manifests because the blood–brain barrier has yet to develop fully, and bilirubin can freely pass into the brain interstitium, whereas more developed individuals with increased bilirubin in the blood are protected. Aside from specific chronic medical conditions that may lead to hyperbilirubinaemia, neonates in general are at increased risk since they lack the intestinal bacteria that facilitate the breakdown and excretion of conjugated bilirubin in the faeces (this is largely why the faeces of a neonate are paler than those of an adult). Instead the conjugated bilirubin is converted back into the unconjugated form by the enzyme β-glucuronidase (in the gut, this enzyme is located in the brush border of the lining intestinal cells) and a large proportion is reabsorbed through the enterohepatic circulation.

Health benefits

In the absence of liver disease, high levels of total bilirubin confers various health benefits. Studies have also revealed that levels of serum bilirubin are inversely related to risk of certain heart diseases.

Blood tests

Bilirubin is degraded by light. Blood collection tubes containing blood or (especially) serum to be used in bilirubin assays should be protected from illumination. For adults, blood is typically collected by needle from a vein in the arm. In newborns, blood is often collected from a heel stick, a technique that uses a small, sharp blade to cut the skin on the infant's heel and collect a few drops of blood into a small tube. Non-invasive technology is available in some health care facilities that will measure bilirubin by using an instrument placed on the skin (transcutaneous bilirubin meter)

Bilirubin (in blood) is in one of two forms: 

Abb.	Name(s)	Water-soluble	Reaction
"BC"	"Conjugated bilirubin"	Yes (bound to glucuronic acid)	Reacts quickly when dyes (diazo reagent) are added to the blood specimen to produce azobilirubin "Direct bilirubin"
"BU"	"Unconjugated bilirubin"	No	Reacts more slowly, still produces azobilirubin, Ethanol makes all bilirubin react promptly, then: indirect bilirubin = total bilirubin – direct bilirubin

Note: Conjugated bilirubin is often incorrectly called "direct bilirubin" and unconjugated bilirubin is incorrectly called "indirect bilirubin". Direct and indirect refer solely to how compounds are measured or detected in solution. Direct bilirubin is any form of bilirubin which is water-soluble and is available in solution to react with assay reagents; direct bilirubin is often made up largely of conjugated bilirubin, but some unconjugated bilirubin (up to 25%) can still be part of the "direct" bilirubin fraction. Likewise, not all conjugated bilirubin is readily available in solution for reaction or detection (for example, if it is hydrogen bonding with itself) and therefore would not be included in the direct bilirubin fraction. 

Total bilirubin (TBIL) measures both BU and BC. Total bilirubin assays work by using surfactants and accelerators (like caffeine) to bring all of the different bilirubin forms into solution where they can react with assay reagents. Total and direct bilirubin levels can be measured from the blood, but indirect bilirubin is calculated from the total and direct bilirubin.

Indirect bilirubin is fat-soluble and direct bilirubin is water-soluble.

Measurement methods

Originally, the Van den Bergh reaction was used for a qualitative estimate of bilirubin. 

This test is performed routinely in most medical laboratories and can be measured by a variety of methods.

Total bilirubin is now often measured by the 2,5-dichlorophenyldiazonium (DPD) method, and direct bilirubin is often measured by the method of Jendrassik and Grof.

Blood levels

The bilirubin level found in the body reflects the balance between production and excretion. Blood test results should always be interpreted using the reference range provided by the laboratory that performed the test. The SI units are umol/L. Typical ranges for adults are:

• 0-0.3 mg/dl - Direct (conjugated) bilirubin level
• 0.1-1.2 mg/dl - Total serum bilirubin level

	μmol/l = micromole/litre	mg/dl = milligram/ decilitre
total bilirubin	<21 nbsp="" span="">	<1 .23="" span="">
direct bilirubin	1.0–5.1	0–0.3 0.1–0.3 0.1–0.4

 

Reference ranges for blood tests, comparing blood content of bilirubin (shown in blue near horizontal center at around 3 mg/L and 3 μmol/L, scroll to the right to view) with other constituents.

Hyperbilirubinemia

Hyperbilirubinemia is a higher-than-normal level of bilirubin in the blood. For adults, this is any level above 170 μmol/l and for newborns 340 µmol/l and critical hyperbilirubinemia 425 µmol/l. 

Mild rises in bilirubin may be caused by:

• Hemolysis or increased breakdown of red blood cells
• Gilbert's syndrome – a genetic disorder of bilirubin metabolism that can result in mild jaundice, found in about 5% of the population
• Rotor syndrome: non-itching jaundice, with rise of bilirubin in the patient's serum, mainly of the conjugated type

Moderate rise in bilirubin may be caused by:

• Pharmaceutical drugs (especially antipsychotic, some sex hormones, and a wide range of other drugs)
  • Sulfonamides are contraindicated in infants less than 2 months old (exception when used with pyrimethamine in treating toxoplasmosis) as they increase unconjugated bilirubin leading to kernicterus.
  • Drugs such as protease inhibitors like Indinavir can also cause disorders of bilirubin metabolism by competitively inhibiting the UGT1A1 enzyme.
• Hepatitis (levels may be moderate or high)
• Chemotherapy
• Biliary stricture (benign or malignant)

Very high levels of bilirubin may be caused by:

• Neonatal hyperbilirubinaemia, where the newborn's liver is not able to properly process the bilirubin causing jaundice
• Unusually large bile duct obstruction, e.g. stone in common bile duct, tumour obstructing common bile duct etc.
• Severe liver failure with cirrhosis (e.g. primary biliary cirrhosis)
• Crigler–Najjar syndrome
• Dubin–Johnson syndrome
• Choledocholithiasis (chronic or acute).

Cirrhosis may cause normal, moderately high or high levels of bilirubin, depending on exact features of the cirrhosis. 

To further elucidate the causes of jaundice or increased bilirubin, it is usually simpler to look at other liver function tests (especially the enzymes alanine transaminase, aspartate transaminase, gamma-glutamyl transpeptidase, alkaline phosphatase), blood film examination (hemolysis, etc.) or evidence of infective hepatitis (e.g., hepatitis A, B, C, delta, E, etc.).

Jaundice

Jaundice may be noticeable in the sclera of the eyes at levels of about 2 to 3 mg/dl (34 to 51 μmol/l), and in the skin at higher levels. For conversion, 1 mg/dl = 17.1 µmol/l.

Jaundice is classified, depending upon whether the bilirubin is free or conjugated to glucuronic acid, into conjugated jaundice or unconjugated jaundice.

Urine tests

Urine bilirubin may also be clinically significant. Bilirubin is not normally detectable in the urine of healthy people. If the blood level of conjugated bilirubin becomes elevated, e.g. due to liver disease, excess conjugated bilirubin is excreted in the urine, indicating a pathological process. Unconjugated bilirubin is not water-soluble and so is not excreted in the urine. Testing urine for both bilirubin and urobilinogen can help differentiate obstructive liver disease from other causes of jaundice.

History

Bilirubin was discovered by Rudolf Virchow in 1847.) It is not always distinguished from hematoidin, which one modern dictionary defines as synonymous with it but another defines as "apparently chemically identical with bilirubin but with a different site of origin, formed locally in the tissues from hemoglobin, particularly under conditions of reduced oxygen tension."