Medical ultrasound

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Medical ultrasound
Sonographer doing echocardiography on a child
ICD-10-PCS	B?4
ICD-9-CM	88.7
MeSH	D014463
OPS-301 code	3-03...3-05
[edit on Wikidata]

Medical ultrasound (also known as diagnostic sonography or ultrasonography) is a diagnostic imaging technique based on the application of ultrasound. It is used to create an image of internal body structures such as tendons, muscles, joints, blood vessels, and internal organs. Its aim is often to find a source of a disease or to exclude pathology. The practice of examining pregnant women using ultrasound is called obstetric ultrasound, and was an early development and application of clinical ultrasonography.

Ultrasound refers to sound waves with frequencies which are higher than those audible to humans (>20,000 Hz). Ultrasonic images, also known as sonograms, are made by sending pulses of ultrasound into tissue using a probe. The ultrasound pulses echo off tissues with different reflection properties and are recorded and displayed as an image.

Many different types of images can be formed. The commonest is a B-mode image (Brightness), which displays the acoustic impedance of a two-dimensional cross-section of tissue. Other types can display blood flow, motion of tissue over time, the location of blood, the presence of specific molecules, the stiffness of tissue, or the anatomy of a three-dimensional region.

Compared to other dominant methods of medical imaging, ultrasound has several advantages. It provides images in real-time and is portable and can be brought to the bedside. It is substantially lower in cost than other imaging modalities and does not use harmful ionizing radiation. Drawbacks include various limits on its field of view, such as the need for patient cooperation, dependence on physique, difficulty imaging structures behind bone and air, and the necessity of a skilled operator, usually a trained professional.

By organ or system

Sonography (ultrasonography) is widely used in medicine. It is possible to perform both diagnosis and therapeutic procedures, using ultrasound to guide interventional procedures such as biopsies or drainage of fluid collections. Sonographers are medical professionals who perform scans which are then traditionally interpreted by radiologists, physicians who specialize in the application and interpretation of a wide variety of medical imaging modalities, or by cardiologists in the case of cardiac ultrasonography (echocardiography). Increasingly, clinicians (physicians and other healthcare professionals who provide direct patient care) are using the ultrasound in office and hospital practice (Point of Care Ultrasound). 

Sonography is effective for imaging soft tissues of the body. Superficial structures such as muscle, tendon, testis, breast, thyroid and parathyroid glands, and the neonatal brain are imaged at a higher frequency (7–18 MHz), which provides better linear (axial) and horizontal (lateral) resolution. Deeper structures such as liver and kidney are imaged at a lower frequency 1–6 MHz with lower axial and lateral resolution as a price of deeper tissue penetration. 

A general-purpose ultrasound transducer may be used for most imaging purposes but specialty applications may require the use of a specialty transducer. Most ultrasound procedures are done using a transducer on the surface of the body, but improved diagnostic confidence is often possible if a transducer can be placed inside the body. For this purpose, specialty transducers, including endovaginal, endorectal, and transesophageal transducers are commonly employed. At the extreme, very small transducers can be mounted on small diameter catheters and placed into blood vessels to image the walls and disease of those vessels.

Anesthesiology

In anesthesiology, ultrasound is commonly used to guide the placement of needles when placing local anaesthetic solutions near nerves. It is also used for vascular access such as central venous cannulation and difficult arterial cannulation. Transcranial Doppler is frequently used by neuro-anesthesiologists for obtaining information about flow-velocity in the basal cerebral vessels.

Angiology (vascular)

Intravascular ultrasound image of a coronary artery (left), with color-coding on the right, delineating the lumen (yellow), external elastic membrane (blue) and the atherosclerotic plaque burden (green).

In angiology or vascular medicine, duplex ultrasound (B Mode imaging combined with Doppler flow measurement) is used to diagnose arterial and venous disease. This is particularly important in neurology, where ultrasound is used for assessing blood flow and stenoses in the carotid arteries (Carotid Ultrasonography) and intracerebral arteries (Transcranial Doppler). 

Intravascular ultrasound (IVUS) uses a specially designed catheter, with a miniaturized ultrasound probe attached to its distal end, which is then threaded inside a blood vessel. The proximal end of the catheter is attached to computerized ultrasound equipment and allows the application of ultrasound technology, such as piezoelectric transducer or CMUT, to visualize the endothelium (inner wall) of blood vessels in living individuals.

In the case of the common and potentially, serious problem of blood clots in the deep veins of the leg, ultrasound plays a key diagnostic role, while ultrasonography of chronic venous insufficiency of the legs focuses on more superficial veins to assist with planning of suitable interventions to relieve symptoms or improve cosmetics.

Cardiology (heart)

Echocardiography is an essential tool in cardiology, assisting in evaluation of heart valve function, such as stenosis or insufficiency, and strength of cardiac muscle contraction. such as hypertrophy or dilatation of the main chambers. (ventricle and atrium)

Emergency medicine

Point of care emergency ultrasound has many applications in emergency medicine. This includes differentiating cardiac causes of acute breathlessness from pulmonary causes, and the Focused Assessment with Sonography for Trauma (FAST) exam for assessing significant hemoperitoneum or pericardial tamponade after trauma. Other uses include assisting with differentiating causes of abdominal pain such as gallstones and kidney stones. Emergency Medicine Residency Programs have a substantial history of promoting the use of bedside ultrasound during physician training.

Gastroenterology/Colorectal surgery

Abdominal and endoanal ultrasound are frequently used in gastroenterology and colorectal surgery. In abdominal sonography, the solid organs of the abdomen such as the pancreas, aorta, inferior vena cava, liver, gall bladder, bile ducts, kidneys, and spleen are imaged. However, sound waves are blocked by gas in the bowel and attenuated to differing degrees by fat, sometimes limiting diagnostic capabilities in this area. The appendix can sometimes be seen when inflamed (as in e.g.: appendicitis) and ultrasound is the initial imaging choice, avoiding unnecessary radiation, although it frequently needs to be followed by other imaging methods such as CT. Endoanal ultrasound is used particularly in the investigation of anorectal symptoms such as fecal incontinence or obstructed defecation. It images the immediate perianal anatomy and is able to detect occult defects such as tearing of the anal sphincter. Ultrasonography of liver tumors allows for both detection and characterization.

Gynecology and obstetrics

Orthogonal planes of a 3 dimensional sonographic volume with transverse and coronal measurements for estimating fetal cranial volume.

 

Gynecologic ultrasonography examines female pelvic organs (specifically the uterus, ovaries, and Fallopian tubes) as well as the bladder, adnexa, and Pouch of Douglas. It commonly uses transducers designed for approaches through the lower abdominal wall, curvilinear and sector, and specialty transducers such as endovaginal. 

Obstetrical sonography was originally developed in the late 1950’s and 60’s by Sir Ian Donald and is commonly used during pregnancy to check on the development and presentation of the fetus. It can be used to identify many conditions that could be potentially harmful to the mother and/or baby possibly remaining undiagnosed or with delayed diagnosis in the absence of sonography. It is currently believed that the risk of leaving these conditions undiagnosed is greater than the small risk, if any, associated with undergoing an ultrasound scan. However, even where sonography is used routinely in obstetric appointments, its use for non-medical purposes such as fetal "keepsake" videos and photos is discouraged.

Obstetric ultrasound is primarily used to:

• Date the pregnancy (gestational age)
• Confirm fetal viability
• Determine location of fetus, intrauterine vs ectopic
• Check the location of the placenta in relation to the cervix
• Check for the number of fetuses (multiple pregnancy)
• Check for major physical abnormalities.
• Assess fetal growth (for evidence of intrauterine growth restriction (IUGR))
• Check for fetal movement and heartbeat.
• Determine the sex of the baby

According to the European Committee of Medical Ultrasound Safety (ECMUS)

Ultrasonic examinations should only be performed by competent personnel who are trained and updated in safety matters. Ultrasound produces heating, pressure changes and mechanical disturbances in tissue. Diagnostic levels of ultrasound can produce temperature rises that are hazardous to sensitive organs and the embryo/fetus. Biological effects of non-thermal origin have been reported in animals but, to date, no such effects have been demonstrated in humans, except when a microbubble contrast agent is present.

Nonetheless, care should be taken to use low power settings and avoid pulsed wave scanning of the fetal brain unless specifically indicated in high risk pregnancies.

Ultrasound scanners have different Doppler-techniques to visualize arteries and veins. The most common is colour doppler or power doppler, but also other techniques like b-flow are used to show bloodflow in an organ. By using pulsed wave doppler or continuous wave doppler bloodflow velocities can be calculated. 

Figures released for the period 2005–2006 by the UK Government (Department of Health) show that non-obstetric ultrasound examinations constituted more than 65% of the total number of ultrasound scans conducted.

Hemodynamics (blood circulation)

Blood velocity can be measured in various blood vessels, such as middle cerebral artery or descending aorta, by relatively inexpensive and low risk ultrasound Doppler probes attached to portable monitors. These provides non-invasive or transcutaneous (non-piecing) minimal invasive blood flow assessment. Common examples are, Transcranial Doppler, Esophogeal Doppler and Suprasternal Doppler.

Otolaryngology (head and neck)

Neck ultrasound.

 

Most structures of the neck, including the thyroid and parathryoid glands, lymph nodes, and salivary glands, are well-visualized by high-frequency ultrasound with exceptional anatomic detail. Ultrasound is the preferred imaging modality for thyroid tumors and lesions, and ultrasonography is critical in the evaluation, preoperative planning, and postoperative surveillance of patients with thyroid cancer. Many other benign and malignant conditions in the head and neck can be evaluated and managed with the help of diagnostic ultrasound and ultrasound-guided procedures.

Neonatology

In neonatology, transcranial Doppler can be used for basic assessment of intracerebral structural abnormalities, bleeds, ventriculomegaly or hydrocephalus and anoxic insults (Periventricular leukomalacia). The ultrasound can be performed through the soft spots in the skull of a newborn infant (Fontanelle) until these completely close at about 1 year of age and form a virtually impenetrable acoustic barrier for the ultrasound. The most common site for cranial ultrasound is the anterior fontanelle. The smaller the fontanelle, the poorer the quality of the picture.

Ophthalmology (eyes)

In ophthalmology and optometry, there are two major forms of eye exam using ultrasound:

• A-scan ultrasound biometry, commonly referred to as an A-scan (short for Amplitude scan). It is an A-mode that provides data on the length of the eye, which is a major determinant in common sight disorders, especially for determining the power of an intraocular lens after cataract extraction.
• B-scan ultrasonography, or B-scan, which is a B-mode scan that produces a cross-sectional view of the eye and the orbit. It is commonly used to see inside the eye when media is hazy due to cataract or any corneal opacity.

Pulmonology (lungs)

In pulmonology, endobronchial Ultrasound (EBUS) probes are applied to standard flexible endoscopic probes and used by pulmonologists to allow for direct visualization of endobronchial lesions and lymph nodes prior to transbronchial needle aspiration. Among its many uses, EBUS aids in lung cancer staging by allowing for lymph node sampling without the need for major surgery.

Urology (urinary)

Urinary bladder (black butterfly-like shape) and hyperplastic prostate (BPH) visualized by medical sonographic technique

 

Ultrasound is routinely used in urology to determine, for example, the amount of fluid retained in a patient's bladder. In a pelvic sonogram, organs of the pelvic region are imaged. This includes the uterus and ovaries or urinary bladder. Males are sometimes given a pelvic sonogram to check on the health of their bladder, the prostate, or their testicles (for example to distinguish epididymitis from testicular torsion). In young males, it is used to distinguish more benign testicular masses (varicocele or hydrocele) from testicular cancer, which is highly curable but which must be treated to preserve health and fertility. There are two methods of performing a pelvic sonography – externally or internally. The internal pelvic sonogram is performed either transvaginally (in a woman) or transrectally (in a man). Sonographic imaging of the pelvic floor can produce important diagnostic information regarding the precise relationship of abnormal structures with other pelvic organs and it represents a useful hint to treat patients with symptoms related to pelvic prolapse, double incontinence and obstructed defecation. It is used to diagnose and, at higher frequencies, to treat (break up) kidney stones or kidney crystals (nephrolithiasis).

Scrotal

Scrotal ultrasonography is used in the evaluation of testicular pain, and can help identify solid masses.

Penile

Ultrasound is an excellent method for the study of the penis, such as indicated in trauma, priapism, erectile dysfunction or suspected Peyronie's disease.

Musculoskeletal

Musculoskeletal ultrasound in used to examine tendons, muscles, nerves, ligaments, soft tissue masses, and bone surfaces. Ultrasound is an alternative to x-ray imaging in detecting fractures of the wrist, elbow and shoulder for patients up to 12 years (Fracture sonography). 

Quantitative ultrasound is an adjunct musculoskeletal test for myopathic disease in children; estimates of lean body mass in adults; proxy measures of muscle quality (i.e., tissue composition) in older adults with sarcopenia.

 

Ultrasound can also be used for guidance in muscle or joint injections, such as in ultrasound-guided hip joint injection.

Nephrology (kidneys)

In nephrology, ultrasonography of the kidneys is essential in the diagnosis and management of kidney-related diseases. The kidneys are easily examined, and most pathological changes in the kidneys are distinguishable with ultrasound. US is an accessible, versatile, inexpensive, and fast aid for decision-making in patients with renal symptoms and for guidance in renal intervention. Renal ultrasound (US) is a common examination, which has been performed for decades. Using B-mode imaging, assessment of renal anatomy is easily performed, and US is often used as image guidance for renal interventions. Furthermore, novel applications in renal US have been introduced with contrast-enhanced ultrasound (CEUS), elastography and fusion imaging. However, renal US has certain limitations, and other modalities, such as CT (CECT) and MRI, should always be considered as supplementary imaging modalities in the assessment of renal disease.

From sound to image

The creation of an image from sound is done in three steps – producing a sound wave, receiving echoes, and interpreting those echoes.

Producing a sound wave

Medical ultrasound scanner

 

A sound wave is typically produced by a piezoelectric transducer encased in a plastic housing. Strong, short electrical pulses from the ultrasound machine drive the transducer at the desired frequency. The frequencies can be anywhere between 1 and 18 MHz, though frequencies up to 50–100 megahertz have been used experimentally in a technique known as biomicroscopy in special regions, such as the anterior chamber of the eye. Older technology transducers focused their beam with physical lenses. Newer technology transducers use phased array techniques to enable the ultrasound machine to change the direction and depth of focus.

The sound is focused either by the shape of the transducer, a lens in front of the transducer, or a complex set of control pulses from the ultrasound scanner, in the (beamforming) technique. This focusing produces an arc-shaped sound wave from the face of the transducer. The wave travels into the body and comes into focus at a desired depth.

Materials on the face of the transducer enable the sound to be transmitted efficiently into the body (often a rubbery coating, a form of impedance matching). In addition, a water-based gel is placed between the patient's skin and the probe.

The sound wave is partially reflected from the layers between different tissues or scattered from smaller structures. Specifically, sound is reflected anywhere where there are acoustic impedance changes in the body: e.g. blood cells in blood plasma, small structures in organs, etc. Some of the reflections return to the transducer.

Receiving the echoes

The return of the sound wave to the transducer results in the same process as sending the sound wave, except in reverse. The returned sound wave vibrates the transducer and the transducer turns the vibrations into electrical pulses that travel to the ultrasonic scanner where they are processed and transformed into a digital image.

Forming the image

To make an image, the ultrasound scanner must determine two things from each received echo:

1. How long it took the echo to be received from when the sound was transmitted.
2. How strong the echo was.

Once the ultrasonic scanner determines these two things, it can locate which pixel in the image to light up and to what intensity. 

Transforming the received signal into a digital image may be explained by using a blank spreadsheet as an analogy. First picture a long, flat transducer at the top of the sheet. Send pulses down the 'columns' of the spreadsheet (A, B, C, etc.). Listen at each column for any return echoes. When an echo is heard, note how long it took for the echo to return. The longer the wait, the deeper the row (1,2,3, etc.). The strength of the echo determines the brightness setting for that cell (white for a strong echo, black for a weak echo, and varying shades of grey for everything in between.) When all the echoes are recorded on the sheet, we have a greyscale image.

Displaying the image

Images from the ultrasound scanner are transferred and displayed using the DICOM standard. Normally, very little post processing is applied to ultrasound images.

Sound in the body

Linear array transducer

 

Ultrasonography (sonography) uses a probe containing multiple acoustic transducers to send pulses of sound into a material. Whenever a sound wave encounters a material with a different density (acoustical impedance), part of the sound wave is reflected back to the probe and is detected as an echo. The time it takes for the echo to travel back to the probe is measured and used to calculate the depth of the tissue interface causing the echo. The greater the difference between acoustic impedances, the larger the echo is. If the pulse hits gases or solids, the density difference is so great that most of the acoustic energy is reflected and it becomes impossible to see deeper.

The frequencies used for medical imaging are generally in the range of 1 to 18 MHz. Higher frequencies have a correspondingly smaller wavelength, and can be used to make sonograms with smaller details. However, the attenuation of the sound wave is increased at higher frequencies, so in order to have better penetration of deeper tissues, a lower frequency (3–5 MHz) is used. 

Seeing deep into the body with sonography is very difficult. Some acoustic energy is lost every time an echo is formed, but most of it (approximately ${\displaystyle \textstyle 0.5{\frac {\mbox{dB}}{{\mbox{cm depth}}\cdot {\mbox{MHz}}}}}$) is lost from acoustic absorption.

The speed of sound varies as it travels through different materials, and is dependent on the acoustical impedance of the material. However, the sonographic instrument assumes that the acoustic velocity is constant at 1540 m/s. An effect of this assumption is that in a real body with non-uniform tissues, the beam becomes somewhat de-focused and image resolution is reduced. 

To generate a 2D-image, the ultrasonic beam is swept. A transducer may be swept mechanically by rotating or swinging. Or a 1D phased array transducer may be used to sweep the beam electronically. The received data is processed and used to construct the image. The image is then a 2D representation of the slice into the body.

3D images can be generated by acquiring a series of adjacent 2D images. Commonly a specialised probe that mechanically scans a conventional 2D-image transducer is used. However, since the mechanical scanning is slow, it is difficult to make 3D images of moving tissues. Recently, 2D phased array transducers that can sweep the beam in 3D have been developed. These can image faster and can even be used to make live 3D images of a beating heart.

Doppler ultrasonography is used to study blood flow and muscle motion. The different detected speeds are represented in color for ease of interpretation, for example leaky heart valves: the leak shows up as a flash of unique color. Colors may alternatively be used to represent the amplitudes of the received echoes.

Modes

Several modes of ultrasound are used in medical imaging. These are:

• A-mode: A-mode (amplitude mode) is the simplest type of ultrasound. A single transducer scans a line through the body with the echoes plotted on screen as a function of depth. Therapeutic ultrasound aimed at a specific tumor or calculus is also A-mode, to allow for pinpoint accurate focus of the destructive wave energy.
• B-mode or 2D mode: In B-mode (brightness mode) ultrasound, a linear array of transducers simultaneously scans a plane through the body that can be viewed as a two-dimensional image on screen. More commonly known as 2D mode now.

B-flow image of venous reflux.

• B-flow is a mode that digitally highlights moving reflectors (mainly red blood cells) while suppressing the signals from the surrounding stationary tissue. It can visualize flowing blood and surrounding stationary tissues simultaneously. It is thus an alternative or complement to Doppler ultrasonography in visualizing blood flow.

• C-mode: A C-mode image is formed in a plane normal to a B-mode image. A gate that selects data from a specific depth from an A-mode line is used; then the transducer is moved in the 2D plane to sample the entire region at this fixed depth. When the transducer traverses the area in a spiral, an area of 100 cm² can be scanned in around 10 seconds.
• M-mode: In M-mode (motion mode) ultrasound, pulses are emitted in quick succession – each time, either an A-mode or B-mode image is taken. Over time, this is analogous to recording a video in ultrasound. As the organ boundaries that produce reflections move relative to the probe, this can be used to determine the velocity of specific organ structures.
• Doppler mode: This mode makes use of the Doppler effect in measuring and visualizing blood flow
  • Color Doppler: Velocity information is presented as a color-coded overlay on top of a B-mode image
  • Continuous wave (CW) Doppler: Doppler information is sampled along a line through the body, and all velocities detected at each time point are presented (on a time line)
  • Pulsed wave (PW) Doppler: Doppler information is sampled from only a small sample volume (defined in 2D image), and presented on a timeline
  • Duplex: a common name for the simultaneous presentation of 2D and (usually) PW Doppler information. (Using modern ultrasound machines, color Doppler is almost always also used; hence the alternative name Triplex.)
• Pulse inversion mode: In this mode, two successive pulses with opposite sign are emitted and then subtracted from each other. This implies that any linearly responding constituent will disappear while gases with non-linear compressibility stand out. Pulse inversion may also be used in a similar manner as in Harmonic mode; see below:
• Harmonic mode: In this mode a deep penetrating fundamental frequency is emitted into the body and a harmonic overtone is detected. This way noise and artifacts due to reverberation and aberration are greatly reduced. Some also believe that penetration depth can be gained with improved lateral resolution; however, this is not well documented.

Expansions

An additional expansion or additional technique of ultrasound is biplanar ultrasound, in which the probe has two 2D planes that are perpendicular to each other, providing more efficient localization and detection. Furthermore, an omniplane probe is one that can rotate 180° to obtain multiple images. In 3D ultrasound, many 2D planes are digitally added together to create a 3-dimensional image of the object.

Doppler ultrasonography

Duplex scan of the common carotid artery

Doppler ultrasonography employs the Doppler effect to assess whether structures (usually blood) are moving towards or away from the probe, and its relative velocity. By calculating the frequency shift of a particular sample volume, for example flow in an artery or a jet of blood flow over a heart valve, its speed and direction can be determined and visualized. Color Doppler is the measurement of velocity by color scale. Color Doppler images are generally combined with grayscale (B-mode) images to display duplex ultrasonography images. Uses include:

• Doppler echocardiography, the use of Doppler ultrasonography to examine the heart. An echocardiogram can, within certain limits, produce accurate assessment of the direction of blood flow and the velocity of blood and cardiac tissue at any arbitrary point using the Doppler effect. Velocity measurements allow assessment of cardiac valve areas and function, any abnormal communications between the left and right side of the heart, any leaking of blood through the valves (valvular regurgitation), calculation of the cardiac output and calculation of E/A ratio (a measure of diastolic dysfunction). Contrast-enhanced ultrasound using gas-filled microbubble contrast media can be used to improve velocity or other flow-related medical measurements.
• Transcranial Doppler (TCD) and transcranial color Doppler (TCCD), which measure the velocity of blood flow through the brain's blood vessels transcranially (through the cranium). They are used as tests to help diagnose emboli, stenosis, vasospasm from a subarachnoid hemorrhage (bleeding from a ruptured aneurysm), and other problems.
• Doppler fetal monitors, although usually not technically -graphy but rather sound-generating, use the Doppler effect to detect the fetal heartbeat for prenatal care. These are hand-held, and some models also display the heart rate in beats per minute (BPM). Use of this monitor is sometimes known as Doppler auscultation. The Doppler fetal monitor is commonly referred to simply as a Doppler or fetal Doppler. Doppler fetal monitors provide information about the fetus similar to that provided by a fetal stethoscope.

Contrast ultrasonography (ultrasound contrast imaging)

A contrast medium for medical ultrasonography is a formulation of encapsulated gaseous microbubbles to increase echogenicity of blood, discovered by Dr Raymond Gramiak in 1968 and named contrast-enhanced ultrasound. This contrast medical imaging modality is clinically used throughout the world, in particular for echocardiography in the United States and for ultrasound radiology in Europe and Asia. 

Microbubbles-based contrast media is administrated intravenously in patient blood stream during the medical ultrasonography examination. Thanks to their size, the microbubbles remain confined in blood vessels without extravasating towards the interstitial fluid. An ultrasound contrast media is therefore purely intravascular, making it an ideal agent to image organ microvascularization for diagnostic purposes. A typical clinical use of contrast ultrasonography is detection of a hypervascular metastatic tumor, which exhibits a contrast uptake (kinetics of microbubbles concentration in blood circulation) faster than healthy biological tissue surrounding the tumor. Other clinical applications using contrast exist, such as in echocardiography to improve delineation of left ventricle for visually checking contractibility of heart after a myocardial infarction. Finally, applications in quantitative perfusion (relative measurement of blood flow) emerge for identifying early patient response to an anti-cancerous drug treatment (methodology and clinical study by Dr Nathalie Lassau in 2011), enabling to determine the best oncological therapeutic options.

Parametric imaging of vascular signatures (diagram)

 

In oncological practice of medical contrast ultrasonography, clinicians use the method of parametric imaging of vascular signatures invented by Dr Nicolas Rognin in 2010. This method is conceived as a cancer aided diagnostic tool, facilitating characterization of a suspicious tumor (malignant versus benign) in an organ. This method is based on medical computational science to analyze a time sequence of ultrasound contrast images, a digital video recorded in real-time during patient examination. Two consecutive signal processing steps are applied to each pixel of the tumor:

1. calculation of a vascular signature (contrast uptake difference with respect to healthy tissue surrounding the tumor);
2. automatic classification of the vascular signature into a unique parameter, this last coded in one of the four following colors:
   • green for continuous hyper-enhancement (contrast uptake higher than healthy tissue one),
   • blue for continuous hypo-enhancement (contrast uptake lower than healthy tissue one),
   • red for fast hyper-enhancement (contrast uptake before healthy tissue one) or
   • yellow for fast hypo-enhancement (contrast uptake after healthy tissue one).

Once signal processing in each pixel completed, a color spatial map of the parameter is displayed on a computer monitor, summarizing all vascular information of the tumor in a single image called parametric image. This parametric image is interpreted by clinicians based on predominant colorization of the tumor: red indicates a suspicion of malignancy (risk of cancer), green or yellow – a high probability of benignity. In the first case (suspicion of malignant tumor), the clinician typically prescribes a biopsy to confirm the diagnostic or a CT scan examination as a second opinion. In the second case (quasi-certain of benign tumor), only a follow-up is needed with a contrast ultrasonography examination a few months later. The main clinical benefits are to avoid a systematic biopsy (risky invasive procedure) of benign tumors or a CT scan examination exposing the patient to X-ray radiation. The parametric imaging of vascular signatures method proved to be effective in humans for characterization of tumors in the liver. In a cancer screening context, this method might be potentially applicable to other organs such as breast or prostate.

Molecular ultrasonography (ultrasound molecular imaging)

The future of contrast ultrasonography is in molecular imaging with potential clinical applications expected in cancer screening to detect malignant tumors at their earliest stage of appearance. Molecular ultrasonography (or ultrasound molecular imaging) uses targeted microbubbles originally designed by Dr Alexander Klibanov in 1997; such targeted microbubbles specifically bind or adhere to tumoral microvessels by targeting biomolecular cancer expression (overexpression of certain biomolecules occurs during neo-angiogenesis or inflammation processes in malignant tumors). As a result, a few minutes after their injection in blood circulation, the targeted microbubbles accumulate in the malignant tumor; facilitating its localization in a unique ultrasound contrast image. In 2013, the very first exploratory clinical trial in humans for prostate cancer was completed at Amsterdam in the Netherlands by Dr Hessel Wijkstra.

In molecular ultrasonography, the technique of acoustic radiation force (also used for shear wave elastography) is applied in order to literally push the targeted microbubbles towards microvessels wall; firstly demonstrated by Dr Paul Dayton in 1999. This allows maximization of binding to the malignant tumor; the targeted microbubbles being in more direct contact with cancerous biomolecules expressed at the inner surface of tumoral microvessels. At the stage of scientific preclinical research, the technique of acoustic radiation force was implemented as a prototype in clinical ultrasound systems and validated in vivo in 2D and 3D imaging modes.

Elastography (ultrasound elasticity imaging)

Ultrasound is also used for elastography, which is a relatively new imaging modality that maps the elastic properties of soft tissue. This modality emerged in the last two decades. Elastography is useful in medical diagnoses as it can discern healthy from unhealthy tissue for specific organs/growths. For example, cancerous tumors will often be harder than the surrounding tissue, and diseased livers are stiffer than healthy ones.

There are many ultrasound elastography techniques.

Interventional ultrasonography

Interventional ultrasonography involves biopsy, emptying fluids, intrauterine Blood transfusion (Hemolytic disease of the newborn).

• Thyroid cysts: The high frequency thyroid ultrasound (HFUS) can be used to treat several gland conditions. The recurrent thyroid cyst that was usually treated in the past with surgery, can be treated effectively by a new procedure called percutaneous ethanol injection, or PEI. With ultrasound guided placement of a 25 gauge needle within the cyst, and after evacuation of the cyst fluid, about 50% of the cyst volume is injected back into the cavity, under strict operator visualization of the needle tip. The procedure is 80% successful in reducing the cyst to minute size.
• Metastatic thyroid cancer neck lymph nodes: The other thyroid therapy use for HFUS is to treat metastatic thyroid cancer neck lymph nodes that occur in patients who either refuse surgery, or are no longer a candidate for surgery. Small amounts of ethanol are injected under ultrasound guided needle placement. A blood flow study is done prior to the injection, by power doppler. The blood flow can be destroyed and the node become inactive, although it may still be there. Power doppler visualized blood flow can be eradicated, and there may be a drop in the cancer blood marker test, thyroglobulin, TG, as the node become non-functional. Another interventional use for HFUS is to mark a cancer node one hour prior to surgery to help locate the node cluster at the surgery. A minute amount of methylene dye is injected, under careful ultrasound guided placement of the needle on the anterior surface, but not in the node. The dye will be evident to the thyroid surgeon when opening the neck. A similar localization procedure with methylene blue, can be done to locate parathyroid adenomas at surgery.

Ultrasound-guided hip joint injection.

• Joint injections can be guided by medical ultrasound, such as in ultrasound-guided hip joint injections.

Compression ultrasonography

Compression ultrasonography is when the probe is pressed against the skin. This can bring the target structure closer to the probe, increasing spatial resolution of it. Comparison of the shape of the target structure before and after compression can aid in diagnosis. 

It used in ultrasonography of deep venous thrombosis, wherein absence of vein compressibility is a strong indicator of thrombosis. Compression ultrasonography has both high sensitivity and specificity for detecting proximal deep vein thrombosis only in symptomatic patients. Results are not reliable when the patient is symptomless and must be checked, for example in high risk postoperative patients mainly in orthopedic patients.

• 

  A normal appendix without and with compression. Absence of comprehensibility indicates appendicitis.
  
• 

  Compression is used in this ultrasonograph to get closer to the abdominal aorta, making the superior mesenteric vein and the inferior vena cava look rather flat.
  

Attributes

As with all imaging modalities, ultrasonography has its list of positive and negative attributes.

Strengths

• It images muscle, soft tissue, and bone surfaces very well and is particularly useful for delineating the interfaces between solid and fluid-filled spaces.
• It renders "live" images, where the operator can dynamically select the most useful section for diagnosing and documenting changes, often enabling rapid diagnoses. Live images also allow for ultrasound-guided biopsies or injections, which can be cumbersome with other imaging modalities.
• It shows the structure of organs.
• It has no known long-term side effects and rarely causes any discomfort to the patient.
• It is capable of imaging local variations in the mechanical properties of soft tissue.
• Equipment is widely available and comparatively flexible.
• Small, easily carried scanners are available; examinations can be performed at the bedside.
• Relatively inexpensive compared to other modes of investigation, such as computed X-ray tomography, DEXA or magnetic resonance imaging.
• Spatial resolution is better in high frequency ultrasound transducers than it is in most other imaging modalities.
• Through the use of an ultrasound research interface, an ultrasound device can offer a relatively inexpensive, real-time, and flexible method for capturing data required for special research purposes for tissue characterization and development of new image processing techniques

Weaknesses

Double aort artifact in sonography due to difference in velocity of sound waves in muscle and fat.

• Sonographic devices have trouble penetrating bone. For example, sonography of the adult brain is currently very limited.
• Sonography performs very poorly when there is a gas between the transducer and the organ of interest, due to the extreme differences in acoustic impedance. For example, overlying gas in the gastrointestinal tract often makes ultrasound scanning of the pancreas difficult. Lung imaging however can be useful in demarcating pleural effusions, detecting heart failure, and detecting pneumonia.
• Even in the absence of bone or air, the depth penetration of ultrasound may be limited depending on the frequency of imaging. Consequently, there might be difficulties imaging structures deep in the body, especially in obese patients.
• Physique has a large influence on image quality. Image quality and accuracy of diagnosis is limited with obese patients, overlying subcutaneous fat attenuates the sound beam and a lower frequency transducer is required (with lower resolution)
• The method is operator-dependent. A high level of skill and experience is needed to acquire good-quality images and make accurate diagnoses.
• There is no scout image as there is with CT and MRI. Once an image has been acquired there is no exact way to tell which part of the body was imaged.

Risks and side-effects

Ultrasonography is generally considered safe imaging, with the World Health Organizations saying:

"Diagnostic ultrasound is recognized as a safe, effective, and highly flexible imaging modality capable of providing clinically relevant information about most parts of the body in a rapid and cost-effective fashion".

Diagnostic ultrasound studies of the fetus are generally considered to be safe during pregnancy. This diagnostic procedure should be performed only when there is a valid medical indication, and the lowest possible ultrasonic exposure setting should be used to gain the necessary diagnostic information under the "as low as reasonably practicable" or ALARP principle.

However, medical ultrasonography should not be performed without a medical indication to perform it. To do otherwise would be to perform unnecessary health care to patients, which bring unwarranted costs and may lead to other testing. Overuse of ultrasonography is sometimes as routine as screening for deep vein thrombosis after orthopedic surgeries in patients who are not at heightened risk for having that condition.

Similarly, although there is no evidence ultrasound could be harmful for the fetus, medical authorities typically strongly discourage the promotion, selling, or leasing of ultrasound equipment for making "keepsake fetal videos".

Studies on the safety of ultrasound

• A meta-analysis of several ultrasonography studies published in 2000 found no statistically significant harmful effects from ultrasonography, but mentioned that there was a lack of data on long-term substantive outcomes such as neurodevelopment.
• A study at the Yale School of Medicine published in 2006 found a small but significant correlation between prolonged and frequent use of ultrasound and abnormal neuronal migration in mice.
• A study performed in Sweden in 2001 has shown that subtle effects of neurological damage linked to ultrasound were implicated by an increased incidence in left-handedness in boys (a marker for brain problems when not hereditary) and speech delays.
  • The above findings, however, were not confirmed in a later follow-up study.
  • A later study, however, performed on a larger sample of 8865 children, has established a statistically significant, albeit weak association of ultrasonography exposure and being non-right handed later in life.

Regulation

Diagnostic and therapeutic ultrasound equipment is regulated in the USA by the Food and Drug Administration, and worldwide by other national regulatory agencies. The FDA limits acoustic output using several metrics; generally, other agencies accept the FDA-established guidelines.

Currently, New Mexico, Oregon, and North Dakota are the only US states that regulate diagnostic medical sonographers. Certification examinations for sonographers are available in the US from three organizations: the American Registry for Diagnostic Medical Sonography, Cardiovascular Credentialing International and the American Registry of Radiologic Technologists.

The primary regulated metrics are Mechanical Index (MI), a metric associated with the cavitation bio-effect, and Thermal Index (TI) a metric associated with the tissue heating bio-effect. The FDA requires that the machine not exceed established limits, which are reasonably conservative so as to maintain diagnostic ultrasound as a safe imaging modality. This requires self-regulation on the part of the manufacturer in terms of the machine's calibration.

Ultrasound-based pre-natal care and sex screening technologies were launched in India in the 1980s. With concerns about its misuse for sex-selective abortion, the Government of India passed the Pre-natal Diagnostic Techniques Act (PNDT) in 1994 to regulate legal and illegal uses of ultrasound equipment. The law was further amended into the Pre-Conception and Pre-natal Diagnostic Techniques (Regulation and Prevention of Misuse) (PCPNDT) Act in 2004 to deter and punish prenatal sex screening and sex selective abortion. It is currently illegal and a punishable crime in India to determine or disclose the sex of a fetus using ultrasound equipment.

History

After the French physicist Pierre Curie’s discovery of piezoelectricity in 1880, ultrasonic waves could be deliberately generated for industry. Thereafter, in 1940, the American acoustical physicist Floyd Firestone devised the first ultrasonic echo imaging device, the Supersonic Reflectoscope, to detect internal flaws in metal castings. In 1941, the Austrian neurologist Karl Theo Dussik was in collaboration with his brother, Friedreich, a physicist, likely, the first person to ultrasonically echo image the human body, outlining thereby the ventricles of a human brain. Ultrasonic energy was first applied to the human body for medical purposes by Dr George Ludwig at the Naval Medical Research Institute, Bethesda, Maryland in the late 1940s. English-born physicist John Wild (1914–2009) first used ultrasound to assess the thickness of bowel tissue as early as 1949; he has been described as the "father of medical ultrasound". Subsequent advances in the field took place concurrently in several countries. It was not until 1961 when David Robinson and George Kossoff's work at the Australian Department of Health, resulted in the first commercially practical water path ultrasonic scanner. Then in 1963 Meyerdirk & Wright launched production of the first commercial hand-held articulated arm compound contact B-mode scanner that ultrasound became generally available for medical use.

France

Léandre Pourcelot, who was a researcher and teacher at INSA (Institut National des Sciences Appliquées) Lyon copublished in 1965 a report at "Académie des sciences" « Effet Doppler et mesure du débit sanguin » (Doppler effect and measure of the blood flow), the basis of his design of a Doppler flow meter in 1967.

Scotland

Parallel developments in Glasgow, Scotland by Professor Ian Donald and colleagues at the Glasgow Royal Maternity Hospital (GRMH) led to the first diagnostic applications of the technique. Donald was an obstetrician with a self-confessed "childish interest in machines, electronic and otherwise", who, having treated the wife of one of the company's directors, was invited to visit the Research Department of boilermakers Babcock & Wilcox at Renfrew, where he used their industrial ultrasound equipment to conduct experiments on various morbid anatomical specimens and assess their ultrasonic characteristics. Together with the medical physicist Tom Brown. and fellow obstetrician Dr John MacVicar, Donald refined the equipment to enable differentiation of pathology in live volunteer patients. These findings were reported in The Lancet on 7 June 1958 as "Investigation of Abdominal Masses by Pulsed Ultrasound" – possibly one of the most important papers ever published in the field of diagnostic medical imaging. 

At GRMH, Professor Donald and Dr James Willocks then refined their techniques to obstetric applications including fetal head measurement to assess the size and growth of the fetus. With the opening of the new Queen Mother's Hospital in Yorkhill in 1964, it became possible to improve these methods even further. Dr Stuart Campbell's pioneering work on fetal cephalometry led to it acquiring long-term status as the definitive method of study of foetal growth. As the technical quality of the scans was further developed, it soon became possible to study pregnancy from start to finish and diagnose its many complications such as multiple pregnancy, fetal abnormality and placenta praevia. Diagnostic ultrasound has since been imported into practically every other area of medicine.

Sweden

Medical ultrasonography was used in 1953 at Lund University by cardiologist Inge Edler and Gustav Ludwig Hertz's son Carl Hellmuth Hertz, who was then a graduate student at the University's department of nuclear physics.

Edler had asked Hertz if it was possible to use radar to look into the body, but Hertz said this was impossible. However, he said, it might be possible to use ultrasonography. Hertz was familiar with using ultrasonic reflectoscopes of the American acoustical physicist Floyd Firestone's invention for nondestructive materials testing, and together Edler and Hertz developed the idea of using this method in medicine. 

The first successful measurement of heart activity was made on October 29, 1953 using a device borrowed from the ship construction company Kockums in Malmö. On December 16 the same year, the method was used to generate an echo-encephalogram (ultrasonic probe of the brain). Edler and Hertz published their findings in 1954.

United States

In 1962, after about two years of work, Joseph Holmes, William Wright, and Ralph Meyerdirk developed the first compound contact B-mode scanner. Their work had been supported by U.S. Public Health Services and the University of Colorado. Wright and Meyerdirk left the University to form Physionic Engineering Inc., which launched the first commercial hand-held articulated arm compound contact B-mode scanner in 1963. This was the start of the most popular design in the history of ultrasound scanners.

In the late 1960s Dr Gene Strandness and the bio-engineering group at the University of Washington conducted research on Doppler ultrasound as a diagnostic tool for vascular disease. Eventually, they developed technologies to use duplex imaging, or Doppler in conjunction with B-mode scanning, to view vascular structures in real-time, while also providing hemodynamic information.

The first demonstration of color Doppler was by Geoff Stevenson, who was involved in the early developments and medical use of Doppler shifted ultrasonic energy.

Manufacturers

The leading manufacturers of Ultrasound Equipment are Hitachi, Siemens Healthineers, GE Healthcare, and Philips.

Vitamin B12 deficiency

From Wikipedia, the free encyclopedia

Vitamin B12 deficiency
Other names	Hypocobalaminemia, cobalamin deficiency
Cyanocobalamin
Specialty	Neurology, hematology
Symptoms	Decreased ability to think, depression, irritability, abnormal sensations, changes in reflexes
Complications	Megaloblastic anemia
Causes	Poor absorption, decreased intake, increased requirements
Diagnostic method	Blood levels below 120–180 picomol/L (170–250 pg/mL) in adults
Prevention	Supplementation in those at high risk
Treatment	Supplementation by mouth or injection
Frequency	6% (<60 20="" old="" years="">60 years old)

Vitamin B₁₂ deficiency, also known as cobalamin deficiency, is the medical condition of low blood levels of vitamin B₁₂. In mild deficiency a person may feel tired and have a reduced number of red blood cells (anemia). In moderate deficiency there may be inflammation of the tongue and the beginning of neurological problems including abnormal sensations such as pins and needles, while severe deficiency may include reduced heart function and greater neurological problems.

 Neurological problems may include changes in reflexes, poor muscle function, memory problems, decreased taste, and in extreme cases psychosis. Sometimes temporary infertility may also occur. In young children symptoms include poor growth, poor development, and difficulties with movement. Without early treatment, some of the changes may be permanent.

Common causes include poor absorption from the stomach or intestines, deficient intake, and increased requirements. Decreased absorption may be due to pernicious anemia, surgical removal of the stomach, chronic inflammation of the pancreas, intestinal parasites, certain medications, and some genetic disorders. Medications that may decrease absorption include proton pump inhibitors and metformin. Decreased intake may occur in vegetarians or people who are malnourished. Increased requirements occur in people with HIV/AIDS, and in those with rapid red blood cell breakdown. Diagnosis is typically based on blood levels of vitamin B₁₂. Elevated methylmalonic acid levels may also indicate a deficiency. A type of anemia known as megaloblastic anemia is often but not always present.

Treatment consists of using vitamin B₁₂ by mouth or by injection; initially in high daily doses, followed by less frequent lower doses as the condition improves. If a reversible cause is found, that cause should be addressed if possible. If no reversible cause is found - or when found it cannot be eliminated - lifelong vitamin B₁₂ administration is usually recommended. Vitamin B₁₂ deficiency is preventable with supplements containing the vitamin: this is recommended in pregnant vegetarians and vegans, and not harmful in others. Risk of toxicity due to vitamin B₁₂ is low.

Vitamin B₁₂ deficiency in the US and the UK is estimated to occur in about 6 percent of those under the age of 60, and 20 percent of those over the age of 60. In Latin America, rates are estimated at 40 percent and they may be as high as 80 per cent in parts of Africa and Asia.

Signs and symptoms

Vitamin B₁₂ deficiency can lead to anemia and neurological disorders. A mild deficiency may not cause any discernible symptoms, but as the deficiency becomes more significant, symptoms of anemia may result, such as weakness, fatigue, light-headedness, rapid heartbeat, rapid breathing and pale color to the skin. It may also cause easy bruising or bleeding, including bleeding gums, gastrointestinal side effects including sore tongue, stomach upset, weight loss, and diarrhea or constipation. If the deficiency is not corrected, nerve cell damage can result. If this happens, vitamin B₁₂ deficiency may result in tingling or numbness to the fingers and toes, difficulty walking, mood changes, depression, memory loss, disorientation and, in severe cases, dementia.

The main type of vitamin B ₁₂ deficiency anemia is pernicious anemia. It is characterized by a triad of symptoms:

1. Anemia with bone marrow promegaloblastosis (megaloblastic anemia). This is due to the inhibition of DNA synthesis (specifically purines and thymidine)
2. Gastrointestinal symptoms: alteration in bowel motility, such as mild diarrhea or constipation, and loss of bladder or bowel control. These are thought to be due to defective DNA synthesis inhibiting replication in a site with a high turnover of cells. This may also be due to the autoimmune attack on the parietal cells of the stomach in pernicious anemia. There is an association with GAVE syndrome (commonly called watermelon stomach) and pernicious anemia.
3. Neurological symptoms: Sensory or motor deficiencies (absent reflexes, diminished vibration or soft touch sensation), subacute combined degeneration of spinal cord, seizures, or even symptoms of dementia and or other psychiatric symptoms may be present. Deficiency symptoms in children include developmental delay, regression, irritability, involuntary movements and hypotonia.

The presence of peripheral sensory-motor symptoms or subacute combined degeneration of spinal cord strongly suggests the presence of a B₁₂ deficiency instead of folate deficiency. Methylmalonic acid, if not properly handled by B₁₂, remains in the myelin sheath, causing fragility. Dementia and depression have been associated with this deficiency as well, possibly from the under-production of methionine because of the inability to convert homocysteine into this product. Methionine is a necessary cofactor in the production of several neurotransmitters. 

Each of those symptoms can occur either alone or along with others. The neurological complex, defined as myelosis funicularis, consists of the following symptoms:

1. Impaired perception of deep touch, pressure and vibration, loss of sense of touch, very annoying and persistent paresthesias
2. Ataxia of dorsal column type
3. Decrease or loss of deep muscle-tendon reflexes
4. Pathological reflexes — Babinski, Rossolimo and others, also severe paresis

Vitamin B₁₂ deficiency can cause severe and irreversible damage, especially to the brain and nervous system. These symptoms of neuronal damage may not reverse after correction of blood abnormalities, and the chance of complete reversal decreases with the length of time the neurological symptoms have been present. Elderly people are at a even higher risk of this type of damage. In babies a number of neurological symptoms can be evident due to malnutrition or pernicious anemia in the mother. These include poor growth, apathy, having no desire for food, and developmental regression. While most symptoms resolve with supplementation some developmental and cognitive problems may persist.

Only a small subset of dementia cases have been found to be reversible with vitamin B12 therapy. Tinnitus may be associated with vitamin B₁₂ deficiency.

Causes

• Inadequate dietary intake of vitamin B₁₂. Vitamin B₁₂ occurs in animal products (eggs, meat, milk, fish) and in some edible algae. B₁₂ isolated from bacterial cultures is also added to many fortified foods, and available as a dietary supplement. Vegans, and to a lesser degree vegetarians, may also be at risk for B₁₂ deficiency due to inadequate dietary intake of B₁₂, if they do not supplement. Children are at a higher risk for B₁₂ deficiency due to inadequate dietary intake, as they have fewer vitamin stores and a relatively larger vitamin need per calorie of food intake.
• Selective impaired absorption of vitamin B₁₂ due to intrinsic factor deficiency. This may be caused by the loss of gastric parietal cells in chronic atrophic gastritis (in which case, the resulting megaloblastic anemia takes the name of "pernicious anemia"), or may result from wide surgical resection of stomach (for any reason), or from rare hereditary causes of impaired synthesis of intrinsic factor. B₁₂ deficiency is more common in the elderly because gastric intrinsic factor, necessary for absorption of the vitamin, is deficient, due to atrophic gastritis.
• Impaired absorption of vitamin B₁₂ in the setting of a more generalized malabsorption or maldigestion syndrome. This includes any form due to structural damage or wide surgical resection of the terminal ileum (the principal site of vitamin B₁₂ absorption).
• Forms of achlorhydria (including that artificially induced by drugs such as proton pump inhibitors and histamine 2 receptor antagonists) can cause B₁₂ malabsorption from foods, since acid is needed to split B₁₂ from food proteins and salivary binding proteins. This process is thought to be the most common cause of low B₁₂ in the elderly, who often have some degree of achlorhydria without being formally low in intrinsic factor. This process does not affect absorption of small amounts of B₁₂ in supplements such as multivitamins, since it is not bound to proteins, as is the B₁₂ in foods.
• Surgical removal of the small bowel (for example in Crohn's disease) such that the patient presents with short bowel syndrome and is unable to absorb vitamin B₁₂. This can be treated with regular injections of vitamin B₁₂.
• Long-term use of ranitidine hydrochloride may contribute to deficiency of vitamin B₁₂.
• Untreated celiac disease may also cause impaired absorption of this vitamin, probably due to damage to the small bowel mucosa. In some people, vitamin B₁₂ deficiency may persist despite treatment with a gluten-free diet and require supplementation.
• Some bariatric surgical procedures, especially those that involve removal of part of the stomach, such as Roux-en-Y gastric bypass surgery. (Procedures such as the adjustable gastric band type do not appear to affect B₁₂ metabolism significantly).
• Bacterial overgrowth within portions of the small intestine, such as may occur in blind loop syndrome, (a condition due to a loop forming in the intestine) may result in increased consumption of intestinal vitamin B₁₂ by these bacteria.
• The diabetes medication metformin may interfere with B₁₂ dietary absorption.
• A genetic disorder, transcobalamin II deficiency can be a cause.
• Alcoholism - if a "diet" of excessive alcohol intake is substituted for a diet adequate in sources of B₁₂.
• Nitrous oxide exposure, and recreational use.
• Infection with the Diphyllobothrium latum tapeworm
• Chronic exposure to toxigenic molds and mycotoxins found in water damaged buildings.
• Increased needs by the body due to AIDS, or hemolysis the breakdown of red blood cells.

Mechanism

The total amount of vitamin B₁₂ stored in the body is between two and five milligrams in adults. Approximately 50% is stored in the liver, but approximately 0.1% is lost each day, due to secretions into the gut—not all of the vitamin in the gut is reabsorbed. While bile is the main vehicle for B₁₂ excretion, most of this is recycled via enterohepatic circulation. Due to the extreme efficiency of this mechanism, the liver can store three to five years worth of vitamin B₁₂ under normal conditions and functioning. However, the rate at which B₁₂ levels may change when dietary intake is low depends on the balance between several variables.

Metabolic

Vitamin B₁₂ deficiency causes particular changes to the metabolism of two clinically relevant substances in humans:

1. Homocysteine (homocysteine to methionine, catalysed by methionine synthase) leading to hyperhomocysteinemia
2. Methylmalonic acid (methylmalonyl-CoA to succinyl-CoA, of which methylmalonyl-CoA is made from methylmalonic acid in a preceding reaction)

Methionine is activated to S-adenosyl methionine, which aids in purine and thymidine synthesis, myelin production, protein/neurotransmitters/fatty acid/phospholipid production and DNA methylation. 5-Methyl tetrahydrofolate provides a methyl group, which is released to the reaction with homocysteine, resulting in methionine. This reaction requires cobalamin as a cofactor. The creation of 5-methyl tetrahydrofolate is an irreversible reaction. If B₁₂ is absent, the forward reaction of homocysteine to methionine does not occur, homocysteine concentrations increase, and the replenishment of tetrahydrofolate stops. Because B₁₂ and folate are involved in the metabolism of homocysteine, hyperhomocysteinuria is a non-specific marker of deficiency. Methylmalonic acid is used as a more specific test of B₁₂ deficiency.

Pathomorphology

A spongiform state of neural tissue along with edema of fibers and deficiency of tissue. The myelin decays, along with axial fiber. In later phases, fibric sclerosis of nervous tissues occurs. Those changes apply to dorsal parts of the spinal cord and to pyramidal tracts in lateral cords. The pathophysiologic state of the spinal cord is called subacute combined degeneration of spinal cord.

In the brain itself, changes are less severe: They occur as small sources of nervous fibers decay and accumulation of astrocytes, usually subcortically located, and also round hemorrhages with a torus of glial cells. Pathological changes can be noticed as well in the posterior roots of the cord and, to lesser extent, in peripheral nerves. Abnormalities might be observed in MRI.

Diagnosis

MRI image of the brain in vitamin B₁₂ deficiency, axial view showing the "precontrast FLAIR image": note the abnormal lesions (circled) in the periventricular area suggesting white matter pathology.

 

MRI image of the cervical spinal cord in vitamin B₁₂ deficiency showing subacute combined degeneration. (A) The midsagittal T2 weighted image shows linear hyperintensity in the posterior portion of the cervical tract of the spinal cord (black arrows). (B) Axial T2 weighted images reveal the selective involvement of the posterior columns.

 

Diagnosis is typically based on vitamin B₁₂ blood levels below 120–180 picomol/L (170–250 pg/mL) in adults. Elevated methylmalonic acid levels (values >0.4 micromol/L) may also indicate a deficiency.

Serum homocysteine and methylmalonic acid levels are considered more reliable indicators of B₁₂ deficiency than the concentration of B₁₂ in blood. The levels of these substances are high in B₁₂ deficiency and can be helpful if the diagnosis is unclear.

Routine monitoring of methylmalonic acid levels in urine is an option for people who may not be getting enough dietary B₁₂, as a rise in methylmalonic acid levels may be an early indication of deficiency.

If nervous system damage is suspected, B₁₂ analysis in cerebrospinal fluid is possible, though such an invasive test should be considered only if blood testing is inconclusive.

The Schilling test was a radio-isotope method, now outdated, of testing for low vitamin B₁₂.

Effect of folic acid

The National Institutes of Health (NIH) has found that "Large amounts of folic acid can mask the damaging effects of vitamin B₁₂ deficiency by correcting the megaloblastic anemia caused by vitamin B₁₂ deficiency without correcting the neurological damage that also occurs", there are also indications that "high serum folate levels might not only mask vitamin B₁₂ deficiency, but could also exacerbate the anemia and worsen the cognitive symptoms associated with vitamin B₁₂ deficiency". Due to the fact that in the United States legislation has required enriched flour to contain folic acid to reduce cases of fetal neural-tube defects, consumers may be ingesting more than they realize. To counter the masking effect of B₁₂ deficiency the NIH recommends "folic acid intake from fortified food and supplements should not exceed 1,000 μg daily in healthy adults." Most importantly, B₁₂ deficiency needs to be treated with B₁₂ repletion. Limiting folic acid will not counter the irrevocable neurological damage that is caused by untreated B₁₂ deficiency.

Treatment

Hydroxocobalamin injection is a clear red liquid solution.

 

B₁₂ can be supplemented by pill or injection and appears to be equally effective in those with low levels due to deficient absorption of B₁₂.

When large doses are given by mouth its absorption does not rely on the presence of intrinsic factor or an intact ileum. Generally 1 to 2 mg daily is required as a large dose. Even pernicious anemia can be treated entirely by the oral route. These supplements carry such large doses of the vitamin that 1% to 5% of high oral doses of free crystalline B₁₂ is absorbed along the entire intestine by passive diffusion.

Epidemiology

Vitamin B₁₂ deficiency is quite common and widespread. In the US and UK, as around 6 percent of people have the deficiency, and this rises to around 20 percent in those over the age of sixty. In less developed countries the rates are higher. For example across Latin America 40 percent, in some parts of Africa 70 percent, and in some parts of India 70 and 80 percent.

History

Adapted from:

• 1849 - Thomas Addison first described a case of pernicious anemia.
• 1877 - William Osler and William Gardner first described a case of neuropathy in this condition.
• 1878 - Hayem first described large red cells in the peripheral blood in this condition, which he called "giant blood corpuscles", now called macrocytes.

• 1880 - Paul Ehrlich first identified megaloblasts in the bone marrow in this condition.
• 1887 - Ludwig Lichtheim first described a case of myopathy in this condition.
• 1926 - George Minot shared the 1934 Nobel Prize with William Murphy and George Whipple, for discovery of an effective treatment for pernicious anemia using liver concentrate, later found to contain a large amount of vitamin B₁₂.
• 1929 - William Castle demonstrated that gastric juice contained an "intrinsic factor" which when combined with meat ingestion resulted in absorption of the vitamin in this condition.

Other animals

Ruminants, such as cows and sheep, absorb B₁₂ synthesized by their gut bacteria. Sufficient amounts of cobalt need to be consumed for this B₁₂ synthesis to occur.

In the early 20th century during the development for farming of the North Island Volcanic Plateau of New Zealand, cattle suffered from what was termed "bush sickness". It was discovered that the volcanic soils lacked the cobalt salts essential for synthesis of the vitamin by their gut bacteria.

The "coast disease" of sheep in the coastal sand dunes of South Australia in the 1930s was found to originate in nutritional deficiencies of the trace elements, cobalt and copper. The cobalt deficiency was overcome by the development of "cobalt bullets", dense pellets of cobalt oxide mixed with clay given orally for lodging in the animal's rumen.